Abstract
Acral melanoma, a distinct form of cutaneous melanoma originating in the glabrous skin of the palms, soles, and nail beds, has a different genetic background from other subtypes of cutaneous melanoma. The roles of oncogenic BRAF mutations of acral melanoma in pathogenesis and patient outcomes have not been fully elucidated. We retrieved a total of 112 patients with primary acral melanoma and checked their BRAF V600E status using immunohistochemical staining of VE1 antibody. Among these cases, 21 acral melanoma samples (18.8%) showed positive BRAF V600E staining, and of those, 11 samples (9.8%) showed a heterogeneous staining pattern, with a mixture of VE1-positive and VE1-negative cells. BRAF V600E positivity was significantly associated with thicker melanoma (p = 0.0015). There was no significant difference in clinicopathological factors between homogeneous and heterogeneous VE1-positive acral melanoma. Both patients with BRAF V600E-positive acral melanoma and those with heterogeneous BRAF V600E had significantly shorter melanoma-specific survival than those with BRAF V600E-negative melanoma in Kaplan–Meier analysis (p = 0.0283 and p = 0.0065, respectively). These findings provide novel insights into the pathobiology of acral melanoma.
Highlights
Malignant melanoma, an aggressive malignant tumor derived from melanocytes, occurs in various sites of the body, but most frequently in the skin
We focused on intratumor BRAF V600E heterogeneity and made several interesting findings
We investigated a relatively large number of acral melanoma using immunohistochemical analysis and found that intratumor BRAF V600E heterogeneity was observed in more than half of BRAF V600E-positive melanomas (52.4%, 11/21). Both BRAF V600E positivity and BRAF V600E heterogeneity were significantly associated with worse patient survival in the Kaplan–Meier analyses
Summary
An aggressive malignant tumor derived from melanocytes, occurs in various sites of the body, but most frequently in the skin. Many driver gene aberrations have been identified in melanoma, including in BRAF, NRAS, NF1, and KIT. These aberrations all activate the mitogen-activated protein kinase (MAPK) pathway, leading to uncontrolled tumor proliferation [2]. Among these driver genes, BRAF is the most important in a clinical setting because BRAF/MEK inhibitors can be used for the treatment of BRAF-mutated melanoma [3,4]. The latest version of the National Comprehensive Cancer Network (NCCN) guidelines recommends BRAF inhibitors in combination with MEK inhibitors as a first-line treatment for unresectable melanoma with BRAF mutations [5]
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