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 [2].
- 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 [1,5,10-12].
- 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. [49,50]
Associated Conditions
- Most adrenocortical carcinomas are sporadic, but some occur as a component of hereditary cancer syndromes. [49,50]
- 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. [51,52]
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 [56,57]. Although loss of heterozygosity at 17p13 is common, only approximately one-third of these tumors have a mutation of TP53 [58-65]. This suggests that another as yet unidentified suppressor gene is present in this locus [65].
Another chromosomal locus that is strongly implicated in the pathogenesis of ACC is 11p, the area of abnormality in Beckwith-Wiedemann syndrome [70] 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 [56,71,72]. However, other growth-related tumor suppressor genes at this locus may also be involved [57].
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 [8].
- 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 [9].
- This pathway is essential for embryonic development of the adrenal [10], and its ectopic constitutive activation is associated with cancer development in a number of tissues [11,12].
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 [20].
- In additional reports, the same mutation was found in over 50 percent of patients with Cushing's syndrome due to adrenal adenomas [17,19,21].
- 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.