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13

Neoplasms of the Testis R O B E R T E . E M E R S O N A N D T H O MA S M . U L B R I G H T

C H A P T E R OU T L I N E Staging 731 Patterns of Metastasis 731 Gross Examination 733 Germ Cell Tumors 733 Classification 733 Histogenesis 733 Epidemiology 735 Germ Cell Neoplasia in Situ and Related Germ Cell Tumors 738 Germ Cell Tumors Not Derived From Germ Cell Neoplasia in Situ 789 Sex Cord–Stromal Tumors 800 Leydig Cell Tumor 800 Sertoli Cell Tumor, Not Otherwise Specified 807 Large Cell Calcifying Sertoli Cell Tumor 811 Intratubular Large Cell Hyalinizing Sertoli Cell Neoplasia 812 Granulosa Cell Tumor 813 Tumors in the Fibroma-Thecoma Group 815 Myoid Gonadal Stromal Tumor 816 Mixed and Unclassified Sex Cord–Stromal Tumors 816 Tumors Containing Both Germ Cell and Sex Cord–Stromal Elements 817 Gonadoblastoma 817 Miscellaneous Tumors of the Testis and Paratesticular Tissue 820 Ovarian-Type Epithelial Tumors 820 Miscellaneous Lesions 821 Juvenile Xanthogranuloma 821 Hemangioma 821 Other Soft Tissue Tumors 821 Hematolymphoid Tumors 824 Lymphoma 824 Plasmacytoma 826 Leukemia, Including Myeloid Sarcoma 827 Rosai-Dorfman Disease 827 Tumors of Collecting Duct and Rete Testis 827 Adenoma 827 Cystic Dysplasia 828 Adenocarcinoma 828 Metastatic Tumors 829 Diagnostic Approach to Testicular Tumors 830

A

lthough weighing only about 19 grams, the testis is responsible for a complex array of neoplasms.1 The rapidly proliferating spermatogenic cells give rise to the majority of testicular tumors, 95% of which are of germ cell derivation. Most are malignant and usually occur in young men, but they can be cured by current therapies; therefore accurate diagnosis is essential. The supporting cells and interstitial cells of the testis are responsible for the less common sex cord–stromal tumors that comprise a disproportionate number of diagnostic problems. Some of these are associated with clinical syndromes that may be suspected based on the testicular pathology.2-7 A number of tumors of soft tissue origin may be identified in the paratestis, and secondary tumors are relatively frequent in both the testis and paratestis. The spectrum of lesions and the capacity of many tumors to mimic others make testicular neoplasia a continuing challenge to surgical pathologists, and this topic has been the subject of several recent reviews.8-13

Staging The currently recommended staging system for testicular cancer is the eighth edition of the Cancer Staging Manual of the American Joint Committee on Cancer (AJCC), published in 2017 (Table 13.1), which replaces the seventh edition, published in 2010.14,15 Interpretation of two difficult areas of staging using 2010 AJCC criteria (tunica vaginalis invasion and hilar fat invasion without vascular invasion) was identified as the most significant area of variation in practice with regard to handling and reporting testicular cancer specimens in a recent survey.16 These points have been clarified in the 2017 AJCC staging manual.14 In the eighth edition, changes include subdivision of the T1 category, for seminoma only, into T1a (tumor less than 3 cm) and T1b (tumor 3 cm or larger), assignment of stage T2 for epididymal or hilar soft tissue invasion independent of vascular invasion, and classification of discontinuous involvement of the spermatic cord by vascular-lymphatic invasion as M1 disease.14 Serum marker studies play a key role in the evaluation of patients with testicular germ cell tumors, so the values of serum α-fetoprotein (AFP), human chorionic gonadotropin (hCG), and lactate dehydrogenase (LDH) are incorporated into the determination of the stage groupings.

Patterns of Metastasis Testicular neoplasms usually first metastasize to retroperitoneal lymph nodes. There tends to be selective lymph node involvement with early-stage tumors, which depends on whether the right or left 731

732 CHA P T E R 13

TABLE 13.1

Neoplasms of the Testis

Eighth Edition AJCC Pathologic Staging System for Testicular Cancer

pT Category

Criteria

pTX pT0 pTis pT1a

pT4

Unknown status of testis No apparent primary (includes scars) Germ cell neoplasia in situ Tumor limited to testis (including rete testis invasion) without lymphovascular invasion, tumor smaller than 3 cma Tumor limited to testis (including rete testis invasion) without lymphovascular invasion, tumor 3 cm or largera Tumor either: limited to testis (including rete testis invasion) with lymphovascular invasion or involving hilar soft tissue or epididymis or penetrating visceral mesothelium of tunica albuginea with or without lymphovascular invasion Tumor invading spermatic cord (although discontinuous involvement of the spermatic cord soft tissue via a vascular thrombus is regarded as pM1) Tumor invading scrotum

pN Category

Criteria

pNX pN0 pN1

Unknown nodal status No regional node involvement Node mass or single nodes
2 cm;
5 nodes involved; no node >2 cm Node mass >2 but <5 cm; or >5 nodes involved; none >5 cm; or extranodal tumor Node mass >5 cm

pT1b pT2

pT3

pN2 pN3

pM Category Criteria pM0 pM1a pM1b

No distant metastases Nonregional nodal or lung metastases Distant metastasis other than nonregional nodal or lung

S Category

Criteria

SX S0 S1

No marker studies available All marker studies normal LDH <1.5  upper limit of normal and hCG <5000 mIU/ mL and AFP <1000 ng/mL LDH 1.5-10  upper limit of normal or hCG 500050,000 mIU/mL or AFP 1000-10,000 ng/mL LDH >10  upper limit of normal or hCG >50,000 mIU/ mL or AFP >10,000 ng/mL

S2 S3

testis is involved. For right-sided tumors, the interaortocaval nodes at about the level of the second lumbar vertebra are usually first involved, although right paracaval and precaval involvement may also occur.17,18 In early stage involvement from right-sided tumors, there is absence of both suprahilar nodal involvement and involvement of the left paraaortic nodes below the inferior mesenteric artery (Fig. 13.1).18 For left-sided tumors, the left paraaortic nodes, in an area bounded by the left ureter, left renal vein, aorta, and origin of the inferior mesenteric artery, are first involved.17 Suprahilar nodal metastases may be seen in early-stage disease from left-sided testicular tumors, in contrast with right-sided lesions (Fig. 13.2).18 As metastases become more widespread, right-sided lesions develop suprahilar and contralateral spread and left-sided tumors develop interaortocaval and precaval involvement, as well as a greater frequency of suprahilar involvement. As the volume of retroperitoneal disease increases, retrograde involvement of iliac and inguinal nodes may be seen.18 Inguinal lymph node involvement may also be seen when the primary tumor has extended to the scrotal skin or a transcrotal approach was used for the primary resection. The extension of the primary tumor to the epididymis also correlates with the development of external iliac nodal spread. Eventually, supradiaphragmatic spread occurs to the mediastinum and supraclavicular and cervical lymph nodes, tending to involve the left supraclavicular nodes much more commonly than the right.19 Seminoma tends to metastasize in an orderly pattern through lymphatics, whereas choriocarcinoma more frequently spreads by hematogenous routes. The other germ cell tumors, such as embryonal carcinoma, tend to have a lymphatic pattern of spread, although hematogenous spread can also be seen. Hematogenous spread is most commonly reflected by lung, liver, central nervous system, and bone involvement.20 Brain involvement is most common with choriocarcinoma and, perhaps unexpectedly, bone involvement with seminoma.20

Stage Grouping 0 I IA IB IS II IIA IIB IIC III IIIA IIIB IIIC

pTis, N0, M0, S0 pT1-4, N0, M0, SX pT1, N0, M0, S0 pT2-4, N0, M0, S0 Any pT, N0, M0, S1-3 Any pT, N1-3, M0, SX Any pT, N1, M0, S0-1 Any pT, N2, M0, S0-1 Any pT, N3, M0, S0-1 Any pT, any N, M1, SX Any pT, any N, M1a, S0-1 Any pT, N1-3, M0, S2 or Any pT, any N, M1a, S2 Any pT, N1-3, M0, S3 or Any PT, any N, M1a, S3 or Any pT, any N, M1b, any S

a

Subclassification based on size criterion applies only to seminomas. Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing.

Fig. 13.1 Pattern of early retroperitoneal lymph node involvement from rightsided testicular tumors. (From Donohue JP. Metastatic pathways of nonseminomatous germ cell tumors. Semin Urol. 1984;2:217–229, with permission.)

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Fig. 13.2 Pattern of early retroperitoneal lymph node involvement from left-sided testicular tumors. (From Donohue JP. Metastatic pathways of nonseminomatous germ cell tumors. Semin Urol. 1984;2:217–229, with permission.)

Neoplasms of the Testis

733

and allowed to thoroughly fix before further processing. After fixation, the neoplasm should be described and measured, with attention paid to the relationships to the tunica albuginea and the testicular hilum. Most examples of extratesticular spread occur by extension through the hilum.22 Multiple blocks of neoplasm should be submitted, because many tumors are quite heterogeneous. Blocks of all the different-appearing areas should be made, including hemorrhagic and necrotic areas, with attention to the testis/parenchymal interface, where lymphovascular invasion is often most apparent. A minimum of one block of neoplasm for every centimeter of maximum tumor dimension or a total of 10 blocks, whichever is greater, is a general rule of thumb. It is prudent to submit blocks quite generously if the gross appearance suggests seminoma, because the discovery of nonseminomatous elements may change therapy. Hence, small seminomas should be totally submitted, and at least 10 blocks of larger tumors (or one block for every centimeter of maximum tumor dimension) should be submitted. The nonneoplastic testis should also be sampled, as well as a block to include the testicular hilum. The epididymis should be incised by multiple, parallel cuts perpendicular to its long axis, any abnormalities noted, and the appropriate blocks submitted.

Germ Cell Tumors Classification

Gross Examination Gross examination and proper handling of the orchiectomy specimen are often neglected, and many diagnostic problems at the microscope can be traced to suboptimal processing of the gross specimen. Under the best circumstances, the testis and accompanying tunics and spermatic cord should be received fresh, dissected, and allowed to thoroughly fix before tissue blocks are submitted. What often happens, however, is that the urologist places the radical orchiectomy specimen intact into fixative, and only hours later is the specimen dissected. The testicular tunics are resistant to penetration of fixative, so this approach results in autolytic changes. It is preferable for the urologist to make a single, nearly through-andthrough incision in the specimen before placing it into fixative if it is not feasible to send it to the laboratory immediately in the fresh state. A radical orchiectomy specimen consists of the testis, tunica vaginalis, and a portion of spermatic cord. The specimen should be weighed, measured in three dimensions, and the length of the cord noted. We recommend examination of the spermatic cord next, before incision of the testis, to avoid the common contamination by “buttered” tumor of the cord, with submission of the cord resection margin and a cross-section adjacent to the testis, just superior to the head of the epididymis.8,21 The tunica vaginalis should then be incised, any abnormalities described, the quantity and nature of any intratunical fluid recorded, and the tunica albuginea carefully inspected and palpated for penetration by neoplasm. The testis should then be bisected in the plane of its long axis, through the testicular hilum, by a long, sharp knife. Fresh tissue may then be harvested for special studies such as cytogenetics, flow cytometry, electron microscopy, and molecular studies, although these are not routinely needed for diagnosis. Photographs may be obtained, and then multiple, serial, parallel cuts at 3-mm intervals should be made, leaving the tunica albuginea intact posteriorly to keep the specimen together. The specimen should then be placed in a generous volume of 10% neutral buffered formalin

About 95% of testicular neoplasms are of germ cell origin. The 2016 World Health Organization (WHO) classification of testicular germ cell tumors (Table 13.2) incorporates recent advances in the understanding of the pathogenesis of these tumors, specifically separating the germ cell neoplasia in situ–related and germ cell neoplasia in situ–unrelated tumors.23 This classification replaces previous classifications including the British Testicular Tumor Panel (BTTP) classification that was sometimes used in Europe.24,25

Histogenesis The histogenesis of testicular germ cell tumors has been clarified over the past several decades by several clinical, morphologic, and immunohistochemical observations. Gene expression profiling and other molecular techniques have allowed a great increase in understanding of the molecular changes in the most common testicular cancers, the germ cell neoplasia in situ–associated tumors, which have also been described as type II germ cell tumors.26-28 Perhaps foremost in importance is the recognition that all of the adult germ cell tumors, with the exceptions of spermatocytic tumor, rare benign teratomas (a category now including epidermoid and dermoid cysts), and even more rare yolk sac tumors, are derived from a common precursor that Skakkebaek originally recognized and described as “carcinoma in situ” of the testis.23,29-32 Intratubular germ cell neoplasia of the unclassified type (IGCNU) had later been considered the appropriate term for this lesion, given the nonepithelial nature of the constituent cells, but the preferred term in the recent WHO classification is germ cell neoplasia in situ (GCNIS).23,33,34 GCNIS consists of a basilar proliferation of seminoma-like cells (occupying the “spermatogonial niche”) with clear cytoplasm and enlarged, hyperchromatic nuclei having one or two prominent nucleoli (Fig. 13.3). Additionally it has many features, apart from its light microscopic appearance, that it shares with seminoma, including ultrastructure, immunohistochemical reactions with various antibodies (M2A/podoplanin/ D2-40, TRA-1-60, placental-like alkaline phosphatase [PLAP],

734 CHA P T E R 13

TABLE 13.2

Neoplasms of the Testis

Classification of Testicular Tumors

Germ Cell Tumors Germ cell tumors Germ cell neoplasia in situ Germ cell tumors derived from germ cell neoplasia in situ Tumors of a single histologic type Seminoma (including seminoma with syncytiotrophoblast cells) Nonseminomatous germ cell tumors Embryonal carcinoma Yolk sac tumor, postpubertal type Trophoblastic tumors Choriocarcinoma Nonchoriocarcinomatous trophoblastic tumors Teratoma, postpubertal type Teratoma with somatic-type malignancy Nonseminomatous germ cell tumors of more than one histologic type Mixed germ cell tumors Germ cell tumors of unknown type Regressed germ cell tumors Germ cell tumors unrelated to germ cell neoplasia in situ Spermatocytic tumor Teratoma, prepubertal type Mixed teratoma and yolk sac tumor, prepubertal type Yolk sac tumor, prepubertal type

Sex Cord–Stromal Tumors Pure tumors Leydig cell tumor Sertoli cell tumor, not otherwise specified Large cell calcifying Sertoli cell tumor Intratubular large cell hyalinizing Sertoli cell neoplasia Granulosa cell tumor Adult granulosa cell tumor Juvenile granulosa cell tumor Tumors in the fibroma-thecoma group Myoid gonadal stromal tumor Mixed and unclassified sex cord–stromal tumors

Tumors Containing Both Germ Cell and Sex Cord–Stromal Elements Gonadoblastoma

Miscellaneous tumors of the testis and paratesticular tissue Ovarian-type epithelial tumors Juvenile xanthogranuloma Hemangioma and other stromal tumors

Hematolymphoid tumors Modified from Moch H, Humphrey PA, Ulbright TM, Reuter V. WHO Classification of Tumours of the Urinary System and Male Genital Organs. 4th ed. Lyon, France: IARC; 2016.

glutathione-S-transferase [isoenzyme π], the 14–3–3 beta protein, OCT3/4, NANOG, stem cell factor, TSPY protein, SOX17 +/ SOX2– immunophenotype), its DNA content, the number of nucleolar organizer regions, and lectin-binding patterns.35-53 The strong similarities between GCNIS and seminoma imply that seminoma is also a precursor for other germ cell tumors. This interpretation is supported by several morphologic, immunohistochemical, and molecular observations. These include autopsy studies showing nonseminomatous elements in patients who died of metastatic germ cell neoplasm after orchiectomy of pure testicular seminoma.20,54 Additionally, seminoma may undergo subtle transition to either embryonal carcinoma or yolk sac tumor.55,56 Also,

Fig. 13.3 GCNIS in seminiferous tubules. There are cells with clear cytoplasm and enlarged, hyperchromatic nuclei along the basilar aspect of tubules lacking spermatogenesis. Sertoli cells are displaced luminally.

10% to 20% of seminomas contain syncytiotrophoblast cells, and some trophoblastic hormone–containing cells in seminoma are not easily distinguished histologically from the surrounding seminoma cells.57-59 Ultrastructural studies of seminoma have demonstrated evidence of epithelial differentiation (seminoma with early carcinomatous features) in some light microscopically typical cases.60 Furthermore, the DNA content of seminoma is consistently higher than in nonseminomatous germ cell tumors, suggesting that nonseminomatous tumors evolve from seminoma as a consequence of gene loss, perhaps caused by loss of cancer suppressor genes.51,61,62 Karyotypic analyses have shown a striking tendency for certain chromosomes to be in parallel excess or deficiency in seminoma and the nonseminomatous germ cell tumors, and loss of heterozygosity studies also show similar patterns of allelic imbalance between coexisting seminoma and nonseminoma in the testis.61,63 These data indicate that seminomas transform to nonseminomatous tumors. Genetic changes precede the development of an invasive germ cell tumor from GCNIS.26,64,65 Although overrepresentation of gene sequences from the short arm of chromosome 12, mostly in the form of an isochromosome [i(12p)], is consistent in invasive germ cell tumors of adult patients, such overrepresentation is not found in the associated GCNIS.66-68 It is believed that additional 12p sequences are essential for invasive growth by inhibiting apoptosis and thereby permitting survival of invasive tumor cells outside of the microenvironment of the seminiferous tubules.67 There are marked similarities between many of the genetic changes in GCNIS and the associated invasive tumor, in support of the precursor role of the former.63,64 Immunohistochemical study has shown that loss of the cell cycle–dependent kinase inhibitors,

CHAPTER 13

p18 and p21, accompanies invasive growth, as does gain of the ubiquitin ligase murine double minute-2 (mdm-2) and increased production of cyclin E.69,70 Transformation of GCNIS to nonseminomatous tumor may apparently occur at the time of invasion, because pure embryonal carcinoma, yolk sac tumor, or choriocarcinoma are associated with GCNIS. Alternatively, these elements may overgrow a small focus of seminoma from which they arose. The common occurrence of seminoma with nonseminomatous elements also supports transformation from invasive seminoma. Allelotyping analysis supports this concept, as loss of heterozygosity is seen at progressively more loci from GCNIS to seminoma and then to embryonal carcinoma.71 Loss of heterozygosity at various loci was frequently shared among the seminoma and embryonal carcinoma components, and heterozygosity was retained in GCNIS, further supporting that the embryonal carcinoma component arose from the seminoma.71 Additional data show that GCNIS adjacent to seminoma or nonseminomatous tumors shares chromosomal abnormalities with the invasive tumor that differ depending on whether the adjacent tumor is seminomatous or nonseminomatous, an observation that supports genetic transformation within the tubules before morphologic change.72 Collectively, these observations led to a revised model of testicular germ cell tumor histogenesis based on the tetrahedron model proposed by Srigley et al. (Fig. 13.4).60 The histogenesis of testicular germ cell tumors in children (excluding those with disorders of sex development) is different from that of postpubertal patients. This is reflected in

Teratoma, prepubertal-type (including dermoid cyst, epidermoid cyst)

Neoplasms of the Testis

735

epidemiologic studies that documented a progressive increase in the incidence of testicular germ cell tumors throughout the twentieth century in postpubertal patients but not in the prepubertal group.73 Unlike the postpubertal tumors, the examples in children (confined to two types of neoplasm, yolk sac tumor and teratoma) lack association with GCNIS.74-78 Furthermore, the teratomas have a diploid DNA content and a normal karyotype, unlike those of postpubertal patients, and the yolk sac tumors lack consistent 12p abnormalities.79-81 The pediatric germ cell tumors therefore have a fundamentally different pathogenesis. These observations and others have led one group to propose that there are five fundamentally different forms of germ cell tumor: type I represented by the pediatric types, type II consisting of the usual postpubertal germ cell tumors, type III consisting only of spermatocytic tumor, type IV represented by ovarian dermoid cyst, and type V consisting of gestational choriocarcinoma.82 Each has its own unique pattern of gene activation and genomic imprinting.

Epidemiology Germ cell tumors of the testis (with the notable exception of spermatocytic tumor) occur mostly in young men, with the incidence accelerating rapidly after puberty and peaking close to 30 years of age (Fig. 13.5). There is a small peak in early childhood, but many cases of “testicular cancer” in elderly men correspond to lymphoma or secondary tumors rather than to germ cell tumors (Fig. 13.5). Whites have a much higher frequency of testicular germ cell tumors than do non-whites, with the exception of the Maori of

Germ cell

Spermatocytic tumor

Yolk sac tumor, prepubertal-type Germ cell neoplasia in situ (GCNIS)

Embryonal carcinoma

Seminoma

Seminoma with syncytiotrophoblast cells

Teratoma, postpubertal-type

Yolk sac tumor, postpubertal-type

Trophoblastic tumors

Fig. 13.4 New model of germ cell tumor histogenesis, based on the tetrahedron model of Srigley et al. (Srigley JR, Mackay B, Toth P, Ayala A. The ultrastructure and histogenesis of male germ neoplasia with emphasis on seminoma with early carcinomatous features. Ultrastruct Pathol. 1988;12:67–86). In this model, seminoma plays a pivotal role as a precursor for many other forms of germ cell tumor. Note the absence of GCNIS for prepubertal-type teratoma, prepubertal-type yolk sac tumor, and spermatocytic tumor.

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Neoplasms of the Testis

12

Rate/100,000

10 8 6 4 2 0 1

10

20

30

40 Age

50

60

70

80

Fig. 13.5 Incidence of testicular tumors according to patient age. Note a small peak in infancy, a nadir at 10 years of age, and a rapid rise after puberty. The peak incidence occurs at 25 to 30 years. The cases in older patients often correspond to nongerminal tumors, mainly lymphoma. (Data from the Surveillance, Epidemiology and End Results [SEER] Program).

New Zealand who have an incidence comparable to white populations.83,84 Native Hawaiians, Native Alaskans, and Native Americans are also at higher risk than other non-whites.85 The rates of increase of testicular cancer in black men (+ 1.67%/year), Hispanic men (+2.94%/year), and American Indian/Alaska Native men (+2.96%/year) in the United States are, however, increasing faster than that of white men (+1.23%/year) in recent decades.86 Denmark and Switzerland have the highest rates of testicular cancer, about 9 cases per 100,000 males per year, compared with the rate in the US white population of 5 to 6 per 100,000 males.86 The rates in Africans and Asians are generally about 1 per 100,000 males.87 In a study of over 1 million Israeli males, risk was strongly associated with birthplace, with odds ratios of 0.10 for those born in North Africa and 0.35 for those born in Asia compared with those born in Israel.88 The incidence of most testicular germ cell tumors increased steadily in the United States during the twentieth century, and recent National Cancer Institute Surveillance, Epidemiology, and End Results Program (SEER) data indicate an increase in the rate of testis cancer in 15- to 39-year-old males in the United States at a time when the incidences of most other cancers in this age group are decreasing.89-91 Increasing testicular cancer rates have been noted in several other countries, including Denmark, Norway, England, Germany, Scotland, New Zealand, Australia, Canada, Iceland, and Japan, although, as noted, the rate remained steady in children.73,84,92-104 Eastern Europe, which previously had a lower rate, has had the most rapid increase in testicular cancer incidence in recent years and now has a rate similar to Northern and Western Europe.105 Numerous studies have demonstrated a higher frequency of testicular germ cell tumors in professional workers or those of higher socioeconomic class compared with laborers or those of lower socioeconomic status.84,85,106-112 Higher rates have also been observed in those with occupational exposures to fertilizers, phenols, heat, smoke, or fumes; farm workers; draftsmen; those involved in food manufacture and preparation; leather workers; pesticide applicators; those exposed to insect repellants; metalworkers; police exposed to handheld radar; aircraft repairmen; motor vehicle mechanics; fishermen; electrical workers, paper and printing workers, and foresters; men of tall stature; and

physicians.84,106,107,113-123 Other studies have implicated in utero exposure to high estrogen levels, dietary iron, testicular trauma, various HLA-haplotypes, a family history of breast cancer, early puberty, early birth order, dizygotic twinship, ichthyosis, Marfan syndrome, the Li-Fraumeni syndrome, the dysplastic nevus syndrome, and HIV infection.124-146 One study has shown a correlation between testicular cancer and a variant allele of the glutathione-S-transferase π gene.147 Another study demonstrated increased risk in the sons of fathers who were wood processors, metalworkers, or employed in the food product industry.148 Recently, baldness and a history of severe acne, both associated with high androgen levels at puberty, have been associated with testicular germ cell tumors.149 Marijuana use has been associated with a 1.7 to 2.2-fold increased risk for testicular nonseminomatous germ cell tumors.150-152 Most of these associations, however, are weak and fail to account for the general increase in testicular germ cell tumors. It is hypothesized that important causative factors in testicular cancer occur in the antenatal period, with a protective effect in European countries for men born during the World War II era.92,153,154 This protective effect leads to the hypothesis that testicular cancer is causally related to prosperity, probably secondary to in utero effects. Environmental endocrine-disrupting chemicals have attracted interest as a possible causative factor for germ cell tumors (and the other components of the proposed testicular dysgenesis syndrome).28,65,155,156 Phthalates, chemicals present in plastics, have attracted interest as an environmental endocrine disruptor, but a causative role remains unproven.65,156 A potential unifying thread to several of the most compelling observations is that maternal obesity (leading to elevated estrogens) and/ or maternal exposure to estrogen simulators or antiandrogens lead to testicular maldevelopment with impaired Sertoli cell function that is key to germ cell neoplasia. The use of alcohol and tobacco, prior vasectomy, radiation exposure, and maternal and paternal occupational pesticide exposure have not been associated with testicular germ cell tumors.83,157-161 Despite the weak correlation of most etiologic factors with testicular germ cell tumors, four contributing factors are proven: cryptorchidism, prior testicular germ cell tumor, family history of testicular germ cell tumors, and certain disorders of sex development.83,162 An estimate of the increased risks associated with these disorders is provided in Table 13.3.

Cryptorchidism An increased frequency of cryptorchidism, varying from 6.5% to 14.5%, has been found in patients with testicular germ cell tumors, which has led to increased risk calculations of 2.5 to 35 times higher among cryptorchid patients.89,125,163-176 Such risk does not manifest before 20 years of age and is probably most accurately assessed as 3.5 to 5.0 times increased over a control population.167,173 If cryptorchidism is unilateral, the noncryptorchid testis is also at increased risk for a testicular germ cell tumor, although at a lower rate than the cryptorchid testis.85,169,171,177-179 Ectopia alone cannot explain the association of cryptorchidism and testicular germ cell tumor, a fact reinforced by the failure of orchiopexy to reduce the risk to that of the general population (although there is probably insufficient experience with orchidopexy in the very young to rule out an ameliorating effect).85,168,169,180,181 Early surgical correction, at 6 to 18 months of age, has been recommended as treatment for cryptorchidism, as the risk reduction is related to age, with a relative risk for developing cancer of 2.2 if orchiopexy is performed before 13 years of age compared with 5.4 if performed after 13 years of age.182-184

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TABLE 13.3

Estimated Increased Risk for Testicular Germ Cell Tumors Associated With Certain Conditions

Condition

Estimated Increased Risk References

Cryptorchidism

3.5-5X

Prior testicular germ cell tumor 5-10X

Family history (first-degree male relative)

3-10X

Gonadal dysgenesis with a Y-chromosome

50Xa

Androgen insensitivity syndrome

15X

a

Pottern, 1985167 Giwercman, 1987173 Giwercman, 19911 Dieckmann, 1999195 Giwercman, 1987218 Loy, 1993219 Dieckmann, 1997236 Fuller, 1986237 Tollerud, 1985238 Forman, 1992239 Giwercman, 19911 Rutgers, 1987253 Hughesdon, 1970254 Giwercman, 19911 Manuel, 1976260 Morris, 1953261 Rutgers, 1991262 Rutgers, 1991265

Includes cases of gonadoblastoma.

It seems likely that cryptorchidism is a marker of patients with a general defect in testicular and genital development and that cryptorchid testes are “dysgenetic,” as supported by abnormalities of the external genitalia or sex chromosomes in some cryptorchid patients with germ cell tumors.179,185-187 This has been conceptualized as the “testicular dysgenesis syndrome,” a collection of findings including cryptorchidism, infertility, disorders of sex development, GCNIS, and germ cell tumors that may share common etiologic factors.65,188,189 A distinctive array of testicular lesions may be seen in the parenchyma adjacent to germ cell tumors, including Leydig cell hyperplasia, microlithiasis, angiopathy, Sertoli cell nodules, tubular atrophy, and multinucleated spermatogonia, supporting an underlying developmental problem.190 Cryptorchidism may disproportionately predispose to seminoma compared with nonseminomatous tumors.163,174,191,192 GCNIS has been estimated to be present in about 2% to 4% of patients with cryptorchidism.193-196 At least 50% of such patients develop germ cell tumor within 5 years.197 Thus bilateral testicular biopsy at 18 to 20 years of age has been recommended for cryptorchid patients.198 A negative result is good evidence of no increased risk, although there are infrequent false-negative results.193,199,200 A positive biopsy should prompt orchiectomy of the affected testis. In testes with extreme atrophy, the biopsy should be directed to sample the region near the rete testis.201 Apart from germ cell tumors, cryptorchid testes have an increased frequency of nodules composed of small tubules lined by immature Sertoli cells, often with central deposits of basement membrane. These Sertoli cell nodules have been termed Pick adenoma, which is a misnomer because they are not true neoplasms.202,203

Prior Testicular Germ Cell Tumor A second germ cell tumor occurs in the remaining testis of 1% to 5% of patients with a previous germ cell tumor.204-217 The risk for

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a second germ cell tumor is higher in patients with seminoma, especially in men 30 years of age or younger.216 Similarly, there is a 3.2% to 6.6% frequency of GCNIS in the opposite testis of patients with a germ cell tumor.210,211,217-220 There is a low risk in the absence of GCNIS on biopsy because of occasional falsenegative biopsies.220 In one study, 5 of 1859 patients (0.3%) who had negative testicular biopsies opposite a germ cell tumor developed a second tumor on follow-up.200 Sensitivity is improved if three biopsies of the contralateral testis are performed.221 If the residual testis is either atrophic or cryptorchid, the risk is greater, with a 23% frequency of GCNIS.218-220,222,223 Unfortunately, almost 50% of cases of contralateral GCNIS would be missed if contralateral biopsies were restricted to patients with atrophy or cryptorchidism.219 One study suggested that atrophy rather than maldescent is the important predictor of contralateral GCNIS.224 Young (but postpubertal) age at onset of the first tumor and bilateral cryptorchidism are also associated with an increased risk for bilateral occurrence.211,224 It is estimated that biopsy of an atrophic testis opposite a germ cell tumor in a patient younger than 31 years of age will detect GCNIS in one-third.224 Prepubertal testicular germ cell tumors, in contrast, do not appear to be associated with an elevated risk for second gonadal cancers.203 About 50% of second primary tumors of the testis occur within 3 to 5 years after diagnosis of the initial germ cell tumor, with a mean of 5.6 to 6.5 years, but intervals of more than a decade can occur.207,215,216,225-227 Concordant or discordant neoplastic types may occur, with some tendency for concordance of pure seminoma.207 The risk for bilateral tumors is increased about fourfold with a positive family history.228,229 Chemotherapy administered for the first tumor has been observed to decrease the risk for a contralateral tumor, but not in all studies.209,212,217 Contralateral tumors may occur even in the absence of GCNIS in biopsies of the opposite testis performed at the time of the first germ cell tumor diagnosis.230 An increased frequency of rare alleles of the HRAS gene is seen in patients with testicular germ cell tumors, and such alleles are associated with bilaterality and early age of onset.231 Androgen receptor polymorphisms (with high or low numbers of CAG repeats) have been associated with testicular cancer risk.232 In one study, 64% of bilateral germ cell tumors had KIT mutations compared with 6% of unilateral tumors, suggesting a causative role for KIT mutations occurring early in embryonal development in patients with bilateral tumors.233 Genetic associations with germ cell tumor risk have been reviewed, and the association with KIT signaling has been confirmed with genome-wide association studies that have found associations with five molecular pathways: KIT signaling, other pathways of male germ cell development, telomerase function, microtubule assembly, and DNA damage repair.234,235

Family History First-degree male relatives of patients with germ cell tumor of the testis have a 3 to 10 times greater risk for a testicular germ cell tumor than the general population.236-239 The risk is highest for brothers (10 times), intermediate for sons (6 times), and lowest for fathers (4 times).240 Also, a family history of testicular germ cell tumor is associated with an 8% to 14% frequency of bilaterality, compared with the 1% to 5% frequency in the general population of patients with testicular germ cell tumors.205-208,216,228,237,240 The occurrence of an unexpected number of testicular germ cell tumors in the relatives of children with soft tissue sarcomas has raised the question of whether testicular germ cell tumors may represent part of the spectrum of the Li-Fraumeni cancer

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syndrome.241,242 It appears, however, that neither germline nor somatic TP53 mutations occur in these cases.243,244 Immunohistochemical demonstration of p53 protein therefore indicates overexpression of nonmutated protein.245,246 Segregation analysis of data regarding familial cases has suggested the presence of a major gene that conveys risk in a recessive model.247 Genetic linkage analysis has implicated a susceptibility gene localized to Xq27 in one study, but this was not confirmed in a second.248,249 Single nucleotide polymorphisms in BAK1, DMRT1, KITLG, and TERT-CLPTM1L genes have been associated with testis cancer risk odds ratios of 1.6 to 2.3.250 In a study including 147 families with either two or more cases of testis cancer or one case of bilateral testis cancer, no rare, highly penetrant susceptibility gene was identified.251 It is believed that, instead, familial testis cancer most likely results from multiple, common, low-penetrance alleles in a manner more similar to type 2 diabetes or familial prostate cancer than to the more well-known adult cancer susceptibility disorders with high-penetrance genes associated with breast, ovarian, and colorectal carcinoma.251 No increase in overall risk for nontesticular cancers was seen in relatives of familial testicular tumor patients in a recent study of 1041 first-degree relatives from 66 multiple case testicular germ cell tumor families, suggesting that tumors other than testis cancer are not part of the association.252

Disorders of Sex Development Patients with some disorders of sex development are at increased risk for germ cell tumors. Patients with gonadal dysgenesis in the presence of a Y-chromosome, including patients with pure 46,XY gonadal dysgenesis (Swyer syndrome) and mixed gonadal dysgenesis, commonly develop gonadal germ cell tumors.253-257 About 25% to 30% of such patients develop gonadoblastoma, and this may serve as the precursor lesion for the development of an invasive germ cell tumor (discussed later in this chapter).253,254,256 GCNIS is also present in about 8% of children and adolescents with gonadal dysgenesis.258 Because an invasive tumor may develop in childhood, gonadectomy is indicated as soon as the diagnosis is established. Patients with androgen insensitivity syndrome, caused by various mutations in the androgen receptor gene, develop a malignant germ cell tumor in 5% to 10% of cases overall.259-263 The tumor usually develops after puberty, and this may permit delayed gonadectomy until full feminization has occurred, although this remains controversial because of an occasional case of invasive germ cell tumor developing at an early age. Delay of prophylactic gonadectomy beyond the early postpubescent period in patients with androgen insensitivity syndrome (AIS) is risky, with a 22% frequency of malignant germ cell tumor in such patients beyond 30 years of age.260,264 Not all testicular masses in patients with the AIS are germ cell tumors; these patients commonly develop hamartomatous nodules composed of Sertoli cell–lined tubules with intervening clusters of Leydig cells in the interstitium, as well as pure Sertoli cell adenomas and occasional juvenile granulosa cell tumors.253,255,262,265 In addition to patients with mutations in the androgen receptor gene, there is a single report of GCNIS in a phenotypic female patient with an XY karyotype and a nonsense mutation in the gene for steroidogenic acute regulatory protein.266 Infertility Patients with infertility have an increased but less than 1% frequency of testicular germ cell tumor.35,195,218,267-269 The relative risk for germ cell tumor in patients with infertility is much lower than that associated with cryptorchidism or a history of

contralateral germ cell tumor.270 It is not clear, however, if infertility is a risk factor for germ cell tumor that is independent of cryptorchidism or gonadal dysgenesis.271 Impaired semen quality, hypospadias, cryptorchidism, and germ cell tumors are the components of the testicular dysgenesis syndrome theoretical construct and are each related to the other.155 Semen quality may be a highly sensitive marker for environmental exposures, which are also related to germ cell tumor incidence.155

Other Associations Testicular microlithiasis, seen ultrasonographically as hyperechogenic foci without shadowing, is observed in about 13% of patients evaluated by this method.272,273 Rare cases of germ cell tumor have been reported in patients, including teenage boys, being followed for testicular microlithiasis.274 It is unusual for a patient with testicular microlithiasis but without other risk factors to have GCNIS on biopsy, so biopsy is only recommended if other risk factors, such as infertility, cryptorchidism, or contralateral tumor, exist.272 Inguinal hernia and genital malformations other than cryptorchidism including hypospadias have also been associated with testicular germ cell tumor risk, although not as strongly as cryptorchidism.272,275

Germ Cell Neoplasia in Situ and Related Germ Cell Tumors Germ Cell Neoplasia in Situ Grossly, the testis with GCNIS may be unremarkable or appear atrophic and fibrotic. Microscopically, intratubular germ cell neoplasia consists of a proliferation of undifferentiated germ cells resembling primitive gonocytes or, less frequently, may be composed of cells of a specific neoplastic type, such as intratubular embryonal carcinoma.32 The primitive gonocyte-like form of intratubular germ cell neoplasia is confined to the basilar aspect of the seminiferous tubules (in the so-called “spermatogonial niche”) and is associated with all types of the postpubertal germ cell tumors, except for spermatocytic tumor and the rare benign teratomas (including dermoid/epidermoid cyst) and prepubertaltype yolk sac tumors.29,30 GCNIS cells have enlarged, hyperchromatic nuclei, often with one or two prominent nucleoli, thickened nuclear membranes, and clear cytoplasm (Fig. 13.3). The median nuclear diameter is 9.7 μm, compared with a median nuclear diameter of spermatogonia of 6.5 μm.276 Spermatogenesis in the affected tubules is usually decreased or absent, and the tubules may have a thickened peritubular basement membrane. Sertoli cells are often displaced luminally (Fig. 13.3). The distribution of GCNIS is characteristically patchy, and adjacent profiles of seminiferous tubules may appear unremarkable with intact spermatogenesis (Fig. 13.6). The patchy distribution has implications for biopsy diagnosis, as a small volume sample may result in a falsenegative diagnosis.277 Leydig cell hyperplasia may occur in the interstitium. GCNIS often spreads into the rete testis in a “Pagetoid” fashion, intermixing with nonneoplastic epithelium, which is displaced toward the lumen (Fig. 13.7).278 The strong similarity of the cells of seminoma and GCNIS suggests that GCNIS could be termed intratubular seminoma; however, this term may falsely suggest that GCNIS is the precursor lesion only for seminoma rather than for virtually all postpubertal germ cell tumors. The term intratubular seminoma has been applied to those proliferations of GCNIS-like cells that fill and distend seminiferous tubules (Fig. 13.8), although such lesions may simply be a more advanced stage of GCNIS.279

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also encountered with CD117.49,300,301 In contrast, intratubular embryonal carcinoma is SOX17 negative and SOX2 positive.49 The positive reactions for PLAP, OCT3/4, CD117, and TRA1-60 support the idea that GCNIS resembles fetal gonocytes.38,40,293 There is some heterogeneity in expression of germ cell markers in cells in GCNIS tubules, and it is the OCT3/4+/ MAGEA4– population of cells that has the higher proliferative activity (relative to OCT3/4+/MAGEA4+ cells) and is thought to progress to invasive tumor.302 By electron microscopy, GCNIS has evenly dispersed chromatin, intricate nucleoli, and sparse cytoplasmic organelles with prominent glycogen deposits. Occasional rudimentary intercellular junctions may be identified.35,303-306 These features are essentially the same as those of seminoma.307 The DNA content of GCNIS is similar to that of seminoma, usually in the triploid and hypotetraploid range.51,308 Some of the genetic features of GCNIS have been previously mentioned. Differential Diagnosis

Fig. 13.6 Patchy distribution of GCNIS. Tubules without GCNIS have spermatogenesis, whereas adjacent tubules with GCNIS lack spermatogenesis.

