Clinical Features

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  Etiology

  
  
  
  
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    Autosomal recessive disorder of cortisol biosynthesis resulting in impaired glucocorticoid feedback inhibition at the hypothalamic and pituitary levels, increased serum levels of CRH and ACTH, and adrenal hyperplasia

    
    
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    Results from a defect in one of the five enzymatic steps involved in steroid synthesis; 90% to 95% of cases are caused by deficiency of 21-hydroxylase (mutation in CYP21A2 ), resulting in marked elevation of 17-hydroxyprogesterone

    
    
    
    
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      Compound heterozygosity with different mutations that vary from mild missense to complete loss of function

      
      
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      Phenotype generally reflects residual enzyme activity of the milder mutation

    
    
    
    
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    Unusual causes: 20,22-desmolase deficiency, 17α-hydroxylase deficiency, 3β-hydroxysteroid dehydrogenase deficiency (mutation in HSD3B2 ), or 11 β-hydroxylase deficiency (mutation in CYP11B1 ); rarely oxidoreductase deficiency (PORD), due to mutations in the cytochrome P450 oxidoreductase ( POR ) gene

    
    
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    Congenital lipoid adrenal hyperplasia

    
    
    
    
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      The most severe form of congenital adrenal hyperplasia (CAH), in which the synthesis of all gonadal and adrenal cortical steroids is markedly impaired

      
      
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      Lipoid CAH may be caused by a defect in either the steroidogenic acute regulatory (StAR) protein or P-450scc

    
    

  
  
  
  
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  Epidemiology

  
  
  
  
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    Classic form occurs in 1 of 5000 to 15,000 live births

    
    
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    Nonclassic form occurs in 0.3% of the white population

  
  
  
  
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  Signs and symptoms

  
  
  
  
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    Clinical presentation correlates with severity of enzymatic deficiency

    
    
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    Virilization in females, precocious puberty in both sexes, varying degrees of adrenal cortical insufficiency and if severe, adrenal crisis, with vomiting, dehydration, hypoglycemia, hypotension, hyperkalemia, and hyponatremia

    
    
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    Most common cause of ambiguous genitalia in newborn females

    
    
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    Classic form

    
    
    
    
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      Can present as salt-wasting form or simple virilizing type

      
      
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      Newborn females typically show virilization at birth as a result of increased circulating androgens (clitoral hypertrophy and pseudohermaphroditism)

      
      
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      Postpubertal females have oligomenorrhea, hirsutism, and acne

      
      
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      Newborn males usually present with salt-losing crisis within days to weeks after delivery due to decreased synthesis of aldosterone (hypovolemia, hyperreninemia, and hyperkalemia can be life-threatening)

      
      
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      Males later show enlargement of external genitalia and precocious puberty

    
    
    
    
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    Non-classical form

    
    
    
    
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      Affected individuals are normal at birth and do not have cortisol and aldosterone deficiency

      
      
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      Develop signs of androgen excess (virilization) in late childhood or puberty

      
      
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      May present as adrenal insufficiency during pregnancy

    
    

  
  
  
  
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  Therapy

  
  
  
  
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    Pharmacologic treatment involves glucocorticoid and mineralocorticoid replacement and the use of androgen and estrogen antagonists

    
    
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    Bilateral adrenalectomy performed in selected cases

    
    
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    Gene therapy studies under way

  
  

Gross Pathology

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  Bilateral adrenal gland enlargement with diffuse thickening of the cortex ( Figure 9.2A )

  
  

  
  

  
  

  

  
  

  
  

  Congenital adrenal hyperplasia (adrenogenital syndrome).

  
  

  A, Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The adrenal glands are diffusely enlarged with lipid-depleted cortex. B, Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Microscopic examination of the diffusely enlarged gland shows a prominent cortex with poor zonation and predominantly compact cells. C, Lipoid congenital adrenal hyperplasia. The adrenal cortex is thickened by large clear adrenal cortical cells containing increased amount of lipid with focal cholesterol clefts and multinucleated giant histiocytes. ( A, Photo courtesy Dr. Glenn P. Taylor, Hospital for Sick Children, Toronto.)

