Merkel cell carcinoma induces lymphatic microvessel formation

J Am Acad Dermatol. 2012 Aug;67(2):215-25. doi: 10.1016/j.jaad.2011.09.002. Epub 2011 Nov 3.


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 μm) and a more than 8-fold increase in the median ratio of the number of small to large lymphatics (<10/≥10 μm) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Carcinoma, Merkel Cell / metabolism
  • Carcinoma, Merkel Cell / pathology*
  • Female
  • Humans
  • Ki-67 Antigen / metabolism
  • Lymphangiogenesis*
  • Lymphatic Vessels / metabolism
  • Lymphatic Vessels / pathology*
  • Macrophages / pathology
  • Male
  • Middle Aged
  • Receptors, Cell Surface / metabolism
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology*
  • Vascular Endothelial Growth Factor C / metabolism
  • Vascular Endothelial Growth Factor D / metabolism
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism
  • Vesicular Transport Proteins / metabolism


  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD163 antigen
  • CD68 antigen, human
  • Ki-67 Antigen
  • LYVE1 protein, human
  • Receptors, Cell Surface
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor D
  • Vesicular Transport Proteins
  • Vascular Endothelial Growth Factor Receptor-3