Special Studies

Glycogen is present in the cytoplasm of 98% of cases of GCNIS (Fig. 13.9), and its demonstration is diagnostically helpful but nonspecific because nonneoplastic spermatogonia and Sertoli cells may also contain glycogen.280,281 The current best immunohistochemical marker for GCNIS is OCT3/4, a nuclear transcription factor with a key role in maintaining pluripotency in embryonic stem cells. OCT3/4 is uniformly sensitive for GCNIS (Fig. 13.10).45,50,282,283 It, as well as other GCNIS markers, is also seen in germ cells with delayed maturation in gonadal dysgenesis, Down syndrome, and undervirilization syndromes that have different features from GCNIS. PLAP is also a good marker for GCNIS.284-287 It highlights the cytoplasmic membranes of most cases (reported sensitivity: 83%-100%; Fig. 13.10A).40,281,288,289 Only rarely (less than 1%) are isolated nonneoplastic spermatocytes (which are unlikely to be confused with GCNIS) PLAP positive, with spermatogonia being PLAP negative.288 Immunohistochemical staining for NANOG, a regulatory factor upstream to OCT3/4, similarly marks GCNIS.46 GCNIS has also been found to react with monoclonal antibodies M2A (D2-40/gp36/podoplanin), 43-9F, TRA-1-60, HB5, HF2, HE11, and with antibodies directed against glutathione-S-transferase, isoenzyme π, CD117 (Fig. 13.10C), angiotensin-converting enzyme, p53, growth differentiation factor 3 (GDF3), stem cell factor, and Kr€ uppel-like factor 4.37,42,47,233,283,289-298 It is negative for the RNA-binding motif protein, in contrast with nonneoplastic germ cells.299 GCNIS is SOX17 positive and SOX2 negative, but SOX17 also marks nonneoplastic germ cells, a problem we have

GCNIS should be distinguished from specific forms of intratubular germ cell neoplasia. Intratubular seminoma fills and distends the tubules, whereas GCNIS is restricted to the basilar area, although the cells are histologically identical. Atypical germ cells that do not resemble GCNIS cells may also occur in seminiferous tubules. These cells may have large nuclei or be multinucleated. They lack the cytoplasmic clarity and nucleolar prominence of GCNIS cells and do not stain for the usual GCNIS markers. Although they may indicate a perturbation in testicular development, as evidence by increased frequency in cryptorchid boys and adjacent to testicular germ cell tumors, their significance is not clear, unlike GCNIS.190,309 Despite some controversy, GCNIS does not occur in prepubertal patients except for those with disorders of sex development. Many purported cases represent germ cells with delayed maturation (Fig. 13.11). These cells may occur in young children who have conditions that place them at increased risk for germ cell tumors, including cryptorchidism, gonadal dysgenesis, Down syndrome, and undervirilization syndromes.285-287,310 They, however, are distinguished from GCNIS by their nonbasilar location in the tubules (Fig. 13.11) and tendency to cluster in areas of the parenchyma. More recently, “pre-GCNIS” has been put forth as a lesion intermediate between maturation delay and GCNIS.23 It differs from them by having the lesional cells in both basilar and nonbasilar loci (Fig. 13.12) and, unlike maturation delay, is associated with expression of stem cell factor in the affected tubules, a feature shared by GCNIS. The full clinical significance of maturation delay is not clear, meaning it is not known how frequently it progresses to an invasive germ cell tumor. It is important to distinguish such cells from GCNIS because it is known that GCNIS will progress in virtually all cases. If GCNIS or pre-GCNIS is found in a prepubertal patient, it is in the context of a disorder of sex development.311 Pre-GCNIS in patients with a disorder of sex development has also been termed infantile GCNIS.312 Prognosis

The practical importance of GCNIS is its progression to an invasive germ cell tumor (either seminomatous or nonseminomatous) in about 50% of cases within 5 years after identification.313 Only a small fraction of patients remain free of an invasive tumor by 7 or 8 years of follow-up (Fig. 13.13), although some patients may not develop a tumor for more than 15 years.314,315 Furthermore, there is no documented case of spontaneous regression of typical GCNIS.315 GCNIS is identified with increased frequency in

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Fig. 13.7 (A and B) GCNIS cells have extended in a pagetoid fashion into the rete testis, with a layer of rete epithelium stretched over them.

patients with cryptorchidism, a previous history of a testicular germ cell tumor, gonadal dysgenesis, androgen insensitivity syndrome, and infertility.35,193,194,197,198,220,224,316-325 GCNIS is also identified in the residual seminiferous tubules of virtually every postpubertal patient with a testicular germ cell tumor, with the exceptions of spermatocytic tumor, prepubertal-type teratoma/dermoid cyst/ epidermoid cyst, and prepubertal-type yolk sac tumor.30,280,326-329 The prepubertal-type germ cell tumors, as mentioned previously, lack association with GCNIS. In our opinion, many reported cases in children (Figs. 13.14 and 13.15) represent reactive enlargement of nonneoplastic germ cells induced by a mass lesion, as described by Hawkins and Hicks, atypical but nonneoplastic germ cells of unknown significance, or examples of delayed maturation of germ cells.330 Biopsy Diagnosis

Testicular biopsies are a sensitive method for detecting GCNIS. Fixatives such as Bouin, B-5, and Stieve enhance cytologic detail and may permit easier detection of GCNIS compared with formalin fixation. Formalin, Bouin, and Stieve fixatives permit immunohistochemical detection of placental alkaline phosphatase, whereas Cleland fluid yields inconsistent results.1 Nonformalin fixation may result in weaker immunohistochemical staining, so formalin may be preferred if immunohistochemical staining is expected.277 Berthelsen and Skakkebaek concluded that one or two 3-mm biopsies of a testis harboring GCNIS will detect virtually every case, although rare false-negative results do occur (0.3% in one study of 1859 biopsies that were initially interpreted as negative).200,331

Two site biopsies have a 17% improvement in sensitivity over one site and have been recommended as standard.332 Another study supported three biopsies, each 5 mm in length, as optimal.221 In cases of severe atrophy, with obliteration of many tubules, it may be necessary to sample the region near the hilum, where GCNIS is more frequently preserved within the epithelium of the rete testis.201 Recently, some authors have considered OCT3/4 immunohistochemistry mandatory for the evaluation of testis biopsies, as it identifies GCNIS in approximately 20% more cases than hematoxylin and eosin staining alone.277 It should be noted that positivity for immunohistochemical markers, including OCT3/4 and D2-40, may be seen before 2 years of age in the absence of GCNIS, so, in younger patients, positive immunohistochemical staining alone does not indicate a positive diagnosis.333 Potential indications for screening biopsies include patients with cryptorchidism (2% to 4% positivity for GCNIS), a prior testicular germ cell tumor (4% to 5% positivity), somatosexual ambiguity (25% positivity), and, less strongly, oligospermic infertility (0% to 1% positivity).195,268,276,315,332,334 A recent study of 4130 germ cell tumor patients found a rate of metachronous germ cell tumor of 1.9% in the cohort who had prior screening biopsies (and treatment if positive) and 3.1% in the unscreened cohort, but this did not reach statistical significance.334 Sperm concentration, contralateral testis volume, and ultrasound echo pattern have been proposed to estimate the risk for contralateral GCNIS in germ cell tumor patients and to select patients for biopsy.335 GCNIS in a biopsy from a patient with retroperitoneal germ cell tumor probably indicates the regression of a prior invasive tumor

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radiation.338 Unilateral GCNIS is usually managed by orchiectomy and bilateral GCNIS with radiation. Because GCNIS is very radiosensitive, low doses are used, permitting preservation of androgen function. Chemotherapy, often given to patients with metastatic disease from a contralateral testicular tumor, may ablate GCNIS in the remaining testis but is not a consistently effective therapy.276,339-342 In a German cooperative group study, radiation treatment was highly effective in curing GCNIS, although failures occur in about 2% of patients.332,343 Chemotherapy reduced the incidence of subsequent germ cell neoplasia, but was much less effective than radiotherapy.343

Seminoma Clinical Features

Fig. 13.8 Distension of seminiferous tubules by seminoma-like cells is referred to as “intratubular seminoma.”

Fig. 13.9 Cytoplasmic glycogen in GCNIS is demonstrated by a periodic acid-Schiff stain.

that metastasized to the retroperitoneum.336,337 Therefore, a patient with presumed primary germ cell tumor of the retroperitoneum may benefit from testicular biopsy.196 Treatment

Because of the high rate of progression of GCNIS to invasive testicular germ cell tumor, these patients should receive appropriate ablative treatment, either orchiectomy or low-dose external beam

Seminoma is the most common pure testicular germ cell tumor, and pure seminoma accounts for about 50% of all cases, although its relative proportion may be declining.344-346 In one study, the percentage of seminomas decreased from 52% to 43% over the 20-year study period.347 It occurs in patients at an average age of 40 years, which is about 10 years older than those with nonseminomatous germ cell tumor.39,55 African Americans may have an earlier age of onset.348 Most patients present with a painless testicular mass, but there may be a dull, aching sensation. Up to 11% have normal-sized or atrophic testes.349 Occasional patients (2% to 3%) present with symptoms of metastases, usually back pain caused by retroperitoneal involvement, but gastrointestinal bleeding, bone pain, central nervous system dysfunction, dyspnea and cough, and other symptoms may rarely be presenting complaints.17 Gynecomastia may occur as a result of elevation of serum hCG caused by intermingled syncytiotrophoblast elements in seminoma and is rarely a presenting feature.350 Very rarely, a paraendocrine form of exophthalmos can be a presenting complaint, as can paraneoplastic hypercalcemia, hemolytic anemia, and limbic encephalopathy.351-355 About 30% of seminoma patients have metastases at the time of diagnosis, and this is probably decreasing as a result of an overall trend for earlier detection of germ cell tumors.39,347 Patients with seminoma usually lack serum AFP and hCG elevations that occur commonly in patients with nonseminomatous germ cell tumors. AFP levels should be normal, although concomitant liver disease (including seminomatous metastases to the liver) may cause modest AFP elevation, and “borderline” elevated AFP levels have been seen in some cases without evidence of nonseminomatous elements.356,357 Most oncologists regard significant AFP elevation in a patient with apparently pure testicular seminoma as evidence of nonseminomatous elements and treat accordingly. About 10% to 20% of patients with clinical stage I “pure” testicular seminoma have elevated serum hCG, and 25% or more with advanced seminoma have hCG elevations.358 At initial diagnosis, 7% to 25% of patients with seminoma have elevated hCG.223,356,359-363 If blood is sampled from the testicular vein, 80% to 85% of patients have elevated hCG.364,365 Such elevation reflects the presence of intermingled syncytiotrophoblast elements in these tumors, and the elevations are generally modest. Although rare, large seminomas with abundant syncytiotrophoblast cells may produce elevations of over 4000 IU/L.366 Elevations of serum hCG exceeding 40 IU/L have been correlated with a poorer prognosis, although this is controversial.359,367,368 Peripheral venous elevations of hCG have been correlated with larger tumors, perhaps explaining the relationship of elevated hCG with adverse prognostic features.365 Elevation of serum levels of lactate dehydrogenase, PLAP, and neuron-specific enolase may also occur in patients with seminoma. Such elevations, however, are neither specific nor

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Fig. 13.10 (A) Cytoplasmic membrane positivity for placental alkaline phosphatase in GCNIS cells in seminiferous tubules and rete testis. (B) Strong nuclear reactivity for OCT3/4 in GCNIS. (C) An identical pattern of positivity for CD117 in GCNIS cells as seen for placental alkaline phosphatase.

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Neoplasms of the Testis

Fig. 13.11 Delayed maturation of germ cells. Gonocyte-like cells (arrows) are present in the center and parabasal positions.

especially sensitive, which limits their clinical utility.358,367,369-372 MicroRNA-based evaluation for miR-371-3 and miR-367 as a potentially more sensitive marker of tumor recurrence is currently being investigated.373,374

Fig. 13.12 “Pre-GCNIS” gonocyte-like cells occupy both central and basilar loci in the tubules. Simultaneous expression of stem cell factor (KIT-ligand, not shown) in the same tubule is also required.

Pathologic Findings

100% Testes with invasive germ cell tumor

Grossly, seminoma is usually cream to tan to pale pink and often multinodular (Fig. 13.16), with occasional yellow foci of necrosis. Infrequently, necrosis is extensive. In some cases, the tumor is diffuse, fleshy, and encephaloid, similar to testicular lymphoma (Fig. 13.17). In contrast with lymphoma, however, only about 10% of seminomas extend into paratesticular structures.375 Intraparenchymal hemorrhage may cause red discoloration.34 The cut surface usually bulges from the surrounding parenchyma (Fig. 13.16). Punctate foci of hemorrhage often correspond to intermingled foci of syncytiotrophoblast elements.376 A fibrous consistency is uncommon but results when prominent fibrous septa develop in the tumor or if there is extensive intratumoral sclerosis. Microscopically, seminoma is usually arranged in a diffuse, sheetlike pattern interrupted by branching, fibrous septa containing an inflammatory infiltrate (Fig. 13.18) consisting chiefly of lymphocytes but often containing plasma cells and sometimes eosinophils. Distinct nodules may be apparent, sometimes with confluent growth imparting a lobulated pattern. In some cases, a prominent cordlike arrangement of cells is present (Fig. 13.19), often at the periphery of nodules showing a sheetlike pattern. Foci of intertubular growth may be seen, with preservation of seminiferous tubules. This pattern is usually most apparent at the

50%

1

2

3

4 Years

5

6

7

Fig. 13.13 Follow-up of patients with GCNIS on biopsy. About 90% have invasive tumor after 7 years. (Data from Skakkebaek NE, Berthelsen JG, Visfeldt J. Clinical aspects of testicular carcinoma-in-situ. Int J Androl. 1981;4 Suppl s4:153–160).

periphery of neoplastic nodules and may be associated with rete testis invasion and aggressive behavior.377 In rare seminomas, an intertubular pattern may predominate (Fig. 13.20), with wellpreserved seminiferous tubules even in the central portions of the neoplasm. Such cases are prone to being overlooked because they do not destroy the seminiferous tubules, and they often do not form a discrete gross mass.378 The presence of a lymphocytic infiltrate may be a clue to intertubular seminoma (Fig. 13.20). This

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Fig. 13.15 Abnormal germ cells adjacent to teratoma in a pediatric patient. These cells lack the features of GCNIS. Fig. 13.14 Abnormal germ cells, some binucleated, adjacent to teratoma in a pediatric patient. These cells lack the features of GCNIS.

pattern is much more common, however, in testicular lymphoma. With time, many seminomas develop foci of scarring. Hyalinized deposits of collagen may separate the neoplastic cells into small nests resembling solid pseudotubules (Fig. 13.21). Extensive collagen deposits may result in broad scars with only a few scattered neoplastic cells. Calcification and even ossification may rarely occur in hyalinized fibrous trabeculae of seminoma.379 Rarely, seminoma may show a distinctly tubular pattern in which a palisade-like arrangement of neoplastic cells occurs at the periphery of tubule-like structures that may contain loosely cohesive neoplastic cells in their “lumens” (Fig. 13.22).380-383 Seminoma may also develop intercellular edema with separation of neoplastic cells and formation of microcystic spaces (Figs. 13.23 and 13.24). These spaces are generally, but not always, irregular in outline and frequently contain visible edema fluid and intracystic exfoliated neoplastic cells that contrast with the “cleaner,” more round and regular microcystic spaces commonly identified in yolk sac tumor.384 Foci of coagulative necrosis are present in about one-half of seminomas and may be extensive in a minority of cases.349 A lymphoid infiltrate is a virtually constant feature of seminoma and is usually most evident in perivascular areas and around fibrous trabeculae, which also contain many capillaries (Fig. 13.25). Lymphocytes are also frequently intermingled with the seminoma cells elsewhere. A florid lymphoid reaction, with formation of germinal

centers, occurs in a minority of cases, but most of the lymphocytes in seminomas are T cells.385-391 Ultrastructural studies have demonstrated a cytolytic effect of the lymphocytes on the seminoma cells, correlating with the observation of some investigators of a better prognosis in cases associated with a prominent lymphocytic reaction.390,392 A variable granulomatous reaction occurs in up to 50% of seminomas. In most cases, it consists of small clusters of epithelioid histiocytes scattered among neoplastic cells (Fig. 13.25). Langhanstype giant cells and other multinucleated giant cells may be present. Intratubular collections of epithelioid histiocytes may also be seen. Rarely, the granulomatous reaction can be extensive and virtually efface the neoplasm (Fig. 13.26); in such cases, it may be difficult to distinguish a florid granulomatous reaction in a seminoma from granulomatous orchitis, and careful search for residual seminoma and GCNIS is indicated. Intravascular granulomas have been reported in 15% of seminomas but were not a significant predictor of tumor recurrence.393 The cells of seminoma have generally clear to lightly eosinophilic cytoplasm, measuring 15 to 25 μm in diameter. The nuclei are relatively uniform, polygonal, usually centrally or slightly eccentrically placed, with finely granular chromatin and one or two prominent nucleoli (Fig. 13.27). Many nuclei have a relatively flat edge that has been described as “squared-off,” lending the nuclei a “boxy” appearance. The nuclear membranes are irregularly thickened. The cell borders are typically well defined in adequately fixed specimens (Fig. 13.27). Abundant cytoplasm separates the

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Fig. 13.16 Cut surface of a seminoma demonstrating a cream-colored, multinodular neoplasm bulging from the surrounding testicular parenchyma.

Fig. 13.18 Sheetlike pattern of a seminoma is interrupted by branching, fibrous septa containing lymphocytes.

Fig. 13.17 Seminoma with a diffusely fleshy, encephaloid appearance and foci of hemorrhage. (Courtesy of RH Young, MD, Harvard Medical School, Boston, MA).

nuclei so that overlapping nuclei are usually not seen. Occasionally, seminoma displays foci of increased cellular atypia with less welldefined cytoplasmic membranes, darker cytoplasm, and enlarged, crowded nuclei (Fig. 13.28). These changes may impart a plasmacytoid appearance to the tumor cells (Fig. 13.29). Such changes may be seen in association with early necrosis and contain pyknotic

nuclear fragments. Such isolated foci, in the absence of distinct epithelial differentiation, do not exclude a diagnosis of seminoma. Rarely seminoma cells develop intracytoplasmic vacuoles that cause a signet ring cell morphology (Fig. 13.30).394 This may be a focal finding in an otherwise usual-appearing tumor. We have also seen prominent aggregates of glycogen create a signet ring cell appearance (Fig. 13.31).394 Mitotic figures in seminoma are prominent, and in the past, when present in sufficient numbers, were considered as evidence of “anaplastic seminoma.”170 Now it is clear that mitotic rate in seminoma does not correlate with prognosis.395-397 Furthermore, there is no immunohistochemical difference between typical and “anaplastic” seminomas.398 Use of the term anaplastic seminoma is therefore discouraged. Although some seminomas behave more aggressively than most, it remains unclear if such cases can be identified prospectively. Tickoo et al. described cases of “seminoma with atypia” based on nuclear pleomorphism and crowding, paucity of lymphocytes, and darker-staining cytoplasm.399 In their experience, such tumors were more likely to present at advanced clinical stage, to express CD30, and to lose KIT expression. It remains unclear, however, if such cases should receive different treatment.

Seminoma With Syncytiotrophoblast Cells Syncytiotrophoblast cells are present in 10% to 20% of seminomas.58 The morphology of these cells is variable, ranging from typical syncytiotrophoblast cells with cytoplasmic lacunae and multinucleation (Fig. 13.32) to large mononucleated or binucleated cells that may not be easily distinguished from the background

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Fig. 13.20 Intertubular growth of a seminoma. There are small nests of seminoma cells between tubules. The lymphocytes are a helpful clue.

Fig. 13.19 Prominent cordlike pattern in a seminoma.

seminoma cells but that are highlighted by immunostains against hCG.400 Intermediate between these extremes are cells containing multiple nuclei in a “mulberry” pattern. Syncytiotrophoblast cells are often located close to capillaries, and microhemorrhages may be seen in these foci. Unlike choriocarcinoma, the syncytiotrophoblast cells are not intermingled with a mononucleated trophoblast cell component but are randomly admixed as single cells or small clusters with seminoma cells. With hCG immunohistochemistry, intratubular trophoblasts can be detected in a substantial fraction of seminoma cases, indicating that differentiation toward trophoblastic elements may occur before invasion.401 Special Studies

Glycogen is usually prominent in seminoma (Fig. 13.33), and most cases show immunoreactivity for PLAP, generally in a peripheral, “membranous” staining pattern (Fig. 13.34A); cytoplasmic staining may also be identified.41,281,402,403 Seminomas are uniformly reactive for OCT3/4 (Fig. 13.34C), a nuclear transcription factor identified in nonneoplastic stem cells and embryonic cells that plays an important role in the maintenance of a pluripotential capacity.282,404,405 OCT3/4 staining is also seen in embryonal carcinoma but not in other testicular tumors.50,282,404,405 Angiotensin-converting enzyme was demonstrated in 100% of 91 seminomas in one study.296 Reactivity for CD117 (c-kit protein) occurs in most seminomas, with a cytoplasmic membrane

pattern similar to PLAP (Fig. 13.34B).406,407 Podoplanin (D2-40) is positive (Fig. 13.35), as is SALL4, a general germ cell tumor marker.408,409 The NANOG protein, a product of a gene located at 12p13, a region frequently amplified in testicular germ cell tumors, is similarly detectable by immunohistochemistry in GCNIS, seminoma, and embryonal carcinoma, but not in teratoma or yolk sac tumor.46,410 SOX17, a nuclear transcription factor, was identified in 95% of seminomas but not in embryonal carcinomas.49,300,301 Many seminomas also express limited degrees of cytokeratin immunoreactivity, although such staining may only be demonstrable using frozen sections, with frequent negativity in routinely processed tissue.411 The most common cytokeratins in seminoma are cytokeratins 7, 8, and 18, although others, including cytokeratins 4, 17, and 19, can be identified occasionally.411,412 Cytokeratin 20 is negative.412 Epithelial membrane antigen (EMA) is only rarely expressed in seminoma, and the combination of positivity for PLAP and negativity for EMA and cytokeratin AE1/AE3 in formalin-fixed, paraffin-embedded tissue is a relatively specific pattern for seminoma.41,170,412,413 Vimentin, LDH, and NSE may be present in seminoma but are not specific.41,411,414 A minority of seminomas may stain for Leu-7, α-1-antitrypsin, desmin, and neurofilament protein.41,411 Desmoplakins and desmoglein are usually present in seminoma.411,415 The syncytiotrophoblast cells that occur in some seminomas contain hCG, and some cells containing hCG may not have an overtly “syncytiotrophoblastic” appearance in routine sections.41,57-59,416 CD30 is usually negative in seminoma, which contrasts with its virtually uniform presence in embryonal carcinoma, except after

Fig. 13.21 Scarring in a seminoma creates a pattern of small nests and solid pseudotubules separated by hyalinized stroma.

Fig. 13.22 Tubular pattern of a seminoma, with palisade-like arrangement of cells at the periphery of tubule-like structures.

Fig. 13.23 Edema in a seminoma creating an irregular, microcystic pattern.

Fig. 13.24 Microcystic pattern in a seminoma.

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Fig. 13.25 Lymphocytes and epithelioid granulomas in a seminoma.

Fig. 13.26 An extensive granulomatous reaction in a seminoma, leaving only rare tumor cells.

chemotherapy, in which case loss of CD30 expression is frequently seen.412,417 Ultrastructurally, seminoma has closely apposed cytoplasmic membranes that usually show only sparse, primitive, intercellular junctions. The cellular organelles consist of scattered mitochondria, occasional cisternae of smooth and rough endoplasmic reticulum, ribosomes and polyribosomes, occasional membrane-bound lysosome-like structures, and occasional Golgi bodies. Glycogen may be present in large quantities but may also be sparse. It is common for the cytoplasmic organelles to be polarized eccentrically in the cytoplasm. The nuclei are round and have evenly dispersed chromatin and intricate, large nucleoli.60,418,419 Occasional seminomas that are typical-appearing at the light microscopic level may show evidence of epithelial differentiation, with small, extracellular lumens, microvilli, and well-defined junctional complexes.60 Such cases, despite “transitional” morphology at the ultrastructural level, appear to behave as typical seminoma.60 The DNA content of seminoma is generally in the triploid to hypotetraploid range and is greater than that of nonseminomatous tumors.51,62,420 The DNA content of seminoma with syncytiotrophoblast cells does not differ from seminoma lacking them, supporting classification as seminoma.421 Evolution of seminoma to other types of germ cell tumor may occur as a result of gene loss.51,62,420,422 As in many testicular germ cell tumors, seminoma frequently contains an isochromosome derived from the short arms of chromosome 12, i(12p).423,424 Numerous other cytogenetic abnormalities have also been described; certain chromosomes are commonly overrepresented (1q, 7, 8, 12, 14q, 15q, 17, 21q,

22q, and X) and others underrepresented (3, 4, 5, 10, 11, 12q, 13q, 16, 18q, and Y).423,425-427 A number of molecular observations are reported in seminoma, including absence of Fas, loss of p18INK4C, upregulation of cyclin E, cyclin D2 expression, and activation of p16INK4 by hypermethylation.70,428-430 Activating exon 17 mutations of the KIT gene are seen in 12% to 13% of cases and about 20% have KIT gene amplification.431,432 Seminomas are reported to have loss of Notch 1, Jagged 2, and Fhit expression, show SMAD4 and ras mutations, and express DAZL1 protein, hst-1, N-myc, Kr€ uppel-like factor 4, and MAGE genes.298,433-443 The MAGE gene products, along with NY-ESO-1, are members of a group known as “cancer testis antigens” which show variable, low-level expression in seminoma.444446 These antigens are consistently strongly expressed in spermatocytic tumors and are infrequently expressed by nonseminomatous germ cell tumors and GCNIS.444-446 Gene expression studies have confirmed significant upregulation of genes previously known to be upregulated in seminoma such as POU5F1 (OCT4), KIT, ALPL, and PROM1 and have also identified upregulation of a number of other genes including BOB1, CD9, THY1, and PUM2.447 Differential Diagnosis

Seminoma can be misinterpreted as the solid pattern of embryonal carcinoma, especially in poorly fixed preparations. The formation of glands, true tubules, or papillae argues against the diagnosis of seminoma; the nuclei of seminoma are more uniform, less crowded, and more evenly spaced than those of embryonal carcinoma, which are pleomorphic, irregularly shaped, crowded, and appear to abut or

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Fig. 13.28 Seminoma with increased nuclear pleomorphism and crowding and denser cytoplasm than usual. Fig. 13.27 Seminoma cells with clear cytoplasm, well-defined cell borders, and nuclei with one or two prominent nucleoli. Lymphocytes are present in a fibrous septum, and some tumor nuclei have “squared-off” edges.

even overlap. The cytoplasmic borders of seminoma are well defined and those of embryonal carcinoma are mostly poorly defined, with occasional exceptions in foci.448 The cytoplasm of embryonal carcinoma is typically denser. Embryonal carcinoma lacks the regular fibrous septa of many seminomas. Cytokeratin reactivity is usually weaker and PLAP reactivity stronger in seminoma than in embryonal carcinoma. CD30 reactivity is rare in seminoma and positive in embryonal carcinoma, and CD30 immunohistochemistry may be especially useful in combination with CD117 (c-kit) to distinguish seminoma (CD30–/CD117+) from embryonal carcinoma (CD30 +/CD117–).283,412,449 Weak staining of embryonal carcinoma for c-kit has been seen in up to 32% of tumors in one study, however.450 Podoplanin (M2A, D2-40), similar to CD117, is typically diffusely positive in seminoma and usually negative or focally reactive in embryonal carcinoma.290,450-452 Monoclonal antibody 43-9F is reported to be strongly reactive in embryonal carcinoma and negative or only weakly positive in seminoma, but additional experience is necessary to confirm this finding.453 An antibody to SOX2, a nuclear transcription factor, appears to be a highly sensitive nuclear marker for embryonal carcinoma and is consistently negative in seminoma.49,283 A related protein, SOX17, in contrast, is positive in seminoma and negative in embryonal carcinoma.49 Immunohistochemical staining for AP-2γ, another nuclear transcription factor, marks a higher percentage of nuclei in embryonal carcinoma than

seminoma, but is probably not of use in differentiating these two tumors, although it may, like OCT3/4, be a useful marker for the two as a group.450 AFP is occasionally positive in embryonal carcinoma and is negative in seminoma. The distinction of seminoma from spermatocytic tumor is discussed in the Spermatocytic Tumor section later in this chapter. Yolk sac tumor with a solid pattern may mimic seminoma. Such cases are usually distinguished from seminoma by the presence of typical patterns of yolk sac tumor, the tendency for microcyst formation in the solid areas, intercellular bandlike deposits of basement membrane, intracellular hyaline globules, nuclear pleomorphism, and absence of lymphocytes and fibrous septa.454 Edematous seminomas, however, may produce a microcystic pattern reminiscent of yolk sac tumor, but the cystic spaces are usually more irregular and contain edema fluid and exfoliated neoplastic cells, in contrast with those of yolk sac tumor, although there are exceptional seminomas with regular and uniform microcysts.384 The typical polygonal cells of seminoma in microcystic areas, however, contrast with the flattened cellular profiles and more variable nuclear appearance of yolk sac tumor cells lining microcystic spaces. AFP is negative in seminoma and usually positive in yolk sac tumor; glypican-3 has a similar pattern of reactivity but is more sensitive for yolk sac tumor.455-457 Cytokeratin is often negative or weak in seminoma (in routinely processed tissues), whereas it is almost always strongly positive in yolk sac tumor. OCT3/4 and podoplanin are strongly positive in seminoma but negative in yolk sac tumor. CD117 is not useful in this differential diagnosis because it is often positive in both.

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Fig. 13.29 Plasmacytoid seminoma. Many cells have dense cytoplasm and eccentric nuclei.

