Sarcomatoid malignancies with strong PD-L1 expression often represent dedifferentiated or undifferentiated melanomas

Despite recent studies showing that dedifferentiated and undifferentiated melanoma (DM/UM) mimic sarcoma histologically, DM/UM continue to pose a diagnostic challenge owing to their under-recognition and frequent misclassification. To address this pitfall, we studied 22 cases of DM/UM initially classified as sarcoma. The patients were typically male (18/22) and older than 55 years (median 65 years, range 40-89 years), often lacking a history of melanoma (15/22). All but one case (21/22) presented with evidence of metastasis, and sites of disease frequently included lymph node basins, especially axilla (10/22). The tumors variably showed spindled and rhabdoid cytomorphology, collagenous or myxoid stroma, and fascicular architecture, imitating sarcoma; all tumors exhibited an intratumoral inflammatory component ranging from moderate to brisk. Molecular testing demonstrated alterations involving BRAF (7/22), NRAS/HRAS (10/22), NF1 (4/14), and TERT promoter (9/13). High tumor mutational burden was present in 13/13 cases (mean 21.8 mutations/Mb) and a UV-related mutational signature was found in 8/8. By immunohistochemistry, 55% (12/22) were negative for melanocytic markers, in keeping with undifferentiated melanoma. Two cases (2/17) were positive for desmin, while SATB2 was positive in 2/2 cases, including one with osteoid. The cohort showed strong expression of PD-L1 in all 22 cases (CPS 80-100, mean 93). In contrast, a separate cohort of 87 sarcomas of varying histotype had an average CPS of 5.6 (median CPS 0), including only three cases with CPS >50. Ten patients received PD-L1-targeted immunotherapy with partial or complete response in 80%. These findings emphasize pitfalls in distinguishing DM/UM from sarcoma and highlight the utility of PD-L1 immunohistochemistry in accurately diagnosing and effectively treating DM/UM.