Differences in Biological Behavior of Colorectal Cancer between Patients With and Without Diabetes

Abstract

Purpose: To study the histopathological differences in colorectal cancer (CRC) between diabetic and non-diabetic populations. Methods: Retrospective analysis was done on 650 patients with CRC. Patients were divided into diabetic and non-diabetic sub-groups based on American Diabetes Association criteria (HbA1C >6.5%, two random glucose levels of >200 mg/dL, and/or two fasting glucose levels of >125 mg/dL). Data were collected for lymphovascular invasion, tumor location, depth invasion, TNM staging, level of differentiation, histological type, and presence of tumor components (mucinous, signet ring, or neuroendocrine). Results: Univariately, diabetic patients had higher TNM staging, greater lymphovascular invasion, and deeper tumor invasion (odds ratio [OR] 2.45; 95% confidence interval [CI] 1.70, 3.52; OR 2.52; 95% CI 1.74, 3.63; OR 2.06; 95% CI 1.37, 3.10, respectively; p<0.001 for all). Covariate adjustment retained the significant effect of diabetes on TNM staging, lymphovascular invasion, and depth invasion (log odds: 0.97±0.20, 3.04±1.02, 0.71±0.22; p<0.005 for all). Multivariable adjustment significantly linked diabetes with signet ring cell carcinoma (log odds: 11.40±5.28; p=0.03) and with the presence of mucinous, signet ring, or neuroendocrine tumor components (log odds: 0.58±0.25; p=0.02). Transverse tumors were seen more frequently in diabetic patients (log odds: 1.74±0.72; p=0.02). Diabetic patients with hyperlipidemia had more well differentiated tumors (log odds: -0.96±0.47; p=0.04). Conclusion: Current literature indicates an increased risk and worse disease-free, cancer-specific, and overall survival in CRC patients with diabetes. Our study suggests a presence of worse biological behavior of CRC in patients with diabetes. Several mechanisms are postulated for increased carcinogenic risk in diabetic patients including hyperglycemia, hyperinsulinemia, increased IGF-1 levels and receptor activation, and increased cytokines production (interleukin-6, plasminogen activator inhibitor-1, and tumor necrosis factor-α). Various underlying physiological and molecular pathways involved in the increased risk of cancer in diabetic patients may also have a role in changing the biological behavior, histopathological features, and phenotypic properties of colorectal tumors. Further research of these pathways could help to develop targeted therapy for prevention and treatment of CRC in patients with diabetes. The role of strict diabetic control and anti-hyperglycemic medications to improve outcomes in CRC might be another area for further studies. Lastly, more aggressive screening and treatment for CRC in patients with diabetes should be considered to diagnose them at an earlier stage and improve outcomes.