Lymphoma must be distinguished from seminoma; most patients with testicular lymphoma are older than 50 years of age, whereas patients with seminoma are usually younger.458-465 Bilateral involvement is more likely in lymphoma than in seminoma.459,461-463,466 Lymphoma usually infiltrates the interstitium, preserving the seminiferous tubules, whereas most seminomas do not show as prominent a degree of intertubular growth, although there are exceptions.378,461,462,467 GCNIS is seen in seminoma but not in lymphoma. Lymphoma often is more pleomorphic than seminoma and may be composed of cells with cleaved and irregularly shaped nuclei that stand in contrast with the polygonal and relatively uniform nuclei of seminoma. The cytoplasm of lymphoma is usually amphophilic and less distinct than that of seminoma. Immunostains directed against PLAP and OCT3/4 are positive in seminoma and negative in lymphoma, whereas leukocyte common antigen (LCA) and other lymphoid markers show opposite results.41,413 Rarely, seminoma with a tubular pattern may be confused with Sertoli cell tumor, a neoplasm that frequently has a tubular architecture.8,380,381,383,468 The cytoplasmic clarity in seminoma is caused by glycogen, whereas lipid is mainly responsible for this appearance in Sertoli cell tumor. Most Sertoli cell tumors have low-grade cytologic atypia and infrequent mitotic figures that contrast with the high-grade atypia and conspicuous mitotic activity of seminoma. GCNIS is present in almost all seminomas but is not associated with Sertoli cell tumor. Tubular patterns in seminoma are usually focal but may be widespread in Sertoli cell tumor.381 Immunostains for PLAP, OCT3/4, and SALL4 are positive in

Fig. 13.30 Seminoma with signet ring cells.

seminoma but negative in Sertoli cell tumor, whereas inhibin and nuclear β-catenin are positive in a substantial proportion (but not all) of Sertoli cell tumors but negative in seminomas. This differential diagnosis may be further complicated by those Sertoli cell tumors that show a mostly diffuse growth pattern, frequently associated with a lymphocytic infiltrate.469 Treatment and Prognosis

Although patients with early seminoma (clinical stage I or nonbulky stage II) have traditionally been treated with orchiectomy and radiation to the paraaortic and paracaval nodes, frequently with ipsilateral pelvic nodal radiation (so-called “dogleg” field) (although the pelvic field component may not be necessary for clinical stage I patients), current American and European treatment guidelines for clinical stage I seminoma consider surveillance an appropriate option, with adjuvant treatment also being discussed.470-476 The American National Comprehensive Cancer Network (NCCN) guidelines state that active surveillance is preferred, but they do not make recommendations between chemotherapy and radiation treatment.475 In contrast, the European Association of Urology Guidelines state that surveillance and carboplatin chemotherapy are recommended and that radiotherapy is not recommended.476 Stratification by risk factors has also been employed, with carboplatin recommended for patients with two risk factors (tumor size > 4 cm and rete testis involvement) and surveillance for those with zero or one of these risk factors, and use of a nomogram considering these two factors has been proposed, but others have found this model for risk stratification to be inadequately predictive and have found only tumor size to be associated with recurrence.477-479

CHAPTER 13

Fig. 13.31 Seminoma with prominent aggregates of glycogen creating a signet ring cell appearance. Many histiocytes with phagocytosed glycogen aggregates are also present.

Radiotherapy for seminoma is associated with a slight (hazard ratio 1.36) increased risk for second malignant neoplasms.480 Most recurrences arise outside of the radiated field, in the mediastinum, cervical lymph nodes, or lungs.472,481 With the increasingly chosen option of surveillance for clinical stage I patients, 13% to 20% of patients will undergo relapse.482-484 Nevertheless, chemotherapy salvages virtually all relapses, and therefore 5-year disease-specific survival for surveillance management approaches 100%.484 About 92% of relapses are within the first 3 years, and 87% are detected by computed tomography (CT) (as opposed to tumor markers).484 Chemotherapy is recommended for patients with bulky retroperitoneal involvement or in more advanced stages. (“Bulky” is defined variously in different studies as metastases greater than 5 cm, 6 cm, or 10 cm in diameter.) There is an 87% progression-free survival for advanced-stage seminoma patients who are initially treated with chemotherapy, whereas such patients who are initially irradiated and then treated with chemotherapy for persistent disease have a 3-year progression-free survival of 69%.485 A four-cycle etoposide and platinum regimen has been evaluated to attempt to limit bleomycin toxicity in patients with germ cell tumors and retroperitoneal disease, but these patients are four times more likely to have active cancer in the retroperitoneal specimen when compared with the standard three-cycle bleomycin, etoposide, and platinum treatment.486 A prominent lymphocytic reaction has been associated with improved prognosis.487,488 Elevation of serum hCG levels may

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751

Fig. 13.32 Seminoma with syncytiotrophoblast cells. Intracytoplasmic lacunae are present in some of the syncytiotrophoblast cells.

Fig. 13.33 Periodic acid-Schiff positivity in a seminoma, indicating abundant glycogen.

indicate a poorer prognosis, although there are contradictory results in the literature.223,359,363,365,367,368,489,490 In one study, primary tumor size (>4 cm), testicular vascular invasion, rete testis invasion, tunica albuginea penetration, spermatic cord invasion, epididymis invasion, and vascular invasion of the cord were predictive of metastasis in univariate analysis, but only tumor size (>6 cm) and rete testis invasion were independently predictive in multivariate analysis.491 Rete testis involvement was not

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Fig. 13.34 Seminoma showing a membranous pattern of positivity for (A) placental alkaline phosphatase and (B) c-kit (CD117). (C) Strong nuclear reactivity for OCT3/4 in seminoma.

independently predictive of relapse of stage in other studies.479,492 In a series of 1954 stage I seminoma patients in Denmark followed on a surveillance program, size, vascular invasion, and epididymis involvement were significant predictors of relapse.493 Lymphovascular invasion, however, is often overdiagnosed in seminoma, with the rate of apparent lymphovascular invasion dependent on the handling of the gross specimen.494 Immunohistochemical expression of p53, Ki67, CD30, and loss of CD117/c-kit expression in a group of 62 seminomas did not correlate with metastasis or other histopathologic risk factors for metastasis, unlike a different study.399,495 In a mixed group of testicular germ cell tumors, high-level microsatellite instability by molecular analysis was significantly predictive of poorer prognosis, and a similarly significant but lower-magnitude difference was observed with loss of mismatch repair protein (MLH1) expression by immunohistochemistry.496 In germ cell tumor patients undergoing postchemotherapy retroperitoneal lymph node dissection, the number of lymph nodes removed has prognostic significance with a calculated 2-year relapse-free probability of 90% when 10 lymph nodes are removed

compared with 97% when 50 lymph nodes are removed.497 Patients with viable seminoma in postchemotherapy retroperitoneal lymph node dissection specimens have decreased 5-year survival, 54% in a recent series.498 Prognostic factors in patients with clinical stage I seminoma have been reviewed.499,500 Rete testis invasion was associated with relapse in some studies, but lymphovascular invasion, young age, and preoperative hCG level were not associated with recurrence. It seems likely that the nonsignificance of lymphovascular invasion stems from the difficulty in judging true versus pseudoinvasion.494 It would be useful to identify a subset of seminoma patients with a poor prognosis at an early stage, because it is likely that initial treatment with chemotherapy would improve the outcome in such a group. It is likely that the poor prognosis relates to the tendency of such cases to transform to nonseminomatous tumors, given the high frequency of nonseminomatous tumors at autopsy in patients who died after resection of pure testicular seminoma.20,54 Testis-sparing surgery, not typically considered appropriate for germ cell tumors, has been performed for small (20 mm or

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limited to those with a disorder of sexual development.39,510-513 It usually presents as a testicular mass, with gynecomastia or symptoms of metastases each occurring in about 10% of cases.514 Rare cases may present with sudden death caused by massive tumor thromboemboli to the lungs.515,516 However, metastases are clinically or radiographically evident in about 40% of patients at presentation, and two-thirds of patients who are pathologically staged have metastases.514 As in seminoma, limbic encephalopathy may be a rare form of presentation.355 Serum AFP elevation in embryonal carcinoma is usually the result of misclassification of mixed germ cell tumor (embryonal carcinoma and yolk sac tumor), and it is uncommon for morphologically pure embryonal carcinoma to be associated with serum AFP elevation.503,517 Many embryonal carcinomas are associated with syncytiotrophoblast cells, accounting for serum hCG elevation in 60% of cases.517 PLAP, LDH, and CA19-9 levels may also be elevated.518,519 Pathologic Features

Fig. 13.35 Membranous podoplanin staining in a seminoma.

smaller), clinical stage I, synchronous or metachronous bilateral germ cell tumors to attempt to allow preservation of fertility.501 Although testosterone production is consistently maintained, almost one-third of patients develop local recurrence, and only one-sixth achieve conception.501 Frequent local recurrences are expected, as, in addition to the frequent presence of GCNIS in these patients, about one-fourth of germ cell tumors are multifocal, and multifocality can be present even in small tumors.502

Grossly, embryonal carcinoma is usually poorly circumscribed and gray-white to pale yellow or tan with prominent areas of hemorrhage and necrosis (Fig. 13.36). Microscopically, there are three major patterns, solid, glandular, and papillary, all of which consist of cohesive groups of primitive, anaplastic epithelial cells. In the solid pattern, the cells are arranged in diffuse sheets (Fig. 13.37).448 In the tubular or glandular pattern, well-defined, glandlike or tubule-like structures are formed by epithelium varying from cuboidal to columnar (Fig. 13.38). Anastomosing (Fig. 13.39) or sievelike (Fig. 13.40) patterns may be seen. The luminal spaces are cleftlike or round. In the papillary pattern, the papillae may or may not have stromal cores (Fig. 13.41). When vascular stromal cores are cut transversely, a radial arrangement of tumor cells at their periphery resembles the endodermal sinus-like structures of yolk sac tumor (“pseudoendodermal sinuses”; Figs. 13.42 and 13.43). Uncommon patterns include nested, micropapillary, pseudopapillary, and blastocyst-like (Fig. 13.44).376,448 A “double-layered” pattern of embryonal carcinoma has also been described in which a papillary arrangement of embryonal carcinoma is accompanied by a parallel layer of flattened neoplastic epithelium (Fig. 13.45).520 This pattern, however, is more accurately classified as embryonal carcinoma with yolk sac tumor and should therefore be regarded as a mixed germ cell tumor.

Embryonal Carcinoma Although very common in mixed germ cell tumors (occurring in 87% of nonseminomatous germ cell tumors,) embryonal carcinoma is less frequent as a pure testicular tumor, comprising only 2.3% of cases in a referral practice and about 10% of testicular tumors in two general series.39,345,503 A decline in the reported proportion of pure embryonal carcinoma among testicular germ cell tumors is largely attributable to the recognition of foci of yolk sac tumor in such cases, leading to their categorization as mixed germ cell tumors. This finding reflects the capacity of embryonal carcinoma to differentiate into other forms of testicular neoplasia, as verified by experimental observations including tissue culture.504-508 Embryonal carcinoma expresses the stage-specific embryonic antigen (SSEA) indicative of a primitive, undifferentiated stage of development, SSEA-3, but not SSEA-1, which indicates a more mature phenotype.509 Clinical Features

The peak incidence occurs at about 30 years of age, and embryonal carcinoma is distinctly rare in prepubertal children and likely

Fig. 13.36 The large yellow-tan nodule is embryonal carcinoma, showing areas of hemorrhage and necrosis.

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Fig. 13.37 Embryonal carcinoma with a solid pattern.

Fig. 13.38 Embryonal carcinoma with a glandular pattern.

At high magnification, the cells have variable staining, abundant cytoplasm, and large, vesicular, irregular nuclei with prominent macronucleoli (Fig. 13.46). The cell borders are characteristically ill defined, unlike seminoma, and the nuclei are often crowded, appearing to abut or overlap. Karyorrhectic fragments are frequent in the background, and the mitotic rate is high. Potentially deceptive histologic features occur in some cases, including foci of cells with clear cytoplasm and well-defined cytoplasmic borders, possibly causing concern for seminoma (Fig. 13.47). Glands lined by tall, columnar cells may be mistaken for teratoma (Fig. 13.48). In both circumstances, the pleomorphic nature of the nuclei supports embryonal carcinoma.448,521 Occasionally, the tumor cells may have clear cytoplasmic vacuoles giving the tumor a “lipoid” appearance (Fig. 13.49). Prominent foci of eosinophilic, coagulative necrosis are common in all forms of embryonal carcinoma. Cells with smudged, hyperchromatic nuclei are distinctive but nonspecific (Fig. 13.50). These commonly appear “applied” to the periphery of tumor nests (“applique” appearance).448 Such cells are considered to be degenerate embryonal carcinoma cells, but they may be misinterpreted as syncytiotrophoblast cells, thereby leading to a misdiagnosis of choriocarcinoma. Unlike syncytiotrophoblast cells, however, these degenerate embryonal carcinoma cells lack hCG and are not usually associated with hemorrhage. The capacity of embryonal carcinoma to generate a minor amount of undifferentiated neoplastic stroma (Fig. 13.51) is widely recognized.25,375 The stroma may either be reactive, fibrous, and

nonneoplastic or a neoplastic derivative of the tumor with atypia and mitotic activity.448 Although some regard neoplastic stroma within the spectrum of embryonal carcinoma, rationalizing that it is part and parcel of a primitive neoplasm recapitulating an early phase of embryonic development, we believe that neoplastic stroma should be considered a teratoma component. Based on the experience of the BTTP, no significant prognostic difference was noted in embryonal carcinoma with or without a stromal component, but these data were obtained in an era before effective chemotherapy.24 Because teratoma components in the testis are associated with an increased risk for persistent tumor in metastatic sites after chemotherapy, those BTTP data should have no bearing on current classification. In about one-fourth of cases, embryonal carcinoma is associated with an intratubular embryonal carcinoma component, which is typically extensively necrotic, having a comedocarcinoma-like appearance (Figs. 13.52 and 13.53).448 Such necrotic foci may undergo dystrophic calcification leading to the formation of socalled “hematoxylin-staining bodies.”522 Such coarse intratubular calcifications in scarred areas are excellent evidence of a regressed germ cell tumor.522,523 The identification of vascular invasion in nonseminomatous germ cell tumors (including embryonal carcinoma) may be helpful in deciding whether patients with clinical stage I tumors are appropriate candidates for “surveillance only” management and is a key

Fig. 13.39 Embryonal carcinoma with an anastomosing pattern.

Fig. 13.41 Embryonal carcinoma with a papillary pattern.

Fig. 13.40 Embryonal carcinoma with a sievelike pattern.

Fig. 13.42 Embryonal carcinoma with papillary structures with central blood vessels resembling the endodermal sinus pattern of a yolk sac tumor.

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Fig. 13.43 Embryonal carcinoma with an endodermal sinuslike pattern at high magnification. The arrangement of tumor cells around the blood vessels resembles a Schiller-Duval body.

feature in tumor staging. Embryonal carcinoma is the angioinvasive element in most cases when such invasion is present. There are some pitfalls in deciding if vascular invasion is present. First, intratubular neoplasm may closely resemble intravascular neoplasm. The presence of residual Sertoli cells in a possible “vessel” is good evidence that it is a tubule (Fig. 13.54). Additionally, intratubular tumors are often extensively necrotic, and the tubules are nonbranching and of relatively similar caliber, whereas intravascular tumors do not typically show extensive necrosis and may occur in branched vessels of different sizes (Fig. 13.55). Second, stringent criteria must be applied such that invaded tissue spaces are clearly lined by endothelial cells before regarding them as vessels. Third, germ cell tumors, and especially embryonal carcinoma and seminoma, are quite cellular and friable, leading to artifactual, knifeimplantation of tumor cells into vascular spaces. Such implants, however, are loosely cohesive and unassociated with vascular thrombosis (Fig. 13.56), whereas legitimate vascular invasion is characterized by neoplasm conforming to the shape of the vessel, which may also show evidence of thrombosis. Commonly, artifactual vascular implants are also associated with implants on the surfaces of tissues. It is usually easiest to appreciate vascular invasion a short distance away from the periphery of the neoplasm. Special Studies

Only a small percentage of cases of pure embryonal carcinoma demonstrate AFP immunoreactivity, but such positivity is more common in the embryonal carcinoma component of a mixed germ

Fig. 13.44 Embryonal carcinoma with a blastocyst-like pattern with tumor cell nests with a central vesicle-like space.

cell tumor, a fact that likely represents early biochemical transformation to a yolk sac tumor component in cases of mixed germ cell tumor before morphologic differentiation.524,525 PLAP positivity occurs in 86% to 97% of cases, but is usually patchy and weaker than in seminoma.41,288,526 Several different cytokeratin classes are present in embryonal carcinoma, most prominently cytokeratins 8 and 18, but also cytokeratin 19, and occasionally cytokeratins 4 and 17.527 Most authors therefore report strong and diffuse positivity for cytokeratins in the majority of embryonal carcinomas, including routinely processed cases.41,528 Immunostains for CD30 (Ber-H2, Ki-1) are positive in 84% of cases (Fig. 13.57), whereas EMA is negative in almost all embryonal carcinomas.41,529,530 CD117 and podoplanin (D2-40), in contrast with seminoma, are negative or only focally positive in embryonal carcinoma. OCT3/4, a nuclear transcription factor, is highly sensitive and mostly specific for embryonal carcinoma (Fig. 13.58), seminoma, and GCNIS, with no staining observed in other germ cell tumor types or sex cord–stromal tumors, and only very rare positivity seen in lung and renal cell carcinomas and in large B-cell lymphomas.44,404 More recently, SOX2 has emerged as a valuable marker for embryonal carcinoma, with negativity in the other germ cell tumors except for immature teratoma.49,50,283,300,301 GATA3 is negative or only very focally positive (as opposed to consistent staining in choriocarcinoma).531 There is therefore a characteristic immunohistochemical profile: positivity for cytokeratin, PLAP, OCT3/4, SOX2, and CD30 and negativity for EMA, CD117, and podoplanin. This profile can be of great value in distinguishing embryonal carcinoma in an extragonadal site (either a metastasis or

CHAPTER 13

Fig. 13.45 The “double-layered” pattern of embryonal carcinoma, consisting of ribbons of embryonal carcinoma with a parallel layer of flattened cells. This is classified as mixed germ cell tumor, sometimes termed diffuse embryoma, and consists of embryonal carcinoma and yolk sac tumor (the flattened layer).

an extratesticular primary) from a poorly differentiated carcinoma of nongerm cell origin (typically, cytokeratin and EMA positive, PLAP variable [but most commonly negative], and negative for CD30 and OCT3/4).413 The presence of CD30 in embryonal carcinoma indicates the necessity for caution and additional supportive evidence before accepting a CD30-positive, poorly differentiated malignant neoplasm as an anaplastic large cell lymphoma. Occasionally, embryonal carcinoma will also stain for α-1antitrypsin, Leu-7, vimentin, LDH, human placental lactogen (hPL), and ferritin.41,414,524,532 The product of the TP53 tumor suppressor gene is often identifiable in embryonal carcinoma, although the absence of mutations with molecular biologic techniques support that this is the result of nonmutated overexpression.243-246 Ultrastructurally, embryonal carcinoma usually resembles a poorly differentiated, primitive adenocarcinoma with ill-defined lumens in solid areas and well-defined, large lumens in glandular areas.60 The lumens are bordered by cells having well-defined junctional complexes with characteristically long tight junctions.533 Short microvilli project into the luminal spaces, and the cytoplasm contains ribosomes, a prominent Golgi body, rough endoplasmic reticulum, teleolysosomes, mitochondria, glycogen, and occasional lipid droplets. The nuclei are large, deeply indented, often contain cytoplasmic inclusions, and have large nucleoli with complex nucleolonema.60

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Fig. 13.46 Embryonal carcinoma. Note the ill-defined cell borders and large, crowded, vesicular nuclei with large nucleoli.

Embryonal carcinoma has a DNA index ranging from 1.4 to 1.6 times normal, which is significantly less than that of seminoma.51,62 Embryonal carcinoma often contains isochromosome 12p, and increased copy numbers of i(12p) have correlated with a more aggressive clinical course.424 The presence of i(12p) or other 12p amplifications in a poorly differentiated carcinoma, either metastatic or a primary neoplasm of an extragonadal site, may be a useful means of separating embryonal carcinoma from other poorly differentiated neoplasms.534,535 The detection of 12p abnormalities can be accomplished in interphase cells obtained from fresh biopsy samples or in paraffin-embedded tumor by the fluorescence in situ hybridization (FISH) technique.536,537 Differential Diagnosis

The distinction of embryonal carcinoma from seminoma was discussed earlier in this chapter. The distinction of embryonal carcinoma from yolk sac tumor depends on the presence, in yolk sac tumor, of one of several distinctive patterns, and the larger and more pleomorphic nature of the neoplastic cells in embryonal carcinoma. Yolk sac tumor often contains hyaline globules and intercellular basement membrane, which are usually lacking in embryonal carcinoma, and AFP is much more likely to be present in yolk sac tumor than in embryonal carcinoma.538 CD30 positivity is characteristic of embryonal carcinoma and is not usually present in yolk sac tumor.283,529 OCT3/4 and SOX2 are positive in embryonal carcinoma and negative in yolk sac tumor.45,282,283 Glypican-3, an immunohistochemical marker for yolk sac tumor,

Fig. 13.49 Embryonal carcinoma with prominent cytoplasmic vacuolization (lipoid appearance).

Fig. 13.47 Embryonal carcinoma with seminoma-like cells.

Fig. 13.48 Embryonal carcinoma with columnar cells resembling teratoma.

Fig. 13.50 Solid pattern of embryonal carcinoma with degenerate,  pattern) and focal necrosis. smudged cells (applique

Fig. 13.51 Neoplastic stroma in an embryonal carcinoma. Classification as embryonal carcinoma and teratoma is recommended, although some regard the neoplastic stroma within the spectrum of embryonal carcinoma.

Fig. 13.53 Intratubular embryonal carcinoma with characteristic abundant necrosis.

Fig. 13.52 Extensive intratubular embryonal carcinoma with prominent necrosis.

Fig. 13.54 Intratubular embryonal carcinoma can be reliably distinguished from vascular invasion if there are residual Sertoli cells.

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Fig. 13.55 Vascular invasion that was peripheral to embryonal carcinoma. Note the branching pattern.

Fig. 13.56 Artifactual “knife implantation” of tumor groups into vascular spaces. Note the loose tumor cell groups unassociated with vascular thrombosis.

is negative in seminoma and positive in 0% to 8% of embryonal carcinomas.455,456 Because embryonal carcinoma may transform into yolk sac tumor, there are foci where the distinction is arbitrary. Such cases, however, invariably show areas of both neoplastic types. The smudged, degenerate cells common in embryonal carcinoma may be misinterpreted as syncytiotrophoblast cells, causing a misdiagnosis of choriocarcinoma. These cells, however, lack hCG, and the background is usually not hemorrhagic, unlike true choriocarcinoma. Large cell lymphoma usually occurs in older patients, lacks the epithelial patterns usually identified in embryonal carcinoma, has an interstitial growth pattern, is not associated with GCNIS, is PLAP negative, only rarely OCT3/4 positive, cytokeratin negative, and LCA positive, features contrasting with those of embryonal carcinoma.413 The differential with “anaplastic” spermatocytic tumor is discussed on the Spermatocytic Tumor section later in this chapter.

20% to 30% of clinical stage I patients with nonseminomatous germ cell tumors relapse on surveillance management protocols.484,539-541 These are almost entirely caused by nondetected retroperitoneal involvement. As evidence for this conclusion, in one series of clinical stage I patients, RPLND confirmed pathologic stage II disease in 28%.542 Adjuvant chemotherapy (two courses of cisplatin, etoposide, and bleomycin) without RPLND for clinical stage I patients has also been evaluated in a prospective trial.543 A recent study of 382 patients with clinical stage I nonseminomatous germ cell tumor randomized to RPLND or one course of chemotherapy (bleomycin, etoposide, and cisplatin) found equivalent quality of life outcomes.544 With surveillance management, relapse can often be detected early by serum marker elevation, allowing almost all relapsing patients to be salvaged by standard chemotherapy. Surveillance thus avoids unnecessary RPLND in the 69% to 81% of clinical stage I patients who are cured by orchiectomy alone.484,542,545,546 A review of 560 clinical stage I patients managed by “surveillance only” found that 97% were tumor-free and that 72% required no therapy after orchiectomy.547 About 90% of patients who relapse do so within 2 years.484 Only 1.6% of patients who relapse do so after 5 years or more.546 Relapse is detected by abdominal CT scan or by serum tumor markers in an approximately equal number of cases.484 With treatment, patients have an excellent prognosis even with relapse, with the 5-year disease-specific survival approaching 100% for the entire group of surveillance-managed clinical stage I nonseminoma patients.484

Treatment and Prognosis

The treatment of nonseminomatous germ cell tumors, including embryonal carcinoma, depends on the clinical stage of the patient. Most patients with clinical stage I tumor receive surveillance management after orchiectomy, although patients at risk for occult metastases of chemoresistant elements (somatic-type malignancies, see the Teratoma with Somatic-Type Malignancy section later in this chapter) are often recommended for nerve-sparing retroperitoneal lymph node dissection (RPLND) tailored to excise the commonly involved nodal groups ipsilateral to the affected testis. From

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Fig. 13.57 Immunostaining for CD30 in embryonal carcinoma with strong membrane reactivity.

Fig. 13.58 Immunostaining for OCT3/4 in embryonal carcinoma showing strong nuclear positivity.

The proportion of clinical stage IA (clinical T1, N0, M0) patients managed by surveillance increased from 65% between 2004 and 2005 to 74% between 2012 and 2013.548 Some clinical stage I patients at high risk for relapse may be less suitable candidates for “surveillance only” and may be identified by a careful, multifactorial analysis of the orchiectomy specimen. Factors that correlate with relapse or occult retroperitoneal metastases include: lymphovascular invasion, large proportion or volume of embryonal

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carcinoma, pure embryonal carcinoma, absence of a yolk sac tumor component, embryonal carcinoma in the absence of teratoma, less than 50% teratoma, the presence of choriocarcinoma, rete testis invasion, high S or G2M +S phase values as determined by flow cytometry, a high proportion of proliferating tumor cells, and highly aneuploid tumor stemlines.514,546,547,549-567 In a recent study of nonseminomatous germ cell tumors, only vascular invasion, rete testis invasion, and hilar soft tissue invasion were predictive of advanced clinical stage in multivariate analysis.568 Embryonal carcinomas with a high Ki-67 labeling index, low apoptosis, and low p53 expression have a better overall survival.569 A pre-orchiectomy AFP value exceeding 80 ng/mL and an abnormally slow decline in AFP values after orchiectomy have also correlated with relapse.554,557 In Europe, lymphovascular invasion has been used as a sole risk factor to recommend one cycle of chemotherapy (if lymphovascular invasion is present) or the choice between chemotherapy and surveillance (if absent).477 Patients having clinically apparent, nonbulky retroperitoneal involvement (clinical stage II) may be managed by RPLND with either close follow-up or a limited course of adjuvant therapy or with initial chemotherapy. Survival in excess of 95% is expected.570,571 For patients with bulky clinical stage II or more advanced tumor, treatment is combination chemotherapy followed by surgical resection of residual masses if the serum markers have normalized. Survival of 70% to 80% is expected.17,572 Specimens resected after chemotherapy must be carefully evaluated pathologically to determine the need for additional chemotherapy.573 Total lymph node count of 28 or more is associated with a slightly decreased risk for relapse after RPLND compared with patients with fewer lymph nodes identified.574 It should be noted that even in the absence of viable tumor in a postchemotherapy RPLND specimen, recurrence may be seen in approximately 18% of patients.575 Several different studies have been conducted to identify prognostic factors in patients with nonseminomatous testicular germ cell tumors. The most important factors are tumor stage, the extent of serum marker elevation, the age of the patient (older being worse), the presence of choriocarcinoma, and the proliferative fraction by flow cytometry.572,576-579 HER2 overexpression was prognostically significant for mixed germ cell tumors in one study but not in another.580,581 Epidermal growth factor receptor (EGFR) immunohistochemical overexpression has been reported in 43% of cases of chemorefractory metastatic embryonal carcinoma, suggesting that anti-EGFR targeted therapy could be a possibility for this group.582 Most of these tumors (71%) have polysomy for chromosome 7 rather than amplification of the EGFR gene.582 Treatment-resistant germ cell tumors are also more likely to have BRAF mutations, lack expression of the mismatch repair proteins MLH1 or MSH6, and demonstrate microsatellite instability on molecular analysis.583 The association with BRAF mutation in particular is of interest because of the possibility of tyrosine kinase inhibitor treatment in patients with relapse after initial chemotherapy.583 A consensus classification of germ cell tumors into good, intermediate, and poor prognosis categories was published in 2013 and reproduced in the recent WHO Classification.23,584 Nonsemionmatous germ cell tumors of gonadal or retroperitoneal location, low serum tumor markers (AFP less than 1000 ng/mL, hCG less than 500 U/L, LDH less than 1.5 times the upper limit of normal), and no extrapulmonary visceral metastases are in the favorable prognosis category. Those with intermediate-level serum tumor marker elevation are in the intermediate prognosis category. Those

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with high-level tumor marker elevation (AFP over 10,000 ng/mL, hCG over 50,000 U/L, LDH greater than 10 times the upper limit of normal) or extrapulmonary visceral metastases are in the poor prognosis category. Late recurrences are seen in a small percentage of patients (1% to 6%), can occur 30 years or more after initial treatment, and are likely to be treatment resistant.585 Somatic-type malignancies are seen in approximately 23% of late recurrences.586 Up-front surgical resection should be considered for late recurrences.587

Yolk Sac Tumor, Postpubertal-Type Yolk sac tumor is the most recently recognized among the five major categories of testicular germ cell tumor. For years, ovarian yolk sac tumor was misclassified, along with ovarian clear cell carcinoma, as “mesonephroma.” Teilum recognized the identity between testicular and ovarian yolk sac tumor and the frequent admixture of the testicular lesion with other forms of germ cell tumor.588 This observation permitted the classification of yolk sac tumor as a form of germ cell neoplasm and removal of the ovarian lesion from the “mesonephroma” category.589 Subsequently, Teilum recognized the resemblance of the mesenchyme of yolk sac tumor to the extraembryonic mesenchyme of development and its glomeruloid structures to the endodermal sinuses of the rat placenta.590,591

Fig. 13.59 Yolk sac tumor, postpubertal-type, showing hemorrhage, cystic degeneration, and myxoid change. (From Sternberg SS. Diagnostic Surgical Pathology. Raven Press, New York, NY; 1989:1885–1947, with permission of Raven Press.)

Clinical Features

Postpubertal patients with yolk sac tumor fall within the usual age spectrum for nonseminomatous testicular germ cell tumor, ranging from 15 to 45 years and averaging 25 to 30 years; rare cases have been reported in elderly patients.592 Prospective studies of nonseminomatous germ cell tumors have shown yolk sac tumor elements in 44% of cases.593 Adults with yolk sac tumor in a mixed germ cell tumor are more likely to have lower-stage disease than those without a yolk sac tumor component, and the absence of a yolk sac tumor component in a mixed germ cell tumor may be a positive predictor of occult metastases in clinical stage I tumors.558 Almost all patients with yolk sac tumor have significant elevation of serum AFP, typically ranging from hundreds to thousands of ng/mL.59,594 Embryonal carcinoma or enteric elements of teratoma may cause minor elevation of serum AFP, but this is unusual.503,594 Pathologic Features

The appearance is usually heterogeneous, with frequent areas of hemorrhage, necrosis, and cystic change (Fig. 13.59). Numerous microscopic patterns are seen in yolk sac tumor and commonly include hybrid, incomplete, and transitional forms. The patterns, modified from Talerman, include: (1) microcystic (honeycomb, reticular, vacuolated); (2) endodermal sinus (perivascular); (3) papillary; (4) solid; (5) glandular/alveolar; (6) myxomatous; (7) sarcomatoid; (8) macrocystic; (9) polyvesicular vitelline; (10) hepatoid; and (11) parietal.595 The microcystic pattern is most common and is characterized by intracellular vacuoles creating attenuated lengths of cytoplasm connected in a spiderweb-like array (Fig. 13.60). The cells often resemble lipoblasts, with vacuoles compressing the nuclei, although they do not contain lipid. In some cases, the cells are arranged in cords and surround extracellular spaces, creating a reticular arrangement (Fig. 13.61). The microcystic pattern is often seen with a myxoid stroma and blends with the myxomatous pattern (Fig. 13.62). The solid pattern is also commonly intermingled with the microcystic (Fig. 13.63).

Fig. 13.60 Microcystic pattern of a yolk sac tumor resulting from intracellular vacuoles.

The endodermal sinus pattern consists of a central vessel rimmed by fibrous tissue that is surrounded by malignant epithelium. This structure is set in a cystic space that is often lined by flattened tumor cells (Figs. 13.64 and 13.65). Oblique cuts of these structures result in fibrovascular cores of tissue that are “draped” or “festooned” by malignant cells with an accompanying complex (“labyrinthine”) arrangement of anastomosing extracellular spaces (Fig. 13.66). This pattern is also designated as a “perivascular” or

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Fig. 13.61 Microcystic pattern of a yolk sac tumor created by cords of cells surrounding extracellular space (also referred to as reticular pattern).

“festoon” pattern, and the endodermal sinus-like structure is termed a glomeruloid or Schiller-Duval body.591 The papillary pattern has papillae, with or without fibrovascular cores, which project into cystic spaces (Fig. 13.67). The cells are often cuboidal to low columnar and may have a “hobnail” configuration secondary to apical protrusion of the nucleus. Exfoliated clusters of neoplastic cells may be present in the cystic spaces. The papillary pattern may blend with the endodermal sinus pattern. The solid pattern is quite common and may resemble seminoma, consisting of sheets of relatively uniform cells with lightly staining to clear cytoplasm and well-defined borders (Fig. 13.68).454 However, the lymphoid component and fibrous septa of seminoma are usually absent, and the cells are more pleomorphic than those of seminoma. Some areas of solid pattern tumor have prominent thin-walled blood vessels, and focal microcysts may also be seen in an otherwise solid pattern (Fig. 13.63). In some cases, the solid pattern has small cells with scant cytoplasm resembling blastema (Fig. 13.69); such foci are intimately intermingled with classic patterns of yolk sac tumor (Fig. 13.70). Well-defined glands, often with enteric features, are common in yolk sac tumor (Fig. 13.71), present in 34% of cases in one series.538 The glands may be contiguous with vesicles typical of the polyvesicular vitelline pattern, or may appear in a background of myxomatous, microcystic, or solid patterns. Usually the glands are simple, round, and tubular, but may show an elaborate branching pattern or become quite intricate and complex (Fig. 13.72). Unlike the glands of teratoma, those of yolk sac tumor are not

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Fig. 13.62 Blending of microcystic and myxoid patterns of a yolk sac tumor. Neoplastic cells appear to “bud” from microcystic structures and blend into a myxoid stroma.

associated with other teratomatous components and lack circumferential smooth muscle that is common but not invariable in teratoma.596 The nuclei of the glands are often more bland than those of the surrounding yolk sac tumor and may show subnuclear vacuolation, reminiscent of early secretory pattern endometrium. As a consequence, predominantly glandular ovarian yolk sac tumor has been termed endometrioid-like.597 Purely or predominantly glandular testicular yolk sac tumor is more rare than in the ovary, but may be associated with a high serum AFP.269 Purely glandular yolk sac tumor is more common after chemotherapy and is therefore usually found in metastases; it is particularly more frequent in late recurrences.586 The myxomatous pattern is common, consisting of neoplastic epithelioid to spindle cells dispersed in a stroma that is rich in mucopolysaccharide, staining only lightly with hematoxylin and eosin (Fig. 13.73). A prominent vascular network is common, and Teilum described this pattern as “angioblastic mesenchyme” that he felt was homologous with the extraembryonic mesenchyme (the “magma reticulare”) of development.598 Myxomatous foci commonly merge with other patterns, and hybrids of microcystic and myxomatous patterns are more the rule than the exception (Fig. 13.62). By light microscopy, the spindle cells appear to arise from solid or microcystic foci by budding from them and blending into the surrounding myxoid stroma (Fig. 13.74). Intense cytokeratin immunoreactivity within these cells supports derivation from the epithelial component of yolk sac tumor.599 These cells are, in fact, pluripotential cells with the capacity to form differentiated

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Fig. 13.63 Mixture of solid and microcystic patterns of a yolk sac tumor.

mesenchymal tissue such as skeletal muscle, cartilage, and bone, thus blurring the distinction between yolk sac tumor and teratoma (Fig. 13.74).599 Classification of such elements as yolk sac tumor is justified by the recognition that the surrounding tissues are typical yolk sac tumor. The uncommon sarcomatoid pattern consists of a cellular proliferation of spindle, and usually also epithelioid, cells (Fig. 13.75) in continuity with other yolk sac tumor patterns, most commonly microcystic. It is distinguished from the solid pattern by the spindle cell nature of the component cells and the myxomatous pattern by its greater size as a single pattern. Despite the sarcomatoid appearance, the spindle cells express cytokeratin and glypican-3 and may also react for SALL4 but not AFP. It is likely that some embryonal rhabdomyosarcomas arising in testicular germ cell tumors derive from differentiation of sarcomatoid spindle cells to rhabdomyoblastic cells.600 The occasional intimate admixture of embryonal rhabdomyosarcoma with yolk sac tumor supports this hypothesis. Spindle cell patterns in yolk sac tumor have also been reported in primary mediastinal examples.601 The macrocystic pattern appears to arise from coalescence of microcystic spaces to form large, round to irregular cysts (Fig. 13.76), and the surrounding pattern is often microcystic. In the uncommon polyvesicular vitelline pattern, vesicle-like structures are lined by flattened, innocuous-appearing epithelium, in a myxoid to fibrous stroma (Fig. 13.77). Sometimes the vesicles have a central constriction, resembling a dumbbell or a figure 8. Teilum compared these vesicles to the embryonic subdivision of the primary yolk sac into the secondary yolk sac.602 At the point of constriction, the epithelium may change from flattened to

Fig. 13.64 Endodermal sinus pattern of a yolk sac tumor. Several endodermal sinuslike structures are present in this field.

