Lymphatic Microvascular Density, Lymphatic Invasion and Endothelial Cell Proliferation as Prognostic Biomarkers in Cutaneous Melanoma: A Systematic Review and Evidence Map
7 affiliations
- 1Doctoral School, Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timișoara, Romania
- 2Department of Microscopic Morphology, Histology, Angiogenesis Research Center, “Victor Babeș” University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timișoara, Romania
- 3ANAPATMOL Research Center, “Victor Babeș” University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timișoara, Romania
- 4Department of Microscopic Morphology, Discipline of Cellular and Molecular Biology, “Victor Babeș” University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timișoara, Romania
- 5Department of Informatics and Medical Biostatistics, “Victor Babeș” University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timișoara, Romania
- 6Faculty of Bioengineering of Animal Resources, University of Life Sciences “King Mihai I” from Timișoara, 119 Calea Aradului, 300645 Timișoara, Romania
- 7Department of Biochemistry and Pharmacology, Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timișoara, Romania
Abstract
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.
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BibTeX
@article{dumitrascu2026lymphatic,
title = {{Lymphatic Microvascular Density, Lymphatic Invasion and Endothelial Cell Proliferation as Prognostic Biomarkers in Cutaneous Melanoma: A Systematic Review and Evidence Map}},
author = {Victor Cristian Dumitrascu and Amalia Raluca Ceaușu and Mihai Mitulețu and Călin Muntean and Roxana Popescu and Gabi Dumitrescu and Pusa Nela Gaje and Marius Raica and Cristian Sebastian Vlad},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18203412},
url = {https://www.mdpi.com/2072-6694/18/20/3412},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Lymphatic Microvascular Density, Lymphatic Invasion and Endothelial Cell Proliferation as Prognostic Biomarkers in Cutaneous Melanoma: A Systematic Review and Evidence Map
AU - Victor Cristian Dumitrascu
AU - Amalia Raluca Ceaușu
AU - Mihai Mitulețu
AU - Călin Muntean
AU - Roxana Popescu
AU - Gabi Dumitrescu
AU - Pusa Nela Gaje
AU - Marius Raica
AU - Cristian Sebastian Vlad
PY - 2026
DA - 2026/10/01
JO - Cancers
DO - 10.3390/cancers18203412
UR - https://www.mdpi.com/2072-6694/18/20/3412
AB - 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.
SN - 2072-6694
ER -