Histopathological Differences Between De Novo and Nevus-Associated Melanoma

Background/Objectives: Cutaneous melanoma arises de novo in the majority of cases; 20–30% develop from pre-existing nevi. Differentiating nevus-associated melanoma (NAM) from de novo melanoma (DNM) is important for understanding melanomagenesis, risk stratification, and prognostic assessment. The objective of this study was to compare the demographic, clinical, and histopathological characteristics of NAM and DNM in a large single-institution retrospective cohort. Methods: A retrospective, longitudinal, observational study was conducted at the Department of Pathological Anatomy, Cluj-Napoca County Emergency Clinical Hospital (2015–2025). Of the 729 initially identified cases, 580 patients with histopathologically confirmed cutaneous melanoma and complete clinical records were included. Analyses comprised Mann–Whitney U and chi-square tests and multivariate logistic regression (p < 0.05). Results: DNM constituted 78.6% (n = 456) and NAM 21.4% (n = 124) of cases. DNM patients were significantly older (median 66 vs. 56 years; p < 0.001). NAM was predominantly located on the trunk (63.7% vs. 45.2%; p = 0.0006), whereas DNM showed greater involvement of the head/neck and upper extremities. Superficial spreading melanoma was more frequent in NAM (79.8% vs. 62.5%; p = 0.004); nodular melanoma was more common in DNM (22.6% vs. 10.5%), and lentigo maligna was exclusive to DNM. DNM demonstrated greater Breslow thickness (median 2.0 vs. 1.25 mm; p = 0.021), more advanced Clark level (p = 0.040), and higher mitotic rate (median 3 vs. 2/mm2; p = 0.049). On multivariate logistic regression, older age (OR = 1.03; 95% CI: 1.02–1.05; p < 0.001) and head/neck localisation (OR = 2.73; 95% CI: 1.39–5.39; p = 0.004) were independent predictors of DNM; histopathological aggressiveness markers did not retain independent significance after adjustment. Conclusions: Although DNM presents with more aggressive histopathological features, these characteristics are driven primarily by patient age and anatomical location rather than an inherent de novo aggressive phenotype, suggesting that observed differences largely reflect cumulative sun-damage pathways and patient demographics.