Rare histologic subtypes of melanoma, including acral, mucosal, uveal, and desmoplastic melanomas, only make up 5% of all diagnosed melanomas and are often underrepresented in large, randomized trials. Recent advancements in systemic therapy have shown marked improvement in pathologic response rates, improving progression-free and overall survival among cutaneous melanoma patients, but there are limited data to demonstrate improved survival among rarer subtypes of melanoma. Acral melanoma has a poor response to immunotherapy and is associated with worse survival. Mucosal melanoma has a large variability in its presentation, a poor prognosis, and a low mutational burden. Uveal melanoma is associated with a high rate of liver metastasis; recent adoption of infusion and perfusion therapies has demonstrated improved survival among these patients. Desmoplastic melanoma, a high-risk cutaneous melanoma, is associated with high locoregional recurrence rates and mutational burden, suggesting this melanoma may have enhanced response to immunotherapy. While these variants of melanoma represent distinct disease entities, this review highlights the clinicopathologic characteristics and treatment recommendations for each of these rare melanomas and highlights the utility of modern therapies for each of them.