  
  
  
  
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  Adrenal glands may weigh up to 10 to 15 times normal weight

  
  
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  Adrenals show a convoluted surface owing to numerous redundant folds

Histopathology

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  Thickened adrenal cortex with markedly thickened zona reticularis (active cells) and loss of zona fasciculate (storage); poorly defined zonation (see Figure 9.2B )

  
  
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  Most cortical cells have lipid-depleted (compact) cytoplasm owing to sustained ACTH stimulation

  
  
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  In lipoid CAH, the gland enlargement results from the accumulation of cholesterol esters in large adrenal cortical cells with clear cytoplasm; further damage with cell rupture and foreign-body granulomatous reaction to cholesterol clefts can be seen focally (see Figure 9.2C )

Special Stains and Immunohistochemistry

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  Noncontributory

Other Techniques For Diagnosis

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  Genetic testing for 21-hydroxylase deficiency, or rarely 20,22-desmolase deficiency, 17α-hydroxylase deficiency, 3β-hydroxysteroid dehydrogenase deficiency, or 11 β-hydroxylase deficiency

Differential Diagnosis

Clinical Features

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  Two forms: primary (ACTH independent) which is usually nodular; and secondary (ACTH dependent), which is usually diffuse but may also form nodules

  
  
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  Etiology: depends on primary versus secondary and type of primary disease

  
  
  
  
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    Primary adrenal cortical hyperplasia, also known as ACTH-independent: due to germline mutations

    
    
    
    
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      ACTH-Independent Macronodular Adrenal Hyperplasia (AIMAH): due to activating mutations of ARMC5 or the ACTH receptor; multiple endocrine neoplasia type 1 (MEN 1) syndrome; familial adenomatous polyposis (FAP); amplification or aberrant expression of membrane receptors (GIP receptor, β-adrenergic receptor, and LH receptor); activating mutations of GNAS 1 in McCune-Albright syndrome

      
      
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      Primary Pigmented Nodular Adrenal-cortical Disease (PPNAD): due to inactivating germline mutations of the PRKAR1A and PDE11A genes, usually associated with Carney complex; rarely isolated

      
      
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      Diffuse zona glomerulosa hyperplasia due to germline alterations in the KCNJ5 gene, rearrangements involving CYP11B1/CYP11B2 (type I familial hyperaldosteronism), chromosomal alterations at 7p22 (type II familial hyperaldosteronism) or the rare germline CACNA1H ^M1549V mutation.

    
    
    
    
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    Secondary (ACTH-dependent) hyperplasia: due to ACTH excess from primary pituitary disease (corticotroph tumor or hyperplasia) or ectopic ACTH production by tumors at other sites

  
  
  
  
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  Signs and symptoms

  
  
  
  
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    Primary disorders may present with a variety of endocrine syndromes including Cushing syndrome, Conn syndrome, or virilization

    
    
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    Secondary disorder presents with severe Cushing syndrome, usually typical when pituitary dependent, and atypical (prominent wasting and pigmentation) when due to ectopic production by other malignancies

  
  
  
  
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  Biochemistry

  
  
  
  
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    Variable, depending on clinical manifestations (Cushing, Conn, and virilization syndromes); ACTH levels usually low (suppressed) with primary forms and high in secondary conditions

  
  
  
  
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  Therapy

  
  
  
  
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    Treatment of primary source of ACTH excess in secondary cases

    
    
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    Medical therapy to reduce glucocorticoid hypersecretion with ketoconazole, other drugs

    
    
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    Laparoscopic adrenalectomy for removal of adrenals followed by replacement therapies

  
  

Gross Pathology

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  Primary is usually nodular ( Figure 9.3A )

  
  
  
  
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    Nodules vary from micronodules <1 cm (characteristic of PPNAD) to macronodules >1 cm (characteristic of AIMAH)

    
    
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    Pigmentation is characteristic of PPNAD

  
  

  
  

  
  

  

  
  

  
  

  Adrenal cortical hyperplasia.

  
  

  A, Macronodular adrenal cortical hyperplasia. Gross photograph showing multiple adrenal cortical nodules. B, Diffuse adrenal cortical hyperplasia. Gross photograph showing a normal adrenal gland (top) and a diffusely enlarged gland with a lipid-depleted cortex in a patient with ectopic adrenocorticotropic hormone syndrome (bottom) . C, Macronodular adrenal cortical hyperplasia. Classic nodular adrenal cortical hyperplasia with multiple poorly defined cortical nodules composed of clear and compact cells. D, Zona glomerulosa hyperplasia. The adrenal gland is lined by a continuous layer of zona glomerulosa that is normally discontinuous. The cells are small and are on average five nests in thickness (inset) . E, Primary Pigmented Nodular Adrenal-cortical Disease (PPNAD) is characterized by nodules of enlarged eosinophilic cells with intervening normal-appearing cortex. F, On higher magnification, the cells comprising the nodules in PPNAD are large with granular eosinophilic cytoplasm and accumulation of pigment.

