Ahadova Aysel, von Knebel Doeberitz Magnus, Bläker Hendrik, Kloor Matthias
Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Fam Cancer. 2016 Oct;15(4):579-86. doi: 10.1007/s10689-016-9899-z.
The implementation of regular colonoscopy programs has significantly decreased the mortality associated with colorectal cancer (CRC) in Lynch syndrome patients. However, interval CRCs in Lynch syndrome that remain undetected by colonoscopy still represent a substantial problem in the management of the syndrome. One possible reason of interval cancers could be a non-polypous pathway of cancer development. To examine the possibility of a non-polypous pathway of CRC development in Lynch syndrome, we analyzed the histological appearance of 46 Lynch syndrome-associated CRCs and compared them to 34 sporadic microsatellite unstable cancers. We observed that 25 (62.5 %) out of 40 assessable Lynch syndrome-associated carcinomas lacked evidence of polypous growth, compared to 17 (50 %) out of 34 sporadic MSI-H cancers. We detected CTNNB1 mutations in 8 (17.4 %) out of 46 Lynch syndrome-associated cancers compared to 0 out of 34 sporadic MSI-H cancers (p = 0.01). The majority of CTNNB1-mutant cancers presented with a histological appearance suggesting immediate invasive growth. Our results suggest that a distinct subgroup of CRCs in Lynch syndrome may in fact emerge from a non-polypous precursor, thus potentially explaining the phenomenon of interval cancers. Such a non-polypous precursor may be the recently described mismatch repair-deficient crypt focus, which remains invisible for the examiner during colonoscopy. This calls for considering the implementation of active, primary preventive measures in the management of Lynch syndrome. Future studies on pathogenic pathways and precursor lesions in Lynch syndrome are strongly encouraged, and the clinical efficacy of new prevention approaches should be evaluated in prospective clinical trials.
常规结肠镜检查项目的实施显著降低了林奇综合征患者结直肠癌（CRC）相关的死亡率。然而，结肠镜检查未检测到的林奇综合征间期CRC在该综合征的管理中仍然是一个重大问题。间期癌的一个可能原因可能是癌症发展的非息肉途径。为了研究林奇综合征中CRC发展的非息肉途径的可能性，我们分析了46例林奇综合征相关CRC的组织学表现，并将其与34例散发性微卫星不稳定癌症进行比较。我们观察到，40例可评估的林奇综合征相关癌中有25例（62.5%）缺乏息肉样生长的证据，而34例散发性微卫星高度不稳定（MSI-H）癌症中有17例（50%）缺乏该证据。在46例林奇综合征相关癌症中，我们检测到8例（17.4%）存在CTNNB1突变，而34例散发性MSI-H癌症中未检测到（p = 0.01）。大多数CTNNB1突变癌的组织学表现提示直接浸润性生长。我们的结果表明，林奇综合征中一个独特的CRC亚组可能实际上起源于非息肉前体，从而潜在地解释了间期癌的现象。这样的非息肉前体可能是最近描述的错配修复缺陷隐窝灶，在结肠镜检查期间检查者无法看到。这就要求在林奇综合征的管理中考虑实施积极的一级预防措施。强烈鼓励对林奇综合征的致病途径和前体病变进行进一步研究，并且应在前瞻性临床试验中评估新预防方法的临床疗效。
