Track

Case Reports

Abstract

A 34-year-old man with xeroderma pigmentosum (XP) and a history of multiple cutaneous malignancies presented with a large metastatic melanoma arising in the same location as a primary melanoma excised a few years earlier and previously treated with pembrolizumab. Imaging identified an 18.3 cm hemorrhagic mass in the left medial proximal thigh. Core biopsy confirmed metastatic melanoma. Following three cycles of neoadjuvant pembrolizumab, the patient underwent surgical resection, which revealed a ≥17.0 cm tumor, lacking epidermal connection, and demonstrating 20% residual viable melanoma cells. Comprehensive genomic profiling showed markedly elevated tumor mutational burden (TMB) along with multiple pathogenic variants, including two separate MAP2K1 mutations and alterations in the TERT promoter, APC, ARID1A, AXIN2, KMT2D, ERCC2, and ERCC6. Consistent with prior XP melanoma studies, no pathogenic BRAF V600E mutation was detected. XP-associated melanomas typically harbor UV-signature mutations, leading to high TMB, which can theoretically enhance tumor immunogenicity. However, MAPK pathway hyperactivation, such as that driven by MAP2K1 alterations, has been linked to immune evasion through reduced tumor-infiltrating lymphocytes, which may counteract the expected benefits of checkpoint inhibition. The coexistence of two pathogenic MAP2K1 mutations in an XP-associated melanoma has not been previously described and may indicate an additive effect on pathway signaling, contributing to aggressive growth and treatment resistance. Although giant melanomas are very rare and often associated with delayed diagnosis, this case progressed to extraordinary size despite prior therapy. This presentation underscores the need for integrated clinicopathologic, molecular, and immunophenotypic evaluation to optimize management strategies in aggressive XP-associated melanoma.