Endometriosis and Melanoma: A Narrative Review of Their Epidemiological and Biological Association

Endometriosis is a chronic, estrogen-dependent inflammatory disorder characterized by the functional engraftment of endometrial-like stroma and glands outside the uterine cavity, encompassing a heterogeneous phenotypic spectrum that ranges from deep infiltrating lesions to subtle, atypical or non-pigmented peritoneal implants. Emerging evidence suggests an association between endometriosis and cutaneous melanoma. The aim of this study was to evaluate whether women with endometriosis have an increased risk of developing melanoma and to explore potential biological mechanisms underlying this association. This review was conducted in accordance with PRISMA guidelines. A comprehensive search of PubMed/MEDLINE, Scopus, and the Cochrane Library was performed for studies published in English up to 1 February 2025. Eligible studies were restricted to cohort and casecontrol designs evaluating the association between histopathologically radiologically verified endometriosis comprising distinct phenotypes and subtle atypical lesions and histologically confirmed cutaneous melanoma. Two independent reviewers executed study selection based on these strict eligibility criteria, and due to marked clinical heterogeneity, data were synthesized qualitatively. A total of 326 records were identified, of which 17 studies met the inclusion criteria. Genetic and biomolecular evidence revealed shared susceptibility loci and common molecular pathways, including TP53, PTEN, CDKN2A, and estrogen receptor mediated signaling, suggesting a biological link between the two conditions. Epidemiological studies consistently reported a modestly increased risk of melanoma in women with endometriosis, with hazard ratios ranging from 1.50 to 1.82 (95% Confidence Interval [CI]: 1.21–2.41). This association appeared more pronounced in younger women and in those with a personal or family history of dysplastic nevi or melanoma. Limited data also suggest a reverse association, with increased occurrence of endometriosis among women with melanoma. Endometriosis and melanoma share distinct genetic architectures, characterized by shared susceptibility loci at the chromosome 9p21 region (encompassing CDKN2A/B), alongside convergent hyperestrogenemic signaling via estrogen receptor-beta (ERβ) and systemic natural killer (NK) cell immunotolerance axes. These shared molecular pathways support a biologically plausible correlation, although causal links remain unproven due to pervasive study heterogeneity and surveillance biases. Current evidence suggests a modest epidemiological link; however, heterogeneity among studies limits definitive conclusions.