General Surgery Unit, Azienda Ospedaliera di Padova, Padua, Italy.
Department of Medicine, Pathology Unit, University of Padova, Padua, Italy.
Surgery. 2022 Jun;171(6):1605-1611. doi: 10.1016/j.surg.2021.12.005. Epub 2022 Jan 6.
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.
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.
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).
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.
微卫星不稳定性通常与林奇综合征中发生的结直肠肿瘤的异时性相关，但并非所有异时性结直肠肿瘤患者都存在微卫星不稳定性。肿瘤浸润淋巴细胞密度是结直肠癌患者预后的独立预测因子，一个有趣的假设是，它们可能参与了结直肠肿瘤的异时性发生。本研究旨在分析散发性和异时性结直肠肿瘤的肿瘤微环境和肿瘤突变频率。
本研究为回顾性研究，检索了 2015 年至 2019 年连续接受结直肠肿瘤手术的一系列患者的临床和病理记录。我们将异时性结直肠肿瘤定义为首次结直肠肿瘤后至少 1 年出现的第二个结直肠肿瘤，将散发性结直肠肿瘤定义为无异时性结直肠肿瘤的患者。对肿瘤内淋巴单核细胞浸润进行组织学分析，对 MLH1、PMS2、MSH2 和 MSH6 进行免疫组织化学分析，并对 BRAF、KRAS 和 NRAS 进行突变分析。比较散发性结直肠肿瘤和异时性结直肠肿瘤。对于小样本量的比较，使用非参数检验。
在这项研究中，2015 年至 2019 年，阿齐亚诺医院普外科对 238 例结直肠肿瘤患者进行了手术。我们发现 26 例患者患有异时性结直肠肿瘤，其中仅 3 例在首次结直肠肿瘤后接受了辅助治疗。异时性和散发性结直肠肿瘤在癌症分期方面无差异。异时性结直肠肿瘤和散发性结直肠肿瘤的错配修复基因缺陷和微卫星不稳定性频率相似（P=0.77）。同样，两组 BRAF 和 KRAs 的突变频率相似（P=0.75 和 P=0.21）。相反，在异时性结直肠肿瘤患者中，肿瘤内淋巴单核细胞浸润缺失（P=0.004）更为常见，且其 NRAS 突变频率较高（P=0.06）。
我们的研究表明，出人意料的是，异时性和散发性结直肠肿瘤的微卫星不稳定性频率相似。此外，我们的数据表明，改变的免疫微环境可能是一个关键因素，允许异时性结直肠肿瘤的发生。事实上，淋巴单核细胞的缺失可能是对癌症新抗原的弱免疫反应的基础，为第二个原发性结直肠肿瘤的发生开辟了道路。
