Adrenal gland & paraganglia

Adrenal cortical adenoma

Adrenal cortical adenoma



Last author update: 1 February 2014
Last staff update: 14 December 2022 (update in progress)

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PubMed Search: Adrenocortical adenoma

Carmen Perrino, M.D.
Debra L. Zynger, M.D.
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Cite this page: Perrino C, Zynger D. Adrenal cortical adenoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/adrenaladenomageneral.html. Accessed January 28th, 2023.
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
  • 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
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)
  • 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
Sites
Pathophysiology
  • 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)
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
  • 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
Laboratory
  • 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

Left adrenal mass

(A) Plain CT and (B) contrast CT show left suprarenal mass

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)
Treatment
  • 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 and central obesity

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

Contributed by @Andrew_Fltv and @SueEPig on Twitter
Adrenal cortical aldosterone producing adenoma

Adenoma

Adenoma

Adenoma



Images hosted on other servers:

External surface, during surgery

Intact capsule

Well circumscribed

1.3 cm left adrenal adenoma

3 x 3 cm exophytic adrenal mass

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

Contributed by Xiaoyin "Sara" Jiang, M.D., Debra Zynger, M.D., @Andrew_Fltv on Twitter and @SueEPig on Twitter

Spironolactone bodies with aldosteronoma

Adenoma with spironolactone bodies

Adrenal cortical aldosterone producing adenoma Adrenal cortical aldosterone producing adenoma Adrenal cortical aldosterone producing adenoma

Adrenal cortical aldosterone producing adenoma


Adenoma Adenoma Adenoma

Adenoma



Images hosted on other servers:

Multiple ACAs comprised of clear cells

Resembles normal adrenal fasciculata

Clear cells

Low power

S100- basement cells

Virtual slides

Images hosted on other servers:

ACA 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
Electron microscopy images

Contributed by Edward Calomeni, B.S.

Spironolactone bodies

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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