A prognostic nomogram based on desmoplastic reaction/tumor deposit modified lymph node staging in colorectal cancer.

Background: Tumor metastasis within the tumor microenvironment (TME) is a primary driver of tumor progression, with tumor deposit (TD) being one pathway of metastasis. However, the mechanisms underlying TD as a prognostic indicator in colorectal cancer (CRC) remain unclear. The 8^th edition of the Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) stage system does not account for the impact of TD quantity on prognosis in TD-positive patients. This study aims to integrate TD numbers into the existing N-stage system, develop a novel nomogram prediction model (newN), and validate its prognostic significance. Desmoplastic reaction (DR), including immature, intermediate, and mature types, is a critical indicator of TME status and a prognostic factor. While immature DR has been associated with TD presence, the relationship between TD quantity and DR type changes (mature-intermediate-immature) remains unexplored, this study seeks to elucidate this relationship.

Methods: This study enrolled 171 patients with TNM stage II or III pT3 or pT4 colorectal adenocarcinoma who underwent complete tumor resection. DR was evaluated, and TD numbers were recorded. Clinicopathological factors related to TD formation, multiple TD, and DR changes were analyzed to explore their relationships. Kaplan-Meier curves and log-rank tests were used to assess recurrence-free survival (RFS). Univariate and multivariate Cox proportional hazards analyses were performed to identify independent risk factors for overall survival (OS), and a nomogram prediction model was developed. The association between TD, DR, and the TME was investigated, along with the mechanisms underlying TD formation and DR changes.

Results: DR classification and the number of TD-positive cases were assessed using the Gamma test, yielding a statistically significant result (statistic =11.419, P<0.001) and a strong positive correlation (correlation coefficient =0.836) between TD-positive numbers and DR classification. Abnormal carcinoembryonic antigen (CEA) levels, T stage, lymph node (LN) metastasis count, vascular invasion, TD numbers, poor histologic grade, immature DR, newN stage, contrastN stage, and existing N stage were associated with reduced RFS. DR, TD, and newN stage were identified as independent risk factors for CRC prognosis. The C-index values for the newN stage model (0.759), contrastN stage model (0.748), and existing N stage model (0.742) confirmed the superior prognostic accuracy of the newN stage model.

Conclusions: This study confirmed a significant correlation between immature DR and TD, as well as an association between DR types and TD quantities. We hypothesize that tumor-cancer-associated fibroblasts (CAFs)-Twist/DR-epithelial-mesenchymal transition (EMT)-tumor budding (TB)-TD interactions within the TME are involved in the mechanism related to TD formation. The revised newN stage system, incorporating TD numbers and the current N stage, provides more accurate OS predictions, highlighting the importance of TD quantity as a critical prognostic factor.