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LEF1 expression in melanocytic tumors cannot accurately predict CTNNB1 mutational status acting as a potential
Dimitrios Goutas1,2,3, Nikolaos Katsoulas4,5, Maria Michelli4
1Second Department of Pathology, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, Chaidari, 12462, Athens, Greece. dimgoutas@med.uoa.gr.
Background:
Most melanocytic lesions develop along a genetic continuum progressing from a nevus to melanoma. Melanocytomas represent an intermediate category of tumors that lie within that spectrum harboring additional genetic alterations that may affect their phenotype. WHO currently recognizes three melanocytoma categories: Pigmented Epithelioid Melanocytomas (PEMs), BAP1-inactivated Melanocytomas (BIMs) and WNT-activated deep penetrating/plexiform melanocytomas (naevus) (WNT-activated DPMNs). Among them, WNT-activated DPMNs represent an underrecognized entity often misinterpreted as other biphenotypic pigmented lesions or melanomas. Therefore, LEF1 has been proposed as a marker of increased utility in the diagnosis of WNT-activated DPMNs.
Materials And Methods:
We assessed LEF1 expression in a series of 61 melanocytic tumors including 10 Spitz nevi, 16 blue nevi, 9 common nevi, 1 combined nevus, 9 melanomas (various subtypes), 12 WNT-activated DPMNs, 2 WNT-activated melanomas and 2 PEMs. Beta-catenin was evaluated in all combined lesions and in one atypical cellular blue nevus (n = 23). Furthermore, CTNNB1 mutational analysis was performed in 49 cases.
Results:
LEF1 nuclear positivity was detected in 43/61 cases, i.e. 6/10 (60%) Spitz nevi, 5/16 (31%) BN (4/5) bi-phasic BN, 0/5 dendritic BN and 1/6 cellular BN), 9/9 (100%) common nevi, 0/1 combined nevus, 9/9 (100%) melanomas, 12/12 (100%) WNT-activated DPMNs, 2/2 WNT-activated melanomas and 0/2 PEMs. Subsequent examination for CTNNB1 molecular status displayed mutations only in WNT-activated lesions. Nuclear beta-catenin was detected in 11/12 WNT-activated DPMNs and in both WNT-activated melanomas; the remaining 10 lesions assessed, including the atypical cellular blue nevus, demonstrated physiological membranous expression only.
Conclusion:
LEF1 expression should be interpreted cautiously in pigmented or combined melanocytic lesions. Its diagnostic value is enhanced when assessed alongside beta-catenin or supported by CTNNB1 mutation analysis.