Tumor Vascularity, Proliferation, and Apoptosis in Human Melanoma Micrometastases and Macrometastases

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Abstract
Background Clinically undetectable or dormant metastases (mircrometastases) probably account for disease recurrence, ie, clinically evident metastases, in patients after disease-free intervals of variable length. Recently developed animal models have shown that dormancy may potentially be explained by the fact that these micrometastases are not vascularized and have comparable rates of cellular proliferation and programmed cell death (apoptosis), enabling them to remain viable indefinitely but not to show progressive growth. Observations We report for the first time that melanoma micrometastases from humans are similarly not vascularized (mean number of microvessels, 10.2), have significantly lower rates of tumor cell proliferation (mean, 2.4%), and comparable rates of proliferation and apoptosis (means, 2.4% and 0.2%, respectively), compared with melanoma macrometastases, which have significantly greater tumor vascularity (mean number of microvessels, 18.7), higher rates of proliferation (mean, 18%), and higher rates of proliferation relative to apoptosis (means, 18% vs 1.6%). Tumor vascularity was quantified using the lectinUlex europaeusagglutinin I to identify the number of microvessels per unit area (microscope ocular grid with an area of 7.84 ×10−2mm2at ×400 magnification). Melanoma cell proliferation rate was assessed with the MIB-1 antibody (Ki-67) as the number of positive nuclei per total number of tumor nuclei counted at ×400 magnification. Apoptosis was quantified using the method of terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate–biotin nick end labeling. The number of positive nuclei were quantified per total number of tumor nuclei; usually 200 tumor nuclei were counted at ×400 magnification. Conclusion We report, for the first time, that human micrometastases demonstrate attributes, ie, the lack of significant tumor vascularity and low but comparable rates of proliferation and apoptosis, that may explain the dormant state.