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Adrenal Glands E R N E ST E . L A C K A N D E D I N A P A A L

C HA PT E R OU T LI N E Embryology and Normal Gross Anatomy 902 Adrenal Cortex 902 Adrenal Medulla 904

Adrenal Neoplasms 922 Adrenal Cortical Neoplasms 922 Pheochromocytoma 929

Microscopic Anatomy 904 Examination of the Adrenal Glands 905

Peripheral Neuroblastic Tumors: Neuroblastoma, Ganglioneuroblastoma, and Ganglioneuroma 934 In Situ Neuroblastoma 935 Peripheral Neuroblastic Tumors 935 Original Age-Linked Classification of Neuroblastoma 937 International Neuroblastoma Pathology Classification 938 Ancillary Techniques 938 Molecular Genetics in Neuroblastomas 938 Staging of Neuroblastoma and Ganglioneuroblastoma 939 Stage IV-S Neuroblastoma and Patterns of Spread by Peripheral Neuroblastic Tumors 940 Ganglioneuroma 940

Congenital and Other Abnormalities 905 Congenital Adrenal Aplasia and Hypoplasia 905 Adrenal Heterotopia 905 Union and Adhesion 906 Adrenal Cytomegaly 906 Adrenoleukodystrophy 906 Congenital Adrenal Hyperplasia 906 Stress-Related Changes of the Adrenal Gland 908 Other Abnormalities 909 Nonneoplastic Diseases 909 Chronic Adrenal Cortical Insufficiency (Addison Disease) 909 Acute Adrenal Cortical Insufficiency 910 Inflammation and Other Infections 911 Adrenal Cortical Hyperplasia 911 Multiple Endocrine Neoplasia Type 1 920 Other Rare Causes of Cushing Syndrome 921 Adrenal Cortical Hyperplasia With Hyperaldosteronism 921 Adrenal Cortical Hyperplasia With Excess Sex Steroid Secretion 921 Adrenal Medullary Hyperplasia 921 Adrenal Cyst 922 Adrenal Hemorrhage 922

Embryology and Normal Gross Anatomy Adrenal Cortex The primordium of the adrenal cortex becomes evident at Carnegie stage 14 (
5 to 7 mm and 32 days), just lateral to the base of the dorsal mesentery near the cranial end of the mesonephros.1,2 The adrenal cortical primordia are of mesodermal origin and, during development in the late embryo and fetus, the portion of the developing cortex that occupies the greatest volume is referred to as the fetal or provisional cortex. This layer of cortex makes up approximately 80% of the newborn adrenal gland and undergoes marked regression in the first weeks of life; this is shown graphically in Fig. 16.1, in which the combined weight of the adrenal glands decreases by almost 50% by the 9th to 14th week after birth.3 The adult, or definitive, cortex forms a much thinner outer zone 902

Other Adrenal Tumors 941 Myelolipoma 941 Adenomatoid Tumor 942 Malignant Lymphoma 942 Mesenchymal Tumors 942 Malignant Melanoma 943 Other Unusual Tumors and Tumor-Like Lesions 943 Tumors Metastatic to the Adrenal Glands 943

beneath the adrenal capsule and ultimately becomes the trilayered adrenal cortex of the adult. Convincing evidence exists for centripetal migration or displacement of adrenal cortical cells in experimental animals, thus supporting the original cell migration theory of Gottschau that proposed that migrating adrenal cortical cells can produce all the major adrenal cortical steroids.3 On gross examination, the late fetal or neonatal adrenal gland is relatively soft, and, in transverse sections, the fetal zone may have rather dark coloration, which at this stage is quite broad. This dark appearance, shown in Fig. 16.2, may be misinterpreted as adrenal hemorrhage or apoplexy. The adrenal glands in newborns have smoother external surfaces than in adults. In the adult, the right adrenal gland is roughly pyramidal and the left is more elongated (Fig. 16.3). Inspection of the intact capsular surface of the gland after removal of periadrenal connective tissue and fat may reveal small capsular extrusions of cortex; some of these are directly connected with the underlying cortex, but others seem to lie free on the

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903

13 12

Combined Weight of Adrenal Glands (g)

11 10 9 8 7 6 5 4

Fig. 16.4 Normal adrenal gland from an adult. An incomplete cuff of cortical cells is present around a central adrenal vein in the medulla. The adrenal vein is present on the ventral surface toward the head of the gland. The dorsal ridge (crista) is flanked by lateral and medial extensions (alae). Medullary tissue is concentrated in the body and head and appears gray-white, in contrast with the bright-yellow cortex.

3 n = 226

2 1

30 33 38 1 Full term

3

9 14

32

1.5

Week

4

8

14

18

25

35

Years Age

Fig. 16.1 Average combined weight of the adrenal glands from 226 autopsies by age. Note the marked reduction in combined weight in the first few weeks of life caused by regression of the fetal (provisional) cortex. (From Lack EE, Kozakewich HPW. Embryology, developmental anatomy, and selected aspects of nonneoplastic pathology. In: Lack EE, ed. Pathology of the Adrenal Glands. New York: Churchill Livingstone; 1990:1–74.)

capsular surface or unattached in periadrenal fat. Transverse sections of adrenal gland in the adult reveal a bright yellow, relatively uniform cortex with a gray-white medulla that is concentrated in the head and body of the gland (Fig. 16.4). A cuff of cortical cells may be noted partially or entirely surrounding larger tributaries of the adrenal vein. The dorsal surface of the adrenal gland has a longitudinal ridge or crista flanked by medial and lateral extensions or alae (wings). The anterior (or ventral) surface of the adrenal gland is relatively smooth, and it is from this surface of the gland that the adrenal veins exit and drain into the inferior vena cava on the right side and the renal vein on the left. The orientation of the adrenal gland in vivo differs from that depicted in gross photographs of specimens in surgical or autopsy material. As seen in Fig. 16.5, the glands are oriented in a more vertical axis, with the ridge (or crista) projecting posteriorly and flanked by medial and lateral alae. The thickness of the adult cortex is approximately 2 mm or more throughout most of the gland, although some variability may be seen from area to area, and cortical nodularity may complicate the morphology.3

Fig. 16.2 Adrenal gland from a newborn infant. Note the dark congested fetal (provisional) cortex and thin rim of pale adult (definitive) cortex. Cortical extrusion is also present centrally.

Fig. 16.3 Normal adrenal glands from an adult. The right is roughly pyramidal (left side of photo), whereas the left is elongated (right side of photo). The longitudinal ridge (crista) is flanked by lateral extensions (alae).

Fig. 16.5 Diagram of transverse cut of abdomen in an adult showing orientation of the adrenal glands and relation with the kidneys. The ventral aspect of both glands is relatively flat, and the dorsal surface has a longitudinal ridge (crista). Lateral extensions (alae) are often referred to as medial and lateral limbs on CT scans.

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Fig. 16.6 Schematic drawing of transverse sections of adrenal gland from an adult. Chromaffin tissue is concentrated in the body and head. Figures indicate the percentage of cross-sectional area occupied by medulla (top row) and ratio of areas of cortex to medulla (bottom row).

Adrenal Medulla Chromaffin tissue of the adrenal medulla in the fetal and newborn adrenal gland is inconspicuous on gross examination of transverse sections of the gland. In the adult, however, chromaffin tissue is concentrated in the body and head of the gland, with the latter regions being directed inferomedially in vivo.3,4 As seen in Fig. 16.6, the ratio of area occupied by cortex relative to that of medulla decreases considerably from the tail to the body and head of the gland. The normal overall ratio of cortex to medulla is approximately 10:1. The distribution and amount of chromaffin tissue within the gland, as well as other factors, such as adrenal weight, may be important in determining whether adrenal medullary hyperplasia (AMH) is present.4 Another consideration is morphologic abnormalities of the adrenal cortex, such as adrenal cortical atrophy, which can affect the overall ratio. The adrenal medulla is composed of chromaffin cells derived from primitive sympathicoblasts of neural crest origin that migrate into the dorsomedial aspect of the adrenal primordium and become apparent at Carnegie stages 16 and 17 (
11 to 14 mm and 41 days).1,2 Most of the developing chromaffin tissue in fetal life is extraadrenal, with the largest collections of cells in the paraaortic region, near the origin of the superior mesenteric and renal arteries down to the aortic bifurcation; these chromaffin structures were first characterized in the human fetus by Zuckerkandl in 1901, who referred to them as aortic bodies.5

Microscopic Anatomy At birth, the thin rim of adult (definitive) cortex blends imperceptibly into cells of the fetal (provisional) cortex. The definitive cortex apparently begins to grow soon after birth, with zonation into the zona glomerulosa and zona fasciculata first appearing at 2 to 4 weeks.6 According to some investigators, the zona reticularis appears at approximately 4 years, but others contend that it appears before 1 year.6,7 The zona glomerulosa contains cells with dark round nuclei and relatively scant cytoplasm arranged in interlacing cords and spherules; this zone is normally thin and ill defined, and it may appear discontinuous in the normal adult gland (Fig. 16.7). This layer blends imperceptibly into the zona fasciculata, which constitutes most of the adult cortex, and consists of long columns of larger cells with pale, finely vacuolated cytoplasm in the unstressed gland. The transition between the innermost zona fasciculata and the zona reticularis contains cells with more compact eosinophilic cytoplasm separated by thin-walled sinusoids and irregular short cords of cells. Reticularis cells may contain prominent granular

Fig. 16.7 Normal adult adrenal cortex. Zona glomerulosa (ZG) is at the top of the field beneath the adrenal capsule and forms a thin, discontinuous layer of cells. Most of the cortex is occupied by radial interconnecting cords of zona fasciculata (ZF), which contain cells with pale-staining, lipid-rich cytoplasm. The zona reticularis (ZR) has interconnecting short cords of cells with compact, eosinophilic cytoplasm and congested microvasculature.

pigment representing lipofuscin. Chromaffin cells of the adrenal medulla are polyhedral and arranged in short anastomosing cords or nests with a prominent vascular network, or a more solid or diffuse arrangement of cells may be seen. Adrenal chromaffin cells secrete predominantly epinephrine, with lesser amounts of norepinephrine.4 In the fetal and neonatal adrenal gland, small nests of primitive neuroblastic cells may be encountered (Fig. 16.8), which may be a part of normal developmental anatomy (see the In Situ Neuroblastoma section later in this chapter).3,4 The zona glomerulosa is the site of aldosterone production and is responsive to stimulation by angiotensin and adrenocorticotropic hormone (ACTH). The zona fasciculata produces corticosteroids such as cortisol, whereas the zona reticularis is responsible for sex steroid production. Longitudinal pillars of smooth muscle are found predominantly in the head of the adrenal gland around tributaries of the adrenal vein and are thought to act as “sluice gates” that retard the flow of blood from the medullary venous sinuses and plexus reticularis during muscle contraction.8 The muscular bundles may help regulate medullary blood flow and influence the degree of congestion in the zona reticularis and zona fasciculata of the adjacent cortex.

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Fig. 16.8 Neuroblastic nodules in the provisional zone of a 16-week fetal adrenal gland.

Examination of the Adrenal Glands Examination of the intact adrenal gland is best accomplished by careful removal of as much investing connective tissue and fat as possible to obtain an accurate weight. The weight of the cleanly dissected gland may provide valuable information regarding adrenal cortical or medullary pathology. In the study by Stoner et al., the average combined weight of the adrenal glands at birth was 10 g (range, 2 to 17 g), whereas the average weight was 6 g at 7 days of age and 5 g at 2 weeks of age.6 Quinan and Berger studied the adult adrenal gland, concentrating on ostensibly healthy subjects who had died suddenly, and found that the average weight of each gland was 4.15 g, with no significant difference between the right and left sides.9 Studzinski et al. examined surgically removed adrenal glands from women with breast cancer and reported an average weight of 4 g, with little variation (standard deviation, 0.8 g).10 Adrenal glands obtained at autopsy from individuals who had not died suddenly or unexpectedly tended to be heavier, with an average individual weight of 6 g; this difference was attributed to the stress of illness and the trophic influence of endogenous ACTH.10 Using these data, each normal adrenal gland should weigh less than 6 g, provided excess periadrenal fat and connective tissue are carefully removed.

Congenital and Other Abnormalities Congenital Adrenal Aplasia and Hypoplasia Congenital adrenal aplasia or agenesis is rare. Unilateral adrenal aplasia has been reported in about 10% of patients with unilateral renal agenesis.11 Complete bilateral adrenal aplasia is also rare and may occur in a familial setting.12 The diagnosis should be viewed with caution because there may be small amounts of residual adrenal tissue present in the suprarenal fat pad that can be missed on sensitive abdominal imaging or routine autopsy.13 Bilateral congenital adrenal aplasia has nonetheless been documented at careful autopsy examination.14 Congenital adrenal hypoplasia refers to distinct clinical conditions characterized by underdevelopment or hypoplasia of the adrenal cortex, and based on its physiopathology can be broadly classified as primary or secondary.15 The causes of adrenal cortical insufficiency in general are complex, even in the congenital category, and can have varied phenotypic

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manifestations. DAX-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X-chromosome) and steroidogenic factor-1 (SF-1) are two important transcription factors that belong to the nuclear receptor superfamily.16 These play an important role in human adrenal and reproductive development. Alterations in the genes encoding these factors (e.g., deletions, mutations) are associated with an ever-expanding range of phenotypic adrenal and reproductive abnormalities. Adrenal hypoplasia congenital (AHC) is not to be confused with the much more common disorder congenital adrenal hyperplasia (CAH). NROB1 is the gene encoding DAX-1 and is the key gene in which alterations are known to cause X-linked AHC with infantile-onset acute primary adrenal insufficiency. This severe adrenoprival disorder in male infants can manifest as vomiting, difficulty feeding, dehydration, and shock caused by salt wasting. If unrecognized or left untreated, acute adrenal insufficiency can be rapidly fatal with hyperkalemia, acidosis, and shock. At autopsy, combined adrenal weights can be markedly decreased (e.g., 0.5 g in the first week of life). In X-linked AHC, several histologic patterns of cortical atrophy have been described. The miniature adult form has small amounts of cortical tissue resembling the adult or definitive cortex, and the cytomegalic form has enlarged cells with abundant cytoplasm and absence or near absence of the adult or definitive cortex. Phenotypic variation can occur with X-linked form of AHC with delayed onset into adult life or variation in manifestation of hypogonadotropic hypogonadism. Other forms of AHC exist, with some having autosomal inheritance and even presentation in females. SF-1 is also a nuclear receptor with encoding gene NR5A1 located on the long arm of chromosome 9. This is a pivotal factor in initiation and fetal maturation of the adrenal cortex. In the absence of SF-1 expression, the adrenal gland does not form as shown by adrenal aplasia in SF-1 knockout mice.16 Alterations in SF-1 are rarely associated with adrenal cortical insufficiency, but a range of reproductive phenotypic abnormalities are more common including 46XY disorders such as gonadal dysgenesis, hypospadias, and anorchia; in 46XX females, alterations in SF-1 are associated with primary ovarian insufficiency.17

Adrenal Heterotopia During embryologic development, the adrenal primordium is in close proximity to the urogenital ridge, accounting for the accessory and heterotopic adrenal tissue that may occur in sites in the upper abdomen and along lines of descent of the gonads.3 Heterotopic adrenal tissue has been described in up to 32% of patients in the region of the celiac axis, and, at this site, approximately one-half of the lesions contained both cortex and medulla.18 Accessory adrenal tissue in sites further removed from the upper abdomen usually consists of cortical tissue alone, without the distinctive zonation of the normal adult adrenal gland. Other sites of heterotopia include the broad ligament near the ovary (23%), the liver, the kidney (6%, usually subcapsular), along the spermatic cord (3.8% to 9.3%; a higher incidence was observed for males undergoing surgery for an undescended testis), the testicular adnexa (7.5%), and other rarely described sites that defy ready embryologic explanation such as the placenta, lung, mediastinum, and an intracranial intradural location.19-29 Only rarely have intratesticular or intraovarian cortical rests occurred within the substance of the gonads.30,31 Cases have been reported of hyperplastic cortical nodules arising from accessory adrenal tissue along the spermatic cord and the broad ligament, and adrenal cortical neoplasms have been reported, rarely, in hepatic parenchyma and the spinal canal.32-36 Intraadrenal bile

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ductules have been reported in association with adrenohepatic fusion; heterotopic intraadrenal liver has also been reported.37,38

Union and Adhesion Union or adhesion of the adrenal gland to kidney or liver has been reported, the distinction being whether a continuous connective tissue capsule separates the two organs.39 Adrenal fusion is a rare anomaly in which the adrenal glands are fused in the midline and may be associated with other congenital midline defects such as spinal dysraphism or indeterminate visceral situs.3 Abnormal adrenal shape has been reported in some cases of renal agenesis, in which the glands may be ovoid with smoother contours.3

Adrenal Cytomegaly Congenital adrenal cytomegaly is usually an incidental finding in an adrenal gland that otherwise appears grossly normal. It has been reported in approximately 3% of newborn autopsies and 6.5% of premature stillborns.40 The cytomegaly affects cells of the fetal (provisional) cortex and may be bilateral or unilateral, focal or diffuse. The cytomegalic cell has an enlarged hyperchromatic nucleus and increased volume of cytoplasm. Nuclei may be markedly pleomorphic and occasionally contain intranuclear pseudoinclusions, which are indentations of the nucleus with invagination of cytoplasm. Despite the marked nuclear abnormalities, mitotic figures are characteristically absent. Adrenal cytomegaly is a characteristic component of the Beckwith-Wiedemann syndrome (Fig. 16.9), sometimes called the EMG syndrome, which refers to a major triad of findings— exomphalos, macroglossia, and gigantism.3,41-43 The estimated frequency of this disorder is 1 in 13,000 births; most reported cases are sporadic, although some seem to have a mendelian pattern of inheritance.3 The disorder is caused by dysregulation of growthregulatory genes within the 11p15 region, resulting in loss of normal growth control and increased incidence of certain cancers.44,45 The adrenal glands in this disorder are enlarged, with combined weights as high as 16 g. The adrenal cytomegaly is usually marked and is typically bilateral and diffuse. Curiously, adrenal chromaffin

tissue may be hyperplastic or inappropriately mature.4,43 Visceromegaly may be present, affecting the kidneys and pancreas, and some infants develop severe neonatal hypoglycemia that may prove fatal. An increased incidence of malignant tumors is seen in this disorder, usually Wilms tumor or adrenal cortical carcinoma (ACC), but other neoplasms have been reported including neuroblastoma, pancreatoblastoma, and hepatoblastoma.3,46-49 The presence of hemihypertrophy in children predicts a greater risk for the development of a malignant neoplasm. Adrenal cytomegaly has also been associated with fetal hydrops resulting from Rh incompatibility or hemoglobin Bart.50

Adrenoleukodystrophy Adrenoleukodystrophy (ALD) is a clinically heterogeneous disease and occurs in multiple forms. Most cases of ALD are X-linked. The molecular basis of X-linked ALD is mutation of the gene (ABCD1) encoding a peroxisomal membrane protein (ALDP), resulting in an increase in very-long-chain fatty acids and reduced oxidation thereof in the peroxisomes.51-54 The lipid material accumulates in tissue as cholesterol esters that may exert a toxic effect on cells, with crystallization of lamellae and disruption of cell membranes.3 This mechanism may account for the pathogenesis of adrenal cortical insufficiency and degeneration of white matter, particularly involving the posterior cerebrum, cerebellum, and descending corticospinal tracts. Three main forms of X-linked ALD are known: (1) the childhood form, which is a progressive central demyelinization leading to total disability within 2 years of onset; (2) the adult form, also known as adrenomyeloneuropathy, in which a slowly progressive spastic paraparesis and distal polyneuropathy occur, with onset usually in the second or third decade of life; and (3) a variant that has a primary presentation of adrenal insufficiency.3 ALD or adrenomyeloneuropathy should be considered in the differential diagnosis of boys or young men who present with unexplained adrenal cortical insufficiency, because neurologic symptoms may not be evident at the time of presentation.51-54 A rare fourth neonatal form usually has an autosomal recessive inheritance.3 The adrenal glands in ALD are often quite small. Thinning of the adrenal cortex occurs, with characteristic enlargement of cortical cells having abundant ground-glass or waxy cytoplasm; these cells have been called balloon cells and may have a fibrillar or striated appearance caused by lipid material being extracted during routine processing.55 On ultrastructural examination, bilamellar and lamellar lipid inclusions can be seen, which are virtually pathognomonic for the disorder. The adrenal cortical insufficiency in this disorder is primary and not caused by pituitary or hypothalamic dysfunction. The recent molecular advances regarding the X-linked form of this disease have major implications for the possibility of gene-based therapy.51,54,56 A comprehensive review of the pathophysiology of X-linked ALD has recently been published.57

Congenital Adrenal Hyperplasia

Fig. 16.9 Adrenal gland in Beckwith-Wiedemann syndrome. Provisional zone of the fetal adrenal gland shows prominent cytomegaly with cells having greatly enlarged hyperchromatic nuclei. Small nests of neuroblastic cells are also evident (arrows).

