Optimal Criteria for G3 (Poorly Differentiated) Stage II Colon Cancer: Prospective Validation in a Randomized Controlled Study (SACURA Trial)

Grade 3 (G3, poorly differentiated) is an important treatment-decision factor in stage II colon cancer, but no unified diagnostic criteria are established. According to previous studies, an intratumoural poorly differentiated area with no glandular formation (POR) that fills the microscopic field of a ×40 objective lens was an essential factor that defined G3. We aimed to prospectively validate this in a randomized controlled study of adjuvant chemotherapy (SACURA trial). We enrolled 991 patients with stage II colon cancer. POR was graded according to the ×40 objective lens rule and the intensity of poorly differentiated clusters (Grade(POR)), and its prognostic power was compared with that of the conventional tumor grade on the basis of predominant histology rule (Grade(conv)). According to Grade(POR), 313, 526, and 152 tumors were classified as G1(POR), G2(POR), and G3(POR), respectively, and the 5-year relapse-free survival (RFS) rates were 91.1%, 82.9%, and 74.7%, respectively (P<0.0001). When G3(POR) and G3(conv) were alternatively added to the prognostic model consisting of 8 conventional factors, only G3(POR) was a significant factor for RFS (P=0.040, Wald test). The adverse impact of G3(POR) on RFS was greater in the microsatellite stable/microsatellite instability–low subset than that in the full analysis set. In the microsatellite stable/microsatellite instability–low subset, the 5-year RFS rate of patients with G3(POR) tumors in the chemotherapy group achieved greater improvement (9.1%) than the surgery-alone group. The least differentiation policy with the ×40 objective lens rule may be highlighted as the diagnostic criterion for G3 because of its validated prognostic value.