Combined WNT-activated deep-penetrating/plexiform melanocytoma: insights into clinicopathological and molecular characterization

In a series of 51 patients who were diagnosed as having combined deep-penetrating tumours, newly renamed as WNT-activated melanocytomas, the results showed that clinically, most raised suspicion of melanoma but had no recurrences or metastases after complete excision, except for one patient with incomplete excision who later developed lymph node melanoma metastasis. Some patients' samples exhibited atypical histological features, loss of p16 expression or a high-proliferative index. Next-generation sequencing analysis revealed double mutations in BRAFV600E and exon 3 CTNNB1, with no TERT-promoter mutations detected. Background A combined deep-penetrating tumour redefined as WNT-activated deep-penetrating/plexiform melanocytoma (DPM), may pose challenging clinical and histological diagnoses.Objectives To review the clinicopathological characteristics of combined DPMs and characterize the molecular profile of atypical and malignant forms.Methods The study included 51 patients with combined DPMs diagnosed at the Hospital Clinic of Barcelona and the University of Florence between 2012 and 2020. Clinical data, dermoscopy images (when available) and histological characteristics were reviewed. Immunohistochemistry for beta-catenin, LEF1, HMB45, Ki67, p16 and PRAME (preferentially expressed antigen in melanoma) was performed. Atypical forms underwent next-generation sequencing (NGS) panel analysis, including driver genes implicated in DPMs, TERT-promoter (p) mutations and the investigation of the 9p21 locus via fluorescence in situ hybridization.Results Among the 51 patients (32 females and 19 males, age range 4-74 years), 68% with available clinical data (15/22) were initially suspected of having melanoma. Except for one patient, complete excision resulted in no recurrences or metastases. One patient who had an incompletely excised combined DPM developed a lymph node melanoma metastasis 10 years later. In the 51 patients, 10 samples (20%) showed atypical histological features; 7 (14%) exhibited a significant loss of p16 expression; and 2 (4%) showed a high-proliferative index (Ki67 over 5%). NGS analysis in 11 patients revealed a double mutation BRAFV600E and exon 3 CTNNB1; no TERTp mutations were detected.Conclusions Clinical suspicion of melanoma is common in combined DPMs, but malignant progression is infrequent in tumours lacking high-grade atypia or proliferation. These findings are congruent with the consideration of these lesions as intermediate-grade tumours or melanocytomas.