  
  
  
  
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  Secondary is usually diffuse hyperplasia of the adrenal cortex (see Figure 9.3B )

  
  
  
  
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    Degree of enlargement dependent on cause

    
    
    
    
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      Severe when due to ectopic ACTH, mild to moderate with pituitary-dependent disease

    
    

  
  
  
  
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  Grossly undetectable when due to zona glomerulosa hyperplasia with Conn syndrome

  
  
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  Almost always bilateral

  
  
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  Combination of nodular and diffuse types may be seen

Histopathology

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  Adrenal cortex with diffuse hyperplasia or multinodular architecture, vague alveolar or trabecular pattern (see Figure 9.3C )

  
  
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  Cells are uniform in size with small, round nuclei

  
  
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  Cells have vacuolated (clear) or eosinophilic (compact) granular cytoplasm

  
  
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  Areas of lipomatous metaplasia may be seen

  
  
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  Zona glomerulosa hyperplasia limited to periphery of gland, characterized by continuous layer of nests of cells with scant cytoplasm averaging five nests in thickness (see Figure 9.3D )

  
  
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  Mixture of large clear cells and small compact cells in AIMAH

  
  
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  Pigmented nodules composed of enlarged, globular cortical cells with variable amounts of granular dark-brown pigment in PPNAD (see Figure 9.3E and F )

  
  
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  Cortical atrophy and disorganization of the normal zonation between nodules in PPNAD, as opposed to AIMAH, which shows characteristic interlobular hyperplasia

Special Stains and Immunohistochemistry

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  PPNAD nodules stain for synaptophysin and 17α-hydroxylase cytochrome P-450; 3β-hydroxysteroid dehydrogenase staining is dominant in AIMAH nodules

Other Techniques for Diagnosis

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  Noncontributory

Differential Diagnosis

Clinical Features

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  Etiology

  
  
  
  
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    Most are sporadic with no known genetic basis

    
    
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    Association with familial disease (MEN 1, Carney complex, FAP, familial hyperaldosteronism, and congenital adrenal hyperplasia) can occur

    
    
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    May arise in patients with McCune-Albright disease due to mosaic embryonic activating mutations of GNAS

    
    
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    Sporadic adenomas associated with Cushing syndrome may have mutations in PRKAR1A, PRKACA, GNAS, PDE11A, PDE8B , or rarely CTNNB1 that encodes beta-catenin

    
    
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    Sporadic adenomas associated with Conn syndrome and hyperaldosteronism have mutations in the KCNJ5 potassium channel selectivity filter or in ATP1A1 and ATP2B3 encoding Na/K ATPases

    
    
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    Comparative genomic hybridization studies have demonstrated genetic alterations in 30% to 60% of adrenal adenomas; losses on chromosomes 2, 11q, and 17p, and gains on chromosomes 4 and 5 are the most common

    
    
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    TP53 and K-ras mutations and loss of heterozygosity (LOH) of 11p15 and ACTH receptor are rare events in adenomas

  
  
  
  
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  Signs and symptoms

  
  
  
  
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    Most adrenal cortical adenomas are asymptomatic (nonfunctional) and found incidentally

    
    
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    Patients may present with Cushing syndrome or hyperaldosteronism (Conn syndrome); virilization is rarely associated with adenomas, and feminization in males is almost exclusively a sign of malignancy (see “Adrenal Cortical Carcinoma”)

    
    
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    Adenomas associated with Cushing syndrome and primary hyperaldosteronism are usually small and solitary; can rarely be multiple and bilateral

  
  
  
  
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  Biochemistry

  
  
  
  
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    Variable, depending on clinical manifestations (Cushing, Conn, and virilization syndromes); ACTH levels usually low (suppressed), except in Conn syndrome

  
  
  
  
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  Therapy

  
  
  
  
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    Laparoscopic tumor removal is the preferred treatment

  
  

Gross Pathology

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  Adenomas associated with Cushing syndrome or hyperaldosteronism are usually solitary and unilateral and weigh less than 50 g

