Clinical significance of micrometastasis in bone marrow of patients with gastric cancer and its relation to angiogenesis

Background. Detection of micrometastasis is an important problem of clinical significance for a better understanding and control of tumor progression, which will improve patients' survival time. Methods. To identify micrometastases in bone marrow, an immunocytochemical assay for epithelial cytokeratin protein was performed in 106 patients with primary gastric cancer. Also, in 40 of the 106 patients, vascular endothelial growth factor (VEGF) expression and intratumoral vessel density were examined by an immunohistochemical staining method. Results. Of the 106 patients, 22 (20.8%) presented with cytokeratin-positive cells in bone marrow at the time of primary surgery. The positive findings were related to depth of invasion, peritoneal dissemination, and liver metastasis. Patients with cytokeratin-positivity in bone marrow had a higher VEGF positive rate (73%; 8/11) than did cytokeratin-negative patients (48%; 14/29). Intratumoral vessel density in VEGF-positive patients was 26.9 ± 10.3, which was significantly higher than that in VEGF-negative patients (13.2 ± 8.7, P < 0.05). Thus, the presence of cytokeratin-positive cells in bone marrow was closely related to angiogenesis in the primary tumor. Conclusions. Cytokeratin staining can be useful for identifying patients at high risk for metastasis. Prophylactic lymph node dissection, adjuvant chemotherapy, and antiangiogenic treatment may be necessary for patients with micrometastasis. Received for publication on Jan. 27, 1999; accepted on Feb. 26, 1999