Malignant melanoma (MM) of mucosal membranes (excluding anus and head-neck) is a rare but aggressive disease with poor outcomes. The knowledge of this tumor's development, etiology, and management is scarce, mainly due to the low case numbers. We presented eight cases and performed a comprehensive literature review on mucosal MM (between 1970 and 2020). We identified 47 manuscripts on 55 patients with primary mucosal MM (limited to urothelium and vagina) and reviewed demographics, tumor specifications (morphology, stage, etc.), management, and survival. We identified 10 manuscripts discussing treatment in 1595 mucosal and non-mucosal MM and extracted the data regarding the non-surgical treatment modalities of mucosal MM patients.In 63 cases, 48 tumors primarily occurred in the urothelium (urethra: 47, bladder: 1) and 15 in the vagina. Molecular studies in a subset of cases revealed alterations in c-KIT, NRAS, BRAF (non-V600E and V600E), TP53, and NF1. Fifty-three patients underwent surgery (with additional chemotherapy, immunotherapy, and radiotherapy in 19, eight, and eight patients, respectively). The outcome was available in 52 cases, showing 21 deaths, 10 without recurrence, two alive with disease, and five lost to follow-up. Shared genetic signatures in mucosal and skin MM suggest a similar development mechanism; however, unlike skin MM, there are less BRAF mutations and more PI3K/AKT/mTOR pathway alterations in mucosal MM. Prolonged chemotherapy (i.e., methotrexate) and immune-modulating agents (i.e., natalizumab) may be risk factors. The stage at diagnosis and proper surgical extirpation are keys to the prognosis and survival of patients.
