Incidentaloma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

The pathophysiology of [disease/malignancy] depends on the histological subtype.

Pathophysiology

• Incidentalomas are adrenal tumors that often discovered as an incidental finding.
• Most incidentalomas are nonfunctional, 9% are found to secrete low levels of cortisol, 4% are pheochromocytomas, and 1.5% are aldosteronomas.
• Malignancy is an uncommon cause of adrenal incidentaloma in patients without a known diagnosis of cancer.
• Frequency of primary adrenal carcinoma is approximately 2 to 5 percent; and 0.7 to 2.5% have nonadrenal metastases to the adrenal gland.
• Adrenal mass size is important because the smaller the adrenocortical carcinoma is at the time of diagnosis, the better the overall prognosis. A 4 cm cutoff had a 93 percent sensitivity of detecting adrenocortical carcinoma with 90% being more than 4 cm in diameter when discovered.
• Most adrenocortical carcinomas are sporadic, but some occur as a component of hereditary cancer syndromes.

Subclinical Cushing's syndrome pathogenesis

The pathophysiology of Cushing's syndrome is linked to hypercortisolism which can develop by excess ACTH secretion or excess cortisol secretion by adrenal glands. The underlying mechanisms are usually genetic mutations or overexpression of proteins.^{[1][2][3][4][5]}

1. Benign Adrenocortical adenoma: Common defects leading to adrenocortical adenoma are mutations or activation of the cAMP-dependent or β-catenin signaling pathways and aberrant expression and function of various G-protein-coupled receptors (GPCR).
2. Adrenal cortical carcinoma It is associated with germline TP53 mutations and MEN syndrome.
3. Bilateral adrenal hyperplasia: It is associated with MEN1, familial adenomatous polyposis, and fumarate hydratase gene mutations. Several inactivating mutations of armadillo repeat containing 5 genes (ARMC5, chromosome 16p11.2) are also identified.

Mechanism of cortisol secretion

• The secretion of cortisol is controlled by hypothalamic-pituitary axis by the following mechanism:^[1][2]

• Paraventricular nuclei in the hypothalamus release corticotropin releasing hormone (CRH).
• CRH is transferred to anterior pituitary via the portal veins.
• CRH stimulates the activity of corticotrophs; cells that produce proopiomelanocortin (POMC) in the anterior pituitary.
• Corticotrophs produce adrenocorticotropic hormone (ACTH) by the post-translational modification of POMC.
• ACTH is drained into systemic circulation via the pituitary capillaries and stimulates the adrenal cortex (zona fasciculata) to produce cortisol.
• Cortisol acts on hypothalamus and pituitary through a feedback mechanism to regulate the secretion of CRH and ACTH.

Pathogenesis of pheochromocytoma

Pheochromocytoma arises from chromaffin cells of the adrenal medulla and sympathetic ganglia. Malignant and benign pheochromocytomas share the same biochemical and histological features, the only difference is to have a distant spread or be locally invasive. ^[1]

Basic physiology of catecholamines

• Epinephrine acts on nearly all body tissues. Its actions vary by tissue type and tissue expression of adrenergic receptors.
• Epinephrine is a nonselective agonist of all adrenergic receptors, including the major subtypes α₁, α₂, β₁, β₂, and β_3:
  • Binding to α₁ receptors causes vasoconstriction. Blood vessels with α₁-adrenergic receptors are present in the skin, the sphincters of the gastrointestinal system, kidney (renal artery) and brain. During the fight-or-flight response vasoconstriction results in decreased blood flow to these organs.
  • Binding to α2 receptors inhibits insulin secretion by the pancreas, stimulates glycogenolysis in the liver and muscle, and stimulates glycolysis and inhibits insulin-mediated glycogenesis in muscle. It suppresses the release of norepinephrine by negative feedback.
  • Binding to β₂ receptors causes Smooth muscle relaxation in the uterus, GI tract, detrusor urinae muscle of bladder wall, and bronchi. It also causes dilatation of smaller coronaryarteries, hepatic artery, arteries to skeletal muscle.
  • Binding to β₁ receptors causes renin release from juxtaglomerular cells and lipolysis in adipose tissue. It Increases cardiac output by:
    • Increase in heart rate in sinoatrial node
    • Increase in atrial cardiac muscle contractility
    • Increases in contractility and automaticity of ventricular cardiac muscle
    • Increases in conduction and automaticity of atrioventricular node

Associated Conditions

• Most adrenocortical carcinomas are sporadic, but some occur as a component of hereditary cancer syndromes.

• Hereditary cancer syndromes 

• Li-Fraumeni syndrome (breast cancer, soft tissue and bone sarcoma, brain tumors), associated with inactivating mutations of the TP53 tumor suppressor gene on chromosome 17p.
• Beckwith-Wiedemann syndrome (Wilms' tumor, neuroblastoma, hepatoblastoma), associated with abnormalities in 11p15.
• Multiple endocrine neoplasia type 1 (MEN1) (parathyroid, pituitary, and pancreatic neuroendocrine tumors and adrenal adenomas, as well as carcinomas), associated with inactivating mutations of the MEN1 gene on chromosome 11q.

Genetics

TP53 gene, located on chromosome 17p13, is the most frequently mutated gene in human cancers. A role for the TP53 tumor suppressor gene in sporadic ACCs is suggested by the frequent finding of loss of heterozygosity (LOH) at the 17p13 locus in sporadic ACCs.

