Malignant Melanoma with Atypical Phenotype and RAC1 Mutation

Abstract

Abstract Introduction/Objective Melanoma, a highly invasive form of skin cancer associated with high mortality rates, poses significant challenges in diagnosis and treatment. RAC1, a member of the RHO family of GTPases, plays a crucial role as a molecular switch in cellular processes. A specific mutation in RAC1, caused by C > T transition induced by UV radiation, leads to P29S alteration, activating the SRF/MRTF pathway and triggering a phenotypic switch towards a mesenchymal phenotype. Methods/Case Report We present a case of a 74-year-old male patient who presented with a six-week history of right neck swelling. Ultrasonography revealed an enlarged lymph node in the right posterior triangle of the neck. PET scan showed a well- defined, moderately metabolically active lesion measuring 1.4x1.7cm. Initial biopsy indicated a diagnosis of malignant metastatic sarcomatous neoplasm. To establish a definitive diagnosis and determine the appropriate treatment plan, excision of the lymph node was performed. Histological examination revealed lymph node involvement by large, highly atypical cells exhibiting prominent nucleoli and frequent mitotic figures. Immunohistochemical analysis demonstrated positive staining for SOX10 and S100, while Melan-A and HMB45 were negative. Epithelial markers were also negative, although focal keratin positivity was observed. Further investigations were conducted to identify a primary or extranodal site. Routine dermatology visits had previously shown no evidence of primary cutaneous melanoma. Results (if a Case Study enter NA) Genomic profiling through next-generation sequencing (NGS) identified multiple alterations, including BRAF (G469R- exon 11, missense alteration), TP53 (R248W, missense alteration in TP53), RAC1 (P29S, missense alteration), TERT (Promoter Site Variant; chr5:g.1295228G>A c.-124C>T), and NF1 (Q1815, nonsense alteration). The tumor exhibited a high tumor mutational burden (TMB) and an ultraviolet (UV) signature characterized by C > T transitions. Conclusion Diagnosing melanoma with RAC1 mutation poses significant challenges due to its potential to induce phenotypic switching. Understanding the role of RAC1 mutations in driving melanoma progression can help improve diagnostic accuracy and guide targeted therapeutic strategies.