Clinically undetectable micrometastases may account for disease recurrence in breast cancer patients after variable disease-free intervals. However, little is known about the cellular mechanisms controlling human breast cancer micrometastases. We compared tumor proliferation rate, apoptotic index, and angiogenesis in human breast cancer micrometastases with those of macroscopic axillary lymph node metastases. Seven breast cancer micrometastases (<2 mm) obtained from the sentinel nodes of seven

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... atients were compared with 13 macrometastases (lymph node replaced with tumor) obtained from 13 patients. The tissue was fixed in formalin, embedded in paraffin, serially sectioned, and evaluated by H&E and immunohistochemistry for cytokeratin. Tumor proliferation rate was assessed as the number of Ki-67-positive nuclei/total number of tumor nuclei. Tumor vascularity was quantified using antibody to factor VIII to identify microvessels per high-power field (at x400). Apoptosis was quantified using the terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling method. Results were analyzed with the Wilcoxon rank-sum test. Median size of micrometastases was 0.5 mm (range, 0.4-1.0), and the median number of tumor nuclei/section was 143 (range, 90-312). Median proliferation rate for macrometastases was greater than for micrometastases (35% versus 12%; P = 0.003). Median microvessel density/high-power field for macrometastases was greater than for micrometastases (17 versus 1; P < 0.001). There was no difference in apoptotic index between macrometastases and micrometastases (1.1% versus 0.7%; P = not significant). Human breast cancer micrometastases have lower tumor proliferation rates and angiogenesis than breast cancer macrometastases. These characteristics may explain their differential growth patterns.