Merkel cell carcinoma induces lymphatic microvessel formation

Background: Merkel cell carcinoma (MCC) is a rare, highly malignant neuroendocrine tumor of the skin characterized by frequent lymphatic metastasis. Objective: We sought to identify lymphovascular anatomy and expression profiles of lymphangiogenic cytokines to give an opinion on lymphangiogenesis in MCC. Methods: We studied lymphatic microanatomy and lymphangiogenic cytokines in 27 MCC by immunohistology or immunofluorescence (D2-40, lymphatic vessel endothelial hyaluronan receptor [LYVE-1], vascular endothelial growth factor [VEGF] receptor-3, VEGF-C, VEGF-D, Ki67/MiB-1, CD68/PG-M1, CD68/KP1, CD163), Merkel cell polyomavirus-specific polymerase chain reaction, and coanalysis with clinical and histologic data. Results: We found a more than 3-fold increase in the mean density of absolute numbers of small lymphatic capillaries (diameter <10 mu m) and a more than 8-fold increase in the median ratio of the number of small to large lymphatics (<10/>= 10 mu m) paratumorally compared with intraindividual controls. VEGF-C(+)CD68(+)CD163(+) cells (interpreted as M2 macrophages) could be identified as an important potentially lymphangiogenesis-inducing cell type. Limitations: Partially lacking follow-up data limited the analysis of the prognostic impact. Conclusions: Our findings strongly indicate lymphangiogenesis in MCC driven by VEGF-C(+)CD68(+)CD163(+) M2 macrophages. (J Am Acad Dermatol 2012;67:215-25.)