Adrenal Gland





Adrenal Cortical Insufficiency (Addison Disease)


Clinical Features


Primary Adrenal Cortical Insufficiency





  • Etiology




    • Autoimmune etiology in 75% to 90% of cases, with circulating autoantibodies to endocrine antigens (21-OH, P-450scc, and 17-OH)



    • Other causes include infectious diseases such as tuberculosis, hemorrhage (sepsis), metastatic tumors, amyloidosis, adrenoleukodystrophy, and drugs




  • Signs and symptoms: weakness, fatigue, salt craving, hypotension, anorexia and weight loss, hyperpigmentation (due to elevated adrenocorticotropic hormone [ACTH] and other pro-opiomelanocortin fragments)



  • Biochemistry: decreased production of cortisol and aldosterone, elevated levels of ACTH and renin; hyponatremia and hyperkalemia may be seen as a result of decreased aldosterone



  • Therapy: corticosteroid and mineralocorticoid replacement; fatal if not treated



Secondary Adrenal Cortical Insufficiency





  • Etiology: inadequate stimulation of the adrenal cortex as a result of low corticotropin-releasing hormone (CRH) or ACTH




    • Commonest cause is prolonged suppression of the hypothalamic-pituitary-adrenal axis by exogenous glucocorticoids



    • May be associated with destructive lesions of the hypothalamus or the pituitary gland




  • Signs and symptoms: weakness, fatigue, anorexia, weight loss, hypopigmentation; hyperpigmentation does not occur



  • Biochemistry: decreased cortisol and aldosterone as well as ACTH; renin and aldosterone levels are typically normal,



Gross Pathology





  • Idiopathic and secondary forms characterized by pale, shrunken adrenal gland, often weighing less than 2 to 3 g, with marked thinning of the cortical zone; severe atrophy in idiopathic disease may impair gross recognition of the adrenal glands



  • Other primary forms often associated with adrenal enlargement and infiltration by inflammation or tumor ( Figure 9.1A )




    Figure 9.1


    Adrenal cortical insufficiency (Addison disease).

    A, Addison disease due to tuberculosis infection. Tissue destruction due to tuberculosis infection results in adrenal enlargement, but the gland is replaced by necrotic yellow material. No normal tissue is identified. The surrounding fat is unremarkable. B, Secondary adrenal cortical atrophy. The gland is small with an inactive cortex that is almost entirely composed of clear cells and lacks a zona reticularis. C, Addison disease due to tuberculosis infection. Caseating granuloma with giant cell reaction present in the adrenal cortex. D, Addison disease due to autoimmune inflammation. The adrenal is atrophic; the cortex is almost completely lost, and there is focal inflammation surrounding the residual medulla. E, Addison disease due to autoimmune inflammation. Inflammatory cells replace the cortex, and fibrosis is evident between the few residual cortical cells.



Histopathology





  • Secondary disease is characterized by small glands with prominent zona fasciculate (storage zone) and no zona reticularis (functional zone); zona glomerulosa is normal (see Figure 9.1B )



  • Idiopathic form exhibits marked atrophy of the adrenal cortex, with intact medulla surrounded by fibrous tissue containing few small islands of atrophic cortical cells; lymphoid infiltrate is often present (see Figure 9.1C and D )



  • Infiltrative forms due to inflammation or malignancy



Special Stains and Immunohistochemistry





  • Special stains for microorganisms: may identify organisms in cases of infectious etiology



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis





  • One must distinguish between primary and secondary adrenal insufficiency



  • If primary, one must attempt to determine etiology




    • Inflammatory; rule out infectious



    • Metastatic tumor



    • Amyloidosis (rare)




Pearls





  • First described by Addison in 1855



  • Must have destruction of more than 90% of adrenal gland before symptoms develop



  • Immune form associated with autoimmune polyglandular syndrome (APS) type 1 and type 2 (Schmidt syndrome); APS type 1 is caused by mutations in the AIRE-1 gene





Selected References




  • Bancos I., Hahner S., Tomlinson J., Arit W.: Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol 2015; 3: pp. 216-226.



  • Fujieda K., Tajima T.: Molecular basis of adrenal insufficiency. Pediatr Res 2005; 57: pp. 62R-69R.



  • Mitchell A.L., Pearce S.H.: Autoimmune Addison disease: pathophysiology and genetic complexity. Nat Rev Endocrinol 2012; 8: pp. 306-316.



  • Pazderska A., Pearce S.H.: Adrenal insufficiency—recognition and management. Clin Med (London) 2017; 17: pp. 258-262.



  • Shikama N., Nusspaumer G., Holländer G.A.: Clearing the AIRE: on the pathophysiological basis of the autoimmune polyendocrinopathy syndrome type-1. Endocrinol Metab Clin North Am 2009; 38: pp. 273-288.



  • Shulman D.I., Palmert M.R., Kemp S.F.: Adrenal insufficiency: still a cause of morbidity and death in childhood. Pediatrics 2007; 119: pp. e484-e494.