Fig. 13.65 Endodermal sinus pattern of a yolk sac tumor. Note also the basement membrane deposits in the peripheral tumor.

cuboidal or columnar; the latter often has enteric features, including an apical brush border. AFP is often present in the epithelium of the vesicles, and hyaline globules are occasionally seen within them. In some cases, a transition from a microcystic to polyvesicular vitelline pattern can be identified. The bland cytologic appearance of the polyvesicular vitelline pattern may falsely suggest a

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Fig. 13.66 Oblique sections of endodermal sinuslike structures result in geographic configurations with festoons of malignant epithelium at the periphery and a complex, labyrinthine pattern of interconnecting, extracellular spaces.

Fig. 13.67 Papillary yolk sac tumor with a single layer of hobnail-type cells on fibrovascular cores.

benign neoplasm, but the presence of other patterns should prevent this pitfall. The polyvesicular pattern is less frequent in testicular yolk sac tumor than in its ovarian counterpart, where it may rarely occur in pure form.603 A hepatoid pattern also occurs in about 20% of yolk sac tumors and consists of small clusters of polygonal, eosinophilic cells arranged in sheets, nests, or trabeculae (Fig. 13.78).538,604 The cells have round, vesicular nuclei with prominent nucleoli and contain abundant AFP; hyaline globules are common in hepatoid foci as are bile canaliculi, although bile is a rare finding.376,605 Hepatoid foci are scattered randomly in yolk sac tumor and usually are minor components; rarely, a more diffuse hepatoid pattern may be seen, although a prominent hepatoid pattern is more common in ovarian tumors and in late recurrences of testicular tumors.586,606,607 The parietal pattern has extensive deposits of extracellular basement membrane, with only scattered neoplastic cells in an abundant, eosinophilic matrix (Fig. 13.79). It is considered the extreme end of parietal differentiation (see later) in which basement membrane is deposited in the extracellular space in a variety of yolk sac tumor patterns. In a true parietal pattern yolk sac tumor, the basement membrane deposits efface the underlying yolk sac tumor pattern. This is a rare pattern, most often seen after chemotherapy, particularly in late recurrences.586,608 There is some overlap with the sarcomatoid pattern when the tumor cells are spindled, and we have seen some cases that, in postchemotherapy resections, mimicked osteosarcoma.

The frequency of the different patterns of yolk sac tumor is difficult to determine because of lack of uniformity in classification. The microcystic, solid, and myxomatous patterns are most common, with glandular, macrocystic, endodermal sinus, hepatoid, and papillary patterns also occurring frequently. The polyvesicular vitelline pattern is less common, and sarcomatoid and parietal patterns are unusual. If only four patterns are employed for classification, the frequency of the patterns diminishes from reticular to solid to endodermal sinus to polyvesicular vitelline. Jacobsen noted a “vacuolated network” in 91% of yolk sac tumors, microcystic pattern in 67%, myxomatous pattern in 51%, macrocystic pattern in 44%, solid pattern in 27%, hepatoid areas in 23%, labyrinthine formations in 17%, and endodermal sinus-like structures in 9%.520 A common feature of yolk sac tumor is the deposition of extracellular basement membrane, identified in 92% of cases.538 These deposits generally are irregularly shaped, eosinophilic bands between the neoplastic cells (Fig. 13.80) and have been referred to as parietal differentiation because of their homology to the parietal layer of the embryonic yolk sac of the rodent, which rests on a thick basement membrane (known as Reichert membrane).538,602 Such intercellular basement membrane, although not specific for yolk sac tumor, is characteristic and can be helpful in diagnosis, particularly in small biopsy samples taken from extratesticular tumors. Another characteristic but nonspecific feature in most yolk sac tumors is the presence of intracellular, round, hyaline globules

Fig. 13.68 Solid pattern of a yolk sac tumor.

Fig. 13.69 Solid areas in a yolk sac tumor composed of small, blastemalike cells.

Fig. 13.70 Solid pattern of a yolk sac tumor with blastema-like focus next to more typical patterns of yolk sac tumor.

Fig. 13.71 Glandular structures in a microcystic (reticular) pattern of a yolk sac tumor.

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Fig. 13.72 Complex glands in a yolk sac tumor. Fig. 13.74 Rhabdomyoblastic cells intermingle with spindle cells in the myxomatous portion of a yolk sac tumor.

Fig. 13.73 Stellate and spindle cells with a few syncytiotrophoblasts are dispersed in a myxoid stroma in the myxomatous pattern of a yolk sac tumor. Overgrowth of this pattern justifies a diagnosis of sarcomatoid yolk sac tumor.

Fig. 13.75 Sarcomatoid yolk sac tumor with a myxoid background.

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Fig. 13.76 Macrocystic pattern of a yolk sac tumor. Note the adjacent microcystic pattern.

Fig. 13.77 Polyvesicular vitelline pattern of a yolk sac tumor is composed of irregular, often constricted, vesicle-like structures lined by flattened epithelium in loose stroma.

of variable size (from 1 to more than 50 μm in diameter) (Fig. 13.81). These globules are PAS-positive and diastase-resistant and may be present in the extracellular space after cell necrosis. Occasionally these globules may stain positively for AFP, but most do not; hence the staining is considered nonspecific. The hyaline globules and basement membrane deposits of yolk sac tumor are separate and distinct findings, although they have sometimes been confused in the literature. Hematopoietic elements, usually erythroblasts, are present in a minority of testicular yolk sac tumors, usually in vascular spaces or myxomatous tissues. Special Studies

Most yolk sac tumors show cytoplasmic AFP positivity on immunostaining; the frequency varies from 50% to 100% depending on the technique employed and the number of blocks examined.41,59,454,524,609 Positivity is characteristically patchy (Fig. 13.82); intense staining is usually present in hepatoid foci. Postpubertal-type yolk sac tumor stains more frequently for AFP than prepubertal-type.524 Glypican-3, a proteoglycan that plays a role in embryonic growth, is positive in yolk sac tumor and is much less commonly expressed in most other forms of testicular germ cell tumor (Fig. 13.83).455,456,610 Glypican-3 is more sensitive for yolk sac tumor than AFP, staining 100% of cases in one study compared with 58% for AFP.457 Staining was seen in all patterns of all cases evaluated, except the solid pattern of a single case.457 Glypican-3 staining has been reported in some tumors

Fig. 13.78 Hepatoid pattern of a yolk sac tumor. Note the islands of eosinophilic cells with round nuclei and prominent nucleoli adjacent to microcystic (reticular) pattern.

other than yolk sac tumor and hepatocellular carcinoma, however, including cholangiocarcinoma, hepatoblastoma, immature teratoma, melanoma, and pulmonary squamous cell carcinoma, so caution is necessary if these tumors are in the differential diagnosis.611 Among other primary testicular tumors, focal staining may

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Fig. 13.79 Diffuse basement membrane deposits characterize the parietal pattern of a yolk sac tumor.

be seen in some embryonal carcinomas, teratomas, and spermatocytic tumors.612 Positivity for α-1-antitrypsin occurs in about 50% of yolk sac tumors, and the enteric glands may stain for carcinoembryonic antigen and villin, which also highlight the purely glandular tumors.41,59,532,538 SALL4, a regulator of OCT3/4, is a nuclear marker that is expressed in essentially all cases of GCNIS, seminoma, spermatocytic tumor, embryonal carcinoma, and pre- and postpubertal type yolk sac tumors.409,613 This marker is consistently negative in testicular tumors other than germ cell tumors (including stromal tumors), so it is useful to identify germ cell tumors as a group.409 It is also useful to identify metastatic germ cell tumors, such as in the setting of a metastatic yolk sac tumor with glandular or solid pattern and absent AFP expression, although occasional somatic malignancies including esophageal, gastric, and colonic adenocarcinomas may show weak staining.614 Among somatic malignancies, ovarian serous carcinoma has the highest (29%) frequency of SALL4 staining, but urothelial and gastric carcinomas stain in almost one-fourth of cases, and other tumors stain in single-digit percentages.613 SALL4 tends to be more diffusely positive in yolk sac tumor (Fig. 13.84) than glypican-3. Cytokeratin is present in virtually all cases, although cytokeratin 7 is characteristically absent.41,454,615 Positivity with HEA 125, an epithelial marker, occurs in most cases.616 Albumin, ferritin, neuronspecific enolase, and Leu-7 are present in a variable number of cases.41,532 Chromogranin reactivity is unusual.616 From 39% to 85% of yolk sac tumors are reported as positive for PLAP, and EMA is usually negative, as is CD99.41,281,288,616 p53 may

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Fig. 13.80 Bands and irregularly shaped deposits of basement membrane constitute parietal differentiation in a yolk sac tumor.

be identified in yolk sac tumor, and laminin and type IV collagen are present in areas of parietal differentiation.245,538 We have noted reactivity of hepatoid foci for hepatocyte-specific antigen (HepPar1; clone OCH1E5) (unpublished observations, 2001) and others have reported HepPar1 positivity in occasional yolk sac tumors in the absence of light microscopically evident hepatoid features.617 In addition to HepPar1, other endodermal lineage markers such as TTF1 (2 of 15 cases) and CDX2 (6 of 15 cases) may show intermediate- to high-level expression in some testicular yolk sac tumors.618 The growth differentiation factor 3 (GDF3) antibody is immunoreactive with yolk sac tumors and a GDF3+/OCT3/4–/CD30– immunophenotype is supportive of the diagnosis in morphologically difficult cases.283 GATA3 is expressed by yolk sac tumor, but choriocarcinomas are also positive; focal staining may be seen in some embryonal carcinomas, and staining is seen in carcinomas of many somatic sites, limiting its usefulness.531 Ultrastructurally, yolk sac tumor shows clusters of epithelial cells joined by junctional complexes. Glands have microvilli with glycocalyceal bodies and long anchoring rootlets.538 Basement membrane material can be identified in the extracellular space, and flocculent material is present within dilated cisternae of endoplasmic reticulum, often with a central lucent zone.60,538,619,620 Cytoplasmic glycogen may be conspicuous.619,621 The nuclei are usually irregular, with complex nucleolonema. Densely osmiophilic, cytoplasmic, nonmembrane bound, round bodies correspond to the hyaline globules observed at the light microscopic level.

Fig. 13.81 Solid and microcystic patterns of a yolk sac tumor with eosinophilic, hyaline globules. Fig. 13.83 Yolk sac tumor with glypican-3 immunoreactivity.

Fig. 13.82 Patchy immunoreactivity for alpha-fetoprotein in a yolk sac tumor.

Fig. 13.84 Yolk sac tumor with SALL4 diffuse nuclear immunoreactivity.

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Differential Diagnosis

Solid pattern yolk sac tumor must be distinguished from seminoma, an issue that has been addressed in the Seminoma section earlier in this chapter. The distinction of yolk sac tumor from embryonal carcinoma has less clinical significance but is based on the distinctive patterns of yolk sac tumor and the less pleomorphic, less atypical nature of the neoplastic cells. CD30, OCT3/4, AFP, and glypican-3 stains are helpful; the first two are positive in embryonal carcinoma but not yolk sac tumor, and the latter two are positive in many yolk sac tumors and usually negative in embryonal carcinomas. Embryonal carcinoma probably transforms to yolk sac tumor, so there are transitional forms that are difficult to categorize.622 A hyperplastic reaction of the rete testis with hyaline globules may be induced by invasion of the rete by a neoplasm, thus simulating yolk sac tumor (Fig. 13.85).623 The arborizing pattern of the rete testis and the bland nature of the hyperplastic cells should prevent this misinterpretation, although immunostains can also be used if doubt persists.623 Treatment and Prognosis

Adult patients with yolk sac tumor are treated in a fashion similar to that outlined previously, although the presence of a yolk sac tumor component in a patient with clinical stage I tumor has been associated with a decreased likelihood of occult metastases.558,624 Patients with metastatic yolk sac tumor do not respond as well to chemotherapy as do patients with other forms of metastatic nonteratomatous testicular germ cell tumor, and therefore seem to have

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a poorer prognosis.625 The greater chemoresistance of yolk sac tumor in adult patients compared with other forms of germ cell tumor is reflected in a higher frequency of yolk sac tumor metastases at autopsy in the chemotherapeutic era compared with the prechemotherapeutic era.626

Choriocarcinoma and Other Trophoblastic Neoplasms Clinical Features

Choriocarcinoma is an uncommon component of mixed germ cell tumors (present in 15% of cases), and pure choriocarcinoma is quite rare, representing only 0.3% of testicular tumors in a registry of 6000 cases and 0.6% of cases in a recent large series.375,593 Most patients with choriocarcinoma present with symptoms secondary to metastases, unlike other testicular tumors in which a palpable mass is the usual presenting complaint. Often the testicular tumor remains occult even after the diagnosis of metastatic choriocarcinoma. Typically, metastases are in a hematogenous distribution, often affecting the lungs, brain, and gastrointestinal tract, although retroperitoneal lymph node involvement may occur. In rare instances, patients may present with cutaneous or pancreatic metastases.627,628 Most patients are in the second and third decades, and choriocarcinoma has not been reported before puberty outside of a disorder of sex development.510 Serum levels of hCG may be highly elevated, resulting in secondary hormonal manifestations such as gynecomastia and thyrotoxicosis caused by similar stimulating effects of hCG, luteinizing hormone, and thyroid-stimulating hormone, because of their shared α-subunits.488,598,629 Pathologic Features

Grossly, the testis may be externally normal; the cut surface usually shows a hemorrhagic and necrotic nodule (Fig. 13.86), although in some instances regression of the primary lesion has occurred, with residual scar as the only evidence of prior neoplasm. Classically, choriocarcinoma consists of a random mixture of mononucleated trophoblast cells with clear to lightly staining cytoplasm (cytotrophoblasts and intermediate trophoblasts) and multinucleated syncytiotrophoblast cells, the latter often with smudged or degenerate-appearing nuclei and densely eosinophilic cytoplasm (Fig. 13.87). Cells of intermediate size with eosinophilic cytoplasm are also common. The syncytiotrophoblast cells may have intracytoplasmic lacunae containing an eosinophilic precipitate or

Fig. 13.85 Rete testis hyperplasia with hyaline globules. Confusion with yolk sac tumor is possible.

Fig. 13.86 Choriocarcinoma of the testis. Note the hemorrhagic nodules.

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Fig. 13.88 Viable choriocarcinoma forms a rim around pools of blood and fibrin.

Fig. 13.87 Characteristic mixture of syncytiotrophoblast cells and mononucleated trophoblast cells in choriocarcinoma. The background is hemorrhagic.

erythrocytes. The area surrounding a choriocarcinoma is almost always hemorrhagic, and the central portions of the neoplasm are typically hemorrhagic and necrotic. Extensive sampling of such tumors may therefore be necessary to demonstrate the diagnostic cell types, usually at the periphery (Fig. 13.88). In the bestorganized examples, the syncytiotrophoblast cells appear to surround or “cap” masses of mononucleated trophoblast cells, like the arrangement in immature placental villi (Fig. 13.89). However, in some cases the syncytiotrophoblast cells are inconspicuous, having relatively scant cytoplasm and a degenerate appearance (Fig. 13.90). In other cases, descriptively characterized as “monophasic choriocarcinoma,” a biphasic pattern of intermingled syncytiotrophoblast and mononucleated trophoblast cells is absent; instead, there occurs a proliferation of atypical trophoblastic cells of varying size.630 These are usually mononucleated and occasionally binucleated trophoblast cells, and the background typically remains hemorrhagic (Fig. 13.91). Lymphovascular invasion is a consistent finding in choriocarcinoma.631

Fig. 13.89 Choriocarcinoma with syncytiotrophoblast cells capping cytotrophoblast cells in a villuslike fashion.

Special Studies

Immunostains for hCG are useful in establishing the diagnosis of a trophoblastic proliferation, including choriocarcinoma. Positivity for hCG is strongest in syncytiotrophoblast cells and in large mononucleated trophoblast cells that may represent transitional forms between cytotrophoblast cells and syncytiotrophoblast cells (Fig. 13.92).41,59,632 Cytotrophoblast cells generally have only weak or absent staining for hCG. Similarly, pregnancy-specific

Fig. 13.90 Choriocarcinoma in which the syncytiotrophoblast cells are subtle, appearing as intermingled, smudged cells. Note the hemorrhage and typical syncytiotrophoblast cells at the bottom.

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Fig. 13.91 “Monophasic” choriocarcinoma. There is a diffuse pattern of mostly mononucleated trophoblast cells in a hemorrhagic background.

β-1-glycoprotein and human placental lactogen (hPL) may be identified in syncytiotrophoblast cells and intermediate-sized trophoblast cells but are not seen in the cytotrophoblast population.632 Inhibin-α is positive in syncytiotrophoblast cells.616,633,634 About one-half of choriocarcinomas stain for PLAP, and carcinoembryonic antigen (CEA) can be identified in both syncytiotrophoblast cells and cytotrophoblast cells in about 25% of cases.41,635 Cytokeratin is readily identifiable in both the syncytiotrophoblastic and cytotrophoblastic components of choriocarcinoma, including cytokeratins 7, 8, 18, and 19.41,376,636 EMA positivity is noted in about one-half of choriocarcinomas, usually within syncytiotrophoblast cells, whereas most other nonteratomatous germ cell tumors of the testis do not express EMA. SALL4 reactivity occurs in the mononucleated trophoblast cells.41,409 Choriocarcinomas are positive for p63 and hPL, with cytotrophoblasts showing p63 staining (Fig. 13.93) and absence of hPL staining, and intermediate trophoblasts are p63 negative and weak or negative for hPL.631 hPL is strongly positive in syncytiotrophoblasts.631 GATA3 is positive in most testicular choriocarcinomas, and GATA3 is also expressed in gestational choriocarcinoma, suggesting that GATA3 is a useful and sensitive trophoblastic marker.637 Ultrastructurally, the multinucleated syncytiotrophoblast cells have prominent cisternae of rough endoplasmic reticulum, which often contain electron dense material, and show interdigitating microvilli on the cell surface.60,638 Cytotrophoblast cells lack the prominent rough endoplasmic reticulum but have numerous free cytoplasmic ribosomes. Desmosomes are identified in all cell types.

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Fig. 13.92 Choriocarcinoma with strongest positivity for hCG in syncytiotrophoblast cells and large mononucleated trophoblast cells.

Fig. 13.93 Choriocarcinoma with p63 immunoreactivity in cytotrophoblast cells.

Differential Diagnosis

Other types of germ cell tumor may contain trophoblast cells, but they are scattered as individual cells or small nests and lack the biphasic pattern of choriocarcinoma. For example, the

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syncytiotrophoblast cells that occur in many seminomas are randomly distributed as separate cells and small islands without accompanying mononucleated trophoblast cells. Neither is there a distinct nodule of trophoblast cells of varying sizes as may be seen in some cases of choriocarcinoma. Embryonal carcinoma may show degenerate cells that mimic choriocarcinoma with a poorly defined syncytiotrophoblastic component. The lack of hemorrhage and hCG reactivity and the presence of OCT3/4 reactivity in such cases distinguish them from choriocarcinoma. Rare cases of embryonal carcinoma may show transformation to choriocarcinoma639; if the background is hemorrhagic and the admixed multinucleated cells are positive for hCG but not OCT3/4, choriocarcinoma should be diagnosed rather than embryonal carcinoma. “Monophasic” variants of choriocarcinoma should be distinguished from seminoma and solid-pattern yolk sac tumor.630 Diffuse hCG reactivity is helpful in this regard, as is the absence of AFP and OCT3/4 staining and a greater degree of pleomorphism compared with seminoma. The placental site trophoblastic tumor and epithelioid trophoblastic tumor may be distinguished from choriocarcinoma based on the absence of a biphasic pattern and their strong and diffuse reactivity for hPL and p63, respectively. GATA3 is consistently expressed by choriocarcinoma and may in some situations be a useful marker, but it should be remembered that yolk sac tumors are also positive, focal staining may be seen in embryonal carcinoma, and staining is seen in many somatic carcinomas.531 Treatment and Prognosis

Choriocarcinoma tends to metastasize before detection of the primary lesion, and most patients have an advanced-stage tumor at the time of diagnosis.631 It often shows a less orderly pattern of metastasis than other germ cell tumors, frequently skipping the retroperitoneum and metastasizing in a hematogenous pattern to the lungs, liver, central nervous system, and other sites.375,640 The prognosis is therefore overall poorer than for other germ cell tumors.631 The prognosis for mixed germ cell tumors with a predominant component of choriocarcinoma is also poorer than that of other germ cell tumors, although a recent study failed to find a negative prognostic impact when the amount of choriocarcinoma was less than 5%.631,641a The aggressive nature of choriocarcinoma is supported by several studies demonstrating a poorer prognosis in patients with nonseminomatous germ cell tumors who had elevated serum hCG levels, and in those with choriocarcinoma in mixed germ cell tumors.488,641-644

Nonchoriocarcinomatous Trophoblastic Tumors There are other trophoblastic tumors in the testis apart from choriocarcinoma. These include placental site trophoblastic tumor, epithelioid trophoblastic tumor, and cystic trophoblastic tumor. Placental site trophoblastic tumor resembles the uterine tumor of the same name (Fig. 13.94).630 It consists of a nodular proliferation of “intermediate” trophoblast cells that stain positively for human placental lactogen and is mostly negative for p63. There is lack of the biphasic pattern of choriocarcinoma. This tumor has been described in a 16-month-old boy who had no evidence of disease at 8 years follow-up after orchiectomy in the absence of any adjuvant therapy.630 Additional cases have been described in a 24-year-old man that was associated with teratoma, had GCNIS and 12p amplification by FISH, and had a favorable outcome with orchiectomy alone, and in a 39-year-old man in association with retroperitoneal teratoma after orchiectomy and chemotherapy for testicular germ cell tumor.645,646

Fig. 13.94 Placental site trophoblastic tumor. There is a sheetlike arrangement of intermediate trophoblast cells with densely eosinophilic cytoplasm in a hemorrhagic background. The tumor cells were strongly and diffusely reactive for human placental lactogen.

Microscopically, discohesive cells and clusters of cells with large nuclei and abundant eosinophilic cytoplasm are seen in a fibrous background, and vascular wall infiltration is characteristic.646 Prognosis is thought to be better than in choriocarcinoma, although experience is limited.646 Epithelioid trophoblastic tumor (Fig. 13.95) consists of mononucleated squamoid chorionic-type intermediate trophoblast cells with pleomorphic, hyperchromatic nuclei, abundant eosinophilic cytoplasm, and prominent cell membranes.646 Apoptotic bodies and fibrinoid necrosis are often admixed. The cells are positive for p63, but hPL is negative or focal.646,647 Inhibin, GATA3, and PLAP are also positive, and staining for hCG is variable.646 Five cases, two testicular and three in resections after chemotherapy, have been reported.646,647 The patients were 19 to 43 years of age, and four of the five tumors were associated with teratoma. As with placental site trophoblastic tumor, the prognosis is thought to be more favorable than in choriocarcinoma.646 Cystic trophoblastic tumors may occur as a spontaneous testicular tumor or after chemotherapy in metastatic sites.648-650 Rarely it may be seen in metastases in patients not previously treated with chemotherapy.651 It consists of mostly mononucleated trophoblast cells that line cysts that may contain fibrinoid material, pinkstaining fluid, or appear mostly empty (Fig. 13.96). The trophoblasts show variable cytoplasmic vacuoles and only rare mitotic figures.648 In testicular specimens, it is usually a minor (10% or less)

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Fig. 13.95 Epithelioid trophoblastic tumor consisting of mononucleate chorionic-type intermediate trophoblast cells. Note admixed, eosinophilic apoptotic bodies.

Fig. 13.96 Cystic trophoblastic tumor showing prominently vacuolated trophoblastic cells lining a space.

component of a germ cell tumor with other components.649,650 Inhibin and hCG are focally positive, and p63 is variable.649,650 Only about 15% of patients with cystic trophoblastic tumor in retroperitoneal lymph node specimens have had choriocarcinoma in the preceding orchiectomy.649,650 The prognosis in retroperitoneal lymph node dissection specimens is similar to teratoma, and no further treatment is required if other components are absent.648

(and/or their regression) occurs before orchiectomy. Metastasis of nonteratomatous elements with subsequent transformation at the metastatic site to teratomatous elements explains the phenomenon of mature teratoma metastasizing as mature teratoma; failure to transform at the site of metastasis explains mature teratoma of the testis associated with metastases of nonteratomatous type. It is of paramount importance to recognize that almost all pure, mature teratomas in postpubertal patients are malignant, although there is now evidence of rare benign cases (analogous to the benign pediatric teratomas).29 Most patients with testicular teratoma present with a testicular mass, although patients may have symptoms secondary to metastases. Serum marker elevation may occur because of admixed yolk sac tumor or syncytiotrophoblast cells either in the primary tumor or in metastases; in addition, mild AFP elevation may occur in patients with pure teratoma secondary to synthesis of AFP by endodermal glandular structures of teratomatous type.57,59,532

Teratoma, Postpubertal-Type Clinical Features

Teratoma, postpubertal-type, usually occurs in adults as a component of a mixed germ cell tumor and is present in more than one-half of all mixed germ cell tumors and in approximately 25% of all nonseminomatous germ cell tumors.345,640 In contrast with teratoma, prepubertal-type, it carries a definite risk for metastases even when present in pure form. Hence, there are reports of “pure mature teratoma” metastasizing as “pure mature teratoma” and also pure mature teratoma associated with metastases of nonteratomatous type, such as embryonal carcinoma.652-658 The explanation for these observations is that postpubertal patients with pure teratoma develop teratoma from GCNIS through an intermediary of invasive, nonteratomatous malignant germ cell tumor.659 This is supported by the frequent identification of GCNIS in seminiferous tubules adjacent to pure teratoma of the testis in postpubertal patients.78 Nonteratomatous malignant elements are initially a component of a teratoma-containing mixed germ cell tumor, but transformation of the nonteratomatous elements to teratoma

Pathologic Features

Grossly, teratoma has a variable appearance. Mature teratoma often contains multiple cysts, generally less than 1 cm in diameter, which contain watery to mucoid fluid (Fig. 13.97). Semi-translucent nodules of gray-white cartilage may be present, and a fibromuscular stroma may be seen among the cartilaginous and cystic structures. In other areas, the tumor may be solid (Fig. 13.98). Fleshy, encephaloid, and hemorrhagic areas usually correspond to foci of immaturity, which, if extensive, may justify a diagnosis of teratoma

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Fig. 13.97 Teratoma with several cysts and cartilage. Fig. 13.99 Teratoma with islands of hyaline cartilage, glandular structures lined by enteric-type epithelium, and fibromuscular stroma.

Fig. 13.98 Teratoma with solid appearance.

with a secondary malignant component. Such foci may also represent intermixed nonteratomatous elements. Microscopically, mature teratoma consists of a variety of somatic-type tissues (Fig. 13.99), commonly including cartilage, smooth and skeletal muscle, neuroglia, enteric-type glands (Fig. 13.100), squamous epithelial islands and cysts, respiratory epithelium, and urothelial islands. Less commonly, bone and pigmented choroidal epithelium, and rarely kidney, liver, meninges, choroid plexus, or prostatic tissues, are present. These tissues are considered mature, but it is quite common to find significant cytologic atypia (Figs. 13.101 and 13.102). This atypia correlates with

the presence of aneuploidy in mature testicular teratoma, reflecting their derivation (see earlier discussion).660 There is no evidence that the grading of the degree of atypia, based on qualitative assessment of nuclear enlargement, hyperchromasia, and mitotic rate, has any prognostic significance. The testicular parenchyma adjacent to postpubertal-type teratomas has GCNIS in about 90% of the cases and usually shows tubular atrophy and sclerosis with hypospermatogenesis.77 Microlithiasis also may be seen. Immature elements are common in postpubertal-type teratoma but are not known to have any prognostic significance. This was recognized in the 2004 WHO classification, which no longer drew a distinction between mature and immature testicular teratomas and is also the case in the current classification.23,661 Such elements are easily recognized when they consist of highly immature tissues such as neuroectoderm, blastema, or embryonic tubules. Neuroectoderm consists of small, hyperchromatic cells arranged in tubules and rosettes (Fig. 13.103). Blastema consists of nodular collections of oval cells with scant cytoplasm and hyperchromatic nuclei (Fig. 13.104); such blastematous elements may be mixed with embryonic tubules lined by cuboidal cells with scant, inconspicuous cytoplasm. When intermixed, these two components resemble a primitive blastomatous neoplasm such as nephroblastoma or pulmonary blastoma (Fig. 13.104). Lower-grade “immature” elements are common, including a hypercellular or a myxomatous, hypocellular mesenchyme (Fig. 13.105). Such stroma likely represents a precursor to smooth muscle, as it is often arranged concentrically around islands of epithelium in a manner similar to

Fig. 13.100 Mature enteric-type epithelium in a teratoma with associated smooth muscle.

Fig. 13.102 Cytologic atypia of hyaline cartilage in a teratoma.

Fig. 13.103 Embryonic-type neuroectoderm in a teratoma. Fig. 13.101 Cytologic atypia of glandular epithelium in a teratoma.

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Fig. 13.104 Cellular nodules of blastema with glands in a teratoma.

muscularis propria of the gastrointestinal or respiratory system (Fig. 13.105). Special Studies

Immunohistochemical staining of teratomatous elements yields results expected for the nature of the particular tissue.615,616,662 AFP may be present within glands of enteric or respiratory type, as well as within liver-like tissue57,59,532; therefore pure teratoma may be associated, theoretically, with modestly elevated serum AFP, although this rarely is manifest. Alpha-1-antitrypsin, CEA, and ferritin may also be produced by teratomatous epithelium, and PLAP-positivity may be expressed in glands of a minority of teratomas.281,288,402,532 Focal SALL4 reactivity occurs in some postpubertal-type teratomas.409 IMP3, an oncofetal protein expressed in many malignancies, is expressed in testicular teratoma and in other testicular germ cell tumor components, but not in ovarian teratoma, supporting the malignant nature of testicular postpubertal-type teratoma.663 Mature postpubertal-type teratoma usually has aneuploid DNA content, frequently in the hypotriploid range.664-666 The i(12p) marker chromosome is also found in most postpubertal-type teratomas.424,666,667 These data support the derivation of postpubertal-type teratoma from GCNIS. As mentioned previously, the karyotype of the prepubertal teratomas is normal. The fibrous stroma of postpubertal-type teratoma has isochromosome 12p or other overrepresentation of 12p similar to the epithelial and other components, supporting its neoplastic nature and common origin with the epithelial components.667

Fig. 13.105 A lower degree of immaturity in this teratoma, compared with Fig. 13.104, with modestly cellular stroma around islands of epithelium.

Differential Diagnosis

It is important to distinguish postpubertal-type and prepubertaltype teratomas because of the benign nature of the latter.29,375,668-672 Dermoid cyst, now considered a subtype of prepubertal-type teratoma, often has grossly evident hair within a largely cystic lesion, unlike postpubertal-type teratoma.661 On microscopic examination, it has an organotypical arrangement of hair and adnexal structures to an epidermal surface, a feature rarely encountered in postpubertal-type teratoma. Although it shares with postpubertal-type teratoma the presence of diverse tissue types, including intestinal mucosa, cartilage, bone, and others, these lack the cytologic atypia that may be seen in postpubertaltype teratoma. Most importantly, dermoid cyst is not associated with GCNIS.670 Similar comments pertain to the nondermoid postpubertal-type teratomas; although these lack the organoid cutaneous-like component, they often show organoid bronchuslike or, less commonly, enteric-type structures. Moreover, even when organoid arrangements are less apparent, prepubertal-type teratomas frequently show prominence of ciliated and squamous epithelium and smooth muscle. Absence of “dysgenetic” tubular changes and GCNIS is also helpful in recognizing them, as is their cytologically bland appearance. Epidermoid cyst, now considered a subtype of prepubertal-type teratoma, is lined with keratinizing squamous epithelium but lacks associated adnexal structures. Unlike postpubertal-type teratoma, epidermoid cysts do not display cytologic atypia, and there is absence of GCNIS.78,673 Although squamous predominant postpubertal-type teratomas

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are infrequently encountered, close inspection almost always discloses nonsquamous elements. Furthermore, the squamous epithelium is typically arranged as multiple nests of different sizes rather than as a single cystic lesion. If additional assurance is needed to make the distinction of postpubertal-type from prepubertal-type teratoma, FISH study of the teratoma can be done for chromosome 12p amplification, which is present in the former but not in the latter. Treatment and Prognosis

Postpubertal-type teratomas have a guarded prognosis. In two referral series of adult patients with “pure mature teratoma,” the frequency of metastases was over 40%, to some extent reflecting referral bias.657,658 Johnson et al. performed orchiectomy and RPLND in 18 patients with “mature teratoma,” some of whom also had a seminomatous component, and reported 100% 5-year survival.674 Conversely, 2 of 12 adult patients with pure teratoma reported by the British Testicular Tumor Panel died of nonteratomatous metastases.656 Dixon and Moore reported 70% 5-year survival for patients with teratoma, with or without seminoma. The prepubertal-type teratomas (including epidermoid and dermoid cyst) are cured by orchiectomy.675

Teratoma With Somatic-Type Malignancy Somatic-type malignancies may occur in association with teratoma, usually in posttreatment specimens but occasionally in the untreated testis. Somatic-type malignant components are encountered most frequently in metastases to the lung or retroperitoneal lymph nodes, but also at other sites.676 These tumors share 12p amplification and loss of heterozygosity, supporting origin from the same progenitor cell.584 They have also been referred to as “teratoma with malignant transformation,” an unfortunate consequence of borrowing terminology that was used for ovarian teratomas, which are mostly of different pathogenetic nature. This term, however, incorrectly suggests that postpubertal-type teratoma in the absence of such transformation is not malignant. Also, somatic-type malignancies may occur after testicular germ cell tumors lacking a teratoma component (30% of cases), and some of these originating tumors express AFP or glypican-3, suggesting that the somatic-type malignancy may be of yolk sac tumor derivation.677,678 A somatic-type malignancy in a teratoma may have either a mature or immature appearance. Carcinoma of somatic type, representing the destructive growth of epithelium with a mature phenotype, is recognized by its invasive features. It forms masses of cytologically malignant epithelium or irregularly configured, infiltrating cords or nests associated with a desmoplastic reaction. Carcinomas showing glandular (Fig. 13.106), squamous, or neuroendocrine differentiation or lacking differentiation may occur. Glandular tumors with glypican-3 and AFP expression and scant to absent keratin 7 and EMA expression may, however, represent glandular pattern yolk sac tumor.677 Glandular pattern yolk sac tumor has a poor prognosis, similar to or poorer than somatic-type adenocarcinoma arising in germ cell tumor.677 SALL4 may be a useful marker for these tumors when seen at distant sites, although it is more consistently positive in glandular pattern yolk sac tumor (71% of cases) than in adenocarcinoma arising from a germ cell tumor (36% of cases).677 It is notable that CDX2 expression is frequent in glandular pattern yolk sac tumors (83% of cases) and adenocarcinomas arising in germ cell tumors (63% of cases).677 Sarcoma may occur either as a specific histologic type (e.g., chondrosarcoma, leiomyosarcoma, well-differentiated

Fig. 13.106 Carcinoma with glandular differentiation showing confluent growth in a teratoma.

liposarcoma) or as a spindle cell sarcoma with no apparent specific differentiation.676 Because invasion of mesenchymal elements is not easily distinguished from atypical mesenchyme that remains an integral component of a teratoma, we require that sarcomas manifest independent growth by producing a pure proliferation of a single type of highly atypical mesenchyme of at least a 4  field (5-mm diameter).679 Overgrowth of embryonic-type neuroectoderm or nephroblastic tissue results in primitive neuroectodermal tumors or Wilms tumors, respectively.680-683 Embryonal rhabdomyosarcoma represents a pure overgrowth of mitotically active primitive rhabdomyoblastic cells (Fig. 13.107). Because identical primitive elements may occur in teratoma, there is need to find a “pure” proliferation of such elements before concluding that one of these types of somatic-type malignancy is present. Sarcomatoid tumors lacking differentiation to a specific tumor type and with expression of keratin AE1/AE3 and glypican-3 may represent sarcomatoid yolk sac tumor (Fig. 13.75 and the discussion of postchemotherapy resections later in this chapter), with prognosis similar to or poorer than sarcoma arising in a germ cell tumor.677,678 SALL4 may be a useful marker to support germ cell origin for sarcomatoid yolk sac tumor at distant sites (positive in about 60% of cases), but expression has not been reported in sarcomas arising from germ cell tumors (0% of cases).677 Sarcomatoid yolk sac tumor may show myxoid tumor “ringlets,” intercellular basement membrane deposits (parietal differentiation), and have variable nuclear atypia.678 Grading using the French Federation of Cancer Centers Sarcoma group system is prognostic for sarcomatoid tumors arising in testicular germ cell tumors.677,684

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Fig. 13.107 Embryonal rhabdomyosarcoma in a teratoma. (A) Low magnification shows tumor overgrowth. (B) High magnification shows primitive cells with differentiated rhabdomyoblasts.

