ANGIOGENESIS AND MOLECULAR BIOLOGIC SUBSTAGING IN PATIENTS WITH STAGE-I NON-SMALL-CELL LUNG-CANCER

Background. Although complete surgical resection remains the primary t reatment for localized stage I non-small cell lung cancer, the cancer recurrence rate is 25% to 40%. If one could identify a subset of patie nts using molecular factors that contribute to tumor aggressiveness, o ne might improve prognosis in this group with additional treatment. Hi gh expression of angiogenesis factor viii has been associated with the presence of nodal metastases in breast cancer; here we examined its r elation to survival with non-small cell lung cancer. Methods. We exami ned angiogenesis using immunohistochemistry on paraffin blocks of tumo r from 275 consecutive patients with stage I non-small cell lung cance r, more than 68 months of follow-up, and a 64% 5-year survival. Angiog enesis was calculated from the microvessel number per ten 200 x micros cope fields measured at the tumor periphery, in the center, and in the area of highest concentration. Results. Measurements in the central a rea were inconsistent due to prominent necrosis. However, microvessel number recorded at the periphery and at the ''hottest'' area correlate d well (r(2) = 0.952; p = 0.001), and a significant survival advantage was noted for low-level expression at both areas (peripheral, p = 0.0 46; ''hottest'', p = 0.006). Multivariate survival analysis using angi ogenesis, protooncogene erbB-2, tumor suppressor gene p53, and the pro liferation marker KI-67 defined angiogenesis as the most significant p rognostic factor in stage I lung cancer. Conclusions. This molecular b iologic substaging system including angiogenesis for stage I non-small cell lung cancer is independent of routine histopathologic factors an d revealed an additive adverse effect with expression of several biolo gic markers (5-year survival: no marker [n = 51] 81%, 1 marker [n = 82 ] 71%, 2 markers [n = 84] 54%, and 3 to 4 markers [n = 58] 49%; p = 0. 0001).