Nonneoplastic Diseases of the Testis

12

Nonneoplastic Diseases of the Testis M A N UE L N I ST A L , R I C A R D O P A N I A G UA A N D P I L A R G O N Z Á L E Z- P E R A M A T O

C H A P T E R OU T L I N E Embryology and Anatomy of the Testis 549 Embryology 549 Prepubertal Testis 560 Adult Testis 566 Congenital Anomalies of the Testis 576 Alterations in Number, Size, and Location 576 Hamartomatous Testicular Lesions 589 Ectopias 597 Undescended Testes 602 Testicular Microlithiasis 612 Disorders of Sex Development 616 Gonadal Dysgenesis 616 Ovotesticular Disorder (True Hermaphroditism) 628 Undermasculinization (Male Pseudohermaphroditism) 631 Infertility 640 Testicular Biopsy 640 Correlation Between Testicular Biopsy and Spermiogram 659 Infertility and Chromosomal Anomalies 664 Other Syndromes Associated With Hypergonadotropic Hypogonadism 675 Secondary Idiopathic Hypogonadism 677 Hypogonadism Secondary to Endocrine Gland Dysfunction and Other Disorders 684 Infertility Secondary to Physical and Chemical Agents 701 Infertility in Patients With Spinal Cord Injury 709 Inflammation and Infection 710 Orchitis 710 Testicular Pseudolymphoma 715 Histiocytosis With Testicular Involvement 716 Other Testicular and Epididymal Lesions 717 Epididymitis Nodosa 717 Epididymitis Induced by Amiodarone 717 Ischemic Granulomatous Epididymitis 717 Vasculitis 717 Amyloidosis 719 Testicular Infarct 720 Other Testicular Diseases 723 Cystic Malformation 723 Disorders of the Rete Testis 725

Embryology and Anatomy of the Testis Embryology Development of the Testis Genetic Mechanisms Involved in Sex Determination and Testicular Differentiation

Sexual differentiation is the result of complex genetic and endocrine mechanisms that are closely associated with the development of both the genitourinary system and the adrenal glands. Formation of the bipotential gonad—and subsequently the testis or the ovary—depends on gene expression in both sex and autosomal chromosomes. Testes secrete steroid and peptide hormones, both of which are necessary for the development of internal and external genitalia. These hormonal actions are mediated by specific receptors that function as transcription regulators. Alteration of genetic events results in sexual dimorphisms involving the internal and external genitalia and may hinder development of other organs.1 Determination of chromosomal gender takes place at the time of fertilization, with formation of an embryo of either 46,XY (male) or 46,XX (female) karyotype. The subsequent cascade of genetic events leads to development of either female (ovaries) or male (testes) gonads, referred to as gonadal gender. Hormonal secretions from the ovaries or testes are essential for development of external genitalia, thereby determining phenotypic gender. The relationship between the individual and the environment determines social gender. Gonadal development comprises two phases. The first phase is characterized by the appearance of the bipotential gonad, or genital ridge, which is an indifferent gonad that is identical in males and females. Cells in the bipotential gonad may develop into either female or male gonads. The second phase is the development of a testis or an ovary.

Development of the Bipotential Gonad Formation of the Gonadal Ridge

In the fourth week of gestation the urogenital ridges appear as two parallel prominences along the posterior abdominal wall. This process is apparently driven by the expression of transcription factors Lim1 and Odd1. Each urogenital ridge gives rise to two important pairs of structures: the genital ridges arising from the medial prominences and the mesonephric ridges deriving from the lateral prominences. The genital ridges are the first primordium of the gonad, appearing as a pair of prominences about the midline. In 30- to 32-day embryos, each genital ridge is lateral to the aorta and medial to the mesonephric duct. The coelomic epithelium

549

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lining the genital ridges undergoes proliferation and thickening, protrudes into the coelomic cavity, and grows into cordlike structures giving rise to the gonadal ridges, the primary sex cords. Expression of steroidogenic factor 1 (SF1), triggered by the WT1 gene (Wilms tumor 1) (+KTS isoform), the transcription factor Pbx1, and the homeobox proteins Emx2 and Lhx9, is essential for cell survival and proliferation during this period. The coelomic epithelium also proliferates to invade the subjacent mesenchymal tissue. Cell proliferation in this phase also depends on Lhx9 expression. The basement membrane underlying the coelomic epithelium appears discontinuous and is rich in laminin content. As the coelomic cells proliferate, laminin production in the gonadal ridge increases, an apparently essential element for germ cell colonization. Immediately beneath the coelomic epithelium are several mesonephric tubules and glomeruli (Figs. 12.1 and 12.2). Primordial Germ Cells: Origin, Migration, and Formation of the Gonadal Blastema

Initially the genital ridges are devoid of primordial germ cells, but they are detected in the third week of gestation in the extraembryonal mesoderm that lines the yolk sac posterior wall near the allantoic evagination. The germ cells are ovoid, 12 to 14 μm in diameter, and immunohistochemically express alkaline phosphatase, OCT3/4, NANOG, and LIN28.2,3 Nuclei are spherical and possess one or two large and prominent central nucleoli.4 The cytoplasm contains mitochondria with tubular cristae,

Fig. 12.2 Longitudinal section of the gonad showing the close relationship between gonadal blastema and mesonephric glomeruli.

lysosomes, microfilaments, lipid inclusions, numerous ribosomes, and abundant glycogen granules. Attracted by chemotactic factors, the primordial germ cells migrate along the mesenchyma of the mesentery and reach the genital ridge by 32 to 35 days.5,6 The appearance of these cells coincides with the expression of several proteins in the extraembryonal mesoderm, including Bmp4, Bmp8, and Blimp1. Primordial germ cells begin to express two membrane proteins, fragilis and brachyurus, and the cells migrate through the primitive streak to settle into the developing endoderm (hindgut).7 The hindgut then invaginates into the future abdominal cavity and approaches the gonadal ridges. Primordial germ cells migrate by ameboid movements along the hindgut mesentery to reach the gonadal ridges. This emigration process occurs along autonomic nerve fibers that support them and requires the interaction of several factors: the integrin CXCR4-β1 (expressed by primordial germ cells), stromal cell–derived factor 1 (expressed by the body wall mesenchyma and gonadal ridges), and several extracellular matrix proteins.8–12 An essential mechanism for adequate primordial germ cell migration, survival, and chemoattraction is the interaction between CD117, expressed in the germ cell surface, and the stem cell factor present in the surrounding tissues.13–15 After entering the gonadal ridges, primordial germ cells colonize them; this process involves the expression of E-cadherin and germ cell interaction with a rich laminin network produced by organizing coelomic cells in the gonadal ridges.16 The association of coelomic-derived somatic cells, primordial germ cells, and a laminin-rich stroma in the gonadal ridge characterizes the gonadal blastema. Once inside the genital ridge, germ cells lose their motility and begin to aggregate. Male–Female Determination

Fig. 12.1 Longitudinal section of a fetus showing the primitive gonad as an elongate structure along mesonephros. In the upper corner of the image the lung can be recognized, and the liver is in front of the gonad.

Normal male determination depends on the expression of the SRY (sex-determining region Y ) gene, located on the Y chromosome. In the absence of SRY, an ovary is formed. In the testicular blastema, SRY is exclusively expressed by the coelomic-derived somatic cells induced to differentiate into pre–Sertoli cells, which form the sex cords.17–19 These cells are believed to act as the organizing center of the male gonad, orchestrating differentiation of all other cell types.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Leydig Cell

Testosterone

Sertoli Cell

AMH

551

Testis WT-1 (+KTS) SF-1 Pbx1 Emx2 Lhx9

SRY WT-1 (+KTS) FGF9 SF-1 SOX9

Bipotential Gonad

Mesoderm Bmp4 Bmp8 Blimp1 c-kit SCF

DAX 1

Ovary

Estrogens Gestagens

Fig. 12.3 Genetic mechanisms involved in sex determination and testicular differentiation.

SRY expression is transient, ceases when sex cords form, and is activated by WT1 (+KTS isoform), which is consistently expressed in the coelomic epithelium and the proliferating coelomic-derived somatic cells.20,21 Gonads lacking WT1 (+KTS) show lower SRY levels per cell and also fewer SRY-positive cells. This observation led investigators to hypothesize that WT1 (+KTS) contributes to SRY activation by increasing the number of pre–Sertoli cells.22 SRY expression is observed first in the anterior and central portions of the gonad and then in the poles.18 Expression of SRY requires proliferating gonadal somatic cells, and both SF1 and fibroblast growth factor 9 (FGF9) play a role in this proliferation.23,24 Immediately after SRY expression begins, FGF9 contributes to maintenance of cell proliferation necessary for sex cord formation.25,26 FGF9 regulates male-specific proliferation that produces pre– Sertoli cells.27 The origin of sex cord formation, and thus the first morphologic distinction between a testis and an ovary, also depends on the expression of SRY-box containing gene 9 (SOX9). This expression occurs in the cytoplasm of somatic elements in the bipotential gonadal ridge. SOX9 is expressed in the pre–Sertoli cells in the same dynamic wave as SRY; it originates in the center of the gonad and then continues to the rostral and caudal poles. Its transcription is activated by the synergistic action of SRY and SF1. SOX9 also stimulates other factors that induce differentiation of Sertoli cells such as FGF9 and prostaglandin D2.28 SOX9 is also expressed in the female gonad, but there are important differences from the male gonad.19,20,29,30 Only males have an increase in SOX9 gene transcription and translocation of its protein product into the nucleus. This event occurs simultaneously with the initiation of sex cord formation. Therefore, like SRY, SOX9 is necessary and sufficient for both Sertoli cell differentiation and testis development.31 SOX9 expression in pre–Sertoli cells remains after sex cord formation, a finding indicating that SOX9 may have additional roles during proliferation and maturation of the testis, although it is dispensable for the development of embryonic and early postnatal testis.32 Contacts among pre–Sertoli cells during sex cord formation are regulated by neurotropic tyrosine receptor kinases (Fig. 12.3).33

Testis Differentiation: Development of Seminiferous Cords and Interstitium Early Organization of the Gonadal Blastema. Somatic coelo-

mic epithelium-derived cells expressing nuclear SOX9 organize into clusters of pre–Sertoli cells as migrating primordial cells aggregate. These clusters are fused and transformed into tubular structures that form the primitive testis cords.17,20,29 The interaction of pre–Sertoli cells with peritubular myoid cells, which appear early, results in acquisition by pre–Sertoli cells of epithelial characteristics, polarization of organelles, and synthesis and deposition of collagen IV and small amounts of laminin.34–37 Myoid peritubular cells secrete fibronectin and collagens I and IV to form the basement membrane of the primitive testis cords. These pre–Sertoli cells express antim€ ullerian hormone under the synergistic action of SOX9 and SF1.20,38 The primitive testis cords have a toroid structure, parallel to each other and aligned along the testicle.39 All have a point of contact in the dorsomedial part of the testicle, anastomosing to form a plexus that will be the future rete testis. The plexus has perforations through which vessels of the mesonephros penetrate. For such development to occur, specific interactions are necessary between germ cells, Sertoli cells, endothelial cells, macrophages, and interstitial cells. Shortly after formation of the gonadal blastema in male gonads, cells of the adjacent mesonephros begin to migrate to the gonadal blastema. This migration depends on SRY expression by coelomic-derived cells and is controlled by the expression of FGF9. The main emigration involves endothelial cells; they originate from the gonad-mesonephros border and migrate radially into the gonadal blastema parallel to the involution of the vascular mesonephric plexus from which they originate.40 When the endothelial cells reach the antimesonephric region, the celomic vessel forms under the coelomic epithelium, the male-specific main testicular artery. Branches of this vessel penetrate the gonad, delimiting about 10 avascular domains that form the cords and subsequently the seminiferous tubules.41 The process is mediated by platelet-derived growth factor receptor A (PDGFA) and vascular endothelial growth factor (VEGF).42,43 The action of VEGF and

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endothelial cells is a requirement for pre–Sertoli cells to organize into testis cords.44,45 Macrophages play an important role at this stage of testicular differentiation. They arise from primitive yolk sac–derived progenitors and initially are in direct contact with pre–Sertoli cells and germ cells. Once the primitive cords form, macrophages remain extratubular with active involvement in regulation of vascularization, morphogenesis of cords, and phagocytosis of pre–Sertoli and germinal cells that remain to be incorporated into the cords (Fig. 12.4).46 It is uncertain whether other cells are incorporated into the testicle from the mesonephros. Undifferentiated cells may penetrate the gonad following the endothelial cells and differentiate into a population of Leydig cells.47 The vessels not only contribute to Leydig cell progenitor migration but also affect their proliferation.48 Most stem Leydig cells arise directly from coelomic epithelium directly.25,36 Leydig cell progenitors express LIM homeobox gene 9, but not gonadal somatic markers such as transcription factors GATA4 and SF1. Fetal Leydig cell differentiation is regulated, at least in part, by three signaling molecules and pathways: desert hedgehog, PDGFA, and Notch signaling.49 The same may apply to peritubular myoid cells that may differentiate either from the coelomic epithelium or from undifferentiated perivascular cells that migrate into the gonad from the mesonephric border, following the endothelial cells. Differentiation of Primordial Germ Cells. Primordial germ cells (that have proliferated in the seminiferous cords) that have undergone mitotic arrest in the G1 and G0 stages of the cell cycle are called gonocytes. Mitotic arrest depends on adequate cord formation and is probably mediated by inhibitory signals provided through

Fig. 12.4 Origin of the different cell types of the testicle.

gonocyte interactions with Sertoli cells.50 These cells remain in mitotic arrest until a few days after birth, when they resume proliferation. Initially, gonocytes are in the central (“luminal”) portion of seminiferous cords. Later, during fetal and neonatal periods, gonocytes migrate toward the cord basement membrane because of gonocyte–Sertoli cell adhesion that is mediated by neural cell adhesion molecule.51,52 Gonocyte mitoses resume as soon as migration begins and may be identified at the basement membrane. These divisions result in the first generation of spermatogonia. Gonocytes that fail to migrate to the basement membrane undergo apoptosis. It has been suggested that Antimüllerian hormone (AMH) plays a role in gonocyte migration and the start of mitotic activity.53 Sertoli Cell Differentiation. Near the end of the seventh week, pre–Sertoli cells differentiate from somatic cells in the sex cords, creating seminiferous cords. It was previously believed that interaction of peritubular myoid cells and pre–Sertoli cells was essential for seminiferous cord formation to promote basal lamina deposition and tubular organization.35,37 However, recent evidence indicates that peritubular myoid cells are not involved in the initial partitioning of the XY gonad into cord regions, which consist of clusters of both pre–Sertoli cells and germ cells. As soon as seminiferous cords are formed by the interaction of peritubular myoid cells and pre–Sertoli cells, primordial germ cells become “entrapped” in tubules. This entrapment is mediated by interactions between primordial germ cells and pre–Sertoli cells through expression of E-cadherin and P-cadherin on the cell surfaces.16 The differentiation of pre–Sertoli cells into Sertoli cells appears as polarization in which they form aggregates that assemble into seminiferous cords. Early events include the following:

CHAPTER 12 Nonneoplastic Diseases of the Testis

development of intercellular junctions between adjacent Sertoli cells; formation of a basal lamina that surrounds the external surface of seminiferous cords; and expression of AMH, sulfated glycoprotein-2, and clusterin by the Sertoli cells.54 Activin A, the major transforming growth factor-β protein, produced by fetal Leydig cells, acts directly on Sertoli cells to promote proliferation during late embryogenesis and plays an essential role in seminiferous cord morphogenesis in the murine testis (Figs. 12.5 to 12.7).55 Peritubular Myoid Cell Differentiation. Peritubular myoid cells share expression of many genes with interstitial cells from early fetal development, so it has been hypothesized that they have an interstitial origin either from the mesenchymal cells that populate the initial genital ridge or from the somatic cells that proliferate from the coelomic epithelium.44 Peritubular myoid cells form a single layer of flattened cells that surround the Sertoli cells and rim the seminiferous cords. Basal lamina formation by peritubular myoid cells is regulated through DHH homologue gene expression by the myoid cells themselves.56 Survival of peritubular myoid cells, and therefore seminiferous cord formation, depends on DAX1 (dosage-sensitive sex reversal,

Fig. 12.5 Longitudinal section of an 8-week-old fetal testis showing sex cord configuration. In the hilum, there are several glomeruli and nephric tubules.

Fig. 12.6 An 8-week-old fetal testis showing intense expression of inhibin in pre–Sertoli cells that form sex cords.

553

Fig. 12.7 Testis from an 8-week-old fetus. Primordial germ cells, located in sex cords, show intense expression of D2–40. Note that some are situated in the celomic epithelium itself.

adrenal hypoplasia critical region, on chromosome X, gene 1) nuclear receptor expression, induced in turn by SF1 expression.57–59 DAX1 expression ceases in seminiferous cords after formation, whereas it is maintained in ovaries, a finding suggesting that dosage and stage-specific expression of this protein may be responsible for ovarian differentiation. Seminiferous cords lose their connection with the coelomic epithelium, whose height decreases to one or two cell layers. Leydig Cell Development. Leydig stem cells proliferate actively and begin differentiation in the eighth week of gestation. Most originate from the same pool of NR5A1+ precursor cells from which Sertoli cells derive; others are perivascular NR5A1
cells from the mesonephros.39,60 Differentiation is independent of hormonal stimulation, caused by two Sertoli cell–derived signaling molecules: DHH and PDGFA.61 Other factors involved in control of the development and functions of fetal human Leydig cells are GATA4 (transcription factor that recognizes the GATA consensus DNA sequence), insulin-like growth factor-1 (IGF1) (both are stimulatory factors), and the basic helix–loop–helix transcription factor POD1 (suppressive factor).61,62 Histochemical detection of 3β-hydroxysteroid dehydrogenase (3β-HSD) is the apparent first signal of differentiation and is completed with acquisition of ultrastructural characteristics of steroidogenesis. As fetal development progresses, new cells differentiate from precursor Leydig cells located in the outer of the two peritubular layers (Fig. 12.8). At 12 weeks of gestation, they begin to express LHCGR. Between weeks 14 and 18, Leydig cell number and testosterone level peak.63 After week 22, tubular walls are reduced to the internal layer. Differentiating Leydig cells are identified by characteristic expression of the androgen receptor (AR) at this stage. Fetal Leydig cells produce androstenedione, which in turn is converted into testosterone by HSD17B3 in Sertoli cells in a gonadotropin-independent process.64 Pituitary gonadotropins control Leydig cell function throughout the second and third trimesters, especially luteinizing hormone (LH). Rete Testis Formation. Rete testis develops from residual cords that persist from the mesonephros in continuity with seminiferous cords. The mesonephros and its testicular connection become progressively thinner and appear circular in cross sections. The testis remains between two ligaments: the cranial suspensory ligament

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Fig. 12.8 Fetal Leydig cells form large accumulations under the albuginea and among the testicular cords in a 10-week-old fetus. Calretinin immunostaining was used.

Fig. 12.9 Transverse section of a fetus showing the relationship of the testis to abdominal organs such as liver, kidney, and digestive tract.

and the caudal ligament. The caudal ligament gives rise to the gubernaculum (Fig. 12.9). Development of the Urogenital Tract. The development of the urogenital tract begins at the stage of the undifferentiated gonad, with the appearance of two different pairs of ducts: the wolffian ducts and the m€ ullerian ducts (Fig. 12.10). Wolffian ducts arise inside the mesonephros, accounting for the close relationship between the reproductive and urinary systems. This pair of ducts originates in the third week of gestation, when the cranial region of the segmented intermediate mesoderm gives rise to 10 pairs of tubules, the nephric tubules, arranged with a segmental distribution. One end of each nephric tubule opens to the coelomic cavity, and the other end empties into an excretory duct.

There are thus two excretory ducts, longitudinally placed at both sides of the embryonal axis, named pronephros. In the fourth week, the pronephros disappears and is replaced by another tubular excretory system, the mesonephros, derived from nonsegmented intermediate mesoderm. The medial ends of the mesonephric tubules are connected to glomeruli at one end and the wolffian ducts at the other end. The caudal ends of the wolffian ducts drain into the urogenital sinus.65 At the end of the second month, the mesonephros is replaced by the metanephros, the definitive kidney. In the male the most caudally located mesonephric tubules persist and give rise to the efferent ducts, whereas the wolffian ducts are the source of the epididymides, vas deferens, seminal vesicles, and ejaculatory ducts.

Testicular development Days 20

30

40

50

Undifferentiated gonad

Sertoli cells Germ cells

60

70

80

90

100

110

Leydig cells

Antimüllerian hormone Testosterone Local General Müllerian ducts

Wolffian ducts

Ductuli efferentes Ductus epidydimidis Seminal vesicles and ejaculatory ducts

Urogenital sinus derivatives: prostate, bulbourethral glands and urethtra Dihydrotestosterone External genitalia: penis, urethra and scrotum

Fig. 12.10 Development of the genital system during the first months of intrauterine life.

120

130

140

CHAPTER 12 Nonneoplastic Diseases of the Testis

Both m€ ullerian ducts originate from two longitudinal invaginations of the coelomic epithelium in the anterolateral aspects of the genital ridges. The cranial end of each duct is a funnel that opens into the coelomic cavity. The initial segments of both ducts run parallel and lateral to their respective wolffian ducts, and as they pass caudally, they cross over to lie medial to the wolffian ducts. Finally, in the distal portions, both m€ ullerian ducts fuse into a single duct that serves as origin for the uterovaginalis duct. This duct elongates caudally to reach the posterior aspect of the urogenital sinus, forming a dilation named the M€ uller tubercle. Each wolffian duct drains at one side of this tubercle.66 The remaining structures of the male genital system are derived from the urogenital sinus. Epithelium of this sinus with endodermal origin forms the prostate, the bulbourethral glands, the urethra, and the periurethral glands. The primitive urogenital sinus derives from the cloaca, a structure that appears at the end of the first month and consists of a dilation of the final portion of the primitive posterior intestine. The cloaca is closed by the cloacal membrane. During the third week, a crown of mesenchymal cells develops on the outer aspect of the cloacal membrane and gives rise to the cloacal folds. A knob in the middle of the cloacal fold is known as the cloacal eminence. In the sixth week the cloacal folds enlarge to form the genital folds, also known as the urethral folds. The cloacal eminence gives rise to the genital tubercle. External to the genital folds, two mesenchymal outgrowths develop to form the genital prominence or genital swellings. In the fifth week the cloaca is divided by a septum into two cavities. The anterior cavity is the primitive urogenital sinus, which is covered by the urogenital membrane. The posterior cavity is the anorectal channel, which is covered by the anal membrane. The primitive urogenital sinus divides further into two new compartments; the anterior compartment, the vesicourethral channel, becomes the urinary bladder and the urethra, whereas the posterior compartment, the definitive urogenital sinus, later differentiates according to gender. Hormonal Control of Male Genital Tract Differentiation

Subsequent development of the male genital system is under hormonal control. The mammalian fetal testis is initially independent of hormonal control, but then becomes LH (and possibly folliclestimulating hormone [FSH]) dependent in the second half of gestation.67 At this point the most important hormones are AMH, testosterone, dihydrotestosterone (DHT), FSH, and LH. AMH, also called m€ ullerian-inhibiting substance, is secreted by Sertoli cells. It consists of a glycoprotein polymer with two identical subunits linked by a disulfide bridge.68–71 AMH is a member of the TGFB superfamily and is synthesized as a precursor peptide with proteolytic cleavage, which is required for hormone activation. AMH is encoded by a 2.75-kb gene, which comprises five exons and is located in the p13.3 region of chromosome 19.72–74 AMH is secreted only by somatic gonadal cells that include male Sertoli cells and female granulosa cells. It is detected from the sixth week of development (eighth to ninth week of gestation), probably as soon as primordial germ cells come in contact with Sertoli cell precursors exactly 1 week before the m€ ullerian ducts lose their responsiveness.75,76 AMH is at high concentration during the second trimester and drops markedly in the third trimester.77 Levels increase again during the first year of postnatal life and decrease during infancy and childhood. At the onset of puberty, AMH drops dramatically to low or undetectable levels, and

555

this persists through adult life. The amount of hormone secreted by Sertoli cells is inversely proportional to their degree of maturation.68,78,79 The regulation of AMH production is incompletely understood. Its expression is regulated by SOX9; SF1 (also called Ad4BP) also seems to be involved.80 SF1 is an orphan nuclear receptor that functions as a transcriptional regulator of all the steroidogenic genes within the P450 complex. It also has a regulatory effect on the SRY factor because SRY expression in Sertoli cells is detected shortly before AMH expression is detected.81 During puberty, AMH is negatively regulated by androgen levels.82 AMH regulates the testis, genital tract, and extragenital structures, causing involution of the ipsilateral m€ ullerian ducts that begins at the caudal end of the testis and progresses rapidly. In adulthood, remnants of this duct may be observed near the cranial (testicular hydatid) and caudal (prostatic utricle or verumontanum) ends of the testis. AMH is also responsible for formation of tunica albuginea, with accumulation of mesenchyma between the coelomic epithelium and the sex cords. The mesenchyma gives rise to collagenized connective tissue that contains several layers of fibers arranged parallel to the testicular surface.83 AMH also hinders spermatogonial proliferation into meiotic spermatocytes and has a paracrine role regulating fetal androgen production.84,85 The most important extragenital function of AMH involves maturation of the fetal lungs.86 Testosterone synthesis by Leydig cells is regulated by human chorionic gonadotropin (hCG) and LH. hCG secretion reaches a peak between 11 and 14 weeks, whereas testosterone peaks between 11 and 17 weeks. From the 18th week forward, hCG declines markedly. hCG-dependent testosterone production plays an important role in genital differentiation. Wolffian duct differentiation occurs only in response to testosterone secretion by the ipsilateral testis, and this differentiation gives rise to the ipsilateral epididymis, vas deferens, and seminal vesicle.87,88 Anomalies of androgen synthesis during embryogenesis lead to incomplete masculinization and cryptorchidism. DHT is formed from testosterone by the action of the enzyme 5α-reductase and causes differentiation of the prostate and development of the external genitalia, including the male urethra, penis, and scrotum. The scrotum is formed by the fusion of the labioscrotal folds in the midline, the so-called scrotal raphe. The penile urethra, initially a urethral groove, is formed by the fusion of urethral folds. The genital tubercle enlarges to form the glans penis. The terminal segment of the penile urethra is derived from an ectodermic invagination of the glans end. The urogenital sinus gives rise to the urinary bladder, the prostatic urethra, and the prostate.66 The first effects of DHT are observed on day 70; by about day 74, the urethral groove is closed; and between the 18th and 20th weeks, development of the external genitalia is complete.89 The actions of testosterone and DHT on the male genital system must occur at precisely programmed times. Failure or delay of secretions or lack of responsiveness to these hormones are the main causes of genital malformations in disorders of sexual differentiation. The fetal hypophyseal hormones FSH and LH play important roles in the last months of gestation. LH is first detected in the blood in the 10th week, peaking in the 18th week. Thereafter, levels decrease slowly until birth. LH controls androgen production in the second half of fetal life; fetal Leydig cells are devoid of luteinizing hormone receptors (LHRs) in the first half of gestation. LH does not exert negative control over LHRs and androgen

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production by fetal Leydig cells, whereas the converse occurs in the adult; also, the steroidogenic ability of fetal Leydig cells is higher than that in the adult.64 Fetal Leydig cells are insensitive to the inhibitory effects of estrogen. FSH is an essential mitogen for Sertoli cells, which undergo maximal mitotic activity at the end of fetal life.90,91 This hormone appears to activate transcription factors such as GATA4, which shows intense Sertoli cell expression from the nineteenth to the 22nd week following an increase in serum FSH. GATA transcription factors are structurally related zinc finger proteins that recognize a consensus DNA sequence (A/T)GATA(A/G), known as GATA motif, which is an essential cis-acting element in promoters and enhancers of multiple genes.92 Fetal Testis Structure

The structure of the fetal testis evolves under the influence of placental hormones and the hypophysis. Changes include modifications in external morphology (from elongate to ovoid) and development and differentiation of the cell types. The degree of development is uniform in both testes, and growth varies with gestational age.93 Supporting Structures. The testicular covering, the tunica albuginea, increases in thickness 10-fold from the 10th to the 41st week of gestation. From the 29th week onward, two layers may be distinguished: an outer fibrous layer and an inner loose layer. Interlobular septa begin to appear between the 17th and 21st weeks and are completely formed between the 25th and 28th weeks. These septa support blood vessels. Nerve fibers are seen for the first time in the 16th week within the loose connective tissue of the albuginea (tunica vasculosa) and in the 20th week in the septa.94 Seminiferous Cords. These irregular compact structures gradually acquire a cylindrical shape as they elongate and become convoluted. The diameter increases slowly up to the 16th week and stabilizes until birth. During fetal life the seminiferous cords consist of Sertoli cells and germ cells, surrounded by a tunica propria. The seminiferous cords are solid structures devoid of lumina. Between the cords the connective tissue forms the testicular interstitium, which contains numerous Leydig cells (Fig. 12.11).95

TABLE 12.1

Fig. 12.11 Testis From a 24-week-old fetus. The seminiferous tubules contain Sertoli cells (small dark nuclei) and gonocytes (spherical cells with larger nuclei and central nucleoli). At this age the interstitium contains numerous Leydig cells.

Germ Cells. In contrast with other species, germ cells in the human fetal testis are not homogeneous, with several cell types that form the basis of different classifications.95a,96–98 Three cell types are identified by immunohistochemistry: gonocytes, intermediate cells, and fetal spermatogonia (prespermatogonia) (Table 12.1).99 Gonocytes refers to the primordial germ cells once they reside in the gonadal ridge. They are prominent for the large size (twice that of the surrounding cells) and location in the center of the seminiferous cords during most of fetal life. Nuclei are spherical and possess prominent central nucleoli.100,101 The cytoplasm contains well-developed Golgi complex, lipid droplets, short rough endoplasmic reticulum cisternae, and microfilaments. Gonocytes connect with Sertoli cells by gap junctions and desmosome-like junctions. Adhesion molecules are present, including neural cell adhesion molecule (NCAM), PB-cadherin, and connexin 43. Immunoreactivity includes octamer-binding transcription factor 4

Evolution Through Fetal Life and First Year of Life of the Immunoexpression of Different Markers in Germ Cells

Marker

Germ Cell Type

First Trimester

Second Trimester

Third Trimester

First Year of Life

PLAP

Gonocyte Prespermatogonia Gonocyte Prespermatogonia Gonocyte Prespermatogonia Gonocyte Prespermatogonia Gonocyte Prespermatogonia

+++ ++ +++ +++ +++

++ +++ ++

++ + +++ +++ +++

++ +++ ++

+
++ ++ +

++ + +

+
+ + +

++ +


Kit OCT3/4 TSPY Ki67

PLAP, Placental alkaline phosphatase. Data are taken from Honecker et al. (2004).99 +, Less than one positive cell per tubule (isolate); ++, one to three positive cells per tubule; +++, four to six positive cells per tubule.

CHAPTER 12 Nonneoplastic Diseases of the Testis

(OCT4), KIT, placental alkaline phosphatase (PLAP), serine/threonine-protein kinase 2 (CHK2), and proliferating cell nuclear antigen (PCNA), with absence of melanoma-associated antigen 4 (MAGE-A4).102–104 Intermediate cells are morphologically similar to gonocytes, although the cytoplasm-to-nucleus ratio is lower, the number of cytoplasmic processes is higher, and rough endoplasmic reticulum cisternae are more numerous. Intermediate cells are connected by cytoplasmic bridges. They express PCNA, weakly express OCT4, but are negative for KIT and MAGE-A4. Fetal spermatogonia are also joined by intercellular bridges, are grouped at the periphery of seminiferous cords, and differ from gonocytes by exhibiting more condensed nuclear chromatin and a higher cytoplasm-to-nucleus ratio. The cytoplasm is pale, and mitochondria are adjacent to one side of the nucleus and joined by electron-dense bars. Rough endoplasmic reticulum and lipid droplets are scant. Immunohistochemically, these cells are MAGE-A4+ and are negative for KIT and PCNA, indicating a quiescent phenotype. The three germ cell types are rich in glycogen granules, polysomes, and chromatoid bodies. Chromatoid bodies consist of finely granular material intermingled with other larger granules, which are similar in size to ribosomes; their mission is to accumulate regulatory RNAs to be used during transcription. The germ cell number per cross-sectional cord reaches a peak between the 12th and 22nd weeks.105 In the 10th week, most germ cells are gonocytes; at approximately the 15th week, many intermediate cells are present together with gonocytes, and fetal spermatogonia may be observed for the first time. From the 16th to the 20th week, germ cell degeneration occurs with Sertoli cell phagocytosis.106 From the 22nd week onward, most germ cells are fetal spermatogonia. Mitotic activity is high in the last trimester of gestation.107 Approximately 22% of testes between 14 and 33 weeks contain ectopic germ cells located beneath the coelomic epithelium, in the connective tissue that separates the testis from the epididymis, or in the rete testis.108 Some gonocytes persist after birth. The majority will be transformed into Ad spermatogonia during the 30th to 90th postnatal days (minipuberty). Sertoli Cells. Fetal Sertoli cells are the most numerous cells in the seminiferous cords, where they form pseudostratified epithelium that rests on the basal lamina. At approximately the 13th week of gestation, Sertoli cells exhibit an indented outline and long cytoplasmic processes, and are connected by desmosomes. Nuclei are spherical and contain small nucleoli. The cytoplasm is electron dense and contains numerous lysosomes, actin microfilaments, and intermediate filaments. Other organelles include microtubules, mitochondria, and well-developed Golgi complexes. In the apical region are numerous, parallel rough endoplasmic reticulum cisternae. The Sertoli cells progressively elongate, their cytoplasm becomes less electron-dense, and filaments predominate in the basal region.5 They express vimentin filaments throughout life, whereas low-molecular-weight cytokeratins (8, 18, and 19) are present until the 20th week.109,110 Desmin filaments may be observed from the 11th to the 14th week.111 Fetal Sertoli cells express inhibin and Stem cell factor (SCF) to secure a niche for gonocytes.112,113 During gestation, the number of Sertoli cells increases even though mitoses are only occasionally observed. The number of Sertoli cells per cross-sectioned cord does not increase during this period, but their proliferation contributes to increased length and tortuosity of the cords. Sertoli cell proliferation and testicular cord expansion take place in response to activin A, which is secreted by Sertoli cells. At the end of gestation, there are approximately 260

557

million Sertoli cells per pair of testes. In the fetal and early postnatal period, the absence of AR expression in Sertoli cells characterizes androgen insensitivity within the male gonad during this period.114 Fetal Sertoli cell functions include AMH secretion, fetal Leydig cell differentiation induction, and prevention of entry of germ cells into meiosis.115,116 Peritubular Myoid Cells. From the 14th week, two types of peritubular cells may be observed: inner myoid cells and fibroblast-like cells. Fibroblast-like cells occupy the outermost layers. In total, there are four to five layers of peritubular cells. At this time the number of myoid cells is low, but are predominate by the 34th week. The probable precursors of myoid cells are the fibroblast-like cells because both coexpress Ki67.111 In the final weeks of gestation the number of peritubular cell layers decreases to only two, perhaps because of intense lengthening of seminiferous cords and Leydig cell differentiation from peritubular cell precursors. The presence of the AR in peritubular myoid cells suggests an important role in Sertoli cells control.117 Leydig Cells. Leydig cells first appear among the seminiferous cords in the eighth week of gestation, and increase in number to 48 million per pair of testes (50% of testicular volume at this moment) between the 13th and 16th weeks, coinciding with the testosterone peak (Fig. 12.12).118,119 Leydig cell number is maintained up to the 24th week, although the testicular volume occupied by Leydig cells is lower at this time because the seminiferous cords have grown markedly during this period. From the 24th week to birth, the number of Leydig cells progressively decreases to 18 million.67,106,120 Leydig cells are polyhedral and measure between 30 and 37 μm in diameter. They have eccentric and pale nuclei, with voluminous nucleoli, and eosinophilic cytoplasm. There is an abundance of smooth endoplasmic reticulum, numerous mitochondria with tubular cristae, and a variable number of lysosomes and lipid droplets. The rough endoplasmic reticulum consists of some groups with a few short, parallel cisternae.121 These cells differ from adult Leydig cells by the absence of Reinke crystals and paracrystalline structures, and by the lesser amount of lipid droplets.122 Histochemical expression included acid phosphatase, glucose-6phosphatase, and 3β-HSD. In addition to testosterone, these cells secrete several peptides that play important roles in endocrine and

Fig. 12.12 A 16-week-old fetal testis showing numerous Leydig cells in the interstitium and slightly convoluted seminiferous tubules.

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paracrine control of testicular function.119 One of these peptides, insulin-like factor 3 (INSL3), is important in testicular descent.123 Other Testicular Cell Types. Macrophages and hematopoietic cells are usually observed in the testicular interstitium of the fetal testis. They derive from yolk sac hematopoietic progenitors and migrate to colonize the testis and other organs. Macrophages are more numerous at the end of the fetal period, probably because of involution of Leydig cells. These cells are likely involved in Leydig cell paracrine regulation. Hematopoietic cells appear in isolated clusters at 17 to 20 weeks in the testis, chiefly located beneath the tunica albuginea or near the testicular mediastinum. In the final weeks of gestation, more than two-thirds of testes show hematopoietic foci. Vascularization of the Fetal Testis. Most fetal testes (72%) receive blood through three arteries: the testicular (inner spermatic) artery, which originates from the abdominal aorta; the deferential (vassal) artery, which originates from the inferior vesical artery; and the cremasteric (outer spermatic) artery, which is a branch of the inferior spermatic artery. In 23% of fetal testes, only two arteries (testicular and deferential) are present, whereas 5% of testes have four arteries.124 Fetal Epididymis. The testis and epididymis form an anatomic and functional complex, but the anatomic relationships vary widely. The most frequent finding (almost 90%) is connection of the testis limited to the caput and cauda of the epididymis. In other cases (about 8%) the testis is intimately attached to all parts of the epididymis (caput, corpus, and cauda), and uncommon cases (3%) have deficiencies in the testis-epididymis junction in the caput or the cauda.125 These variations are not related to the position of the testis or to the side of the body (right or left). During fetal life, androgenic receptors are observed in epithelial cells of both efferent ducts, the epididymal duct, and the peritubular stroma.117

region. This dynamic formation undergoes multiple morphologic changes. At this level of the abdominal wall, the gubernacular cells persist as simple mesenchyma, whereas the remaining abdominal wall cells differentiate into muscle. The mesenchymal cells give rise to the inguinal canal. Thus the testis lies on a continuous column of mesenchyma (plica gubernaculum) limited by the cranial testicular ligament in the upper pole and the plica gubernaculum joining the testis to the future scrotal region in the inferior pole. The periphery of this mesenchyma is invaded by the vaginal process, which develops from a blind peritoneal pouch that opens cranially into the abdominal cavity. The pouch partially encircles the gubernaculum except for its dorsal aspect, and divides the gubernaculum into two portions: central (plica gubernaculum) and peripheral (pars vaginalis gubernaculum). Once the inguinal canal and the plica gubernaculum are formed, development slows. In the seventh month the processus vaginalis undergoes active growth, the cremasteric muscle develops from the mesenchyma outside the processus vaginalis, and the distal end of the gubernaculum enlarges markedly. Gubernacular thickening occurs from weeks 16 to 24 of gestation, produced by an increase in number of cells and quantity of glycosaminoglycans and hyaluronic acid.130 This tissue later absorbs water to create the final volume of the gubernaculum. The tissue is reminiscent of Wharton jelly of the umbilical cord. By this time the testis-epididymis complex is pear shaped, and its largest component is the gubernaculum. The inguinal descent of the testis behind the gubernaculum begins in week 25. The testis and epididymis slide through the inguinal canal behind the gubernaculum. Simultaneously, development of the processus vaginalis concludes, and the gubernaculum begins to shorten and fibrose, located caudal to the testis and epididymis (gubernacular regression); the epididymis develops further, with lengthening of testicular blood vessels and vas deferens (Figs. 12.13 and 12.14).126

Testicular Descent

Testicular descent results from hormonal and mechanical influences that mediate migration through the abdominal wall and the inguinal canal to the scrotum.126 The process of descent begins between weeks 8 to 15 of gestation, accelerating from weeks 24 to 26.127 At week 23, most testes (90%) are still in the abdomen, and from weeks 26 to 28 they pass through the deep inguinal ring. Testicular displacement through the inguinal canal lasts a few days. At approximately week 28, they pass through the superficial inguinal ring and reach the scrotum, a process completed within 4 weeks. After week 35, descent is normally complete.128 Anatomic Structures Involved in Testicular Descent. Three phases are classically recognized in testicular descent: nephric, transabdominal, and inguinal. In the nephric phase the gonad detaches from the metanephros (primitive kidney) by week 7. Transabdominal descent consists of the displacement from the posterior abdominal wall to the future inguinal region (inner inguinal ring, also called the deep ring) by week 15. This displacement is associated with regression of the cranial suspensory ligament and enlargement of the caudal suspensory ligament (gubernaculum). At the same time, marked growth of the lumbar backbone takes place, and as a result the testis moves away from kidneys.129 Inguinal descent refers to the entry into the inguinal canal and complete descent into the scrotal pouch, occurring between week 28 of gestation and birth. Testicular descent is directed by the gubernaculum testis, a structure that appears at approximately week 6 of gestation as an elongate condensation of mesenchymal cells (the caudal ligament) extending from the genital ridge to the presumptive inguinal

Epididymis Testis Vas deferens

Abdominal wall

M. rectus abdominis

Extermal inguinal ring

M. cremaster Processus vaginalis

Pars vaginalis gubemaculi Plica gubernaculi

Scrotum

Pars infravaginalis gubemaculi

Fig. 12.13 Development of the gubernaculum and related anatomical structures.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.14 Panoramic view of testis, epididymis, and gubernaculum of a 34-week gestation newborn. The size of the gubernaculum exceeds that of the testis and epididymis combined.

Prerequisites for Testicular Descent. Testicular descent is a complex process integrating several essential factors that probably act sequentially and synergistically. The main prerequisites are normal hormonal stimulation, intraabdominal pressure, development of epididymis and spermatic vessels, development of the gubernaculum, and harmonic development of the processus vaginalis. Normal Hormonal Stimulation. The critical role of hormonal function in testicular descent is exerted through placental gonadotropins, the hypothalamic–pituitary-testicular axis function, and successful synthesis and action of testosterone produced by the testis.131 In animal models, destruction of the pituitary blocks testicular descent. Anencephalic fetuses and patients with familial hypogonadotropic hypogonadism usually have undescended testes. Many cryptorchid patients have transient neonatal hypogonadotropic hypogonadism. Some cryptorchid testes descend after treatment with hCG or gonadotropin-releasing hormone (GnRH). Defective Leydig cell function caused by absence of LH, defective testosterone synthesis, or defective ARs interferes with testicular maldescent. Adequate Intraabdominal Pressure. Another important prerequisite for the testicular descent is adequate abdominal pressure.132–134 In prune belly syndrome, bilateral abdominal cryptorchidism is associated with urologic malformations and lack of abdominal wall musculature. In a variant termed pseudo–prune belly syndrome, a positive correlation is seen between the development of abdominal wall musculature and testicular descent. The more developed the abdominal wall musculature is, the further the testes descend.135 Adequate Development of the Processus Vaginalis. Development of the processus vaginalis also plays a critical role in testicular descent. Growth of the processus vaginalis into the gubernaculum takes place harmoniously. If this structure is invaded, even partially, by fibrous tissue, the testis will descend in an abnormal direction, thus giving rise to ectopia. If fibrous tissue completely replaces the gubernaculum, the processus vaginalis and cremasteric muscle fail to develop fully, and as a result the testis is mechanically blocked in its route of descent.136 There is a close relationship between the development of the processus vaginalis and descent. If the processus does not extend far from the abdominal wall, then the testis remains

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intraabdominal. The processus protrudes throughout the outer inguinal ring only when testicular descent is initiated, and descends into the scrotum only after the testis has entered the inguinal canal. Factors That Regulate Testicular Descent. Given that nephric displacement consists only of detachment of the testis from the mesonephros, descent may also be classified as occurring in two phases, each regulated by different factors. The most important factor for transabdominal displacement is androgen-independent peptide INSL3 (also called INSF3 or IGF3), a member of the relaxin-insulin family that is produced by fetal Leydig cells.136–139 This peptide reaches high levels in the first half of gestation, stimulating gubernacular swelling by the production of hyaluronic acid and glycosaminoglycan that trap large amounts of water.140–145 In animal models, mutations in the genes that encode INSL3 or its receptor LGR8 (leucine-rich repeatcontaining G protein–coupled receptor 8) or another receptor called RXFP2 (relaxin/insulin-like family receptor 2) cause cryptorchidism by disrupting transabdominal descent.146,147 In humans, however, mutations in the genes that encode INSL3 or its receptors have been found in only 1% of cryptorchid patients, even in studies of familial cryptorchidism.148–150 The low frequency of such mutations in human cryptorchid patients may account for the infrequent disruption of the first phase of descent in humans, but the inguinoscrotal phase is usually impaired.149 Analyses of other potential candidate genes for human cryptorchidism, such as homeobox genes HOXA10 and HOXA11, and the estrogen receptor ESR1, also fail to elucidate mechanisms underlying cryptorchidism.150 Androgens facilitate regression of the cranial suspensory ligament, which also seems to contribute to positioning of the gonad. In contrast, the inguinoscrotal phase of testicular descent depends on androgenic action, as explained by the genitofemoral nerve (GFN) hypothesis.151,152 The nucleus of the GFN is located in the spinal cord. The nerve courses along the anteromedial surface of the psoas muscle, and the genital branch crosses the inguinal canal to innervate the cremaster muscle, whose rhythmic contractions are likely transmitted to the gubernaculum, orienting it in a scrotal direction. Based on this hypothesis, androgens act on the GFN nuclei rather than directly on the gubernaculum. Under androgenic action, GFN neurons then undergo masculinization.151 Male mice have a greater number of neurons than females, and the neurons secrete calcitonin gene–related peptide (CGRP), which is a GFN neurotransmitter. The gubernaculum tip may contain an area of primitive mesenchymal cells. Growth of the gubernaculum apparently results from CGRP-induced cell proliferation and prevention of apoptosis.153 The range of GFN-mediated androgenic effects is broad and may include obliteration of the processus vaginalis, inguinal canal differentiation, cremaster muscle myocyte differentiation, and initiation of transabdominal descent through involution of the testicular cranial suspensory ligament.126 Other factors that influence testicular descent include epidermal growth factor (EGF) and estrogens.154,155 EGF has a positive effect on descent through stimulation of the placental-gonadal axis. Maternal EGF levels increase just before fetal masculinization.154 The placenta has an elevated concentration of EGF receptors, and placental stimulation by EGF may stimulate hCG production, which in turn may stimulate Leydig cells to produce androgens that, alone or combined with other factors, may stimulate descent. In contrast, estrogens play a competing role in descent by preventing regression of the cranial gonadal ligament, gubernaculum growth, and Leydig cell proliferation, resulting in a decrease in androgen and INSL3 secretion.156–160 Exposure to environmental

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Transabdominal phase

ANDROGENS

Inguinoscrotal phase

CSL

T

Fig. 12.15 The main factors involved in testicular descent. CGRP, calcitonin gene–related peptide; CSL, cranial suspensory ligament; INSL3, insulinlike factor 3; LGR8, leucine-rich repeat-containing G protein–coupled receptor 8.

T

T G

G

Abdominal wall

G

INSL3 LGR8 / GREAT

ANDROGENS CGRP

Gubernacular thickening

Gubernacular migration

8-15 weeks

endocrine disrupters such as estrogen in utero has a negative effect on male genital tract development. During the first trimester of gestation, mothers of cryptorchid infants have free estradiol serum concentrations that are significantly higher than those of controls.156 Experimental studies have shown that estradiol diminishes gubernaculum swelling and stabilizes m€ ullerian ducts; therefore estradiol may inhibit the cell proliferation that causes swelling through a reduction of INSL3 secretion by Leydig cell damage (Fig. 12.15).158,159,161 After birth the gubernaculum and processus vaginalis involute. The gubernaculum is replaced by fibrous tissue that forms the scrotal ligament. Once the testis has descended, the processus vaginalis undergoes atrophy and reabsorption, mainly in its cephalic portion. Failure of the processus vaginalis to regress may be a common cause of acquired cryptorchidism.162 In some patients a noticeable and wide processus vaginalis is associated with inguinal hernia and cryptorchidism, whereas a narrow processus vaginalis appears associated with hydrocele; if there is partial obliteration of the lumen with persistence of the processus vaginalis, the testis could be retractile.163

28-35 weeks

Fig. 12.16 Longitudinal section of the testis and the caput and tail of epididymis from a newborn. Intratesticular septa split the testis into lobules that converge in the mediastinum.

Prepubertal Testis From birth to puberty the testis is a dynamic structure, an important consideration when interpreting biopsy results in children. All testicular components undergo waves of proliferation and differentiation before puberty.164,165 Morphometric analyses and endocrinologic studies in infants and children revealed that the number of Sertoli cells and germ cells increases during this period, accompanied by significant production of AMH and inhibin.166,167 During the prepubertal period, three waves of germ cell proliferation occur: during the neonatal period, in infancy, and at puberty. Germ cell proliferation at puberty gives rise to the adult testis with complete spermatogenesis. Leydig cell proliferation also has three waves (fetal, neonatal, and pubertal), the last of which corresponds to the pubertal wave of germ cell proliferation.

Development of the Testis From Birth to Puberty The Testis at Birth

The newborn testis has a volume of approximately 0.6 mL, and it is covered by a thin tunica albuginea from which the intratesticular

septa arise.168 These septa divide the testis into approximately 250 lobules containing the seminiferous tubules and testicular interstitium (Fig. 12.16). The seminiferous tubules measure 60 to 65 μm in diameter, form solid cords with no apparent lumina filled with Sertoli cells and germ cells, and are surrounded by a thin basement membrane and isolated myoid cells and fibroblasts. Sertoli cells are the most abundant cells, with 26 to 28 per tubular cross section (Fig. 12.17). They form a pseudostratified cellular layer and have elongated to oval nuclei with darker chromatin than that of mature Sertoli cells, as well as one or two small peripheral nucleoli. The apical cytoplasm contains abundant rough endoplasmic reticulum, several Golgi complexes, and numerous vimentin filaments, with inhibin B expression (Fig. 12.18). Interdigitations and small junctions of the occludens and adherens types join adjacent Sertoli cells, and desmosome-like junctions are present between Sertoli cells and germ cells. Mitotic figures are occasionally seen. These cells express AMH and vimentin, as well as weak staining for M2A oncofetal antigen.169 Also, in the apical pole, spherical

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.17 The seminiferous tubules contain Sertoli cells, the most numerous ones and two germ cell types: gonocytes and spermatogonia. The gonocytes have large nuclei with large central nucleoli. The spermatogonia have smaller nuclei and pale cytoplasm. Several Leydig cells are seen in the interstitium.

Fig. 12.18 Newborn testis. Both Sertoli cells and Leydig cells are intensely immunoreactive for inhibin.

or ovoid bodies show intense immunostaining with inhibin (Fig. 12.19).170 Germ cells comprise fetal spermatogonia, spermatogonia A dark (Ad), and gonocytes. Spermatogonia are present chiefly on the basal lamina in a discontinuous pattern, possessing smaller nuclei and less cytoplasm than gonocytes; nucleoli are peripheral and small. At birth, most spermatogonia correspond to the adult type A (Germ cell-Spermatogonia) (Fig. 12.20). Spermatogonia Ad have smaller nuclei, and barely visible nucleoli are peripherally distributed. Gonocytes are usually located near the center of the tubules, with spherical and voluminous nuclei and large central nucleoli.171 Most gonocytes are immunoreactive with PLAP and KIT. Seminiferous tubules are surrounded by the tunica propria, which comprises a basal lamina, myoid cells, fibroblasts, collagen fibers, and extracellular matrix. The peritubular myoid cells express intense nuclear immunostaining for AR, with expression similar to

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Fig. 12.19 Newborn testis. Inhibin inclusion in the apical pole of Sertoli cells. The clear unstained spaces correspond to germ cells.

Fig. 12.20 Spermatogonia show wide cytoplasm and regularly outlined nuclei with eccentric nucleoli. The cytoplasm contains mitochondria joined by electron-dense bars.

interstitial cells, easily distinguished from the negative staining in Sertoli cell nuclei.167 The testicular interstitium is a loose connective tissue that contains fetal Leydig cells that resemble adult Leydig cells but lack Reinke crystalloids (Fig. 12.21).172,173 These cells have welldeveloped smooth and rough endoplasmic reticulum, filament bundles, and lipid droplets. In addition, mast cells, macrophages, and hematopoietic cells are present.170 Neonatal Development of the Testis

Minipuberty is first important postnatal development. It involves changes in germ cells, Sertoli cells, and Leydig cells caused by a transient increase in secretion of FSH and LH during the third postnatal month.174–180 Testicular weight and volume increase twofold from birth to 5 months of age.181–183 FSH induces Sertoli cell proliferation, increasing fivefold to sixfold during the first year of life.184–186 Under the influence of LH, resident Leydig stem cells undergo

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Fig. 12.21 Leydig cells have eccentric, round nuclei, abundant smooth endoplasmic reticulum and mitochondria, lysosomes, and stacks of rough endoplasmic reticulum cisternae.

stimulation, with new ones differentiating from peritubular myoid cells, and the number increases, peaking between 2 and 4 months after birth.173,187 In the following months, this cellular population declines rapidly so that by the end of the first year, Leydig cells are rare. As a consequence of the changes in Sertoli and Leydig cells, serum levels of inhibin B, testosterone, and INSL3 increase.136 Inhibin B, a Sertoli cell marker, remains elevated even when FSH and LH levels have decreased.180 The total number of germ cells per testis increases up to threefold in the first months of life to the end of the neonatal period, and drops later.171,188 Gonocytes move from the center of the seminiferous tubule toward the basal lamina. This migration is probably facilitated by cell adhesion molecules on the immature Sertoli cell surface, including P-cadherin.189 Transformation of gonocytes into spermatogonia Ad is enhanced by testosterone and probably also by AMH, which is found at high levels between the 4th and 12th months of life (Fig. 12.22).53 This transformation is complete by age 6 months and coincides with total loss of fetal germ cell markers PLAP and KIT by the end of the year one.

Fig. 12.22 Testis from a 4-day-old infant. Gonocytes are strongly immunoreactive for KIT.

Fig. 12.23 Newborn epididymis showing a paraganglion around the epididymal duct.

Paraganglia are often observed in epididymides and spermatic cords in newborns. This finding is not surprising because paraganglia are the main source of catecholamine before birth (Fig. 12.23).190 Testis in Infancy

From the sixth month to approximately the second half of the third year of life, the testis is in a resting period. Tubular diameters decrease (from 80 to 60 μm), and spermatogonial proliferation is rarely observed. Leydig cells involute so that by the end of this period, only a few of these cells persist and are not easily detected in routine specimens. The thickness of the albuginea diminishes to 250 μm. Despite these findings, which permit investigators to define a resting period of the testis, Sertoli cells maintain active hormone synthesis. During these years Sertoli cells produce high levels of AMH and inhibin.180,191,192 AMH modulates the number and function of Leydig cells by hindering the differentiation of these cells from their mesenchymal precursors and diminishing synthesis of steroidogenic enzymes.193 Inhibin B plays a role in the inhibition of FSH during infancy. Immunohistochemically, its expression is observed throughout the cytoplasm and in a granular pattern in the apical pole. This quiescence is broken at the end of the third year by the second wave of germ cell proliferation, the so-called growth period.168 The number of Ap spermatogonia increases, and B spermatogonia (derived from Ap spermatogonia) appear. In some normal testes from children who are older than 4 years, meiotic primary spermatocytes and round spermatids (Sa + Sb types) are observed (Fig. 12.24).194 This second spermatogenic attempt fails, and many degenerate germ cells may be present but are phagocytosed by Sertoli cells.195,196 The testis continues to produce AMH (by Sertoli cells) and inhibin B.180,191 AMH modulates the number and function of Leydig cells by regulating differentiation of the mesenchymal precursors and expression of steroidogenic enzymes.193 Inhibin B plays a role in FSH inactivation during infancy. The cause of this second wave of germ cell proliferation is unknown; no elevation of FSH or LH serum concentrations occurs between 6 months and 10 years of life. After the sixth year, there is a slight increase in adrenal androgens, but testicular testosterone levels increase only after the tenth year.197,198 By the third year, most Leydig cells have degenerated: from a peak of approximately

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.24 Testis from a 4-year-old infant. The seminiferous tubules have spermatogonial proliferation and contain a central group of primary spermatocytes.

18 million at birth, only 60,000 remain by the age of 6 years. At this age, testosterone levels are similar to those of girls, and most androgens are of adrenal origin.197 Testosterone levels during infancy are much higher in the tunica vaginalis than in plasma.199 It also could be important that Sertoli cells begin to express the AR in their nuclei at this age (Fig. 12.25).167 Expression is probably related to development of this wave of proliferation and differentiation of germ cells. The Testis in Childhood

From the fourth to the ninth year of life, the seminiferous tubules and testicular interstitium undergo active growth and development. The seminiferous tubules increase in length, width, and diameter, and the epithelium changes from pseudostratified to columnar. Sertoli cell nuclei remain ovoid, but the outlines become increasingly irregular. The number of cells decreases gradually while the seminiferous tubules lengthen, and the result is that the total number of Sertoli cells per testis increases. At the same time, all spermatogonia types (Ad, Ap, and B) increase in number. The lamina propria now contains one to four fibroblasts embedded in collagen fibers.

Fig. 12.25 Testis from an infant at the end of the third year of age showing androgen receptor–positive immunostaining in myoid peritubular cells and some nuclei of Sertoli cells.

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Cholinergic and adrenergic nerves are observed, with cholinergic nerves ending in the tubular basal lamina.200,201 The testicular interstitium apparently lacks classic morphologic Leydig cells. Isolated Leydig cells persist that are fetal in origin or else developed during minipuberty, with pronounced signs of dedifferentiation, alongside a large number of fibroblast-like cells corresponding to adult Leydig stem cells.202 The tunica albuginea becomes progressively thicker and more collagenized. At the end of the growth period, between the fourth and ninth years of life, moderate degeneration of spermatogonia occurs. During this period the control of gonadotropic secretion is likely mediated by inhibiting neuroendocrine secretions, whereas testicular hormone levels are low.203 There is autonomic innervation of Leydig cells, with three different types of nerve endings. Type I contains many small agranular vesicles (30 to 60 nm) and occasionally large granular vesicles (100 nm); they are probably cholinergic fibers. Type II nerve endings, with many small granular vesicles (30 to 60 nm) and occasionally large granular vesicles (100 nm), are probably adrenergic fibers. Type III contains large granular vesicles of the mixed type. Most of these nerve fibers are “boutons en passant,” characterized by fibers are separated from Leydig cells by at least 150 nm, but true contact (20 nm) has also been reported.204 At approximately 9 years of age, the maturation period begins. The third and definitive wave of spermatogenesis occurs, coinciding with a significant elevation of LH.205 This is followed by additional increases in the level of this hormone between 13 and 15years of age. LH induces fibroblast-like Leydig cell precursors to differentiate into mature Leydig cells in the seminiferous tubule walls and in the interstitium.206 By the end of puberty, the number of Leydig cells per testis is estimated to be 786 million. Leydig cells secrete androgens that, together with the rise in FSH between 11 and 14years of age, cause Sertoli cell maturation, germ cell development, and appearance of tubular lumina (Fig. 12.26), thus increasing the size of the testes between the ages of 11.5 and 12.5 years.207,208 At 10years of age, the testicular volume is 1.5 mL (three times that of the first year of life).209 This enlargement is assumed to be the first clinical manifestation of puberty. The spermarche, defined as the first spermaturia, occurs early, and may precede other androgen effects such

Fig. 12.26 Testis from an 11-year-old boy. Germ cell development varies from one tubule to another. The number of spermatogonia is lower than that of the adult testes. Residual immature Sertoli cells show elongate nuclei with small nucleoli. Leydig cells are scant.

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as the development of secondary sex characteristics and the pubertal growth spurt.210–214 Spermaturia is a constant finding when testicular volume is greater than 4 mL (or even lower).215 Morphologic changes occurring at puberty involve all testicular structures. Sertoli cells undergo active proliferation in the prepubertal period, a prerequisite to ensure normal spermatogenesis, beginning at about 11 years of age, but is not completed until 13 years of age.172,216,217 Sertoli cell nuclei become enlarged and irregular with indentations; the chromatin becomes looser, and nucleoli acquire a tripartite structure.218 Prominent cytoplasmic changes include development of endoplasmic reticulum (smooth and rough), elongation of mitochondria with longitudinal cristae, increase in the amount of lysosomes and lipid droplets, appearance of annulate lamellae and Charcot-B€ottcher crystals, and development of inter-Sertoli junctional specializations that form the blood-testis barrier.219 The degree of Sertoli cell maturation may be deduced from AMH levels: high levels when Sertoli cells are immature, with marked decrease after puberty with the advent of meiotic spermatocytes and rise of testosterone.220,221 Proliferation of Sertoli cells is accompanied by an increase in the number of peritubular myoid cells induced by PDGF ligands. The myoid cells in turn contribute to elongation of the seminiferous tubes.222 Germ cell proliferation finally achieves efficient spermatogenesis, although morphologic anomalies of spermatozoa are frequent up to the end of puberty. The mean age for appearance of spermatozoa is 13.4 years. Leydig cell differentiation is rapid, and many interstitial Leydig cell clusters are seen before seminiferous epithelium development is complete.202 Collagenization of the tunica albuginea progresses up to the end of puberty, when thickness reaches 400 to 450 μm. Final testicular volume is approximately 20 mL.223

Relationship of Testis and Epididymis During Infancy, Childhood, and Puberty From the first month of postnatal life to the 18th year of age, the most common testis-epididymis configuration is connection by the caput and cauda epididymidis (84% of cases), resulting in a digital fossa present between testis and epididymis.224 A less frequent configuration (12%) is complete testis-epididymis union. Other configurations are pathologic. Interpretation of Testicular Biopsy From Prepubertal Testes Testicular biopsy in children is necessary to determine the nature of the gonads in those with ambiguous genitalia, a history of leukemia or lymphoma whose testes underwent rapid enlargement, or precocious testicular maturation of unknown cause. Testicular biopsy has been replaced by fine needle aspiration in the study of enlargement in patients with leukemia or lymphoma. In other situations the value of biopsy is less clearly established. For example, biopsy of cryptorchid testes during orchidopexy is controversial, although routine performance of such biopsies provided information on precocious development of lesions in cryptorchidism, including explanations of the causes of cryptorchid lesions such as testicular dysgenesis or transient hypogonadotropic hypogonadism, and to abandon the disproven hypothesis of temperature-induced lesions. Evaluation of biopsy samples of the prepubertal testis should involve assessment of tunica albuginea thickness, mean tubular diameter (MTD), and the number of germ cells, Sertoli cells, and Leydig cells.

Tunica Albuginea

The most frequent anomaly of the tunica albuginea is the presence of thin, poorly collagenized, altered tissue layers arranged parallel to the surface resembling ovarian stroma. There may be irregular seminiferous tubules protruding from the testicular surface, a configuration classically known as testicular dysgenesis, including mixed gonadal dysgenesis, dysgenetic male pseudohermaphroditism, and persistent m€ ullerian duct syndrome (PDMS).83 This alteration results from insufficiency or defective action of AMH.225 This anomaly may affect all or part of the tunica albuginea. This lesion should not be misinterpreted as simple seminiferous tubule ectopy, such as that seen in an otherwise normal, wellcollagenized tunica albuginea and an orderly arrangement of layers. Focal ectopy of seminiferous tubules is a frequent finding in both normal and cryptorchid testes.226,227 In these testes, ectopic seminiferous tubules after puberty may undergo normal germ cell development or become hyalinized. Occasionally, ectopic tubules have cystic dilation that forms a bulbous zone that may be macroscopically visible (Table 12.2). In patients with disorders of sex differentiation, groups of ovocytes may replace the tunica albuginea, the characteristic structure of ovotestis. Seminiferous Tubules

Evaluation of seminiferous tubules includes qualitative study of the morphology of the epithelial cells and quantitative estimates of MTD and number of germ cells and Sertoli cells. Mean Tubular Diameter. The MTD is an excellent indicator of development of the seminiferous epithelium. In the prepubertal testis, tubular diameter depends principally on the number and trophism of Sertoli cells, thus indicating whether there is adequate stimulation by FSH. Tubular diameter varies throughout, being smallest at the end of the third year of life, slowly enlarging up to 9 years of age, and rapidly enlarging thereafter up to 15 years, when the tubule reaches its definitive diameter (160 to 190 μm) (Fig. 12.27). The most frequent abnormality in the prepubertal testis is a low MTD. This is seen in undescended testes and hypogonadotropic or hypergonadotropic hypogonadism (Table 12.3). In the latter condition the lesion results from anomalous Sertoli cell responsiveness to FSH.211 The three levels of severity of low tubular diameter are slight tubular hypoplasia (10% reduction in relation to the diameter normal for the age), marked tubular hypoplasia (from 10% to 30% reduction), and severe tubular hypoplasia (>30% reduction). High MTD is observed in precocious puberty.228 There is a focal increase in diameter (precocious tubular maturation) of tubules at the periphery of Leydig cell tumors. This enlargement seems to be produced by elevated androgen concentration, which would also be responsible for precocious tubular maturation.229 The same occurs with some Sertoli cell tumors. Diffuse increase in MTD may be unilateral or bilateral (Table 12.3). Unilateral increase is found in monorchidism (compensatory testicular hypertrophy), as well as in some testes that are

TABLE 12.2 • • •

Frequent Anomalies of the Tunica Albuginea

Thin, poorly collagenized albuginea, ovarian-like stroma Focal ectopy of testicular parenchyma Presence of ovocytes in an ovarian-like stroma

200

20

150

15

100

10

150

SCN (number of cells)

MTD (mm) and TFI (%)

CHAPTER 12 Nonneoplastic Diseases of the Testis

5

MTD TFI SCN

0

0 0

3

6 9 Years of age

12

15

Fig. 12.27 Changes in mean tubular diameter (MTD), tubular fertility index (TFI), and Sertoli cell number per cross-sectioned tubule (SCN) from birth to puberty.

TABLE 12.3

Anomalies in Tubular Diameter

Decrease in tubular diameter Hypogonadotropic hypogonadism Hypergonadotropic hypogonadism Undescended testis

Increase in tubular diameter Diffuse Compensatory hypertrophy Precocious puberty Benign idiopathic macroorchidism Macroorchidism associated with fragile X chromosome Familial testotoxicosis Macroorchidism associated with hypothyroidism

Focal Megatubules, ring-shaped tubules, tubules with eosinophilic bodies with microliths Sertoli cell intratubular neoplasia

contralateral to cryptorchid testes.230,231 Most frequently, diffuse enlargement occurs in benign idiopathic macroorchidism, macroorchidism associated with fragile X chromosome, familial testotoxicosis, hypothyroidism, and other forms of precocious puberty.232–235 Focal increase in MTD is usually associated with precocious maturation of the seminiferous epithelium in tubules at the periphery of Sertoli cell tumors and Leydig cell tumors. Frequently, infantile testicular biopsies of undescended testes contain several types of malformations such as nearly straight tubules or ramified tubules. Other findings are large tubules (megatubules or ring-shaped tubules), which are malformed tubules displaying a tight spiral course, or bell-shaped deformities (bell-shaped tubules). Megatubules may surround and isolate connective tissue that often develop eosinophilic bodies or microliths.236 These tubules are likely an indicator of poor prognosis in those with infertility. The presence of one or more groups of enlarged tubules with marked thickening of the basal lamina in infant testes suggests

565

intratubular Sertoli cell neoplasia. This pattern is frequently seen in infants with Peutz-Jeghers syndrome. Some infantile testicular biopsies show enlarged tubules with prominent lumina or cystically dilated tubules. Testicular fluid is not produced before puberty, so normal prepubertal tubules do not contain lumina. Therefore the observation of such findings suggests cystic dysplasia of the rete testis. This disorder may include absence or dysplasia of the ipsilateral kidney and urinary excretory ducts. Germ Cell Number. Germ cells may be counted in two ways: calculation of the number of cells per tubular cross section or determination of the tubular fertility index (TFI). The first method counts the number of germ cells in a light microscopic field and divides this by the number of cross-sectioned tubules. In the first 6 months of postnatal life, the normal testis has two germ cells per cross-sectioned tubule, dropping to 1.5 at the end of the first year and to 0.5 at the end of the third year. The number then increases to 1.8 cells at the age of 3 to 4 years, which coincides with the appearance of spermatocytes in some tubules.237 This number then increases slowly up to 8 years of age, decreases again up to 9 to 10 years, and increases once more, rising markedly from 12years of age to the end of puberty.195,238 Separation of spermatogonia and gonocyte counts reveals time of last transformation of gonocytes into Ad spermatogonia. TFI reflects the percentage of tubular sections containing germ cells. In newborns, 68% of tubular sections contain at least one germ cell. From birth to 3 years, this decreases to 50%, followed by a progressive increase to 100% at puberty.168 The most accurate measure is calculation of total germ cell number per testis. This is more difficult because it requires morphometric assessment of intratubular volume and careful clinical measurement of the three axes of the testis. Three levels of severity of germinal hypoplasia are recognized: slight (TFI > 50), marked (TFI between 50 and 30), and severe (TFI < 30). Marked and severe germinal hypoplasia is usually associated with marked or severe tubular hypoplasia, in most cases resulting from tubular dysgenesis. It may also be useful to determine whether the seminiferous tubules devoid of germ cells are randomly distributed. If grouped, they probably belong to the same lobule or group of lobules that will never develop normally. Congenital decrease of germ cells occurs in numerous conditions, including trisomies 13, 18, and 21; some forms of primary hypogonadism such as Klinefelter syndrome; anencephaly; cryptorchid testes and posterior urethral valves; and severe obstruction of urinary ducts (Table 12.4).239,239a,240 Congenital germ cell TABLE 12.4

Variation in Tubular Fertility Index

Decrease in tubular fertility index Congenital 13, 18, 21 trisomies. Klinefelter syndrome. Anencephalia. Cryptorchidism. Patients with posterior urethral valves.

Acquired Treatments with antitumoral chemotherapy. Treatments with immunosuppression. Therapies in transplantation.

Increase in tubular fertility index Parenchyma close to either germ cell tumors or gonadal-stroma tumors.

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decrease may result from deficient colonization of genital ridges by primordial germ cells, reduced germ cell proliferation, or increased germ cell loss. In Klinefelter syndrome, defective germ cell colonization has been suggested as the cause because of the high incidence of extragonadal germ cell tumors in such patients.240 During infancy and childhood a significant reduction in the number of spermatogonia occurs in children undergoing chemotherapy or immunosuppression. An increased number of germ cells may be seen at the periphery of germ cell tumors, gonadal-stromal tumors, and paratesticular sarcomas.241,242 Other altered germ cells include multinucleate or hypertrophied spermatogonia and gonocyte-like cells. Multinucleate spermatogonia have two to four nuclei, and Ap and Ad nuclei may coexist within the same cell, representing a failure of cytokinesis. Hypertrophic spermatogonia are located over the basal lamina and exhibit large, usually hyperchromatic nuclei and abundant cytoplasm, findings indicating polyploid cells that are unable to complete cellular division. Most of the hypertrophic spermatogonia degenerate rapidly. Gonocyte-like cells are located among Sertoli cells in the center of tubules, appearing as large cells with ovoid nuclei, large central nucleoli, and small heterochromatin granules. These cells should not be misinterpreted as cells from germ cell neoplasia in situ (GCNIS). Tumoral cells of GCNIS, which share with gonocytes immunoreactivity for PLAP, KIT, and OCT3/4, also show immunoreactivity for SCF.243 The presence of gonocytes is common in gonads of patients with disorders of sexual differentiation, and this finding often indicates delay in germ cell maturation. Complete maturation of the seminiferous epithelium at early ages may occur in patients with precocious puberty, as well as in the testicular parenchyma at the periphery of Leydig cell tumors. Sertoli Cell Number. The number of Sertoli cells per tubular cross section varies during childhood as a result of slow proliferation from 4 to 12 years and redistribution as seminiferous tubules become longer and broader.185 An apparent decrease in Sertoli cell number results from cellular displacement as a consequence of slow growth in length and tortuosity of tubules and not from degeneration. The pseudostratified cellular pattern characteristic of Sertoli cells at birth and the first months of life changes slowly to a columnar pattern during later infancy. During puberty, three phenomena occur: proliferation of Sertoli cells with emergence of pseudostratified seminiferous epithelium that ensures growth of tubules; Sertoli cell maturation; and subsequent transformation of pseudostratified epithelium into the columnar epithelium that is characteristic of the adult testicle.244 Proliferation is under the control of FSH and testosterone, ensuring optimum sperm production.245 Testicular biopsies may reveal hypoplasia or hyperplasia of Sertoli cells. Hypoplasia may indicate congenital hypogonadotropic hypogonadism, Kallmann syndrome, Prader Willi syndrome, DAX1 mutation, or multiple pituitary hormone deficiency. Hyperplasia may be observed in several pathologic states and manifests itself at different moments of development. In childhood, hyperplasia is observed in most cases of macroorchidism, because most of the volume of the testis at this time depends on the number of Sertoli cells. This also applies for patients with the syndrome of fragility of the X chromosome and in those with peripheral precocious pseudopuberty, a component of McCune-Albright syndrome (MAS). Sertoli cell hyperplasia seen at the beginning of puberty is characteristic of cryptorchid testicles and reflects the inability of the growth in length and tortuosity of the seminiferous tubules, and, to a lesser extent, an absolute increase in number of Sertoli cells. This is considered a sign of tubular dysgenesis.246 Biopsies may reveal one or several tubular sections containing Sertoli cells with eosinophilic and granular cytoplasm that is positive for CD68 and

α1-antitrypsin, oncocytic changes that result from lysosomal accumulation; this is considered a primary anomaly.247 Leydig Cell Number

Calculation of Leydig cell number during childhood is difficult because of the low numbers.206 Use of semithin sections or immunohistochemistry to detect cells containing testosterone or calretinin may be helpful.207 Selection of the appropriate denominator to express the Leydig cell population is another problem. The most frequent measures are Leydig cell number per tubular section or per unit area, or total Leydig cell number per testis.208 Low numbers of Leydig cells are observed in undescended testes, hypogonadotropic hypogonadism, disorders of sexual differentiation caused by an anomaly in LHRs, and anencephaly.248 High numbers occur in congenital Leydig cell hyperplasia, triploidy, variants of precocious puberty, and several syndromes such as leprechaunism and Beckwith-Wiedemann syndrome (Table 12.5).249–251 Focal accumulation of Leydig cells with broad and microvacuolated cytoplasm caused by the presence of lipids is characteristic of patients with sexual developmental disorders secondary to mutations of the NR5A1 (SF1) gene.252 They may also be seen in patients with defects in androgen synthesis. Intertubular Connective Tissue

The seminiferous tubules are normally closely packed, separated only by a small amount of loose connective tissue that maintains cohesion among the tubules and contains scant Leydig cells, macrophages, mast cells, blood vessels, and nerves. This intertubular connective tissue may be altered, including increased amount, increased cellularity, abnormal development of lymphatic vessels, and the presence of cell types that are unusual in this location.253 An apparent increase in loose connective tissue is found in patients with marked tubular hypoplasia. The cellular basis for increased connective tissue is uncertain. Some testes have thick fusiform cell bundles that separate groups of closely packed seminiferous tubules. These cells are reminiscent of the cells that form ovarian stroma and are the most characteristic histologic finding in Botella-Nogales-Morris syndrome (a sex differentiation disorder secondary to androgen insensitivity).254 Other alterations include the presence of overly developed lymphatic vessels (congenital testicular lymphangiectasis), focal hematopoiesis, leukemic infiltrate, and the presence of cells reminiscent of the adrenal cortex (tumors of the adrenogenital syndrome).

Adult Testis Anatomy The adult testis is an egg-shaped organ suspended in the scrotum from the spermatic cord, the retroepididymal surface, and the TABLE 12.5

Variation in Leydig Cell Number

Decrease in Leydig cell number Hypogonadotropic hypogonadism. Undescended testes. Defects in luteinizing hormone receptors. Anencephalic fetuses.

Increase in Leydig cell number Congenital hyperplasia of Leydig cells (maternal diabetes mellitus). Malformative syndromes (Beckwith-Wiedemann syndrome, leprechaunism). Precocious puberty.

CHAPTER 12 Nonneoplastic Diseases of the Testis

scrotal ligament. Mean weight in white men is 21.6  0.4 g for the right testis and 20  0.4 g for the left. Mean testicular diameter is 4.6 cm (range, 3.6 to 5.5 cm) for the longest axis and 2.6 cm (range, 2.1 to 3.2 cm) for the shortest.255–258 Testicular volume varies from 15 to 25 mL. Testicular volume correlates with height, weight, body mass index, and body surface area, and it decreases in adulthood.259

Supporting Structures The tunica albuginea and interlobular septa make up the connective tissue framework of the testis. The tunica albuginea consists of three connective tissue layers: an outer layer of mesothelium apposed to the basal lamina (tunica vaginalis), a middle layer of dense fibrous tissue, and an inner layer of loose connective tissue (tunica vascularis) with nerve fibers and abundant blood and lymphatic vessels. From the outer to the inner layers, the amount of collagen fibers decreases, whereas the number of cells increases. The fibers and cells in the two outermost layers form planes parallel to the testicular surface; cell types include fibroblasts, myofibroblasts, mast cells, and nervous fibers. Myofibroblasts are more numerous in the posterior portion of the testis (Fig. 12.28). The thickness of the tunica albuginea increases with age from 400 to 445 μm in young men to more than 900 μm in older men.260 The tunica albuginea acts as a semipermeable membrane that produces the fluid of the vaginalis cavity. The presence of many contractile cells showing high concentrations of guanosine monophosphate suggests that the tunica albuginea undergoes cycles of contraction and relaxation. The cells may regulate testicular size and favor the transport of spermatozoa into the epididymis.261,262 The interlobular septa consist of fibrous connective tissue with blood vessels supplying the testicular parenchyma. The interlobular septa divide the testis into approximately 250 pyramidal lobules, with the bases at the tunica albuginea and vertices at the mediastinum testis. Each lobule contains two to four seminiferous tubules and numerous Leydig cells.263 Seminiferous Tubules Adult seminiferous tubules are 180 to 200 μm in diameter and 30 to 80 cm long. The total combined length of the seminiferous tubules is approximately 540 m (range, 299 to 981 m).264 These

Fig. 12.28 Testis located in vaginal cavity. It is externally covered by tunica albuginea, which is a thick layer formed by collagenized fibrous tissue. The parietal layer has abundant smooth muscle fibers, whereas the innermost layer of albuginea contains large vessels (tunica vasculosa).

567

tubules are highly convoluted and tightly packed within the lobules. The seminiferous tubules comprise approximately 80% of testicular volume.265 The tubular lining of germ cells and Sertoli cells is surrounded by a lamina propria (tunica propria) (Fig. 12.29). Sertoli Cells

Sertoli cells are columnar cells that extend from the basal lamina to the tubular lumina, with 10 to 12 cells per cross-sectioned tubule. They are easily identified by their nuclear characteristics. Nuclei are located near the basal lamina and appear triangular with an indented outline. They are euchromatic, as expected of cells that express a great proportion of the genome to synthesize a large variety of substances required for its multiple functions. Nucleoli are central and voluminous (Fig. 12.30). The cytoplasm has lateral

Fig. 12.29 Cross section of seminiferous tubule with complete spermatogenesis surrounded by tunica propria. Both interstitium and tunica propria blood vessels may be observed. Among seminiferous tubules, small groups of Leydig cells may be observed.

Fig. 12.30 Germ cell development progresses from the basal lamina toward the lumen of the tubule. Each germ cell type forms a different layer in the seminiferous tubules and may be identified by its nuclei. Spermatogonia are basal cells with pale cytoplasm, round nuclei, and eccentric nucleoli. Above these cells, the Sertoli cell nuclei may be recognized by their large central nucleoli. The inner layers consist of primary spermatocytes showing the chromatin pattern characteristic of meiosis (semithin section).

568 C H A P T E R 1 2

Nonneoplastic Diseases of the Testis

processes that spread out and surround adjacent germ cells and touch other Sertoli cells, facilitating direct contact with 40 to 50 germ cells and 6 to 7 adjacent Sertoli cells. Charcot-B€ottcher crystals and lipid droplets often are visible in the cytoplasm.266–269 The number of Sertoli cells per testis decreases from approximately 250 million in young men to 125 million in men who are older than 50 years of age.270,271 A positive correlation exists between the number of Sertoli cells and daily sperm production.272 Sertoli cells are the target of FSH and androgen action.273–275 In adulthood these cells produce testicular fluid through an active transport mechanism, creating and maintaining the lumen of the seminiferous tubule. Testicular fluid is isosmotic, with a high content of potassium that exposes various membrane and water transporters.276 The fluid provides an optimal milieu for developing spermatozoa and a vehicle to transport them from the testis. Ultrastructurally, Sertoli cells have characteristic nucleoli, plasma membranes, and cytoplasmic components. Nucleoli have a tripartite structure with round fibrillar centers, compact granular portions, and three-dimensional nets composed of intermingled fibrillar and granular portions.218,277,278 The plasma membrane has two types of intercellular junctions that develop at puberty: junctions between adjacent Sertoli cells and junctions between Sertoli cells and germ cells.279 The ectoplasmic junction is a unique and specific junction that consists of Sertoli-Sertoli cell junctions (basal ectoplasmic specializations) and Sertoli-germ cell junctions (apical specializations). Sertoli-Sertoli junction specializations consist of adherens, tight junctions, and gap junctions that are dynamically remodeled to allow the movement of germ cells across the seminiferous epithelium and the timely release of spermatids into the tubular lumens.219 This dynamic remodeling of cell junctions is mediated by several mechanisms at transcription and posttranslation.280 In addition, ectoplasmic specializations also confer cell orientation and polarity in the seminiferous epithelium.281 Within the plasma membrane are adhesion molecules such as connexin 43 that may regulate other proteins of intercellular junctional complexes that occur between adjacent cells.282 The presence of connexin depends on the seminiferous epithelium stage, absent at stages II and III when primary spermatocytes cross from the basal to the adluminal compartment.283 Three different types of membrane protein have been identified in the testis: occludin, claudins, and adherens junction molecules.280,284,285 In addition, beneath the Sertoli cell plasma membrane and cisterns of the endoplasmic reticulum, several molecules are recognized: actin filaments, anchorage molecules, vinculin, zonula occludens 1 (ZO-1) and ZO-2, plakoglobin, radixin, and nectins.286,287 The inter-Sertoli cell junctions are the morphologic basis for the blood-testis barrier and divide the seminiferous epithelium into two compartments; the basal compartment contains spermatogonia and newly formed primary spermatocytes, whereas the adluminal compartment contains meiotic primary spermatocytes, secondary spermatocytes, and spermatids.288 These junctions permit each compartment to have its own microenvironment for spermatogenic development.219,289,290 The Sertoli cells, the only cell types present in both compartments, together with primary spermatocytes, become the key to control the passage of information from one compartment to another.291 There is a transient compartment between the basal and adluminal compartments, where preleptotene and leptotene spermatocytes linger before entering the adluminal compartment. The blood-testis barrier is always secured by the existence of tight junctions both apically and basally to the cells.292 Definitive establishment of the blood-testis barrier is

complete when Sertoli cell proliferation and maturation ceases, features coinciding with the initiation of meiosis. Terminal differentiation of Sertoli cells is regulated to a great extent by retinoblastoma protein.293 Sertoli cell-germ cell junctions (desmosomes and tight junctions) persist from the primary spermatocyte stage through spermatozoon release. Adhesion of Sertoli cells and germ cells is mediated by N-cadherin.294 These glycoproteins are involved in maintaining the seminiferous epithelium architecture and germ cell migration from the basal to the adluminal compartment. These junctions may also be present between spermatogonia.292,295 Sertoli cell basal cytoplasm contains abundant smooth endoplasmic reticulum (involved in steroid synthesis), scant rough endoplasmic reticulum (involved in protein synthesis), annulate lamellae, Golgi complex, lysosomes, residual bodies, glycogen granules, lipid droplets in amounts that vary with the seminiferous tubule cycle, Charcot-B€ottcher crystals (structures several micrometers long, formed of multiple parallel laminae of protein), and ribosomes.296–298 The apical cytoplasm contains elongate mitochondria, numerous microtubules, and large numbers of vesicles with degraded cytoplasmic fragments derived from phagocytosis of residual bodies of spermatids.299 Sertoli cells are immunoreactive for inhibin, WT1 (Fig. 12.31), GATA4, SOX9, follicle-stimulating hormone receptor (FSHR), vimentin, nuclear AR (Fig. 12.32), F-actin filaments, and αtubulin in the cytoplasm. Actin filaments appear in both interSertoli cell junctions and ectoplasmic specializations that surround germ cells.300 F-actin bundles contribute to formation of SertoliSertoli cell junctions arranged at regular intervals beneath the plasma membrane and cistern of the endoplasmic reticulum connected to microtubules.301 Actin distribution varies during the cycle of the seminiferous epithelium. It is more abundant next to the heads of elongate spermatids (ectoplasmic specializations) and in the Sertoli cell cytoplasm that surrounds spermatids.302,303 Actin filaments, intermediate filaments (vimentin), and microtubules make up the cellular cytoskeleton, one of the more developed somatic cell cytoskeletons (Fig. 12.33).304

Fig. 12.31 Cross section of a seminiferous tubule. Immunostaining in the nuclei of Sertoli cells and in endothelial cells with the WT1 antibody is observed.

CHAPTER 12 Nonneoplastic Diseases of the Testis

TABLE 12.6

Sertoli Cell–Leydig Cell Regulatory Interactions

Paracrine Factor

Origin

Receptor

Action

Androgens

Leydig cell

Sertoli cell

Proopiomelanocortin peptides β-Endorphin

Leydig cell Leydig cell Sertoli cell Sertoli cell Sertoli cell Sertoli cell Sertoli cell Sertoli cell

Sertoli cell Sertoli cell Leydig cell Leydig cell Leydig cell Leydig cell Leydig cell Leydig cell

Regulate/maintain function and differentiation Decrease FSH actions

GnRH-like factor Estrogens TGFA Interleukin-1 Fig. 12.32 Sertoli cells and peritubular myoid cells show immunoexpression of androgen receptor in the nuclei.

569

IGF1 Inhibin

Decrease steroidogenesis Decrease steroidogenesis Decrease steroidogenesis Decrease steroidogenesis Decrease steroidogenesis Increase steroidogenesis Increase steroidogenesis

FSH, Follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; IGF1, insulin-like growth factor; TGF, transforming growth factor A.

Fig. 12.33 Cross section of seminiferous tubule showing Sertoli cells that are intensely immunoreactive for vimentin. Positive staining is also observed in peritubular and endothelial cells.

Sertoli cells synthesize multiple products to ensure the nutrition, proliferation, and maturation of germ cells; they also stimulate other cells such as Leydig cells and peritubular cells, and contribute to hormonal regulation (inhibin secretion) (Table 12.6).305,306 Transport of small molecules (<600 to 700 Da) such as pyruvate, lactate, and probably choline from the Sertoli cell to germ cells occurs through gap junctions. Large or small soluble molecules are transported by proteins that are synthesized by Sertoli cell and include androgen-binding protein (ABP), transferrin, ceruloplasmin, sulfated glycoproteins, α2-macroglobulin, and γ-glutamyl transpeptidase.307,308 Activin and inhibin are Sertoli cell–secreted proteins that induce proliferation and differentiation of germ cells. Activin stimulates FSH production and resultant spermatogonial proliferation, and controls the seminiferous epithelium cycle, whereas inhibin B inhibits FSH secretion and is an important marker of spermatogenesis (Fig. 12.34).309,310 Other Sertoli cell secretions include interleukins, mainly IL1, and growth factors such as TGFB, IGF1 and IGF2, and seminiferous growth factor.311 Some of these growth factors, such as TGFA, TGFB, and IGF1,

Fig. 12.34 Cross section of part of three seminiferous tubules showing intense immunoreactivity for inhibin in the cytoplasm of Sertoli cells.

are involved in regulation of Leydig cell function. Other secreted substances include clusterin, the steroid 3-α-4-pregnen-20-one, and prostaglandin D synthase (PGDS) (Table 12.7). Sertoli cells are also involved in migration of differentiating germ cells toward the tubular lumens. This movement leads to continuous remodeling of the plasma membrane and requires synthesis of several proteases, including urokinase, tissue-type plasminogen activator, cyclic protein 2, collagenase IV, other metalloproteins, and several antiproteases, such as cystatin C, tissue inhibitor of metalloproteinase type 2, and α2-macroglobulin.312 Differentiation of germ cells

570 C H A P T E R 1 2

TABLE 12.7

Nonneoplastic Diseases of the Testis

Major Sertoli Cell Secretory Products

Products

Functions/Characteristics

Transport-Binding Proteins Androgen-binding protein (ABP) Transferrin Ceruloplasmin Sulfated glycoprotein-1

Androgen transport Iron transport Copper transport Sphingolipid binding

Regulatory Proteins Inhibin M€ullerian duct inhibitory agent Sulfated glycoprotein-2

Endocrine-paracrine agent Development Sperm coating, immunosuppressant

Growth Factors GDNF FGF2 TGFA TGFB IGF1 Interleukin-1

Glial cell–derived neurotrophic factor Fibroblast growth factor 2 Growth stimulation Growth inhibition Maintain growth/differentiation Growth regulation

Metabolites Lactate-pyruvate Estrogens

Energy metabolites Steroid hormone, endocrine-paracrine agents

Proteases/Inhibitors Plasminogen activator Cyclic protein-2 α2-Macroglobulin

Plasminogen activation Cathepsin activity Protease inhibitor

Extracellular Matrix Components Laminin Collagens I and IV Proteoglycans IGF1, Insulin-like growth factor; TGFA, transforming growth factor A; TGFB, transforming growth factor B.

of adjacent Sertoli cells. Nuclei are spherical, contain several peripheral nucleoli, and have four different patterns according to their shape, size, and nuclear staining features: Ad (dark), Ap (pale), Al (long), and Ac (cloudy).314,315 The cytoplasm of Type A spermatogonia contains a moderate number of ribosomes, small ovoid mitochondria joined to each other by electron-dense bars, and Lubarsch crystals. These are several micrometers long and are composed of numerous 8- to 15-nm parallel filaments intermingled with ribosome-like granules. Ad spermatogonia are thought to be stem cells in spermatogenesis, and under normal conditions do not divide.316 Some Ad spermatogonia replicate their DNA and acquire an elongate shape (Al spermatogonia). They later divide to make another Ad (maintaining the stem cell reservoir) and an Ap spermatogonia. During replication, Ap spermatogonia become Ac and then divide by mitosis to form two type B spermatogonia.317–319 Type B spermatogonia are the most numerous, and their contact with the basal lamina is less extensive than that of type A. Nuclei usually are more distant from the basal lamina than are those of type A spermatogonia and contain one or two large central nucleoli. The cytoplasm contains more ribosomes than type A spermatogonia, and intermitochondrial bars are usually not observed. Type B spermatogonia divide to form primary spermatocytes. Although all type A spermatogonia are located on the basal membrane, their distribution varies in the seminiferous tubules from one area to another. Spermatogonial stem cells (SSCs) are in specific areas of the basal membrane known as the SSC niche.320 The niche may be defined as a space limited by somatic cells (Sertoli cells) and basal membrane. The number of SSCs and niches is determined by the Sertoli cells.321 The niches are preferably located in those segments of seminiferous tubules that line the small intertubular spaces between three or four seminiferous tubules that frequently contain small blood vessels and Leydig cells. In contrast, the spermatogonia in differentiation reside along the basal membrane, where seminiferous tubules are in contact with each other (Fig. 12.35). Sertoli cells, Leydig cells, myoid cells, macrophages, and endothelial cells with several growth and transcription factors participate, either directly or indirectly, in regulation of self-renewal or

requires different molecules such as SCF, bone morphogenetic protein 4, and retinoic acid. Sertoli cells also regulate germ cell apoptosis. Approximately one-half of spermatogonia in differentiation undergo apoptosis. Dead cells are degraded by Sertoli cells and then recycled.313 Regulation of apoptosis occurs by production of Fasligand, which binds to its receptor (APO-1, CD95) in germ cell plasma membranes. In addition, Sertoli cells possess receptors for several factors such as the nerve growth factor produced by spermatocytes and young spermatids, underscoring the complexity of the Sertoli cell–germ cell relationship. Sertoli cells also produce steroid hormones (estradiol and testosterone) and several components of the seminiferous tubule wall, including laminin, type IV collagen, and heparin sulfate–rich proteoglycans. Germ Cells

Germ cells of the adult testis include spermatogonia, primary and secondary spermatocytes, and spermatids (Fig. 12.29). Spermatogonia. There are two types of spermatogonia: A and B. Type A spermatogonia are approximately 12 μm in diameter, rest on the basal lamina, and are surrounded by the cytoplasm

Fig. 12.35 Leydig cells may be observed in the space among three seminiferous tubules. Seminiferous tubules show numerous type A spermatogonia in the center and type B spermatogonia in the peripheral areas.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Sertoli cell

GDNF FGF2 CXCL12 ERM

Seminiferous tubule

IGF1 CSF1

CSF1 RA Myoid peritubular cell

GDNF CSF1

CSF1 VEGF O2

571

Leydig cell

Macrophage

Interstitium

Vessels

Fig. 12.36 Regulation of proliferation, self-renewal, and expansion of spermatogonial stem cells. GDNF, glial cell line–derived neurotropic; FGF2, fibroblast growth factor 2; CXCL12, C-X-C motif chemokine ligand 12; ERM, ezrin-radixin-moesin protein family; CSF1, colony-stimulating factor 1; IGF1, Insulin like growth factor 1; VEGF, Vascular Endothelial Growth Factor.

differentiation of spermatogonia. The best-known growth factors are glial cell line–derived neurotropic factor (GDNF), FGF2, SCF, activin A, bone morphogenic protein 4 (BMP4), and colony-stimulating factor 1 (CSF1). GDNF and FGF2 are secreted by Sertoli cells, and CSF1 is secreted by Leydig cells, myoid cells, macrophages, and endothelial cells. Different factors regulate proliferation, self-renewal, and expansion of SSCs.322 Among transcription factors, the following have similar actions: Bcl6c, Etv5, and Lhx1 dependent on GDNF, Taf4b (TATA box-binding protein-associated factor 4b), and Plzf. Activin A, SCF, and BMP4, produced by Sertoli cells, seem to be involved in stem cell differentiation (Fig. 12.36).323 Each step in differentiation of spermatogonia, including formation of spermatocytes and spermatids, is regulated by the microenvironment. Spermatocytes. Primary spermatocytes at interphase of the cell cycle lose contact with the basal lamina and inhabit cavities formed by the Sertoli cell cytoplasm. Their cytoplasm contains more rough endoplasmic reticulum than that of spermatogonia, and the Golgi complexes are more developed.324 Meiotic primary spermatocytes are tetraploid and are readily identified by their chromatin pattern. The leptotene spermatocyte, with filamentous chromatin, leaves the basal compartment and migrates first to an intermediate compartment and then to the adluminal compartment.325 In the zygotene spermatocyte, chromosomes are shorter, and pairing of homologous chromosomes begins. Ultrastructural studies show coarse chromatin masses in which synaptonemal complexes and sex pairs may be present. Nucleoli acquire a peculiar pattern of segregation of the fibrillar and granular portions. Associated with nucleoli are the round bodies that contain proteins but no nucleic acids.314 In pachytene spermatocytes, homologous chromosomes are completely paired, and ultrastructurally show chromatin masses that are larger and less numerous than in zygotene spermatocytes. In diplotene spermatocytes, the larger spermatocytes, paired

homologous chromosomes begin to separate and remain joined by the points of interchange (chiasmata); neither synaptonemal complexes nor sex pairs are observed. Diakinesis spermatocytes show maximal chromosome shortening, and the chiasmata begin to resolve by displacement toward the chromosomal ends. Nuclear envelopes and nucleoli disintegrate. The spermatocytes complete the other phases of the first meiotic division (metaphase, anaphase, and telophase), thus forming two secondary spermatocytes; the first meiotic division lasts 24 days.326 Prophase of the first division usually lasts from 1 to 3 weeks, whereas the remaining phases of the first meiotic division occur in less than 2 days. Secondary spermatocytes are haploid cells, smaller than primary spermatocytes, and contain coarse chromatin granules and abundant rough endoplasmic reticulum cisternae.327 These cells rapidly undergo second meiotic division and within 8 hours give rise to two spermatids. The newly formed spermatids have smaller nuclei with homogeneously distributed chromatin, unlike secondary spermatocytes. Spermiogenesis. Transformation of spermatids into spermatozoa is called spermiogenesis. During this process pronounced changes occur in the nuclei and the cytoplasm.328 Nuclei become progressively darker and elongate, and chromatin is rearranged before it becomes completely condensed.329,330 The cytoplasm develops the acrosome and flagellum, mitochondria cluster around the first portion of the spermatozoon tail, and the remaining cytoplasm is phagocytized by Sertoli cells.299,331,332 By electron microscopy, four transient stages of spermatid development are seen: Golgi, cap, acrosome, and maturation. These stages correspond to those defined by light microscopy of nuclear morphology: Sa, Sb, Sb1, Sb2, Sc, Sd1, and Sd2.333,334 These phases may be grouped as early (or round) spermatids that comprise the stages with round nuclei (Sa + Sb) and as late (or elongate) spermatids that comprise the stages with elongate nuclei (Sc + Sd). Mature

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spermatids (Sd2) are the spermatozoa released into the tubular lumens (spermiation). The presence of spermatids and phagocytosis of their residual bodies stimulates the Sertoli cells to initiate a new cycle of the seminiferous epithelium and to produce tubular fluid, inhibin, ABP, IL1, and IL6.335,336 All germ cells derived from the same stem cell remain interconnected by cytoplasmic bridges to ensure synchronous maturation during the spermatogenic process.337 Cycle of the Seminiferous Epithelium. At first glance the germ cells in the seminiferous tubules appears disordered. However, closer study reveals that these cells are grouped into six successive steps, designated I to VI. In contrast with other mammals, in humans the volume occupied by each step is small, so several steps may be observed in the same tubular cross section. Stereologic studies have shown that the successive steps are organized helically along the length of the seminiferous tubule.269,337–339 Each association persists for a specific number of days (I, 4.8 days; II, 3.1 days; III, 1 day; IV, 1.2 days; V, 5 days; and VI, 0.8 days), and each successively transforms into the following association. Finally, at the end of step VI, the cycle is repeated; the spermatogenic process requires several cycles.340 The time from initiation of spermatogenesis to the appearance of sperm in the ejaculate is only 64 days, instead of 74 days, as was formerly believed (Fig. 12.37).325,326,341,342 The succession of different steps probably depends on cyclic Sertoli cell activity. Cyclic changes in the mitochondria, rough endoplasmic reticulum, Golgi complexes, lysosomes, and lipid droplets have been reported.297,343,344 This cyclic activity is probably regulated by numerous factors, both intrinsic (Sertoli and germ cells) and extrinsic (androgens and retinoic acids).345,346 The efficiency of spermatogenesis (daily sperm production per gram of parenchyma) in humans is only 25% to 35% of that found in most species, including other primates, and is no more than 3 to 7 million per gram of testis per 24 hours. Germ cell degeneration at the end of meiosis is important.347,348 The ratio of spermatids to primary spermatocytes is 2.45:1 instead of the expected 4:1 because of a high degree of spontaneous apoptosis, which mainly

affects primary spermatocytes but also involves spermatogonia and spermatids.349 When spermatogenesis is defective, the number of stages that may be observed in the same cross-sectioned tubule decreases. Tunica Propria

The seminiferous tubules are surrounded by a 6-μm-thick lamina propria (tunica propria) consisting of a basement membrane, myofibroblasts (peritubular myoid cells), fibroblasts, collagen and elastic fibers, and extracellular matrix.218,350 The basement membrane measures 100 to 200 nm in thickness and has three layers: the lamina lucida (beneath the Sertoli cells), lamina densa (basal lamina), and lamina reticularis (a discontinuous layer containing fibers). The basal lamina contains laminin, type IV collagen, entactin (nidogen), and heparan sulfate.351 External to the basal lamina are five to seven discontinuous layers of flat elongate peritubular cells.352 The two outer layers are formed by fibroblasts and the remainder by peritubular myoid cells.353 Peritubular myoid cells, also known as myofibroblasts, form three or five innermost layers of the tubular walls. Ultrastructurally these cells have numerous actin and myosin-immunoreactive filaments, dense plaques, an abundance of free ribosomes, small mitochondria, and poorly developed rough endoplasmic reticulum and Golgi complexes. Peripheral borders of myofibroblasts are divided into laminar prolongations arranged in two planes. Myofibroblasts express ARs, smooth muscle cell antigens (smooth muscle actin, αactin, desmin, GB-42, and myosin) (Fig. 12.38), and fibroblast antigens (vimentin, fibroblast surface protein).302,354 The cells are contractile and secretory, facilitating rhythmic tubular contractions that propel spermatozoa toward the rete testis.355–357 They also synthesize numerous products, including those involved in paracrine regulation of Sertoli cells such as PModS (peritubular modifies Sertoli) that modulates the secretion of ABP, transferrin, inhibin, IGF1, bFGF, and many interleukins. Others such as GDNF and CSF1 are involved in regulation of SSC renewal. Finally, myoid cells contribute to formation of tubular walls, secreting fibronectin, collagens, proteoglycans and entactin, and Fig. 12.37 The six different germ cell associations of the seminiferous tubules and the sequence of spermatogenesis. Completion of spermatogenesis requires more than four cycles and lasts for approximately 64 days. Each association is indicated by Roman numerals with its corresponding duration. Ad, Dark type of A spermatogonia; Ap, pale type of a spermatogonia; B, B spermatogonia; I, interphase primary spermatocyte; II, secondary spermatocyte (only in stage VI); L, leptotene primary spermatocyte; P, pachytene primary spermatocyte; Z, zygotene primary spermatocyte. Sa, Sb1, Sb2, Sc, Sd1, and Sd2 represent the progressive stages of spermatid differentiation into spermatozoa.