Disseminated somatic-type malignancies do not respond well to the usually effective chemotherapy for metastatic germ cell tumors, so aggressive surgical resection is the crucial component of treatment.676,685 Compared with patients with other metastatic germ cell tumors, the prognosis is worse for these patients, especially when the somatic component is primitive neuroectodermal tumor or rhabdomyosarcoma.679,680,686-688 The secondary malignancies in such cases have been shown to have the abnormalities of chromosome 12p.685,689 The clinical significance of teratoma with a secondary malignant component in the testis in the absence of known metastatic disease is not clear. Patients with such tumors probably more commonly develop chemoresistant “nongerm cell” neoplasms after chemotherapy.679,690 Ahmed et al. with 5 patients and Colecchia et al. with 12 patients did not document a poor prognosis in germ cell tumors with somatic-type malignant components that were clinically confined to the testis.676,687

Primitive Neuroectodermal Tumor This neoplasm results from overgrowth of embryonic-type neuroectodermal elements that are a common component of immature testicular teratoma. It is best to reserve the term “primitive neuroectodermal tumor” of the testis for those rare cases that are a pure proliferation of such elements, and to diagnose cases with residual teratomatous or other germ cell tumor elements as having areas of primitive neuroectodermal tumor with other germ cell tumor components.34,691-693 The distinction of such cases from teratoma

depends on overgrowth of a primitive neural component, as previously described. These cases occur in the typical age range for adult-type germ cell tumors, but may rarely occur in children.694 Gray-white, partially necrotic tumors are identified. Microscopically, the tumors contain small, hyperchromatic, poorly differentiated neural-type cells arranged in rosettes, tubules, or diffusely (Fig. 13.108).691,693 The tumors most commonly resemble medulloepithelioma of the central nervous system, and may show glial differentiation that is reflected by immunoreactivity for glial fibrillary acidic protein and sometimes by features that are of overtly malignant glial type (Fig. 13.109).680,695 Similar to central nervous system primitive neuroectodermal tumors, most germ cell tumor–derived cases lack the t(11;22) translocation typical of peripheral primitive neuroectodermal tumor.695 Very rare cases of peripheral primitive neuroectodermal tumor of the testis, however, may have chromosome 22 rearrangement detectable by FISH.696 Neurosecretory granules may be identified ultrastructurally.693 Immunohistochemical studies utilizing neural markers, including chromogranin, synaptophysin, and CD99, may be useful if positive, but neuroendocrine markers other than CD57 are frequently negative.680,695 Other small cell tumors in the differential diagnosis include teratoma with embryonic-type neuroectodermal elements, metastatic small cell carcinoma, malignant lymphoma, and nephroblastoma. As discussed earlier, the distinction from teratoma is based on the amount of primitive neural tissue. Small cell carcinoma does not form the well-defined tubules

Fig. 13.108 (A) Primitive neuroectodermal tumor with neural-type cells arranged in rosettes, tubules, and diffusely. (B) Stratified, hyperchromatic tumor cells line tubules.

Fig. 13.109 (A) A primitive neuroectodermal tumor (PNET, top) shows an area of malignant glial differentiation (bottom). (B) At high power, the PNET shows a small focus (bottom) with glial differentiation.

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and rosettes that occur in most primitive neuroectodermal tumors and usually shows more intense and widespread cytokeratin reactivity that contrasts with the focal, weak, or absent reactivity in primitive neuroectodermal tumor. The absence of GCNIS in small cell carcinoma metastatic to the testis contrasts with its usual presence in testicular primitive neuroectodermal tumor. Additionally, small cell carcinoma tends to occur in older patients who often have a history of lung cancer or cancer at another appropriate primary site.693 The absence of GCNIS, tubules, and rosettes and the tendency for interstitial growth help in the differential with lymphoma, although immunohistochemistry offers a powerful method for distinction. Overgrowth of blastema and epithelium in a teratoma can produce a tumor resembling a nephroblastoma that is easily confused with a primitive neuroectodermal tumor (Fig. 13.110).683 Distinction may require immunohistochemistry for neural markers, which are negative in nephroblastoma-like tumors, and WT1. Ultrastructural or immunohistochemical studies permit separation of the other alternative diagnoses. Testicular germ cell tumors with primitive neuroectodermal tumor behave more aggressively than germ cell tumors lacking it as a component. Seven of 15 clinical stage I patients with a component of testicular primitive neuroectodermal tumor either had metastases or relapsed on surveillance management.681 Of the 23 patients who presented with metastatic primitive neuroectodermal tumor and received chemotherapy, only three had a complete response.681 The mainstay of treatment therefore is complete surgical excision of metastatic lesions.685

Fig. 13.110 Teratoma with overgrowth of blastema, epithelium, and stroma resembling nephroblastoma.

Mixed Germ Cell Tumor Mixed germ cell tumors have more than one type of germ cell tumor component, including one or more nonseminomatous elements, and are thus classified as nonseminomatous tumors, even if seminoma is the chief neoplastic type. Mixed germ cell tumors are common, accounting for about one-third of germ cell tumors and 69% of all nonseminomatous germ cell tumors of the testis.39 Virtually any combination of elements may be present. Frequent combinations include: embryonal carcinoma and teratoma; embryonal carcinoma and seminoma; embryonal carcinoma, yolk sac tumor, and teratoma; embryonal carcinoma, teratoma, and choriocarcinoma; embryonal carcinoma, teratoma, and seminoma; and teratoma and seminoma.39 Although seminoma with syncytiotrophoblast cells is histopathologically a mixed germ cell tumor, it is classified as a variant of seminoma rather than a mixed, nonseminomatous neoplasm because the natural history and treatment are similar to seminoma. Clinical Features

Patients with mixed germ cell tumor have the same clinical features as those with nonseminomatous germ cell tumor, and most present with a testicular mass. Those with a predominance of embryonal carcinoma average 28 years of age, whereas patients with a predominance of seminoma average 33 years.697 AFP and hCG elevation occurs in about 60% and 55% of patients with mixed germ cell tumor, respectively.358 Pathologic Features. Grossly, mixed germ cell tumors are often variegated because of their different components (Fig. 13.111). Foci of hemorrhage and necrosis are common. The microscopic features are like those of the individual components described elsewhere in this chapter. It is common for foci of yolk sac tumor with microcystic or vacuolated patterns to be contiguous with areas of embryonal carcinoma, and such foci are easily overlooked (Fig. 13.112). A “double-layered” pattern of embryonal carcinoma has been described in which ribbons of columnar embryonal carcinoma cells are accompanied by a parallel ribbons of flattened tumor cells (Fig. 13.45); the intense AFP immunoreactivity of this flattened cell layer, together with its morphology, indicates yolk sac

Fig. 13.111 Variegated appearance of mixed germ cell tumor, with hemorrhagic, cystic, and fleshy areas.

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Fig. 13.112 (A) Luminal spaces lined by embryonal carcinoma cells with yolk sac tumor cells on the adluminal aspect. (B) OCT3/4 highlights the nuclei of the embryonal carcinoma but spares those of the yolk sac tumor.

tumor differentiation, and this pattern should therefore be classified as a form of mixed germ cell tumor (embryonal carcinoma and yolk sac tumor).520,698 This pattern has sometimes been described as “necklace-like” or “diffuse embryoma” (see later).

expected immunohistochemical reactivities.703,704 The “doublelayered” tumor pattern (Fig. 13.45) may also be considered “diffuse embryoma.” The behavior and treatment of polyembryoma and diffuse embryoma is similar to other mixed germ cell tumors with these components.

Polyembryoma and Diffuse Embryoma

Polyembryoma is a distinct form of mixed germ cell tumor that recapitulates the embryo at approximately 13 to 18 days of gestation and is very rare as a dominant pattern.699,700 The embryoid body consists of a central core of cuboidal to columnar, sometimes stratified, embryonal carcinoma cells, a “ventral” yolk sac tumor component forming a yolk sac–like vesicle, and a “dorsal” space similar to that of the amniotic sac and lined by flattened epithelium (Fig. 13.113).701,702 The embryoid body is surrounded by loose, myxomatous, richly vascular tissue, similar to extraembryonic mesenchyme, which is also commonly identified in yolk sac tumor (Fig. 13.113). Because of the yolk sac tumor component, patients with polyembryoma may have substantial AFP elevation.701 In some cases, intestinal and squamous differentiation of the “amniotic” epithelium is present, as well as hepatic differentiation in the yolk sac–like zone.701 Imperfectly formed embryoid bodies are occasionally seen in mixed germ cell tumors, consisting of small nodular collections of embryonal carcinoma admixed with yolk sac tumor, surrounded by a myxomatous to fibrous stroma (Fig. 13.114). Diffuse embryoma consists of a sheetlike admixture of embryonal carcinoma and yolk sac tumor in approximately equal proportions (Fig. 13.115), with the two components retaining their

Treatment and Prognosis

Patients with mixed germ cell tumors are managed like patients with nonseminomatous tumors. Tumors consisting of embryonal carcinoma and teratoma are less likely to metastasize than tumors having the same volume of embryonal carcinoma but lacking a teratomatous component, suggesting that the ability of embryonal carcinoma to differentiate is associated with a decrease in metastatic potential.705 A similar observation has been made for cases having a yolk sac tumor component, with a decrease in metastatic potential.558 However, improved prognosis with a yolk sac tumor component has not always been observed, as in a recent series of 615 patients, where yolk sac tumor in the primary tumor was associated with a poor prognosis, with coexisting yolk sac tumor and seminoma having the poorest outcome.706 This seems likely related to the poorer chemosensitivity of yolk sac tumor when metastatic.

Germ Cell Tumors of Unknown Type Regressed Germ Cell Tumors

Some patients with extragonadal germ cell tumor lack clinical evidence of a primary testicular tumor.707-710 Some have primary extragonadal germ cell tumor, especially those with tumor confined to the mediastinum or pineal region without retroperitoneal

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Fig. 13.113 (A) Polyembryoma consists of embryoid bodies in a myxoid stroma. (B) Embryoid body composed of a central core of embryonal carcinoma, a “ventral” yolk sac tumor component, and a “dorsal” amnion.

involvement. Current evidence suggests that retroperitoneal tumor, frequently thought in the past to be a common site of primary extragonadal germ cell tumor, is often caused by metastasis with regression of a primary testicular tumor.336,710 Such cases are treated as testicular primary tumors.711 Examination of the testis in cases with retroperitoneal germ cell tumor often demonstrates foci of testicular scarring and, less frequently, GCNIS.336 This phenomenon of primary testicular tumor regression in the presence of metastases is documented in autopsy studies in which almost 10% of patients who die of metastatic testicular germ cell tumor show “burnt-out” primary tumors.712 In our experience, essentially all types of germ cell tumor are susceptible to regression and, not unexpectedly, regressed seminoma composes the single greatest proportion of cases, given the large fraction of testicular germ cell tumors that seminoma represents.523 It is also clear that many (possibly all) cases of “pure” postpubertal-type teratoma of the testis represent what were originally mixed germ cell tumors that had regression of the nonteratomatous components.713 Regression can be recognized from a constellation of findings (Figs. 13.116 to 13.118). All cases have scarred areas that may have either nodular or stellate configurations. These scars often contain a variably intense lymphoplasmacytic infiltrate and have prominent curvilinear blood vessels. They usually also have “ghost” remnants of hyalinized seminiferous tubules, which therefore do not represent evidence for a nonneoplastic process causing scarring.185,523 Coarse intratubular calcifications in the scar provide very good evidence for a regressed germ cell tumor that had an intratubular embryonal carcinoma component, because these

commonly undergo comedonecrosis in the tubules with dystrophic calcification. Peripheral to the scar, there invariably is tubular atrophy and sclerosis with impaired spermatogenesis, reflecting the usual testicular background on which postpubertal-type germ cell tumors develop. Additional findings include GCNIS in about onehalf of cases, tubular microliths in about one-third, and prominent clusters of Leydig cells in about 40%.523 We consider intratubular coarse calcifications within expanded tubular outlines in a scar or GCNIS peripheral to a scar to be diagnostic of a regressed germ cell tumor, whereas the other features are supportive but not entirely specific. Postchemotherapy Specimens

Chemotherapy in patients with metastatic testicular germ cell tumor often results in a marked decrease in tumor size, although large masses may persist. Persistent masses are often surgically excised, and the pathologic findings are of prime importance in determining the future treatment for these patients.573,714 Following chemotherapeutic cytoreduction, residual masses may consist of necrosis (often associated with a xanthomatous reaction), fibrosis, and viable-appearing germ cell tumor histologically similar to the original tumor or with an altered morphology. Additionally, malignant neoplasms resembling non–germ cell tumors (e.g., sarcoma, primitive neuroectodermal tumor, and carcinoma) may occur.573,679,686 Patients with teratoma in postchemotherapy retroperitoneal lymph node specimens have a significantly more favorable prognosis than patients with nonteratomatous components.715 Patients with necrosis, fibrosis, and mature (although

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Fig. 13.114 Complex embryoid body. Fig. 13.115 Diffuse embryoma consists of an approximately equal mixture of embryonal carcinoma and yolk sac tumor.

often atypical-appearing) teratomatous lesions after chemotherapy are not usually treated with additional chemotherapy; conversely, those who have persistent embryonal carcinoma, yolk sac tumor, choriocarcinoma, or seminoma are candidates for second-line (“salvage”) chemotherapy, sometimes with bone marrow transplantation. The treatment of postchemotherapy sarcoma, primitive neuroectodermal tumor, and carcinoma is problematic and often ineffective, but is usually primarily by surgical resection.681,685,686 In one study of 101 patients with advanced, nonseminomatous germ cell tumor treated with cisplatin-based chemotherapy and resection of residual masses, 51% had necrosis or fibrosis; 37% had residual mature teratoma; and 12% had residual malignant, nonteratomatous germ cell tumor.716 Necrotic foci in postchemotherapy resections often appear as tan, granular nodules surrounded by a thin yellow rim (Fig. 13.119). Microscopically, there is central, coagulative necrosis consisting of eosinophilic debris with ghostlike outlines of necrotic tumor cells, typically lacking prominent karyorrhectic debris. Macrophages with abundant, foamy cytoplasm surround the areas of necrosis (Figs. 13.120 and 13.121), accounting for the grossly visible yellow rim. The nuclei of these cells may be mildly atypical, which, in conjunction with the clear cytoplasm, can lead to misinterpretation as seminoma (Fig. 13.121).573 The absence of significant atypia and inconspicuous mitotic activity are usually sufficient to permit separation without resorting to special stains for glycogen, placental alkaline phosphatase, OCT3/4, and macrophage markers. If immunohistochemical staining is necessary, OCT3/4 immunohistochemistry is a sensitive and specific

marker for metastatic seminoma and embryonal carcinoma.717 An active fibroblastic proliferation may be intermingled with the foamy macrophages, creating a fibroxanthomatous reaction. Grossly, fibrosis in postchemotherapy resections is firm and white and, microscopically, consists of scattered spindle cells set in dense collagenous tissue. Some spindle cells may be enlarged and cytologically atypical but do not form fascicles and are scattered randomly, creating a hypocellular appearance (Fig. 13.122). Some of the apparent fibrous lesions may represent postchemotherapy persistence of the hypocellular, spindled cell component of yolk sac tumor, based on the identification of this yolk sac tumor pattern in the orchiectomy specimen and the intense cytokeratin reactivity of the spindle cells.600 It is probably best, however, to consider the hypocellular, collagenous lesions as “fibrosis” rather than creating clinical confusion by characterizing it as persistence of a yolk sac tumor component, because it does not merit additional chemotherapy. Some spindle cell lesions after chemotherapy display increased cellularity and mitotic activity in a more myxomatous background.600 They have a fibrous (Fig. 13.123) to myxoid stroma (Fig. 13.124) and variable cellularity (Figs. 13.123 and 13.124) and often have a component of epithelioid cells. Tumor cell “ringlets” showing an empty space with surrounding tumor cells occur in a minority (Fig. 13.124). Based on their reactivity for cytokeratins, glypican-3, and SALL4, as well as their “magma reticulare”– like appearance, they should be classified as sarcomatoid yolk sac

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Fig. 13.116 Regressed germ cell tumor consisting of a discrete scar containing dystrophic, intratubular, coarse calcifications—a pathognomonic finding.

tumors.677,718 AFP positivity is usually absent in these lesions, as it is in the spindle cell component of the primary lesion.600 Their cellularity and mitotic activity distinguishes them from the similarly derived examples of “fibrosis” discussed in the preceding paragraph. We have seen some of these sarcomatoid proliferations eventually evolve to embryonal rhabdomyosarcoma after multiple recurrences characterized by gradually increasing cellularity (Fig. 13.125). The prognosis of patients with high-grade spindle cell lesions in postchemotherapy resections is guarded.600,677 Teratomatous lesions after chemotherapy are common, and are readily diagnosed by those aware that metastatic teratoma may be seen after orchiectomy for germ cell tumors in which it is absent.715,719 Metastatic teratoma usually appears as a multicystic mass with intervening fibrous or muscular tissue (Fig. 13.126); the cysts typically contain clear, serous fluid, but mucoid or hemorrhagic cyst contents may also be seen. Microscopically, there are often glands, squamous nests, islands of cartilage, smooth and striated muscle, and intervening fibromuscular stroma. Significant cytologic atypia can be identified in these tumors.8,698,720 Glandular epithelium, although confined to round, noninvasive glands, may be stratified with enlarged, hyperchromatic, and mitotically-active nuclei, which raise a concern for embryonal carcinoma (Fig. 13.127). However, the primitive, vesicular nuclei and macronucleoli of embryonal carcinoma are absent. These glands often have intestinal differentiation, with goblet cells and eosinophilic absorptive-type cells. Squamous nests and cartilage may also display cytologic atypia. Stromal invasion by highly atypical

Fig. 13.117 Regressed germ cell tumor with scarring, lymphocytes, and prominent vessels.

elements indicates a diagnosis of carcinoma or sarcoma; criteria for invasion are the same as in primary teratoma with a secondary malignant component. Metastatic teratoma may be life threatening. Mature teratoma may undergo progressive enlargement and impinge on vital structures, especially in the mediastinum. This has been described as the “growing teratoma syndrome” and is one reason for complete excision of metastatic teratomatous tumor whenever feasible.721-724 Although often diagnosed as mature teratoma, these tumors contain cells with a malignant genotype (as well as phenotype) based on karyotypic and ploidy studies.660,725,726 Consequently, such lesions should be surgically excised before evolution of more aggressive clones of cells results in overgrowth with a malignancy of teratomatous origin.665,726,727 Despite the cytologic atypia that occurs in metastatic teratomatous lesions after polychemotherapy, such atypia, in the absence of evolution to an invasive malignant neoplasm, does not have known prognostic significance.720 A variety of malignancies resembling tumors of non–germ cell origin (“somatic-type” malignancies) may be identified in postchemotherapy resections. Tumors with both yolk sac tumor and seminoma are most likely to undergo somatic transformation, and pure seminoma only rarely does so.706,728 These consist of fleshy or necrotic areas among fibrous tissue and cysts. Embryonal rhabdomyosarcoma and primitive neuroectodermal tumor are the most common tumors of this type; others include malignant glioma, adenocarcinoma, undifferentiated carcinoma, and undifferentiated sarcoma.679 One report describes a case with two distinct somatic-

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Fig. 13.118 Regressed germ cell tumor showing lymphocytes, coarse intratubular calcifications in expanded tubular profiles, and hyalinized tubules within a scar.

Fig. 13.119 Tumor necrosis after chemotherapy. A tan, granular nodule is surrounded by a yellow rim with peripheral fibrosis.

type malignancies, adenocarcinoma and leiomyosarcoma.729 About one-fourth of sarcomatoid neoplasms in the postchemotherapy setting show glypican-3 and keratin AE1/AE3 reactivity and can be considered sarcomatoid yolk sac tumors (Figs. 13.123 and 13.124), which share the poor prognosis of the somatic-type malignancies.728 The prognosis of germ cell tumors with somatic-type malignancies is guarded, with 5-year cancer-specific survival of approximately 64%.685,728 For germ cell tumors with

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Fig. 13.120 The fibroxanthomatous reaction that often surrounds foci of tumor necrosis induced by chemotherapy may be highly cellular.

sarcoma or sarcomatoid yolk sac tumor, grading with the French sarcoma grading system may have prognostic value.684,728 The morphology of persistent, postchemotherapy, nonteratomatous germ cell tumor is usually like that of primary testicular neoplasms. However, exceptions to this rule occur, particularly with trophoblastic proliferations. Unlike the biphasic proliferation of syncytiotrophoblast and cytotrophoblast cells in classic choriocarcinoma, the trophoblastic proliferations in postchemotherapy resections often lack definite syncytiotrophoblast cells. Instead, mononucleated trophoblast cells may be identified in the absence of a syncytiotrophoblast component. Mazur described this pattern in patients treated for gestational choriocarcinoma as “atypical choriocarcinoma,” but we prefer “monophasic” choriocarcinoma (Fig. 13.91).730 In some cases, the trophoblast cells are exclusively mononuclear and form the epithelial lining of cysts, closely mimicking teratomatous cysts composed of atypical squamous epithelium (Fig. 13.128) but having focal hCG and/or inhibin reactivity.731 The distinction between these cystic trophoblastic tumors and teratoma does not appear to be clinically important if there is no evidence of stromal invasion. We found no difference in outcome when such cystic trophoblastic tumors were identified with teratoma in postchemotherapy resections compared with historical outcomes for teratoma alone in the same setting.648 They may, however, be associated with minor elevation in serum hCG. Solid, monophasic proliferations of trophoblastic cells, in contrast, merit additional chemotherapy, when feasible. Additionally, we have found that the appearance of yolk sac tumor may be different in postchemotherapy resections, especially in the context

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Fig. 13.121 The histiocytes in the fibroxanthomatous reaction adjacent to a necrotic tumor may show mild cytologic atypia.

of late recurrence. There tends to be a predominance of glandular (Fig. 13.129A), hepatoid (Fig. 13.129B), and parietal patterns in this setting, often to the extent that the clinical history of late recurrence can be predicted from the morphology.586 A potential pitfall in the interpretation of postchemotherapy retroperitoneal resections is the presence of paraganglionic tissue. The pale cytoplasm in these structures and diffuse to nested arrangement may lead to misinterpretation as persistent metastatic seminoma (Fig. 13.130). They are not, however, present in nodal tissue; the cytoplasm shows a subtle basophilic granularity; they are associated with small nerves; and the nuclear features are bland. If doubt remains, immunostains are diagnostic. The outcome of patients undergoing excision of persistent masses after chemotherapy for metastatic testicular germ cell tumor varies depending on the pathologic findings. Eighty-eight percent of patients with only necrosis in retroperitoneal lymph node dissections were well on follow-up.732 Similarly, only 1 of 25 patients (4%) with “fibrosis” relapsed on follow-up.733 Residual mature teratoma is also associated with a favorable prognosis; a combination of three series reported benign follow-up in 90% of 42 cumulative patients.733-735 Conversely, 24 of 30 patients (80%) with malignant, somatic-type neoplasms developed recurrent tumor after resection, and another series reported a 5-year survival of 51%.686,720,736 For patients with persistent, apparently viable germ cell tumor other than teratoma in postchemotherapy resections, the prognosis is also guarded. Those who do well include patients who have complete surgical excision of persistent tumor, who have received only primary chemotherapy before resection, and who also receive postresection chemotherapy; patients with retroperitoneal tumor who meet these criteria have a 70% disease-free survival.737 Patients who have persistent retroperitoneal germ cell tumor other than teratoma after salvage therapy and who are completely resected have a 40% disease-free survival.737 Inability to completely resect

Fig. 13.122 (A) Fibrous lesion after chemotherapy contains widely scattered spindle and stellate cells. (B) High power shows mild cytologic atypia.

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Fig. 13.123 Increased cellularity, especially at left, in conjunction with supporting immunoreactivity, justifies classification as sarcomatoid yolk sac tumor.

viable germ cell tumor other than teratoma after primary or salvage chemotherapy carries a poor prognosis, with only 9% remaining clinically tumor free.737 Additionally, only about one-third of patients with late recurrence of nonteratomatous germ cell tumor remain disease free after resection.586

Germ Cell Tumors Not Derived From Germ Cell Neoplasia in Situ Spermatocytic Tumor

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Fig. 13.124 Myxoid sarcomatoid yolk sac tumor.

times as frequently as seminoma, and there does not appear to have been a definite increase in incidence over time.86,740,748 Most patients with spermatocytic tumor are older than those with other types of testicular germ cell tumor. In various case series, the average age varied from 52 to 59 years, compared with an average of 40 years for patients with seminoma.39,743,748-750 Nonetheless, 30% are in the fourth decade.748 Most are white, but occurrence in African Americans and Asians has been reported.743 Most patients present with painless, often long-standing, testicular enlargement.740,743 Serum marker studies (AFP, hCG, and LDH) are negative.

Clinical Features

Historically this tumor, known previously as “spermatocytic seminoma,” was considered a variant of seminoma. Today it is recognized as a unique clinicopathologic entity with morphology, clinical features, and pathogenesis distinct from seminoma and other postpubertal germ cell tumors.738 Originally described by Masson in 1946, spermatocytic tumor is an unusual neoplasm that represents only 1% to 2% of testicular germ cell tumors and occurs with about one-twentieth the frequency of seminoma.39,739,740 Unlike other types of germ cell tumor, it occurs only in the testis (or, in one unique case, a dysgenetic gonad), slightly more frequently on the right side.741-744 Also, unlike almost all other germ cell tumors that occur in postpubertal patients, spermatocytic tumor is not associated with cryptorchidism, GCNIS, or other types of germ cell tumor.329,740 It occurs as a pure lesion, except in rare cases in which it is associated with a sarcoma.743,745-747 Spermatocytic tumor is bilateral in up to 9% of cases, about four

Pathologic Features

Grossly, spermatocytic tumor usually ranges 3 to 15 cm in diameter and has a variable appearance, with zones of fleshy, white to tan tissue, mucoid or gelatinous change, friability, hemorrhage, and cystic degeneration (Fig. 13.131).740 Necrosis, however, is uncommon. A multinodular appearance is frequent (Fig. 13.131), and paratesticular extension is infrequent.743,751 Several patterns may be identified, often including a diffuse, sheetlike pattern that may be interrupted by follicle-like (Fig. 13.132) or irregular spaces (Fig. 13.133) caused by edema, which is present in up to 90% of cases. Multiple, cellular tumor nodules that are separated by an edematous stroma are also characteristic (Fig. 13.134). A partial surrounding rim of fibrin may occur at the periphery of some nodules (Fig. 13.135).748 In about 20% of cases, intricate anastomosing tumor islands are seen (Fig. 13.136).748 Corded growth occurs in a minority (20%) of cases, usually at the tumor

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Fig. 13.125 Embryonal rhabdomyosarcoma after chemotherapy.

Fig. 13.126 Metastatic mature teratoma after chemotherapy, showing the characteristic multicystic appearance.

periphery. A prominent infiltrate of lymphocytes is uncommon (8% of cases), although rare clusters are present in about 40% (Fig. 13.137).748 Granulomatous reactions are virtually never encountered, unlike seminoma. Apoptosis is almost always present and may be prominent, with many clusters of apoptotic cells (Fig. 13.138). The microscopic hallmark of spermatocytic tumor is a polymorphous population of cells (Fig. 13.139) that consists of three major types: a small, lymphocyte-like cell 6 to 8 μm in

Fig. 13.127 High-grade epithelial atypia in a teratomatous gland embedded in atypical stroma.

diameter; an intermediate-sized cell averaging 15 to 20 μm in diameter; and giant cells, some of which may be multinucleated (Fig. 13.139), averaging 50 to 100 μm in diameter. The smallest cell has smudged, degenerate-appearing chromatin and scant eosinophilic to basophilic cytoplasm. The intermediate-sized cell has a round nucleus, usually with granular chromatin and scant cytoplasm. The nucleoli in the intermediate and giant cells are variably prominent. In some intermediate-sized and giant cells, the chromatin has a distinctive filamentous appearance that is like the chromatin of meiotic-phase, nonneoplastic spermatocytes (“spireme” chromatin). The borders between the cells, in contrast with seminoma, are generally indistinct. Intratubular growth is common (Fig. 13.140), and probably gives rise to separate invasive foci that cause the common multinodular or lobulated pattern of the tumor.752 An “anaplastic” variant of spermatocytic tumor was described in 1996, and isolated cases have been reported since then.753 These tumors have conventional areas but, additionally, large areas with a uniform population of cells with vesicular nuclei and prominent nucleoli (Fig. 13.141) that may resemble either usual seminoma or embryonal carcinoma. Nonetheless, the immunohistochemical features are those of spermatocytic tumor (see later), including negativity for PLAP, OCT3/4, and cytokeratins. Because there is, yet, no clear evidence that these tumors behave more aggressively than other spermatocytic tumors, we discourage the use of this terminology, which is not recognized in the current WHO Classification.

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Fig. 13.128 Cystic trophoblastic tumor showing (A) intracystic proliferation of stratified trophoblast cells, some of which have cytoplasmic lacunae. (B) High power of the trophoblast cells lining the cyst.

Special Studies

In contrast with seminoma, spermatocytic tumor lacks glycogen. Most immunohistochemical markers are negative, including OCT3/4, vimentin, actin, desmin, AFP, hCG, NSE, carcinoembryonic antigen, and leukocyte common antigen.282,404,407,742,743,753,754 Stains for placental alkaline phosphatase are also generally negative, although rare, focal positivity for PLAP may occur in isolated clusters of cells.743,754 Cytokeratin stains are also usually negative, although perinuclear, dotlike positivity for cytokeratin 18 can be seen infrequently.411,742 CD117, in contrast, is frequently positive in spermatocytic tumor, and such reactivity represents a potential pitfall in mistaking spermatocytic tumor for seminoma.407,755 More recently, spermatocytic tumor has been found to be reactive for SALL4, a general germ cell tumor marker.614 Spermatocytic tumor also expresses a variety of proteins, known as cancer testis antigens, that are characteristic of spermatogonia and spermatocytes (synaptonemal complex protein 1, synovial sarcoma on X chromosome, and xeroderma pigmentosa type A), indicating a more “mature” form of tumor differentiation than classic seminoma.446,756 Several cancer testis antigens, GAGE7, NY-ESO-1, MAGE-A4, and NUT (nuclear protein in testis), may be used as diagnostic markers with high specificity if only diffuse strong staining is considered a positive result.23,757 Differential expression of OCT2 and SSX family member 2-4 protein may divide spermatocytic tumor into subtypes resembling different stages of spermatogonial maturation.752 Spermatocytic tumors show a characteristic amplification of a portion of chromosome 9 that encompasses the DMRT1 gene; hence immunostains for DMRT1 protein are also positive. Ultrastructurally, spermatocytic tumor may show intercellular bridges similar to those described in spermatocytes, as well as leptotene stage-type chromosomes (filamentous chromosomes with

lateral fibrils).758,759 These features suggest meiotic phase differentiation, but their presence and specificity are disputed.760 Adjacent cells occasionally show macula adherens type junctions, and a Golgi body is a variably prominent feature. Other features include scattered mitochondria, occasional profiles of rough endoplasmic reticulum, nuclei with prominent nucleoli, and a thin basement membrane surrounding nests of tumor cells.758,760 One ultrastructural feature of spermatocytic tumor is the presence of “nuage,” cytoplasmic electron-dense deposits that lack a membrane and may be free in the cytoplasm or appear to bind mitochondria together (“intermitochondrial cement”).761 The presence of both nonmitochondria-associated nuage and intermitochondrial cement is characteristic of, and relatively specific for, normal male and female germ cells, but it is not seen in usual seminoma.761 This observation may provide further support for the concept that spermatocytic tumor represents a more differentiated phenotype than usual seminoma.761 Flow-cytometric studies have demonstrated variable DNA content, including hyperdiploidy, peritriploidy, diploidy, peridiploidy, tetraploidy, and aneuploidy.329,407,754,760 No haploid population has ever been found, arguing against spermatocytic tumor being postmeiotic. These variable results probably reflect the heterogeneous population of these neoplasms, because static cytophotometry of spermatocytic tumor has demonstrated a diploid or near-diploid DNA content in the small cell component, and a DNA content ranging up to 42C in the giant cell population, with intermediate values in the intermediate-sized cells.762 One study suggested that the cells of spermatocytic tumor arise after cycles of polyploidization, refuting the notion of a meiotic phase tumor.763 A karyotypic and differential gene profiling study (versus usual seminoma) found that spermatocytic tumor

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Fig. 13.129 Glandular (A) and hepatoid (B) patterns in postchemotherapy yolk sac tumor.

showed consistent gain in chromosome 9, failed to express the stem cell–associated genes typical of usual seminoma, and expressed genes associated with prophase of meiosis I.764 These data support the derivation of spermatocytic tumor from the primary spermatocyte. Either HRAS or fibroblast growth factor receptor (FGFR3) gene mutations are seen in approximately 20% of cases.752 Treatment and Prognosis

There are only four cases of metastasizing spermatocytic tumor in which there was histologic documentation of the metastatic tumor.765-768 Three of these cases had known lymphovascular invasion, which is ordinarily identified in only about 10% of cases.748 At least some reported cases of metastatic spermatocytic tumor represent misinterpretations of lymphoma.744 Because several hundred cases of spermatocytic tumor have been reported in the literature, the frequency of malignant behavior is well under 1%. Therefore orchiectomy alone is adequate treatment; adjuvant therapy is not indicated and may be harmful.740,750 Differential Diagnosis

The major differential diagnosis of spermatocytic tumor is seminoma. A summary of features helpful in this distinction is listed in Table 13.4. For the “anaplastic” variant, embryonal carcinoma is a consideration. The presence of the usual triphasic appearance of spermatocytic tumor, at least in foci, is quite helpful in such cases, as is the round nuclear contour that contrasts with the much more irregularly shaped nuclei of embryonal carcinoma. Absence

of GCNIS supports spermatocytic tumor, although some examples of intratubular spermatocytic tumor may mimic GCNIS (Fig. 13.142). Strong cytokeratin, OCT3/4 (nuclear), and CD30 (membranous) reactivity is expected for embryonal carcinoma but absent in spermatocytic tumor.769 Positive markers for spermatic tumor are now available and include NUT, GAGE7, MAGE-A4, NY-ESO-1, and DMRT1.757,764 Nuclear immunoreactivity should be strong and diffuse to be considered supportive of spermatocytic tumor, and a scoring system has been presented.757 CD117 positivity is supportive of spermatocytic tumor but may be negative in valid cases (and is, of course, also expected in seminoma).

