Analysis of KIT gene mutations in patients with melanoma of the head and neck mucosa: a retrospective clinical report

Abstract

Unlike their cutaneous counterparts, head and neck mucosal malignant melanomas (HNMM) are more aggressive, and their prognostic markers have not been fully elucidated. This study, comprising 28 patients with HNMM, aimed to establish the relationship between different mutations and outcome, define the incidence of KIT mutations in HNMM, and identify the correlation among therapeutic options, histopathological findings, demographic data, and clinical response. Clinical analysis included patient characteristics, staging, primary and palliative treatments, and disease-free survival and overall survival (OS). Progression-free survival and OS were analyzed. Paraffin blocks were selected following histologic analyses, enabling DNA extraction. PCR amplification of exons 9, 11, 13, and 17, with different DNA concentrations, was performed. Patients were predominantly females (57%) and aged 27–85 years. All patients underwent surgery; 17 received adjuvant radiotherapy, and recurrences occurred in 82% patients. Oncologic mutations in KIT were found in 7 of 7 tumors, 3 in exon 9, 3 in exon 11, and 1 in exon 13. Predictive factors for recurrence were mitotic rate, vascular invasion, and perineural spread. There were no significant differences in DFS and OS according to KIT mutation. Our study results suggest that some patients might benefit from appropriate targeted therapy with kinase inhibitors.

CD117 immunoexpression in oral and sinonasal mucosal melanoma does not correlate with somatic driver mutations in the MAPK pathway

“…The 4.2% prevalence of KIT mutations in our samples agrees with the minimum value of the range of frequencies previously reported in SNM (4% to 12.5%) but is inferior to the 15% and 27% reported in OM and the 25.9% of other POSNM series . An intriguing finding of this series is the low frequency of KIT mutations (4.2%), despite simultaneously high C‐KIT protein expression.…”

“…It has been proposed that mucosal melanoma patients could benefit from TKI treatment, since KIT L576P and K642E mutations are sensitive to imatinib, BRAF V600E to vemurafenib and NRAS Q61R to trametinib (MEK inhibitor); however, despite their success in advanced cutaneous melanoma, long‐term clinical trials are needed to corroborate response rates and outcomes in the setting of metastatic mucosal melanoma . Our findings of the mutational profile and C‐KIT immunoexpression indicate an overlap of molecular activities, which demands a compound strategy for the treatment of POSNM and corroborates the contention that C‐KIT immunoexpression is not useful as a diagnostic marker for KIT mutation, suggesting that it an insufficient criterion for decisions on possible candidates for imatinib treatment …”

“…The anatomical site of the tumour could partially explain the different frequencies of KIT mutations between mucosal melanomas since higher rates among vulvovaginal cases have been reported compared to POSNM cases . This might be linked with the potential of neural crest cells to differentiate in melanocytes or could also be associated with ethnic origins, as it is found at a higher frequency in mucosal melanomas among Asiatic compared to Caucasian patients …”

Mucosal Melanoma of the Head and Neck: From Diagnosis to Treatment

“…Activating mutations and amplifications generate activation of growth and proliferation pathways, which seem to be important and common in acral and mucosal melanoma, both tumors unrelated to sun exposure [8]. Screening for KIT aberrations may have diagnostic value, given the evidence of a possible pathogenic role of this gene in mucosal melanomas, as well as a possible a therapeutic target in these patients [12]. Therapeutic c-KIT blockade could be useful in the treatment of patients with activating KIT mutation [6].…”

“…The key molecular events that trigger the malignancy development and progression is still unknown, which makes it difficult to work on new specific or multimodal treatment for this disease [12]. We can observe that mucosal melanoma is one unique subgroup in a vast emerging molecular classification system of melanoma.…”