III 1 day

II 3.1 days Ad

Ad Ap

Ap B

I P

P Sa

Sb1 Sd2

I 4.8 days

Ad

Ap

B

P

Sa Sd1 Sc II Z-P B

Ap Ad VI 0.8 days

Sb2

P

L

Ap

Sc P L-Z Ap Ap Ad V 5 days

Ad

IV 1.2 days

CHAPTER 12 Nonneoplastic Diseases of the Testis

573

contain capillaries and Leydig cells. These cells are similar to interstitial Leydig cells and are referred to as peritubular Leydig cells.

Testicular Interstitium The interstitium between the seminiferous tubules contains Leydig cells, macrophages, neuron-like cells, mast cells, blood vessels, lymphatic vessels, and nerves, accounting for 12% to 20% of testicular volume.366 Connective Tissue Cells

Fig. 12.38 The three to five layers of myofibroblasts surrounding seminiferous tubules show intense immunostaining for muscle-specific actin.

TABLE 12.8

Major Peritubular Myoid Cell Secretory Products and Target Structures

Products

Functions/Characteristics

Paracrine Regulation of Sertoli Cells P-mod-S IGF1, βFGF, several interleukins Plasminogen activator inhibitor

Modulate ABP, transferrin, and inhibin secretion Regulate multiple functions Inhibition of plasminogen activator activity

Niche CDNF and CDF1

Self-renewal of spermatogonia stem cells

Tubular Wall Formation Fibronectin, collagen I, proteoglycans, and entactin Angiogenic (VEGF-C) and antiangiogenic (PEDF) factors

Extracellular matrix component Prevent seminiferous tubule vascularization

The most numerous connective tissue cells are fibroblasts and myofibroblasts. Fibroblasts are also known as interstitial dendritic cells or CD34+ stromal cells. They display a network around the seminiferous tubules and Leydig cells, and form the outermost layers of the tubular wall (Fig. 12.39).367 This distribution begins in fetal life. Some of these cells are in contact with typical macrophages, so it has been suggested that they may be involved in immune surveillance. Myofibroblasts, in addition to their presence in the inner layer of the tubular wall, are numerous in the tunica albuginea. Leydig Cells

Leydig cells are distributed singly or in clusters, comprising approximately 3.8% of testicular volume.368,369 Most are in the interstitium, although they may also be found in ectopic locations such as inside the tubular tunica propria, mediastinum testis, tunica albuginea, epididymis, and spermatic cord. Extratesticular Leydig cells are usually seen within or near nerve trunks.368,370–372 Leydig cells have spherical eccentric nuclei with one or two eccentric nucleoli and prominent nuclear lamina. The cytoplasm is abundant and eosinophilic, containing lipid droplets and lipofuscin granules (residual bodies) (Fig. 12.40). Reinke crystalloids are found only in adults. Although it was formerly believed that these crystals were present exclusively in humans, they have also been observed in the wild bush rat. Reinke crystalloids dissolve completely in formalin and partially in alcohol. They stain with anti–3β-HSD antibodies.373 Reinke crystalloids are rodlike, up to 20 μm long and 2 to 3 μm wide, consisting of a complicated meshwork of 5-nm filaments with a trigonal lattice arrangement. Depending on the plane of section, three basic aspects of this lattice may be discerned. Frequently the crystalloids display pale lines,

ABP, Androgen-binding protein; EGF, epidermal growth factor; IGF1, insulin-like growth factor; P-mod-S, protein modulating Sertoli cell; TGF, transforming growth factor; βFGF, Fibroblast growth factor; CDNF, Cerebral dopamine neurotrophic factor; CDF1, Cycling DOF factor 1; VEGF-C, Vascular endothelial growth factor; PEDF, Pigment epithelium-derived factor.

angiogenic factors such as vascular endothelial growth factor-C and antiangiogenic pigment epithelium-derived factor involved in the avascularity of the seminiferous tubules (Table 12.8).358,359 Most functions of peritubular cells are under androgenic control. Contractile function is regulated by angiotensin II activin via type angiotensin receptor, oxytocin, PDGF, neurotransmitters, and prostaglandins.360–363 Tumor necrosis factor-α strongly upregulates production of proinflammatory interleukins.364 Fibroblasts in the two outermost layers lack desmin filaments and have less actin and myosin than the myofibroblasts.354 Two types of fiber may be found: collagen and elastic fibers. Collagen fibers are present among the peritubular cells and are abundant between the basal lamina and the peritubular cells. Elastic fibers are located mainly at the periphery of peritubular cells. Elastic fibers appear at puberty, so their absence in adults is a sign of tubular immaturity or dysgenesis.365 In addition, the tubular walls may

Fig. 12.39 A network of CD34+ stromal cells forms the frame of testicular interstitium surrounding seminiferous tubules, Leydig cell groups, and blood vessels.

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Fig. 12.40 Leydig cells with round nuclei, abundant smooth endoplasmic reticulum, mitochondria with tubular cristae, and Reinke crystalloids.

considered to be potential planes of cleavage. The filaments are grouped into 19-nm-wide hexagons visible on cross section. Some areas have aggregates of electron-dense, rod-shaped structures. Leydig cells may harbor other types of paracrystalline inclusions, the most common of which are multiple parallel-folded laminae.374 Leydig cells contain abundant, well-developed smooth endoplasmic reticulum, pleomorphic mitochondria with tubular cristae, numerous lysosomes, and peroxisomes. Marked morphologic changes in Leydig cells occur during the six stages of the seminiferous epithelium cycle.375 Leydig cells in the adult originate at puberty from fibroblast-like precursor cells under LH stimulation.82,376 Studies in adult rats reveal that Leydig cells originate from peritubular cells, vascular smooth muscle cells, and blood capillary pericytes.377,378 Leydig cell precursors resemble nervous system stem cells because of their expression of nestin and some neuron and glial cells features.379 Adult Leydig cells infrequently undergo mitosis.380 The human testis contains approximately 200 million Leydig cells. This number decreases with age; the testes of 60-year-old men contain approximately one-half as many Leydig cells as do those of 20year-old men.381,382 Leydig cells in aging men often show cytoplasmic hypertrophy to balance the loss in number, and some of these cells are giant and multinucleate.382 Lipids and lipofuscin increase progressively. Testosterone production is maintained at normal levels up to the end of the fifth decade because of the high number of persistent Leydig cells.383 Most elderly men have increased LH levels, but only 22% have low testosterone levels.384 Leydig cells comprise a specialized population of cells with endocrine, neuroendocrine, and paracrine functions.385 They are immunoreactive for LHRs, 3β-HSD, relaxin-like factor, inhibin, and ghrelin.93,386,386a Relaxin-like factor, more commonly known as INSL3, is a peptide involved in testicular descent that may be found in serum.387 Its concentration is a marker of Leydig cell functional status.388 As occurs with testosterone, INSL3 production is associated with LH.389a Leydig cells are immunoreactive for calretinin, a 29-kDa calcium-binding protein that has a buffering effect to avoid abnormal increase in intracellular calcium.389 Calretinin is a more sensitive, albeit less specific, marker than inhibin (Fig. 12.41).390 Leydig cells also contain VEGF and its two receptors (Flt-1 and KDR) and endothelin and its two receptors (α and β). VEGF and endothelin are involved in paracrine and autocrine control of Leydig cells. These cells also contain certain

Fig. 12.41 Leydig cells form small intertubular clusters that are immunostained for calretinin.

substances that suggest neuroendocrine function, including oxytocin, proopiomelanocortin, substance P, endorphin, NCAM, and microtubule-associated protein-2 (MAP2). Immunohistochemical studies have demonstrated synaptophysin, chromogranins A and B, neurofilament proteins, neuron-specific enolase, S100 protein, and gliofibrillary acidic protein expression in Leydig cells adjacent to nerves, justifying inclusion in the diffuse endocrine system or paraneuron family.391–394 Leydig cells are the targets of LH and several paracrine and growth factors produced by Sertoli cells and other cells, including IGF1 (secreted by Sertoli cells and by the Leydig cell itself) that improves Leydig cell response to hCG administration; inhibin and activin, which enhance Leydig cell function; and IL1 (synthetized by Sertoli cells, germ cells, Leydig cells, and macrophages), a stimulant of DNA synthesis in immature Leydig cells. TGFB (produced by Leydig cells and Sertoli cells) is a potent Leydig cell inhibitor. In response to LH stimulation, Leydig cells produce testosterone and other androgens necessary for maintenance of spermatogenesis and many structures of the male genital tract and other tissues of the body (bone, muscle, and skin).369,383,395,396 Mean daily testosterone production by Leydig cells is 6 to 7 mg, representing more than 95% of the circulating testosterone, reaching levels of intratesticular concentration more than 100 times serum levels.397 These cells are also the main source of estrogen in adult males.398 Testosterone influences Sertoli cells either directly or indirectly through the P-mod-S (protein modulating Sertoli cell) factor secreted by peritubular myofibroblasts in the tunica propria.358,375,399–401a Nuclear testosterone receptors are found in Sertoli cells, Leydig cells, and peritubular myofibroblasts.402 Leydig cells also secrete numerous nonsteroidal factors, including oxytocin, which acts on myofibroblasts and stimulates seminiferous tubule contraction; β endorphin, which inhibits Sertoli cell proliferation and function; and other factors with less certain actions such as angiotensin, proopiomelanocortin-derived peptide, which inhibits Sertoli cell proliferation and function, some other proopiomelanocortin peptides, and α-melanotropic–stimulating hormone (Table 12.9). EGF is secreted in the testes mainly by Leydig cells, modulating spermatogenesis by stimulating germ cell differentiation and reducing spermatogonial proliferation. EGF is also an autocrine regulator of Leydig cells.385 Together with Sertoli cells, peritubular cells, and endothelial cells, Leydig cells produce Nitrous oxide (NO), which has a relaxing effect on smooth muscle

CHAPTER 12 Nonneoplastic Diseases of the Testis

TABLE 12.9

Major Leydig Cell Secretory Products

Products

Functions/Characteristics

Androgens

Steroid hormone/endocrine-paracrine agent Steroid hormone/endocrine-paracrine agent Maintenance growth/differentiation Self-renewal of spermatogonia stem cells Self-renewal of spermatogonia stem cells Opiates/proopiomelanocortin regulatory agents

Estrogens Insulin-like growth factor 3 (INSL3) Colony-stimulating factor 1 (CSF1) Proopiomelanocortin peptides

of seminiferous tubules and blood vessels, thus regulating spermatozoon transport and testicular blood flow, respectively.403 Leydig cells are spatially related to adrenergic and cholinergic nerve fibers.201 Varicosities containing synaptic vesicles have been found near Leydig cells, and nerves that end on Leydig cells have been identified. The functional meaning of this innervation is unknown.404 Macrophages, Neuron-like Cells, and Mast Cells

Macrophages are a normal component of the testis.405,406 Young adult men have one macrophage per 10 to 50 Leydig cells, and this number increases with age.407 They are classified by phenotype into two groups: resident (M2 macrophages), which are the most numerous, and activated (M1 macrophages). Both express CD68, but only resident macrophages express CD163.408 Resident macrophages appear in the testis early in development, present in the urogenital ridges, and are believed to be derived from fetal yolk sac progenitors.46 Activated macrophages are likely derived from circulating monocytes. Macrophages help maintain normal testicular function and homeostasis, including interaction with Leydig cells. Slender Leydig cell cytoplasmic expansions penetrate deep into the cytoplasm of the macrophages.405 One of the factors that favorably influence steroidogenesis in Leydig cells is 25-hydroxycholesterol.409,410 Macrophages regulate spermatogenesis through CSF1 and enzymes involved in the synthesis of retinoic acid, and participate in proliferation and differentiation of Leydig cell fibroblastic precursors and in the proliferative activity of newly formed cells.411 Activated macrophages secrete abundant antiinflammatory cytokine IL10, and produce IL1 and IL6, tumor necrosis factor-α, and TGFA, which is important in the control of bacterial infections.412,413 Immunohistochemistry has revealed the presence of fusiform or star-shaped cells known as neuron-like cells in the interstitium. Their number is low in adult testes.414 These cells express neuron-specific intermediate filament NF-200, voltage-activated sodium (Na) channel, and intratesticular catecholamines, which appear to be increased in some disorders such as Sertoli cell–only syndrome and hypospermatogenesis. Mast cells are a normal finding in the interstitium, in peritubular and perivascular locations, among Leydig cells, and inside interlobular septa and the tunica vasculosa.415,415a The number decreases with age, and this change seems not to be influenced by Sertoli Growth Factor (SGF) produced by Sertoli cells. The main product

575

of mast cells is tryptase. Among mast cell functions, participation in intercellular matrix formation may be fundamental.414 The number of mast cells increases in several diseases, and it is greatly increased in patients with nonobstructive azoospermia.416–418 Blood and Lymphatic Vessels

The testis is supplied by the testicular artery, which arises from the abdominal aorta. In the spermatic cord the testicular artery gives rise to two or three branches that obliquely penetrate the tunica albuginea, spawning multiple branches that run along the intralobular septa of the testis.419,420 These centripetal arteries lead to the mediastinum testis. Along their course the centripetal arteries give off branches that abruptly reverse direction, the socalled centrifugal arteries. At puberty, both the centripetal and centrifugal arteries develop pronounced spiral architecture.421,422 The centrifugal arteries develop additional branches in the interstitium that give rise to arterioles and capillaries that form intertubular plexuses, some of which are apposed to the tunica propria.423,424 Capillaries are of the continuous type, except for the seminiferous tubule capillaries, which are partially fenestrated, and their endothelial cells are similar to those of brain capillaries, with scant pinocytosis, intercellular junctions of the fascia adherens type, and low permeability.425 The mediastinum testis is poorly vascularized. The inner two-thirds of the testicular parenchyma is drained by veins that follow the interlobular septa to the mediastinum testis (centripetal veins). The outer one-third is drained by veins that lead to the tunica albuginea (centrifugal veins). Both centripetal and centrifugal veins join and anastomose, exiting the testis by the veins of the pampiniform plexus, which drains the testis via the spermatic cord. Lymphatic vessels are poorly developed in the testis and are limited to the tunica vasculosa, interlobular septa, and mediastinum, where they accompany arterioles and venules.426 Prelymphatic vessels have been reported in the interstitium and probably drain interstitial fluid into the true interlobular lymphatic vessels. Nerves

Efferent innervation of the testis is mainly supplied by neurons of the pelvic ganglia, where contralateral and bilateral neural connections occur. Postganglionic nerve fibers enter the testis via the pelvic nerves, extend throughout the tunica vasculosa, and follow the interlobular septa to reach the interstitium. These nerve fibers end in the walls of arterioles, the walls of seminiferous tubules, and the Leydig cells.190 Adrenergic nerve fibers innervate the tunica albuginea and blood vessels of the tunica vasculosa, but do not enter the testicular parenchyma.427,428 Most nerve fibers are peptidergic.429 Afferent nerve endings form corpuscles like those of Meissner and Pacini in the tunica albuginea. In summary, testicular histology may be understood only by considering the different autocrine, endocrine, and paracrine relationships that occur among the different cells of the testicular parenchyma. Only in that way may we understand the complex processes of cellular interrelation that take place in spermatogenesis and that culminate in spermatozoon production with adequate morphology, vitality, and fertilizing capacity. Rete Testis

The rete testis is a network of channels and cavities that connects the seminiferous tubules with the ductuli efferentes. Differences in the configuration and size of channels and cavities distinguish three

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present as true congenital testicular absence or vanishing testis. Monorchidism is estimated to occur in approximately 4.5% of cryptorchid testes, in 40% of the testes that are impalpable on physical examination, and in 1 in 5000 males. Bilateral anorchidism occurs in approximately 1 in 20,000 males.432–435 Evaluation of a child with a solitary palpable testis begins with scrotal palpation. Laparoscopy is required for patients in whom no apparent testicular nubbin tissue is found in the scrotum or for those with a patent vaginal processus.436 Monorchidism

Fig. 12.42 Rete testis showing cavities lined by flat squamous epithelium interspersed with small groups of columnar cells, which are usually located in angles. Connective tissue among cavities is dense.

portions of the rete testis: septal (intralobular), composed of the tubuli recti; mediastinal, composed of a network of interconnected channels; and extratesticular, composed of dilated cavities (3 mm in diameter) termed the bullae retis. The tubuli recti are short tubules (0.5 to 1 mm long) that connect the seminiferous tubules to the mediastinal rete, although some seminiferous tubules, principally those in the central region of the testis, may connect directly to the mediastinal rete. The tubuli recti are lined by cuboidal epithelium. There are approximately 1500 tubuli recti (or their analogous seminiferous tubule segments). The tubuli recti in the cranial, central, and anterior testis are perpendicular to the mediastinal rete testis channel into which they drain, and those in the caudal testicular region are parallel to their respective channels. The transitional segments between the seminiferous tubules and the tubuli recti are formed by modified Sertoli cells.430 The epithelium of the mediastinal rete testis consists of flattened cells interspersed with small areas of columnar cells (Fig. 12.42). Both cell types have a single centrally located cilium and numerous microvilli on their free surfaces and contain keratin and vimentin filaments.431 Interdigitations are present between adjacent cells. The epithelium rests on a basal lamina surrounded by a layer of myofibroblasts and a rim of fibroblasts and collagen and elastic fibers. The rete channels and cavities are traversed by the chordae rete, columns 15 to 100 μm long and 5 to 40 μm wide, arranged obliquely to the long axis of the cavity. The chordae rete consists of fibrous connective tissue and fibroblasts covered by flattened epithelium. The rete testis probably has the following functions: damping of differences in pressure between the seminiferous tubules and the ductuli efferentes; reabsorption of protein and potassium from tubular fluid; and, occasionally, phagocytosis of spermatozoa.

Congenital Anomalies of the Testis Alterations in Number, Size, and Location Anorchidism Anorchidism refers to absence of one (monorchidism) or both testes (testicular regression syndrome). Unilateral anorchidism may

The hormonal pattern in prepubertal patients with monorchidism is similar to that of normal children, whereas children lacking both testes have undetectable levels of AMH and elevated levels of gonadotropins that fail to respond to stimulation with hCG even in the first months of postnatal life.78,435,437–442 Although hCG stimulation challenge is often positive in children with bilateral cryptorchidism, it is negative in some children with bilateral intraabdominal cryptorchidism, further complicating the differential diagnostic separation of anorchidism and cryptorchidism.443 Exceptionally, anorchidism may be associated with hypogonadotropic hypogonadism. For unknown reasons the left testis is more frequently absent (69%) than the right. In such cases the contralateral scrotal testis undergoes compensatory hypertrophy, and its volume increases to more than 2 mL.444 Compensatory hypertrophy has also been reported in association with abdominal cryptorchid testis.231 The absence of testicular parenchyma should be confirmed before diagnosing monorchidism. Laparoscopy has been proposed as the usual procedure to localize a nonpalpable or absent testis.445 At exploration the finding of a vas deferens ending near or in a hypoplastic epididymis is not sufficient for the diagnosis of monorchidism. The only acceptable finding is blind-ending spermatic vessels. If inguinoscrotal exploration fails to identify these vessels, intraabdominal exploration is required to exclude undescended testis and avoid development of a testicular tumor.446 All remnants found at exploration should be removed.447 Testicular Regression Syndrome

Testicular regression syndrome refers to a variety of conditions, including agonadism, anorchidism, testicular agenesis, rudimentary testes, hypoplastic testes, and embryonal testicular dysgenesis.448–450 Each syndrome shares complete absence or involution of both testes, but they differ in the time of testicular disappearance during development.451 The most frequently observed are Swyer syndrome (see discussion of Disorders of sex development (Gonadal dysgenesis)), true agonadism, rudimentary testes, bilateral anorchidism, vanishing testes syndrome, and Leydig cell–only syndrome (Table 12.10). True Agonadism (46,XY Gonadal Agenesis Syndrome). Patients are phenotypically girls, and the male gender may be discovered only at the time of referral for other symptoms such as primary amenorrhea.452,453 External genitalia are female with or without clitoromegaly, labioscrotal fusion, and short vagina. Examination of the internal genitalia demonstrates the absence of m€ ullerian and wolffian derivatives, although the presence of uterine and uterine fallopian hypoplasia may occur. No gonads (not even in an ectopic location) are found. Early testicular regression occurs between the seventh and eighth weeks of embryonal development, just after the onset of AMH secretion. Sporadic and familial cases are both with associated extragenital anomalies. In some cases the cause is heterozygous mutation

CHAPTER 12 Nonneoplastic Diseases of the Testis

TABLE 12.10

Testicular Regression Syndromes EMBRYONAL PERIOD

M€ullerian structures Wolffian structures External genitalia

577

FETAL PERIOD

Early

Late

Early

Middle

Late

Vestigial Vestigial Female

Differentiated Vestigial Female

Differentiated/vestigial Vestigial/differentiated Ambiguous

Vestigial Differentiated Ambiguous-male

Vestigial Differentiated Male

of WT1.454 In most familial cases, inheritance is either recessive autonomic or X-linked, and the cause seems to be either unknown anomalies in the WT1 gene or known anomalies in other genes involved in development.455 SRY molecular defect has never been observed.456 Agonadism may be associated with several syndromes, including PAGOD (hypoplasia of lungs and pulmonary artery, agonadism, omphalocele/diaphragmatic defect, dextrocardia), Seckel, and CHARGE (ocular coloboma [C], heart disease [H], choanal atresia [A], retarded growth or development [R], genitourinary defects or hypogonadism [G], and ear anomalies or deafness [E]).457–460 Rudimentary Testes Syndrome. Patients with rudimentary testes have a normal male phenotype. M€ ullerian remnants are absent, and wolffian derivatives are usually present.461 The testes are cryptorchid and small, less than 0.5 cm long. Seminiferous tubules are few in number (Fig. 12.43). Testicular regression occurs between the weeks 14 and 20 of gestation. This syndrome has been reported in several members of the same family, a finding suggesting genetic transmission, but this is not a constant feature.462–464 Congenital Bilateral Anorchidism. Congenital bilateral anorchidism is defined as complete absence of testicular tissue in a patient with a normal male karyotype and phenotype.441 Congenital bilateral anorchidism occurs in 1 in 20,000 newborns.465–468a Patients have male external genitalia, but the internal genitalia consists only of normal wolffian derivatives without m€ ullerian derivatives, a finding suggesting that the testes were present and functionally active up to approximately the 20th week of gestation, thus producing sufficient amounts of AMH and

Fig. 12.43 Cross-sectioned rudimentary testis from a 2-year-old infant. Testicular lobules are separated by wide septa and contain scant seminiferous tubules.

androgens. Patients have male external genitalia with hypoplasia of both the scrotum and penis.469 The disorder may be associated with other malformations, such as anal atresia, rectourethral and rectovaginal fistula, and urinary exstrophy. Patients diagnosed in adulthood have male phenotype, androgen insufficiency symptoms, and elevated levels of both FSH and LH.442,470 The cause of congenital bilateral anorchia is uncertain, with numerous hypotheses, including intrauterine torsion of both testes, endocrinologic or immunologic disfunction, or genetic abnormality. The possibility of genetic anomaly was suggested by the occurrence of several familial cases.471 However, isolated mutations in the SF1 gene have been identified in only one case to date, and no mutations have been found in the SRY gene, the INSL3 gene (necessary for correct testicular descent), or in the gene of its receptor.472–475 The basal plasma concentration of AMH, inhibin B, and testosterone is undetectable in anorchic patients.476 The increase in testosterone levels after GnRH or hCG administration is low or undetectable.442,443,477,478 FSH and LH levels are abnormally high during the first months of life and then progressively decrease. LH decreases more rapidly to normal levels than does FSH in 70% of anorchic patients until pubertal age, when gonadotropins increase to high levels.479 A case of bilateral anorchidism was reported in association with hypogonadotropic hypogonadism in a pubertal patient with Kallmann syndrome.480 Vanishing Testes Syndrome. Vanishing testes syndrome applies to disappearance of one or both testes between the last months of intrauterine life and the beginning of puberty.481–484 Two criteria are required for diagnosis: (1) absence of a palpable testis on examination with the patient under anesthesia; and (2) blind-ending spermatic vessels visualized within the retroperitoneum, or spermatic vessels and vas deferens seen exiting a closed internal inguinal ring. Testicular regression occurs after the seventh month of embryonal life, so exploration finds the vas deferens in the inguinal canal or high in the scrotum; it may be accompanied by the epididymis and less frequently by testicular remnants consisting of small groups of seminiferous tubules (Figs. 12.44 and 12.45). Patients who lack both testes experience hypergonadotropic hypogonadism after puberty, with gynecomastia, infantile phallus, hypoplastic scrotum, and impalpable prostate. The condition is usually secondary to perinatal scrotal torsion, although rarely it has a genetic cause.436,475,485 Leydig Cell–Only Syndrome. Patients with Leydig cell–only syndrome have agonadism without eunuchoidism and normal male phenotype, although meticulous surgical exploration fails to find testicular remnants. Study of serial sections from the spermatic cord reveals clusters of Leydig cells.486 Detection of testosterone in spermatic vein blood indicates that these ectopic Leydig cells are functionally active and synthesize testosterone in amounts sufficient to induce a rudimentary male phenotype but are insufficient to support complete development of secondary sex characteristics.467

578 C H A P T E R 1 2

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Fig. 12.44 Spermatic cord in anorchidism. Fibrous connective tissue with dystrophic calcification that probably would correspond to the testis adjacent to the distal end of the vas deferens.

69% to 83% of cases.492 Vas deferens is the most constant finding (79%), followed by epididymis (36%) and seminiferous tubules (0% to 20%).447,493–496 These tubules may or may not contain germ cells.497–499 Small vessel groups are present in 83% of patients, but in only 24% is the number of vessels sufficient to identify them as spermatic vessels. Blind-ending cord structures have been found in the abdomen (21% of cases), the inguinal canal (59%), the superficial inguinal ring (18%), and the scrotum (2%).500 Areas of dystrophic calcification, hemosiderin deposition (Fig. 12.46), and giant cell reaction may be found within the mass in place of the testis. Other reported findings include arterial and venous vessels (88%), fat (44%), and nerves that may resemble traumatic neuroma (56%).501 The minimum requirement for diagnosis is identification of either a vascularized fibrous nodule with calcification or hemosiderin, or a fibrous nodule with cord elements.502 There are few histologic studies of evanescent testes removed in adulthood that refer to residual testicular parenchyma. In three cases from our files, we have not observed areas of calcification or macrophages with hemosiderin. All contained tubules with complete spermatogenesis mixed with Sertoli cell–only tubules with dysgenetic characteristics (mixed atrophy [MAT]); the interstitium had significant Leydig cell hyperplasia (Figs. 12.47 and 12.48). No GCNIS cells were observed.

Fig. 12.46 Next to the vas deferens, fibrous tissue with numerous macrophages with hemosiderin may be observed where the testis should have been. Fig. 12.45 Vanishing testis. The testis is reduced to connective tissue, a small group of seminiferous tubules, the rete testis, numerous blood vessels, and a thickened albuginea.

Macroscopic and histologic findings in patients with testicular absence differ according to the cause of anorchidism (true congenital absence or disappearance of a former testis). In true congenital absence the lack of testis is associated with absence of both the ductus epididymis and ductus deferens. In acquired testicular absence, the morphology of spermatic cord remnants is similar to monorchidism and testicular regression syndrome occurring after the 20th week of gestation.487–490 The ductus deferens, testicular artery, and a venous plexus may usually be identified in spermatic cord sections.491 Grossly, a small, firm mass is found at the end of the spermatic cord (Fig. 12.44). Histologic examination reveals vas deferens, epididymis, or small groups of seminiferous tubules in

Fig. 12.47 Vanishing testis in an adult. The central nodular formation corresponds to the testis. It is surrounded by the body and tail of the epididymis. In the upper part the onset of the vas deferens may be observed.

CHAPTER 12 Nonneoplastic Diseases of the Testis

579

for genetic or hormonal studies to identify the underlying disease or syndrome. For example, some patients with Kenny-Caffey syndrome exhibit short stature, cortical thickening and medullary stenosis of long bones, delayed closure of anterior fontanelles, hypoparathyroidism, and ocular abnormalities. FSH serum level is elevated in some cases, whereas LH and testosterone levels are normal. Adult testes are small, with seminiferous tubules showing complete but diminished spermatogenesis. Leydig cells are hyperplastic. Unlike patients with the rudimentary testes syndrome, a patient with microorchidism has a normal-sized penis and no epididymal or prostatic atrophy.514 The most frequent causes of adult microorchidism are Klinefelter syndrome, testicular maldescent, varicocele, secondary atrophy, and other idiopathic clinical disorders. Most patients have azoospermia or oligoasthenoteratozoospermia.515

Fig. 12.48 Vanishing testis (same case as Fig. 12.47). Testicular parenchyma shows mixed atrophy. Tubules with spermatogenesis have marked ectasia, and the remaining only Sertoli cells. Note also a diffuse hyperplasia of Leydig cells.

Optimal management of the testicular remnant associated with the vanishing testis syndrome is controversial.503 Some urologists advocate surgical exploration, either laparoscopic or through an inguinal scrotal approach, whereas others believe these procedures are unnecessary based on the low percentage (21%) of seminiferous tubules found in the removed testicular nubbins; only 14% contain seminiferous tubules with germ cells, and thus the probability of a tumor is minimal.493,496,498 Only one case of GCNIS has been reported.497 Thus some authors defend conservative management, whereas others believe that these remnants should be removed, given the potential for malignant degeneration.493,496,498,504 Most cases of unilateral and bilateral testicular loss apparently occur during the fetal period after the testis has inhibited the m€ ullerian ducts and induced differentiation of wolffian duct derivatives, or else postnatally. Two hypotheses account for the disappearance of the testes. The first involves atrophy secondary to a vascular lesion such as thrombosis or intrauterine torsion, trauma, or neonatal scrotal hematoma.505–508 The presence of macrophages with hemosiderin and dystrophic calcification suggests a vascular event.469 In addition, the morphology of the contralateral testis is normal. If the disappearance resulted from hormonal influences, the contralateral testis would show abnormalities, as is typical in the contralateral testis in cryptorchidism.471 The second hypothesis of disappearance invokes a primary anomaly of the gonad such as a true congenital testicular absence, which would be responsible for only 27% of nonpalpable testes. This theory is supported by multiple factors: histologic presence of dysgenetic lesions in the residual testicular parenchyma; absence of evidence of old hemorrhage or ischemia; evidence of disturbance in endothelial development leading to a reduction in vascular formation; and the occasional presence of malformations of the urogenital system, such as absence of the kidney, cystic seminal vesicles, or ipsilateral renal dysgenesis.509–511

Microorchidism The clinical term microorchidism refers to diverse conditions characterized by small testicular size, including Klinefelter syndrome, hypogonadotropic hypogonadism, and bilateral cryptorchidism.512,513 In adulthood, microorchidism refers to testes with a volume  12 mL. Patients with microorchidism are candidates

Polyorchidism Polyorchidism refers to congenital presence of more than two testes. It is a rare condition, with slightly more than 200 reported cases.516,517 The first histologic description appeared in 1880, and the first case treated surgically and confirmed histologically was reported in 1895.518,519 Although the existence of three testes is the most common presentation, four testes have been reported in 10 patients, and five testes in one case report that lacked histologic confirmation.520–532 The age at diagnosis varies from newborn to 74 years, with a mean of 17 years. Most patients are phenotypically similar to persons of their age. With the exception of isolated cases with 46,XX karyotype with XY mosaicism and deletion of the long arm of chromosome 21, patients typically do not have chromosomal abnormalities. Testicular duplication is usually an incidental finding during surgery for inguinal hernia, cryptorchidism, or testicular torsion, but has also been detected in patients with infertility or unexplained fertility after bilateral vasectomy.533–535 The extra testis is often intrascrotal (75%) and less frequently inguinal (20%), abdominal, or retroperitoneal (5%).536–540 Duplication is three times more frequent on the left side than on the right.541 Testicular maldescent (40%), inguinal hernia (30%), hydrocele (9%), varicocele, and contralateral cryptorchidism are the most frequently associated anomalies.542–547 Testicular torsion (13%) and testicular cancer (6.4%) are occasional complications.534,543,548 In isolated cases, imperforate anus, idiopathic infertility, and contralateral anorchidism have been observed.549–553 High-resolution sonography is indicated, followed by magnetic resonance imaging (MRI) when sonographic findings are inconclusive.521,554,555 The extra testis may be histologically normal, but usually is not, containing Sertoli cell–only tubules, hypospermatogenesis, maturation arrest, or microlithiasis.311,542,556–558 Lack of spermatogenesis has been attributed to the anomalous location of the testis and the absence of communication between the testis and excretory ducts, although in some cases the lesions are probably primary.557,559 Embryologic origin of polyorchidism remains uncertain, and the following mechanisms have been proposed to account for the variety of findings in different cases (Fig. 12.49): • Duplication of the genital ridge. All structures of the genital ridge and mesonephric ducts are duplicated. Each of the two testes resulting from duplication has an excretory duct and develops active spermatogenesis.519,535,560–562 • Longitudinal division of the genital ridge. Of the two resulting testes, the medial loses its connection with the mesonephric ducts and undergoes atrophy. • High transverse division of the genital ridge. The two resulting portions are in continuity with the mesonephric ducts that give

580 C H A P T E R 1 2

Nonneoplastic Diseases of the Testis

Longitudinal division

Genital ridge duplication Cranial

Medial

A

B

Transverse division

C rise to the ductuli efferentes. Each testis may have its own ductus epididymidis or shares a common one, but there is a separate vas deferens for each.557,563 • Low transverse division of the genital ridge. The more caudal testis has no excretory ducts.544 Several classifications of polyorchidism have been proposed, including one based on embryology and another on reproductive potential.564–566 In embryologic classification, type II is the most frequent variation (Table 12.11), and types II and III together comprise more than 90% of cases.564 This classification does not consider certain isolated cases such as the occurrence of double testes on one side, each connected to their own epididymis and vas

TABLE 12.11

Fig. 12.49 Possible mechanisms of polyorchidism. (A) Genital ridge duplication gives rise to two testes with their respective epididymides. (B) Longitudinal division of the genital ridge. The testis derived from the medial region has no epididymis. (C) Transverse division of the genital ridge. The resulting testes either share a single epididymis or one testis is devoid of epididymis.

deferens. This finding may be explained embryologically by complete splitting of the genital ridge and entire mesonephros with wolffian duct elements along the dorsoventral line of cleavage. Embryologic classification also fails to consider double testes on one side that are not connected with an epididymis or vas deferens; this anomaly is explained by horizontal splitting of the genital ridge to form the gonad. In the reproductive potential classification (Table 12.12), type I includes types II, III, and IV of the embryologic classification, but excludes type II and all ectopic testes (types IB and IIB).565 Supernumerary testis type IA may be excluded if the patient has at least one intrascrotal testis with normal drainage, if the testicular biopsy of the supernumerary testis shows a Sertoli cell–only pattern or malignancy, or if difficulties in patient follow-up are expected.567

Embryologic Classification of Polyorchidism

Type I: A supernumerary testis lacks an epididymis or vas deferens and has no attachment to the usual testes (division of the genital ridge only). Type II: The supernumerary testis drains into the epididymis of the usual testis, and they share a common vas deferens (division of genital ridge occurs in the region where the primordial gonads are attached to the metanephric ducts, although the mesonephros and metanephric ducts are not divided; i.e., incomplete division). Type III: The supernumerary testis has its own epididymis, and both epididymides (that of the supernumerary testis and that of the ipsilateral testis) drain into one vas deferens (complete transverse division of mesonephros, as well as the genital ridge). Type IV: Complete duplication of the testes, epididymis, and vas deferens (vertical division of the genital ridge and mesonephros). Data are from Leung AK. Polyorchidism. Am Fam Physician 1988;38:153–156.

TABLE 12.12

Reproductive Potential Classification of Polyorchidism

Type I: The accessory testis (supernumerary testis) is attached to the draining epididymis and vas deferens with reproductive potential (30% of polyorchidism). Type IA: The accessory testis is intrascrotal. Type IB: The accessory testis is in an ectopic location. Type II: The testis lacks such an attachment and has no reproductive potential. Type IIA: The accessory testis is intrascrotal. Type IIB: The accessory testis is in an ectopic location. Data are from Singer BR, Donaldson JG, Jackson DS. Polyorchidism: functional classification and management strategy. Urology 1992;39:384–388.

CHAPTER 12 Nonneoplastic Diseases of the Testis

TABLE 12.13

581

Modified Reproductive Potential Classification of Polyorchidism

Type A1: The drained supernumerary testis has its own epididymis and vas. Type A2: The drained supernumerary testis may have its own epididymis but shares a common deferens duct with its neighbor. Type A3: The drained supernumerary testis may share a common epididymis (and duct) with its neighbor. Type B1: The undrained supernumerary testis does have its own epididymis. Type B2: The undrained supernumerary testis does not have its own epididymis and thus consists of testicular tissue only. Data are from Bergholz R, Koch B, Spieker T, Lohse K. Polyorchidism: a case report and classification. J Pediatr Surg 2007;42:1933–1935.

Proposed modification of the reproductive potential classification is shown in Table 12.13.566 The clinical differential diagnosis of polyorchidism includes other conditions that enlarge the scrotum and spermatic cords, including spermatocele, hydrocele, cyst and tumor of the spermatic cord, crossed testicular ectopia, adrenal cortical ectopia, and splenogonadal fusion. Orchidectomy has been replaced as treatment of choice for atrophic and nonscrotal testes by fixation of the testis to the scrotal pouch and re-creation of a “simple testis” when permitted by the anatomic condition and after exclusion of malignancy.568 This treatment may allow spermatogenesis, as well as psychological and cosmetic benefits.569 Intrascrotal rhabdomyosarcoma, testicular teratoma, and seminoma have been reported in patients with polyorchidism.570–572

Testicular Hypertrophy (Macroorchidism) Macroorchidism may be unilateral or bilateral, and is caused by excessive development of seminiferous tubules, Leydig cells, or both. It may be associated with chromosomal anomalies, tumors, or endocrine alterations. An increase in the testicular parenchyma occurs in several conditions, including congenital Leydig cell hyperplasia, compensatory hypertrophy, benign idiopathic macroorchidism, bilateral megalotestes with low gonadotropins, fragile X chromosome, and testicular hypertrophy observed in juvenile hypothyroidism.573

Fig. 12.50 Congenital Leydig cell hyperplasia. Fetal Leydig cells form large clusters surrounding groups of seminiferous tubules.

Fig. 12.51 Congenital Leydig cell hyperplasia. Multiple nodules of Leydig cells are present in the mediastinum testis, as well as deep in the parenchyma.

Congenital Leydig Cell Hyperplasia

Congenital Leydig cell hyperplasia is uncommon and may be diffuse or nodular.544 Diagnosis of diffuse Leydig cell hyperplasia requires quantification of Leydig cells by morphometry using normal newborn testes as controls (Fig. 12.50). Nodular Leydig cell hyperplasia is characterized by the presence of nonencapsulated cellular aggregates in the mediastinum testis, adjacent testicular parenchyma, and connective tissue among the ductuli efferentes (Figs. 12.51 and 12.52). The differential diagnosis of nodular Leydig cell hyperplasia includes intratesticular adrenal rests and bilateral Leydig cell tumor. Excluding adrenogenital syndrome, intratesticular adrenal rests are rare. Rests are encapsulated, except with adrenogenital tumors, and consist of radially arranged cells with vesicular nuclei and small nucleoli displacing the rete testis or seminiferous tubules. Leydig cell tumors may be bilateral, poorly circumscribed, and surrounded by testicular parenchyma, features making it difficult to distinguish from Leydig cell hyperplasia. However, Leydig cell tumors are rarely congenital, whereas those occurring during infancy often induce precocious maturation of the adjacent seminiferous tubules and early macrogenitosomia.

Fig. 12.52 Congenital nodular hyperplasia of Leydig cells. The nodules occupy much of the section. They are located between the rete testis and the scarce peripheral testicular parenchyma.

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Nonneoplastic Diseases of the Testis

Congenital Leydig cell hyperplasia is caused by large quantities of hCG entering the fetal circulation.574 Mothers with diabetes, particularly those with hypertension, may experience development of hyperplacentosis; the resulting edema in the placental villi alters vascular permeability and allows passage of hCG to the fetus. Congenital Leydig cell hyperplasia decreases rapidly during the first months of postnatal life after maternal hCG is gone. Combined diffuse and nodular Leydig cell hyperplasia occurs in several malformative syndromes, including Beckwith-Wiedemann syndrome, leprechaunism, triploid fetuses, and fetuses with Rh isoimmunization, as well as in several complications of pregnancy.544,545,575,576 Compensatory Hypertrophy of the Testis

Compensatory hypertrophy may occur in monorchidism, cryptorchidism (Fig. 12.53), and varicocele, as well as after testicular injury.544,577,578 The disorder is characterized by increased volume of the descended testis, defined as more than two standard deviations of the corresponding size in normal children. A volume greater than 2 mL or even lower is considered to be predictive of monorchidism.579,580 Compensatory hypertrophy develops between birth and 3 years of age, and the testis may reach a volume twice normal when the other testis is absent.231 Hypertrophy persists and may increase during childhood and puberty, but ceases thereafter; the hypertrophied testis then becomes normal or remains slightly enlarged.230,581 The degree of compensatory hypertrophy is determined by three factors: (1) volume of the remaining testicular parenchyma, (2) age at which the underlying pathologic event occurred, and (3) functional ability of the descended testis.208 Compensatory hypertrophy results from alteration of hypophyseal hormonal feedback, followed by an increase in secretion of FSH, evidence that the hypertrophied testis is normal. In monorchidism, it is likely that the absent testis was initially of normal size during fetal development, but later underwent progressive shrinkage.433 When 50% reduction of testicular mass occurs (probably before birth), endocrine feedback changes, and the resulting secretion of FSH (before or immediately after birth) causes accelerated growth of the contralateral testis. The hypertrophied testis contains an increased number of germ cells, explaining why patients with solitary testis may not necessarily be at additional risk for infertility.582 In cryptorchidism the reduction in overall testicular mass is less pronounced than in monorchidism, and the scrotal testis may also be abnormal, resulting in less marked compensatory hypertrophy.

Fig. 12.53 Contralateral scrotal testis from a cryptorchid patient showing a group of large seminiferous tubules that stands out from the surrounding small tubules.

Idiopathic Benign Macroorchidism

Some prepubertal and pubertal patients have pronounced unilateral or bilateral testicular hypertrophy in the absence of other pathologic findings.583–586 This condition probably results from hormonal receptivity in the testicular parenchyma. Clinical manifestations are usually related to the onset of the puberty. Several disorders, such as bilateral testicular tumor (germ cell, stromal tumor, leukemia, or lymphoma), adrenal rest tumor, X-linked mental retardation, hypothyroidism, and idiopathic or cerebral precocious puberty, should be excluded before testicular enlargement is diagnosed as idiopathic benign macroorchidism. Morphometric studies indicate that testicular enlargement results from an increase in length of the seminiferous tubules, although increases in tubular diameter and Sertoli cell number have also been observed. Elevated FSH serum level, reported in some cases, or hyperactive FSH receptors (FSHR) could cause excessive Sertoli cell proliferation and lengthening and thickening of seminiferous tubules.232,587,588 In addition, Leydig cell hyperplasia and deficient spermatogenesis are frequent findings in adult life. In some cases the underlying mechanism is unclear because the sequential analysis of 10 exons of the FSHR was normal.589 The development of the two testes may be asynchronous during puberty, so some cases of unilateral macroorchidism may reveal differences that are unusually exaggerated. This situation is also known as transitory unilateral testis enlargement of puberty. The enlarged testis, usually on the right (75% of cases), may reach 20 mL in volume at the onset of puberty. The contralateral testis grows during puberty until it reaches the same volume as the hypertrophic testis, whereas growth of the hypertrophic testis slows. After puberty neither testis is larger than 25 mL in volume.590 Bilateral Megalotestes With Low Gonadotropins

Approximately 2% of adults with fertility problems have enlarged testes, with volumes greater than 25 mL, and low levels of FSH, LH, testosterone, prolactin, and estradiol.591 Despite these important hormonal changes, sperm concentration and total number of spermatozoa are higher than normal. Low FSH levels may be attributable to increased inhibin secretion because the number of Sertoli cells is elevated, but reduction in other hormone levels is of unknown cause. Fragile X Chromosome; Martin-Bell Syndrome

Fragile X chromosome is the best-known form of inherited mental retardation, with an incidence of 1 in 4000 males and 1 in 6000 females.592 Inheritance is dominant and X-chromosome linked, with a low penetrance in females and variable expression in males.593 In addition to facial dysmorphia (large ears, prognathism, high forehead, and arched palate), macroorchidism (Martin-Bell syndrome) is often an associated finding first described in 1943.594–604 The impaired gene, the fragility mental retardation 1 gene (FMR1 gene), is mapped to Xq27.3, which is genetically fragile in these patients. The gene alteration is caused by lengthening of trinucleotide CGG repeat that results in FMR1 gene silencing. The repeat is present in the 50 -untranslated region of the FMR1 gene and shows 5 to 50 CGC units in the normal population.605–607 If the CGG sequence is repeated fewer than 200 times, the disorder is considered a premutation, and males show no symptoms; if the number of repetitions exceeds 200, mutation is complete, and all affected persons show the disorder.599,601,602 Full mutations involve hypermethylation of the gene promoter and lead to transcriptional silencing of the gene, with resulting total or partial loss of the FMR1 protein. This protein is present in many cells

CHAPTER 12 Nonneoplastic Diseases of the Testis

and regulates the translation of numerous proteins with a central role for cerebral maturation and function.608 Genotype and phenotype are associated in patients with fragile X chromosome. Great CGC unit repeats correlate with the most severe forms of the phenotype. Conversely, nonmethylated CGC repeats show little or no semiologic repercussion.609 Some syndromes result from intragenic FMR1 variants.610 In affected men, mean testicular volume is more than 70 mL (four times greater than normal). The penis is larger than normal, and both anomalies are apparent in infancy. Testicular enlargement probably begins during fetal life.611 The scrotum is also enlarged and prematurely pigmented. This precocious genital development is difficult to explain because the hypothalamopituitary-gonadal axis is normal, but the condition may be caused by increased sensitivity to stimulation by FSH.612 Testicular biopsies from adults may be normal or show interstitial edema and hypospermatogenesis (Fig. 12.54). Usually, one sees normal testicular parenchyma with focally reduced spermatogenesis and Sertoli cell hyperplasia (Fig. 12.55) or tubules containing only immature Sertoli cells. In other cases, severe pathologic changes have been reported, including

Fig. 12.54 Martin-bell syndrome (fragile X chromosome). The seminiferous tubules show variable degrees of dilatation and marked hypospermatogenesis.

583

Fig. 12.56 Martin-bell syndrome (fragile X chromosome). Seminiferous tubules with immature Sertoli cells with granular changes.

marked tubular ectasia and atrophy of the seminiferous epithelium, granular changes in Sertoli cells (Fig. 12.56), MAT with or without Sertoli cell hyperplasia, and Sertoli cell nodules. Testicular enlargement is chiefly the result of lengthening and coiling of seminiferous tubules as a consequence of Sertoli cell proliferation.232 The low number of spermatids is attributed to atrophy caused by compression of the seminiferous epithelium by marked increase in intratubular fluid.613 Meiotic anomalies have been excluded. The fragile X syndrome is second in frequency only to Down syndrome as a cause of mental retardation.593,604,614 However, this chromosomal anomaly is not always associated with mental retardation or macroorchidism, and some men with fragile X syndrome are otherwise normal.611 The terms fragile X–negative Martin-Bell syndrome and mental retardation–macroorchidism refer to patients with X-linked mental retardation–macroorchidism or X-linked mental retardation and macroorchidism who have the Martin-Bell syndrome phenotype, but not the fragile X site. The gene responsible for this disorder is mapped to Xq12-q21.615 Isolated patients with fragile X chromosome have experienced testicular torsion or neoplasms (testicular or extratesticular).616,617 Other Causes of Testicular Hypertrophy

Fig. 12.55 Martin-bell syndrome (fragile X chromosome). The seminiferous tubules show marked hypospermatogenesis. Several groups of dysgenetic Sertoli cells are seen near the lumen.

Testicular hypertrophy is associated with several glandular disorders such as FSH-secreting pituitary adenoma, hyperprolactinemia, hypoprolactinemia, and hypothyroidism.468,618,619 The most frequent association of testicular hypertrophy is with hypothyroidism. Children with hypothyroidism often show testicular enlargement without virilization.619 Approximately 80% of these patients have macroorchidism, most have elevated FSH levels, and one-half have increased LH levels.235,620,621 Testosterone levels are normal during infancy. The response of FSH and LH to GnRH is altered, and no pulsatile LH release occurs (Fig. 12.57).622 Testicular biopsies before puberty show accelerated development with pubertal maturation of seminiferous tubules, but not Leydig cells. Testicular biopsies in untreated adults show tubular and interstitial hyalinization with few Leydig cells.623–625 Testicular size in this type of macroorchidism diminishes as soon as substitution therapy starts.620,626,627 The etiopathogenesis of macroorchidism associated with primary hypothyroidism may be explained by several hypotheses:

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or gonadotropin independent, mediated by sex steroid hormones secreted by the testis or adrenal glands; and a mixed group that first appears as peripheral precocious puberty and, thereafter, because of the secondary response of the hypothalamus, becomes gonadotropin dependent. Central Precocious Puberty

Fig. 12.57 Macroorchidism in a 3-year-old infant with hypothyroidism. The Sertoli cells have spherical nuclei that contain small heterochromatin granules. Two mitotic figures are seen. The testicular interstitium has no Leydig cells.

increase in gonadotropin secretion caused by thyrotropin-releasing hormone (TRH) stimulation of gonadotropic cells628,629; direct thyroid-stimulating hormone (TSH) effect on the testis resulting from structural similarity between TSH receptors and FSHRs in the testis630,631; and lack of steroid hormones that are required for testicular maturation (in their absence, Sertoli cell proliferation is excessive, giving rise to testicular enlargement).632–635 Macroorchidism associated with secondary hypothyroidism is related to loss-of-function mutations in IGSF1, hyperprolactinemia, and alterations in steroid metabolism of testicular cells.636–638 Testicular Hypertrophy Secondary to Follicle-Stimulating Hormone–Secreting Pituitary Adenoma

Most adenomas that are considered nonfunctioning secrete variable amounts of FSH, although only exceptionally do they have any clinical manifestations.639,640 Functioning pituitary adenoma, with FSH secretion during infancy and puberty, gives rise to variable clinical symptoms in relation to size and accelerated development of pubic hair and genitalia. In adults, macroorchidism secondary to length growth of the seminiferous tubules is accompanied by normal spermatogenesis.641 Once the most frequent causes of macroorchidism have been ruled out, diagnosis is suggested by a discrepancy between normal or elevated FSH and decreased LH, as well as by the detection of elevated inhibin B. Atypical cases of FSH-secreting pituitary adenoma are accompanied by hypogonadism with erectile dysfunction, loss of libido, and absence of macroorchidism.642

Precocious Puberty Precocious puberty is defined by the onset of secondary sex characteristics at a chronologic age that is younger than the mean middle age for the population, 2.5 standard deviations lower than the mean of a defined population. For practical purposes, this is before 8 years of age in girls and 9 years in boys. The incidence is estimated at between 1 in 5000 and 1 in 10,000, with a female-to-male ratio higher than 20:1. In boys the first symptom is rapid testicular enlargement followed by growth of pubic and axillary hair, enlargement of the penis, and acceleration of skeletal growth.643 According to hypothalamopituitary-gonadal axis function, precocious puberty may be classified into three groups: central or gonadotropin dependent, which results from activation of this axis; peripheral

Central precocious puberty (CPP), also known as true precocious puberty, is isosexual. CPP is caused by premature activation of the hypothalamic-hypophyseal-gonadal axis. The first manifestation in boys is an increase in volume (>4 mL) or length (>2.5 cm) of the testes. It is the most common form of precocious puberty in girls and accounts for more than 50% of cases in boys. Age of presentation is between 4 and 10 years.644 The cause is known in only 60% of cases; most are related to lesions in the central nervous system, whereas others are usually idiopathic.645 Increasingly, cases previously considered idiopathic are found to have an underlying genetic basis.646 Lesions in the central nervous system that cause CPP share alterations of specific areas, including the posterior hypothalamus (median eminence and tuber cinereum), mammillary bodies, the bottom of the third ventricle, or the pineal gland.647,648 The most frequent causes are as follows: • Tumor of the hypothalamus (astrocytoma, ganglioneuroma, ganglioglioma, craniopharyngioma, cyst of the third ventricle, and suprasellar cyst of the arachnoid space), pineal cyst, hamartoma (gangliocytoma) of the tuber cinereum and mammillary body, tumor of the pineal gland (teratoma and pinealoma), tumor of the optic nerve (glioma), cerebral and cerebellar astrocytoma, and granular cell tumor of the neurohypophysis649–653 • Cerebral trauma (including postpartum and accidental trauma) that stimulates extrahypothalamic areas responsible for hypothalamic activation654–656 • Infections such as meningitis, encephalitis, toxoplasmosis, and syphilis • Cerebral malformations, including hydrocephaly, microcephaly, and craniosynostosis, pituitary duplication, and midline defects657,658 • Hereditary diseases such as neurofibromatosis and tuberous sclerosis; children with type I neurofibromatosis often also have optic pathway tumors659 • Cerebral irradiation, as occurs in hypothalamopituitary selective irradiation, prophylactic irradiation in children with acute lymphoblastic leukemia, and irradiation of cerebral tumor that is far from the hypothalamopituitary region660–663 Knowledge of the etiology in male patients has expanded with the use of computed tomography (CT) and MRI.664,665 One of the most important contributions of these techniques is the finding of high numbers of hamartomas in children with precocious puberty.666–668 These lesions, also known as gangliocytomas, consist of abnormally located neurons and glial cells. Lesions are usually multiple, small, and located on the hypothalamus between the anterior part of the mammillary body and the posterior part of the tuber cinereum. These neurons contain LH-releasing hormone– positive neurosecretory granules, a finding suggesting that this hormone may be released into the blood draining the hypophyseal portal system and reach the gonadotropic cells.669 Other hamartomas associated with CPP do not show immunohistochemical reactivity to GnRH, but they do show reactivity to TGFA protein and its messenger RNA (mRNA), as well as to the receptors for TGFA and EGF, which could also be involved in precocious pubertal development.670

CHAPTER 12 Nonneoplastic Diseases of the Testis

Precocious puberty resulting from cerebral tumors usually occurs at an advanced stage of the tumor, preceded by symptoms such as hydrocephaly, papillary edema, or psychic alterations. The same occurs when precocious puberty results from cerebral inflammation or malformation. Although pineal gland tumor is rare in children, 30% of these produce precocious puberty, principally in boys. This tumor is usually a teratoma or nonparenchymatous tumor that destroys the pineal gland, thus hindering its antigonadotropic action and initiating puberty.671 In contrast, pinealocyte-derived tumor secretes great amounts of melatonin, which delays the onset of puberty. Idiopathic precocious puberty. The cause of CPP cannot be determined in approximately 80% of girls and 40% of boys. This difference between the sexes may be attributed to the higher sensitivity of female gonadotropic cells to GnRH stimulation. The presentation of idiopathic precocious puberty is familial in nearly 50% of cases, and puberty starts after 7 years in most of these boys. Inheritance may be autosomal recessive or sex linked with variable penetrance.672 Genetic causes may play an important role in the development of some cases.673 Activating mutation (P745) in the KISS1 gene, encoding GPR54s ligand (Kisspeptin), may occur in boys with CPP.674,675 Mutations resulting in MKRN3 gene deficiency induce pulsatile secretion of GnRH, and that triggers precocious puberty.676,677 The diagnosis of CPP is easy when there are elevated gonadotropins (both basal values and in response to GnRH) associated with high testosterone levels and an increase in either the LH/ FSH ratio or in LH and FSH values after stimulation with GnRH agonists. However, in some cases it is necessary to measure nocturnal LH secretion to identify secretion pulses before a dynamic test may reveal the pubertal pattern. The treatment of choice is GnRH agonists.678 Associated disorders that have been reported are intrauterine growth retardation, Silver-Russell syndrome, bilateral retinal degeneration, epilepsy, cryptorchidism, and inguinal hernia.679 Peripheral Precocious Puberty

Peripheral precocious puberty is also known as precocious pseudopuberty. It may be caused by a primary testicular disorder, lesion in other endocrine glands, or hormonal treatment. Primary testicular disorders causing precocious pseudopuberty include familial testotoxicosis, functioning testicular tumor, excessive aromatase activity, and Leydig cell hyperplasia with focal spermatogenesis. The principal secondary anomalies include adrenal cortical anomaly (congenital adrenal hyperplasia, virilizing tumor of the adrenal, and Nelson syndrome) and hCG-secreting tumor, which accounts for one-half of cases of precocious pseudopuberty; testicular germ cell tumor and tumors of the retroperitoneum, mediastinum, and pineal gland are responsible for the other one-half (Table 12.14).680–685 The best-known treatment that may cause precocious puberty is long-term administration of hCG.684 Familial Testotoxicosis: Gonadotropin-Independent Precocious Puberty or Familial Male-Limited Precocious Puberty. Familial testotoxicosis is a form of male sexual precocity characterized by early differentiation of Leydig cells and initiation of spermatogenesis in the absence of stimulation by pituitary gonadotropin. This condition is assumed to be a primary testicular abnormality with autosomal dominant inheritance that is limited to male patients.251,686,687 Some cases occur sporadically. The patients, usually 1 to 4 years of age, have signs of pubertal development, including rapid virilization, acceleration of growth with eventual closure of epiphyses, and short adult stature. Although the testes are enlarged, testicular size does not correlate with the degree of

TABLE 12.14

585

Causes of Peripheral Precocious Puberty

Familial testotoxicosis Gonadotropin-independent precocious puberty Familial male-limited precocious puberty

Precocious pseudopuberty secondary to functioning tumors Leydig cell tumor Intratubular hyalinizing large cell Sertoli cell tumor Large cell calcifying Sertoli cell tumor Adrenal cortex virilizing tumors Hepatoblastoma Extratesticular human chorionic gonadotropin–secreting germ cell tumors Teratoma Choriocarcinoma Seminoma.

Precocious pseudopuberty secondary to disorders of aromatase activity. Precocious pseudopuberty secondary to Leydig cell hyperplasia with focal spermatogenesis.

virilization. Histologic and ultrastructural studies confirm adult Leydig cell pattern and complete spermatogenesis, although many spermatids are abnormal (Fig. 12.58).688,689 The cause of familial testotoxicosis is a constitutive activating mutation of the LH/CGR gene.234,690–693 This gene comprises 11 exons and has been mapped to 2p21, and approximately two dozen LH/CGR gene mutations have been reported.694,695 Hormonal measurements show elevated serum levels of testosterone and low levels of dehydroepiandrosterone sulfate, androstenedione, 17-hydroxyprogesterone, GnRH, and LH, as well as absence of a pulsatile pattern. In addition, serum level of inhibin B appears elevated before the normal age of onset of puberty.696 In some patients a mutation in the LHR may induce Leydig cell hyperplasia.689,697 Patients do not respond to treatment with GnRH analogues, which are used for treatment of CPP. Therapy with the antifungal drug ketoconazole is effective, but patients may experience significant hepatotoxicity and, in some cases, suffer escape phenomenon (secondary CPP), which requires additional therapy with

Fig. 12.58 Testotoxicosis. Leydig cell hyperplasia and seminiferous tubules with deficient spermatogenesis.

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GnRH agonists.698 A proposed alternative to GnRH analogue therapy is administration of cyproterone acetate or the aromatase inhibitor anastrozole, as well as bicalutamide, a nonsteroidal antiandrogen.699–701 Inactivating mutations of GnRH cause male undermasculinization as a result of the absence or hypoplasia of Leydig cells. Precocious Pseudopuberty Secondary to Functioning Tumors. Precocious pseudopuberty may be caused by Leydig cell tumor, Sertoli tumor, adrenal cortex virilizing carcinoma, and extratesticular hCG-secreting germ cell tumor. With Leydig cell tumor, the involved testis is enlarged in response to tumor growth and maturation of the seminiferous tubules adjacent to the tumor; such maturation results from androgen secretion by tumor cells (Figs. 12.59 and 12.60).702 An activating mutation of the LHR gene, Asp578His has been detected in some patients with Leydig cell tumors.703 In most cases the contralateral testis is not enlarged.704,705 Occasionally, tumors cause only precocious tubular maturation, and symptoms of precocious pseudopuberty are absent, probably because of early diagnosis.705

Fig. 12.59 Precocious pseudopuberty secondary to a Leydig cell tumor.

Fig. 12.60 Maturation of the seminiferous tubules located at the periphery of a Leydig cell tumor.

Fig. 12.61 Seminiferous tubule with abundant spermatogonia and firstorder spermatocytes in a 3-year-old child at the periphery of a hyalinizing intratubular Sertoli cell neoplasia.

Intratubular large cell hyalinizing Sertoli cell neoplasia and large cell calcifying Sertoli cell tumor may give rise to precocious pseudopuberty that is isosexual (development of musculature and axillary and pubic hair) and heterosexual (gynecomastia). This precocious testicular maturation and the development of the tumor itself cause testicular enlargement (Fig. 12.61). Tumor cells may stimulate Leydig cells to produce androgens that are aromatized to estrogens by the Sertoli tumor cells themselves, thus accounting for the clinical symptoms.706,707 These tumors are frequently observed in Peutz-Jeghers syndrome and Carney complex.708–711 Most infants with adrenal cortex virilizing tumor have small testes, but hypertrophy has also been observed.712 Testicular development in these cases is attributed to adrenal androgenic action on seminiferous tubules.713 In untreated (or maltreated) congenital adrenal hyperplasia, both testes may be enlarged because of growing masses of cells resembling adrenal cortex.714 Patients with Nelson syndrome may have a similar condition. Surgical removal of virilizing adrenocortical carcinoma may induce CPP that requires treatment.715 Testicular enlargement is modest in paraneoplastic precocious pseudopuberty secondary to hepatoblastoma or extratesticular hCG-secreting germ cell tumor, although nodular or diffuse precocious maturation has been occasionally reported.716–720 These nodules consist of hyperplastic Leydig cells and seminiferous tubules that may show complete spermatogenesis. Outside the nodule the seminiferous tubules maintain their prepubertal pattern. In some cases, only diffuse Leydig cell hyperplasia is observed.721 Precocious Pseudopuberty Secondary to Disorders in Aromatase Activity. Biosynthesis of C18 estrogens from C19 androgens occurs by three consecutive oxidative reactions that are catalyzed by an enzymatic complex known as estrogen synthetase or aromatase.722 This complex has two components: P450 arom (a product from the CYP19 gene located on 15p21.1), which joins C19 substrate and catalyzes the insertion of oxygen in C19 to form C18 estrogens; and reduced nicotinamide-adenine dinucleotide phosphate–cytochrome P450 reductase, a ubiquitous flavoprotein that conveys reducing equivalents to any form of cytochrome P450 it meets.723,723a Aromatase is in the endoplasmic reticulum of estrogen-synthesizing cells and is expressed in placenta, ovarian granulosa, Sertoli cells, Leydig cells, adipose tissue, and several central nervous system regions, including the hypothalamus, amygdala, and hippocampus.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Aromatase Excess Syndrome. Excessive aromatase causes massive conversion of androgens to estrogen.723 It is a genetic disorder with autosomal dominant inheritance caused by gain-offunction mutation in the aromatase (CYP19A1) gene that results in heterosexual precocious pseudopuberty with gynecomastia in boys and isosexual precocity and macromastia in girls. Ultimately, patient stature is short because of the potent ability of androgens to accelerate epiphyseal closure. FSH, LH, and serum testosterone are decreased.724 Although many patients have mild hypogonadotropic hypogonadism, testicular size in adults is normal, and most are fertile and have normal libido.725 Generally the inhibitory estrogenic effect on testicular function is less than that observed with estrogen-producing tumors or in patients treated with exogenous estrogens.726 Patients with aromatase excess syndrome are effectively treated with aromatase inhibitors.727 Aromatase Deficiency Syndrome. Aromatase deficiency syndrome, a rare recessive autosomal disorder, was first reported in 1991.727 It is the result of several mutations in the coding region of the CYP19A1 gene that lead to decrease or loss of enzymatic function with subsequent estrogenic deficit. Most patients are homozygous for inactivating mutations because they are sons of consanguineous parents. Other patients are compound heterozygous from nonrelated patients. In both sexes the first symptom appears in the mothers during pregnancy; these women become progressively virilized because of the placental incapacity to aromatize androgens. In a female fetus, excessive exposure to androgens in utero leads to ambiguous external genitalia. In puberty, normal adrenarche is present; however, these patients have primary amenorrhea, absence of mammary development, and progressive hypergonadotropic hypogonadism with hyperandrogenism. In children, FSH and LH levels and the gonadotropin response to GnRH are normal findings suggesting that the role of estrogens in pituitary regulation is weak during infancy.728 Most cases are diagnosed at puberty.729 The most significant symptom is continuous linear growth in adulthood. In both genders, epiphyseal closure is delayed because the absence of estrogen results in failure of growth plate fusion despite high levels of androgens, and patients develop a eunuchoid habitus.730 Men have small testes, severe oligozoospermia, and complete asthenozoospermia; FSH and LH levels are high, testosterone levels are normal, and serum estrogen levels are low. All patients with aromatase deficit have tall stature, with continuing linear growth into adulthood, unfused epiphyses, osteoporosis, bilateral genu valgum, and eunuchoid proportions.731 Many male patients are obese with dyslipidemia, hyperinsulinemia, acanthosis nigricans, and diabetes mellitus. Estrogens play an important role in pituitary regulation in male adults, so men with aromatase deficit have low libido and infertility.732 Hormonal analysis reveals undetectable estradiol and estrone levels and elevated gonadotropins, findings suggesting a lack of negative regulation of both FSH and LH by estrogens.733 Androstenedione and testosterone may be normal or increased.734 There is macroorchidism with normal consistency in some cases, and the testes are small with severe oligozoospermia and 100% immotile spermatozoa in other cases.735,736 A syndrome like that in men with aromatase deficit is found in patients with estrogen resistance caused by disruptive mutations of the ER gene. These patients have macroorchidism, increased testosterone level, and increased levels of FSH, LH, estradiol, and estrone.737 The spermiogram reveals a low number of spermatozoa (25 million/mL) with decreased viability (18%).738

587

Estrogen therapy in patients with aromatase deficit is effective in achieving epiphysial closure, but this treatment does not improve spermatogenesis.735–737,738a The role of estrogens in male infertility has yet to be discussed.739,740 Precocious Pseudopuberty Secondary to Leydig Cell Hyperplasia With Focal Spermatogenesis. This entity may manifest with clinical symptoms like those of functioning Leydig cell tumor; this is a form of precocious pseudopuberty with ipsilateral testicular enlargement.741,742 The testis contains hypertrophic Leydig cell nests associated with normal spermatogenesis. No tumor mass is present. Leydig cells do not contain Reinke crystalloids and do not compress seminiferous tubules. Tubules with spermatogenesis and infantile immature tubules are clear delimited. The differential diagnosis between this entity and Leydig cell tumor with precocious pseudopuberty is based on histologic pattern. Open excisional testicular biopsy is recommended; if the patient has a Leydig cell tumor, or if the diagnosis by frozen section is not conclusive, testicular removal is advisable.743,744 There is no evidence to suggest that this hyperplasia may develop into Leydig cell tumor. Mixed Precocious Puberty

The best-known form of mixed precocious puberty is the MAS, characterized by the association of “coffee and milk” pigmentary lesions in the skin, bone lesions (polyostotic fibrous dysplasia), enlarged testes, prepubertal size of the penis, and the absence of pubic and axillary hair.745,746 Although testicular enlargement is usually bilateral, unilateral macroorchidism may be the first symptom.747 The diagnosis may be delayed until adulthood.748 This syndrome is caused by mutations that activate the guanine nucleotide– binding protein α-subunit gene (GNAS1), which encodes the α subunit of the trimeric G protein (20q13.32).749 Because these mutations are lethal in utero, male patients with MAS bear mosaicism chromosomal constitution for this deficiency.750,751 The anomaly is followed by inactivation of both LHR and FSHR.752 An interesting finding is that the onset of testicular maturation is induced by the testis itself, which produces steroid secretion secondary to autonomous hyperfunction of Sertoli cells without evidence of Leydig cell involvement.753 This secretion causes early maturation of the hypothalamopituitary-testicular axis and subsequently true precocious puberty.754 The testicular parenchyma shows maturation of both seminiferous tubules and Leydig cells. Testicular microlithiasis is a frequent finding (62%).755,756 The previously described developmental pattern is the rule. However, some cases with a different hormonal or clinical pattern have been reported. Some patients have isolated Sertoli cell hyperfunction, whereas others have only Leydig cell hyperfunction. The macroorchidism resulting from autonomous Sertoli cell hyperfunction shows abnormally elevated serum levels of inhibin B and AMH in correlation with decreased FSH and testosterone. Therefore pubertal inhibin B serum level suggests Sertoli cell hyperfunction that would exert negative feedback on FSH secretion. These testes show Sertoli cell hyperplasia and absence of maturation of both germ cells and Leydig cells, with subsequent lack of steroidogenesis (Figs. 12.62 and 12.63).753 This peculiar condition has been related to the presence of a somatic mutation in the GNAS1 gene in Sertoli cells, but not in Leydig cells.757 The different early embryologic origin of precursor cells that contribute to Sertoli cell and Leydig cell lineages may underlie the differential occurrence of the mutated GNAS1 gene. In other cases, and preferentially in late childhood and adult patients, clinical, biochemical, and histologic data suggest isolated Leydig cell hyperfunction with Leydig cell hyperplasia but without precocious activation of Sertoli cells;

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Fig. 12.62 Precocious puberty in a 5-year-old child. The seminiferous tubules are cellular. The interstitium lacks Leydig cells.

Fig. 12.64 Different locations of ectopic testis.

• • •

Fig. 12.63 Sertoli cell hyperplasia (same patient as in Fig. 12.62). Seminiferous tubules contain more than twice as many Sertoli cells as controls. Immunostaining for androgen receptor was performed.

this condition leads to complete spermatogenesis in some tubules.758,759 In these cases, autonomous testicular function and the gonadotropin suppression may persist for a long time. Therapy in MAS is symptomatic. Precocious puberty is treated with aromatase inhibitors, which block the conversion of testosterone into estradiol; hypophyseal surgery in some cases of fibrous dysplasia; and bromocriptine, cabergoline, and long-acting somatostatin analogues to stop growth hormone (GH) secretion.760

Testicular Ectopia A testis is ectopic when it is located outside the normal path of descent. Unlike cryptorchidism, ectopic testes are nearly normal in size and accompanied by spermatic cord that is normal or even longer than normal, as well as by a normal scrotum.761 Testicular ectopia is estimated to account for about 5% of all undescended testes. Testicular ectopia is classified according to location (Fig. 12.64).762–766 In decreasing order of frequency, major sites are: • Interstitial or inguinal superficial ectopia. This is the most frequent form and may be confused with inguinal cryptorchidism. After passing through the external inguinal ring, the testis

•

• •

ascends to the anterosuperior iliac spine and remains on the aponeurosis of the major oblique muscle. These testes are more likely to be normal histologically than cryptorchid testes. Femoral or crural ectopia. After passing through the inguinal canal, the testis lodges in the high crural cone in the Scarpa triangle. Perineal ectopia. The testis is located between the raphe and the genitocrural fold in a subcutaneous location.762,764,765 Bilateral cases have been reported.767 Transverse or crossed ectopia. This condition is also referred to as pseudoduplication, unilateral double testis, and transverse aberrant maldescent, first reported in 1886.768 Both testes descend through the same inguinal canal and lodge in the same scrotal pouch. The ectopic testis may be located in the internal inguinal ring, the inguinal canal, or the contralateral hemiscrotum. Each testis possesses its own vascular supply, epididymis, and vas deferens. In addition, ipsilateral hernia is present.769–778 More than 150 cases have been reported, mostly in adults. External genitalia ranges from normal to severe undermasculinization.77,779–782 Most cases are diagnosed during herniotomy surgery; others are identified by sonography, CT, or MRI.783 Isolated cases have been identified through treatment of incarcerated inguinal hernia or testicular torsion.784–787 Transverse ectopia must be suspected in cases of inguinal hernia associated with the absent contralateral testis. Treatment consists of transeptal orchiopexy or extraperitoneal transposition of the testis. Between 20% and 40% of patients have PMDS.77,780,788 M€ullerian remnants must be removed with caution, if at all. It is better to leave them in place than to perform extensive dissection that may harm spermatic cord structures.789 High incidence of germ cell tumor (18%) has been reported.790–792 Pubopenile ectopia. The ectopic testis is on the back of the penis near the symphysis pubis.793–796 Penile ectopy associated with groin testicular ectopy and scrotal absence was reported in a patient with popliteal pterygium syndrome.797 Approximately 60% of patients show genital anomalies.798 Pelvic ectopia. The testis is in the pelvis, usually deep in the Douglas cul-de-sac. Other unusual testicular ectopias include retroumbilical, craniolateral to the inner inguinal opening between the outer and inner oblique muscles, subumbilical, and anterior abdominal wall.799–805

CHAPTER 12 Nonneoplastic Diseases of the Testis

Ectopic testes in locations other than the superficial inguinal region typically exhibit histologic changes similar to cryptorchid testes. Findings include low germ cell number, low testicular volume, persistence of the vaginal process, and epididymal anomalies. Microlithiasis may occur in a patient with transverse testicular ectopy.806 Approximately 8% of patients with ectopic testes have contralateral cryptorchid testis.807 There are multiple hypotheses explaining the different types of ectopia.808–810 Accepting that testicular descent occurs in two phases, some ectopias may be explained by failure in the first phase and others by a failure in the second phase. The first phase requires the gubernaculum to be attached to the abdominal wall at the site of the future inguinal canal. Attachment to the wrong side or disruption of that attachment would result in the following ectopias: attachment to femoral canal would result in femoral ectopia; attachment to the Spigelian triangle would result in Spigelian ectopia; absence or loss of attachment to the inguinal canal would result in transverse ectopia or pelvic ectopy. In the second phase of descent the gubernaculum must emigrate from the inguinal canal to the scrotum. This event is under the control of CGRP from the GFN. The GFN has two main branches, the genital branch supplying the scrotum and the femoral branch supplying the inner side of the thigh. Erroneous distribution of GFN sensory fibers or altered secretion of CGRP occurring in the wrong branch would disrupt the usual path of emigration of the gubernaculum. If the femoral branch of the GFN directs migration, femoral ectopia occurs; if the genital branch reaches the perineum instead of the scrotum, perineal ectopia occurs; and if the genital branch supplies the penis instead of the scrotum, pubopenile ectopia occurs. Finally, there are ectopias that occur despite normal attachment of an abnormally developed gubernaculum. This occurs in patients with defects in AMH in whom an excessively long gubernaculum allows ample displacement that may lead the testicle even to the contralateral vaginal process.

Testicular Exstrophy (Scrotoschisis) In testicular exstrophy the testis and the spermatic cord are prolapsed externally through a defect in the scrotal wall.811–815 The lesion may be unilateral or bilateral. The gubernaculum is normal, and testicular descent is not impaired. Testicular exstrophy may result from mesodermal failure, similar to what causes the defect of the anterior abdominal wall in newborns with gastroschisis, scrotal wall necrosis secondary to meconium peritonitis, and iatrogenic trauma during cesarean section.813,816,817

589

polyorchidism, follow-up with ultrasound imaging is recommended because of the higher risk for testicular tumor development.

Hamartomatous Testicular Lesions Hamartoma is a term used to refer to abnormal and excessive development of structures that usually form part of the testis, epididymis, or spermatic cord. Hamartomatous lesions of the testis and sperm excretory ducts include cystic dysplasia of the rete testis, hamartoma of the rete testis, fetal gonadoblastoid testicular dysplasia (FGTD), Sertoli cell nodule, tubular hamartoma, congenital testicular and epididymal lymphangiectasis, and muscular hyperplasia of paratesticular structures. The main concern with hamartoma is not the biologic behavior, which is always benign, but their significance, because most are associated with specific disorders or are markers of complex syndromes.

Cystic Dysplasia of the Testis Cystic Dysplasia of the Rete Testis

Cystic dysplasia of the rete testis is a congenital lesion characterized by cystic transformation of an excessively developed rete testis that may extend to the tunica albuginea of the opposite pole. It was first reported in 1973 as “cystic dysplasia of the testis,” arising in a 4-year-old with right renal agenesis.823 To date, approximately 50 cases have been reported, mostly in children, with median age at presentation of 6 years (range, 0 to 23 years).824–826 The most remarkable clinical symptom is scrotal swelling, followed by scrotal pain suggesting testicular tumor in some cases. Approximately 35% have abdominal cryptorchidism. Ultrasound images are characteristic: small cystic formations of variable size, located in the testicular mediastinum, extend to the proximal testicular parenchyma and cause its compression. In addition, small hyperechoic foci, originating in the interphase between the walls of distal cystic and adjacent parenchyma, are observed. The observation of ipsilateral renal anomalies in ultrasound exploration may be of great importance for diagnosis.827 Macroscopically the testis in adult patients has a cut surface reminiscent of the thyroid, with cysts of varying size filled with colloid-like material (Fig. 12.65). The extent of the cystic transformation is widely variable. Small groups of cysts may be limited to

Testicular Fusion Testicular fusion is a rare anomaly characterized by fusion of the testes to form a single structure, usually in the midline. Each testis has its own epididymis and vas deferens. This anomaly is often associated with other malformations such as fusion of the adrenal glands or horseshoe kidney. Testicular fusion was also observed in a patient with transverse testicular ectopia and PMDS. The fused testes had a single vas deferens.818 Bilobed Testis Bilobed testicle is a rare malformation, with only four cases reported.819–822 Patients have enlarged hemiscrotum related to testicular enlargement and hydrocele formation. The contralateral testis is normal. Sonography may exclude a tumor and thus avoid surgical exploration and testicular biopsy. This condition is considered an incomplete expression of polyorchidism. As in

Fig. 12.65 Cystic dysplasia of the rete testis in an adult patient. The testis consists of numerous variable-sized cysts filled with a colloid-like material except for a peripheral crescent.

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the region of the mediastinum testis, or cysts may extend throughout the entire testis. In extensive cases, residual seminiferous tubules occupy only a small crescent beneath the tunica albuginea, and the testis is grossly spongy.828 Cysts, which may be of variable size (from microscopic to several millimeters), arise in the septal and mediastinal rete testis (Fig. 12.66). They are interconnected and contain acellular, eosinophilic, periodic acid–Schiff+ (PAS+) material. The cavities are lined by cuboidal cells that resemble those of normal rete testis both immunohistochemically (expressing both cytokeratin and vimentin) and ultrastructurally.829–832 Immunoreactivity to epithelial membrane antigen, which is usually not expressed in the normal rete testis, has been reported in some cases.833 Connective tissue between the cysts is scant and histologically similar to interstitial connective tissue. In some cases this tissue is so abundant that it partially collapses the cavities, and psammoma bodies and small inflammatory infiltrates may be present beneath the epithelium. In cystic dysplasia, during infancy and childhood the residual testicular parenchyma may mature normally, and cryptorchid testes with cystic dysplasia have a marked decrease in spermatogonial number (Fig. 12.67). However, in all cases the proximal end (the opening to the rete testis) of the seminiferous tubules shows a small dilatation. The seminiferous tubules may be dilated and atrophic; this is more evident after puberty.834–838 Cystic dysplasia occurs in normally descended and cryptorchid testes, both in children and adults, and may affect one or both testes.839 In adults, residual parenchyma often shows morphologic characteristics of obstructive lesions: complete tubular sclerosis or hypospermatogenesis with intratubular accumulation of spermatozoa and Leydig cell pseudohyperplasia. In most cases the epididymis is altered.840 The head of the epididymis is small and contains few ductuli efferentes with irregular, usually dilated lumina, and abundant loose stroma. The ductus epididymidis is dilated, with atrophic epithelium consisting of cuboidal cells lacking stereocilia. Thick connective tissue replaces the muscular layer (Fig. 12.68). Marked epididymal hypoplasia has been described. The ductus deferens may also be dilated. Ipsilateral absence of the ductus deferens occurs infrequently. Cystic dysplasia is frequently associated with severe anomalies of the kidney or the urinary system. These problems greatly

Fig. 12.66 Cystic dysplasia of the rete testis in an adult patient. Transverse section of the testis showing numerous anastomosed cavities that reach the albuginea.

Fig. 12.67 Cystic dysplasia of the rete testis in a newborn. There is cystic transformation of the rete testis and adjacent seminiferous tubules.

Fig. 12.68 Marked luminal dilation of the ductus epididymidis in an infant with cystic dysplasia of the rete testis.

overshadow the significance of the testicular changes. Renal agenesis (51%), renal dysplasia (21%), hydronephrosis (8%), hydroureter, dilated or cystic epididymis (8%), absence of ipsilateral ureteric orifice (6%), ureteral duplication (4%), urethral stenosis, ectopic ureter draining to the seminal vesicle, ipsilateral renal agenesis and contralateral crossed ectopia, and genitourinary manifestations of VATER (vertebra/anus/cardiac/trachea/esophagus/radius/ renal anomalies) syndrome have been reported ipsilateral to testicular cystic dysplasia.823,832,839,841–847 The clinical differential diagnosis consists of all cystic lesions involving the prepubertal testes, including epidermoid cyst, cystic teratoma, juvenile granulosa cell tumor, testicular lymphangiectasis, simple cyst of the testis, and posttorsion cystic degeneration of the testis.848,849 Previously, total or partial orchiectomy was the treatment of choice.850 Currently, conservative therapy is recommended if the ultrasound diagnosis is highly suggestive, and results of α-fetoprotein and hCGβ subunit assays are negative.851,852 Spontaneous regression may occur.826,853–855 However, it is uncertain whether attempts to save the testis preserve spermatogenesis. The etiology and pathogenesis of cystic dysplasia are uncertain. Given that the rete testis is a mesonephric derivative and most of

CHAPTER 12 Nonneoplastic Diseases of the Testis

the associated renal malformations are apparently caused by failure of induction of renal blastema by the mesonephros, cystic dysplasia is the result of abnormal mesonephros. During childhood the normal rete testis has no lumina because these form during puberty. The adult rete testis is a conduit for the passage of tubular fluid and spermatozoa, and actively reabsorbs part of this fluid while adding ions, proteins, and steroids.856 Primary lesion of mesonephric cells that form the rete testis could result in abnormal function of the rete testis epithelium, which could produce fluid with abnormal composition at an inappropriate time. Lesions similar to cystic dysplasia of the rete testis have been experimentally induced by sodium intoxication after administration of salt-retaining hormones or deoxycorticosterone acetate in fowls, as well as by estradiol administration in newborn rats.857,858 Cystic Dysplasia of the Epididymis

Cystic dysplasia of the epididymis (CDE) is a recently described anomaly characterized by the presence of irregular, segmental cystic dilatation of the epididymal ducts with aberrant forms and immature appearance (Fig. 12.69).859 There is a significant decrease in the number of sections of efferent ductules without lesions in the lining epithelium. The irregular cystic dilatations cause loss of epididymal head architecture (loss of typical hemispherical shape). It may affect one segment of the epididymal duct in association with lesions in the head of the epididymis or as an isolated lesion. CDE was observed in 19 fetal and neonatal autopsies of males from 27 weeks of gestation to 10 days of life, and in one surgical specimen from a 4-year-old. The lesion was bilateral in all evaluable cases. Eighteen of 20 cases had renal or urinary tract anomalies, including renal dysplasia (8 cases), renal agenesis (4 cases), autosomal recessive polycystic renal disease (1 case), and renal hypoplasia (1 case). In eight cases, testes were cryptorchid. One patient had associated ipsilateral testicular cystic dysplasia. CDE is a novel congenital anomaly of mesonephric differentiation that should be added to the spectrum of male excretory system disorders associated with renal and urinary malformations.

Hamartoma of the Rete Testis Only one case of rete testis hamartoma has been reported. It was in a 3-year-old who presented with a testicular mass. The lesion

Fig. 12.69 Cystic dysplasia of the epididymis. The caput of the epididymis is formed by a few efferent ducts showing irregular dilations.

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consisted of a disordered tubular proliferation lined by epithelium like that of the rete testis within a loose connective tissue stroma.860 A peculiar hamartoma that consisted of three separate components (cystic dilatation of the rete testis, diffuse interstitial smooth muscle proliferation, and extensive stroma with myxoid areas) was reported in a 26-year-old.861

Fetal Gonadoblastoid Testicular Dysplasia FGTD refers to abnormally differentiated testicular parenchyma. This disorder was first described in 1986 in a 28-week premature newborn who died 1 hour after delivery.862 The only remarkable antecedent during pregnancy was polyhydramnios. The karyotype was 46,XY. The most relevant data from autopsy were hypertelorism, low-set ears, fenestrated secundum-type atrial septal defect, idiopathic bilateral hydronephrosis without apparent urinary duct obstruction, unilateral double renal collecting system, and pleural effusion. Genitalia were characteristic of a normal male infant.863 Three other cases (18-week-old fetus, 22-week-old fetus, and a 3-year-old) were later reported, all in association with WalkerWarburg syndrome (WWS; https://www.omim.org/entry/ 236670), including left ureter malformations and ipsilateral renal cystic dysplasia. Two additional cases of FTGD were observed. The most interesting autopsy findings were hydrops, muscular lesions suggesting mitochondrial myopathy that did not fit the diagnostic criteria of WWS, and undescended testes lodged near the inferior pole of both kidneys.864 Weinberg reported a 10month-old with WWS whose gonads were located in the inguinal canal and consisted of epididymis, vas deferens, and a rete testis that ended blindly in fibrous streaks; “follicle-like structures” were noted microscopically.865 This observation lends support to the notion of an association between WWS and FGTD. Incidentally, Weinberg’s case appears to describe the oldest patient in whom FGTD has been identified. In contrast, Whitley and colleagues reported a patient with WWS in whom testicular abnormalities included small size attributed to shortening of seminiferous tubules and low numbers of Leydig cells.866 No features resembling FGTD were present. WWS represents the most severe of the dystroglycanopathies, in which defective interaction between membrane receptors and extracellular matrix components results in muscle, brain, and nerve derangements.867 Two new cases of GTD have been reported in association with Noonan syndrome.868 In all cases of FGTD, the testes were grossly unremarkable, with normal tunica albuginea, and the histologic testicular pattern was similar. Seminiferous tubules were well developed (number of germ cells and Sertoli cells per cross section within normal limits) only in the central zone of the testicular parenchyma, although with reduced numbers of seminiferous cords. Beneath the tunica albuginea, the peripheral testicular parenchyma showed a crescent-like zone with large malformed tubules, cords, and solid nodules of spherical or irregular shape embedded in fibrous connective tissue reminiscent of ovarian stroma organized into several concentric layers. Each of these solid nodules was surrounded by a delimiting basement membrane (Fig. 12.70). Each structure was composed of three cell types: cells with vesicular nuclei and vacuolated cytoplasm, cells with hyperchromatic nuclei, and germ cell– like cells. The former two cell types were arranged at the periphery, forming a pseudostratified epithelium with the long axes perpendicular to the nodule periphery. The third cell type resembled fetal spermatogonia and was fewer in number, although number varied from one tubular formation to another. These structures contained eosinophilic, PAS+ material, similar to Call-Exner bodies

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Fig. 12.70 Fetal gonadoblastoid testicular dysplasia. Several nodules are present at the periphery of the testicular parenchyma.

Fig. 12.71 Fetal gonadoblastoid testicular dysplasia. A nodule contains numerous Sertoli-like cells, Call-Exner bodies, and isolated germ cells. The nodule is surrounded by two cell layers: fusiform cells (inner layer) and Leydig cells (outer layer).

