Clinical, Morphologic, and Genomic Differences in Deep Penetrating Nevi and Deep Penetrating Nevus-like Melanomas

Lu Chen; Alice Chen; Natasha Sharma; Pragi Patel; Afua Konadu Addo; Julia Edwin Jeyakumar; Haya Mary Beydoun; Shantel Olivares; David Dittmann; Erica Vormittag-Nocito; Lucas Santana Dos Santos; Lawrence Jennings; Pedram Gerami

doi:10.1016/j.modpat.2025.100707

Clinical, Morphologic, and Genomic Differences in Deep Penetrating Nevi and Deep Penetrating Nevus-like Melanomas

Mod Pathol. 2025 Jan 8:100707. doi: 10.1016/j.modpat.2025.100707. Online ahead of print.

Affiliations

¹ Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL.
² Department of Molecular Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
³ Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL. Electronic address: pedram.gerami@nm.org.

PMID: 39793705
DOI: 10.1016/j.modpat.2025.100707

Abstract

Deep penetrating nevi (DPNs) are characterized by activating mutations in the MAP kinase and Wnt/beta-catenin pathways that result in large melanocytes with increased nuclear atypia, cytoplasmic pigmentation, and often mitotic activity. Together with a lack of maturation, this constellation of findings creates challenges for pathologists to distinguish deep penetrating nevus (DPN) from DPN-like melanoma. To assess the utility of next generation sequencing (NGS) in resolving this diagnostic dilemma, we performed NGS studies on 35 lesions including 24 DPNs and 11 DPN-like melanomas to characterize the specific genomic differences between the two groups and elucidate the genetic events involved in malignant transformation of DPNs. Compared to DPNs, DPN-like melanomas were clinically larger in size (1.1 vs 0.6 cm, p=0.02) and on histopathologic examination more frequently showed high grade nuclear atypia (11/11 vs 9/24; p=0.00052), increased mitotic activity (mean 3.9 vs 1.3 per mm²; p=0.0004), sheet-like growth pattern (5/11 vs 2/24; p=0.01), and involvement of the subcutis (4/5 vs 3/13; p=0.026). From a genomic standpoint, DPN-like melanomas had a higher tumor mutation burden (mean 37.1 vs 7.8 mutations/megabase; p=0.002) than DPNs and more frequently harbored NRAS mutation (3/11 vs 1/24; p=0.046) whereas MAP2K1 in frame deletions were only identified in DPNs (0/11 vs 5/24). There was no statistically significant difference in the frequency or type of CTNNB1 or APC mutations between the two groups. Within progression genes, DPN-like melanomas were more frequently found to have pathogenic variants in TERT promoter (7/11 vs 0/24; p<0.00001), CDKN2A (4/11 vs 0/24; p=0.0008), and protein subunits of the SWI/SNF complex (7/11 vs 3/24; p=0.02) compared to DPNs. Our findings provide a framework for employing NGS in the evaluation of deep penetrating melanocytic tumors.

Keywords: Deep Penetrating Nevus; Deep Penetrating Nevus-like Melanoma; Malignant Melanoma; Malignant Melanoma Arising in Association with a Deep Penetrating Nevus; Next Generation Sequencing.