CAH, also known as adrenogenital syndrome, is a rare autosomal recessive disorder usually caused by a deficiency of one of five different enzymes in the steroid biosynthetic pathway of the adrenal cortex (Fig. 16.10).3,58 The first description of a case of CAH was in 1865 by the Italian anatomist de Crecchio, who dissected the cadaver of an apparent male of approximately 40 years of age who had bilateral cryptorchidism and partial hypospadias; however, further examination revealed a vagina, uterus, fallopian tubes, ovaries, and very large adrenal glands.59 The subject was also said to

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Cholesterol a Pregnenolone c

b Progesterone d

c

g 17-Hydroxyprogesterone d

Dehydroepiandrosterone b h

11-Deoxycorticosterone e Corticosterone i

Deoxycortisol e Cortisol

Androstenedione

Estrone

f Testosterone

(glucocorticoids)

Aldosterone (mineralocorticoids) Fig. 16.10 Normal biosynthetic pathway of adrenal cortical steroid synthesis. a ¼ 20,22 hydroxylase and 20,22 desmolase; b ¼ 3β-hydroxysteroid dehydrogenase; c ¼ 17-hydroxylase; d ¼ 21-hydroxylase; e ¼ 11β-hydroxylase; f ¼ 17-ketosteroid reductase; g ¼ 17,20 desmolase; h ¼ P450 aromatase; i ¼ 18-hydroxylase and 18-aldehyde synthetase.

have had frequent diarrhea and vomiting and in his final days had extreme weakness and exhaustion, which almost certainly represented an addisonian crisis. The most common cause of CAH is 21-hydroxylase deficiency, which accounts for approximately 90% to 95% of cases.58,60 This deficiency has been divided into a classic form, with an incidence of 1 in 5000 to 15,000 live births in most white populations; a nonclassic form, which is among the most frequent of autosomal recessive disorders in the white population; and a cryptic form in which patients are asymptomatic despite having the same biochemical abnormality.58,60 Mutations in the encoding gene have been confirmed as the basis of endocrine disease in all adrenal steroidogenic enzymes required for the synthesis of cortisol. In 21-hydroxylase deficiency, insufficient production of cortisol occurs, resulting in a lack of negative feedback at the hypothalamic-pituitary level and secondary trophic stimulation of the adrenal glands by increased ACTH levels. In approximately two-thirds of cases of the classic disorder, biosynthesis of aldosterone is also affected, leading to salt wasting; if unrecognized or severe enough, this may result in death in the first few weeks of life.3 The remaining one-third of cases have simple virilizing disease, without significant impairment of aldosterone biosynthesis. Because of the enzymatic block, precursor steroids accumulate and spill over into the sex steroid pathway with increased androgen production. The development of external genitalia is under the control of androgens in utero, and, because of this, affected females usually have ambiguous genitalia with clitoromegaly and fusion of the labioscrotal folds, although the internal female organs develop normally. In females, the ambiguous genitalia may be so extreme that the child is incorrectly assumed to be male. Affected males usually appear normal at birth. For this reason, males with the disorder may not be diagnosed until they present with more severe symptoms, often related to a potentially fatal salt-wasting crisis. The identification of mutations in the CYP21 gene, which encodes the 21hydroxylase enzyme, has led to advances in DNA diagnosis, including prenatal and newborn screening programs.

Approximately 5% to 8% of cases of CAH are caused by the classic form of 11β-hydroxylase deficiency because of mutations in the CYP11B1 gene.61 Other enzymatic defects causing CAH include deficiency of 3β-hydroxysteroid dehydrogenase, 17αhydroxylase, and the rare mutation in the gene encoding steroidogenic acute regulatory protein (StAR), which seriously interferes with adrenal and gonadal steroidogenesis by a defect in the conversion of cholesterol to pregnenolone.62 The latter defect causes congenital lipoid hyperplasia.

Pathology of Adrenal Glands in Congenital Adrenal Hyperplasia Today it is very uncommon to examine the adrenal glands of patients who died of unrecognized or untreated CAH. Grossly, the adrenal glands are enlarged, often with a convoluted or cerebriform surface with excess cortical plications and folding. The glands frequently have a light-brown color reminiscent of the zona reticularis, resulting from the sustained trophic effect of ACTH and the conversion of lipid-rich, pale-staining cells to cortical cells with lipid-depleted compact eosinophilic cytoplasm (Fig. 16.11). In children, the weight of each adrenal gland may be 10 to 15 g, whereas in older individuals each gland may weigh 30 to 35 g.3 Congenital lipoid hyperplasia is the most fatal form of CAH in which there is accumulation of cholesterol and cholesterol esters giving the adrenal glands a bright-yellow or white appearance on cross-section.62 Testicular Adrenal Rest Tumors in Congenital Adrenal Hyperplasia Male patients with CAH—particularly but not exclusively the saltwasting form of 21-hydroxylase deficiency—may develop one or more testicular adrenal rest tumors (TARTs). In a study of 244 patients with CAH, the prevalence of TART on ultrasound examination was 33% in boys and 44% in men.63 The tumors are often bilateral (83%) and may cause testicular pain and tenderness.64 Several reports in the literature clearly document that the tumors

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Fig. 16.11 Adrenal gland in congenital adrenal hyperplasia. (A) Note the convoluted or cerebriform surface of the gland in this whole-mount section. (B) Microscopically, the adrenal cortical cells have a compact eosinophilic cytoplasm with depletion of the normal lipid content.

are ACTH dependent, as evidenced by reduction in testicular size and associated symptoms with suppressive doses of dexamethasone and recrudescence of testicular enlargement with ACTH stimulation. Laboratory testing also has demonstrated ACTH-dependent steroidogenesis by the tumors.65 The tumors may be 2 to 10 cm in diameter in older patients. Most of the smaller tumors appear to be in the hilum of the testis, but with larger tumors the precise site of origin is difficult to determine.64 Rete testis–associated nodular steroid cell nests have been reported with immunoreactivity for melan A, inhibin, and calretinin, and may represent the putative histogenetic cell for TART.66 On cross-section, TARTs often have a lobulated appearance with bulging, tan to dark-brown nodules. The histologic appearance resembles that of a Leydig cell tumor; however, some features may distinguish these two tumors. Nuclei are usually round to oval with a single prominent nucleolus, which may be central or somewhat eccentric. Cells have granular, pink cytoplasm with relatively distinct cell borders. The cells are usually arranged in sheets or small nests with intersecting fibrous bands, and reticulum stain often demonstrates an intimate pattern of isolation of individual and small clusters of cells. As opposed to Leydig cell tumors, TARTs lack Reinke crystalloids, exhibit more extensive fibrosis, and may contain lymphoid aggregates. Nuclear pleomorphism is reportedly prominent in contrast with Leydig cell tumors, and mitotic activity is rare. Most TARTs are strongly positive for synaptophysin, whereas only rare Leydig cell tumors are immunoreactive with synaptophysin.67 Virtually identical testicular tumors of this type have been reported in males with Nelson syndrome (pituitary adenoma after bilateral adrenalectomy); rarely, a female with Nelson syndrome may develop similar adrenal rest tumors in the region of the ovaries, where heterotopic adrenal cortical tissue occasionally is found.68 Rare examples of histologically similar tumors have been reported in the ovary of women with CAH.69,70 It is unclear whether TARTs are true neoplasms or hyperplastic nodules. In favor of hyperplasia are their ACTH dependence and bilaterality.

Other Tumors Associated With Congenital Adrenal Hyperplasia Rare cases of adrenal cortical adenoma (ACA) and ACC have been reported in patients with CAH.3,71,72 It has been suggested that persistent ACTH stimulation may result in neoplastic transformation of some adrenal cortical cells, but this is unproved.

Other tumors have been reported in association with CAH, including bilateral adrenal myelolipomas, osteosarcoma, and Ewing sarcoma, but their relationship with CAH and the underlying biochemical abnormality is unclear.73,74

Stress-Related Changes of the Adrenal Gland One of the most common histologic changes observed in the adrenal gland of patients under stress is the conversion of lipid-rich, pale-staining cortical cells of the zona fasciculata to cells with compact, lipid-depleted eosinophilic cytoplasm. This is particularly common in acquired immunodeficiency syndrome (AIDS) (Fig. 16.12). Another abnormality reported in stress-related conditions is degeneration of the outer zona fasciculata, initially described as tubular degeneration; this abnormality appears with scattered necrosis of cortical cells, shedding of vacuolated cytoplasm, and exudation of fluid into cords of cortical cells in the outer zona fasciculata.75 A peculiar vacuolization of the fetal adrenal cortex has been described in infants with erythroblastosis fetalis, and nearly identical changes have been observed in thalassemia major.3 A relationship with intrauterine stress and hypoxia has been

Fig. 16.12 Adrenal gland of an adult who died of acquired immunodeficiency syndrome. The cortex showed severe lipid depletion, characterized by numerous cells with compact eosinophilic cytoplasm. The capsule of the adrenal gland is present on the far right.

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suggested. A pattern of focal lipid depletion has been reported as lipid reversion, which suggests recovery from stress and replenishment of lipid in cells of the inner zona fasciculata. In areas of lipid reversion, the outer aspect of the adrenal cortex contains little or no lipid, although lipid is prominent in the inner zona fasciculata.7

Other Abnormalities Conspicuous iron accumulation occurs in the form of hemosiderin in cells of the outer cortex, particularly the zona glomerulosa, in conditions such as primary hemochromatosis and transfusion hemosiderosis.3 In some cases, associated hypothalamic-pituitary dysfunction is caused by excess iron deposition, which may result in endocrine insufficiency of the gonads, thyroid gland, and adrenal glands. A variety of drugs and cytotoxic agents have direct antiadrenal activity; examples include dichlorodiphenyltrichloroethane (DDT) and its derivative o,p0 DDD, which has been used for palliative treatment of patients with ACC because of its adrenolytic effect on normal and neoplastic cortical cells. Another agent with antiadrenal activity is ketoconazole, a broad-spectrum antifungal drug that blocks adrenal steroid synthesis.3 Linear hyaline fibrosis has also been reported in the zona reticularis after radiation, probably because of structural damage of the vascular plexus in this zone.76 Anencephaly is a severe developmental defect of anterior neural tube structures with agenesis of much of the brain and cranial vault. The pituitary gland is difficult to find grossly but is often identified in histologic sections, albeit reduced in amount. The adrenal glands are often extremely small in this disorder, with an average combined weight in one study of 1.8 g, but a significant number weighed less than 1 g.77 The fetal cortex is often normal in size and structure until approximately 20 weeks of gestation, after which it progressively involutes, like changes that normally occur after birth; chromaffin tissue may appear relatively prominent.

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The adrenal gland in this disorder may be greatly reduced in size and volume, making gross identification difficult at autopsy unless numerous tissue blocks from the suprarenal bed are examined. The adrenal cortex has a large endocrine reserve, and it is estimated that up to 90% or more of the cortex must be ablated before functional impairment is apparent.3 In some cases, intercurrent illness, infection, or surgery may precipitate an addisonian crisis. The residual cortex is often thin and discontinuous, with scattered islands of cortical cells (Fig. 16.13) admixed with lymphocytes, plasma cells, and occasional lymphoid follicles, sometimes with reactive germinal centers. Cortical cells may be enlarged, with ample compact, eosinophilic cytoplasm and occasional nuclear alteration, including pseudoinclusions. On occasion, residual cortex may be difficult to identify, and little or no inflammation may be present. Adrenal medulla may appear relatively prominent. APS is characterized by the association of two or more organspecific disorders and has been divided into two forms: APS type 1, also known as autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) and APS type 2. APS type 1 is a rare autosomal recessive disorder with endocrine insufficiency involving various organs, including the adrenal cortex. Numerous mutations in the gene responsible for the disease, AIRE (autoimmune regulator), have been identified. The gene is located on

Nonneoplastic Diseases Chronic Adrenal Cortical Insufficiency (Addison Disease) Idiopathic or Autoimmune Addison Disease In developed countries, 80% to 90% of cases of primary adrenal insufficiency are caused by autoimmune adrenalitis that can be isolated (40%) or part of an autoimmune polyendocrine syndrome (APS; 60%).78 The most common type of Addison disease is idiopathic or autoimmune and is regarded as an organ-specific autoimmune form of adrenalitis. It has been suggested that Addison disease has a strong genetic component, including APS and, more often there is expression of disease susceptibility with alleles associated with organ-specific autoimmunity (MHC, CTLA4, PTPN22), and those that encode proteins of innate immune response.79 It has been shown that presence of autoantibodies directed against the enzymes of steroid hormone production, predominantly 21-hydroxylase, and their detection may be helpful in predicting the risk for developing the disease.79,80 A recent detailed review summarizes adrenal insufficiency including epidemiology and pathophysiology.78 The frequency of the causes of primary adrenal insufficiency in children differs substantially from that in the adult population. Genetic forms are more common, with the most frequent cause of primary adrenal insufficiency being CAH (72%) with other genetic causes accounting for another 6%; autoimmune Addison disease was diagnosed in only 13%.81

Fig. 16.13 Primary idiopathic or autoimmune form of Addison disease. Atrophic adrenal cortex (right side) contains cells with compact, eosinophilic cytoplasm. The medulla is present on the left.

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chromosome 21 (21q22) and encodes a protein involved in transcriptional regulation.82-85 This disorder has a variety of manifestations including Addison disease.86 APS type 2 is defined by the occurrence of Addison disease, thyroid autoimmune disease, or type 1 diabetes mellitus. The combination of nontuberculous Addison disease and thyroid insufficiency is sometimes referred to as Schmidt syndrome.87

Adrenal Tuberculosis Adrenal tuberculosis once was the leading cause of Addison disease.88 According to the review by Guttman of cases between 1900 and 1929, 70% resulted from tuberculosis, and 19% were caused by primary or idiopathic atrophy.89 The endemic nature of bovine tuberculosis in the early decades of the twentieth century is reflected in the comment by Dunlop, who characterized cream on top of the milk in those days as often being composed of “tuberculous pus.”90 The tuberculous adrenal gland is often enlarged, with extensive areas of caseous necrosis. A classic granulomatous reaction with numerous epithelioid histiocytes is present typically in extraadrenal sites but not the adrenal, suggesting that the locally high levels of adrenal corticosteroids dampen the host inflammatory response.3 Histoplasmosis and Other Fungal Infections Disseminated histoplasmosis is a recognized cause of Addison disease and typically involves the glands bilaterally. In a study of almost 100 cases, 7% of patients had chronic adrenal cortical insufficiency.91 Similar to tuberculosis, extensive caseous necrosis is a common finding, although a granulomatous response is the exception rather than the rule. Perivasculitis involving extracapsular adrenal vessels may lead to extensive infarction and caseous necrosis, resulting in loss of adrenal parenchyma and development of Addison disease. Other mycotic infections causing Addison disease are less frequent, including North American blastomycosis, South American blastomycosis, coccidioidomycosis, and paracoccidioidomycosis.3,92 On microscopic examination, the organisms are often found clustered within the cytoplasm of macrophages (Fig. 16.14). They are spherical to oval and typically have single buds attached by a relatively narrow base.

Fig. 16.15 Amyloidosis of the adrenal cortex. Only small nests of cortical cells remain (arrows).

Amyloidosis The adrenal gland may be involved in primary and secondary forms of amyloidosis. In primary amyloidosis, involvement of arterioles tends to occur; whereas, in the secondary form, there is usually extensive involvement of the cortex by the characteristic homogeneous eosinophilic material, resulting in severe atrophy and distortion of cells in the zona fasciculata and zona reticularis (Fig. 16.15). In advanced cases, cortical function can be impaired.93 A historical review of amyloidosis is provided elsewhere.94

Acute Adrenal Cortical Insufficiency

Fig. 16.14 Histoplasma capsulatum infection of the adrenal gland (left). Fungal organisms present within macrophages are highlighted by Gomori methenamine silver stain (right).

Acute adrenal cortical insufficiency can occur in the setting of systemic infection with Waterhouse-Friderichsen syndrome but is seldom documented by laboratory or biochemical studies. Waterhouse-Friderichsen syndrome is seen classically in meningococcemia, but occasionally other bacteria, such as Streptococcus species, staphylococci, Rickettsiae, Ehrlichia, Clostridium species, Klebsiella species, Legionella species, Bacillus anthracis, and Treponema pallidum, are responsible.95 The course of the disease is usually fulminant, with a fatal outcome within 48 hours of onset, and accompanied by mucocutaneous petechial hemorrhages and vascular collapse. The adrenal gland is usually intensely hemorrhagic, with confluent areas of coagulative necrosis, often associated with

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small fibrin deposits within sinusoids; occasionally more extensive hemorrhage occurs, with expansion of the gland and periadrenal hemorrhage (Fig. 16.16).

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911

Inflammation and Other Infections Nonspecific Adrenalitis Focal chronic adrenalitis is common and has been found in up to 48% of autopsies, appearing as small aggregates of lymphocytes admixed with plasma cells adjacent to veins or venules in the corticomedullary junction.96 Focal chronic adrenalitis of this type is not considered to be a primary adrenal disorder but may represent a nonspecific inflammatory reaction, possibly related to inflammation in neighboring organs, such as chronic pyelonephritis. Autoantibodies may be directed against adrenal medullary or chromaffin cells in type 1 (insulin-dependent) diabetes mellitus, and this organ-specific autoimmunity might be related to diabetic autonomic neuropathy.4 Herpetic Adrenalitis Members of the herpes virus group may infect the adrenal gland, including herpes simplex virus, cytomegalovirus (CMV), and varicella-zoster virus. A characteristic pattern of herpetic adrenalitis occurs with disseminated herpes simplex infection in newborns, referred to as neonatal hepatoadrenal necrosis and first described by Hass in 1935. The foci of herpes simplex or varicella-zoster infections tend to be small, circumscribed, punched-out areas of coagulative necrosis, with scant inflammation.97 The necrosis within the cortex may become widespread and confluent.3 Eosinophilic Cowdry type A intranuclear inclusions are the diagnostic hallmark, usually occurring in cells bordering the zones of necrosis (Fig. 16.17A). It may not be possible to distinguish varicella-zoster infection from herpes simplex by routine light microscopy. Disseminated CMV infection in newborns involves a wide variety of organs and tissues, including the adrenal gland. Some infants may have multiple mobile blue-gray subcutaneous nodules caused by dermal erythropoiesis. The appearance of the pigmented nodules may be striking, giving the infant an appearance described as a “blueberry muffin.”3 The viral cytopathic effect in CMV adrenalitis is virtually pathognomonic, with sharply defined large amphophilic intranuclear inclusions having characteristic halos and small, basophilic granules within the cytoplasm (Fig. 16.17B). CMV adrenalitis was relatively common in patients with AIDS; death is attributed in part in some cases to adrenal cortical insufficiency. In one study, approximately 50% of patients with AIDS had evidence of CMV infection at autopsy, and the adrenal glands were most commonly involved (75%) with cortical or medullary necrosis.98 Necrosis of the medulla caused by CMV infection may be greater than that of the cortex, but it is useful to note that there is no deficiency syndrome caused by destruction of the adrenal medulla. CMV infection of the adrenal gland in AIDS may result in latent or overt adrenal cortical insufficiency, requiring prophylactic treatment with corticosteroids.99

Fig. 16.16 Adrenal glands in Waterhouse Friderichsen syndrome. (A) In situ photograph showing bilateral hemorrhagic adrenal glands in a suprarenal location (autopsy specimen, from files of Armed Forces Institute of Pathology, Washington, DC). (B) Extensive necrosis and hemorrhage are seen in this adrenal gland and extend into periadrenal connective tissue. (From Lack EE, Kozakewich HPW. Pathology. In: Javadpour N, ed. Principles and Management of Adrenal Cancer. Berlin: Springer-Verlag; 1987:19–55).

Rare Infections Rarely, the adrenal gland is involved by other infectious agents, such as Pneumocystis jiroveci (Fig. 16.18), the most common opportunistic infection in patients with AIDS that rarely occurs in immunocompetent individuals.100,101 Malakoplakia of the adrenal gland has been reported.102,103 Echinococcal cyst of the adrenal gland is usually an incidental autopsy finding.104 A review of adrenal infections by Paolo and Nosanchuk is available.105

Adrenal Cortical Hyperplasia Nodular Adrenal Gland Cortical nodularity in the adrenal gland can pose significant diagnostic problems for the pathologist at the autopsy table and in

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Fig. 16.17 Herpetic adrenalitis. (A) Herpes simplex virus infection. Note the multiple intranuclear eosinophilic Cowdry type A inclusions (arrows) with peripheral displacement of nuclear chromatin (inset). (B) Cytomegalovirus infection. The adrenal cortical cells infected by the virus show the characteristic cytomegalic changes. Insets highlight the large, amphophilic intranuclear inclusions with peripheral halo.

Fig. 16.18 (A) Adrenal gland extensively involved by Pneumocystis jiroveci infection in a patient with acquired immunodeficiency syndrome. Note the characteristic foamy exudate in the cortex. (B) Gomori methenamine silver stain shows several P. jiroveci organisms (arrow); some organisms have cup-shaped indentations when viewed in profile.

surgical material. Nodularity usually occurs in individuals without biochemical or clinical signs or symptoms of adrenal cortical hyperfunction. By definition, hyperplasia refers to an increase in the number of cells in tissue or in an organ, which may result in hypertrophy. In the adrenal cortex, the changes may be diffuse unilateral or bilateral with or without formation of cortical nodules (Fig. 16.19). The morphologic spectrum of diffuse and nodular adrenal cortical hyperplasia is broad. The incidence of cortical nodularity with eucorticalism can be analyzed from material obtained at autopsy or in patients who are discovered to have incidental cortical nodules in vivo.

Incidental Cortical Nodule/Adenoma at Autopsy Early studies of incidental adrenal cortical nodularity at autopsy considered any solitary adrenal cortical nodule greater than 3 to 5 mm in diameter to be a nonfunctional adenoma.3 Several autopsy studies have shown that the incidence of cortical nodularity increases with age and may be associated with hypertension and diabetes mellitus.106,107 The early study by Spain and Weinsaft identified solitary ACA in 29% of elderly women.108 Another autopsy study reported a cortical adenoma 1.5 cm or larger in up to 20% of hypertensive individuals in contrast with only 1.8% of normotensive patients.109 In two of the largest autopsy studies of ACA (study population over 16,000), lesions were detected in 1.5% to 2.9% of cases.110,111 More recent data indicate a prevalence of an incidental adrenal mass to occur in approximately 3% to 7% of the adult

Fig. 16.19 Schematic view of nodular adrenal gland in transverse section. Accessory nodules of cortical cells may be seen lying free within periadrenal fat, on the capsular surface, or attached to the underlying cortex (capsular extrusion). A dominant macronodule within the cortex can simulate a neoplasm. Multiple small capsular arterioles are present on the surface of the gland. The central adrenal vein in the medullary compartment has discontinuous bundles of smooth muscle, allowing close contact of chromaffin cells or cortical cells with vascular lumina. Occasionally a mushroom-like intravascular protrusion by cortical or medullary cells can be seen.

population.112 The average size of the incidental adrenal cortical nodule/adenoma in one study was 2.8 cm, but some reached 5 cm in diameter. The autopsy study by Dobbie showed that incidental adrenal cortical nodules may be present in virtually every

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region of the cortex, with the degree of nodularity varying widely from gland to gland.106 Adrenal nodularity was almost always bilateral, and, in some cases, there was significant disparity in the weights of the glands from an individual patient. Some nodules were as large as 3 cm in size and may display lipomatous or myelolipomatous metaplasia. Although no specific size criteria have been developed for distinguishing cortical nodules and adenomas, most cortical nodules are less than 1 cm in size. Some cortical nodules seemed to be related to capsular arteriopathy which, in turn, is related to aging, and one theory in pathogenesis of cortical nodules was localized ischemia with secondary regenerative change.106 Based on this theory, most cortical nodules could be regarded as secondary to hypertension rather than a cause of it. Other investigators have logically questioned the validity of this theory.

