Acral Melanoma: Epidemiology and Treatment Outcomes

Abstract

Acral melanomas are a subtype of melanoma which affect the palms, nails and soles of the feet. Acral melanomas are characterised by different mutation signatures, prognoses and treatment outcomes compared to other forms of melanoma. Given the non-UV mutation signature in acral melanomas, the aetiology is thought to be a distinct but unknown driving factor. These two systematic reviews and meta-analyses presented in this thesis aimed to investigate the association of chronic mechanical stress with acral melanoma of the lower limbs, and the treatment outcomes of patients with metastatic acral melanoma. A systematic database search was performed using PubMed, EMBASE and MEDLINE, with the grey literature also comprehensively searched using Google Scholar and Google Search. The references of included articles were examined for relevant studies. Studies were included if they met pre-determined specified criteria. Study quality was assessed using published critical appraisal tools. Random-effects models were used to calculate prevalence and to estimate the summary event rate, 95% confidence intervals and heterogeneity. Publication bias was assessed using Egger’s regression test and funnel plots. All statistical analysis was performed with the software Comprehensive Meta-analysis (version 3.0), Biostat. Englewood, NJ (2014). Our first study identified that melanoma had a predilection to affect certain locations on the plantar surface of the foot, and these areas appeared to correlate with areas of chronic mechanical stress. Subungual melanoma in the feet disproportionally affected the first toe, also an area of the foot most frequently exposed to acute and chronic trauma. These findings in combination suggest repetitive force may be a contributing factor in the pathogenesis of plantar melanoma. Our second study revealed that treatment outcomes for patients with metastatic acral melanoma were poorer than other forms of cutaneous melanomas (acral overall survival: median 15 months, 95% CI 13.7-16.3 months, non-acral cutaneous: median 24 months, 95% CI 22.6-25.4 months, p<0.001). Patients with acral melanoma treated using anti-PD-1 therapy had higher overall survival at 12 months (53%) compared with anti-CTLA-4 monotherapy (34%; p<0.001) In conclusion, this study supports the evidence of acral melanoma being a distinct subtype, with chronic mechanical stress acting as a possible aetiological factor. In addition, the estimates of treatment response for metastatic acral melanoma, demonstrated low levels of responses to current approved therapy, including anti-PD-1, one of the most active treatments in melanoma to date.