General
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• Benign neoplasm arising from adrenal cortical cells
• May or may not be functional

Terminology
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• Adrenal cortical adenoma (ACA)
• Incidentaloma: small adenoma discovered incidentally during workup of other conditions (Mod Pathol 2011;24:S58)
• Black (pigmented) adenoma: diffusely pigmented, brown-black ACA presumably due to lipofuscin

Epidemiology
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• F>M
• More common in adults, 5th-7th decade
• Equal predilection for right and left adrenal glands
• True incidence unknown because many are not functional, estimates include 8.7% in autopsy series and 4% in radiology series (Mol Cell Endocrinol 2013 Nov 9 [Epub ahead of print])

Sites
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• Adrenal cortex, all 3 layers
• May be ectopic, reported sites include gastric wall (World J Gastroenterol 2013;19:778) and spinal cord (Am J Surg Pathol 1990;14:481)

Pathophysiology
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• When functional, may secrete one or more of the 3 major classes of adrenal steroids (from external to internal layers):
  • Zona glomerulosa: mineralocorticoids (aldosterone)
  • Zona fasciculata: glucocorticoids (cortisol)
  • Zona reticularis: androgens (testosterone, dihydrotestosterone [DHT], androstenedione, dihydroepiandosterone [DHEA])
• Hyperaldosteronism/Conn's syndrome: ↑aldosterone → impacts distal tubules & collecting ducts of nephron → ↑ sodium and water retention, ↓ potassium retention → ↑ blood pressure
• Hypercortisolism/Cushing's syndrome: ↑cortisol → ↓ corticotropin releasing hormone (CRH), ↓ adrenocorticotropic hormone (ACTH), ↑ blood glucose
• Virilization: ↑ DHEA, ↑ DHEA-sulfate (DHEA-S), ↑ androstenedione, ↑ testosterone, ↑ DHT → ↑ urinary 17-ketosteroids (metabolic product)
• Feminization: ↑ androgens → aromatization → ↑ estrogen, ↑ estradiol → ↑ urinary 17-ketosteroids (metabolic product)

Etiology
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• Neoplastic proliferation of adrenal cortical cells
• May arise from any of the 3 layers, but zona fasciculata most common (Mod Pathol 2011;24:S58)

Clinical features
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• Minority are functional, may produce a pure or mixed endocrine syndrome (from most to least common):
  • Hyperaldosteronism/Conn's syndrome: hypertension, proximal muscle weakness, headache, polyuria, tachycardia with/without palpitation, hypokalemia, hypocalcemia
  • Hypercortisolism/Cushing's syndrome: central obesity, moon facies, plethora, striae, thin skin, easy bruising, hirsutism, telangiectasias, hyperhidrosis
  • Virilization:
    • Females: increased muscle mass (Herculean habitus), clitoromegaly, facial hair, deep voice, pubic hair
    • Males: penile enlargement, pubic hair
  • Feminization: gynecomastia, impotence

Diagnosis
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• Well-circumscribed lesion comprised of cells resembling any of the 3 layers of the normal adrenal cortex
• Difficult to differentiate ACA from normal adrenal cortex in adrenal core needle biopsies

Laboratory
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• Hyperaldosteronism/Conn's syndrome: ↑aldosterone, hypernatremia, hypokalemia
• Cushing's syndrome: ↑cortisol, ↓CRH, ↓ACTH, hyperglycemia
• Virilization: ↑DHEA, ↑DHEA-S, ↑androstenedione, ↑testosterone, ↑DHT, ↑urinary 17-ketosteroids
• Feminization: ↑estrogen, ↑estradiol, ↑urinary 17-ketosteroids

Radiology
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• Computed tomography (CT):
  • Rounded, well delineated borders, homogeneous, clear separation from and no extension into surrounding structures, decreased attenuation compared to uninvolved adrenal parenchyma on non-contrast CT (≤10 HU), contrast enhancing (Theranostics 2012;2:516)
• Magnetic resonance imagining (MRI):
  • Used to visualize microscopic fat (favoring ACA), "chemical shift" phenomenon (increased "in phase" signal intensity, decreased "out of phase" signal) (Theranostics 2012;2:516)
• 18FDG-PET:
  • Malignant lesions have greater 18FDG uptake than liver (Theranostics 2012;2:516)