Incidental Adrenal Mass Discovered in Vivo With increasing use of high-resolution abdominal imaging, an adrenal mass may be detected as an incidental finding that is often referred to as an adrenal “incidentaloma,” but the significance in most cases is unclear.112-114 Fortunately, the prevalence of malignant tumors among incidentaloma is relatively low. In a study from the Mayo Clinic, there were a large number of patients with an adrenal mass detected by computed tomography (CT) scan and following exclusion of patients with known malignancy, tumors previously documented by biochemical study, and adrenal nodules less than 1 cm in size, there were 342 patients remaining with an adrenal tumor. Histologic proof of diagnosis was obtained in 55 patients at the time of adrenalectomy; 5 patients had a malignant tumor (1.4%), 4 had an ACC, and 1 had a metastatic carcinoma of unknown primary site. Interestingly, the smallest malignant tumor was 5 cm in size, and of the benign, incidentally discovered lesions, only 6% were 5 cm or larger.115 Another study showed that the likelihood of malignancy doubles to 10% with tumors 4 cm or larger and there is more than a ninefold increase in the likelihood of malignancy in tumors 8 cm or larger.116 Magnetic resonance imaging (MRI) may provide some information on tissue characterization of adrenal masses; T2-weighted pulse sequences provide some specificity in separating nonhyperfunctioning cortical adenomas, which have low signal intensity, from metastases with intermediate signal intensity and pheochromocytomas, which tend to have high signal intensity.117 Pheochromocytomas, however, are not always “light bulb bright” on T2-weighted MRI. This imaging modality does not allow for clear distinction between functional and nonfunctional (or nonhyperfunctional) ACA or small ACC that lack necrosis and other secondary changes. Adrenal cortical scintigraphy with a radioiodinated cholesterol precursor often showed tracer uptake, indicating cortical steroid synthesis.118,119 Various enzymes involved in cortical steroid synthesis are present, based on immunohistochemical staining, indicating that the nodules have the capacity for corticosteroidogenesis, although not in sufficient amounts to elicit signs or symptoms of endocrine hyperfunction or abnormal biochemical findings to alter the hypothalamic-pituitary-adrenal axis.120 Many incidental cortical nodules (or adenomas) are therefore considered nonhyperfunctional rather than nonfunctional, without excess production of adrenal cortical steroids. Cortical nodularity in this setting has been compared with nodular euthyroid (nontoxic) goiter. Incidental Pigmented Cortical Nodule Incidental pigmented nodules of adrenal cortex usually vary from 0.1 to 1.5 cm in size and are usually located in or straddle the zona

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913

Fig. 16.20 Incidental pigmented adrenal cortical nodule. The adjacent cortex contained numerous small pale-yellow nodules.

Fig. 16.21 Incidental pigmented adrenal cortical nodule. Cells contain abundant granular lipofuscin pigment. Nuclei are uniform, and many contain a small central to eccentric nucleolus.

reticularis, often with expansion and distortion of the adjacent cortex or medulla (Fig. 16.20). The frequency of grossly identifiable pigmented nodules at autopsy varies according to the method of adrenal sectioning, the number of sections examined, and the level of interest of the pathologist in specifically searching for the lesions. Retrospective studies of autopsy material reported pigmented adrenal cortical nodules in 2.2% to 10.4% of cases.121,122 When the glands were thinly sectioned in a prospective study, pigmented nodules were detected in 37% of cases.121 Pigmented nodules are usually solitary but may be multiple, and in 11% of cases are bilateral. Histologically, the cells have compact eosinophilic cytoplasm with variable amounts of intracellular granular brown pigment, which has staining characteristics like those of lipofuscin (Fig. 16.21). One study suggested the presence of neuromelanin.122

Management of the Incidental Adrenal Mass Discovered in Vivo There have been a number of recommendations over the past few decades addressing the strategy or algorithm in the workup of patients with an incidentaloma.113,114,123,124 According to the National Institutes of Health consensus panel (Table 16.1), all patients with incidentaloma should undergo a 1-mg dexamethasone suppression test and measurement of plasma-free metanephrines. Patients with hypertension should undergo measurement of serum potassium and plasma aldosterone concentration–plasma renin activity ratio. Patients with biochemical evidence of pheochromocytoma, patients with tumors larger than 6 cm, and patients with tumors larger than 4 cm who meet other criteria should undergo

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TABLE 16.1 • • • • • • •

•

•

•

Adrenal Glands

National Institutes of Health Consensus Conference on Adrenal Incidentalomas

All patients with an incidentaloma should have a 1-mg dexamethasone suppression test and measurement of plasma free metanephrines. Patients with hypertension should also undergo measurement of serum potassium and plasma aldosterone concentration–plasma renin activity ratio. A homogenous mass with a low attenuation value (<10 Hounsfield units) on computed tomography is probably a benign adenoma. Surgery should be considered in all patients with functional adrenal cortical tumors that are clinically apparent. All patients with biochemical evidence of pheochromocytoma should undergo surgery. Data are insufficient to indicate the superiority of a surgical or nonsurgical approach to manage patients with subclinical hyperfunctioning adrenal cortical adenomas. Recommendations for surgery based on tumor size are derived from studies not standardized for inclusion criteria, length of follow-up, or methods of estimating the risk for carcinoma. Nevertheless, patients with tumors >6 cm usually are treated surgically, and those with tumors <4 cm are generally monitored. In patients with tumors between 4 and 6 cm, criteria in addition to size should be considered in the decision to monitor or proceed to adrenalectomy. The literature on adrenal incidentaloma has proliferated in the past several years. Unfortunately, the lack of controlled studies makes formulating diagnostic and treatment strategies difficult. Because of the complexity of the problem, the management of patients with adrenal incidentalomas will be optimized by a multidisciplinary team approach involving physicians with expertise in endocrinology, radiology, surgery, and pathology. The paucity of evidence-based data highlights the need for well-designed prospective studies. Open or laparoscopic adrenalectomy is an acceptable procedure for resection of an adrenal mass. The procedure choice will depend on the likelihood of an invasive adrenal cortical carcinoma, technical issues, and the experience of the surgical team. In patients with tumors that remain stable on two imaging studies done at least 6 months apart and do not exhibit hormonal hypersecretion over 4 years, further follow-up may not be warranted.

Data from Anonymous. NIH state-of-the-science statement on management of the clinically inapparent adrenal mass (“incidentaloma”). NIH Consens State Sci Statements. 2002; 19:1–25; and Grua JR, Nelson DH. ACTH-producing pituitary tumors. Endocrinol Metab Clin N Am. 1991;20:319–362.

surgical resection. Incidentaloma smaller than 4 cm should be followed by imaging. These masses may grow over time. If the growth is rapid, surgical resection is considered. It is estimated that up to 20% of patients with incidentalomas have abnormal cortisol production and could be classified as having subclinical Cushing syndrome.125 In general, all functional incidentalomas should be surgically resected. A detailed flowchart for incidentalomas detected on CT or MRI was developed by the Incidental Findings Committee of the American College of Radiology and provides useful guidelines for these patients.112 Fine-needle aspiration under CT or ultrasound guidance may provide valuable information, particularly when it is not possible to reliably distinguish a metastasis from an adrenal cortical nodule or neoplasm (Fig. 16.22). The distinction between ACA and ACC is not always reliable by fine-needle aspiration. Occasionally, aspiration yields cells with bare nuclei stripped of cytoplasm, which might be confused with a small cell malignancy. Correlation of cytologic findings with imaging results, clinical findings, and endocrinologic data is essential.

Adrenal Cortical Hyperplasia With Hypercortisolism Cushing syndrome has several basic endogenous or noniatrogenic causes (Fig. 16.23). A more detailed tabulation of causes of endogenous Cushing syndrome is given in Table 16.2.126 The three most common causes of Cushing syndrome are pituitary-dependent ACTH overproduction, commonly referred to as Cushing disease, which accounts for approximately 60% to 70% of cases in adults; adrenal cortical neoplasm with autonomous overproduction of cortisol: ACA 10% to 22% and ACC 5% to 7% of cases in adults; and ectopic production of ACTH (5% to 10% of cases); or, very rarely, ectopic production of corticotropin-releasing hormone. In childhood, Cushing syndrome is most often caused by a cortisolproducing cortical neoplasm, particularly in the very young, whereas older children are more likely to have an ACTHdependent form of hypercortisolism (Cushing disease).127 Most patients with an ACTH-dependent form caused by ACTH overproduction have a pituitary microadenoma or macroadenoma. In some cases, no pituitary tumor is detected, and the disease may result from hyperplasia of ACTH-producing corticotrophs or abnormal hypothalamic regulation with secondary ACTH hypersecretion by corticotrophs, which has been referred to as tertiary hypercortisolism.

Fig. 16.22 Adrenal incidentaloma. (A) Fine-needle aspiration (Diff-Quik stain) of adrenal cortical adenoma showing clusters of adrenal cortical cells with microvesiculated cytoplasm and eccentrically placed, round to oval nuclei. (B) The corresponding cell block preparation (hematoxylin and eosin stain) shows a proliferation of adrenal cortical cells, some with microvesiculated, lipid-filled cytoplasm (right) interspersed by cells with a more compact eosinophilic cytoplasm (left).

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Fig. 16.23 (A) Normal hypothalamic-pituitary-adrenal axis (upper left). Pituitary (or adrenocorticotropic hormone)-dependent hypercortisolism (upper right) is characteristic of Cushing disease. Ectopic adrenocorticotropic hormone syndrome (lower half) with enlarged, dark adrenal gland caused by trophic influence of adrenocorticotropic hormone with predominance of cells with compact, lipid-depleted cytoplasm. (B) Noniatrogenic causes of Cushing syndrome. Cortisolsecreting cortical neoplasm (upper left) with autonomous hyperfunction and feedback inhibition of adrenocorticotropic hormone release from adenohypophysis. Rare examples of Cushing syndrome are caused by primary pigmented nodular adrenal cortical disease (upper right) and macronodular hyperplasia with marked adrenal enlargement (lower half).

Pituitary or Adenocorticotropic Hormone–Dependent Hypercortisolism (Cushing Disease) Diffuse and Micronodular Adrenal Cortical Hyperplasia

With the high success rate of transsphenoidal adenomectomy for ACTH-producing pituitary neoplasms, the pathologist rarely has the opportunity to examine adrenal glands in this disorder. Bilateral adrenalectomy is usually done only after failed resection of a pituitary adenoma or when the primary (ectopic) ACTH-secreting neoplasm cannot be identified or removed. Bilateral laparoscopic adrenalectomy has gained an increasing role as a safe and effective therapeutic option.128 The pathologic alterations in the resected adrenal gland(s) may be so subtle that the gland might be regarded as normal if the alterations are not correlated with clinical and biochemical data.3,71 The size and weight of the mildly stimulated gland may be only slightly increased—usually between 6 and 12 g; the average weight in the study by Smals et al. was 8.2 g.129 On transverse sectioning, the adrenal gland may have a somewhat rounded contour, and the larger glands may demonstrate a mild degree of nodularity (Fig. 16.24) with nodules up to 3 mm in diameter randomly distributed throughout the cortex. Capsular extrusions may appear accentuated, as well as the cuff of cortical cells around tributaries of the central adrenal vein. The microscopic

hallmark of ACTH stimulation in Cushing disease is conversion of lipid-rich, pale-staining cortical cells in the inner one-third to onehalf of the cortex into cells with compact eosinophilic cytoplasm, like those in the zona reticularis (Fig. 16.25). The net effect is what appears to be a greatly expanded zona reticularis except for the absence of lipochrome pigment in the outer part, which is zona fasciculata.3,71 The extent to which vacuolated, lipid-rich cells are converted into compact, lipid-depleted cells is variable and may be influenced by a variety of physiologic factors.3 The zona glomerulosa may be even more difficult to identify because of expansion of the zona fasciculata. Some cortical cells may extend irregularly into periadrenal adipose tissue or intermingle in irregular nests with chromaffin cells. Some of these changes may be subtle, particularly in mildly stimulated glands, and correlation with clinical and biochemical data is crucial.3,71 Macronodular Hyperplasia

Macronodular hyperplasia is present in approximately 20% of cases of hyperplasia with Cushing disease, but this is variable.3,130,131 The morphology may be more confusing than that of diffuse or micronodular hyperplasia. Nodules up to 2 cm in diameter or

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TABLE 16.2

Adrenal Glands

Causes of Endogenous Cushing Syndrome

ACTH-dependent Cushing disease Corticotroph adenoma Corticotroph hyperplasia Ectopic ACTH* Malignant neuroendocrine tumours Benign neuroendocrine tumours Occult neuroendocrine tumours Ectopic CRH ACTH-independent Unilateral adrenal Adenoma Carcinoma Bilateral adrenal Bilateral macronodular adrenal hyperplasia† Aberrant G-protein-coupled receptors Autocrine ACTH production Sporadic or familial (ARMC5) Bilateral micronodular adrenal hyperplasias Primary pigmented nodular adrenocortical disease Isolated or familial with Carney complex Isolated micronodular adrenocortical disease Primary bimorphic adrenocortical disease McCune-Albright syndrome Bilateral adenomas or carcinomas

Proportion (%)

Age (peak)

Female:male

Features

70–80 60–70 60–70 Very rare 5–10 About 4

·· ·· 3rd–4th decades ·· ·· 5th–6th decades

·· ·· 3–5:1 ·· ·· 0·6–1:1

·· ·· Roughly 50% non-visible on MRI ·· ·· Might have very high ACTH

About 6

3rd–4th decades

··

Might respond to dexamethasone, CRH, desmopressin

About 2

··

··

··

Very rare 20–30 ·· 10–22 5–7 1–2 <2

·· ·· ·· 4th–5th decades 1st, 5th–6th decades ·· 5th–6th decades

·· ·· ·· 4–8:1 1·5–3:1 ·· 2–3:1

··

··

··

Causes pituitary corticotroph hyperplasia ·· ·· Most pure cortisol secretion Mixed cortisol and androgen frequent ·· Modest cortisol secretion compared with size; raised steroid precursors; might have combined androgen and mineralocorticoid cosecretion ··

·· ·· <2

·· ·· ··

·· ·· ··

·· ·· Adrenal size often normal

Rare

1st–3rd decades

Rare

1st–3rd decades

0·5:1 <12 years 2:1 >12 years ··

Frequent paradoxical increase of urine free cortisol with Liddle’s oral dexamethasone suppression test ··

Very rare

Infants

··

Non-pigmented adrenal micronodules

Very rare

Infants

··

··

Rare Rare

Infants (<6 months) 4th–5th decades

1:1 2–4:1

Internodular adrenal atrophy ··

ACTH =adrenocorticotropic hormone. CRH= corticotropin-releasing hormone.*Most frequent sources of ectopic ACTH syndromes are small cell lung carcinoma and neuroendocrine tumours of lung, thymus, and pancreas. Less frequent causes include medullary thyroid carcinoma, gastrinoma, phaeochromocytoma, prostate carcinoma, and several others. †In bilateral macronodular adrenal hyperplasia tissues, autocrine and paracrine ACTH might be produced and contribute to cortisol secretion. If confirmed by in-vivo studies, the ACTH-independent classification will need to be modified in the future. From Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet. 2015;386:913–927.

larger (Fig. 16.26) protrude from one or more sides of the gland; they also may be situated deep within the adrenal gland, identifiable only when the gland is sectioned in the transverse plane. Smals et al. used the designation macronodular hyperplasia for grossly visible nodules 0.5 cm or more in diameter, with some nodules up to 5 cm in size.129 Separation of micronodular and macronodular hyperplasia is difficult, and a morphologic continuum exists between the two processes, making this distinction arbitrary. Macronodular hyperplasia is often characterized by disparity in size and weight between the adrenal glands. In the study by Smals et al., the female-to-male ratio for macronodular hyperplasia was 5:1, identical to that for diffuse and micronodular hyperplasia.129 However, there were several important differences between micronodular and macronodular hyperplasia. The average age of patients with macronodular hyperplasia (44 years) is considerably older than those with diffuse and micronodular hyperplasia (31 years), and disease duration is longer with macronodular hyperplasia (8 years versus 2 years). The average adrenal gland in macronodular

hyperplasia weighed 16 g, nearly twice the observed weight in diffuse and micronodular hyperplasia.129 As noted by Cohen et al., the medullary compartment may be compressed by the prominent cortical nodules and, in many sections, it may be difficult to recognize (Fig. 16.27).131 Foci of lipomatous or myelolipomatous metaplasia may be present. Ectopic Adrenocorticotropin Hormone Syndrome With Secondary Hypercortisolism

Approximately 5% to 10% of cases of Cushing syndrome in adults result from ectopic production of ACTH by neoplasms such as bronchial carcinoid tumor, bronchogenic small cell carcinoma, pancreatic endocrine neoplasm, medullary thyroid carcinoma, pheochromocytoma, or other rare tumors.132,133 Ectopic production of corticotropin-releasing hormone may occur, very rarely, and be accompanied by orthotopic ACTH secretion by the pituitary gland (tertiary hypercortisolism).3,71 Nearly all normal tissues are capable of producing small amounts of the inactive precursor of

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Fig. 16.24 Transverse sections of a 3.5 g adrenal gland with mild nodularity surgically resected from an 8-year-old boy with Cushing disease. Patient underwent several attempts at transsphenoidal pituitary resection. The patient was also treated with radiation (4800 cGy), but the tumor recurred on several occasions. Nelson syndrome subsequently developed, with radiologically detectable changes in the sella.

Fig. 16.25 Adrenal gland in Cushing disease caused by an adrenocorticotropic hormone–producing pituitary adenoma. The cortex is hyperplastic, with conversion of many cells throughout the zona fasciculata into reticularis-type cells with compact, eosinophilic cytoplasm caused by lipid depletion.

ACTH, probably proopiomelanocortin. Cancers may overproduce this substance, although few convert it into ACTH; in this regard, ectopic ACTH production may not be ectopic.134 Correct identification of the source of ACTH secretion is essential to avoid unnecessary pituitary surgery.135 In ectopic ACTH syndrome, serum levels of ACTH are usually quite elevated, sometimes greater than 250 pg/mL, whereas in Cushing disease ACTH levels are rarely over 200 pg/mL and are commonly in the upper range of normal or only slightly elevated.71 Inferior petrosal sinus sampling can identify a pituitary source of ACTH via central (petrosal sinus) to peripheral blood concentration gradient with a high degree of accurracy.136 Some patients with aggressive, fast-growing tumors, such as bronchogenic small cell carcinoma, lack signs and symptoms of Cushing syndrome, with the clinical findings dominated by electrolyte disturbances and cachexia. Some slowly growing

Fig. 16.26 Macronodular adrenal cortical hyperplasia in a patient with multiple endocrine neoplasia, type 1, who developed Cushing syndrome caused by a presumed adrenocorticotropic hormone–producing pituitary adenoma. Multiple pale cortical nodules range up to 1.5 cm in diameter, including small capsular extrusions (arrow). (Modified from Lack EE, Travis WD, Oertel JE. Adrenal cortical nodules, hyperplasia, and hyperfunction. In: Lack EE, ed. Pathology of the Adrenal Glands. New York: Churchill Livingstone; 1990:75–113.)

neoplasms, such as bronchial carcinoid tumor, may be associated with marked changes of Cushing syndrome, although the primary tumor remains occult, sometimes for years.137 On gross examination, the adrenal glands are often symmetrically enlarged with rounded contours and frequently weigh 10 to 15 g each; occasionally, the individual adrenal gland may weigh more than 20 g or, rarely, 30 g.3,71 In this setting, the adrenal glands are under intense and persistent trophic stimulation by ACTH and on transverse sectioning may be tan to brown because of the conversion of lipid-rich, pale-staining cortical cells to cells with more compact eosinophilic cytoplasm (Fig. 16.28). The cortex is hyperplastic, being 0.3 to 0.4 cm thick, but, in some cases, may be even thicker. Typically, diffuse cortical hyperplasia is present, but sometimes vague nodularity may be seen (Fig. 16.29). Primary Pigmented Nodular Adrenal Cortical Disease

Primary pigmented nodular adrenal cortical disease (PPNAD) is a rare form of pituitary or ACTH-independent hypercortisolism

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Fig. 16.27 Pituitary-dependent macronodular adrenal cortical hyperplasia (same as in Fig. 16.26). Irregular expansile cortical nodules blend with adjacent hyperplastic cortex. The adrenal medulla was difficult to identify in random transverse sections of the gland. (From Lack EE. Tumors of the Adrenal Glands and Extraadrenal Paraganglia. Atlas of Tumor Pathology, Series 4. Washington, DC: Armed Forces Institute of Pathology; 2007:75.)