Although loss of heterozygosity at 17p13 is common, only approximately one-third of these tumors have a mutation of TP53. This suggests that another as yet unidentified suppressor gene is present in this locus.

Another chromosomal locus that is strongly implicated in the pathogenesis of ACC is 11p, the area of abnormality in Beckwith-Wiedemann syndrome and the site of the insulin-like growth factor-2 (IGF-2) gene. LOH at the 11p15 locus and overexpression of IGF-2 have been associated with the malignant phenotype in sporadic ACCs. However, other growth-related tumor suppressor genes at this locus may also be involved.

Most adrenocortical tumors are monoclonal, suggesting that they result from accumulated genetic abnormalities, such as activation of proto-oncogenes and inactivation of tumor suppressor genes.

Beta-catenin mutations (CTNNB1) 

• Constitutive activation of beta-catenin in the Wnt signaling pathway has been identified as a frequent alteration in benign and malignant adrenocortical tumors.
• The increased occurrence of adrenal tumors in patients with mutations of adenomatous polyposis coli (APC) suggested that the Wnt/beta-catenin pathway could be involved in adrenal tumorigenesis.
• This pathway is essential for embryonic development of the adrenal, and its ectopic constitutive activation is associated with cancer development in a number of tissues.

Aberrant receptors 

• Cortisol hypersecretion is the most frequent hormonal abnormality detected in patients with functioning unilateral adrenal adenomas. It had been assumed that the mechanism for this was non-ACTH-dependent autonomous cortisol secretion from the adenoma.

Somatic mutations of protein kinase A (PKA) catalytic subunit (PRKACA) were identified in patients with overt Cushing's syndrome but not in adenomas secreting less cortisol.

• In additional reports, the same mutation was found in over 50 percent of patients with Cushing's syndrome due to adrenal adenomas.
• The most frequent hotspot p.Leu206Arg mutation is located in the active cleft of the catalytic subunit, inactivating the site where the regulatory subunit RII-beta usually binds, thus causing a constitutive PKA activation.

Mutations in aldosterone-producing adenomas 

• The most frequent causes of primary aldosteronism include bilateral idiopathic hyperplasia and unilateral aldosterone-producing adenoma.
• Somatic mutations in KCNJ5 have been identified in patients with primary aldosteronism due to APAs.
• These mutations are more common in women than men; APAs with KCNJ5mutations are larger than those without mutations.
• Somatic mutations in other important genes implicated in regulation of aldosterone synthesis (ATP1A1, ATP2B3, CACNA1D, CTNNB1, ARMC5) have also been identified.

Gross Pathology

Adrenocortical adenoma

On gross pathology, adrenocortical adenoma is a well circumscribed, yellow tumour in the adrenal cortex, which is usually 2–5 cm in diameter. The color oftumorr, as with adrenal cortex as a whole, is due to the stored lipid (mainly cholesterol), from which the cortical hormones are synthesized

Myelolipoma

On gross pathology, myelolipoma are usually found to occur alone in one adrenal gland, but not both. They can vary widely in size, from as small as a few millimetres to as large as 34 centimeters in diameter. The cut surface has colours varying from yellow to red to mahogany brown, depending on the distribution of fat, blood, and blood-forming cells. The cut surface of larger myelolipomas may contain haemorrhage or infarction.

Grossly, adrenocortical carcinomas are often large, with a tan-yellow cut surface, and areas of hemorrhage and necrosis. 

On gross pathology, A multinodular and multicentric pattern of growth of pheochromocytoma may be seen. 

• 
  Adrenocortical adenoma gross pathology, source: By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5938524
• 
  Adrenocortical carcinoma gross pathology, source: By AFIP Atlas of Tumor Pathology - [1], Public Domain, https://commons.wikimedia.org/w/index.php?curid=6719487
• 
  Myelolipoma gross pathology,source: By Mattopaedia - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5668284
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  Bilateral pheochromocytoma in MEN2. Gross image, source: By AFIP Atlas of Tumor Pathology - [1], Public Domain, https://commons.wikimedia.org/w/index.php?curid=4288117

Microscopic Pathology

On microscopic examination, the tumor usually displays sheets of atypical cells with some resemblance to the cells of the normal adrenal cortex. The presence of invasion and mitotic activity help differentiate small cancers from adrenocortical adenomas.^[5]

On microscopic pathology, Pheochromocytoma typically demonstrates a nesting (Zellballen) pattern on microscopy. This pattern is composed of well-defined clusters of tumor cells containing eosinophilic cytoplasm separated by fibrovascular stroma. 

• 
  Adrenal adenoma microscopic picture, source: By Michael Feldman, MD, PhDUniversity of Pennsylvania School of Medicine - CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=535950
• 
  Adrenocortical carcinoma microscopic picture, source: By AFIP Atlas of Tumor Pathology - [1], Public Domain, https://commons.wikimedia.org/w/index.php?curid=6719510
• 
  Myelolipoma microscopic picture, source: By Mattopaedia - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5688142
• 
  Micrograph of pheochromocytoma, source: By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5938524
• 
  Histopathology of adrenal pheochromocytoma. Adrenectomy specimen, source: Wikipedia
• 
  Micrograph of pheochromocytoma, source: Wikipedia
• 
  Micrograph of pheochromocytoma, source: Wikipedia