BackgroundRecent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal.MethodsTo inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers.ResultsStage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5–2.5, 2.5–3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III–IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14).ConclusionsThe CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.

中文翻译：

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Lynch 综合征的筛查间隔与癌症分期之间缺乏关联可能是由于过度诊断所致；前瞻性林奇综合征数据库报告

背景最近的流行病学证据表明，尽管专家中心经常进行结肠镜检查，但在致病性错配修复 (path_MMR) 变异的携带者中仍继续发生结直肠癌 (CRC)。这一观察结果与去除所有可见息肉应预防 path_MMR 携带者中的绝大多数 CRC 的范式相冲突，前提是筛查间隔足够短且结肠镜检查是最佳的。方法为了了解辩论，我们在前瞻性 Lynch 综合征数据库中进行了检查(PLSD)，自上次结肠镜检查以来的时间是否与前瞻性监测期间诊断出 CRC 的病理阶段有关。通过结肠镜检查招募 Path_MMR 携带者进行前瞻性监测。仅包括由 InSiGHT 变体解释委员会评分为 4 级和 5 级（临床可操作）的变体。在第一次计划的结肠镜检查时或在此之后一年内检测到的 CRC 被排除为流行癌症。结果 209 名患者的诊断阶段和最后一次前瞻性监测结肠镜检查与诊断之间的间隔是可用的，其中 218 例 CRC，包括 162 路径_MLH1、45 路径_MSH2、10 path_MSH6 和 1 个 path_PMS2 载波。自上次结肠镜检查后 < 1.5、1.5-2.5、2.5-3.5 和 > 3.5 年内检测到的癌症数量分别为 36、93、56 和 33。其中，16.7%、19.4%、9.9% 和 15.1% 分别为 III-IV 期（p = 0.34）。在最后一次结肠镜检查后超过 2.5 年检测到的癌症并不比早期诊断的癌症更晚期（p = 0.14）。结论 CRC分期和自上次结肠镜检查后的间隔不相关，这与加速腺瘤-癌范式相冲突。我们之前曾报道，更频繁的结肠镜检查与预期的 path_MMR 携带者的 CRC 发病率降低无关。相比之下，点估计显示更高的发病率和更短的检查间隔，这种情况可能与乳腺癌筛查中的过度诊断相似。我们的研究结果提出了 path_MMR 携带者中的一些 CRC 可能会自发消失的可能性：宿主免疫反应不仅可以去除 path_MMR 携带者中的 CRC 前体病变，还可以去除浸润性癌症。如果得到证实，我们建议的解释将对 path_MMR 携带者的监视政策产生影响。