Fig. 16.28 Ectopic adrenocorticotropic hormone syndrome caused by a bronchial carcinoid tumor that was occult for several years. The right adrenal gland weighed 12 g and the left 11 g. The dark appearance on cross-section is caused by intense stimulation by adrenocorticotropic hormone with conversion of lipid-rich cortical cells to lipid-depleted cells with compact, eosinophilic cytoplasm. (From Lack EE. Tumors of the Adrenal Glands and Extraadrenal Paraganglia. Atlas of Tumor Pathology, Series 4. Washington, DC: Armed Forces Institute of Pathology; 2007:90.)

typically seen in young individuals, with a predilection for females. It is a benign, bilateral adrenal cortical hyperplasia that can be seen as an isolated/sporadic process, but most are characteristic components of Carney complex (see later discussion).138-142 The associated Cushing syndrome may be severe, with bone pain and pathologic fractures.138 A variety of endocrinologic studies, including dynamic endocrine testing, indicate a primary adrenal source for the hypercortisolism. Imaging studies of the sella and pituitary fossa reveal no abnormalities, and selective venous sinus sampling of the inferior petrosal sinus excludes a pituitary origin for PPNAD. The adrenal glands in PPNAD are usually normal on CT scan, but unilateral or bilateral nodularity may be present, including macronodules greater than 1 cm in diameter.71 The weight of each

Fig. 16.29 Ectopic adrenocorticotropic hormone syndrome. The adrenal cortex is markedly hyperplastic, with columns and cords of lipid-depleted cells. Faint nodularity was evident in some areas.

Fig. 16.30 Primary pigmented nodular adrenal cortical disease. Transverse section of the adrenal gland shows numerous dark-pigmented nodules, one nearly 1 cm in diameter (arrow). Another nodule (arrowhead) is pale-yellow and has small foci of necrosis. The patient was a member of a family with the complex of myxomas, spotty pigmentation, and endocrine overactivity. (From Lack EE. Tumors of the Adrenal Glands and Extraadrenal Paraganglia. Atlas of Tumor Pathology, Series 4. Washington, DC: Armed Forces Institute of Pathology; 2007:86.)

gland varies from 0.9 to 13.4 g, with an average combined weight of 9.6 g; the gland is usually normal in size.138 Small pigmented micronodules, 1 to 3 mm in diameter, may be seen through the intact capsular surface of the gland, but transverse sections usually reveal the pigmented nodules to better advantage (Fig. 16.30). Complete removal of the investing connective tissue and fat may be impeded by these small nodules when they protrude through the capsule or extend into the periadrenal fat. The pigmented nodules are light gray, gray-brown, dark brown, or jet black. The term micronodular is somewhat arbitrary because many of the intensely pigmented nodules are grossly apparent, even when they are less than 1 mm in size. The gross pathology of the pigmented nodules is often much more striking than the histologic features (Fig. 16.31). The pigmented nodules are usually round to oval and are present within the zona reticularis or interface with the adjacent medulla. Their configuration varies from hourglass and strings of beads to links

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Fig. 16.31 Pigmented nodules contain cells that are argentaffin positive, causing them to stand out in contrast with the remaining gland. Some areas show marked atrophy of the internodular cortex.

Fig. 16.32 Several pigmented micronodules in primary pigmented nodular adrenal cortical disease (arrowheads) are located in the inner aspect of the cortex and impinge on the medulla.

of sausages. The pigmented nodules are typically unencapsulated but have expansile borders and may cause distortion or compression of adjacent uninvolved cells (Fig. 16.32). Occasionally, intraluminal projection of a small pigmented nodule into tributaries of the central adrenal vein at sites with interrupted bundles of smooth muscle may be seen. In most nodules, the cells contain compact eosinophilic cytoplasm with variable amounts of coarse granular pigment, which usually has the staining characteristics of lipofuscin. Some nodules contain cells with pale-staining, lipid-rich cytoplasm; occasionally, cells may be large with a ballooned appearance. Sparse lymphocytic infiltrates have been noted, rarely, around vessels or within the nodules, and, occasionally, a lipomatous or even myelolipomatous metaplastic component may be seen.71 Regardless of whether familial or isolated/sporadic, PPNAD is linked to mutation of PRKAR1A, a gene encoding the regulatory subunit of a cyclic adenosine monophosphate (cAMP)-dependent protein kinase that is located on chromosome 17 (17q22–24). Studies of families with Carney complex raise the possibility of a second locus affected in the disease on chromosome 2 (2p16).141

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The exact pathogenesis of PPNAD is unknown, but several theories have been proposed such as hamartomatous malformation or dysplasia of the cortex; primary abnormality of the zona reticularis; occult adrenocorticotropic hormone–producing pituitary adenoma with adrenal cortical nodules becoming functionally autonomous; embryonic developmental error in the cortex at the adrenarche; block in evolution of zona fasciculata cells into cells of the zona reticularis, with accumulation of autonomous cells at the interface; and an organ-specific autoimmune hypercortisolism (Cushing syndrome). The autoimmune theory of hypercortisolism is based on reports of circulating adrenal-stimulating immunoglobulin in this disorder; the adrenal-stimulating immunoglobulin is presumably directed against ACTH receptors or receptor-binding sites.143 Further study should determine whether PPNAD is an autoimmune disorder or one in which the circulating adrenal-stimulating immunoglobulin is merely an epiphenomenon. An immunohistochemical study of PPNAD revealed the nodules to be strongly reactive for synaptophysin, whereas the extranodular or internodular cortex was nonreactive.144 This immunohistochemical differential may be helpful in the detection of small nodules in apparently unaffected cortex and suggest a possible neuroendocrine role for the genes involved. A previous report revealed intense immunoreactivity for all enzymes involved in steroidogenesis in cells of the cortical nodules, particularly those with abundant eosinophilic cytoplasm, unlike cells of the internodular cortex.145 The treatment of choice for PPNAD is bilateral adrenalectomy, with the removal of both adrenal glands even if they appear normal or small.146 In some cases, subtotal resection may be possible, although approximately one-third of patients initially treated by unilateral or subtotal adrenalectomy require completion or total adrenalectomy because of persistence or recurrence of Cushing syndrome.146 It is important to note that Nelson syndrome has not been reported after bilateral adrenalectomy in patients with PPNAD. Recently the original four cases of PPNAD were revisited after 30 years, and none of the patients’ primary relatives had Cushing syndrome or Carney complex; these original four patients also had an isolated form of PPNAD without stigmata of Carney complex.147 Complex of Myxomas, Spotty Pigmentation, and Endocrine Overactivity: Carney Complex

This is a complex array of diverse abnormalities that, in the review by Carney et al., included cardiac myxoma (72%); spotty mucocutaneous pigmentation (65%); testicular tumors, particularly large cell calcifying Sertoli cell tumor (56% of males); PPNAD (45%); cutaneous myxoma (45%); mammary myxoid fibroadenoma (30% of females); and other abnormalities such as growth hormone–secreting pituitary tumor and psammomatous melanotic schwannoma.3,71,148 Carney et al. reported four cases of unusual congenital bone tumors associated with Carney complex that they have provisionally named osteochondromyxoma of bone.149 Carney complex has an autosomal dominant inheritance. Two chromosomal loci, 17q22–24 and 2p16, have been identified that are believed to harbor the genes for PPNAD and/or Carney complex.140,141 Germline inactivating mutations (PRKAR1A) have been observed in both Carney complex and PPNAD.150-153 Cardiac myxomas have a significant risk for morbidity and mortality, especially in the setting of Cushing syndrome. Therefore, if a patient has two or more elements of this complex, particularly PPNAD, bilateral large cell calcifying Sertoli cell tumor of the testis, or mucocutaneous pigmentation, investigation for cardiac myxoma (which

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may be multiple) is recommended for early detection and treatment. Recently, 37 cases of Carney complex were studied at the Mayo Clinic with 29 having clinical, pathologic, or laboratory evidence of an adrenal cortical disorder; 17 were found to have classic Cushing syndrome, 15 had PPNAD proven by total or subtotal adrenalectomy, and 2 patients were left untreated.154 Macronodular Hyperplasia With Marked Adrenal Enlargement

Macronodular hyperplasia with marked adrenal enlargement (MHMAE) is a rare primary autonomous form of adrenal hypercortisolism that is ACTH and pituitary independent.3,71 It is a heterogeneous disorder in which cortisol secretion can be mediated by hormones other than ACTH because of the aberrant or ectopic expression of various hormone receptors. Ectopic receptors for gastric inhibitory polypeptide, β-adrenergic receptor agonists, vasopressin, and 5-hydroxytryptamine have been identified, which can act as cortisol secretagogues.155-157 Careful endocrinologic investigation, including dynamic endocrine testing, usually reveals elevated plasma cortisol levels, depressed or undetectable ACTH levels, and loss of diurnal rhythmicity, suggesting a primary adrenal cortical neoplasm. Paradoxically, radiographic imaging reveals bilateral adrenal gland enlargement, with no detectable abnormality of the sella or pituitary fossa, including in one patient who was reinvestigated almost 26 years later.158 An unusual case of ACTHindependent MHMAE occurred in a male patient who presented with feminization and Cushing syndrome; the combined adrenal glands weighed 86 g.71 Another reported case describes massive adrenal gland enlargement, with the left gland weighing 199 g and the right gland weighing 93 g.159 The average patient age is approximately 50 years, with a slight male preponderance (although one series reports a 3:1 female preponderance), and the duration of Cushing syndrome ranges from approximately 1 to 10 years.160 The adrenal glands in MHMAE are significantly enlarged and can simulate an adrenal neoplasm.71 Typically, the combined weight ranges from 60 to 180 g, with an extraordinary degree of nodular cortical hyperplasia; the nodules in one study ranged in size from 0.2 to 3.8 cm (Fig. 16.33).161 The nodules are yellow or golden-yellow, typically unencapsulated, and blend imperceptibly with the hyperplastic cortex. The medullary compartment may be distorted and difficult to recognize in random sections of the gland, similar to macronodular hyperplasia. Cortical cells have a variable amount of finely vacuolated, lipid-rich, pale-staining cytoplasm (Fig. 16.34). Scattered cells with compact eosinophilic cytoplasm may be seen. Rarely, cells with large ballooned vacuolated cytoplasm are present, and occasionally there is a small component of lipomatous or myelolipomatous metaplasia. Weak

Fig. 16.34 Macronodular adrenal cortical hyperplasia with marked adrenal enlargement. Note the multiple irregular nodules of hyperplastic adrenal cortex. Most hyperplastic cells had lipid-rich, pale-staining cytoplasm.

immunoreactivity in MHMAE is seen for 3β-hydroxysteroid dehydrogenase and other enzymes involved in steroidogenesis, whereas strong staining is noted in ACA and PPNAD.145,162 In situ hybridization study of P-450c17 has been used to localize the site of steroidogenesis, and results suggest that the degree of corticosteroidogenesis by individual cortical cells is low and that a significant increase in cell numbers is necessary before excessive cortisol production causes Cushing syndrome.162 As indicated in Fig. 16.35, some had questioned a possible relationship between MHMAE and macronodular hyperplasia of Cushing disease, but current evidence does not support this. Recently the genetic basis of a significant number of cases of MHMAE has been elucidated and found to be associated with germline mutations in armadillo repeat containing 5 (ARMC5) and may coexist with somatic second hit mutations of ARMC5 in MHMAE.156,157 Recently, it has been shown that in addition to cortisol secretion being controlled by aberrant receptors within MHMAE, ACTH is also produced within the adrenal cortical tissue, which may act as a local amplifier for the action of these receptors through some autocrine mechanism(s).155 Some cases, therefore, may not be entirely ACTH independent. The treatment proposed for this rare disorder is bilateral adrenalectomy. As in macronodular hyperplasia in Cushing disease, the clinical, imaging, and biochemical features may be misleading and suggest an underlying adrenal cortical neoplasm.

Multiple Endocrine Neoplasia Type 1

Fig. 16.33 Macronodular adrenal cortical hyperplasia with marked adrenal enlargement. Transverse sections of one adrenal gland are displayed. The combined weight of both glands was approximately 90 g.

Multiple endocrine neoplasia (MEN) type 1 (Wermer syndrome) occurs as an autosomal dominant trait with somewhat variable expression or affects family members in whom manifestations are detectable only after close scrutiny.163 The genetic defect is located on chromosome 11q13.164 In a review by Ballard et al., adrenal findings at autopsy included cortical adenoma, miliary adenoma, hyperplasia, multiple adenomas, and nodular hyperplasia, but only 1 in 31 patients had clinical hypercortisolism.165 Cushing disease may occur in MEN1, but it is rare (Figs. 16.26 and 16.27).166 There is a study reporting 12 malignant endocrine neoplasms in 42 cases of MEN1, 2 of which were ACC; thus, although malignancies tend to play a lesser role in MEN1 than in the other

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Fig. 16.35 Schematic diagram of progression of pituitary (or adrenocorticotropic hormone)-dependent Cushing disease into micronodular and macronodular adrenal cortical hyperplasia. Macronodular adrenal cortical hyperplasia with marked adrenal enlargement appears to be a primary form of adrenal hypercortisolism (Cushing syndrome) by sensitive imaging and biochemical studies. The relationship with macronodular adrenal hyperplasia (lower left) is uncertain.

MEN syndromes, patients still need to be examined and followed with this possibility in mind.167

Other Rare Causes of Cushing Syndrome Cushing syndrome has several other rare causes. One of these is McCune-Albright syndrome (triad of polyostotic fibrous dysplasia, caf
e au lait spots, and precocious puberty), with hyperfunction of various endocrine glands, including adrenal hypercortisolism resulting from a somatic mutation of the GNAS1 gene (a stimulatory gene of the G-protein family) and activation of a signal transduction pathway generating cAMP.168,169 Histologically, the predominant finding is an alternating pattern of nodular cortical hyperplasia and distinct pattern of cortical atrophy thus constituting a bimorphic cortical pathology.170

Adrenal Cortical Hyperplasia With Hyperaldosteronism Endocrine causes of secondary hypertension include primary hyperaldosteronism (5% to 10% of hypertensive patients) and much less commonly (<1%) Cushing syndrome, pheochromocytoma, hyperparathyroidism, and hypo- and hyperthyroidism.171,172 The most common form of primary hyperaldosteronism is idiopathic, with bilateral hyperplasia of the zona glomerulosa accounting for 60% to 70% of cases (Table 16.3).172 Patients are usually managed medically; adrenalectomy is reserved for patients with unilateral disease, most frequently an aldosterone-producing adenoma, because of a more predictable response in terms of amelioration or normalization

TABLE 16.3

Causes of Primary Hyperaldosteronism

Cause

Proportion

Idiopathic bilateral hyperplasia Aldosterone-producing adenoma Familial hyperaldosteronism (FH) • FH Type 1 (glucocorticoid remediable) • FH Type 2 (linked to chromosome 7p22 mutation) • FH Type 3 (linked to KCNJ5 potassium channel mutation) Adrenal cortical carcinoma

60%-70% 30%-35% <1%

<1%

Modified from Velasco A, Vongpatanasin W. The evaluation and treatment of endocrine forms of hypertension. Curr Cardiol Rep. 2014;16:528.

of systemic hypertension.173,174 Recent reports identify 14% to 17% of unilateral adrenal disease to be unilateral hyperplasia.175

Adrenal Cortical Hyperplasia With Excess Sex Steroid Secretion Adrenal cortical hyperplasia with excess sex steroid secretion is essentially limited to cases of CAH.

Adrenal Medullary Hyperplasia AMH has been reported in a sporadic setting as a distinct entity.176 AMH had been reported as a precursor lesion for

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pheochromocytoma in MEN2a and MEN2b, where it could be diffuse or nodular and is often multicentric and bilateral.177-180 A cutoff of 1 cm in size was proposed for the diagnosis of pheochromocytoma, because this was the smallest tumor in the publication by Karsner.178,181 AMH in this familiar setting is now regarded as a small or micropheochromocytoma because it shows the same genetic abnormalities.182 Sporadic AMH has been reported in patients with symptoms of pheochromocytoma including paroxysmal or sustained hypertension, headache, palpitations, and diaphoresis; surgical exploration fails to reveal a catecholamine-secreting tumor. AMH in this setting may be unilateral and enters into the differential diagnosis of pseudopheochromocytoma. AMH also has been reported in patients with cystic fibrosis and Beckwith-Wiedemann syndrome.4,43,71

hemorrhagic cyst should be distinguished from a necrotic adrenal cortical neoplasm. Breast carcinoma has initially manifested as metastasis to an adrenal cyst, and mature adipose tissue and myelolipomatous metaplasia have been described within adrenal pseudocysts.193 Microscopic cysts are a frequent histologic finding in the permanent cortex of fetal and premature adrenal glands, being reported in up to 62% of stillbirths under 35 weeks gestational age.194 A significant correlation with short gestation and short survival after birth has been reported.195 Three possible pathogenetic mechanisms have been proposed: an intrinsic developmental process, infection, and a generalized reaction to stress.

Adrenal Cyst

Adrenal hemorrhage can complicate cardiac disease, thromboembolic disease, sepsis, postoperative or postpartum state, or coagulopathy (e.g., heparin administration).3 A recent autopsy study found that 61% of individuals dying of bacterial sepsis develop some degree of adrenal hemorrhage.95 Patients may become symptomatic with abdominal or lower chest pain and fever. Newborn infants may present with manifestations of adrenal hemorrhage or hematoma formation.3 Occasionally, adrenal hemorrhage is bilateral and massive.196 Unfortunately, the diagnosis is made only infrequently during life. A high index of suspicion is required because of the nonspecific clinical presentation and the frequent comorbidity of other factors. Imaging techniques are useful in establishing a timely diagnosis so that appropriate intervention can prevent a poor outcome.197

Nonneoplastic adrenal cysts are uncommon, usually occurring in the fifth and sixth decades of life, although cases have been reported from birth to 76 years.183 A predilection for women is seen, with a female-to-male ratio of approximately 3:1.184 Adrenal cysts may be small and discovered incidentally at autopsy. Rarely, they may be extremely large, containing several liters of fluid and compressing the abdominal contents. Adrenal cysts have been classified as parasitic (7% of cases, usually echinococcal), epithelial (9%), endothelial (45%), and pseudocyst (39%).183,185 Epithelial cysts are subdivided into three categories: true glandular or retention cysts; embryonal cysts lined by cylindrical epithelium derived from displaced urogenital tissue that has undergone cystic transformation; and cystic change within an adrenal adenoma, carcinoma, or pheochromocytoma.186 It has also been proposed that an epithelial-lined adrenal cyst rarely may develop from entrapped mesothelium.187,188 Adrenal pseudocysts are the most common type of adrenal cyst seen at surgery and often appear as a large unilocular cyst with an irregular lining, containing red-brown bloody fluid (Fig. 16.36). Some adrenal pseudocysts probably arise by hemorrhage into normal or pathologic adrenal glands; a small number result from hemorrhage into an underlying tumor.183,186,189 Immunohistochemical studies show a vascular endothelial lining in some adrenal pseudocysts.190-192 Some hemorrhagic cysts may arise when hemorrhage occurs in an existing vascular malformation.191 Entrapment of nests of cortical cells by extravasated blood may occur, and this

Fig. 16.36 Adrenal pseudocyst on cross-section contains grumous, soft, pale-tan debris. Dystrophic calcification was present in the cyst wall.

Adrenal Hemorrhage

Adrenal Neoplasms Adrenal Cortical Neoplasms Adrenal Cortical Adenoma With Cushing Syndrome ACA is usually small, weighing less than 50 g. In one series, the tumors had an average weight of 36 g (range, 12.5 to 126 g).198 On transverse section, it usually appears as a sharply circumscribed or encapsulated mass.71,199 Almost all tumors are unilateral and solitary, although rare exceptions have been noted.200,201 Adenomas may be yellow or golden-yellow throughout or have irregular mottling or diffuse dark brown areas (Fig. 16.37). The color of the tumor depends on many factors, including the presence of congestion or hemorrhage and the content of neutral lipid and lipofuscin.71,199,202 Although many tumors appear grossly encapsulated, histologic study may reveal a relatively smooth expansile border, in some cases with formation of a pseudocapsule. Compression of adjacent adrenal parenchyma and connective tissue, including the expanded adrenal capsule itself, contributes to the encapsulation of the ACA. Adenomas usually consist of cells with relatively abundant pale, lipid-rich cytoplasm resembling the zona fasciculata, but cells with more compact eosinophilic cytoplasm may be seen. Architecturally, the cells are arranged in short trabeculae, blunt cords, or a nesting or alveolar pattern (Fig. 16.38). Nuclei are usually vesicular, with a single, small nucleolus. Nuclear enlargement and pleomorphism may occur, but it is usually focal and mild to moderate in degree (Fig. 16.39). Also, foci of lipomatous or myelolipomatous metaplasia may be found. Endocrinologic data and clinical information are often essential to distinguish an adrenal cortical neoplasm associated with Cushing syndrome from an incidental nonhyperfunctioning adenoma or one associated with a different endocrine syndrome.71,199 An important clue to the presence of

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Fig. 16.37 Adrenal cortical adenoma in Cushing syndrome.

Fig. 16.38 Adrenal cortical adenoma in Cushing syndrome. Cells are arranged in alveoli or short cords.

Cushing syndrome is cortical atrophy in the attached adrenal or the contralateral gland. In most cases, ultrastructural study reveals abundant intracytoplasmic lipid (Fig. 16.40). Mitochondria may have tubulovesicular cristae, similar to normal cells of zona fasciculata, or lamellar cristae characteristic of the zona reticularis. Smooth endoplasmic reticulum is usually abundant. The Carney triad was described in 1977 and currently is composed of gastric stromal sarcoma, pulmonary chondroma, and extraadrenal paraganglioma. ACA has recently been recognized as the fourth component of the Carney triad, and has been associated with subclinical Cushing syndrome.203 Incidentalomas, as previously noted, have become increasingly common as more abdominal imaging is performed, and the most common secretory syndrome is subclinical Cushing syndrome, also referred to as adrenal mild hypercortisolism.204 Duan et al. provide a detailed overview of clinicopathologic correlates of adrenal Cushing syndrome including an in-depth discussion of molecular and genetic abnormalities.205

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Fig. 16.39 Adrenal cortical adenoma in Cushing syndrome. Note the focal variability in nuclear size and hyperchromasia. Many cells in this field have compact, eosinophilic cytoplasm, and some have nuclear pseudoinclusions (arrow).

