Uncommon Subtypes of Malignant Melanomas: A Review Based on Clinical and Molecular Perspectives

Abstract

Malignant melanoma represents the most aggressive type of skin cancer. Modern therapies, including targeted agents and immune checkpoint inhibitors, have changed the dismal prognosis that characterized this disease. However, most evidence was obtained by studying patients with frequent subtypes of cutaneous melanoma (CM). Consequently, there is an emerging need to understand the molecular basis and treatment approaches for unusual melanoma subtypes. Even a standardized definition of infrequent or rare melanoma is not clearly established. For that reason, we reviewed this challenging topic considering clinical and molecular perspectives, including uncommon CMs—not associated with classical V600E/K BRAF mutations—malignant mucosal and uveal melanomas, and some unusual independent entities, such as amelanotic, desmoplastic, or spitzoid melanomas. Finally, we collected information regarding melanomas from non-traditional primary sites, which emerge from locations as unique as meninges, dermis, lymph nodes, the esophagus, and breasts. The aim of this review is to summarize and highlight the main scientific evidence regarding rare melanomas, with a particular focus on treatment perspectives.

Anorectal and Genital Mucosal Melanoma: Diagnostic Challenges, Current Knowledge and Therapeutic Opportunities of Rare Melanomas

“…In particular: BRAF codon V600 mutations are less than 10%, while non-canonical BRAF mutations, namely K601, L597, D594 and G469 are much more frequent [ 19 , 20 ]; BRAF fusions, described in around 5% of triple wild type ( BRAF , NRAS , NF1 ) CMs, are not related to UV exposure [ 21 ] and have been found in a similar percentage in mucosal ones [ 19 ]. KIT gene, encoding for the transmembrane tyrosine kinase receptor KIT, has been found to be mutated in less than 20% of MM, most mutations localized at exon 11 and 13 [ 18 , 22 , 23 ]. The location of the primary tumour seems to be not indifferent, since its alterations are more common in anorectal and genital areas, according to Beadling et al [ 24 ]; among these sites, however, an imbalance was observed, with a higher prevalence of KIT mutations in vulvar and penile melanoma and an absence in vaginal melanoma, suggesting different biological processes [ 25 ].…”

3D-Printed Collagen Scaffolds Promote Maintenance of Cryopreserved Patients-Derived Melanoma Explants

“…To provide a more practical alternative for researchers conducting preclinical drug evaluations, we sought to integrate the use of 3D bioprinting and PDX modeling. Baseline patient melanoma generally undergoes reanimation engraftment after cryopreservation [ 16 , 17 ]. The efficacy of reanimating cryopreserved primary melanoma patient tumors and their PDX has typically been low or not investigated [ 16 , 17 ].…”

“…Baseline patient melanoma generally undergoes reanimation engraftment after cryopreservation [ 16 , 17 ]. The efficacy of reanimating cryopreserved primary melanoma patient tumors and their PDX has typically been low or not investigated [ 16 , 17 ]. To confirm this low efficacy, we established MPDX models ( Figure 1 A).…”

The Anticancer Potential of Doxycycline and Minocycline—A Comparative Study on Amelanotic Melanoma Cell Lines

“…The amelanotic subtype occurs usually in sun-exposed skin, especially in type I patients in the Fitzpatrick scale, and clinically manifests as red or pink-colored skin, erythematous macule or patch, or as a nodule with or without ulceration [ 41 , 42 ]. Late recognition, delayed treatment, and more aggressive pathological features such as deeper tumor thickness and higher mitotic rate contribute to poor prognosis and short survival [ 41 , 43 , 44 ].…”