(Fig. 12.71). There may be continuity between these structures and normal seminiferous tubules. Immunohistochemically, cells within the nodular lesions revealed a gradient in the expression of inhibin, most strongly at the periphery and negative in the center. The surrounding spindle stromal cells expressed vimentin and muscle-specific actin. Laminin and collagen type IV were expressed in the basement membrane and revealed deep invaginations of basement membrane material toward the center of the nodules, resembling Call-Exner bodies (Fig. 12.72). Only isolated cells morphologically resembling germ cells expressed PLAP, but most were negative for all markers. Cytokeratin (AE1/AE3) expression was only focally positive. The remaining parenchyma showed normal development according to age and revealed expression of vimentin in Sertoli cells. Inhibin was intensely and diffusely expressed in Sertoli and Leydig cells.864 The differential diagnosis includes conditions with anomalous seminiferous tubules at the gonadal periphery, including dysgenetic testis and gonadoblastoma. Dysgenetic testis also exhibits

Fig. 12.72 Fetal gonadoblastoid testicular dysplasia. There is positive expression for collagen IV both in the bodies and the wall of the vessels that penetrate the nodules.

tubular or cordlike structures, but these are differentiated (some form true seminiferous tubules) and may also be present within a poorly collagenized tunica albuginea. Both contain intertubular stroma consisting of fibrous connective tissue similar to the ovarian-like stroma characteristic of dysgenetic gonads. However, patients with dysgenetic testis are 46,XY disorder of sex development (DSD) with m€ ullerian remnants, a condition that is absent in FGTD. Distinguishing FGTD from gonadoblastoma is more difficult. Gonadoblastoma is usually found in an ovarian streak gonad or dysgenetic gonad and contains granulosa–Sertoli cells and germ cells that are like those of dysgerminoma or seminoma; these cells are absent in FGTD. FGTD has been reported in patients with WWS, so one could hypothesize that the genetic deficiency causing this syndrome may also be responsible for normal testicular development.863 Other hypotheses suggest a defect in segmentation of primitive cords secondary to poor fetal development of the vascular system or mutations in the PTPN11 gene because two patients were carriers of Noonan syndrome.869 One may also speculate about the potential progression pathway of FGTD. Given that no patient has survived beyond a few months of life, it is not possible to ascertain how the lesion would have progressed. Incidentally, it is puzzling to recognize the vague resemblance between FGTD and granulosa cell tumor of the juvenile type, another congenital testicular tumor. The determination whether FGTD is a precursor lesion of full-blown gonadoblastoma, juvenile granulosa cell tumor, or another neoplasm, or would rather undergo atrophy, as may be surmised by the observations of Weinberg, awaits identification of FGTD in patients with longer survival.865

Sertoli Cell Nodule (Hypoplastic Zones or Dysgenetic Tubules) Sertoli cell nodule consists of the presence in the adult testis of one or several foci of infantile (immature) seminiferous tubules. The term “Sertoli cell nodule” was first reported in 1973, although Pick described a lesion in 1905 known as Pick adenoma that has similar characteristics.870,871 This lesion has also been reported as Sertoli cell hyperplasia, tubular dysgenesis, or hypoplastic zones.872–874

CHAPTER 12 Nonneoplastic Diseases of the Testis

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Each group of tubules appears well delimited but unencapsulated. Nodule size usually varies from microscopic to 5 mm; however, in at least 10 reported cases, size has reached up to 10 mm, termed macroscopic Sertoli cell nodule.875–877 These patients may have palpable nodules at presentation. The nodules may be single or multiple. On section, each nodule is distinguished by its whitish color. Ultrasonography may suggest testicular tumor. Sertoli cell nodule is found in about 60% of adult cryptorchid testes, regardless of when the testes descended.878 It is also present in 22% of normal scrotal testes in some series and is an occasional finding in men with idiopathic infertility and in the parenchyma surrounding germ cell tumor.874 The seminiferous tubules have a prepubertal diameter and may be anastomotic. The epithelium is columnar or pseudostratified, devoid of lumina, and usually consists only of Sertoli cells (Fig. 12.73). The cells have elongate hyperchromatic nuclei with one or several peripherally placed small nucleoli.874 The interstitium varies from scant to well collagenized. Leydig cells are usually absent in these areas, and, if present, their numbers are low; exceptionally, they are abundant (Fig. 12.74). In some

nodules, isolated germ cells may be observed (Fig. 12.75). Study of serial sections sometimes reveals continuity between some tubules and normal tubules. Sertoli cell nodules change with advancing age. These changes are not related to a significant enlargement of the size because that remains unaltered, but rather reflect development of structures inside the lesions. The Sertoli cells produce large amounts of basal lamina that become intensely PAS+ and protrude inside the hypoplastic tubules. In transverse and oblique sections, these protrusions may be misinterpreted as intratubular accumulations of basal lamina material (Fig. 12.76). This material may undergo calcification to form microliths. Immunohistochemical study reveals two components of the basal lamina (collagen IV and laminin), thus confirming extracellular origin; the protrusions consist mainly of laminin, whereas collagen IV delimits the outer profile of the seminiferous tubules. So, although the amount of collagen IV is uniform around the tubules, the depth of laminin varies within the same tubule and from one to another tubule. Sertoli cells in this lesion also show immunohistochemical markers of immature cells, including expression of D2–40,

Fig. 12.73 Sertoli cell nodule. This adult cryptorchid testis contains compact groups of small seminiferous tubules with pseudostratified cell layers without lumina.

Fig. 12.75 Sertoli cell nodule. Tubular formations with immature Sertoli cells and spermatogonia.

Fig. 12.74 Sertoli cell nodule. Among tubular formations with irregular contours and prepubertal maturation, abundant Leydig cells are observed.

Fig. 12.76 Sertoli cell nodule. Sertoli cell–produced material, similar to the basal lamina material, forms finger-like protrusions inside the hypoplastic tubules. The Sertoli cells are arranged in a ring around this material.

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AMH, calretinin, and inhibin bodies.170 The diameter of hypoplastic tubules is usually smaller than that of the adjacent tubules, but in some cases the inverse occurs because of hypertrophy of Sertoli cells, which show some evidence of pubertal maturation without reaching full maturation of adult cells. Sertoli cell nodules are assumed to be primary testicular lesions and are included in the spectrum of testicular dysgenesis syndrome.879 They represent seminiferous tubules that are unable to undergo pubertal development despite the same hormonal stimuli as adjacent normal tubules. This dysgenesis includes immature Sertoli cell pattern showing D2–40 immunoexpression, low inhibin secretion, absence of ARs, and lack of maturation of peritubular myoid cells that fail to synthesize elastic fibers (Fig. 12.77).880 The presence of hypoplastic zones (Sertoli cells nodules) in a testicular biopsy is an adverse prognostic sign for fertility, as is the presence of isolated dysgenetic tubules or hypoplastic tubules in testicular parenchyma. Attempts have been made to identify the precursor zones of these hypoplastic zones in prepubertal biopsies to obtain an additional predictor of fertility in cryptorchidism. Infantile precursor hypoplastic zones are not as well delimited as definitive hypoplastic zones of adults. Differences in diameter between hypoplastic tubules and the other tubules of the testicular parenchyma are not as clearly marked in infants as in adults. Although small tubules predominate in the hypoplastic zone precursors of the infantile testis, the degree of maturation of these tubules may be similar to or more advanced than the outer tubules of the parenchyma (Fig. 12.78). The most reliable histologic findings for identifying the precursor zones in infant testes are the cordlike arrangement of these tubules, occurrence of anastomoses among the cords, scant cellularity (Sertoli number is lower than in the remaining testicular parenchyma), and wide Sertoli cell cytoplasm, which often shows granular changes. The differential diagnosis includes Sertoli cell adenoma, tubular hamartoma in androgen insensitivity syndrome (AIS), testis with focal Sertoli cell–only tubules (MAT of the testis), Sertoli cell neoplasm, and gonadoblastoma. Sertoli cell adenoma and tubular hamartoma are characteristic findings in AIS. Like Sertoli cell nodule, adenoma and tubular hamartoma contain nodules composed of solid tubules of immature Sertoli cells without a capsule. The three lesions differ macroscopically in size; adenoma and tubular hamartoma are usually larger than Sertoli cell nodule. Histologically, both Sertoli cell

Fig. 12.77 Sertoli cell nodule. Tubular organization is complex and may show different patterns. Note the ring-shaped tubules in some areas and anastomosed tubules in others, both with immature Sertoli cells.

Fig. 12.78 Sertoli cell nodule. Group of anastomosed tubules lined by Sertoli cells with prepubertal maturation showing spherical nuclei, central nucleoli, and vacuoles in the cytoplasm.

adenoma and tubular hamartoma are formed by Sertoli cells with spherical, rather than elongate, nuclei that do not display pseudostratification. Although the tubular wall may be widened, it does not have nodular intratubular projections. In Sertoli cell adenoma, tubules are back to back, and the sparse interstitium does not usually contain Leydig cells. The interstitium may be densely cellular in tubular hamartoma, with fusiform cells. Tubular hamartoma always has many Leydig cells, whereas these cells are lacking or scant in Sertoli cell nodule.254 The parenchyma surrounding tubular hamartoma has the same grade of development as the lesion. In contrast, the testes in patients with Sertoli cell nodule are always delayed in development. Testes with focal Sertoli only–cell tubules show two seminiferous tubule types: Sertoli cell–only tubules and tubules with germ cells, although the spermatogenetic degree may vary widely in the tubules with germ cells. Sertoli cell–only tubules do not form clusters such as those seen in the hypoplastic tubules of Sertoli cell nodules. In addition, the tubular size and the degree of Sertoli cell maturation are higher in Sertoli cell–only tubules to such an extent that even lumina may be observed in some tubules. Finally, the usual cell components of the testicular interstitium (Leydig cells, macrophages, and some mast cells) are found in these Sertoli cell–only tubules. Sertoli cell tumor not otherwise specified consists of larger cells with vesicular nuclei and prominent nucleoli with isolated atypical nuclei and mitotic figures arranged in cords and tubules without significant widening of basal membrane that is characteristic of Sertoli cell nodule. Intratubular large cell hyalinizing Sertoli cell neoplasia may resemble Sertoli cell nodule at low magnification because both may produce multiple nodules and show widened basal membranes and intratubular projections of basal membrane–derived material. However, the tubules in intratubular large cell hyalinizing Sertoli cell neoplasia are not anastomotic and are larger in diameter than those seen in Sertoli cell nodule. Sertoli cells have an apparent higher grade of maturation (vesicular nuclei with central nucleoli and large eosinophilic cytoplasm). Immunohistochemically the cells express cytokeratin that is usually absent in Sertoli cell nodule. Also, intratubular hyalinizing Sertoli cell neoplasia does not contain germ cells, usually develops in scrotal testis, and is associated with Peutz-Jeghers syndrome.710,881,882

CHAPTER 12 Nonneoplastic Diseases of the Testis

Sex cord tumor with annular tubules is exceptionally rare in the testis. The resemblance to Sertoli cell nodule is high, but features favoring this diagnosis include large size of the lesion and greater complexity of the tubular organization, with solid areas and hyalinized stroma. When Sertoli cell nodule contains germ cells, the differential diagnosis of gonadoblastoma should be considered. Most germ cells in Sertoli cell nodules are spermatogonia; these cells are scant, do not show signs of proliferation, and are TSPY+ (testis-specific protein Y-encoded+). In rare cases, Sertoli cell nodule contains gonocyte-like cells in both the basal membrane and the center of the tubules; these cells express OCT3/4. These gonocyte-like cells thus represent GCNIS (Fig. 12.79). In these cases the lesion itself is like gonadoblastoma. Criteria for ruling out gonadoblastoma are as follows: Sertoli cell nodule with GCNIS is surrounded by or near germ cell tumor, and gonadoblastoma characteristically arises in malformed gonads (gonadal dysgenesis, dysgenetic testis in DSDs), whereas Sertoli cell nodule is found in well-configured testes. The disposition of tumor cells is also important. In Sertoli cell nodule, tumor cells are preferentially disposed at the center of the lesion, whereas in gonadoblastoma, the distribution is more diffuse.883 Another entity that should be included in the differential diagnosis is sex cord–stromal tumor of the testis with entrapped germ cells. These tumors measure several centimeters in diameter. The cells are arranged in cords and tubules and may show germ cells without atypia, mainly at the periphery.884

Tubular Hamartoma (Androgen Insensitivity Syndrome) Tubular hamartoma consists of unencapsulated whitish nodules that are well delimited from the parenchyma containing small seminiferous tubules and numerous Leydig cells. It is also known as Sertoli–Leydig cell hamartoma (see later discussion of Androgen Insensitivity Syndromes). Lymphangiectasis Congenital Testicular Lymphangiectasis

Congenital testicular lymphangiectasis is characterized by abnormal and excessive development of lymphatic vessels in the tunica albuginea, mediastinum testis, interlobular septa, and testicular interstitium.253,885,886 Ultrastructurally these dilated vessels are similar to normal lymphatic capillaries, although some are markedly dilated, and the testicular interstitium is slightly edematous

Fig. 12.80 Congenital testicular lymphangiectasis. Ectatic lymphatic vessels are seen in the tunica vasculosa and interlobular septa, as well as among the seminiferous tubules, causing compression.

(Fig. 12.80). Testicular lymphangiectasis occurs in both cryptorchid and scrotal testes. One patient had Noonan syndrome. It does not seem to affect the seminiferous tubules, and low numbers of spermatogonia and reduced tubular diameters are observed only in cryptorchid testes. The epididymis and spermatic cord are not affected, and congenital testicular lymphangiectasis is not associated with pulmonary, intestinal, or systemic lymphangiectasis. During fetal life, lymphatic vessels are visible only immediately beneath the tunica albuginea and in the interlobular septa.887 During childhood the number and size of the septal lymphatic vessels decrease.426 By adulthood the vessels are inconspicuous, although ultrastructural and immunohistochemical evidence of their presence is visible in the interstitium, and they are easily identified by staining with monoclonal antibody D2–40.888 In lymphangiectasis, septal lymphatic vessels are large and often massively dilated. It occurs only in childhood, a finding suggesting that these dilated vessels undergo involution at puberty or that pubertal development of the seminiferous tubules masks the lymphangiectasis. Testicular lymphangiectasis may result from alterations in lymphatic drainage caused by surgical treatment of the inguinal region, radiation therapy of retroperitoneal lymph nodes, or chronic inflammation of the spermatic cord. Lymphatic dilatation involves vessels that were previously normal, resulting in development of small cysts chiefly in the tunica vasculosa and epididymis. Similar dilatations have been observed in cryptorchid testes and in patients with Morris syndrome. Epididymal Lymphangiectasis

Fig. 12.79 Sertoli cell nodule showing atypical gonocytes among prepubertal Sertoli cells in an adult patient with germ cell tumor.

595

Epididymal lymphangiectasis has been described in adults as “lymphangiectasis” and “lymphangioma,” terms referring to pseudotumoral lesions consisting of abnormal development of lymphatic vessels in the caput epididymis. Dilated vessels compress the ductuli efferentes and cause irregular dilation by compression, thereby distorting the normal architecture (Fig. 12.81). In some cases, these malformative or hamartomatous lesions are likely primary, and the diagnosis is made by examination of orchiepididymectomy for suspected tumor or lesion.889–891 In other cases, it is considered secondary to previous herniorrhaphy, and only epididymectomy is performed.891

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Fig. 12.81 Epididymal lymphangiectasis. There are multiple cystic formations of different size, apparently without content surrounding the epididymis.

of the cauda epididymis (interstitial), the seminiferous tubules (peritubular hamartoma) (Fig. 12.83), or the tunica albuginea (Fig. 12.84). In periductal hamartoma, ductus deferens thickness (normally 3 mm) can reach 10 mm. The cauda epididymis (normally 0.5 to 0.7 mm) may enlarge up to 2 mm. Smooth muscle cells create a concentric pattern around sperm excretory ducts and blood vessels. In other hamartomas such as those in the tunica albuginea and the interstitial tissue of the cauda epididymis, muscle bundles are irregularly arranged and intermingled with variable amounts of connective tissue (Fig. 12.85).894 Most muscular hyperplasias are assumed to be hamartomas, similar to smooth muscle proliferations in other organs, including the gingiva, palate, esophagus, gastric pylorus, small intestine, large intestine, trachea, and breast.895–902 Differential diagnosis includes leiomyoma, but hyperplasia lacks characteristic features of leiomyoma such as the cohesive pattern of smooth muscle bundles, nodularity, and well-defined delimitation from the adjacent tissues.

Other Hamartomatous Testicular Lesions Smooth muscle is a normal component of sperm excretory ducts, as well as of two other specific structures: the tunica albuginea of the inferior pole and the interstitial tissues of the cauda epididymis among the numerous folds of the ductus epididymis. Muscular hyperplasia involving any of these structures has been reported in patients from puberty to 81 years of age. The minimum size required for diagnosis is not well defined, but previously reported cases indicate that the width of muscular proliferation was 0.6 to 7 cm. In young men, smooth muscle hyperplasia is especially frequent in those with AIS. The lesion has been reported as leiomyoma, and it may be associated with multiple tubular hamartomas.892,893 This smooth muscle proliferation is located in the inferior pole, involves the tunica albuginea and the adjacent soft tissue (i.e., in the zone that should be occupied by the cauda epididymis), and may form nodules measuring more than 1 cm in diameter (Fig. 12.82). In other adult patients the reported distribution of smooth muscle hyperplasia has been related to the ductus deferens (periductal), the surrounding vessels (perivascular), the different structures

Fig. 12.83 Peritubular hamartoma. Proliferation of myofibroblasts concentrically arranged around two seminiferous tubules.

Fig. 12.82 Smooth muscle hamartoma in the lower pole of the testicle. The lesion is in continuity with the albuginea.

Fig. 12.84 Smooth muscle hamartoma within enlarged tunica albuginea.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.85 Smooth muscle hamartoma in the lower pole of the testicle. There are bundles of loose compact muscle cells and abundant vessels (immunostaining for smooth muscle actin).

Ectopias Persistence of Gonadal Blastema The term persistence of testicular blastema refers to the presence of gonadal blastema in an otherwise normal testis for age. Testicular blastema includes immature sex cords, germ cells, and mesenchymal components. The primitive tissue gives rise to testicular parenchyma and is not expected to be present in completely developed testes. This infrequent ectopia occurs in newborns as a rare autopsy finding. It was present in both testes of three fetuses from a total of more than 3000 consecutive autopsies: one fetus was spontaneously aborted as a result of chorioamnionitis; one was electively aborted because of a neural tube defect, omphalocele, and asymmetric arthrogryposis; and a third had trisomy 18 and classic phenotypic features of Edwards syndrome.227 The blastema is near the upper testicular pole at the implantation site of the caput of the epididymis. It has a crescent shape and extends throughout the depth of the tunica albuginea and the adjacent parenchyma. Blastema consists of epithelial cords of cells or solid masses in continuity with mesothelium (Fig. 12.86). These cells are intermingled with others that are larger, with pale cytoplasm, vesicular nuclei, and prominent nucleoli. This second population, resembling germ cells, is less frequently seen, sparsely distributed among the cords. The remaining parenchyma, tunica albuginea, and epididymis are normal for age. Blastomatous epithelial cells display immunoreactivity for vimentin, laminin, type IV collagen, and cytokeratin; the expression of cytokeratin in the most superficial cells is like that of mesothelial cells and decreases in intensity in the deeper cells. This characteristic suggests that these may be pre–Sertoli cells. The cordlike structures are delimited by laminin and type IV collagen. The larger cell type is immunoreactive for PLAP on the surface, and lacks vimentin and cytokeratin expression, suggesting that it is related to the gonocyte. Leydig cells have not been observed among the cords of gonadal blastema.227 The differential diagnosis of gonadal blastema ectopia includes ovotestes. The small size of the gonocytes distinguishes these cells from ovocytes, which are several times larger. In addition, no intersex condition is observed.

597

Fig. 12.86 The blastema is located between the lining epithelium of the testis and the seminiferous tubules occupying an expansion of the albuginea. The major population consists of small nucleus cells (pre-Sertoli), among which there are larger ones (gonocytes).

The most likely evolution of blastema is differentiation toward testicular parenchyma. This possibility is supported by two features: the disorder may occur only in newborns, and in the zone where blastema cells are found (superior testicular pole), ectopic seminiferous tubules or ectopic Leydig cells have also been observed.

Seminiferous Tubule Ectopia The presence of seminiferous tubules within the tunica albuginea is a rare and usually incidental histologic finding.226 Ectopic tubules are present in approximately 0.8% of pediatric autopsies and 0.3% of adult autopsies. The lower incidence in adults may be explained by proportionally less sampling. The lesion ranges from microscopic to a few millimeters in diameter, and it may be visible in children as rounded macules on the surface of the testis as minute bulges in which multiple small vesicles protrude through a thin tunica albuginea.903,904 Histologically, there are groups of seminiferous tubules in the tunica albuginea, sometimes accompanied by Leydig cells. In children, ectopic tubules appear normal (Fig. 12.87), whereas in adults they are usually slightly dilated (Fig. 12.88), although some tubules may be hyalinized. Serial sections reveal continuity with the intraparenchymatous seminiferous tubules. Ectopia of the seminiferous tubules is probably congenital, although it has been found in older men.905 It does not appear to be the result of trauma. The malformation probably arises in the sixth week of gestation, when the primordial sex cords have formed and are branching toward the gonadal surface, and the developing testes are covered by only one to three layers of coelomic epithelium. Later, the tunica albuginea forms around the sex cords and under the coelomic epithelium. Failure of insertion of the tunica albuginea between the sex cords and coelomic epithelium may entrap seminiferous tubules. Ectopia differs from testicular dysgenesis, a distinctive form of 46, XY DSD with m€ ullerian remnants. Numerous features characteristic of ectopic seminiferous tubules distinguish ectopia from other conditions, including normal thickness and collagenization of the tunica albuginea, absence of interstitial tissue resembling ovarian stroma (characteristic of testicular dysgenesis), and clear delimitation of

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Fig. 12.87 Testis from 2-month-old infant showing ectopic seminiferous tubules within the tunica albuginea in the upper testicular pole.

Fig. 12.89 Cluster of ectopic seminiferous tubules and Leydig cells in the wall of a hernia sac in an adult as an incidental finding.

Fig. 12.88 Ectopic seminiferous tubules in albuginea in an adult. Seminiferous tubules show ectasia, and ectopic tubules have markedly atrophic seminiferous epithelium.

Fig. 12.90 Ectopic seminiferous tubules in the wall of a hernia sac. Two clusters of seminiferous tubules with intense immunoexpression of inhibin. (Inset) androgen receptor immunoreactivity in Sertoli and Leydig cells of the ectopic cluster.

the tunica albuginea and testicular parenchyma (see discussion of Disorders of Sex Development (Dysgenetic testis), below). In a unique case, multiple clusters of seminiferous tubules and Leydig cells were present in the wall of a hernia sac that accompanied an undescended testis removed from an adult. The ectopic tubules were not surrounded by tunica albuginea and were like those in cryptorchid testicular parenchyma with only dysgenetic Sertoli cells (Fig. 12.89).906 Sertoli cells in the tubules expressed inhibin and ARs (Fig. 12.90). In another case, ectopic seminiferous tubules immunoreactive for inhibin were in the epididymis next to extratesticular rete testis (Fig. 12.91). These extratesticular seminiferous tubules were surrounded by loose stroma and seemed to be connected to the extratesticular rete testis.

Leydig Cell Ectopia Leydig cells occur normally in the testicular interstitium (interstitial Leydig cells) and in the wall of the seminiferous tubules (peritubular Leydig cells).375 However, clusters of cells are often observed in other locations in the testis, in the epididymis, or in the spermatic cord.907,908 In men the incidence rate is 40% to 90%.909

Inside the testis, ectopic Leydig cells may be found in the interlobular septa, rete testis, or tunica albuginea (Figs. 12.92 to 12.94), as well as within hyalinized seminiferous tubules.370,910–916a Intratubular Leydig cells are found only in tubules with advanced atrophy and marked thickening of the tunica propria, including the tubules in adult cryptorchid testes, those of men with Klinefelter syndrome, and in some other primary hypogonadisms (Fig. 12.95). Immunohistochemical studies suggest that the endocrine function of these Leydig cells is low.917 Several theories have been offered to account for these ectopic cells, including in situ differentiation, migration from the testicular interstitium, and trapping of peritubular Leydig cells in the tunica propria during its thickening and seminiferous tubule shortening in atrophy progression.917 The presence of small capillary vessels within the intratubular Leydig cell clusters would favor the last hypothesis. Leydig cells are commonly found in the epididymis, as well as in the spermatic cord, both in newborns and adults.910,918,919 Extratesticular Leydig cells usually form small groups within or adjacent to nerves (Fig. 12.96), present in 41% of autopsies.368,920,920a

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.91 Ectopic seminiferous tubules in epididymis. (Inset) Seminiferous tubules with prepubertal development showing immunoexpression for inhibin.

Fig. 12.92 Ectopic Leydig cells in an interlobular septum associated with nerve fibers.

Fig. 12.93 Ectopic Leydig cells around a nerve in albuginea.

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Fig. 12.94 Ectopic Leydig cells in the tunica vasculosa protruding inside a lymphatic vessel.

Fig. 12.95 Ectopic Leydig cells inside a hyalinized seminiferous tubule. This picture contrasts with that of the dysgenetic Sertoli cell–only tubule, which shows a patent basal membrane located between the dysgenetic Sertoli cells and the tubular wall.

Fig. 12.96 Ectopic Leydig cells inside and around a spermatic cord nerve. Ectopic Leydig cells are distinguished from neuronal ganglion cells by their smaller size.

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Extraparenchymal Leydig cells arise in more than 90% of orchiectomy specimens, and study of tissue microarrays found an incidence rate of 35%.847 Extratesticular location of Leydig cells is apparently common, and thus finding them depends only on the number of sections obtained. In most cases, these cells are in proximity to small nerves or even inside the nerves and vegetative nervous system ganglia.370 These cells, probably originating from in situ differentiation of Leydig cell precursors, express testosterone.908 Inhibin and calretinin are other useful immunohistochemical markers to enhance detection of ectopic Leydig cells. Calretinin is more sensitive but less specific than inhibin. Ectopic Leydig cells, both intratesticular and extratesticular, suffer the same atrophic and hyperplasic alterations as their eutopic counterparts, including disappearance during childhood. In older men and in those with chronic alcoholism, ectopic Leydig cells may show atrophic features, whereas in patients with hCG-secreting germ cell tumors, they show hyperplasia. The occurrence of ectopic Leydig cells in the tunica albuginea, epididymis, or spermatic cord may account for rare cases of Leydig cell tumor in these paratesticular structures.907 Ectopic Leydig cells should not be misinterpreted as tumor cells (infiltration or metastasis) when malignancy of a testicular Leydig cell tumor is suspected.

Adrenal Cortical Ectopia Adrenal cortical ectopia is a frequent finding outside of the testis, although it has also been observed inside. Ectopic adrenal cortex is the most frequent incidental finding in male urologic surgery.921 In a series of boys who underwent inguinoscrotal surgery the incidence rate of this finding varied from 3% to 3.8%.922,923 The frequency was higher (5.1%) in a series of children with cryptorchid testis who underwent more complete exploration of the spermatic cord.924 Most adrenal cortical ectopias are found in extratesticular locations such as the epididymis (Figs. 12.97 and 12.98), tunica albuginea, and hernia sacs (Fig.12.99).925,926 Macroscopically, ectopic adrenal tissue forms firm yellowish nodules, measuring 1 to 4 mm in diameter, spherical or ovoid, and sometimes umbilicated. The nodules are covered by a capsule, have three welldefined layers of adrenal cortex, and lack medulla. Adrenal ectopia represents aberrant adrenal tissue that has accompanied the testis in its descent.927

Fig. 12.98 Cortical adrenal ectopia surrounded by extratesticular rete testis cavities in a cryptorchid testis with immature and hyalinized tubules.

Fig. 12.99 Ectopia of adrenal cortex in the wall of a hernia sac in an adult. The ectopic adrenal tissue is surrounded by a thick capsule and still retains a radial structure.

Ectopia of cells similar to adrenal cortex may also be found inside the testis. Adrenal ectopia has been observed between the rete testis and adjacent seminiferous tubules, as well as in the parenchyma near the tunica albuginea.928–930 Adrenal ectopic nodule may be solitary or multiple. Cytomegalic cells have been observed in newborns with adrenal cytomegaly, both in patients with Beckwith-Wiedemann syndrome and in isolated cases of adrenal cytomegaly (Fig. 12.100). The origin of these intratesticular nodules may be pluripotential testicular hilus steroid cells.931,932 Intratesticular nodules may undergo hyperplasia, thus causing testicular enlargement that suggests a tumor in two disorders: adrenogenital syndrome and Nelson syndrome (see later).

Fig. 12.97 Ectopia of adrenal cortex in the epididymis in a newborn. The adrenal cortex nodule is the same size as the caput of the epididymis.

Other Ectopias Other rare forms of ectopia are found within and outside the testis. Osseous and adipose tissue and ectopic ductus epididymis may be formed within the testis. Extratesticular ectopia includes splenic ectopia (splenogonadal fusion), hepatic ectopia (hepatotesticular fusion), and renal blastema ectopia.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.100 Intratesticular adrenal cortical ectopia next to the rete testis in a boy. Adrenal-like cells show cytomegalic changes.

Cartilaginous heterotopia, which may appear as small immature cartilage nodules in the caput of the epididymis, has been attributed to metaplasia of metanephric rests. Osseous heterotopia (testicular osteoma, stone in the testicle, testicular calculus) is a rare type of metaplasia that occurs in areas of the parenchyma with fibrosis. It is possible that some cases are secondary to prior tuberculosis, hematoma resorption, or traumatic injury. In some cases, such lesions cannot be distinguished from a tumor, prompting orchiectomy (Fig. 12.101).933–936 Reported cases and our own observations reveal that osseous metaplasia manifests as hard intraparenchymatous nodules that vary from a few millimeters to several centimeters. These nodules consist of compact osseous tissue surrounded in all cases by cholesterol clefts and a fibrous pseudocapsule. They probably represent a metaplastic process in response to testicular trauma or damage. Adipose metaplasia is frequent in undescended testes and older men. Adipose cells are preferably located in the proximity of the rete testis (Fig. 12.102). Adipocytes are frequently found at the periphery of intratesticular adrenal cortical tumors and in some Leydig cell tumors.937 Testicular lipomatosis is associated with

Fig. 12.101 Osseous metaplasia in an ischemic testis. Compact osseous tissue is surrounded by hyalinized seminiferous tubules and absence of Leydig cells.

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Fig. 12.102 Adult cryptorchid testis showing metaplastic fat cells between the seminiferous tubules and the rete testis.

Cowden syndrome (usually bilateral), Proteus syndrome, and Bannayan-Riley-Ruvalcaba syndrome.938 These syndromes, together with adult Lhermitte-Duclos disease and autism spectrum disorders associated with macrocephaly, collectively form the PTEN hamartoma tumor syndrome (PHTS), which is related to PTEN gene mutations.939 Intratesticular lipomatosis associated with these syndromes is visualized by ultrasound as multiple bilateral hyperechoic lesions.940,941 Given the rarity of intratesticular lipoma, the presence of lipomatosis may be an indicator of underlying PTEN mutation.942 Intratesticular and paratesticular mesonephric remnants. Most of the structures derived from embryonic remnants (testis and epididymis hydatids, aberrant upper and lower ducts, the Giraldes organ) have a specific location and are well-known wolffian or m€ ullerian derivatives. However, in systematic study of surgical specimens of testis, epididymis, spermatic cord, and hernial sacs, glandular or tubular formations may frequently be found that are reminiscent of the epididymis but may be misinterpreted as either normal structures of the spermatic pathways or, more significantly, as primary or secondary neoplasm. These mesonephric remnants may be found in other parts of the urogenital tract, including the kidney, renal pelvis, prostate, prostatic urethra, and paratesticular and intratesticular regions.943 Histologically, mesonephric remnants have variable patterns, ranging from small acini or tubules lined by low columnar epithelium with or without colloid type material inside. They resemble both histologically and immunohistochemically the efferent ducts, the main duct of the epididymis or the vas deferens, but differ by smaller size and absence of a well-structured muscular cell layer.944 Mesonephric remnants in the spermatic cord are the most frequent and are observed in 28% of cords at autopsy. Most are incidental, but some present clinically as cystic structures with or without papillary formations.945 Most glandular inclusions in the wall of hernial sacs represent mesonephric remnants, with an incidence rate of 1.5% to 6%. Less frequent is the presence of mesonephric remnants in the testicular tunic, where these remnants, whose epithelium usually resembles that of efferent ducts, may produce cysts in the tunica albuginea.946 Even rarer is the appearance of remnants inside vestigial structures of m€ ullerian origin, as is the case of aberrant epididymal tissue reported in a testicular hydatid.947,948

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Intratesticular mesonephric remnants are of special interest with respect to histogenesis and because they may be confused with neoplasm. Intratesticular structures reminiscent of efferent ducts or the main epididymal duct were found bilaterally in 5 of 1442 autopsies, and in 1 patient from a series of 271 orchiectomies.949 Patient age ranged from 69 to 75 years. In autopsy cases, both testes were shrunken. The lesion was found in an orchiectomy specimen from a 67-year-old with suspected testicular tumor. The testicles showed multiple whitish areas located in the central part, as well as near the rete testis and under the tunica albuginea. Most of the mesonephric remnants corresponded to epididymis-like or efferent ductile-like structures. The luminal size varied from that of seminiferous tubules to cystic formations. Interiorly, there was granular or fibrillar PAS+ eosinophilic material with microcalcifications and Liesegang rings. A muscular layer surrounded most of the formations. Frequently the intratubular material was extravasated, triggering a minimal inflammatory reaction. The number and extent of these formations was so great in the reported orchiectomy specimen that in comparison with remnants observed in other organs, one could speak of florid hyperplasia of intratesticular mesonephric remnants. In most testes the adjacent parenchyma had large areas of tubular hyalinization, likely of ischemic origin (Figs. 12.103 through 12.105). The differential diagnosis includes teratoma and burned-out germ cell tumor, but the distinction is not difficult. The location of these epididymal-like tubular formations within the parenchyma is difficult to explain from an embryologic point of view. Such displacement would have to occur at an early stage, before differentiation of the albuginea by AMH secreted by the Sertoli cells. Mesonephric cords would be trapped between nests consisting of pre–Sertoli and germ cells. An alternative hypothesis is metaplastic change in Sertoli cells.

Fig. 12.104 Transverse section of an adult testis showing two tubular formations with characteristics of epididymal duct (pseudostratified epithelium with stereocilia) surrounded by seminiferous tubules with decreased spermatogenesis.

Undescended Testes Testicular descent is not always complete at birth, and approximately 3% of full-term newborns have incompletely descended testes. Most of these testes descend within 3 months, and only 1% of infants have incompletely descended testes 12 months after birth. Fig. 12.105 Ectopic epididymal-like formation showing positive CD10 expression in adluminal border and stereocilia.

Spontaneous testicular descent is exceptional after the first year. In recent decades there has been a significant increase in the incidence of cryptorchidism.950 Only 5% of patients with impalpable testes are devoid of testes. Other causes include true cryptorchidism, testicular ectopia, and retractile testes.951 True cryptorchidism includes abdominal, inguinal, and high scrotal testes that cannot be moved to the scrotum on physical exploration.482 Ectopic testes are those located out of the normal path of testicular descent, most frequently in the superficial inguinal pouch. Other rare locations of ectopia include the abdominal wall, upper thigh, perineum, and base of the penis. Retractile testes may be moved to the scrotum at exploration and account for approximately one-third of clinically diagnosed undescended testes.

Fig. 12.103 Intratesticular mesonephric remnants. Much of the testicular parenchyma is replaced by tubular formations showing cystic transformation, eosinophilic material, and intratubular and extratubular calcifications.

True Cryptorchidism Patients with true cryptorchidism account for approximately 25% of cases of empty scrotum. These testes most frequently are found in the inguinal canal or upper scrotum; arrest within the abdomen

CHAPTER 12 Nonneoplastic Diseases of the Testis

is less frequent and accounts for only 5% to 10% of cases. Cryptorchidism is slightly more frequent on the right side than on the left (46% versus 31%, respectively), and in approximately 23% of cases is bilateral.952 Family history of cryptorchidism is present in 14%.953,954 Cryptorchid testis is usually smaller than the contralateral one, and this difference is often discernible at 6 months of age.955 One-third of cryptorchid testes are soft. Etiology

The causes of testicular maldescent are probably multiple and have not been fully elucidated. Several conditions are predictive of high risk for cryptorchidism, including increased maternal age, maternal obesity, pregnancy toxemia, bleeding during late pregnancy, exposure to phthalates, alcohol consumption and smoking, tall stature, paternal subfertility antecedents, cesarean birth, low birth weight, preterm birth, twin birth, hypospadias, other congenital malformations, and birth from September to November, as well as May to June.956–958 Of these associations, low birth weight seems to be the most important.959 Cryptorchidism may be congenital or acquired. Congenital Cryptorchidism. This type of cryptorchidism is mainly caused by anomalies of development or hormonal mechanisms involved in testicular descent (see earlier). Impalpable undescended testes are infrequent because the transabdominal phase follows the simple mechanism of relative movement of the testis. Conversely, palpable undescended testes are more frequent because the second phase of testicular descent is more complex. Unilateral cryptorchidism may be caused by androgen failure, which leads to either an ipsilateral lesion in the development of GFN neurons or defect in CGRP release that hinders normal migration of the gubernaculum.960 Acquired Cryptorchidism. Normally descended testis may become cryptorchid and may even settle in the abdominal cavity.961 Acquired cryptorchidism has a prevalence rate of 1% to 7% and peaks at approximately 8 years of age.962 Two categories of acquired undescended testis have been described: postoperative trapped testis and spontaneous ascent from unknown causes. Postoperative trapped testis is a normally descended testis that leaves the scrotal pouch after surgery for inguinal hernia or hydrocele.963–965 This iatrogenic cryptorchidism occurs in 1% of children after herniotomy. Adherence of the testis or the cremasteric muscle to the surgical incision causes testicular ascent when the incision heals and undergoes retraction. Various mechanisms have been proposed for spontaneous ascent from unknown causes, including inability of spermatic blood vessels to grow adequately, anomalous insertion of the gubernaculum and reabsorption of the vaginal process, failure in postnatal elongation of the spermatic cord, and prenatal and postnatal androgen disruption because boys with severe hypospadias are at increased risk for acquired and retractile testes.966–973 The spermatic cord measures 4 to 5 cm at birth and reaches 8 to 10 cm by 10 years of age. This growth does not occur if the peritoneal-vaginal duct becomes a fibrous remnant. The cause may be a defect in postnatal CGRP release by the GFN.960,974,975 Acquired undescended testis spontaneously descends at puberty in 78% of cases.976 Pathogenesis

Testicular maldescent has multiple causes, including anatomic anomalies of the gubernaculum testis, hormonal dysfunction (hypogonadotropic hypogonadism), mechanical impairment (insufficient intraabdominal pressure, short spermatic cord, underdeveloped processus vaginalis), dysgenesis (primary anomaly of the

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testis), neuromuscular conditions (CGRP and cremaster nucleus), genetic factors (mutations in INLS3 or its receptor), and other hereditary or acquired conditions.977–979 Most cases of cryptorchidism likely appear to be caused by a deficit of fetal androgens or an excess of maternal estrogens. Androgen insufficiency seems to be slight and transient because anomalies other than hypoplasia of the epididymis are not seen.142 It may result from deficient gonadotropic pituitary stimulation or low production of placental gonadotropins. Elevated maternal estrogens could cause diminution of FSH secretion by the fetal pituitary, thus leading to low Sertoli cell proliferation, and could create decreased testosterone production because of the inhibitory effect of estrogens on Leydig cells.980,981 Three mechanisms seem to be involved in this process: • Primary testicular anomaly. Cryptorchid testes may bear an anomalous germ cell population.982 More than 40% of cryptorchid patients have a marked decrease in the TFI, even with nearly normal numbers of spermatogonia; these cells also have abnormal DNA content.239,983 • Lesions secondary to transient perinatal hypogonadotropic hypogonadism. Cryptorchid patients do not have gonadotropin elevation, which normally occurs between 60 and 90 days after birth, and this deficiency of LH could cause Leydig cell involution. Subsequent androgen deficiency could account for failure of gonocytes to differentiate into spermatogonia.984–986 • Injury caused by increased temperature. This was suggested in the past based on animal studies. In follow-up biopsies from testes that were descended surgically or with hormonal treatment, the sole factor that improved during childhood was tubular diameter. Diameter depends on Sertoli cells, so temperature may be more important for Sertoli cells than for spermatogonia.239 The most frequent findings in congenital and acquired cryptorchidism in infancy are decreased germ cell numbers and diminished tubular diameter.987,988 In the normal testis, transient formation of spermatocytes occurs at 4 to 5 years of age. This meiotic attempt is probably an androgenic event that does not occur in cryptorchid testes and corresponds to the characteristic low numbers of spermatogonia in the prepubertal age.989 Histology Prepubertal Testes: Morphologic Classification. Undescended

testis is usually smaller than contralateral, descended testis, a difference that is already significant at 6 months of age.955,990 However, no functional studies have revealed the existence and severity of congenital lesions in cryptorchid testes. Numerous biopsy studies of cryptorchid testes in the first years of life have been conducted, but no agreement exists about the severity of damage or time of onset.989,991,992 The presence of lesions in the first year of life in most suggests that they are primary rather than acquired as a consequence of long-standing cryptorchidism. One should not forget that the testis is a dynamic structure, with waves of proliferation and differentiation from birth to puberty. Moreover, the parameters usually applied to studies of the adult parenchyma should not be used for the prepubertal testis.709 The pathologist should evaluate both semiquantitative and qualitative parameters to obtain as much information as possible from histologic study of biopsies from undescended testes. Semiquantitative morphometric parameters include MTD, TFI, number of germ cells per cross-sectioned tubule, Sertoli cell index (SCI), and number of Leydig cells in the interstitium. Qualitative findings include the pattern of germ cell distribution in the parenchyma (regular or irregular), abnormal spermatogonia

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TABLE 12.15

Nonneoplastic Diseases of the Testis

Classification of Histologic Lesions in Prepubertal Cryptorchid Testis According to Morphometric Parameters

Type of Lesion (Incidence Rate)

MTD

TFI

SCN

Spermatogonia Distribution

Type I (31%) Type II (29%) Type III (40%)

Slightly decreased (90% normal values) Markedly decreased (60%–90% normal values) Severely decreased (<60% normal values)

>50% 30%–50% 0%–30%

Normal Decreased Low

Regular Irregular Irregular

MTD, Mean tubular diameter; SCN, Sertoli cell number (average Sertoli cell number per cross-sectioned tubule); TFI, tubular fertility index (percentage of tubules containing germ cells).

(multinucleated, hypertrophic, or atypical), focal granular changes in Sertoli cells, abnormal tubules (megatubules, ring-shaped tubules), microliths, and ARs in children who are older than 4 years. Based on the evaluation of four parameters (TFI, MTD, SCI, and the spermatogonial distribution pattern), most testicular biopsies from cryptorchid testes of children may be classified into one of three groups (Table 12.15).239 • Type I (testes with slight alterations) (about 31% of cases). TFI is higher than 50, and MTD is normal or slightly (<10%) decreased (Fig. 12.106). • Type II (testes with marked germinal hypoplasia) (about 29% of cases). TFI is between 30 and 50, and MTD is 10% to 30% lower than normal. The spermatogonia are distributed irregularly, and most are in tubular sections that are grouped in the same testicular lobule (Fig. 12.107).993 • Type III (testes with severe germinal hypoplasia) (about 40% of cases). TFI is less than 30, and MTD is less than 30% of normal. Many spermatogonia are giant with dark nuclei (Fig. 12.108). The testicular interstitium is wide and edematous. The seminiferous tubules of testes with type II or III lesions have a thickened lamina propria during childhood and, at puberty, Sertoli cell hyperplasia, and more than 30% of these testes have microliths (Fig. 12.109), ring-shaped tubules, and granular changes in Sertoli cells (Fig. 12.110).991 Intense immunoexpression for inhibin is observed in Sertoli cells in all types of cryptorchid testes (Fig. 12.111). Patients with bilateral cryptorchidism have a higher incidence of type II and III lesions than those with unilateral cryptorchidism. Approximately 8% of testes with type I lesions

contain many multinucleated spermatogonia (with three or more nuclei; Fig. 12.112), and both KIT expression and PLAP expression persist in approximately 5% of immature germ cells.994 Type I lesions are comparable with those seen in experimental cryptorchidism: normal testes in which lesions are induced by increased temperature.992 Testes with type II or III lesions bear

Fig. 12.106 Cryptorchidism. Seminiferous tubules with type I lesions show slightly decreased diameters and a normal tubular fertility index.

Fig. 12.108 Cryptorchidism. Seminiferous tubules with type III lesions show severe reduction in both tubular diameter and tubular fertility index.

Fig. 12.107 Cryptorchidism. Seminiferous tubules with type II lesions show markedly decreased diameters and an irregular distribution of germ cells.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.109 Microlithiasis in an infant cryptorchid testis. The seminiferous tubules show type III lesions and contain numerous microliths.

Fig. 12.110 Cryptorchidism. Type III lesions, in which the interstitium is expanded by edema. The cytoplasm of the Sertoli cells contains numerous eosinophilic granules of variable size.

variable degrees of dysgenesis that, in addition to germ cells, involves Sertoli cells, peritubular myofibroblasts, and Leydig cells. The dysgenesis of these other cell types is evident only after puberty and is more severe in intraabdominal testes.995,996 In approximately 25% of cases the contralateral scrotal testis also has histologic lesions of variable severity. This finding supports the hypothesis of bilateral defect in many cases of unilateral cryptorchidism. Microdeletions in the long arm of Y-chromosome genes (DAZ, RBM, [azoospermic factor] AZFa, b, and c) are not increased in cryptorchidism.997 Unilateral cryptorchidism with normal contralateral testis may result from end-organ failure.998 In cryptorchidism secondary to spontaneous ascent, lesions are like those of congenital cryptorchidism, whereas in cryptorchidism secondary to herniotomy, germ cell depletion is slight and becomes important only after 5 years of age.999–1001 Pubertal and Adult Testes. Most pubertal and adult cryptorchid testes have anomalies in all testicular structures. During puberty, undescended testes show severe maturation delay in both

605

Fig. 12.111 Cryptorchidism. Slightly tortuous seminiferous tubules with decreased diameter showing intense immunoexpression of inhibin. Only one germ cell may be seen at the left lower corner.

Fig. 12.112 Prepubertal cryptorchid testis. The seminiferous tubules have Sertoli cells with elongate nuclei, pseudostratified growth pattern, and isolated spermatogonia, some of which are multinucleate or contain hypertrophic nuclei.

tubular and interstitial components (Fig. 12.113).246 Seminiferous tubules display apparent Sertoli cell hyperplasia as a result of failure in lengthening and coiling of the seminiferous tubule during pubertal development, and tubules also have decreased diameter and delayed germ cell proliferation when these cells are present. Frequently, as puberty progresses, testicular development is irregular, varying from one lobule to another. Seminiferous tubules that have initiated spermatogenesis are adjacent to other tubules showing prepubertal maturative pattern. Careful study reveals a delay in Sertoli cell maturation, estimated by nuclear morphology. Irregular expression of ARs is found in these Sertoli cells (Fig. 12.114).880 Tubules with a prepubertal pattern also show delayed maturation in mural myofibroblasts, which are unable to express musclespecific actin. Surgically removed cryptorchid testes from adults reveal that most have histologic lesions in all structural components and the rete testis and epididymis. Seminiferous tubules have decreased

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Fig. 12.113 Pubertal cryptorchidism. Testis from 12-year-old boy showing irregular maturation of the parenchyma. Tubular diameter and Sertoli cell maturation varies from one to another area. interstitium shows scarce Leydig cells.

Fig. 12.115 Adult ex-cryptorchid testis that was surgically descended at the age of 2 years. Tubular sections show a pattern varying from spermatogonial maturation arrest to complete, although decreased, spermatogenesis.

Fig. 12.114 Pubertal cryptorchidism. Testis from 12-year-old boy showing a correlation between Sertoli cell delayed maturation and androgen receptor immunoexpression. Central area shows lower androgen receptor immunoexpression than surrounding areas.

Fig. 12.116 Adult ex-cryptorchid testis that was surgically descended at infancy. Seminiferous tubules with spermatogonial maturation arrest and dysgenetic Sertoli cells adjacent to hypoplastic seminiferous tubules lined by tall Sertoli cells with granular changes in their cytoplasm.

diameters and deficient spermatogenesis. In decreasing order of frequency, the most common germ cell lesions are tubules with a Sertoli cell–only and spermatogonia-only pattern, tubules with Sertoli cells (dysgenetic) only, tubular hyalinization, and MAT. The lamina propria has scant elastic fibers, as well as irregular deposits of collagen IV and laminin in the basal lamina.995,1002 Peritubular myoid cells in experimental cryptorchidism show disorganization of actin filaments.1003 Sertoli cells are present in greater number and do not mature normally except in tubules with germ cells (Fig. 12.115).246,993 In tubules with advanced spermatogenesis, the morphology of Sertoli cell nuclei is normal.1004 In addition to being immunoreactive for vimentin, similar to normal adult Sertoli cells, the dysgenetic Sertoli cells in Sertoli cell–only tubules immunoexpress cytokeratins and desmin in the basal cytoplasm. These immunoreactions are also positive in intraluminal accumulations of sloughed Sertoli cells.1005 Often, groups of tubules containing only Sertoli cells with a prepubertal pattern (small

diameter and total absence of maturation) may be found and are considered hypoplastic (showing a small lumen and a thick wall lined by a tall columnar epithelium, formed only by Sertoli cells of eosinophilic cytoplasm) (Fig. 12.116), dysgenetic, or hamartomatous; seminiferous tubules with granular changes in Sertoli cells may also be present.1006 Areas of apparent Leydig cell hyperplasia are frequent (Fig. 12.117), and many of these cells contain vacuolated lipid-laden cytoplasm (Fig. 12.118). The rete testis is hypoplastic in most cases, lined by columnar epithelium with rare areas of flattened cells. Cystic dilation is common, and adenomatous hyperplasia may be present.1007 Most cryptorchid testes, and especially those with Sertoli cell–only tubules, contain underdeveloped rete testis whose epithelium has not differentiated between squamous and columnar cells (conversely to what normally occurs during puberty), retaining an infantile pattern referred to as “dysgenetic” (Fig. 12.119). Near the rete testis, the parenchyma frequently contains metaplastic

CHAPTER 12 Nonneoplastic Diseases of the Testis

607

fat. In some cryptorchid testes, several tubular segments are destroyed by inflammation that probably has an autoimmune cause (focal orchitis).1008 Epididymal tubules are poorly developed, and peritubular tissue is immature. Needle aspiration biopsy of the normally descended contralateral testis shows a variety of histologic patterns, varying from normal to with alterations like those of cryptorchid testes.1009 This variability is probably related to the cause of cryptorchidism. Bilateral lesions suggest congenital or genetic cause, whereas normal contralateral testis suggests local anatomic anomalies.1010 Validation of the Morphologic Classification of the Prepubertal Undescended Testes Lesions

Fig. 12.117 Nodular Leydig cell hyperplasia in an adult ex-cryptorchid testis.

Fig. 12.118 Contralateral testis of an adult ex-cryptorchid patient with infertility. Spermatogenesis is complete. Leydig cells are increased in number and show intense cytoplasm vacuolization with a signet ring morphology.

Fig. 12.119 Undescended testes of an adult. In the panoramic view a hypoplastic rete testis and enlarged interlobular walls may be observed.

Study of serial sections of bilateral testicular biopsies allow comparison of histologic findings in boys with cryptorchidism at the time of orchidopexy and in adulthood (performed for evaluation of infertility).1011 One report described diffuse and complete spermatogenesis in such testes with higher TFI (normal testes and those with type I lesions) in more than two-thirds of cases, accompanied by a quantitatively abnormal number of germ cells; MAT developed in the other one-third of cases.993 MAT is defined as synchronous occurrence of tubules containing germ cells (with variable degrees of spermatogenesis) and Sertoli cell–only tubules (Fig. 12.120).1012 All testes with type II lesions and 85% of those with type III lesions experience development of MAT, indicating that MAT is the most frequent lesion (68%) in adult excryptorchid patients presenting with infertility (Table 12.16). In most patients with unilateral cryptorchidism, MAT is observed in both the undescended testis and contralateral descended testis, even if the surgical correction occurred at an early age. There is an inverse correlation between severity of the lesions in childhood and amount of spermatogenesis in adulthood. Approximately 85% of adult testes with type III lesions in infancy experience MAT, with spermatogenesis in less than 50% of tubules; another 5% develop hypospermatogenesis and spermatocyte I sloughing; and the remaining 10% have Sertoli cell–only tubules. Patients whose prepubertal testes had clustering of germ cell–containing tubules usually had incomplete spermatogenesis in adulthood, and when

Fig. 12.120 Adult ex-cryptorchid testis that was surgically descended at infancy showing mixed atrophy. Most seminiferous tubules contain only Sertoli cells. The remaining show complete spermatogenesis, although quantitatively decreased.

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TABLE 12.16 Type of Lesion Type I

Type II Type III

Nonneoplastic Diseases of the Testis

Postpuberal Evolution of the Lesions in Testes Descended in Infancy

Postpubertal Testicular Pathology Adluminal compartment lesions (57%) Mixed testicular atrophy (29%) Basal and adluminal compartment lesions (14%) Mixed testicular atrophy (100%) Mixed testicular atrophy with <50% tubules with spermatogenesis (85%) Sertoli cell–only tubules (10%) Hypospermatogenesis + spermatocyte I sloughing (5%)

spermatogenesis was complete, it occurred in less than 50% of tubules.1011 Sperm excretory duct anomalies occur in 9% to 36% of cryptorchid patients.1013–1015 These anomalies may cause obstruction of the excretory ducts, so biopsies may also reveal an obstructive pattern superimposed on the seminiferous tubule lesions. In summary, the classification of testicular lesions in childhood into three types (I, II, and III) correlates with the amount of spermatogenesis found in postpubertal biopsies. The most important parameter is TFI. Spermatogenesis may also be impaired by an obstructive process that is complete or incomplete, and functional or organic. Biopsy allows adequate evaluation of congenital or obstructive lesions, and detects testes with focal spermatogenesis to establish the possibility of treatment with assisted reproductive techniques. Effectiveness of Treatment in Undescended Testes

Optimal treatment of undescended testis is controversial. The European Association of Urology recommends mandatory surgical treatment in infancy; patients with palpable inguinal cryptorchid testes should undergo orchidopexy within 1 year and no later than 2 years of age.1016–1020 The Nordic Consensus statements recommend anticipating orchidopexy as early as the first 6 to 12 months of life.1021 Surgical treatment benefits all patients with primary cryptorchidism and retractile testis, even those whose testes are surgically descended at an older age.1022 The efficacy of hormonal treatment after orchidopexy remains controversial. Results are contradictory because great variations in the effects of hormonal treatment have been reported. Whereas use of hCG and GnRH in the treatment of cryptorchidism was found effective in some cases, it was useless in others.1021,1023–1025 Metaanalysis showed that approximately 15% to 20% of retained testes descend during hormonal treatment, although one-fifth subsequently reascend. Moreover, treatment with hCG increases germ cell apoptosis, with subsequent damage to future spermatogenesis.1026 Testicular biopsy is the only sure method for identification of cryptorchid boys who need hormonal treatment with luteinizing hormone-releasing hormone (LHRH) after successful surgery; consequently, some advocate mandatory biopsy during orchidopexy.1027 Neonatal gonocytes transform into type A spermatogonia at 3 to 12 months, and this process is disrupted in undescended testes, although there is a chance of reversal by orchidopexy at an early age. The presence of Ad spermatogonia at surgery is an excellent prognostic parameter for future fertility. Cryptorchid boys who lack these cells experience infertility despite successful orchidopexy at an early age.1024 In those whose testes

contain a low number of Ad spermatogonia and suboptimal response to hCG stimulation, hormonal treatment is advised to increase the number of germ cells. It is uncertain whether different modalities and periods of hormonal therapy in patients with impaired Leydig cell response can improve histologic features prognosis for future fertility.1028,1029 In childhood the chance of detecting occult cancer or precancer by biopsy is low because intratubular germ cell neoplasia is not diffusely distributed throughout the testis. Nonetheless, testicular biopsy should be performed in all patients with intraabdominal testes, abnormal external genitalia, or abnormal karyotype.1030 Autotransplantation has been used in some patients with high intraabdominal testes as an alternative to the Fowler-Stephens technique.1031–1033 These testes represent approximately 5% of all undescended testes.1034 Histologic studies performed after autotransplantation reveal evidence of Leydig cell development, tubular diameter increase, and spermatogenetic development, although paternity has not been reported.1035,1036 Congenital Anomalies Associated With Undescended Testes

Most cryptorchid patients have a patent processus vaginalis, and 65% to 75% have a hernia sac, although most hernias are not clinically visible.445 Urologic anomalies are present in 11%, the most frequent being hypospadias, complete duplication of the urinary tract, nonobstructive ureteral dilatation, kidney malrotation, and posterior urethral valves.1037 Cryptorchidism is more frequent in those with microcephaly, myelomeningocele, bifid spine, omphalocele, gastroschisis, micropenis, imperforate anus, and cloacal exstrophy.1038–1041 The incidence of sperm excretory duct anomalies is high in patients with undescended testes, and these anomalies involve both the intratesticular and extratesticular ducts. Dysgenesis of the rete testis is observed in more than 80% of adult undescended testes.1042 The incidence of extratesticular spermatic duct anomalies varies from 9% to 79%.482,1013,1043–1048 Sperm excretory duct anomalies are classified into three types1014: • Ductal fusion anomalies (25% of cases). These consist of anomalous fusion of the caput of the epididymis to the testis or segmental atresia of the epididymis and vas deferens. This category is chiefly associated with intraabdominal or high scrotal cryptorchid testes. • Ductal suspension anomalies (59% of cases). The caput of the epididymis is attached to the testis, whereas the corpus and the cauda of the epididymis are separated from the testis by a mesentery. A variant consists of excessively long cauda of the epididymis that descends along the inguinal duct to the scrotum (Fig. 12.121). • Anomalies associated with absent or vanishing testes (16% of cases). The ductuli efferentes and the ductus epididymidis of cryptorchid patients show evidence of abnormal development from infancy. Remarkably, epithelial cell height of both types of ducts is low, and the muscular wall is poorly developed. In adults, ductuli efferentes show an inner circular outline instead of the wavy outline that is characteristic of normal caput of epididymidis, reflecting different epithelial cell heights.1049 Incomplete development of the muscular wall suggests that propulsion of testicular fluid is compromised, resulting in stasis of ductuli efferentes, rete testis, and even seminiferous tubules. Patent vaginal process is associated with epididymal anomalies, regardless of the location of the cryptorchid testis, with an incidence rate as high as 80%, compared with only 5% in those with descended testes with a closed vaginal process.1050

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Fig. 12.121 Undescended testicle of a 3-year-old boy with marked enlargement of the interstitium showing small tortuous seminiferous tubules. Epididymis is elongate with hypoplasia of the caput and separation of the body and tail of the epididymis from the testis.

Anomalies of the gubernaculum are also frequent in cryptorchidism. Comparative studies between normal fetuses and cryptorchid infants reveal differences in the union of the gubernaculum to the testis and epididymis (72% vs 99% incidence rate, respectively). The gubernaculum is joined exclusively to the testis (the cauda epididymis is free) in 22% of cryptorchid testes and in 1% of normal fetal testes. The gubernaculum is joined exclusively to the cauda epididymis in 6% of cryptorchid testes, whereas this condition is not observed in normal fetuses.1051 Another anomaly is the occurrence of short spermatic vessels that hinder testicular descent. This is a frequent finding in cryptorchid testes with type III lesions and, to a lesser extent, in those with type II lesions. This observation further supports the dysgenetic nature of these testes.1052 Many unfavorable results obtained after surgical descent of these testes may be explained by ultrasonographic images that reveal anomalies associated with undescended testes.1053 Cryptorchidism may be isolated, or is often be associated with congenital, endocrine, or chromosomal disorders, as well as with disorders in sexual differentiation.1054,1055 Cryptorchidism may occur in patients with GnRH deficit; Kallmann, Prader-Willi (PWS), Klinefelter, Noonan, Smith-Lemli-Opitz (SLOS), Aarskog-Scott, Rubinstein-Taybi, prune belly (Fig. 12.122), Cornelia de Lange, and caudal regression syndromes; testicular feminization syndromes caused by AR anomalies such as 5α-reductase deficiency (an enzyme required for conversion of testosterone to DHT); several types of undermasculinization caused by AMH absence; DiGeorge syndrome; Beckwith-Wiedemann syndrome; CHARGE association; and trisomies 13, 18, and 21. The association of impalpable testes with hypospadias suggests a disorder of sexual differentiation (this suggestion was confirmed in 27% to 30% of cases).1056–1058 Cryptorchidism is part of the testicular dysgenesis syndrome, first described in 2001.1059–1063 This syndrome consists of a spectrum of male reproductive disorders with a range of clinical presentations, including abnormal testicular development that predisposes to cryptorchidism, hypospadias, spermatogenetic alterations, and testicular cancer. The association of these disorders with cryptorchidism has been corroborated by numerous clinical, epidemiologic, and genetic studies. The least severe form of this syndrome is defect in spermatogenesis; the most severe is testicular cancer.

Fig. 12.122 Prune belly syndrome in a boy with the triad: renal dysplasia, megaureter-megabladder, and bilateral cryptorchidism.

A constellation of histologic lesions is common in the testes of men with testicular dysgenesis, including Sertoli cell–only pattern, MAT, hypoplastic tubules (Sertoli cell nodules), testicular microlithiasis, malformed tubules, granular changes in Sertoli cells, nodular Leydig cell hyperplasia, and GCNIS. It is assumed that the lesions develop prenatally as a result of several genetic, environmental, or endocrine disruptor factors that would interfere with the estrogen-to-androgen ratio and possibly lead to disruption of Sertoli or Leydig cell function.1063–1066 The initial disorder is probably an imbalance between estrogens and androgens during fetal life related to increased estrogen exposure in utero.1067 Exposure to environmental toxins, acting as endocrine disruptors, could disrupt fetal sexual differentiation by an estrogenic or antiandrogenic effect.1068 Various environmental chemicals may alter endogenous levels of androgens (certain phthalates) and estrogens (polychlorinated biphenyls, polyhalogenated hydrocarbons).980,1069,1070 Estrogens may induce cryptorchidism and hypospadias by suppressing androgen production or action, or by suppressing INLS3.1064–1066,1071,1072 Although testicular dysgenesis syndrome still raises many questions of epidemiology and pathogenesis, it is accepted as a single unifying hypothesis, particularly when so little is known of etiology.1073–1075 Complications of Cryptorchidism

The main complications of cryptorchidism are testicular cancer, infertility, testicular torsion, and psychological problems derived from an empty scrotum.1076 Testicular Cancer. Approximately 1% of 1-year-olds have cryptorchidism, and approximately 10% of patients with testicular cancer had cryptorchidism. Cancer risk of undescended testis is 6.3

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versus 1.7 of the contralateral testis by metaanalysis.1077 The risk for testicular cancer in cryptorchid boys and men is 4 to 10 times higher than that of the general population.1078,1079 Cancer risk in abdominal testes is six times higher than that of other cryptorchid testes in an inferior location.1080,1081 Testes with an elevated number of multinucleated spermatogonia have a higher risk for cancer during adulthood.994 The risk increases when cryptorchidism is bilateral and associated with external genitalia anomalies or chromosomal anomalies such as 45,X/46,XY.1082 Approximately 5% of biopsies in children contain cells similar to those seen in GCNIS, although possible evolution to invasive malignancy remains a subject of controversy (Fig. 12.123).1083,1084 The presence of GCNIS may be missed in infancy because in the prepubertal testis atypical gonocytes may not be located directly on the basal lamina; instead, these gonocytes may be present in the center of the tubules, and their number may be low.1085 Approximately 2% to 3% of adult cryptorchid testes have evidence of GCNIS, and the most frequent tumor in these patients is seminoma.1086–1089 Regardless of timing, orchidopexy does not reduce the risk for cancer, although it facilitates early detection because the intrascrotal testis is palpable.1090 Twenty percent of testicular tumors arise in properly descended testes contralateral to cryptorchid testes; this finding suggests a primary bilateral testicular anomaly in cryptorchidism. Intraabdominal testes also have a higher incidence of tumors, with a similar prognosis.1080–1087,1089–1091 Infertility. Infertility is the most frequent problem caused by cryptorchidism. In a series of patients with infertility, almost 9% had cryptorchidism (Fig. 12.124).1092 Hormonal serum levels in ex-cryptorchid patients show high levels of FSH, normal LH, and low testosterone.1093 Infertility is influenced by several factors, including bilaterality, number of germ cells, location and size of the testis, germ cell distribution, anomalous DNA content in germ cells, Leydig cell dysfunction, congenital anomalies of sperm excretory ducts, and possible iatrogenic injury to the testes, epididymis, ductus deferens, or spermatic cord during orchidopexy.1094 The most important risk factors are bilaterality and germ cell number; 16% to 25% of men with bilateral cryptorchidism have

Fig. 12.123 Adult ex-cryptorchid testis that was surgically descended at infancy. The patient was infertile. The smallest seminiferous tubule shows intratubular germ cell neoplasia, undifferentiated type. The relative tumor cell homogeneity contrasts with the variety in shape and size of the cells in the adjacent seminiferous tubule with complete spermatogenesis.

Fig. 12.124 Ex-cryptorchid testicle of an adult patient. The albuginea is thin. The seminiferous tubules contain only Sertoli cells and spermatogonia. The interstice shows a normal number of Leydig cells.

normal sperm counts (20 million/mL).1095,1096 Highest sperm counts occur with testes in the superficial inguinal pouch. Patients with bilaterally impalpable testes are usually azoospermic.1097 Fertility rates in unilateral cryptorchidism vary from 25% to 81%.1098 Many patients with repaired bilateral cryptorchidism require assisted reproductive techniques such as intracytoplasmic sperm injection to obtain successful fertilization.1099 The number of germ cells per cross-sectioned tubule is the most important prognostic factor. Patients with no increase in inhibin B during the postoperative period usually have a low number of spermatogonia and low TFI.1100 Usually a cryptorchid boy with less than 0.2 spermatogonia per cross-sectioned tubule will have a deficient spermiogram in adulthood, and fertility will be decreased. In unilateral cryptorchidism, fertility depends on the number of spermatogonia in the contralateral testis. However, if the number of germ cells per cross-sectioned tubule in the cryptorchid testis is less than 1% of normal, the risk for infertility is 33%, increasing to 75% to 100% in bilateral cryptorchidism.1095,1101–1105 Spermatogonial number correlates with sperm number in the spermiogram, volume of surgically repaired testis, inhibin B serum level, and volume of this testis in adulthood. In a series of 142 azoospermic men with history of cryptorchidism, testicular sperm extraction (TESE) was successful in 62% of cases overall and 63% of those with bilateral cryptorchidism, favorably altering the prospect of fertility. Those patients whose FSH level is normal or testicular volume is higher than 10 cm3 have an even better prognosis because the rate of TESE with positive sperm retrieval is 75%.1106 Preoperative location of the unilaterally cryptorchid testis and the small size of the testis at the time of orchidopexy cannot predict likelihood of fertility.1107–1109 Patients with high scrotal testes or superficial inguinal pouch testes have the best spermiograms, whereas those with intraabdominal or canalicular testes are oligozoospermic or azoospermic. Testicular damage may result either from the presence of more severe histologic lesions or injury produced during orchidopexy because these testes require more mobilization those in lower locations.1097–1110 Patients whose testes are nearly normal in size also have better spermiograms.1096 An important fertility factor is the permeability of sperm excretory ducts. Between birth and 4 years of age, patient age at orchidopexy

CHAPTER 12 Nonneoplastic Diseases of the Testis

may also influence fertility, although this has not been proven. Beyond 4 years, orchidopexy does not enhance fertility.1102,1111 Testicular Torsion. Undescended testes have a 10-fold higher risk for spermatic cord torsion than do normally located testes. This increased risk results from the abnormal suspension system.1112–1115 Fixation of the contralateral testis should be performed using orchidopexy if anomalies in testicular suspension are observed.1116 The percentage of testes that may be preserved is low because of the delay in seeking consultation and making the diagnosis.1117 Tunica albuginea calcifications, coinciding with site of fixation, are found in adult testes that were fixed at orchidopexy. These calcifications appear mainly when chromic suture material was used, and tare not related to pathologic features present in the cryptorchid testis at the time of orchidopexy or will develop later. Intraabdominal testes may also undergo torsion.1118,1119 Iatrogenic Atrophy. The high number of children subjected to orchidopexy has led to knowledge of postsurgical atrophy. The frequency of this complication is estimated to be 1% to 5% for inguinal canal testes and 25% for intraabdominal testes (Fig. 12.125).1105,1120 Psychological Problems. The importance of having two testes should be considered before orchidopexy because of potential damage to the male identity.1121 Studies carried out in adults whose testes were surgically descended before puberty revealed normal male development and behavior, although these men seemed to be sexually less active than controls. This observation does not appear to be related to treatment method or age when treated.1122 Patients should be offered testicular prosthesis and information on the risks involved (infection, migration).1123

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even in the best of cases. If complete spermatogenesis occurs, this may be associated with obstruction of sperm excretory ducts. In childhood, risk for occult cancer or precancer at biopsy is low because GCNIS is not diffusely distributed throughout the testis. Testicular biopsy is recommended in patients with intraabdominal testes, abnormal external genitalia, or abnormal karyotype.1126 The situation is different in adults because GCNIS is present in 2% to 3% of cases and is diffuse.1086,1087 When GCNIS is detected in a child, further examination of the testis and repeat biopsy after puberty are recommended.1088 In adults, if GCNIS is unilateral, orchiectomy should be performed, but if bilateral, radiation therapy may be used to eradicate neoplasm while maintaining Leydig cell function.1088

Obstructed Testes Obstructed testes are in the superficial inguinal pouch (DenisBrowne pouch) and are considered ectopic by some authors and cryptorchid by others.501,1127 Histologic studies reveal that most obstructed testes bear the same lesions as true cryptorchid testes. Type I lesions are observed in one-half, type II lesions are seen in more than one-third, and the remaining lesions are type III. The higher proportion of type I lesions suggests a better prognosis than in true cryptorchidism.

Testicular biopsies of infantile testes at orchidopexy are useful for determining baseline germ cell status and whether surgery should be supplemented by hormonal treatment.1124,1125 However, even if biopsy supplies significant data, it is not considered a routine procedure. When the number of spermatogonia is nearly normal, spermatogenesis may not occur because of deficient spermatogonium development during childhood or failure of spermatogenesis at puberty,

Retractile Testes Some authors assume that retractile testes are normal and exclude them from studies of cryptorchidism.974,1128 However, these testes may have significant lesions, and many consider them to be a form of cryptorchidism.1126,1129,1130 Retractile testes may not always be movable to the lower scrotum (70 to 75 mm from the pubic tubercle), and in 50% of cases are smaller than scrotal testes.1131 Approximately 50% of retractile testes remain high after age 6 years, when cremasteric activity declines.1132 Retractile testes have a 32% risk for becoming ascending or acquired undescended testes. The risk is higher in boys younger than 7 years or when the spermatic cord is tight or inelastic.1133 During childhood, MTD and TFI decrease.1126 Adults with retractile testes that descended spontaneously but late may be fertile or infertile.1134,1135,1135a Usually there is germ cell atrophy that varies in severity from lobule to lobule (Fig. 12.126).1126 Regular examination of retractile testes is

Fig. 12.125 Testicular atrophy in a child after descent done 3 years earlier. The most affected parenchyma is the peripherally situated parenchyma in which the seminiferous tubules are barely distinguished in the testicular stroma.

Fig. 12.126 Infertile patient with oligozoospermia and retractile testicles. Seminiferous tubules with slight thickening of the basal membrane, marked variation in size, and variable spermatogenesis from one tubule to another.

Benefit of Testicular Biopsy in Patients With Cryptorchidism

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advisable during childhood, and if complete testicular descent does not occur, orchidopexy is indicated. In 14% of patients with retractile testicles treated by orchiopexy, abnormalities of the epididymis are similar to those observed in cryptorchid testes.1136

Testicular Microlithiasis Calcifications may arise in the testis, but the high frequency of this finding has emerged with routine use of ultrasonography. Histologic studies combined with ultrasonography have elucidated the nature and significance of microliths, macroliths, clumps or calcified scars, phlebolites, stones, or calculus. Testicular microlithiasis is characterized by the presence of numerous calcifications diffusely distributed throughout the parenchyma. Classically the term testicular microlithiasis was used to describe cases containing a large number of microliths.1137 Microlithiasis may occur in infancy or adulthood, associated with tumoral and nontumoral pathologic features. In infancy, it may be seen in undescended testes, Klinefelter syndrome, Down syndrome, developmental delay and testicular asymmetry, undermasculinization XY testicular hydatid torsion, polyorchidism, congenital adrenal hyperplasia, and secondary hypogonadism, as well as in otherwise normal patients studied for other conditions.239,755,1138–1147 In adults, microliths are frequently observed in cryptorchid and ex-cryptorchid testes, in seminiferous tubules located at the periphery of germ cell tumors, in patients with GCNIS, in testicular dysgenesis, in testes with ischemic injury, in infertile men, and in some with orchialgia.1148–1158 Isolated cases associated with pulmonary microlithiasis and calcifications in the vegetative and central nervous system have been reported.239,1159 Ultrasonography is used to quantify calcifications, usually revealing multiple < 2-mm diameter hyperechoic foci without posterior acoustic shadow and diffusely distributed throughout the parenchyma (“snowstorm” pattern), or radiography is used, usually revealing multiple uniformly distributed microcalcifications.1143,1160–1164 Ultrasonography identifies two types of testicular microlithiasis: classic type, in which the number of microliths is five or more; and limited type, with fewer than five microliths (Fig. 12.127).

Fig. 12.127 Testicular microlithiasis showing the characteristic “snowstorm” pattern.

Incidence The incidence of testicular microlithiasis varies according to the diagnostic method used (light microscopy, radiography, or ultrasonography), whether the population is symptomatic or asymptomatic, and the nature of the disease process being studied (cryptorchidism, infertility, or testicular tumor). In histologic studies, testicular microlithiasis is found in approximately less than 1% of testicular pediatric biopsies, in 1% of biopsies of infertile men, and in 4% of adult male autopsies.239,1153,1165 The incidence rate in two radiologic series varied from 1% to 74%.1149,1166 The real incidence of testicular microlithiasis has been established by the routine use of ultrasonography in evaluating intrascrotal abnormalities. The prevalence rate of testicular microlithiasis in infants is less than 3%. Classic testicular microlithiasis is found in 2% and limited testicular microlithiasis in 2% of asymptomatic boys.1142 The prevalence rate of classic testicular microlithiasis in children with disorders such as cryptorchidism, hydrocele, scrotal swelling, chromosomal anomalies, orchialgia, and testicular torsion who were evaluated ultrasonographically varied from 1% to 3%.1077,1167–1169 Several cases of testicular microlithiasis have also been observed in infant testes with neoplasm.1168,1170 The prevalence seems to increase from birth to adolescence. The prevalence of classic testicular microlithiasis in asymptomatic young men varies from 2% to 6% in the general population between 18 and 35 years of age, and is bilateral in 66% of affected patients.1171,1172 The incidence shows ethnic differences; it is low in whites (4%), high in blacks (14%), and intermediate in Hispanics (9%) or Asian or Pacific Island men (6%). Ultrasonographic studies performed in adults with several disorders showed a prevalence rate varying from 1% to 4%.1169,1173–1176 In adults, testicular microlithiasis is most often identified during investigations for infertility, pain, or testicular asymmetry.1154 In series of infertile patients, the incidence varied from 2% to 18%.1177,1178 The incidence ranged from 5% to 20% in subfertile patients, and it was 10% in ex-cryptorchid testes.1156,1179,1180 Testicular microlithiasis is observed in 30% to 50% of adult testes with germ cell tumor.1176,1181–1184 It has also been observed in the contralateral, apparently normal testis, sometimes in association with GCNIS.1185–1187 Pain is the most common clinical symptom in patients without a palpable testicular mass, attributed to dilation of seminiferous tubules secondary to obstruction by microliths. Pathology and Histogenesis In the prepubertal testis, microliths are surrounded by a double layer of Sertoli cells and measure up to 300 μm in diameter. When microliths are large, the seminiferous epithelium may be destroyed, and the microlith is surrounded by peritubular cells. Testes with microliths have subnormal MTD and TFI.239,1137 Adult testes with microliths have incomplete spermatogenesis (Fig. 12.128). Microliths may appear in the tubular wall, in the seminiferous epithelium, or free in the tubular lumen. Some seminiferous tubules with microliths are cystically dilated and lined by markedly thin atrophic epithelium (Fig. 12.129). The cause of this cystic transformation may be the obstruction caused by microliths that pass through the thin tubuli recti. Microliths are also numerous in the conglomerates of hypoplastic tubules of the so-called Sertoli cell nodule or hypoplastic zone (Fig. 12.130), which are mainly observed in cryptorchid testes. However, microliths may also be observed in seminiferous tubules away from these areas.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.128 Extratubular and intratubular microliths in an adult testis with isolated spermatogonia and Sertoli cells.

Fig. 12.129 Testicular microlithiasis. Seminiferous tubules with dilated lumina in a patient who underwent biopsy for infertility. The central tubule contains a microlith that developed in the tubular wall and protrudes into the lumen.

Fig. 12.130 Testicular parenchyma with hyalinized tubules. In the center of the image a hypoplastic zone with microliths may be recognized.

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The origin of microliths is hypothesized to represent sloughed germ cells or glycoprotein secretions concentrated inside seminiferous tubules.1140,1147,1188,1189 Some have hypothesized that they arise from disordered tunica propria, forming extratubular eosinophilic bodies that mineralize and pass into tubular lumina.236 The material surrounding microliths expresses laminin and type IV collagen, both important components of basal lamina, which suggests an extratubular origin.236,1190 This observation has led to the hypothesis that microliths originate from eosinophilic basal lamina material, giving rise initially to a spherical body, which advances toward the center of the tubule, displacing the basal lamina components and Sertoli cells that are in the path. Microliths thus become surrounded by these two elements. After internalization the nodular eosinophilic material becomes mineralized. In infantile testes, nonmineralized round eosinophilic bodies may be observed in normal and malformed seminiferous tubules. Many of the largest malformed tubules are known as ring-shaped tubules. Study of serial sections of these tubules reveals that they have a bell shape and contain eosinophilic bodies showing different degrees of mineralization, embedded in connective tissue. X-ray diffraction and Raman spectroscopy studies suggest that the mineralized material corresponds to hydroxyapatite crystals.1191,1192

Microlithiasis and Testicular Cancer The possible association between microlithiasis and testicular cancer is controversial.1151,1187,1193,1194 Testicular microlithiasis is associated with both GCNIS and germ cell tumors (Figs. 12.131 through 12.133). In infancy, it is associated with GCNIS and gonadal stromal tumors, but only in isolated cases.1168,1170,1195–1197 Several findings favor this association: (1) nearly one-half of testes with germ cell tumors also show testicular microlithiasis; (2) patients with testicular microlithiasis may later experience development of testicular tumor; (3) patients with testicular microlithiasis and extratesticular germ cell tumor, either retroperitoneal or mediastinal, have been reported; and (4) increased prevalence of testicular microlithiasis is noted in men with familial testicular cancer and in their relatives.1196,1198–1205 The most important finding that mitigates against an association between testicular microlithiasis and cancer is the unquestionably

Fig. 12.131 Seminiferous tubules containing both GCNIS and microliths in the periphery of a seminoma.

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Fig. 12.132 Testicular parenchyma with fibrosis of a burned-out tumor next to intratubular calcifications of an intratubular germ cell neoplasia.

When testicular microlithiasis is associated with infertility, the incidence of cancer varies according to the unilateralism or bilateralism of testicular microlithiasis.1179 Subfertile patients with unilateral and bilateral microlithiasis have GCNIS in 0% and 20%, respectively. Therefore only patients with bilateral testicular microlithiasis should undergo rigorous follow-up. The nexus between testicular microlithiasis and cancer does not seem to be the predisposition of one disorder toward the other, but rather the predisposition of both to develop in abnormal testes, accounting for frequent coincidence. This may also explain the association between testicular microlithiasis and infertility or subfertility, and these entities may be expressions of testicular dysgenesis syndrome.1213 In patients with germ cell tumor, other forms of calcification may be observed. The most frequent are conglomerates of microcalcifications around the tumor or amorphous intratubular calcifications in necrotic intratubular tumors such as embryonal carcinoma, calcifications in the scar of burned-out tumors, and calcifications associated with intratubular hyalinizing Sertoli cell tumor or calcifying large cell Sertoli cell tumor. Dystrophic calcifications and ossification may be observed in the testis and paratesticular structures in patients with a history of orchitis, epididymitis, trauma, or testicular infarction.

Fig. 12.133 Microlithiasis associated with germ cell neoplasia in situ. Immunostaining for placental alkaline phosphatase.

Rete Testis, Epididymis, and Vaginal Microlithiasis and Calcifications Microlithiasis also occurs in the rete testis or sperm excretory ducts. The disorder is asymptomatic and in most cases is not associated with testicular cancer (Figs. 12.134 and 12.135). Calcifications in the epididymis or in diverticula of the cauda of the epididymis have long been observed.1214–1216 More than 70% of young adults undergoing kidney transplant experience development of calcifications (Fig. 12.136).1217 Idiopathic microlithiasis of the epididymis and rete testis is much less frequent than testicular microlithiasis in adults. Incidence is 1 case per 1000 autopsies, and it is found in 3% of orchidoepididymectomy specimens. Epididymal microlithiasis is characterized by the presence of multiple and small calcifications with lamellated structures like those of psammoma bodies. This asymptomatic process is not related to testicular cancer.1214,1218

high incidence of testicular microlithiasis compared with the low incidence of testicular germ cell tumors in adults. Isolated microlithiasis that is not associated with another disorder does not require follow-up.1152,1198-1200,1202,1206 Three methods have been proposed for surveillance of patients with testicular microlithiasis when needed: abdominal and pelvic CT, ultrasound and testicular tumor marker study, or simple ultrasonography and physical examination every 6 months.1181,1183,1186,1202,1207,1208 The risk for malignancy is higher in classic than in limited testicular microlithiasis.1209 The surveillance policy may be modified depending on the associated disorders.1206 Patients found in infancy to have isolated testicular microlithiasis without other associated disorders warrant yearly physical examination, whereas follow-up sonography should be limited to the subgroup of patients with other associated risk factors.1210,1211 Yearly ultrasound examination is recommended in patients with testicular microlithiasis associated with cryptorchidism, infertility, atrophic testes, or contralateral testis with germ cell tumor.1185,1212 Testicular biopsy should be performed when clinically indicated.

Fig. 12.134 Microlithiasis of rete testis. The three microliths are probably located in the thickness of a tendinous cord of the rete testis. The seminiferous tubules show abundant spermatogenesis.

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Fig. 12.135 Microlithiasis of the rete testis associated with infiltration of the testicular mediastinum by seminoma. Microliths were also observed in the conserved testicular parenchyma. The rete testis does not present pagetoid infiltration by germ cell neoplasia in situ cells.

615

occurring with testicular microliths. They may also be formed by Liesegang ring calcifications. These eosinophilic bodies range from 10 to 800 μm in diameter and have characteristic concentric laminated cores with radial striations that are observed in obstructive processes of the spermatic pathway (Fig. 12.137).1220 Interstitial microlithiasis is mainly located in the body and tail of the epididymis. Epididymal rupture and extravasation into the interductal tissue may cause a histiocytic reaction around microliths that resembles malakoplakia (Fig. 12.138). The larger size and the radial structure of microliths enable correct diagnosis. As in malakoplakia, the inflammatory infiltrate is eventually replaced by fibrosis. Interstitial microlithiasis may arise after perforation of diverticula that are frequently present in the tail of the epididymis.1221 After perforation, microliths derived from total or partial mineralization of Liesegang rings make contact with the immune system in the interstitium and may induce an immune response. The histologic differential diagnosis of Liesegang rings and microliths includes Michaelis-Gutmann bodies seen in

Fig. 12.137 Microlithiasis of the epididymis. Inside a dilated duct a myriad of microliths are observed (many with laminated structure) surrounded by an amorphous material with abundant spermatozoa. Fig. 12.136 Calculus at the tail of the epididymis. There are two diverticula. The central one contains a partial calcification of the intratubular material.

Sonographic appearance is characteristic, with multiple cometshaped foci of microcalcification throughout the epididymis.1219 In infancy, rete testis microlithiasis is associated with paratesticular embryonal remnants, cystic dysplasia of the rete testis, and undescended testes. In adulthood, rete testis microlithiasis is infrequently associated with testicular microlithiasis and malignancy. It is also found in older men, possibly related to ischemic injury. Characteristic rete testis calcium deposits, known as intracystic polypoid nodular proliferation, have been reported only in adults with poor peripheral circulation. Epididymal microlithiasis may occur both in association with testicular microlithiasis in prepubertal boys and as an isolated finding. Histologic studies have been reported only for the isolated form. Microliths may be found in three different locations: subepithelial, intraluminal, and interstitial. Although some microliths may originate from the testis or rete testis, most form under the epithelium and are cleared into the lumen by a mechanism like that

Fig. 12.138 Epididymal microlithiasis. Numerous microliths displaying a psammoma body–like appearance are set in hyalinized stroma.

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Fig. 12.139 Scrotal pearl. Concentric lamina formation with central calcification in a patient operated on for hydrocele.

malakoplakia, calcium deposits, and parasites such as the giant kidney worm Dioctophyma renale.1222 In infancy and adulthood, “pearls” or scrotal calculi may appear that are freely mobile, spheroid, <7-mm calcified bodies lying between the layers of the tunica vaginalis (Fig. 12.139). They are observed in 2% to 3% of cases during routine ultrasound examinations.1223 The incidence rate is as high as 5% in hydrocele patients, 7% in equestrians, and 81% in extreme mountain bikers.1224,1225 Scrotal calculi consist of calcium deposits, oxalate or phosphorous, covering nondescript material that may originate from torsion of hydatid, small hemorrhage, or desquamated mesothelial cells. Fewer than one-half of the cases are associated with scrotal pain.1223 The effect of scrotal calculi on testicular function is unknown.1226

Disorders of Sex Development Gonadal Dysgenesis Classically, gonadal dysgenesis refers to disorders characterized by amenorrhea and streak gonads in phenotypically female patients with hypoplastic uterus and fallopian tubes. Streak gonad, when understood as a pathologic concept, allows syndromes with different clinical phenotypes (Turner, Swyer, and Sohval) to be included within the spectrum of disordered gonadal dysgenesis. Clinical manifestations, which are grouped under the term male pseudohermaphroditism with m€ ullerian rests, should also be considered syndromes of gonadal dysgenesis, including Sohval syndrome, male with uterus, and dysgenetic male pseudohermaphroditism with preferential testicular differentiation of one or both gonads. Consensus classification of intersex disorders was reported by the International Consensus Conference on Intersex in 2005 (Table 12.17).1227 Conferees considered use of some terms (e.g., pseudohermaphroditism, hermaphroditism, sex reversal, and intersex situation) obsolete and introduced the term DSDs to designate all intersex disorders. This classification has given rise to numerous critical comments because it is based on chromosomal constitution (peripheral karyotype of leukocytes) and phenotype.1228

Specifically, in cases of gonadal dysgenesis, entities with completely different histopathologic features, such as 45,X0 Turner syndrome and its variants and mixed gonadal dysgenesis (45,X0/45,XY), are included together with Klinefelter syndrome and variants under the same term DSDs. The same may be said of the unfortunate inclusion of congenital adrenal hyperplasia in females as DSD.1229 Several inconsistencies contribute to the unresolved problem of classification. The same karyotype may give rise to different phenotypes. Furthermore, it is increasingly understood that instead of having one cellular line, gonadal dysgenesis has mosaicisms or more complex chromosomal constitutions. This problem is complicated further with the results of chromosomal studies of the gonads. Finally, the same clinical entity may be produced by different karyotypes as occurs in patients with ovotesticular DSD (46,XX, 46,XY, mosaicisms, or genetic abnormalities).1230 Therefore classification of these disorders that encompasses different points of view (e.g., genetic, endocrinologic, clinical, and histopathologic) remains elusive. Pathologists rely on critical assessment of the nature of the gonad they are examining. This vantage point places them at the center of the controversy. On one side, pathologists understand which genetic mutations contribute to the condition of the gonad, and on the other side, they can explain the variability of clinical symptoms in terms of the anatomy of the gonad. Gonadal dysgenesis may be defined as incomplete or defective gonadal differentiation because of disturbance in germ cell migration or its correct organization in the gonadal ridge. This anomaly is morphologically expressed as levels of differentiation toward ovary, testis, or both. The term gonadal dysgenesis comprises a broad spectrum of lesions ranging from absence of the gonad or persistence of undifferentiated gonadal tissue (UGT) to classic streak gonad or the presence of a testis surrounded by stroma similar to the ovarian cortex. In other words, the term includes the spectrum of gonads observed before the architecture of the ovary or the testis is fully defined. It is possible that all forms of gonadal dysgenesis are part of a spectrum of the same disorder.1231 Patients with DSDs can be classified into two groups: (1) those with gonadal dysgenesis including 45,X0 gonadal dysgenesis, 46, XX gonadal dysgenesis, 46,XY gonadal dysgenesis, mixed gonadal dysgenesis, dysgenetic male pseudohermaphroditism, PMDS, and ovotesticular dysgenesis (Fig. 12.140); and (2) patients with architecturally normal testes and different degrees of undermasculinization, which includes androgen synthesis deficiencies and impaired androgen metabolism in peripheral tissues (Table 12.18).

Types of Gonads in Patients With Gonadal Dysgenesis and Correlation With Clinical Syndromes To gain a better understanding of gonadal dysgenesis, the pathologist should realize the utility of considering that several histologic patterns may arise from an undifferentiated gonad. When differentiation is toward ovary, two different stages may be seen: streak gonad with or without ovarian follicles and hypoplastic ovary. When differentiation is toward testis, streak gonad with epithelial cords and dysgenetic testis may be observed. If the gonad has incomplete differentiation toward either testis or ovary, but without forming ovotestis, streak testis is formed, or the undifferentiated gonad may even disappear (Fig. 12.140). At the beginning of differentiation, the gonad may manifest as UGT arrested at the fetal stage. In the literature, these gonads have been considered either as streak gonad or as ovary. In fact, UGT may appear as a streak gonad with epithelial cord–like structures

CHAPTER 12 Nonneoplastic Diseases of the Testis

TABLE 12.17

New Nomenclature of Disorders of Sex Development after Chicago Consensus Meeting 2005 46,XY DSD

Sex Chromosome DSDs 45,X Turner and variants 47,XXY Klinefelter and variants 45,X/46,XY MGD Chromosomal ovotesticular DSD

617

Disorders of Testicular Development Complete gonadal dysgenesis Partial gonadal dysgenesis Gonadal regression Ovotesticular DSD

46,XX DSD

Disorders of Androgen Synthesis/Action

Disorders of Ovarian Development

Androgen synthesis defect Luteinizing hormone receptor defect Androgen insensitivity 5α-Reductase deficiency Disorders AMH Timing defect Endocrine disrupters Cloacal exstrophy

Ovotesticular DSD Testicular DSD Gonadal dysgenesis

Fetal Androgen Excess CAH 21-OHdeficiency 11-OH deficiency

Non-CAH Aromatase deficiency P450 oxidoreductase gene defect Maternal luteoma Iatrogenic

DSD, Disorder of sex development; MGD, Mixed gonadal dysgenesis; CAH, Congenital adrenal hypertrophia; AMH, Antimüllerian hormone.

TYPES OF GONADS IN DISORDERS OF SEXUAL DIFFERENTIATION

Histopathology Absence of gonad

Clinical syndrome and karyotype True agonadism

Turner’s syndrome

Classic streak gonad

Hypoplastic ovary

45X0/46XX

45X/46XX/47XXX Gonadal dysgenesis mosaicism 45X0/47XXX

Pure gonadal dysgenesis

46 XX

Swyer’s syndrome

46XY 45X0/46XY

c Testi

Streak gonad with epithelial cord-like structures

Pure gonadal dysgenesis Sohval’s syndrome

Dysgenetic testis

Bipotential

dif ferentiatio

n

ular d

if fere

ntiati

on

Undifferentiated gonad

Ovary differentiation

45,X0 Gonadal dysgenesis

46 XY 46 XX

Streak testis Ovotestes

45X0/46XY Asymmetric gonadal differentiation 46XY 45X0/47XYY Mixed gonadal dysgenesis Male dysgenetic pseudohermafroditism

46XY 45X0/46XY

Persistent Müllerian duct syndrome 46XY (Male with uterus)

Fig. 12.140 Gonadal dysgenesis. Different types of gonads and correlation with clinical syndromes.

or focally in several types of gonads such as dysgenetic testis, streak testis, or ovotestis. UGT recognition is of great interest because of the high incidence of transformation into gonadoblastoma.1232 The most significant characteristics of this peculiar gonad are discussed later with streak gonad with epithelial cord–like structures. Numerous germ cells are arranged neither in follicles nor in seminiferous cords, but are rather enclosed in an ovarian-like stroma or in cords of immature Sertoli cell–like/granulosa cells (Fig. 12.141).

Grossly, regardless of differentiation, the streak gonad is an elongate, fibrous, pearly formation located at the site of the normal ovary. The streak gonad measures 2 to 3 cm in length and 0.5 cm in width in the adult and may contain hilar cells or rete ovarii. Classic Streak Gonad

Microscopically, streak gonad may consist of bundles of fibrous connective tissue or as whorled, ovarian-like stroma. This is the classic gonad seen in 45,X0 gonadal dysgenesis or Turner

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TABLE 12.18

Nonneoplastic Diseases of the Testis

Disorders of Sex Development With Architectural Normal Testis and Undermasculinization in Adult Patients Wolffian Derivatives

M€ullerian Derivatives

Leydig Cells

Female

Absent or hypoplastic Normal

Absent or rudimentary Absent

Diffuse hyperplasia Xanthomized

Female

Hypoplastic

Absent

Absent

Absent

Defect in Sertoli cells, Leydig cells, and germ cells

Lutein hormone receptor inactivating mutation Chromosomopathy

Male

Normal

Absent

Absent or focal

Androgen insufficiency

Male

Normal

Absent

Nodular hyperplasia Focal hyperplasia

Defects in target organs

5-α reductase deficiency

Female

Hypoplastic

Absent

Defect in Sertoli cells Defect in Leydig cells

Cause

Phenotype

Androgen receptor absence Defect in androgen synthesis

Female

Hyperplasia

Spermatogenesis

Entity

Absent

Morris syndrome

Absent

Congenital adrenal hyperplasia Absence of response to gonadotropins XXY Klinefelter syndrome Cryptorchidism

Absent Maturation arrest Mixed atrophy Absent Hypospermatogenesis

5-α Reductase deficiency

Data are referred to complete forms.

syndrome. Some classic streak gonads may contain germ cells enclosed in primordial and eventually primary follicles (Fig. 12.142). These germ cells express VASA and KIT, and are negative for OCT3/4, PLAP, and TSPY. In some patients, regardless of age, atretic follicles, multiple cortical cysts (Figs. 12.143 and 12.144), abundant hilar cells, or glandular-like groups of clear cells in the hilus may be observed. This gonad is observed in patients with Turner syndrome with chromosomal mosaicism, as well as in 46,XX pure gonadal dysgenesis.

not have the form of a streak gonad, but are ovoid, small, with a smooth surface. Primary follicles, and occasionally follicles in development, may be observed in the cortex with a regular pattern of distribution. This gonad is characteristic of 46,XX pure gonadal dysgenesis and some cases of ovotesticular dysgenesis (ovotesticular disorder). Streak Gonad With Epithelial Cord–like Structures

The development of the ovary is an active process that is based, at least in part, on the absence of SRY, the testis-determining gene on the Y chromosome. Dysgenetic ovaries or hypoplastic ovaries do

The gonad consists of ovarian cortex-like stroma traversed in all directions by epithelial cord–like structures (sex cords) that form an anastomosing network. The cords may be thin or thick with coarse outlines (Fig. 12.145). These cordlike structures contain two types of cells (Fig. 12.146). Most numerous are small cells with hyperchromatic nuclei that are likely pre–Sertoli cells or immature

Fig. 12.141 Gonadal dysgenesis. Undifferentiated gonadal tissue. Streak gonad showing nests and cords with two types of cells: the most numerous, small-sized cells and large cells with voluminous nuclei and pale cytoplasm (germ cells).

Fig. 12.142 Streak gonad. The elongate formation lacks germ cells and consists of an ovarian cortex-like stroma and tubular structures resembling rete ovarii in the deeper part.

Hypoplastic Ovary (Dysgenetic Ovary)

CHAPTER 12 Nonneoplastic Diseases of the Testis

619

Sertoli/granulosa cells. These cells are intensely positive for AE1/ AE3 and calretinin (Fig. 12.147) and moderately positive for inhibin (Fig. 12.148); D2–40 and AMH are weakly expressed. The epithelial cord–like structures abut a basal membrane of variable thickness. In the thickest areas, spiculated or nodular projections inside the cords may be observed. The second type of cells are germ cells, which may be isolated within the stroma, forming cords, or in between Sertoli/granulosa cells. The number is variable, and some cords may even form small nests. These germ cells are immunoreactive for OCT3/4, KIT, PLAP, TSPY, and VASA. The histologic pattern of the gonad is that of UGT. Some streak gonads with epithelial cord–like structures are devoid of germ cells, although it is probable that the gonad contained germ cells at some point in development, but the cells were eliminated by apoptosis. Fig. 12.143 Streak gonad with inclusion cysts lined by cuboidal epithelium.

Fig. 12.144 Streak gonad showing numerous cystic or pseudoglandular formations lined by mucous epithelium.

Fig. 12.145 46XY gonadal dysgenesis. Streak gonad with epithelial cordlike structures containing Sertoli/granulosa and germ cells.

Fig. 12.146 46XY gonadal dysgenesis. Solid cords anastomosed with cells of hyperchromatic nucleus (Sertoli/granulosa) and larger cells of pale cytoplasm (gonocytes).

Fig. 12.147 46XY gonadal dysgenesis. Streak gonad with epithelial cordlike structures showing intense immunoexpression of calretinin in Sertoli/ granulosa cells of the cords.

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Fig. 12.148 46XY gonadal dysgenesis. Sertoli/granulosa cells from the epithelial cords show intense immunostaining for inhibin.