Fig. 16.40 Adrenal cortical adenoma in Cushing syndrome. Cells contain large lipid globules and prominent smooth endoplasmic reticulum (3500). (From Lack EE, Travis WD, Oertel JE. Adrenal cortical neoplasms. In: Lack EE, ed. Pathology of the Adrenal Glands. New York: Churchill Livingstone; 1990:115–171.)

Adrenal Cortical Adenoma With Primary Hyperaldosteronism (Conn Syndrome) An estimated 30% to 35% of cases of primary hyperaldosteronism are caused by an aldosterone-secreting ACA (Table 16.3).172 Recent data indicate that idiopathic bilateral hyperplasia is a more frequent cause, particularly if mild examples are included. Three types of familial primary hyperaldosteronism have been identified, all inherited in an autosomal dominant manner and together account for less than 1% of primary hyperaldosteronism.172,206 A variety of genetic abnormalities have been reported in primary hyperaldosteronism and are addressed elsewhere in recent publications.207,208 The aldosterone-secreting ACA is an important surgical lesion because it may be a curable form of systemic hypertension. Adrenal

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vein sampling is a widely accepted method for localizing aldosterone-secreting ACA and is useful in distinguishing adenomas from hyperplasias.209 The prevalence of an aldosteronesecreting adenoma in the hypertensive population ranges from 0.5% to 8%, although Conn suggested that primary hyperaldosteronism may be the cause of up to 20% of all cases of essential hypertension based on the incidence of a solitary adenoma 1.5 cm or more in diameter reported in hypertensive individuals at autopsy (20%).109,199,210 However, incidental cortical nodules are relatively common in patients 50 to 80 years of age and those with hypertension.106 It is unclear whether hypertension results from the incidental nodule or adenoma or is a cause of it, perhaps in some cases related to capsular arteriopathy. This controversy can forever be rekindled, however, because it can be postulated that, over time, conversion may occur of glomerulosa-type cells within these incidental nodules to cells having different functional characteristics. When the incidental adenoma is discovered, the patient may already have established systemic hypertension without the expected biochemical profile of an aldosterone-secreting adenoma.199 Aldosterone-secreting ACA (aldosteronoma) is usually solitary, small, and measures only a few centimeters in diameter; many are smaller than 2 cm, although most are large enough to be visible on abdominal CT.199 Grossly, the tumor may project from one portion of the gland, although it may be difficult to appreciate in the intact gland without transverse sectioning. It is often homogeneous, diffusely bright yellow-orange, and may be sharply demarcated from the adjacent cortex, simulating encapsulation (Fig. 16.41). Architectural patterns include alveolar or nesting arrangement, short cords, or trabeculae of cells (Fig. 16.42). Four types of cells have been described by light microscopy, often with multiple types in the same tumor.7,211 The most common cell type is large, with pale-staining, lipid-rich cytoplasm resembling cells of the zona fasciculata. This cell type has been associated with the genetic mutation KCNJ5.207 A second cell type appears as clusters of smaller cells resembling those of the zona glomerulosa, with a high nuclear-to-cytoplasmic ratio and a small amount of vacuolated cytoplasm. The third type consists of scattered cells with compact eosinophilic cytoplasm similar to cells of the zona reticularis. The fourth cell type, hybrid cell, has morphologic features intermediate between those of zona glomerulosa– type and zona fasciculata–type cells. The attached or contralateral adrenal gland may show hyperplasia of the zona glomerulosa, with a broad focal or discontinuous zone beneath the capsule

Fig. 16.41 Aldosterone-secreting adrenal cortical adenoma. The tumor was 1 cm in diameter and yellow-orange on cross-section.

Fig. 16.42 Aldosterone-producing adrenal cortical adenoma. Most cells have lipid-rich, finely vacuolated cytoplasm.

Fig. 16.43 Hyperplasia of the zona glomerulosa is apparent as a continuous band of cells beneath the capsule. Numerous foci such as this may be present in the cortex adjacent to aldosterone-secreting adenomas.

(Fig. 16.43), sometimes with small tongues of glomerulosa-type cells extending inward from the capsule.7,211 The term hybrid refers to the capacity of the cell to synthesize cortical steroids, which are normally produced by the zona glomerulosa (aldosterone) or the zona fasciculata (cortisol). Aldosterone-secreting adenomas may originate from hybrid cells or zona fasciculata–type cells. This would account for the functional behavior of tumor cells in vivo, as evidenced by modulation of aldosterone secretion by ACTH, lack of responsiveness to angiotensin II (the dominant secretagogue and trophic hormone for the glomerulosa-type cells under normal conditions), secretion of the hybrid steroids in large quantities, and the ability of the cells to produce cortisol in vitro and sometimes in large quantities in vivo.212 Ultrastructurally, these cells show morphologic heterogeneity, including round to elongated mitochondria with cristae that are short and tubular, vesicular, or lamellar, typical of zona glomerulosa–type cells.71,213 Spironolactone bodies are lightly eosinophilic, scroll-like intracytoplasmic inclusions that have been described in the zona glomerulosa of the nonneoplastic cortex in patients treated

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with the aldosterone antagonist spironolactone (Aldactone) (Fig. 16.44).214 Occasionally, these inclusions can be seen within the tumor cells.71,199 Ultrastructural study suggests origin from tightly packed tubules of endoplasmic reticulum.215 The spironolactone bodies typically range in size from 2 to 12 μm, but most are equal in size or slightly larger than the adjacent nucleus. These structures may be highlighted with Luxol fast blue stain because of their rich phospholipid content.71,199 Although the specificity of these inclusions has been questioned, they are generally regarded as rather specific markers for spironolactone administration. In one study, the number of spironolactone bodies within cells of the aldosterone-secreting adenoma correlated positively with the proportion of glomerulosa-type cells.216

Functional Pigmented (Black) Adrenal Cortical Adenoma Pigmented (black) ACA is characterized by diffuse black pigmentation on cross-section (Fig. 16.45), although some areas may be dark brown or yellow-brown.217 Pigmented ACA is usually diagnosed in the third to the fifth decades of life, with a distinct predilection for females.199 This tumor is most often associated with

Fig. 16.44 Spironolactone bodies appear as single scroll-like, eosinophilic inclusions within zona glomerulosa cells. Many are surrounded by a clear space.

Fig. 16.46 Pigmented (black) adenoma causing Cushing syndrome. Tumor cells form nests and short cords and have abundant intracytoplasmic granular lipofuscin pigment.

Fig. 16.47 Black adenoma of adrenal gland from a patient with Cushing syndrome. Note the numerous electron-dense structures, some containing small lipid droplets. (17,000).

Cushing syndrome, although it also has been reported with primary hyperaldosteronism.71,199 Microscopically, the architectural patterns are similar to those of other adenomas. The histologic hallmark is the conspicuous brown or golden-brown granular pigment in the cytoplasm (Fig. 16.46), which has the staining characteristics of lipofuscin. One study, however, suggested that some of the pigment may be neuromelanin.122 As with other adenomas, areas of lipomatous or myelolipomatous metaplasia may be present.71 Ultrastructurally, the cells contain relatively few lipid globules but have a variable number of electron-dense structures that are often associated with small lipid vacuoles (Fig. 16.47) characteristic of lipofuscin.71,199 No melanosomes or premelanosomes are seen.

Fig. 16.45 Pigmented (black) adrenal cortical adenoma with Cushing syndrome. The tumor is 3.5 cm in diameter. Sectioned surfaces of tumor are diffusely black, with vague lobulation. Residual adrenal gland (lower row) shows marked cortical atrophy.

Adrenal Cortical Neoplasms With Virilization or Feminization Adrenal cortical neoplasms associated with virilization or feminization are clinically important because of the potential for malignant behavior. Many have unfavorable gross or microscopic findings such as large size and areas of necrosis. A review of women with

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virilizing adrenal cortical tumors found that at least 17% were clinically malignant; an even greater proportion of feminizing adrenal cortical neoplasms were malignant.218,219 Histologically, a predominance of cells with compact eosinophilic cytoplasm is often seen, but this histologic pattern is not specific. Virilization has been reported with tumors classified as Leydig cell adenoma of the adrenal gland, which contain Reinke crystalloids, a pathognomonic feature of Leydig (or hilus) cells.220 Rarely, Leydig cells have been reported in the adrenal cortex, probably because of the close embryologic relation between developing adrenal primordia and gonads.221 Virilization is present with many of the childhood adrenal cortical tumors and may be part of a mixed endocrine along with Cushing syndrome.

Oncocytic Adrenal Cortical Neoplasms (Adrenal Oncocytoma) Rarely, adrenal cortical neoplasms are composed of cells with abundant, finely granular, eosinophilic cytoplasm typical of oncocytoma (Fig. 16.48).222-225 Eosinophilic cytoplasmic inclusions have been described in some of these tumors that are thought to be a mitochondria-associated degenerative change and not specific for the adrenal cortex or its products.226 The vast majority of these tumors are clinically nonfunctional, but some may exhibit low levels of enzyme activity in cortical steroidogenesis.223 Although most adrenal cortical oncocytic neoplasms are benign, cases of oncocytic carcinomas have been reported.227-231 It has been suggested that oncocytic carcinomas represent low-grade ACC. Adrenal Cortical Carcinoma ACC is rare, occurring annually in approximately 0.7 to 2 cases per million population in the United States.232 Many large series of ACC have been reported in the last few decades, mainly in adults. A slight female preponderance is seen. The age distribution is bimodal, with peak incidence in the fifth to seventh decades of life with a second peak in childhood.233 Presenting signs and symptoms include abdominal pain, a palpable mass, fatigue, weight loss, and, in 10% to 20% of patients, intermittent low-grade fever that may be caused by tumor necrosis.71,199 Regional or distant metastases occur in 25% or more of patients.71,199,234,235 Because ACCs are usually inefficient producers of steroids, clinical evidence of

Fig. 16.48 Incidental nonhyperfunctional adrenal cortical adenoma is composed of cells with abundant, granular eosinophilic cytoplasm (oncocytoma). Nuclei are moderately pleomorphic and hyperchromatic, with occasional nuclear pseudoinclusions (arrow). The tumor weighed less than 15 g.

excess hormone secretion usually does not become apparent until the tumor is large. Some tumors are therefore classified clinically as nonfunctional or functionally inactive. When adrenal cortical neoplasms are functional, they most commonly produce cortisol, but in some cases the patient may present with a mixed endocrine syndrome (e.g., Cushing syndrome and virilization). Purely virilizing ACC is uncommon in adults, and feminizing ACC is rare. Primary hyperaldosteronism caused by ACC is also relatively uncommon.71,199 A study reported five adrenal cortical neoplasms clinically mimicking pheochromocytoma with biochemical evidence of elevated catecholamine secretion in serum or urine; two were ACC and three were ACA.236 ACC is usually large, and careful gross examination often may suggest malignancy, with areas of necrosis, hemorrhage, and cystic change.71,199 On cross-section, the tumors are often variegated in color, ranging from yellow, yellow-orange, to tan-brown. Larger tumors are often coarsely lobulated with intersecting fibrous bands (Fig. 16.49). The average recorded weight in several series ranged from 705 to 1210 g.71 Tang and Gray reported that all adrenal cortical tumors over 95 g were malignant, whereas those weighing less than 50 g were benign.237 However, weight alone is not entirely reliable as a distinguishing characteristic, because some small ACCs have metastasized, including tumors weighing 40 g or less.71,191,238 Also, some adrenal cortical neoplasms weighing more than 1000 g may prove to be clinically benign after prolonged follow-up. Size has also been reported to be an important indicator of malignancy. The clear majority of ACCs are greater than 6 cm in diameter, but several cases of small ACC measuring less than 5 cm have been reported.239 The reverse is also true. ACA may be quite large— more than 5 cm—sometimes because of central degeneration, hemorrhage, or calcification and fibrosis.240 A study of the Surveillance Epidemiology and End Results (SEER) database indicated that for adrenal cortical neoplasms 4 cm or larger the likelihood of malignancy essentially doubles to approximately 10% and increases more than ninefold in tumors 8 cm or larger.116 ACC has a variety of architectural patterns, including trabecular, alveolar (nesting), and solid (diffuse). The most characteristic pattern is a trabecular arrangement of cells with broad anastomosing columns separated by delicate elongated vascular spaces (Fig. 16.50). Some of the trabeculae, when cut in cross-section or oblique planes, appear as free-floating islands of tumor cells.

Fig. 16.49 Adrenal cortical carcinoma. Note the coarsely nodular cut surface.

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Fig. 16.50 Adrenal cortical carcinoma. The tumor has broad anastomosing trabeculae and gaping sinusoids with delicate endothelium. Tumor cells have compact, eosinophilic cytoplasm and small, uniform nuclei. The patient died of metastases within 1 year of diagnosis and at autopsy had massive invasion of the inferior vena cava.

Rarely, a pseudoglandular arrangement of cells may be seen, or the tumor may have a myxoid appearance.71,199 Most tumor cells in ACC have compact, eosinophilic cytoplasm that is lipid poor. Foci of vascular invasion when present usually appear as unattached plugs of tumor within vascular spaces. Nuclear pleomorphism and hyperchromasia can be spectacular in ACC, but nuclear atypia alone is not a reliable indicator of malignancy and can also be seen in ACA (Fig. 16.51).71,199 Mitotic figures may be numerous in ACC and are rare in ACA and adrenal hyperplasia (Fig. 16.52). In the study by Weiss, only two nonmetastasizing adrenal cortical tumors contained fewer than 3 mitotic figures per 50 high-power fields (hpf), whereas 78% of ACCs contained more than 5 mitotic figures per 50 hpf, and 17% had more than 50 per 50 hpf.241 In addition to mitotic activity, tumor necrosis is more frequent in ACC than in ACA.235,242-246 One investigation of 56 cases reported no necrosis in 8 of the ACA reviewed, whereas 45 of the 48 ACCs displayed variable amounts of necrosis.235 An unusual feature of ACC (and some adenomas) is the presence of intracytoplasmic hyaline globules, similar to those commonly seen

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Fig. 16.51 Adrenal cortical neoplasm that proved to be benign and hence atypical adenoma. Tumor cells have marked nuclear pleomorphism and hyperchromasia. The tumor was found incidentally on computed tomography and weighed 99 g. The patient was alive and well 11 years later.

in pheochromocytoma (Fig. 16.53).71 An ACC or ACA with an alveolar growth pattern and cells with compact, eosinophilic cytoplasm along with intracytoplasmic globules may be mistaken for a pheochromocytoma. Another pitfall in the diagnosis of adrenal cortical neoplasms is immunoreactivity for synaptophysin or neuron-specific enolase, markers that are used for documenting neuroendocrine differentiation.247,248 Ultrastructurally, intracytoplasmic lipid vacuoles are often sparse or absent and cellular organelles may be moderate or few in number.249 Flattened cisternae of rough endoplasmic reticulum in stacks or short parallel lamellae may be seen. Smooth endoplasmic reticulum may form an intricate anastomosing network. Many studies have proposed histologic criteria to predict malignant behavior. Hough et al. reported that the strongest predictors were broad fibrous bands, a diffuse growth pattern, and vascular invasion.242 Weiss et al. analyzed the predictive value of nine histologic parameters and found that recurrence or metastasis occurred only in tumors with a mitotic rate greater than 5 per 50 hpf, atypical mitotic figures, and invasion of venous structures.245 Van Slooten et al. used a histologic index based on seven histologic

Fig. 16.52 (A) Adrenal cortical carcinoma with several mitotic figures seen in this single, high-power field. (B) Another case of adrenal cortical carcinoma composed of cells with dense, compact eosinophilic cytoplasm arranged in a trabecular growth pattern; an atypical mitotic figure is highlighted (inset).

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Fig. 16.53 Adrenal cortical adenoma with intracytoplasmic globules, similar to what is more commonly encountered in pheochromocytoma. Right, Highpower image of globules.

parameters to predict outcome.243 Volante et al. introduced an algorithmic approach to evaluate adrenal cortical neoplasms that may be useful in borderline cases.244 This approach incorporates evaluation of the reticulin network with the modified Weiss criteria. Based on this approach, all adrenal cortical tumors with a disrupted reticulin network qualify for carcinoma as do those with maintained reticulin pattern and any one of the following: mitoses greater than 5 per 50 hpf, necrosis, or venous invasion. Despite these findings, it is clear that a small but significant number of adrenal cortical neoplasms have unpredictable biologic behavior, and long-term follow-up in some of these troublesome cases is the final arbiter in diagnosis.234 Mitotic rate has been used to separate low-grade and high-grade ACC; the median survival for patients with low-grade ACC (20 mitotic figures per 50 hpf) was 58 months in contrast with 14 months for high-grade tumors (>20 mitotic figures per 50 hpf).245 Immunohistochemistry for cell cycle regulatory proteins has been applied to ACC; with Ki-67, there was a 5% cutoff, and none of the 33 ACA reached this cutoff value; more than 75% of ACCs in this study had 6 or more mitoses per 50 hpf.250 A large international study has recently concluded that current practices in Ki-67 scoring assessment vary greatly, and novel digital microscopy-enabled methods could provide critical aid in improving reproducibility and reliability in the clinical setting.251 DNA ploidy analysis has been used to predict outcome, but the results have been controversial.71,252-256 According to some investigators, the greatest value of DNA ploidy analysis in predicting outcome is in patients undergoing potentially curative surgical resection.256 More recently, molecular studies have revealed multiple chromosomal aberrations that may be related to ACC.257,258 Some chromosomal loci correlate with abnormal familial syndromes including Li-Fraumeni syndrome (p53, 17p13), MEN1 (11q13), Beckwith-Wiedemann syndrome (11p15.5 associated with IGFII overexpression), and Carney complex (2p16). Additionally, loss of heterozygosity on chromosomes 11p, 13q, and 17p has been reported in ACC, whereas these chromosomal changes have not been seen in ACA or hyperplasia. Numerous other studies on chromosomal and immunohistochemical associations with malignancy in adrenal cortical tumors have been reported in recent years, the results of which are beyond the scope of this chapter.257,258 Suffice it to say, as our understanding of the molecular pathogenesis of these neoplasms progresses, improved diagnostic and treatment strategies may become available.

The pattern of metastasis of ACC reflects both lymphatic and hematogenous dissemination. The sites of metastases in patients dying of ACC include liver (92%), lung (78%), retroperitoneum (48%), intraabdominal lymph nodes (32%), intrathoracic lymph nodes (26%), and other sites such as bone.199 On rare occasion, the tumor can extend into the inferior vena cava with occlusion of this vessel and even extend into the right atrium.71,259 Percutaneous fine-needle aspiration may be helpful in the preoperative diagnosis of ACC, but extreme caution must be exercised in trying to differentiate ACC from a benign adrenal cortical neoplasm on cytologic features alone.71,199 A major drawback to the cytologic differentiation of ACC versus adenoma is sampling error. If a good specimen with obvious cytologic features of carcinoma is obtained, the diagnosis can be made with a fair amount of certainty.71 However, if the specimen has only minor cytologic abnormalities that could be seen in ACA, to definitively rule out the possibility of carcinoma on a fine-needle aspiration specimen would not be prudent. Careful correlation with clinical and endocrinologic data is needed, combined with knowledge of other features such as tumor size and imaging characteristics.71 The same can be said for core needle biopsy specimens. The differential diagnosis of ACC may be aided by special studies, including immunohistochemistry. Typically, adrenal cortical neoplasms are positive for vimentin and negative for epithelial markers such as cytokeratin, CAM5.2, and epithelial membrane antigen; however, occasionally, adrenal cortical neoplasms may express keratin reactivity, especially with low-molecular-weight cytokeratins.260 Antibodies to the α subunit of inhibin have been found to be expressed by adrenal cortical tissue, both normal and neoplastic (Fig. 16.54); additionally, the majority of adrenal cortical neoplasms are immunoreactive with calretinin and melan A.260 Another antibody that shows sensitive and specific reactivity is SF-1.261 Immunohistochemistry is quite useful in differentiating adrenal cortical neoplasms from other neoplasms such as pheochromocytoma and metastatic tumors, especially renal cell carcinoma.261,262 Disease-free and overall survival rates have been strongly correlated with ACC stage. Most patients have relatively advanced disease at the time of diagnosis; only approximately 30% of patients have tumor confined to the adrenal gland (Table 16.4).71,263 ACCs have been stratified to three risk groups: the low-risk group includes stage I to II disease with a mitotic rate of 9 or fewer per 50 hpf; the intermediate-risk group includes stage I to II disease with mitoses

Fig. 16.54 Adrenal cortical adenoma (ACA) and adrenal cortical carcinoma (ACC), both showing strong cytoplasmic staining with antibodies to the α subunit of inhibin.

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TABLE 16.4

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Staging of Adrenal Cortical Carcinoma

%

Stage

TNM

2.8

I

T1N0M0

T1

Tumor 5 cm, no extraadrenal invasion

Staging Criteria

29

II

T2N0M0

T2

Tumor >5 cm, no extraadrenal invasion

19.3

III

T1N1M0

T3

Tumor of any size, locally invasive but not involving adjacent organs

T3 Any N M0

T4

Tumor of any size, with invasion of adjacent organs or large blood vessels

T2N1M0 48.9

IV

Any T, any N, M1

N0

Negative regional lymph nodes

T3, N1

N1

Positive regional lymph nodes

T4

M0 M1

No distant metastases Distant metastases

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.

greater than 9 per 50 hpf or stage III to IV disease and a mitotic count of 9 or fewer per 50 hpf; and the high-risk group includes stage III to IV disease with a mitotic count greater than 9 per 50 hpf.263 Adrenal cortical neoplasms in children remain somewhat of an enigma for pathologists. Their clinical and biologic behavior can be quite distinct from that of histologically similar counterparts in adults. Attempts to identify pathologic criteria of malignancy have been made, with some success, but further studies are required for a better understanding of adrenal cortical neoplasms in children.246,264,265 A big factor in the difficulty of assessing these lesions is the rarity with which ACC occurs in this population.

