Pathology Outlines - Adrenocortical adenoma

Adrenal gland and paraganglia
Adrenocortical adenoma and related entities
General

Authors: Carmen Perrino, M.D., Debra Zynger, M.D.

Topic Completed: 1 February 2014

Revised: 8 December 2019

Copyright: 2003-2019, PathologyOutlines.com, Inc.

PubMed Search: Adrenocortical adenoma

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Table of Contents

Cite this page: Perrino C. Adrenocortical adenoma - general. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/adrenaladenomageneral.html. Accessed December 13th, 2019.

Definition / general

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

Terminology

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

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)

Sites

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

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

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

Diagnosis

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

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:
- Malignant lesions have greater 18FDG uptake than liver (Theranostics 2012;2:516)

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

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

Surgical excision
Nonfunctioning, small (<4 cm), <10 HU on noncontrast CT, ACA can be managed conservatively with long term followup (Indian J Urol 2012;28:179, Endocr Pract 2009;15:1)

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:
- 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

Images hosted on other servers:

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

Low power

S100- basement cells

Virtual slides

Images hosted on other servers:

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

Cytology description

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

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

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

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

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

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