Dysgenetic Testis

This gonad is usually cryptorchid and small, with a compact central core containing seminiferous tubules with or without germ cells. The peripheral zone, instead of showing a well-collagenized tunica albuginea as occurs in normal testes, has an ovarian stroma with or without malformed seminiferous cords (Fig. 12.149). The seminiferous cords have strange anastomoses, and diameter varies from superficial to deep areas without exact topographic features. Seminiferous tubules or cords are separated by a wide and loose stroma. Sertoli cells express inhibin, D2–40, AMH, and, like Leydig cells, calretinin, preferentially in superficial seminiferous cords. However, in the central areas of the testis, calretinin is expressed only in small tubules usually devoid of germ cells and in Leydig cells. Germ cells are found in seminiferous tubules and adjacent to the basal membrane. The germ cell phenotype is positive for VASA, TSPY, and D2–40, and a subpopulation is positive for OCT3/4, KIT, and PLAP.

Fig. 12.149 Dysgenetic testis. The gonad consists of a central part with compact packing of seminiferous tubules and an outer part with irregular seminiferous tubules reaching the surface of the gonad.

There are a modest number of studies of dysgenetic testes in pubertal and adult patients. The whorled stroma in the tunica albuginea and irregular contour with distorted seminiferous tubules are conserved. Maturation of Sertoli cells is incomplete, as expressed by absence of tubular lumina and nuclei characteristic of dysgenetic cells (round or ovoid nuclei instead of triangular nuclei with deep grooves of adult Sertoli cells). Most tubules are devoid of germ cells. The interstitium shows apparent Leydig cell hyperplasia that is diffuse and peritubular. Immunohistochemical techniques allow a better understanding of the peculiar relationships among Leydig cells, peritubular cells, and Sertoli cells. Anticalretinin and antiinhibin antibodies may show the number of Leydig cells that form concentric circles in the tubular wall. Leydig cells are located among peritubular cells or between peritubular cells and the basal membrane. Although most tubules are devoid of germ cells, as previously mentioned, some groups of tubules with GCNIS may be observed. This gonad corresponds to that described as “dysgenesis,” and is observed in the three syndromes that are classically included in male pseudohermaphroditism with m€ ullerian rests: (1) mixed gonadal dysgenesis (Sohval syndrome or asymmetric gonadal differentiation), whose usual karyotypes are 45,X0/46,XY, 46,XY, and 45,X0/47,XYY; (2) male dysgenetic pseudohermaphroditism, which usually shows the karyotype 46,XY or 45,X0/46,XY; and (3) m€ ullerian duct persistence syndrome (male with uterus), which has 46,XY karyotype. Both the degree of m€ ullerian duct regression and the AMH levels may be correlated with number of seminiferous tubules present in the dysgenetic testis.1233,1234 Streak Testis

This gonad has two intimately joined zones. The largest zone consists of dysgenetic testis with ovarian cortex–like stroma close to the tunica albuginea. The stroma is in continuity with streak gonad, which may or may not contain epithelial cords or ovarian follicles (Fig. 12.150). This gonad is observed in some of the three previously mentioned syndromes: mixed gonadal dysgenesis, dysgenetic male pseudohermaphroditism, and m€ullerian duct persistence syndrome.

Fig. 12.150 Streak testis consisting of a streak gonad connected to a testis that shows the characteristic lesions of testicular dysgenesis.

CHAPTER 12 Nonneoplastic Diseases of the Testis

True Agonadism True agonadism is characterized by the absence of both gonads in patients who show female external genitalia. These patients usually present with 46,XY karyotype (46,XY gonadal dysgenesis syndrome), although a few patients with 46,XX karyotype have been reported. Internal genitalia usually include a uterus and uterine tubes, although both m€ ullerian and wolffian remnants may be absent. Gonads are not present anywhere, even in ectopic locations. These patients are raised as girls. The diagnosis may be delayed until puberty or adulthood, when patients seek medical care for other symptoms such as absence of mammary development, small stature, or hypergonadotropic hypogonadism.452,1235 No androgenic response is observed after hCG stimulation test, and AMH is undetectable. Cases may be sporadic or familial, and associated extragenital anomalies have also been observed. In some cases the cause is heterozygous WT1 mutation.452 In most familial cases, inheritance is autosomal recessive or X-chromosome linked, and the cause seems to be either other WT1 anomalies or anomalies in other genes involved in development.455 No molecular defect in the SRY gene may occur in this syndrome.456 Agonadism may be associated with other syndromes, including PAGOD, Kennerknecht, Seckel, CHARGE and congenital adrenal hyperplasia.457–460,1236–1239 45,X0 Gonadal Dysgenesis 45,X0 gonadal dysgenesis is one of the most common chromosomal anomalies (from 1 in 2500 to 1 in 5000 in female newborns), although 99% of zygotes with this karyotype abort in the first stages of embryonal development.1255,1256 The incidence among patients with delayed growth rises to 5% in some series.1257 Patients with 45,X0 gonadal dysgenesis have characteristic stigmata of Turner syndrome, including short stature, pterygium coli, lymphedema, and cardiac malformations. External genitalia are female and infantile, with typical streak gonads (Figs. 12.151 and 12.152). Turner syndrome is defined by the combination of physical features and complete or partial absence of one or both X chromosomes, frequently associated with mosaicism.1258 Most patients have a characteristic neurocognitive profile.1259 Other anomalies, known as turnerian stigmata, may also be present and are classified into four groups: skeletal anomalies such as cubitus valgus, shortening of the fourth metacarpal, and Madelung

Fig. 12.151 Gonadal dysgenesis. Streak fibroblastic stroma resembling ovarian cortex.

621

Fig. 12.152 Streak gonad in Turner syndrome (45,X0 gonadal dysgenesis) showing a glandiform proliferation lined by Sertoli-like cells.

deformity characteristic of Leri-Weill dyschondrosteosis; soft tissue anomalies such as webbed neck, low posterior hair line, and puffy hands and feet; visceral anomalies such as aortic coarctation, horseshoe kidney, polycystic kidney, urethral stenosis, and vesicourethral reflux; and miscellaneous anomalies such as nevus pigmentosus.1251,1260–1263 SHOX (short stature homeoboxcontaining gene) haploinsufficiency is likely responsible, at least in part, for short stature and turnerian stigmata.1264 Most patients have 45,X0 chromosomal constitution that results from loss of the paternal sex chromosome.1265,1266 Molecular techniques, such as fluorescence in situ hybridization and polymerase chain reaction (PCR), show that 50% to 75% of patients have chromosomal mosaicisms or structurally abnormal X or Y chromosomes. The most frequent mosaicisms are 45,X0/ 46,XX (10% to 15%), 45,X0/46,XY (2% to 6%), 45,X0/46,Xi (Xq), 45,X0/46,X,del(Xp), and 45,X0/46,XX/47,XXX. Alterations of sex chromosomes may include aberration of X structure, total or partial deletion of the short arm of the X chromosome (46,X0,del[Xp]), isochromosome of the long arm of the X chromosome (46,X,i[Xq]), ring chromosome (46,Xr[X]), and marker chromosome (46,X + m).1267–1269 Some authors consider mosaicism in Turner syndrome to be a prerequisite for survival in early pregnancy.1270 More than 85% of patients have Y chromosome, or at least material derived from this chromosome.1242,1271 Internal genitalia with 45,X0 karyotype are female but infantile. Streak gonads consist of ovarian-like stroma, which may contain hilar cells and rete ovarii (Fig. 12.142).1272 During embryonic life, gonads show normal germ cell number up to the third month, when germ cell proliferation ceases.1233,1273 Ovogenesis stops in meiosis I, usually before the pachytene stage. The cause seems to be generalized meiotic pairing errors with the start of apoptosis to avoid formation of abnormal gametes.1274 Massive apoptosis of ovocytes occurs between the 15th and 20th weeks.1275 Surviving germ cells disappear throughout fetal life, and the number at birth is usually low.1276 About 3% of patients retain scattered germ cells after puberty. This feature explains the occurrence of menstruation for a few years.1277,1278 The rare reported cases of pregnancy result in a high rate of miscarriages, stillbirths, and malformed babies.1279 These statistics are changing with the practice of ovocyte donation and good uterine preparation before implantation.1280 During adulthood, the usual condition is

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Turner syndrome without signs of virilization are taken into account, the risk for tumor is lower.1249,1250 Patients with 46,Xi(Xq) have streak gonads and somatic anomalies similar to those of 45,X0 patients. Half of 46X,del(Xq)(p11) patients have amenorrhea and gonadal dysgenesis.1251,1252 Patients with Turner syndrome have a high frequency of autoimmune diseases such as hypothyroidism, celiac disease, and diabetes mellitus.1253 Long-term estrogen administration for patients with this or other forms of gonadal dysgenesis is a risk factor for endometrial carcinoma.1254

Fig. 12.153 Streak gonad in Turner syndrome. Group of hilar cells in the vicinity of nerve fibers.

hypergonadotropic hypogonadism, but isolated cases of hypogonadotropic hypogonadism have been reported.1281,1281a Streak gonads may contain inclusion cysts, rete ovarii cysts, and clusters of Leydig cells (Fig. 12.153). Molecular testing detects different Y-specific sequences (SRY, Ycen, and Yq12) in different tissues (oral epithelial cells, lymphocytes, and ovarian tissue) from 10% to 20% of 45,X0 patients.1282 The SRY gene is a marker of testicular tissue and of gonadoblastoma, so gonad removal has been recommended in such patients, as well those with 45,X0/46,XY karyotype.1283,1284 Gonadoblastoma, dysgerminoma, and mixed germ cell tumor have also been reported.1285,1286 Patients With Chromosomal Mosaicisms

The most frequent chromosomal mosaicisms associated with this gonadal dysgenesis are 45,X0/46,XX, 45,X0/47,XXX, 45,X0/46, XX/47,XXX, and 45,X0/46,XY. The first is most common, whereas the last two are rare.1240 The second cell line of each mosaicism may be present in a few cells only. Phenotype depends on the ratio between the Y portion and 45,X0 cells lines in the body.1241 No two patients with mosaic Turner syndrome have the same genotype–phenotype.1242 In general, anomalies associated with mosaicisms are less severe and fewer in number than are those of 45,X0 patients.1243 Approximately 12% of patients with mosaicism menstruate, but only 3% of 45,X0 patients menstruate. This finding suggests the possibility of a short period of fertility.1244 Approximately 18% of patients show breast development; this percentage is also lower (5%) in 45,X0 patients. Stature is also higher than in 45,X0 patients. Patients with 45,X0/46,XY comprise 1.5 in 10,000 consecutive newborns, and their phenotype varies widely.1245 There is no relationship between the degree of mosaicism and somatic features, genital development, or gonadal structure These patients may present with Turner syndrome, varied forms of undermasculinization DSD, ovotesticular disorder, hypospadias, dysgenetic streak ovaries, or mixed gonadal dysgenesis. Among patients diagnosed by prenatal amniocentesis, 95% have normal male genitalia, although only 27% presented with normal gonadal histology.1246–1248 Overall, the estimated incidence rate of germinal tumors for patients with 45,X0/46,XY is 15%; however, if only patients with

46,XX Gonadal Dysgenesis Patients with 46,XX gonadal dysgenesis have normal stature, female phenotype, well-developed external genitalia, and absence of turnerian stigmata. The anomaly is usually detected when patients present with primary amenorrhea, delayed puberty, infertility, and hypergonadotropic hypogonadism. This syndrome is sporadic and familial, and may be linked to recessive autosomal inheritance.1287–1289 Gonadal development varies, even among members of the same family, from streak gonads to severe ovarian hypoplasia (only a few ovocytes are present) (Fig. 12.154).1290 Patients have no predisposition to gonadal neoplasia because the incidence of tumors in these patients is low, and the most common tumor is dysgerminoma.1291–1293 Approximately two-thirds of cases have a genetic cause, and the remainder are secondary to infection, infarct, or infiltrative or autoimmune disease.1294–1296 The syndrome may result from absence of a hypothetical substance that induces gonadal development, failure in germ cell formation, defective germ cell migration, or excessive germ cell loss in ovaries during fetal life. Genes responsible for ovarian development seem to be located in proximal regions of Xp and distal regions of Xq.1297 Some patients with familial cases have balanced translocation in the X chromosome (from the long arm to the short arm).1298,1299 Gonadal dysgenesis or early ovarian failure may occur in patients with Xq26-qter deletion, Xp28 mutations (QM gene), or balanced translocations occurring either in X;autosome or 1;11 chromosomes.592,1300–1302 Given that FSH is necessary for ovarian follicle development, investigation has also been focused on mutations of the FSHR gene located on chromosome 2. These mutations have been observed in familial cases, as well as in unrelated cases, but they are absent in other patients.1302a,1303–1305

Fig. 12.154 46,XX gonadal dysgenesis in an 18-year-old patient. Streak gonad showing isolated primordial follicles and one atresic follicle.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Because FSH is necessary for ovarian follicle development, investigation has also focused on mutations of the FSHR gene located in chromosome 2. Several autosomal recessive mutations of the WNT4, R-spondin, PSMC3IP/HOP2, MCM9, MCM8, and STAG3 genes have been described for FSHR genes and SYCE1, X-linked recessive mutations in BMP15, or recessive missense mutation in nucleoporin-107 (NUP107).1306 Association with somatic anomalies is rare. The most frequent anomaly is neurosensory hearing loss (phenotype known as Perrault syndrome).1307,1308 Other anomalies observed in isolated cases are achondroplasia and fatal lung fibrosis with immunodeficiency.1309,1310

46,XY Gonadal Dysgenesis 46,XY gonadal dysgenesis (Swyer syndrome) is characterized by female phenotype and external genitalia, absence of turnerian stigmata, occasionally fused labia majora, and hypertrophic clitoris.1311 The incidence of Swyer syndrome is 1 in 100,000.1312 Breasts develop at puberty when most cases are diagnosed. Sexual infantilism persists in adulthood, and eunuchoidism and amenorrhea appear. These patients have elevated serum gonadotropins, low estradiol, and normal female levels of androgens. Some have mosaic karyotype with one of the lines containing Y chromosome. 46,XY gonadal dysgenesis may be complete and incomplete. Patients with the complete type have female external genitalia and classic streak gonads with epithelial cord–like structures, although cases with ovarian tissue have been reported.1313 Internal genitalia reflect well-developed m€ ullerian structures. The cause is unknown in approximately 70% to 80% of cases.1314 In 80% of patients with 46,XY gonadal dysgenesis, SRY is apparently normal. In the remainder, multiple genetic abnormalities are observed, including mutations in the DHH, WT1, SOX9, ARX, AXX, CBX2, DMRT1, GATA4, MAMLD1, MAP3K1, NR0B1, WNT4, WWOX, and WNT4 genes.1315 SRY gene is deleted in up to 10% to 15% and mutated in an additional 10% to 15%.1316–1323 SRY genotype is related to gonadal histology. SRY mutation is associated with complete type of dysgenetic gonad, whereas immature seminiferous tubules may be observed when SRY is normal. The degree of masculinization and the development of internal genitalia mirror the degree of testicular differentiation. In most cases, there is failure in early gonadal development (sixth to eighth week of gestation) that results in absence of m€ ullerian duct inhibiting factor, testosterone, and DHT, culminating in development of female phenotype. Patients with incomplete 46,XY gonadal dysgenesis have ambiguous external genitalia and variable degrees of development of the m€ ullerian and wolffian structures. Gonads vary from a classic streak gonad, streak gonads with epithelial cord–like structures, and dysgenetic testes. Patients do not have mutations in the two major genes required for gonadal development: SRY and WT1, although some have altered NR5A1 gene.1324–1328 Epithelial cords of the most streak gonad express cytokeratins (AE1/AE3), inhibin, and D2–40, whereas germ cells are positive for PLAP and OCT3/4. Clitoromegaly may be caused by androgens secreted by hyperplastic Leydig cells in the streak gonad.1329 Cases of 46,XY gonadal dysgenesis may occur with coexistence of normal testes and ambiguous external genitalia, well-developed m€ ullerian structures, and poorly differentiated wolffian structures. This genital pattern likely results from late testicular determination rather than testicular differentiation defect. Although the testis produces testosterone and AMH, both hormones are inefficient

623

because the critical period of hormonal receptiveness has passed.1330 Some patients with 46,XY gonadal dysgenesis present with extragonadal anomalies and multiple syndromes, including camptomelic dysplasia and renal disorder; myotonic dystrophy and terminal renal disease; progressive renal insufficiency and gonadoblastoma (Frasier syndrome) (Figs. 12.155 through 12.158); mental retardation with or without facial anomalies or short stature; renal insufficiency and Wilms tumor (Denys–Drash syndrome); combination of cleft palate, micrognathia, kyphosis, scoliosis, and clubfoot (Gardner-Silengo-Wachtel syndrome or genitopalatocardiac syndrome); multiple pterygium syndrome; Graves disease; and congenital universalis alopecia, microcephaly, cutis marmorata, short stature, and peripheral neuropathy.1330–1347 Most cases are sporadic, although the syndrome has been reported in several members of the same family, and multiple forms of inheritance (X-linked, autosomal recessive, and male-limited autosomal dominant) have been proposed.1238,1321,1348–1357 In addition to infertility, patients with 46,XY gonadal dysgenesis have

Fig. 12.155 46,XX gonadal dysgenesis patient. Streak gonad enlarged by several nodules of variable size corresponding to a gonadoblastoma.

Fig. 12.156 Frasier syndrome in a 16-year-old patient. The two streak gonads contain gonadoblastoma. The nodules consist of Sertoli/granulosa cells and gonocytes. In the interstitium there are numerous Leydig cells.

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Fig. 12.157 Frasier syndrome. The cell surface and golgi zone of the atypical gonadoblastoma germ cells are immunoreactive for KIT.

Fig. 12.158 Streak gonad with a dissecting gonadoblastoma. The lesion is characterized by the presence of solid epithelial cords and small nests in which, two cell types, Sertoli/granulosa cells and gonocytes, are identified. There is a nodule of Leydig cells.

AMH, also known as m€ ullerian duct inhibiting factor or MIS, is a dimeric protein that belongs to the TGFB family and consists of two identical subunits of 72 kDa each, joined by disulfide bridges. The hormone is synthesized by the Sertoli cell. Its type II receptor is a serine/threonine kinase homologous to the receptors of other members of the same superfamily.1371 The AMH gene is located on the short arm of chromosome 19.72 The best-known AMH functions occur in fetal life and include m€ ullerian duct inhibition and tunica albuginea collagenization. Both actions are ipsilateral to the testis that produces the hormone. Patients with this type of undermasculinization, in addition to the AMH defect, may also present with androgenic deficiency. This syndrome accounts for approximately 15% of DSDs. A few patients are raised as boys, although their external genitalia are usually ambiguous as a result of fetal virilization. The penis is clitoriform, and the urethra opens in the perineum (Fig. 12.159). Most have cryptorchid testes and are raised as girls, becoming virilized at puberty. The diagnosis is not always made in infancy, and diagnosis as late as 66 years of age has been reported.1372 In adult patients, spermatogenesis is absent or deficient, and infertility is a common symptom.1373 Leydig cells show variable development and produce sufficient androgens to ensure pubertal virilization and lengthening of the phallus.1374 The etiology is heterogeneous: one-third of patients have turnerian features, in accordance with the presence of the 45,X0/46,XY karyotype in more than 50% of patients.1375–1377 Other observed karyotypes are 46,XY (13.6%) and 45,X0/47,XYY, 45,X0/46,XX/ 46,XY, 45,X0/46,XYq-, 45,X0/46,XYp-, 45,X0/46,X add (Y) (p11.3), 45X/46,Xr(Y), and 45,X0/46,X dic (Yp), and “inverted” Y chromosome.1378–1381 Approximately 81% of patients have one Y chromosome.1382,1383 Mutation in the SRY gene has not been found.1384 If the gonads are intraabdominal, the labioscrotal folds may appear as either normal labia or empty scrotal sacs (Fig. 12.159). In the former, the syndrome cannot be recognized in the newborn unless a peniform clitoris is present. If the gonad is descended, it is usually testis accompanied by hernia. M€ ullerian derivatives such as fallopian tubes are usually associated with streak gonad (95% of cases), but may also be associated with testicular tissue (74%). Ipsilateral to the testis are one epididymis and vas deferens. On the

a high risk for germ cell tumor, including gonadoblastoma, dysgerminoma, teratoma, and choriocarcinoma.1358–1364 The presence of calcifications, regardless of whether associated with gonadoblastoma, is a frequent finding. No relationship between SRY status and gonadoblastoma has been found. This risk is approximately 5% in the first decade of life and 25% to 30% overall, and thus prophylactic gonadectomy is recommended.1287,1365–1367 A few patients have had successful pregnancy and delivery of a healthy infant after in vitro fertilization using donor oocytes and embryo transfer.1368

Mixed Gonadal Dysgenesis Mixed gonadal dysgenesis, also known as asymmetric gonadal differentiation or Sohval syndrome, is characterized by streak gonad with or without UGT, streak testis on one side and contralateral testis (often cryptorchid), or streak testis on both sides.1369,1370 Classically, it is included in the categories of gonadal dysgenesis and male pseudohermaphroditism with m€ ullerian remnants, attributed to AMH gene mutations or target organ insensitivity.77

Fig. 12.159 Mixed gonadal dysgenesis in a 3-year-old child with ambiguous external genitalia, hypoplastic uterus, dysgenetic testis on the right side, and streak gonad on the left side.

CHAPTER 12 Nonneoplastic Diseases of the Testis

contralateral side, no gonad or a streak gonad and a fallopian tube are present. Hypoplastic uterus and poorly developed vagina are frequent findings. The gonads have three different patterns: testicular dysgenesis (Fig. 12.160), streak gonads, and streak testis. The testes in mixed gonadal dysgenesis are incapable of m€ ullerian duct inhibition and allow complete differentiation of wolffian derivatives, virilization of external genitalia, and in most cases, testicular descent. Patients with mixed testicular dysgenesis do not produce AMH or produce it in scant amounts. Nevertheless, some cases of dysgenetic testis with normal AMH levels and normal regression of m€ ullerian ducts have been reported.1385 Differentiation of isolated ovocyte contained in streak testis and ovotestis remains controversial.1386,1387 Tumors arise in these gonads in 15% to 25% of cases, with increase in relation to age with a marked increase after puberty.1388–1392 The most frequent tumor is gonadoblastoma, although all germ cell tumor types (except for spermatocyte seminoma) have been reported, including juvenile granulosa cell tumor.1393,1394 Removal of all streak gonads is recommended, as well as intraabdominal testes, except for testes that may be moved into the scrotum and are not associated with ipsilateral m€ ullerian derivatives. Scrotal testes should be retained.

Dysgenetic Male Pseudohermaphroditism Dysgenetic male pseudohermaphroditism is a DSD characterized by bilateral dysgenetic testes or streak testis, persistent m€ullerian structures, cryptorchidism, and incomplete virilization. This syndrome is considered a variant of mixed gonadal dysgenesis (Fig. 12.161).1395,1396 The karyotype may be 46,XY or 45,X0/ 46,XY, and turnerian stigmata may be present. The uterus and fallopian tubes are present, and both are usually hypoplastic.1397 The testes show lesions characteristic of dysgenetic testis, decreased tubular diameter, TFI, and increased number of Sertoli cells during infancy (Figs. 12.162 through 12.164).1397 In adults, spermatogenesis is reduced in some tubules and is incomplete, usually reaching maturation up to spermatocyte I. The remaining seminiferous tubules contain only Sertoli cells that are frequently immature. Sertoli cell number varies from one tubule to another, from markedly decreased to hyperplastic. Tubules with low number of Sertoli cells show higher maturation (Fig. 12.165). Tubules with immature Sertoli cells show an absence of immunoexpression of AR. Diffuse

Fig. 12.160 Dysgenetic testis. Several irregularly shaped seminiferous tubules are observed within a thin, poorly collagenized tunica albuginea.

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Fig. 12.161 Dysgenetic male pseudohermaphrodite with bilateral dysgenetic testis.

Fig. 12.162 Dysgenetic testis. The gonad has a central portion showing a testicular pattern and a peripheral band consisting of poorly collagenized connective tissue that contains seminiferous tubules that reach the gonadal surface.

Fig. 12.163 Dysgenetic testis. The albuginea is scored by seminiferous tubules and epithelial cords in all directions.

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Fig. 12.164 Dysgenetic male pseudohermaphroditism. Strong positive immunostaining for D2–40 in seminiferous tubules, located both in the peripheral loose stroma and in the central part, as an expression of tubular immaturity.

dependent structures (penis, scrotum, vas deferens, epididymis, prostate, and seminal vesicles) are well developed. Hormonal assays reveal that testosterone and response to hCG stimulation are normal. Plasma AMH levels vary according to the molecular basis of the syndrome. Measurement of this hormone in prepubertal patients is useful for diagnosis.1401 Exceptional cases of hernia uteri inguinalis occur in patients whose phenotype is that of normal female, and the gonads are normal ovaries.1402 PMDS is sporadic or familial, with autosomal recessive or X-linked inheritance.1403,1404 The incidence is estimated at 0 to 1 per 100,000 live births.1405 Although the external genitalia are male, one (25% of cases) or both testes (75% of cases) are cryptorchid. The syndrome usually also includes inguinal hernia contralateral to the undescended testis, with uterus and fallopian tubes within the hernia sac.1406 Presenting complaints are inguinal hernia, cryptorchidism, infertility, or testicular tumor.1396,1407–1410 The anatomy of the syndrome is varied and complex.163 Based on the location of the testicles and m€ ullerian duct derivatives, PMDSs have been classified into three types. Type 1, the “male form,” is most frequent (60% to 80%) and includes those patients with at least one testis present in the hernia sac. The contralateral testis is lodged in a hernia sac or scrotum, which also contains both a uterus and a fallopian tube (hernia uteri inguinalis (Figs. 12.166 through 12.168).1400,1411–1413 Type 2, “male with transverse testicular ectopy,” accounts for 20% to 30% of cases of PMDSs, presenting with both testes in the same scrotal pouch, within a hernia sac that also contains a fallopian tube and uterus.147,782,1414–1419 Type 3, the “female form,” is characterized by the presence of intraabdominal testes located in the anatomical site of the ovaries. Each is attached to its vas deferens and is associated with a uterine tube connecting with a uterus in the normal female pelvic position. Patients other than these with bilateral cryptorchidism do not usually present with inguinal hernias. They represent between 10% and 20% of cases.1406 The molecular basis of PMDSs is heterogeneous and recognized in almost 85% of cases. Most “males forms” (45% of cases) are due to defect in AMH synthesis caused by mutation in the AMH gene.1420 The “female form” is due to resistance of target organs

Fig. 12.165 Dysgenetic male pseudohermaphroditism in an adult patient showing pubertal maturation in Sertoli-only seminiferous tubules with irregular contours and diffuse Leydig cell hyperplasia.

or nodular Leydig cell hyperplasia is present. Leydig cells show nuclear pyknosis, grooves in the nuclear membrane, and empty nuclei. The incidence rate of germ cell tumors is high: 46% of 40-year-old patients.1398 Approximately 25% of patients experience development of gonadoblastoma and 10% experience GCNIS.1399

€llerian Duct Syndrome Persistent Mu PMDS has many names, including male with uterus, tubular hermaphroditism, inner male pseudohermaphroditism, persistent oviduct syndrome, and hernia uteri inguinalis.1400 It is a rare form of gonadal dysgenesis characterized by the presence of m€ ullerian derivative structures (fallopian tube, uterus, and upper part of the vagina) in an otherwise genetically and phenotypically normal male. The vagina opens into the posterior urethra in the verumontanum. It is the most characteristic form of isolated AMH deficiency, and more than 200 cases have been reported. Androgen-

€llerian duct syndrome. Fimbria portion of the uterFig. 12.166 Persistent mu ine tube with follicular hydrosalpinx image fused to the lower pole of the testis.

CHAPTER 12 Nonneoplastic Diseases of the Testis

€llerian duct syndrome. Cross-sectioned hypoFig. 12.167 Persistent mu plastic uterus. In its tunica adventitia and parallel to it, a folded vas deferens is seen.

€llerian duct syndrome. Uterus with atrophic endoFig. 12.168 Persistent mu metrium and hypoplastic myometrium within a hernia sac.

to this hormone caused by mutations in the receptor II for this hormone (40% of cases).1371,1420,1421 Other cases arise from failure in the action of AMH immediately before the eighth week of gestation (16% of cases). Variation in the site of the testes results from absence of AMH, in which patients undergo normal regression of the cranial suspensory ligament (which is under androgen control) and feminization of the gubernaculum (elongate and thin gubernaculum). These two features permit great mobility of the testis.163,1421a,1421b Some patients present with strong connections between the m€ ullerian structures and both the testis and the spermatic cord, thus hindering normal testicular descent and even causing ectopy. In childhood the testes have low TFI and decreased tubular diameter. In adults the tunica albuginea is variably thickened, contains connective tissue resembling ovarian stroma, and may contain tubular structures, alterations typical of dysgenetic testes. The seminiferous tubules are usually atrophic and hyalinized. Tubules with reduced spermatogenesis or patterns suggesting MAT (seminiferous tubules with spermatogenesis intermingled with Sertoli cell– only tubules) have also been reported.1422 The Leydig cells appear hyperplastic. Azoospermia or oligozoospermia are common, and

627

€llerian duct syndrome. Seminiferous tubules conFig. 12.169 Persistent mu taining germ cell neoplasia in situ (GCNIS) cells that stand out by large nuclei with several large nucleoli. Leydig cell hyperplasia is shown in the interstitium.

paternity is exceptional.1423 These patients have a higher risk for testicular tumor (18%) than that associated with simple cryptorchidism (Fig. 12.169). All types of germ cell tumors have been observed.1419,1424–1427 These tumors usually develop in the undescended testis, and in some cases tumors are bilateral.225,1428–1430 Other tumors observed in the syndrome are colonic adenocarcinoma and medullary carcinoma of the thyroid gland.1371 Orchidectomy should not be performed during infancy because these patients have male phenotype and the virilizing ability of testes should be preserved, but it is important that the testes occupy a scrotal location. The fallopian tube and rudimentary uterus should be maintained because these structures rarely produce symptoms, and their removal may injure the vas deferens.72,1431 Despite orchiopexy, as is the case in simple cryptorchidism, germ cell tumors may occur in later life.1428,1432,1433 Orchidectomy is performed only in testes that cannot be mobilized to a palpable location. Another potential complication is testicular torsion secondary to testicular hypermotility.1412

Other Forms of Gonadal Dysgenesis Of the dysmorphic syndromes associated with incomplete virilization of external genitalia, the best-known are Denys–Drash, WAGR (Wilms tumor, aniridia, genital anomalies, and mental retardation), and camptomelic dysplasia. In Denys–Drash syndrome, undermasculinization is associated with nephroblastoma and renal insufficiency.1434,1435,1436 The DSD is usually mixed gonadal dysgenesis, dysgenetic male pseudohermaphroditism, 46,XY pure gonadal dysgenesis, or ovotesticular DSD.1437–1441 The most common nephropathy is diffuse mesangial sclerosis.1442,1443 Although the most common gonadal types are streak gonads and dysgenetic testes, at least three cases with normal testes have been reported, two in patients with m€ ullerian structures.1444–1447 Most have mutations in the WT1 gene, which is expressed in the genital ridge in the sixth week of gestation.1448 Mutations in this gene may give rise to streak gonads or dysgenetic testes; if there is a delay in testicular determination, normal testes form.1449 Testes in Denys–Drash syndrome produce testosterone and AMH, but this production is delayed, and hormonal actions are not ineffective.

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The prevalence rate for WAGR syndrome is estimated at between 1% and 2% of patients with Wilms tumor. The syndrome is related to the syndromes of Denys–Drash and Frasier (a variety of 46,XY gonadal dysgenesis).1335,1450,1451 All share mutations in the WT1 gene located on chromosome 11 (11p13).1452,1453 WT1 product is a transcription factor expressed in different tissues which participates in embryogenesis and cell differentiation such as glomeruli precursor cells in fetal kidney, stromal cells of spleen and gonads, and mesothelial cell precursors of pleura, pericardium, and peritoneum. Mutations lead to the production of an anomalous protein that causes alterations in renal function, gonadal anomalies, and loss of tumor suppressor function. Six variants of alleles have been described: isolated Wilms tumor, mesothelioma, isolated diffuse mesangial sclerosis, Denys–Drash syndrome, Frasier syndrome, and WAGR syndrome. Frasier syndrome is caused by mutations in the donor zone of the intron 9 link, with subsequent loss of the +KTS isoform (imbalance in KTS isoforms), whereas large deletions or loss of genetic material that comprises the WT1 gene and other contiguous genes (PAX6 or AN) will lead to the WAGR syndrome.1454–1456 The most frequent genitourinary anomalies are cryptorchidism (60%) and ambiguous external genitalia. Camptomelic dysplasia is an autosomal dominant syndrome with multiple osseous malformations, including bowing of long bones, especially the femora and tibiae; winging of the scapulae; the presence of fewer ribs than normal; narrow iliac wings; and clubbed feet.1457,1458 Patients have the 46,XY karyotype and external genitalia that are ambiguous or female.1459 Gonadal histology varies from testes to dysgenetic ovaries with primary follicles, streak testes, and even ovotestes.1460–1464 Gonadal pathology may be present even in the absence of skeletal dysplasia.1465 The incidence of gonadoblastoma is low.1465a,1466 Dysgerminoma may occur in the gonad contralateral to the streak gonad.1466 The syndrome is caused in 75% of cases by mutations in SOX9, located in 17q24.3–25.1; this gene has pleiotropic effects on the skeletal and genital systems.1467–1470 Death usually occurs in the neonatal period from respiratory insufficiency. Only 5% to 10% survive.

Ovotesticular Disorder (True Hermaphroditism) Ovotesticular disorder of sexual development is an abnormality of gonadal differentiation characterized by the presence in the same individual of both testicular and ovarian tissue. This disorder affects less than 10% of the population with DSDs, with an incidence of 1 in 100,000 live births.1471–1474 This rare condition is usually difficult to diagnose because these patients do not show characteristic phenotype. As a result, only 25% of male hermaphrodites are identified before age 20 years.1475 The age spectrum at the time of diagnosis varies from newborns to 60-year-old patients.1476 Failure to recognize this disorder may lead to repeated surgical intervention for hernia or hypospadias repair or orchidopexy.1477 The most frequent karyotype is 46,XX (60%), followed by several mosaicisms (33%) that, in decreasing order of frequency, are 46,XX/46,XY, 46,XY/47,XXY, 45,X0/46,XY, 46,XX/47,XXY. The 46,XY karyotype is the least common (7%). Isolated cases with the following karyotypes have been reported: 47,XYY/46, XY/45,X0 and 46, XderY/45,X0 with rearranged Y chromosome.1478,1479 The incidence of some karyotypes varies around the world. Mosaicism is found in 41% of European cases, but in only 21% of North American cases. Conversely, most African true hermaphrodites (97%) have 46,XX karyotype. The karyotype

46,XY is rare and its frequency is similar in Europe, Asia, and North America.1480,1481 Most cases are sporadic, and families with several affected members also have 46,XX males without ovotesticular disorder. This finding suggests that both genetic anomalies are alternative forms of a single genetic defect, which probably consists of an autosomal dominant mutation with incomplete penetrance or an X-chromosome–linked mutation.1482–1486 Pathogenetic theories proposed to explain true hermaphroditism begin with the understanding that, if patients have testes, TDF (produced by the SRY gene) is present. The following mechanisms are easy to explain when the karyotype is 46,XY, mosaicism 46,XX/45,XY, or chimera 46,XY. However, the presence of testicular parenchyma in the karyotype 46,XX (the most common) may result from: (1) hidden mosaicism including a line with the Y chromosome; (2) translocation of paternal Y chromosomal material that includes the SRY gene to the X chromosome; (3) autosomal mutation with variable penetrance; and (4) X-chromosome–linked mutations that either are coupled with a rare X-chromosome inactivation or permit testicular differentiation in the absence of SRY, or mutations in genes such as SOX9 and FGF9 that regulate the action of SRY, NR5A1, a transcriptional regulator of genes involved in adrenal and gonadal development, RSPO1, partial deletion of DMRT1, and SOX3 duplication.1487–1494 Molecular studies have shown that only a few 46,XX true hermaphrodites have Y-DNA chromosome sequences, in contrast with the socalled XX males, who have Y-chromosome material including TDF in 80% of cases.1483,1495,1496 Some 46,XX true hermaphrodites who are SRY
in lymphocyte studies show positive reactions to SRY in DNA obtained from the testicular parenchyma of the ovotestis.1497–1499 The phenotype of true hermaphrodites varies from normal male to female. Hermaphrodites with male phenotype do not exceed 10% of the total.1482,1500 The phenotype is related to the presence of the SRY gene. In XX patients the phenotype could depend on two features: the length of Y translocated material (the higher the length of Yp fragment, the more complete is the masculinization) or the X chromosome where the SRY gene is translocated. If the translocation involves the active X chromosome, phenotype will be XX male (with masculinized external genitalia), whereas if the translocation involves the inactive X chromosome, the phenotype will be ambiguous genitalia. Most patients raised as boys display symptoms for the first time at puberty because of breast development (95% of hermaphrodites have some degree of gynecomastia), periodic hematuria (if they have a uterus ending in the urinary tract), or cryptorchidism.1501–1503 46,XX male without SRY and complete male phenotype with absence of female internal genitalia and presence of a prostate has been reported.1504 Hermaphrodites raised as girls initially present with irregular menstruation or clitoromegaly and, rarely, cyclic pain in a descended or undescended gonad.1505 True hermaphroditism should be suspected in all children with ambiguous sex characteristics (Fig. 12.170).1506 The gonads of these patients are ovotestes (44%), ovaries (33%), or testes (22%), with all possible combinations.1507 True hermaphroditism may be: (1) unilateral, if there are both testicular and ovarian tissues (forming one ovotestis or two separate gonads) on one side and a testis or an ovary on the other side (50%)1475,1508; if there is no gonadal tissue on the latter side, unilateral hermaphroditism is incomplete; (2) bilateral, if testicular and ovarian tissues are present on both sides (20%); or (3) alternate, if there is a testis on one side and an ovary on the other side. Other rare presentations include patients with ovotestis and

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.170 Patient with ovotesticular disorder showing external genitalia that display transverse folds and a slightly hypertrophic clitoris.

contralateral streak gonad and those with crossed ectopy consisting of a left-sided ovotestis that is displaced to the right scrotum.1509,1510 The degree of gonadal descent mirrors the amount of testicular tissue present. The gonadal nature may be suspected during physical examination. High testosterone levels suggest the presence of Leydig cells, and therefore the presence of a testis. High levels of estradiol after human menopausal gonadotropin stimulation suggest the presence of an ovary.1511 Ovotestis is the most frequent gonadal type in true hermaphroditism. It is more common on the right side and is in the abdomen (50% of cases), labioscrotal folds, inguinal canal, or external inguinal ring. Only 5% of patients with bilateral ovotestis show complete gonadal descent.1512,1513 The ovotestis has a bilobate or ovoid shape (Fig. 12.171). In the bilobate ovotestis the testis and ovary are connected by a pedicle, whereas in the ovoid ovotestis the ovarian tissue forms a crescent capping the testicular parenchyma. The proportion of ovary to testis varies widely (Figs. 12.172 and 12.173). Clear-cut separation between ovarian and testicular tissue is evident in some cases, or ovocytes may be diffusely distributed between seminiferous tubules or even inside the tubules. The testicular zone next to the ovarian component

Fig. 12.171 Ovotesticular disorder. The ovotestis contains ovarian follicles arranged in a crescent. There is cystic transformation of the rete testis. The epididymis is hypoplastic.

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Fig. 12.172 Ovotesticular disorder. Ovotestis from a 2-year-old. The ovarian and testicular tissues are sharply demarcated.

Fig. 12.173 Ovotestis. Oocyte inside a seminiferous tubule.

shows important changes in interstitium and tunica albuginea. Interstitial tissue has a stroma similar to ovarian stroma, instead of the characteristic loose connective tissue of normal testes. The tunica albuginea that covers the testicular zone shows poor differentiation, with persistence of tubular structures within it, or tubules that cross the tunica albuginea to reach the mesothelial surface. The mesothelial lining of this zone may be columnar, instead of flattened. These findings are like those observed in male pseudohermaphrodites with persistence of m€ ullerian structures.1479 In a large series of South African true hermaphrodites, three different types of ovotestes were observed. The ovotestes were separated by gross appearance into mixed type and bipolar (89% and 11%, respectively). The mixed-type ovotestes had an outer mantle consisting of ovarian tissue, which encapsulated an inner core of two distinct types of gonad. The first was an admixed ovotestis (constituting 44% of the mixed ovotestes); the central core consisted of gonadal stroma, with scattered foci of separate ovarian and testicular tissue. The second type was the compartmentalized ovotestis (constituting 56% of the mixed ovotestes); here, the outer mantle was thickened in the upper pole and encapsulated a large core of testicular tissue in the lower pole of the gonad. Histologically the bipolar ovotestis had a strictly polar distribution of ovarian

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and testicular tissue, which had an irregularly interdigitating junction between the two types of tissue. There is no correlation between the type of gonadal tissue and any clinical or genital features.1514 During adulthood, ovarian follicles mature and corpora lutea or corpora albicantia may be seen. The seminiferous tubules rarely develop complete spermatogenesis, often contain a higher number of dysgenetic Sertoli cells only, and frequently undergo hyalinization (Figs. 12.174 and 12.175). The interstitium usually contains Leydig cells (Fig. 12.176). Ovotestis is associated with the fallopian tube in 65% of cases (Fig. 12.177) and with the vas deferens in the

Fig. 12.176 Ovotestis. Irregularly anastomosed seminiferous tubules showing prepubertal features characterized by Sertoli cell pseudostratification and eosinophilic bodies in the apical cytoplasm of Sertoli cells. The interstitium shows Leydig cell pseudohyperplasia.

Fig. 12.174 Ovotesticular disorder. Ovotestis in an adult patient containing several corpora albicans in the periphery and seminiferous tubules in the center of the gonad. In the outer portion of the gonad, there is a cystic formation that corresponds to the uterine tube; in its periphery, epididymal ducts are observed.

Fig. 12.177 Ovotesticular disorder. Epididymis and fallopian tube in an adult hermaphrodite raised as a female.

Fig. 12.175 Ovotesticular disorder. Ovotestis in an adult patient showing a clear delimitation between ovarian and testicular areas of the gonad that consist of one corpus albicans and seminiferous tubules with deficient spermatogenesis and hyalinization, respectively.

remainder. If the patient has ovotestis/ovary, a completely developed uterus is present. If the patient has bilateral ovotestis (13%), uterine agenesis is frequent.1480 The testis of patients with ovotesticular disorder is most often on the right side (60%) and is located anywhere from the abdomen to the scrotum. These testes have low TFI during childhood (Fig. 12.178). After puberty the seminiferous tubules remain small, often containing only dysgenetic Sertoli cells, similar to the tubules of cryptorchid testes. Isolated groups of microvacuolated Leydig cells are also observed. Incomplete spermatogenesis has been reported, but complete spermatogenesis is exceptional. The ovary of hermaphrodites is most frequently on the left side (63%) and usually is hypoplastic with few primordial follicles (Fig. 12.179). However, in occasional patients the ovary is histologically and functionally normal. More than two dozen pregnancies in patients with ovotesticular disorder have been reported.1515–1523 This contrasts with the

CHAPTER 12 Nonneoplastic Diseases of the Testis

631

into account.1283,1481 Many of these patients experience development of a gonadal tumor after long-term follow-up. The most frequent tumors are gonadoblastoma, dysgerminoma/seminoma, choriocarcinoma, and yolk sac tumor. Other reported tumors are mature teratoma, carcinoid, and granulosa cell tumor.1507,1529–1534 Tumors that develop in these gonads, like tumors in cryptorchid testes, may reach a great size before their diagnosis. The risk for cancer may be reduced if some precautions are taken, including removal of the testis if it has not descended and surveillance of the residual gonad with periodic ultrasound studies, especially in patients with chromosomal mosaicisms.

Undermasculinization (Male Pseudohermaphroditism) Fig. 12.178 Infantile testis contralateral to ovotestis showing apparent Sertoli cells hyperplasia, immature Sertoli cells, and isolated spermatogonia.

Normal male development requires adequate differentiation of the testes in the fetal period, synthesis and secretion of testicular hormones, and proper response of target organs. AMH produced by Sertoli cells inhibits development of m€ ullerian derivatives that would otherwise form the uterus and fallopian tubes. Testosterone produced by Leydig cells stimulates differentiation of wolffian ducts into male genital ducts. Conversion of testosterone into DHT by the enzyme 5α-reductase ensures development of male external genitalia. Alterations in these processes may cause varying degrees of undermasculinization.

Impaired Leydig Cell Activity Impaired Leydig cell activity may be present in two different conditions: insufficient androgen synthesis caused by enzymatic defects and absence or hypoplasia of Leydig cells. Androgen Synthesis Deficiencies

Fig. 12.179 Infantile ovary contralateral to ovotestis showing numerous primordial and primary follicles and one atretic follicle.

exceptional cases of paternity. The origin of oocytes could be an ovotestis or an ovary.1524,1525 Most patients develop hypergonadotropic hypogonadism. The treatment of ovotesticular DSD is complex because it involves the patient’s relatives and several medical specialties, given that genetic sex, gonadal sex, social gender, and psychological gender must be considered.1526 Management of patients with ovotesticular disorder depends on the patient’s age at the time of diagnosis, the nature and location of the gonads, and the developmental stage of the external genitalia.1527 Genetic sex determined by karyotype and Y-chromosome sequence detection are not considered useful criteria.1528 Although bilateral castration may be justified to avoid the risk for neoplasia, gonadal preservation may be desirable until adulthood. In this case, if the patient is raised as a girl, puberty will occur spontaneously, and there is a small chance of fertility.1527 However, the high risk for malignancy (estimated at 4.6% for those with 46,XX karyotype and 10% when the karyotype is 46,XY or mosaicism 46,XX/XY) should be taken

These autosomal recessive syndromes are characterized by an error in testosterone synthesis that results in incomplete or absent virilization.1535,1536 Five enzymes are responsible for testosterone synthesis. The absence of or deficit in one of these enzymes decreases androgen production. Three (20,22-desmolase, 3β-HSD, and 17α-hydroxylase) are also involved in synthesis of adrenal androgens, and deficit results in congenital adrenal hyperplasia. Deficit or absence of either of the other two (17,20-desmolase and 17βHSD) mainly impairs gonadal synthesis of testosterone and estrogens. Cholesterol is the source of synthesis of androgens, estrogens, and other steroid hormones through multiple steps. First, the steroidogenic acute regulatory (STAR) protein transfers cholesterol into mitochondria; STAR gene mutations cause congenital lipoid adrenal hyperplasia. Second, within mitochondria, the cholesterol side-chain cleavage enzyme P450scc transforms cholesterol into pregnenolone; a disorder of this enzyme is rare because it is highly lethal in embryonic life. Third, pregnenolone undergoes 17αhydroxylation by microsomal P450c17; deficiency in 17αhydroxylase causes female sexual infantilism and hypertension. Fourth, 17-OH-pregnenolone is converted into Dehydroepiandrosterone (DHEA) by 17,20-lyase activity of P450c17. The ratio of 17,20-lyase to 17α-hydroxylase activity of P450c17 determines the ratio of C21 to C19 steroids produced. The ratio is regulated by at least three factors, including the electron-donating protein P450 oxidoreductase (POR), cytochrome b5, and serine phosphorylation of P450c17. Mutations in POR are present in Antley-Bixler skeletal dysplasia syndrome, as well as in a variant of polycystic ovarian syndrome. Fig. 12.180 shows the enzymes involved in the previously mentioned steps. The enzyme 3β-HSD transforms

632 C H A P T E R 1 2

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Cholesterol Outer StAR

Mitochondrial membrane Inner

Cholesterol 1 3

4

Pregnenolone

Dehydroepiandrosterone

17OH-Pregnenolone

2

2

2

3

4

Androstendione

17OH-Progesterone

Progesterone

5

Deoxycorticosterone

11-Deoxycortisol

Testosterone

Estrone

6

Corticosterone

Dehydrotestosterone

Cortisol

5

Estradiol

18-OH-Corticosterone

Aldosterone

1

CYP11A1 (20,22 desmolase, 20α-hydrolase)

4

CYP17A1, 17-20-lyase

2

3β-hydroxysteroid dehydrogenase

5

17β-hydroxysteroid dehydrogenase

3

CYP17A1, 17α-hydroxilase

6

5α-reductase

Fig. 12.180 Enzymatic defects in impaired testosterone biosynthesis.

DHEA to androstenedione, and the enzymatic complex called aromatase transforms androstenedione into estrone and testosterone into estradiol. In some patients, cholesterol synthesis is also impaired, and congenital adrenal hyperplasia is superimposed on androgen deficiency. Deficient testosterone synthesis may result from abnormalities in the enzymes involved in pregnenolone formation (congenital lipoid adrenal hyperplasia), including 3β-HSD, 17αhydroxylase, 17,20-desmolase, and 17β-HSD (Fig. 12.180). Congenital Lipoid Adrenal Hyperplasia. Congenital lipoid adrenal hyperplasia is the most severe form of congenital adrenal hyperplasia.1537,1538 The disorder is characterized by a deficit in steroid hormone synthesis in the adrenal cortex and gonads that produces 46,XY genetic males with female phenotype and severe salt-loss syndrome. Conversion of cholesterol to pregnenolone requires the enzymes 20α-hydroxylase, 20,22-desmolase, and 22α-hydroxylase. Failure of any of these leads to deficits in cortisol, aldosterone, and testosterone.1539 The enzymatic defect is usually caused by a deficit in the StAR protein; in other cases the deficit is in P450ssc.1540 The mitochondrial StAR protein promotes cholesterol transfer from the outer to the inner mitochondrial membrane, where cholesterol serves as a substrate for P450scc and initiates steroidogenesis.1541–1543 Any of 48 possible mutations in the STAR gene result in congenital lipoid adrenal hyperplasia.1544–1547 As a result, cholesterol is not converted to pregnenolone, which is required for the synthesis of mineralocorticoids, glucocorticoids, and sex hormones. The disorder is rare in most countries, but it is common in Japan and Korea.1548,1549 The mutation p.Q258X accounts for

70% of affected alleles in Japan and 95% of the alleles reported to date in Korea. The disorder is also observed in Palestinian Arabs in bearers of different mutations, in Arabs from the Eastern Province of Saudi Arabia and nearby Qatar, all of whom carry the mutation p.R182H, and in the Swiss by the mutation p.L260P. Patients usually present with salt-losing crisis in the first 2 months of life.1550,1551 In most cases, males have female external genitalia, reflecting absence of testosterone synthesis between weeks 6 and 12 of gestation. A few patients have ambiguous external genitalia and a blind-sac vagina, hypoplastic wolffian derivatives, absence of m€ ullerian structures, and cryptorchidism.1552 The adrenals usually appear enlarged and contain lipid accumulations that eventually diminish with age, and the adrenals shrink.1553,1554 Histologic studies of the testes of these patients are limited in number and lack consistency. In childhood, seminiferous tubules usually show Sertoli and germ cells or only Sertoli cells.1539,1555 In the testes, lipid accumulations may be absent or present in Leydig cells (Fig. 12.181).1537,1553,1556–1561 The testes of pubertal patients are usually normal for age, or lipid accumulation in Sertoli cells is noted.1559,1560,1562 The epididymis and vas deferens are normally developed. GCNIS was reported in one case.1563 Given that these patients are infertile, early gonadectomy may avoid development of testicular tumor.1564 Most patients die of adrenal insufficiency. Survivors have female phenotype and require administration of glucocorticoids, mineralocorticoids, and gonadal steroids.1539,1562 Prenatal diagnosis may be made by several methods.1565 Nonclassic congenital lipoid adrenal hyperplasia is a new term to designate a disorder of the StAR protein that is caused by

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.181 Congenital lipoid adrenal hyperplasia in a 21-year-old patient. Seminiferous tubules show thickening of the basement membrane and contain only Sertoli cells with some cytoplasmic vacuoles. Leydig cells show large and microvacuolated cytoplasm.

mutations that retain 10% to 25% of function.1566 This disorder is characterized by the onset of glucocorticoid deficiency after 2 years of age, as well as mild defects in mineralocorticoids and sex steroid synthesis. Rare mutations in P450scc result in both classic and nonclassic hormonal syndromes that are indistinguishable from congenital lipoid adrenal hyperplasia, but with small adrenals.1567 3β-Hydroxysteroid Dehydrogenase Deficiency. 3βHydroxysteroid dehydrogenase deficiency, first reported in 1961, is also known as type VI adrenal hyperplasia.1568 Patients have two main problems: salt-loss syndrome produced by reduced aldosterone secretion and incomplete virilization.1568 At puberty, virilization increases and gynecomastia develops.1569,1570 The enzyme 3β-HSD catalyzes the conversion of 5-3βhydroxysteroids such as pregnenolone, 17-hydroxypregnenolone, and DHEA into 4-3β-ketosteroids progesterone, 17hydroxyprogesterone, and androstenedione, respectively.1571 There are two 3β-HSD genes located on the p11-p13 region of chromosome 1. The type I gene is expressed in the placenta, kidney, and skin, whereas the type II gene is expressed only in the gonads and adrenal glands. Complete absence of the 3β-HSD gene is lethal; therefore most reported cases have only partial 3β-HSD deficits.1536,1572–1575 These deficits account for approximately 10% of cases of congenital adrenal hyperplasia. The classic form of salt-losing 3β-HSD deficit is diagnosed in the first months of life because of insufficient aldosterone synthesis and subsequent loss of salt. The other form of 3β-HSD deficit does not involve salt loss, and its diagnosis may be delayed until puberty. Both forms are caused by mutations in the type II 3β-HSD gene (HSD3B2).1570 Severe forms of 3β-HSD deficiency are associated with deficits in aldosterone, cortisol, and estradiol. Symptoms may vary widely because enzymatic activity in the adrenal gland is not the same as in the testis. Most patients show salt loss and adrenal insufficiency; they have incomplete masculinization and may develop premature puberty and gynecomastia.1569,1576,1577 Patients with mild forms have normal genitalia and normal mineralocorticoid levels. Some patients have only hypospadias or micropenis.1578,1579 The testes are smaller and softer than normal. The diagnosis is

633

made by serum and urine determinations of elevated levels of 17α-hydroxy-5-pregnenolone, DHEA, DHEAS, and other 3βhydroxy-5 steroids.1580 17α-Hydroxylase/17,20-Lyase Deficiency. This deficit, also known as type V congenital adrenal hyperplasia, was first described in a woman in 1966.1581 The first reported male patient was a 24year-old man with male pseudohermaphroditism, ambiguous external genitalia, absence of male secondary characteristics, and prominent breast development at puberty.1582 Testicular biopsy performed at 16 years of age showed a delay in seminiferous tubule development with the presence of early spermatogenesis and Leydig cell hyperplasia. Deficits in the enzymes 17α-hydroxylase and 17,20-lyase are caused by mutations of the CYP17 gene that encodes cytochrome P450c17.1583 The CYP17 gene is located on chromosome 10q24q25, and 50 different mutations have been described.1584–1586 P450c17 catalyzes the 17α-hydroxylation of pregnenolone to 17-OH-pregnenolone and of progesterone to 17α-OH-progesterone. This enzyme also catalyzes 17,20-lyase activity, thus transforming 17-OH-pregnenolone to DHEA. The P450c17 microsomal enzyme is expressed in the reticularis and fasciculate zones of the adrenal glands, Leydig cells, and theca cells of the ovary. It has two distinct activities: (1) 17α-hydroxylase, which catalyzes the 17α-hydroxylation of C21 steroids necessary for the synthesis of cortisol; and (2) 17,20-lyase, which catalyzes cleavage of the C17–21 bond and converts C21 compounds to C19 steroids in the androgen-estrogen synthesis pathway.1587 The classic form of 17α-hydroxylase deficit is caused by severe deficiencies in CYP17; less severe defects give rise to the isolated 17,20-lyase deficit. 17α-Hydroxylase deficit impairs the synthesis of both cortisol and testosterone.1588 Low cortisol levels stimulate ACTH secretion, thereby causing hypersecretion of aldosterone precursors and the development of hypokalemic hypertension.1589 The deficit in testosterone secretion by fetal testes leads to male undervirilization. Patients are raised as girls. At puberty, patients may have amenorrhea, scant axillary and pubic hair, eunuchoid appearance, and gynecomastia.1590,1591 Elevated levels of progesterone, pregnenolone, and corticosteroids are detected in plasma. 17,20-Desmolase Deficiency. 17,20-Desmolase deficiency was first described in three male siblings.1592 The enzyme 17,20desmolase cleaves the side chain of 17-hydroxypregnenolone and 17-hydroxyprogesterone to form DHEA and androstenedione, respectively. This enzyme is encoded by a gene that has been mapped on chromosome 10. Varying degrees of 17,20-desmolase deficiency are seen, resulting in varied development of external genitalia that ranges from female phenotype to virilization with microphallus, bifid scrotum, perineal hypospadias, and cryptorchidism, secondary to insufficient testosterone production during fetal life.1593 In childhood the testes contain reduced numbers of spermatogonia (Figs. 12.182 and 12.183).1592,1594 At puberty, complete masculinization without gynecomastia occurs. Patients have low levels of testosterone, androstenedione, DHEA, and estradiol, and high levels of pregnanetriolone (a metabolite of 17α-hydroxyprogesterone).1594 In adulthood, some patients with 17,20-desmolase deficit may develop an additional deficiency of 17α-hydroxylase with hypertension.1595,1596 The cause may be mutations in one of the genetic loci encoding P450c17, flavoprotein POR, or cytochrome b5.1597 17β-Hydroxysteroid Dehydrogenase Deficiency. This syndrome was first reported in 1970.1598,1599 The highest incidence (1 in 100 to 1 in 150 males) may occur in the Arabian population

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Fig. 12.182 Undermasculinization with androgen synthesis deficiency. The external genitalia are ambiguous.

Fig. 12.183 Intense Leydig cell vacuolation in an infant with androgen synthesis deficiency.

of Israel (Gaza).1600 The enzyme transforms androstenedione into testosterone and converts estrone into estradiol, with deficit caused by mutations in the HSD17B3 gene located on 9q22.1601–1604 The enzymatic defects are sex linked and have a familial occurrence. Most patients have female phenotype at birth and are raised as girls, but at puberty undergo virilization.1605–1608 Androstenedione serum levels are increased, in contrast with low testosterone levels that do not rise after hCG stimulation. One or both testes may be cryptorchid or located in the labia majora. Normal spermatogenesis has never been observed. The most common testicular patterns are hypospermatogenesis, MAT, or Sertoli cell–only tubules, and Leydig cell hyperplasia is constant.1609–1612 Germ cell injury was initially attributed to cryptorchidism, but is now thought to be due to a primary testicular disorder because even young patients lack germ cells.1613 Leydig Cell Hypoplasia

Leydig cell hypoplasia is also known as inherited defect in Leydig cell gonadotropin receptors, Leydig cell agenesis, Leydig cell

hypoplasia, absence of response to gonadotropins, abnormal Leydig cell differentiation, Leydig cell hypofunction, and Leydig cell hypogenesis.1614–1621 This variant of undermasculinization DSD is defined by insufficient testosterone secretion; predominance of female external genitalia; absence of secondary sex characteristics (male or female) at puberty; absence of a uterus and fallopian tubes, and presence of an epididymis and vas deferens; 46,XY karyotype; low serum testosterone in spite of the increased gonadotropin levels; lack of response to hCG stimulation; absence of an enzymatic defect in testosterone synthesis; and small undescended testes that are gray and mucoid on sectioning.1616,1617,1619,1621–1623 Age at diagnosis varies from 4 months to 35 years, although most cases are diagnosed at puberty. The syndrome is sporadic and familial.1618,1624 The best-known cause of Leydig cell hypoplasia is inactivating mutation of LHR in these cells.1625–1627 Both LH and hCG have essential roles in male sexual differentiation. The action of both hormones is mediated by the LH/CG receptor (LHCGR), a member of the G protein–coupled receptor family that is expressed in Leydig cells, granulosa-lutein cells, and theca cells. The LHCGR gene is located on chromosome 2p21 and consists of 11 exons and 10 introns resulting in overall protein length of 674 amino acids.1628,1629 In 50% of cases, the cause seems to be an inactivating mutation in LHCGR, although there are isolated cases of mutations only in certain exons such as 4, 6A, 7, and 8 or coexistence of two mutations in the same LHCGR gene locus.1630–1632 In the remaining cases with clinical symptoms of Leydig cell hypoplasia, no mutations have been found, suggesting the possibility of defects in other genes or other unexplored regions of LHCGR.1633,1634 During fetal life, there is inadequate response to placental hCG initially and subsequently to pituitary LH.1626,1627,1635 Patients with 46,XY with inactivating mutations of LHR show abnormal Leydig cell differentiation, resulting in reduced production of testosterone and, subsequently, DHT.1625 Phenotypes vary widely according to the presence of complete or partial loss of receptor function, ranging from male undermasculinization with female external genitalia in type I Leydig cell hypoplasia (LCHT1) to male phenotype with micropenis, hypospadias, pubertal delay, and primary hypogonadism in type II Leydig cell hypoplasia (LCHT2). The different mutations detected may give rise to partial or complete loss of LHR function and explain the variability in phenotypes.1636,1637 In LCHT1 the testes contain small seminiferous tubules with Sertoli cells, spermatogonia, and thickened basement membranes. Leydig cells are rare, absent, or immature, in contrast with Leydig cell hyperplasia seen in other types of undermasculinization, such as those arising from defects in androgen synthesis or androgen action on peripheral tissues (e.g., 5α-reductase deficit).1638–1641 Some patients with Leydig cell hypoplasia possess androgendependent structures, including epididymis and ductus deferens, although these structures are usually hypoplastic or atrophic. This finding suggests a certain amount of androgenesis during embryonal development or involvement of other factors in addition to androgens in wolffian duct differentiation. Leydig cell hypoplasia results in low serum testosterone, lack of virilization, and lack of spermatogenesis. The absence of m€ ullerian derivatives suggests normal function of Sertoli cells, which synthesize AMH. In LCTH2, adult testes show maturation arrest of spermatogenesis in young spermatids, as well as a few incompletely differentiated Leydig cells.1623,1638,1642

CHAPTER 12 Nonneoplastic Diseases of the Testis

Impaired Androgen Metabolism in Peripheral Tissues Androgens exert their function on differentiation and development of the normal male phenotype via a single receptor protein, the AR. AR is expressed in fetal tissues as early as 8 weeks of gestation, before the onset of androgenic action, and is activated in a ligand-dependent manner to coordinate expression of suitable responsive genes. In the human embryo, testes begin to secrete androgens by the ninth week of gestation. Testosterone reaches a peak between 11 and 18 weeks of gestation and is responsible for wolffian duct differentiation into the epididymis, ductus deferens, and seminal vesicles. Testosterone conversion into a more powerful androgen, DHT, by the 5α-reductase enzyme initiates prostate development from the urogenital sinus and masculinization of the primordial external genitalia into the penis and scrotum. Deficiencies in the peripheral actions of androgens result in complete and incomplete testicular feminization syndromes, as well as 5α-reductase deficiency syndrome. Androgen Insensitivity Syndromes

Testosterone penetrates target tissues by passive diffusion. A small amount of this hormone is converted to DHT by the enzyme 5α-reductase. Both hormones have high binding affinity for AR located in the cytoplasm (cytosol receptors). AR complexes enter the nucleus and stimulate transcription of mRNAs involved in the synthesis of proteins responsible for peripheral androgen effects. Resistance to androgen stimulation is the cause of several syndromes with phenotypes varying from female (complete testicular feminization) to normal male, with intermediate degrees of undermasculinization.1643–1645 The karyotype is usually 46,XY, but 47, XXY and several mosaicisms have been observed.1646 These syndromes are caused by partial or complete lack of response by the target organs to androgen effects, because of the absence, diminution, or impairment of AR, abnormality of intracellular AR, or postreceptor anomaly.254,1646a,1647–1649 The gene for AR is located on the X chromosome (Xq11-q12). It contains eight exons, and X-linked transmission occurs in two-thirds of cases. Molecular analysis of the gene for AR reveals that varied clinical presentations result from different mutations in this gene. More than 800 AR mutations have been reported in AIS.1650– 1656 The four main mutations are interruptions of AR open reading frame, mutations in the DNA-binding domain of AR, amino acid substitutions in the hormone-binding domain of AR, and amino acid substitutions causing absent ligand binding.1657–1659 These syndromes affect 1 in 20,000 to 1 in 40,000 newborns, and transmission is recessive X-linked in two-thirds of cases. The diverse phenotypes associated with androgen insensitivity may be classified as complete AIS (CAIS) or testicular feminization syndrome; partial AIS (PAIS) or partial testicular feminization syndrome, which includes the syndromes of Lubs, Gilbert-Dreyfus, Reifenstein, and Rosewater, as well as Kennedy disease; and mild AIS (MAIS), which includes infertile men with minimal androgen insensitivity. Classification of AIS similar to that of congenital adrenal hyperplasias has been proposed in which patients with a normal male phenotype comprise type 1 and those with female phenotype comprise types 6 and 7 according to the presence (type 6) or absence (type 7) of axillary and pubic hair (Table 12.19).1650 Complete Androgen Insensitivity Syndrome (Complete Testicular Feminization Syndrome). CAIS, formerly known as testicular feminization syndrome, first described in 1952, is characterized by female phenotype with testes.1660 It accounts for 15% to 20% of all DSDs. Karyotype is usually 46,XY, although mosaicisms

635

and 47,XXY patients have been reported.1646,1661–1664 Mutations in AR are present in 95% of patients. CAIS is rarely diagnosed during childhood. Exceptions include children with hernia (1% to 2% of female patients with inguinal hernia have CAIS), repair of which reveals testes, inguinal tumor, or family history of male undermasculinization.1665–1670 Puberty is usually delayed, and stature is above the median. Primary amenorrhea is the principal presentation in adults. The testes may be in the abdomen, inguinal canal, or labia majora. Seminiferous tubules with scant germ cells and hypertrophy and hyperplasia of Leydig cells may be seen on histologic examination of the testicular parenchyma.1671 The incidence of abdominal testes is higher in patients with complete female phenotype and absence of pubic hair.1672 During the first year of life, the testis may be normal histologically except for reduced tubular diameter and low TFI. Thereafter, decreased germ cell numbers become evident, and the few remaining spermatogonia are concentrated in clusters of seminiferous tubules.1673 The interstitium contains numerous spindle cells arranged in bundles that recall ovarian stroma, and during the first year of life, there are Leydig cells with abundant eosinophilic or vacuolated cytoplasm (Figs. 12.184 and 12.185). At puberty, patients have female external genitalia, a short and blind-ended vagina, feminine breast development, and sparse pubic and axillary hair.1643,1674 The testes show delay in seminiferous tubule maturation in relation to the interstitium. Seminiferous tubules retain an infantile morphology, whereas the interstitium has adult Leydig cells (Fig. 12.186). There is intense cytoplasmic immunoreactivity for AMH and diffuse nuclear staining of SOX9 in Sertoli cells, as well as focal weak cytoplasmic PGDS expression. Spermatogonia show focal weak nuclear PGDS

TABLE 12.19

Spectrum of Phenotypes in Androgen Insensitivity Syndromes

Androgen insensitivity syndromes and phenotype grade Complete Type 7: Complete androgen insensitivity syndrome without axillary or pubic hair. Type 6: Complete androgen insensitivity syndrome with axillary or pubic hair.

Incomplete Type 5: Lubs syndrome. Female phenotype, clitoromegaly, or minimal posterior labial fusion. Type 4: Gilbert-Dreyfus syndrome. Ambiguous phenotype, small phallus, intermediate between penis and clitoris, urogenital sinus without perineal opening, labioscrotal folds with or without wrinkles and posterior fusion. Type 3: Reifenstein syndrome. Predominant male phenotype, micropenis, perineal hypospadias, cryptorchidism, or bifid scrotum. Type 2: Male with hypospadias. Male phenotype, mild defect in fetal virilization, isolated hypospadias. Type 1: Rosewater syndrome. Normal male phenotype, gynecomastia, infertility. Kennedy disease. Normal male phenotype, spinal and bulbar muscular atrophy, X-chromosome linked. Infertile male syndrome. Normal male phenotype, infertility. Modified from Quigley CA, De Bellis A, Marschke KB, et al. Androgen receptor defects: historical, clinical and molecular perspectives. Endocr Rev 1995;16: 271–321.

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Fig. 12.184 Complete androgen insensitivity syndrome. Seminiferous tubules with prepubertal maturation separated by thick septa of hyalinized stroma.

Fig. 12.186 Complete androgen insensitivity syndrome in an adult. Small seminiferous tubules with immature Sertoli cells surrounded by thick basement membranes and numerous Leydig cells.

Fig. 12.185 Complete androgen insensitivity syndrome in a 5-year-old boy. Seminiferous tubules lack germ cells. The interstitium shows a group of Leydig cells with highly vacuolated cytoplasm.

Fig. 12.187 Complete androgen insensitivity syndrome. Inhibin immunostaining showing intense expression in seminiferous tubules with prepubertal features. Note the inhibin-positive bodies in the apical pole of Sertoli cells.

expression. No AR immunoreactivity is observed.1675 Hormonal studies show increased levels of testosterone, Sex Hormone Binding Globulin (SHBG), LH, β-estradiol (a by-product of peripheral conversion of testosterone), and AMH (which remains increased in spite of the presence of testosterone because normal AR signaling in Sertoli cells is a prerequisite for the repressive effect on AMH).1676 FSH levels are normal or decreased.1677 The SHBG androgen sensitivity test is a simple diagnostic tool for detection of AR malfunction.1678 In adults, both in complete and partial forms of androgen insensitivity, the testes vary from small to large, are tan brown, and have small seminiferous tubules without lumina and usually contain only Sertoli cells.1679,1680 Most tubules contain Sertoli cells that show immunoexpression for inhibin, have inhibin positive bodies (Fig. 12.187), variable positivity for D2–40 and calretinin, and are negative for AR immunostaining. Leydig cells are sometimes arranged diffusely, and others surround groups of seminiferous tubules (Fig. 12.188). Focally, seminiferous tubules appear as epithelial cords two to three cells wide in cross section. In one-third of

patients, both Sertoli cells and spermatogonia are present.1681 Ultrastructurally, Sertoli cells lack Charcot-B€ottcher crystals and annulated lamellae; inter–Sertoli cell specialized junctions are not well developed, and in cryofracture studies the arrangement of membrane particles has an immature pattern.1682,1683 Leydig cells are abundant and contain lipid inclusions, but few contain Reinke crystalloids. Frequently, spherical or ovoid eosinophilic inclusions larger than nuclei may be observed in the cytoplasm. Focally, Leydig cells show intense immunostaining for cytokeratin AE1/AE3. Ectopic Leydig cells are frequent. Often, areas in the testicular interstitium resemble ovarian stroma. Some patients, probably with a form of androgen sensitivity, have more complete tubular development and a certain degree of spermatogenesis. In approximately two-thirds of patients with CAIS, the testes contain grossly visible prominent white nodules, referred to as Sertoli-Leydig hamartomas (Figs. 12.189 and 12.190). Histologically the nodules are well delimited from the parenchyma and consist of clusters of small seminiferous tubules with immature Sertoli cells, hyalinized lamina propria, numerous Leydig cells, and an

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.188 Complete androgen insensitivity syndrome. Leydig cells, demonstrated with calretinin, are preferably distributed around groups of seminiferous tubules in contact with the ovarian-like stroma.

637

Fig. 12.190 Complete androgen insensitivity syndrome. Cross-sectioned testis with multiple well-demarcated nodules.

Fig. 12.191 Sertoli-Leydig hamartoma. Immunostaining for D2–40 shows that Sertoli cells of the hamartoma are even more immature than Sertoli cells in the rest of the parenchyma.

Fig. 12.189 Complete androgen insensitivity syndrome. Both testes are enlarged and contain several gray-white nodules. The poorly delimited nodule in the lower pole corresponds to a muscular hamartoma.

absence of elastic fibers. α-Inhibin is expressed in the Sertoli cells and Leydig cells of nodules and the parenchyma, and there is stronger immunoreactivity for D2–40 in Sertoli cells of the nodules than in those of the surrounding tubes (Fig. 12.191).1684 Approximately 25% of testes contain Sertoli cell adenoma, which may measure up to 14 cm in diameter and up to 1 kg in weight (Fig. 12.192).1685–1687 These tumors consist of tubules resembling infantile testis but lack germ cells and peritubular myofibroblasts. No Leydig cells are present between the tubules (Fig. 12.193).1686 Other benign tumors include Sertoli cell tumor (large cell calcifying Sertoli cell tumor and sex cord tumor with annular tubules), Leydig cell tumor, leiomyoma, and fibroma.1680 Approximately 60% of patients with CAIS have small cystic structures closely apposed to the testes that may be several

Fig. 12.192 Large Sertoli cell adenoma in an abdominal testis from a 65year-old patient with complete androgen insensitivity syndrome.

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Nonneoplastic Diseases of the Testis

Fig. 12.193 Sertoli cell adenoma showing tubular clusters with a hyalinized wall in a stroma devoid of Leydig cells.

centimeters in diameter, and approximately 80% of patients have thick bundles of smooth muscle fibers resembling myometrium near the testis.1688,1689 These structures may fuse in the midline of the body and suggest bicornuate uterus, which in rare instances may exhibit a uterine cavity.1690 True myometrium has been demonstrated in a patient who underwent estrogen treatment for several years.1691,1692 Hypoplastic fallopian tubes are present in approximately one-third of cases. In approximately 70% of patients, the epididymis and vas deferens are rudimentary; the only explanation for this is residual activity of the mutated AR.1693 Exceptionally, some testes show spermatogenesis within apparently normal seminiferous tubules admixed with hyalinized tubules with Sertoli cells only. Approximately 10% of testes from patients with testicular feminization syndrome develop malignancy. The frequency increases with age, but tumors rarely appear before puberty. The risk for tumor is estimated at 4% in 25-year-old patients and 33% in 33-year-old patients.1388 These tumors include GCNIS (Fig. 12.194), several types of germ cell tumor, which is bilateral

Fig. 12.194 Germ cell neoplasia in situ, undifferentiated type, in a phenotypically female patient with inguinal testes. The tumor cells stand out by virtue of their large size, pale cytoplasm, and prominent nucleoli.

in some cases, and sex cord tumor.1598,1689,1694–1700 Thus the gonads should be removed immediately after puberty.1701 Partial Androgen Insensitivity Syndrome (Partial Testicular Feminization Syndrome). The phenotype of patients with PAIS varies from normal female to normal male, with several intermediate forms giving rise to the following well-defined syndromes1640: • Lubs syndrome, characterized by partial fusion of labioscrotal folds, a definitive introitus, clitoromegaly, pubic and axillary hair, male skeletal development, and poor breast development1702–1706 • Gilbert-Dreyfus syndrome, characterized by progressively greater male phenotypic features with general male habitus that include small phallus, hypospadias, incomplete development of wolffian derivatives, and gynecomastia1707 • Reifenstein syndrome, or male with micropenis, characterized by hypospadias, weak or absent virilization, cryptorchidism, testicular atrophy, gynecomastia, azoospermia, and infertility1640,1708–1714 • Rosewater-Gwinup-Hamwi syndrome, characterized by infertile men whose only abnormal feature is gynecomastia1715 The correlation between genotype and phenotype has been studied in patients with AIS. There is no phenotype variation in CAIS-affected families, whereas the phenotype in PAIS is extremely variable and is rarely predicted by the AR genotype.1716 Patients with completely defective AR function have some pubic hair, Tanner stage P2, and vestigial wolffian duct derivatives despite the absence of AR expression.1674 PAIS must be differentiated from other entities in patients with karyotype 46,XY such as testosterone biosynthesis defects, 5α-reductase deficiency, and partial gonadal dysgenesis. Serum determinations of testosterone, DHT, and AMH are useful. Normal or high levels of testosterone and DHT suggest PAIS and rule out defects in testosterone biosynthesis. Low testosterone levels suggest partial or complete gonadal dysgenesis. AMH is elevated in PAIS, and its values are low in gonadal dysgenesis.1717 In adult patients the presence of streak gonads and functioning m€ ullerian structures in the absence of spontaneous breast development suggest gonadal dysgenesis.1718 Only 25% of patients have mutations in the AR gene.1719 Mild Androgen Insensitivity Syndrome. Spermatogenesis requires high levels of intratesticular testosterone. A minor form of androgen insensitivity may be observed in some patients with male phenotype who present with infertility.1720 The frequency of androgen resistance among azoospermic and oligozoospermic men is estimated at approximately 19% or lower.1721–1723 MAIS is also observed in phenotypically male patients whose external genitalia are underdeveloped or who have subtle alterations such as simple coronal hypospadias or prominent midline raphe of the scrotum.1724 At puberty, MAIS has two phenotypic forms, although both present with variable degrees of gynecomastia, high-pitched voice, sparse pubic and axillary hair, and impotence. In some patients, spermatogenesis is normal or at least sufficient for fertility, whereas others are infertile, with impaired spermatogenesis.1654,1725 Some patients have loss of AR gene exon 4, which encodes a protein subunit that enhances the transport of the AR-androgen complex from the cytoplasm to the nucleus in target cells. In the absence of this exon, transport also occurs, but with markedly lower efficiency.1726 Mutations in exons 6 and 7 and larger trinucleotide repeat size have also been reported.1723,1727,1728 The ranges vary for ejaculate volume, testosterone level, estradiol level, and androgen sensitivity index significantly between men with and without AR gene mutations.1713,1729 Patients with mild forms of

CHAPTER 12 Nonneoplastic Diseases of the Testis

androgen insensitivity may show improvements in spermiogram after treatment with tamoxifen, clomiphene citrate, or mesterolone.1710,1730,1731 Kennedy Disease. Kennedy disease (spinal and bulbar muscular atrophy) is an X-linked recessive disorder of adult men.1732,1733 It is characterized by loss of motor neurons in the spinal cord and brainstem, and is associated with less significant loss of sensory neurons and atrophy caused by skeletal muscle denervation.1732,1734 Onset occurs at approximately 20 years of age with muscular weakness, cramps, and fasciculations.1735 Disease progression is usually slow. Atrophy and muscular weakness begin in the proximal leg muscles and then involve the muscles of the superior extremities and face; if laryngeal or pharyngeal muscles are damaged, dysarthria or dysphagia may occur.1736,1737 The most frequent cause of death is pneumonia secondary to respiratory difficulties. In most cases the male reproductive system is impaired.1735,1738,1739 The testes may be normal in initial stages, and many patients are fertile; however, as the disease progresses, secondary testicular atrophy and gynecomastia develop. Testosterone levels are decreased in some cases. The disease results from mutations in the first exon of the AR gene.1740 The SMBA gene, located on Xq11–12, has expansion of a repetitive CAG sequence in exon A coding for a polyglutamine (PolyQ) tract in the N-terminal transactivation domain of the AR protein. The number of CAG repeats is 21 (range, 17 to 26) in control men and more than 40 in men with Kennedy disease.1733,1741–1744 Neuronal alterations are thought to result from the action of PolyQ AR, whereas muscular anomalies are secondary to denervation.1745 Severity of the disease increases in successive generations (genetic anticipation).1746,1747 Patients with CAG repetitive sequence between 26 and 35 have male infertility, hirsutism, and cryptorchidism. Intranuclear inclusions corresponding to mutant AR protein have been identified in motor neurons of the spinal cord and brainstem, as well as in nonnerve cells of other tissues such as skin, scrotum, dermis, kidney, heart, and testis.1748,1749 These inclusions show epitope features, detectable by antibodies that recognize a small portion of the N terminus of the AR protein. Immunoultrastructural studies reveal clusters of granular, AR-positive, membrane-unbound material.1750

639

During childhood, patients have a clitoriform penis, bifid scrotum, and a vagina that opens into the urethra or urogenital sinus, as well as testes in the inguinal canal or labioscrotal folds. These malformations led investigators to designate this syndrome pseudovaginal perineoscrotal hypospadias.1751,1752 Wolffian duct derivatives are present, but m€ ullerian derivatives are absent. Many patients grow up as girls. In some cases the phenotype is male, or the only malformation is hypospadias.1762,1763 The main differential diagnostic consideration is incomplete androgen insensitivity because both diseases may show a similar phenotype and elevated basal testosterone levels. The presence of well-developed androgendependent structures (epididymis, ductus deferens) supports the diagnosis of 5α-reductase deficit, confirmed by analysis of steroid 5a-reductase type 2 gene (SRD5A2). At puberty, these patients acquire the male phenotype, with development of male habitus, enlargement of the penis and scrotum, and change of the voice.1764 Adults have normal libido and are capable of penile erection and ejaculation. They have scant body hair, thin beard, small prostate, and lack of temporal hairline recession (male pattern baldness). Male sexual behavior acquired after puberty may be maintained with adequate treatment.1611,1763a,1765 Serum levels of FSH, LH, and testosterone are increased, but DHT is decreased.1766,1767 The ratios of 5αsteroids to 5β-steroids and etiocholanolone to androsterone are reduced, and there is excessive response to gonadotropin stimulation with LHRH. Some patients also have hyperprolactinemia. In the first years of life, testes may show normal histologic features.1768 Later, primary spermatocytes, which are usually observed at 4 to 6 years of age, are absent.1769 As in normal boys, Sertoli cells manifest gradual loss of cytokeratin 18, D2–40, and AMH near puberty, and residual Leydig cells have vacuolated cytoplasm (Fig. 12.195).1770 After onset of puberty, important changes occur. The seminiferous tubules show reduced diameter, and most of them lack lumina; the only cell components of the seminiferous epithelium are numerous Sertoli cells showing incomplete maturation.1767 Spermatogenesis is rarely evident. The testicular interstitium contains an increased number of Leydig cells, which have apparently normal morphology or vacuolated

5α-Reductase Deficiency

5α-Reductase deficiency is a rare variant of male undermasculinization DSD caused by a lack of the enzyme 5α-reductase, with failure of conversion of testosterone to DHT in peripheral tissues such as external genitalia and prostate.1751,1752 It was first noted and described in 24 affected individuals in 13 families living in an isolated rural community in the Dominican Republic.1751 The same syndrome was diagnosed in two sibling black men and was described as incomplete male pseudohermaphroditism type 2.1752 Patients with the 46,XY karyotype have two isoenzymes: isoenzyme 1 is encoded by the gene SRD5A, located on 5p15, and isoenzyme 2 is encoded by the gene SRD5A2 on 2p23.1753–1754 Deficit in 5α-reductase has been demonstrated in more than 50 families, and more than 90 mutations have been reported in all of the five exons of gene SRD5A2, including missense, non-sense, regulatory, gross deletions, small deletions, small insertions, small indels, or splicing mutations.1755 A correlation between genotype and phenotype has not been established yet.1754,1756–1761 Transmission is autosomal recessive.

Fig. 12.195 Testis from an infant with 5α-reductase deficiency showing hyperplastic Leydig cells that have marked cytoplasmic vacuolation and surround a seminiferous tubule lacking germ cells (immunostain for calretinin).

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cytoplasm. In contrast with AISs, the epididymis is well developed, and its epithelial cells show AR immunoexpression similar to normal epididymis. The defect in 5α-reductase is genetically heterogeneous. This feature explains why cultured fibroblasts obtained from nongenital skin show either normal or defective 5α-reductase activity, and root hair cells show variable activity of this enzyme.1751,1766,1771,1772

Other Forms of Male Undermasculinization Many dysmorphic syndromes are associated with incomplete masculinization of external genitalia including RSH syndrome, Opitz syndrome (GBBB syndrome), ATR-X syndrome, Gardner-Silengo-Wachtel syndrome, Meckel syndrome, brachioskeletogenital syndrome, Down syndrome, and other trisomies. These syndromes are directly associated with mutations in genes that regulate different steps of sexual differentiation. Smith-Lemli-Opitz Syndrome

SLOS, or RHS syndrome, is a disorder with multiple malformations, dysmorphic facial features, and mental retardation.1773 It is caused by mutation in the gene encoding for 7dehydrocholesterol reductase (DHCR7). The gene DHCR7 maps to chromosome 11, q12–13 band, and its product is a microsomal, membrane-bound protein. Many different missense, non-sense, and splice-site mutations, as well as duplications and deletions, have been reported.1774–1779 Defective DHCR7 impairs cholesterol synthesis, resulting in accumulation of the steroid precursor, 7-dehydrocholesterol, with a subsequent lack of cholesterol.1780–1783 SLOS is an autosomal recessive disorder frequent in the white population, with an estimated incidence of 1 in 20,000 to 40,000 births. SLOS is rare in African and Asian populations.1784–1786 There is little correlation between genotype and phenotype.1787 The most severe forms are lethal before birth, and fetuses show postnatal oligodactyly (instead of polydactyly) and, sometimes, severe hydrops.1788 Postnatal lethal forms are characterized by severe growth failure, semiobtunded state, lack of psychomotor development, microcephaly, congenital cataracts, characteristic facies, broad anteriorly rugose alveolar ridges with cleft palate, unilobulate lungs, male undervirilization or female external genital phenotype in 46,XY patients, postaxial polydactyly of the hands and feet, congenital heart defects, and renal anomalies.1789 Hepatic and renal insufficiency are also frequent.1790 Boys with the least severe forms may have normal genitalia, but 70% exhibit genital anomalies. These anomalies include hypospadias (sometimes severe) with or without cryptorchidism and numerous small anomalies that, together, are characteristic of the syndrome. Most patients suffer from mental retardation and severe behavioral problems.1349 Prenatal diagnosis is possible by a combination of ultrasonographic, cytogenetic, and biochemical analyses in the second trimester in pregnant woman with abnormal maternal serum screening results, specifically low levels of unconjugated estriol.1791 Opitz Syndrome

Patients with Opitz syndrome (GBBB syndrome) are typically males with ventral midline anomalies: hypertelorism and severe unilateral or bilateral labial cleft, laryngeal cleft, severe dysphagia with major or minor life-threatening aspiration, hypospadias, and, occasionally, imperforate anus. Internal anomalies of the

tracheobronchial tree, cardiovascular system (defects in heart septation), and gallbladder are prominent, suggesting subjacent defect of the developing ventral midline. The syndrome is genetically heterogeneous, combining two entities formerly described separately. The syndrome is caused by at least two mutant genes: the ADOS gene (autosomal dominant Opitz syndrome or G syndrome characterized by gastrointestinal anomalies), which maps to 22q11.2; and the XLOS gene (X-kinked Opitz syndrome or BBB syndrome characterized by labial or palatal cleft and mental retardation), which is located in Xp22.3 and is caused by mutations in the RING finger protein MID1.1349,1792–1796 ATRX Syndrome

ATRX syndrome is characterized by the presence of mild α-thalassemia (not from deletion of the α genes), severe mental retardation, facial dysmorphism, and X-linkage.1797 The association between α-thalassemia and mental retardation was first observed in 1981.1798 The disease is rare, with an estimated incidence lower than 1 in 100,000 liveborn boys.1799 Facial anomalies are associated with genital abnormalities, including undescended testes, small or dysgenetic testes, shawl-like or hypoplastic scrotum, penile hypoplasia, and hypospadias. The most severely affected boys grow up as girls; puberty may be delayed, and gonads vary from dysgenetic testes to streak gonad. Patients usually present with gastrointestinal problems, especially feeding difficulties, regurgitation and vomiting, abdominal pain or distention, and chronic constipation. Death in early childhood from aspiration of vomitus or pneumonia presumed to be secondary to aspiration has been recorded.1800 Hemoglobin H inclusions in red blood cells are characteristic.1801 The syndrome is caused by mutations in the ATRX gene (synonyms XNP, XH2), locus Xq13.3, that belongs to the helicase superfamily whose protein products have a number of regulatory functions ranging from DNA recombination and repair to control of transcription.1802–1806

Infertility Infertility affects not only the healthcare system but also the social environment.1807 It is defined as inability of a couple to conceive naturally after 12 months of regular unprotected sexual intercourse. Infertility affects 13% to 15% of couples worldwide. In more than one-half, the cause lies in the male partner with or without a concomitant female partner problem. Causes include varicocele, spermatic pathway obstruction, primary testicular failure, cryptorchidism, gonad toxin exposure, genetic anomalies, infections, hormonal dysfunction, immunologic conditions, ejaculatory or sexual dysfunction, cancer, and systemic disease.1808 In 28% of cases of male infertility, the cause is idiopathic.1809 Approximately one-half of infertile males have conditions that are potentially correctable by surgical or medical treatment.

Testicular Biopsy Testicular biopsy as a tool to diagnose infertility began in the 1940s, and most of the diagnostic terms used today were created at that time.1810–1812 These terms are usually descriptive and reflect subjective analysis except for a few (e.g., normal testes, Sertoli cell–only tubules, tubular hyalinization). The terms maturation arrest and hypospermatogenesis apply to biopsies in more than 50% of cases of infertility, but the criteria for these conditions vary widely among pathologists.1813–1815

CHAPTER 12 Nonneoplastic Diseases of the Testis

There are two forms of maturation arrest: spermatogenic arrest and spermatocytic arrest, or its equivalent, meiotic arrest. True spermatogenic arrest is rare because germ cell maturation usually does not arrest at the level of a defined germ cell type.1816 To avoid confusion, the term irregular hypospermatogenesis has been proposed for testicular biopsies with decreased numbers of germ cells, subclassified as slight, moderate, or severe.1817 However, this diagnosis is of little help to clinicians. The reported frequency of spermatocytic (meiotic) arrest in infertile men varies from 12% to 32%, and this disorder is present in one or both testes in approximately 18% of oligozoospermic or azoospermic patients.1814,1818–1819 If observed in only one testis, the contralateral testis contains histologic changes ranging from normal spermatogenesis to hyalinized tubules. Disorganization of the seminiferous tubular cell layers is another frequent diagnosis in biopsies, but this term is rejected by many pathologists.1812,1820,1821 Actual disorganization of the seminiferous tubular cells is unlikely and has not been demonstrated in ultrastructural studies. In most cases the apparent disorganization is an artifact induced by handling or fixation.1822,1823 Tubular blockage was used to describe biopsies with at least 50% of seminiferous tubules devoid of central lumina and showing spatial disorganization of germ cells.1821 This morphology was found in 28% of testicular biopsies from infertile men, mainly men with obstructive azoospermia.1824 Although this appearance may result from improper fixation, accumulation of Sertoli cells and immature germ cells in the centers of the tubules suggests a specific lesion, a variant of germ cell sloughing.1825 Diagnostic confusion decreased the interest and trust of urologists and andrologists in the study of testicular biopsies. Subsequent studies attempted to correlate semen spermatozoa concentration with testicular size and biochemical findings such as serum levels of FSH, and biopsies were undertaken only in a limited number of oligozoospermic and azoospermic patients.1822,1825,1826 However, these studies were also disappointing because FSH was found to correlate poorly with number of spermatozoa in the semen but better with numbers of spermatogonia in the seminiferous tubules.1827 Normal numbers of spermatozoa may be produced by relatively small testes, whereas some large testes have no spermatogenesis. Flow cytometry studies to evaluate the presence of germ cells in seminal fluid have not yielded satisfactory results.1828 Inhibin B serum levels correlate positively with both spermatozoon number and serum FSH levels.1829,1830 Evaluation of semen for the presence of cell-free mRNA and specifically DEAD (Asp-Glu-Ala-Asp) box polypeptide 4 (DDX4 or VASA) is considered an excellent marker for the presence of germ cells in the testis.1831,1832 Although such studies may have relevance, they do not always allow correlation with histology in nonobstructive azoospermia or oligozoospermia, and therefore serve only a complementary function in evaluating infertility.1833,1834 The development of morphometry caused a resurgence of interest in biopsies, and many semiquantitative and quantitative studies were conducted.1817,1835–1842 The greatest achievements were enhanced reproducibility and better evaluation of the reversibility of lesions. Morphometry has emerged as the best method for objectively evaluating seminiferous tubular cells.1843 The scoring method of Johnsen, estimation of the germ cell/Sertoli cell ratio for each germ cell type, and the calculation of germ cell number per unit length of seminiferous tubules are reliable and useful.1836,1851–1855

641

Several methods are available to evaluate the Leydig cell population, including mean number of Leydig cells per seminiferous tubule and per Leydig cell cluster, mean number of Leydig cell clusters per seminiferous tubule, the ratio of Leydig cell area to seminiferous tubule area, and the ratio of Leydig cells to Sertoli cells.1844,1845 These methods have shown that the appearance of Leydig cell hyperplasia described in many conditions is false, and that true Leydig cell hyperplasia is rare. In summary, histologic study of the parenchyma is the only method to determine conditions inside the testis. The more information biopsy may give us, the higher its value will be. Histologic study may provide information not only on the real condition of the parenchyma but also on the reversibility or progression of lesions and their causes. Nonetheless, the practice of biopsy has been criticized as lacking cost-effectiveness, and is subject to complications related to its invasive nature.1135

Indications Indications for testicular biopsy may be diagnostic, prognostic, or therapeutic. Diagnostic biopsy is recommended in all cases of obstructive azoospermia to confirm the presence of normal spermatozoa if surgical correction is considered. Patients who have previously undergone vasectomy or those with congenital absence of the vas deferens are not included unless they also have testicular atrophy or high FSH levels. Diagnostic biopsy is also indicated if there is clinical concern for the possibility of GCNIS in patients with small testis associated with microlithiasis, history of cryptorchidism or contralateral germ cell tumor, or inhomogeneous testicular echogenicity. GCNIS occurs in 1% to 5% of infertile men.1846 Prognostic biopsy is recommended in all patients with cryptorchidism, regardless of the time at which the testis becomes located in the scrotum (prepubertal or pubertal). In both unilateral and bilateral cryptorchidism, when Ad spermatogonia are not detected, the patient will be infertile despite surgical treatment. Hormonal treatment increases the number of germ cells.1847 Therapeutic biopsy is used to extract spermatozoa from men with nonobstructive azoospermia.1848 Histologic study enables identification of the testicular lesion and exclusion of GCNIS.1849 Optimal interpretation of biopsies depends on the surgical technique by which the sample is taken, the care and delicacy with which it is handled, and proper fixation and processing. The size of the sample should not be larger than a grain of rice (i.e., no diameter should be >3 mm). This amounts to approximately 0.1% of testicular volume (normal volume is approximately 20 mL). The biopsy should be bilateral because in more than 28% of patients the findings differ between the testes. At the time of the biopsy the testicular axes should be measured as the basis of quantitative studies. The tissue should be taken opposite the rete testis through a 4- to 5-mm incision in the tunica albuginea. Parenchyma herniates through the incision and may be carefully snipped off. If only light microscopy is to be performed, the specimen should be fixed in either Bouin fluid for 24 hours or Stieve solution, as the European Germ Cell Cancer Consensus Group recommends.1084 Both fixatives allow excellent conservation of spermatogenesis, although they have the disadvantage of false-negative results in some cases when immunohistochemistry is used to detect GCNIS. One alternative is neutral-buffered formaldehyde, which diminishes the shrinkage artifacts of formalin.1850 If electron microscopy is indicated, a small biopsy fragment should be fixed in glutaraldehyde-osmium tetroxide or similar fixative. To perform meiotic studies, biopsy

642 C H A P T E R 1 2

Nonneoplastic Diseases of the Testis

should be processed according to air-drying or surface-spreading methods. Examination includes qualitative and quantitative evaluation, and correlation between the biopsy and spermiogram.

Qualitative and Quantitative Evaluation Various methods of analysis of biopsies have been proposed, but most are of limited clinical utility.1836,1851–1855 A method developed by our group provides information on the number of each type of germ cell and the proportions among these cells, thus achieving functional exploration of spermatogenesis and associated disorders of the Sertoli cells or interstitium.709 Examination of biopsies involves several steps: first, quantitative evaluation of seminiferous tubular cells, which permits the identification of the affected germ cell or cells, when the numbers are compared with normal values; second, qualitative evaluation, which may provide additional data on a particular type of cell; and finally, establishment of a correlation between elongate spermatids (Sc + Sd) and the number of spermatozoa per milliliter in the ejaculate, to evaluate the permeability of the spermatic pathway. Light microscopy at low magnification immediately reveals whether the lesion is focal or diffuse. If focal, the percentage of tubules showing each lesion (e.g., Sertoli cell–only, hyalinization, tubular hypoplasia) should be calculated. It is useful to evaluate elastic fibers with a special stain because this highlights groups of small tubules that may be missed with hematoxylin and eosin. A minimum of 30 cross-sectioned tubules should be studied (this is usually possible when 5 or 6 histologic sections are available). The diameter of each seminiferous tubule should be measured, and the numbers of spermatogonia, primary spermatocytes, young spermatids (also called round spermatids or Sa + Sb spermatids), mature spermatids (also called elongate or Sc + Sd spermatids), Sertoli cells, and, in some cases, peritubular cells counted. The presence of tubular diverticula, maturation of Sertoli cells, and morphologic anomalies in germ cells should also be noted.1856,1857 Evaluation of the testicular interstitium should include the number of Leydig cells per tubule (or the number of Leydig cell clusters per tubule), the presence of angiectasis (phlebectasis), and the occurrence of peritubular or perivascular inflammation. Normal values are tabulated in Table 12.20. For a clear and rapid understanding of the results, data may be presented using cartesian axes.

