Virchows Archiv : an international journal of pathology · 2026
LEF1 expression in melanocytic tumors cannot accurately predict CTNNB1 mutational status acting as a potential pitfall in bi-phenotypic lesions.
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Goutas Dimitrios, Katsoulas Nikolaos, Michelli Maria, Nifora Martha, Papadakis Pavlos, Stofas Anastasios, Koufopoulos Nektarios I, Lakiotaki Eleftheria, Theochari Irini, Saetta Angelica Α, Panayiotides Ioannis G, Foukas Periklis G, Korkolopoulou Penelope, Damaskou Vasileia, Siozopoulou Vasiliki, de la Fouchardiere Arnaud
Аннотация
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.
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.