Clinical value of extended biologic staging by bone marrow micrometastases and tumor-associated proteases in gastric cancer

Objective To investigate whether extended staging, including biologic grading and aspects of an early systemic disease component, would give additional prognostic information on patients with curatively resected gastric cancer. Background Tumor-associated proteolytic mechanisms have been shown to be essential for invasion and metastasis. The urokinase-type plasminogen activator (uPA) system is of major biologic impact, but different interactive proteases and inhibitors with modulating effects also must be considered. The detection of early tumor cell dissemination indicates the systemic character of a primarily local gastric cancer. The confrontation of the organism with these cells determines the often unpredictable course of an individual tumor after presumed curative primary treatment. Methods In a prospective study of 247 consecutive patients with gastric cancer, detection of disseminated tumor cells in bone marrow aspirates was immunocytochemically performed in 180 patients. The expression of uPA, activators of uPA (cathepsin D, antithrombin III), uPA substrates (plasminogen, matrix-metalloproteinase 2 [collagenase IV, 72 kD; MMP-2]), uPA/plasmin inhibitors (plasminogen activator inhibitor type 1 and 2 [PAI-1, PAI-2], alpha 1-antitrypsin, alpha 2-antiplasmin), uPA receptor (uPA-R), and parameters of the uPA-R cycle (alpha 2-macroglobulin, alpha 1-antichymotrypsin) could be determined immunohistochemically and were scored semiquantitatively in 203 patients. Kaplan-Meier statistical techniques and multivariate Cox regression models were used for prognostic analyses. Results In multivariate analysis considering all the established risk factors, disease-free survival was independently predicted by PAI-I (relative risk 2.21, 1.32-3.73) and cathepsin D (relative risk 2.98, 1.28-6.91) besides pT, pN, and extended resection. Tumor cell dissemination was found to be an additional prognostic factor in early tumor stages (pT1, T2) and lymphnode-negative patients. Stepwise regression analysis revealed an extended staging system with new risk groups. Node-positive, curatively resected pT1/2 patients with low expression of PAI-I had a favorable prognosis (mean recurrence-free survival [MRT] 54.84 months), similar to that of node-negative patients (MRT 54.76 months). in node-negative, curatively resected pT1/2 patients, detection of bone marrow tumor cells and high expression of PAI-1 defined a subgroup with a steep decrease of prognosis (MRT 36.60 months), which was worse than that of node-positive patients (MRT 45.81). Conclusion This new staging model gives better prognostic differentiation of subgroups, which should be considered in future adjuvant therapy protocols. In addition, it indicates that the uPA system might be a future therapeutic target.