  
  
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  Well-defined tumors appear encapsulated

  
  
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  Adenomas associated with Cushing syndrome may be bright yellow or tan and are associated with atrophy of the adjacent nontumorous gland ( Figure 9.4A )

  
  

  
  

  
  

  

  
  

  
  

  Adrenal cortical adenoma—gross appearance. A, Adrenal cortical adenoma associated with Cushing syndrome. Gross photograph shows that the nodule is well-delineated and yellow with focal hemorrhage, and the adjacent gland shows marked atrophy. B, Adrenal cortical adenoma associated with Conn syndrome. Gross photograph shows that the tumor is well-delineated and bright golden-yellow. The adjacent adrenal is unremarkable. C, Adrenal cortical adenoma with pigmentation (“black adenoma”). Gross photograph shows that the nodule is well-delineated and dark black owing to pigment deposition.Part 2 Adrenal cortical adenoma—microscopy.

  
  

  D, Adrenal cortical adenoma associated with Cushing syndrome. On microscopy, there is a large, well-delineated but unencapsulated adenoma, and the adjacent gland exhibits marked atrophy with complete loss of the zona reticularis, indicating lack of adrenocorticotropic hormone stimulation. E, Adrenal cortical adenoma associated with Conn syndrome. On microscopy, there is a large, well-delineated but unencapsulated clear cell adenoma, and the adjacent gland has zona glomerulosa hyperplasia (see Figure 9.3D ). F, Adrenal cortical adenoma associated with Cushing syndrome. On microscopy, the adenoma has mixed clear and compact cell morphology with small round nuclei and abundant cytoplasm that varies from chromophobic to eosinophilic. G, Adrenal cortical adenoma associated with Conn syndrome. On microscopy, the tumor cells have abundant clear cytoplasm. H, Adrenal cortical adenoma, pigmented type. High-power view showing proliferation of a monomorphic population of adrenal cortical cells with large amounts of eosinophilic cytoplasm containing yellow-brown pigment. I, Adrenal cortical adenoma associated with Conn syndrome. The LFB stain highlights spironolactone bodies.

  
  

  Part 3 Adrenal cortical adenoma—electron microscopy.

  
  

  J, Adrenal cortical adenoma associated with Cushing syndrome. Electron microscopy shows that the tumor cells have abundant smooth endoplasmic reticulum, and the mitochondria have tubulovesicular cristae, consistent with differentiation as steroid-producing cells. K, Adrenal cortical adenoma associated with Conn syndrome. Electron microscopy shows that the tumor cells have abundant smooth endoplasmic reticulum; the mitochondria have flat platelike cristae, consistent with zona glomerulosa differentiation and mineralocorticoid production; and there are lamellated spironolactone bodies. L, Adrenal cortical adenoma, pigmented type. Electron microscopy shows that the tumor cells have abundant smooth endoplasmic reticulum and numerous mitochondria, and there are large electron-dense granules consistent with complex lysosomes containing lipofuscin.

  
  

  
  

  

  
  
  
  
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  Adenomas associated with Conn syndrome have a characteristic bright-yellow or golden-yellow color (see Figure 9.4B )

  
  
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  Adenomas may show focal hemorrhage or necrosis (typically in larger lesions)

  
  
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  Rarely, adenomas are diffusely pigmented black (pigmented adenoma) (see Figure 9.4C )

  
  
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  Oncocytic adrenal cortical adenomas have a dark-tan to mahogany-brown cut surface

Histopathology

See Figure 9.4D–I .

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  Circumscribed tumor with pushing borders, lacks true capsule (see Figure 9.4D and E )

  
  
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  Typically has trabecular or alveolar (nesting) architecture

  
  
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  Tumor cells are large and have round, regular nuclei with small, dotlike nucleoli; focal pleomorphism and large prominent nucleoli may be seen

  
  
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  Absent or rare mitotic activity; never atypical mitoses

  
  
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  Cytoplasm is abundant and “clear” or “compact”

  
  
  
  
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    In adenomas associated with Cushing syndrome, cytoplasm may be clear or eosinophilic (compact), and in most tumors, both types may be seen (see Figure 9.4F )

    
    
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    In adenomas associated with Conn syndrome, cytoplasm is clear, lipid rich, and vacuolated (see Figure 9.4G ).