TABLE 12.20

Testicular Parameters in Normal Adult Testes (Per Cross-Sectioned Tubule)

Parameter Seminiferous Tubules Mean tubular diameter (μm) No. of spermatogonia No. of primary spermatocytes No. of young (Sa + Sb) spermatids No. of mature (Sc + Sd) spermatids No. of Sertoli cells No. of Sertoli cell vacuoles Lamina propria thickness (μm) No. of peritubular cells

193  8 21  4 31  6 37  7 25  4 10.4  2 0.8  0.3 5.3  1 21  4

Testicular Interstitium No. of Leydig cell clusters per tubule No. of Leydig cells per tubule

1.2  0.3 5  0.2

Sa+Sb, Round spermatids; Sc+Sd, elongate spermatids.

lamellae, Charcot-B€ottcher crystals, and specialized junctional complexes with other Sertoli cells. The pubertal increase in both length and width of the seminiferous tubules replaces the infantile pseudostratified pattern with a simple columnar distribution. Five variants of the Sertoli cell–only syndrome are identified by morphology, the degree of development of seminiferous tubules, and the presence or absence of interstitial lesions.1858 These variants are designated by the appearance of the predominant Sertoli cell population: immature Sertoli cells, dysgenetic Sertoli cells, adult Sertoli cells, involuting Sertoli cells, and dedifferentiated Sertoli cells (Fig. 12.196). Each type is associated with other tubular and interstitial alterations (Table 12.21).

Common Lesions The most frequently observed lesions are Sertoli cell–only tubules, tubular hyalinization, alterations in spermatogenesis in either the adluminal or basal compartments of seminiferous tubules, and mixed tubular atrophy. Sertoli Cell–Only Syndrome

Sertoli cell–only syndrome includes any azoospermia in which the seminiferous epithelium consists only of Sertoli cells. To understand this syndrome, it is necessary to consider morphologic and functional changes induced in the Sertoli cell by hypophyseal gonadotropin secretion during puberty. During childhood, Sertoli cells are pseudostratified, and nuclei are dark, small, and round or elongate, with regular outlines and one or two small peripherally placed nucleoli. The cytoplasm lacks specialized organelles.216 The apical cytoplasm contains one or several inhibin bodies.170 Adult Sertoli cells have characteristically pale, triangular nuclei with irregular, indented outlines. Nucleoli are large and have tripartite structures. The cytoplasm contains abundant smooth endoplasmic reticulum and specialized structures, including annulated

Mean  SD

Fig. 12.196 Sertoli cell types.

CHAPTER 12 Nonneoplastic Diseases of the Testis

TABLE 12.21

643

Differential Diagnosis of the Sertoli Cell–Only Syndrome VARIANTS OF THE SERTOLI CELL–ONLY SYNDROME Immature Sertoli Cells

Dysgenetic Sertoli Cells

Adult Sertoli Cells

Involuting Sertoli Cells

Dedifferentiated Sertoli Cells

Markedly decreased Small or absent Thin

Decreased

Decreased

Decreased

Decreased

Small or absent Enlarged

Normal Normal or enlarged

Normal Enlarged

Absent

Decreased

Normal Normal or enlarged Normal

Normal

Normal

Increased

Increased

Pseudostratified

Normal or increased Columnar

Normal or increased

Distribution

Markedly increased Pseudostratified

Columnar

Nuclear shape Nuclear outline Chromatin Nucleolus

Ovoid Regular Dark Small, peripheral

Round or ovoid Regular Pale with granules Developed, central

Vacuoles Lipids Vimentin filaments

Absent Absent Basal

Present Absent Basal

Inhibin bodies Antim€ullerian hormone Interstitium Leydig cells

Present Present Scant Absent

Clinical symptoms

Hypogonadotropic hypogonadism

Absent Present Increased Pleomorphic, vacuolated, increased or decreased Infertility

Testis Pattern Tubular diameter Tubular lumen Lamina propria thickness Elastic fibers in lamina propria Sertoli cells Number

The most frequent types of Sertoli cell–only syndrome in patients with infertility are dysgenetic Sertoli cells, adult Sertoli cells, and involuting Sertoli cells. The clinical manifestations are similar, including normal external genitalia, well-developed secondary male characteristics, azoospermia, elevated serum FSH levels, normal or elevated serum LH levels, and normal or slightly low testosterone levels. These clinical and histologic features were long thought to constitute a single syndrome, Del Castillo syndrome, but more recent ultrastructural, histochemical, immunohistochemical, and cytogenetic studies showed that this condition results from a variety of syndromes that may be primary or secondary (Table 12.22).334,1859–1862 Some patients with adult Sertoli cell or dysgenetic Sertoli cell variant have a few spermatozoa in the spermiogram. This discrepancy between oligozoospermia and histologic findings is caused by the presence of some seminiferous tubules with complete spermatogenesis elsewhere in the parenchyma.1863 In these patients the assessment of DDX4 cell-free seminal mRNA is of great value.1864 Sertoli Cell–Only Syndrome With Immature Sertoli Cells. Sertoli cells in adult testes with this variant of Sertoli cell–only syndrome have an immature prepubertal appearance with pseudostratification. The number of cells per cross-sectioned tubule is greater than normal. Other tubular and interstitial features suggest

Triangular Few indented Pale Developed, central Present Decreased Basal and perinuclear Absent Absent Normal Normal

Lobated Markedly indented Pale Developed, central

Columnar or pseudostratified Round Regular Pale Small, central or peripheral

Abundant Abundant Basal and perinuclear

Abundant Abundant Basal

Absent Absent Normal/fibrosis Decreased, many lipofuscin granules

Present Absent Fibrosis Decreased, many lipofuscin granules

Infertility, orchitis

Infertility, hypergonadotropic hypogonadism, chemotherapy or radiation therapy

Treatment with estrogens, antiandrogens, or cisplatinum; chronic hepatopathy

immaturity, including small tubular diameters (<80 μm), tubules lacking central lumina, thin lamina propria lacking elastic fibers, and interstitium lacking mature Leydig cells.404,1865,1866 Immunohistochemistry shows that these Sertoli cells have prepubertal characteristics with expression of cytokeratin 18, AMH, and inhibin bodies.170 This syndrome is caused by a deficiency of both FSH and LH. This deficit begins in childhood and is responsible for lack of maturation of Sertoli cells, tubular walls, and interstitium. Subsequently, no renewal or differentiation of germ cells occurs, and these cells eventually disappear. When patients have been treated with hormones, the biopsy may show some degree of spermatogenesis or thickening and hyalinization of the tubular basement membrane. Biopsies from patients with CAIS also show seminiferous tubules with only immature Sertoli cells, but differ from the condition described earlier in several important respects. Sertoli cells in CAIS lack AR, the interstitium contains abundant spindle cells that simulate the ovarian stroma, and there are a large number of Leydig cells.1867 Sertoli Cell–Only Syndrome With Dysgenetic Sertoli Cells. Dysgenetic Sertoli cells begin pubertal differentiation but variably deviate from normal maturation, so that the morphology of dysgenetic Sertoli cells differs among tubules and even among Sertoli

644 C H A P T E R 1 2

TABLE 12.22

Hyalinized tubule size Tubular lumen Peritubular cells Elastic fibers Leydig cells Folliclestimulating hormone Luteinizing hormone Testosterone

Nonneoplastic Diseases of the Testis

Differential Diagnosis in Tubular Hyalinization Dysgenetic

Hormonal Deficit

Ischemia

Excretory Duct Obstruction

Postinflammatory Hyalinization

Physical or Chemical Agents

Minimum

Minimum

Minimum

Markedly decreased

Minimum

Markedly decreased

Absent Decreased Decreased Increased or decreased, pleomorphic Increased

Absent Decreased Normal Absent

Absent Decreased Normal Absent

Present Increased Normal Normal

Absent Decreased or increased Normal Pseudohyperplasia

Absent Decreased Normal Decreased

Decreased

Increased

Increased

Increased

Increased

Increased

Decreased

Increased

Increased

Increased

Increased

Normal or decreased

Decreased

Normal or decreased

Normal

Normal

Normal or decreased

cells within the same tubule. Nuclei usually have both mature features (pale chromatin and a centrally located, tripartite nucleolus) and features of immaturity (in some cases, they are small, ovoid, or round with regular outlines; in others, elongate, with major axis perpendicular to the basal lamina). Both types of nuclei may contain dense chromatin granules (Figs. 12.197 through 12.200).246 These Sertoli cells show immunoexpression of vimentin, AMH, and cytokeratin 18.1868,1869 Immunoreactivity for AMH and cytokeratin 18 is assumed to be a sign of immaturity because, under normal conditions, it is not detected after puberty. Other signs of immaturity are poor development of the hematotesticular barrier and absence of tubular lumina.1870 Tubular lumina are small or even absent in most dysgenetic Sertoli cell–containing tubules because the ability to produce testicular fluid is greatly reduced. Sertoli cell number per cross-sectioned tubule is high, and MTD is lower than 120 μm. Tubular walls have few elastic fibers, and most show a variable degree of tunica propria hyalinization.1002

Fig. 12.197 Sertoli cell–only syndrome with dysgenetic Sertoli cells. Seminiferous tubules show slightly thickened tunica propria. The Sertoli cells are increased and have elongate nuclei and abundant apical cytoplasm.

Fig. 12.198 Seminiferous tubule with dysgenetic Sertoli cells only. Elongate nuclei, pseudostratified arrangement.

Fig. 12.199 Sertoli cell–only syndrome with dysgenetic Sertoli cells. The seminiferous tubules are small and lack lumens. The interstice contains isolated groups of Leydig cells.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.200 Seminiferous tubule with spherical nuclei in dysgenetic Sertoli cells. Thickening of tubular wall and isolated Leydig cells.

Completely hyalinized tubules are common. The testicular interstitium contains a variable number of Leydig cells (normal, decreased, or apparently increased), many of which are pleomorphic with abundant paracrystalline inclusions.1770,1871 The morphologic findings may be observed in biopsies from men with cryptorchid testes, at the periphery of germ cell tumors in biopsies from men with chromosomal anomalies such as 46,XX 48,XYYY, Y-chromosome anomalies, and in biopsies from men with idiopathic infertility.1872,1873 Sertoli Cell–Only Syndrome With Mature Sertoli Cells. In this variant, most Sertoli cells appear mature, with nuclei like those of normal mature Sertoli cells, but are present in increased numbers (14  0.8 Sertoli cells per cross-sectioned tubule).1874 The seminiferous tubules have small diameters, but larger than in the two variants described above, and central lumina are visible. The lamina propria is normal or slightly thickened. Leydig cells are normal. Ultrastructurally the cytoplasm of the Sertoli cells contains abundant vacuoles that communicate with the tubular lumina (Figs. 12.201 and 12.202). The lateral cell surfaces have many unfolding and extensive specialized junctions with other Sertoli cells (from the basement membrane to the apical cytoplasmic portion). Lipid droplets, usually derived from phagocytosis of spermatid tubulobulbar complexes and dead germ cells, are scant.1859 Vimentin filaments are abundant in the basal and perinuclear cytoplasm.110 Serum testosterone is normal or nearly normal, and FSH and LH levels are elevated.1875–1877 This syndrome is probably caused by failure of migration of primordial germ cells from the primitive yolk sac to the gonadal ridge.1878 This failure may result from deletion in the AZFa region in Yq11, a mutation in the genes that encode KIT or its ligand (SCF), responsible for the migration, proliferation, and survival of germ cells or PLK4 mutations.1879,1880 Sertoli Cell–Only Syndrome With Involuting Sertoli Cells. Testes with this variant of Sertoli cell–only syndrome have numerous changes. Sertoli cell nuclei may have lobulated shapes with irregular outlines, coarse chromatin granules, and inconspicuous nucleoli. Seminiferous tubules have central lumina, decreased diameters, and variable thickening of the basement membrane (Figs. 12.203 and 12.204). Elastic fibers are present in normal or diminished amounts. Leydig cells are variably involuted.

645

Fig. 12.201 Sertoli cell–only syndrome with mature Sertoli cells. The seminiferous tubules are lined by normal adult Sertoli cells, many with cytoplasmic vacuoles.

Fig. 12.202 Sertoli cell–only syndrome with adult Sertoli cells. Note the presence of triangular nuclei of Sertoli cells with large nucleoli and €ttcher subnuclear crystals. Charcott Bo

This syndrome may be a primary disorder or secondary to irradiation or cytotoxic therapy, such as cancer chemotherapy or treatment for nephrotic syndrome.1881 It is not usually possible to determine the etiology from the biopsy findings alone. Changes in the tubular walls are more pronounced in patients with a history of cyclophosphamide treatment, combination chemotherapy, or radiation therapy. The interstitium may be fibrotic in patients treated with cis-platinum or cyclophosphamide.1882 Syndromes with involuting Sertoli cells associated with decreased amounts of elastic fibers are an expression of primary testicular anomaly with involuting and dysgenetic Sertoli cells within the same tubule. Sertoli Cell–Only Syndrome With Dedifferentiated Sertoli Cells. The presence of immature-appearing Sertoli cells in otherwise mature tubules is the most striking feature of this variant of Sertoli cell–only syndrome. Sertoli cells appear abnormally numerous because of shortening of the tubule, and nuclei are either

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levels of testosterone.1883,1884 The use of ultrastructural, histochemical, immunohistochemical, cytogenetic, and molecular biology studies has increased our knowledge of these syndromes.1859–1862,1872,1885,1886 Tubular Hyalinization

Fig. 12.203 Sertoli cell–only syndrome with involuting Sertoli cells. The Sertoli cell nuclei are hyperchromatic and have irregular outlines.

Fig. 12.204 Sertoli cell–only syndrome with involuting Sertoli cells. More than one-half of the cells have retracted hyperchromatic nuclei with irregular surface. Marked thickening of the tubular wall. Leydig cell atrophy is shown.

round or elongate. Round nuclei have single, small, central, or peripheral nucleoli, whereas elongate nuclei have dense, clumped chromatin and small peripheral nucleoli. The tubular wall is thickened and contains elastic fibers, increased amounts of collagen fibers, and elevated numbers of peritubular cells as a result of shortening. MTD is markedly decreased to <90 μm. The interstitium contains few Leydig cells, and these appear dedifferentiated or contain increased amounts of lipofuscin. This variant may occur after androgen deprivation therapy for prostatic cancer, estrogen treatment for transsexuality, and cancer chemotherapy with cis-platinum. In summary, most patients seeking consultation for infertility who have Sertoli cell–only pattern have one of the following variants: dysgenetic, adult, or involutive Sertoli cells. Clinical features of all are similar: azoospermia, normal external genitalia, well-developed male sexual characteristics, elevated levels of FSH, normal or increased levels of LH, and normal or low-normal

A few azoospermic patients have diffuse hyalinization of seminiferous tubules. The incidence is difficult to estimate, given that these patients usually do not undergo biopsy because their testes are small, and the diagnosis is obtained from clinical, hormonal, or cytogenetic data. Hyalinization of seminiferous tubules is the end point of tubular atrophy and includes the absence of both germ cells and Sertoli cells with alterations in the lamina propria and Leydig cells. The etiology may be determined from several histologic features and clinical data, including the following: • General histologic appearance: the extent and topography of the hyalinized tubules and the presence of isolated tubules containing germ cells or Sertoli cells only (dysgenetic, adults, involuting, or dedifferentiated) • Appearance of atrophic tubules, all showing the same pattern or variable degrees of atrophy: tubular diameter; trophism of peritubular cells; the presence of elastic fibers; the degree of collagenization of the lamina propria; and the presence of cell remnants or unusual cells in the tubules. • Appearance of the interstitium: the number and morphology of Leydig cells; vascular lesions; and lymphoid infiltrates • Chronology of testicular shrinkage The most common causes of tubular hyalinization include dysgenetic hyalinization, hormonal deficit, ischemia, obstruction, inflammation, and physical or chemical agents. The differential diagnosis is given in Table 12.22. Dysgenetic Hyalinization. Dysgenetic hyalinization is a diffuse lesion in which most tubules are uniformly hyalinized (Fig. 12.205). There is a lack seminiferous tubular cells and a reduced number of peritubular cells. The few preserved tubules usually contain only Sertoli cells, although rarely a few tubules with spermatogenesis are present. Dysgenetic hyalinization is seen in Klinefelter syndrome, in testes that remain cryptorchid through puberty, and in some, hypergonadotropic hypogonadisms associated with myopathy. Focal lesions are seen in MAT of the testis.

Fig. 12.205 Dysgenetic hyalinization. Fully hyalinized seminiferous tubules and a few peritubular cells among Leydig cell clusters.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Tubular hyalinization is pronounced in Klinefelter syndrome, and from infancy the seminiferous tubules are small, containing reduced numbers of Sertoli cells and few or no spermatogonia. At puberty the dysgenetic Sertoli cells fail to mature and soon disappear. The tubules collapse, thus giving the appearance of phantom tubules.1887 Peritubular cells fail to differentiate, and their number is low.1888 They form a discontinuous ring around the hyalinized tubules and are incapable of synthesizing elastic fibers and other components of the lamina propria. Dysgenesis also involves the interstitium; Leydig cells exhibit a characteristic adenomatous pattern, although the total number is decreased. The morphology of the Leydig cell is not uniform, with shrunken, normal, and large forms. Most Leydig cells contain reduced amounts of lipofuscin granules and lipid droplets. Reinke crystalloids are uncommon, and paracrystalline inclusions are abundant.1871 Despite the hyperplastic adenomatous appearance of the Leydig cells, testosterone secretion is markedly decreased, and the resulting hypogonadism is the most important clinical feature of Klinefelter syndrome. Tubular hyalinization in the cryptorchid testis is also dysgenetic. However, in contrast with the atrophic collapse seen in Klinefelter syndrome, cross sections of the hyalinized tubules in cryptorchidism are targetoid. This morphology, which results from the arrangement of the peritubular cells into two layers, suggests an atrophic process that has evolved over a longer period than in Klinefelter syndrome or has a lesser degree of dysgenesis.995 Elastic fibers are diminished.1002 Leydig cells appear hyperplastic, forming large aggregates, although their absolute number is decreased. Leydig cell pleomorphism is less intense than in Klinefelter syndrome. Many Leydig cells have abundant vacuolated cytoplasm. Whereas tubular hyalinization in Klinefelter syndrome is secondary to the effect of pubertal gonadotropin secretion on dysgenetic tubules, tubular hyalinization in cryptorchidism probably results from the effect of increased temperature on the dysgenetic tubules. However, other mechanisms are also involved in cryptorchid tubular hyalinization, including obstruction of sperm excretory ducts (anomalies in these ducts are frequent in cryptorchidism) and ischemia (principally in testes that could be only incompletely descended at surgery). Hyalinization Caused by Hormonal Deficit. Hormonal deficit causes diffuse tubular hyalinization, although the tubules may be recognized as cellular cords surrounded by hyaline material. Sertoli cells, a few spermatogonia, and rare primary spermatocytes may be identified in these cords. When hyalinization is complete, only the elastic fibers in the lamina propria indicate the structure of the previously normal adult testis. Peritubular myofibroblasts decrease in number and form a ring at the periphery of the lamina propria. Leydig cells disappear as hyalinization progresses, and the few remaining cells have pyknotic nuclei and shrunken cytoplasm with abundant lipofuscin granules. This process manifests clinically as postpubertal hypogonadotropic hypogonadism and is usually caused by lesions in or near the pituitary, such as adenoma, craniopharyngioma, and trauma to the cranial base or sella turcica (see later discussion of Hypogonadism Secundary to Sndocrine Gland Dysfuction and Other Disorders (Hypothalamus-hypophysis-Hypopituitarism)). Ischemic Hyalinization. Ischemic atrophy is usually caused by torsion of the spermatic cord, vascular injury during inguinal surgery, polyarteritis nodosa (PAN), and severe arteriosclerosis.1889,1890 Except for cases caused by torsion of the spermatic cord, these patients usually are not seen in infertility clinics.

647

Torsion of the spermatic cord is often not listed among the causes of infertility. However, follow-up of those with torsion reveals marked alteration in the spermiogram. Several hypotheses have been offered to explain the low number of sperm produced by the contralateral normal testis; the most promising hypotheses include response to release of antigens by the ischemic testis and primary lesions of the contralateral testis (see earlier Testicular Torsion section).1891 Testicular anoxia caused by torsion rapidly produces severe lesions that are irreversible without adequate treatment. After 8 hours, intense hemorrhagic infarction of the seminiferous tubular cells occurs. Chronic anoxia leads to tubular hyalinization and loss of Leydig cells (Fig. 12.206). Testicular atrophy secondary to inguinal hernia surgery may occur in <1% of patients in the first repair, and in 1% to 5% of patients who undergo surgical repair of recurrent hernia. Atrophy is most frequent in cases that require extensive dissection of the spermatic cord. Postobstructive Hyalinization. Obstruction of the sperm excretory ducts may cause atrophy of seminiferous tubules. To produce tubular hyalinization, the obstruction must be close to the testis because the ductuli efferentes in the caput of the epididymis absorb approximately 90% of tubular fluid and protect the testis from excessive intratubular pressure. Obstructive tubular hyalinization is usually focal and secondary to varicocele and other disorders involving dilation of the channels of the rete testis. These disorders may be congenital, as in epididymis-testis dissociation, or acquired, as rete testis dilation secondary to epididymal atrophy caused by arteritis, arteriosclerosis, or androgen insufficiency. Obstructive tubular hyalinization also occurs in the seminiferous tubules at the periphery of the testis in patients who have had orchitis.1892 Obstructive hyalinization has a mosaic distribution: lobules of completely hyalinized tubules are intermingled with lobules of normal tubules (Fig. 12.207). The diameter of the hyalinized tubules is not as small as in hyalinization of other causes, and the tubules occasionally contain Sertoli cells. In the center of many is a small lumen, or a vacuole may be present in the cytoplasm of a residual Sertoli cell.1893 The lamina propria is thick and contains hypertrophic peritubular cells and abundant extracellular material. Finally,

Fig. 12.206 Ischemic tubular hyalinization. Fully hyalinized seminiferous tubules are surrounded by peritubular cells. The testicular interstitium lacks Leydig cells and shows arteriolar hyalinization.

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hyalinization are more than autoimmune hyalinization in association with testicular tumors. Hyalinization Caused by Physical or Chemical Agents. Radiation and a wide variety of chemicals cause tubular hyalinization. Prolonged chemotherapy combined with radiation therapy invariably causes hyalinization. Children’s testes are most sensitive to radiation. Radiation therapy for testicular leukemia frequently causes tubular hyalinization. In addition, radiation induces dense interstitial fibrosis and loss of peritubular cells, thus obscuring the borders between the interstitium and tubules. This makes the tubules difficult to see in hematoxylin and eosin–stained sections. Leydig cells are atrophic and decreased in number. Ischemia secondary to radiation-induced vascular injury also contributes to hyalinization. In tubular hyalinization associated with chemotherapy, in addition to direct toxicity of drugs in seminiferous tubular cells (see earlier Sertoli Cell–Only Syndrome With Involuting Sertoli Cells section), nutrition deficiencies cause hypogonadotropic hypogonadism.1897,1898

the peritubular cells dedifferentiate, and only fibroblasts remain.1888,1893a The interstitium contains a normal number of Leydig cells, forming small clusters, some of which are among hyalinized tubules. This feature is not seen in other patterns such as ischemic hyalinization. In addition, dilated veins with eccentrically hyalinized walls may be seen in testes associated with varicocele. This lobular pattern of tubular atrophy causes a peculiar ultrasound image that has been described as striated pattern.1894,1895 This pattern is nonspecific and has also been described in patients with neoplasia, fibrosis, and orchitis.1896 Postinflammatory Hyalinization. Many infections of the testis cause irreversible lesions in the seminiferous tubules. In bacterial infections the epididymis is usually involved, resulting in obstructive azoospermia. In viral infections the testis is often affected, even without symptoms. Two types of viral orchitis often cause infertility: mumps orchitis and coxsackie B orchitis. Tubular atrophy caused by viral infection has a mosaic topography in which hyalinized and normal tubules are intermingled. In fully hyalinized tubules the only recognizable cells are peritubular cells that form an incomplete peripheral ring around the hyalinized material. The presence of elastic fibers in these tubules distinguishes this condition from dysgenetic hyalinization. Leydig cells form clusters of variable size, but total number is normal. In bacterial infections the pattern of tubular hyalinization is variable. Tubular atrophy of unknown etiology may be caused by an autoimmune response. This occurs in hypogonadism associated with disorders in other endocrine glands, including Addison disease associated with gonadal insufficiency, adrenal-thyroid-gonadal insufficiency, diabetes, hypogonadism, adrenal insufficiency, and hypothyroidism. The testicular lesions are morphologically like those seen in seminiferous tubules at the periphery of germ cell tumors and with burned-out germinal cancer. In the initial stages of hyalinization associated with germ cell neoplasm, tubules are small and contain GCNIS and dysgenetic Sertoli cells, and the lamina propria is infiltrated by macrophages, lymphocytes, and plasma cells. In the final stages the intratubular cells have degenerated, inflammation has disappeared, and seminiferous tubules are replaced by areas of hypocellular or acellular fibrosis (Fig. 12.208). Obstructive, ischemic, and dysgenetic types of

Histophysiologic studies identify two compartments in seminiferous tubules: basal and adluminal. The blood-testis barrier separates these compartments, and each contains different cell types with diverse hormonal and nutrition requirements. On this basis, lesions may be classified as involving only the adluminal compartment or both the basal and adluminal compartments. The following discussion of spermatogenic lesions uses this newer concept of tubular pathophysiology while conserving the classic terminology as much as possible. Lesions in the Adluminal Compartment of Seminiferous Tubules. This category includes all infertile testes with normal number of spermatogonia, normal or decreased number of spermatocytes and young spermatids, and variable number of adult spermatids. A descriptive term for this disorder is immature germ cell sloughing. A few immature germ cells are normally seen in the lumina of seminiferous tubules, a finding that correlates with the presence of these cells in the ejaculates of fertile men.1898,1899 When such cells make up more than 4% of cells in the ejaculate, this finding is

Fig. 12.207 Postobstructive hyalinization. Seminiferous tubules with marked ectasis with hyalinized tubules. Leydig cell clusters are seen among the hyalinized tubules.

Fig. 12.208 Postinflammatory hyalinization. Most of the testis consists of cicatricial tissue with no recognizable seminiferous tubules.

Diffuse Lesions in Spermatogenesis

CHAPTER 12 Nonneoplastic Diseases of the Testis

abnormal and results from premature sloughing of spermatids and, in some cases, of spermatocytes.1900,1901 Some authors have attempted to establish a correlation between the number of sloughed immature germ cells and severity of lesions of seminiferous epithelium by using light and electron microscopy.1902,1903 Lesions in the adluminal compartment are classified according to the most abundant type of germ cell whose maturation is arrested and that then sloughs young spermatids, late primary spermatocytes, or early primary spermatocytes (Fig. 12.209). Young Spermatid Sloughing. Young spermatid sloughing is present when the ratio of elongate (Sc + Sd) spermatids to round (Sa + Sb) spermatids is lower than normal. The implication of this pattern is that many round spermatids are incapable of further differentiation and slough (Fig. 12.210). Late Primary Spermatocyte Sloughing. In this condition, spermatogenesis develops normally to the level of interphase primary spermatocytes, which are present in normal numbers. These spermatocytes later degenerate without achieving meiosis and slough into the tubular lumen. All types of spermatids are greatly reduced in number. When biopsies are not properly fixed, seminiferous tubules acquire target-like appearance, with numerous cells in the lumen, an appearance that sometimes has been referred to as tubular blockage or spermatogenic arrest. The latter term is often inadequate because some spermatids are present, and the number of primary spermatocytes is usually not increased as would occur if the transformation of spermatocyte into spermatid were blocked (Fig. 12.211). Late spermatocyte sloughing more accurately names this condition and is preferred. Primary spermatocyte sloughing occurs at the pachytene or diplotene stage of meiosis.

Normal control testes Average values in normal testes Hypospermatogenesis Hypospermatogenesis + sloughing of spermatocytes I Spermatogonial maturation arrest

649

Fig. 12.210 Seminiferous tubule showing a dilated lumen and moderate young spermatid sloughing.

Early Primary Spermatocyte Sloughing. This lesion is characterized by the presence of a normal number of spermatogonia and decreased number of primary spermatocytes (Fig. 12.212). Seminiferous tubules may contain a few spermatids. The term early primary spermatocyte sloughing does not necessarily imply an early meiotic lesion, which is quite rare.1819,1901 Rather, it refers to sloughing of newly formed spermatocytes. Sertoli cells may show vacuolation of the apical cytoplasm as an expression of germ cell loss. This lesion is more severe than that in testes with late primary spermatocyte sloughing and likely results from failure of the Sertoli cells to maintain the adluminal compartment. Etiology Overview. The mechanisms causing adluminal compartment lesions may be classified as obstructive or nonobstructive. Obstruction is present in more than 70% of cases and is characterized by the variability of involvement among lobules and the presence of at least two of the following abnormalities: enlargement of tubular diameter and lumen with remarkable differences among lobules; Sertoli cells with adherens germ cells protruding into the lumen, thus giving an indented outline; intense apical

45

Cell numbers per cross-sectioned tubule

40 35 30 25 20 15 10 5 0 Spermatogonia

Spermatocytes 1

Sa + Sb

Sc + Sd

Fig. 12.209 Germ cell numbers per cross-sectioned tubule in patients with lesions in the adluminal compartment of seminiferous tubules.

Fig. 12.211 Seminiferous tubule showing sloughing of both primary spermatocytes and young spermatids.

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Fig. 12.212 Seminiferous tubules showing dilated lumens, apical vacuolation of Sertoli cells, normal number of spermatogonia, and decreased number of other germ cell types.

vacuolation of Sertoli cell cytoplasm; accumulation of spermatozoa in lumina of some tubules; or number of spermatids Sc + Sd higher than that of Sa + Sb (see the later discussion of Correlation Between Testicular Biopsy and Spermiogram (Obstructive Azoospermia and Oligozoospermia)).1903a The three levels of severity of adluminal compartment lesions emphasized by the terms young spermatid sloughing, later primary spermatocytes sloughing, and early primary spermatocyte sloughing depend on the degree (total or partial) of obstruction and the level of the sperm excretory duct obstruction; the closer the obstruction is to the testis, the greater the severity. Obstruction may be extratesticular (epididymis, vas deferens, and ejaculatory ducts) or intratesticular (rete testis or any level of the seminiferous tubule length). The most frequent causes of extratesticular excretory duct obstruction are vasectomy, inflammation (epididymitis, prostatitis), mucoviscidosis (congenital bilateral absence of vas deferens), and testis-epididymis dissociation. Rete Testis Obstruction. Varicocele is the most frequent cause of obstruction of the rete testis. More than 50% of testes with varicocele have a mosaic pattern of tubular lesions, together with marked dilation and eccentric mural fibrosis of intratesticular veins. In normal testes, walls of veins are extremely thin, and lumina are nearly collapsed. Patients with varicocele also often have spermatozoa with characteristically elongate heads with thin bases.1904 Initially, abnormalities are confined to the testis ipsilateral to the varicocele, but eventually both testes are affected, although abnormalities are more severe in the ipsilateral testis. Elevated pressure in the pampiniform plexus is transmitted to the veins within the testes, principally to the centripetal veins that cross the testicular mediastinum and drain most of the parenchyma (Fig. 12.213).1905 Dilated centripetal veins compress the intratesticular sperm excretory ducts, a finding that explains the mosaic distribution of the tubular lesions.1905a Seminiferous Tubule Obstruction. Obstruction at the level of seminiferous tubules may be dysgenetic or postorchitic. Dysgenesis may be suspected in specimens with mosaic distribution of lesions and seminiferous tubules with small diameters, thickened lamina propria, and an unusual tubular cell layer consisting of cuboidal Sertoli cells and spermatozoa that clog the lumina (Fig. 12.214). Diagnosis is confirmed by study of serial sections demonstrating

Fig. 12.213 Mediastinum testis from a young man with varicocele. Marked venous dilation (intratesticular varicocele) disrupts and compresses rete testis cavities, causing partial obstruction of the tubuli recti.

continuity between the altered tubules and those with conserved spermatogenesis.1821,1906 This tubular stenosis appears to result from primary anomaly of Sertoli cells and peritubular cells. Postorchitic obstruction should be suspected in cases of tubular atrophy with a mosaic pattern without dysgenetic tubules or varicocele. Some patients have histories of orchitis associated with parotiditis, whereas in others the only findings are oligozoospermia and small testes.1907 Biopsy with sampling of the periphery reveals the consequences of obstruction, similar to lesions observed with varicocele. However, some postinflammatory changes are also present, including hyalinized tubules, dilated tubules lined by cuboidal Sertoli cells, or complete spermatogenesis. Occasionally, modest perivascular or peritubular inflammation and angiectasis are noted.1908,1909 Approximately 30% of testes with lesions in the adluminal compartment have no obstruction, and most have primary anomalies of germ cells. This claim is supported by the pronounced decrease of germ cell type when the preceding type is greatly increased in

Fig. 12.214 Segmented dysgenesis of seminiferous tubules. The two central tubules, which display only dysgenetic Sertoli cells, contain numerous spermatozoa that come from adjacent seminiferous tubules with normal spermatogenesis.

CHAPTER 12 Nonneoplastic Diseases of the Testis

spermatogonia. Most seminiferous tubules contain few spermatids. Approximately 8% of patients with hypospermatogenesis have focal tubular hyalinization.1918 Two variants of hypospermatogenesis have been quantitatively distinguished: pure hypospermatogenesis and hypospermatogenesis associated with sloughing of primary spermatocytes. Pure hypospermatogenesis is defined as a proportionate decrease in the number of all types of germ cells. The number of spermatogonia per cross-sectioned tubule is lower than 17 and usually higher than 10. The number of primary spermatocytes is equal to or higher than that of spermatogonia. The number of round spermatids is higher than that of primary spermatocytes, and the number of elongate spermatids is equivalent to that of spermatogonia (Fig. 12.217). Hypospermatogenesis associated with primary spermatocyte sloughing is characterized by two features: low numbers of spermatogonia and primary spermatocytes (with spermatocytes more numerous than spermatogonia), and degeneration and sloughing of many primary spermatocytes. The remaining spermatocytes give rise to the few spermatids observed in the tubules (Fig. 12.218). Etiology of Hypospermatogenesis: Overview. Hypospermatogenesis may result from hormonal dysfunction, congenital germ cell deficiency, Sertoli cell dysfunction, Leydig cell dysfunction, androgen insensitivity, exposure to chemical or physical agents, and vascular malfunction.

60 55 50 Cell numbers per cross-sectioned tubule

number, the normal correlation between number of mature spermatids in the biopsy and number of spermatozoa in the spermiogram, and the presence of numerous malformed germ cells in the adluminal compartment. Decrease in the number of germ cell types may be so significant that spermatogenesis is arrested, with subsequent azoospermia. In some cases, maturation arrest is only partial and results in severe oligozoospermia. This maturation arrest is observed mainly in primary spermatocytes and young spermatids. Primary spermatocyte sloughing may also result from meiotic anomalies (Fig. 12.215). The observation of increased number of spermatocytes arrested in preleptotene-leptotene or, more frequently, pachytene, suggests the diagnosis.1819,1901 The lesion is always bilateral. Spermatocytes arrested in pachytene are usually increased in size and later degenerate. In addition, some spermatids have large, diploid, spherical, hyperchromatic nuclei. The anomaly does not always affect all spermatocytes, and a higher number of spermatids is produced.1819 Primary meiotic arrest may result from lack of expression of several genes such as the absence of BOULE protein expression, altered expression of heat shock transcription factor, Y chromosome (HSFY), HSPA2, downregulation of microRNA-383, lack of expression of survivin, or lack of expression of BET genes.1910–1915 Meiotic arrest is also associated with copy number variations and TEX11 deletions and mutations.1916,1917 Young spermatid sloughing not associated with obstruction may result from meiotic anomalies or defective spermiogenesis. Meiotic anomalies give rise to the appearance of many multinucleate, polyploid, hyperchromatic young spermatids. In defective spermiogenesis, young spermatids are incapable of transforming into mature spermatids, and only round spermatids appear in the ejaculate. Lesions in the Basal and Adluminal Compartments of Seminiferous Tubules. Lesions in the basal and adluminal compartments of seminiferous tubules are the most frequent finding in biopsies from infertile men and are classified as hypospermatogenesis or spermatogonial maturation arrest (Fig. 12.216). Hypospermatogenesis: Types and Etiology. Hypospermatogenesis is defined as reduced number of spermatogonia and primary spermatocytes, with primary spermatocytes outnumbering

651

Normal control testes Average values in normal testes Young spermatid sloughing Late sloughing of spermatocytes I Early sloughing of spermatocytes I Meiotic anomalies

45 40 35 30 25 20 15 10 5

Fig. 12.215 Meiotic abnormalities. The seminiferous tubules contain a normal number of spermatogonia and a disproportionately high number of primary spermatocytes, which do not complete meiosis. No spermatids are seen.

0 Spermatogonia

Spermatocytes 1

Sa + Sb

Sc + Sd

Fig. 12.216 Germ cell numbers per cross-sectioned tubule in patients with lesions in the basal and adluminal compartments of seminiferous tubules.

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Fig. 12.217 Pure hypospermatogenesis in a patient with severe oligozoospermia. The seminiferous tubule shows slight ectasis and a proportionate decrease of all germ cell types.

Hormonal Dysregulation. Although complete spermatogenesis may be observed in men with low levels of FSH and LH, production of normal numbers of spermatozoa requires normal gonadotropin levels. Hypospermatogenesis may occur in patients with abnormal pulsatile secretion of FSH and LH, low gonadotropin secretion, biologically inactive gonadotropins, mutation in the gonadotropin β subunit, inactivating mutations of the FSHR gene, hyperprolactinemia, and adrenal and thyroid dysfunction (see later Hypogonadism Secondary to Endocrine Gland Dysfunction and Other Disorders section).1753,1919–1922 Congenital Germ Cell Deficiency. Testicular biopsy of cryptorchid patients after orchidopexy reveals that spermatogonial proliferation is decreased and germ cell development is insufficient in adulthood even if the number of spermatogonia was normal in infancy. This poorly understood primary anomaly of germ cells is likely present in some cases of hypospermatogenesis. Sertoli Cell Dysfunction. For many years, primary germ cell deficiency was considered the most common cause of hypospermatogenesis; today, Sertoli cell failure is recognized as the cause of

Fig. 12.218 Hypospermatogenesis associated with primary spermatocyte sloughing in an azoospermic patient. Spermatogonia and primary spermatocytes are the sole germ cell types.

many cases of germ cell deficiency. This conclusion is based on several findings. Sertoli cells of infertile patients are often markedly abnormal, with increase in number of glycogen granules and acid phosphatase activity, decrease in number of lipid droplets, and alterations in the cytoskeleton, nucleus, and cytoplasmic organelles.1753,1859,1923–1925 Sertoli cells may have abnormal maturation, with elongate nuclei containing coarse chromatin masses instead of triangular nuclei with pale chromatin. Anomalies in Sertoli cell FSHRs may be present in idiopathic oligozoospermia associated with elevated levels of FSH.1926 Serum inhibin B concentration may be used as a marker to estimate Sertoli cell function.1927 Leydig Cell Dysfunction. Testosterone synthesis by Leydig cells is necessary for normal spermatogenesis, and abnormal Leydig cell function is detected in 10% to 20% of patients with azoospermia or oligozoospermia and idiopathic infertility.1928–1931 Leydig cell dysfunction should be suspected when the cells appear diffusely hyperplastic. Patients have elevated serum LH with depletion of rapid-release testosterone, revealing lack of early response of Leydig cells to GnRH stimulation. The ratio of testosterone to LH in plasma indicates the severity of Leydig cell dysfunction. Decreased ratio with normal testosterone suggests compensated dysfunction. Patients with a ratio less than 1:5 and otherwise normal parameters may complete spermatogenesis.1931 In development of this dysfunction of Leydig cells, overexpression of CYP19A1 aromatase by chronic stimulation of LH may play an important role. This situation would lead to higher production of estradiol, which would negatively affect androgen biosynthesis by Leydig cells.1932 Androgen Insensitivity. Some patients with severe oligozoospermia or azoospermia have a defect in AR responsiveness, similar to that noted in Reifenstein syndrome.1700,1933,1934 The abnormality may arise from a genetic defect in the eight exons that code for this receptor, mapped to Xq11–12, or from posttranslational errors.1726,1730,1935 This defect is also referred to as infertile male syndrome and MAIS, and patients have male phenotype with somatic features of slight androgen deficit.1936 Histologically the testis is similar to that observed in Leydig cell dysfunction or MAT, although the mechanism causing Leydig cell hyperplasia is quite different (Fig. 12.219). Peripheral resistance to testosterone action alters regulation of the hypothalamohypophyseal-testicular axis, and LH and testosterone levels are elevated. The frequency of RA mutations in patients with azoospermia or oligozoospermia who consult for infertility is estimated at 2% to 3%.1937 In such cases, spermatogenesis improves with administration of tamoxifen citrate, clomiphene citrate, or androgen therapy.1710,1731,1938 Calculation of the index of androgen insensitivity may be helpful: plasma LH (mIU/mL)  plasma testosterone levels (ng/mL). In patients with androgen insensitivity the index is greater than 200 (normal is 102). Physical and Chemical Agents. The number of chemicals implicated in infertility increases daily. Detailed history is invaluable in evaluating these patients. The same is true of physical agents such as prolonged exposure to heat, ionizing radiations, or microwave radiation.1939 Etiology of Hypospermatogenesis Associated With Primary Spermatocyte Sloughing. Most testes with primary spermatocyte sloughing have varicocele, and this is commonly associated with infertility.573,1940–1942 Varicocele is found in 15% of the general population and is present in 30% to 40% of infertile men. The mechanism by which varicocele affects fertility is unknown. Clinical varicocele may occur without a testicular lesion (or only phlebectasis), and subclinical varicocele may be associated with severe spermatogenic lesions. Increased testicular temperature and

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.219 Hypospermatogenesis due to androgen receptor defect. The seminiferous tubules show hypospermatogenesis associated with diffuse Leydig cell hyperplasia.

compression of intratesticular sperm excretory ducts by dilated veins are the most plausible mechanisms.1905a,1943,1944 In other cases, primary spermatocyte sloughing results from anomalies of primary spermatocytes and spermatids, a finding suggesting meiotic anomaly. Finally, in some patients the cause may be the presence of involuting Sertoli cells. Spermatogonial Maturation Arrest. Spermatogonial maturation arrest is defined by the presence of fewer than 17 spermatogonia per cross-sectioned tubule and even fewer primary spermatocytes. Spermatids are usually absent. Attempts have been made to correlate the etiology of spermatogonial maturation arrest with the Sertoli cell type.1945 Immature Sertoli cells are characteristic of hypogonadotropic hypogonadism and some AISs (Fig. 12.220). Mature Sertoli cells, if their presence is unilateral, are observed in varicocele, epididymitis, and ipsilateral testicular traumatism, but if they appear in both testes, the etiology is unknown. Involuting Sertoli cells are usually present bilaterally; some cases are idiopathic, whereas others are associated with a history of alcoholism or chemotherapy. Dedifferentiated Sertoli cells are found in spermatogonial maturation arrest caused by gonadotropin inhibition in treatment with estrogen, GnRH agonists, or antiandrogen.1946,1947 Focal Lesions in Spermatogenesis (Mixed Atrophy). Mixed atrophy (MAT) is a descriptive term for the coexistence, in the same testis, of Sertoli cell–only tubules and tubules with complete or incomplete spermatogenesis (Fig. 12.221).1948 This disorder includes patchy failure of spermatogenesis and partial Del Castillo syndrome. The extent of Sertoli cell–only tubules varies widely. Tubules with spermatogenesis may be normal or partially atrophic. Tubular hyalinization is occasionally seen. The interstitium shows an increase in mast cell number.1949 MAT is more common than suggested by the literature, and many cases are included under other diagnoses, such as “hypospermatogenesis with severe germ cell depletion in such a way that some Sertoli cell–only tubules are seen” and “Sertoli cell–only syndromes with focal spermatogenesis.”1950 Serial sections from testes with MAT reveal that the two different types of tubules are grouped according to their histologic pattern, a finding suggesting that their distribution is by testicular

653

Fig. 12.220 Spermatogonial maturation arrest. The seminiferous tubules have increased numbers of Sertoli cells and nearly normal number of spermatogonia, whereas the remaining germ cell types are scant. The testicular interstitium shows diffuse Leydig cell hyperplasia.

Fig. 12.221 Mixed atrophy. Seminiferous tubules showing slight ectasis and complete spermatogenesis adjacent to Sertoli cell–only pattern. The tubular lesions probably belong to a different lobule.

lobules. In cases of MAT the percentage of tubules with spermatogenesis, the degree of spermatogenic development in these tubules, and the type of Sertoli cells present should be reported. Correlation of the first two with the spermiogram gives an indication of prognosis, whereas the Sertoli cell type identifies the nature (primary or secondary) of the lesion (Fig. 12.222).245 MAT (probably primary) is observed in idiopathic infertility, cryptorchidism (even if orchidopexy was done in infancy, in both the cryptorchid and contralateral descended testes), retractile testes, macroorchidism, intravaginal torsion of the spermatic cord (in both twisted and contralateral testis), and chromosomal anomalies such as Down syndrome, 47,XYY karyotype, 46,XX karyotype, giant Y chromosome, Klinefelter syndrome with chromosomal mosaicism, Y-chromosome microdeletions, PAIS, some undermasculinization male (DSD), and in parenchyma peripheral to germ cell tumor.1951,1952 Secondary MAT is sometimes seen in patients undergoing chemotherapy, receiving glucocorticoid

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Fig. 12.222 Mixed atrophy. Tubules on the left have complete although quantitatively abnormal spermatogenesis, and Sertoli cell–only tubules on the right have Sertoli cells with nuclei of dysgenetic characteristics and intensely eosinophilic cytoplasm suggesting a primary lesion. Leydig cells show microvacuolated cytoplasm.

Fig. 12.223 Hypertrophic spermatogonia in a seminiferous tubule showing marked decrease in the number of spermatogenetic cells.

therapy, with a history of viral orchitis, and in the parenchyma peripheral to a germ cell tumor.1882

Germ Cell Anomalies in Infertile Patients In addition to identifying anomalies in seminiferous tubules, examination of the biopsy should include morphology of the germ cells. Giant Spermatogonia

Isolated giant spermatogonia are normal components of the seminiferous epithelium. These cells may be altered spermatogonia in the S or G2 phase of the cell cycle. They rest on the basal lamina, and have pale cytoplasm and ovoid nuclei measuring at least 13 μm in diameter. The frequency of these cells in normal and infertile men is approximately 0.65 cells per 50 cross-sectioned tubules, although the number is usually higher in MAT. These cells should not be mistaken for GCNIS; they are also present in normal numbers in tubules at the periphery of germ cell tumor (Fig. 12.223).1953 Multinucleate Spermatogonia

Multinucleate spermatogonia are common in cryptorchid testes that were surgically corrected, in infertile patients, and in old men. Nuclei of both Ad and Ap spermatogonial types may be seen within the same cell. Dislocated Spermatogonia

Normally, spermatogonia are present in the transition zone between the seminiferous tubule basal layer and tubuli recti. Dislocated spermatogonia may be found throughout the testis in old age, in infertile patients with a variety of lesions, after long-term estrogen therapy, and in seminiferous tubules with intratubular germ cell neoplasia.1954–1956 Megalospermatocytes

Megalospermatocytes are large primary spermatocytes arrested in the leptotene stage (Fig. 12.224), which exhibit asynapsis of chromosomes.1957,1958 Joined by cytoplasmic bridges, they form small groups. These cells may be clones of synchronously degenerating

Fig. 12.224 Megalospermatocytes. The seminiferous tubule contains a group of large primary spermatocytes displaying fine chromatin and eosinophilic cytoplasm.

spermatocytes.1959 They are frequently found in older men and are a nonspecific finding in infertile patients. Multinucleate Spermatids

The presence of spermatids with multiple nuclei (from 2 to 86) is frequent in old age.1960 Similar cells with fewer nuclei have also been reported in infertility secondary to cryptorchidism or hyperprolactinemia, as well as in idiopathic infertility (Fig. 12.225).1961 Malformed Spermatids

At least four teratozoospermic syndromes may be easily identified by biopsy, although the diagnosis of most previously relied on morphologic study of the spermiogram: (1) round-headed spermatids (characteristic of spermatozoa lacking acrosomes) (Fig. 12.226); (2) Sc + Sd spermatids with elongate head (characteristic of varicocele) (Fig. 12.227); (3) macrocephalic Sc + Sd spermatids whose DNA content suggests an anomaly in the first meiotic division; and (4) Sc + Sd spermatids with voluminous eosinophilic cytoplasmic droplets (syndrome of spermatozoa with short, thick flagella or fibrous sheath dysplasia1962).

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.225 Multinucleation of both spermatids and spermatocytes.

In some patients, Sa + Sb spermatids are present in the initial phases of spermiogenesis and eventually become sloughed.1963 Other testes have macrocephalic Sc + Sd spermatids with anomalous DNA content, findings suggesting an anomaly in the first meiotic division.

Morphologically Abnormal Spermatozoa Ultrastructural study of spermatozoa is sometimes necessary to determine the cause of male infertility. Some morphologically abnormal spermatozoa are seen in all semen samples, including those from fertile men, but abnormal spermatozoa are most numerous in infertile patients. Ultrastructural study of spermatozoa is valuable for identifying spermatozoal disorders, but it is also useful for assisted reproductive technology and genetic risk assessment; it is advised in all cases of asthenozoospermia, in teratozoospermia when the number of spermatozoa showing the same morphologic anomaly is high, and in cases with apparently normal spermatozoa that fail to fertilize in vitro.1964–1966 Classification is based on light microscopic findings of lesions in the head and tail.1967

Fig. 12.226 Testicular biopsy showing spermatids with small spherical nuclei, a finding characteristic of round spermatozoa lacking acrosomes. The remaining germ cells are morphologically normal.

655

Fig. 12.227 Elongate spermatids showing a bell-clapper nucleus in a varicocele patient.

Anomalies of the Spermatozoal Head

Anomalies of the spermatozoal head are defined by changes in the shape of the spermatozoal head and usually involve both the nucleus and acrosome. Some anomalies, such as pear-shaped, candle-shaped, or egg-shaped heads, are regarded as minor variants of normal.426,1968 Significant abnormalities are the elongate, microcephalic, macrocephalic, and crater defect forms. The most frequent abnormal head shape is elongate with a narrow base (tapered head spermatozoa), commonly associated with varicocele.1969 Microcephalic spermatozoa have spherical (globozoospermia) or irregularly shaped heads. Microcephalic spermatozoa with spherical heads contain round nuclei with poorly condensed chromatin and lack acrosomes, postacrosomal sheaths, and a nuclear ring (Figs. 12.228 and 12.229). Most cases are sporadic, but this lesion was also reported in two pairs of infertile brothers.1970–1972 Microcephalic spermatozoa with irregularly shaped heads have small and irregular acrosomes that usually are not in contact with the nucleus. This anomaly may be congenital, as in Aarskog-Scott syndrome, or secondary to heat exposure or hashish smoking.1973 In both types of microcephaly, loss of connection between the acrosomal vesicle and spermatozoal head is attributed to a deficiency in basic proteins of the sperm perinuclear theca that promotes nuclear envelope organization and adhesion of the acrosomal vesicle.1974 Acrosin is reduced or absent in spermatozoa lacking acrosomes and in those with small acrosomes.1975 Motility may be normal. The occurrence of aneuploidy and disomy of sex chromosomes in some cases should be evaluated before performing Intracytoplasmatic sperm injection (ICSI).1976–1978 The responsible genetic defect of most cases is 200-kb homozygous deletion of DPY19L2.1979 This transmembrane protein, located in the inner nuclear membrane, ensures attachment of the acrosome to the nucleus. Because of defect, the acrosome is not formed and manchette does not produce elongation of the nucleus. Other genes responsible of globozoospermia are SPATA16, PICK1, and DPY19L2.1980–1982 Macrocephalic spermatozoa (macronuclear spermatozoa) have enlarged, irregular heads and deficient chromatin condensation. Both types (multiple tails and aflagellate) have abnormal DNA content (many are tetraploid), a finding suggesting meiotic anomaly, and are associated with increased frequency of

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Fig. 12.228 Microcephalic spermatozoa with spherical nuclei lacking acrosome and poorly condensed chromatin. Ultrastructural anomalies are observed.

premature sloughing, as occurs in varicocele, and should not be misinterpreted as spermatozoa with excess residual cytoplasm.1993 These spermatozoa are often abnormal, and the residual cytoplasm may be located around the intermediate piece or surrounding the head. These spermatozoa also have other flagellar anomalies. Bent Tail. A bend in the tail may occur at the level of the connecting piece or the intermediate piece. In bends of the connecting piece the tail is laterally implanted and forms an angle with a nucleus that displays a thin base. Bends of the intermediate piece are associated with cytoplasmic droplets, malposition of mitochondria, and loss of parallel arrangement of the dense outer fibers. Spermatozoa with bent tail may show anomalies secondary to a mutation in Septine12, a testis-specific gene critical for terminal differentiation of male germ cells.1994 Coiled Tail. Spermatozoa with coiled tail are a frequent finding in centrifuged semen, but may also be a true abnormality. These spermatozoa have a perinuclear cytoplasmic remnant containing a flagellum that is coiled around the nucleus and along the middle or principal pieces (Fig. 12.230). This finding is frequently associated with abnormalities of the periaxonemal structures. Tail Stump (Short-Tail Spermatozoa). The presence of many spermatozoa with short, thick tails in semen represents a welldefined teratozoospermic syndrome (Fig. 12.231).1995 Ultrastructural examination reveals hypertrophy and hyperplasia of the fibrous sheath (Figs. 12.232 and 12.233), hence this syndrome has also been termed fibrous sheath dysplasia.1996,1997 Additional axonemal malformations may be identified, including absence of the central pair of microtubules, lack of dynein arms, and anomalies in head–neck junction.1998,1999 Anomalies in the fibrous sheath may be demonstrated using antibodies against antiacetylated tubulin and anti-FSC1 (the major protein components of the fibrous sheath).2000 Approximately 24% of patients have respiratory disease from an early age, including rhinosinusitis, bronchitis, and bronchiectasis. Similar findings have been reported in the cilia of the upper respiratory tract, and thus a relationship between fibrous sheath dysplasia and immotile cilia syndrome has been assumed. The clinical presentation may be sporadic or familial. The cause of the fibrous sheath dysplasia and subsequent lack of motility in spermatozoa is probably related to deletions in AKAP3

Fig. 12.229 Microcephalic spermatozoa without acrosome (globozoospermia).

aneuploidy.1983–1987 Most patients harbor homozygous truncating mutations in the aurora kinase gene (AURKC), which acts preferentially in meiotic chromosomal segregation and cytokinesis.1988,1989 Irregular spermatozoa are characterized by altered shape of the nucleus or acrosome.1990 In crater defect syndrome the acrosome penetrates an invagination of the nuclear envelope. The tail is morphologically normal, and motility is only slightly reduced. In spermatozoa with spoon-shaped nuclei the defect is probably genetic. Other anomalies include double-headed spermatozoa with two nuclei sharing a single acrosome.1991 Anomalies of the Spermatozoal Tail

Spermatozoal tail anomalies are classified as generalized anomalies or anomalies of defined tail components such as the connecting piece, the axoneme, or periaxonemal structures.1992 Cytoplasmic Remnants. The presence of cytoplasmic droplets is normal during spermiogenesis. Increased number of spermatozoa with cytoplasmic droplets in semen is associated with

Fig. 12.230 Spermatozoa with coiled tails. The anomaly occurs in the principal pieces. The intermediate pieces show variable lengths, absence of parallelism in the outer dense fibers, and large cytoplasmic droplets. This teratozoospermia was found in two infertile brothers.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.231 Dysplasia of the fibrous sheath associated with hypoplasia of the intermediate piece in a patient with short and thick spermatozoa under light microscopy.

657

Fig. 12.233 Dysplasia of the fibrous sheath associated with disorganization of dense fibers and microtubules.

Anomalies of the Connecting Piece

Fig. 12.232 Tail-stump spermatozoal malformation. Longitudinal section of two spermatozoa showing a marked thickening of the principal piece with both hypertrophy and hyperplasia of the fibrous sheath. The one on the left also shows a short intermediate piece.

Anomalies of the connecting piece are classified as acephalic spermatozoa, deficient organization of the connecting piece, or separation between the head and the tail. Acephalic spermatozoa are known as “pin-headed,” although they lack a true head; the small, cephalic, knoblike thickening is actually a cytoplasmic droplet with variable degree of mitochondrial organization giving rise to variable degree of motility.2004 This anomaly is secondary to early failure in spermiogenesis. It may be familial in some cases.2005,2006 Spermatozoa with deficient organization of the connecting piece have narrowing at this level, with loss of alignment of the head and flagellum axes. This may occur through one of the following mechanisms: (1) failure in the postnuclear region to form the basal plaque and the implantation fossa, (2) chemical anomaly of the filamentous material present between the capitellum and the basal plaque, or (3) abnormal position of the tail over the caudal pole of the nuclei during flagellum development.2007,2008 Spermatozoa with a separated head and flagellum, known as decapitated and decaudated spermatozoa, also result from an anomaly in spermiogenesis, but separation between head and tail may occur during spermiation or at any level of the sperm excretory ducts. Failure of the head-tail coupling apparatus is caused by centriole dysfunction and deficient assembly of the manchette.2009,2010 Anomalies of the Axoneme

and AKAP4 genes and absence of AKP4 protein in the fibrous sheath.2001 Multiple Tails. The presence of more than two tails is associated with macrocephalic spermatozoa.1135 Sperm Tail Agenesis. Teratozoospermia with 100% sperm tail agenesis has been reported in patients with a high degree of consanguinity. These spermatozoa also have defects in chromatin condensation and residual cytoplasmic droplets.2002 Sperm With Abnormal Elongation of the Tail. Abnormally elongate tails are associated with frequent ruptures at different levels, coiled tails, and a strongly rolled axoneme, among other malformations. These abnormalities are considered to have a genetic origin.2003

Abnormalities of the axoneme are classified as numeric anomalies, microtubule ectopia, or the immotile cilia syndrome. The most common numeric anomalies are the absence of one or both microtubules of the central pair and the complete lack of the axoneme. Spermatozoa lacking the central microtubule pair also lack the central sheath and are immotile, although they appear normal by light microscopy (Fig. 12.234). Familial cases have been reported.2011 This anomaly may be associated with ciliary dyskinesia.2012 The immotile cilia syndrome (primary ciliary dyskinesia) refers to patients having low mucociliary clearance associated with otitis, sinusitis, bronchitis, bronchiectasis, and immotile spermatozoa.2013 Most patients have the same defect in the axoneme and cilia of the respiratory mucosa. The frequency of this syndrome

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Fig. 12.236 Cross section of the principal piece from spermatozoa lacking in dynein arms and showing a supernumerary microtubule doublet. Fig. 12.234 Cross section of the main piece of a spermatozoid showing absence of the pair of central microtubules and the central sheath.

is estimated at between 1 in 20,000 and 1 in 60,000 men. Clinical symptoms consist of reduced clearance of ciliary mucus in the airway, with onset in infancy. To prevent subsequent development of bronchiectasis, ultrastructural study of the respiratory mucosa is advisable if other disorders have been excluded, including cystic fibrosis (CF), allergy and other immune disorders, α1-antitrypsin deficiency, and cardiovascular and metabolic diseases.2014 The most frequent anomalies are absence of the following: microtubule doublets and peripheral junctions, central microtubule pair, outer dynein arms, central junctions, the two dynein arms, and the inner dynein arm plus the peripheral junctions (Figs. 12.235 and 12.236). Spermatozoa lacking the two dynein arms or peripheral junctions are immotile. Reduced motility is seen in spermatozoa with only one dynein arm. Kartagener syndrome is a variant of the immotile cilia syndrome characterized by the classic triad of situs inversus, bronchiectasis, and chronic sinusitis. It is autosomal recessive, and found in

20% to 25% of patients with situs inversus.2015,2016 Although spermatozoa are immotile, pregnancy has been achieved with assisted reproductive techniques such as subzonal insemination; ICSI, either isolated or associated with hypoosmotic swelling test; and in vitro fertilization.2017–2020 The cause of primary ciliary dyskinesia has been identified in 50% of cases, particularly in mutations of several genes and chromosomal loci. The most common causes are mutations in DNAH5 (28%).2021–2022 Other genes responsible for isolated cases are DNAI2, DNAH11, TXNDC3, DNAAF3, mutations in RSPH9 and RSPH4A encoding two radial spoke head proteins that produce defects in the central pair, and mutations in CCDC39 and CCDC40 causing misplacement of the central pair of microtubules.2023,2024 Mutations in genes encoding cytoplasmic proteins such as KTU and LRRCSO may also be implicated in assembly of dynein arms.2025 Anomalies of Periaxonemal Structures

Periaxonemal abnormalities include mitochondrial sheath defects; malposition or the annulus; alteration in number, shape, or length of the outer dense fibers; and absence, thickening, or disruption of the fibrous sheath.1997,2026,2027 Many of the asthenozoospermias, present in 30% of infertile men, may be attributable to deficient mitochondrial function that is measured by respiratory control ratio.2028 The 7436-bp deletions of mitochondrial DNA are one of the most common causes of nonmotile sperm.2028,2029 Abnormalities of dense fibers are associated with deficient motility. Abnormalities of the fibrous sheath include previously mentioned dysplasia, absence, and redundant fibrous sheath material associated with deficit or lack of mitochondria.2030,2031 The three defects are probably inherited. Spermatozoa with fewer mitochondrial gyres have a shorter midpiece, whereas spermatozoa with a great number of gyres have a larger midpiece.2032

Fig. 12.235 Cross section of intermediate piece of a spermatozoid with absence of both dynein arms.

Presence of Tumoral Cells The incidence rate of GCNIS in infertile patients is 0.4% in England, 0.7% in Spain, 0.73% in Germany, and 1.1% in Denmark.2033–2036 A higher risk occurs in patients with severe oligozoospermia (<10 million spermatozoa/mL), azoospermia associated with unilaterally or bilaterally diminished

testicular volume, history of maldescent, or unilateral testicular cancer.1078,2037–2039 The cells of GCNIS are in seminiferous tubules with decreased tubular diameter that lack spermatogenesis. The cells are large, have pale cytoplasm, and display large and irregular nuclei with one or several prominent nucleoli. They stain intensely with PAS and express PLAP, KIT, OCT3/4, and the cell adhesion molecule CD44.2040

Anomalies of Leydig Cells Absence or paucity of Leydig cells is infrequent in infertility. It occurs in hypogonadotropic hypogonadisms secondary to LH deficit and in patients with biologically inactive LH. Leydig cell hyperplasia is common.1656 It may occur in Klinefelter syndrome, cryptorchidism, undermasculinization, minor androgen insensitivity, infertility secondary to Leydig cell dysfunction, varicocele, after treatment with 5α-reductase inhibitors or nonsteroidal antiandrogens, and in older men. Hyperplasia may give rise to hypoechoic or hyperechoic images that may be misdiagnosed as tumor.2041 Mast Cells A close relationship exists between testicular dysfunction and elevated mast cell number in the testis, epididymis, and seminal fluid. An increase in interstitial and peritubular mast cells occurs in many patients with azoospermia or oligozoospermia.417,2042–2044 A significant increase in mast cells has also been observed in semen from patients with varicocele and idiopathic asthenozoospermia.2045,2046 Surgical treatment of varicocele and daily administration of ketotifen, an antihistamine-like drug with mast cell–stabilizing effect, significantly improves spermiogram parameters in some patients.2047,2048 Macrophages Macrophages are a common component of the interstitium, maintaining a paracrine relationship with Leydig cells. The CD68+ macrophage count is increased in patients with obstructive azoospermia when compared with patients with nonobstructive azoospermia.2049

Correlation Between Testicular Biopsy and Spermiogram For effective therapy, it is important to know whether azoospermia or oligozoospermia is the result of obstruction.1826,2050

Obstructive Azoospermia and Oligozoospermia Azoospermia caused by obstruction is usually easily diagnosed, but identification is more difficult with oligozoospermia. Obstruction of the ductal system should be suspected when there are more than 20 mature spermatids (Sc + Sd) per cross-sectioned tubule and fewer than 10 million spermatozoa in the spermiogram (Fig. 12.237).2051,2052 Obstructive azoospermia is implicated in 7% to 14% of cases of male infertility. Classification of Obstructive Azoospermia by Location

Obstruction is classified as proximal, distal, or mixed according to the distance from the testis to the point of obstruction in the ductal system. Proximal Obstruction. Obstruction is considered proximal when the lesion lies between the seminiferous tubules and the distal end of the ampulla of the vas deferens. Epididymal obstruction,

Sc + Sd number per cross-sectioned tubule

CHAPTER 12 Nonneoplastic Diseases of the Testis

659

30 25 20 15 10 5 0 0

10

40 50 60 20 30 Number of spermatozoa per mL

70

Fig. 12.237 Power curve showing the correlation between the number of spermatozoa in the spermiogram and the number of mature spermatids (Sc +Sd) per cross-sectioned tubule. If the number of mature spermatids is correlated to that of spermatozoa in spermiogram, the oligozoospermia is of the pure secretory type. If the number of mature spermatids is higher than that of spermatozoa in spermiogram, the disorder is either an obstructive azoospermia with “normal” testicular biopsy or a mixed obstructive secretory oligozoospermia.

principally of the caput-corpus transition zone, accounts for 66% of cases. Rarely, defective connection is present between the rete testis and epididymal ductuli efferentes. The seminal vesicles are normal, so men with proximal obstruction have normal volume of semen (the testicular contribution to semen is only 5% of the total volume). When obstruction is in the cauda of the epididymis, levels of epididymal markers, including carnitine, glycerophosphorylcholine, and α-glycosidase, are low.2053 The nearer the obstruction is to the caput of the epididymis, the higher the levels. Distal Obstruction. Distal obstruction is located between the ampulla of the vas deferens and the junction of the ejaculatory ducts and urethra. These patients present with sacral, perineal, or scrotal pain on ejaculation. Rectal examination often reveals enlarged seminal vesicles. The volume of semen is low and consists of watery fluid that fails to coagulate. Seminal vesicle secretions are lacking. The concentration of prostatic secretions, such as acid phosphatase and citric acid, is increased because of the lack of semen dilution. Vasography may help in the diagnosis because higher segments fail to fill.2054 Transrectal ultrasonography is the most accurate imaging modality for the diagnosis of ejaculatory duct obstruction. Needle aspiration of seminal vesicle fluid may show spermatozoa that have entered the seminal vesicles by reflux. Mixed Obstruction. Mixed obstruction refers to lack of patency of the vas deferens or the epididymis and alterations in ejaculatory ducts or seminal vesicles (low ejaculate volume and absence of fructose). The most frequent cause is mucoviscidosis. One-third of patients with congenital bilateral absence of vas deferens have agenesis or hypoplasia of seminal vesicles. The cause of epididymal obstruction in patients with anomalies of the prostatevesiculodeferential junction is difficult to determine.

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Etiology of Obstructive Azoospermia

Obstructive azoospermia may be caused by congenital or acquired lesions. Congenital Azoospermia. The most frequent anomalies associated with congenital azoospermia are testis-epididymis dissociation, epididymal malformation in cryptorchidism, bilateral absence of the vas deferens, congenital unilateral absence of the vas deferens associated with a pathologic process of the contralateral testis or its sperm excretory ducts, seminal vesicle agenesis, and ejaculatory duct obstruction (Table 12.23). Agenesis of All Mesonephric Duct Derivatives. Agenesis of all mesonephric duct derivatives is a rare disorder that gives rise to varied anatomic anomalies, depending on the stage of embryonic development at which the mesonephric duct derivatives disappear. If failure occurs before the fourth week, the ipsilateral kidney and ureter are absent, although the testis may be present, or other renal anomalies may occur. If failure occurs during the fourth week and the ureteral bud is already formed, the ureter and kidney may develop normally. If failure occurs between the 4th and 13th weeks, there is a variable constellation of anomalies that most frequently include normal development of the testis and globus major, and hypoplasia of the other excretory duct segments or agenesis of an excretory duct segment (epididymis, vas deferens, or seminal vesicle). Epididymal Anomalies. The most frequent epididymal anomalies are absence of the epididymis, testis-epididymis dissociation, defective connection of the vas deferens and the epididymis, epididymal cysts, and anatomic abnormalities of the epididymis. Complete absence of the epididymis is frequent in monorchidism and anorchidism. The epididymis is replaced by a small mass of cellular connective tissue with abundant blood vessels at the blind end of the vas deferens. Partial absence of the epididymis is more frequent than complete absence. Absence of the corpus of the epididymis gives rise to a characteristic malformation called bilobed epididymis. This

TABLE 12.23

varies from simple strangulation to complete separation of the caput and cauda. These anomalies are often associated with absence of the vas deferens. Testis-epididymis dissociation is found in 1% of cases of obstructive azoospermia and is usually associated with cryptorchidism. Defects in connection of the ductuli efferentes and ductus epididymidis are rarely complete. In the incomplete form, some of the 5 to 30 ductuli efferentes in the epididymis are short and end blindly. Epididymal cyst usually arises from blind-ending ductuli efferentes and contains spermatozoa. Spermatocele retains its epithelial lining, although it becomes atrophic (Figs. 12.238 through 12.240). Spermatozoa may be obtained from such a cyst. Some epididymal cysts arise from embryonic remnants, do not contain spermatozoa, and are lined by columnar or pseudostratified epithelium. Wolffian cysts, unlike m€ ullerian cysts, are immunoreactive in the apical border of epithelial cells for CD10, with linear immunostaining.2054 Cysts lined by clear cells with or without papillae raise concern for von Hippel–Lindau disease.2055 Large epididymal cysts require removal and must be excised with great care to avoid damaging the ductuli efferentes and creating obstruction. Epididymal cysts are present in approximately 5% of male patients, and

Congenital Anomalies of the Male Mesonephric Ducts

I. Agenesis of All Mesonephric Duct Derivatives II. Epididymis

Fig. 12.238 Gross section of the caput of epididymis showing several cysts.

Agenesis of the epididymis. Testis-epididymis dissociation. Failure in the connection between ductuli efferentes and ductus epididymidis. Cysts of the epididymis. Anomalies in epididymal configuration. Elongate epididymis. Angulated epididymis. Free epididymis.

III. Vas Deferens Agenesis of the vas deferens. Persistent mesonephric duct.

IV. Seminal Vesicle Agenesis of the seminal vesicle. Cysts of the seminal vesicle. Opening of the ureter into the seminal vesicle.

V. Ejaculatory Duct Agenesis of the ejaculatory duct. Fig. 12.239 Several cysts in the periphery of the caput of epididymis.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.240 Infertile patient with bilateral epididymal cysts. The cystic wall appears collapsed and folded on the epididymis.

the incidence rate is high (21%) in those exposed to diethylstilbestrol during gestation.2056 Anomalies in epididymal configuration that alter its shape and location are frequent in men with cryptorchidism and uncommon in those with descended testes. The most common malformations are elongate epididymis, angulated epididymis, and free epididymis. Elongate epididymis is found in approximately 68% of undescended testes. The length of the epididymis may be several times that of the testis, and in abdominal or inguinal cryptorchidism the epididymis extends several centimeters below the testis. Angulated epididymis is characterized by long epididymis that has a sharp bend in the corpus, with or without stenosis. With free epididymis, all or part of the epididymis is unattached to the testis. The most common variant is epididymis with free cauda. Vas Deferens Anomalies. The most frequent anomalies of the vas deferens are congenital absence, segmental aplasia, ectopia, duplication, diverticula, and crossed dystopia.2057 Congenital absence is defined as unilateral or bilateral absence of the whole vas deferens or only a segment. Obviously, azoospermia occurs with bilateral absence. The frequency of this malformation varies among populations. At autopsy the prevalence rate is 0.5%, but the clinical incidence rate is 1% in infertile men and 10% to 25% in patients with obstructive azoospermia.2058 Unilateral complete absence is three times more frequent than bilateral, and absence of only a segment is even more frequent. The affected segment may be absent or reduced to a fibrous cord. Absence of the vas deferens may be associated with other malformations of the sperm excretory ducts or the urinary system. The most frequent malformations of the excretory ducts are absence of the ejaculatory ducts (33% of cases) and, less frequently, absence of the seminal vesicles. Approximately 71% of patients with bilateral absence of the vas deferens have partial aplasia of the epididymis. The most frequent malformations of the urinary system are absence of the ipsilateral kidney and other renal anomalies. Complete or partial absence of the vas deferens occurs frequently in patients with CF. Persistent mesonephric duct consists of the ureter joined to the vas deferens, forming a single duct that opens into an ectopic orifice between the trigone and verumontanum. This malformation may be associated with cystic transformation or absence of the seminal vesicle. The kidney may be normal or dysplastic.

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Anomalies of Seminal Vesicle and Ejaculatory Duct. The most frequent anomalies are agenesis of the seminal vesicles or ejaculatory ducts, cyst of the seminal vesicle, and ectopic opening of the ureter into the seminal vesicle. The last anomaly is the most common and often is associated with ipsilateral renal dysplasia.2059 Acquired Azoospermia. Inflammation and trauma are the main causes of acquired azoospermia. Epididymitis is a frequent cause; Chlamydia trachomatis and Escherichia coli are currently the most common infectious causes.2060–2062 Infections with Neisseria gonorrhoeae and mycobacteria also are implicated, and nonspecific epididymitis is significant.2063 Apart from elective vasectomy the most frequent traumatic causes of azoospermia are surgical accidents during herniorrhaphy in children, orchidopexy, varicocelectomy, hydrocelectomy, deferentography, and removal of epididymal cyst.2064–2066 Obstructive azoospermia may also result from blockage of the ejaculatory ducts after transurethral resection or as a result of long-term urethral catheterization. Testicular and Epididymal Lesions Resulting From Obstruction of Sperm Excretory Ducts. Lesions of the testis and epididymis may result from obstructed sperm excretory ducts, depending on the location, origin (congenital or acquired), and duration of the obstruction (Fig. 12.241). Location of Obstruction. Obstruction at the level of the ampulla of the vas deferens, seminal vesicles, or ejaculatory ducts does not usually cause significant lesions in the testis or epididymis. More proximal obstruction at the level of the vas deferens, epididymis, or testis-epididymis junction usually causes severe lesions in both the sperm excretory ducts and the testicular parenchyma. Obstruction of the vas deferens causes increased pressure within the ductus epididymis. As a result the epididymal lumina dilate, the epithelium atrophies, and fluid containing few spermatozoa and some spermiophages accumulates in the lumina (Fig. 12.242). The most dilated epididymal segment is the caput. The ductuli efferentes often become cystically dilated and filled with spermatozoa and macrophages. Reabsorption and lysosomal degradation of this protein-rich fluid occurs, causing the epithelium to accumulate lipofuscin granules or acquire apical eosinophilic granules (Paneth-like change) (Fig. 12.243).2067 Rupture of the wall gives rise to spermatic granulomas (Fig. 12.244) or granulomas rich in histiocytes with eosinophilic and granular cytoplasm that mimics malacoplakia (Fig. 12.245). Rupture of the vas deferens gives rise to microgranulomas and ceroid granulomas

Fig. 12.241 Gross section of testis and epididymis. A marked cystic dilatation may be observed in the tail of epididymis.

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Fig. 12.242 Obstructive azoospermia in a patient with history of epididymitis. The caput epididymidis shows a marked dilation of the ductuli efferentes that contain numerous spermatozoa.

Fig. 12.243 Paneth-like changes in the epithelial cells of the efferent ducts. Abundant eosinophilic granulations at the apical pole of the cells.

(Fig. 12.246). Macrophages and lymphocytes often are present in the intertubular connective tissue.2068 The most frequent testicular lesions in proximal obstructions involve the adluminal compartment. These lesions result from the negative effect of hydrostatic pressure on the seminiferous epithelium and, in particular, on the Sertoli cell (Figs. 12.247 through 12.249). Etiology of Obstruction. Congenital ejaculatory duct obstruction and congenital absence of the vas deferens usually causes minimal testicular injury, mainly dilation of the seminiferous tubules, and an increase in number of mature (Sc + Sd) spermatids.2069 Lesions resulting from vasectomy are more important. Increased intraluminal pressure in the epididymis may give rise to pain (late postvasectomy syndrome).2070,2071 Testicular lesions depend on the surgical technique used: they are slight if the proximal end of the vas deferens is not ligated or a sperm granuloma forms at the site of vasectomy. Spermatogenic rhythm in the testis is slower than before vasectomy, and lesions characteristic of obstruction develop, including thickening of the lamina propria and fibrosis

Fig. 12.244 Spermatic granuloma. Abundant spermatozoa in the intertubular interstitium of the epididymis both free and inside the cytoplasm of macrophages.

Fig. 12.245 Granuloma in the epididymis with abundant histiocytes of eosinophilic and granular cytoplasm suggesting malacoplakia. The lesion is located in the wall of a dilated efferent duct with abundant spermatozoa.

Fig. 12.246 Ceroid granuloma in a patient with a history of sperm excretory duct obstruction.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.247 Seminiferous tubules with marked luminal dilation, moderate decrease in cellularity, and occasional vacuolation of the Sertoli cell cytoplasm.

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of the interstitium.397 In testicular obstruction secondary to herniorrhaphy in infancy, lesions are mild. Lesions may be significant if the epididymis is damaged by hydrocelectomy, consisting mainly of primary spermatocyte sloughing. Hyalinized tubules may also be present when obstruction is caused by inflammation. Duration of Obstruction. In acquired obstruction, testicular lesions worsen with time. Obstruction in the caput of the epididymis causes disappearance of all germ cells in the adluminal compartment of seminiferous tubules. The tubules become dilated, and Sertoli cells become vacuolated. Testicular alterations after vasectomy may not be related to the duration of the obstruction, but rather to the initial injury, and may disappear with time as the intraluminal pressure decreases.2072,2073 However, if a significant amount of time elapses after vasectomy, the possibility of attaining a normal spermiogram with vasovasostomy is low. Vasal patency is restored in most cases of reanastomosis, but paternity rates are markedly lower (25% to 51%) than normal (85%).2074 Results improve with the use of robotic microsurgery, novel instrumentation, and adhesive sealants.2075 The best results are obtained in patients with high inhibin B levels. At first, spermatozoa obtained from the testis are of better quality than those from the epididymis.2076

Functional Azoospermia and Oligozoospermia Some azoospermic patients have biopsies with minimal histologic abnormalities or minor tubular dilation without detectable excretory duct obstruction. These findings are characteristic of two main conditions: Young syndrome and alterations in spermatozoal transport. Young Syndrome

Fig. 12.248 Seminiferous tubules with slight luminal dilation. The seminiferous tubular cell layers have a “toothed” pattern. Degenerating megalospermatocytes may be seen in the seminiferous epithelium.

Young syndrome is defined by the following constellation of findings: azoospermia, sinusitis, bronchitis or bronchiectasis, and normal spermatozoal flagella.2077 The incidence is probably higher than that recorded in the literature, and Young syndrome should be suspected in all patients with obstructive azoospermia without a history of epididymitis or scrotal trauma. Patients have a lesion at the junction of the caput and corpus that gives the epididymis a characteristic gross appearance of distension, with the ductuli efferentes containing yellow fluid and numerous spermatozoa, whereas the remaining epididymal segments are normal. The ductus epididymidis is blocked by thick fluid.2078 Young syndrome should be distinguished from other causes of infertility also associated with chronic sinusitis and pulmonary infections, including ciliary dyskinesia and CF. Ciliary dyskinesia consists of morphologic, biochemical, and functional alterations in cilia and flagella, including immotile cilia syndrome, Kartagener syndrome, and miscellaneous syndromes characterized by imperfectly defined abnormalities of cilia and flagella.2079 In Young syndrome, sinusitis and pulmonary infections develop in childhood and stabilize or improve in adolescence; in other conditions the pulmonary damage increases with age, and cilia and flagella are ultrastructurally abnormal.2080 Alterations in Spermatozoon Transport

Fig. 12.249 Seminiferous tubules with marked ectasis and atrophy of the seminiferous epithelium in a patient with epididymal obstruction.

Normally, spermatozoa detach from Sertoli cells and traverse the intratesticular and extratesticular excretory ducts, where they are stored, mainly in the cauda of the epididymis, and ultimately released from the corpus by ejaculation or eliminated by phagocytosis. Only approximately 50% of spermatozoa are ejaculated. Whereas the release of spermatozoa from the corpus is intermittent, transit through the sperm excretory ducts is continuous.

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Transit is accomplished by peristaltic contractions of myofibroblasts in the wall of the seminiferous tubules and ductuli efferentes, and by smooth muscle cells in the wall of the ductus epididymidis and vas deferens. Spermatozoa are propelled along the length of the epididymis in a mean of 12 days (range, 1 to 21 days). The walls of the seminiferous tubules and extratesticular excretory ducts are under hormonal and neural control. The myofibroblasts in the seminiferous tubules have oxytocinic, α1-adrenergic, β-adrenergic, and muscarinic receptors. Unmyelinated nerve fibers penetrate the tubular lamina propria, pass among the myofibroblasts, and end near the Sertoli cells.200 Along their length the nerve fibers have varicosities containing sympathetic vesicles. The ductus epididymidis is innervated by sympathetic adrenergic nerve fibers that end among smooth muscle cells. Several hormones, including oxytocin, endothelin-1, vasopressin, and prostaglandins, act on the musculature of the ductus epididymidis. The peristaltic contractions begin in the caput and propagate toward the cauda. The frequency and amplitude of contractions vary from region to region; they are higher in frequency near the caput and of maximal amplitude in the initial portion of the cauda. The progressive increase in amplitude parallels the progressive increase in the thickness of the muscular wall and the requirement for greater force to propel the fluid as it becomes progressively more viscous with a higher concentration of spermatozoa. The distal portion of the cauda is usually at rest because it is the main reservoir of spermatozoa between ejaculations. Several times daily, vigorous contractions of the distal cauda impel the spermatozoa from the cauda toward the vas deferens.2081 Several drugs that favor contraction of the muscular wall (α1-blocking agents and F2α prostaglandins) have been successfully used in the treatment of alterations in the spermatozoon transport.2082

Summary of Diagnostic Groups Suggested by Testicular Biopsy Testicular biopsy provides enough information to identify three types of pathologic processes: obstructive disorders of spermatic pathways (posttesticular causes), primary testicular disorders (testicular causes), and disorders secondary to alterations in hypophyseal-pituitary-testicular axis or other endocrine disorders. Clues for diagnosis are given in Table 12.24. Biopsy provides prognostic information regarding the fertility of the patient. When findings associated with a poor prognosis are present, patients may require assisted reproductive techniques. Prognostic factors are listed in Table 12.25.

Infertility and Chromosomal Anomalies Knowledge about the incidence of chromosomal abnormalities in male infertility has progressed in parallel with advances in technology, including karyotype studies in peripheral blood, meiotic and chromosomal studies of biopsies, analysis of chromosomes in spermatozoa, and analysis of DNA in blood and spermatozoa for detection of chromosome Y deletions.2083 The incidence rate of chromosomal anomalies in the infertile population is 2% to 7%, whereas in the general population it is less than 0.5%. The frequency of chromosomal abnormalities increases in an inverse relationship with the number of spermatozoa in the ejaculate.2084

Abnormalities in Sex Chromosomes Klinefelter Syndrome Genetic and Clinical Aspects. Klinefelter syndrome is charac-

terized by an abnormal number of X chromosomes and primary

TABLE 12.24 Keys to Classify Diagnostic Groups in Testicular Biopsy for infertility Obstructive Pathology of Spermatic Pathway Data from quantitative study Increased MTD and remarkable differences in MTD and lumen among lobules. Lesions in the adluminal compartment: most are obstructive (exception: absence or markedly decreased Sa + Sb with normal or increased spermatocytes I). Lesions in the basal compartment: only those testes with better conserved MTD and hypospermatogenesis with mild spermatocyte I sloughing. Number of Sc + Sd spermatids higher than that of Sa + Sb.

Data from qualitative study Mosaic pattern of spermatogenesis lesions. Tubular ectasis. Tubules with indented outline. Accumulation of spermatozoa in the lumen of some tubules. Intense apical vacuolation of the Sertoli cell cytoplasm. Tubular hyalinization of obstructive mechanism. Primary testicular pathology.

Data from quantitative study Decreased MTD. All lesions in the basal compartment. Some lesions in the adluminal compartment (sharp interruption in spermatocytes I or round spermatid maturation).

Data from qualitative study Testis with germ cell abnormalities. Anomalies in spermatogonia: high number of hypertrophic, multinucleate, and dislocated spermatogonia.

Anomalies in spermatids: high number of multinucleate, macrocephalic, round, without acrosome, or short- and thick-flagellum spermatids. Testis with Sertoli cell abnormalities. All Sertoli cell–only syndromes with dysgenetic Sertoli cells. Most Sertoli cell–only syndromes with adult and involutive Sertoli cells. All mixed atrophies with dysgenetic Sertoli cells. Most of the mixed atrophies with adult and involutive Sertoli cells. Testis with tubular hyalinization of dysgenetic mechanism. Tubules with absent or decreased elastic fibers. Testis with Leydig cell anomalies. Dysgenetic Leydig cells. Some Leydig cell hypertrophies and hyperplasias. Testicular pathology secondary to alteration in hypothalamopituitary-testicular axis and other endocrine disorders.

Data from quantitative study Markedly decreased MTD (<120 μm). Lesions in the basal compartment.

Data from qualitative study Testis with infantile or pubertal pattern. Testis with immature Sertoli cells. Testis with dedifferentiated Sertoli cells. Tubular hyalinization by hormonal deprivation. Absence or decrease of Leydig cells. MTD, Mean tubular diameter; Sa + Sb, round spermatids; Sc + Sd, elongate spermatids.

CHAPTER 12 Nonneoplastic Diseases of the Testis

TABLE 12.25

Predictors of Poor Prognosis in Testicular Biopsy

More than 25% of hyalinized tubules. More than 50% of Sertoli cell–only tubules. Diffuse thickening of tunica propria. Adluminal and basal compartment lesions with disproportionate sloughing of spermatocytes or round spermatids. Most of maturation arrest in spermatogonia. Testis with meiosis anomalies and anomalies in spermiogenesis. Presence of interstitial and peritubular inflammatory infiltrates.

testicular insufficiency. The original description was of a man with eunuchoidism, gynecomastia, small testes, mental retardation, and elevated levels of serum gonadotropins.2085 His case drew attention to the significant lesions observed in the testes of such patients. Lesions involve seminiferous tubules and interstitium: (1) tubular atrophy may lead, through a hyalinization process, to complete disappearance of tubules, with only ghost tubules remaining; and (2) there is an apparent increase in the number of Leydig cells, which form characteristic nodules that tend to coalesce and delete the testicular structure. This syndrome is the most common genetic cause of male infertility.2086 Frequency varies according to the population studied: 1 in 500 newborns and infants, 1 in 100 of patients in mental institutions, 3.4 in 100 of infertile men, 0.7 in 100 oligozoospermic patients, and 11% of azoospermic patients.2087–2089 At least 11% of azoospermic men have Klinefelter syndrome, although the initial pathologic investigations of the lesions were focused on adult patients studied for infertility.2090–2093 Later, when the primary dysgenetic nature of the testicular lesions was known, studies extended to infancy and childhood. Even though the estimated incidence of this disorder is 1 in 600 male newborns, and many children with Klinefelter syndrome present with language and behavior problems, as well as mental retardation, only a few patients (10%) are diagnosed before puberty.2094–2097 With increasingly frequent use of amniocentesis and histologic studies of fetuses, testicular lesions can now be identified before birth. Study of Klinefelter syndrome currently involves a search for X-chromosome genes involved in triggering and development of testicular lesions.2098–2100 In about 80% of cases, the karyotype is 47,XXY. The remaining 20% have chromosomal mosaicism with at least two X chromosomes, most frequently 46,XY/47, XXY (10%). The other uncommon karyotypes include 46,XY/ 48,XXXY, 46,XX/47,XXY, 47,XXY/46,XX/46,XY, 46,XY/45, XO/47,XXY, 46,XX/47,XXY/48,XXXY, 48,XXXY/49,XXXXY, and 47,XXi(Xq)Y.1571,2101–2104 The 47,XXY lesion results from nondisjunction of sex chromosome migration during the first or second meiotic division of the spermatocyte or ovule. Mosaicisms are caused by mitotic nondisjunction in the zygote after fertilization.2105 Study of the Xg antigen in blood revealed that the extra X chromosome is maternal in 73% of cases and paternal in 27%. Advanced maternal age increases the incidence of children with the 47,XXY karyotype. The diagnosis of Klinefelter syndrome in infants, who may have few clinical stigmata of the disorder, calls for other techniques besides microscopic analysis of G-banded chromosomes. Although this technique is the gold standard, it is time consuming, requires experience, and is expensive. Screening for transcripts of the XIST

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(X-inactive–specific transcript) gene by PCR may be helpful. Somatic cells express gene products only when they have more than one X chromosome.2106 Up to 20% of cases with Klinefelter syndrome are not detected with this technique because of RNA instability. Alternatively, copy number of the AR gene located in Xq11.2-q12 may be measured by quantitative real-time PCR technique. This method is specific and accurate.2107 Most 47,XXY patients with Klinefelter syndrome are diagnosed in adulthood. Only 25% are recognized in the pediatric age group, principally during adolescence.2108 The most common clinical findings are as follows2109: • Eunuchoid phenotype with increased stature. Increased height is caused by disproportionate lengthening of lower extremities. The ratio of span to height is less than 1. • Incomplete virilization. This is variable and ranges from normal development to the absence of secondary sex characteristics. • Gynecomastia, usually bilateral. This is present in 50% of patients. • Mental retardation. This is seen in many patients, although 80% have an intelligence quotient (IQ) that permits them to be functional in society. These patients have been described as immature, lacking in initiative, and emotionally unstable, with poor concentration capacity.2110 Two classic stigmata, female escutcheon and gynecomastia, are present in 32% and 12% of patients, respectively.2111 Other commonly associated conditions include the following: chronic bronchitis; varicose veins; cervical rib; kyphosis; scoliosis or pectus excavatum; and a high incidence of hypothalamic, hypophyseal, thyroid, and pancreatic dysfunction.2112 External genitalia often appear to be normal. The testes are usually less than 2.5 cm long, although in some cases of chromosomal mosaicism they are of normal size.2113 Consistency is firm in 50% of cases and soft in 20%. The incidence of cryptorchidism is low in 47,XXY patients, but increased in mosaicism variants with more than two X chromosomes.2114 Supernumerary X-chromosome material is associated with reduction of gray matter in the left temporal lobule, a finding correlated with verbal and language deficits.2115 Histochemical, immunohistochemical, and ultrastructural studies from testes of pubertal and adult 47,XXY patients reveal diffuse abnormalities. A better knowledge of Sertoli and Leydig cell physiology has led investigators to establish a strong correlation between hormonal changes and lesions.2116 In adults the testes show the classic histologic picture of tubular dysgenesis with small, hyalinized seminiferous tubules lacking elastic fibers and pseudoadenomatous clustering of Leydig cells (Figs. 12.250 and 12.251).2085 Most biopsy samples show some tubules with a few Sertoli cells.2092 Two types of Sertoli cell–only tubules may be distinguished: (1) type A tubules, whose Sertoli cells have dysgenetic morphology (pseudostratified distribution, elongate hyperchromatic nuclei with small, peripherally placed nucleoli, absence of annulate lamellae, and weak immunoreaction to AMH); and (2) type B tubules, which display central lumina and whose Sertoli cells show an adult, mature pattern or some signs of involution (many nuclear folds). In some testes, both types are present.2090,2092 Dysgenetic Sertoli cells of type A tubules are sex chromatin negative, whereas adult mature Sertoli cells of type B tubules may be either positive or negative.2117 This finding suggests either testicular mosaicism of the X chromosome or heterochromatinization of both X chromosomes. In mosaicism the Sertoli cell–only tubules may be more numerous than hyalinized tubules.

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Fig. 12.250 Klinefelter syndrome. Leydig cell nodules mingle with hyalinized tubules.

Fig. 12.251 Klinefelter syndrome. Most seminiferous tubules, even those with Sertoli cell only, have scant elastic fibers that may be demonstrated with orcein stain. The intense staining observed in the inner elastic lamina of arterioles provides a positive control.

Reduced testicular volume imparts an appearance suggestive of Leydig cell hyperplasia, but quantitative studies show that the total number of Leydig cells is lower than normal.2091,2093 Many are pleomorphic, and some are multivacuolated. Immature fibroblast-like Leydig cells may be present, and cells with hypertrophic cytoplasm and those with signs of exhaustion may also be observed.1871,2118 The abnormally differentiated Leydig cells have nuclei with coarsely clumped chromatin, deep unfolding of the nuclear envelope, multiple paracrystalline inclusions instead of Reinke crystalloids, multilayered concentric cisternae of smooth endoplasmic reticulum, large masses of microfilaments, and scant lipid droplets.2119 Sex chromatin is apparent in 40% to 70% of Leydig cells. Leydig cell function is insufficient, and androgen levels are less than 50% of normal. Basal FSH and LH levels are markedly increased.2112,2120,2121 In a few patients, testicular damage is less prominent; biopsies show isolated groups of Sertoli cell– only tubules or even some tubules show spermatogenesis.2122 Exceptionally, complete spermatogenesis and even paternity have

been reported.2123 Although 47,XXY patients are classically azoospermic and have been considered infertile, 8% have some spermatozoa in their ejaculates.2124 This finding opens new expectations regarding potential fertility, and 50% of patients with Klinefelter syndrome may have offspring as a result of TESE and assisted fertilization technologies.2125 In these patients, prepubertal Sertoli cells do not mature into adult Sertoli cells at puberty, and the cells that focally persist have dysgenetic or involutive features.246,2090 This finding correlates with the low synthesis of inhibin B. Peritubular cells have impaired myoid differentiation and are unable to produce elastic fibers.1888 Despite the presence of Leydig cells, most patients do not produce normal levels of testosterone.917 The causes of early germ cell loss and inability of spermatogonia to proliferate and complete meiosis in 47,XXY patients are uncertain. It is likely that an abnormal proportion of some genes in the X chromosome changes germ cell division or apoptotic rate.2126 The presence of XIST expression in blood cells of patients with Klinefelter syndrome (absent in 46,XY males) suggests that somatic cells inactivate the supernumerary X chromosome, as do somatic cells in normal females.2106,2127 Inactivation of some X-linked genes (an essential process in meiosis regulation) could hypothetically explain the inability to complete meiosis. Focal spermatogenesis, as occurs in some patients, may originate in euploid germ cells.2128 Klinefelter Syndrome 46,XY/47,XXY. The 46,XY/47,XXY karyotype is the most frequent variant of Klinefelter syndrome. In this setting, clinical abnormalities may be attenuated. Gynecomastia is present in 33% of cases, compared with a frequency of 55% in men with 47,XXY karyotype. Azoospermia is found in 50% of cases (93% in XXY men). The testes are larger and spermatogenesis is more developed than in men with 47,XXY because spermatogonia with normal chromosomal constitution are present (Fig. 12.252).2129 Patients with 47,XXY karyotype who have spermatozoa in seminiferous tubules have 46,XY spermatogonia and also 47,XXY spermatogonia, whereas those who have no spermatozoa harbor only 47,XXY spermatogonia; these 47,XXY spermatogonia may include some spermatozoa with 23,X or 23,Y chromosomal complement, elevated numbers of both 24,XY and 24,XX spermatozoa, and a high frequency of spermatozoa with 21 disomy. This 21 disomy may be an important risk factor for gonosomy, as well as for trisomy 21.2130,2131

Fig. 12.252 Klinefelter syndrome mosaicism showing focal spermatogenesis in two seminiferous tubules located within a Leydig cell nodule.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Although a few decades ago patients with Klinefelter syndrome were considered sterile, currently successful sperm recovery rate with micro-TESE is 57% and pregnancy rates with TESE plus ICSI per embryo transfer are greater than 25%.2132,2133 The risk for aneuploidy in children is low. Klinefelter Syndrome 48,XXYY. In 1960 the first report of the chromosomal constitution 48,XXYY was published and annotated as the “double male.”2134,2135 The incidence of the 48,XXYY karyotype is estimated to be approximately 1 in 17,000 to 1 in 50,000 males, or 2% of patients with Klinefelter syndrome.2136–2140 This karyotype may be associated with aggressive character, antisocial behavior, significant mental retardation, and a higher frequency of congenital malformations than the 47,XXY karyotype.2141– 2144 Foot ulcers are observed in some cases.2145 Men with 48,XXYY karyotype also have characteristic dermatoglyphics with increase in arches, decrease in total finger ridge count, and ulnar triradii associated with changes in the hypothenar region.2146 Male patients with 48,XXYY are tall, with an adult height of more than 6 feet. They have eunuchoid habitus with long legs, small penis and testicles, gynecomastia, and hypergonadotropic hypogonadism. Testicular biopsy shows hyalinized tubules, dysgenetic Sertoli cell–only tubules, and Leydig cell hyperplasia (Fig. 12.253). A peculiar finding is the presence of concentric lamellae of smooth endoplasmic reticulum cisternae in the Leydig cell cytoplasm (Fig. 12.254).2118 Klinefelter Syndrome 48,XXXY and 49,XXXYY. Patients with 48,XXXY karyotype were first reported in 1964.2147 They may be of average or tall stature, with hypertelorism, epicanthus, flat nasal bridge, simplified ears, and mild prognathism. Men with 48,XXXY or 49,XXXYY karyotype often have skeletal malformation, principally fifth-finger clinodactyly, elbow malformations with radioulnar synostosis, and slow molar development.2148 Their IQs are between 40 and 60 with severely delayed speech, and are typically passive and immature, but may be aggressive.2149 Cryptorchidism is frequent.2150 Hypergonadotropic hypogonadism, gynecomastia, and in 25% of cases, hypoplastic penis may also be present.2151 Testes show tubular hyalinization and occasionally focal spermatogenesis.2152 Pentasomy 49,XXXXY is one of the rarest chromosomal defects and is associated with a clinical syndrome characterized by delayed

Fig. 12.253 Postpubertal patient with 48,XXYY Klinefelter syndrome showing diffuse tubular hyalinization except for on Sertoli only–cell tubule with dysgenetic Sertoli cells surrounded by abundant Leydig cells.

