Adrenal gland and paraganglia
Adrenocortical adenoma
Adrenocortical adenoma-General

Author: Carmen Perrino, M.D. (see Authors page)

Editor: Debra Zynger, M.D.

Revised: 14 January 2016, last major update February 2014

Copyright: (c) 2003-2016,, Inc.

PubMed Search: Adrenocortical adenoma
Cite this page: Adrenocortical adenoma-general. website. Accessed July 23rd, 2018.
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

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

Images hosted on other servers:

Resembles normal adrenal fasciculata

Focal cytologic atypia

Hyperchromatic nuclei with prominent nucleoli

Clear cells

Uniform cells without mitoses or necrosis

Low power

S100 neg 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

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