Clinical and molecular features of subungual melanomas are site-specific and distinct from acral melanomas

Abstract

Subungual melanomas (SUM) arise beneath the nails of the hands and feet, and account for 0.7–3.5% of all malignant melanomas. Most studies include SUM in the category of acral melanoma, but understanding the specific features of SUM is critical for improving patient care. In this study, we performed a site-specific comparison of the clinical and molecular features between 54 cases of SUM and 78 cases of nonsubungual acral melanoma. Compared to patients with acral melanoma, patients with SUM were younger at diagnosis, had a higher prevalence of primary melanomas on the hand, and had more frequent reports of previous trauma at the tumor site. SUM was deeper than acral melanoma at diagnosis, which correlated with an increased frequency of metastases. Analysis of common melanoma driver genes revealed KIT and KRAS mutations were predominantly found in SUM, whereas BRAF and NRAS mutations occurred almost exclusively in acral melanoma. We also discovered molecular differences in the cell cycle pathway, where CDK4/CCND1 amplifications were more frequent in SUM and CDKN2A/B loss occurred mostly in acral melanoma, and in the PI3K/mTOR pathway, where RICTOR amplification and TSC1 K587R mutations were exclusively in SUM and PTEN loss and AKT1 mutations were exclusively in acral melanoma. Comparison of hand versus foot tumors revealed more frequent ulceration of SUM foot tumors, which correlated with more distal metastases and poorer overall survival. In summary, we find SUM are both clinically and molecularly distinct from acral melanoma, and our data suggest KIT, CDK4/6, and mTOR inhibitors may be particularly relevant and effective treatments for patients with SUM.

The Molecular Landscape of Primary Acral Melanoma: A Multicenter Study of the Italian Melanoma Intergroup (IMI)

“…In particular, BRAF-mutated cases were correlated with a lower frequency of gains in the CCND1 locus compared to TWT AMs (29% and 61%, respectively), as reported by Curtin and colleagues [18]. No BRAF mutations were detected in subungual melanomas, confirming its rarity in this site [26,27]. The importance of this pathway in AM was also highlighted by the high percentage of cases with gains in the BRAF locus (47%).…”

“…According to the literature, the rate of BRAF-mutated AMs (35%) was lower than those reported for the other non-acral cutaneous melanomas [1,15,17,18]. However, it was higher than those usually found in this melanoma subtype, which rarely exceeds 20% of cases [15,16,24,25,27]. An explanation could be the fact that the present series only included Italian patients.…”

“…The reported frequency of NRAS mutations in AM ranges from about 10% to 30% of cases, with markedly lower rates in melanomas of the nail apparatus [16,[22][23][24][25][26][27]. In the present study, NRAS mutations were detected in 28% of AMs, none in subungual cases, and almost all in the acral lentiginous melanoma histotype.…”

“…BRAF mutations have been reported to occur at a significantly lower rate in AM than in other non-acral skin melanomas (about 10-20% of cases versus 50% of cases, respectively) [15][16][17][18]23]. Mutated NRAS and KIT have been detected in about 15% of cases, with a respective range of 7-47% and 6-21% among the studies [16,17,[22][23][24][25][26][27][28]. TP53 mutations have been reported as a rare and late event in AM [16,19,29].…”

Identification of genetic mutations related to invasion and metastasis of acral melanoma via whole‐exome sequencing

“…Several recent studies suggest that nail apparatus melanoma (NAM) differs from non‐nail apparatus acral melanoma (NNAM) 23–25 . Holman et al 23 . reported that NAM and NNAM show clinical and molecular differences.…”