Other Adrenal Cortical Neoplasms Several examples of adrenal carcinosarcoma have been reported in adults, consisting of mixtures of sarcomatous elements and ACC.266-269 An example of virilizing adrenal cortical blastoma was reported in an infant who had an elevated serum level of α-fetoprotein.270

Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor arising from neural crest–derived chromaffin cells of the sympathoadrenal system. It is relatively uncommon in surgical pathology practice, with an estimated average annual incidence of 8 per 1 million person-years (excluding familial cases).271 It has been suggested that for every pheochromocytoma diagnosed during life, two remain undiscovered, but recent data show more of them diagnosed during life, probably reflecting increased clinical awareness, heightened diagnostic acumen, and more sensitive laboratory testing. The peak age at diagnosis is in the fifth decade, but pheochromocytoma can affect any age group. Most clinical series report a roughly equal sex incidence.

Hereditary Pheochromocytoma–Paraganglioma Pheochromocytoma has been referred to as the “10% tumor”— 10% familial, 10% malignant and 10% extraadrenal, and 10% occurring in childhood—but this may no longer apply given the advances in identifying genetic markers for increased susceptibility for hereditary/familial pheochromocytoma/paraganglioma.272 There have been at least 14 susceptibility genes identified since 1990, and 10 have been validated in large studies (Table 16.5).273 Additional genes will probably be tested and

TABLE 16.5

Detected Germline Mutations in 3694 Pheochromocytoma/Paraganglioma Patients

Mutation

Frequency

SDHB (paraganglioma 4) SDHD (paraganglioma 1) VHL RET NF-1 SDHC (paraganglioma 3) SDHA (paraganglioma 5) SDHAF2 (paraganglioma 2) TMEM 127 MAX

10.3% 8.9% 7.3% 6.3% 3.3% 1.0% <2% <2% <2% <2%

From Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:1915–1942.

validated in future studies.274 In lieu of the “10% tumor,” some have proposed the “10-gene tumor.” Pheochromocytoma/paraganglioma is a significant heritable form of neoplasia in humans with about 40% of cases associated with familial syndromes having autosomal dominant traits.273 These include neurofibromatosis type 1, MEN2a and MEN2b, von Hippel-Lindau disease, renal cell carcinoma with SDHB mutation, Carney triad, and CarneyStratakis dyad (paraganglioma and gastric stromal tumor).275,276 The profile for possible hereditary/familial pheochromocytoma/ paraganglioma includes a family history of such tumors (or the presence of syndromic features) or the presence of tumors with some of the following: (1) multiple tumors (e.g., >1 paraganglioma or pheochromocytoma including bilateral pheochromocytoma); (2) multifocal tumors, synchronous or metachronous, in different anatomic sites; (3) malignant tumors; and (4) early onset (e.g., <45 years).273 It is notable that germline mutations have been found in 24% of patients who presented with nonsyndromic apparently sporadic pheochromocytoma, and the following features were significantly associated with mutations: younger age, multifocal tumors, and extraadrenal tumors (paraganglioma).277 Eight studies, each having more than 200 patients, have been involved with genotyping of the main pheochromocytomaparaganglioma susceptibility genes (SDHB, SDHD, VHL, and RET), with the total cohort of patients being 3694; of these, 1250

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individuals harbored germline mutations (33.8%), indicating that at least one-third of all patients with pheochromocytomaparaganglioma have disease-associated genetic mutations.273 Genotypic/phenotypic correlations have been identified in pheochromocytoma-paraganglioma syndromes with at least 40% or more of tumors with SDHB mutations exhibiting malignant behavior.273,278,279 In addition, tumors having any of the SDH mutations tend to be more often extraadrenal, whereas those with a RET mutation are usually confined to the adrenal or immediate area. Five of the susceptibility genes in Table 16.5 were found in 2% or fewer of cases studied including two of the more recently reported genes, TMEM127 and MAX (MYC-associated factor X).273,280,281 A task force organized to formulate clinical practice guidelines for pheochromocytoma-paraganglioma has recommended that genetic testing should be considered in each patient, but this does not mean to imply that genetic testing should be done on each patient. Genetic testing has limited incremental value in patients with unilateral pheochromocytoma, no syndromic or malignant features, and absence of positive family history.273 Evidence available in the literature apparently justifies SDHB genetic testing in patients with malignant pheochromocytoma-paraganglioma.

Pathology of Pheochromocytoma Sporadic pheochromocytoma usually forms a unicentric spherical or ovoid mass that is often sharply circumscribed and may appear encapsulated. Histologic sections taken at the periphery of the tumor often show a fibrous pseudocapsule or, at times, no capsule at all. Most pheochromocytomas are 3 to 5 cm in diameter, with an average weight in several large series ranging from 73 to 156.5 g.4,71,272 The average weight of clinically malignant tumors tends to be greater than that of benign tumors. Pheochromocytoma is usually resiliently firm, with a glistening gray-white surface (Fig. 16.55), which may be altered by degenerative change such as congestion, hemorrhage, or necrosis, and some tumors undergo cystic change that may be marked. Rarely, pheochromocytoma grows into the inferior vena cava and may extend into the right atrium, mimicking renal cell carcinoma.4,71,272 Pheochromocytoma usually has an anastomosing cell cord pattern (Fig. 16.56), or sometimes an alveolar or zellballen architectural growth pattern in which the neoplastic cells form rounded to oval nests that are surrounded by a delicate fibrovascular network of supporting cells, the most characteristic cell being the sustentacular cell. Sustentacular cells typically are not apparent on routine stained sections. Occasionally, tumor cells are arranged in a predominantly solid or diffuse pattern (Fig. 16.57). A compressed fibrous pseudocapsule may be present between the

Fig. 16.55 Pheochromocytoma. Cross-section of a 3.5-cm tumor on the right is fleshy and pale tan, with mottled areas of congestion. Two other portions of the same tumor fixed in Zenker solution show a positive chromaffin reaction with a mahogany brown color.

Fig. 16.56 Pheochromocytoma with an anastomosing cell cord pattern. The cells have a finely granular, basophilic cytoplasm with round to oval, eccentrically placed nuclei.

Fig. 16.57 Pheochromocytoma with a solid or diffuse growth pattern. Cells have abundant amphophilic cytoplasm. Note the marked nuclear pleomorphism and hyperchromasia and nuclear pseudoinclusions (arrow).

pheochromocytoma and the adjacent cortex, but sometimes no intervening fibrous connective tissue is present (Fig. 16.58), and there may be intermingling with nonneoplastic cortical cells at the periphery. Alterations in the supporting stroma, including sclerosis, edema, and changes in the vasculature, which could create diagnostic confusion, also may be present. One study reported amyloid deposition in 14 of 20 pheochromocytomas (70%), but no electron microscopic illustrations were provided.282 Another study identified amyloid deposition in only 2 of 22 cases (9.1%) examined with supporting special stains, immunohistochemical stains, and electron microscopy.283 The pheochromocytoma cells, or pheochromocytes, are typically polygonal in shape with a finely granular cytoplasm that is basophilic to lightly eosinophilic. Nuclear pseudoinclusions have been reported in approximately one-third of pheochromocytomas, typically appearing as sharply defined round to oval structures that contain cytoplasm having the same staining intensity as the remainder of the cell, although they sometimes appear pale or empty (Fig. 16.59).4,272 Some tumors contain cells with prominent nuclear hyperchromasia and pleomorphism, but these

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Fig. 16.58 Pheochromocytoma with a vague alveolar or nesting pattern. Section taken through the periphery of the tumor shows junction with the residual cortex (arrows) and lack of encapsulation.

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Fig. 16.60 Pigmented pheochromocytoma with abundant granular pigment that is consistent with lipofuscin. Ultrastructural study revealed no melanosomes or premelanosomes. A heavily pigmented tumor such as this may be mistaken for a pigmented black adenoma or malignant melanoma.

have a jet-black gross appearance caused by an abundance of intracytoplasmic granules of lipofuscin (Fig. 16.60). The differential diagnosis of pigmented (black) adrenal neoplasms includes cortical adenoma, pheochromocytoma, and malignant melanoma (primary or secondary).

Fig. 16.59 Pheochromocytoma. A nuclear pseudoinclusion is present on the right side of the field viewed en face. The nucleus of the tumor cell on the left side shows a deep indentation with a jagged border that represents a pseudoinclusion viewed in profile (toluidine blue stain, 1000.)

features alone are not useful in predicting biologic behavior. Cytoplasmic hyaline globules can be found in some pheochromocytomas and are characteristically positive for periodic acid–Schiff stain and resistant to diastase predigestion. The globules are slightly refractile and identical to those that may be found in the normal medullary chromaffin cells. These globules are detected in almost 50% of cases of sympathoadrenal paragangliomas and are possibly related to secretory activity.284 Rarely, in some tumors, the cytoplasm is deeply eosinophilic and copious representing oncocytic change. Lipid degeneration gives the cytoplasm a clear, vacuolated appearance that can mimic an adrenal cortical neoplasm.285,286 Some pheochromocytomas contain scattered cells resembling neuronal or ganglion cells with tapering cytoplasmic processes and peripheral aggregation of basophilic material resembling Nissl substance. Periadrenal brown fat may be associated with pheochromocytoma, but its incidence and functional importance are unclear.287,288 Pigmented pheochromocytomas and extraadrenal paragangliomas are extremely rare.71,289,290 These tumors may

Pheochromocytoma in Multiple Endocrine Neoplasia Type 2 MEN2a (Sipple syndrome) is an autosomal dominant disorder with a high degree of penetrance, including various combinations of pheochromocytoma, medullary thyroid carcinoma, and parathyroid hyperplasia.291 MEN2b also has an autosomal dominant mode of inheritance, but some patients appear to have the isolated or sporadic form of the disorder. The molecular background of MEN2a and MEN2b syndromes is activating mutations of the RET protooncogene.292 It is possible that clinically aggressive medullary thyroid carcinoma that occurs in the setting of MEN2b causes death at an early age without the patient being able to pass the genetic syndrome on to a future generation.4 Some cases may be truly sporadic as a result of gene mutations. The pheochromocytoma in MEN2a and MEN2b are frequently multicentric (Fig. 16.61) and bilateral (Fig. 16.62), and in some cases in which residual chromaffin tissue is recognizable, extratumoral medullary hyperplasia may be seen.293 Gross morphologic features may be sufficiently distinctive that the surgical pathologist may be alerted to the possibility of the associated syndrome.4,293 In older literature, AMH in MEN2 was considered to be the precursor of pheochromocytoma.176,177 AMH in this setting is now regarded as a small or early pheochromocytoma because they share the same genetic abnormality.182 In MEN2a and MEN2b, one of the earliest manifestations of early pheochromocytoma is an elevated ratio of epinephrine to norepinephrine in the urine.176 One suggested treatment for such patients is bilateral total adrenalectomy. Others suggest good long-term results with conservative unilateral adrenalectomy, with removal of the larger gland. Involvement of the adrenal glands may be symmetric or asymmetric. Carney et al. had adopted a cutoff point of 1 cm in size to diagnose pheochromocytoma, but even smaller nodules can be regarded as tumors in the setting of MEN2.178 This size was chosen because it was the lower limit in size range for pheochromocytoma reported in the first series

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Fig. 16.61 Multifocal early pheochromocytomas in multiple endocrine neoplasia 2a (Sipple syndrome). The adrenal glands had a similar gross appearance. Transverse sections of the left adrenal gland show multiple nodules expanding the medullary compartment, with the largest nodule 1.5 cm in diameter.

Fig. 16.62 Bilateral pheochromocytoma in multiple endocrine neoplasia 2a. The tumors weighed 168 and 220 g. One gland is depicted here; the outer surface is on the right, and the cut surface is on the left.

fascicle from the Armed Forces Institute of Pathology dealing with tumors of the adrenal gland.181 A recent study showed identical molecular changes in these lesions and pheochromocytoma from patients with MEN2 and concluded that these are not hyperplastic but instead neoplastic (i.e., a small pheochromocytoma).182 Histologically, the lesions consist of expansile nodular growth of the medulla with distortion of the adjacent cortex or adjacent normalappearing medulla. There may be numerous extensively vacuolated cells, as well as intracytoplasmic hyaline globules, some of which appear to be present in the extracellular space. Mitotic figures may be present but usually are not numerous, and some nuclear pleomorphism may be seen. In a study of MEN2 and pheochromocytoma, DNA content was found to be diploid or euploid in normal and hyperplastic glands, whereas 87% of clinically benign pheochromocytoma and all malignant pheochromocytoma had nondiploid or aneuploid DNA histograms.180 The phenotypic expression of MEN2b is very distinctive. Medullary thyroid carcinoma in this syndrome is usually aggressive, and recurrence and metastasis are its most pernicious components.4,272

Fig. 16.63 Patient with multiple endocrine neoplasia 2b. The tongue is studded with neuromatous nodules, particularly along the lateral borders and the tip. (From Lack EE. Tumors of the Adrenal Glands and Extraadrenal Paraganglia. Atlas of Tumor Pathology, Series 4. Washington, DC: Armed Forces Institute of Pathology; 2007:245.)

Pheochromocytoma is often preceded by what used to be called AMH.176,177 In MEN2b, there is a low incidence of clinical and biochemical hyperfunction of the parathyroid glands, in contrast with that in MEN2a.4,272 Characteristic mucosal neuromatous proliferation involves the lips, tongue (Fig. 16.63), oral mucosa, and conjunctivae; ganglioneuromatosis may involve the upper aerodigestive and lower gastrointestinal tracts. This may lead to a variety of intestinal manifestations, including motility disorders and megacolon mimicking Hirschsprung disease.4,272 Other findings include ocular abnormalities such as thickened corneal nerves, conjunctival and eyelid neuromatous lesions, and, rarely, failing vision. Various neuromuscular abnormalities have been described, such as marfanoid habitus, elongated facies, dolichocephaly, laxity of joints, lordosis, kyphosis, pes cavus, and coxa valga. The gastrointestinal manifestations in MEN2b are important to recognize because they may form a prominent component of the syndrome, often antedating the endocrine neoplasms.294

Composite Pheochromocytoma The term composite pheochromocytoma refers to a pheochromocytoma in which a component resembles neuroblastoma,

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Fig. 16.64 Composite pheochromocytoma-ganglioneuroma. Mature ganglion cells within the ganglioneuroma component (left), marked by arrows.

ganglioneuroblastoma, ganglioneuroma (Fig. 16.64), or malignant peripheral nerve sheath tumor (malignant schwannoma).4,71 A few have secreted vasoactive intestinal peptide (VIP), causing the watery diarrhea syndrome. The capacity for synthesis and secretion of VIP has been associated with a neuronal or ganglionic phenotype, but this is not always apparent. Neoplastic chromaffin cells in vitro may exhibit intense neuritic outgrowth of cell processes, indicative of one of several neuronal characteristics. The existence of composite pheochromocytoma with neural and endocrine features in vivo is ample testimony to the close morphologic and functional kinship of the nervous system and the endocrine system.4 An example of composite pheochromocytoma-ganglioneuroma of the adrenal gland has been reported in a patient with MEN2a.295

Pseudopheochromocytoma The term pseudopheochromocytoma refers to the unusual circumstance in which a patient has signs or symptoms of a pheochromocytoma, but no neoplasm is found on surgical exploration. Reported examples include AMH, adrenal myelolipoma, renal cyst, coarctation of the abdominal aorta, and astrocytoma.4,272 Rarely, patients may develop signs and symptoms suggesting pheochromocytoma after surreptitious administration of epinephrine or other agents that produce provocative clinical manifestations.4 Rarely adrenal cortical tumor has been reported mimicking pheochromocytoma.236 Immunohistochemistry and Other Features The catecholamine-synthesizing enzymes tyrosine hydroxylase, dopamine β-hydroxylase, and phenylethanolamine Nmethyltransferase have been identified in pheochromocytoma and correlate with the functional capacity of this tumor to produce norepinephrine and epinephrine.4 The ratio of epinephrine to norepinephrine in the normal adrenal medulla is approximately 4:1, whereas norepinephrine predominates in pheochromocytoma.4 The immunohistochemical profile of pheochromocytoma is quite broad; it typically expresses neuron-specific enolase and other neuroendocrine markers such as chromogranin A, synaptophysin, and CD56.286 Pheochromocytoma also can express a broad array of other regulatory peptides and hormones, including enkephalins, somatostatin, VIP, substance P, ACTH, and calcitonin.296 Rare

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Fig. 16.65 Pheochromocytoma. Sustentacular cells are demonstrated by immunostaining for S100 protein, which highlights nuclei and slender cytoplasmic extensions. These cells are located at the periphery of nests and cords of pheochromocytoma cells.

cases are associated with a paraneoplastic syndrome caused by the secretion of one of the neuropeptides, such as VIP, with watery diarrhea syndrome and ACTH with Cushing syndrome.4 Sustentacular cells are the supporting cells in pheochromocytoma, appearing as S100 protein immunoreactive cells at the periphery of cords and clusters of neoplastic chromaffin cells (Fig. 16.65). Cytokeratin reactivity has been reported in an oncocytic pheochromocytoma.297 However, another report fails to support keratin reactivity in more traditional pheochromocytoma, but immunopositive staining for keratin (CAM5.2 and AE1/3) was noted in a few extraadrenal paragangliomas.298 The ultrastructural hallmark of pheochromocytoma is the presence of dense-core neurosecretory-type granules, which have variable distribution and density within neoplastic cells.299 Sparse numbers of these granules in some cells may help explain a low to equivocal intensity of immunostaining for neuroendocrine markers such as chromogranin A in some cases. Tannenbaum found that granule morphology correlated with catecholamine content as determined biochemically.300 Two distinct types of granules were recognized. Those associated with norepinephrine storage had a distinctly prominent, eccentric halo or electron lucent space adjacent to the dense core; and those associated with epinephrine storage were more uniform (Fig. 16.66). Given the wide array of neuropeptides and hormones that may be detected in pheochromocytoma, the distinction based solely on granule morphology is no longer tenable.4,272 Some granules, in fact, may be quite pleomorphic, and some could conceivably contain more than one peptide. Fine-needle aspiration of pheochromocytoma may create problems in cytologic interpretation, and a malignant diagnosis rendered solely on the basis of cytologic and nuclear atypia may be erroneous.4 Occasional complications also have been reported, including catecholamine crisis with a marked alteration in blood pressure and sometimes with uncontrollable intraabdominal hemorrhage.4 In smear and imprint preparations of pheochromocytoma, nuclei may appear suspended in a syncytium of ill-defined cytoplasm, and considerable variations in nuclear size and shape may be seen (Fig. 16.67). Other cytologic features include intranuclear pseudoinclusions and enlarged hyperchromatic nuclei, sometimes stripped of cell cytoplasm.4

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Fig. 16.66 Pheochromocytoma. Electron micrograph shows numerous dense-core neurosecretory granules; some have an investing membrane with a uniform thin halo (curved arrow), whereas others have an eccentric dense core with a wide asymmetric halo (straight arrow). Other neurosecretory granules are pleomorphic. (15,000.)

Fig. 16.67 Pheochromocytoma. Touch imprint smear of resected tumor shows marked variation in nuclear size, which might lead to a presumptive diagnosis of malignancy (Diff-Quik stain).

Malignant Pheochromocytoma The incidence of clinically malignant pheochromocytoma is relatively low, and it is important to consider these separately from intraabdominal extraadrenal paragangliomas, which tend to have a significantly higher incidence of malignant behavior.4 Early reviews cite a frequency of malignant behavior in pheochromocytoma of 2.4% to 2.8% in adults, whereas in children 2.4% were malignant.301-303 A study from 2006 reports a relatively high incidence (47%) of malignancy in 30 children with

pheochromocytoma and extraadrenal paraganglioma.304 In this study, however, 18 of the children had extraadrenal paraganglioma and only 12 had pheochromocytoma (defined as tumors arising from the adrenal medulla), which may account for the higher incidence. Overall, recent studies show an incidence of malignancy ranging from 7% to 14%.4 It is notoriously difficult on gross and histologic evaluation to predict which tumors will prove to be malignant. The histology of benign and malignant pheochromocytoma overlaps to such an extent that the most important criterion acceptable for malignancy is the presence of metastases to sites where nonneoplastic chromaffin tissue is not normally found.305 However, some histologic features have been noted to be more frequently associated with malignant behavior.306 In the study by Thompson, the following features were more frequent in malignant pheochromocytoma: loss of the small alveolar or nesting pattern, to be replaced by larger cell nests lacking the wellformed fibrovascular supporting network; a diffuse growth pattern; tumor cell spindling; confluent tumor necrosis; increased mitotic rate (>3 per 10hpf); and the presence of atypical mitotic figures.307 Based on these findings, a scoring system (pheochromocytoma of the adrenal gland scaled score [PASS]) for pheochromocytoma was proposed to separate benign from malignant tumors. Selected features were weighed to come up with a single score, with a total score of 4 or more suggesting malignancy. Another scoring system that was proposed for both pheochromocytomas and extraadrenal paragangliomas is the grading system for adrenal pheochromocytoma and paraganglioma (GAPP).308 There is no universal agreement on the applicability and reproducibility of PASS, and probably the same may apply to the GAPP system.274 In some studies, DNA quantification has suggested that ploidy may be an independent prognostic factor, because there were fewer deaths of patients with diploid pheochromocytoma.309,310 Aneuploid histograms have been reported, however, in pheochromocytomas that are clinically benign or cured by surgery. A low proportion (or absence) of S100 protein immunoreactive cells has been correlated with malignant behavior of paragangliomas, but this may not be a reliable discriminator in the evaluation of individual cases.311-313 Other markers recently investigated as possible predictors of high risk for malignant/recurrent pheochromocytoma include Ki-67 labeling greater than 4% and absence of S100 positive sustentacular cells.314 Cell cycle and apoptosis markers, including p53, Bcl-2, mdm-2, cyclin D1, p21, and p27, seem to play no significant role in predicting malignant behavior.315 Surgical resection has been the mainstay of treatment for pheochromocytoma. Laparoscopic adrenalectomy may be a less invasive procedure for patients, but, for suspected malignant pheochromocytoma, conversion to open surgery may be indicated. A case has been reported of local spillage of tumor during laparoscopic manipulation resulting in iatrogenic pheochromocytomatosis.316

Peripheral Neuroblastic Tumors: Neuroblastoma, Ganglioneuroblastoma, and Ganglioneuroma Peripheral neuroblastic tumors are defined as embryonal tumors of the sympathetic nervous system derived from the neural crest and arise in anatomic sites paralleling the distribution of the sympathoadrenal neuroendocrine system. Peripheral neuroblastic tumors include a spectrum of tumors ranging from neuroblastoma and ganglioneuroblastoma to fully mature ganglioneuroma. The

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TABLE 16.6

Peripheral Neuroblastic Tumor Classification Recommended by the International Neuroblastoma Pathology Committee

Category

Subtype

Neuroblastoma (schwannian stroma-poor)

• Undifferentiated • Poorly differentiated • Differentiating

Ganglioneuroblastoma, intermixed (schwannian stroma-rich) Ganglioneuroblastoma, nodulara Ganglioneuroma (schwannian stroma-dominant)

• Maturing • Mature

a

Ganglioneuromatous component may be stroma-rich or stroma-dominant, and nodule(s) may be composed of undifferentiated, poorly differentiated, or differentiating neuroblastoma. Modified from Shimada H, Ambros IM, Dehner LP, Hata J, Joshi VV, Roald B. Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee. Cancer. 1999;86:349–363.

current terminology for peripheral neuroblastic tumors is shown in Table 16.6, which is adopted by the International Neuroblastoma Pathology Committee and based on a modification of the earlier Shimada age-linked classification.317-320 This classification defines the various categories of peripheral neuroblastic tumors. Subtypes of neuroblastoma are undifferentiated, poorly differentiated, and differentiating. Subtypes of ganglioneuroblastoma are intermixed and nodular. The amount of spindle cell schwannian stroma delineates neuroblastomas from ganglioneuroblastomas and ganglioneuromas because in neuroblastomas the amount of schwannian stroma is less than 50% of the total surface area of the tumor in representative histologic sections.

