Wnt/β-Catenin Pathway Activation in Adrenocortical Adenomas Is Frequently due to Somatic CTNNB1-Activating Mutations, Which Are Associated with Larger and Nonsecreting Tumors: A Study in Cortisol-Secreting and -Nonsecreting Tumors

Background: Abnormal beta-catenin immunohistochemistry and mutations of the beta-catenin gene (CTNNB1) have been reported in adrenocortical adenomas (ACAs), but the frequencies of these defects and the phenotype of such tumors have not been clearly determined. Objective: The objective of the study was to describe the Wnt/beta-catenin pathway alterations in 100 ACAs and their association with clinicopathological characteristics. Patients and Methods: One hundred consecutive ACAs (excluding Conn's adenomas) were studied clinically by beta-catenin immunohistochemistry and direct sequencing of CTNNB1. Results: Thirty-five ACAs were nonsecreting adenomas(NSAs), 19 were subclinical cortisol secreting adenomas(SCSAs), and 46 were cortisol secreting adenomas(CSAs). Fifty-one tumors had abnormal cytoplasmic and/or nuclear beta-catenin immunohistochemical staining, indicating Wnt/beta-catenin pathway alteration. Thirty-six tumors showed CTNNB1 mutations, which all showed abnormal immunohistochemical beta-catenin accumulation. Among the 64 nonmutated tumors, only 15 (23%) showed cytoplasmic and/or nuclear beta-catenin staining (P < 0.0001). Tumors with CTNNB1 mutations were predominantly nonsecreting (61% NSAs, 22% SCSAs, 16% CSAs) whereas nonmutated tumors were predominantly secreting (20% NSAs, 17% SCSAs, 62% CSAs) (P < 0.0001). Mean tumor size and weight were, respectively, 4.2 cm (+/- 1.3) and 28.4 g (+/- 21.4) for tumors with CTNNB1 mutations vs. 3.4 cm (+/- 0.9) and 18.2 g (+/- 8.2) for nonmutated tumors (P < 0.01). Conclusions: Abnormal cytoplasmic and/or nuclear beta-catenin immunohistochemical staining occurs in about half of ACAs. This suggests the activation of the Wnt/beta-catenin pathway, which could be explained by activating mutations of CTNNB1 in 70% of the cases. CTNNB1 mutations are mainly observed in larger and nonsecreting ACAs, suggesting that the Wnt/beta-catenin pathway activation is associated with the development of less differentiated ACAs. (J Clin Endocrinol Metab 96: E419-E426, 2011)