Adrenal gland & paraganglia

Adrenal cortical adenoma


Topic Completed: 1 February 2014

Minor changes: 20 August 2021

Copyright: 2003-2022,, Inc.

PubMed Search: Adrenocortical adenoma

Carmen Perrino, M.D.
Debra L. Zynger, M.D.
Page views in 2021: 26,320
Page views in 2022 to date: 1,418
Cite this page: Perrino C, Zynger D. Adenoma. website. Accessed January 21st, 2022.
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
  • Hypercortisolism: sometimes used synonymously for Cushing syndrome
  • Pre-clinical / sub-clinical Cushing syndrome: hypercortisolism in the context of an incidentally discovered adrenal mass without overt clinical manifestations of Cushing syndrome Arq Bras Endocrinol Metabol 2007;51:1272)
  • Primary hypercortisolism: due to secretion of cortisol by the adrenal gland versus secondary hypercortisolism: due to increased secretion of ACTH by pituitary or to secretion of cortisol by an ectopic tumor
  • 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)
  • Incidence has been increasing due to increasing utilization of imaging, estimated 0.2 to 0.4% in general population (Endocrinol Metab (Seoul) 2014;29:5)
  • Incidence increases with age, reported in <1% of patients under 30 years and in up to 7% of patients over 70 years (Indian J Endocrinol Metab 2013;17:S59)
  • Children
    • Generally uncommon in children; only ~25 cases annually in U.S. in those < 20 years (Braz J Med Biol Res 2000;33:1225)
    • Bimodal age distribution; most commonly < age 5, second peak ages 9 - 16 years
    • Incidence higher in females, M:F ratio 1:1.6 (J Clin Oncol 2004;22:838)
    • Higher incidence in southern Brazil, associated with specific p53 mutation (R337H TP53)
    • Associated with several genetic syndromes:
      • Beckwidth-Wiedemann syndrome: hemihypertrophy, splanchnomegaly, macroglossia, intraabdominal neoplasms (i.e. adrenal cortical neoplasms, nephroblastoma, hepatoblastoma), due to alteration of 11p15 region
      • Li-Fraumeni syndrome (SBLA syndrome): sarcoma (rhabdomyosarcoma), breast/brain tumors, leukemia, laryngeal carcinoma, lung cancer, adrenal cortical carcinoma; due to alteration of p53 on chromosome 17p
      • Carney triad: malignant gastrointestinal stromal tumor, pulmonary chondroma, extra-adrenal paraganglioma, adrenal cortical adenoma
      • Adrenogenital syndrome: adrenal cortical neoplasms, congenital adrenal hypertrophy
    • No proven relationship with environmental factors
  • Approximately 90% of ACAs are nonfunctional
  • 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)
  • Children: predisposing genetic factors are present in ~50% of children with adrenal cortical tumors, most commonly Li-Fraumeni syndrome and Beckwith-Wiedemann syndrome (see above); may arise due to defective apoptosis (J Clin Endocrinol Metab 2000;85:2048)
  • 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
  • Adrenal lesion discovered with imaging used to work up unrelated clinical symptoms, therefore usually no detectable hormonal abnormalities or clinical symptoms (Pol J Radiol 2013;78:47)
  • Work up may include observation (serial imaging, laboratory tests) or fine needle aspiration / core biopsy (rarely indicated, mainly for ruling out non-adrenal metastases) (J Clin Endocrinol Metab 2010;95:4106)
  • 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
  • Atypical histologic features are commonly found in children, making adrenal cortical adenomas difficult to distinguish from adrenal cortical carcinoma
  • Battery of endocrine tests usually within normal limits, although a minority may have subclinical hormone production with slight abnormalities
  • Suggested endocrine tests include: dexamethasone suppression test, ACTH levels, plasma free metanephrine/normetanephrine, 24 hour total urinary metanephrines, ratio plasma aldosterone:plasma renin (Indian J Endocrinol Metab 2013;17:S59)
  • Adrenal tumors in patients with previously unrecognized clinical symptoms attributable to the tumor are not considered incidentalomas (Pol J Radiol 2013;78:47)
  • 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:
Radiology images

Images hosted on other servers:

Homogeneous left adrenal mass with distinct borders

Heterogeneous retrohepatic mass

Homogeneous, solid right suprarenal mass

Flank mass with echogenic focus

Left flank mass with calcification

Heterogeneous mass, necrosis, capsule-like rim

Prognostic factors
  • Distinguishing ACA from adrenocortical carcinoma (ACC) is difficult 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
  • 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)
  • 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)
  • 66 year old woman with laparoscopic adrenalectomy for bilateral metachronous aldosteronomas (JSLS 2011;15:100)
  • 72 year old woman with ectopic adrenal cortical adenoma in the gastric wall (World J Gastroenterol 2013;19:778)
  • Most adrenal lesions > 4 cm should be removed regardless of imaging findings because of increased risk of ACC (BMC Surg 2013;13:57)
  • If large (> 4 cm), functional, worrisome characteristics on imaging: surgical resection
  • If small (< 4 cm), non-functional, benign features on imaging: clinical observation and follow up (exact guidelines not well established)
    • Repeat laboratory studies to assess functional status, yearly for 4 years
    • Repeat CT scan 6 - 12 months after diagnosis, if no increase in size then no further follow up needed
Clinical images

Images hosted on other servers:

Moon facies, acne, bitemporal excess hair

Moon facies and central obesity

Facial and chest hair, absence of breasts

Back acne

Penile enlargement

Clitoromegaly and pubic hair

Gross description
  • 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
Gross images

Images hosted on other servers:

External surface, during surgery

Intact capsule

Smooth, homogeneous cut surface

Well circumscribed

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

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
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
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)
  • Gene expression profiling shows decrease in expression of major histocompatibility complex (MCH) class II genes in ACC when compared to ACA in children (Cancer Res 2007;67:600)
  • 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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