Clinical, pathomorphological, and molecular genetic differences between primary amelanotic and melanotic cutaneous melanoma

Abstract

Introduction. Cutaneous melanoma (CM) is a highly aggressive malignant tumor characterized by pronounced heterogeneity and high metastatic potential. Although CM accounts for only about 2 % of all malignancies, it contributes to 80 % of skin cancer-related mortality. Aim. To perform a comparative analysis of the clinical, anamnestic, pathomorphological, and molecular genetic characteristics of amelanotic cutaneous melanoma (ACM) and melanotic cutaneous melanoma (MCM) to determine prognostic criteria and assess the risk of disease progression. Materials and methods. A retrospective single-center study was conducted including 93 patients aged 18–90 years with histopathologically verified primary stage I–II CM who received radical surgical treatment (wide local excision, R0) between 2021 and 2024. Sentinel lymph node biopsy was performed for tumor thickness 0.8 mm. Patients were divided into two groups: ACM (n = 33) and MCM (n = 60). Exclusion criteria were stage III–IV disease, hypomelanotic melanoma, uveal melanoma, mucosal melanoma, multiple primary tumors, and metastases of unknown primary site. Results. No significant differences in patient age were observed between the groups; females predominated in both cohorts. ACM was more frequently localized on the trunk (45 % of cases) and lower extremities (24 % of cases), whereas MCM was located on the trunk (57 % of cases) and upper extremities (20 % of cases). ACM predominantly exhibited a nodular growth pattern (75.7 % of cases), while MCM was mostly superficial spreading (53 % of cases). ACM was diagnosed at stage IIC in 36.4 % of cases, whereas MCM was diagnosed at an early stage (IA) in 50 % of cases. ACM demonstrated extremely aggressive morphological parameters: median Breslow thickness was 4.05 mm (versus 1 mm in MCM), and the rate of epidermal ulceration was 60 % (versus 21.6 % in MCM). The median mitotic rate per 1 mm² in ACM was 8 times higher than in MCM. Compared to MCM, the molecular genetic profile of ACM was characterized by a higher frequency of mutations in both the BRAF gene (57.5 % vs 47 %) and the NRAS gene (18.1 % vs 5 %). Conclusion. Amelanotic cutaneous melanoma significantly differs from the melanotic form by the predominance of the vertical growth phase (nodular subtype), manifestation at advanced localized stages (stage IIC), and a combination of highly unfavorable morphological parameters (high mitotic activity, pronounced Breslow thickness, ulceration) along with a high frequency of BRAF and NRAS gene mutations. This complex of features determines the aggressive biological potential of ACM and accounts for a high risk of tumor progression.