Spermatocytic Tumor With Sarcoma Several cases of spermatocytic tumor associated with sarcoma have been reported.743,745-748 Some of the patients gave histories of stable testicular masses that underwent rapid enlargement or became painful.745,746 Some patients had symptoms secondary to metastases.745 Grossly, many of the tumors were hemorrhagic, necrotic, and had a whorled appearance on cut surface.745,746 Microscopically, the sarcoma was often admixed with the spermatocytic tumor (Fig. 13.143A) and usually described as an undifferentiated spindle cell sarcoma (Fig. 13.143B) or embryonal rhabdomyosarcoma, although chondrosarcomatous differentiation is also possible.743,745-748,770 In contrast with pure spermatocytic tumor, over one-half of the reported cases of spermatocytic tumor with sarcoma metastasized, frequently with a fatal outcome.745-747 The metastases were in a hematogenous distribution, with the lung being the most common metastatic site, and consisted solely of sarcoma.

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Fig. 13.130 Paraganglionic tissue in a retroperitoneal resection associated with small nerves. Fig. 13.132 Follicle-like spaces in an edematous spermatocytic tumor. Note the multinucleated tumor giant cell.

Fig. 13.131 Cut surface of spermatocytic tumor showing a multinodular, tan-yellow tumor with a central zone of hemorrhage. (Courtesy of RH Young, MD, Harvard Medical School, Boston, MA).

Teratoma, Prepubertal-Type Teratoma is the second (after yolk sac tumor) most common form of testicular germ cell tumor (14% to 18% of cases) in children according to some registry series, but is a higher proportion (48%) in the combined experience in four pediatric centers.510,771,772 In a recent single hospital series of pediatric testicular lesions, teratoma was more common than yolk sac tumor,

suggesting that the previous series finding that yolk sac tumor was more common may have been subject to referral bias.773 Prepubertal-type teratoma occurs mostly as a pure neoplasm, at a median age of 13 months, and is commonly found during routine physical examination or by a parent.771 Prepubertal-type teratoma in patients older than 4 years of age is unusual, but is now recognized to rarely occur in adult patients.29,771 The pathogenesis of prepubertal-type teratomas is fundamentally different from postpubertal-type teratomas, a supposition supported by the absence of GCNIS in prepubertal-type teratomas.76,78 These tumors do not develop from an invasive malignant germ cell (as is the case with postpubertal-type teratoma) but derive from a benign germ cell through an unknown mechanism. This viewpoint is supported by the normal karyotype of prepubertal-type teratomas, their benign outcome, differences in their patterns of genomic imprinting compared with postpubertal-type germ cell tumors, and absence of 12p amplification.29,79,80,82,656,774-776 Prepubertal-type teratomas have a different appearance than postpubertal-type teratomas. Those that are of dermoid type (see later), which are now considered a subtype of this group, may show the grossly evident hair and keratinous material commonly seen in the ovarian examples. The nondermoid prepubertal-type teratomas are not necessarily distinguishable from their postpubertal counterparts but frequently show cysts, keratinous material, a mucoid quality (Fig. 13.144), and no necrosis. They have a more organoid arrangement of elements that contrasts with the more frequently random arrangements of the postpubertal-type (Fig. 13.145). Ciliated respiratory-type epithelium is often prominent and invested

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Fig. 13.135 A rim of fibrin surrounds tumor cell nodules in some spermatocytic tumors. Fig. 13.133 Sheets of tumor cells are interrupted by edema, creating irregular spaces and cords in a spermatocytic tumor.

Fig. 13.134 Highly cellular tumor nodules in a spermatocytic tumor.

by thick bundles of smooth muscle and with associated seromucinous acini, thus resembling bronchus (Fig. 13.145). Other teratomatous elements, including cysts lined by squamous or intestinaltype epithelium, intestinal type mucosa with accompanying muscularis mucosa, gastric pyloric-type epithelium, thyroid, pancreas,

Fig. 13.136 Anastomosing tumor islands in a spermatocytic tumor.

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Fig. 13.137 Small clusters of spermatocytic tumor cells are separated by edematous stroma. Note the admixed lymphocytes, an unusual feature.

salivary gland, cartilage, smooth muscle, adipose tissue, and bone may also be seen.29,375,668-670,777-779 Prepubertal-type teratoma must be diagnosed with caution in adults because of its differing prognosis and treatment (versus postpubertal-type teratoma). Careful evaluation for GCNIS, absence of “dysgenetic” testicular changes (i.e., tubular atrophy, peritubular sclerosis, impaired spermatogenesis, microlithiasis), absence of cytologic atypia, and FISH evaluation for isochromosome 12p/12p amplification are important to exclude postpubertal-type teratoma.29,779 In contrast with postpubertal-type teratomas, immaturity may be germane in prepubertal-type teratomas. Although immaturity does not have prognostic significance in the postpubertal setting, it is much more commonly seen in this group and was therefore described with postpubertal-type teratomas. Prepubertal-type teratomas are almost invariably cured by orchiectomy, with only a single report of metastasis in a 6-month-old infant who had an 11-cm “immature” teratoma in an intraabdominal testis resected 3 months previously.780 Testissparing surgery has been used successfully for prepubertal boys with pure teratoma.781-783

Dermoid Cyst Dermoid cysts are considered a subset of prepubertal-type teratoma. They are cystic masses filled with friable, keratinous debris and hair. Analogous to the common ovarian counterpart, the wall of the cyst is composed of epidermis and dermis with hair

Neoplasms of the Testis

795

Fig. 13.138 Spermatocytic tumor with apoptotic cells.

follicles, sebaceous glands, and apocrine and eccrine sweat glands (Fig. 13.146), and a mural protuberance may also be present.668,784 Other teratomatous elements, similar to those of the nondermoid prepubertal-type teratomas, may also be seen.785,786 A helpful finding is a lipogranulomatous reaction in the adjacent parenchyma caused by leakage of sebaceous/keratinous cyst contents (Fig. 13.147). Patients ranged in age from 14 to 42 years in two series totaling fifteen cases.670 GCNIS is absent, as is 12p amplification.29,670 These tumors are benign, and testis-sparing surgery has been successful.670,787

Epidermoid Cyst This lesion is now classified as a subtype of prepubertal-type teratoma like dermoid cyst and the nondermoid prepubertal-type teratomas; it is not associated with GCNIS, and it is uniformly benign.78,672,673 It characteristically occurs in patients in the second to fourth decades of life.671,788 The ultrasonographic appearance may be characteristic, with most cases having an “onion ring”–like laminated appearance.788 Grossly, an epidermoid cyst usually is 2 to 3 cm in diameter, typically located at the periphery of the testis close to the tunica albuginea, and filled with white to yellow, friable, often pungent keratinous material (Fig. 13.148).789 Microscopically, there is a single cyst lined by squamous epithelium with a granular cell layer and a fibrous wall of variable thickness (Fig. 13.149). The lining is often compressed to just a few flattened layers of cells. Unlike dermoid cyst, there are no adnexal structures in the wall of the cyst. It is crucial to examine the surrounding testis for GCNIS, which is an indication of postpubertal-type teratoma. Epidermoid cysts lack

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Fig. 13.139 The characteristic polymorphous cell population of a spermatocytic tumor. Several cells have granular to filamentous chromatin.

isochomosome 12p and 12p overrepresentation, in contrast with postpubertal-type teratoma, so FISH studies may be helpful in problematic cases.790 The epidermoid cyst requires no additional therapy after orchiectomy.671,672 In cases in which testicular preservation is considered essential, it may be justifiable to locally excise the cyst and a rim of surrounding testis, with frozen section examination to determine the presence of GCNIS or other forms of germ cell tumor.778,791 Testis-sparing surgery has been used successfully in pediatric patients, and follow-up in conservatively managed patients has been uneventful, but it is important to sample enough of the testicular parenchyma to confidently exclude GCNIS.673,781,783,792

Well-Differentiated Neuroendocrine Tumor (Monodermal Teratoma) Well-differentiated neuroendocrine tumor, formerly termed carcinoid tumor, of the testis is considered a monodermal form of teratoma; and in support of this concept, 15% to 28% of testicular carcinoid tumors are associated with other teratomatous elements.793-796 These rare tumors constituted 0.17% of testicular tumors in the files at the Armed Forces Institute of Pathology.794 They have been said to occur more frequently than other germ cell tumors in older patients, with a median age of 45 to 50 years, with some cases in elderly men, although some occur in the typical age range of most germ cell tumors, and the mean age in a recent series of 29 cases was 36 years.793-798 Rare cases are in children.799 Most

patients present with a testicular mass; carcinoid syndrome is uncommon (occurring in 7% to 12% of cases) but correlates with increased metastatic potential.795,796 It is more common to identify serotonin in tissue or serum, or its metabolites in urine, than for clinical carcinoid syndrome to occur.795 AFP and hCG levels are normal (except for a single case associated with yolk sac tumor that had AFP elevation).796 If metastases occur (16% of cases), they are usually in a hematogenous distribution, affecting liver, lung, bone, soft tissue, heart, and skin.799 Grossly, testicular well-differentiated neuroendocrine tumors are solid, yellow to tan, and well-circumscribed, varying from 0.3 to 8 cm in diameter (Fig. 13.150).793,795,796 Associated cystic spaces may represent a teratomatous component; calcification occurs in about 10% of cases.795 Microscopically, a pattern of mid-gut carcinoid tumor is the usual finding, with solid nests and acini of cells in a fibrous to hyalinized stroma that tends to retract from the epithelium (Fig. 13.151). The cells have eosinophilic, granular cytoplasm and round nuclei with a punctate or “salt-and-pepper” chromatin pattern. Vascular invasion or extratesticular extension occur in about 20% of testicular carcinoids, but they do not correlate with clinical malignancy in most instances.795,798 Argyrophil and argentaffin stains are typically positive, and luminal mucin can be identified in some cases. Rarely a pure trabecular pattern or spindle cell pattern may occur.796,797 Serotonin, substance P, chromogranin, synaptophysin, neuron specific enolase, gastrin, vasoactive intestinal polypeptide, neurofilament protein, and cytokeratin have been identified in these tumors, and one would expect to find positivity for other substances typical of mid-gut type carcinoid tumors in many cases.795,800-803 Immunohistochemical stains for OCT3/4, CD30, c-kit, TTF-1, and CDX-2 are negative.804 Ultrastructurally, the tumor cells contain pleomorphic neurosecretory granules typical of mid-gut carcinoid tumor.793,795,800 Flow cytometry has demonstrated aneuploid or tetraploid DNA values and variable S-phase fractions.795,798 Despite the relationship of well-differentiated neuroendocrine tumor to teratoma, the cases we and others have seen have lacked GCNIS, including the 29 cases in a recent report, although there are contradictory reports suggesting the possibility of a dual genetic pathogenesis.796,802,804-807 Similarly there are conflicting data on the presence of isochromosome 12p, with some reports of absence and others of its presence.796,804 It is prognostically important to differentiate primary welldifferentiated neuroendocrine tumor from metastasis to the testis. The occurrence of other teratomatous elements in some testicular well-differentiated neuroendocrine tumors is an indication of their primary nature. The occurrence of bilateral involvement, multifocal tumor, vascular invasion, or extratesticular spread favor welldifferentiated neuroendocrine tumor metastatic to the testis rather than a primary testicular tumor. Primary well-differentiated neuroendocrine tumor is a low-grade malignancy; in their comprehensive review, Stroosma and Delaere found a metastatic rate of 16%; in a paper that postdates that of Stroosma and Delaere, Wang et al. identified malignant behavior in only 1 of the 23 cases with follow-up.796,799 Large size (average diameter of metastasizing tumors ¼ 7.3 cm versus average diameter of nonmetastasizing tumors ¼ 2.9 cm) and the carcinoid syndrome were the strongest predictors of metastasis in one study.795 Features of atypical carcinoid/grade 2 neuroendocrine tumor (2 mitoses/10 highpower fields and/or necrosis) may be the best indicator of malignant potential; Wang et al. in their review found no convincing evidence of metastasis from classic carcinoid tumor of the testis and argued that all metastatic cases were atypical carcinoids.796 Most cases are

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797

Fig. 13.140 (A) Intratubular spermatocytic tumor. (B) High magnification shows cells with variable nuclear size, including some large nuclei with granular to filamentous chromatin.

cured by orchiectomy. The course of patients with metastases is often indolent, and the utility of retroperitoneal lymph node dissection is unknown. Very rare tumors (other than well-differentiated neuroendocrine tumors; see the Teratoma, Prepubertal-Type section earlier in this chapter) have been considered monodermal teratomas. Monodermal teratomas such as well-differentiated neuroendocrine tumor (carcinoid tumor) are now considered to belong in the prepubertal-type teratoma category. However, identification of coexisting GCINS in a tumor composed of one tissue type is supportive of germ cell origin and potential for malignant behavior. Additionally, one published case of pure cartilaginous teratoma (with retroperitoneal metastasis) lacked morphologic evidence of GCNIS, but showed chromosome 12p overrepresentation by FISH.808

Mixed Teratoma and Yolk Sac Tumor, Prepubertal-Type Mixed teratoma and yolk sac tumor, prepubertal-type, is composed of a combination of prepubertal-type teratoma and yolk sac tumor and occurs about one-tenth as frequently as prepubertal-type yolk sac tumor.23 In one pediatric case, an apparently pure prepubertaltype teratoma was associated with an elevated AFP and recurred as a retroperitoneal metastasis composed of yolk sac tumor.809 Mixed teratoma and yolk sac tumor of prepubertal-type should be treated as would prepubertal-type yolk sac tumor.810 Mixed teratoma and yolk sac tumor of prepubertal type, lacking GCNIS and 12p overrepresentation, may also rarely occur in adulthood, as in two cases in the recently reported series of

Oosterhuis et al., one of which was primarily teratoma and one of which was primarily yolk sac tumor.30 Behavior was favorable without treatment other than orchiectomy.

Yolk Sac Tumor, Prepubertal-Type In registry series of prepubertal testicular tumors, yolk sac tumor is the most common neoplasm, accounting for 82% of testicular germ cell tumors and the majority of all testicular neoplasms.510 This dominance, however, is questioned as secondary to reporting bias because yolk sac tumors represented only 15% of the cases in the combined experience at four centers with testicular tumors in patients younger than 12 years of age.772 In a recent single-hospital study, yolk sac tumors were 20% of pediatric germ cell tumors.773 They occur in children from birth to 9 years of age, with a median age of 17 to 18 months.771,811,812 They are rare after 3.5 years of age.813 Unlike postpubertal-type yolk sac tumors, those of prepuberta type are usually pure without other germ cell tumor components; when another element is present, it is invariably teratoma. The usual epidemiologic associations of testicular germ cell tumor do not apply to prepubertal type yolk sac tumor. There is no association with cryptorchidism, and the predilection for whites more than other races is lacking.814 Additionally, unlike the postpubertal-type tumors, whose incidence steadily increased during the twentieth century, the pediatric germ cell tumors showed a stable rate. Children with yolk sac tumor almost always present with a painless testicular mass; clinical evidence of metastasis is rare at presentation, occurring in only 6% of cases.811,815

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TABLE 13.4

Spermatocytic Tumor

Seminoma

Mean age Proportion of germ cell tumors Sites

55 years 1%

40 years 40%-50%

Testis only

Associated with cryptorchidism Association with GCNIS Association with sarcoma Composition

No

Testis, ovary (dysgerminoma), mediastinum, pineal, RP Yes

No

Yes

Rare

No

Three cell types, with denser cytoplasm, round nuclei Common Scanty Rare to absent Virtually never Absent to scant Absent to scant Absent Absent Rare

One cell type, often clear cytoplasm, “boxy” nuclei Less common Prominent Prominent Often prominent Abundant Prominent Prominent Present in 10% Common

Intercellular edema Stroma Lymphoid reaction Granulomas Glycogen PLAP staining OCT3/4 staining hCG staining Metastases

Fig. 13.141 “Anaplastic” spermatocytic tumor. There is a predominance of intermediate-sized cells with prominent nucleoli.

In a series of pediatric testicular tumors, serum AFP differed significantly between yolk sac tumor patients (mean: 4600 ng/mL) and patients with teratoma (mean: 20 ng/mL).781 It is possible that rare yolk sac tumors of the pediatric type (type I, lacking GCNIS and excess i12p by in situ hybridization) may present in early adulthood.30 Grossly, prepubertal-type yolk sac tumor appears as solid, gray/ white to tan, relatively homogeneous nodules with myxoid or gelatinous cut surfaces (Fig. 13.152); cystic change may be present. The microscopic features are not distinguishable from the postpubertal form. The most common histologic pattern is reticularmicrocystic, but macrocystic, papillary, endodermal sinus (with Schiller-Duval bodies), myxomatous, labyrinthine, glandular, and solid patterns can also be seen.812 Immunohistochemical features are largely similar to those of yolk sac tumor, postpubertaltype, but yolk sac tumor, prepubertal-type stains less frequently for AFP than postpubertal-type.524 These cases lack i(12p) on karyotypic analysis, although very rare cases may have gains of 12p by FISH.79,81,727 About 30% of prepubertal-type yolk sac tumors are diploid, with peritetraploid values in the remainder, whereas postpubertal-type tumors are almost invariably nondiploid.61 Hypermethylation of the promoter of a probable tumor suppressor gene, RUNX3, and loss of heterozygosity at 1p36.1 are typical of prepubertal-type yolk sac tumor but not postpubertal-type.816 Juvenile granulosa cell tumor may mimic yolk sac tumor; both may be seen in very young children, but juvenile granulosa cell tumor usually (90% of cases) is seen in children younger than

Comparison of the Clinical and Pathologic Features of Spermatocytic Tumor and Typical Seminoma

GCNIS, Germ cell neoplasia in situ; hCG, human chorionic gonadotropin; PLAP, placental-like alkaline phosphatase; RP, retroperitoneum. Modified from Murphy WM. Urological Pathology. WB Saunders, Philadelphia, PA; 1989:314– 379; and Scully RE. Spermatocytic seminoma of the testis. A report of 3 cases and review of the literature. Cancer. 1961;14:788–794.

6 months of age, whereas yolk sac tumor tends to occur in older children, the peak being at 17 to 18 months of age.771,811,817,818 Histologically both tumors may show microcystic, macrocystic, and solid patterns, as well as high mitotic rates and cellular atypia. Follicles lined by multiple layers of tumor cells and a lobular arrangement are key to the recognition of juvenile granulosa cell tumor. The presence of other characteristic patterns is helpful in recognizing yolk sac tumor; intracellular AFP, glypican-3, PLAP, and nuclear SALL4 do not occur in juvenile granulosa cell tumor but are usually seen in pediatric yolk sac tumor.34,616 Positivity for inhibin-α and CD99 occur in juvenile granulosa cell tumor but not in yolk sac tumor.616 Serum AFP levels may be physiologically “elevated” in infants younger than 6 months of age, and should not be overinterpreted to support the diagnosis of yolk sac tumor rather than juvenile granulosa cell tumor.819 Eighty to 90% of prepubertal-type yolk sac tumors are pathologic stage I, and most with clinical stage I tumors (including postorchiectomy AFP levels) receive surveillance management rather than RPLND.811,815,820,821 Prepubertal-type yolk sac tumor has an increased frequency of hematogenous metastases to the lung (relative to postpubertal-type one), and the reported frequency of retroperitoneal involvement is 0% to 14% of cases, significantly less than the postpubertal-type tumor. RPLND is usually no longer thought to be indicated in children without persistent retroperitoneal disease after chemotherapy, persistently elevated AFP after

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chemotherapy without apparent tumor on imaging, or normal or unknown AFP level before chemotherapy (making AFP unreliable as a tumor marker).812,820,822 The prognosis of childhood yolk sac tumor is good, with a 5year survival of more than 90%.512,823 Differences in prognosis with respect to age in children are no longer identified, perhaps as a result of contemporary therapies.512,771,811 Presence of two or more risk factors (tumor size >4.5 cm, rete testis and/or epididymis invasion, and necrosis) in stage I cases has been associated

Fig. 13.142 A single layer of tumor cells in intratubular spermatocytic tumor, a mimic of GCNIS.

Fig. 13.144 Teratoma, prepubertal-type consists of a myxoid, lobulated, and variegated tumor with focal hemorrhage.

Fig. 13.143 A spermatocytic tumor (A) with a spindle cell sarcoma component (B).

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Fig. 13.145 Prepubertal-type teratoma with serous acini and ciliated epithelium with surrounding smooth muscle.

with poorer outcome, but in this study none of the 24 patients diagnosed after 1956 with follow-up died of yolk sac tumor.812

Sex Cord–Stromal Tumors Sex cord–stromal tumors make up only about 4% of testicular neoplasms.170,789 These include Leydig cell tumor, Sertoli cell tumor, granulosa cell tumor, and sex cord–stromal tumors of mixed and unclassified (indeterminate) types. Many authors also include within the sex cord–stromal tumor category those hyperplastic or hamartomatous lesions of the testis in patients with the adrenogenital syndrome, Nelson syndrome, and the AIS, which are derived from interstitial cells and Sertoli cells, although those occurring with the adrenogenital syndrome and Nelson syndrome are almost always hyperplasias induced by high levels of adrenocorticotrophic hormone. These lesions are discussed with the neoplasm that they most closely resemble: Leydig cell tumor (for the adrenogenital syndrome and Nelson syndrome) and Sertoli cell tumor (for the androgen insensitivity syndrome).

Leydig Cell Tumor Clinical Features Leydig cell tumor accounts for about 3% of testicular neoplasms.824 It has two age peaks, with about 20% of cases occurring in children (most commonly between 5 and 10 years of age and exceptionally rare in infants younger than 2 years of age) and 80% occurring in adults (most commonly between 20 and 60 years with an average of 47 years).824-829 Children usually present with significantly smaller tumors because of the early clinical detection

of androgen production manifest by isosexual pseudoprecocity, the presenting feature in virtually all pediatric cases.824 Such patients may not have palpable tumors, and testicular ultrasound or differential testicular vein sampling for androgens may be required for clinical diagnosis. About 10% of children have gynecomastia superimposed upon virilization.826 Adults, in whom neoplastic androgen production is much less evident than in children, most commonly present with a testicular mass, with about 30% of patients developing gynecomastia.824 Bilateral involvement occurs in about 3% of cases.824 Leydig cell tumors share some of the epidemiologic features of testicular germ cell tumors, occurring more commonly in patients with cryptorchidism, testicular atrophy, and infertility, but the predominant sparing of African Americans that occurs in the germ cell tumors (3% of cases) is absent in Leydig cell tumors (24% of cases).317,829 Familial occurrence is described, and Leydig cell tumors may be seen, along with hereditary leiomyomatosis and renal cell carcinoma, in association with germline fumarate hydratase mutations.830,831 Additionally, some of the Leydig cell tumors in children have been found to have acquired activating mutations in the luteinizing hormone receptor.832-834

Pathologic Features Most Leydig cell tumors appear as yellow, brown, or tan, solid, sometimes lobulated, intratesticular nodules, infrequently with areas of necrosis or hemorrhage (Fig. 13.153). The majority are 2 to 5 cm in diameter, but some exceed 10 cm; children more often have Leydig cell tumors less than 1 cm in diameter. Extratesticular extension occurs in about 10% of cases.824 A variety of light microscopic patterns may be seen; the solid, sheetlike pattern is most common (Figs. 13.154 and 13.155), but pseudoglandular

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Fig. 13.146 Dermoid cyst. Note the skinlike arrangement of adnexal structures and the additional glandular cyst (bottom).

(Fig. 13.156), cordlike (trabecular), and compact nested patterns may also be present, often in the same neoplasm. Rare tumors may have a microcystic pattern, potentially causing confusion with yolk sac tumor (Fig. 13.157), and also rare are cases in which the tumor cells are spindle-shaped, either focally or as the predominant pattern (Fig. 13.158).835,836 It is frequent for nodular aggregates of tumor cells to be separated by edematous or fibrous stroma (Fig. 13.159). The cells are polygonal, with abundant, eosinophilic cytoplasm, round, variably sized nuclei, and conspicuous, central nucleoli (Figs. 13.155 and 13.160). Finely granular lipofuscin pigment is present in the cytoplasm of some tumors from postpubertal patients (Fig. 13.160) (usually giving a tan to brown gross appearance), and careful search allows the identification of rod-shaped, intracytoplasmic crystals of Reinke in up to 40% of cases (Fig. 13.155).789 Eosinophilic cytoplasmic globules may correspond to precursors of these crystals (Fig. 13.161). Cytoplasmic accumulation of lipid imparts a clear, finely vacuolated appearance resembling the zona fasciculata of the adrenal cortex in some cases and, in rare tumors, the cells may have optically clear cytoplasm (Fig. 13.162). Infrequently, fat cells are seen as a component of Leydig cell tumors (Fig. 13.163) either deriving from lipid accumulation within tumor cells or from differentiation of stromal cells.836,837 Rarely, calcifications and ossification may be seen, apparently more frequently in tumors with fatty metaplasia.836,838,839 Mitotic figures are usually infrequent, and a rate of 3 or more per 10 high-power fields is a feature that suggests

Neoplasms of the Testis

801

Fig. 13.147 Lipogranulomatous reaction adjacent to a dermoid cyst.

Fig. 13.148 Epidermoid cyst containing friable, yellow-white keratinous material. Note the proximity to tunica albuginea.

malignancy (see later). The nuclei may have a ground-glass appearance (Fig. 13.164). Immunohistochemistry can assist with the diagnosis of Leydig cell tumor. Inhibin-α is positive in almost all Leydig cell tumors, as are stains for Melan-A (MART1) and calretinin.616,840-843 The steroidogenic factor 1 (SF1) immunohistochemical stain appears to be the most sensitive marker for sex cord–stromal tumors as a group.844 CD99 is detected in about two-thirds of cases.616 p53

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Fig. 13.149 Epidermoid cyst showing a thin, compressed layer of stratified squamous epithelium (right) lining a space filled with keratin. The surrounding seminiferous tubules show intact spermatogenesis with no evidence of GCNIS.

is detected in some malignant cases and may be helpful in recognizing malignant examples.845,846 Infrequently, Leydig cell tumors may stain for placental alkaline phosphatase.616 Vimentin is the dominant cytoplasmic intermediate filament, although cytokeratin reactivity may also be seen.847 One case with enkephalin immunoreactivity has been described.848 Ultrastructurally, Leydig cell tumors have features of steroid hormone–synthesizing cells, including abundant lipid droplets, prominent cisternae of smooth endoplasmic reticulum, and mitochondria with tubular cristae.849,850 Reinke crystals appear as sharply demarcated geometric shapes, such as hexagons, rectangles, and rhomboids, which have a lattice-like substructure.851 A specific activating mutation of the luteinizing hormone receptor gene (D578H) has been observed in Leydig cell tumors, but can also be present in Leydig cell hyperplasia.852

Treatment and Prognosis The frequency of malignant behavior in Leydig cell tumors has historically been described as approximately 10%, but it has been suggested that this may currently be an overestimate, perhaps because tumors now present at smaller size (40% less than 2 cm).829,853 This viewpoint is supported by a review of Leydig cell tumors from the Surveillance, Epidemiology, and End Results (SEER) program, which found a cancer-specific mortality of 6.6%.829 In the patients who ultimately died, the median survival was 12 months. Some

Fig. 13.150 Testicular well-differentiated neuroendocrine tumor (carcinoid tumor) with a solid, tan appearance. (Courtesy of RH Young, MD, Massachusetts General Hospital, Boston, MA).

clinical features correlate with the natural history of Leydig cell tumors, including that older patients are more likely to have malignant tumors, that malignant behavior has not been reported before puberty (although there is a reported case of a histologically malignant Leydig cell tumor in a 13-month-old without documented metastasis), and that gynecomastia is more common with benign cases.824,825,828,854,855 Malignant behavior also correlates with a number of pathologic features (Fig. 13.165), including: larger tumors (>5 cm), higher mitotic rates (>3 to 5 mitotic figures per 10 high-power fields), atypical mitotic figures, vascular space invasion, significant nuclear atypia, necrosis, infiltrative borders, invasion of the rete testis or beyond, DNA aneuploidy, high proliferative activity (>5%) as assessed by staining with the MIB-1 antibody, and increased expression of p53 protein by the tumor cells.824,845,846,856,857 In a study by Kim et al. that included as risk factors size 5 cm, infiltrative margins, lymphovascular invasion, necrosis, a mitotic index of >3 per 10 high-power fields, and grade 2 or 3 cytologic atypia, 5 of 5 clinically malignant cases had 4 criteria, whereas 12 of 14 clinically benign cases had none, 1 had one, and 1 had three.824 In a recent series of testicular sex cord–stromal tumors, 37 patients with either no (34 patients) or one (3 patients) high-risk factor underwent surveillance, and none recurred.858 Among patients in this series with RPLND performed for pathologic risk factors in the absence of radiographic evidence of retroperitoneal disease, only 1 of 6 had involvement in the RPLND specimen.858 None of the malignant/high-risk features, however, is pathognomonic of malignancy, and, indeed, malignant

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803

Fig. 13.151 (A) Insular, glandular, and trabecular patterns in testicular well-differentiated neuroendocrine tumor. (B) Note the punctate chromatin and cytoplasmic granules.

behavior has been found in 0.9% of cases of “testicular stromal tumors” (that included 70% Leydig cell tumors) where no risk factor was found.859 Orchiectomy is the standard treatment, but testis-sparing surgery has been employed in patients with bilateral tumors and has gained acceptance for single tumors in the pediatric group as well as being discussed in clinical stage I adult patients.36,860,861 Small (<2.5 cm) lesions with negative tumor markers have been treated

Fig. 13.152 Yolk sac tumor, prepubertal-type. Solid, tan-yellow, focally hemorrhagic nodule with a myxoid quality.

by testis-sparing surgery with favorable results.792,853,862-864 In a recent series of 31 testicular sex cord–stromal tumors (27 Leydig cell tumors and 4 Sertoli cell tumors) with a median size of 0.7 cm there were no metastases, although there was one local recurrence requiring orchiectomy, and in another series of 22 patients there were no local recurrences or metastases.863,865 Radiation and chemotherapy are not effective in the treatment of malignant Leydig cell tumor.865 Retroperitoneal lymphadenectomy may be curative in patients with clinical stage II disease.865 It may also be performed in clinical stage I tumors with malignant features/recurrence risk factors, but the role of this intervention remains unclear.865,866 Late metastases are infrequent but may develop more than a decade after orchiectomy.

Differential Diagnosis Several entities should be considered in the differential diagnosis of Leydig cell tumor.789 Leydig cell hyperplasia, although usually diffuse, may form nodules that mimic Leydig cell tumor. However, this is an interstitial, nondestructive process that preserves many seminiferous tubules.867 It may be seen in patients with elevated gonadotropin levels, including those with elevated hCG levels. Apparent Leydig cell hyperplasia occurs in many cases of testicular atrophy because of a normal population of Leydig cells in a reduced testicular volume. It is seen in Klinefelter syndrome where other pathologic features of that disorder are present and help with the diagnosis. Patients who have the adrenogenital syndrome or Nelson syndrome (Cushing syndrome associated with occult pituitary adenoma that becomes clinically evident with high levels of

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Fig. 13.153 Leydig cell tumor with a solid, yellow-tan cut surface.

Fig. 13.155 Prominent Reinke crystals in a Leydig cell tumor. Note the uniform nuclei with single, conspicuous nuclei.

Fig. 13.154 Sheets of eosinophilic cells in a Leydig cell tumor.

adrenocorticotrophin after bilateral adrenalectomy) may develop testicular nodules that closely resemble Leydig cell tumors.868872 These nodules appear to be hyperplastic and are usually distinguished from Leydig cell tumors by their multifocality, bilaterality,

uniform absence of Reinke crystals, frequent fibrous bands (Fig. 13.166), tendency for prominent lipofuscin deposits, and clinical history, although some patients present in the absence of known adrenogenital syndrome.789 An additional helpful feature is the occurrence of small basophilic cytoplasmic granules in the cytoplasm of some of the adrenogenital syndrome–associated nodules that are not a feature of Leydig cell tumor (Fig. 13.167). Although both may be reactive for synaptophysin, the testicular tumor of the adrenogenital syndrome (TTAGS) shows stronger, more widespread reactivity. The TTAGS also shows greater reactivity for CD56 than Leydig cell tumors, and is negative for androgen receptor, in contrast with Leydig cell tumors.870 Other markers of adrenal and testicular steroidogenesis have been evaluated, and a DLK1 +/INSL3– immunophenotype supports TTAGS, with the opposite pattern typical of Leydig cell tumors.871 TTAGS often regresses when treated with glucocorticoid to suppress adrenocorticotrophin levels. Clinical history is of value in such cases. It is hypothesized that the TTAGS derives from nodular steroid cell nests that are normally located near the testicular hilum (Fig. 13.168). These, by themselves, may cause some concern for Leydig cell tumor, but they are less than 3 mm in size, occur in the absence of a history of endocrine disorder, and often have a trabecular architecture and sinusoidal vasculature.873 Large cell calcifying Sertoli cell tumor, an entity that is associated with Carney complex, may resemble Leydig cell tumors because the neoplastic cells are usually polygonal with abundant eosinophilic cytoplasm.2,4,874,875 Unlike Leydig cell tumors, large cell calcifying Sertoli cell tumors may be bilateral and multifocal (when Carney

Fig. 13.156 Pseudoglandular pattern in a Leydig cell tumor.

Fig. 13.157 Microcystic change in a Leydig cell tumor. The more usual, solid pattern is also present.

Fig. 13.158 Leydig cell tumor with a vaguely fascicular arrangement of spindle cells.

Fig. 13.159 Nodular pattern in a Leydig cell tumor.

Fig. 13.162 Leydig cell tumor with clear cytoplasm. Fig. 13.160 Leydig cell tumor with intracytoplasmic lipofuscin. Note the eosinophilic cytoplasm and round nuclei with moderate-sized nucleoli.

Fig. 13.161 Leydig cell tumor with eosinophilic cytoplasmic globules.

Fig. 13.163 Leydig cell tumor with fatty metaplasia.

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Fig. 13.164 Leydig cell tumor with ground glass nuclei.

complex associated), lack Reinke crystals, are more consistently associated with calcifications (and sometimes ossification), may show intratubular growth, and tend to have a more myxoid stroma, often with a neutrophilic infiltrate.4,789 There is significant overlap in the immunostaining patterns of these two neoplasms, although it has been claimed that patchy (as opposed to diffuse) positivity for Melan-A and CD10, as well as reactivity for S100 protein-β, favor large cell calcifying Sertoli cell tumor.432,876 Young and Talerman reported metastatic prostate carcinoma to the testis mimicking Leydig cell tumor, but immunostains against prostate specific antigen and prostatic acid phosphatase were positive, resolving the differential diagnosis.789 Leydig cell tumor with prominent cytoplasmic clarity may be misinterpreted as seminoma, but the clarity is caused by lipids, often yielding a finely vacuolated appearance, rather than glycogen, as in seminoma, which causes a “water-clear” appearance. Additionally, there is no association with GCNIS, and the characteristic lymphoid infiltrate and granulomatous reaction of seminoma are absent. Malakoplakia may resemble Leydig cell tumor but has intratubular infiltrates of eosinophilic histiocytes and cytoplasmic calcifications (Michaelis-Gutmann bodies) that are not seen in Leydig cell tumors.

