Prognostic Significance and Molecular Associations of Tumor Growth Pattern in Colorectal Cancer

Infiltrative growth pattern at the tumor margin has been associated with shorter patient survival. However, little is known about the prognostic significance of tumor growth pattern, independent of tumoral molecular alterations and other histologic features. Utilizing a database of 1139 colon and rectal cancer patients in two prospective cohort studies, histologic features including tumor growth pattern, tumor differentiation, lymphocytic reaction, mucinous component, and signet ring cell component were recorded by a single pathologist. Cox proportional hazard model was used to compute mortality hazard ratio, adjusting for clinical, pathologic, and tumor molecular features, including microsatellite instability, the CpG island methylator phenotype, long interspersed nucleotide element 1 (LINE-1) methylation, and and mutations. Among 1139 colorectal cancers, we observed expansile growth pattern in 372 tumors (33%), intermediate growth pattern in 610 tumors (54%), and infiltrative growth pattern in 157 tumors (14%). Compared to patients with expansile growth pattern, those with infiltrative growth pattern experienced shorter cancer-specific survival (log rank < 0.0001; multivariate hazard ratio 1.74; 95% confidence interval 1.22-2.47) and overall survival (log rank < 0.0001; multivariate hazard ratio 1.78; 95% confidence interval 1.33-2.39). The prognostic association of infiltrative growth pattern was confined to patients with stage I-III disease ( (interaction) with stage = 0.0001). Infiltrative growth pattern was associated with worse prognosis among stage I-III colorectal cancer patients, independent of other clinical, pathologic, and molecular characteristics.