Adrenal gland and paraganglia
Adrenal cortical adenoma

Topic Completed: 1 February 2014

Minor changes: 16 January 2020

Copyright: 2003-2020,, Inc.

PubMed Search: Adrenocortical adenoma

Carmen Perrino, M.D.
Debra Zynger, M.D.
Page views in 2019: 19,040
Page views in 2020 to date: 8,167
Cite this page: Perrino C, Zynger D. Adrenal cortical adenoma. website. Accessed May 26th, 2020.
Definition / general
  • Benign neoplasm arising from adrenal cortical cells
  • May or may not be functional
  • 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
  • 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 2014;386:67)
  • 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)
  • 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
  • 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
  • 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
  • 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 description
  • 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:
Prognostic factors
  • 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
Gross description
  • 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:
Gross images

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Adenoma is well circumscribed and golden yellow

Microscopic (histologic) description
  • 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
Microscopic (histologic) images

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Resembles normal adrenal fasciculata

Focal cytologic atypia

Hyperchromatic nuclei with prominent nucleoli

Clear cells

Low power

S100- basement cells

Virtual slides

Images hosted on other servers:

ACA with fasciculata-like appearance


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

ACA in a 46 year old woman with hyperaldosteronism

Cytology description
Positive stains
  • 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
Electron microscopy description
  • 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

Images hosted on other servers:

Neurosecretory dense granules

Molecular / cytogenetics description
  • 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 2014;386:67)
  • 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 2014;386:67)
    • 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 2014;386:67)
    • 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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