    
    
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    Pigmented adenomas have cells with eosinophilic cytoplasm containing prominent granular yellow-brown pigment (lipofuscin) (see Figure 9.4H ).

    
    
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    Oncocytic adenomas have cells with abundant granular eosinophilic cytoplasm; focal marked nuclear pleomorphism and nuclear pseudoinclusions may be seen

  
  
  
  
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  Histologic appearance of the tumor cannot reliably predict accompanying clinical presentation; examination of the adjacent nontumorous gland is more helpful

  
  
  
  
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    Atrophy of the normal cortex with loss of zona reticularis indicates Cushing syndrome with suppression of ACTH

    
    
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    In patients with Conn syndrome, there may occasionally be hyperplasia of the zona glomerulosa (paradoxical hyperplasia)

    
    
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    Spironolactone bodies (small eosinophilic laminated intracytoplasmic inclusions) may develop in the tumor and in cells of the zona glomerulosa if patient is treated with spironolactone; these are best seen with the Luxol fast blue (LFB) stain (see Figure 9.4I )

  
  

Special Stains and Immunohistochemistry

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  LFB for spironolactone bodies (see Figure 9.4I )

  
  
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  MIB1 or Ki-67 labeling index usually below 2.5

  
  
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  Immunostaining for HSD3B1/2 (3β-hydroxysteroid dehydrogenase type 1 and type 2) and CYP11B1/2 (cytochrome P450 family 11 subfamily B member 1 and member 2) can distinguish tumors making aldosterone from those making cortisol; in particular, CYP11B2 (aldosterone synthase) is most useful to identify aldosterone-producing tumors

Other Techniques for Diagnosis

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  Electron microscopy

  
  
  
  
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    Cells contain abundant lipid and prominent smooth endoplasmic reticulum; mitochondria are also numerous (see Figure 9.4J )

    
    
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    Mitochondrial morphology correlates with function: aldosterone-producing cells (zona glomerulosa differentiation) have flat, platelike, “lamellar” cristae (see Figure 9.4K ), whereas glucocorticoid and sex steroid-producing cells (zona reticularis and fasciculata) have round or spherulated cristae (see Figure 9.4J )

    
    
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    Pigmented adenomas contain many electron-dense granules consistent with lipofuscin (see Figure 9.4L )

    
    
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    Spironolactone bodies are composed of concentric whorls of membranes

  
  

Differential Diagnosis

Clinical Features

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  Etiology

  
  
  
  
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    Sporadic adrenal cortical carcinoma is most common; however, it also occurs in hereditary syndromes: Li-Fraumeni, Beckwith-Wiedemann, MEN1, Carney complex, FAP, and hereditary isolated glucocorticoid deficiency syndrome as well as Lynch syndrome

    
    
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    Sporadic carcinomas can harbor similar molecular defects, including germline and somatic mutations of TP53 , beta-catenin , and 17p13 LOH; rare menin mutations, but frequent 11q13 LOH; 17q22–24 LOH (PRKAR1A); 11p15 LOH and IGF-II overexpression; 18p11 LOH ( MC2-R ); mutations of APC , CTNNB1 encoding beta-catenin and MUTYH

  
  
  
  
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  Epidemiology

  
  
  
  
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    Rare tumor; occurs in about 1 per 1 million population

    
    
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    Typically presents in fourth and fifth decades of life; less common in pediatric population

    
    
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    Equal incidence in males and females

  
  
  
  
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  Signs and symptoms

  
  
  
  
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    Usually presents as incidental finding or associated with abdominal or flank pain; may present with a palpable abdominal mass or with evidence of distant metastasis

    
    
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    About 79% of carcinomas secrete hormones, and most functional tumors secrete cortisol with marked virilization owing to co-secretion of 17-ketosteroids and dehydroepiandrosterone (DHEA)

    
    
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    Less often, virilization in women and feminization in men can result from secretion of free testosterone and androstenedione, respectively

    
    
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    Mineralocorticoid excess is rare; however, combined secretion of cortisol and mineralocorticoid can occur

  
  
  
  
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  Therapy

  
  
  
  
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    Tumor removal is the preferred treatment

    
    
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    Residual unresectable tumor or metastases treated with mitotane

  
  

Gross Pathology

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  Usually large tumors weighing between 100 and 1000 g; may measure more than 20 cm (average, 14 to 15 cm) ( Figure 9.5A )

  
  

  
  

  
  

  

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