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Fig. 12.254 48,XXYY Klinefelter syndrome showing a Leydig cell that contains giant mitochondria and a wheel of smooth endoplasmic reticulum.

prenatal and postnatal growth, microcephaly with short stature, and severe mental retardation.2153 Patients are typically shy and friendly, and their IQs range between 20 and 60.2154 They have hypoplasia of the external genitalia, cardiac malformations, radioulnar synostosis, proximal tibiofibular synostosis, and high arched palate.2153,2155–2161 The incidence is 1 in 85,000 male births.2162 The syndrome results from maternal nondisjunction during both meiosis. Cryptorchidism is frequent. Testes show decreased or normal germ cell numbers in the fetal period.2163–2165 At puberty, patients experience hypergonadotropic hypogonadism with low testosterone levels, tubular hyalinization, and Leydig cell hyperplasia. Many patients require hormonal replacement therapy.2166 One of the 176 reported patients had Leydig cell tumor.2167 Association With Malignancy. Patients with Klinefelter syndrome have a higher incidence of malignancy than the general population, related to higher incidence of leukemia and lymphoma, and a 20-fold increase in the incidence of breast carcinoma because of hormonal imbalances (Fig. 12.255).2168–2174 Although testicular germ cell tumors are rare in these patients, extragonadal germ cell tumor is 30 to 40 times more frequent than in the general population.2175–2177 Most tumors occur in the mediastinum (71%).2178 This means that approximately 8% of chromatinpositive men will experience development of these tumors.2179 Less commonly, germ cell tumors have been observed in the pineal gland, the spinal cord, the retroperitoneum, gastrointestinal tract, and prostate.2180–2184 The most frequent types are teratoma associated with yolk sac tumor, followed by choriocarcinoma.2185 Pure embryonal carcinoma, seminoma, and yolk sac tumor are rare.2186–2192 In patients younger than 8 years, a gain of chromosome 20 or 20p is frequent (70%), whereas in adolescents older than 8 years, gains of 12p (69%) and X (59%) are most common.2187,2193 Extragonadal origin of germ cell tumors has been attributed to abnormal germ cell migration from the yolk sac. In the mediastinum, possible origin from primordial thymus cells has been postulated.2193a Development of malignancy has been attributed to either high hormonal levels or the abnormal chromosomal constitution of germ cells.2172,2194–2196 The incidence of other solid tumors in patients with Klinefelter syndrome (bronchogenic carcinoma, urothelial carcinoma of the bladder, adrenal carcinoma, prostatic adenocarcinoma, testicular

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Fig. 12.255 Klinefelter syndrome with nodular hyperplasia of Leydig cells. Perivascular and interstitial leukemic infiltrates.

Fig. 12.256 Klinefelter syndrome at infancy. Seminiferous tubules showing decreased diameters, isolated germ cells, and a ring-shaped tubule that contains a microlith.

Leydig cell tumor, and epidermoid cyst) is comparable with that of the general population.2185,2197–2202 Occurrence in Childhood. Early identification of Klinefelter syndrome is possible through systematic cytogenetic study of newborns with positive sex chromatin or mental retardation.2203 Several clinical stigmata suggest Klinefelter syndrome, including decreased muscle tone, delayed speech, poor language skills, reading difficulties, dyslexia, mental retardation, psychiatric problems, excessive stature for age, disproportionately long legs, micropenis, and small testes with advancing age.1536,2095,2109,2204–2206 Infants often have low body weight at birth, and 6% show incomplete descent in one or both testes. Androgen deficiency is an early finding.2207 Prepubertal children show a slight increase in FSH, whereas LH and inhibin levels are normal.2208,2209 In pubertal boys, LH level increases markedly, although testosterone remains low.203 Testicular lesions occur early in Klinefelter syndrome. Biopsy reveals few or no germ cells. Germ cell number in genital ridges does not differ from normal, but early cell loss takes place once testis differentiation begins.2210 The number of germ cells in 47,XXY fetuses is significantly lower than in normal 46,XY fetuses. This fact has been confirmed in 47,XXY fetuses at abortion between weeks 18 and 22 of gestation. Most 47,XXY newborns have TFI of less than 30% and decreased germ cell number per tubular section. Germ cell loss is associated with irregular distribution of germ cells: tubules with germ cells alternate with vacant tubules. Neither the Leydig cells nor the remaining testicular structures show lesions. Testosterone levels in the umbilical cord vary from low to normal.2208,2211 Seminiferous tubules have reduced diameters, particularly those devoid of germ cells. The number of Sertoli cells is reduced. Megatubules, ring-shaped tubules, and intratubular eosinophilic bodies are common (Fig. 12.256). In some cases of Klinefelter syndrome associated with Down syndrome, tubular hyalinization is observed in childhood.1139 The interstitium is wide and contains few Leydig cell precursors. If one testis is undescended, its histologic features do not differ from those of the contralateral testis. The testicular pattern remains constant through childhood.2155 At puberty, before maturation of the tunica propria, the seminiferous tubules rapidly hyalinize, and Leydig cell precursors differentiate into Leydig cells.2212

The first two waves of germ cell proliferation (at “minipuberty” and at 4 years of age) that occur in normal testis are not observed in 47,XXY patients. On the contrary, germ cells decrease in number (or even totally disappear) from the second year of life onward in cases with associated cryptorchidism despite the presence of testosterone.2213 FSH, LH, AMH, and inhibin B levels are similar to those in normal boys, and even testosterone peak may occur in the first months of life coinciding with “minipuberty.2214 During infancy, tubular diameter remains low and static, with subsequent small testicular volume (1 to 1.5 mL instead of 1.8 mL that is reached at the end of childhood).2155,2203,2208 However, secretion of inhibin B and AMH by Sertoli cells continues normally, and FSH and LH serum levels do not differ from those of controls.2208,2214,2215 Based on small testicular volume in Klinefelter syndrome, we may assume that, in infancy, these testes have at least two impaired cell types: Sertoli cells and germ cells. Whether the defect is in both or only in Sertoli cells remains speculative. In early adolescence, testicular size increases to greater than 3 mL, coinciding with normal hypothalamic–pituitary-testicular axis activation and increase in FSH, LH, testosterone, and inhibin B levels. Permanent hypergonadotropic hypogonadism is rapidly established. When a new wave of germ cell proliferation would be expected, if it actually takes place, it occurs only in some tubules, where a few spermatocytes may be observed; otherwise germ cells completely disappear.2212,2216–2218 In most cases, as puberty progresses, residual spermatogonia disappear and Sertoli cell degeneration becomes evident. Between 12 and 14 years of age, there is onset of tubular hyalinization and progressive increase in Leydig cell number; however, in occasional cases, isolated seminiferous tubules with Sertoli cell–only pattern persists (Fig. 12.257). Testicular volume stabilizes. The levels of inhibin B and AMH are normal at the onset of puberty, but decrease soon thereafter. The decline in inhibin B occurs in parallel with Sertoli cell involution, whereas the decrease and ultimate cessation of AMH production in adult men is the result of both Sertoli cell loss and testosterone increase.2215 Association With Precocious Puberty. Precocious puberty refers to development of secondary sex characteristics in a boy before the age of 9 years.2219 Mean age of puberty is earlier with Klinefelter syndrome than in unaffected boys.2209 47,XXY

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.257 Pubertal patient with klinefelter syndrome showing Sertoli only– cell pattern, variable thickening of tubular walls, and groups of Leydig cells.

Klinefelter syndrome and its variants may begin clinically with CPP, but this is not a characteristic finding in Klinefelter syndrome. Karyotyping in older boys with mental retardation, gynecomastia, small testes, and precocious puberty is advisable. Typically the cause of precocious puberty is hCG-secreting germ cell tumor in the mediastinum.2220–2222 Infrequently, precocious puberty is idiopathic, and it rarely results from hamartoma in the third ventricle.2223,2224 Association With Hypogonadotropic Hypogonadism. Klinefelter syndrome is often associated with pituitary disorders such as panhypopituitarism or incomplete hypopituitarism.2225,2226 Deficits in FSH, LH, or both have been reported.2227–2231 The cause of this association is unknown, and diverse causative factors such as trauma, immunologic disorders, and genetic deficiencies have been postulated. Alternatively, the syndrome may result from exhaustion of pituitary gonadotropinsecreting cells after years of GnRH stimulation.2226 In patients deficient in both gonadotropins, testicular biopsy shows diffuse tubular hyalinization and marked reduction or absence of Leydig cells. The histologic picture is similar to that of hypogonadotropic hypogonadism occurring after puberty except for the presence of isolated tubules containing only dysgenetic Sertoli cells and absence of elastic fibers in the hyalinized tubular wall (Figs. 12.258 and 12.259).2230 In patients with isolated LH deficit, the histologic picture is that of Sertoli cell–only tubules with dysgenetic Sertoli cells and variable number of hyalinized tubules.2227 In patients with isolated FSH deficit, the histologic findings are similar to classic 47,XXY Klinefelter syndrome. 46,XX Males (XX Sex Reversal, Testicular Disorder of Sex Development)

The 46,XX karyotype may be present in three phenotypes: male phenotype including normal external genitalia; male undermasculinization, with a variable degree of ambiguity in external genitalia ranging from hypospadias to micropenis; and true male hermaphroditism. 46,XX Males With Male Phenotype and Normal External Genitalia. The first case of a 46,XX male with male phenotype and normal external genitalia was reported in 1964.2232 Some considered this a variant of Klinefelter syndrome.1680 Men with

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Fig. 12.258 Klinefelter syndrome with hypogonadotropic hypogonadism showing diffuse tubular hyalinization associated with absence of Leydig cells. Only tubules with dysgenetic Sertoli cells are present.

Fig. 12.259 Klinefelter syndrome with hypogonadotropic hypogonadism. Absence of Leydig cells between hyalinized tubules.

46,XX karyotype have clinical features similar to those of Klinefelter syndrome, including small testes, small or normal penis, azoospermia, gynecomastia, and minimal development of secondary sex characteristics. However, these men exhibit normal body proportions, normal or slightly short stature, and normal intelligence, in contrast with men with Klinefelter syndrome.2233–2235 The incidence of 46,XX males is low: 1 in 10,000 to 1 in 25,000 live births, accounting for approximately 0.2% of infertile men.1245,2234,2236–2238 Most cases are sporadic, although familial cases have been reported.1485,2239,2240 Male patients with 46,XX karyotype have hypergonadotropic hypogonadism with elevated serum level of FSH and, to a lesser degree, elevated LH, with normal or slightly decreased testosterone. All patients are infertile. The probable cause is absence of AZF, a locus of the Y chromosome where several genes required for primordial germ cell migration and maintenance of spermatogenesis are found. During childhood, testicular biopsy in 46,XX males reveals decreased numbers of germ cells.2234,2241 Biopsies from adults show one of the three patterns: histologic features similar to those

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of 47,XXY men, including diffuse tubular hyalinization with prominent Leydig cell populations (Fig. 12.260); Sertoli cell–only tubules with numerous dysgenetic Sertoli cells (Fig. 12.261); or both patterns intermingled with less prominent Leydig cell population.2242–2247 The last pattern is the most frequent. Some tubules in any of the patterns may show isolated spermatogonia and even primary spermatocytes (Fig. 12.262). Ultrastructural studies reveal an increase in intermediate filaments and absence of annulate lamellae in Sertoli cells, absence of Reinke crystalloids, and an abundance of intracytoplasmic and intranuclear paracrystalline inclusions in Leydig cells.2247,2248 46,XX Males With Ambiguous External Genitalia. Some males with the 46,XX karyotype have ambiguous external genitalia or hypospadias and are assumed to have male undermasculinization.2249 Such patients are found in families whose members have ovotesticular DSD, suggesting that these disorders are different manifestations of the same genetic defect.2250 Several authors have Fig. 12.262 Testicular biopsy of a XX male. The predominant pattern is that of dysgenetic Sertoli-only cell. There are isolated hyalinized tubules and a slightly increased number of Leydig cells.

Fig. 12.260 Testis from a 46,XX male showing Sertoli cell–only tubules together with hyalinized tubules, and nodular and diffuse Leydig cell hyperplasia.

Fig. 12.261 Testicular biopsy of a XX male. Next to fully hyalinized tubules, other tubules show spermatogonia and first-order spermatocytes.

found that different phenotypes are compatible with the same 46,XX genotype.2251–2253 Etiology. The origin of 46,XX male status may be difficult to determine. Given that testicular differentiation requires genes located on the Y chromosome, 46,XX males have been classified by cytogenetic studies as those having the SRY gene, those lacking the SRY gene, and those with XX/XY mosaicism. Male patients with the SRY gene comprise 80% of 46,XX males.2254 This likely occurs by translocation of the short arm of the Y chromosome to the X chromosome.2255 The amount of translocated Y-chromosome material is variable.2256 According to this hypothesis, during paternal meiosis the homologous pseudoautosomal regions in the short arms of X and Y chromosomes interchange the terminal portions of their short arms, thus giving rise to X chromosome with translocated SRY gene.2257,2258 Infertility would be the consequence of deletion of Yq involving the DAZ gene.2259–2268 Alternatively, the SRY region may be inserted into an autosome.2269,2270 Most 46,XX patients who are SRY+ have normal male phenotype.2271,2272 Approximately 10% of 46,XX males are SRY
, and most have ambiguous genitalia.1488,2273–2275 Some have a normal male phenotype but are infertile.2276–2278 The underlying basis of a 46,XX SRY
male phenotype is unknown. Although SRY is assumed to be the most important regulatory factor of testicular determination, possible causes include unknown X-linked or autosomal gene involved in testis differentiation or hidden Y-chromosome mosaicism limited to the gonad.2251,2279–2281 A few cases result from duplication of SOX9, which is sufficient to initiate testis differentiation in the absence of SRY.2282 The same occurs in partial duplication of chromosome 22q or overexpression of the SOX10 gene at 22q13, mutations in the RSPO1 gene, translocation 12;17, and SOX3 gain of function.2280,2283–2285 Testes show diffuse tubular hyalinization and Leydig cell hyperplasia.2243 Approximately 10% of 46,XX males have XX/XY mosaicism or another karyotype with the chromosomal complement Y.1495,2286 In these cases, detection of the specific DNA sequences of the Y chromosome may be difficult because this chromosome may be present in only some tissues or in small numbers of cells, including testes or skin, but not lymphocytes.2234,2270,2287

CHAPTER 12 Nonneoplastic Diseases of the Testis

47,XYY Syndrome

47,XYY syndrome was first described in 1961 in the father of a girl with Down syndrome.2288 The only clinical findings were excessive height and pustular acne. Study of other cases suggests that some have a predisposition to psychopathic and antisocial behavior, and may exhibit neurodevelopmental disorders such as delayed speech, reading difficulties, and motor difficulties.2289,2290 Aggressive behavior was found in only 1% to 2%, a finding that questions whether an extra Y chromosome by itself predisposes to aggressive behavior.2291,2292 The incidence rate of 47,XYY patients is estimated to be 0.01%, including 0.2% of men who smoke, 0.7% to 0.9% of men in prison, and 1.8% of sexual homicide criminals.1571,2293–2295 Since 2000, many cases of 47,XYY syndrome have been diagnosed prenatally. From birth, patients have weight, stature, and cephalic circumferences greater than mean values and a higher risk for delayed language or motor development. Approximately 50% of children have psychological and psychiatric problems such as autism; although intelligence is normal, many are referred to special education programs.2296 As adults, they have normal external genitalia and secondary sex characteristics. Some patients have decreased fertility, and others are infertile, although, as in the first reported case, paternity may occur.2297,2298 Serum levels of LH and testosterone are normal.2299 FSH may be elevated in patients with small testes and severe lesions of the seminiferous epithelium.2300 Hypogonadotropic hypogonadism has exceptionally been observed. Most patients have normal testicular size.2301 Biopsies typically reveal mixed tubular atrophy characterized by spermatogenesis associated with Sertoli cell–only tubules (Fig. 12.263).2302–2304 Tubules with spermatogenesis may show normal spermatogenesis or have lesions in the adluminal or basal compartments; about 64% of pachytene cells have three sex chromosomes, and many XYY spermatocytes degenerate during meiosis.2305 The number of normal spermatozoa in the ejaculate is low. The incidence of both YY and XY spermatozoa and disomy 18 is high.2306 The extra Y chromosome originates from nondisjunction during paternal second meiotic division. The presence of different tubular types (normal spermatogenesis, maturation arrest of

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primary spermatocytes, and Sertoli cell–only tubules) in the same biopsy is explained by postulating the disappearance of spermatocytes that were unable to pair their sexual chromosomes during meiosis or, later, during the round spermatid stage.2307–2310 Typically, there is a high rate of XYY cell degeneration during meiosis. Germ cells with X or Y chromosomes that fail to pair in the pachytene stage would be eliminated during the first or second meiotic division, or even later in the stage of round spermatids.2310–2312 Spermatocytes that form trivalent chromosomes (instead of bivalents) would be more protected and are initially viable.2311 The ultimate trivalent chromosome segregation yields aneuploid and euploid cells in equal numbers. Sertoli cell–only tubules are attributed to either spermatogonial damage by substances released from degenerated spermatocytes or absence of testicular colonization by primordial germ cells.2313 One concern is whether the spermatozoa of these patients have a high rate of aneuploidy. This has not been observed in XO/XYY, whereas men with other constitutions such as 47,XYY/46,XY have a higher risk for fathering children with a hyperdiploid chromosomal constitution.2314 Spermatozoa should be studied genetically to evaluate this risk before an ICSI program is begun.2315 The 47,XYY syndrome has been reported to be associated with 21 trisomy and fragile X syndrome.2316,2317 Men with three and four Y chromosomes have been reported.2318 Men with the 48,XYYY karyotype are tall and have a normal male phenotype, slight mental retardation, azoospermia, and, during childhood, frequent infections of the upper respiratory tract.2319 Mosaicisms with 48,XYYY line produce additional anomalies. Biopsy shows Sertoli cell–only tubules, severe hyalinization of the tubular basement membranes, and diffuse Leydig cell hyperplasia. The chromosomal complement of parents may be normal.2320 This karyotype probably results from fertilization of a normal ovule by a YYY spermatozoon.2321 Men with 49,XYYYY have no significant phenotypic abnormalities (except for cases of chromosomal mosaicism). Slight mental retardation, infertility, and antisocial behavior are reported.2322 Rarely patients have facial dysmorphism and various skeletal abnormalities.2323 Because the fathers of these patients have a normal karyotype, the explanation for this anomaly is nondisjunction in spermatogonial mitosis followed by a second nondisjunction in meiosis.2324 Structural Anomalies of the Y Chromosome

Fig. 12.263 47,XYY syndrome. The testis shows tubules with complete spermatogenesis, Sertoli cell–only tubules, and tubules with spermatogonial maturation arrest.

The Y chromosome is essential for gender determination and spermatogenesis, and Y-chromosomal abnormalities often lead to infertility. Cytogenetic studies showed that deletion of the distal euchromatic region is associated with infertility.2325 The relationship between Y-chromosomal abnormalities and infertility is best understood in azoospermic men with alterations in the distal region of the euchromatic part of the long Y arm. This region contains the gene (or genes) assumed to be responsible for spermatogenesis and named the azoospermic factor gene or AZF gene, located in the bands that extend from Yq11.21 to Yq11.23 (Fig. 12.264).2326–2331 DNA of the Y chromosome contains approximately 60 megabases (Mb), equivalent to 60 million base pairs (bp). The euchromatic transcriptionally active region contains 30 to 40 Mb and comprises the short arm, the centromere, and the proximal portion of the long arm. The heterochromatic (condensed) region has a variable length and no known important functions. The short arm euchromatic region starts in the telomere, with a pseudoautosomal region (2.7 Mb), which is homologous with the X chromosome

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PAR 1 SRY ZFY PRKY

Yp

1 2 3

GBY TS/GCY

4

5A 5B

AZFa

AZFa 5C 5D 5E 5F 5G 5H 5I 5J

Yq

CDY2 XKRY SMCY RBMY1

AZFb

AZFd TTY2 RMBY DAZ BPY2 PRY CDY1

P5/proximal-P1 (AZFb) P5/distal-P1

Male specific region of the Y (MSY)

USP9Y DBY UTY TB4Y

PRY TTY1 TTY2 TSPY

P4/distal-P1

5K 5L 5M 5N 5P 5Q 6A 6B

b2/b4 (AZFc) 6C

b1/b3 b2/b3

6D

AZFc

6E

gr/gr

6F

More frequent

7

PAR 2

Fig. 12.264 Scheme of Y chromosome showing azoospermic factor (AZF) regions.

short arm terminal region and contains genes that encode the granulocyte-monocyte colony-stimulating factor receptor α subunit (SCFrRA) and T cell adhesion factor (MICS). This euchromatic region continues with a 280-kilobase (kb) region that contains the sex determining genes (SRY), a ribosomal protein gene (RPS4Y), and a zinc finger protein (ZFY). Next is a region that is homologous with Xp21, as well as a short segment that is homologous with Xp22 and contains the amelogenin gene (AMGL). This region is followed by the centromere, a region homologous with Xp22, and the long arm heterochromatic region. The long arm proximal portion begins with the gene responsible for Kallmann syndrome (KAL1), followed by the genes that encode steroid sulfatase (STDP), the AZF, the gonadoblastoma factor, and the growth factor. Y-chromosome sequencing was completed in 2003; to date, 122 genes and 110 pseudogenes have been identified.2332 The following deletions and microscopically visible rearrangements affecting Yq11 region are recognized clinically: monocentric Yq-

chromosomes, dicentric Yq-chromosomes of the short arm (dicYp), Y chromosomes with ring structure (rin-Y), Y/Y translocation chromosomes, and translocation of Y chromosome to an autosome or the X chromosome. Deletions and Microscopically Visible Rearrangements in Infertile Patients Monocentric Deleted Yq Chromosome. Partial deletion of the

distal portion of the Yq11 euchromatic region is associated with azoospermia secondary to loss of AZF.2333,2334 Men have normal external genitalia except for small testes, normal testosterone and LH serum levels, and increased FSH.2325 The most frequent finding is Sertoli cell–only pattern, although many other patterns have been reported.2335 The number of Leydig cells is normal or increased. These findings suggest that adequate AZF function is required for early spermatogenesis.2336 If the breakpoint of Yq11 is proximal to the centromere, patients are short because the gene that controls stature is close to that for AZF.2337,2338

CHAPTER 12 Nonneoplastic Diseases of the Testis

Dicentric Yq Isochromosomes. Dicentric chromosomes are the most common structural change in the Y chromosome. Sterility is frequent.2339 This anomaly is usually associated with the 45,X cell line. The proportion of this line varies among patients and between cell types (fibroblasts and lymphocytes). When the point of breakage and fusion of the two Y chromosomes is in the distal region, Yq11 and the second centromere are inactivated. The Y isochromosome is of normal size but does not stain with quinacrine, and thus is called nonfluorescent Y chromosome (Ynf). Because the breakpoint is in the Yq11 region, AZF function is altered.1872,2340,2341 Development of external genitalia varies from ambiguous to normal. Some patients have sex reversal and short stature, whereas others have turnerian stigmata.2342–2345 This variability is probably related to the extent of XO present.2342 Biopsy findings are similar to those of men with monocentric deleted Yq chromosomes (i.e., Sertoli cell–only tubules with dysgenetic Sertoli cells and Leydig cell hyperplasia) (Fig. 12.265).2346–2348 Patients with dicentric Y chromosome without mosaicism may show male phenotype and maturation arrest of primary spermatocytes.2349,2350 Ring Y Chromosome. Men with ring Y chromosomes have a normal male phenotype, azoospermia, and in some cases, short stature.2351 Most have a mosaic karyotype with 45,X line.2352 In some cases, biopsy resembles that of men with monocentric deleted Yq chromosome, but in other cases one sees premeiotic arrest of spermatocyte maturation.2353,2354 This finding is attributed to difficulty in pairing the X and Y chromosomes during meiosis. Many patients have deletion of some AZF regions.2355,2356 Vertical transmission following assisted reproductive technology and ICSI has been reported.2357 Y/Y Translocation Chromosome. Patients have azoospermia, small and soft testes, and primary spermatocyte maturation arrest as a result of defective pairing of the X and Y chromosomes. The karyotype may be a mosaic with 45,X line.2358 Translocation of Y Chromosome to X Chromosome. This anomaly comprises two groups of patients: those with nonvisible or visible X;Y translocations. Nonvisible translocations are most common and have been observed in infertile patients with 46,XX karyotype.2359 The phenotype differs from that of patients with Klinefelter syndrome by shorter stature, absence of mental retardation, and small tooth size. Biopsy reveals Sertoli cell–only pattern.

Fig. 12.265 Testis from a male with dicentric Yq isochromosome showing seminiferous tubules with Sertoli cell–only pattern and slight Leydig cell hyperplasia.

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The clinical characteristics of patients with visible translocations resemble those of patients with Klinefelter syndrome more than patients with nonvisible translocations. Biopsy reveals tubular hyalinization and nodular Leydig cell hyperplasia. Autosomal translocation of Y Chromosome. Translocation of the distal heterochromatic portion of the Y chromosome to the short arm of an acrocentric chromosome occurs occasionally. The most frequent translocations are to chromosomes 5, 18, 13, 15, and 22.2360–2362 Fertility of these men depends on the site of breakage.2363 If breakage occurs in the Yq12 heterochromatic region, the patient has a male phenotype and is fertile. If the point of breakage is in the Yq11 region, the patient is infertile and has small testes.2363,2364 Seminiferous tubules may show only Sertoli cells, spermatogenetic arrest in the early stages of meiosis followed by apoptosis and primary spermatocyte sloughing, or an infantile pattern.2365,2366 Other Y-chromosome abnormalities associated with infertility include paracentric and pericentric inversions.2367,2368 Microdeletions of Y Chromosome. The Y chromosome is divided into seven deletion intervals: numbers 1 to 4 correspond to the short arm and centromeric region, and numbers 5 to 7 correspond to the long arm. Most deletions in infertile patients occur in three nonoverlapping subregions of Y chromosome (Yq11), located at intervals 5 and 6: AZFa, AZFb, and AZFc. AZFa is located in the proximal portion of the deletion interval 5, AZFb is present in the proximal end of interval 6 and the distal part of interval 5, and AZFc is in the distal portion of interval 6.2369,2370 Y-chromosome microdeletions are observed in up to 18% of cases of idiopathic male infertility, with ethnic and geographic differences, as well as differences related to the method of investigation. When only patients with idiopathic azoospermia are studied, the incidence rate is estimated between 14% and 15%.2371,2372 In Asia the incidence is even higher: 21% in Hong Kong, 24% in Taiwan, 30% in northwestern Iran, and 52% in southern Iran.2373–2376 Among patients with severe oligozoospermia, the incidence is also variable: 2% in Germany; 5% in Italy; up to 14% in Australia, Scandinavia, China, India, Japan, and Russia; and up to 18% in the United States.2377 Some patients present with complete deletion of the AZF region, but most have deletion of only one subregion. AZF deletions result from recombination of large palindromic sequences that have an identity greater than 99.9% and consist of long direct or indirect repeats called amplicons.2332 The ampliconic portion of the masculine-specific region of the Y chromosome contains a high density of genes from nine gene families, with each gene existing in multiple (2 to 35), nearly identical copies. These genes are predominantly or exclusively expressed in the testis. Clinically, 90% of patients with Y-chromosome microdeletion have small testes, increased FSH level, and azoospermia or severe oligozoospermia. Microdeletions of the AZFa subregion represent 5% of Ychromosome microdeletions. This subregion contains single copies of the DFFRY (Drosophila fat-facets related Y) and DBY genes. The DFFRY gene has been mapped to Yq11.2.2378–2380 This gene is a member of a gene family that encodes deubiquitinating enzymes (which remove ubiquitin from protein-ubiquitin conjugates), and it is ubiquitously expressed in embryonal and adult tissues, including the testis.2381 Although this gene does not appear to be essential for spermatogenesis, it may play an important role in normal development.2382 Complete deletion produces a Sertoli cell–only pattern.2383,2384 Partial microdeletions do not alter spermatogenesis.2385

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Microdeletions of the AZFb subregion represent 10% to 16% of Y-chromosome microdeletions. RBM1 and RBM2 are located in this region, and both are specifically expressed in the testis and germ cells. These genes codify RNA-binding proteins that localize to the nucleus of all germ cells and are involved in spermatogenesis.2386,2387 Patients with complete deletion of the AZFb subregion have azoospermia, and biopsy shows either Sertoli cell–only pattern or maturation arrest (Fig. 12.266).2388 In a study of patients with incomplete AZFb deletion, 50% had spermatozoa in the ejaculate.2389,2390 Microdeletions of the AZFc subregion are the most frequent of all microdeletions (80%), present in 5% to 10% of all patients with azoospermia or severe oligozoospermia.2391–2396 The DAZ (deleted in azoospermia) gene family is the most important in terms of infertility in deletions of this subregion.2397 Four functional copies (DAZ1, DAZ2, DAZ3, and DAZ4) are arranged in two clusters.2398 DAZ encodes a testis-specific RNA-binding protein containing 8 to 24 amino acids sequences, known as DAZ repeat. DAZ gene deletions produce a variety of effects on the testis. DAZ1/DAZ2 deletion is associated with incomplete maturation arrest of primary spermatocytes (Fig. 12.267), maturation arrest of spermatids, or MAT, whereas DAZ3/DAZ4 deletion may be observed in fertile and infertile patients.2369,2397,2399,2400 Partial deletion of the AZFc subregion known as gr/gr leads to subfertility because it removes at least two copies of DAZ and one copy of chromodomain protein Y-linked 1 (CDY1) and several other transcription units.2401–2403 Investigation for microdeletions of chromosome Y is recommended in all patients with severe oligozoospermia or azoospermia before intervention using ejaculated sperm and any surgical procedure to identify spermatozoa in the setting of azoospermia.2404 Sons conceived with sperm from men with Y-chromosome microdeletions are expected to inherit the abnormal Y chromosome and infertility problems.2394,2405,2406 They also have a potential risk for development of 45,X0 Turner syndrome or other forms of sex chromosome mosaicism, including hermaphroditism.2407 Clinically, primary use of donor sperm rather than TESE is recommended for men with deletions that involve complete loss of the AZFa or AZFb subregion.2377

Fig. 12.267 Microdeletion of AZFc region of Y chromosome in an infertile patient with severe oligozoospermia. Seminiferous tubules show maturation and scarce spermatogenesis with isolated adult spermatids.

The correlation between genotype and phenotype is inexact, but most microdeletions in AZFa, AZFb, and AZFc are associated with Sertoli cell–only syndrome, maturation arrest, and spermatid maturation arrest or mixed testicular atrophy, respectively.2408,2409 Structural Anomalies of the X Chromosome

46,XY patients with duplication of distal Xp may exhibit male, female, or ambiguous genitalia, and gonadal dysgenesis is frequent. Male genitalia, when present, are hypoplastic, and these patients have hypogonadotropic hypogonadism and frequently multiple congenital anomalies and mental retardation.2410 Clinical symptoms are related to the genetic content of the duplicated segment.2411 Male patients with translocation of the X chromosome to an autosome may have disturbed spermatogenesis with subfertility or infertility.2412–2414 47,XXX patients have mental retardation, gynecomastia, normal stature, scrotal hypoplasia, well-formed small penis, small testes, and scant pubic hair. Serum testosterone level is markedly decreased. Seminiferous tubules show severe hyalinization. The 47,XXX genotype results from abnormal X-Y interchange during paternal meiosis and X-X nondisjunction during maternal meiosis.2415 Transcriptionally inactive X chromosome is required for adequate spermatogenesis. It is possible that, in patients with translocation of the X chromosome to an autosome, this latter anomaly reactivates the X chromosome.2416

Anomalies in Autosomes Autosomal anomalies are frequently linked with infertility. However, the causes are not fully understood because the same anomaly is associated with infertility in some patients, but not in others. Chromosomal Translocations and Inversions

Fig. 12.266 Microdeletion of the AZFb in a patient with azoospermia. Seminiferous tubules with only Sertoli cells. In the intestinum there is a large cluster of Leydig cells and in the wall of a tubule, between the myoid cells, there are several peritubular Leydig cells.

Robertsonian translocations are found in 0.7% of infertile men (9% higher than in the normal population) and are more frequent in oligozoospermic than in azoospermic men; 25% of patients have normal sperm parameters.2417 The most common balanced Robertsonian translocations are 13;14 and 14;21. The incidence rate of reciprocal translocations in infertile patients is 1% (0.1% in the general population) and increases to 0.8% in patients with azoospermia or severe oligozoospermia.2418

CHAPTER 12 Nonneoplastic Diseases of the Testis

The most frequent reciprocal translocations in infertile men are 11;22 and 17;21. Paracentric and pericentric inversions (except for the pericentric inversion of the heterochromatic region in chromosome 9) are eight times more frequent in infertile patients (0.16%) than in the general population. The highest risk for infertility is associated with pericentric inversion of chromosome 1.2419,2420 The presence of small supernumerary marker chromosomes in the infertile population is much more frequent than in the general population. Partial trisomy of some genes and mechanical alteration of meiosis might account for infertility.2421 The most common testicular lesions in men with autosomal anomalies are spermatogonial maturation arrest, primary spermatocyte sloughing sometimes associated with hypospermatogenesis, and Sertoli cell–only pattern.1886 Down Syndrome

The most frequent autosomal trisomy associated with prolonged survival is found in Down syndrome, with an estimated incidence of 1 in 1000 newborns. More than 80% patients reach or exceed 50 years. In addition to trisomy 21 and the characteristic appearance, patients with Down syndrome usually have cryptorchidism, small testes, hypoplasia of the penis and scrotum, and hypospadias.2422 Patients experience development of leukemia more frequently, and testicular, brain, and hepatocellular tumors less frequently.2423 Adults have oligozoospermia or azoospermia secondary to primary testicular deficiency. Levels of FSH and LH are elevated, but testosterone level is normal or slightly diminished.2424 Isolated cases of paternity have been reported.2425,2426 In utero, there is marked delay in germ cell development.2427 Histologic studies of prepubertal testes at autopsy reveal decreased tubular diameter and TFI. Eosinophilic bodies or microliths may be present in some tubules (Fig. 12.268). Adult testes have deficient spermatogenesis and MAT, with some tubules showing complete spermatogenesis and others containing only Sertoli cells.2428 Isolated cases of azoospermia associated with trisomy 18 have been reported.2429

Fig. 12.268 Prepubertal testis in down syndrome. There are megatubules, ring-shaped tubules, and small seminiferous tubules. Germ cell number is low in all these tubules. Eosinophilic bodies or microliths are present in some tubules.

675

Other Syndromes Associated With Hypergonadotropic Hypogonadism Hypergonadotropic hypogonadism is found in several myopathies (myotonic dystrophy and progressive muscular dystrophy) and dermopathies (Bloom, Rothmund-Thomson, Werner, Cockayne, and Tay syndromes), with histologic features resembling those of Klinefelter syndrome. Hypogonadism is also observed in Noonan syndrome, cerebellar ataxia (with milder testicular lesions), and a miscellaneous group of syndromes with variable histologic findings.2430 Myotonic dystrophy accounts for approximately 30% of men with muscular disorders, and approximately 80% have testicular atrophy. The estimated incidence is 1 in 8000 live births. The abnormality involves the distal muscles of the extremities. Patients may also have premature baldness, posterior subcapsular cataracts, cardiac conduction defects, impotence, gynecomastia (rarely), and dementia (at later stages).2431 Myotonic dystrophy is autosomal dominant inherited with variable penetrance. Two loci are associated with the disease phenotype: DM1 in 19q13.3 and DM2 in chromosome 3. Mutation in DM1 results in serine/threonine protein kinase deficiency that causes expansion of the CTG repeat (from 50 to several hundred repeats) located on the 30 -untranslated region of the dystrophy myotonic–protein kinase gene. The number of repeats correlates with the severity of the disease and is negatively correlated with age of clinical onset.2432–2434 DM2 is caused by mutation in 3q21.3 of the ZNF9 gene and accounts for CCTGrepeat expansion (from 75 to 11,000 repeats) in intron 1 of this gene. Common clinical symptoms result from gain of function of RNA mechanism in CUG and CCUG repeats altering cellular function, including alternative splicing of various genes.2435 The severity of the disease increases in successive generations.2436 The number of CTG repeats is not associated with male subfertility.2437 Hypogonadism is hypergonadotropic in most cases and not related to the number of CTG repeats.2438,2439 Testicular lesions probably begin late because 65% of patients father children. Biopsies have variable findings, ranging from nearly normal to fully hyalinized tubules, with the number of Leydig cells varying from increased to decreased. The cause of germ cell disappearance is related to decrease in SIX5 level. The SIX5 gene is necessary for germ cell survival and spermatozoa maturation, and is silenced by CTG expansion in DM1.2440 In some patients, hypogonadism is hypogonadotropic, and the testes show an infantile pattern. Infertility may be the first symptom of myotonic dystrophy.2441 Progressive muscular dystrophy is a multisystemic X-linked recessive disease. It is usually associated with gonadal atrophy caused by a defective locus in chromosome 19. Patients rarely live more than 20 years. The incidence is approximately 1 in 4000 live births. In both Duchenne and Becker forms, the cause is a defect in the dystrophin gene located in Xp21. Dystrophin is a structural protein of skeletal and myocardial muscular cells.2442–2446 The most common endocrine alteration is hypogonadotropic hypogonadism with delayed puberty and low serum testosterone.2447,2448 Several cases of an association between Becker progressive muscular dystrophy and Klinefelter syndrome have been reported.2449 Bloom, Rothmund-Thomson, and Werner syndromes are caused by a homozygous defect in human RECEQ helicases in chromosome 15. The RecQ family of DNA helicases comprises essential proteins in prokaryotes and eukaryotes because these helicases catalyze unwinding of double-stranded DNA to provide simplestranded templates for replication, repair, recombination, and transcription.2450,2451 Of the five members of this gene family

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(RECQ1, BLM, WRN, RECQ4, and RECQ5), three produce autosomal recessive inherited diseases. Mutations of the BLM gene have been identified in patients with Bloom syndrome, WRN has been shown to be mutated in Werner syndrome, and mutations of RECQ4 have been associated with Rothmund-Thomson syndrome.2452–2454 Despite similar genetic abnormalities in the three syndromes, the syndromal elements are different. Bloom syndrome is characterized by short stature, narrow face with prominent nose, facial patchy skin color changes that become more marked with sunlight exposure, high-pitched voice, and increased susceptibility to respiratory diseases, cancer, and leukemia.2455 Severe oligozoospermia and azoospermia are common. Leydig cell function is conserved.2456 Rothmund-Thomson syndrome is characterized by poikiloderma, juvenile cataracts, sparse hair, short stature, skeletal defects, dystrophic teeth and nails, and hypogonadism. These patients are predisposed to skin cancer and osteogenic sarcoma.2457–2459 Werner syndrome (progeria adultorum) manifests in young adults who appear much older than their chronologic age. The prevalence in the United States is estimated to be 1 in 200,000.2460 The youngest confirmed patient was diagnosed at the age of 6 years.2461 However, most patients have normal development up to the end of the first decade of life. In the second decade, symptoms develop that may include low stature, premature graying hair and baldness, cataracts, atrophy followed by fibrosis and calcification of muscular and adipose tissues, wrinkling of the skin, keratosis, osteoporosis, telangiectasis, atheroma, diabetes mellitus type 2, gynecomastia, and hypergonadotropic hypogonadism. Fertility declines soon after sexual maturity. Nonetheless, paternity at a young age has been reported.2462 Inheritance is autosomal recessive. Experiments with cultured cells from these patients have shown that several cell types, such as fibroblasts, have a shorter life than that of control cells.2463 The gene mutated in Werner syndrome, WRN, encodes both a 30 ! 50 DNA helicase and a 30 ! 50 DNA exonuclease.2453,2464,2465 These patients have a high incidence of sarcoma. Cockayne syndrome is a rare autosomal recessive neurodegenerative disorder.2466 Signs and symptoms include failure to thrive in infancy; short stature; poorly developed trunk; premature aging; neurologic alterations; retinitis pigmentosa; optic atrophy; cataract; deafness; microcephaly; micrognathia; photosensitivity; delayed eruption of primary teeth; congenital absence of some permanent teeth; partial macrodontia; atrophy of the alveolar process and caries; limited articular movements in elbows, knees, and fingers; abnormally small eccrine glands; and hypergonadotropic hypogonadism.2467,2468 Three general presentations have been reported: Cockayne syndrome type I or classic Cockayne syndrome, in which the major features of the disease become apparent by 1 or 2 years of age; Cockayne syndrome type II, the most severe form, whose symptoms are recognized at birth or in the early neonatal period; and Cockayne syndrome type III, a milder and later-onset form. This rare disease is linked to biallelic mutations in the CSB/ ERCC6 and CSA/ERCC8 genes. Mutations of CSB and CSA genes jeopardize transcription-coupled repair of damaged nuclear and mitochondrial DNA, and the resumption of replication and transcription-encoding proteins involved in the transcriptioncoupled DNA repair pathway.2469–2471 Tay syndrome was first described in 1980, with an account of two Asian siblings whose parents were first cousins.2472 The term trichothiodystrophy (TTD) was introduced in 1980 to describe the hair anomalies in these patients.2473 Patients with TTD have brittle hair and nails (associated with reduced content of cysteine-rich matrix proteins), ichthyosis, cataracts, and physical and mental

growth retardation. Hair from patients with TTD, when examined under polarized light microscopy, reveals alternating light and dark bands known as the “tiger tail” anomaly. The diagnosis may be confirmed by sulfur content analysis of hair shafts, which show decreased sulfur and cysteine content. Approximately one-half of patients with TTD have photosensitivity and are designated as TTD-photosensitive patients; the rest are nonphotosensitive patients and are designated as TTD-nonphotosensitive patients.2474 TTD is part of a more broadly defined group of diseases identified as IBIDS (ichthyosis, brittle hair, impaired intelligence, short stature). Photosensitive cases are also identified as PIBIDS (photosensitivity with IBIDS). These syndromes are caused by mutations in genes encoding subunits of the transcription/repair factor IIH.2475 In both forms of TTD, patients have decreased fertility. Hypergonadotropic hypogonadism has been reported in one patient.2476 Noonan syndrome is characterized by multiple malformations reminiscent of Turner syndrome, including short statute, pterygium coli, and cubitus valgus, although patients have normal male karyotype. Pulmonary artery stenosis has been found in 62% and hypertrophic myocardiopathy in 20%.2477–2479 As in Turner syndrome, aortic coarctation may also be present.2478,2480 Malformations in the peripheral vascular system may be occasionally observed.2481,2482 The incidence is 1 in 1000 to 1 in 2500 live births and autosomal dominant inheritance, with sporadic occurrence in approximately 50% of cases. Fathers of one-half of the patients show some of the characteristic features of this syndrome.2483,2484 A locus for dominant forms has been mapped to 12q24.1.2485 Mutation in PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11) accounts for one-half of the cases, although similar germline mutations also cause Leopard syndrome, Costello syndrome, and cardiofaciocutaneous syndrome.2486,2487 These syndromes are genetically heterogeneous, but they share several symptoms. Noonan syndrome is caused by activating mutations in genes encoding upstream factors of the Ras–mitogen-activated protein kinase pathway, including PTPN11 that encodes SHP2 and SOS1, as well as KRAS, SHOC2, and NRAS genes.2488–2493 The characteristic Noonan stigmata are likely the result of a malformative sequence caused by a failure in one or more lymphogenic genes.1251 Aberrant lymphatic endothelial differentiation produces lymphatic stasis, and subsequent distention and lymphedema exert mechanical pressure on the adjacent tissues and organs.2494,2495 Cryptorchidism is present in approximately 70% of patients and is usually bilateral.2496 Testes are small and, in the first year after birth, show delayed disappearance of gonocytes.2497 Biopsies from infants have low TFI and decreased MTD.2498 Patients may present with testicular and epididymal lymphangiectasis. Puberty is usually delayed.2499 Laboratory data from pubertal patients, either with or without cryptorchidism, show that LH level is normal, whereas FSH is increased, and inhibin B is low or just above the lower limit of normality. These findings suggest Sertoli cell dysfunction.2500 Puberty is often delayed, and hypogonadotropic or hypergonadotropic hypogonadism occurs during adulthood. Ultrastructural studies reveal morphologic anomalies in germ cells.2501 Although spermatogenesis is generally impaired, some patients are fertile (Fig. 12.269). Noonan syndrome may be associated with Klinefelter syndrome and Becker muscular dystrophy.2502,2503 Patients with Noonan syndrome, as well as those with Costello syndrome or cardiofaciocutaneous syndrome, have a high incidence of malignancies.2504,2505 In rare instances, germ cell tumor has been reported.2506

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basis of the distinction. The most frequent types of hypogonadism caused by hypothalamohypophyseal failure are those resulting from a deficit of GnRH, bioinactive FSH and LH, or a deficit in GH, as well as those types associated with PWS and Laurence-Moon-Rozabal-Bardet-Biedl syndrome.

Fig. 12.269 Testis from a 15-year-old boy with Noonan syndrome. Most seminiferous tubules are small and contain Sertoli cells and isolated spermatogonia. The most dilated tubules have complete, although quantitatively decreased, spermatogenesis.

Cerebellar atrophy may be associated with hypogonadism. Patients are infertile and have moderate ataxia. Infertility results from morphologic abnormalities of spermatozoa caused by decreased expression of MAP2 (the most important microtubule-associated protein) and a defect in erythroid ankyrin.2507,2508 Both proteins are involved in cytoskeletal protein assembly and are essential for normal germ cell morphogenesis. The most frequent malformations are nuclear deformation, acrosome separation or loss, rolling of the tail inside the cytoplasm, and loss of mitochondrial and dense fibers. Although hypogonadism observed in ataxia patients is usually hypogonadotropic, patients with cerebellar ataxia and hypergonadotropic hypogonadism have been reported.2509,2510 Many other syndromes also manifest with primary hypogonadism. The best known are Alstr€om, Weinstein, B€orjeson-ForssmanLehmann, Marinesco-Sj€ogren, Richards-Rundle, Robinow, and Silver-Russell syndromes.

Secondary Idiopathic Hypogonadism Age of onset of puberty depends on genetic (ethnic and familial) and environmental factors. Genetic factors determine an estimated 50% to 80% of these age differences.2511 The onset of puberty depends on many genes; among them, the KISS1/GPR54 system stands out.2512 Mutations in many genes impair hypothalamohypophyseal-testicular axis development at different levels. SF1 and DAX-orphan nuclear receptors are expressed at multiple levels throughout the reproductive axis. KAL, FGFR1, and NELF are related to anosmia or hyposmia and abnormal GnRH neuron migration from the nasal cavity to the hypothalamus. Leptin, leptin receptor, ghrelin, and PC1 are related to obesity. HESX1, LHX3, and PROP1 impair differentiation or function of pituitary gonadotropic cells, thus causing mutations in the GnRH receptor and in gonadotropic genes LHB and FSHB, with resulting structural anomalies in these hormones and in gonadotropin actions.674,2513,2514 Hypogonadotropic hypogonadism or hypogonadism of hypothalamohypophyseal origin is classified according to whether the hypothalamohypophyseal failure occurs before or after puberty. Eunuchoidism, present only in the former, is the

Gonadotropin-Releasing Hormone Deficit The onset and maintenance of the hypothalamohypophysealgonadal axis depend on pulsatile GnRH secretion by approximately 1500 neurons of the nucleus arcuatus hypothalamus, with release into the pituitary portal system and subsequent stimulation of GnRH receptors on the surface of gonadotropin-secreting cells in the anterior pituitary lobule. The GnRH gene is located on 4q13.2515 Patients with GnRH deficit have partial or complete absence of GnRH-induced pulsatile LH secretion and normalization of pituitary and gonadal secretions after exogenous GnRH administration. Imaging studies of the hypothalamohypophyseal region are normal, as are findings in the remaining hypothalamopituitary axes. GnRH secretion starts early in embryonal life. LH and FSH are detected in the pituitary during the 19th week. GnRH levels in fetal blood reach a peak approximately halfway through gestation and decrease later, when the mechanisms for negative feedback are developed. During the neonatal period, evidence of GnRH secretion is based on persistence of pulsatile gonadotropin secretion.2516 In boys, 6 months after birth, GnRH secretion begins to decrease to low levels. During infancy the hypothalamohypophyseal-testicular axis remains quiescent. At the beginning of puberty the hypothalamohypophyseal axis starts to secrete. This activity is characterized by an increase in the amplitude of pulsatile, GnRH-induced, LH secretion during sleep. With advancing puberty, gonadotropin secretion occurs night and day. In adulthood, LH pulses are produced in men approximately every 2 hours. Clinical symptoms vary by age at presentation (congenital or acquired) and severity (complete or partial deficit). Clinical presentations include delayed puberty, idiopathic hypogonadotropic hypogonadism (IHH; isolated gonadotropin deficit), Kallmann syndrome, isolated FSH deficit, and isolated LH deficit (fertile eunuch syndrome). Congenital GnRH deficit may be diagnosed occasionally in the neonatal period, during investigation for cryptorchid patients who have micropenis associated with low serum gonadotropin levels. During adolescence the diagnosis is prompted by failure of the onset of puberty and failure to develop secondary sex characteristics. Acquired GnRH deficit has been reported in patients who, after going through normal puberty, experience diminished libido and fertility. In some cases the hormonal pattern resembles that of congenital GNRH deficit.2517 In other cases, hormonal deficits are not so pronounced. This disorder may occur in athletes during training and may be reversed with clomiphene citrate.2518 Constitutional Delay of Growth and Puberty Normal puberty is a period of development that results in complete growth and maturation to adulthood. It includes sexual development and acquisition of specific psychosocial behaviors. Delayed puberty is one of the most common reasons why adolescent boys are referred to an endocrinologist. The most common cause of delayed puberty in males is constitutional delay of growth and puberty (CDGP), followed, in decreasing order of frequency, by delayed puberty secondary to

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underlying chronic disease (functional hypogonadotropic hypogonadism), permanent hypogonadotropic hypogonadism, and permanent hypergonadotropic hypogonadism.2519 CDGP is assumed to be a minor form of GnRH deficit.2520 Many cases are likely inherited as an autosomal dominant, recessive, or X-linked trait. Single-gene defects have not yet been identified.2521,2522 CDGP is characterized by delayed sexual maturation in otherwise healthy adolescent boys. Patients are short and usually have a family history of delayed puberty. Puberty usually begins at 13 to 14 years of age and progresses over 2 years. If a 14-year-old boy has not begun pubertal changes such as testicular enlargement (the testis has not reached 4 mL in volume or the major axis measures <2.5 cm), growth in height, and development of secondary sex characteristics, delayed puberty should be suspected.2523–2527 Among the different causes invoked to explain delayed sexual maturity in adolescent boys with CDGP is conjunction of elevated serum ghrelin and decreased leptin concentration.2528 Ghrelin is mainly synthesized in the stomach, and among its numerous functions is control of GH secretion, food intake, energy balance, and adiposity.2529 Leptin is secreted by adipose tissue and directly acts on hypothalamic nuclei to suppress food intake and increase energy expenditure.2530 Biopsy reveals delayed development at the tubular and interstitial level and a great variety of tubular patterns. Tubules of prepubertal diameter predominate, devoid of lumina and containing only immature Sertoli cells or isolated spermatogonia (Fig. 12.270). Sertoli cells still express D2–40 and show focal immunoreactivity to AR (Fig. 12.271). Other irregularly distributed tubules contain a greater number of spermatogonia, spermatocytes I, and even some spermatids. The main problem in patients with CDGP is that different types of hypogonadotropic hypogonadism require different treatments. Simple pubertal delay that spontaneously resolves quickly without treatment must be distinguished from hypogonadotropic hypogonadism. The latter should be suspected when any of the following symptoms are present in the patient or his family: midline defect, anosmia, or pubic hair without testicular development. In addition, low testicular volume (<3 mL) is much more frequent in hypogonadotropic hypogonadism than in CDGP. Hormonal assays may also assist in the diagnosis. Valuable tests include

Fig. 12.270 Testis from a 15-year-old boy with delayed puberty. Seminiferous tubules have initial pubertal maturation, showing spermatogonia and isolated spermatocytes. The interstitium has scarce Leydig cells.

Fig. 12.271 Testis from a 15-year-old boy with delayed puberty. Seminiferous tubules with variable immunoexpression of androgen receptor. Some tubules have intense expression adjacent to other tubules showing minimal or absent expression.

nocturnal LH sampling, Prolactin (PRL) response to TRH, daily urine excretion of FSH and GnRH, and hCG stimulation, although no single test is absolute.2531 The most useful test seems to be the combination of GnRH test with 3-day (short) hCG and 19-day (extended) hCG stimulation.2532 This differential test may also be made on the basis of plasma inhibin B and AMH concentrations.2533,2534 Inhibin B and AMH remain high in patients with CDGP, a fact that does not occur in patients with hypogonadotropic hypogonadism.2535 If a patient between 16 and 18 years old has prepubertal gonadotropin levels, he probably has hypogonadotropic hypogonadism. The incidence of delayed puberty associated with chronic illness is unknown. Delayed puberty may be associated with recurrent infections, immunodeficiency, gastrointestinal disease, renal disturbances, respiratory illnesses, chronic anemia, or endocrine disease. Malnutrition is probably the most important mechanism responsible for delayed puberty.2536,2537 The degree of growth and pubertal development impairment in chronic illness depends on the type of disease, patient age at onset of illness, duration and severity of the disorder, and individual factors. In milder cases of delayed puberty, treatment is often not required. However, evidence indicates the efficacy and safety of short courses of low-dose testosterone therapy in select individuals.2538

Isolated Gonadotropin Deficit A variant of hypogonadotropic hypogonadism, isolated gonadotropin deficit (IHH), is characterized by absence of pubertal development, low levels of gonadotropins secondary to hypothalamushypophyseal axis abnormalities, and infertility. IHH results from defects in GnRH neuron fate, specification, or migration, as well as from anomalies in GnRH secretion or action causing defects in synthesis or release of FSH and LH; other hypophyseal functions are normal. The estimated incidence is 1 in 10,000 males and 1 in 50,000 females.2539 The disorder is heterogeneous both clinically and genetically.2540 Only 15% to 20% of patients with IHH have a demonstrable genetic basis. KAL1, GNRHR, and FGFR1 mutations are the most frequently detected abnormalities. Other genes implicated are nuclear receptor subfamily 0, group B member 1

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(NR0B1), G protein–coupled receptor 54 (GPR54), leptin (LEP), leptin receptor (LEPR), proprotein convertase subtilisin/kexin type 1 (PCSK1), KISS1 metastasis suppressor (KISS1), nasal embryonic LHRH factor (NELF), prokineticin 2 (PROK2), prokineticin receptor 2 (PROKR2), chromodomain helicase DNA-binding protein (CHD7), tachykinin B (TAC3), and tachykinin B receptor (TAC3R).2541,2542 The IHH phenotype may also be observed in combined hypophyseal deficiencies resulting from mutations in HESX homeobox 1 (HESX1), prophet of PIT1 (PROP1), and Lim homeobox gene 3 (LHX3).2543–2545 Patients with IHH may be normosmic, anosmic (in Kallmann syndrome), or suffer from LH deficit (fertile eunuch syndrome).

Idiopathic Normosmic Hypogonadotropic Hypogonadism This form of IHH has classically been reported in patients who have eunuchoid phenotype, with small testes and penis, scant body and facial hair, high-pitched voice, and poorly developed muscles.2523 It is caused by defective GnRH action on gonadotropin secretion. Genetic anomalies implicate the following genes: GnRH receptor (GNRHR), FGF receptor 1 (FGFR1), G protein–coupled receptor 54 (GPR54), cadherin 7 (CDH7), and the genes that encode tachykinin B (TAC3) and its receptor NK3R (TAC3R).2546 Of these, the gene most frequently involved is GNRHR, of which nearly two dozen different mutations have been reported.2547–2549 The frequency of FGR1 mutations varies from 3% to 7%.2550,2551 Loss-of-function mutations of the GPR54 gene have been reported in several members of the same family.2552 Patients have low levels of FSH, LH, testosterone, and estrogen. AMH levels are greatly elevated in this and other forms of hypogonadotropic hypogonadism. This finding is expected because Sertoli cells are immature. In normal boys, AMH concentrations decrease to undetectable levels at puberty when adequate testosterone synthesis is established. The same occurs in hypogonadotropic hypogonadism after treatment with hCG or testosterone.2553 Clomiphene citrate treatment fails to increase FSH and LH.2339 Pulsatile administration of GnRH is useful to promote both androgen production and spermatogenesis. The LH–Leydig cell–testosterone axis is usually normal, but normalization of the FSH–Sertoli cell–inhibin axis is not achieved in all cases. Basal inhibin levels higher than 60 pg/mL, preceding a history of sexual maturation and absence of cryptorchidism, are favorable predictors of acquisition of normal testicular size and acceptable spermatogenesis.2554 Biopsy reveals an immature pattern (Fig. 12.272). Seminiferous tubules have neither lumina nor elastic fibers (Fig. 12.273). Sertoli cells are immature, and differentiated Leydig cells are lacking.1866 Spermatogonia are found in low numbers and do not undergo proliferation. Some patients have Sertoli cell–only testes with immature Sertoli cells.1865 Hypogonadism Associated With Anosmia Two syndromes are included: Kallmann syndrome and CHARGE syndrome. Kallmann Syndrome

Kallmann syndrome is a specific type of IHH characterized by hypogonadotropic hypogonadism, anosmia, neurologic defects, facial midline defects, and renal abnormalities. A syndrome characterized by the association of hypogonadism with anosmia was first described in 1856.2555 Eighty-eight years later the same syndrome was reported in three families, and the suggestion was made regarding genetic transmission.2556 In 1954, testicular atrophy was

Fig. 12.272 Isolated gonadotropin deficit. The seminiferous tubules have prepubertal diameter, pseudostratified distribution of the Sertoli cells, and several spermatogonia per tubular section.

Fig. 12.273 A 17-year-old patient with hypogonadotropic hypogonadism. Absence of elastic fibers in the wall of seminiferous tubules (orcein).

identified in 14 of 31 patients with olfactory bulb agenesis, and the condition was named “olfactory-genital dysplasia.”2557 Patients may have hypogonadotropic hypogonadism and anosmia, or only one. Hypogonadism is caused defective hypothalamic GnRH secretion that causes failure in pituitary secretion of LH and FSH. Anosmia may be caused by olfactory bulb agenesis or neuronal dysfunction, because olfactory bulbs are present in 25% of patients.2558 The anosmia may be unilateral by aplasia of the ipsilateral olfactory tract and bulb.2559 Although many patients experience delayed puberty, the diagnosis is usually made in the third decade of life.2560 Autopsy studies in patients with anosmia and hypogonadism reveal agenesis of the olfactory bulbs that may be partial or complete and unilateral or bilateral, together with an apparently normal hypophysis and normal or hypoplastic hypothalamus. This syndrome is the least severe form of holoprosencephalyhypopituitarism complex, a spectrum of developmental anomalies associated with impaired midline cleavage of the embryonic forebrain, aplasia of olfactory bulbs and tracts, and midline dysplasia

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of the face. Associated abnormalities include cryptorchidism, mental retardation, color blindness, facial asymmetry, nerve deafness, epilepsy, shortening of the fourth metacarpal, tarsal navicular fibrous dysplasia, diabetes mellitus, hyperlipidemia, gynecomastia, lip, maxillary or palate cleft, choanal atresia, dental agenesis, cardiovascular abnormalities, and neurologic disorders such as cerebellar ataxia, sensory-neural hearing loss, oculomotor abnormalities, and synkinesis (mirror movements of extremities).2561–2564 Renal agenesis has also been reported.2565 One patient experienced development of seminoma.2566 Kallmann syndrome may be associated with X-linked ichthyosis or punctata chondrodystrophy. Both disorders form part of a contiguous gene syndrome caused by large terminal or interstitial deletions of the Xp22.3 region.2567–2569 Presentation is heterogeneous and, within the same family, may include the full spectrum, anosmia only, hyposmia or anosmia limited to certain odors, and IHH only. Heterogeneity is also seen with associated somatic defects, as well as in the severity of hypogonadotropic hypogonadism. Many cases occur spontaneously, but others have a genetic cause. In the latter cases, inheritance may be X-linked recessive, autosomal dominant with variable expression, or autosomal recessive.2570–2573 Inheritance pattern may correlate with mutations in specific genes. Most patients with X-linked inheritance (30% to 70%) and 5% of patients without a family history have mutations in the KAL1 gene, mapped to the Xp22.3 region.2574 This gene encodes the protein anosmin-1, similar to other nerve cell adhesion molecules (NCAM, NCAMLl, TAGI, and contactin) involved in axonal growth and development.2575 KALIG-1 seems to be involved in spatial orientation of growth in GnRH neurons and may have various mutations (termed Kal-X, KALIG1, and ADMLX), complete deletion, and point mutations.2576 Autosomal-dominant presentation (occurring in 10% of cases) results from loss of function of FGFR1. Interaction between KAL1 and FGFR1 is required for neuronal migration. The predominant mutations are in FGFR1, prokineticin receptor 2 (PROKR2), prokineticin 2 (PROK2), FGF8, and nasal embryonic LHRH factor (NELF).2577,2578 The autosomal recessive form is caused by mutations in PROKR2 and PROK2. Currently, KS is classified into six subtypes: type 1 or X-linked KS associated with KAL1 mutation; subtypes 2, 3, 4, 5, and 6 linked, respectively, with mutations in FGFR1, PROKR2, PROK2, CHD7, and FGF8.2579 For a full understanding of the importance of these proteins, it is best to keep in mind a summary of embryonal development of some anatomic structures.2580 Olfactory sensory neurons originate from the olfactory placode (embryo) or neuroepithelium (postnatal life). Projections of these neurons occur in a stereotyped manner. Olfactory sensory neurons that express receptors for specific odors cross the cribriform lamina and converge to form a few glomeruli in the olfactory bulb.2581 These glomeruli establish synapses with dendrites of mitral cells whose axons form the olfactory tract. Mitral cells secrete a glycosylated 600-amino acid protein, referred to as KAL or anosmin, that induces odor-sensitive olfactory sensory neuron axons to grow and penetrate the olfactory bulb to establish synapses with mitral cells.2582 The neuroepithelium also gives rise to a population of neuroblasts that migrate to reach the medial basal hypothalamus, where they originate in cells that secrete GnRH.2583 GnRH reaches the anterior lobule of the hypophysis by the portal system. This migration occurs in two stages. First, neuroblasts exit the olfactory placode, cross the cribriform lamina, and reach the vicinity of olfactory sensory neurons. Second, the neuroblasts migrate from the olfactory bulb to the hypothalamus

following the vomeronasal nerve and produce GnRH neurons. Axons of the vomeronasal nerve secrete cell adhesion molecules of the CAM type to ensure this migration.2584 These neurons secrete GnRH, the peptide that controls FSH and LH secretion by gonadotropic cells in the hypophyseal anterior lobule. In Kallmann syndrome, mitral cells fail to secrete KAL protein, and axons of the olfactory bulb neurons do not penetrate the brain but instead form a tangle between the cribriform lamina and forebrain. Migration of GnRH neurons also remains blocked. This anomaly is not limited to patients with Kallmann syndrome, but has also been observed in arhinencephalic disorders such as CHARGE syndrome, trisomy 13, and trisomy 18.2585 In human fetuses with Kallmann syndrome, GnRH neurons, as well as the axons of olfactory neurosensory neurons, vomeronasal nerves, and axon terminals, end in the meninges and form an abnormal neural tangle.2583 GnRH neurons do not penetrate the brain and may be found in nasal cavities or the dorsal surface of the cribriform lamina. These alterations lead to aplasia or agenesis of the olfactory bulb and olfactory tract and to hypothalamic aplasia, and may be easily demonstrated by MRI.2586 Pituitary structure and its response to pulsatile GnRH stimulation are normal. In infancy and puberty, the most important findings suggesting the diagnosis of Kallmann syndrome are anosmia or hyposmia, hypoplasia of the penis (65%) and cryptorchidism (73%), cleft lip/palate (13% to 14%), hearing loss (28%), renal agenesis, or synkinesis.2587 Diagnosis is confirmed by the absence of olfactory bulbs and olfactory tract on MRI. Adult patients are classified into two groups according to the partial or complete absence of GnRH. Complete absence is diagnosed by the absence of spontaneous pulses of LH, FSH, and testosterone during a 24-hour period.2588 These patients show an increase in FSH only after GnRH administration.2589 Testes are histologically infantile; tubules have small diameters that may be even smaller than that of infantile seminiferous tubules, lack lumina, and contain immature Sertoli cells and isolated spermatogonia.2590 The interstitium is wide and consists of acellular connective tissue with no recognizable Leydig cell precursors (Fig. 12.274).2591 Partial absence of GnRH is diagnosed by the

Fig. 12.274 Hypogonadism associated with anosmia in a previously treated patient. The testis shows marked hyalinization of the tubular wall. Some spermatogonia may be observed among the Sertoli cells. The testicular interstitium lacks Leydig cells.

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presence of spontaneous pulses of LH, FSH, and testosterone during a 24-hour period, and biopsies show some degree of pubertal maturation. Treatment also varies. If only virilization is desired, androgenic therapy is sufficient. If the aim is to promote fertility, hCG alone or in combination with recombinant human FSH or hMG or pulsed administration of GnRH may be used.2592 CHARGE Syndrome

The term CHARGE syndrome, proposed in 1987, incorporates letters from the most characteristic anomalies of this disorder: coloboma, congenital heart disease, choanal atresia, retarded growth, mental retardation, or central nervous system anomalies, genital hypoplasia, and ear anomalies or deafness.2593 Most cases are sporadic; in familial cases, autosomal dominant inheritance is suggested. The syndrome is caused by mutations in the CHD7 gene (chromodomain helicase DNA-binding protein 7) located on chromosome 8q12.1, which belongs to a protein family that participates in chromatin organization in fetal development.2594– 2596 CHARGE syndrome is present in 1 in 10,000 newborns and has no gender distinction. Micropenis and cryptorchidism are frequent findings, indicative of hypogonadotropic hypogonadism, and associated with anosmia by olfactory bulb hypoplasia or aplasia in 81% of patients.2597–2600

Isolated Luteinizing Hormone Deficiency The first reports of patients with eunuchoid habitus, conserved spermatogenesis (“fertile eunuchs”), LH deficit, spermatozoa, and absence of Leydig cells appeared in the 1950s.2601–2603 Patients have eunuchoid habitus, small testes, decreased libido, female distribution of pubic hair, and high-pitched voice. Other frequent findings include gynecomastia, anosmia, ocular lesions, and pituitary tumor.2603 FSH level is normal, but LH and testosterone are low.2604 The negative response to clomiphene citrate suggests hypothalamic anomaly.2605,2606 Mutations in the LH β-subunit gene and the GnRH receptor have been reported.2607–2611 The clomiphene test result is usually negative, and GnRH stimulation produces a normal response, increased LH, and to a lesser degree, FSH, and suggests that pituitary gonadal function is normal.2612 Biopsy shows seminiferous tubules with normal or slightly decreased diameters and complete spermatogenesis; however, the number of all germ cell types is lower than normal. Leydig cells are rare or absent (Fig. 12.275). Maintenance of spermatogenesis in the absence of Leydig cells and serum testosterone may be explained only by assuming occurrence of testosterone secretion sufficient for spermatogenesis, but not high enough to be detectable in the blood. LH increase, produced by pulsatile GnRH secretion, occurs during monitored sleep.2613 Under FSH stimulation, Sertoli cells secrete large ABP amounts, which induce testosterone level elevation that is enough to maintain spermatogenesis.2614 Treatment with testosterone or hCG improves spermatogenesis. Isolated Follicle-Stimulating Hormone Deficiency Isolated FSH deficiency is a rare syndrome characterized by azoospermia or oligozoospermia in normally virilized patients with normal sexual potency.2615 It is an exceptional clinical situation caused by FSH β-subunit gene mutations.2616–2619 Serum levels of LH and testosterone are normal, but FSH is low or undetectable.2620 Clomiphene stimulation gives variable results, whereas the GnRH test induces only normal LH response.2621 Biopsy in puberty shows a reduced number of Sertoli cells, absence of germ cells, Leydig cell hyperplasia, and thickened basement membrane in

Fig. 12.275 Isolated deficiency of luteinizing hormone. Most seminiferous tubules have a central lumen, numerous spermatogonia, and increased number of Sertoli cells. Spermatocytes and spermatids are observed only in isolated tubules. The testicular interstitium lacks Leydig cells.

seminiferous tubules.2622 Biopsy in adults shows maturation arrest at the spermatocyte level, hypospermatogenesis, or partial Sertoli cell–only pattern.2623 Gonadotropin treatment increases spermatozoal numbers in most cases, and fertility may be induced after as little as 20 weeks of treatment.2624

Bioinactive Follicle-Stimulating Hormone and Luteinizing Hormone In addition to adequate hypothalamic function, spermatogenesis requires that FSH and LH be biologically active for adequate Leydig cell stimulation.2625,2626 LH is a heterodimer, composed of two subunits: α (common to FSH and LH) and β (specific for LH). The genes for the β subunit are on 19q13.32, close to another cluster of genes and pseudogenes that encode the hCGβ subunit. If both alleles are mutated, LH is biologically inactive, although it may be detectable in standard hormone assay. Homozygous patients have an elevated serum level of LH, normal FSH, and testosterone, failure of puberty, infantile testes, and infertility. Heterozygous patients are infertile but otherwise normal.2627 Patients with mutation in the β subunit of the FSH gene are oligozoospermic or azoospermic.2628 Low-bioactive FSH has been detected in patients with idiopathic oligozoospermia.2629 Mutations in Gonadotropin Receptor Genes Activating and inactivating mutations of gonadotropin receptor genes may occur.2630–2632 Activating mutation of the LH/hCG receptor gene causes familial precocious puberty (see earlier Familial Testotoxicosis section).690,2633 Complete inactivation of this gene by mutation results in a male with completely female phenotype secondary to poor differentiation and activity of Leydig cells (see Disorders of Sex Development (Leydig Cell Hypoplasia)). Partial LH/hCG resistance results in male phenotype with micropenis and hypospadias. Inactivating mutation of the FSHR gene produces only mildly impaired spermatogenesis, a finding emphasizing the limited role of FSH in spermatogenesis.1922 Activating mutation of this gene was reported in a patient who experienced panhypopituitarism after surgical removal and irradiation of pituitary adenoma. Despite low gonadotropin levels, the patient had a normal seminal study.2634

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Growth Hormone Deficit GH plays an important role in the development and functional maintenance of male and female reproductive systems.2635 Patients with GH deficit (isolated GH deficit, resistance to GH action, multiple hormonal pituitary deficiencies, or men with dwarfism such as the Laron type) may have delayed puberty and hypogonadotropic hypogonadism.2636,2637 Some patients with spermatogenetic maturation arrest or idiopathic oligozoospermia have relative deficit of GH.2638,2639 This hormone apparently directly stimulates Sertoli cells or Leydig cells to secrete IGFI, which likely stimulates spermatozoa maturation in a paracrine-autocrine way.2640 Prader-Willi Syndrome or Hypotonia-HypomentiaHypogonadism-Obesity Syndrome PWS or hypotonia-hypomentia-hypogonadism-obesity syndrome is characterized by hypogonadism, obesity, muscular hypotonia, mental and physical retardation, acromicria, and hyperphagia.2641 Other frequent findings include strabismus, non–insulindependent diabetes mellitus, hypothyroidism, and short stature.2642–2644 Symptoms begin during gestation, during which negligible fetal motility is seen. Difficulties in delivery and postnatal feeding have also been observed. The incidence is estimated at between 1 in 12,000 and 15,000 newborns, and is higher in boys (60% of cases). Most cases are sporadic, but familial inheritance has been reported.2645 In infants, there is a transient rise in postnatal testosterone levels that gives rise to “minipuberty,” but hereafter, delayed and incomplete puberty is the norm. During infancy the penis and testes may be either normal or hypoplastic, and cryptorchidism is present in approximately 70% of cases (bilateral in 45% of cases) (Fig. 12.276).2646–2648 Hypogonadism is present in 87% of adult patients with PWS and has classically been described as hypogonadotropic. However, hormonal data and biopsy findings suggest a special form of hypogonadism consisting of a combination of central and peripheral hypogonadism. Hormonal assays show low serum levels of LH, testosterone, estradiol, and B inhibin, whereas FSH is high.2649 Patients frequently have deficits in other hypophyseal hormones, findings in accord with the small size of the anterior pituitary.2650 At birth the gubernaculum shows altered concentrations of collagen and elastic fibers.2651 During infancy and childhood the testes have reduced tubular diameters for age, and spermatogonia are

Fig. 12.276 Testis from a 7-year-old child with Prader-Willi syndrome. The seminiferous tubules have a reduced diameter and lack germ cells.

scant or completely absent.2652,2653 Adult patients have small testes with infantile tubular diameters and common absence of spermatogonia.2654 Despite normal serum levels of FSH, Sertoli cells do not undergo pubertal maturation. This syndrome is caused by an anomaly of chromosome 15, usually in the 15p11-q13 band, a chromosomal region that contains the imprinted genes SNRPN, PAR1, PAR5, ZNF127, and IPW7. Cytogenetically, deletions in this region of chromosome 15 occur in 70% of patients.2655 These deletions always occur in the paternal chromosome.2656–2660 Chromosome 15 deletions are demonstrable either by G-banding techniques or fluorescence in situ hybridization.2661 Maternal uniparental disomy of chromosome 15 is observed in 25% of cases, and mutations altering the imprinting process are found in 5%.2662,2663 These latter mutations usually alter the small nucleolar ribonucleoprotein N gene (SNRPN gene) or involve translocations in chromosome 15.2664–2670 Diagnosis by molecular testing revealed that 17% of patients do not fulfill clinical criteria established in 1993. To avoid overdiagnosis, an adequate, age-related evaluation of the patient’s clinical symptoms is recommended when molecular techniques are not available.438,2671 Association of PWS and 47,XYY syndrome has been reported.2672

Bardet-Biedl Syndrome Bardet-Biedl syndrome (BBS), first described in 1920, is a pleiotropic disorder characterized by obesity (72% to 96%), mental retardation (>50%), postaxial polydactyly (69%), retinal dystrophy or retinitis pigmentosa (>90%), hypogonadism (98%), and renal structural abnormalities or functional impairment (100%).2673–2675 Expression and severity of the various clinical BBS features show interfamilial and intrafamilial variability.2676 The prevalence of BBS in Europe and North America varies from 1 in 125,000 to 175,000 newborns, and is markedly increased (1 in 13,500) in highly consanguineous Arab-Bedouin communities and in Newfoundland, Canada.2677 Mean age at diagnosis is 9 years, but BBS may be suspected in patients with associated polydactyly, precocious obesity, and hyperechogenic kidneys.2678 BBS is more frequent and severe in males. Men are infertile, and approximately 74% show hypogonadism that is usually characterized by cryptorchidism, which is found in 42% of male patients and is bilateral in 28%; hypoplastic or bifid scrotum; and small penis. Testes are prepubertal, in keeping with the hypothalamic origin of this hypogonadotropic hypogonadism.2679 However, three exceptions have been reported: (1) patient with normal serum testosterone, increased FSH, and tubular hyalinization and germinal aplasia; (2) patient with normal testosterone and gonadotropins, as well as germinal aplasia; and (3) patient who presented with delayed puberty, followed by hypogonadotropic hypogonadism that reversed, ending with normal gonadotropins and normal spermatogenesis.2680–2682 Patients are infertile except for isolated cases.2683 There is a high incidence of pituitary anomalies by MRI (63%) and hormonal derangements (45%). Prominent structural pituitary abnormalities include tumoral changes, hypoplastic hypophysis, and Rathke cleft cysts. Endocrinologic anomalies include delayed puberty, hypogonadotropic hypogonadism, GH deficiency, and hyperprolactinemia.2684 Mutations in 21 genes (BBS1 to BBS20 and NPHP1) have been cloned to date and are present in 70% to 80% of BBS-affected families.2685 In whites, mutations in BBS1 and BBS10 genes are responsible for 45% to 50% of cases.2686,2687 Mutated proteins in BBS are ones involved in regulation of microtubule-based

CHAPTER 12 Nonneoplastic Diseases of the Testis

transport processes and are included in the ciliopathy family of disorders that also includes Joubert syndrome and Meckel-Gruber syndrome.2688 Dysfunction of these proteins is responsible at least for the ocular and renal lesions.2678,2689–2698

683

inactivation of A-T mutated kinase, a critical protein kinase that regulates the response to DNA double-strand breaks by selective phosphorylation of a variety of substrates.2723 Friedreich Ataxia

Hypogonadotropic Hypogonadism Associated With Dermatologic Diseases Associations between ichthyosis, hypogonadism, epilepsy, mental retardation, dwarfism, and macrocytic anemia have been reported since 1927.2699 Inheritance is heterogeneous. Currently, several different ichthyosis types are recognized, each with its own characteristics.2700 Most cases of ichthyosis associated with hypogonadism are X linked. Approximately 15% of patients have cryptorchidism, small testes, micropenis, and a high risk for testicular cancer. The cause is a defective microsomal enzyme, steroid sulfatase, which catalyzes hydrolysis of several sulfated 3β-hydroxysteroids in fibroblasts, leukocytes, and keratinocytes. Hydrolysis causes accumulation of cholesterol sulfate that hinders sloughing of the cornified layer of the epidermis. The gene responsible for this enzyme is mapped to Xp22.3. The associated hypogonadism is usually hypogonadotropic. Some patients also have anosmia or hyposmia because involvement of adjacent genes causes a contiguous gene defect.2701–2703 Johnson-McMillin neuroectodermic syndrome is a rare autosomal dominant disorder characterized by alopecia, hypogonadotropic hypogonadism, anosmia or hyposmia, deafness, prominent ears, microtia, or atresia of the external auditory meatus, and pronounced tendency to dental caries. Both genders are affected.2704–2706 Hypogonadotropic Hypogonadism Associated With Ataxia Hypogonadism associated with ataxia is rare.2707–2709 Most are children from a consanguineous marriage. Inheritance is autosomal recessive.2710,2711 Patients show eunuchoidism, absence of secondary sex characteristics and libido, firm and small testes, and infertility.2712,2713 The most frequent syndromes are Louis-Bar syndrome (ataxia-telangiectasia) and Friedreich ataxia. Ataxia-Telangiectasia

Ataxia-telangiectasia is the most common inherited ataxia (autosomal recessive; 1 in 50,000), with an estimated carrier frequency of 1 in 110 in the European population. It is characterized by cerebellar ataxia that begins in infancy and develops progressively to include mucocutaneous telangiectasis, anomalies of the immune system that cause pulmonary infection, hypersensitivity to ionizing radiation resulting from impairment of DNA repair, and high risk for lymphoid neoplasia.2714 Immunologic anomalies involve both humoral and cellular immunity, and cause low T cell response to mitogens and antigens, decreased number of CD4 cells, increased numbers of γ-δ T cells, low serum levels of immunoglobulin A (IgA), IgE, and often IgG, and elevated IgM.2715–2718 Bronchiolitis obliterans is the most characteristic disease resulting from the immunologic impairment.2719 Cytomegalic cells with telescoped nuclear inclusions have been observed in the pituitary. This disorder starts with progressive gait and limb ataxia; symptoms begin before 25 years of age. Other symptoms are loss of vibration and position sense, areflexia, dysarthria, skeletal abnormalities, and hypertrophic cardiomyopathy that frequently leads to precocious death.2720 Gonadal alterations are more important in females and are manifest by precocious puberty and early menopause.2721 The gene responsible is on 11q22-q23.1.2722 Ataxia results from

Friedreich ataxia is a neurodegenerative disorder characterized by degeneration of dorsal root ganglia and spinocerebellar tracts.2724 Its onset typically occurs during childhood or adolescence.2725 The disease is characterized by gait and limb ataxia, dysarthria, usually absent tendon reflex, bilateral Babinski sign, impairment of position and vibratory senses, scoliosis, pes cavus, and a high incidence of hypertrophic cardiomyopathy. The incidence is estimated at 1 in 40,000 children.2726 Symptoms and the rapidity of disease development vary even within members of the same family. The associated hypogonadism is usually hypogonadotropic, although cases of hypergonadotropic hypogonadism have also been reported. This syndrome is the first trinucleotide disease with autosomal recessive inheritance. It is caused by defects in the FXN gene, which encodes a 210-amino acid mitochondrial protein that is a precursor of frataxin.2727 FXN mRNA levels in these patients are reduced to 13% to 30% and to 40% in carriers. The residual level of frataxin protein in patients with this disorder varies between 5% and 30% of normal levels, whereas healthy heterozygous carriers express more than 50% of normal frataxin levels.2728,2729 Frataxin deficiency causes a range of metabolic disturbances, which include oxidative stress, deficit of iron–sulfur clusters, and defects in heme synthesis, sulfur amino acid and energy metabolism, stress response, and mitochondrial function.2730 Mitochondrial iron deposition in the heart usually accompanies hypertrophic cardiomyopathy, the main cause of death.2731 Approximately 95% of patients are homozygous for unstable trinucleotide (GAA) expansion located in the first intron of the FXN gene on chromosome 9q13.2732 The normal gene has up to 35 or 40 triplet repeats, whereas patients with ataxia carry 70 to more than 1000 GAA triplets.2733 Extent of the expanded allele is directly proportional to severity of disease, early onset, and development of cardiac abnormalities.2734 Other ataxias associated with hypogonadism are Kearns-Sayre (see later), Boucher-Neuh€auser, and GordonHolmes syndromes. Boucher-Neuh€ auser Syndrome

Characteristics of the autosomal recessive Boucher-Neuh€auser syndrome are cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy.2711,2735,2736 Boucher-Neuh€auser syndrome is caused by mutations in the PNPLA6 gene.2737 A characteristic finding in these patients is the occurrence of hypersegmented neutrophils. Although this finding is frequent in other processes, it may be useful to support the diagnosis in the presence of other symptoms suggestive of Boucher-Neuh€auser syndrome.2738 Gordon-Holmes Syndrome

Gordon-Holmes syndrome is characterized by progressive cerebellar ataxia and hypogonadotropic hypogonadism. This rare autosomal recessive disorder was first recognized more than 100 years ago. The genetic causes of this syndrome are biallelic inactivating mutations in the RNF216 gene or the combination of deleterious mutations in RNF216 and OTUD4 genes.2739 GnRH pulsatile administration does not increase gonadotropins because of a hypothalamic defect.2740 However, treatment with exogenous gonadotropins is efficacious in establishing spermatogenesis.2741

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Carpenter Syndrome

The autosomal recessive disorder Carpenter syndrome, also known as acrocephalopolysyndactyly type II, was first reported in 1901.2742 Carpenter syndrome is characterized by craniosynostosis, peculiar facies, prolonged retention of primary teeth or hypodontia, brachysyndactyly of fingers, preaxial polydactyly, syndactyly, congenital heart disease, obesity, mental retardation, umbilical hernia, cryptorchidism, and hypogonadism.2743,2744 The disorder is caused by mutations in the RAB23 gene, which encodes a member of the RAB-family of small guanosine triphosphatase involved in vesicle trafficking.2745,2746 Biemond Syndrome

Biemond syndrome is characterized by hypogonadotropic hypogonadism, coloboma of the iris, short stature, severe mental retardation, and postaxial polydactyly.2746a This is one of the syndromes included in retinal ciliopathies.2746b Fraser Syndrome (Meyer-Schwickerath Syndrome or UllrichFeichtiger Syndrome)

Fraser syndrome is an inherited autosomal recessive multisystemic disorder first reported in 1962.2747 Its incidence is estimated to be 0.43 in 100,000 live-born infants and 11 in 100,000 stillbirths.2748,2749 The syndrome is characterized by unilateral or bilateral cryptophthalmus, facial anomalies (abnormal hairline, coloboma of alae nasi, midfacial cleft, cleft lip and palate, ankyloglossia, small ears), conductive hearing loss, syndactyly, umbilical hernia, cryptorchidism, and hypogonadotropic hypogonadism.2750 It is genetically heterogeneous, and three genes are involved: FRAS1 on 4q21.21, FREM2 on 13q13.3, and GRIP1 on 12q14.3. In 50% of cases, a causative mutation is detected. Approximately one-half of the families with Fraser syndrome carry mutations in the FRAS1 gene on chromosome 4, and the remainder have about an equal incidence of mutations in the other two genes.2751,2752 FRAS1 and FREM proteins are expressed on the basal surface of epithelial cells in many embryonic tissues and contribute to embryonic epithelial-mesenchymal integrity. Its function is replaced once terminated in embryogenesis by type VII collagen.2753

Hypogonadism Secondary to Endocrine Gland Dysfunction and Other Disorders Maintenance of spermatogenesis requires synchronous actions of several endocrine glands and proper functioning of other tissues. Although only 2% of infertile men have stigmata of endocrinopathy, more than 9% have abnormal endocrine studies.2754 Hypogonadism may be present in disorders involving the hypothalamushypophysis, thyroid, adrenals, pancreas, liver, kidney, and gastrointestinal tract, and may be associated with AIDS, chronic anemia, obesity, starvation, inherited metabolic diseases, and neoplasia. Hypogonadotropic hypogonadism may also be found in some patients (especially women) who perform rigorous sports (longdistance runners, swimmers, dancers, and rhythmic gymnasts).2518

Hypothalamus-Hypophysis Hypopituitarism

Hypogonadism may result from destruction of the hypothalamus or hypophysis caused by primary or secondary hypothalamic tumor; granulomatous disease (histiocytosis X or Langerhans cell histiocytosis) (Figs. 12.277 and 12.278); fracture of the cranial

Fig. 12.277 Frontal section from an 18-year-old patient showing destruction of the hypothalamus caused by Langerhans cell histiocytosis.

Fig. 12.278 Langerhans cell histiocytosis X with hypothalamic affectation. A severe infiltrate with large cells with grooved nuclei and abundant eosinophilic leukocytes may be observed.

base; radiation therapy for malignancy of the nasopharynx, central nervous system, or orbit; pituitary adenoma (Fig. 12.279) and cyst; aneurysm of the internal carotid artery; and chronic and nutrition disease. Many of these processes cause panhypopituitarism with varied symptoms, and sometimes lead to a selective decrease in secretion of LH and FSH.2755–2757 Clinical manifestations of hypogonadism in patients with pituitary lesions vary according to the time of onset (childhood or after puberty).2758 In prepubertal hypopituitarism the testes retain an infantile appearance into adulthood. Proliferation of spermatogonia and development of primary spermatocytes are rare. Biopsy shows variable hyalinization of tubules. In postpubertal hypopituitarism, there is a decrease in ejaculate volume and testicular volume, as well as low testosterone, FSH, and LH levels. Histology ranges from complete spermatogenesis to tubular hyalinization (Fig. 12.280). The presence of elastic fibers in tubular walls indicates that pubertal maturation occurred before the development of hypopituitarism. Leydig cells have pyknotic nuclei and retracted cytoplasm with abundant lipofuscin.2756 In some patients, recovery of spermatogenesis occurs after administration of hCG.2759 In

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abnormal PRL secretion have been reported in boys: one is characterized by hyperprolactinemia, testicular enlargement, and primary hypothyroidism; the other consists of PRL deficiency, obesity, and enlarged testes.621,2766–2769 In adults, testicular hypertrophy may also be secondary to FSH-secreting pituitary adenoma.2770

Fig. 12.279 Radiologic image of a pituitary macroadenoma showing important enlargement of sella turcica.

Fig. 12.280 Tubular hyalinization caused by hormonal deprivation and decreased Leydig cell number in a 28-year-old patient who underwent surgery because of pituitary adenoma. The seminiferous tubules contain dedifferentiated Sertoli cells and isolated spermatogonia.

some cases, pituitary adenoma secretes FSH and LH, thus inducing testosterone hypersecretion and elevated sperm count.2760 A significant number of patients have macroorchidism. Testicular enlargement is due to an increase in the length of the seminiferous tubules.618,641 Hyperprolactinemia

PRL inhibits GnRH secretion and hence FSH and LH secretion. In addition, PRL has a direct inhibitory effect on androgens in target tissues. In men, hyperprolactinemia causes impairment of spermatogenesis, impotence, loss of libido, and depressed serum testosterone.2761 Some patients seek treatment because of oligozoospermia and infertility. Hyperprolactinemia is also associated with dysfunction of PRL receptors.2762 The spermiogram usually shows oligozoospermia and an elevated level of fructose, although not all male patients with hyperprolactinemia have subnormal testicular function.2763,2764 Biopsy reveals variable testicular atrophy. The most frequent lesion is in the tubular adluminal compartment, with degenerative changes in the apical cytoplasm of Sertoli cells, sloughing of young spermatids, and increased lipid droplets in Leydig cells.2763,2765 In addition to prolactinoma, two other conditions associated with

Thyroid Gland Thyroid hormone plays an important role in testicular development and function by influencing steroidogenesis and spermatogenesis, mainly in infancy. Triiodothyronine (T3) is involved in control of Sertoli cell proliferation and functional maturation, as well as postnatal Leydig cell differentiation and steroidogenesis.2771 Infertility caused by thyroid gland malfunction is rare but reversible. It accounts for approximately 0.5% of cases of male infertility. Testicular function is impaired more by hypothyroidism than by hyperthyroidism. Patients with hyperthyroidism may have gynecomastia, impotence, and infertility. Levels of FSH and LH in serum are normal or increased, with elevated SHBG, increased testosterone concentration, reduced non-SHBG–bound testosterone, and little or no change in free testosterone.2772,2773 Patients with Graves disease have pronounced inhibition of gonadal steroidogenesis.2774 In patients with hyperthyroidism, spermatozoa may be normal or reduced in number, and progressive motility is low. Primary hypothyroidism in adults causes hypergonadotropic, hypogonadotropic, or normogonadotropic hypogonadism, but testicular function is rarely impaired, and patients are usually fertile.2775,2776 The cause of testicular damage is decreased gonadotropins or hyperprolactinemia.2777 Congenital central hypothyroidism is characterized by impaired secretion of TSH, which may or may not be accompanied by impaired secretion of other pituitary hormones. Testes are small. A form of central X-linked congenital hypothyroidism known as immunoglobulin superfamily member 1 (IGSF1) deficiency syndrome characterized by loss-of-function mutations in the IGSF1 gene apart from hypothyroidism shows variable prolactin deficiency, occasional GH deficiency, and, frequently, macroorchidism.636 Prepubertal hypothyroidism may impair function by causing precocious or delayed puberty. In delayed puberty, hypothyroidism leads to hypogonadotropic hypogonadism, with testes showing incomplete maturation arrest and hydrocele in severe myxedematous hypothyroidism.623 In experimental hypothyroidism, enlargement is frequently associated with increased spermatid production.2778a Children with hypothyroidism usually have precocious pseudopuberty, and frequently have testicular enlargement without virilization.619,2778 Approximately 80% have macroorchidism, most have increased FSH level, and 50% have elevated LH level.620,621,2779 Testosterone level is normal during infancy. Prepubertal biopsy shows accelerated development with pubertal maturation of seminiferous tubules, but not Leydig cells. Testicular size in this type of macroorchidism diminishes as soon as substitutive therapy starts.620,626,627 Etiopathogenesis is based on three hypotheses: increase in gonadotropin secretion caused by TRH stimulation of gonadotropic cells, direct TSH effect resulting from structural similarity between TSH receptors and FSHRs present in the testis, and lack of steroid hormones required for testicular maturation (in their absence Sertoli cell proliferation is excessive, giving rise to testicular enlargement).628–630,632–635 Adrenals Adrenal disorders most frequently associated with infertility are adrenal hypoplasia, adrenal hyperplasia, Cushing syndrome (CS), and adrenal cortical tumors.

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Congenital Adrenal Hypoplasia With Hypogonadotropic Hypogonadism

Congenital adrenal hypoplasia with hypogonadotropic hypogonadism, first reported in 1975, is an X-linked recessive disorder that gives rise to adrenal insufficiency in the first months of life with symptoms such as delayed growth, poor feeding, vomiting, weight loss, muscular weakness, and lethargy: all symptoms run parallel to involution of the fetal adrenal cortex.2780,2781 The disorder is also characterized by cryptorchidism and delayed puberty.2782,2783 This rare disorder is caused by mutations or complete deletion of the NROB1 gene that encodes the DAX-1 protein. The responsible gene, DAX1 on Xp21, is expressed in the adrenals, testes, pituitary, and hypothalamus.2784 DAX-1 protein has 470 amino acids, and the N-terminal portion contains four incomplete repeats of a new structural motif encoding DNA-binding function. The Cterminal half of the protein has high homology with the ligandbinding domain (E domain) of the nuclear hormone receptor superfamily, especially with the E domain of the retinoid x receptor and orphan receptor subfamily.2785 Most patients have deletions or point mutations of DAX-1.2786-2789 Large mutations may also alter genes located next to DAX-1. This could explain the association of congenital adrenal hypoplasia with hypogonadotropic hypogonadism and Duchenne muscular dystrophy, glycerol kinase deficiency, short stature, and psychomotor delay.2790,2791 The resulting hypogonadism may be either pure or mixed (hypophyseal and testicular). In the mixed form, hypogonadism is partial.2789 In some patients the cause of hypogonadism seems to be pituitary failure because levels of FSH, LH, and testosterone are low, and FSH and LH increase in response to GnRH stimulation.2792,2793 Other patients present with mixed and partial hypogonadism, both pituitary and testicular; basal levels of FSH and LH are normal or high, and do not increase after GnRH stimulation.2794 It is conceivable that, during the first years of life, the hypothalamohypophysealtesticular axis acts properly.2795 Then, at the onset of puberty, transient hypergonadotropic hypogonadism occurs, and in adulthood, hypogonadotropic hypogonadism is established.2796,2797 Cases of precocious puberty with testicular and penile enlargement likely secondary to persistent ACTH stimulation have been reported.2798,2799 Autopsy studies of infants who died with congenital adrenal hypoplasia suggest that adrenal lesions are like those of the so-called fetal or cytomegalic form of adrenal hypoplasia.2800 The adrenal glands are small and have abnormal architecture. The adrenal cortex is poorly developed, and no clear distinction between the zona glomerulosa and zona fasciculata may be established. Adrenal cortical cells are abnormally large and pleomorphic.2801 Most adult patients have azoospermia or oligozoospermia. Biopsy from one of our adult patients (Fig. 12.281) demonstrated lesions that suggested primary testicular alteration consisting of seminiferous tubules with only dysgenetic Sertoli cells, together with tubules showing spermatogonial maturation arrest, as well as hypertrophy and hyperplasia of Leydig cells (Fig. 12.282).2802–2804 Exogenous gonadotropin treatment is ineffective in reestablishing spermatogenesis.2805 Congenital Adrenal Hyperplasia

Infertility is common in patients with minor forms of congenital adrenal hyperplasia (Fig. 12.283), and these patients often seek consultation regarding infertility. Most patients present with a deficiency of 21-hydroxylase or 11β-hydroxylase.2806 In untreated patients, the testes become enlarged by testicular adrenal rest

Fig. 12.281 Congenital adrenal hypoplasia with hypogonadotropic hypogonadism treated. Seminiferous tubules lacking lumen with only Sertoli cells.

