New molecular staging with G-factors (VEGF-C and Reg IV) by supplementing TNM classification in colorectal cancers

Staging classification of colorectal cancers is performed by the UICC/TNM classification system, which is the global gold standard. However, we often experience in clinical practice that there are considerable differences in prognoses between patients who have the same classification particularly in stage II and III cancers. The aim of this study was to propose a new TNM-G classification to predict prognosis and recurrence by supplementing the conventional TNM classification. A total of 220 cases of colorectal cancer, including 77 at stage II and 143 at stage III, were registered from four independent facilities. Immunohistochemical staining for 7 molecules, such as p53, vascular endothelial growth factor (VEGF)-A, VEGF-C, regenerating islet-derived family, member 4 (Reg IV), olfactomedin 4, Claudin-18 and matrix metalloproteinase-7 (MMP-7), was performed to investigate the correlation between clinicopathological factors and expression of each molecule. Based on the results, no significant correlation was observed between the immunostaining expression of these 7 factors and recurrence in total colorectal cancer. Recurrence in stage II (77 cases) was significantly higher in cases positive for Reg IV expression (P=0.042). On analysis of overall survival (OS) and disease-free survival (DFS), VEGF-C and Reg IV expression had a correlation with poor prognosis, therefore, these factors were selected and applied to G-factor classifications so that cases negative for both could be classified as G0, cases positive for either of the factors could be classified as G1, and cases positive for both factors could be classified as G2. While no significant correlation was observed in the recurrence rates between G0 and G2, OS and DFS in stage II cases were significantly poorer for G2 cases in comparison with G0 or G1 cases. The survival curves of OS and DFS in stage II G2 were similar to that of stage III cases. According to these results, prognosis of VEGF-C/Reg IV both positive G2 cases in stage II colorectal cancer was found to be almost equal to the poor survival in stage III cases, and the advancement of one stage up migration based on G-factors may be supposed to be highly feasible for clinical application. In conclusion, the combination of VEGF-C and Reg IV may be a promising factor for clinical staging to supplement the classical TNM classification system, and it may suggest a good indication of adjuvant chemotherapy for G2 cases in stage II colorectal cancers.