Congenital Adrenal Hyperplasia (Adrenogenital Syndrome)


Clinical Features





  • Etiology




    • 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



    • 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




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



      • Phenotype generally reflects residual enzyme activity of the milder mutation




    • 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



    • Congenital lipoid adrenal hyperplasia




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



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





  • Epidemiology




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



    • Nonclassic form occurs in 0.3% of the white population




  • Signs and symptoms




    • Clinical presentation correlates with severity of enzymatic deficiency



    • 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



    • Most common cause of ambiguous genitalia in newborn females



    • Classic form




      • Can present as salt-wasting form or simple virilizing type



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



      • Postpubertal females have oligomenorrhea, hirsutism, and acne



      • 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)



      • Males later show enlargement of external genitalia and precocious puberty




    • Non-classical form




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



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



      • May present as adrenal insufficiency during pregnancy





  • Therapy




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



    • Bilateral adrenalectomy performed in selected cases



    • Gene therapy studies under way




Gross Pathology





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




    Figure 9.2


    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.)



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



  • Adrenals show a convoluted surface owing to numerous redundant folds



Histopathology





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



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



  • 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





  • Noncontributory



Other Techniques For Diagnosis





  • 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


Adrenal Cortical Hyperplasia





  • Primary hyperplasias are usually nodular unlike CAH; may be impossible to distinguish morphologically from ACTH-dependent hyperplasia



Adrenal Cortical Adenoma





  • Discrete adrenal cortical nodule rather than diffuse hypertrophy, and usually unilateral



Pearls





  • Defective adrenomedullary organogenesis owing to lack of glucocorticoids results in epinephrine deficiency and hypoglycemia



  • Several reported cases of cortical adenomas and cortical carcinomas developing in children with congenital adrenal hyperplasia; may be related to persistent ACTH stimulation



  • Adrenal cortical tumors may be seen developing in the testes/ovaries of patients with congenital cortical hyperplasia; believed to arise from ectopic adrenal cortical rests





Selected References




  • El-Manoush D., Arit W., Merke D.P.: Congenital adrenal hyperplasia. Lancet 2017; 390: pp. 2194-2210.



  • Lekarev O., New M.I.: Adrenal disease in pregnancy. Best Pract Res Clin Endocrinol Metab 2011; 25: pp. 959-973.



  • New M.I., Abraham M., Yuen T., et. al.: An update on prenatal diagnosis and treatment of congenital adrenal hyperplasia. Semin Reprod Med 2012; 30: pp. 396-399.



  • Ogilvie C.M., Crouch N.S., Rumsby G., et. al.: Congenital adrenal hyperplasia in adults: a review of medical, surgical and psychological issues. Clin Endocrinol 2006; 64: pp. 2-11.


Adrenal Cortical Hyperplasia


Clinical Features





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



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




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




      • 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



      • 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



      • 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.




    • 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




  • Signs and symptoms




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



    • 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




  • Biochemistry




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




  • Therapy




    • Treatment of primary source of ACTH excess in secondary cases



    • Medical therapy to reduce glucocorticoid hypersecretion with ketoconazole, other drugs



    • Laparoscopic adrenalectomy for removal of adrenals followed by replacement therapies




Gross Pathology





  • Primary is usually nodular ( Figure 9.3A )




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



    • Pigmentation is characteristic of PPNAD




    Figure 9.3


    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.



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




    • Degree of enlargement dependent on cause




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





  • Grossly undetectable when due to zona glomerulosa hyperplasia with Conn syndrome



  • Almost always bilateral



  • Combination of nodular and diffuse types may be seen



Histopathology





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



  • Cells are uniform in size with small, round nuclei



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



  • Areas of lipomatous metaplasia may be seen



  • 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 )



  • Mixture of large clear cells and small compact cells in AIMAH



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



  • 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





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



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Adrenal Cortical Adenoma





  • Presence of solitary, unilateral lesions with evidence of autonomous growth favors adenoma



  • Presence of small nodules adjacent to a larger nodule favors adrenal hyperplasia



  • Definitive distinction between nodular hyperplasia and adrenal cortical adenoma can often be difficult or even impossible



Pearls





  • Hyperplasia of the adrenal cortex (micronodular and diffuse) has been reported in cases of familial hyperaldosteronism type I (glucocorticoid-remediable aldosteronism), an autosomal dominant disorder caused by a hybrid gene formed by crossover between the ACTH-responsive regulatory portion of the 11 β-hydroxylase (CYP11B1) gene and the coding region of the aldosterone synthase (CYP11B2) gene; as a result, there is ACTH-responsive ectopic secretion of aldosterone in the zona fasciculata





Selected References




  • Assie G., Libe R., Espiard S., et. al.: ARMC5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome. N Engl J Med 2013; 369: pp. 2105-2114.



  • Cazabat L., Ragazzon B., Groussin L., Bertherat J.: PRKAR1A mutations in primary pigmented nodular adrenocortical disease. Pituitary 2006; 9: pp. 211-219.