Fig. 12.282 Congenital adrenal hypoplasia with hypogonadotropic hypogonadism treated. Leydig cell hyperplasia; many cells have vacuolated cytoplasm.

tumors (TARTs), the so-called tumors of the adrenogenital syndrome first described in 1940 (Figs. 12.284 through 12.288).2807–2811 Some TARTs are palpable, but others require ultrasonographic or MRI studies for detection. Grossly the tumors consist of well-delimited, but not encapsulated, yellow nodules, up to several centimeters in greatest dimension located in the parenchyma. They are composed of large, microvacuolated cells that are similar to cells that comprise Leydig cell tumors. Distinction of TART from Leydig cell tumor may be difficult (Table 12.26).2812 Although CD56 immunoexpression has been reported to be diffuse and strong in tumors of adrenogenital syndrome and focally weak to moderate or negative in Leydig cell tumors, this finding is inconsistent and unreliable.2813 Delta-like 1 homolog (DLK1) is expressed in TART, whereas INSL3 is expressed in Leydig cell tumors.2814 Patients seeking consultation for infertility present with oligospermia (60%) or azoospermia (40%). Parenchyma shows complete spermatogenesis with reduced numbers of all germ cells. The characteristic histologic finding is decreased number of Leydig

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Fig. 12.283 Congenital adrenal hyperplasia. Adrenal gland with cerebroid surface.

Fig. 12.284 Tumor of the adrenogenital syndrome in an adult patient. Nodules in testicular mediastinum protruding into rete testis cavities.

Fig. 12.285 Tumor of the adrenogenital syndrome in an adult patient. Trabeculae of tumoral cells with spheric nuclei separated by thick hyalinized conjunctive tracts.

cells.2807–2810 Infertility has been explained by: (1) hypogonadotropic hypogonadism, because the high levels of adrenal androgens would be aromatized to estrogens either peripherally or in the central nervous system, and thus suppress gonadotropin secretion; and (2) rete testis obstruction by tumor nodules.2815,2816

Fig. 12.286 Tumor of the adrenogenital syndrome in an adult patient. Tumoral cells with severe pleomorphism and granular eosinophilic cytoplasm. Surrounding seminiferous tubules show variable grades of spermatogenesis.

Fig. 12.287 Tumor of the adrenogenital syndrome in an adult patient. Tumoral cells show CD56 immunoexpression, typically in basal membrane and peripheral cytoplasm.

Treatment with glucocorticoid therapy corrects adrenal insufficiency and, in many cases, improves the spermiogram by decreasing nodule size. If treatment fails to diminish TART size, testis-sparing surgery may be performed, but it is not always successful in improving function.2817

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Fig. 12.288 Tumor of the adrenogenital syndrome in an adult patient. Tumoral cells do not show immunoreactivity for androgen receptors, contrasting with intense expression in Sertoli cells of adjacent seminiferous tubules.

Deficit in 17β-Hydroxylase. The enzyme 17β-hydroxylase

transforms 12-hydroxyprogesterone and 11-deoxycortisone (also known as deoxycorticosterone) into cortisone. Enzyme deficiency results in increased levels of deoxycorticosterone, which leads to water and salt retention, renal activity suppression, decreased aldosterone secretion, and hypertension in one-half of affected patients. The high concentration of ACTH stimulates testosterone precursors and gives rise to virilization. In some cases, virilization is not evident before puberty. Testes show the same alterations as in patients with 21-hydroxylase deficit.2810,2818 Deficit in 20α-Hydroxylase. 20α-Hydroxylase deficiency, also known as Prader syndrome or lipoid congenital adrenal hyperplasia, results in defective conversion of cholesterol to 20α-cholesterol, resulting in deficiency in all three types steroid hormones that are synthesized by the adrenal gland and testes. External genitalia are female. Histologic study of the testes and adrenals reveals excessive lipid deposits. Affected patients typically have short a life span despite adequate treatment.

TABLE 12.26

Deficit in 3β-Hydroxysteroid Dehydrogenase. 3βHydroxysteroid dehydrogenase is an enzyme that converts pregnenolone to progesterone, 17-OH-pregnenolone to 17-OHprogesterone, and DHEA to androstenedione in the adrenal glands and gonads. Deficiency of this enzyme hinders formation of cortisol, aldosterone, and testosterone.2819,2820 Patients have salt-loss syndrome and ambiguous external genitalia. Gynecomastia develops at puberty, probably because of lack of testosterone during fetal life, resulting in failure of inhibition of the mammary anlage.2821 Steroid 17α-Hydroxylase Deficiency. Deficiency of 17αhydroxylase (CYP17A1, also known as P450c17) accounts for 1% of cases of congenital adrenal hyperplasia. CYP17A1 catalyzes two different paths in the steroidogenesis pathway: 17α-hydroxylase and 17,20-lyase.2822 CYP17A1 deficiency results in hypermineralocorticoidism and low androgen level. The low androgen level results in ambiguous external genitalia. At puberty, adequate virilization does not occur, patients experience development of hypergonadotropic hypogonadism, and gynecomastia is frequent.2823 Cushing Syndrome

Physiologic levels of glucocorticosteroids are necessary for maintenance of gonadal function. Patients treated with long-term corticoid therapy, such as those with Crohn disease, Cushing disease, ulcerative colitis, rheumatoid arthritis, or asthma, may have reduced fertility (Fig. 12.289). The mechanism by which corticosteroids act is twofold. First, they induce an inhibitory effect on the hypothalamic–pituitary-gonadal axis through direct or indirect action on synthesis and release of GnRH, LH, and FSH. Second, they are powerful inhibitors of testosterone synthesis because most testicular receptors for corticoids are in Leydig cells. CS may be endogenous or exogenous. Endogenous CS has adrenocorticotropic hormone (ACTH)-dependent and ACTHindependent causes. ACTH-dependent CS results from either ACTH-secreting adenoma or ectopic ACTH syndrome. ACTHsecreting adenoma is the most frequent cause of endogenous CS in children older than 5 years and adolescent boys, comprising 75% to 80% of pediatric cases. Ectopic ACTH syndrome is rare in children; it may occur in those with carcinoid tumor in different locations, clear cell sarcoma, malignant neuroendocrine tumor of

Differential Diagnosis of Tumors of the Adrenogenital Syndrome and Leydig Cell Tumor

Gross Features

Bilaterality

Location

Trabeculae

Reinke Crystals

Tumors of the adrenogenital syndrome

Multiple extratesticular frequent

Usually

Adjacent to rete testis

Frequent

No

Leydig cell tumor

Single

Rarely

No preference

Infrequent

40%

Immunology CD56 + Synapto +++ AR AR + DLK1 +++ INSL3 CD56 + Synapto + AR +++ DLK1 INSL3 +

AR, Androgen receptor; Synapto, synaptophysin. Findings without value in the differential diagnosis: adipose metaplasia, osseous metaplasia, lymphocyte infiltrate, or lipofuscins.

Regression After Dexamethasone Treatment

Association

Decrease

Congenital adrenal hyperplasia

No regression

Precocious pseudopuberty

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In adults, adrenal carcinoma may cause marked reduction in fertility as a result of conversion into estrogen of large amounts of DHEA produced by the tumor. Feminizing tumor has striking clinical manifestations because of elevated estrogen, including progressive loss of male secondary sexual characteristics and gynecomastia. Testicular atrophy results from the inhibitory effect of estrogen on pituitary gonadotropins. Similar symptoms may be observed in patients with prostatic adenocarcinoma treated with estrogens or those receiving long-term estrogen therapy for gender change, as well as in other conditions with excessive estrogen production such as Sertoli cell or Leydig cell tumor.2837 Primary Pigmented Adrenocortical Disease

Fig. 12.289 Patient with rheumatoid arthritis treated with corticoids for several years. The seminiferous epithelium is reduced to Sertoli cells of vacuolated cytoplasm and spermatogonia. The tubular wall is thickened. Leydig cells show signs of atrophy.

the pancreas, Wilms tumor, adrenal neuroblastoma, and pheochromocytoma.2824 Median age at presentation is 9.5 years. ACTH-independent CS is produced by adrenocortical tumor (adenoma and carcinoma) and primary bilateral adrenal hyperplasia (micronodular and macronodular). Exogenous CS is caused by long-term glucocorticoid therapy (e.g., treatment of asthma, eczema, and arthritis).2825 To avoid negative effects on fertility, administration should be limited in time and restricted to the acute stage of disease. Adrenal Cortical Tumors

Adrenal carcinoma is often associated with excessive secretion of hormones that cause hyperaldosteronism, CS, virilization, or feminization. Virilizing tumors in infancy have their own characteristics that differ from those of the same tumors in adults. The infantile form may be associated with other disorders, such as hemihypertrophy and Beckwith-Wiedemann syndrome, and may be included in the spectrum of families with cancer predisposition as a result of abnormalities in genes that encode transcription factors implicated in cell proliferation, differentiation, senescence, apoptosis, and genomic instability. Less than 10% of pediatric adrenal cortical tumors occur in Li-Fraumeni syndrome.2826,2827 Disorders in which adrenal cortical tumors may be observed include multiple endocrine neoplasia type I (mutations in the MEN1 gene), familial adenomatous polyposis (mutations in APC gene), Beckwith-Wiedemann syndrome (deregulation of imprinted genes in the 11p15.5 chromosomal region), Carney complex (mutations in PRKAR1A), and MAS (mutations in the GNAS1 gene).2828–2830 Most adrenal tumors are clinically benign. The differential diagnosis between adenoma and carcinoma may be difficult even for an experienced pathologist.2831 Both tumors may be hormonally active, thus giving rise to hyperaldosteronism, CS, virilization, or feminization. Tumors secreting androgens and cortisol simultaneously are frequent. Virilizing tumors produce precocious pseudopuberty in infancy.2832 Feminizing tumors in infancy produce gynecomastia and pubic hair development.2833,2834 Even small tumors may produce significant clinical manifestations.2835 Onethird of pediatric patients have hypertension.2836

Primary pigmented adrenocortical disease represents 10% of cases of ACTH-independent CS. Two types are distinguished clinically and histopathologically: bilateral micronodular and macronodular adrenal hyperplasia. Primary pigmented nodular adrenocortical disease is an infrequent form of bilateral micronodular hyperplasia characterized by the presence of multiple, small (from submicroscopic to 10 mm in diameter), unencapsulated cortical nodules. These nodules, usually black and brown, are formed by large cells with abundantly pigmented eosinophilic cytoplasm. The internodular cortical tissue is usually atrophic. Half of patients with primary pigmented adrenocortical disease have familial association with Carney complex, an autosomal dominant multiple neoplasia syndrome characterized by cardiac myxoma, spotty skin pigmentation, and endocrine overactivity.2838 The presence of testicular tumor in Carney complex, mainly large cell calcifying Sertoli cell tumor, is a well-known feature.2839 Adrenocorticotropic Hormone–Independent Macronodular Adrenal Hyperplasia

CS in MAS often occurs in the first year of life, is ACTH independent, and may spontaneously resolve.2840 ACTH-independent macronodular adrenal hyperplasia, a rare condition that occurs in children, consists of massive enlargement of both adrenal glands and is frequently associated with hypogonadism and gynecomastia in boys.2841,2842 When adrenal hyperplasia develops in MAS (adrenocortical hyperplasia associated with MAS), it has an aggressive course and frequently requires unilateral or bilateral adrenalectomy.2843,2844

Pancreas Diabetes Mellitus

Alterations in carbohydrate, lipid, and protein metabolism characteristic of diabetes mellitus adversely affect the genital system, although most patients with diabetes are fertile. Gonadal impairment depends on the type of diabetes and time of disease onset (infancy and childhood, puberty, or adulthood).2845,2846 Even the newborn of a diabetic mother has a high mortality rate; there is typically Leydig cell hyperplasia in the fetal testis.249 Puberty may be delayed in patients with diabetes, although the cause is unknown. Other gonadal alterations appear at puberty, and men with diabetes who have not been adequately treated may be infertile and have sexual dysfunction. Serum levels of FSH, LH, and testosterone are decreased, and spermatozoan mitochondrial function is abnormal.2847–2849 Spermiograms reveal low number and progressive decline in motility of spermatozoa.2850 PRL levels are increased, and testosterone level is low or nearly normal. Seminiferous tubules have reduced diameter, thickening of the lamina propria, and alterations in the adluminal compartment

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consisting of degenerative changes in the Sertoli cell apical cytoplasm and sloughing of immature germ cells. The major lesions are in the interstitial connective tissue and Leydig cells. Small interstitial blood vessels show diabetic microangiopathy characterized by enlargement and duplication of the basal lamina, pericyte degeneration, and endothelial cell alterations. There is an increase in the number of fibroblasts and amount of collagen and intercellular matrix in the interstitial connective tissue.2851 Leydig cells are decreased in number and contain an abundance of lipid droplets and lysosomes. Tubular lesions are attributed to low serum testosterone level, probably because of deficient Leydig cell stimulation by insulin (or a decrease in insulin-dependent FSH) and abnormal carbohydrate metabolism of Sertoli cells. Sexual dysfunction is present in more than one-half of patients, who complain of impotence, decreased libido, disorders of intercourse, and retrograde ejaculation.2852 Hypogonadotropic hypogonadism has been associated with obesity, but not duration of diabetes, elevated glycosylated hemoglobin, or the presence of microvascular lesions.2853 Causes of impotence are multiple, including microangiopathy and macroangiopathy, hormonal deficiencies, psychological factors, and autonomic neuropathy affecting the parasympathetic system. Neuropathy is probably chiefly responsible for erectile failure in men with diabetes.2854 Alterations in sperm excretory ducts may be associated with diabetes. The most frequent are enlargement and calcifications of seminal vesicles and vasa deferentia. Calcifications are found in the muscular layers and display a concentric arrangement (Fig. 12.290).2855 Mucoviscidosis

The principal symptoms of mucoviscidosis, also called cystic fibrosis (CF), are progressive chronic pulmonary disease, pancreatic insufficiency, and increased level of chlorine in sweat. Although CF was recognized before 1940, its effects on the male genital system were not recognized until the 1970s.2856,2857 This may be explained by improvements in medical care during childhood that allowed survival of many patients to adulthood and recognition of CF in patients who had been diagnosed with chronic bronchitis and hepatic or digestive dysfunction. In the United States, CF is the most lethal congenital disease, with a prevalence of 1 in 2500 children and carrier status of 1 in 25 white men.2858 In some countries

Fig. 12.290 Patient with diabetes with dystrophic calcification in the ductus deferens muscular wall.

such as Japan, this disease is extremely rare.2858a Lesions in sperm excretory ducts involve (in decreasing order of frequency) the vas deferens (congenital bilateral absence, unilateral absence), ejaculatory ducts (bilateral obstruction), epididymis (diffuse or segmental hypoplasia), and seminal vesicles (incomplete development). The most proximal part of the epididymis is usually present.2859,2860 Thus most patients with CF (99%) are infertile owing to obstructive azoospermia.2861,2862 Most patients with CF have congenital bilateral absence of the ductus deferens, sometimes associated with agenesis or atresia of the epididymis and seminal vesicles. Those with congenital bilateral absence of the ductus deferens, even without other characteristic symptoms of CF, are usually carriers of a minor form (genital form) of CF.2863 Before initiating treatment for infertility, the possibility that the patient is a carrier of the CF gene should be evaluated.2864,2865 The second most frequent presentation of CF is unilateral absence of the ductus deferens, although this disorder may also appear without CF. The third presentation, in order of frequency, comprises a group of healthy infertile patients with abnormal seminal parameters or nonobstructive azoospermia. These patients have an increased frequency of cystic fibrosis transmembrane regulator (CFTR) mutations, with an incidence rate of 17% versus 1% to 4% in the general population.2866 The possibility of this form of CF should be considered during genetic counseling in patients who desire ICSI.2867 Malformation of the genital system plays the most important role in infertility in CF.2868 Lesions begin in the 10th week of gestation when the wolffian duct forms the sperm excretory ducts.2857 Variable penetrance of the CF gene accounts for the diversity of malformations affecting different regions of the male genital system. Whether the lesions of sperm excretory ducts correspond to agenesis or atresia remains controversial. The finding that 12to 18-week aborted fetuses with CF show ductus deferens, as well as ultrasonographic assessment of the presence of sperm excretory ducts in many infants, supports the hypothesis that initial normal development is interrupted by accumulation of inspissational secretions in the lumina of the ducts and culminates in atresia.2869 This process of atresia may be of early onset in some patients and is found at birth in some newborn autopsies. As a result, epididymides are small, ductus deferentia are only epithelial cords, and the walls contain only some rings of loose connective tissue. Testicular development in patients with CF is often delayed at puberty. Histologic studies in children reveal that the vas deferens and ductus epididymis are absent or reduced to small ductuli with reduced or absent lumina and thin, poorly muscularized walls (Fig. 12.291). The testes are normal during childhood, but show hypospermatogenesis and spermatid malformations by adulthood (Fig. 12.292). The spermiogram is characteristic of obstructive azoospermia, with acid pH, decreased semen volume and fructose concentration, and increased citric acid and acid phosphatase.2870 In adulthood, slight diminution of testicular size occurs, although some degree of spermatogenesis is maintained. Most testes show tubular ectasia with minimal lesions of the adluminal compartments. These lesions are probably secondary to obstruction, which may be superimposed on those derived from chronic nutrition deficiency. Whether these secondary lesions are superimposed on primary lesions of spermatogenesis has been debated because the CFTR protein also plays a role in spermatogenesis and sperm maturation.2866 Given that the median life expectancy of patients with CF is approximately 40 years, some patients desire assisted reproductive techniques, and it is mandatory that they receive appropriate genetic, medical, and psychological counseling.2860,2871

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Liver The liver has a primary role in metabolism, detoxification, and excretion of sex steroid hormones. Chronic hepatic failure damages the hypothalamohypophyseal-testicular axis and consequently all related endocrine glands. Hypogonadism is frequent in the final stages of severe chronic liver diseases, including alcoholism and nonalcoholic fatty liver diseases. Hypogonadism, Liver Disease, and Excessive Alcohol Consumption

Fig. 12.291 Epididymis in cystic fibrosis. Sections of the ductus epididymidis show decreased lumen diameter with surrounding concentric rings of loose connective tissue.

The association of atrophy with gynecomastia and hepatic cirrhosis is referred to as Silvestrini-Corda syndrome.2874,2875 Alcohol has a direct toxic effect on Leydig cells. Acute alcoholic intoxication suppresses serum testosterone level in male nonalcoholic volunteers and laboratory animals. Long-term alcohol ingestion, even in the absence of cirrhosis, causes hypogonadism, with symptoms of Leydig cell failure, including testicular atrophy, infertility, decreased libido, impotence, and reduced size of the prostate and seminal vesicles.2876 Patients with chronic alcoholism with cirrhosis also have symptoms of hyperestrogenism, including gynecomastia, female escutcheon, and female fat distribution pattern. Most men with chronic alcoholism, with or without cirrhosis, have significant testicular lesions. Seminiferous tubules have reduced diameters, thickened lamina propria, and decreased or absent germ cells. Leydig cells are reduced in number and contain abundant lipofuscin granules (Fig. 12.293). The epididymis becomes atrophic, mainly in the ductuli efferentes, as a result of androgen deprivation. The epithelium of the rete testis becomes cuboidal or columnar in response to estrogens. The spermiogram correlates with variability of histologic findings, and usually shows marked reduction in number and motility of spermatozoa and increase in the percentage of morphologically abnormal spermatozoa.2877,2878 Approximately 20% of patients initially have an elevation in serum testosterone; with advanced disease, testosterone level decreases. The initial increase is caused by an elevation in SHBG concentration and reduced testosterone metabolism by the liver.2879 Serum estrogen level also increases because of increased conversion of testosterone to estrogen in peripheral adipose and muscular tissue.2880

Fig. 12.292 Patient with cystic fibrosis and obstructive azoospermia. The seminiferous tubules show only slight ectasia.

The disease is a genetic disorder with autosomal recessive inheritance. The impaired gene (the CF gene) is on chromosome 7 (7q31), consists of 27 exons, and encodes the 1480-amino acid CFTR protein.2872 In CF the deficiency results from mutations altering CFTR gene function. More than 1500 CF-causing CFTR mutations have been identified.2872a The most frequent mutation in whites is D-F508, caused by deletion of Phe-508 and responsible for 70% of cases. The protein product controls chlorine ion flux throughout the plasma membrane and plays an important role in hydration of epithelial secretions.2873 The epithelia showing absence or dysfunction of CFTR are impermeable to chlorine ions. Secretions subsequently become thick and sticky, producing obstructions in the excretory ducts of many glands (respiratory tract, pancreas, sweat glands), as well as in the developing sperm excretory ducts, such as the ductus epididymis and ductus deferens.2864 Patients with CF usually present with delayed puberty, which is a result of both the disease itself and malabsorption secondary to pancreatic insufficiency.

Fig. 12.293 Testis from a patient with alcoholic cirrhosis. The seminiferous tubules show decreased diameter, thickening of the tubular wall, and spermatogonia and Sertoli cells exhibiting intense vacuolation of the adluminal compartment. The testicular interstitium shows marked Leydig cell atrophy and numerous macrophages.

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Nonalcoholic Liver Diseases and Infertility

Different clinical situations are grouped under the term nonalcoholic fatty liver diseases: steatosis, nonalcoholic steatohepatitis, liver fibrosis, and cirrhosis.2881 Effects on gonadal function vary according to the severity of disease.2882 Patients have decreased level of total and biologically active free testosterone. Hormonal alterations are not as severe as in alcoholics, a finding emphasizing the direct action of alcohol on Leydig cells. Hypogonadism in young patients may result from severe chronic liver disease. Patients with viral hepatic cirrhosis have increased serum estradiol, androstenedione, and SHBG levels, and reduced serum testosterone and DHEA levels. In α1-antitrypsin deficiency, testicular function and fertility are conserved for years; only in advanced stages of the disease do minor biochemical alterations occur.2883 In Alagille syndrome (intrahepatic biliary duct hypoplasia), hypogonadism is associated with cholestasis; frequent vertebral, cardiac, and facial malformations; and mental retardation. Hypogonadism is manifest by small testes, delayed puberty, and, in adults, lack of germ cell development.2884

Kidney Autosomal Dominant Polycystic Renal Disease

Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disease characterized by the presence of multiple cysts in both kidneys leading to renal failure. It is associated with cysts in liver and pancreas, cardiovascular pathology (aneurysms), and infertility. It is caused by mutation in PKD1 or PKD2 genes. The condition affects 1 in 1000 in the general population. Patients with this disease comprise 10% of those with end-stage renal failure.2885 Infertility may become apparent even before renal insufficiency begins. Oligoteratozoospermia and necrospermia are frequent findings.2886,2887 Serum levels of FSH, LH, PRL, testosterone, and estradiol remain normal for a long time before the onset of renal insufficiency. The most frequent causes of infertility in patients with ADPKD are thought to be obstruction of the spermatic pathway by epididymal cysts or seminal vesicle cysts, which have a high incidence in patients with polycystic renal disease (5.2%); abnormal spermatogenesis as a result of abnormal polycystins; uremia; and stationary cilium syndrome described in some patients.591,2011,2888,2889 Chronic Renal Insufficiency

Chronic renal insufficiency is associated with disturbed endocrine function in the pituitary, thyroid, parathyroids, and testes. The associated sexual dysfunction consists of erectile dysfunction, diminution of libido and semen volume, oligozoospermia or azoospermia, and infertility. In children, skeletal development and puberty are delayed.2890 In adults, bilateral testicular volume is decreased in patients undergoing hemodialysis. Hormonal studies reveal elevated levels of FSH, LH, and PRL, but testosterone level is low.2891,2892 Biopsy shows seminiferous tubules with reduced diameters and reduced or absent germ cells (Fig. 12.294).2893,2894 The interstitium contains a normal number of Leydig cells, increased number of macrophages, and fibrosis.2895 Hypospermatogenesis, late maturation arrest, and germ cell aplasia are the most frequent histologic findings in patients undergoing hemodialysis.2896 In addition, patients with chronic renal insufficiency secondary to glomerulonephritis have thickening of the tubular lamina propria and decreased number of Leydig cells. Patients with end-stage renal disease who undergo dialysis, especially older patients and those receiving prolonged dialysis, show calcifications in several organs and tissues, including the male genital system (epididymidis, tunica albuginea,

Fig. 12.294 Testis from a patient with chronic renal insufficiency. The seminiferous tubules show premature sloughing of primary spermatocytes and Sertoli cells with vacuolation of the apical cytoplasm. An intraepithelial microlith is present.

and cavernous tissue) in 87% of cases, with isolated cases of calcification of the testicular parenchyma and microlithiasis.2897 Elevated serum level of phosphorus, increased calcium-phosphorus product, and severe hyperparathyroidism contribute to the development of calcifications. Uremic calcification is a cell-mediated process in which elevated levels of TGF, vitamin K–dependent proteins such as osteocalcin and atherocalcin, and defects in calcium-regulatory proteins such as fetuin are implicated.2898 Uremic patients receiving dialysis exhibit decreased testicular function, low serum testosterone level, low ejaculate volume, and azoospermia. Dialysis does not restore spermatogenesis. Accumulations of urate and oxalate crystals are found in the rete testes and ductuli efferentes (Fig. 12.295). These crystals are deposited beneath the epithelium and are often sloughed into the lumen. Reactive changes in the rete testis, including cystic transformation, are frequent.2899 Some patients with chronic renal insufficiency show enlargement of the caput of the epididymis (Fig. 12.296). The etiology of gonadal dysfunction in this condition is unclear. Several factors are probably involved, including impaired testicular

Fig. 12.295 Deposits of urates in the testicular mediastinum and rete testis walls. Minimum lymphoid infiltrate.

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Inflammatory Bowel Disease

Fig. 12.296 Hyperplasia of caput of the epididymis in a chronic renal insufficiency patient. Ductules efferentes show pseudostratified epithelium of large columnar cells with clear cytoplasm.

steroidogenesis, reduced clearance of pituitary hormones, secretory defects of the pituitary and hypothalamus, and oxidative stress.2900–2906 The response to renal transplantation is not immediate and is related to the glomerular filtration rate. Patients with rates lower than 50 mL/min experience atrophy of the seminiferous epithelium.2901 Patients with long-term and early-onset uremia along with corticosteroid or cyclosporine combined with azathioprine treatments experience the most severe gonadal dysfunction.2907

Chronic Inflammatory Bowel Disease Celiac Disease

Celiac disease is associated with numerous disorders, including type 1 diabetes mellitus, autoimmune thyroid disease, Addison disease, osteoporosis, secondary hyperparathyroidism, vitamin D or iron deficiency, fertility problems, hypogonadism in men, and autoimmune hypopituitarism.2908,2909 The relationship of celiac disease with subfertility has been a matter of controversy, and some affected men are infertile. Earlier studies suggested that hypogonadism is a frequent finding in men with celiac disease and results in clinical symptoms in 5% to 10% of untreated patients. Spermiograms show reduced motility and numerous morphologic anomalies in spermatozoa. Hormonal studies show elevated serum FSH level in more than 25% of men with celiac disease. LH also is increased in more than 50%. The response of FSH and LH to GnRH stimulation is excessive. Affected men have signs of tissue resistance to androgens. The cause of pituitary derangement is unknown, but one possible cause is deficiency of fat-soluble vitamins, such as A and E. Vitamin A is important for Sertoli cell function, as well as for early spermatogenetic phases. Vitamin E supports proper differentiation and function of epididymal epithelium, spermatic maturation, and secretion of proteins by the prostate.2910 Sperm anomalies are not always corrected by a gluten-free diet. Recent studies suggest that celiac disease is not a risk factor for infertility in men, whereas in females it is responsible for delayed puberty, infertility, and predisposition to spontaneous abortion, conditions that are rapidly corrected with a gluten-free diet.2911–2913

Patients with quiescent Crohn, ulcerative colitis, or indeterminate (unclassified) colitis are usually as fertile as the general population, although those with active Crohn disease and ulcerative colitis have problems with fertility (27% and 24% of patients, respectively).2914,2915 Those with ulcerative colitis and regional enteritis have low sperm count, impaired motility, and ultrastructural alterations, including nuclear pleomorphism and chromatin malcondensation and decondensation. Zinc deficit may be responsible for similar alterations in Crohn disease, apparently related to the extent of intestinal involvement and severity of symptoms.2916,2917 Younger patients who undergo pharmacologic treatment or pelvic or abdominal surgery frequently exhibit pubertal delay and impaired spermatogenesis without involvement of endocrine function.2918 The main drugs used for inflammatory bowel disease (sulfasalazine, methotrexate, or infliximab) adversely affect semen parameters. Spermiogram parameters improve when treatment ceases.2919 Surgical treatment does not seem to affect erectile function, sexual desire, orgasm, or sexual satisfaction, although retrograde ejaculation is common.2920

AIDS More than 17% of HIV-infected men have hypogonadism, which may be present even in those whose viral replication is under control and have a normal number of CD4 lymphocytes.2921 Patients frequently experience early andropause, marked by dysregulation of the hypothalamopituitary-testicular axis.2922 Hypogonadism is more frequent in HIV-infected men with wasting syndrome, and may warrant physiologic androgen replacement therapy.2923–2926 The incidence rate of hypogonadism in men with AIDS is estimated to be 50%.2927–2929 According to autopsy studies, this percentage increases to 100% in the 3 to 24 months before death.2929 Histologic studies reveal that 28% of patients have complete but quantitatively abnormal spermatogenesis, and the remainder have spermatocytic arrest or Sertoli cell–only pattern. Chronic Anemia In patients with chronic anemia who require multiple transfusions, excess iron accumulates in tissues and forms reactive oxygen species causing irreparable damage (secondary hemochromatosis). Pituitary, thyroid, liver adrenals, and testes are the most compromised organs (Fig. 12.297). The latter show reduced spermatogenesis and iron storage in Leydig cells. The most frequent chronic anemias are β-thalassemia, sickle cell anemia, and Fanconi anemia. β-Thalassemia

β-Thalassemia is autosomal dominant with three manifestations: thalassemia trait (heterozygous β-thalassemia), intermediate thalassemia, and major β-thalassemia. The cause is mutation in the β-globin gene, resulting in ineffective erythropoiesis, hemolysis, and anemia. The β-thalassemia trait is present in 2% to 3% of the general population, and incidence is higher in Mediterranean and African people. Nearly 20% of patients with major thalassemia have delayed puberty.2930–2932 Loss of libido with erectile or ejaculatory dysfunction is common, and 69% of patients have hypogonadotropic hypogonadism.2933–2941 Gonadal dysfunction persists in most patients despite improvements in intensive chelation therapy (Fig. 12.298).2942,2943 Spermiogram studies demonstrate poor quality of most seminal parameters.2944 Hypogonadism probably has multiple causes: extensive iron deposition in the pituitary and testis as a result of multiple transfusions, hypoxia

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hemoglobin. The gene responsible for the disease is located on chromosome 11, and more than 90% of synthesized hemoglobin is type A. Homozygous sickle cell anemia (SS) is found in 0.2% of the African American population, whereas heterozygous sickle cell trait (AS) is present in 8%. Patients may present with delayed puberty, hypogonadism that varies from slight to severe, eunuchoid habitus, decreased libido, erectile dysfunction, priapism, and poor semen quality. In most patients, hypogonadism is hypogonadotropic, although 25% have increased FSH level, and 50% of these patients also have increased LH and low testosterone. Testicular size may be normal but is usually diminished.2950 Causes of hypogonadism in these patients may be multiple and include CDGP, hypothalamic dysfunction, pituitary infarcts, primary testicular failure, and zinc deficit. Testicular function usually improves with advancing age.2951–2957 Fanconi Anemia Syndrome Fig. 12.297 Major thalassemia in a patient who underwent multiple blood transfusions. The testicular interstitium and atrophic tubules show Perl stain–positive iron deposits.

Fig. 12.298 Testis from a man with chronic anemia with chelation therapy showing complete spermatogenesis and abundant macrophages in the interstitium that are negative for Perl stain and intensely immunoreactive for CD68. Leydig cells do not show significant alterations.

subsequent to ineffective erythropoiesis in spite of marked erythroid hyperplasia, liver disorders, diabetes mellitus, and zinc deficiency.2945 Testosterone replacement therapy is indicated.2946 α-Thalassemia

α-Thalassemia has two different clinical presentations: hemoglobin Bart hydrops fetalis (Hb Bart) syndrome and hemoglobin H disease. Patients with Hb Bart syndrome, the most severe form, are affected during gestation and are born with generalized edema, pleural and pericardial effusions, and severe hypochromic anemia. Hydrocephaly, hepatosplenomegaly, extramedullary erythropoiesis, urologic defects (ambiguous genitalia, undescended testis, and hypospadias), and cardiac defects are common. Most die during the neonatal period.2947,2948 Patients with hemoglobin H disease are only mildly affected and do not have genital anomalies.2949 Sickle Cell Anemia

Sickle cell anemia is autosomal recessive with a constellation of findings resulting from abnormal synthesis and structure of

Fanconi anemia is a rare inherited disorder characterized by chromosomal instability, bone marrow failure, developmental defects, and predisposition to cancer. Fanconi anemia, together with ataxia telangiectasia, Nijmegen breakage syndrome, Bloom syndrome, xeroderma pigmentosum, Cockayne syndrome, and TTD, belongs to a group of genetic disorders termed chromosomal breakage syndromes or DNA-repair disorders. These disorders share susceptibility to chromosomal breakages and increased frequency of breaks and interchanges, occurring either spontaneously or after exposure to various DNA-damaging agents.2958 Patients with Fanconi anemia show hypogenitalism with small penis and testes, as well as delayed puberty. Fertility has not been routinely studied.2959 Autopsy study of an adolescent boy showed seminiferous tubules containing only Sertoli cells and isolated spermatogonia.2960 During adulthood, hypergonadotropic hypogonadism may occur.2961

Obesity A high percentage of people in developed countries are overweight, and the incidence of obesity has increased considerably in recent decades. Nonetheless, few studies have addressed the effect of obesity on gonadal development in childhood, recognizing that there may be an effect on hypothalamopituitary-gonadal function.2962 The brain constantly monitors nutrition state by glucose level and circulating factors such as leptin, insulin, and ghrelin. In obese boys, testosterone level is decreased, including basal testosterone or testosterone level after hCG administration.2962,2963 Basal PRL level is normal, but mean peak PRL response and mean increment in PRL level after TRH administration are significantly lower in prepubertal obese children. These findings suggest that neuroendocrine regulation of PRL is impaired in prepubertal children even with mild to moderate obesity. This impairment could be secondary to altered neurotransmitter status at the hypothalamic level.2964 Obesity is a component of certain complex syndromes with specific genetic defects that are responsible for abnormalities of spermatogenesis. Examples include Alstr€om syndrome, which results from a loss of function of a simple gene (ALMS1 gene); and PWS and Angelman syndrome, which are caused by chromosomal anomaly in 15q11-q13. It is generally agreed that obesity has adverse effects on fertility. The underlying problems likely include erectile dysfunction, decreased sexual intercourse, and alterations of the hypothalamic–pituitary-testicular axis. Obesity causes alterations in most semen parameters, including sperm morphology, sperm concentration, total sperm count, total motility sperm count, and DNA

CHAPTER 12 Nonneoplastic Diseases of the Testis

fragmentation, independent of development of other disorders associated with obesity, such as hypertension, diabetes mellitus, heart disease, and stroke. Patients with morbid obesity have hypogonadotropic hypogonadism.2965 Hormonal measurements demonstrate important alterations in the hypothalamichypophyseal-testicular axis. Obesity is associated with decreased levels of free and total testosterone and SHBG, increased level of serum estradiol, and decreased FSH/LH ratio and inhibin B, as well as a lower amplitude of LH pulses and increased circulating estrogen.2966–2968 Testosterone reduction is not followed by a compensatory increase in gonadotropins, thus resulting in hypogonadotropic hypogonadism.2969–2971 Numerous hormones are involved in regulation of food intake, including leptin, adiponectin, ghrelin, resistin, and endocannabinoids.2972,2973 Testicular abnormalities begin with the adluminal compartment and later involve the basal compartment. Patients also have Leydig cell atrophy, cuboidal metaplasia of the rete testis, and epididymal atrophy. Fertility rate improves after weight loss.2974 The utility of bariatric surgery for improving male fertility in obese patients is uncertain.2975,2976

Starvation Starvation inhibits GnRH secretion, resulting in hypogonadotropic hypogonadism. Inhibition appears to be mediated by leptin. Low serum FSH, LH, and testosterone levels usually normalize when normal weight is reached.2977 Autoimmune Polyglandular Syndrome Autoimmune polyglandular syndromes, also known as autoimmune polyendocrine syndromes, affect endocrine glands and nonendocrine organs, characterized by coexistence of more than one organ-specific autoimmune disorder. Pluriglandular autoimmune syndromes are relatively frequent among patients who are seeking consultation in endocrinologic centers.2978 The four types of autoimmune polyglandular insufficiency syndromes are PGA1 (Blizzard syndrome), PGA2 (Schmidt syndrome), PGA3, and PGA4; the most frequent are PGA1 and PGA2.2979,2980 PGA1 is autosomal recessive, also known by the acronym APECED (autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy) or MEDAC (multiple endocrine deficiency autoimmune candidiasis syndrome) or Whitaker syndrome, defined by the presence of at least two of three characteristic features, including Addison disease, hypoparathyroidism, and chronic mucocutaneous candidiasis.2981–2984 The spectrum of associated diseases includes other autoimmune endocrinopathies (hypergonadotropic hypogonadism, insulindependent diabetes mellitus, autoimmune thyroid and anterior hypophysis diseases), autoimmune or immune-mediated intestinal diseases (atrophic chronic gastritis, pernicious anemia, malabsorption), active chronic hepatitis, autoimmune skin diseases (vitiligo and alopecia), ectodermal dystrophy, keratoconjunctivitis, cellular and humoral immunologic diseases, asplenia, and cholelithiasis.2985 PGA1 starts early and affects males and females equally. The syndrome is more frequent in Iranian Jews (1 in 6500 to 9000) and Finnish people (1 in 25,000), whereas low frequency is observed in Norway with an incidence of 1 in 80,000.2986–2988 The AIRE gene (autoimmune regulator), responsible for PGA1, is on 21q22.3, and the disorder is autosomal recessive.2989–2991 The syndrome is genetically homogeneous, although phenotype varies widely.2992,2993 R257X mutation is responsible for 82% of Finnish PGA1 alleles.2994a

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Chronic mucocutaneous candidiasis manifests in children younger than 5 years, followed by hypoparathyroidism (<10 years of age), and, finally, Addison disease (<15 years of age). Hypergonadotropic hypogonadism is frequent.2995 Patients with PGA1 syndrome have antibodies against many autoantigens, intracellular enzymes including the P450 side-chain cleavage enzyme 17α-hydroxylase, 21-hydroxylase, glutamic acid decarboxylase 65, aromatic L-amino acid decarboxylase, tyrosine phosphatase– like protein IA-2, tryptophan hydroxylase (TPH), tyrosine hydroxylase, and cytochrome P450 1A2.2996,2997 Testing for antibodies is recommended for diagnosis in patients whose clinical symptoms suggest a polyglandular autoimmune syndrome and to establish which organs may be affected.2994,2995,2998,2999 Abnormal Tcell–mediated immunity is the likely underlying deficit.3000 PGA2 or Schmidt syndrome is mainly observed in adult patients. Prevalence is 1.4 to 4.5 per 100,000 persons. Male-tofemale ratio is 3:1. PGA2 is defined by the presence of two or more disorders, including primary adrenal insufficiency; Graves disease or Hashimoto thyroiditis; insulin-dependent diabetes mellitus; primary hypogonadism; myasthenia gravis; celiac disease; and other relatively frequent conditions such as vitiligo, alopecia areata, serositis, pernicious anemia, and essential thrombocythemia.3001,3002 PGA2 is a complex polygenetic disease that shows familial aggregation and is associated with HLA-DR3 and HLA-DR4 and environmental factors.3003 The incidence rate of hypogonadism is 5%, and is hypergonadotropic in most cases.3004,3005 PGA3 is defined by the association of thyroiditis with diabetes mellitus, pernicious anemia, vitiligo, or alopecia.3006 Adrenal cortical insufficiency is not part of this syndrome. PGA4 includes patients who do not meet the diagnostic criteria of PGA1 to PGA3.3007 Features of Hypogonadism in Patients With Polyglandular Autoimmune Syndrome

Hypogonadism is present in 14% of male patients and 60% of female patients with primary adrenal insufficiency; hypogonadism in these patients is hypergonadotropic. The testes appeared atrophic, and seminiferous tubules show reduced diameter, absence of elastic fibers, and only some dysgenetic Sertoli cells in numbers that vary widely from one tubule to another. Spermatogonia are only occasionally seen. Deposits of immunoglobulin in basal membrane may be observed. In patients without adrenal insufficiency, the hypogonadism is usually hypogonadotropic. Even patients with better-conserved testicular function are infertile because they have oligozoospermia or antisperm antibodies.1281,2983 Hypogonadism may result from autoimmune destruction of testicular cells or pituitary gonadotropin-secreting cells (Fig. 12.299).3008,3009

Inherited Metabolic Diseases Hereditary metabolic diseases affecting the testis may be classified as: (1) diseases associated with accumulation of toxic substances (hemochromatosis and galactosemia); (2) diseases associated with disturbances in energy required for hormone synthesis (mitochondrial disorders); and (3) defects in degradation or synthesis of complex molecules (comprising both peroxisomal diseases [adrenoleukodystrophy (X-ALD), primary hyperoxaluria, and D-bifunctional protein (DBP) deficiency] and lysosomal diseases [Fabry disease, Wolman disease, Niemann-Picks disease, and cystinosis], as wells as disorders of intracellular trafficking and abnormal transverse protein [Alstr€om syndrome and selenoprotein deficiency disorders]).3010

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Fig. 12.299 Testis from a man with autoimmune polyglandular syndrome showing selective lymphoid infiltrates in a Leydig cell cluster. Reinke crystalloid may be recognized. The seminiferous tubules contain Sertoli cells and isolated spermatogonia.

Hemochromatosis and Infertility

Hereditary hemochromatosis is the most frequent genetic disease in the Northern Hemisphere. It results from excessive iron absorption and accumulation in multiple tissues and organs, and leads to cirrhosis, diabetes, hypogonadism, and arthralgia. It is estimated that 1.5 million Americans are affected, although most patients remain undiagnosed.3011 This figure represents 1 in 124 to 133 U.S. residents. In northern Europe and Australia, data are similar.3012–3015 The prevalence is lower in African Americans, southern Europeans, Ashkenazi Jews, and Australian aborigines.3016 The male-to-female ratio is 1.5:1. In men the disease appears at a younger age than in women and usually is more severe.3017 Iron homeostasis depends on many genes that act in a coordinated manner, and the exact function is not well known. Iron balance depends on intestinal absorption, regulated by the hepatic peptide hormone hepcidin through its receptor, the cellular exporter ferroportin, and adequate iron recycling.3018 It is assumed that normal individuals absorb 1 to 2 mg/day of iron, whereas homozygous patients with hereditary hemochromatosis absorb up to 3 to 4 mg/day. Excessive iron absorption is due to hepcidin deficiency or insensitivity of ferroportin to hepcidin. Iron deposits accumulate in the liver, pancreas, hypophysis, heart, adrenals, and gastric mucosa. Once intracellular ferritin saturation occurs, excess free iron participates in generating intracellular redox reactions, generating toxic reactive oxygen species, and causing cell injury or cell death. Eventual consequences include liver dysfunction (cirrhosis and cancer in 5% to 10% of patients), pancreatic dysfunction (diabetes in 80% of patients), cardiac pathology (myocardiopathy), musculoskeletal disorders (arthritis), and hypophyseal injury (hypogonadism) (Fig. 12.300).3019 Five types of hereditary hemochromatosis have been described based on genetic, biochemical, and clinical characteristics.3020–3023 Type 1, the most frequent, is caused by mutation in type 1 hereditary hemochromatosis gene (HFE) (C282Y), which encodes the high iron HFE protein, thus leading to increased intestinal absorption of iron, supersaturation of iron deposits, and damage in multiple organs. This type mainly affects male patients, and the clinical course is slow. The HFE gene is located on the short arm of chromosome 6.3020,3024 A cysteine-tyrosinase amino acid substitution, caused by a G8945A transition at codon 282 (C282Y), is found in

Fig. 12.300 Perl stains decorate the voluminous iron deposits in cells of the anterior pituitary in a patient with hemochromatosis.

85% to 100% of patients with inherited hemochromatosis who have northern European ancestors.3024 Other mutations observed in gene HFE are H63D and S65C.3022 The protein encoded by HFE is expressed mainly in intestinal crypt epithelial cells, and its function is to interact with the transferrin receptor to decrease affinity of this receptor for iron-bound transferrin. Therefore HFE is a negative regulator of transferrin-iron capture. Type 2 gene is a juvenile form of hereditary hemochromatosis that manifests before the age of 30 years in both sexes and has a rapidly progressive course; it is associated with severe cardiomyopathy and hypogonadism.3025,3026 Two subtypes of juvenile hemochromatosis are distinguished: type A and type B. Type A juvenile hemochromatosis is related to mutations in the HJV gene (formerly named HFE2) encoding the hemojuvelin protein. Type B juvenile hemochromatosis is related to the HAMP gene (formerly named HFE3) encoding the hepcidin protein.3027 Type 3 gene defects on chromosome 7q22 impair the transferrin 2 receptor. Consequences are like those of the type I receptor defect. Type 4 hemochromatosis is caused by mutation in the ferroportin (SLC40A1) gene on 2q32. It is autosomal dominant and affects the basolateral iron carrier ferroportin 1, resulting in iron deposition in macrophages. Types 1, 2, and 3 have recessive autosomal inheritance and show a similar distribution pattern of iron deposits. In all five types, there may be alteration of gonadal function. Hypogonadism may be the first sign of disease when it starts in adult life as in type 2 hemochromatosis and may be the initial symptom.3028 With age, hypogonadism becomes hypogonadotropic, with low serum levels of testosterone, LH, and FSH in more than 40% of patients, except when early treatment is initiated.3029,3030 The most frequent findings are atrophy with diminished MTD, tubular wall thickening, progressive decrease in spermatogenesis, and increased lipofuscin granules in Leydig cells. The cause of these testicular disorders may be preferential deposition of iron in gonadotropic cells.3031 Iron deposits are not observed in the testis. Given that early diagnosis is possible in all types of hemochromatosis, clinicians in countries with a high prevalence of the disease should be vigilant, thereby allowing affected patients to begin treatment at an early age and thus avoid later complications.3032 Deferasirox treatment and aggressive phlebotomy therapy decrease iron deposits and improve hormonal dysfunction.3030,3033–3037 Liver

CHAPTER 12 Nonneoplastic Diseases of the Testis

transplantation in patients with cirrhosis restores hormonal balance in a high percentage of cases, with recovery of libido within 6 weeks and gradual return of spermatogenesis in one-half.3038 ICSI enables paternity in some cases.3039 Testosterone administration may be useful to treat impotence and failure of ejaculation.3040,3041 Galactosemia

Classical galactosemia is a rare autosomal recessive galactose metabolism disorder caused by mutation in the galactose-1-phosphate uridyltransferase (GALT) gene. Galactosemia may produce important abnormalities of the genital system. In infancy the incidence rate of cryptorchidism is high (25%).3042 Pubertal development is delayed in up to 20% of patients.3043 In adult males, there is low seminal volume, and the levels of testosterone and inhibin B are at the lower limits of normality, whereas gonadotropin levels are normal, suggesting a subtle defect in Leydig and Sertoli cell function.3044 Kearns-Sayre Syndrome

Kearns-Sayre syndrome primarily affects the neuromuscular and endocrine systems and manifests before the age of 20 years. The principal characteristics of this syndrome are progressive external ophthalmoplegia, pigmentary retinopathy, cardiac conduction defects, and cerebellar ataxia. Disorders of the reproductive system, including cryptorchidism, delayed puberty, testicular hypoplasia, and low gonadotropin levels, are found in 20% to 30% of cases.3045 Other endocrine alterations are hypothyroidism, short stature with or without GH deficit, diabetes mellitus, and hypoparathyroidism.3046 The syndrome belongs to a group of multisystemic disorders (Kearns-Sayre syndrome, Pearson marrow-pancreas syndrome, and chronic progressive external ophthalmoplegia) caused by mutations in the mitochondrial genome. In Kearns-Sayre syndrome, most mitochondrial DNA deletions are sporadic and probably occur at the germ cell level or early in embryonic development.3047–3049 As in other mitochondrial disorders the syndrome is inherited exclusively from the mother because all mitochondria in the zygote have maternal origin, and spermatozoa do not contribute to this cell organelle.3050 Presentation of this syndrome depends on the level of dysfunction of the conduction system, which appears in most of the patients aged between 15 and 20 years.3051,3052 Adrenoleukodystrophy (Adrenal Testicular Myeloneuropathy)

Adrenoleukodystrophy (X-ALD) is a rare and progressive sexlinked recessive disorder that chiefly involves the central nervous Fig. 12.301 Adrenoleukodystrophy in a child. Adrenal cortex shows marked atropy.

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system and causes progressive demyelization, adrenal insufficiency, and testicular failure.3053 It is caused by a defect in β-oxidation of very-long-chain fatty acids (VLCFA), principally hexacosanoic (C26:0), pentacosanoic (C25:0), and tetracosanoic (C24:0) acids.3054,3055 These acids are easily detected in serum.3056,3057 Their accumulation in various tissues results in disease manifestations. The incidence is estimated to be 1 in 20,000, with no differences among ethnic groups.3058,3059 The gene responsible for X-ALD, ABCD1, is located on the terminal end of the Xchromosome long arm (Xq28) and occupies approximately 26 kb of genomic DNA, with 10 exons encoding 745 amino acids.3060 The gene product, ALDP, is a peroxisomal transmembrane protein belonging to the family of adenosine triphosphate–binding cassette (ABC) transporters. It acts to transport VLCFA into peroxisomes, where VLCFA is subject to β-oxidation.3061 X-ALD is the most common peroxisomal disorder. More than 1000 mutations in the ABCD1 gene have been registered in the international database (http://www.x-ald.nl). Despite being X-linked, disease effects are not limited to males; 20% to 50% of female carriers experience symptoms. The phenotype is varied, but no correlation exists between genotype and phenotype. Six phenotypes were initially recognized, based on age of onset and clinical manifestations: the childhood cerebral form (CCALD), with cerebral demyelization and childhood onset; the adolescent cerebral form; the adult cerebral form; adrenomyeloneuropathy (AMN), with axonopathy of the pyramidal and somatosensory tracts and peripheral neuropathy; the olivopontocerebellar form; and Addison disease only. Today, at least nine phenotypes are identified in male patients and two in female patients.3062,3063 Only CCALD and AMN are discussed in this chapter. CCALD is the most common form, with onset in school age. Cerebral demyelization is initially manifest by attention-deficit/ hyperactivity disorder, ophthalmic or ear abnormalities, and psychological problems.3064 In many patients, diagnosis is confirmed by the onset of seizures, gait disturbances, and other neurologic symptoms. Ultimately, demyelization leads to a vegetative state, and patients do not reach adulthood.3063–3066 Testes are small. Seminiferous tubules have greatly reduced diameters, with thickened walls and an epithelium with low number of Sertoli cells and few spermatogonia. The interstitium lacks Leydig cells. In addition to atrophy of seminiferous tubules, there is marked atrophy of the efferent ductule, which presents as cellular cords (Figs. 12.301 through 12.304).

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Fig. 12.302 Adrenoleukodystrophy. Testis of a child with marked atrophy. The caput of the epididymis is reduced to a loose connective tissue in which the silhouettes of the efferent ducts are hardly observed.

Fig. 12.304 Sections of efferent ducts of the same patient of the previous figures. Most of the ducts lack lumens and show significant peritubular fibrosis.

Fig. 12.303 The seminiferous tubules of this prepubertal patient with adrenoleukodystrophy are reduced to epithelial cords. The interstitium appears greatly enlarged.

Fig. 12.305 Adrenoleukodystrophy. Adrenal gland showing severe atrophy of the cortex and globoid cells at the periphery. Medulla is preserved in the center of the figure.

AMN presents clinically at approximately 30 years of age, and one-half of patients show cerebral effects within 10 years of onset.3067 The first symptoms include progressive paraparesis, thin scalp skin, alterations in sphincters, peripheral neuropathy, and adrenocortical failure.3068 Most men have symptoms of gonadal dysfunction, including decreased libido (46%), erectile dysfunction (58%), and testicular descent failure (15%). Physical examination shows scant pubic hair (50%), gynecomastia (35%), and small testes (12%).3069 Spermiogram reveals azoospermia or oligozoospermia and low ejaculate volume. Most patients experience primary testicular failure. FSH serum level is elevated in 32% to 57% of patients, and increased LH level is observed in 16% to 63% of patients. Response of LH to GnRH stimulation is abnormally high in 47% of patients, whereas response of FSH to stimulation is excessively low in 16%. Testosterone level is similar to controls, although free testosterone level is lower. Testosterone/LH ratio, a sensitive marker of Leydig cell function, is decreased in most patients (82%).3069–3072

Histologic changes follow the development of the disease. At the onset, spermatogenesis and sperm count may be normal, although teratozoospermia and asthenozoospermia are frequent. Later, spermatogenesis undergoes rapid deterioration, with variable degree of germ cell arrest and azoospermia.3073 Characteristic findings in biopsies are observed in Leydig cells, which have specific lamellar cytoplasmic inclusions that are also found in adrenal cortical cells and cerebral cells (Figs. 12.305 and 12.306).3070,3074 Treatment of patients with X-ALD consists of steroid replacement therapy to counteract the clinical effects of adrenal cortical insufficiency, although treatment does not alter neurologic deterioration. Patients in the early phases may benefit from hematopoietic cell transplantation, whereas those with advanced disease are candidates for experimental therapies.3075–3078 Primary Hyperoxaluria

Primary hyperoxaluria is an autosomal recessive disease of glyoxylate metabolism that results in excessive production of oxalate. The

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.306 Testis from a patient with adrenoleukodystrophy. Seminiferous tubules contain mainly Sertoli cells with only isolated spermatogonia. In the interstitium, Leydig cells with vacuolated cytoplasm may be observed.

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and cerebrovascular dysfunction develop. Patients usually have cutaneous angiokeratomas, posterior capsular cataracts, and tortuous retinal veins. Death occurs between the third and fourth decades of life. All endocrine glands tend to accumulate Gb3.3090 Through systematic pedigree analysis, the incidence of the disease and clinical manifestations in pediatric patients are better understood. The most frequent clinical symptoms in children are acroparesthesia, hypohidrosis, and cornea verticillata. Other symptoms such as tinnitus, recurrent vertigo, headache, diminished level of activity, fatigue, and depression may also be observed. Renal disease may appear in adolescence. Age of onset is the same between sexes.3091 Diagnosis is made by the presence of marked decrease of activity of α-galactosidase A in white blood cells or cultured skin fibroblasts.3092 Testes and excretory spermatic ducts are significantly damaged. Some alterations, including those in endothelial cells, smooth muscle cells, and fibroblasts, are nonspecific; other changes are specific, including those in myofibroblasts, Leydig cells, and epididymal epithelium (Figs. 12.307 and 12.308). Patients have asthenozoospermia, oligozoospermia, or both. Seminiferous tubules show

most frequent form of primary hyperoxaluria is type I, caused by deficient or absent activity of liver-specific peroxisomal alanine/ glyoxylate aminotransferase enzyme. Renal effects include recurrent nephrolithiasis, nephrocalcinosis, and early renal failure. Massive deposition of calcium oxalate in tissues is known as oxalosis.3079 Neither dialysis nor kidney transplantation permanently eliminates renal oxalate deposition. Liver transplantation is the most effective therapy. Only a single report of an effect is recorded: a man with obstructive azoospermia related to seminiferous tubule obstruction by calcium oxalate crystals achieved paternity after TESE-ISCI.3080 D-Bifunctional Protein Deficiency

DBP deficiency is an autosomal recessive disorder that compromises beta fatty acid oxidation in the peroxisome caused by mutations in the HSD17B4 gene. The most frequent clinical symptoms are neonatal hypotonia, altered psychomotor development, dysmorphism, loss of hearing and vision, and abnormalities of the central nervous system Most patients die before the age of 2 years, but when DBP deficiency is incomplete, patients are able to reach adulthood. Involvement of the genital tract varies from hypergonadotropic hypogonadism with azoospermia and low serum testosterone to patients with normal testicular function and paternity.3081,3082

Fig. 12.307 Fabry disease. Both basal and principal cells of the epididymis show pale and vacuolated cytoplasms, due to lipid deposits.

Fabry Disease

Fabry disease is an X-linked metabolic disorder first reported in 1898, characterized by intralysosomal deposits of globotriaosylceramide (Gb3) resulting from α-galactosidase deficiency due to mutation in the GLA gene.3083,3084 The incidence of Fabry disease may be as high as 1 in 3100 live births.3085,3086 Symptoms depend on the type of mutation of α-galactosidase A and residual enzymatic activity.3087–3089 Progressive accumulation of Gb3 in endothelial cells, pericytes, smooth muscle cells, renal epithelial cells, myocardium, and nervous system cells of dorsal ganglia produces most of the symptoms. Clinical manifestations may begin with what it is known as “Fabry crisis” (strong, burning pain in the palms and feet associated with fever and elevated erythrocyte sedimentation rate). After that, severe painful neuropathy and progressive renal, cardiovascular,

Fig. 12.308 Fabry disease. The deposits observed in the ductus epididymidis epithelium consist of multiple, parallel-arranged laminae (zebra bodies).

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decreased diameter and tunica propria thickening. Sertoli cells accumulate lipids, and germ cells are limited to a few spermatogonia. Leydig cells are normal in number; nuclei are small, and cytoplasm contains numerous lipofuscin granules.3093 All damaged cell types except germ cells contain large cytoplasmic vacuoles, consisting of deposits of complex lipids that stain with oil red O, Sudan black, or acid hematein. Ultrastructurally, the deposits appear as multiple, concentrically arranged lamellae surrounded by membrane (myelin-like bodies). Deposits are scant in Sertoli cells and Leydig cells, but myelin-like bodies are abundant in the epithelia of the ductus deferens and ductus epididymidis. Cell organelles are scant, and stereocilia are absent. Similar myelin-like bodies have been observed in endothelial cells, smooth muscle, fibroblasts, and myofibroblasts. The placenta shows significant deposits of Gb3 in the intermediate trophoblast, amniotic epithelial cells, and endothelial and muscular cells of the decidua and umbilical cord vessels.3094 Enzyme replacement with α-galactosidase prevents glycosphingolipid deposition and reduces glycosphingolipid levels, so this therapy is recommended as soon as possible.3095–3099 Wolman Disease

Wolman disease is a rare inherited lysosomal disease characterized by deficit in acid lipase/cholesteryl ester hydrolase whose genetic mutation is mapped to 10q23.2-q23.3.3100 Complete enzymatic deficiency (Wolman disease) causes death in infancy as a result of accumulation of cholesterol esters and triglycerides in numerous organs such as the liver, adrenal cortex, and intestines.3101,3102 Partial deficiency is known as cholesteryl ester storage disease. Patients tend to experience premature atherosclerosis.3103 The diagnosis should be suspected when a child exhibits hepatomegaly, vomiting, diarrhea, failure to thrive, adrenal calcifications, and elevated levels of low-density lipoprotein-cholesterol or low levels of high-density lipoprotein-cholesterol with elevated transaminase activity.3104 Histologic examination reveals deposits in the interstitium. Leydig cells appear hypertrophic and foamy, containing autofluorescent and birefringent lipid material that consists ultrastructurally of giant lysosomes containing acicular inclusions. Cell organelles are scant. Increased numbers of interstitial macrophages are present, bearing granular cytoplasm that contains ceroid material. Cholesteryl ester accumulates in Leydig cells because these cells use large amounts of lipoprotein-bound cholesteryl ester as substrate for hormonal synthesis. Cholesteryl ester accumulation is not apparent in macrophages in tissues other than the testis. This finding suggests that testicular macrophages play an important role in normal protein turnover and emphasizes the relationship between testicular macrophages and Leydig cells.3105 Fertility is not usually decreased in patients with cholesteryl ester storage disease.3106 Enzyme replacement therapy with sebelipase alfa delays the appearance of complications and increases life expectancy.3107 Niemann-Pick Disease

Niemann-Pick disease consists of a heterogeneous group of autosomal recessive diseases characterized by storage of different kinds of lipids in the reticuloendothelial system and other tissues. Four types (A, B, C, and D) are recognized, according to the clinical and biochemical characteristics of the disease.3108 Type A (NPA) is a neuropathic infantile form, and type B (NP-B) is a nonneuropathic infantile form. In NP-A and NP-B the principal storage lipid is sphingomyelin. The genetic defect is recessive mutation in the sphingomyelin phosphodiesterase 1 (SMPD1) gene located in

11p15.1–4, which encodes a lysosomal hydrolase. NP-A is the most frequent of the four types, comprising 75% to 80% of all cases. NP-A is a severe neurodegenerative form that usually leads to death by 3 years of age. Patients with type B (NP-B) experience hepatosplenomegaly and respiratory disorders, but have little or no neurologic involvement and may survive into adolescence or adulthood.3109 Type C (NP-C) is the neuropathic juvenile form, and type D (NP-D) is a geographic variant of NP-C involving several families in Nova Scotia; in both types, patients have massive accumulation of cholesterol, glycosphingolipids, and other lipids within the endosomal-lysosomal system caused by failure of intracellular trafficking of cholesterol and consequent failure of lipid homeostasis.3110 The mutant gene responsible for more than 95% of the cases is in the 18q11–12 region and termed NPC1.3111 The remaining cases are caused by mutations in the NPC2 gene.3112 NP-C is heterogeneous clinically.3113 NPC1 mutant mice (models of NPC disease) and Drosophila NPC1 mutants are infertile. Mutant mice show decreased steroidogenesis and decreased number of spermatozoa with a high frequency of morphologic anomalies. The Drosophila NPC1 mutants have larval death and infertility.3114 Histologic studies show partial arrest of spermatogenesis. Testicular findings in boys consist of lipid accumulations in interstitial macrophages. Ultrastructural studies show abundant lipid vacuoles in Sertoli cells, Leydig cells, macrophages, epididymal epithelial cells, and spermatozoa.3115,3116 Cystinosis

Cystinosis is an autosomal recessive metabolic disease characterized by alteration in cystine transport from lysosomes to the cytosol that results in intralysosomal accumulation of cystine. The incidence is estimated at 0.5 to 1 per 100,000. The main gene responsible for the disease (CTNS) is on chromosome 17p13 and encodes a lysosomal membrane protein named cystinosin, which is involved in transport.3117 A second gene (CARKL), which encodes a protein with carbohydrate kinase activity, has also been identified.3118 Neither gene is expressed in one-half of the patients with cystinosis. Cystine storage occurs in all body tissues, but predominantly in bone marrow, lymph nodes, kidney, thyroid, endocrine pancreas, muscles, central nervous system, cornea, conjunctiva, and testis. Renal parenchymal deposits result in nephropathic cystinosis, a form of renal failure that may present in infancy, adolescence, or adulthood. Severity of the disease is widely variable; it may be asymptomatic in adults and may even be incidentally diagnosed by the presence of corneal deposits.3119 Testicular function is severely altered in those with nephropathic cystinosis, many of whom have azoospermia. Patients experience hypergonadotropic hypogonadism with elevated serum levels of FSH and LH, and reduced response of testosterone to hCG stimulation. Paternity has not been reported.3120 Cystine crystals stand out by their hexagonal pattern, appear doubly refractive under polarized light, and are located in the cytoplasm of interstitial macrophages. Involvement of the testicular interstitium may be massive.3120 Associated lesions include hypospermatogenesis, interstitial fibrosis, and hydrocele.3121 Treatment with cysteamine probably worsens testicular function by an effect on Sertoli and Leydig cells through somatostatin and ghrelin.3122 Testosterone replacement is possible.3123 CDG1 (Abnormal Glycosylated Proteins)

Congenital disorders in glycosylation comprise a group of metabolic diseases, previously identified as glycogenosis, that result from

CHAPTER 12 Nonneoplastic Diseases of the Testis

deficiency in synthesis of N-linked oligosaccharides. More than 85 congenital disorders in glycosylation are identified. Twenty-one different enzymes are involved in synthesis.3124 The most frequent variant of this disorder (83%), CDG-Ia, is produced by deficiency in phosphomannomutase (PMM) caused by mutation in the PMM2 gene, mapped to chromosome 16p13. Most patients (more than 700 reported to date) are diagnosed in infancy, and about 20% do not reach adulthood. Most organs are affected. The most important clinical symptoms are mental retardation, cerebellar hypoplasia, peripheral neuropathy, hepatic dysfunction, strokelike episodes, growth retardation, hemorrhagic episodes, and seizures.3125 Men exhibit decreased testicular volume and hypogonadotropic or hypergonadotropic hypogonadism.3126 € m Syndrome Alstro

Alstr€om syndrome is a rare autosomal recessive disorder that is characterized by pigmentary retinal degeneration, sensorineural hearing loss, obesity, insulin-dependent diabetes mellitus, and chronic nephropathy.3127,3128 Hypergonadotropic hypogonadism, acanthosis nigricans, hepatic dysfunction, hepatic steatosis, alopecia, hyperlipidemia, hypothyroidism, short stature, and dilated myocardiopathy are occasionally present.3129,3130 Estimated prevalence rate is less than 0.001%.3131 ALMS is caused by mutations in the ALMS1 gene located on the short arm of chromosome 2 (2p13.1). Most mutations are located in exons 8, 10, and 16.3130,3132 This gene encodes a protein linked with centrosomes and ciliary basal bodies implicated in formation, maintenance, and function of primary cilia (including hypothalamic neurons).3133 ALMS is included in the list of disorders known as ciliopathies.3134 Phenotypic expression varies widely, and not all symptoms are evident in early childhood, but eventually develop during the first and second decades of life. There is no correlation of genotype and phenotype.3135 In male adolescents, testes and penis are small. Onset of puberty is sometimes delayed. Secondary sexual characteristics are usually normal.3136 The presence of normal to high FSH and LH levels and low testosterone level suggest primary hypogonadism. Gynecomastia and low sperm counts are frequent. Histologically, seminiferous tubules show atrophy and fibrosis, whereas the interstitium has scant Leydig cells.3131 An association between ALMS and Klinefelter syndrome has been reported.3137

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In the pituitary, damage to gonadotropic cells may be caused by estrogen. In the testes, gonadotoxic agents may selectively impair a select cell type, but global dysfunction occurs later. For example, there is direct toxicity to Sertoli cells by phthalates used as plasticizers, nitroaromatic compounds used in production of dyes and explosives, and γ-diketones used as solvents. Cadmium and bisphenol A perturb the blood-testis barrier. Direct toxicity on spermatogenesis is seen with ionizing radiation. Many drugs that impair epididymal fluid or spermatozoon transport damage sperm excretory ducts, with subsequent loss of fertility.2965,2966

Occupational Exposure The relationship between infertility or subfertility and certain professions or exposures to environmental agents is well known.1939,3142,3143 Adverse effects on spermatogenesis have been demonstrated for organic solvents such as carbon disulfide, chlorinated solvents, aromatic solvents and varnishes, degreasers, thinners, and adhesives; certain pesticides, notable DDT, linuron, and polychlorinated biphenyls; metals such as lead, cadmium, mercury, arsenic, copper, manganese, and molybdenum; industrial wastes such as dioxins and ethylene dibromide; phthalates and polyvinyl chloride; oral contraceptives; radiation or high temperature; recreational drugs and those used for athletic doping; and many other agents with potentially harmful effects on testicular function.3142,3144–3150 Carbon Disulfide

Carbon disulfide is used as a solvent in the production of rayon. Continuous exposure is toxic to the nervous system and causes decreased spermatogenesis and libido, and increased FSH and LH serum levels because of direct damage to Sertoli cells via an endoplasmic reticulum apoptotic pathway.3150–3154 Dibromochloropropane

Dibromochloropropane is used as a soil fumigant to control nematodes. Lengthy exposure causes oligozoospermia, azoospermia, increased FSH and LH levels, and Y-chromosome nondisjunction.3155,3156 Workers exposed to 2-bromopropane (used as an alternative to ozone-depleting cleaning solvents) have reduced number of premeiotic spermatocytes because of germ cell apoptosis.3157 Lead

Selenoprotein Deficiency Disorder

Selenium is a component of the SBP2 selenoprotein that is essential for human health. More than 200 selenoproteins have been identified, functioning as oxidases involved in thyroid hormone metabolism.3138 Development of effective spermatogenesis requires an optimal level of selenium in the testis. Selenium deficiency and excess are both deleterious to spermatogenesis and sperm maturation. Lack of testis-enriched selenoproteins produces delayed puberty and oligoasthenozoospermia.3139 Serum testosterone level is normal, whereas inhibin B is markedly decreased, suggesting alteration of Sertoli cells.3140 Selenoproteins such as mGPx4 and snGPx4 are structural components of mature spermatozoa, whereas others such as GPx1, GPx3, mGPx4, cGPx4, and GPx5 protect spermatozoa during maturation against oxidative damage.3141

Infertility Secondary to Physical and Chemical Agents Physical and chemical agents may impair testicular function by direct action on the pituitary, testes, or sperm excretory ducts.

Inorganic lead is more dangerous than the organic form. Exposure of workers to inorganic lead in smelting, battery, and stained-glass plants may cause direct spermatogenic damage.3158 Affected patients have asthenospermia, teratozoospermia, and oligozoospermia.3159,3160 In addition to impaired spermatogenesis, lead toxicity affects steroidogenesis and the redox (reduction–oxidation reaction) system.3161 Oral Contraceptive Manufacture

Workers in pharmaceutical plants generating synthetic estrogens and progestins may experience hyperestrogenism with gynecomastia, decreased libido, and impotence.3162 Neonatal exposure of boys to diethylstilbestrol (DES) may induce cryptorchidism, testicular hypoplasia, epididymal cysts, and severe anomalies in semen production.437,3163,3164 However, the risk for infertility is only slightly increased.3165

Endocrine-Disrupting Compounds Estrogen-like effects are produced by a variety of naturally occurring estrogens (so-called phytoestrogens) and numerous synthetic

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compounds such as phthalates, pesticides, and polychlorinated biphenyls.3166–3170 These endocrine disruptors mimic natural hormones, inhibit the action of hormones, or alter the normal regulatory function of the endocrine system. These substances have potential hazardous effects on the male reproductive axis, including possible infertility, because they target testicular spermatogenesis, steroidogenesis, and the function of both Sertoli and Leydig cells3171; they also affect testicular function through induction of oxidative stress and apoptosis.3172 Principal modes of contact with potential endocrine-disrupting compounds are environmental exposure and the dietary ingestion of milk, fish, meat, fruits and vegetables, and soy.3173–3175 Heightened risk for cryptorchidism, hypospadias, testicular cancer, and poor semen quality may be related to the negative influence of environmental factors on the testis during fetal life.3176 The term testicular dysgenesis syndrome has been proposed to designate this constellation of putative syndromes.1059 Estrogen exposure in utero may disrupt development of the testes and the entire male reproductive tract. Estrogen may hinder FSH secretion by the fetal pituitary and may also interfere with subsequent Sertoli cell proliferation, and hence secretion of AMH required for regression of m€ ullerian ducts. Persistence of m€ ullerian derivatives is associated with failure of testicular descent. Changes in AMH secretion may also account for altered germ cell proliferation during fetal life. Exposure to high concentrations of estrogen may compromise testosterone production, as well as masculinization of external genitalia (hypospadias) and inguinal descent of the testis (cryptorchidism). Abnormal development of Sertoli cells and low germ cell number may cause diminished spermatozoon production and infertility.3177

Recreational Drugs and Doping Drug use may be an important cause of male infertility, and adverse effects have been reported on the hypothalamopituitary-testicular axis, sperm function, and testicular structure.3178 Marijuana decreases sperm density, motility, and the acrosomal reaction, and increases the number of morphologically abnormal spermatozoa. Inhibitory effects are mediated by dysregulation of the hypothalamic-hypophyseal-testicular axis and direct action of cannabinoids on sperm through the activation of the cannabinoid receptor subtype CNR1 that has been shown to be expressed in mature sperm.3179–3181 Marijuana is also a potent inhibitor of mitochondrial oxygen consumption in human sperm.3182 Cocaine induces apoptosis in the rat testis.3183 Approximately 20% of injectable drug users have low serum testosterone level. Consumption of more than 80 g/day alcohol adversely affects spermatogenesis in two-thirds of patients.3184 Biopsy showed maturation arrest of germinal cells at the pachytene stage with no mature sperm cells. Rapid and dramatic improvement of semen characteristics may occur after alcohol withdrawal. Patients should be questioned about alcohol intake before assisted reproductive technology is performed.3185 Smoking causes deterioration of all sperm parameters.3186,3187 Abuse of anabolic steroids by athletes causes hypogonadotropic hypogonadism and transient azoospermia.3188–3190 Radiation The testicular parenchyma is one of the most radiosensitive tissues of the body, and germ cells are the most radiosensitive testicular cells at all ages, including male fetuses.3191 Ionizing radiation causes alterations in spermatogenesis and hormonal regulation. Men treated with brachytherapy for prostate cancer have abnormal

sperm DNA fragmentation index, indicating likely infertility.3192 Some patients recover fertility a few years after radiation exposure.3193 The effects of nonionizing radiation are less severe, although increased use of newer technologies may decrease fertility potential by increasing long-term exposure to nonionizing radiation.3194 Electromagnetic radiation from cell phones carried in the pocket of trousers near the testis impairs spermatozoon motility.3195–3198 Reduced libido and reduced number of spermatozoa have been reported in men exposed to microwaves.3199 Laptop computers with Wi-Fi connect through radiofrequency electromagnetic waves may damage spermatozoa through microwave radiation.3200,3201 Whether laptop computers connected wirelessly to the Internet decrease sperm motility and increase sperm with DNA fragmentation by a nonthermal effect is debated.3202–3205 Magnetic and electromagnetic fields induce oxidation of phospholipids, which are a major component in the sperm mitochondrial sheath.3206 Additionally, portable computers generate high temperatures, thus increasing scrotal temperatures, which may produce deleterious effects on spermatogenesis.3207,3208

Heat Normal intratesticular temperature is 31 °C to 33 °C, approximately 4 °C to 6 °C lower than core body temperature. Deterioration in the quality of semen has been verified in taxi drivers, welders, and habitual users of the sauna.3209 Conditions causing higher testicular temperature, such as varicocele and cryptorchidism, also cause damage, with decreased numbers of spermatozoa and an elevated percentage of spermatozoa with abnormal forms and low motility.3210,3211 Exposure to intermittent heat in healthy people produces greater damage in spermatogenesis than continuous heat exposure.3212 Scrotal heat stress produces alterations in semen quality, DNA integrity chromatin condensation, and caspase-3.3213 Primary spermatocytes at the end of the pachytene stage are most sensitive to heat. The mechanism by which heat produces testicular lesions is uncertain, although heat stress is closely associated with oxidative stress, and that is followed by apoptosis of germ cells.3214 Hyperthermia affects the activity of enzymes such as ornithine decarboxylase and carnitine acetyl transferase, both necessary for metabolism and proliferation of seminiferous tubular cells.3215–3217 Synthesis of DNA and RNA by germ cells also depends on temperature. DNA synthesis by spermatogonia and preleptotene primary spermatocytes is higher at 31 °C than at 37 °C. RNA and protein synthesis is normal at temperatures between 28 °C and 37 °C, but both decrease markedly at 40 °C.3218 Testicular Trauma Injury to male external genitalia is uncommon when compared with injury in other parts of the body, accounting for <1% of all trauma-related injuries, with a peak between 10 and 30 years of age.3219 Testicular trauma most commonly results from sports injuries, road traffic accidents, and gunshot wounds, and is especially frequent among athletes.3220–3222 Testicular trauma to the newborn during breech birth, whether by vaginal delivery or not, adds to the statistics.507,3223 Protection from damage is afforded by relative seclusion and mobility of the genitalia. Testes have some mechanisms for protection from injury such as mobility, the cremasteric reflex, toughness of the elastic tunica albuginea, and, in infancy, the small size. However, testes may be injured by wounds or penetrating force against the pubic symphysis, the pubic ramus, or the upper thigh. Trauma may result in a wide variety of lesions, including hematoma (Figs. 12.309 and 12.310)

CHAPTER 12 Nonneoplastic Diseases of the Testis

703

Fig. 12.309 Magnetic resonance image of a hematoma in the central region of right testis showing a target pattern.

Fig. 12.311 Testicular traumatism. Extrusion of dark-colored testicular parenchyma through an albuginea break.

Fig. 12.310 Histologic section of a testicular hematoma showing a blood collection among seminiferous tubules.

Fig. 12.312 Hematocele in reabsorption phase. Granulomatous reaction with abundant cholesterol crystal in the epididymis surface.

contusion with or without hematocele, rupture, dislocation, and spermatogenic impairment.

spongy material several times larger than the testicular volume. Most of this material is fibrin and cholesterol granulomas (Fig. 12.312).3230–3232 In chronic hematocele the blood clot is totally or partially organized and consists of connective tissue that contains numerous newly formed blood vessels and hemosiderinladen macrophages. Connective tissue facing the tunica cavity is lined by fibrin remnants. In its final stages the lesion consists of a thickened, fibrosed, and calcified tunica sac (Fig. 12.313), which may also show osseous metaplasia (Fig. 12.314).3233 Hematocele should be evacuated as quickly as possible to avoid pressure atrophy of the parenchyma.3234 Rare complications include infection, suppuration, and scrotal gangrene. Repair of rupture may be difficult, especially if it is circumferential. In such cases a large portion of parenchyma is herniated and may already be necrotic.3235,3236 Newer surgical techniques are used to preserve as much viable testicular tissue as possible.3237 In some patients who have suffered penetrating trauma, the testis herniate through the scrotal skin lacerations. Many patients with scrotal injuries also have epididymal and spermatic cord lesions.3238 Diagnostic ultrasonography is generally useful but does not allow an exact diagnosis

Traumatic Hematocele

Traumatic hematocele usually results from testicular rupture (80% of cases) or a tear in the pampiniform plexus veins.3224,3225 It is important to distinguish between hematocele that follows blunt testicular contusion with an intact tunica albuginea that would not require surgery and hematocele secondary to testicular rupture that requires immediate repair (except for selected cases) to avoid ischemic necrosis or abscess formation.3226 Approximately 45% of patients with blunt testicular trauma present with tunica albuginea break (Fig. 12.311). Special care should be taken to evaluate the testes of children and adults who have suffered blunt abdominal trauma to avoid delayed diagnosis of significant testicular injury.3227,3228 Differential diagnosis of hematocele includes testicular tumor, testicular torsion, and epididymoorchitis.3229 In hematocele of recent occurrence the tunica sac contains coagulated fresh blood. If the hematocele is older, the tunica sac appears filled with

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50% of cases.3254 Other reported sites of displacement include tissues adjacent to the superficial inguinal ring; suprapubic, inguinal canal, perineum, intraabdominal, and retrovesical sites; and acetabular or crural areas.3249,3255–3257 Canalicular or intraabdominal dislocation occurs only in the setting of preexisting patent processus vaginalis.3246–3248 Dislocation has also been reported in cases of pelvic fractures.3258 More force is necessary to produce luxation in an adult than that which causes rupture of the tunica albuginea.3259 Manual reduction is the treatment of choice for acute traumatic dislocation of the testis. Open reduction is advisable for delayed cases when testicular rupture or possible torsion is suspected, or if manual reduction fails.3260 Prompt surgical intervention is crucial because the testis may be salvaged if surgical repair is performed within 72 hours of injury.3261 In one remarkable case, bilateral orchiopexy 13 years after traumatic dislocation was successful in restoring spermatogenesis.3262 Fig. 12.313 Old hematocele. Vaginal cavity is filled up with calcified laminar formations that compress an atrophic testis.

Fig. 12.314 Old hematocele. Around the testicular parenchyma an albuginea with marked fibrosis, a trabecular bone parallel to it, and fissures of cholesterol in the periphery are observed.

in all cases.3239,3240 The same is true of CT, whereas MRI usually provides the correct diagnosis.3241,3242 In children, peritumoral and retroperitoneal hemorrhage, splenic rupture, and adrenal cortical hemorrhage have reportedly caused hematocele by tracking of blood into a communicating hepatocele.3243–3245 Testicular Dislocation or Luxation

Testicular dislocation or luxation, first reported in 1818, involves displacement of one or both testes to a nonscrotal location such as the inguinal canal, abdominal cavity, or acetabular area, or distant locations such as the perineum, subcutaneous tissues, or superficial to the outer oblique fascia.3246–3250 This injury is characteristic of motorcycle accidents and is caused by direct testicular contusion against the gas tank or the handlebars.3251,3252 Widespread use of motorcycles in Asian countries accounts for the high frequency of reported cases in the Asian literature. Most cases are unilateral (90%).3253 In displacement, muscular attachments of the spermatic cord are broken and the testis becomes lodged between the external oblique fascia and subcutaneous tissue in more than

Testicular Trauma and Infertility

Few studies have addressed the relationship between testicular injury and infertility. Direct testicular injury is not considered a classic cause of spermatogenic impairment and testicular dysfunction. However, 17% of reported patients with unexplained infertility have a history of trauma. The spermiogram of such patients usually shows low number of spermatozoa, decreased motility, and high number of abnormal forms. In one report of patients with bilateral testicular trauma, all had more than 20 million/mL spermatozoa.3235 Conversely, another study revealed that less than 50% of patients who underwent unilateral orchiectomy or open repair had decrease in sperm density and motility several months later, whereas those who underwent conservative treatment had minimal alterations.3263,3264 Therefore it is compulsory to protect testes adequately while engaging in some sports. Biopsies show decreased spermatogenesis and groups of completely hyalinized tubules. These observations suggest that testicular lesions are underestimated. The most constant hormonal finding is an increase in estradiol level.3265 Possible causes of altered spermatogenesis include direct effect of trauma, formation of antisperm antibodies in response to disruption of the bloodtestis barrier, and sperm excretory duct lesion.

Cancer Therapy Sexual dysfunction occurs in 25% to 50% of patients treated for cancer.3266 Testicular cancer, Hodgkin disease, and leukemia are the most frequent malignancies during the reproductive years. Other cancers in children are Wilms tumor, non-Hodgkin lymphoma, germ cell tumor, Ewing sarcoma, osteosarcoma, soft tissue sarcoma, retinoblastoma, and brain tumors.3267 Approximately 1 in 600 children experiences development of cancer before the age of 15 years. Remarkable progress has been made in the treatment of cancer in infants and children, and up to 80% are now cured.3268 In 2010, it was estimated that 1 in 250 young adults between the ages of 20 and 29 years was a survivor of childhood cancer.3269,3270 Concerns have been raised about the possible mutagenic effect of chemotherapy on sperm. Therefore preservation of fertility requires selection of less gonadotoxic therapeutic regimens; if paternity is planned, cryopreservation of semen before treatment may be considered. Cancer treatments such as surgery, radiation therapy, and chemotherapy may achieve relatively high rates of remission and long-term survival. Despite continuous improvement in cancer treatment, altered testicular function and infertility frequently represent major adverse effects. Gonadal damage in boys treated for cancer may result from chemotherapy or

CHAPTER 12 Nonneoplastic Diseases of the Testis

radiation therapy involving the spinal or pelvic area. The testis is highly susceptible to the toxic effects of cancer therapy throughout life.3271 Damage may involve the somatic cells of the testis (Sertoli and Leydig cells), as well as the germ cells. The main risk factors that adversely affect fertility in child cancer survivors are age at the time of the treatment, use of alkylating agents, and irradiation of reproductive organs or the hypothalamus/pituitary.3272 Many other aspects of cancer treatment also impair fertility, and the disease itself may contribute to male gonadal dysfunction. For example, up to 70% of patients with Hodgkin disease, assessed before the beginning of treatment, have impaired semen quality.3273–3275 This impairment also seems to occur with other malignancies to a lesser extent. Patients with testicular germ cell tumor bear the highest risk for having poor semen quality before cancer treatment.3276,3277 The association of testicular germ cell tumor and impaired spermatogenesis is well known, and both are included in the testicular dysgenesis syndrome. In patients with testicular cancer, individuals with certain genotypes may be more susceptible to treatment.3278 Delayed maturation in spermatogenesis may be found in prepubertal patients before treatment of solid mesenchymal tumors.3279 The mechanisms involved in testicular dysfunction in patients with cancer are poorly understood, but are likely multifactorial. Possibilities include primary germ cell deficiency, release by tumor cells of substances that are toxic to seminiferous tubules and Leydig cells, and alteration of the hypothalamohypophyseal axis.3280,3281 Paraneoplastic phenomena, such as fever, anorexia, and pain, may also impair semen quality.3282,3283

705

Fig. 12.315 A 27-year-old patient who consulted for infertility. He had a history of radiotherapy treatment for a retroperitoneal ganglioneuroblastoma. Seminiferous tubules of variable caliber with only Sertoli cells whose number varies from one tubule to another. Diffuse Leydig cell hyperplasia.

Radiation Therapy

Testicular parenchyma is one of the most radiosensitive tissues of the body, and germ cells are the most radiosensitive cells of the testis at all ages.3191 In children, radiation-induced gonadal damage is most often encountered after direct irradiation used for management of testicular relapse of leukemia, or after total body irradiation that is given before bone marrow transplantation. The degree and persistence of damage depend on the total dose, patient age, extent and site of the treatment field, and the fractionation schedule. Fractionation may be more harmful to testicular function because it reduces the time available for repair.3193,3284 Experimental irradiation of volunteers with a single dose revealed that late spermatogonia (Ap and B) are more radiosensitive than early (Ad) spermatogonia. Ap and B spermatogonia may be destroyed with doses as low as 0.1 to 1.2 Gy (1 Gy ¼ 100 rad), whereas Ad spermatogonia tolerate doses higher than 4 Gy. Type A spermatogonia, spermatids, and spermatozoa are, respectively, 100, 200, and 10,000 times less radiosensitive than B spermatogonia. Doses of more than 4 Gy may produce permanent damage to spermatogenesis, and doses higher than 6 Gy produce Sertoli cell–only pattern.3285 Testicular irradiation (16 to 18 Gy) therapy as used to treat GCNIS is associated with a high rate of permanent sterility.3276 Leydig cells are more resistant to damage than the germinal epithelium, and function of these cells is usually preserved up to 20 Gy in prepubertal boys and at up to 30 Gy in men. This finding explains why development through puberty with normal testosterone level is the rule, and why many patients develop secondary sexual characteristics despite severe impairment of spermatogenesis.3286 Patients treated for Wilms tumor, retroperitoneal ganglioneuroblastoma, or paratesticular rhabdomyosarcoma may have delayed puberty and, in adulthood, oligozoospermia or azoospermia with elevated level of FSH; these findings suggest that Leydig cells are also damaged (Figs. 12.315 and 12.316).

Fig. 12.316 Testis from a 26-year-old patient who, at the age of 9 years, underwent surgery followed by radiotherapy for paratesticular rhabdomyosarcoma. The testicular biopsy shows postirradiation lesions, including germ cell absence and peritubular and interstitial fibrosis.

A special case is that of children with acute lymphoblastic leukemia involving the testis. Radiation therapy with doses of 20 to 25 Gy, either alone or with chemotherapy, causes irreversible damage to Leydig cells and induces hyalinization of seminiferous tubules. Patients experience azoospermia and hypogonadotropic hypogonadism with low serum testosterone level. In addition, radiation induces dense interstitial fibrosis and loss of peritubular cells, thus obscuring the border between the interstitium and tubules. This makes the tubules difficult to identify in hematoxylin and eosin–stained sections. Leydig cells are atrophic and decreased in number. Ischemia secondary to radiation-induced vascular injury also contributes to hyalinization. Tumors of the central nervous system are the most common solid malignancy in the pediatric population. Cranial irradiation is frequently used as a therapeutic modality in these children. Although this treatment does not harm the gonads directly, fertility may be impaired by disruption of the hypothalamopituitary-

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gonadal axis. Patients receiving radiation doses of 35 to 45 Gy experience deficiencies in FSH and LH secretion. The clinical sequelae of gonadotropin deficiency vary in severity from subclinical abnormalities detectable only by an abnormal GnRH test to significant reduction in circulating sex hormone levels, delayed puberty, and infertility.3282,3287 Sertoli cells tolerate up to 60 Gy, although they show ultrastructural alterations after low doses of radiation, as well as increased phagocytosis of germ cell remnants.3282 Recovery of spermatogenesis takes place from surviving stem cells (type A spermatogonia) and depends on the dose of radiation. Complete recovery requires 9 to 18 months after irradiation of 1 Gy, 30 months after exposure of 2 to 3 Gy, and 5 years or more after exposure of 4 Gy.3285 Despite optimal protection, the contralateral testis absorbs 0.2 to 1.4 Gy during adjuvant therapy for rectal cancer or when the opposite testis is irradiated,3288,3289 a dose sufficient to cause temporary azoospermia. Similarly, irradiation of iliac or inguinal lymph nodes for Hodgkin disease or other forms of lymphoma exposes the testes to approximately 5 Gy.3290 Restoration of testicular function is time dependent, requiring at least 2 years.3291,3292 Fertility in patients with thyroid cancer who received radioiodine131 (131I) therapy decreases transiently.3293 Chemotherapy

Use of cytotoxic chemotherapy is associated with a wide variety of adverse side effects, including gonadotoxicity. The prepubertal testis is especially vulnerable, probably because of the steady turnover of early germ cells that undergo spontaneous degeneration before the haploid stage is reached.3294 It is postulated that this activity is essential for normal adult function, and thus reduced fertility (as a consequence of cytotoxic treatment) is anticipated when children receive chemotherapy. Chemotherapeutic agents kill rapidly proliferating cells, differentiating spermatogonia, and stem cells. In addition, stem spermatogonia that do survive fail to differentiate, resulting in permanent infertility. Leydig cells are more resistant than germ cells due to lower turnover rate. Leydig cell dysfunction after chemotherapy is usually limited to elevated LH concentration with normal or low normal testosterone level, and thus secondary sexual characteristics develop normally. Less frequently, patients show hypogonadism.3295 Numerous chemotherapeutic agents are gonadotoxic, and the nature and extent of gonadal injury depend on the drug administered, cumulative dose, treatment duration, combination used, age, pretreatment gonadal status, and individual sensitivity (Fig. 12.317).3296,3297 The adverse effects of chemotherapy on spermatogenesis are caused by chromosomal aberrations (platinum antineoplastic agents and topoisomerase inhibitors), maturation arrest by inhibiting microtubule polymerization (vinca alkaloids), mutagenic effect in all stages of spermatogenesis (alkylating agents), and impairment of spermatozoa motility. Taxanes inhibit microtubule function, thereby inhibiting cell division, and cause reduction of inhibin B and reciprocal elevation of FSH, which are associated with significant gonadal damage.3298 Certain treatment regimens, such as that used for Hodgkin disease, are especially prone to infertility. Combination chemotherapy makes it difficult to ascertain which specific agent is responsible for azoospermia and Leydig cell dysfunction. Comparative studies of chemotherapy for acute lymphoblastic leukemia, extragonadal solid tumors, Hodgkin disease, Ewing sarcoma, and other soft tissue sarcomas in children and pubertal boys have shown that alkylating agents (chlorambucil, cyclophosphamide, and melphalan) cause the most severe testicular damage.1080,3299–3302 Injuries are

Fig. 12.317 A 12-month-old child with severe combined immunodeficiency who had received bone marrow transplantation. Small-sized seminiferous tubules with absence of germ cells. Note decreased Leydig cells.

dose dependent and occur regardless of tumor type, age, or pubertal status at diagnosis. Seminiferous epithelium is the most vulnerable cell type to the detrimental effects of this chemotherapy. Alkylating agents destroy the seminiferous tubular cells and induce tubular atrophy, thus shrinking the testis and increasing FSH serum concentration.3303 These agents also impair Leydig cell function and lower testosterone level despite normal or elevated serum level of LH and an exaggerated response of LH to GnRH administration.3304 Cyclophosphamide appears to be responsible for the greatest incidence of temporary or permanent cases of azoospermia after chemotherapy. This agent acts directly on the spermatogenic stem cells, and recovery depends on the number of surviving cells.3301 In children, cyclophosphamide reduces seminiferous tubule diameter and germ cell number; nuclei in the residual spermatogonia are enlarged. Puberty may progress, even during treatment, and the adult testis may show a Sertoli cell–only pattern.1080 In adults, cyclophosphamide treatment may cause irreversible testicular damage (Figs. 12.318 and 12.319). Administered alone, 20 g/m2 produces permanent azoospermia in 50% of men. If cyclophosphamide is administered with doxorubicin, vincristine, dacarbazine, or dactinomycin (drugs that alone do not cause azoospermia), doses of 7.5 g/m2 will cause azoospermia in 50% of patients. Fludarabine, used for the treatment of chronic lymphocytic leukemia, produces testicular damage with diminution of ejaculate volume, oligozoospermia, increased serum levels of FSH and LH, and decreased testosterone level. DNA in spermatozoa is markedly abnormal, an effect that persists for several months.3305 High dosage of ifosfamide-based therapy for osteosarcoma causes a high rate of azoospermia.3306 Cisplatin-based regimens used in the treatment of testicular germ cell tumor cause azoospermia at high dosage (400 to 600 mg/m2).3307 There are few data for newer drugs such as taxanes, oxaliplatin, irinotecan, monoclonal antibodies. and tyrosine kinase inhibitors. Inhibin B was slightly reduced after treatment with oxaliplatin.3308 Experimental studies in prepubertal mice found that Irinotecan metabolite SN38 induces marked dose-dependent sensitivity in germ cells.3309 Imatinib mesylate (tyrosine kinase inhibitor), used in the treatment of chronic myeloid leukemia, produces severe oligozoospermia.3310

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.318 Testis from a patient with Hodgkin disease after chemotherapy. The seminiferous tubules are small and contain only vacuolated Sertoli cells. The testicular interstitium has pseudohyperplasia of Leydig cells.

Fig. 12.319 A 36-year-old patient with Hodgkin disease who required bone marrow transplantation. He died of infectious complications. Seminiferous tubule with only Sertoli cells. The interstitium contains abundant macrophages and lymphocytes.