Prognostic factors
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• Distinguishing ACA from adrenocortical carcinoma (ACC) is difficult particularly in children, and several systems have been proposed
• In general, most reliable factors include size, necrosis, mitotic activity, atypical mitoses (Mod Pathol 2011;24:S58)
• Weiss System (Am J Surg Pathol 1984;8:163): most widely used criteria
  • Criteria (≥3 criteria indicates malignancy): high mitotic rate, atypical mitoses, high nuclear grade, low percentage of clear cells, necrosis, diffuse tumor architecture, capsular invasion, sinusoidal invasion, venous invasion
• Modified Weiss System (Am J Surg Pathol 2002;26:1612): >5 mitoses per 50 high powered fields, <25% clear cells, atypical mitotic figures, necrosis, and capsular invasion
  • Calculation:
    • 1 point each for the presence of atypical mitotic figures, necrosis, and capsular invasion
    • 2 points each for the presence of >5 mitoses per 50 high powered fields and <25% clear cells
    • Total score ranges from 0 to 7, and score of >3 highly correlates with subsequent malignant behavior

Case reports
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• 8 year old girl with tumor of spinal canal (Am J Surg Pathol 1990;14:481)
• 14 year old boy with adrenocortical tumor and familial adenomatous polyposis (Hum Pathol 1998;29:302)
• 24 year old woman with unusual presentation of Carney complex (Endocr J 2012;59:823)
• 33 year old woman with Cushing's syndrome during pregnancy secondary to adrenal adenoma (Acta Med Iran 2012;50:76)
• 34 year old woman with eplerenone use in primary aldosteronism during pregnancy (Hypertension 2012;59:e18)
• 35 year old man with primary adrenal angiosarcoma and functioning adrenocortical adenoma (Eur J Endocrinol 2012;166:131)
• 36 year old woman with cortisol producing adrenal adenoma associated with latent aldosteronoma (Intern Med 2012;51:395)
• 46 year old woman with black adrenal adenoma causing preclinical Cushing's syndrome (Tokai J Exp Clin Med 2010;35:57)
• 50 year old woman with myelolipomata arising within adrenocortical adenoma ipsilateral to synchronous clear cell renal cell carcinoma (Malays J Pathol 2010;32:123)
• 52 year old woman with adrenalectomy by retroperitoneal laparoendoscopic single site surgery (JSLS 2010;14:571)
• 53 year old man with a compound adrenal medullary tumor (pheochromocytoma and ganglioneuroma) and a cortical adenoma in the ipsilateral adrenal gland (Am J Surg Pathol 1988;12:559)
• 56 year old woman with coexistence of Cushing syndrome from functional adrenal adenoma and Addison disease from immune-mediated adrenalitis (J Am Osteopath Assoc 2012;112:374)
• 56 year old man with generalized glucocorticoid resistance accompanied with an adrenocortical adenoma and caused by a novel point mutation of human glucocorticoid receptor gene (Chin Med J (Engl) 2011;124:551)
• 57 year old man with adrenal cortical adenoma with adrenalin-type neurosecretory granules clinically mimicking a pheochromocytoma (Arch Pathol Lab Med 2002;126:1530)
• 66 year old woman with laparoscopic adrenalectomy for bilateral metachronous aldosteronomas (JSLS 2011;15:100)
• 69 year old woman with massive hemorrhage and thrombosis, resembling angiosarcoma on microscopic examination (Am J Surg Pathol 1991;15:699)
• 72 year old woman with ectopic adrenal cortical adenoma in the gastric wall (World J Gastroenterol 2013;19:778)

Treatment
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• Surgical excision
• Nonfunctioning, small (<4 cm), <10 HU on non-contrast CT, ACA can be managed conservatively with long term follow-up (Indian J Urol 2012;28:179, Endocr Pract 2009 Jul-Aug;15 Suppl 1:1)

Gross description
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• Adrenocortical adenoma:
  • Weight usually <50 grams (in pediatric patients may weight up to 500 grams) (Mod Pathol 2011;24:S58)
  • Size usually <5 cm
  • Unilateral, solitary, golden yellow
  • May have focal dark areas corresponding with hemorrhage, lipid-depletion, increased lipofuscin
  • Functional adenoma may result in atrophy of ipsilateral or contralateral adrenal cortex
• Adrenocortical carcinoma:
  • Weight usually >100 grams (Ann Oncol 1997;8:423)
  • Usually >5 cm, median size 11 cm in one large case series (Eur J Endocrinol 2013;169:891)
  • Variegated appearance (nodularity, fibrous bands) suggests carcinoma (Mod Pathol 2011;24:S58)

Gross images
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Adenoma is well circumscribed and golden yellow

