Published online before print May 31, 2007

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(American Journal of Pathology. 2007;171:338-348.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060589

Radiogenic Lymphangiogenesis in the Skin

Susanne Jackowski^*, Matthias Janusch^*, Eckhard Fiedler^*, Wolfgang C. Marsch^*, Eva J. Ulbrich, Gabriele Gaisbauer^*, Jürgen Dunst, Dontscho Kerjaschki^¶ and Peter Helmbold^{* ||}

From the Departments of Dermatology,^* Gynaecology, and Radiotherapy, Martin Luther University Halle-Wittenberg, Halle, Germany; the Department of Radiotherapy, University of Lübeck, Lübeck, Germany; the Institute of Pathology,^¶ Medical University of Vienna, Vienna, Austria; and the Department of Dermatology,|| University of Heidelberg, Heidelberg, Germany

The time course of microvascular changes in the environment of irradiated tumors was studied in a standardized human protocol. Eighty skin biopsies from 40 patients with previously treated primary breast cancer were taken from irradiated skin and corresponding contralateral unirradiated control areas 2 to 8 weeks, 11 to 14 months, or 17+ months after radiotherapy (skin equivalent dose 30 to 40 Gy). Twenty-two biopsies of 11 melanoma patients who had undergone lymph node dissection were used for unirradiated control. We found an increase of total podoplanin⁺ lymphatic microvessel density resulting mainly from a duplication of the density of smallest lymphatic vessels (diameter <10 µm) in the samples taken 1 year after radiation. Our findings implicate radiogenic lymphangiogenesis during the 1st year after therapy. The numbers of CD68⁺ and vascular endothelial growth factor-C⁺ cells were highly elevated in irradiated skin in the samples taken 2 to 8 weeks after radiotherapy. Thus, our results indicate that vascular endothelial growth factor-C expression by invading macrophages could be a pathogenetic route of induction of radiogenic lymphangiogenesis.