Update on mucosal and uveal melanoma

Mucosal melanoma makes up 1% of all melanomas in a Caucasian population, although the proportion is much higher, up to 23%, in a Chinese population. The most common sites are sino-nasal, ano-rectal and vulvovaginal. Surgery remains the mainstay of treatment. However complete surgical resection with clear margins is often difficult to achieve due to the anatomical location of tumour. Narrow margin resection with adjuvant radiotherapy is now a standard of care, but achieving this without extensive surgery is often not possible. Furthermore, despite good local control with surgery and radiotherapy, the long term prognosis is poor, with 1-year survival of 80% but 5-year survival of just 25%, compared to 80% for cutaneous melanoma. Systemic treatment options for mucosal melanoma remain limited, with no established targeted treatment for the 90% of patients with BRAF wild-type disease, although the tyrosine kinase inhibitor imatinib has demonstrated an ORR of 54% in patients whose tumours harbour an activating mutation in C-KIT (10-15% of patients with mucosal melanoma). Advanced mucosal melanoma is less responsive to immunotherapy than cutaneous melanoma, with response rates approximately half those seen in cutaneous melanoma. However, this remains a standard of care. Uveal melanoma is the most common ocular malignancy in adults, representing approximately 85% of all tumours. It represents 3-5% of melanomas diagnosed in the US. Treatment for primary tumour includes brachytherapy, proton beam or surgery. The majority of patients have localised disease at presentation although 50% of patients will go on to die from metastatic disease, with the liver being the most common site of metastatic disease. A number of drivers with mutations have been identified with greater than 80% of tumours having mutations in GNAQ or GNA11, resulting in activation of the amount of kinase pathway. Other common mutations include BAP1 which is associated with a loss of chromosome 3, SF3B1 and EIF1AX. Molecular profiling using DecisionDX-UM classifies patients into Class 1 and class 2 with better and worse prognosis. Currently there is no proven standard of care treatment options for patients with metastatic uveal melanoma. Systemic chemotherapy has little to offer patients with metastatic disease. Isolated hepatic perfusion is associated with an increase response rate and emerging evidence suggesting survival benefits. The SUMIT Trial showed no benefit for the addition of the MEK inhibitor selumetinib to DTIC chemotherapy in terms of progression free survival. Conventional checkpoint inhibitors seem to have little role, though immunotherapy approaches have shown a signal of activity. Guidelines on the management of Uveal Melanoma have recently been published.