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

J Clin Endocrinol Metab. 2011 Feb;96(2):E419-26. doi: 10.1210/jc.2010-1885. Epub 2010 Nov 17.


Background: Abnormal β-catenin immunohistochemistry and mutations of the β-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/β-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 β-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 β-catenin immunohistochemical staining, indicating Wnt/β-catenin pathway alteration. Thirty-six tumors showed CTNNB1 mutations, which all showed abnormal immunohistochemical β-catenin accumulation. Among the 64 nonmutated tumors, only 15 (23%) showed cytoplasmic and/or nuclear β-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 β-catenin immunohistochemical staining occurs in about half of ACAs. This suggests the activation of the Wnt/β-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/β-catenin pathway activation is associated with the development of less differentiated ACAs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / genetics*
  • Adenoma / metabolism
  • Adenoma / pathology
  • Adrenal Cortex Neoplasms / genetics*
  • Adrenal Cortex Neoplasms / metabolism
  • Adrenal Cortex Neoplasms / pathology
  • Adult
  • DNA Mutational Analysis
  • DNA, Neoplasm / genetics
  • Female
  • Humans
  • Hydrocortisone / metabolism*
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Mutation / physiology*
  • Phenotype
  • RNA, Neoplasm / genetics
  • Signal Transduction / genetics*
  • Wnt Proteins / genetics*
  • beta Catenin / genetics*


  • CTNNB1 protein, human
  • DNA, Neoplasm
  • RNA, Neoplasm
  • Wnt Proteins
  • beta Catenin
  • Hydrocortisone