# Integrating lymphovascular and perineural invasion into TNM staging: a novel ITNM system for enhanced prognostic stratification in colorectal cancer

## TL;DR

This study introduces a new ITNM staging system for colorectal cancer that improves survival predictions by including lymphovascular and perineural invasion.

## Contribution

The novel ITNM system integrates lymphovascular and perineural invasion into the N stage for more accurate prognostic stratification.

## Key findings

- LVI and PNI are independent predictors of worse overall survival in CRC patients.
- The ITNM system shows better discriminative ability and calibration than the standard TNM system.
- The new system significantly improves reclassification and net benefit for survival prediction.

## Abstract

The standard TNM staging system for colorectal cancer (CRC) fails to reflect true tumor biology because it ignores key histopathologic features such as lymphovascular and perineural invasion. We therefore developed and validated an “ITNM” classification that folds these two factors into the N stage, yielding more accurate prognoses and greater clinical value.

A retrospective cohort of 442 stage I–III CRC patients underwent radical resection (2015–2021). Propensity score matching (PSM) created balanced exposure (LVI/PNI-positive, n = 185) and control (LVI/PNI-negative, n = 257) groups. The ITNM system was constructed by upstaging the N category based on LVI/PNI status. Predictive performance was evaluated using C-index, ROC-AUC, calibration curves, decision curve analysis (DCA), net reclassification improvement (NRI), and integrated discrimination improvement (IDI).

Multivariate analysis confirmed LVI (HR = 2.10, p = 0.018) and PNI (HR = 2.28, p = 0.025) as independent predictors of overall survival (OS). The LVI/PNI-positive group had significantly lower 5-year OS (69.5% vs. 88.2%, p < 0.001). The ITNM system demonstrated superior discriminative ability for 5-year OS (C-index = 0.715; AUC = 0.735, 95% CI: 0.691–0.776), excellent calibration (p = 0.489), and higher net benefit on DCA. Significant reclassification improvement was confirmed (NRI = 0.306, p < 0.001; IDI = 0.061, p < 0.001).

The ITNM system significantly enhances prognostic accuracy by integrating LVI and PNI into TNM staging, enabling risk-adapted therapeutic decision-making and representing a paradigm shift in CRC stratification.