Metachronous colorectal cancer have a similar microsatellite instability frequency but a lower infiltration of lymphomononuclear cells than primary lesions

Background: An increased risk of metachronous colorectal cancer is usually associated with microsatellite instability occurring in Lynch syndrome. However, not all patients with metachronous colorectal cancer have microsatellite instability. The density of tumor-infiltrating lymphocytes is an independent predictor of outcome in patients with colorectal cancer, and a fascinating hypothesis is that they can be involved in the onset of metachronous colorectal cancer. The aim of this study was to analyze the tumor microenvironment and tumor mutation frequency in sporadic and metachronous colorectal cancer.

Methods: The clinical and pathological records of a series of consecutive colorectal cancer patients who were operated on from 2015 to 2019 were retrieved for this retrospective study. We defined metachronous colorectal cancer as a second colorectal cancer that appeared at least 1 year after the primary one, and sporadic colorectal cancer as those that did not have a metachronous colorectal cancer. Histology for the infiltration of intratumoral lymphomononuclear cells, immunohistochemistry for MLH1, PMS2, MSH2, and MSH6, and mutational analysis of BRAF, KRAS, and NRAS were all performed. Sporadic colorectal cancer and metachronous colorectal cancer were compared. Nonparametric tests were used for small sample size comparison.

Results: In the study, 238 patients were operated on for colorectal cancer at the General Surgery Unit of the Azienda Ospedaliera di Padova from 2015 to 2019. We identified 26 patients with metachronous colorectal cancer, and only 3 of them had had adjuvant therapy after the primary colorectal cancer. No difference was observed in terms of cancer stage between metachronous and sporadic colorectal cancer. Mismatch repair gene deficiencies and microsatellite instability frequency was similar in metachronous colorectal cancer and in sporadic colorectal cancer (P = .77). Likewise, the mutation frequency of BRAF and KRAs was similar in the 2 groups (P = .75 and P = .21, respectively). To the contrary, the absence of infiltration of lymphomononuclear cells within the tumor (P = .004) in patients with metachronous colorectal cancer was more frequent and they tended to have a higher frequency of NRAS mutation (P = .06).

Conclusion: Our study showed that, rather unexpectedly, microsatellite instability frequency was similar in metachronous and sporadic colorectal cancer. Moreover, our data suggest that an altered immune microenvironment may be a crucial factor, permitting the occurrence of metachronous colorectal cancer. In fact, the absence of lymphomononuclear cells can be the substrate for a weak immune response to cancer neoantigens, opening the way to a second primary colorectal cancer.