Acral Melanoma: A Review of Its Pathogenesis, Progression, and Management

Abstract

Acral melanoma is a distinct subtype of cutaneous malignant melanoma that uniquely occurs on ultraviolet (UV)-shielded, glabrous skin of the palms, soles, and nail beds. While acral melanoma only accounts for 2-3% of all melanomas, it represents the most common subtype among darker-skinned, non-Caucasian individuals. Unlike other cutaneous melanomas, acral melanoma does not arise from UV radiation exposure and is accordingly associated with a relatively low tumor mutational burden. Recent advances in genomic, transcriptomic, and epigenomic sequencing have revealed genetic alterations unique to acral melanoma, including novel driver genes, high copy number variations, and complex chromosomal rearrangements. This review synthesizes the current knowledge on the clinical features, epidemiology, and treatment approaches for acral melanoma, with a focus on the genetic pathogenesis that gives rise to its unique tumor landscape. These findings highlight a need to deepen our genetic and molecular understanding to better target this challenging subtype of melanoma.

Keywords: acral melanoma; genetics; genomics; therapy.

Figure 1

An overview of the most frequently reported genetic and epigenetic alterations in acral melanoma.

Figure 2

Clinical images of acral melanomas. Acral melanomas on the finger (a), fingertip and nail matrix (b) (courtesy of Dr. Arthur Tong), dorsum of foot (c), and plantar surface (d).

Figure 3

Landscape of genetic and genomic abnormalities in acral melanomas. (a) Mutations in different loci identified through whole genome sequencing of 87 acral melanomas. Tumors were from the soles (n = 59), palms (n = 6), and subungual regions (15 toenail, 7 thumbnail/fingernail). (b) Focal areas of recurrent amplification (red) and deletion (blue) as identified by GISTIC2. Data and figure modified from Newell et al. [19]. Permission granted under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/ accessed on 26 November 2024). Abbreviations: SMG—significantly mutated genes; SNV/Indel—single nucleotide variant/insertion–deletion; SV—structural rearrangement variants.

Figure 4

Graphic representation of common molecular pathways involved in acral melanoma and their pharmacological inhibitors. KIT mutations or amplifications can lead to constitutive activation of its downstream MAPK/ERK and PI3K/AKT pathways. Within the MAPK/ERK pathway, N/K-RAS mutations hyperactivate RAF kinases that activate downstream MEK and ERK. ERK promotes cyclin-D1 expression, which binds to CDK4/6 and phosphorylates Rb protein. This phosphorylation inactivates Rb, leading to the release of E2F transcriptional factors that drive G1–S cell cycle progression. CDKN2A encodes two tumor suppressors: p16^INK4A, which inhibits CDK4/6, and p14^ARF, which inhibits MDM2/4 and prevents p53 degradation. Loss of CDKN2A leads to unchecked cell cycle progression and growth. Within the PI3K/AKT pathway, PTEN loss leads to hyperactivation of PI3K signaling, which leads to increased mTOR signaling and drives cellular growth and protein synthesis. Dysregulation of transcriptional factor EP300 leads to altered histone acetyltransferase activity, and TERT promoter mutations lead to telomerase overexpression and cell immortalization. In AM, proteins with activating changes (e.g., amplification or missense mutations) are colored in red, while inactivating changes (e.g., deletions or deleterious point mutations) are colored in black. Existing inhibitors are shaded in blue.

Figure 5

Chromothripsis. Chromosomal fragmentation generates multiple double-stranded DNA breaks, followed by error-prone repair processes that reassemble the resulting DNA fragments in a random order and orientation. Chromosomal segments that fail to reintegrate into chromosomes may self-ligate, forming extrachromosomal DNA (ecDNA) structures, or may be eliminated, resulting in deletions. Figure was prepared using BioRender.