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Raymond L. Barnhill, MD; Michael W. Piepkorn, MD, PhD; Alistair J. Cochran, MD; Evelyn Flynn; Themis Karaoli; Judah Folkman, MD

Arch Dermatol. 1998;134:991-994.

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 lectin Ulex europaeus agglutinin I to identify the number of microvessels per unit area (microscope ocular grid with an area of 7.84 x10^-2 mm² at x400 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 x400 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 x400 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.

From the Dermatopathology Division, Department of Pathology, Brigham and Women's Hospital (Dr Barnhill and Mr Karaoli), and Surgical Research, Children's Hospital (Ms Flynn and Dr Folkman), Harvard Medical School, Boston, Mass; the Departments of Medicine (Dermatology) and Pathology, University of Washington School of Medicine, Seattle (Dr Piepkorn); and the Department of Pathology, University of California at Los Angeles (Dr Cochran). Dr Barnhill is now with the Division of Dermatopathology and Oral Pathology, The Johns Hopkins Medical Institutions, Baltimore, Md.

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