In Situ Neuroblastoma The concept of in situ neuroblastoma was introduced in 1963 and refers to a small adrenal tumor similar histologically to classic childhood neuroblastoma but without gross or microscopic evidence of tumor elsewhere in the body.321 In situ neuroblastoma has been detected in about 1 in 200 autopsies on infants up to 3 months of age. The lesions consist of poorly differentiated neuroblasts. Apoptotic figures and microcysts may be present, but mitoses are infrequent. In situ neuroblastoma is much more frequent than clinical neuroblastoma, and if truly neoplastic then the clear majority must be assumed to undergo spontaneous regression or maturation. It should be noted that neuroblastic foci are an integral part of normal development of the adrenal gland and may linger until early infancy, and their distinction from in situ neuroblastoma may be problematic.

Peripheral Neuroblastic Tumors Neuroblastoma ranks fourth in frequency of malignant tumors in patients younger than 15 years of age, exceeded only by leukemia, brain tumors, and malignant lymphoma.322 The incidence of neuroblastoma and ganglioneuroblastoma is estimated at 9.1 per million. Age is a strong factor bearing on incidence, with neuroblastoma predominating in children younger than 5 years of age and making up most tumors arising during infancy.322 A

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slightly increased incidence of neuroblastoma is seen in males (9.8 per million) in contrast with females (9.2 per million). In a series of 118 patients from Boston Children’s Hospital, 88% were 5 years of age or younger at diagnosis, with a median age of 21 months.323 Neuroblastomas and ganglioneuroblastomas are rare in the second decade of life and exceedingly rare in adults.324 When these tumors do arise in adolescents or adults, they appear to have different biologic characteristics from their pediatric counterparts and have a poor prognosis regardless of stage.324 Occasionally, neuroblastoma appears in several members of a family, and some data suggest an autosomal dominant pattern of inheritance. However, obvious difficulties exist in determining the incidence and penetrance of an inherited susceptibility because of the capacity for regression or spontaneous maturation, as well as early death and long-term treatment complications that prevent reproduction and the evaluation of multiple pedigrees.325,326 Neuroblastomas and ganglioneuroblastomas may have some unusual associations: watery diarrhea syndrome resulting from VIP production, Cushing syndrome, opsoclonus/myoclonus, and alopecia. Horner syndrome and heterochromia iridis have been reported because of involvement of cervical sympathetic ganglia.4,327 Occasional tumors are associated with Beckwith-Wiedemann syndrome, neurofibromatosis types 1 and 2, Hirschsprung disease, central hypoventilation syndrome (Ondine’s curse) secondary to PHOX2B mutation, and other syndromes and congenital malformations. The first screening for neuroblastoma began in Japan in 1974, and other studies have followed.4,328,329 Screening in Japan has resulted in an increased annual detection rate for these tumors (93 per million) in contrast with the baseline rate of 13.3 per million. Children are screened at 6 months of age with a qualitative vanillylmandelic acid spot test. The prognosis for children with neuroblastoma detected by screening is favorable because of low clinical stage and early age at diagnosis, both important independent prognostic factors.4,327 Most infants are considered to be in a low-risk subgroup with potential for spontaneous regression, and although screening programs do increase the number of newly diagnosed cases, they do not appear to reduce population-based mortality in infants, nor do they result in a decreased incidence of advanced-stage disease in older children.330-333 Screening infants could potentially result in overdiagnosis and lead to unnecessary diagnostic and therapeutic procedures with possible physical and psychological harm. The anatomic location of peripheral neuroblastic tumors parallels that of the sympathoadrenal neuroendocrine system with tumors arising in any location from the neck to the pelvis. The anatomic distribution of primary tumors in the series of 118 patients from Boston Children’s Hospital was as follows: intraabdominal (67.8%), with most arising in the adrenal glands (38.1%) and 29.7% being nonadrenal; intrathoracic (20.3%); cervical (3.4%); and pelvic (3.4%); in 5.1%, the precise anatomic origin was undetermined.323 Patients with neuroblastoma and ganglioneuroblastoma may have spinal cord compression caused by an extradural intraspinal (“dumbbell”) configuration of the tumor; similar spinal cord compression may occasionally be seen with ganglioneuroma.4,327 Neuroblastoma and ganglioneuroblastoma usually present as a solitary spherical or ovoid mass, and tumors can be quite large, measuring up to 10 cm or more.4,327 On cross-section, they are variable in appearance and consistency depending on the amount of immature neuroblastic component present. Neuroblastomas of the undifferentiated or poorly differentiated subtypes may be soft and friable with areas of hemorrhage (Fig. 16.68). The tumors may have coarse lobulations. Yellow flecks of calcification or pale foci of

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Fig. 16.68 At autopsy, neuroblastoma virtually replaces the entire adrenal gland and compresses the adjacent kidney. The cut surface of the tumor has coarse lobulations and is hemorrhagic.

necrosis may be present. With increasing differentiation, the cut surface may be tan-yellow and less friable. Undifferentiated and poorly differentiated neuroblastoma is the prototypical “small, blue cell tumor” of childhood, and often has an ill-defined lobular or nesting growth pattern with delicate incomplete fibrovascular septa.334 Some tumors have a more diffuse or solid pattern. Typical Homer Wright rosettes can be found in some tumors (Fig. 16.69A), with the center consisting of a pale-staining tangled skein of neuritic cell processes.335 This neurofibrillary matrix has been likened to neuropil of the central nervous system and may form the center of rosettes or form broad mats with irregular contour. Rarely, rosettes may have a rhythmic or palisaded configuration. In undifferentiated neuroblastoma (Fig. 16.69B), the neurofibrillary matrix is absent or equivocally present, and the tumor may require ancillary techniques (e.g., immunohistochemistry or electron microscopy) to establish a correct diagnosis. In differentiating neuroblastoma, the tumor cells are transitioning to ganglion cells and show synchronous enlargement of nucleus and cytoplasm. The diameter of the cell should be two times the diameter of the nucleus to qualify as a differentiating neuroblast, and at least 5% of the cells should have this appearance for a tumor to be designated as a differentiating neuroblastoma. Nucleoli are inconspicuous, and chromatin may be finely dispersed with a “salt-and-pepper” pattern (Fig. 16.70). Morphologic evidence of ganglion cell differentiation includes nuclear enlargement, increased amount of eosinophilic cytoplasm, distinct cell borders, prominent nucleolus, and peripheral granular material within the cytoplasm that represents Nissl substance (Fig. 16.71). The degree of ganglion cell differentiation varies from tumor to tumor and within different areas of the same tumor. Some peripheral neuroblastic tumors have unusual histopathologic features such as a sclerosing pattern, spindle-shaped neuroblasts, and a dense lymphoplasmacytic component, and the latter may be related to tumor regression in some cases. Anaplastic neuroblastoma has marked cellular and nuclear pleomorphism, but this finding has no apparent impact on survival after controlling for disease stage.336,337 Cystic neuroblastoma is uncommon and may simulate an adrenal cyst or hematoma.338 Pigmented ganglioneuroblastoma is very rare with cytoplasmic pigment thought to be neuromelanin.339 Ganglioneuroblastoma is classified as a schwannian stroma-rich tumor with schwannian matrix accounting for at least 50% of the surface area in representative histologic sections. There may be

Fig. 16.69 Neuroblastoma. (A) Stroma-poor in the Shimada classification. The cells are closely packed, with indistinct cellular borders. Note the Homer Wright rosettes. (B) Undifferentiated neuroblastoma. Sheets of small blue cells with elongated nuclei and indistinct cellular borders. Nuclear chromatin is stippled (salt and pepper). Neuropil is absent.

Fig. 16.70 Touch imprint of neuroblastoma (stroma-poor in the Shimada classification). Nuclei have dispersed chromatin (salt-and-pepper nuclei), and are separated by pale pink cytoplasm with indistinct borders.

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examination, the cut surface of ganglioneuroblastoma intermixed is yellow to tan, rubbery, and less friable. In ganglioneuroblastoma nodular, there are one or more grossly visible neuroblastic nodules usually sharply demarcated and often hemorrhagic in a tumor that elsewhere conforms to ganglioneuroblastoma intermixed or ganglioneuroma. In some examples of ganglioneuroblastoma nodular, the neuroblastic nodule(s) may be poorly delimited or overwhelm the schwannian-rich or schwannian-dominant component with only a narrow rim of ganglioneuroblastoma intermixed or ganglioneuroma identified. Another variation of ganglioneuroblastoma nodular occurs when a small neuroblastic nodule may be overlooked in a ganglioneuroblastoma intermixed or ganglioneuroma, but there is metastatic neuroblastoma in another site.

Fig. 16.71 Ganglioneuroblastoma with well-developed ganglion cells that have Nissl substance in peripheral cytoplasm and prominent nucleoli (toluidine blue).

clusters of neuroblasts accompanied by neurofibrillary matrix and showing cytodifferentiation into recognizable ganglion cells or their immediate precursors. Two types of ganglioneuroblastoma are recognized: ganglioneuroblastoma intermixed and ganglioneuroblastoma nodular.320,340,341 Ganglioneuroblastoma intermixed has microscopic nests of neuroblasts with differentiating neuroblasts or immature ganglion cells predominating. Poorly differentiated neuroblasts are less conspicuous or absent. On gross Fig. 16.72 (A) Stroma-rich neuroblastoma according to the Shimada age-linked classification of neuroblastoma proposed in 1984. Survival data are indicated for the favorable and unfavorable groups. (B) Stroma-poor neuroblastoma according to the Shimada age-linked classification. Favorable and unfavorable prognosis groups are indicated along with survival data. MKI, Mitosis-karyorrhexis index; y/o, years old. (From Lack EE, ed. Pathology of adrenal and extraadrenal paraganglia. In: Major Problems in Pathology. Vol 29. Philadelphia: Saunders; 1994:315–370.) Newer revised classification of neuroblastic tumors is shown in Tables 16.6 and 16.7.

Original Age-Linked Classification of Neuroblastoma In 1984, Shimada et al. introduced an age-linked classification of neuroblastoma, based on the patient’s age at diagnosis, degree of maturation or percentage of differentiating elements, and the mitosis-karyorrhexis index (MKI).317,342 The stroma-rich category showed extensive growth of schwannian and other supporting elements, with three groups (Fig. 16.72A): the well-differentiated and intermixed groups had a favorable prognosis (92% to 100% survival), and the nodular group had a poor prognosis (18% survival). The stroma-poor category had two groups (Fig. 16.72B): the favorable group had a survival of 84%, and the unfavorable group had a survival of 4.5%.

Well-differentiated

Favorable Prognosis Groups 100% survival (n = 13)

Absent 92% survival (n = 25)

Intermixed

Stroma-rich tumors

Nodules

Unfavorable Prognosis Groups

A

Present

Nodular

18% survival (n = 22)

M K

<150 y/o

84% survival (n = 125)

M

stroma-poor tumors

Age

>5 y/o

B

1.5–4 y/o

Differentiating

Undifferentiatied

K

>100

<200

Favorable Prognosis Groups

<100

>200

Unfavorable Prognosis Groups 4.5% survival (n = 110)

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International Neuroblastoma Pathology Classification The morphologic classification of peripheral neuroblastic tumors incorporating age at diagnosis as just noted was initially proposed in 1984, established a few years later, and revised in 2003; this classification was recently summarized in an updated WHO classification on tumors of endocrine organs.320 Basically, tumors are classified as favorable histology or unfavorable histology (Table 16.7) based on the following: (1) the amount of spindle cell schwannian stroma (stroma-poor, stroma-rich, and stromadominant); (2) the degree of neuroblastic differentiation (undifferentiated, poorly differentiated, and differentiating); (3) the MKI score (low, intermediate, or high); and (4) the age of the patient at diagnosis.320 The MKI is defined as the number of mitotic figures and karyorrhectic cells per 5000 neuroblastic cells, and one of three scores is reported: (1) low: less than 2% (<100/5000); (2) intermediate: 2% to 4% (100 to 200/5000); and high: greater than 4% (>200/5000). Hyperchromatic nuclei that are not fragmented

Histopathologic Age-Linked Prognostic Indicators According to the International Neuroblastoma Pathology Classification

TABLE 16.7

Favorable Histology

Unfavorable Histology

Less Than 1.5 Years (18 Months) • Neuroblastoma (schwannian stroma-poor) poorly differentiated with low/intermediate MKI • Neuroblastoma (schwannian stroma-poor), differentiating with low/intermediate MKI

1.5-5 Years (18-60 Months) • Neuroblastoma (schwannian stroma-poor), differentiating with low MKI

• Neuroblastoma (schwannian stroma-poor), poorly differentiated • Neuroblastoma (schwannian stroma-poor), differentiating with intermediate MKI

More Than 5 Years (60 Months) • Neuroblastoma (schwannian stroma-poor), of any subtype

Any Age • Ganglioneuroblastoma, intermixed (schwannian stroma-rich) • Ganglioneuroma (schwannian stroma-dominant), maturing or mature

• Neuroblastoma, (schwannian stroma-poor), undifferentiated • Neuroblastoma, (schwannian stroma-poor), any subtype with high MKI

Ganglioneuroblastoma, nodular (composite, schwannian stroma-rich/dominant and schwannian stroma-poor) is classified in either the favorable or unfavorable histology group depending on the characteristics of its neuroblastomatous nodules. For this distinction, the same age-dependent evaluation criteria for grade of neuroblastic differentiation and MKI are applied to the neuroblastomatous components as are used in the neuroblastoma (schwannian stroma-poor) category. Modified from Shimada H, DeLellis RA, Tissier F. Neuroblastic tumors of the adrenal gland. In: Lloyd RV, Osamura RY, Kl€oppel G, Rosai J, World Health Organization, International Agency for Research on Cancer, eds. WHO Classification of Tumours of Endocrine Organs. Lyon, France: International Agency for Research on Cancer (IARC); 2017:196–203.

are not included in the MKI. The microscopic fields selected for the MKI should be representative of the tumor with avoidance of necrotic zones. A Ki-67 index has recently been proposed as a surrogate marker for the MKI.343 As shown in Table 16.7, favorable histology tumors include poorly differentiated or differentiating neuroblastoma (schwannian stroma-poor) with low or intermediate MKI until 1.5 years (18 months) of age; differentiating neuroblastoma (schwannian stroma-poor) with a low MKI 1.5 to 5 years (18 to 60 months) of age; and ganglioneuroblastoma intermixed (schwannian stroma-rich) and ganglioneuroma (schwannian stroma-dominant) of either subtype, mature or maturing at any age. Unfavorable histology tumors include undifferentiated neuroblastoma (schwannian stroma-poor) at any age and neuroblastoma of any subtype with a high MKI at any age; poorly differentiated neuroblastoma (schwannian stroma-poor) and differentiating neuroblastoma (schwannian stroma-poor) with an intermediate MKI at 1.5 to 5 years (18 to 60 months) of age; and neuroblastoma (schwannian stroma-poor) of any subtype over 5 years of age. With ganglioneuroblastoma nodular, placement into the favorable or unfavorable histology categories is dependent on the histology or character of the neuroblastic (schwannian stroma-poor) component described previously. For this distinction, the same age-dependent evaluation criteria for grade (or subtype) of neuroblastic differentiation and MKI are applied to the neuroblastomatous components as are used in the neuroblastoma (schwannian stroma-poor) category.320

Ancillary Techniques Neuroblastomas are characteristically immunoreactive for a variety of neural markers such as chromogranin, synaptophysin, PGP 9.5, CD 57, neurofilament protein, and PHOX2B.320,344 Immunostaining for S100 protein highlights slender dendritic cells near fibrovascular septa, which represent Schwann cells. Large numbers of S100 protein immunoreactive cells in undifferentiated neuroblastoma have been associated with a more favorable prognosis.345 Conversely, large numbers of ferritin-positive cells have been associated with a poor prognosis.4,327 Undifferentiated neuroblastomas are immunoreactive for PHOX2B and PGP 9.5 and are sometimes positive for tyrosine hydroxylase; these tumors are usually negative for other neural markers.346 Ultrastructural characteristics of neuroblastoma and ganglioneuroblastoma include neuritic extensions with neurofilaments, neurotubules, and dense-core neurosecretory granules, which are usually few (Fig. 16.73).334

Molecular Genetics in Neuroblastomas A variety of molecular and genetic changes are present in neuroblastomas involving mutations, as well as gains and losses of whole chromosomes and segmental chromosome alterations.320,341,347-350 MYCN amplification occurs in about 20% of neuroblastomas and produces an excess of Myc-N protein that prevents cellular differentiation and promotes cellular proliferation and apoptosis; it is an ab initio finding in a subset of aggressive tumors.320,341,349,351 Thus tumors with MYCN amplification are usually undifferentiated or poorly differentiated subtypes of neuroblastoma with increased mitotic rate and karyorrhectic cells—that is, high MKI. MYCN amplification is an important oncogenic driver, and the presence of more than 10 copies is associated with a poor prognosis. Another important oncogenic driver is an activating mutation of the ALK gene, which is found in 8% to 10% of neuroblastomas, or amplification of a wild-type ALK gene in another 2% to 4% of

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proportion of metastatic neuroblastomas, mainly in children and adolescents with a chronic but progressive clinical course. ARID1A and ARID1B are mutated in about 2% to 3% of neuroblastomas and are found in a subset of highest-risk neuroblastomas.357 Other mutations have recently been reported in clinically aggressive neuroblastomas, including CHD9, TERT, PTK2, NAV1, NAV3, and FZD1.350,359 Various chromosomal abnormalities are common in neuroblastomas. An unbalanced gain of 17q is found in more than one-half of neuroblastomas, often as part of an unbalanced translocation between chromosomes 1 and 17, and is associated with more aggressive neuroblastomas.360 Deletion of 1p indicates a poor prognosis and is observed in most tumors with MYCN amplification.361 DNA ploidy analysis has shown that near-diploid tumors have a poor prognosis, whereas near-triploid ones tend to manifest at a lower stage and thus have a more favorable prognosis.362-364 There are other molecular and genetic abnormalities in peripheral neuroblastic tumors that cannot be covered in the limited space herein.

Staging of Neuroblastoma and Ganglioneuroblastoma

Fig. 16.73 Neuroblastoma. Neuritic processes contain microtubules (curved arrow) and sparse numbers of dense-core neurosecretory granules (straight arrows) (27,000).

neuroblastomas.352-355 Mutations in genes involved in chromatin remodeling are found in neuroblastomas including ATRX, ARID1A, ARID1B, and DAXX.356-358 ATRX in particular is mutated in a high

TABLE 16.8

Stage I

Stage IIa

Stage IIb

Stage III

Stage IV

Stage IV-S

The staging classification proposed by Evans et al. has been popular for decades.365,366 In 1992, an interim working staging system was also proposed, with incidence and survival data based on stage of tumor at diagnosis (Table 16.8).367 Of patients with neuroblastoma and ganglioneuroblastoma, 60% to 70% have metastases at the time of presentation (stages IV and IV-S) and 30% to 40% have localized disease (stages I, II, and III).4 Children with a tumor primary in the cervical, intrathoracic, or pelvic areas have a more favorable prognosis stage than do patients with intraabdominal primaries, but a disproportionate number may have a lowstage tumor or be younger than 2 years of age and frequently younger than 1 year of age at diagnosis.4 Revisions of the International Neuroblastoma Staging System have been reported (Table 16.9) and vary slightly from those in Table 16.8.368 More recent is the International Neuroblastoma Risk Group Staging System, which incorporates overall staging based on the extent of disease

Staging System Proposed by the International Staging System Working Party with Incidence and Survival According to Stage of Tumor and Diagnosis

Staging Criteria

Incidence (%)

Survival at 5 years (%)

Localized tumor confined to the area of origin, complete gross excision, with or without microscopic residual disease; identifiable ipsilateral and contralateral lymph nodes negative microscopically Unilateral tumor with incomplete gross excision; identifiable ipsilateral and contralateral lymph nodes negative microscopically Unilateral tumor with complete or incomplete gross excision; with positive ipsilateral regional lymph nodes; identifiable contralateral lymph nodes negative microscopically Tumor infiltrating across the midline with or without regional lymph node involvement; or midline tumor with bilateral regional lymph node involvement Dissemination of the tumor to distant lymph nodes, bone, bone marrow, liver, and/or other organs (except as defined in stage IVS) Localized primary tumor as defined for stage I or II with dissemination limited to liver, skin, and/or bone marrow

5

90

10

70-80

25

40-70 (depending on completeness of surgical resection)

60

>60 if age at diagnosis is younger than 1 year; 20 if age at diagnosis is older than 1 year and younger than 2 years; 10 if age at diagnosis is older than 2 years >80

5

From Philip T. Overview of current treatment of neuroblastoma. Am J Pediatr Hematol Oncol. 1992;14:97–102.