  • Chui M.H., Ozbey N.C., Ezzat S., et. al.: Case report: adrenal LH/hCG receptor overexpression and gene amplification causing pregnancy-induced Cushing’s syndrome. Endocrine Pathol 2009; 20: pp. 256-261.



  • Duan K., Giordano T.J., Mete O.: Adrenal cortex.Mete O.Asa S.L.Endocrine Pathology.2016.Cambridge University PressCambridge:pp. 588-627.



  • Lacroix A.: ACTH-independent macronodular adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab 2009; 23: pp. 245-259.



  • Mete O., Duan K.: The many faces of primary aldosteronism and Cushing syndrome: a reflection of adrenocortical tumor heterogeneity. Front Med (Lausanne) 2018; 5: pp. 54.


Adrenal Cortical Adenoma


Clinical Features





  • Etiology




    • Most are sporadic with no known genetic basis



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



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



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



    • 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



    • 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



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




  • Signs and symptoms




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



    • 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”)



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




  • Biochemistry




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




  • Therapy




    • Laparoscopic tumor removal is the preferred treatment




Gross Pathology





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



  • Well-defined tumors appear encapsulated



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




    Figure 9.4


    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.





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



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



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



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



Histopathology


See Figure 9.4D–I .




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



  • Typically has trabecular or alveolar (nesting) architecture



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



  • Absent or rare mitotic activity; never atypical mitoses



  • Cytoplasm is abundant and “clear” or “compact”




    • 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 )



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



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



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




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




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



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



    • 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





  • LFB for spironolactone bodies (see Figure 9.4I )



  • MIB1 or Ki-67 labeling index usually below 2.5



  • 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





  • Electron microscopy




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



    • 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 )



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



    • Spironolactone bodies are composed of concentric whorls of membranes




Differential Diagnosis


Adrenal Cortical Carcinoma





  • Usually large mass with gross evidence of hemorrhage and necrosis



  • Infiltrative borders typically invading into surrounding tissue



  • Tumor cells show marked pleomorphism and frequent mitotic activity



Epithelioid Angiomyolipoma





  • An uncommon mesenchymal tumor with malignant potential, frequently associated with tuberous sclerosis complex



  • Composed of sheets or nests of large polygonal epithelioid cells with abundant eosinophilic or occasionally clear cytoplasm, often with prominent nucleoli; may include multinucleated and markedly pleomorphic forms



  • Exhibit immunoreactivity for both melanocytic and myoid markers



  • Ultrastructural evidence of melanosomes and premelanosomes



Pearls





  • Histologic appearance of adrenal cortical adenoma cannot be used to predict associated endocrine abnormality or syndrome, although the adjacent adrenal cortex may show atrophy (Cushing syndrome), or hyperplasia of the zona glomerulosa (Conn syndrome)



  • In tumors associated with Cushing syndrome, PRKACA-mutant adenomas usually occur in young patients, and are small tumors associated with pronounced hypercortisolism; PRKAR1A-mutant adenomas may exhibit paradoxical increase in urinary cortisol in response to dexamethasone; tumors with CTNNB1 mutations are large with less severe hypercortisolism.



  • Treatment is typically resection of the adrenal gland containing the adenoma





Selected References




  • Beuschlein F., Boulkroun J., Osswald A., et. al.: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet 2013; 45: pp. 440-444.



  • Funder J.W.: The genetic basis of primary aldosteronism. Curr Hypertens Rep 2012; 14: pp. 120-124.



  • Mete O., Asa S.L.: Morphologic distinction of cortisol-producing and aldosterone-producing adrenal cortical adenomas: not only possible but a critical clinical responsibility. Histopathology 2012; 60: pp. 1015-1016.



  • Mete O., Asa S.L., Giordano T.J., et. al.: Immunohistochemical biomarkers of adrenal cortical neoplasms. Endocr Pathol 2018; 29: pp. 137-149.



  • Mete O., Duan K.: The many faces of primary aldosteronism and Cushing syndrome: a reflection of adrenocortical tumor heterogeneity. Front Med (Lausanne) 2018; 5: pp. 54.



  • Mete O., van der Kwast T.H.: Epithelioid angiomyolipoma: a morphologically distinct variant that mimics a variety of intra-abdominal neoplasms. Arch Pathol Lab Med 2011; 135: pp. 665-670.



  • Young W.F.: The incidentally discovered adrenal mass. N Engl J Med 2007; 356: pp. 601-610.


Adrenal Cortical Carcinoma


Clinical Features





  • Etiology




    • 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



    • 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




  • Epidemiology




    • Rare tumor; occurs in about 1 per 1 million population



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



    • Equal incidence in males and females




  • Signs and symptoms




    • 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



    • 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)



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



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




  • Therapy




    • Tumor removal is the preferred treatment



    • Residual unresectable tumor or metastases treated with mitotane




Gross Pathology



Mar 11, 2021 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Adrenal Gland
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