Nuclear β-catenin localization and mutation of the CTNNB1 gene: a context-dependent association

Abstract

Although the majority of low grade, early stage endometrial cancer patients have good survival with surgery alone, patients who recur tend to do poorly. Identification of patients at high risk of recurrence who would benefit from adjuvant treatment or more extensive surgical staging would help optimize individualized care of endometrial cancer patients. CTNNB1 (encodes β-catenin) mutations identify a subset of low grade, early stage endometrial cancer patients at high risk of recurrence. Mutation of CTNNB1 exon 3 is classically associated with translocation of the β-catenin protein from the membrane to the nucleus and activation of Wnt/β-catenin signaling. Given the clinical utility of identifying endometrial carcinomas with CTNNB1 mutation, the purpose of this study was to determine if immunohistochemistry could act as a surrogate for CTNNB1 gene sequencing. Next-generation sequencing was performed on 345 endometrial carcinomas. Immunohistochemical localization of β-catenin was determined for 53/63 CTNNB1 exon 3 mutant tumors for which tissue was available and a subset of wildtype tumors. Nuclear localization of β-catenin had 100% specificity in distinguishing CTNNB1 mutant from wildtype, but sensitivity was lower (84.9%). Nearly half of CTNNB1 mutant cases had only 5–10% of tumor cells with β-catenin nuclear localization. The concordance between pathologists blinded to mutation status in assessing nuclear localization was 100%. Extent of β-catenin nuclear localization was not associated with specific CTNNB1 gene mutation, tumor grade, presence of non-endometrioid component, or specific concurrent gene mutations in the tumor. For comparison, nuclear localization of β-catenin was more diffuse in desmoid fibromatosis, a tumor also associated with CTNNB1 mutation. Thus, nuclear localization of β-catenin assessed by immunohistochemistry does not detect all endometrial cancers with CTNNB1 gene mutation. Extent of nuclear localization may be tumor-type dependent. For endometrial cancer, immunohistochemistry could be an initial screen, with CTNNB1 sequencing employed when nuclear localization of β-catenin is absent.

Nuclear β‐catenin and CDX2 expression in ovarian endometrioid carcinoma identify patients with favourable outcome

“…The lack of sensitivity may be due to the focal nature of nuclear β‐catenin expression. Kim and colleagues reported that nearly 40% of CTNNB1 mutated cases showed nuclear β‐catenin in <10% of tumour cells . We observed two cases harbouring a CTNNB1 mutation at >30% allelic frequency, with fewer than 1% of tumour cell nuclei showing nuclear β‐catenin expression using full sections from endometrial biopsies .…”

“…We utilised immunohistochemistry as the surrogate test for CTNNB1 mutational status. In endometrial EC, nuclear β‐catenin expression has been shown to have good agreement with CTNNB1 mutational status, with 93–100% specificity and 80–85% sensitivity . In other words, cases with no detectable CTNNB1 mutation almost always show non‐nuclear β‐catenin staining, while cases with mutation lack nuclear staining in 15–20%.…”

Practical roles for molecular diagnostic testing in ovarian adult granulosa cell tumour, Sertoli–Leydig cell tumour, microcystic stromal tumour and their mimics

“…Although ovarian Sertoli cell tumours have not been studied, their testicular counterparts routinely show nuclear staining of β‐catenin . Some ovarian and endometrial endometrioid carcinomas show nuclear staining of β‐catenin …”

“…It is possible that such patterns may raise consideration of solid pattern endometrioid carcinoma of the ovary, either primary or metastatic from the endometrium. Caution is advised in using β‐catenin staining alone to resolve this differential diagnosis, as a subset of endometrioid cancers are known to show nuclear staining of β‐catenin and harbour CTNNB1 mutations . Therefore, in this scenario, FOXL2 staining and the use of epithelial markers such as epithelial membrane antigen and/or keratins, which should be positive in a carcinoma, are advised in conjunction with the use of β‐catenin and CD10.…”

“…71,72 Some ovarian and endometrial endometrioid carcinomas show nuclear staining of b-catenin. [73][74][75]…”