Micro description
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• In comparison to surrounding adrenal gland, adenoma cells are larger with different cytoplasm, increased variation in nuclear size
• Distinct cell borders, cells have abundant foamy cytoplasm reminiscent of zona fasciculata
• Balloon cells: clusters of cells with enlarged lipid-rich cytoplasm (seen in Cushing syndrome)
• Histologic variants: oncocytic, myxoid

Micro images
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Compact cells in nests and cords

Abundant eosinophilic granular cytoplasm

Resembles normal adrenal fasciculata

Bi- and multinucleated cells

Focal cytologic atypia

Hyperchromatic nuclei with prominent nucleoli

Clear cells

Uniform cells without mitoses or necrosis

Low power

S100 neg basement cells

Virtual slides
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ACA with fasciculata-like appearance

ACA

ACA in a 43 year old woman with Cushing's syndrome

ACA in a 46 year old woman with hyperaldosteronism

ACA

Cytology description
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• Difficult to impossible to distinguish from unremarkable adrenal cortex (Diagn Cytopathol 2005;33:26)
• Cellularity varies, generally loose clusters of large cells (Diagn Cytopathol 2005;33:26, Diagn Cytopathol 1996;14:126)
• Foamy / vacuolated cytoplasm (Diagn Cytopathol 2005;33:26, Diagn Cytopathol 1996;14:126)
• Round to oval nuclei with smooth contours, may have naked nuclei, variation in nuclear size/shape has little significance (Diagn Cytopathol 2005;33:26, Diagn Cytopathol 1996;14:126)

Positive stains
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• Usually positive: α-inhibin, MelanA/Mart1, steroidogenic factor-1 (SF-1), calretinin, Oil Red O (fresh frozen tumor, highlights intracytoplasmic lipid), bcl2 (Mod Pathol 1998;11:716), D2-40 (J Clin Pathol 2008;61:293)
• Sometimes positive: synaptophysin, neuron-specific enolase (NSE), low molecular weight cytokeratin (AE1/AE3, CAM5.2)
• Rarely positive: vimentin (Am J Pathol 1990;136:1077)
• Low Ki-67 index (usually <5%)

Negative stains
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• EMA, CEA, B72.3, S100, chromogranin (stains adrenal medulla), vimentin, carbonic anhydrase IX (CAIX)

Electron microscopy description
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• Abundant intracytoplasmic lipid droplets of varying sizes
• Prominent microvillous projections along cell borders
• Abundant smooth endoplasmic reticulum
• Prominent, round to oval mitochondria; cristae may have tubular to vesicular (zona fasciculata) or lamellar (zona reticularis) profile

Electron microscopy images
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Neurosecretory dense granules

Molecular / cytogenetics description
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• Tumorigenesis not well understood
• Outside of immunohistochemistry for diagnosis, adjunct molecular studies not currently utilized for clinical purposes (i.e. treatment, prognosis, distinction from ACC)
• Usually monoclonal and diploid, versus ACC monoclonal and aneuploid/polyploid (Mol Cell Endocrinol 2013 Nov 9 [Epub ahead of print])
• Usually sporadic, but may be associated with genetic syndrome
  • Cortisol-producing ACA may be associated with McCune-Albright syndrome, primary pigmented nodular adrenocortical disease or Carney complex (Mol Cell Endocrinol 2013 Nov 9 [Epub ahead of print])
  • Comparative genomic hybridization (CGH) studies showed adrenal tumors have complex pattern of chromosomal alterations, with ACCs having more more chromosomal gains/losses than ACAs (Mol Cell Endocrinol 2013 Nov 9 [Epub ahead of print])
  • Single nucleotide polymorphism (SNP) arrays confirm high genetic variability in ACAs (Neoplasia 2012;14:206)
    • Chromosomes with most frequent gains are #5, 3, 6, 11, 2
    • Chromosomes with most frequent losses are #1, 6, 2
    • Candidate genes include NOTCH1, CYP11B2, HRAS, IGF2

Differential diagnosis
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• Adrenal cortical carcinoma: see criteria above; vimentin strongly positive, cytokeratin weakly positive, synaptophysin weakly positive, chromogranin negative (Am J Pathol 1990;136:1077)
• Corticomedullary adenoma: mixed adrenocortical adenoma-pheochromocytoma
• Hepatocellular carcinoma
• Melanoma
• Metastatic carcinoma
• Pheochromocytoma
• Renal cell carcinoma, clear cell type

Additional references
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• Lack: Tumors of the Adrenal Glands and Extraadrenal Paraganglia (ARP, 2007)

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