Sertoli Cell Tumor, Not Otherwise Specified Clinical Features Sertoli cell tumor, not otherwise specified (NOS) is infrequent but, in our experience, probably not as rare as the commonly cited 1% of testicular neoplasms for children and adults.877 A review of

Neoplasms of the Testis

807

Fig. 13.165 Malignant leydig cell tumor. There is cellular pleomorphism and an elevated mitotic rate.

SEER data found it was about 40% as frequent as Leydig cell tumor.829 Like Leydig cell tumors, it does not show the marked proclivity of the germ cell tumors to occur in white men.829 It can occur at virtually any age but is most common in middle age, with a median age of 39 years.829 Most patients present with a testicular mass, but estrogen production by the tumor can cause gynecomastia or impotence, which can be the presenting complaints.826,878 Isolated gynecomastia may be the initial manifestation of Sertoli cell tumor in a child; children with Leydig cell tumor, in contrast, do not develop gynecomastia without virilization.826 Patients with Peutz-Jeghers syndrome have been reported with testicular Sertoli cell tumor, but most of these appear to represent a different neoplastic process that is intratubular.3,6

Pathologic Features Grossly, Sertoli cell tumor typically is a solid, gray, white, tan, or yellow nodule, usually under 4 cm in diameter, although larger tumors may occur but should raise concern for malignancy (Fig. 13.169).879 Occasional tumors have cystic change. On microscopic examination, the hallmark is tubule formation.468 These may be either hollow or solid, usually in a fibrous (often hyalinized) to myxoid stroma (Fig. 13.170). Sheetlike arrays of tumor cells (Fig. 13.171), solid nests (Fig. 13.172), trabeculae, and cords may also occur but are not diagnostic alone. Rarely a retiform pattern may be seen (Fig. 13.173). A combination of solid, tubular, and nested patterns is not uncommon (Fig. 13.174). The tumor cells typically have scant to moderate amounts of pale to clear

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Fig. 13.166 Testicular tumor of the adrenogenital syndrome with nodules of hyperplastic Leydig cells that are characteristically multifocal, bilateral, lack Reinke crystals, and are segregated by fibrous bands.

cytoplasm (Fig. 13.172), but it may also be eosinophilic (Fig. 13.175). Prominent cytoplasmic vacuolization may create a microcystic pattern or signet ring-like appearance (Figs. 13.174 and 13.176), and some have considered tumors where this was a prominent feature a separate lesion, a viewpoint we disagree with.880,881 The nuclei are round to oval, relatively uniform, and usually lack large nucleoli. The cytoplasmic clarity is caused by abundant cellular lipid, which may be demonstrable on fresh tissue with special stains. Zones of fibrosis with sclerotic blood vessels and elastic fibers encrusted by calcium and hemosiderin deposits may be seen in some cases. One case of a Sertoli cell tumor with a heterologous sarcomatous component has been reported.882 The so-called “sclerosing Sertoli cell tumor” is now considered a morphologic variant of Sertoli cell tumor rather than a separate entity. It has been found in patients with an average age of 35 to 37 years and a range of 18 to 80 years, and has clinical features similar to the nonsclerotic cases.883,884 The gross features only differ by a firmer consistency, reflected by a stromal predominance. Because the hypocellular stroma comprises at least 50% of the lesion, the tumor cells are often compressed to cords or trabeculae, although small nests and tubules also may be seen (Fig. 13.177).884 Mitotic activity and cytologic atypia are infrequent.883 Frequent CTNNB1 gene mutations and nuclear positivity for β-catenin are typical of sclerosing Sertoli cell tumors, as they are of Sertoli cell tumors, NOS.883-889 On immunohistochemical study, 30% to 90% of Sertoli cell tumors are inhibin-α reactive, 60% to 80% are positive for cytokeratin, 90% to 100% are positive for vimentin, 30% to 64% are positive for S100, 0% to 82% are positive for chromogranin,

45% are reactive for synaptophysin, and they are usually negative for EMA, although in our experience with malignant examples, EMA reactivity occurred in most.469,616,840,890-892 About one-half of Sertoli cell tumors, NOS, in our experience, stain for calretinin, although such positivity may be quite focal. NSE positivity has been described in several cases, and very focal reactivity for antim€ ullerian hormone has been reported.879,893 Newer immunohistochemical markers such as SF1, SOX9, and FOXL2 appear to be more sensitive than inhibin and calretinin, but are not especially useful in the distinction from other sex cord–stromal tumors.844 Nuclear β-catenin immunoreactivity is seen in 64% of Sertoli cell tumors, NOS and correlate with mutation in the CTNNB1 gene.885,894 Only membranous and cytoplasmic β-catenin staining is seen in other sex cord–stromal tumors such as Leydig cell tumors, large cell calcifying Sertoli cell tumors, adult and juvenile granulosa cell tumors, and sex cord–stromal tumors, unclassified.894 Features of steroid synthesizing cells are identified ultrastructurally, including abundant cisternae of smooth endoplasmic reticulum and numerous intracytoplasmic lipid droplets. Adjacent cells are connected by desmosomes.895 Charcot-B€ottcher filaments (perinuclear arrays of filaments) are considered pathognomonic of Sertoli cell differentiation. They have been identified in ovarian Sertoli cell tumor and in large cell calcifying Sertoli cell tumor, but most reports of testicular Sertoli cell tumor, NOS have not mentioned their presence.875,896-898 A higher proportion of Sertoli cell tumors are clinically malignant as compared with Leydig cell tumors. Although about 10% of Sertoli cell tumors were considered malignant in some studies, review of the SEER database for 2004 to 2012 showed that

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Fig. 13.167 Testicular tumor of the adrenogenital syndrome may also have small basophilic cytoplasmic granules in some cells, a feature not seen in Leydig cell tumors.

35% of cases presented with advanced-stage disease.829 In contrast with Leydig cell tumor, malignant cases may occur in children.164,469,878,879,899 Gynecomastia appears to be more common in malignant tumors than in benign ones.879 As in Leydig cell tumors, malignant behavior in Sertoli cell tumors, NOS may be difficult to predict from pathologic features alone. Features that correlate with an increased likelihood of malignancy include: size of 5 cm or more, significant cytologic atypia and pleomorphism, invasive borders, mitotic activity in excess of 5 mitotic figures per 10 high-power fields, vascular invasion, and necrosis (Fig. 13.178).879,900-902 In the study by Young et al., which did not include invasive borders as a criterion, the malignant cases had at least two of these features.468 MIB1 proliferation index greater than 30% correlates with malignant behavior, and we noted malignant behavior in a group of Sertoli cell tumors with a predominance of a diffuse growth pattern.469,891 The sclerosing variant appears to have a better overall prognosis, with only 1 of 31 reported cases having a malignant course, and this tumor had both an invasive growth pattern and lymphovascular involvement.884,903

Differential Diagnosis Sertoli cell tumor must be distinguished from the rare seminoma with a tubular pattern, a differential diagnosis discussed in the Seminoma section earlier in this chapter.380 Patients with the

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809

Fig. 13.168 Nodular steroid cell nest near the testicular hilum. These nests are less than 3 mm in size and typically have a trabecular and sinusoidal architecture; they are hypothesized to be the source of the adrenogenital syndrome “tumors.”

Fig. 13.169 Sertoli cell tumor with a gray-white cut surface.

AIS (also known as the testicular feminization syndrome) may develop multiple hamartomatous testicular nodules composed of closely spaced tubules lined by Sertoli cells, but, in contrast with true Sertoli cell tumors, these lesions also have intervening Leydig cells within the interstitium (Fig. 13.179).253,262 About 25% of patients with AIS also develop multifocal, bilateral Sertoli cell adenomas composed of pure proliferations of Sertoli cell–lined tubules (Fig. 13.180).262 These lesions may be indistinguishable from well-differentiated Sertoli cell tumors, and it is uncertain if they are neoplastic or hamartomatous. Some have a prominent component of globular basement membrane deposits. Malignant

Fig. 13.170 Sertoli cell tumor composed of mostly solid tubules.

Fig. 13.172 Solid nests and focal tubules in a Sertoli cell tumor.

Fig. 13.171 Sertoli cell tumor showing both tubular/trabecular and diffuse patterns.

Fig. 13.173 Retiform pattern in a sertoli celltumor.

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Neoplasms of the Testis

811

In patients with germ cell tumors, they may be colonized by GCNIS, simulating gonadoblastoma (Fig. 13.184). Sertoli cell tumors may show large areas of sheetlike arrangement and, furthermore, have an associated lymphocytic infiltrate and prominence of clear or pale cytoplasm (Fig. 13.185). These features mimic seminoma and can be a source of serious diagnostic error.469 Features of assistance include, in Sertoli cell tumor, the absence of GCNIS, foci with typical tubules, less-atypical-appearing nuclei, and lower mitotic rates. Immunohistochemistry is helpful as well, with OCT3/4, SALL4, and PLAP being negative in Sertoli cell tumors and positive in seminomas.469 The distinction of a Sertoli cell tumor from a Leydig cell tumor depends on the formation of tubules, at least focally, in the former. Additionally, the eosinophilic cytoplasm of most Leydig cell tumors contrasts with the less conspicuous and lighter-staining cytoplasm of most Sertoli cell tumors, although exceptions may be seen. Leydig cell tumors may show Reinke crystalloids, unlike Sertoli cell tumors. Inhibin-α is less consistently expressed in Sertoli cell tumors than in Leydig cell tumors, being positive in 30% to 80% of Sertoli cell tumors but in virtually all Leydig cell tumors.616,891 CD99 is also more commonly expressed in Leydig cell tumors than in Sertoli cell tumors.616 About two-thirds of Sertoli cell tumors express nuclear β-catenin, but not Leydig cell tumors.894

Fig. 13.174 Sertoli cell tumor with multiple patterns including tubular, signet ring cells, and solid/diffuse.

behavior in pure Sertoli cell proliferations in patients with AIS have not been reported; thus the term Sertoli cell adenoma is appropriate even though it connotes a neoplastic process.253,262 A unique case of a malignant sex cord–stromal tumor in a patient with AIS did not have the features of a typical Sertoli cell adenoma and more closely resembled juvenile granulosa cell tumor, although ultrastructure supported Sertoli cell differentiation.904 The cordlike pattern of the sclerosing variant may be misinterpreted as trabecular carcinoid tumor, but most primary welldifferentiated neuroendocrine tumors have an insular pattern, and they may be associated with teratomatous elements. The presence of a cordlike or tubular pattern with vacuolated cells may also suggest an adenomatoid tumor, but the primarily paratesticular location of adenomatoid tumors and immunohistochemical negativity for inhibin and strong reactivity for EMA and mesothelial markers are helpful differential features. Mostly microscopic, nonencapsulated nodules composed of small tubules lined by immature-appearing Sertoli cells are common incidental findings in orchiectomy specimens, and may be more common in cryptorchid testes (Fig. 13.181).202,203,905 Rarely, they are sufficiently large to be clinically detectable (Fig. 13.182).906 These “Sertoli cell nodules” often contain central accumulations of basement membrane that can be seen in continuity with thickened peripheral basement membrane surrounding the tubules. In contrast with true Sertoli cell tumors, these are almost always incidental microscopic findings, although rarely they may be up to 1 cm or more, and sometimes have admixed spermatogonia (Fig. 13.183), unlike Sertoli cell tumors, NOS.905-907

Treatment and Prognosis Standard treatment for primary tumors is orchiectomy (and is, of course, required for diagnosis in most cases), but for small (less than 2 cm) lesions, testis-sparing surgery has been used with favorable results.862,865 Metastatic Sertoli cell tumors do not usually respond to radiation and chemotherapy. Retroperitoneal lymphadenectomy therefore remains an important option if the tumor has not disseminated beyond the scope of the dissection.

Large Cell Calcifying Sertoli Cell Tumor Large cell calcifying Sertoli cell tumor is a variant that has some unique clinical associations.7,908-910 Some are a component of the Carney complex characterized by lentigines of the face; myxomas of the heart, skin, soft tissue, and elsewhere; myxoid fibroadenomas of the breast; blue nevi of the skin; pigmented nodules of the adrenal cortex associated with Cushing syndrome; growth hormone–producing adenomas of the pituitary gland; and psammomatous melanotic schwannomas.2,7,875,911-914 Many of these patients have a germline mutation in the PRKAR1A gene on the long arm of chromosome 17. Some sporadic tumors may have acquired PRKAR1A mutations.915 About 40% of large cell calcifying Sertoli cell tumors are associated with the Carney complex, so its diagnosis should prompt consideration of this association because of the potential life-threatening complications of cardiac myxomas and, rarely, adrenocortical carcinoma.916 Typically the patients with Carney complex are found in childhood or adolescence with small, bilateral, and multifocal testicular tumors, whereas those with sporadic tumors have solitary lesions and are older.4,889 A testicular mass is the usual presenting complaint, but gynecomastia and isosexual pseudoprecocity may also occur, especially in those cases that are syndrome associated.897,917 The hormones responsible for these manifestations may be produced by the neoplasm or by associated nodules of hyperplastic Leydig cells. Grossly, large cell calcifying Sertoli cell tumor is usually tan or yellow with associated “gritty” calcification and may be multifocal, with a 40% frequency of bilaterality.874,911 Microscopically,

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Fig. 13.175 Metastasizing Sertoli cell tumor showing (A) foci of necrosis (bottom right) and (B) cytologic atypia and mitotic figures.

there are nests and cords of cells with abundant, eosinophilic cytoplasm in a myxoid to collagenous stroma that is calcified or even ossified in about one-half of cases (Fig. 13.186). A neutrophilic stromal infiltrate is characteristic. Intratubular neoplasm and calcifications are common. Nuclei are usually round and may have prominent nucleoli, but mitotic figures are typically rare. Malignant cases do occur but are uncommon.4,874,918 They usually develop on a sporadic basis in patients older than 25 years of age rather than in association with Carney complex; hence malignant tumors are solitary and can mostly be recognized as having metastatic potential on the basis of size greater than 4 cm, extratesticular growth, tumor cell necrosis, high-grade atypia, vascular space invasion, or mitotic rate in excess of 3 mitotic figures per 10 high-power fields.4,889,918 Malignant cases typically exhibit at least two of these features, and benign tumors typically lack all of them.4 Immunohistochemical study has shown vimentin, inhibin, calretinin, SF1, S100, NSE, desmin, EMA, and focal cytokeratin reactivity.4,841,844,909,919,920 Ultrastructural studies have demonstrated Charcot-B€ottcher filaments and other features of Sertoli cells.875,897 The main differential diagnostic problem posed by a large cell calcifying Sertoli cell tumor is separation from a Leydig cell tumor, which was previously discussed.

Intratubular Large Cell Hyalinizing Sertoli Cell Neoplasia Fig. 13.176 Sertoli cell tumor with prominent cytoplasmic vacuolization creating a signet ring-like appearance.

Patients with the Peutz-Jeghers syndrome develop multifocal, bilateral intratubular proliferations of Sertoli cells having abundant

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Fig. 13.177 “Sclerosing Sertoli cell tumor,” now considered a morphologic variant of Sertoli cell tumor, not otherwise specified, with cordlike growth and densely collagenous stroma.

eosinophilic cytoplasm, similar to those seen in the large cell calcifying Sertoli cell tumor.5,6,921 Descriptively termed large cell hyalinizing Sertoli cell neoplasia, these intratubular lesions occur in conjunction with thickened, peritubular basement membrane that is internalized into the expanded tubules and infrequently calcified (Fig. 13.187).6 These expanded tubules occur in lobular clusters throughout the parenchyma. Most of the patients present in childhood with gynecomastia, which is the result of tumor-produced aromatase converting endogenous androgens to estrogens. Occasional invasive tumors are seen in association with the intratubular tumor, and these may be very similar in appearance to the large cell calcifying Sertoli cell tumor, but they more commonly do not have calcifications or the prominent fibromyxoid stroma with neutrophils.6 Patients may have a mutation of the STK11 gene on the short arm of chromosome 19, different from the mutation associated with the large cell calcifying Sertoli cell tumor. Conservative management of patients with aromatase inhibitors who have no evidence of an invasive tumor (the majority) by ultrasonographic follow-up permits testicular preservation in many patients, although the development of a distinct mass or hormonal complications may necessitate orchiectomy. Malignant behavior has not been reported.5,6 The differential diagnosis includes the large cell calcifying Sertoli cell tumor, which, in contrast with the Peutz-Jeghers lesion, is dominated by invasive tumor. Furthermore, the intratubular component in these cases does not show as great a degree of tubular expansion or as prominent basement membrane deposits and often

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813

Fig. 13.178 Sertoli cell tumor, not otherwise specified, with focus of necrosis.

displays conspicuous calcifications. Despite these differences in morphology and genetics, and abundant literature has considered the Peutz-Jeghers tumors to be large cell calcifying Sertoli cell tumors, a viewpoint we disagree with. Sertoli cell nodules may also be confused with the Peutz-Jeghers lesion because of their clustered seminiferous tubules with basement membrane deposits, but they have small fetal-type Sertoli cells and may contain spermatogonia.

Granulosa Cell Tumor Adult Granulosa Cell Tumor There are two major types of granulosa cell tumor of the testis: adult and juvenile. The adult type is rare, occurring in patients from 14 to 87 years of age.789,922-929 These tumors have been associated with hyperestrogenism, and were described as often causing gynecomastia in previous reports.926 However, a recent large series reported endocrine symptoms in none of 32 patients, so this appears to be an uncommon presentation.929 Grossly, the tumor may be solid, cystic, or both, and is typically yellow to gray.789,924,929 Gross hemorrhage and necrosis may correlate with malignant behavior.927 Microscopically, the patterns of the more common granulosa cell tumor of the ovary may be identified, including microfollicular, macrofollicular, trabecular, gyriform, insular, and diffuse (Fig. 13.188). Call-Exner bodies are characteristic of the microfollicular pattern. The cells have scant, lightly staining cytoplasm, and the nuclei are pale, angulated to oval, and frequently grooved. Mitotic figures are usually infrequent but there may rarely be up to 6 to 18 per 10 high-power

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Fig. 13.179 Nodule of seminiferous tubules lined by small, immatureappearing Sertoli cells with intertubular Leydig cells in a patient with the androgen insensitivity syndrome. Such lesions are considered hamartomas.

fields.927,929 Positivity for inhibin, calretinin, vimentin, cytokeratins 8 and 18, smooth muscle actin, S100, and CD99 has been reported, although one study reported an absence of cytokeratin reactivity in five of five cases.922,925,927-931 EMA is negative.922,925,927,930 FOXL2 and SF1 immunohistochemical stains are consistently positive but not specific, as staining is also seen in other sex cord–stromal tumors.844 Ultrastructural studies have shown results similar to ovarian granulosa cell tumor.923,925 FOXL2 (forkhead box L2) 402C! G mutation, consistently seen in ovarian adult granulosa cell tumors, is seen in a minority of testicular adult granulosa cell tumors.932 Most reported cases have been benign, but malignant behavior is a possibility.926,927 A recent series with review of previous studies estimates a metastatic frequency of 16%.929 Large tumor size (>7 cm), vascular invasion, hemorrhage, and necrosis have been considered useful in identifying cases with the greatest risk for malignant behavior, but a recent literature review found only tumor size (>5 cm) to be statistically associated with malignancy.927,933

Juvenile Granulosa Cell Tumor Juvenile granulosa cell tumor of the testis is similar in appearance to its ovarian counterpart but occurs in a more restricted age range, with most patients younger than 5 months of age.817,818,934-938 There are a few cases of this tumor presenting later in childhood in 4- to 10-year-old boys and a single report in a 27-year-old man.818,939,940 There are no well-established risk factors, although

Fig. 13.180 Sertoli cell adenoma in a patient with the androgen insensitivity syndrome. There is a circumscribed proliferation of closely packed tubules lined by immature Sertoli cells. Basement membrane deposits are prominent.

a disproportionate number occur in patients with either gonadal dysgenesis or anomalies of sex chromosomes, including patients with X/XY mosaicism.255,818,941,942 A testicular mass is invariably the presenting feature. Grossly, it consists of a solid to cystic, gray to yellow nodule (Fig. 13.189).817 The cystic foci are filled with mucoid to watery fluid. Microscopically, juvenile granulosa cell tumor has solid, cellular zones admixed with follicle-like, cystic structures filled with watery, eosinophilic to basophilic, faintly mucicarminophilic fluid (Fig. 13.190). Often the follicles are lined by several layers of stratified tumor cells and surrounded by a spindle cell stroma (Fig. 13.190A). The “solid” areas may display small inconspicuous (Fig. 13.190B) to absent follicles (Fig. 13.191), although even in the latter there typically is seen a lobular arrangement (either follicular or solid), with an intervening hypocellular fibromuscular stroma (Figs. 13.190 and 13.191). Columnar cells lining spaces create gland-like structures in about one-fourth of the cases.818 Many neoplastic cells have abundant pale to eosinophilic cytoplasm with round, hyperchromatic nuclei and identifiable nucleoli (Fig. 13.190B).789,817 Mitoses and cellular apoptosis may be prominent (Fig. 13.190B), but malignant behavior has not been reported, another feature that differs from ovarian juvenile granulosa cell tumor.817,892,943,944 A recent large series described intratubular growth in 43% of cases.818 Immunohistochemical studies reveal inhibin, vimentin, CD99, and focal cytokeratin, smooth muscle actin, and desmin reactivity.892,937,943,945 FOXL2 and SF1 are the most sensitive markers and are consistently

CHAPTER 13

Fig. 13.181 Sertoli cell nodule in a cryptorchid testis. The tubules are smaller than the surrounding seminiferous tubules, are lined only by fetal-type Sertoli cells, and have focal central accumulations of basement membrane.

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815

Fig. 13.183 Sertoli cell nodule with admixed spermatogonia.

expression, which is not seen in the normal testis but is characteristic of granulosa cell differentiation, even if not specific.844,946 Because of the exclusive occurrence in infants and young children; the solid, cystic, and reticular patterns; and (physiologically) elevated serum AFP in some cases, juvenile granulosa cell tumor may be confused with testicular yolk sac tumor.818 (This differential diagnosis was discussed previously.) Behavior has been uniformly benign.818 Testis-sparing enucleation has been suggested for suspected juvenile granulosa cell tumors in infants with serum AFP in the normal range for age.938,944

Tumors in the Fibroma-Thecoma Group

Fig. 13.182 Macroscopic sertoli cell nodule.

expressed.818 AFP and SALL4 are negative. The histogenesis of this tumor is unknown; intratubular growth may indicate Sertoli cell derivation that exhibits aberrant differentiation based on FOXL2

Testicular tumors resembling ovarian fibroma or thecoma are rare; some reported examples likely represent unclassified sex cord–stromal tumors with a predominance of spindle cells. Cases have been reported in men over a wide age range (16 to 69 years) with a mean age of 44 years.947 Patients present with palpable masses.947,948 They are circumscribed, solid, yellow-white to tan tumors that lack necrosis. On microscopic examination, there is moderate to dense cellularity and short fascicles or storiform arrangements of uniform spindle to ovoid cells (Fig. 13.192). Acellular, hyaline plaques of collagen may be seen (Fig. 13.192), as well as prominent interstitial deposits of collagen. Mitotic activity is usually less than 5 mitotic figures per 10 high-power fields, but may be up to 10 per 10 highpower fields without known adverse prognosis.947 Inhibin, calretinin, vimentin, actin, desmin, SF1, FOXL2, and SOX9 are frequently positive on immunohistochemical study.844,947,948 Behavior is benign.947

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Fig. 13.184 Sertoli cell nodule partially populated by GCNIS cells. Fig. 13.185 This malignant Sertoli cell tumor has a sheetlike pattern of pale cells and a prominent inflammatory reaction that mimic seminoma.

Myoid Gonadal Stromal Tumor Some of the purely spindled unclassified “sex cord–stromal tumors” represent myoid gonadal stromal tumors that express both S100 protein and smooth muscle markers similar to the peritubular myoid cells.949-952 Because they lack a sex cord component, they should be considered a pure gonadal stromal neoplasm. These very rare tumors are composed of fascicles of fusiform to elongated spindled cells (Fig. 13.193), occur at a mean age of 37 years, and are not associated with hormonal symptoms.952 In addition to S100 and SMA expression that is required for diagnosis, SF1 and FOXL2 expression is typical and focal inhibin staining is common.844 Behavior has been benign in the small number of reported cases.952 Tumors may also have a combination of spindled and sex cord components with S100 and smooth muscle actin expression in the spindled component, and CD99 and inhibin reactivity occurring in the sex cord component, but these tumors should be placed in the unclassified sex cord–stromal tumor category.952-955 In other cases, the presence of myofilaments in spindled stromal tumors suggests origin from myofibroblastic cells of the testicular interstitium.950,951,956 Such cases should probably be classified as pure mesenchymal tumors rather than unclassified sex cord–stromal tumors.

Mixed and Unclassified Sex Cord–Stromal Tumors A sizable group of sex cord–stromal neoplasms of the testis show admixtures of various forms of differentiation or incomplete

differentiation. Such cases are classified as mixed or unclassified sex cord–stromal tumors, respectively. An example of a mixed sex cord–stromal tumor is adult granulosa cell tumor with tubules lined by Sertoli cells. Unclassified sex cord–stromal tumors consist of proliferations of incompletely differentiated sex cord or stromal elements that cannot be further characterized at the light microscopic level. These neoplasms are heterogeneous and have been grouped into a “wastebasket” category. Mixed and unclassified sex cord–stromal tumors occur at all ages, with 50% of cases occurring in children.957 They usually present as a testicular mass, and 15% of cases are associated with gynecomastia.789 Most consist of gray, tan, or yellow solid nodules of variable size. Both epithelial (sex cord) and stromal differentiation may be apparent at the light microscopic level (Fig. 13.194), and reticulum stains may enhance the different elements, surrounding groups of sex cord–like cells and individual stromal cells. In some tumors, sex cord elements of nonspecific type may compose most or the entire tumor. In other cases, the stromal component may be dominant, consisting of a relatively pure spindle cell proliferation.953,955,958 Many of those cases are small (1 to 2 cm), occur close to the rete testis, and have benign features.954 Occasional cases are overtly sarcomatoid, sometimes having “heterologous” mesenchymal differentiation.959 Inhibin is often scant in the stromal cells and more impressive in the sex cord cells. SF1 and FOXL2 are more consistently expressed.844 The demonstration of epithelial features by electron microscopy and immunohistochemistry suggests that some of these “stromal” tumors are spindled forms of epithelial (sex cord) origin.955,960

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Fig. 13.186 Large cell calcifying sertoli cell tumor. Note the focal calcification and neutrophilic infiltrate.

Mixed and unclassified sex cord–stromal tumors have thus far behaved in a benign fashion in children younger than 10 years of age, but metastases develop in 20% of older patients.943,957,961 The presence of cellular atypia and pleomorphism, a high mitotic rate, necrosis, vascular invasion, invasive margins, and large tumor size are features that identify patients at risk for metastases. These tumors are usually managed by radical orchiectomy, with retroperitoneal lymph node dissection reserved for patients with clinical evidence of metastatic involvement or “high-risk” pathologic features.

Tumors Containing Both Germ Cell and Sex Cord–Stromal Elements Gonadoblastoma Clinical Features Gonadal pathology in individuals with disorders of sex development has been recently reviewed.962 Gonadal dysgenesis, a disorder of sex development resulting from a mutation or deletion of a gene upstream from SOX9 (a transcription factor essential in Sertoli cell development) in the presence of a Y chromosome (or that portion of the Y chromosome including the TSPY locus), is associated with a distinctive tumor known as gonadoblastoma.962 Gonadoblastoma is composed of a mixture of seminoma-like cells, immature germ cells, spermatogonia-like cells, and sex cord cells having some features of both granulosa cells (with strong nuclear FOXL2 nuclear reactivity) and Sertoli cells (with weaker SOX9 reactivity

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Fig. 13.187 Cluster of expanded seminiferous tubules containing proliferations of large Sertoli cells with abundant, eosinophilic cytoplasm and prominent basement membrane deposits in a patient with Peutz-Jeghers syndrome.

and Charcot-B€ottcher filaments in the cytoplasm).963-966 Among patients with gonadoblastoma, 80% are phenotypically female and 20% are phenotypically male, but ambiguous genitalia occur in many cases.967 Phenotypically male patients present in childhood or early adolescence with cryptorchidism, hypospadias, or other anomalies of the external genitalia and gynecomastia. Surgical exploration of the cryptorchid testes often demonstrates persistence of female-type internal genital structures stemming from failure of involution of the m€ ullerian ductal system.265 Bilateral involvement by gonadoblastoma occurs in about one-third of cases.967 Karyotypic analysis of the patients, regardless of sexual phenotype, almost always reveals a Y-chromosome, with 46,XY and 45,X/46,XY occurring most commonly.265 In patients with 45,X or 46,XX peripheral karyotypes, it is most likely that there is mosaicism with the gonads harboring nondeleted Y-chromosomal material. In children with 45,X/46,XY mosaicism, germ cell tumor risk varies by observed external masculinization, with highest risk among those with ambiguous phenotype, intermediate risk among boys with mild undervirilization, and lowest risk among girls with female (Turner syndrome) phenotype.968

Pathologic Features Grossly, gonadoblastoma usually forms solid, yellow and tan nodules with gritty calcifications (Fig. 13.195). Microscopically, the nodules usually consist of well-defined, rounded nests of large, pale

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quite prominent, sometimes assuming a “mulberry-like” profile. In the stroma adjacent to gonadoblastoma, collections of Leydiglike cells lacking Reinke crystals may be seen in about two-thirds of cases.253,967 In many classic gonadoblastomas, a trabecular growth pattern of seminoma-like cells and frequently inconspicuous sex cord cells may occur in tandem (Fig. 13.197). This pattern, which has been termed dissecting gondadoblastoma of Scully because of Dr. R.E. Scully’s use of this nomenclature, appears to represent the same variation in gonadoblastoma morphologically as “undifferentiated gonadal tissue.”969 Biopsies of such tissue, however, may be difficult to recognize because the germ cells and sex cord cells are frequently relatively inconspicuous within a dominant nonneoplastic stroma. If the sex cord component is overlooked, it may be misinterpreted as a corded pattern of germinoma. An additional “dissecting” variant that mimics germinoma is represented by “expansile” confluent nests of gonadoblastoma that, however, retain the germ cell heterogeneity, sex cord cells, and basement membrane deposits (Fig. 13.198).

Fig. 13.188 Testicular granulosa cell tumor of the adult type showing a mostly diffuse pattern with occasional Call-Exner bodies.

Special Studies Many of the germ cells of gonadoblastoma have the immunohistochemical reactivities seen in GCNIS.295 Some appear to be germ cells with delayed maturation that also express fetal-type germ cell markers.286 The sex cord component stains for inhibin and the Wilms tumor gene protein (WT1).970 The morphologically ambiguous sex cord cells of gonadoblastoma coexpress SOX9 (a transcription factor involved in Sertoli cell development) and, more strongly, FOXL2 (a transcription involved in granulosa cell tumor development), supporting that the cells are incompletely differentiated.966 FISH in patients with gonadoblastoma and 45,X/46,XY mosaicism has demonstrated disproportionate representation of the Y chromosome in the gonadoblastoma cells, implicating it in tumor genesis.971 Mapping studies have defined a susceptibility region on the Y chromosome that encompasses five candidate genes.972–974 Accumulation of OCT3/4-positive germ cells and loss of expression of testis-specific protein on the Y chromosome (TSPY) has been observed by immunohistochemistry in the progression from gonadoblastoma to invasive germ cell tumor.975 Treatment and Prognosis Gonadoblastoma is a premalignant lesion from which invasive germ cell tumors can develop; most are seminomas, but any nonseminomatous germ cell tumor may occur.967 Excision of a gonad with gonadoblastoma before development of an invasive lesion is curative. Bilateral gonadectomy is indicated because of the dysgenetic nature of the gonads and the high frequency of bilaterality of gonadoblastoma.

Fig. 13.189 Juvenile granulosa cell tumor has a solid and cystic, yellow to tan cut surface. (Courtesy of Carlos Galliani, MD, Fort Worth, TX).

seminoma-like cells admixed with small, dark, angular, sex cord cells that may form a peripheral palisade around the cellular nests (Fig. 13.196). Close inspection also discloses that some of the germ cells lack a seminoma-like morphology and appear more like spermatogonia or primitive gonocytes, in keeping with molecular data.286,295 Foci of hyalinized basement membrane can be seen in the center of these nests and at the periphery. Calcifications appear initially on this basement membrane, and may become

Differential Diagnosis Sertoli cell nodules colonized by GCNIS may be misinterpreted as gonadoblastoma (Fig. 13.184). However, this lesion is mostly microscopic rather than macroscopic, and the associated gonad is not dysgenetic, nor does the patient have somatosexual ambiguity. In some cases, the colonization by GCNIS is focal, and the seminoma-like cells are not uniformly distributed throughout the Sertoli cell nodule, whereas gonadoblastoma contains seminoma-like cells that are an integral and diffusely distributed component. Additionally, the constituent cells of these lesions contain both X and Y chromosomes by FISH, unlike gonadoblastoma.976 This distinction is important because the diagnosis of gonadoblastoma implies an underlying dysgenetic gonad and much higher risk for bilateral

Fig. 13.190 Juvenile granulosa cell tumor with (A) follicle-like structures lined by multiple layers of tumor cells and containing watery to mucoid secretion and (B) solid foci with mitotic figures and apoptosis.

Fig. 13.191 Juvenile granulosa cell tumor with absent follicles. A lobular pattern with intervening fibromuscular stroma is appreciable.

Fig. 13.192 Cellular fibroma. Note the plaques of hyalinized collagen.

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Fig. 13.193 Myoid gonadal stromal tumor with circumscribed profile (A) and fascicles of fusiform to elongated spindled cells (B).

gonadal involvement by a premalignant lesion. In contrast, a patient with a Sertoli cell nodule with GCNIS probably has a risk for bilateral involvement like that of any patient with GCNIS in one testis, approximately 1% to 5% of cases. SOX9 expression is greater and FOXL2 staining is absent in Sertoli cell nodule with GCNIS as compared with gonadoblastoma (where less intense SOX9 staining and positive FOXL2 staining are seen).966 The dissecting patterns of gonadoblastoma require distinction from a germinoma. This can be accomplished by appreciation of their sex cord components, usual basement membrane deposits, and frequent heterogenous nature of their germ cells. Immunostains can assist with this recognition if necessary. An additional consideration is sex cord–stromal tumor with entrapped, nonneoplastic germ cells.977 It, however, does not have a discretely nested arrangement of the lesional cells, nor do the germ cells show reactivity for GCNIS markers but retain features of spermatogonia (Fig. 13.199).

Miscellaneous Tumors of the Testis and Paratesticular Tissue Ovarian-Type Epithelial Tumors Tumors that resemble the surface epithelial tumors of the ovary may occur in and near the testis. More commonly they occur in the paratestis, involving the surface of the testis or structures such as the epididymis, and these are discussed in chapter 14.

