Establishing Criteria for Tumor Necrosis as Prognostic Indicator in Colorectal Cancer

Abstract

Tumor necrosis has been reported to represent an independent prognostic factor in colorectal cancer, but its evaluation methods have not been described in sufficient detail to introduce tumor necrosis evaluation into clinical use. To study the potential of tumor necrosis as a prognostic indicator in colorectal cancer, criteria for 3 methods for its evaluation were defined: the average percentage method (tumor necrosis percentage of the whole tumor), the hotspot method (tumor necrosis percentage in a single hotspot), and the linear method (the diameter of the single largest necrotic focus). Cox regression models were used to calculate cancer-specific mortality hazard ratios (HRs) for tumor necrosis categories in 2 colorectal cancer cohorts with more than 1800 cases. For reproducibility assessment, 30 cases were evaluated by 9 investigators, and Spearman's rank correlation coefficients and Cohen's kappa coefficients were calculated. We found that all 3 methods predicted colorectal cancer-specific survival independent of other prognostic parameters, including disease stage, lymphovascular invasion, and tumor budding. The greatest multivariable HRs were observed for the average percentage method (cohort 1: HR for ≥ 40% vs. <3% 3.03, 95% CI, 1.93-4.78; cohort 2: HR for ≥ 40% vs. < 3% 2.97; 95% CI, 1.63-5.40). All 3 methods had high reproducibility, with the linear method showing the highest mean Spearman's correlation coefficient (0.91) and Cohen's kappa (0.70). In conclusion, detailed criteria for tumor necrosis evaluation were established. All 3 methods showed good reproducibility and predictive ability. The findings pave the way for the use of tumor necrosis as a prognostic factor in colorectal cancer.

FIGURE 1

Three evaluation methods for tumor necrosis in colorectal cancer. (A) Overview of a tumor sample. (B) Evaluation of tumor necrosis using the average percentage method. (C) Evaluation of tumor necrosis using the hotspot method. (D) Evaluation of tumor necrosis using the linear method. Scale bars correspond to 2.5 mm.

FIGURE 2

Tumor necrosis evaluation methods and survival. Kaplan-Meier cancer-specific survival curves for the 3 tumor necrosis evaluation methods in cohort 1 (A-C) and cohort 2 (D-F).

FIGURE 3

Reproducibility analysis for the 3 tumor necrosis estimation methods. The reproducibility was measured with Spearman rank correlation analysis (A) and Cohen’s kappa (B–C).GIP, gastrointestinal pathologist; R, researcher; SP, specializing pathologist.