Lymphoid enhancer-binding factor 1 (LEF1) immunostaining as a surrogate for β-catenin () mutations.

Aims: Mutations affecting exon 3 of the β-catenin () gene result in constitutive activation of WNT signalling and are a diagnostic hallmark of several tumour entities including desmoid-type fibromatosis. They also define clinically relevant tumour subtypes within certain entities, such as endometrioid carcinoma. In diagnostics, β-catenin immunohistochemistry is widely used as a surrogate for mutations. Yet, it is often difficult to assess in practice, given that the characteristic nuclear translocation may be focal or hard to distinguish from the spillover of the normal membranous staining.

Methods: We therefore examined lymphoid enhancer-binding factor 1 (LEF1) immunostaining, a nuclear marker of WNT activation that serves as a potential surrogate for mutations.

Results: In a cohort of endometrial carcinomas with known mutation status (n=130) LEF1 was 85% accurate in predicting mutation status (64% sensitivity, 90% specificity) while β-catenin was 76% accurate (72% sensitivity; 77% specificity). Across a variety of entities characterised by mutations as putative drivers, we found diffuse and strong expression of LEF1 in 77% of cases. LEF1 immunostaining proved easier to interpret than β-catenin immunostaining in 54% of cases, more difficult in 1% of cases and comparable in the remaining cases.

Conclusion: We conclude that LEF1 immunostaining is a useful surrogate marker for mutations. It favourably complements β-catenin immunohistochemistry and outperforms the latter as a single marker.