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Ludwig M. Heindl, Carmen Hofmann-Rummelt, Leonard M. Holbach, Gottfried O. Naumann, Friedrich E. Kruse, Claus Cursiefen; Tumor-Associated Lymphangiogenesis in the Development of Conjunctival Malignant Melanoma. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4755.
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Conjunctival malignant melanoma (CMM) with a propensity for lymphatic spread into the regional lymph nodes may develop most commonly from the premalignant precursor conjunctival melanocytic intraepithelial neoplasia (C-MIN). Tumor-associated lymphangiogenesis is considered as the initial step in lymphogenic metastasis of several tumors. The purpose of the present study was to evaluate whether tumor-associated lymphangiogenesis accompanies the development from premalignant C-MIN into invasive CMM and to study its association with prognosis and other tumor characteristics.
Twenty patients with invasive CMM were closely matched with twenty C-MIN with atypia and twenty C-MIN without atypia patients regarding tumor size, tumor location, tumor extension, and patients’ age. All conjunctival specimens were analyzed for the immunohistochemical presence of proliferating lymphatic vessels using LYVE-1 and podoplanin as specific lymphatic endothelial markers and Ki-67 as proliferation marker. Lymphatic vascular density was measured within the tumor mass (intratumoral) and within an area ≤ 500 µm from the tumor border (peritumoral), and correlated with metastasis and survival rates.
C-MIN without atypia revealed neither intra- nor peritumoral proliferating lymphatic vessels. Intratumoral proliferating lymphatic vessels increased in density from discrete hotspots in C-MIN with atypia toward a branching network in invasive CMM. Peritumoral proliferating lymphatics condensed from C-MIN with atypia toward invasive CMM. Invasive CMM revealed a significantly higher intra- and peritumoral density of proliferating lymphatics than C-MIN with atypia (p<0.001). Higher intratumoral lymphatic densities were significantly associated with larger tumor size (p=0.004), lower tumor-to-fornix distance (p<0.001) and higher TNM categories (p=0.016). Metastasis-free survival rates decreased significantly with higher intratumoral lymphatic densities (p<0.001).
Development of conjunctival malignant melanoma is accompanied by the outgrowth of new conjunctival lymphatic vessels. This active tumor-associated lymphangiogenesis seems to be associated with an increased risk of metastasis and mortality in these patients, suggesting a potential for topical anti-(lymph)angiogenic therapy using e.g. bevacizumab eye drops.
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