Combinations of chemotherapy drugs heighten the negative effects on testicular function. Procarbazine, used alone to treat Hodgkin disease, causes permanent azoospermia in 30% of patients; however, when combined with mustine, vincristine, and prednisolone, it causes 97% of male patients to became permanently sterile.3285 LH concentration is raised, suggesting Leydig cell impairment. Patients treated with procarbazine, cyclophosphamide, vincristine, and prednisone do not recover spermatogenesis even if the cyclophosphamide dose does not exceed 4.8 g/m2. Newer protocols with different drugs and doses are constantly introduced to reduce gonadotoxicity. Studies of young adults add negative data about fertility restoration in patients with cancer. Approximately 17% those who received chemotherapy are azoospermic at the initial diagnosis.3311 In a different way, damage may impair the number, morphology, and motility or DNA integrity of spermatozoa. The causes of this damage may be more complex than increased catabolic state,

707

malnutrition, or increase in stress hormones and decrease in gonadotropic levels.3281 Chemotherapeutic regimens that include neither alkylating agents nor procarbazine, such as the ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or VBM (vinblastine, bleomycin, and methotrexate) regimens produce reversible azoospermia in 36% of patients. Alternating use of MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) and ABVD causes testicular dysfunction in 87% of patients, but spermatogenesis recovers in 40%.3312 Patients with germ cell malignancy who received chemotherapy with BEP regimens (cisplatinum, etoposide, and bleomycin) become azoospermic 7 to 8 weeks after starting treatment. When the total doses reach 600 mg/m2, infertility is irreversible; at lower dosages, fertility may be recovered over a period of approximately 2 to 5 years (50% and 80% of patients, respectively), although a high percentage of spermatozoa with DNA abnormalities will persist.3313,3314 Therefore fertility preservation after cancer treatments requires careful selection of the least gonadotoxic therapeutic regimen, as well as male fertility preservation surgical approaches.3315,3316 International guidelines recommend discussion with the patient or parents about infertility, fertility preservation options, and potential need for contraception before initiating therapy.3317,3318 Cryopreservation of semen is now standard practice and should be offered to all men who are about to receive potentially sterilizing therapy. Advances in assisted reproductive techniques increase the likelihood of successful pregnancy using cryopreserved spermatozoa.3297 Cryopreservation of immature testicular tissue or isolated germ cells from prepubescent males to achieve restoration of fertility after treatment, either by germ cell transplantation or by in vitro maturation of the germ cells harvested, remains experimental.3279,3282,3319–3321 Research in the field of spermatogenic stem cells offers promise with options such as autotransplant of stem cells for repopulation of the testes after treatment.3298 Research efforts are also concentrated on techniques for maturation and proliferation of immature gametes after thawing.3322 However, effective gonadal function-preserving drugs are not yet available for use in male patients.3323 A recent animal study reported the protective effect of humanin analog on germ cells during chemotherapy in male mice, but clinical studies have not yet begun.3324 Apart from causing gonadotoxicity, other treatments may also impair gonadal function by inducing endocrine disorders. Opioids used for pain management inhibit gonadal function and cause hyperprolactinemia.3316 Hypogonadism in childhood cancer survivors may be related to local or brain irradiation.3325 Potential for Fertility After Cancer Treatment in Childhood

The wide spectrum of gonadal insults after chemotherapy or radiation therapy makes it difficult to accurately predict potential fertility for individual patients. Risk for subfertility may be categorized according to the type of malignancy and the associated treatment (Table 12.27).3295,3315,3326 Low risk for development of subfertility is observed after treatment of acute lymphoblastic leukemia, Wilms tumor, stage 1 sarcoma, germ cell tumor (with opposite gonadal preservation and no radiation therapy), retinoblastoma, and brain tumor treated with surgery only or cranial irradiation lower than 24 Gy. Medium risk for subfertility is observed with acute myeloblastic leukemia, hepatoblastoma, osteosarcoma, Ewing sarcoma, high-stage sarcoma, neuroblastoma, non-Hodgkin lymphoma, Hodgkin disease treated with “alternating therapy,”

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Nonneoplastic Diseases of the Testis

Risk for Gonadal Subfertility due to Cytotoxic Drugs and Current Treatments for Disease

High Risk

Medium Risk

Low Risk

Limited Data

Platinum analogues Cisplatin Carboplatin Doxorubicin BEP ABVD

Plant derivatives Vincristine Vinblastine Antibiotics Bleomycin Dactinomycin Antimetabolites Methotrexate Mercaptopurine 5-Fluoruracil

Taxanes Oxaliplatin Irinotecan Tyrosine kinase inhibitors Monoclonal antibodies

Acute myeloblastic leukemia Hepatoblastoma Osteosarcoma Ewing sarcoma Soft tissue sarcoma Neuroblastoma Non-Hodgkin lymphoma Hodgkin disease: “alternating therapy” Brain tumor: craniospinal radiotherapy Cranial irradiation >24 Gy

Acute lymphoblastic leukemia Wilms tumor Soft tissue sarcoma: stage 1 TGCT (gonadal preservation and no radiotherapy) Retinoblastoma Brain tumor (surgery only) Cranial irradiation <24 Gy

Drugs Alkylating drugs Cyclophosphamide Ifosfamide Busulfan Melphalan Chlorambucil Chlormethine Procarbazine

Disease/Treatment Total body irradiation Localized radiotherapy: pelvic/testicular Chemotherapy conditioning for bone marrow transplant Hodgkin disease: alkylating agent-based therapy Soft tissue sarcoma: metastatic

BEP, Cisplatinum, etoposide and bleomycin; ABVD, Doxorubicin, bleomycin, vinblastine and dacarbazine; TGCT, Testicular germ cell tumor. Adapted from Brydoy M, Fossa SD, Dahl O, Bjoro T. Gonadal dysfunction and fertility problems in cancer survivors. Acta Oncol 2007;46:480-489; and Brougham MF, Kelnar CJ, Sharpe RM, Wallace WH. Male fertility following childhood cancer: current concepts and future therapies. Asian J Androl. 2003;5:325-337.

and brain tumor treated with craniospinal radiation therapy or cranial irradiation higher than 24 Gy. High risk for development of subfertility is associated with total body irradiation, localized radiation therapy either in the pelvic or testicular region, chemotherapy conditioning for bone marrow transplant, alkylating agent–based therapy in Hodgkin disease, and treatment of metastatic sarcoma.3282 A high percentage of children with cancer reach adulthood, so infertility is a serious potential long-term side effect of treatment (Fig. 12.320). Prevention of sterility in survivors of childhood cancer is a major challenge. However, early detection of gonadal damage is not currently possible because there is no sensitive or specific marker of gonadal function in the prepubertal age group. At present, there is great interest in plasma inhibin B or the inhibin B/FSH ratio as a potential marker of gonadotoxicity in this age group.3282,3327–3329 Interdisciplinary cooperation among patients, pediatric oncologists, surgeons, immunologists, and endocrinologists is required on a routine basis to provide individualized options for fertility preservation.3330–3333

Estrogen and Antiandrogen Therapy Estrogen treatment is used for adults with prostate cancer and those with gender dysphoria undergoing sex reassignment surgery to female. In the latter group, cross-sex hormone treatment is a prerequisite for sex reassignment surgery. Patients with prostate cancer treated with estrogens have reduced spermatogenesis, Sertoli cell–only pattern, or spermatogonia-only– containing tubules, reduced Leydig cell number, and hyalinized tubules (Fig. 12.321).3334

Fig. 12.320 Adult man consulting for infertility who was treated with chemotherapy for a nephroblastoma in his infancy. The testicular parenchyma shows mixed atrophy with one seminiferous tubule with Sertoli cell–only pattern and Sertoli cells of adult type and the other two tubules with spermatogenesis. BEP: Cisplatinum, etoposide and bleomycin; ABVD: Doxorubicin, bleomycin, vinblastine and dacarbazine; TGCT: Testicular germ cell tumor.

In patients with gender dysphoria changing from male to female, testicular changes have been studied in bilateral orchiectomy specimens after sex reassignment surgery. Estrogen exposure during adulthood causes atrophy and induces true dedifferentiation of adult human Sertoli cells, including induction of immature

CHAPTER 12 Nonneoplastic Diseases of the Testis

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48% of patients show spermatogenesis.3336 Long-term treatment causes pronounced Sertoli cell changes, initial nuclear rounding followed by elongation with the development of dark chromatin masses.3337 Eventually, nuclei come to resemble those of infantile Sertoli cells, including pseudostratification. Tubules become hyalinized and peritubular cells increase, whereas Leydig cells may disappear,3335,3338 decline or increase in number, or remain unchanged.1947,3335,3338 Estrogens act on the pituitary, by inhibiting LH secretion, and on Leydig cells.3339 The action of GnRH agonist analogues is limited to the pituitary. Treatment with nonsteroid antiandrogens, which are highly selective, do not produce alterations in Leydig cells or seminiferous tubules.

Fig. 12.321 Hypogonadism caused by estrogen therapy for prostate cancer. The seminiferous tubules contain isolated spermatogonia and dedifferentiated Sertoli cells with spherical nuclei, small nucleoli, and pseudostratified infantile distribution. The interstitium contains scattered Leydig cells.

immunophenotype such as reexpression of antim€ ullerian hormone, D2–40, and inhibin bodies.1947,3335 Histologic findings in these patients may be classified into three groups: (1) complete but quantitatively decreased spermatogenesis with low number of spermatocytes and spermatids; (2) predominantly pubertal-like seminiferous tubules (the most frequent pattern); and (3) mainly infantile seminiferous tubules. In 72% of cases, spermatogenesis is pubertal-like, with seminiferous tubules containing Sertoli cells and spermatogonia only, or spermatogonia and primary spermatocytes, as the only germ cells. Spermatogonial numbers are highly variable; Sertoli cell nuclei are round instead of indented as in normal adults, and tubular walls are thickened (Fig. 12.322). Sertoli cell–only tubules in patients treated with estrogens contain dedifferentiated Sertoli cells. A correlation exists between the degree of Sertoli cell dedifferentiation and the dose and timing of treatment with estrogens or antiandrogens. Brief treatment induces germ cell loss and inconspicuous Sertoli cell changes, and up to

Fig. 12.322 Patient with long-term estrogen therapy for gender change showing tubular structures reminiscent of Sertoli cell nodules.

Surgery Sexual function is often adversely affected in patients who undergo bilateral retroperitoneal lymph node dissection for nonseminomatous testicular cancer. Up to 90% lose antegrade ejaculation, although libido, erection, and orgasm are normal. Loss of antegrade ejaculation results from removal of or injury to sympathetic ganglia and the hypogastric nervous plexus during surgery. Unilateral surgery, especially if limited to the right side, and modern nervesparing techniques reduce this complication by preserving antegrade ejaculation and fertility.3340–3343 Hypospermatogenesis may develop after surgery for rectal cancer, perhaps as a result of vascular compromise.

Infertility in Patients With Spinal Cord Injury Spinal cord injury is common, with more than 10,000 new cases annually in the United States, predominantly involving young adults.3344 Fertility is impaired in 90% of male patients with spinal cord injury. Major sexual dysfunctions in these patients include lack of erection and ejaculation and poor semen quality.3345–3351 Failure of ejaculation occurs in 95% of patients. Most of these men demonstrate defective seminal emission as well (entrance of semen into the posterior urethra).3352 Erectile dysfunction is successfully treated with oral and injectable medications, the use of vacuum devices, and penile prosthetic implants. Semen may be obtained by means of vibratory stimulation of the penis or electroejaculation in more than 90% of cases, but quality is low, with increased number of dead spermatozoa, markedly low motility, and reduced fertilization rate.3353–3355 Low semen quality does not seem to be related to changes in scrotal thermal regulation, frequency of ejaculation, or duration of spinal cord damage, but rather to factors related to the seminal plasma.3065 Possible explanations include genitourinary tract infection, endocrine anomaly, and impaired spermatogenesis because men with spinal cord injuries experience defects in the secretory function of Leydig cells, Sertoli cells, and male accessory genital glands.3352 Recurrent infection occurs in 60% to 70% of patients. Compared with controls, semen in these patients has significantly increased numbers of neutrophils and macrophages, and markedly higher levels of reactive oxygen species.3356,3357 These findings, coupled with the presence of elevated cytokine levels, are likely linked to the low quality of semen.3358 Neutralization of target cytokines does not damage sperm DNA or sperm viability, a finding indicating that this method may hold promise for improving sperm motility in these men.3359 Endocrine anomalies are transient, and hormone levels return to normal a few months after cord injury. More than 50% of patients have abnormalities of the adluminal compartment of the seminiferous tubules, with varying

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degree of immature germ cell sloughing.3360 In 50% of patients, the number of mature spermatids per cross-sectioned tubule is less than 10 (normal is >21). Possible etiologies include increase in testicular temperature resulting from vascular dilation or alteration in scrotal thermoregulation secondary to impaired sympathetic innervation from prolonged wheelchair restraint; alteration in sperm transport secondary to nerve injury that results in sperm stagnation in seminal vesicles, a hostile environment that normally is devoid of spermatozoa; and abnormal composition of seminal fluid with consequent deterioration of spermatozoa that, in the epididymis and ductus deferens, had good motility.3361,3362 More than 25% of patients with spinal cord injury have browntinged semen in some ejaculations.3363 Although the cause is unknown, it could be related to seminal vesicle dysfunction. When spermatozoa cannot be obtained by electroejaculation or vibratory stimulation, vasal aspiration or surgical sperm retrieval may be offered.3364 Most patients have at least a few mature spermatids in some seminiferous tubules; therefore TESE followed by intravaginal insemination, intrauterine insemination, or ICSI is a reasonable consideration in azoospermic patients.3360,3365 Successful pregnancy with sperm from male partners with spinal cord injury may occur despite abnormal semen quality.

Fig. 12.323 Orchitis caused by cytomegalovirus in a patient with HIV. The inflammatory infiltrate of the testicular interstitium has two characteristic intranuclear inclusions.

Inflammation and Infection Infectious agents may reach the testis and epididymis through blood vessels, lymphatics, sperm excretory ducts, or directly from a superficial wound. Infection transmitted through the blood mainly affects the testis and causes orchitis, whereas infection ascending through sperm excretory ducts usually causes epididymitis. Acute inflammation is accompanied by enlargement of the testis or epididymis. The tunica albuginea is covered by a fibrinous exudate, and the testicular parenchyma is yellow or brown. Bacterial infection may cause abscess formation. In some cases the infection heals with deposition of granulation tissue and fibrosis; in others, infection may persist as an active process, resulting in chronic orchiepididymitis.3366

Orchitis Viral Orchitis The most common viral causes of orchiepididymitis are mumps virus and coxsackie B virus; others include influenza, infectious mononucleosis, echovirus, lymphocytic choriomeningitis, adenovirus, coronavirus, Rio Bravo virus, varicella, vaccinia, rubella, dengue, and phlebotomus fever. Subclinical orchitis probably occurs during other viral infections (Fig. 12.323). Before vaccination was widely used, mumps orchiepididymitis complicated 14% to 35% of adult mumps cases and was bilateral in 20% to 25% of cases (Fig. 12.324). Nevertheless, miniepidemics still occasionally occur.3367,3368 Japan has one of the highest incidences among developed countries with more than 1 million annual cases.3369 Incidence is also high in other countries where vaccination is not obligatory.3370 In approximately 85% of cases of mumps orchitis, the epididymis is also involved, but epididymal involvement alone is rare.3371 Clinical symptoms of orchitis usually appear 4 to 6 days after symptoms of parotitis, but orchitis may also appear without parotid involvement.3372 Testicular involvement is diffuse and consists of acute inflammation of the interstitium and seminiferous tubules. The tubular lining is destroyed, leaving behind only hyalinized tubules and clusters of Leydig cells.3373

Fig. 12.324 Orchitis secondary to mump virus infection in a patient consulting for infertility. A group of tubules with complete spermatogenesis surrounded by completely hyalinized tubules may be observed.

With time the testes shrink and become soft. If infection is bilateral, the patient usually becomes infertile, with severe oligozoospermia or azoospermia, although biopsy may reveal the presence of mature spermatids in some tubules, thus allowing sperm extraction for paternity.3374,3375 If only one testis is affected, sperm concentration may be normal or slightly decreased and fertility is maintained. Occasionally, testicular damage is so severe that testicular endocrine function is impaired, causing hypergonadotropic hypogonadism, with low testosterone level and regression of secondary sex characteristics. Mumps orchiepididymitis is infrequent in childhood.

Bacterial Orchitis Most cases of bacterial orchitis are associated with bacterial epididymitis (Fig. 12.325). Orchitis secondary to suppurative epididymitis caused by E. coli is most common.3376 Tubules are effaced by intense acute inflammation (Fig. 12.326). Chronic orchitis with microabscesses is caused by E. coli, streptococci,

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.325 Bacterial orchitis in an adult patient. Gross image of the testis showing congestion and separation of lobules by intense edema.

Fig. 12.326 Bacterial orchitis. Inflammatory infiltrate as microabscesses directly related to seminiferous tubules. The interstitium also shows abundant inflammatory infiltrate.

staphylococci, pneumococci, Salmonella enteritidis, and Actinomyces israelii.3377–3379 In some cases of chronic bacterial orchitis the testis contains an inflammatory infiltrate consisting of numerous histiocytes with foamy cytoplasm (xanthogranulomatous orchitis) (Fig. 12.327), similar to that of idiopathic granulomatous orchitis but lacking intratubular giant cells.3380–3382 Rarely, as in Whipple disease, large numbers of bacilli are present in histiocytes in the interstitium, vascular walls, and seminiferous tubules (Fig. 12.328). The most frequent complications of pyogenic bacterial orchiepididymitis are abscesses (Fig. 12.329), involving the testis or tunica sac, and chronic draining scrotal sinus. Small fragments of testicular parenchyma may be eliminated through the scrotal skin, a condition known clinically as fungus testis. Another complication is testicular infarct (Fig. 12.330), resulting from compression or thrombosis of veins in the drainage system of the scrotal contents.3383,3384

711

Fig. 12.327 Xanthogranulomatous orchitis showing a dense infiltrate of macrophages with vacuolated cytoplasm surrounded by atrophic seminiferous tubules.

Fig. 12.328 Whipple disease. Seminiferous tubules and interstitium with histiocytes showing microvacuolated cytoplasm.

Granulomatous Orchiepididymitis Most cases of chronic orchiepididymitis are associated with granulomas in the testis. Specific causes may require special stains, cultures, or serologic tests and include tuberculosis, syphilis, leprosy, brucellosis, mycoses, and parasitic diseases. In sarcoidosis and idiopathic granulomatous orchitis the causative agent is unknown. Tuberculosis

The incidence of tuberculous orchiepididymitis declined after the development of effective antibiotics, but it has experienced resurgence among people who have emigrated from countries with a high incidence of the disease, as well as in the increasing population of immunologically compromised patients. Most cases of tuberculous orchiepididymitis are associated with involvement elsewhere in the genitourinary system.3385 Tuberculous epididymitis is usually the result of ascent of mycobacteria from tuberculous prostatitis, which in turn is often secondary to renal or pulmonary tuberculosis, although tuberculous epididymoorchitis without renal involvement has also been observed.3386 The pattern of spread is different in children: more than one-half

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Fig. 12.329 Testicular tissue abscess secondary to orchiepididymitis. Note a peripheral subalbugineal crescent of testicular parenchyma.

Fig. 12.331 Tuberculous orchitis in a 38-year-old patient with a white-gray nodule that has a pseudotumoral pattern and caused testicular enlargement.

Fig. 12.330 Testicular necrosis showing silhouettes of seminiferous tubules occupied by bacterial colonies.

Fig. 12.332 Tuberculous orchitis showing central necrosis surrounded by numerous granulomas, some of which contain giant cells in their centers.

Syphilis

have advanced pulmonary tuberculosis, and the testis is infected through the blood.3387 More than 50% of patients with renal tuberculosis experience development of tuberculous epididymitis, and orchitis occurs in approximately 3% of patients with genital tuberculosis, usually secondary to epididymal tuberculosis. Tuberculous orchiepididymitis may be sexually transmitted.3388 It occurs mainly in adults: 72% of patients are older than 35 years, and 18% are older than 65 years. Signs and symptoms may be mild, consisting only of testicular enlargement and scrotal pain or enlargement mimicking tumor.3389 In such cases, fever is infrequent, and constitutional symptoms may be absent.3390 Typical caseating and noncaseating granulomas destroy the seminiferous tubules and interstitium (Figs. 12.331 and 12.332). In immunosuppressed patients the granulomas consist of epithelioid histiocytes and a few lymphocytes with rare giant cells. Acid-fast bacilli tend to be more numerous in immunosuppressed patients. Similar lesions may be observed in orchiepididymitis caused by bacillus Calmette-Guerin, which is usually used for intravesical instillation in patients with vesicular urothelial carcinoma.3391,3392

Syphilitic orchitis may be congenital or acquired, with similar histologic findings. In congenital syphilitic orchitis, both testes are enlarged at birth. If diagnosis is delayed until puberty, the testis often shows retraction and fibrosis. In adults, acquired orchitis is a complication of the tertiary stage of syphilis and has two characteristic histologic patterns: interstitial inflammation and gumma formation. Early in the disease, patients with interstitial orchitis have painless enlargement. Grossly the parenchyma is gray with translucent areas. Plasma cells are abundant. Inflammation begins in the mediastinum testis and septa, and later extends through the parenchyma as the tubular cellular lining sloughs and undergoes sclerosis. Initially, arteries show obliterans type of endarteritis.3393 Small gummas may be observed. Eventually, inflammation subsides and is replaced by fibrosis. The epididymis is usually not affected. Gummatous orchitis, a rare entity with only 11 reported cases since the 1950s, is characterized by the presence of one or several well-delineated, grossly gray-yellow zones of necrosis.3394,3395 Histologically, ghostly silhouettes of seminiferous tubules are

CHAPTER 12 Nonneoplastic Diseases of the Testis

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visible within the gumma, surrounded by inflammation consisting of lymphocytes, plasma cells, and scattered giant cells. In most cases spirochetes may be demonstrated histochemically with Warthin-Starry silver stain, immunohistochemical stains, or by using PCR in paraffin-embedded material.3396 Leprosy

The testis may be infected in patients with lepromatous or borderline leprosy. Frequent involvement results from the relatively low intrascrotal temperature that promotes growth of the bacilli. Orchitis is usually bilateral, although the degree of involvement may differ. Occasionally, testicular involvement may be the sole indication of the infection, and diagnosis may be made by biopsy.3397 Histologic findings vary with the duration of the infection. Initially, there is perivascular lymphocytic inflammation and interstitial macrophages that contain numerous acid-fast bacilli. Later, seminiferous tubules undergo atrophy, Leydig cells cluster, and blood vessels show endarteritis obliterans. Final stages are characterized by fibrous tissue with scattered lymphocytes and macrophages containing acid-fast bacilli. Most patients with lepromatous leprosy show hypogonadism and are infertile, even if the orchitis was clinically mild.3398,3399

Fig. 12.333 Nonnecrotic granuloma composed of multinucleated giant cells, epithelioid cells, and minimal lymphocytic infiltrate in a patient with sarcoidosis.

Brucellosis

Brucellosis is common in some parts of the world, including the Middle East.3400,3401 Orchitis occurs in some patients and may be the first sign of disease. Brucellosis should be suspected when enlargement occurs in young patients with undulating fever, malaise, sweats, weight loss, and headache.3402 Occasionally it may mimic testicular tumor. There is dense lymphohistiocytic inflammation with occasional noncaseating granulomas in the interstitium. Seminiferous tubules are infiltrated by inflammatory cells and undergo atrophy. The diagnosis is made by clinical and laboratory findings, including blood culture, the Bengal rose test, and high Brucella agglutination titers, or by reverse transcriptase PCR assay of urine.3403–3405 Sexual transmission of Brucella from male to female has been reported.3406 Sarcoidosis

Sarcoidosis is a systemic granulomatous disease of unknown etiology that preferentially affects young black adults. Clinical involvement of the genitourinary tract occurs in only 0.5% of patients with sarcoidosis, but involvement of the genitourinary tract is evident in 5% at autopsy. Fewer than 30 cases of isolated epididymal involvement have been reported, and approximately 12 of these also involved the testis.3407,3408 Isolated testicular involvement is exceptional.3407,3409,3410 Testicular sarcoidosis is usually unilateral and nodular, and is often asymptomatic and found at autopsy.3411 The testis contains noncaseating granulomas similar to sarcoid granulomas at other locations, noncaseating epithelioid cell granulomas with multinucleate giant cells, minimal lymphocyte infiltrate, and Schaumann and asteroid bodies (Fig. 12.333). Before confirmation of diagnosis, other granulomatous lesions should be excluded, including tuberculosis, sperm granuloma, granulomatous orchitis, and seminoma. Seminoma may induce an intense, sarcoid-like reaction, and examination of multiple histologic sections may be necessary to find diagnostic foci.3412 Mediastinal sarcoidosis and testicular cancer may be linked.3413 Genital involvement by sarcoidosis may cause temporary or intermittent azoospermia that may improve after corticosteroid therapy.3414

Fig. 12.334 Malakoplakia of the testis showing macrophages with granular and eosinophilic cytoplasm that contains several Michaelis-Gutmann bodies.

Malakoplakia Malakoplakia is a chronic inflammatory disease that was initially described in the bladder, although subsequently found in most other organs.3415 The testes (alone or together with the epididymis) are involved in 12% of cases involving the urogenital system.3416,3417 Grossly the testes are enlarged and have brownyellow parenchymal discoloration, often with abscesses.3418 Malakoplakia causes tubular destruction associated with dense infiltrates of macrophages with granular eosinophilic cytoplasm, often containing Michaelis-Gutmann bodies (Fig. 12.334).3419,3420 The etiology is probably multifactorial. Inefficient phagocytosis by a lysosomal deficit, generally against gram-negative organisms (E. coli in 76% of the cases), has been proposed, similar to Whipple disease. Imbalance of cyclic adenosine monophosphate (cAMP) and guanosine monophosphate in favor of cAMP would give rise to deficient lysosomal degranulation and, consequently, impaired ability of phagocytes to digest bacteria completely. This hypothesis is supported by the high incidence of malakoplakia in immunosuppressed patients and others with chronic debilitating diseases.3421,3422

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The differential diagnosis includes idiopathic granulomatous orchitis and Leydig cell tumor. Inflammation in idiopathic granulomatous orchitis includes intratubular multinucleated giant cells; in malakoplakia it is difficult to identify the tubular outlines, and giant cells are usually absent. Leydig cell tumor is not usually associated with inflammation, but may contain mononucleated or binucleated cells with abundant eosinophilic cytoplasm. Reinke crystalloids are identified in up to 40% of cases of Leydig cell tumor but are absent in malakoplakia. Leydig cell tumors do not contain Michaelis-Gutmann bodies.

Orchiepididymitis Caused by Fungi and Parasites Fungal orchitis is rare; most cases are associated with blastomycosis, coccidioidomycosis, histoplasmosis, and cryptococcosis.3423 The genital tract may be involved in widespread blastomycosis. Organs most frequently affected (in decreasing order) are the prostate, epididymis, testis, and seminal vesicles. Grossly, there are small abscesses that may have caseous centers. Fungi are present measuring 8 to 15 μm in diameter with double refringent contours in giant cells rimming granulomas, and these stain with PAS and methenamine silver.3424 Coccidioidomycosis is endemic in California, the southwestern United States, and Mexico, and may manifest as epididymal disease after remission of systemic symptoms.3425 Granulomas are similar to those of tuberculosis and contain 30- to 60-μm diameter sporangia with endospores that stain with PAS. Dissemination of histoplasmosis and cryptococcosis frequently occurs after steroid therapy and may give rise to granulomatous orchitis with extensive necrosis.3426,3427 Histoplasma capsulatum measures 1 to 5 μm in diameter and may be demonstrated with silver stain. Cryptococcus is identified by its thick wall that stains with mucicarmine. Most parasites that reach the genital tract, such as Filaria and Schistosoma, are in the spermatic cord, and testicular lesions are secondary to vascular injury.3428 Testicular infection has also been reported in patients with visceral leishmaniasis, congenital and acquired toxoplasmosis (Figs. 12.335 and 12.336), Echinococcus infection, and orchitis caused by Trichomonas vaginalis.3429,3430

Idiopathic Granulomatous Orchitis Idiopathic granulomatous orchitis is a chronic inflammatory condition of older adults (mean, 59.2 years). It was first described in 1926.3431 The most prominent clinical symptom is unilateral enlargement suggesting malignancy.3432 Most patients have a history of scrotal trauma, surgical procedure, or epididymitis; 66% have symptoms of urinary tract infection with negative cultures, and 40% have sperm granuloma in the epididymis. An autoimmune etiology has been suggested. The testis is enlarged, with a nodular cut surface and areas of necrosis or infarction. Two histologic forms are seen, according to whether the lesion is predominantly in the tubules (tubular orchitis) or interstitium (interstitial orchitis). In tubular orchitis, germ cells degenerate, and Sertoli cells have vacuolated cytoplasm and vesicular nuclei. Plasma cells and lymphocytes infiltrate the walls of the seminiferous tubules to form concentric rings. Multinucleated giant cells are present in tubular lumina and sometimes in the interstitium (Figs. 12.337 and 12.338). Vascular

Fig. 12.335 Well-delimited necrotizing lesion affecting both the seminiferous tubules and the interstitium in an adult patient with toxoplasmosis.

Fig. 12.337 Idiopathic granulomatous orchitis showing seminiferous tubules with peritubular fibrosis. Numerous lymphocytes and macrophages are present in the interstitium and within seminiferous tubules. Multinucleated giant cells are present in some tubules.

Fig. 12.336 Orchitis caused by toxoplasmosis. The giant cells in the testicular interstitium and those in the seminiferous tubules or walls contain numerous organisms.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Fig. 12.338 Idiopathic granulomatous orchitis. Selective destruction of seminiferous tubules by inflammatory infiltrate with giant cells (silver methenamine).

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Fig. 12.339 Peritumoral granulomatous orchitis. The infiltrates are preferably located in the wall of the seminiferous tubule. In none of the tubular sections is germ cell neoplasia in situ observed (peripheral testicular parenchyma to a seminoma).

thrombosis and arteritis are common. In interstitial orchitis, inflammation is predominantly interstitial. Ultimately, tubular atrophy and interstitial fibrosis prevail in both forms, which may arise from different immune mechanisms.3433 Tubular orchitis histologically resembles experimental orchitis caused by injection of serum from animals with orchitis, whereas interstitial orchitis resembles orchitis produced by the transfer of cells from immunized animals. The differential diagnosis of idiopathic granulomatous orchitis is infectious orchitis caused by bacteria, spirochetes, fungi, or parasites. A useful clue in the tubular form is the presence of giant cells within seminiferous tubules without caseation.

Peritumoral Granulomatous Orchitis This lesion resembles idiopathic granulomatous orchitis and specifically tubular orchitis. It is observed in the parenchyma adjacent to some germ cell tumors, especially seminoma, characterized by the presence of giant cell epithelioid granulomas in the walls of seminiferous tubules. It differs from idiopathic granulomatous orchitis in the topography of the lesions and the density of the inflammatory infiltrates. Inflammation occurs in tubular walls between myoid cells and the basal lamina (Fig. 12.339 and 12.340). The seminiferous epithelium, often consisting only of Sertoli cells, is displaced toward the tubular lumen. Eventually, inflammatory cells including multinucleated giant cells exfoliate into the tubule. The tubular and interstitial infiltrates are not as prominent as in idiopathic granulomatous orchitis. The topography of the lesions suggests an immune response to components of the tubular walls. Focal Orchitis (Primary Autoimmune Orchitis) This lesion is characterized by the presence of inflammation around one or more seminiferous tubules. Initially, neutrophils form microabscesses between the peritubular cells and the basal lamina. Later, T lymphocytes predominate, followed by B lymphocytes and macrophages (Figs. 12.341 and 12.342). Clinical manifestations are infertility, asymptomatic orchitis (rarely with testicular mass), and the presence of antisperm-specific antibodies (ASA).3434 The occurrence of focal lymphoid cell infiltrates in the interstitium is common in infertile patients, after surgical treatment for bilateral inguinal hernia, after vasectomy complicated

Fig. 12.340 Peritumoral granulomatous orchitis. The wall of the seminiferous tubule shows in the thickness of the peritubular cells layer a giant multinucleated cell and some lymphocytes. Inside the tubule some macrophages and lymphocytes have penetrated.

by post-infection obstruction, after testicular piercing, and in cryptorchidism.1008,3435–3439 The topography of the inflammation suggests an immunologic response to components of the seminiferous epithelium that have gained access to the interstitium by alteration of the hematotesticular barrier (Fig. 12.343).

Testicular Pseudolymphoma Pseudolymphoma is a benign reactive process with a lymphoid cell proliferation so intense that it may be mistaken for lymphoma; it consists of an abundance of lymphocytes and plasma cells that partially or totally destroy the parenchyma.3440–3442 The differential diagnosis includes lymphoma, various forms of orchitis, and seminoma. The diagnosis of lymphoma may be excluded by the lack of atypia and polyclonal nature of the inflammation. Syphilitic orchitis also produces a plasma cell–rich inflammatory infiltrate, but pseudolymphoma does not have other

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Fig. 12.341 Focal orchitis showing infiltrates of lymphoid cells and macrophages within a seminiferous tubule. There is persistence of Sertoli cells and isolated spermatogonia.

Fig. 12.343 Focal orchitis. Infertile patient with obstructive azoospermia. Marked ectasia of some seminiferous tubules. Dense lymphocytic infiltrates in relation to a tubule full of spermatozoa.

Fig. 12.342 Focal orchitis. A predominantly peritubular and interstitial lymphoid infiltrate that mimics a leukemic infiltrate or lymphoma.

Fig. 12.344 Testis of a prepubertal patient with liver transplantation showing abundant macrophages that express CD68.

characteristic features of syphilitic orchitis such as endarteritis obliterans; spirochetes cannot be demonstrated by special stains. The absence of granulomas or significant numbers of macrophages, together with the negative results of specific histochemical stains, also helps exclude idiopathic granulomatous orchitis, tuberculosis, leprosy, sarcoidosis, and fungal infection. Finally, although the presence of a prominent inflammatory infiltrate and, in many cases, numerous lymphoid follicles may suggest the diagnosis of seminoma, the presence of seminoma cells can be easily demonstrated with Best carmine stain, PAS, PLAP, SALL4, or OCT 3/4. The term plasma cell granuloma refers to a reactive process characterized by the presence of polyclonal adult plasma cells that are absent in testicular plasmacytoma.3443,3444

common in such cases (Fig. 12.344). Accumulation of macrophages has also been observed in the parenchyma at the periphery of burned-out germ cell tumor (Fig. 12.345). Three situations deserve special comment: sinus histiocytosis with massive lymphadenopathy, Erdheim-Chester disease, and histiocytosis in treatment with hydroxyethyl starch plasma expander. Sinus histiocytosis with massive lymphadenopathy (or RosaiDorfman disease) is a benign proliferation of S-100 protein immunoreactive histiocytes that uniquely contain numerous lymphocytes in their cytoplasm. Involvement of the urogenital system is rare; the organ most frequently affected is the kidney followed by the testis. Lesions may be unilateral or bilateral.3445,3446 Some cases are associated with systemic hematopoietic diseases.3447 Erdheim-Chester disease is a non-Langerhans cell histiocytosis of unknown etiology. It affects the long bones of lower extremities, central nervous system, heart, lung, liver, spleen, retroperitoneum, skin, orbit, and testicles. Patients experience development of hypogonadotropic hypogonadism with testicular atrophy. The lesion is characterized by an interstitial infiltrate of lipid-laden foamy

Histiocytosis With Testicular Involvement Increased number of interstitial macrophages may be observed in autopsy material from more than two-thirds of adult males. A history of previous abdominal surgical procedure or peritonitis is

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fibrosis. The lesion and its pathogenesis are similar to vasitis nodosa (Fig. 12.346).3450,3451

Epididymitis Induced by Amiodarone

Fig. 12.345 Cryptorchid testis with burned-out germ cell tumor showing seminiferous tubules with dysgenetic Sertoli cells, hypertrophic and hyperplasic Leydig cells, and macrophage accumulations intensely stained with periodic acid–Schiff.

histiocytes. The cells have spherical nuclei without folds. Macrophages are immunoreactive for CD68, but not CD1a or S-100 protein, distinguishing this condition from other histiocytoses.3448 Histiocytosis in treatment with hydroxyethyl starch plasma expander. Interstitial macrophages are prominent owing to large size and multivacuolated cytoplasm, suggesting thesaurosis. There is no evidence of mucin glycoproteins, proteoglycans, starch, lipids, glycogen, or foreign body material. Most patients lack clinical symptoms other than pruritus and persistent erythema.3449

Other Testicular and Epididymal Lesions Epididymitis Nodosa Epididymitis nodosa is a proliferation of small, irregular ducts whose epithelium lacks characteristic features of the epididymal epithelium. The disorder is associated with inflammation and

Fig. 12.346 Epididymitis nodosa. Some ducts with regenerative epithelium and variable size and shape may be observed among ecstatic epididymal ducts.

Amiodarone is widely used in the treatment of arrhythmias. In several tissues, including the testis, amiodarone is concentrated up to 300 times its plasma level, with resulting testicular atrophy and increased serum levels of FSH and LH in some patients.3184,3452 The incidence rate of epididymitis during amiodarone therapy varies from 3% to 11% depending on dosage and duration of usage, and more than 35 cases (in several cases involvement was bilateral) have been reported.3453–3457 The disorder may occur at any age.3458 Epididymitis induced by amiodarone is clinically characterized by chronic epididymalgia without fever or leukocytosis. Although etiology is unknown, the disorder has been attributed to the ability of epididymal tissue to concentrate amiodarone and its metabolites.3459 Autopsy studies show focal areas of fibrosis and nonspecific lymphoid cell infiltrates. When amiodarone dosage is cut in half to 300 mg/day, symptoms resolve within a few weeks.3460 Recognition of this side effect of amiodarone is important to avoid unnecessary antibiotics or aggressive surgery.

Ischemic Granulomatous Epididymitis Ischemic granulomatous epididymitis refers to a lesion preferentially located in the head of the epididymis and characterized by noninfectious necrosis with production of polypoid masses of inflamed granulation tissue. It usually arises in elderly patients or those with advanced arteriosclerosis (Fig. 12.347). Granulomas containing multinucleated giant cells with cholesterol crystals develop within the efferent ducts or walls of epididymal ducts. There may be sperm microgranulomas with ductal neoformation like that of epididymitis nodosa and ceroid granulomas (Fig. 12.348). Cause is unknown, but it may result from ischemia.3461

Vasculitis The testicular arteries may be affected by systemic disorders such as Sch€onlein-Henoch purpura, Wegener disease, Cogan disease,

Fig. 12.347 Ischemic epididymitis. Caput of the epididymis showing ducts with necrotic epithelium that is total or partially sloughed in the lumens of efferent ducts.

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Fig. 12.350 Polyarteritis nodosa involving several intraparenchymal arteries. Fig. 12.348 Efferent ducts with epithelial necrosis, cholesterol crystals inside, and an infiltrate with abundant macrophages in the interstitium.

Behc¸et disease, thromboangiitis obliterans, giant cell arteritis, relapsing polychondritis, rheumatoid arthritis, and dermatomyositis, but most frequent involvement is with PAN.3462–3467

Polyarteritis Nodosa Approximately 80% of patients with PAN have testicular or epididymal involvement, but only 2% to 18% of these cases are diagnosed during life; rarely, these sites are the first manifestation of the disease. Symptoms may suggest orchitis, epididymitis, testicular torsion, or tumor.3467–3471 The testis usually shows arterial lesions in different stages of evolution, including fibrinoid necrosis, inflammatory reaction, thrombosis, or aneurysm. The parenchyma initially has zones of infarction (Figs. 12.349 and 12.350). Histologic findings similar to those of PAN may occasionally be observed as an isolated finding, referred to as isolated arteritis of the testis and epididymis, differing from classic polyarteritis by lack of vascular thrombosis, aneurysm, or infarct.3472 The etiology of isolated arteritis is unknown, but the prognosis is excellent.3473 The etiology and pathogenesis of both systemic and localized PAN are unknown.

Fig. 12.349 Necrosis of most of the testicular parenchyma secondary to polyarteritis nodosa lesions in testicular vessels and epididymis.

Some patients with systemic PAN have autoimmune (erythematous lupus, rheumatoid arthritis) or infectious diseases (hepatitis B or C, HIV). Only three patients with PAN in the male reproductive tract have malignancy in other organs (prostatic adenocarcinoma, myeloid leukemia, and hepatocellular carcinoma). Isolated arteritis of the testis and epididymis coexisted with associated germ cell tumor.3474 We have observed similar findings in other germ cell tumors, both seminomas and nonseminomatous tumors. It may be possible that antigens of tumor cells cross-react with those of the endothelium in an appropriate environment to trigger the inflammatory reaction. Identification of necrotizing arteritis in the testis or epididymis should be followed by clinical, hematologic, and biochemical studies to exclude systemic arteritis.3475,3476

Wegener Disease Testicular involvement in this multisystemic disease associated with cytoplasmic antineutrophil antibody is rare, occurring in less than 1% of affected individuals.3463,3464,3477,3478 The testis and epididymis may be affected separately or jointly. Vessels contain

Fig. 12.351 Wegener vasculitis. Patient with spermatic cord tumor. Necrotizing lesion of the wall of a longitudinally sectioned vessel. Granulomas are seen both in the wall and in the periadventitial tissue.

CHAPTER 12 Nonneoplastic Diseases of the Testis

fibrinoid necrosis, intense infiltration of neutrophils, and numerous giant cells both within and at the periphery of the vessel wall (Fig. 12.351).3479 Multiple infarcts develop in the testis. A peculiar form of nonsystemic granulomatous vasculitis affecting the testis and epididymis may occur in patients with classical seminoma in both the ipsilateral and contralateral testes. The most important features of the lesion are circumferential inflammation, preferential involvement of the media and adventitia, an abundance of epithelioid cells and multinucleated giant cells, and stenosis of the vascular lumen. It is possible that the lesions are secondary to circulating tumor antigens.

Thromboangiitis Obliterans Thromboangiitis obliterans is a rare disease that may affect the vessels of the spermatic cord, and this may be the only site of involvement. The clinical findings may mimic tumor.3480 Indurations are found along the spermatic cord, representing involvement of arteries and veins. In early lesions, thrombi and microabscesses with

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multinucleated giant cells predominate. In later lesions the inflammatory infiltrate involves all layers of the cord. Eventually, thrombi recanalize and fibrosis develops, affecting the arteries, veins, and nerves (Figs. 12.352 and 12.353).

Giant Cell Arteritis The vessels of the spermatic cord, epididymis, and testis are sometimes affected in this condition. Clinical findings may mimic neoplasm.3481 Lesions are characterized by an inflammatory reaction with giant cells that are preferentially located in the intimae, destroying and phagocytizing the internal elastic lamina. €nlein Purpura Henoch-Scho Henoch-Sch€onlein purpura disease is characterized by the classic triad of purpura, arthritis, and abdominal pain, and is most frequent in 4- to 6-year-old boys. Involvement of scrotal content is reported in up to 38% of cases.3482 Patients experience scrotal pain that invokes all the entities that constitute the clinical picture of acute scrotum.3483–3485 It is histologically characterized by the presence of leukocytoclastic vasculitis as a consequence of the deposition of immune complexes containing IgA antibody. Cogan Disease Systemic vasculitis may occur in this autoimmune disease that preferably affects the eye (interstitial keratitis) and auditory system (sensorineural deafness and vestibular dysfunction).3486 About 5% of patients have testicular involvement.3465

Fig. 12.352 Thromboangiitis obliterans. The patient consulted for tumor of the spermatic cord. Most vessels in the spermatic cord are not recognized. A fibrosis that includes the different structures of the cord stands out.

Behc¸et Disease This systemic vasculitis is characterized by recurrent aphthous oral and genital ulcers, relapsing uveitis, and cutaneous lesions. The epididymis and testis are affected with an incidence rate that varies widely, from 2% in France to 44% in Russia.3466 Clinical presentation is that of epididymoorchitis. Testicular infarction may ensue.3487,3488

Amyloidosis

Fig. 12.353 Thromboangiitis obliterans. The vessels show partially recanalized thrombosis and an inflammatory infiltrate extending into the perivascular tissue.

The testis is frequently affected in amyloidosis, which may alter testicular function. Up to 77% of patients have secondary infertility, and only 6% have normal spermatogenesis.3489 Testicular involvement is present in 85% of patients with secondary amyloidosis (type AA amyloidosis), in which it may be the first manifestation of the disease,3490,3491 in 91% of patients with primary systemic amyloidosis (amyloidosis with AL deposits), and in most patients with hereditary apolipoprotein A-I amyloidosis, in which testicular involvement may also be the first manifestation of the disease. The testis is less frequently affected in amyloidosis with beta-2 M deposits and in amyloidosis with transthyretin deposits. In amyloidosis with AA and AL deposits, the media and adventitia of arteries and veins are preferentially affected, but amyloid deposits in walls of capillaries and seminiferous tubules may also be observed (Figs. 12.354 and 12.355).3492 In beta-2 M amyloidosis, deposits are located under the endothelium of the veins; when massive deposition occurs, the adventitia and interstitium are also involved (Fig. 12.356). In amyloidosis with AL deposits and apolipoprotein A-I hereditary amyloidosis, deposits may be so massive that, instead of producing small atrophic testis, as is typically the case, they induce macroorchidism.3493,3494

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Fig. 12.354 Amyloid deposits on the wall of intraparenchymal vessels. The amyloid material is circularly arranged. Seminiferous tubules still retain spermatogenesis.

Fig. 12.355 Cross section of the spermatic cord showing several vessels with amyloid deposits on their wall (Congo red).

Testicular Infarct Torsion of the spermatic cord is the most frequent cause of testicular infarct, followed by trauma, incarcerated inguinal hernia, epididymitis, and vasculitis.

Spermatic Cord Torsion Spermatic cord torsion is a surgical emergency. If repair is delayed more than 8 hours, testicular viability is usually compromised. It may appear at any age; peak incidences are in the perinatal period and puberty. The annual incidence of torsion is estimated at 4 to 5 in 100,000 males up to 25 years of age.3495 Factors that predispose to testicular torsion are anatomic anomalies in testicular suspension and abnormal position of the testis. Many affected men have abnormally high reflection of the tunica vaginalis that gives rise to the “bell-clapper” deformity. Other anomalies include elongate mesorchium, separation between the

Fig. 12.356 Amyloid beta-2 M deposits in the vessels of the pampiniform plexus (Congo red).

Fig. 12.357 Highly evolved intravaginal testicular and epididymal torsion in a prepubertal patient.

epididymis and testis, and absent or elongate gubernaculum. The frequency of torsion is high in cryptorchid and retractile testes. There are two classic anatomic forms of testicular torsion: high (supravaginal or extravaginal) and low (intravaginal). Each appears at a different age. Extravaginal torsion typically occurs in infancy and childhood, whereas intravaginal torsion is more frequent at puberty and in adulthood. Neonatal torsion is bilateral in 12% to 21% of cases.3496 Most torsion observed during the first years of life is intrauterine.3497 Pubertal and adult torsion cause testicular pain that may radiate to the abdomen or other sites. Approximately 36% of patients have a previous history of pain or swelling in one or both testes. The differential diagnosis includes all causes of acute scrotum (Fig. 12.357).3498,3499 Torsion causes hemorrhagic infarction of the testis (Fig. 12.358). In old neonatal torsion the histologic findings are so advanced that only collagenized tissue containing calcium and hemosiderin deposits is seen. In adults, three degrees of histologic lesion may be distinguished.3500 Degree I (26.5% of adult twisted

CHAPTER 12 Nonneoplastic Diseases of the Testis

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patient and the contralateral testis, is approximately 50%.3502 Testes that do not bleed into the albugineal incision within 10 minutes are assumed to be nonviable and should be removed.3503 Little attention has been paid to intermittent testicular torsion, and only a few cases are reported in adults.3504 However, at least 50% of boys with testicular torsion have antecedent testicular pain caused by intermittent torsion.3505 Early orchiopexy not only eliminates the pain in most cases but also eliminates testicular loss at a later date. It is hypothesized that testes that undergo intermittent torsion become progressively smaller and excessively mobile because most have the bell-clapper deformity.3506 Intermittent testicular torsion is thought to cause vascular congestion with or without decreased arterial flow, leading to histologic damage such as decreased spermatogenesis and tubular hyalinization. Histologic diagnosis of torsion does not usually pose a problem (Fig. 12.360). However, we have observed two histologic findings that may cause diagnostic difficulties. One set of findings resembles lymphoma (Fig. 12.361), and the other resembles sarcoma. In the

Fig. 12.358 Hemorrhagic infarct in a newborn testis. The hemorrhagic areas are near the rete testis and follow the course of the centripetal veins.

Fig. 12.360 Hemorrhagic infarct. The entire testicular parenchyma is necrotic. Peripherally, at the level of the albuginea there is a dense ring of myofibroblastic proliferation. At the epididymis level there are several whitish areas with a geographical outline of lipomembranous fat necrosis. Fig. 12.359 Hemorrhagic infarct grade ii in a 13-year-old boy. There is interstitial hemorrhage, focal sloughing of the seminiferous tubular cells, and intense Sertoli cell vacuolation.

testes) is characterized by edema, vascular congestion, and focal hemorrhage. Seminiferous tubules are dilated, with sloughed immature germ cells, apical vacuolation of Sertoli cells, and dilated lymphatic vessels.1764 Degree II (26.5% of testes) has pronounced interstitial hemorrhage and sloughing of all germ cell types in the seminiferous tubules. The lesion is more severe in the center of the testis, and thus biopsy could provide erroneous information (Fig. 12.359). Degree III lesions (45% of testes) are characterized by necrosis of the seminiferous epithelium. The duration of torsion correlates with severity of the histologic findings.3501 Degree I occurs in torsion with a duration of less than 4 hours, degree II occurs in torsion lasting between 4 and 8 hours, and degree III occurs in torsion lasting more than 12 hours. Exceptions may relate to the number of twists in the spermatic cord (degrees of testicular rotation) and other factors. The testicular salvage rate, defined as testicular growth and development that reflect the age of the

Fig. 12.361 Dense lymphoid infiltrate resembling a testicular lymphoma in a recurrent testicular torsion.

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first instance, some testes of patients in the early stage of hemorrhagic infarcts have, apart from testicular enlargement, dense, interstitial, and intratubular inflammation consisting of lymphocytes, usually T lymphocytes. The lesion varies from lobule to lobule. The presence of macrophages and multinucleate giant cells may mimic idiopathic granulomatous orchitis. The second set of histologic findings consists of reactive myofibroblastic proliferation surrounding necrotic parenchyma (Figs. 12.362 and 12.363). Mitotic figures are frequent. The myofibroblastic cells express specific muscle actin. A polymorphous infiltrate of polymorphonuclear leukocytes, lymphocytes, and macrophages is typically present as well. Some adults with untreated testicular torsion experience fat necrosis of the spermatic cord.3507 Patients report pain in the high scrotum. At this level a small nodule corresponds to remnants of the twisted testis. The epididymis and proximal spermatic cord characteristically exhibit fat necrosis (Fig. 12.364). Adults with prior spermatic cord torsion often seek consultation for infertility. The mechanisms underlying spermiogram alteration are not well established, and three hypotheses have been proposed:

Fig. 12.362 Pseudosarcomatous reaction in testicular covers in a degree III testicular torsion.

Fig. 12.363 Pseudosarcomatous myofibroblastic reaction with intense expression of actin adjacent to seminiferous tubules with necrosis of the epithelium.

Fig. 12.364 Lipomembranous fat necrosis in a 14-year-old boy who presented with a history of several weeks of intense scrotal pain. Giant cell granulomatous reaction around the membranes had developed.

• Autoimmune process. Ischemic injury breaks the blood-testis barrier, and antigens released from the necrotic germ cells activate macrophages and lymphocytes in the interstitium, thus stimulating the formation of antibodies against these antigens. The antibodies enter the blood circulation and may presumably damage the contralateral testis.3508 • Alterations in microcirculation. After testicular torsion, blood flow decreases in the contralateral testis and causes an increase in the characteristic products of hypoxia, such as lactic acid and hypoxanthine.3509 Intense apoptosis involving mainly spermatocytes I and II may occur.3510 The long-term effects are unknown. • Primary testicular lesions. Many torsed testes have lesions that are obviously preexisting, such as hypoplastic tubules, testicular microlithiasis, and focal spermatogenesis. In addition, more than one-half of biopsies from the contralateral testis show significant spermatogenetic abnormalities.3511 These findings suggest that torsion occurs in congenitally abnormal testes.

Fig. 12.365 Longitudinally sectioned testis from a 4-year-old infant who had previously undergone orchidopexy. The testis shows marked fibrosis and numerous calcifications except for the periphery of the testicular parenchyma.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Other Causes of Testicular Infarct Trauma and disease affecting vessels of the spermatic cord may also cause infarction.3263 Ischemic atrophy is a risk for inguinoscrotal surgical procedures, including herniorrhaphy, varicocelectomy, hydrocelectomy, and orchiopexy for undescended testis (Fig. 12.365). The incidence rate of atrophy after inguinal herniorrhaphy varies from 0.1% in primary herniorrhaphy up to 8% after surgical treatment of recurrent hernia, depending on the difficulty of the procedure and extent of the hernia (Fig. 12.366).1889,3512 Atrophy may rarely follow thrombosis of the vena cava or spermatic artery.3513 Segmental infarction must be included in the differential diagnosis of acute testicular pain in males of all ages, but is most common in adulthood. It may be associated with vasculitis, epididymitis, intimal fibroplasia of spermatic artery, polycythemia, sickle cell disease, trauma, and laparoscopic inguinal hernia repair.3514,3515 However, in most cases the cause is unknown. Clinical symptoms of infarct mimic tumor and torsion. Diagnostic strategies include tumor biomarker testing and radiologic imaging. Color Doppler ultrasound confirms diagnosis in most cases, reveal-

Fig. 12.366 Ischemic atrophy of the testis in an adult patient with a history of herniorrhaphy.

Fig. 12.367 Segmental infarct showing sharp delimitation between necrotic and conserved testicular parenchyma.

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ing an avascular, wedge-shaped, hypoechoic lesion with welldefined borders.3516–3518 Complementary evaluation with contrast-enhanced ultrasound and real-time tissue elastography are useful.3519 Accurate evaluation of clinical and imaging symptoms may prevent unnecessary orchiectomy (Fig. 12.367).

Other Testicular Diseases Cystic Malformation Cystic malformation of the tunica albuginea and testicular parenchyma was first described in the nineteenth century and was considered rare.3520–3522 With systematic use of ultrasonography the incidence rate of cysts is much higher than previously believed.3523 Nonneoplastic cysts are found in 2% to 10% of testes.3524–3527

Cyst of the Tunica Albuginea Cyst of the tunica albuginea is usually an incidental finding in patients in the fifth or sixth decade of life. It is located in the anterolateral aspect of the testis and may be unilocular or multilocular, ranging from 2 to 4 mm and containing clear fluid without spermatozoa.946,3528 Some cysts may become calcified or contain small crystals of carbonate-apatite, hydroxyl apatite, or calcium carbonate (milk of calcium) associated with low-grade inflammation or psammoma bodies.3529 The cyst may be embedded within the connective tissue of the tunica albuginea, protrude from the inner surface of the tunica albuginea into the testicular parenchyma (Fig. 12.368), or protrude from the outer surface forming a blue lump in the tunica albuginea (Fig. 12.369). The epithelium lining the cyst may be simple columnar or stratified cuboidal, supported by a thin layer of collagenized connective tissue. The columnar epithelium usually includes ciliated cells, and the cuboidal epithelium is composed of two layers of nonciliated cells (Fig. 12.370).3530 Cysts may be numerous and enlarge sufficiently to cause atrophy of the parenchyma. Cystic change restricted to the parietal layer of the tunica vaginalis results in formation of large clusters of cysts that protrude into the tunica sac (Fig. 12.371). Tunica albuginea cysts, previously thought to result from trauma or inflammation, are now believed to represent mesothelial inclusions, mesothelial metaplasia, or embryonic remnants.3531–3533 Mesothelial cysts are lined by flat epithelium whose cells express

Fig. 12.368 Multilocular cyst in the tunica albuginea. The largest cavity protrudes into the testicular parenchyma.

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Fig. 12.371 Multiple cysts in testicular vaginal associated with a cyst of the albuginea. Fig. 12.369 Multiple cysts of the albuginea in a patient with hepatorenal polycystic disease.

Fig. 12.372 Partially collapsed mesothelial cyst protruding into the testis (immunostaining for D2–40). Fig. 12.370 Cyst of embryonic remnants. The epithelium with ciliated and nonciliated cells is like that of the efferent ducts (same case as in Fig. 12.368).

calretinin, cytokeratins 8, 18, and 19, and D2–40 (Fig. 12.372).946 Areas of cuboidal or tall columnar epithelium with ciliated and nonciliated cells may be identified and may be in continuity with mesothelium, but do not express mesothelial markers. Such cells may express androgen and progesterone receptors, but do not express estrogen receptor. The morphology and immunoprofile of these cells is like that of the fallopian tubes and areas of endosalpingiosis in women, and therefore likely represent mesothelial metaplastic changes. Extreme examples of this type of change have been described as florid cystic m€ ullerianosis of the testis (Fig. 12.373).3534 Cellular inclusions and cysts of the tunica albuginea that resemble von Brunn nests of the urothelium also likely represent metaplastic change (Fig. 12.374). Cysts lined by pseudostratified epithelium are likely in most instances to have originated from remnants of mesonephric ducts.3530,3535–3537

€llerianosis of the vaginal tunic. The epithelium Fig. 12.373 Florid cystic mu that covers the multiple cysts presents characteristics similar to that of the uterine tube.

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Fig. 12.374 The tunica albuginea presents small mesothelial inclusions parallel to the surface and two epithelial formations with central lumens reminiscent of von brown nests.

Fig. 12.376 Rete testis cyst. It is lined by flat cells alternating with islets of cylindrical cells. It contains abundant sperm.

Fig. 12.375 Rete testis cyst. Cystic formation located in the lower pole of the testis near the testicular mediastinum in an elderly patient.

Fig. 12.377 Simple cyst of the testicle. Half of the testicular parenchyma is occupied by a cystic formation with thin walls. No content is observed.

Cyst of the Rete Testis Cyst of the rete testis exhibits a distinctive epithelial lining composed of areas of flattened cells intermingled with tall columnar cells. Spermatozoa are frequently found within such cysts; hence cyst of the rete testis is also called intratesticular spermatocele (Figs. 12.375 and 12.376).3538,3539 It may be associated with cystic transformation of the rete testis and multiple epididymal cysts. Rete testis cyst is not always attached to the rete and may be found distant from it. Simple Cyst of the Testis Simple cyst of the testis is usually lined by cuboidal epithelium and contains no spermatozoa (Fig. 12.377).3540,3541 Simple cyst ranges from 2 to 18 mm in diameter.3542,3543 It may appear from 5 months of age to 84 years, with a bimodal distribution with peaks at 8 months and 60 years.3544 It may occur bilaterally, and two simple cysts have been reported in the same testis.3531,3545 Simple cyst

of the testis may be of mesothelial origin or may arise from ectopic rete testis epithelium.3546 These cysts are unrelated to epidermoid cyst and differ in their ultrasonographic and histologic features (see earlier Hamartomatous Testicular Lesions section).3547,3548 Ultrasound studies indicate that simple testicular cyst has little potential for growth.3547,3549 Currently, excision is recommended in children only when there is concern that the cyst may impair testicular development.3550

Disorders of the Rete Testis Dysgenesis Dysgenesis of the rete testis is characterized by inadequate maturation and persistence of infantile or pubertal characteristics in adults.1007 This disorder is frequent in undescended adult testes. The lesion involves the rete testis segments referred to as septal, mediastinal, and extratesticular. There is poor development of the cavities and their epithelial lining, which become cuboidal or

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Fig. 12.378 Dysgenesis of the rete testis. Rete testis with microcystic hypoplasia. The most important characteristic is the presence in an adult of a rete testis that retains characteristics of the prepubertal rete testis with cubic or cylindrical epithelia and low and abnormal development of the mediastinal rete testis.

Fig. 12.379 Reactive hyperplasia of rete testis. The cavity of the rete testis is occupied by a proliferation of epithelial cells associated with isolated inflammatory cells in a patient with orchitis. Hyperplasia mimics carcinoma.

columnar instead of flattened with areas of columnar cells. The lumina of the rete testis cavities may be completely absent (simple hypoplasia) or, conversely, may undergo microcystic dilation (cystic hypoplasia) (Fig. 12.378). In a few cases the rete testis develops papillary, cribriform, or tubular formations (adenomatous hyperplasia).

Acquired Disorders of the Rete Testis Metaplasia

The epithelium of the rete testis is usually flattened, with scattered areas of columnar cells. Metaplasia of the rete testis is characterized by replacement of the flattened epithelium by cuboid or columnar cells. This change occurs in mouse testis exposed to DES.3551,3552 In estrogen-treated patients and in those with chronic hepatic insufficiency or functioning tumor that secretes estrogens or hCG, the rete testis epithelium may diffusely transform into tall columnar epithelium. Except for the last group, metaplasia of the rete testis seems to be an estrogen-dependent process, and estrogen receptors are present in the rete testis epithelium.3553 Rete testis epithelial metaplasia may also be related to inflammatory processes in the vicinity (orchitis or epididymitis), severe hydroelectrolytic changes such as those observed in acute renal insufficiency, marked testicular atrophy, or associated with other cystic lesions of the rete testis. Reactive Hyperplasia of the Rete Testis

Reactive hyperplasia of the rete testis is characterized by proliferation of the rete testis epithelium that completely or partially fills most of the cavities of the septal and mediastinal rete. This proliferation may take different patterns of growth: solid, trabecular, or cribriform (Figs. 12.379 through 12.381). The cells have morphologic characteristics (polyhedral cells, deep folded nuclei, eosinophilic cytoplasm) and immunophenotype (positivity for cytokeratins and vimentin) reminiscent of normal rete testis epithelium. Some cells contain eosinophilic bodies in the cytoplasm. Mitotic activity is generally limited. The proliferation is confined

Fig. 12.380 Reactive hyperplasia of rete testis secondary to testicular torsion in an adult. Epithelial proliferation associated with accumulation of red cells both within the cavities and in the testicular mediastinum.

to luminal spaces. In many cases, reactive hyperplasia of rete testis is associated with adjacent lymphoid infiltrates or granulation tissue. Reactive hyperplasia of the rete testis is a nonspecific finding that may be associated with various inflammatory and neoplastic testicular entities such as testicular torsion, orchitis, epidermoid cyst, sex cord/gonadal stromal tumor, germ cell tumor, testicular sarcoma, or primary testicular lymphoma. When a solid or cribriform pattern predominates, the differential includes intratesticular adenomatoid tumor, adenocarcinoma of the rete testis, and extension of germ cell tumor. The intracavitary location of the reactive hyperplasia and its multicentric disposition excludes adenomatoid tumor. The absence of infiltrating growth or invasion of adjacent testicular parenchyma excludes adenocarcinoma. Germ cell tumors may involve the rete testis either

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Fig. 12.381 Reactive hyperplasia of rete testis in a patient with embryonal carcinoma associated with yolk sac tumor. The nontumor nature of intracavitary reticular proliferation was confirmed by immunohistochemical study.

Fig. 12.383 Inside the cavities, apart from isolated spermatozoa, we may observe nodular formations of radial structure reminiscent of colonies of actinomyces (same case as in Fig. 12.382).

Fig. 12.382 Cystic transformation of rete testis secondary to ischemia of the caput of the epididymis. The cavities of the rete testis are lined by a highly flattened epithelium.

Fig. 12.384 Cystic transformation of the rete testis secondary to a lesion in the caput epididymidis in a patient with chronic epididymitis.

by pagetoid spread or direct extension from an adjacent tumor. Immunohistochemical staining may help resolve the diagnostic dilemma. Cystic Ectasia of the Rete Testis (Acquired Cystic Transformation)

Acquired cystic transformation of the rete testis is common, and incidence increases with age and associated disorders.3554 Ultrasound and MRI studies reveal characteristic images that suggest the diagnosis without biopsy or orchiectomy.3555–3558 The lesion has three forms: simple, associated with epithelial metaplasia, and with crystalline deposits. Simple Cystic Transformation

Simple cystic transformation is the most frequent form and consists of dilated cavities with normal epithelium. It is a diffuse and homogeneous lesion causing symmetrical dilatation, resulting from

obstruction that obliterates efferent ducts at the epididymal-testis union, the epididymis, or the initial portion of the vas deferens. The obstruction may be explained by three different mechanisms: • Ischemia. In aging men with arteriosclerosis, the superior epididymal artery, a small collateral branch of the testicular artery, is frequently affected and causes ischemia of the majority of the head of the epididymis.1890 Efferent duct atrophy causes loss of the absorptive capacity of their cells and obstruction of fluid that accumulates in a retrograde manner in the rete testis (Figs. 12.382 and 12.383). • Mechanical obstruction. Epididymal obstruction occurs in two situations. One situation is extrinsic compression by epididymal and spermatic cord cyst or tumor, long-term hematocele, or congested veins in varicocele. Ectasia of the rete testis in varicocele may be either at the extratesticular level by varicose vein compression of the ductuli efferentes or at the intratesticular level by compression or distortion of centripetal veins.

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Dilatation of the rete testis in this situation is not pronounced, and it is always asymmetric. The other situation is interruption of epididymal outflow in patients who have undergone epididymectomy.3559 • Inflammation. Ectasia is produced in patients with previous epididymitis by direct inflammatory swelling of acquired fibrotic obstructive changes in the head of the epididymis (Fig. 12.384). • Malformation. The most common of such entities are testisepididymis dissociation, partial or total agenesis of epididymis, and absence of the initial portion of the vas deferens.3560 • Iatrogenic causes. Epididymectomy or excision of epididymal cyst results in outflow obstruction.3559,3561 Cystic Transformation With Epithelial Metaplasia

Cystic transformation with epithelial metaplasia is a frequent finding at autopsy.3562 It is the combination of two lesions, cuboidal or columnar metaplasia and cystic transformation of the rete testis, produced by the same etiologic mechanism or by several mechanisms. It is probably caused by the concurrence of sperm excretory duct obstruction and conditions with increased serum estrogen level, such as chronic liver insufficiency and hormonally active testicular tumor. Another possible cause is inflammation of the rete testis. Two mechanisms may be involved in this form of cystic ectasia of the rete testis: • Hormonal. Estrogens cause cystic transformation of the rete testis when they are experimentally administered in the neonatal period.858 Epithelial changes of the rete testis observed in chronic hepatic insufficiency may also result in increased estrogen levels, whereas cystic transformation may be the consequence of atrophy of the head of the epididymis or hypoandrogenism.2879 The same hormonal mechanism causes metaplasia of the epithelium of the rete testis in testicular tumors producing estrogens or hCG. Cystic transformation in the absence of atrophy of the epididymis or spermatic pathway obstruction could be explained by hyperproduction of fluid by tumoral testis that would create imbalance in production, transport, and reabsorption. • Inflammatory. In some cases of chronic orchitis involving the mediastinum testis, and in testicular tumor with abundant lymphoid infiltrates, cystic transformation of the rete testis may be observed. It is usually irregular and asymmetric. Epithelial changes are reactive. Inflammatory exudates are frequently present in cystically dilated lumens. Cystic Transformation With Crystalline Deposits

Cystic transformation with crystalline deposits has also been called cystic transformation of the rete testis secondary to renal insufficiency.3562 It is a bilateral lesion of adult testes characterized by the concurrence of three findings: cystic transformation of the rete testis, cuboidal or columnar metaplasia of the epithelium, and the presence of urate and oxalate crystalline deposits that may be recognized using polarized light. The lesion is seen exclusively in patients with chronic renal insufficiency who are receiving dialysis. Crystalline deposits are initially formed beneath the epithelia of the rete testis and efferent ducts; later they protrude into the lumina, where they are finally released. Inflammation is absent or minimal, although there may be scattered giant cells and small fibrotic areas (Figs. 12.385 and 12.386). Large quantities of deposits in secondary oxalosis may simulate testicular tumor.3563

Fig. 12.385 Changes in the rete testis associated with dialysis. Dilation of the rete testis and initial portion of the efferent ducts may be observed. Crystalline structures, mainly rhomboidal in shape, accumulate inside and outside the tubules.

Fig. 12.386 Renal dialysis-associated cystic transformation of the rete testis with oxalate crystals demonstrated by polarized light.

Cystic transformation of the rete testis in these patients is related to efferent duct obstruction by the deposits or efferent duct atrophy caused by ischemia secondary to arteriosclerosis or hypertension that is frequently present. This lesion resembles the cystic lesion described in kidneys of these patients.3564 This is hardly surprising because embryologic origin of mesonephric ducts and their derivatives in the testis (rete testis and ductuli efferentes) are related to embryologic origin of the kidney. Cystic transformation with crystalline deposits develops slowly. In most cases, lesions usually arise 30 months or more after the start of dialysis. Cystic ectasia of the rete testis should be differentiated from cystic dysplasia of the rete testis. Criteria for diagnosing cystic ectasia of the rete testis are bilaterality, occurrence in older patients, absence of genitourinary malformations, and presence of spermatozoa inside the cavities.

CHAPTER 12 Nonneoplastic Diseases of the Testis

Adenomatous Hyperplasia

Adenomatous hyperplasia is characterized by diffuse or nodular proliferation of tubular or papillary structures derived from rete testis epithelium. It may arise in both cryptorchid or normally descended testes in newborns, children, and adults.1042,3565 Adenomatous hyperplasia in newborn and infantile testes consists of enlargement of the mediastinum testis by cordlike or tubular structures derived from rete testis epithelium. The lesion may occupy up to one-third of the testicular volume. Despite hyperplastic changes, normal connections with seminiferous tubules and efferent ducts remain intact. Presentation may be unilateral or bilateral. When unilateral, it is associated with cryptorchidism or vanishing testis. When bilateral, it is associated with bilateral renal dysplasia. Efferent ducts may show luminal dilation and irregular outlines. The origins of the lesion may be like those of cystic dysplasia of the testis.1042 Adenomatous hyperplasia in adults is usually an incidental finding at autopsy, in cryptorchid testes, or in testes with germ cell tumor.3566,3567 The rete testis epithelium forms nonencapsulated proliferations that are either nodular or diffuse. Nodules may be large enough to raise concern for neoplasia. The epithelium consists of cuboidal cells with ovoid nuclei, deep nuclear folds, and peripheral nucleoli. Atypia and mitotic figures are absent (Fig. 12.387). The ultrastructure and immunophenotype of the epithelium are like that of normal rete testis. Spermatozoa may be present inside the lumina. In most instances the testis shows varying degrees of tubular atrophy. When found incidentally, etiology is unknown, although it may be related to hormonal or chemical agents.860,3568,3569 In cryptorchid testes and in cases associated with testicular tumor the most probable cause is a primary anomaly that is part of the testicular dysgenesis syndrome.1061 Adenomatous hyperplasia should be distinguished from three entities: rete testis pseudohyperplasia, which appears in atrophic testes; primary rete testis tumor; and metastatic adenocarcinoma. In pseudohyperplasia, lesions are focal, microscopic, and usually located in the septal rete, although the mediastinal rete shows few or no alterations. Benign rete testis tumor such as adenoma (solid and papillary variants) and cystadenoma are isolated and

Fig. 12.387 Adenomatous hyperplasia of the rete testis. The epithelium is columnar and supported by a well-collagenized stroma.

729

focal, whereas rete testis hyperplasia is diffuse.3570 Adenocarcinoma of the rete testis is a tumor that displays abundant mitotic activity, cytologic atypia, and infiltrates adjacent structures.3571 Metastatic prostatic adenocarcinoma alters the rete testis architecture; immunostains for prostate specific membrane antigen (PSMA) and NKX3.1 may aid in establishing that diagnosis. Hyperplasia With Hyaline Globule Formation

This reactive lesion is characterized by the presence of intracytoplasmic accumulation of hyaline eosinophilic globules in epithelial cells of the rete testis. The epithelium may be hyperplastic, but does not contain mitotic figures or nuclear atypia. Globules are up to 15 μm in diameter (Fig. 12.388). This lesion is associated with tumors and inflammatory processes occurring near the mediastinum testis, and may be observed in association with 75% of cases of mixed testicular germ cell tumor, 47% of seminomas, and 20% of nongerm cell testicular tumors such as adenomatoid tumor of the testis.3572 Yolk sac tumor infiltrating the rete testis may closely resemble this type of rete testis hyperplasia. Positive immunoreactions for α-fetoprotein, SALL4, and OCT4 are helpful to distinguish germ cell neoplasia from this rete testis hyperplasia.3573 Intracavitary Polypoid Nodular Proliferation

Intracavitary polypoid nodular proliferation, described as nodular proliferation of calcifying connective tissue in the rete testis, is characterized by the presence of multiple nodules that originate from the rete testis lining and subjacent connective tissue, protruding into channels of the rete testis. These nodules consist of cellular connective tissue covered by several layers of fibrin-like material, which in turn is covered by rete testis epithelium. The nodules may be totally or partially calcified (Fig. 12.389), or may take the form of a myriad of spherical or ovoid calcifications simulating parasite eggs (Fig. 12.390).3574 The lesion is an incidental finding at autopsy in patients with impaired peripheral perfusion. Selective location of the lesion in the walls of the cavities and chordae rete testis is probably related to poor vascularization of these structures. The etiopathogenetic mechanism may be anoxia, necrosis, fibrin deposition, proliferation of connective tissue, or

Fig. 12.388 Rete testis hyperplasia with hyaline globules. The globulecontaining cells protrude into the lumina of the rete testis channels.

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Fig. 12.389 Nodular proliferation of calcifying connective tissue in the rete testis with large calcium deposits.

dystrophic calcification. Intracavitary growth could result from the lower intracavitary pressure and from the stiff structure of the mediastinum testis. References are available at expertconsult.com

Fig. 12.390 Intracavitary parasite eggs.

polypoid

nodular

calcification

simulating

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370. 371. 372. 373. 374. 375.

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1101. 1102.

1103. 1104.

1105. 1106.

1107. 1108. 1109. 1110. 1111. 1112. 1113. 1114. 1115. 1116. 1117.

1118.

1119. 1120. 1121. 1122. 1123.

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1124. Hadziselimovic F, Zivkovic D, Bica DT, Emmons LR. The importance of mini-puberty for fertility in cryptorchidism. J Urol. 2005;174:1536–1539; discussion 1538-1539. 1125. Nistal M, Gonzalez-Permato P, Serrano A. Helpful data for evaluating an undescended testis in childhood. Cham, Switzerland: Springer, 2017. 1126. Nistal M, Paniagua R. Infertility in adult males with retractile testes. Fertil Steril. 1984;41:395–403. 1127. Herzog B, Steigert M, Hadziselimovic F. Is a testis located at the superficial inguinal pouch (Denis Browne pouch) comparable to a true cryptorchid testis? J Urol. 1992;148:622–623. 1128. Huff DS, Hadziselimovic F, Snyder HM, 3rd, Blythe B, Ducket JW. Histologic maldevelopment of unilaterally cryptorchid testes and their descended partners. Eur J Pediatr. 1993;152(Suppl 2):S11–S14. 1129. Alexandre C. Les testicules oscillants. forme degradee de cryptorchidie? J Gynecol Obstet Biol Reprod (Paris). 1977;6:71–74. 1130. Ito H, Kataumi Z, Yanagi S, et al. Changes in the volume and histology of retractile testes in prepubertal boys. Int J Androl. 1986;9:161–169. 1131. Keys C, Heloury Y. Retractile testes: a review of the current literature. J Pediatr Urol. 2012;8:2–6. 1132. Wyllie GG. The retractile testis. Med J Aust. 1984;140:403–405. 1133. Agarwal PK, Diaz M, Elder JS. Retractile testis—is it really a normal variant? J Urol. 2006;175:1496–1499. 1134. Puri P, Nixon HH. Bilateral retractile testes—subsequent effects on fertility. J Pediatr Surg. 1977;12:563–566. 1135. Caroppo E, Colpi EM, Gazzano G, et al. Testicular histology may predict the successful sperm retrieval in patients with nonobstructive azoospermia undergoing conventional TESE: a diagnostic accuracy study. J Assist Reprod Genet. 2017;34:149–154. 1135a. Caroppo E, Niederberger C, Elhanbly S, et al. Effect of cryptorchidism and retractile testes on male factor infertility: a multicenter, retrospective, chart review. Fertil Steril. 2005;83:1581–1584. 1136. Anderson KM, Costa SF, Sampaio FJ, Favorito LA. Do retractile testes have anatomical anomalies? Int Braz J Urol. 2016;42: 803–809. 1137. Priebe CJ, Jr., Garret R. Testicular calcification in a 4-year-old boy. Pediatrics. 1970;46:785–788. 1138. Sohval AR. Histopathology of cryptorchidism a study based upon the comparative histology of retained and scrotal testes from birth to maturity. Am J Med. 1954;16:346–362. 1138a. Nistal M, Paniagua R, Diez-PardoJ A. Testicular microlithiasis in 2 children with bilateral cryptorchidism. J Urol. 1979;121: 535–537. 1139. Lanman JT, Sklarin BS, Cooper HL, Hirschhorn K. Klinefelter’s syndrome in a ten-month-old mongolian idiot: report of a case with chromosome analysis. N Engl J Med. 1960;263:887–890. 1140. Bunge RG, Bradbury JT. Intratubular bodies of the human testis. J Urol. 1961;85:306–310. 1141. Vachon L, Fareau GE, Wilson MG, Chan LS. Testicular microlithiasis in patients with Down syndrome. J Pediatr. 2006;149: 233–236. 1142. Goede J, Hack WW, van der Voort-Doedens LM, Sijstermans K, Pierik FH. Prevalence of testicular microlithiasis in asymptomatic males 0 to 19 years old. J Urol. 2009;182:1516–1520. 1142a. Goede J, Hack WW, Sijstermans K, Pierik FH. Testicular microlithiasis in a 2-year-old boy with pseudoxanthoma elasticum. J Ultrasound Med. 2008;27:1503–1505. 1143. Moran JM, Moreno F, Climent V, Nistal M. Idiopathic testicular microlithiasis: ultrastructural study. Br J Urol. 1993;72:252–253. 1144. Kwan DJ, Kirsch AJ, Chang DT, Goluboff ET, Berdon WE, Hensle TW. Testicular microlithiasis in a child with torsion of the appendix testis. J Urol. 1995;153:183–184. 1145. Rajbabu K, Morel JC, Thompson PM, Sidhu PS. Multi-cystic (rete testis) supernumerary testis in polyorchidism with underlying microlithiasis: ultrasound features. Australas Radiol. 2007; 51 Spec No.: B56-58.

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1146. Poyrazoglu S, Saka N, Agayev A, Yekeler E. Prevalence of testicular microlithiasis in males with congenital adrenal hyperplasia and its association with testicular adrenal rest tumors. Horm Res Paediatr. 2010;73:443–448. 1146a. Wasniewska M, Raiola G, Teresa A, et al. Gynecomastia disclosing diagnosis of Leydig cell tumour in a man with thalassemia, secondary hypogonadism and testis microlithiasis. Acta Biomed. 2009;80: 286–268. 1147. Bieger RC, Passarge E, McAdams AJ. Testicular intratubular bodies. J Clin Endocrinol Metab. 1965;25:1340–1346. 1148. Mullins TL, Sant GR, Ucci AA, Jr., Doherty FJ. Testicular microlithiasis occurring in postorchiopexy testis. Urology. 1986;27: 144–146. 1149. Ikinger U, Wurster K, Terwey B, Mohring K. Microcalcifications in testicular malignancy: diagnostic tool in occult tumor? Urology. 1982;19:525–528. 1150. Kang J, Rajpert-De Meyts E, Giwercman A, Skakkebaek NE. The association of testicular carcinoma “in situ” with intratubular microcalcifications. J Urologic Pathol. 1994;2:235–242. 1151. Wegner HE, Hubotter A, Andresen R, Miller K. Testicular microlithiasis and concomitant testicular intraepithelial neoplasia. Int Urol Nephrol. 1998;30:313–315. 1152. Hoei-Hansen CE, Sommer P, Rajpert-De Meyts E, Skakkebaek NE. A rare diagnosis: testicular dysgenesis with carcinoma in situ detected in a patient with ultrasonic microlithiasis. Asian J Androl. 2005;7:445–447. 1153. Schantz A, Milsten R. Testicular microlithiasis with sterility. Fertil Steril. 1976;27:801–805. 1154. Sasagawa I, Nakada T, Kazama T, Satomi S, Katayama T, Matuda S. Testicular microlithiasis in male infertility. Urol Int. 1988;43:368–369. 1155. Gonzalez Sanchez FJ, Encinas Gaspar MB, Napal Lecumberri S. Microlitiasis testicular asociada a infertilidad. Arch Esp Urol. 1997;50:71–74. 1156. Mazzilli F, Delfino M, Imbrogno N, Elia J, Spinosa V, Di Nardo R. Seminal profile of subjects with testicular microlithiasis and testicular calcifications. Fertil Steril. 2005;84:243–245. 1157. Duchek M, Bergh A, Oberg L. Painful testicular lithiasis. Scand J Urol Nephrol Suppl. 1991;138:231–233. 1158. Jara Rascon J, Escribano Patino G, Herranz Amo F, Moncada Iribarren I, Hernandez Fernandez C. [Testicular microlithiasis: diagnosis associated with orchialgia]. Arch Esp Urol. 1998;51:82–85. 1159. Coetzee T. Pulmonary alveolar microlithiasis with involvement of the sympathetic nervous system and gonads. Thorax. 1970;25:637–642. 1160. Smith WS, Brammer HM, Henry M, Frazier H. Testicular microlithiasis: sonographic features with pathologic correlation. AJR Am J Roentgenol. 1991;157:1003–1004. 1161. Doherty FJ, Mullins TL, Sant GR, Drinkwater MA, Ucci AA, Jr., Testicular microlithiasis. A unique sonographic appearance. J Ultrasound Med. 1987;6:389–392. 1162. Janzen DL, Mathieson JR. Testicular microlithiasis and seminoma. Clin Radiol. 1993;48:219–220. 1163. Whitman GJ, Boston MA, Hall DA. Testicular microlithiasis: US features and significance [abstract]. Radiology. 1994;193:335. 1164. Backus ML, Mack LA, Middleton WD, King BF, Winter TC, 3rd, True LD. Testicular microlithiasis: imaging appearances and pathologic correlation. Radiology. 1994;192:781–785. 1165. Renshaw AA. Testicular calcifications: incidence, histology and proposed pathological criteria for testicular microlithiasis. J Urol. 1998;160:1625–1628. 1166. Hobarth K, Susani M, Szabo N, Kratzik C. Incidence of testicular microlithiasis. Urology. 1992;40:464–467. 1167. Dagash H, Mackinnon EA. Testicular microlithiasis: what does it mean clinically? BJU Int. 2007;99:157–160. 1168. Leenen AS, Riebel TW. Testicular microlithiasis in children: sonographic features and clinical implications. Pediatr Radiol. 2002;32:575–579.

1169. Miller FN, Rosairo S, Clarke JL, Sriprasad S, Muir GH, Sidhu PS. Testicular calcification and microlithiasis: association with primary intra-testicular malignancy in 3,477 patients. Eur Radiol. 2007;17:363–369. 1170. Drut R. Yolk sac tumor and testicular microlithiasis. Pediatr Pathol Mol Med. 2003;22:343–347. 1171. Serter S, Orguc S, Gumus B, Ayyildiz V, Pabuscu Y. Doppler sonographic findings in testicular microlithiasis. Int Braz J Urol. 2008;34:477–482; discussion 482-484. 1172. Peterson AC, Bauman JM, Light DE, McMann LP, Costabile RA. The prevalence of testicular microlithiasis in an asymptomatic population of men 18 to 35 years old. J Urol. 2001;166:2061–2064. 1173. Cast JE, Nelson WM, Early AS, et al. Testicular microlithiasis: prevalence and tumor risk in a population referred for scrotal sonography. AJR Am J Roentgenol. 2000;175:1703–1706. 1174. Skyrme RJ, Fenn NJ, Jones AR, Bowsher WG. Testicular microlithiasis in a UK population: its incidence, associations and followup. BJU Int. 2000;86:482–485. 1175. Ganem JP, Workman KR, Shaban SF. Testicular microlithiasis is associated with testicular pathology. Urology. 1999;53:209–213. 1176. Derogee M, Bevers RF, Prins HJ, Jonges TG, Elbers FH, Boon TA. Testicular microlithiasis, a premalignant condition: prevalence, histopathologic findings, and relation to testicular tumor. Urology. 2001;57:1133–1137. 1177. Kessaris DN, Mellinger BC. Incidence and implication of testicular microlithiasis detected by scrotal duplex sonography in a select group of infertile men. J Urol. 1994;152:1560–1561. 1178. Aizenstein RI, DiDomenico D, Wilbur AC, O’Neil HK. Testicular microlithiasis: association with male infertility. J Clin Ultrasound. 1998;26:195–198. 1179. de Gouveia Brazao CA, Pierik FH, Oosterhuis JW, Dohle GR, Looijenga LH, Weber RF. Bilateral testicular microlithiasis predicts the presence of the precursor of testicular germ cell tumors in subfertile men. J Urol. 2004;171:158–160. 1180. Nicolas F, Dubois R, Laboure S, Dodat H, Canterino I, Rouviere O. [Testicular microlithiasis and cryptorchism: ultrasound analysis after orchidopexy]. Prog Urol. 2001;11:357–361. 1181. Miller RL, Wissman R, White S, Ragosin R. Testicular microlithiasis: a benign condition with a malignant association. J Clin Ultrasound. 1996;24:197–202. 1182. Berger A, Brabrand K. Testicular microlithiasis—a possibly premalignant condition. Report of five cases and a review of the literature. Acta Radiol. 1998;39:583–586. 1183. Kim B, Winter TC, 3rd, Ryu JA. Testicular microlithiasis: clinical significance and review of the literature. Eur Radiol. 2003;13:2567–2576. 1184. Rashid HH, Cos LR, Weinberg E, Messing EM. Testicular microlithiasis: a review and its association with testicular cancer. Urol Oncol. 2004;22:285–289. 1185. Parra BL, Venable DD, Gonzalez E, Eastham JA. Testicular microlithiasis as a predictor of intratubular germ cell neoplasia. Urology. 1996;48:797–799. 1186. Kaveggia FF, Strassman MJ, Apfelbach GL, Hatch JL, Wirtanen GW. Diffuse testicular microlithiasis associated with intratubular germ cell neoplasia and seminoma. Urology. 1996;48:794–796. 1187. Holm M, Hoei-Hansen CE, Rajpert-De Meyts E, Skakkebaek NE. Increased risk of carcinoma in situ in patients with testicular germ cell cancer with ultrasonic microlithiasis in the contralateral testicle. J Urol. 2003;170:1163–1167. 1188. Blumensaat C. Euber einen neuen Befund in Knabenhoden. Virchows Arch Pathol Anat. 1929;273:51–63. 1189. Vegni-Talluri M, Bigliardi E, Vanni MG, Tota G. Testicular microliths: their origin and structure. J Urol. 1980;124:105–107. 1190. Drut R, Drut RM. Testicular microlithiasis: histologic and immunohistochemical findings in 11 pediatric cases. Pediatr Dev Pathol. 2002;5:544–550.

CHAPTER 12

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1402. Mandel DC, Beste T, Hope W. Hernia uterine inguinale: an uncommon cause of pelvic pain in the adult female patient. J Minim Invasive Gynecol. 2010;17:787–790. 1403. Sloan WR, Walsh PC. Familial persistent Mullerian duct syndrome. J Urol. 1976;115:459–461. 1404. Carre-Eusebe D, Imbeaud S, Harbison M, New MI, Josso N, Picard JY. Variants of the anti-Mullerian hormone gene in a compound heterozygote with the persistent Mullerian duct syndrome and his family. Hum Genet. 1992;90:389–394. 1405. Renu D, Rao BG, Ranganath K, Namitha. Persistent mullerian duct syndrome. Indian J Radiol Imaging. 2010;20:72–74. 1406. Sheehan SJ, Tobbia IN, Ismail MA, Kelly DG, Duff FA. Persistent Mullerian duct syndrome. Review and report of 3 cases. Br J Urol. 1985;57:548–551. 1407. Pappis C, Constantinides C, Chiotis D, Dacou-Voutetakis C. Persistent Mullerian duct structures in cryptorchid male infants: surgical dilemmas. J Pediatr Surg. 1979;14:128–131. 1408. Potashnik G, Sober I, Inbar I, Ben-Aderet N. Male Mullerian hermaphroditism: a case report of a rare cause of male infertility. Fertil Steril. 1977;28:273–276. 1409. Hershlag A, Spitz IM, Hochner-Celnikier D, et al. Persistent mullerian structures in infertile male. Urology. 1986;28:138–141. 1410. Malayaman D, Armiger G, D’Arcangues C, Lawrence GD. Male pseudohermaphroditism with persistent m€ ullerian and wolffian structures complicated by intra-abdominal seminoma. Urology. 1984;24:67–69. 1411. Loeff DS, Imbeaud S, Reyes HM, Meller JL, Rosenthal IM. Surgical and genetic aspects of persistent mullerian duct syndrome. J Pediatr Surg. 1994;29:61–65. 1412. Imbeaud S, Faure E, Lamarre I, et al. Insensitivity to anti-mullerian hormone due to a mutation in the human anti-mullerian hormone receptor. Nat Genet. 1995;11:382–388. 1413. Saleem M, Ather U, Mirza B, et al. Persistent mullerian duct syndrome: A 24-year experience. J Pediatr Surg. 2016;51:1721–1724. 1414. Beheshti M, Churchill BM, Hardy BE, Bailey JD, Weksberg R, Rogan GF. Familial persistent mullerian duct syndrome. J Urol. 1984;131:968–969. 1415. Giannopoulos A, Pantazopoulos D, Michalopoulos A. Association d’une forme rare d’ectopie testiculaire, d’un “syndrome de persistance du canal de M€uller” et d’un epididyme ectopique surnumeraire. Ann Urol. 1986;20:267–270. 1416. Mouli K, McCarthy P, Ray P, Ray V, Rosenthal IM. Persistent mullerian duct syndrome in a man with transverse testicular ectopia. J Urol. 1988;139:373–375. 1417. Hutson JM, Baker M, Terada M, Zhou B, Paxton G. Hormonal control of testicular descent and the cause of cryptorchidism. Reprod Fertil Dev. 1994;6:151–156. 1418. Lima M, Domini M, Libri M. Persistent Mullerian Duct Syndrome associated with transverse testicular ectopia: a case report. Eur J Pediatr Surg. 1997;7:60–62. 1419. Berkmen F. Persistent mullerian duct syndrome with or without transverse testicular ectopia and testis tumours. Br J Urol. 1997;79:122–126. 1420. Belville C, Marechal JD, Pennetier S, et al. Natural mutations of the anti-Mullerian hormone type II receptor found in persistent Mullerian duct syndrome affect ligand binding, signal transduction and cellular transport. Hum Mol Genet. 2009;18:3002–3013. 1421. Guerrier D, Tran D, Vanderwinden JM, et al. The persistent Mullerian duct syndrome: a molecular approach. J Clin Endocrinol Metab. 1989;68:46–52. 1421a. Souto CAV, Olivera MD, Telöken C, et al. Persistence of müllerian duct derivative syndrome in 2 male patients with bilateral cryptorchidism. J Urol. 1995;153:1637–1638. 1421b. Chamrajan S, Vala NH, Desai JR, Bhatt NN. Persistent mullerian duct syndrome in a patient with bilateral cryptorchid testes with seminoma. J Hum Reprod Sci. 2012;5:215–217.

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CHAPTER 12

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1507. Nichter LS. Seminoma in a 46,XX true hermaphrodite with positive H-Y antigen. A case report. Cancer. 1984;53:1181–1184. 1508. van Niekerk WA, Retief AE. The gonads of human true hermaphrodites. Hum Genet. 1981;58:117–122. 1509. Berkovitz GD, Rock JA, Urban MD, Migeon CJ. True hermaphroditism. Johns Hopkins Med J. 1982;151:290–297. 1510. Lim DJ, Mullins DL, Stevens PS. Crossed ectopia of ovotestis in a case of true hermaphroditism. J Pediatr Surg. 1996;31:1440–1442. 1511. Mendez JP, Schiavon R, Diaz-Cueto L, et al. A reliable endocrine test with human menopausal gonadotropins for diagnosis of true hermaphroditism in early infancy. J Clin Endocrinol Metab. 1998;83:3523–3526. 1512. Kropp BP, Keating MA, Moshang T, Duckett JW. True hermaphroditism and normal male genitalia: an unusual presentation. Urology. 1995;46:736–739. 1513. McDaniel EC, Nadel M, Woolverton WC. True hermaphrodite with bilaterally descended ovotestes. J Urol. 1968;100:77–81. 1514. Wiersma R, Ramdial PK. The gonads of 111 South African patients with ovotesticular disorder of sex differentiation. J Pediatr Surg. 2009;44:556–560. 1515. Narita O, Manba S, Nakanishi T, Ishizuka N. Pregnancy and childbirth in a true hermaphrodite. Obstet Gynecol. 1975;45: 593–595. 1516. Mayou BJ, Armon P, Lindenbaum RH. Pregnancy and childbirth in a true hermaphrodite following reconstructive surgery. Br J Obstet Gynaecol. 1978;85:314–316. 1517. Kim MH, Gumpel JA, Graff P. Pregnancy in a true hermaphrodite. Obstet Gynecol. 1979;53:40s–42s. 1518. Tegenkamp TR, Brazzell JW, Tegenkamp I, Labidi F. Pregnancy without benefit of reconstructive surgery in a bisexually active true hermaphrodite. Am J Obstet Gynecol. 1979;135:427–428. 1519. Williamson HO, Phansey SA, Mathur RS. True hermaphroditism with term vaginal delivery and a review. Am J Obstet Gynecol. 1981;141:262–265. 1520. Talerman A, Verp MS, Senekjian E, Gilewski T, Vogelzang N. True hermaphrodite with bilateral ovotestes, bilateral gonadoblastomas and dysgerminomas, 46,XX/46,XY karyotype, and a successful pregnancy. Cancer. 1990;66:2668–2672. 1521. Verp MS, Harrison HH, Ober C, et al. Chimerism as the etiology of a 46,XX/46,XY fertile true hermaphrodite. Fertil Steril. 1992;57:346–349. 1522. Tanaka Y, Fujiwara K, Yamauchi H, Mikami Y, Kohno I. Pregnancy in a woman with a Y chromosome after removal of an ovarian dysgerminoma. Gynecol Oncol. 2000;79:519–521. 1523. Schultz BA, Roberts S, Rodgers A, Ataya K. Pregnancy in true hermaphrodites and all male offspring to date. Obstet Gynecol. 2009;113:534–536. 1524. Tiltman AJ, Sweerts M. Multiparity in a covert true hermaphrodite. Obstet Gynecol. 1982;60:752–754. 1525. Minowada S, Fukutani K, Hara M, et al. Childbirth in true hermaphrodite. Eur Urol. 1984;10:414–415. 1526. Jingde Z, Xin X, Entan G, Junhui L, Chunyu X, Xiaoyun W. Surgical treatment of hermaphroditism: experience with 25 cases. Ann Plast Surg. 2009;63:543–551. 1527. Nihoul-Fekete C, Lortat-Jacob S, Cachin O, Josso N. Preservation of gonadal function in true hermaphroditism. J Pediatr Surg. 1984;19:50–55. 1528. Parada-Bustamante A, Rios R, Ebensperger M, Lardone MC, Piottante A, Castro A. 46,XX/SRY-negative true hermaphrodite. Fertil Steril. 2010;94: 2330.e2313-2336. 1529. Malavaud B, Mazerolles C, Bieth E, Chevreau C, Le Frere MA, Alric L. Pure seminoma in a male phenotype 46,XX true hermaphrodite. J Urol. 2000;164:125–126. 1530. Malik V, Gupta D, Gill M, Salvi AL. Seminoma in a male phenotype 46XX true hermaphrodite. Asian J Surg. 2007;30: 85–87. 1531. Kini U, Bantwal G, Ayyar V, Idiculla J. Bilateral gonadoblastomas with a left sided dysgerminoma in a true hermaphrodite (disorder

CHAPTER 12

1532. 1533.

1534.

1535. 1536. 1537.

1538. 1539.

1540. 1541.

1542. 1543. 1544.

1545. 1546.

1547. 1548. 1549.

1550. 1551. 1552.

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2218. 2219. 2220. 2221. 2222.

2223. 2224. 2225. 2226. 2227. 2228. 2229. 2230. 2231. 2232. 2233. 2234. 2235.

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3259.

3260. 3261. 3262.

3263. 3264. 3265. 3266. 3267.

3268.

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