Occasionally, however, they are found within the parenchyma and therefore merit a few comments here. Borderline tumors of serous or mucinous types may occur in the testis, as may mucinous cystadenomas, serous cystadenofibromas, benign or malignant Brenner tumors, serous carcinomas, endometrioid adenocarcinomas, and mucinous adenocarcinomas.978-990 They occur over a wide age range and typically present as palpable masses or as a hydrocele. These are usually cystic lesions, in keeping with their frequently borderline nature. The histologic appearances are like those seen in the much more common ovarian examples. In our experience, the serous tumors are the most common (Fig. 13.200). In the mucinous tumors, several of the cases we have seen were associated with mucin extravasation into the parenchyma with consequent fibrosis and dystrophic calcifications (Fig. 13.201). Some of the cases had marked cytologic atypia in the absence of stromal invasion, so-called “intraepithelial carcinoma.”981 The distinctive appearance of the serous borderline tumors readily permits their diagnosis, although this diagnosis in the paratestis is complicated by the differential with papillary mesothelioma.991-993 Mucinous tumors and Brenner tumors are potentially subject to confusion with teratoma. The absence of other teratomatous elements, cytologic atypia (usually), and of GCNIS assists with this differential, which may be facilitated by an older patient age, although there is overlap in the age range with patients having teratomas.994 Additionally, at least in younger patients, the absence of “dysgenetic” parenchymal changes (i.e., tubular atrophy, peritubular sclerosis, tubular hyalinization, Sertoli cell–only tubules, microlithiasis) can

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providing the basis for endometrioid tumors.995 Orchiectomy appears to be curative for tumors lacking stromal invasion.

Miscellaneous Lesions Juvenile Xanthogranuloma In infants, juvenile xanthogranuloma, including a series of three cases, has been described as a solitary testis mass.996 These tumors are composed of an interstitial infiltrate of round and spindled mononuclear cells (Fig. 13.202) that are positive for CD68, vimentin, and factor XIIIa and negative for S100 protein and CD1a.996 Touton giant cells, although characteristic, may be sparse to absent.

Hemangioma

Fig. 13.194 Unclassified sex cord–stromal tumor has clusters of sex cord cells admixed with spindle cells.

Testicular hemangioma (including epithelioid hemangioma) has been reported in isolated reports.997-1004 In a recent series of 8 cases, patient age ranged from 9 to 54 years (mean, 32 years), mean tumor size was 1.7 cm, and 3 of the 8 were recognized as hypervascular lesions by ultrasound preoperatively.1005 Hemangiomas commonly have an infiltrative appearance and may extend between seminiferous tubules; they may show capillary, cavernous, or epithelioid morphology and always lack endothelial nuclear atypia or atypical mitoses.1005 Several of them have anastomosing architecture (“anastomosing hemangioma”; Fig. 13.203).1005 These, however, lack the cellular stratification and hyperchromasia of angiosarcoma. Vascular markers such as CD31, CD34, ERG, and factor VIII–related protein are positive.1005,1006 Behavior has been benign, including in a case with up to 5 mitoses per high-power field.1005,1006 Testicular hemangioendothelioma has also been reported and, along with angiosarcoma, would be considered for a vascular tumor with nuclear atypia and/or atypical mitoses.1007-1009 Angiosarcoma in the testis is usually a teratoma-associated somatic-type malignancy, so associated germ cell tumor would need to be carefully excluded. Very rare primary testicular angiosarcomas in the absence of germ cell tumor may occur in elderly men with chronic hydrocele.1010 The possibility of angiosarcoma metastatic to the testis should also be considered.

Other Soft Tissue Tumors

Fig. 13.195 Bilateral gonadoblastomas composed of solid, yellow and tan nodules with a gritty consistency. There are associated pink and white germinomas. (Photograph courtesy of RH Young, MD, Boston, MA).

assist in the differential diagnosis with postpubertal-type teratoma. Endometrioid tumors may be positive on estrogen and progesterone receptor protein immunohistochemical staining.989 Rare cases of paratesticular endometriosis have been reported in men with prostate cancer treated with estrogen hormonal therapy and may represent metaplasia of the stromal cells of the tunica vaginalis, thus

Numerous other soft tissue tumors of the testis may rarely be seen, and some can be difficult to separate from unclassified sex cord–stromal tumors, but this distinction should be based on the absence of recognizable sex cord or epithelial differentiation and, possibly, lack of inhibin reactivity. Thus neurofibroma, fibroma of gonadal stromal origin, leiomyoma, inflammatory myofibroblastic tumor, osteosarcoma, chondrosarcoma, leiomyosarcoma, fibrosarcoma, rhabdomyosarcoma, and unclassified sarcoma of the testis have been reported.997,1011-1025 Some of these may represent overgrowth of teratomatous elements of a germ cell tumor; we have seen several cases of pure testicular embryonal rhabdomyosarcoma associated with GCNIS, and one other case has been reported in the literature, suggesting that some testicular sarcomas are of teratomatous origin.1026 Because patients who have testicular sarcoma developing from germ cell tumor may have conventional germ cell tumor elements at metastatic sites (which would be amenable to chemotherapy), the distinction of primary sarcoma versus sarcoma of germ cell tumor origin is important. The occurrence of testicular sarcoma in younger adult

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Fig. 13.196 Gonadoblastoma. (A) There are multiple, circumscribed, discrete nests. (B) The nests contain germ cells (some with a seminoma-like appearance and others resembling spermatogonia), sex cord cells, and round deposits of basement membrane, some with calcification.

Fig. 13.197 Gonadoblastomas (A and B) with a trabecular growth pattern of seminoma-like cells and frequently inconspicuous sex cord cells, a pattern that has been termed dissecting gonadoblastoma of Scully.

Fig. 13.198 An additional “dissecting” variant mimicking germinoma with confluent nests of gonadoblastoma that retain sex cord cells and basement membrane deposits.

Fig. 13.200 Ovarian-type tumor resembling serous borderline tumor.

Fig. 13.199 Sex cord–stromal tumor with entrapped, nonneoplastic germ cells may mimic gonadoblastoma. It does not have a discretely nested arrangement of the lesional cells or germ cells reactivity for GCNIS markers.

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Fig. 13.201 Borderline mucinous tumor with extravasated mucin. Note the characteristic filigree pattern of the lining epithelium.

patients is a suspicious finding for sarcoma in the context of germ cell tumor. The identification of chromosome 12p amplification also indicates that a testicular sarcoma is derived from germ cell neoplasia. Additionally, some sarcomas may occur as a “dedifferentiation” phenomenon in Leydig cell tumors and spermatocytic tumors.745,746,836

Hematolymphoid Tumors Lymphoma Lymphoma in the testis usually represents secondary spread from lymph nodes, although there are occasional cases that meet the criteria for primary testicular lymphoma.412,414,461,463,467,1027 These criteria include principal involvement of the testis and absence of nodal involvement after careful staging.461 However, these restrictions may be inadequate for recognizing lymphoma originating in the testis. The tendency of apparently primary testicular lymphoma to progress rapidly after excision, with high rates of recurrence, supports the belief that many originated elsewhere but spread to the testis and became clinically evident.461,463,464,1028,1029 Consistent clonal rearrangements of the immunoglobulin light-chain genes in synchronous, bilateral testicular lymphoma likely indicates occult dissemination of lymphoma with seeding of the testes, and argues against primary bilateral testicular lymphoma.1030 The unfavorable survival of patients with bilateral lymphoma provides

Fig. 13.202 Juvenile xanthogranuloma composed of an interstitial infiltrate of round and spindled mononuclear cells. Occasional seminiferous tubules remain.

additional support for this view.1027 In many studies of testicular lymphoma, it is not clear if the tumor is primary extranodal lymphoma or lymphoma that originated elsewhere and subsequently spread to the testis, making interpretation of this literature difficult.

Clinical Features Patients with testicular lymphoma are usually older than those with germ cell tumors, with a mean age of about 60 years458-463,1027; 50% of testicular neoplasms occurring in patients older than 60 years of age are lymphomas.789 Although most patients present secondary to a testicular mass, systemic symptoms such as fever, sweats, and weight loss also occur.461 Bilateral testicular involvement occurs in about 20% of cases and is usually metachronous but may also be synchronous.459,461-463,1031,1032 Pathologic Features Grossly, testicular lymphoma forms a fleshy, white-gray to pink mass that often diffusely replaces the testicular parenchyma (Fig. 13.204). Foci of necrosis may be conspicuous. It may be difficult to distinguish grossly from seminoma, although extension into the paratesticular structures suggests lymphoma rather than seminoma.467,1027 Microscopically, lymphoma often has an interstitial pattern, with neoplastic cells surrounding but not replacing seminiferous tubules deep within the tumor

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Fig. 13.203 “Anastomosing hemangioma” with interconnecting vascular channels. Note the lack of cellular stratification and hyperchromasia.

Fig. 13.204 Lymphoma in the testis. Note the fleshy, pink to creamcolored tumor.

(Fig. 13.205). Transtubular migration of the neoplastic cells may occur, and there may rarely be conspicuous intratubular involvement (Fig. 13.206).1033 Despite interstitial growth, the seminiferous tubules may eventually be destroyed and replaced by tumor, so the absence of an interstitial pattern does not exclude lymphoma. Most testicular lymphomas in adults are diffuse large cell type of B-cell immunophenotype.387,458, 460-462,1027,1029,1034-1036 They are furthermore mostly of the nongerminal center cell type of B-cell lymphoma, a type associated with a more aggressive course.1037 They are generally not

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Fig. 13.205 Typical interstitial pattern of lymphoma, with preservation of several seminiferous tubules.

associated with Epstein-Barr virus or human herpes virus 8.1034 Many express bcl-2 protein in the absence of a 14:18 chromosomal translocation.1038 In children, Burkitt lymphoma is the most common one in the testis, and shows the characteristic features, including small, mitotically active cells with round nuclei having several small nucleoli intermixed with macrophages containing phagocytosed nuclear debris.1031 Rare cases of Burkitt lymphoma of the testis have occurred in adults.1039 Hodgkin lymphoma involving the testis was not seen in a large testicular lymphoma case series, although a single case has been reported.1027,1031,1040,1041 Infrequent cases of pediatric testicular follicular lymphoma have been reported, with very favorable outcomes.1042,1043 Several additional types have been described in the testis: anaplastic large cell lymphoma (sometimes showing conspicuous intratubular involvement), nasal-type T/natural killer cell lymphoma, follicular lymphoma, low-grade T-helper cell lymphoma, B-lymphoblastic lymphoma, and histiocytic sarcoma.1033,1043-1056 A discussion of the features of these lymphomas is beyond the scope of this chapter.

Prognosis The stage of testicular lymphoma is the most important prognostic factor. In patients with stage I disease, there is a 60% 5-year tumorfree survival, whereas patients with more advanced stage disease have only a 17% 5-year tumor-free survival.1027 Histologic classification is also prognostically useful; in a multivariate analysis, lymphoma with sclerosis had a significantly more favorable outcome,

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condition and has been described as testicular “pseudolymphoma”; its distinction from lymphoma is based on the same criteria used at other sites.1058

Plasmacytoma Plasmacytoma of the testis is rare and usually occurs in older patients with an established or concurrent diagnosis of multiple myeloma.1059-1063 Some of these patients may have bilateral involvement, either synchronous or asynchronous.1062,1063 Even more rarely, however, testicular plasmacytoma may be an apparently isolated finding, and, in such cases the patient must be carefully worked up and followed for multiple myeloma, although some have not progressed.1061,1062,1064,1065 The testis may be the site of relapse of treated multiple myeloma, suggesting that the blood–testis barrier may make the testis a sanctuary site, as in acute lymphoblastic leukemia.1066 Autopsy studies of patients with multiple myeloma demonstrate an approximately 2% frequency of testicular involvement, but the majority of such involvement remains clinically inapparent.789 Grossly, plasmacytoma often appears as a soft, fleshy, gray-white and hemorrhagic intratesticular mass. Microscopically, sheets of variably differentiated neoplastic plasma cells are identified, often with an interstitial pattern of involvement (Fig. 13.207). Unlike chronic orchitis, a polymorphic cell population is absent and there is light chain restriction. In the poorly differentiated examples, misinterpretation as seminoma, lymphoma, or metastatic melanoma is possible.1062

Fig. 13.206 Unusual growth pattern of large cell lymphoma within seminiferous tubules. Note the comedo-like tumor necrosis.

and, for unclear reasons, so did right-sided testicular lymphoma.462,1027 A recent series of 43 primary testicular lymphomas found Eastern Cooperative Oncology Group (ECOG) performance status, infiltration of adjacent tissues (such as epididymis or spermatic cord), and bulky disease (>9 cm) were independently prognostically significant factors and also predicted benefit from rituximab treatment (with only the low-risk patients showing benefit).1057

Differential Diagnosis A major differential diagnostic consideration in testicular lymphoma is seminoma, which is addressed in the Seminoma section earlier in this chapter. Anaplastic large cell lymphoma with intratubular growth may be confused with embryonal carcinoma. Both are CD30 reactive and may show prominent comedo-type necrosis of the intratubular component, but the strong cytokeratin and OCT3/4 reactivity of embryonal carcinoma and its negativity for lymphoid markers serve to assist in the distinction, as does the absence of GCNIS in lymphoma. A potential pitfall in this differential diagnosis, however, is the uncommon occurrence of OCT3/4 reactivity in large cell lymphomas (Tickoo, S.K., 2013, personal communication), illustrating the benefit of a panel of immunostains. Chronic orchitis may also be confused with lymphoma but contains a heterogeneous cell population, consisting of lymphocytes, polyclonal plasma cells, and neutrophils without atypia. Reactive lymphoid hyperplasia within the testis is a rare

Fig. 13.207 Plasmacytoma with sheets of neoplastic plasma cells in an interstitial pattern.

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Immunostains for light chain restriction, CD138, CD79a, and with monoclonal antibody VS38 are often helpful in identifying plasmacytoma.

Leukemia, Including Myeloid Sarcoma Leukemic infiltrates occur commonly in the testis, with frequency rates at autopsy of 40% to 65% of patients with acute leukemia and 20% to 35% of patients with chronic leukemia.1040,1067 Leukemia is the most common neoplasm to involve the testis in children.773 Acute lymphoblastic leukemia is especially prone to testicular involvement, and the testis may be a “sanctuary” site for leukemic cells such that testicular biopsy may detect leukemic infiltrates during periods of otherwise complete remission. The detection of leukemia in the testis in such cases occurs in 5% to 10% of patients and is predictive of subsequent systemic relapse.1068-1070 The probability of a second remission from non–B-cell childhood leukemia is higher for patients with isolated testicular relapse than those with relapse at other sites.1071 The leukemic testis is usually not enlarged, and the diagnosis is established by biopsy of patients at risk. Occasionally, diffuse testicular enlargement, induration, or a testicular mass may be observed.1070 Bilateral involvement is common. Exceptionally, leukemia may initially present as testicular enlargement.789,1072 Microscopically, leukemia usually shows an interstitial pattern of infiltration, similar to lymphoma. The neoplastic cells are characteristic of the leukemia. It may not be possible to morphologically distinguish between some types of lymphoma and leukemia, and clinical information regarding peripheral blood involvement and bone marrow studies are required. The distinction between neoplastic monocytic and myelocytic infiltrates and lymphoid neoplasia may require histochemical and immunohistochemical studies. Rarely, myeloid sarcoma occurs in the absence of leukemia; typically, subsequent leukemia is found, although one patient who was treated for lymphoma because of pathologic misinterpretation survived for 12 years without evidence of leukemia.1073-1076 In one case of myeloid sarcoma presenting in the testis of an infant, cerebrospinal fluid was involved at presentation but bone marrow involvement was not histopathologically identified.1077 Myeloid sarcoma, because of its frequent paratesticular involvement and overlapping morphology, is prone to misinterpretation as lymphoma or plasmacytoma.1075,1076 If eosinophilic myelocytes are present, the correct diagnosis is greatly facilitated. CD45 may be positive and therefore may not discriminate between myeloid sarcoma and lymphoma.1076 More helpful are stains directed against myeloperoxidase and lysozyme, as well as chloroacetate esterase stains.1076

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827

Tumors of Collecting Duct and Rete Testis Adenoma Adenoma of the rete testis is rare, consisting of papillary or glandular proliferations of cytologically bland cells.1080-1082 Four adenomas were reported in patients from 21 to 79 years of age.1083 They ranged from 1.5 to 3.6 cm in diameter and were composed of cysts lined by bland, sometimes stratified or tufted epithelium, with prominent intervening fibrous stroma. About 25 cases of Sertoliform cystadenoma of the rete testis have now been reported since the original elaboration of its features by Jones et al.1083-1085 In the largest series of 15 cases, the patients were 1 to 84 years of age, and all presented with masses except for one that was incidental in an orchiectomy specimen.1085 These cystic and solid lesions are centered in the testicular hilum and have an appearance similar to that of a Sertoli cell tumor, although most of the proliferation occurs within the dilated channels of the rete testis (Fig. 13.208). They form hollow and solid tubules, cords, and nests in a hyalinized to myxoid stroma and, less commonly, solid sheets, festoons, individual cells, and papillae.1085 The lesional cells are cuboidal to columnar and have bland cytologic features with few (0 to 2 per 10 high-power fields) mitotic figures.1085 They usually express SF1 and inhibin.1085 Follow-up has been benign. Cystadenomas, adenofibromas, and a complex multilocular cystic lesion of the rete testis with smooth muscle hyperplasia have also been reported.1083,1086,1087 Approximately 54% of men with von

Rosai-Dorfman Disease Testicular Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) may occur over a wide age range but is most common in middle-age adults.1078,1079 These lesions are composed of a mixed inflammatory infiltrate with lymphocytes, plasma cells, and large histiocytes with emperipolesis. The disorder is an abnormal proliferation of S100-positive histiocytic cells with characteristic phagocytosis of lymphocytes.1078,1079 The differential diagnosis could include germ cell tumors, hematolymphoid tumors, metastatic tumors such as melanoma, and granulomatous orchitis. Occasional patients have had a history of previous lymphoproliferative disease.1078

Fig. 13.208 Sertoliform cystadenoma of the rete testis with a tubular and papillary proliferation of epithelium within dilated channels of the rete testis.

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Hippel–Lindau disease have enlargement of the epididymis compatible with epididymal cystadenoma.1088 Hartwick et al. described adenomatous hyperplasia of the rete testis in a series of nine cases in patients ranging from 30 to 74 years of age; in three cases, the hyperplasia produced grossly evident, solid, and cystic masses in the testicular hilum.1089 Nistal et al. reported 20 cases in patients ranging from 2 months to 74 years of age, 11 associated with cryptorchidism and 4 with a germ cell tumor.1090 Microscopically, these lesions are tubulopapillary proliferations of bland cells within distended rete testis. Whether these cases are distinct from adenoma is unclear; they do not appear to be similar to the hyperplastic reaction of the rete testis typically seen in cases of germ cell tumor (Fig. 13.85).623 Conservative surgical treatment (excision rather than orchiectomy) for small lesions has been recommended.1091

Cystic Dysplasia Scattered case reports describe cystic dysplasia of the rete testis associated with absence or dysplasia of the ipsilateral kidney.1092,1093 These lesions mostly present in children and young adults as a painless scrotal swelling with a multicystic appearance on ultrasound and negative tumor markers.1094 Rarely the lesion may present as a painful and solid mass.1095 There is often prominent dilatation of the rete testis with compression of residual testicular parenchyma.

Adenocarcinoma Adenocarcinoma of the rete testis is very rare, occurring in patients from 20 to 91 years of age.1083,1096,1097 Most patients are older than 60 years of age.1083 Many present with symptoms of testicular pain and swelling. The initial clinical impression is often epididymitis or hydrocele, and hydrocele is found associated with the tumor in 25%.1096 Because of the posterior location of the tumor, a mass may be difficult to palpate. Some patients present with metastatic scrotal or perineal nodules. Grossly, there is a white to tan, yellow, or brown, ill-defined mass near the testicular hilum, often with extension into paratesticular structures. Some degree of cystic change may be present but is usually not prominent. Microscopically the tumor displays solid, papillary, and glandular patterns. The tumor often has an intraluminal component, which distends the spaces of the rete, as well as a component that infiltrates the supporting stroma of the rete (Fig. 13.209). There may be associated rete testis hyperplasia, and, ideally, a transition from benign to malignant epithelium is seen in the lining of the rete (Fig. 13.209B), but this finding may not be demonstrable and may furthermore be mimicked by metastatic carcinomas that involve the rete testis and undermine its epithelial lining.1096,1098,1099 The solid pattern is often punctuated by slitlike lumens, and a spindle cell pattern rarely occurs.1100 The papillae may have hyalinized fibrous cores and project into cysts. The tumor cells typically have round to oval nuclei, sometimes with grooves, and scant cytoplasm. Immunohistochemical studies typically yield

Fig. 13.209 Adenocarcinoma of the rete testis with (A) an intraluminal component and infiltrating component in the supporting stroma of the rete. (B) In the central tubule there is transition from cytologically bland rete epithelium to dysplastic epithelium.

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positive reactions for cytokeratins and EMA and less consistent reactivity for CEA. Lymphatic metastases occur most commonly and initially involve retroperitoneal lymph nodes; sometimes there is involvement of the skin of the scrotum or perineum.1101 The prognosis is poor, with only 36% of patients being tumor-free on follow-up.1096 The differential diagnosis includes carcinomas and borderline tumors of ovarian epithelial type; these occur more commonly in the paratesticular area, probably from metaplasia of the mesothelium or m€ ullerian remnants, but also rarely occur within the testis, perhaps from metaplasia of mesothelial inclusions. It is likely that some cases of papillary serous borderline tumor have been reported as adenocarcinoma of the rete testis, thus leading to an overly optimistic prognosis for rete testis carcinoma.1096 Psammoma bodies, squamous metaplasia, or mucinous cell type should raise the question of m€ ullerian-type neoplasms. The differential is probably not of great importance except when it involves the distinction of a borderline tumor from an invasive carcinoma. Mesothelioma, which in some cases is associated with a history of asbestos exposure, should also be considered, and immunohistochemical studies to distinguish between adenocarcinoma and mesothelioma may help in difficult cases.1102 Malignant mesothelioma of the tunica vaginalis consistently expresses calretinin, WT-1 (nuclear), and EMA, and thrombomodulin, cytokeratin 7, and cytokeratin 5/6 reactivity is also seen in most cases, although many of these may also occur in rete adenocarcinoma.993,1102,1103 More helpful are positivity in rete adenocarcinoma for PAX8 and with antibodies BerEp4 and MOC31. Prostatic carcinoma may involve the rete testis, but the clinical history and immunostains for prostate-specific antigen should allow its identification.

Metastatic Tumors Metastases to the testis are most commonly identified in patients with known malignancies, and the most common sites of origin (excluding leukemia and lymphoma) are the prostate, stomach, lung, skin (melanoma), colon/rectum, kidney, urinary bladder, and elsewhere.786,1104-1115 It is likely that the predominance of the prostate in this ranking represents at least a partial selection bias resulting from examination of therapeutic orchiectomy specimens from patients with metastatic prostatic carcinoma.1116 In children, there is a predominance of neuroblastoma and rhabdomyosarcoma, but metastatic rhabdomyosarcoma may also involve the testis in adults.1107,1117-1121 Rarely metastases to the testis may present as apparent primary testicular tumors, including those originating in the prostate, lung, kidney, gastrointestinal tract (stomach and colon), urinary bladder, skin (melanoma), thyroid gland (medullary carcinoma), pancreas, and liver, and well-differentiated neuroendocrine tumor.786,789,1109,1112,1122-1124 One case of occult gastric signet ring carcinoma presented as a spermatic cord and testis mass (and was considered a “Krukenberg tumor in a male patient”).1125 Although bilateral involvement may be seen in some cases, often the tumors are unilateral and solitary masses, complicating the distinction from primary tumors.786,1107,1109,1125 A proclivity to involve the right testis has been identified in several studies.786,1107,1109 Misinterpretation of metastatic carcinoma or melanoma as embryonal carcinoma, Leydig cell tumor, or Sertoli cell tumor may occur, or metastatic well-differentiated neuroendocrine tumor may be misinterpreted as primary testicular well-differentiated neuroendocrine tumor.786,794,1109,1112 We have seen several metastatic prostate carcinomas that had a prominent intratubular component (Fig. 13.210) or that prominently involved the rete testis (Fig. 13.211), potentially causing confusion

Fig. 13.210 Metastatic prostate carcinoma to the testis with a prominent intratubular component.

with primary testicular neoplasms, especially for the latter, Sertoliform cystadenoma of the rete testis or rete testis carcinoma. The nested and tubular pattern of metastatic renal cell carcinoma of clear cell type is prone to misinterpretation as Sertoli cell tumor.786 Some metastatic melanomas may show prominent foamy tumor cells, overlapping with an appearance that may be seen in Leydig cell tumors.1109 Additionally melanomas may have relatively scant cytoplasm and display prominent intertubular growth, features that are readily confused with lymphoma (Fig. 13.212). The presence of an extensive interstitial pattern, prominent microvascular involvement, multifocality, and bilaterality are features that favor metastasis rather than primary testicular tumor, but they are not always present.1112,1116,1126 The clinical history may also be of value because patients with metastatic lesions to the testis are, on average, older (mean age, 57 years) than patients with a germ cell tumor such as embryonal carcinoma (mean age, 30 years). However, patients with metastatic stomach and small intestinal cancer may fall within the usual age range of those with testicular germ cell tumor.1127 Serum AFP and hCG levels are much more likely to be elevated in patients with germ cell tumor. The absence of GCNIS in the surrounding seminiferous tubules increases the probability of a metastatic tumor over germ cell tumor, as do EMA positivity and PLAP, SALL4, and OCT3/4 negativity.413,1126 Other immunohistochemical studies may prove useful, including prostate-specific antigen, renal cell carcinoma and melanoma markers, and inhibin stains.

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Fig. 13.211 Metastatic prostate carcinoma with prominent intrarete growth. The pattern is similar to sertoliform cystadenoma of the rete (Fig. 13.208), although the cytologic features and immunoreactivity are distinctly different.

Diagnostic Approach to Testicular Tumors From the preceding information, it is apparent that several recurring morphologic patterns are observed in testicular tumors. The differential diagnostic considerations for tumors with certain patterns may include tumors of germ cell origin, tumors of sex cord–stromal origin, and secondary tumors. In most cases, careful attention to the morphologic features, along with the clinical history, will allow establishment of the correct diagnosis, and the most important differential diagnostic considerations have been discussed earlier and elsewhere.8,10,284,1128-1132 In some of these cases, immunohistochemical staining provides crucial supportive evidence.13 Some of the common patterns include solid tumors composed of cells with pale cytoplasm; tumors with a glandular and/or tubular pattern; tumors with a microcystic pattern; oxyphilic tumors with a predominant solid pattern; and tumors with spindle cell morphology.1128 Solid tumors composed of cells with pale cytoplasm may include seminoma, spermatocytic tumor, solid-pattern embryonal carcinoma, solid-pattern yolk sac tumor, metastatic adenocarcinoma, Sertoli cell tumor, Leydig cell tumor, and lymphoma. Several light microscopic features and immunohistochemical reactions assist the separation of these entities (Fig. 13.213). These may be distinguished based on the presence of associated GCNIS, the presence of focal glandular architecture, the presence of a predominantly interstitial growth pattern, and the immunohistochemical

Fig. 13.212 Metastatic melanoma. The tumor cells show prominent interstitial growth, mimicking the low-power appearance of lymphoma.

staining pattern for OCT3/4, SALL4, PLAP, CD30, AFP, inhibin, SF1, and LCA (Fig. 13.213). Tumors with a glandular or tubular pattern include embryonal carcinoma, yolk sac tumor, tubular pattern seminoma, rete testis neoplasm, metastatic adenocarcinoma, and Sertoli cell tumor (Fig. 13.214). These may be distinguished based on the presence of associated GCNIS, nuclear features and the presence of elongated glandular spaces, the presence of hyaline globules and other patterns of yolk sac tumor, the presence of intertubular growth pattern or solid tubules, and OCT3/4, SALL4, PLAP, CD30, AFP, keratin, and inhibin staining patterns (Fig. 13.214). Tumors that may have a microcystic pattern include yolk sac tumor, seminoma, Sertoli cell tumor, Leydig cell tumor, juvenile granulosa cell tumor, and adenomatoid tumor (Fig. 13.215). Features helpful in distinguishing these tumors include patient age, the presence of GCNIS, nuclear features such as nuclear size variability and flattened cellular profiles within the cysts, the presence of cords of tumor cells and lipid-rich cells, and staining for keratin, OCT3/ 4, AFP, SALL4, PLAP, inhibin, and calretinin (Fig. 13.215). Oxyphilic tumors with a predominantly solid pattern include Leydig cell tumor, large cell calcifying Sertoli cell tumor, hepatoid pattern yolk sac tumor, well-differentiated neuroendocrine tumor, metastatic adenocarcinoma, melanoma, plasmacytoma, and adenomatoid tumor (Fig. 13.216). Cytoplasmic lipofuscin or Reinke crystals, the presence of associated fibromyxoid stroma, the presence of GCNIS, the presence of insular and trabecular patterns or teratomatous elements, the presence of overtly malignant nuclear features and intratubular growth, and staining patterns

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831

Solid tumor composed of cells with pale cytoplasm Polygonal, relatively uniform nuclei, fibrous septa with lymphocytes, absence of glandular or papillary foci?

Yes

No

Yes

No

Focal glandular architecture?

Three distinct cell types?

No

Yes Consider seminoma (OCT3/4+, PLAP+, CD30-) Yes

Large, irregular partially clear nuclei?

Consider solid pattern embryonal carcinoma (OCT3/4+, PLAP+, CD30+)

No

Yes

No Consider solid pattern yolk sac tumor (OCT3/4-, PLAP+, CD30-, AFP+)

Predominantly interstitial growth pattern?

GCNIS present?

Consider metastatic adenocarcinoma (strongly keratin+, OCT3/4-, PLAP-, inhibin-)

Consider lymphoma (LCA+, OCT3/4-, PLAP-, inhibin-)

No

Yes

Consider spermatocytic tumor (OCT3/4-, PLAP-, CD30-, CD117±)

Consider Sertoli cell tumor (inhibin±, Leydig cell tumor (inhibin+) or “anaplastic” spermatocytic tumor

Fig. 13.213 A general approach for the diagnosis of tumors with a diffuse arrangement of pale to clear cells. (Modified from Emerson RE, Ulbright TM. Morphological approach to tumours of the testis and paratestis. J Clin Pathol. 2007;60:866–880.)

Tumor with a glandular and/or tubular pattern

Cells with large, crowded, irregular nuclei lining elongated glandular spaces?

Yes

No

No

No

Yes

Consider embryonal carcinoma (OCT3/4+, PLAP+, CD30+) Yes

Consider yolk sac tumor (keratin+, AFP+, OCT3/4-, PLAP+, CD30-)

Prominent intertubular and intralymphatic growth?

GCNIS present?

Variably sized cells, hyaline globules, other pattern of tumor? No

Consider tubular pattern seminoma (keratin±, AFP-, OCT3/4+, PLAP+, CD30-)

Tubular growth with solid tubules?

Yes Consider Sertoli cell tumor (inhibin±, SF1+, nuclear bcatenin±)

Yes

Consider metastatic adenocarcinoma (keratin+, OCT3/4-, PLAP-, inhibin-)

No

Consider rete testis neoplasm (keratin+, CEA+, EMA+, PAX8+)

Fig. 13.214 A general approach for the diagnosis of tumors with a glandular/tubular arrangement. (Modified from Emerson RE, Ulbright TM. Morphological approach to tumours of the testis and paratestis. J Clin Pathol. 2007;60:866–880.)

832 CHA P T E R 13

Neoplasms of the Testis

Fig. 13.215 A general approach for the diagnosis of tumors with a microcystic pattern. (Modified from Emerson RE, Ulbright TM. Morphological approach to tumours of the testis and paratestis. J Clin Pathol. 2007;60: 866–880.)

Tumors with a microcystic pattern

Variably sized nuclei and flattened nuclei lining the cysts?

Yes

Prominent cords of tumor cells, lipid rich cells, hyalinized stroma?

No

GCNIS Yes present? Yes Consider postpubertal type yolk sac tumor (keratin+, AFP+, OCT3/4-, PLAP+, CD30-)

No

No

Consider seminoma (keratin usually-, AFP-, OCT3/4+, PLAP+, CD30-)

Consider Sertoli cell tumor (inhibin±, PLAP-, OCT3/4-)

Yes Consider juvenile granulosa cell tumor (AFP-, inhibin+)

Consider Leydig cell tumor (inhibin+, PLAP-, OCT3/4-) adenomatoid tumor (keratin+ calretinin+, PLAP-, OCT3/4-, inhibin-)

Consider adenomatoid tumor (keratin+ calretinin+, PLAP-, OCT3/4-, inhibin-)

Abundant eosinophilic cytoplasm?

Yes

No

Fig. 13.216 A general approach for the diagnosis of tumors composed mostly of oxyphilic cells. (Modified from Emerson RE, Ulbright TM. Morphological approach to tumours of the testis and paratestis. J Clin Pathol. 2007;60:866–880.)

Associated fibromyxoid stroma with neutrophils and calcifications?

No

Consider extrinsic neoplasms (metastatic adenocarcinoma: keratin+, inhibin-; metastatic melanoma: S100+, HMB45+; plasmacytoma: CD79a+, CD138+; lymphoma: various lymphoid markers+)

No

Consider prepubertal-type yolk sac tumor (keratin+, AFP+, OCT3/4-, inhibin-)

Oxyphilic tumors with a predominant solid pattern

Consider Leydig cell tumor (inhibin+)

No

Neonate?

Yes Round nuclei, prominent nucleoli, +/cytoplasmic lipofuscin or Reinke crystals?

Consider welldifferentiated neuroendocrine tumor (keratin Cam 5.2+, chromogranin+, inhibin-)

No

Yes Consider large cell calcifying Sertoli cell tumor (inhibin +)

Presence of other patterns, conspicuous mitotic activity, associated GCNIS? Yes

Consider hepatoid pattern yolk sac tumor (keratin+, AFP+, OCT3/4-, inhibin-, PLAP+, CD30-)

No

Yes

No

Highly pleomorphic nuclei, prominent intratubular growth patter?

Yes No

Insular and trabecular patterns, coarse chromatin, +/- associated teratomatous elements)

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with keratin, inhibin, SALL4, PLAP, calretinin, and markers specific for extrinsic neoplasms can be useful in differentiating these tumors (Fig. 13.216). Tumors with a largely or entirely spindle cell pattern may include Leydig cell tumor, unclassified sex cord–stromal tumor, sarcomatoid carcinoma, mesothelioma, some benign mesenchymal lesions such as testicular tunic fibroma, and a variety of sarcomas (Fig. 13.217).

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833

These may be distinguished based on the presence of foci of recognizable oxyphilic Leydig cells, nuclear cytology and mitotic activity, and immunohistochemical staining pattern for actin, desmin, CD34, keratin, inhibin, and S100 protein (Fig. 13.217). References are available at expertconsult.com

Tumors with a spindle cell morphology

Consider unclassified sex cord-stromal tumor (inhibin+) Yes

Consider Leydig cell tumor (inhibin+)

Yes

Foci with oxyphilic cells with round nuclei, prominent nucleoli, +/cytoplasmic lipofuscin or Reinke crystals?

No

Longitudinal nuclear grooves, location near rete testis, small size? No Relatively bland nuclear cytology, absent mitotic activity?

Yes

Smooth muscle actin, S100 immunoreactivity?

Lacking smooth muscle actin and S100 coexpression: consider fibroma-thecoma

Smooth muscle actin and S100 coexpression: consider myoid gonadal stromal tumor

Keratin, S100, desmin immunoreactivity?

Keratin+/S100-/ desmin-: consider sarcomatoid carcinoma and mesothelioma

No

Keratin-/S100+/ desmin-: consider MPNST, melanoma, liposarcoma

Keratin-/S100-/ desmin+: consider rhabdomyosarcoma, leiomyosarcoma

Fig. 13.217 A general approach for the diagnosis of tumors composed mostly of spindle cells. (Modified from Emerson RE, Ulbright TM. Morphological approach to tumours of the testis and paratestis. J Clin Pathol. 2007;60:866–880.)

833.e1

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834.

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