Epidemiology and Molecular Profile of Mucosal Melanoma: A Population-Based Study in Southern Europe

Abstract

Background: Mucosal melanoma is a rare neoplasm on which few epidemiological population-based studies have been published. A good surgical approach is the standard treatment, but the prognosis is worse than that of skin melanoma. The analysis of mucosal melanoma’s mutational profile can help to develop target therapies in advanced disease or adjuvant settings. Methods: We analyzed the database of the Cancer Registry of Girona, a region located in the north-east of Spain, in the period of 1994–2018. We selected cases of primary invasive melanoma, excluding those located in the skin, eye, central nervous system and an unknown primary site. Epidemiological analysis included incidence and survival. Mutational profile analysis was performed with a custom gene panel. Results: Forty-two patients were identified: 14 (33%) had vulvar-vaginal melanoma, 15 (35.7%) had rectal melanoma, 12 (28.6%) had melanoma located in the head and neck sphere and 1 male patient had a urethral melanoma. European age-standardized incidence rates for vulvar-vaginal, rectal and head and neck melanoma were 0.09, 0.1 and 0.09 cases/100,000 inhabitant-years, respectively. Five-year observed survival rates were 37.5%, 20% and 25% for these types of cancers. NRAS Q61 was the most frequent mutation found. Conclusion: Our study confirms the steady incidence and low survival of mucosal melanomas in a region of southern Europe. NRAS and NF1 play a role in the molecular landscape of mucosal melanoma. MEK and PI3K/mTOR inhibitors could be reasonable treatment options and are being studied in clinical trials.

Vulvar Malignant Melanoma: A Narrative Review

“…BRAF mutation was found more after the introduction of NGS technology [ 31 , 40 , 41 , 42 ]. Recently, Carbó-Bagué et al [ 43 ], Shi et al [ 25 ], and Zarei et al [ 44 ] did not find the BRAF mutation, regardless of the use of NGS. However, Carbó-Bagué et al and Zarei et al only considered primary melanoma, whereas Shi et al did not specify the primary or metastatic origin of their sample.…”

“…KIT is frequently mutated in VM, such as other urogenital melanomas, regardless of the employed technology [ 25 , 31 , 32 , 34 , 35 , 36 , 37 , 38 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. Exon 11 L576P KIT mutation has been frequently detected [ 31 , 32 , 35 , 36 , 40 , 41 , 43 , 46 ], suggesting Imatinib or Sunitinib as a possible use [ 31 , 46 ].…”

“…KIT is frequently mutated in VM, such as other urogenital melanomas, regardless of the employed technology [ 25 , 31 , 32 , 34 , 35 , 36 , 37 , 38 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. Exon 11 L576P KIT mutation has been frequently detected [ 31 , 32 , 35 , 36 , 40 , 41 , 43 , 46 ], suggesting Imatinib or Sunitinib as a possible use [ 31 , 46 ]. Furthermore, overexpression of KIT is often detected when immunohistochemical staining (IHC) is performed [ 28 , 31 , 35 , 36 , 37 , 38 , 41 ]: increased expression of c-kit is a strong predictor of poor DFS and early relapse of disease [ 28 ].…”

“…VM harbors NRAS mutation: exon 2 Q61 mutation is present in its Q61R/L/K/H variants [ 25 , 31 , 32 , 33 , 38 , 41 , 42 , 43 , 48 ], like 90% of melanomas with NRAS mutation (25% of all melanomas) [ 52 ]. Additionally, G12 and G13 mutations of NRAS has been detected [ 32 , 38 , 41 , 44 ]: Q61 and G12 are both activating mutations, with a clear pathologic significance [ 53 ].…”

“…Aulmann et al [ 38 ] showed the coexistence of NRAS and KIT mutations in three cases of VM, while Rouzbahman et al [ 42 ] demonstrated this in one case. Beyond NRAS, BRAF, and KIT mutations, Carbó-Bagué et al [ 43 ] showed multiple mutations simultaneously hosted in a single patient. In this series, KIT L576P is associated with the POLE, ERBB3, and JAK2 mutations.…”