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]
- 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]
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].
In contrast, a distinct germline TP53 mutation (R337H) has been identified in a high percentage of children with adrenocortical tumors from southern Brazil [58,59] and North America [66,67], which may at least partly explain the higher frequency of ACC in this population. Amplification of the steroidogenic factor 1 (SF-1) gene in tumors also has been reported in this population [68].
In a study that used next-generation sequencing to determine the contribution of germline predisposing gene mutations in 1051 children and adolescents with cancer, mutations that were deemed to be pathogenic or probably pathogenic were identified in 90 patients (8.5 percent). The 39 patients with adrenocortical cancers carried the highest prevalence of mutations (69 percent), which were mostly in the TP53 gene [69]. Importantly, family history did not predict the presence of an underlying predisposition syndrome in most patients.
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].