Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH 44195, USA.
Mod Pathol. 2012 Oct;25(10):1423-31. doi: 10.1038/modpathol.2012.98. Epub 2012 Jun 8.
Although the serrated neoplasia pathway is thought to give rise to the majority of sporadic microsatellite instability-high (MSI-H) colon cancer, the exact proportion of these tumors that arise from serrated precursors has not been fully studied. Tubular and tubulovillous adenomas with features of the serrated neoplasia pathway have been described, and unlike sessile serrated adenomas, these lesions lack BRAF mutations. The contribution of these adenomas to sporadic MSI-H colon cancer is unclear. To this end, we conducted an analysis of right-sided sporadic MSI-H and microsatellite stable (MSS) colon cancer, with emphasis on precursor lesions. Overall 25% (19/75) of MSI-H colon cancer had a precursor, of which only 4 were recognized histologically as arising from a sessile serrated adenoma, and the remaining were best classified as adenomas. Of the 31 (of 89) MSS colon cancers with a precursor, only 1 was a sessile serrated adenoma (P=0.06). Histological analysis of the precursor adenomas to sporadic MSI-H colon cancer demonstrated a high frequency of crypt serrations compared with MSS colon cancer (93 vs 36%, P<0.001). BRAF mutations were found in 57/75 (76%) sporadic MSI-H and 10/89 (11%) MSS colon cancers (P<0.001). Molecular analysis demonstrated BRAF mutations in 11/12 adenoma and 3/3 sessile serrated adenoma precursors adjacent to BRAF-mutated MSI-H colon cancer. Similarly, all 4 precursors to BRAF-mutated MSS colon cancer were also BRAF mutated. The presence of BRAF mutations in these adenomatous precursors suggests that they represent sessile serrated adenomas with complete cytologic dysplasia. Finally, patients with sporadic MSI-H colon cancer were more likely to harbour synchronous sessile serrated adenomas (20 vs 8%; P=0.023). This is the largest study to rigorously evaluate the precursor and synchronous lesions in patients with right-sided colon cancer. Detailed molecular and histological analysis of these lesions confirms the importance of serrated precursors in the development of sporadic MSI-H colon cancer.
虽然锯齿状肿瘤通路被认为是大多数散发的微卫星不稳定性高（MSI-H）结肠癌的起源，但这些肿瘤中有多少是由锯齿状前体发展而来的尚未完全研究清楚。管状和绒毛状腺瘤具有锯齿状肿瘤通路的特征，与无蒂锯齿状腺瘤不同，这些病变缺乏 BRAF 突变。这些腺瘤对散发的 MSI-H 结肠癌的贡献尚不清楚。为此，我们对右侧散发的 MSI-H 和微卫星稳定（MSS）结肠癌进行了分析，重点是前体病变。总体而言，25%（19/75）的 MSI-H 结肠癌有前体，其中只有 4 例在组织学上被认为是起源于无蒂锯齿状腺瘤，其余的最好归类为腺瘤。在 31 例（89 例）MSS 结肠癌中有前体的患者中，只有 1 例是无蒂锯齿状腺瘤（P=0.06）。对散发的 MSI-H 结肠癌前体腺瘤的组织学分析显示，与 MSS 结肠癌相比，隐窝锯齿状结构的频率较高（93%比 36%，P<0.001）。BRAF 突变在 75 例散发的 MSI-H 结肠癌中的 57 例（76%）和 89 例 MSS 结肠癌中的 10 例（11%）中发现（P<0.001）。分子分析显示，在 11/12 例腺瘤和 3/3 例无蒂锯齿状腺瘤前体中发现 BRAF 突变，这些前体紧邻 BRAF 突变的 MSI-H 结肠癌。同样，BRAF 突变的 MSS 结肠癌的 4 例前体也都是 BRAF 突变。这些腺瘤前体中存在 BRAF 突变表明它们代表完全细胞学异型增生的无蒂锯齿状腺瘤。最后，散发的 MSI-H 结肠癌患者更有可能同时存在无蒂锯齿状腺瘤（20%比 8%；P=0.023）。这是一项最大规模的研究，对右侧结肠癌患者的前体和同步病变进行了严格评估。对这些病变进行详细的分子和组织学分析证实了锯齿状前体在散发的 MSI-H 结肠癌发生中的重要性。