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TABLE 16.9

Adrenal Glands

International Neuroblastoma Risk Group Staging System

Stage

Definition

L1

Localized tumor, not involving vital structures as defined by the list of image-defined risk factors and confined to one body compartment Locoregional tumor with the presence of one or more imagedefined risk factors Distant metastatic disease (except stage MS) Metastatic disease in children younger than 18 months of age with metastases confined to the skin, liver, and/or bone marrow (<10% of all nucleated cells)

L2 M MS

Modified from Louis CU, Shohet JM. Neuroblastoma: molecular pathogenesis and therapy. Annu Rev Med. 2015;66:49–63.

and preoperative, radiographic, and image-defined risk factors used to assess resectability (Table 16.9).369 The recently proposed International Neuroblastoma Risk Group Consensus Pretreatment Classification Schema protocol currently incorporates stage, age, histology, ploidy, MYCN status, and the presence or absence of 11q aberrations into risk stratification and treatment protocols.348

Stage IV-S Neuroblastoma and Patterns of Spread by Peripheral Neuroblastic Tumors Stage IV-S (S ¼ special) neuroblastoma refers to a distinctive group of patients with disseminated neuroblastoma involving liver, skin, or bone marrow without radiologic or other evidence of bone metastases and limited to age younger than 1 year (median,
3 months).4,327,367,368 These children usually have a small adrenal primary, but, in a minority of cases, no primary can be identified. Overall the prognosis is favorable, with survival rates of 80% or more, and many of the tumors undergo spontaneous regression. There is a small subset of children with stage IV-S neuroblastoma, usually in the first 6 weeks of life, who have marked abdominal distention because of massive liver involvement by the tumor. The outlook for these patients is less favorable, because massive hepatomegaly may cause secondary complications such as compromise in cardiorespiratory function.370 Some investigators speculate that stage IV-S neuroblastoma is a mass of hyperplastic nodules of mutated cells that lack the genetic events for transformation into an overtly malignant tumor.371 A fascinating aspect of neuroblastoma and ganglioneuroblastoma is the occasional spontaneous regression or maturation into fully mature ganglioneuroma.4,327,372 The concept of Collins law has been applied to children with neuroblastoma and gives a rough approximation of the doubling time of a tumor measured as a period of risk that is equal to the patient’s age at diagnosis plus 9 months.373 According to this concept, a child with neuroblastoma who has not been cured of the tumor will relapse within this time span; theoretically, older children must therefore be followed for a much longer time because of the expanded period of risk. Two syndromes of metastatic neuroblastoma can be found in the early literature, the Pepper syndrome with prominent hepatic metastases and the Hutchison syndrome with skull metastases manifesting at a somewhat later age.374 The cases described by Pepper in 1901 probably correspond to stage IV-S neuroblastoma.4,327 Because no correlation exists between the laterality of the adrenal tumor and the pattern of metastases, the concept of these syndromes is

obsolete. Metastatic spread of neuroblastoma and ganglioneuroblastoma occurs by both hematogenous and lymphatic routes, with involvement of sites such as bone and lymph nodes. Cranial involvement by metastatic neuroblastoma is usually confined to calvarial bone, leptomeninges, and dura, with intrinsic involvement of brain parenchyma being rare.4,327

Ganglioneuroma Ganglioneuroma consists of mature or mildly dysmorphic ganglion cells set in an abundant mixture of mature Schwann cells.4,327 Most patients with ganglioneuroma are older than 10 years of age at diagnosis, and the tumor is usually located in the posterior mediastinum; it also may be seen in the retroperitoneum but is relatively uncommon in the adrenal gland.4,327 Other, more unusual locations include cervical and parapharyngeal area, urinary bladder, prostate, pancreas, orbit, and appendix. Ganglioneuroma typically manifests as a circumscribed tumor that is firm, rubbery, and graywhite to tan-yellow (Fig. 16.74). Grossly, the cut surface of ganglioneuroma may have a trabecular or whorled appearance reminiscent of leiomyoma. Larger tumors may have degenerative features such as hemorrhage and cystic change. Histologically, considerable variation is often seen in the distribution and density of ganglion cells (Fig. 16.75); areas with a paucity or absence of ganglion cells may be mistaken for a neurofibroma or schwannoma. Ganglion cells may be exceedingly well differentiated with Nissl substance and a complete or partial collarette of satellite cells, and some ganglion cells may contain granular tan to brown pigment resembling lipofuscin or neuromelanin; red granules may be present possibly representing megamitochondria. In the International Neuroblastoma Pathology Committee scheme, ganglioneuroma is in the category ganglioneuroma (schwannian stroma-dominant) mature subtype, and should not be confused with ganglioneuroma (schwannian stroma-dominant) maturing subtype, where, in the latter, dispersed individual differentiating neuroblasts and maturing ganglion cells are seen.

Fig. 16.74 Ganglioneuroma is homogeneous pale tan on cross-section. The tumor measured 7  5  4 cm.

CHAPTER 16

Fig. 16.75 Ganglioneuroma. A tumor with ganglion cells mingling with Schwann cells replacing much of the cortex. Small islands of residual adrenal cortex are noted (arrow).

Diagnosis of mature ganglioneuroma requires the absence of any neuroblastomatous component. Thus when making a diagnosis of mature ganglioneuroma, it is imperative that one examines the tumor thoroughly to be certain that no areas of immature neuroblastic tissue exist, even in small amounts. Whether ganglioneuroma arises de novo or by maturation (differentiation) of a preexisting neuroblastoma or ganglioneuroblastoma remains controversial. Transformation of ganglioneuroma to malignant peripheral nerve sheath tumor (malignant schwannoma) has been rarely observed.4,71 In some cases, malignant schwannoma has arisen de novo without any history of chemotherapy, radiation treatment, or von Recklinghausen disease, but other cases have developed after radiotherapy. A few examples have been reported of adrenal ganglioneuroma with hilus or Leydig cells containing typical crystalloids of Reinke; the tumor reported by Aguirre and Scully was associated with masculinization.375,376

Other Adrenal Tumors

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age, with a roughly equal gender predilection.386 Most patients are asymptomatic, and most cases are discovered incidentally. When patients are symptomatic, it is usually because of the large size of the myelolipoma, resulting in abdominal or flank pain, dysuria, hematuria, or, rarely, catastrophic spontaneous retroperitoneal hemorrhage.387 It may occur in patients with concurrent endocrinologic disorders such as Cushing disease, Cushing syndrome, Conn syndrome, Addison disease, and CAH.71,388-390 A case of subclinical Cushing syndrome caused by adrenal myelolipoma has been reported.391 Grossly, myelolipoma forms a soft, well-circumscribed mass that is variegated yellow to red-brown (Fig. 16.76). It ranges in size from a few millimeters to 34 cm. Microscopically, hematopoietic tissue contains various combinations of the three cell lines, with an admixture of mature adipose tissue (Fig. 16.77). Bony trabeculae, hemorrhage, and fibrosis are occasionally seen. Myelolipoma is detected more frequently with the advent of CT and MRI. Fineneedle aspiration biopsy has proved useful in preoperative diagnosis. Treatment varies from radiographic surveillance for small

Fig. 16.76 Adrenal myelolipoma. The tumor is well circumscribed with a thin fibrous capsule. On cross-section, it is red-brown because of abundant hematopoietic elements with a focal area of hemorrhage. The lesion appears quite large and is enveloped by abundant adipose tissue.

Myelolipoma Adrenal myelolipoma is a benign tumefactive lesion consisting of mature adipose tissue admixed with a variable amount of hematopoietic elements. This lesion occurs most frequently in the adrenal gland, although it also occurs in extraadrenal sites, including the retroperitoneum, stomach, liver, mediastinum, pleura, spleen, nasal cavity, and presacral region.186,377-383 The pathogenesis is unknown, although some data suggest that it arises under hormonal influence by metaplasia of adrenal cortical or stromal cells.186 Intraadrenal fat and hematopoietic tissue have been induced experimentally by injecting crude pituitary ACTH extract into adrenal glands, and myelolipomatous foci may be seen in patients with excess cortical activity, such as a hyperfunctioning ACA or adrenal cortical hyperplasia.71,384 Others suggest that myelolipoma derives from emboli from the bone marrow or from embryonic rests of hematopoietic tissue.186 A recent study suggests a clonal origin for myelolipoma, as supported by nonrandom X chromosome inactivation.385 The incidence of adrenal myelolipoma at autopsy is 0.01% to 0.2%, and it is most common in individuals older than 40 years of

Fig. 16.77 Myelolipoma consists of fat mixed with hematopoietic elements, including megakaryocytes. Note the rim of compressed adrenal cortical tissue (top).

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lesions in asymptomatic patients to surgical excision of large or symptomatic lesions.

tonofilaments, and long “bushy” cytoplasmic microvilli typical of mesothelial cells.

Adenomatoid Tumor

Malignant Lymphoma

Although rare, adenomatoid tumors have been described in extragenital sites, including the adrenal gland.392-397 Adenomatoid tumors of the adrenal gland are benign tumors of mesothelial origin, with the characteristic histomorphology of adenomatoid tumors more commonly seen in or near the genital tract. The tumor may have an infiltrative border and typically has a sievelike appearance. It is composed of epithelioid cells with uniform nuclei and intracytoplasmic vacuoles forming tubular or glandlike spaces (Fig. 16.78). Recently a cystic adrenal adenomatoid tumor was reported resembling a cystic lymphangioma.398 Immunohistochemical evaluation shows strong immunoreactivity for cytokeratin and vimentin, weak reactivity for epithelial membrane antigen, and negative immunostaining for carcinoembryonic antigen, factor VIII–related antigen, and CD34. Strong staining for calretinin also is seen (Fig. 16.79). Electron microscopy reveals desmosomes,

Malignant lymphoma secondarily involving the adrenal gland usually occurs in the setting of widespread or advanced-stage tumor, with an incidence in fatal cases of 18% to 25%.4,186 Bilateral adrenal involvement has been reported in 9% of cases of Hodgkin disease and 18% of non-Hodgkin malignant lymphoma.186 Malignant lymphoma rarely manifests primarily in the adrenal gland without detectable extraadrenal involvement, although several cases have been reported.399,400 Rarely, Addison disease may result from massive involvement of the adrenal glands by malignant lymphoma, and the adrenal cortical insufficiency may resolve after treatment with combination chemotherapy.71,186,401 Adrenal cortical insufficiency also has been reported with a form of malignant lymphoma having prominent vascular involvement and intravascular lymphomatosis, previously referred to as malignant angioendotheliomatosis. Plasmacytoma manifesting primarily in the adrenal gland is extremely unusual and may represent an early stage of malignant lymphoma with plasmacytoid features.186,402 A study suggesting a possible association between Epstein-Barr virus infection and the development of adrenal lymphoma has been reported.403

Mesenchymal Tumors

Fig. 16.78 Adenomatoid tumor. Note the uninvolved adrenal cortical tissue (upper right) intimately adjacent to the tumor cells, forming cystic, tubular, and glandlike spaces. The inset demonstrates strong staining of the tumor cells with antibodies to cytokeratin (AE1/AE3).

Fig. 16.79 Adenomatoid tumor. Immunohistochemical stain showing the tumor cells immunoreactive for calretinin.

Primary vasoformative neoplasms of the adrenal glands are extremely unusual. Adrenal hemangioma may be found incidentally at autopsy, but several cases have been detected during life as a surgical lesion.404 A case has also been reported in association with subclinical Cushing syndrome.405 At times, a cortical adenoma may show hemorrhage with extensive degenerative change with vascular organization that may mimic hemangioma (Fig. 16.80). Visceral hemangioma also may occur in the setting of hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome), but adrenal involvement is very rare.186 Adrenal hemangioma is usually of the cavernous type, although capillary hemangioma has been reported. Adrenal angiosarcoma has been reported rarely and may have epithelioid features that include

Fig. 16.80 Adrenal cortical adenoma with hemorrhage showing organization. This pattern may be mistaken for hemangioma. Note the residual cortical adenoma at the periphery.

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the presence of epithelial-specific immunohistochemical markers such as cytokeratin.406-408 Both leiomyoma and leiomyosarcoma occur, rarely, in the adrenal gland, with histologic features similar to smooth muscle neoplasms occurring in other sites.71,409-411 A case of adrenal leiomyosarcoma has been reported in association with AIDS.412 Adrenal lipoma and even liposarcoma have rarely been reported.413 Neurilemoma and neurofibroma arising in the adrenal gland are extremely unusual.71,414,415 Malignant peripheral nerve sheath tumor (malignant schwannoma) has been reported and in one case was part of a composite pheochromocytoma.416,417

Malignant Melanoma Primary malignant melanoma of the adrenal gland is extremely rare and highly malignant, usually occurring in middle-aged individuals.71,418-420 Origin of a malignant melanoma within the adrenal gland is reasonable given the common embryogenesis of adrenal chromaffin cells and melanocytes from the neural crest. Melanin pigment is typically present in varying amounts, but the tumor may be amelanotic. There may be a nesting pattern or a biphasic growth pattern consisting of epithelioid and spindle cells. Rarely, a meningothelial-like growth pattern may be seen. Immunohistochemical studies are important in confirming the diagnosis. The neoplastic cells of an adrenal melanoma, like those of other melanomas, typically show strong reactivity with S100, HMB45, and tyrosinase. Immunostain for melan A (MART-1) is positive, but there also may be staining of an adrenal cortical neoplasm that might enter into the differential diagnosis of melanoma. It may be very difficult to exclude the possibility of primary mucocutaneous malignant melanoma that has metastasized to the adrenal gland.

Other Unusual Tumors and Tumor-like Lesions Ovarian thecal metaplasia is an incidental microscopic lesion composed of bland spindle cells. It is typically wedge-shaped and attached to the adrenal capsule, and may contain small nests of cortical cells.3,71 Foci measure up to 2 mm and may be multiple.421 Most cases occur in females, but rare cases have been seen in males. Rarely, such lesions may arise in association with ectopic adrenal cortical tissue.71 A recent case was reported in association with Beckwith-Wiedemann syndrome.422 Some regard the lesion as a radial scarlike spindle cell nodule composed of myofibroblasts.423 Macroscopic tumefactive spindle cell lesions of the adrenal glands have been described in two individuals, one male and one female, and S100 protein immunoreactivity suggested an origin from Schwann cells.424 A case of granulosa cell tumor of the adrenal gland also has been reported.425 Leydig cells have been described in the adrenal gland as an incidental finding, a component of adrenal ganglioneuroma, or, rarely, a pure adrenal Leydig cell tumor. Other rare adrenal tumors include solitary fibrous tumor, inflammatory myofibroblastic tumor, calcifying fibrous tumor, Ewing sarcoma/primitive neuroectodermal tumor, and malignant perivascular epithelioid cell tumor.426-430

Tumors Metastatic to the Adrenal Glands The adrenal gland is the fourth most common site of metastatic cancer after lung, liver, and bone; per unit weight, it is more

Fig. 16.81 Metastatic renal cell carcinoma. (A) The tumor cells have optically clear cytoplasm in contrast with the adrenal cortex (upper-left corner) showing pale staining, finely vacuolated lipid-rich cytoplasm. (B) CD10 immunostain is strongly positive.

frequently involved than the other sites, probably because the adrenal vascular supply has a high flow volume and a sinusoidal vascular pattern.71,186 Metastases to the adrenal gland most commonly originate in the lung and breast, but other primary sites include the kidney (Fig. 16.81), stomach, pancreas, and skin (malignant melanoma). Rarely, metastases to the adrenal gland are massive, resulting in adrenal cortical insufficiency (Addison disease).71,186 CT-guided or ultrasound-guided fine-needle aspiration biopsy may be useful in documenting the presence of adrenal metastases. Metastatic carcinoma to the adrenal gland can simulate poorly differentiated ACC. The views expressed in this chapter are those of the authors and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, Department of Veterans Affairs, or US government. References are available at expertconsult.com

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Adrenal Glands

406. Livaditou A, Alexiou G, Floros D, Filippidis T, Dosios T, Bays D. Epithelioid angiosarcoma of the adrenal gland associated with chronic arsenical intoxication? Pathol Res Pract. 1991;187: 284–289. 407. Ben-Izhak O, Auslander L, Rabinson S, Lichtig C, Sternberg A. Epithelioid angiosarcoma of the adrenal gland with cytokeratin expression. Report of a case with accompanying mesenteric fibromatosis. Cancer. 1992;69:1808–1812. 408. Wenig BM, Abbondanzo SL, Heffess CS. Epithelioid angiosarcoma of the adrenal glands. A clinicopathologic study of nine cases with a discussion of the implications of finding “epithelial-specific” markers. Am J Surg Pathol. 1994;18:62–73. 409. Lack EE, Graham CW, Azumi N, et al. Primary leiomyosarcoma of adrenal gland. Case report with immunohistochemical and ultrastructural study. Am J Surg Pathol. 1991;15:899–905. 410. Alteer M, Ascoff-Evans BH, Conradie M. Leiomyoma: a rare cause of adrenal incidentaloma. J Endocrinol Met Diab S Afr. 2013;18: 71–74. 411. Zhou Y, Tang Y, Tang J, Deng F, Gong G, Dai Y. Primary adrenal leiomyosarcoma: a case report and review of literature. Int J Clin Exp Pathol. 2015;8:4258–4263. 412. Zetler PJ, Filipenko JD, Bilbey JH, Schmidt N. Primary adrenal leiomyosarcoma in a man with acquired immunodeficiency syndrome (AIDS). Further evidence for an increase in smooth muscle tumors related to Epstein-Barr infection in AIDS. Arch Pathol Lab Med. 1995;119:1164–1167. 413. Lam KY, Lo CY. Adrenal lipomatous tumours: a 30 year clinicopathological experience at a single institution. J Clin Pathol. 2001;54:707–712. 414. Zhou J, Zhang D, Wang G, et al. Primary adrenal microcystic/reticular schwannoma: clinicopathological and immunohistochemical studies of an extremely rare case. Int J Clin Exp Pathol. 2015;8:5808–5811. 415. Gupta P, Aggarwal R, Sarangi R. Solitary neurofibroma of the adrenal gland not associated with type-1 neurofibromatosis. Urol Ann. 2015;7:124–126. 416. Ayala GE, Ettinghausen SE, Epstein AH, et al. Primary malignant peripheral nerve sheath tumor of the adrenal gland: case report and literature review. J Urol Pathol. 1994;2:265–272.

417. Min KW, Clemens A, Bell J, Dick H. Malignant peripheral nerve sheath tumor and pheochromocytoma. A composite tumor of the adrenal. Arch Pathol Lab Med. 1988;112:266–270. 418. Dao AH, Page DL, Reynolds VH, Adkins RB, Jr. Primary malignant melanoma of the adrenal gland. A report of two cases and review of the literature. Am Surg. 1990;56:199–203. 419. Granero LE, Al-Lawati T, Bobin JY. Primary melanoma of the adrenal gland, a continuous dilemma: report of a case. Surg Today. 2004;34:554–556. 420. Bastide C, Arroua F, Carcenac A, Anfossi E, Ragni E, Rossi D. Primary malignant melanoma of the adrenal gland. Int J Urol. 2006;13:608–610. 421. Fidler WJ. Ovarian thecal metaplasia in adrenal glands. Am J Clin Pathol. 1977;67:318–323. 422. Wassal EY, Habra MA, Vicens R, Rao P, Elsayes KM. Ovarian thecal metaplasia of the adrenal gland in association with BeckwithWiedemann syndrome. World J Radiol. 2014;6:919–923. 423. Mete O, Raphael S, Pirzada A, Asa SL. Is adrenal ovarian thecal metaplasia a misnomer? Report of three cases of radial scar-like spindle cell myofibroblastic nodule of the adrenal gland. Endocr Pathol. 2011;22:222–225. 424. Carney JA. Unusual tumefactive spindle-cell lesions in the adrenal glands. Hum Pathol. 1987;18:980–985. 425. Orselli RC, Bassler TJ. Theca granuloma cell tumor arising in adrenal. Cancer. 1973;31:474–477. 426. Toniato A, Boschin IM, Pelizzo MR. A very rare bilateral adrenal tumor. Endocrine. 2014;45:502–503. 427. Tran-Dang MA, Banga N, Khoo B, Bates AW. Inflammatory myofibroblastic tumour arising in the adrenal gland: a case report. J Med Case Rep. 2014;8:411. 428. Lau SK, Weiss LM. Calcifying fibrous tumor of the adrenal gland. Hum Pathol. 2007;38:656–659. 429. Sasaki T, Onishi T, Yabana T, Hoshina A. Ewing’s sarcoma/primitive neuroectodermal tumor arising from the adrenal gland: a case report and literature review. Tumori. 2013;99:e104–e106. 430. Pant L, Kalita D, Chopra R, Das A, Jain G. Malignant perivascular epithelioid cell tumor (PEComa) of the adrenal gland: report of a rare case posing diagnostic challenge with the role of immunohistochemistry in the diagnosis. Endocr Pathol. 2015;26:129–134.