Methodological considerations in interpreting lymph node yield as a surrogate for immune response in colon cancer

We read with great interest the study by Bækgaard et al., which revealed an association between lymph node yield (LNY) and mismatch repair (MMR) status, offering a new perspective on understanding the prognosis of colon cancer [1]. However, we believe there are several aspects worth further discussion. First, the conclusions may be influenced by unmeasured surgical heterogeneity and residual confounding from tumour characteristics. For example, D3 dissection can significantly increase LNY, yet the study did not differentiate between D2 and D3 dissection. dMMR status is associated with right-sided colon tumours and larger tumour volumes, which are themselves independently linked to higher LNY. Therefore, the observed differences in LNY may be partially attributable to these confounding factors rather than being entirely driven by the host immune response [2]. Second, the study's core hypothesis—that LNY can serve as a proxy for antitumour immunity—lacks direct biological evidence. An increased number of lymph nodes does not directly equate to an effective functional immune state. Tumour prognosis depends more on the composition of the immune microenvironment within lymph nodes, particularly the density and activation status of cytotoxic T lymphocytes. Without evaluating the functional state of lymph nodes, the causal relationship between LNY and survival remains speculative [3]. Finally, the use of overall survival as the study endpoint may compromise the precision of the conclusions due to competing risks. Given the higher median age in the dMMR cohort, non-cancer deaths represent a significant competing event. This could lead to an overestimation of the hazard ratio for all-cause mortality in the low LNY group, thereby amplifying its specific oncological impact. Employing a competing risk model to analyse cancer-specific mortality would be essential for more accurate risk quantification [4]. We believe that these considerations can contribute to a more comprehensive interpretation of the study's findings. Youping Zhang: Conceptualisation, Writing—original draft. Liwei Li: Writing—review and editing. Jianxin Lu: Supervision, Writing—review and editing. The authors have nothing to report. This work was supported by the Ningbo Second Hospital. The authors declare no conflicts of interest. The authors have nothing to report. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.