Expanding the Molecular Landscape of Deep Penetrating Nevus-like Melanomas Beyond CTNNB1 and APC Mutations

Deep penetrating nevus (DPN)-like melanomas are believed to arise through sequential activation of the mitogen-activated protein kinase (MAPK) and Wnt/β-catenin signaling pathways, followed by additional mutations. Due to their rarity and lack of standardized diagnostic criteria, their molecular landscape and clinical behavior remain still poorly understood. Here, we report the largest cohort to date of 14 DPN-like melanomas. These tumors predominantly affected middle-aged adults (median, 46 y), with the head and neck skin as the most common site. One rare case involved a mucosal site (epiglottis). DPN-like melanomas exhibited infiltrative growth, prominent vertical growth phase, severe nuclear atypia with occasional multinucleation, and increased mitotic activity (median, 3.5/mm 2 ). The median Breslow thickness was 3.3 mm (range: 1.2 to 9.2 mm), with all cases showing microscopic satellitosis, sentinel lymph node positivity, or synchronous metastasis. Most cases (93%) harbored MAPK pathway-activating mutations, predominantly in BRAF (77%), followed by NRAS and EGFR (an upstream regulator of the MAPK pathway). In addition, 79% of cases had mutations activating the canonical Wnt/β-catenin signaling pathway, mainly in CTNNB1 and APC . Two CTNNB1 / APC wild-type cases exhibited alternative mutations in genes indirectly modulating this pathway, such as ARID1A , EZH2 , FAT1 , and SETD2 , along with other mutations, including TERT promoter mutations (TPMs). TPMs were present in 56%, and the median tumor mutational burden was 30 mutations/Mb. After a median follow-up of 33.5 months, 36% of patients developed distant metastases, and 2 patients died of disease 8 and 32 months, respectively, after initial diagnosis. These findings expand the molecular diversity of DPN-like melanomas and provide valuable insights into their clinical outcomes.