Abstract
Purpose::
To evaluate the spatial distribution of mature versus angiogenic vasculature in human uveal melanoma, as they may impact antiangiogenic therapies for the treatment of uveal melanoma.
Methods::
This study was approved by the IRB of the University of Miami. Enucleated tumor-containing eyes (n=14) from patients with uveal melanoma were evaluated. Immunohistochemical analyses were performed to assess total (Lectin staining), angiogenic (endoglin staining), and mature vasculature (pericyte marker α-sma staining), and cellular proliferation (Ki67 staining). The spatial distribution of mature and angiogenic vasculature was analyzed for every tumor specimen by 3 independent raters, who showed excellent agreement (weighted kappa=0.83). Each tumor was examined for PAS patterns' distribution and tumor morphology (H&E staining).
Results::
Tumor vasculature is present throughout the tumor. Central areas of the tumors had higher mean gradings of endoglin (3.3±1.0) than α-sma (2.5±0.9, p=0.036). Endoglin gradings were greater for apical, left, and right areas, but not significantly so (p=0.17, 0.34, and 0.63, respectively); while basal gradings were greater for α-sma (3.4±1.6) than for endoglin (3.1±1.0), but not significantly so (p=0.47). We found extraocular tumor extension in one specimen characterized by mature vessels, while being negative for endoglin and Ki67. Ki67 co-localized to angiogenic areas and regions that delineated mature and angiogenic vascular areas. The prevalence of each PAS pattern was similar across locations, except for straight (1/14 apical vs. 5 to 7/14 at all other locations) and parallel (7/14 basal vs. 2/4 at all other locations). Averaged over all locations, α-sma gradings were borderline significantly correlated with tumor size (r=0.46, p=0.095), but endoglin gradings were not (r=0.11, p=0.72).
Conclusions::
Significant differences exist in the spatial distribution of mature versus angiogenic vasculature in human malignant uveal melanoma. Blood vessel maturation may limit anti-angiogenic treatments that mainly target immature vasculature. Thus, the heterogeneity in melanoma vasculature is clinically significant, since it provides a rationale to give vascular targeting therapy and demonstrates why pure anti-angiogenic therapies may be limited. The development of future tumor treatment modalities such as pericyte targeting agents will provide a more comprehensive therapeutic approach for the treatment of uveal melanoma.
Keywords: melanoma • vascular cells • oncology