Molecular Analysis of Cutaneous Sarcomatoid Neoplasms Frequently Identifies Melanoma Driver Variants

Primary cutaneous neoplasms that lack definitive histologic and immunophenotypic evidence of differentiation are a heterogeneous group of tumors with diverse prognoses and management options. These include undifferentiated and dedifferentiated melanoma (UM/DM), atypical fibroxanthoma (AFX), pleomorphic dermal sarcoma (PDS), and sarcomatoid squamous cell carcinoma. Diagnosis requires careful correlation between the clinicopathologic and molecular features, and the finding of a MAPK pathway variant commonly associated with melanoma may support the diagnosis of melanoma over other tumors in this group. To examine the frequency of typical melanoma-associated MAPK pathway-related variants ( BRAF, NRAS, KIT, GNAQ, GNA11 ) among a cohort of primary cutaneous sarcomatoid neoplasms, we conducted a retrospective analysis of 37 cases of immunohistologically unclassifiable primary cutaneous neoplasms, submitted for targeted NGS analysis. All cases lacked a history of a prior relevant tumor, were negative for melanocytic markers (S100, SOX10, HMB45, and Melan-A), or showed <5% staining with 1 or 2 of these markers. Other lineage markers were negative. We identified typical melanoma driver variants in 7 cases (7/37, 19%), including NRAS (5/37, 14%), KIT (1/37, 3%), and GNAQ (1/37, 3%). There were no significant differences in age, sex, tumor site, or mitotic rate between patients with and without a melanoma driver variant. Melanoma cases were thicker (16.3 vs. 9.25 mm, P =0.041) and more likely to show epithelioid cell phenotype ( P =0.008). In our cohort, nearly 20% of patients with immunohistologically unclassifiable cutaneous tumors could be reclassified as having primary UM/DM after molecular testing, thereby opening alternative management pathways.