Lymphatic Microvascular Density, Lymphatic Invasion and Endothelial Cell Proliferation as Prognostic Biomarkers in Cutaneous Melanoma: A Systematic Review and Evidence Map

Background/Objectives: Cutaneous melanoma spreads preferentially through the lymphatic system, and sentinel lymph node status is among the strongest prognostic factors. Whether tumour angiogenesis and lymphangiogenesis add prognostic information beyond conventional histopathology has been examined in many immunohistochemical studies, with heterogeneous results. We conducted a systematic review, reported according to PRISMA 2020 and not registered, of blood microvascular density (MVD), lymphatic vessel density (LVD) in the intratumoral and peritumoral compartments, proliferating (Ki-67-positive) lymphatic vessels and lymphatic invasion (LI) as prognostic markers in primary cutaneous melanoma. Methods: PubMed/MEDLINE was searched to 10 September 2026, supplemented by a Web of Science export and by citation tracking of the reference meta-analysis by Pastushenko et al. (2014). Twenty-one cutaneous study units (25 reports) and four ocular studies providing indirect evidence were included, and risk of bias was rated with the QUIPS tool. Results: In the reference meta-analysis, peritumoral LVD and LI, but not MVD or intratumoral LVD, were associated with metastasis. The newer cohorts confirmed this pattern and provided adjusted effect sizes: peritumoral LVD predicted disease-free (HR 2.14) and melanoma-specific survival (HR of 2.74; 95% CI 1.31 to 5.73), immunohistochemically detected LI predicted sentinel node metastasis (33% vs. 11% positive nodes) and overall survival, and a Ki-67-positive lymphatic endothelium predicted melanoma-specific mortality (adjusted HR of 2.03; 95% CI 1.33 to 3.10) in 264 patients. Blood MVD and blood endothelial proliferation were not prognostic. Heterogeneity of markers, counting methods and effect measures precluded re-pooling. Conclusions: Peritumoral LVD, LI and proliferating lymphatics are promising adjunct biomarkers for selecting patients for sentinel node biopsy, adjuvant therapy and closer follow-up, pending standardised, digital-pathology-based quantification.