<p>Conjunctival Melanoma: Update on Genetics, Epigenetics and Targeted Molecular and Immune-Based Therapies</p>

Abstract

Purpose: To present the molecular mechanisms involved in the pathogenesis of conjunctival melanoma (CM) and review the existing literature on targeted molecular inhibitors as well as immune checkpoint inhibitors for the management of locally advanced and metastatic disease. Methods: A comprehensive review of the literature was performed using the keywords "conjunctival melanoma", "immune checkpoint inhibitors", "BRAF inhibitors", "MEK inhibitors", "CTLA4 inhibitors", "PD1 inhibitors", "c-KIT mutations", "BRAF mutations", "NRAS mutations", "dabrafenib", "trametinib", "vemurafenib", "ipilimumab", "pembrolizumab", and "nivolumab". A total of 250 articles were reviewed and 120 were included in this report. Results: Mutations of mediators in the MAP kinase pathway, such as RAS, BRAF, MEK and ERK, and mutations of the PI3K/AKT/mTOR pathway play a major role in the pathogenesis of conjunctival melanoma. In addition, alterations of c-KIT, NF1, TERT, chemokine receptors as well as chromosomal copy number alterations and micro RNAs are thought to have a causative association with CM development. Targeted molecular inhibitors, such as BRAF and MEK inhibitors, are currently being implemented in the therapy of BRAF-mutated CM. Furthermore, immune checkpoint PD-1 and CTLA4 inhibitors with favorable clinical outcomes in the treatment of cutaneous melanoma have increased recurrence-free survival and reduced metastatic spread in CM cases. Conclusion: The complex molecular mechanisms that contribute to the development of CM can be targeted both by molecular inhibitors of oncogenic pathways as well as immune checkpoint inhibitors in order to halt progression of the disease and increase survival.

BRAF and NRAS prognostic values in conjunctival melanoma: analysis and literature review

“…The study showed positivity for BRAF V600E and Q61X NRAS mutations in 25% of the cases each, which is similar to the data described by Griewank et al (20) (29% and 20%). However, other publications, such as Kenawy et al (18) and Larsen et al (19) , identified BRAF V600E mutations in primary tumors with much higher numbers, 40.4% and 50%, respectively. Recently, Gkiala et al (17) have shown that in a literature review with 563 CMs, 29.7% (n=167) harbored BRAF mutations and only 6.4% (n=36) harbored NRAS mutations.…”

“…No differences were found in terms of sex or age at presentation. However, CM with alterations in these markers has been occurring more frequently in young males (18,19) , although without statistical significance.…”

Connecting the dots: Melanoma cell of origin, tumor cell plasticity, trans‐differentiation, and drug resistance

“…Conjunctival melanocytes are derived from the neural crest as uveal and cutaneous melanocytes, although they migrate in different waves (Hu et al, 2007; Iwamoto et al, 2002). Although more population studies are needed, current evidence suggests that the most common driver mutations in conjunctival melanoma are in the BRAF (~30%–70%), NF1 (~20%–30%), NRAS (~17%), and c‐KIT (~8%) genes that lead to constitutive activation of the MAPK pathway as well as mutations that result in activation of the PI3K/AKT/mTOR signaling pathway (Gkiala & Palioura, 2020).…”

New Insights on the Diagnosis and Management of Malignant Tumors of the Ocular Surface

“…In recent decades, the incidence of conjunctival melanoma has been increasing similar to cutaneous melanoma, while the incidence of uveal melanoma has remained relatively stable. This is thought to be related to the result of environmental exposure to UV light (25)(26)(27). Conjunctival melanoma mostly arises from PAM (53-75%), but can also arise from conjunctival nevi (18-30%) or de novo (5%) (21,24).…”