Sessile Serrated Adenoma With Early Neoplastic Progression: A Clinicopathologic and Molecular Study
Sessile Serrated Adenoma With Early Neoplastic Progression: A Clinicopathologic and Molecular Study
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DOI：
10.1097/pas.0b013e318205df36
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发表时间：
2011-02-01
影响因子：
5.6
通讯作者：
Oda, Yoshinao
中科院分区：
文献类型：
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作者：
Fujita, Kohei;Yamamoto, Hidetaka;Oda, Yoshinao
无梗锯齿状腺瘤(SSA)，又称无梗锯齿状息肉，已被认为是微卫星不稳定癌的前驱病变。然而，从SSA向早期浸润性癌逐步发展的机制尚不清楚。本研究旨在阐明P53、β-连环蛋白、BRAF、KRAS和PIK3CA在SSA发生发展中的组织学特征及其可能的作用。对12例SSA伴肿瘤进展(SSAN)进行免疫组织化学和基因突变分析，并与53例SSA和66例增生性息肉(HPS)进行比较。组织学上，75%(9/12)的SSAN在HGD/粘膜内癌成分中表现为管状或管状或叶状生长，而不是锯齿状生长。5例浸润性癌均失去锯齿状结构，粘膜下癌成分中细胞外粘蛋白增多，这是粘液腺癌的一贯特征。50%(6/12)和41.7%(5/12)的SANS中可见β-连环蛋白和P53的核聚积，且仅见于HGD/癌区。相比之下，HPS和SSA中既没有核β-连环蛋白表达，也没有P53表达(P<；0.0001)。45.8%(11/24)的HPS、60.9%(14/23)的SSA和63.6%(7/11)的SSAN存在BRAF基因突变(V600E)，且SSA和癌/HGD区的BRAF突变频率相同。KRAS基因外显子1突变在3组中均不常见(分别为4.2%、4.4%和0%)。所有病例均未发现PIK3CA外显子9或外显子20突变。这些发现表明，BRAF突变可能与SSA的发病机制有关，但进展为HGD或早期浸润性癌可能与其他因素有关，如P53和β-连环蛋白的改变。此外，我们的组织学观察表明，SSAN和粘液腺癌之间可能存在密切的联系。
Sessile serrated adenoma (SSA), also referred to as sessile serrated polyp, has been proposed as a precursor lesion to microsatellite unstable carcinoma. However, the mechanism of stepwise progression from SSA to early invasive carcinoma has been unclear. The purpose of this study was to elucidate the histologic characteristics and possible role of p53, beta-catenin, BRAF, KRAS, and PIK3CA in the development and progression of SSA. We analyzed 12 cases of SSA with neoplastic progression (SSAN), including 7 cases of intraepithelial high-grade dysplasia (HGD) and 5 cases of submucosal invasive carcinoma, and compared them with 53 SSAs and 66 hyperplastic polyps (HPs) by immunohistochemistry and gene mutation analysis. Histologically, 75% (9 of 12) of SSANs showed tubular or tubulovillous growth patterns rather than serrated ones in the HGD/intramucosal carcinoma component. All 5 SSANs with invasive carcinoma lost their serrated structure and developed increased extracellular mucin in their submucosal carcinoma component, a consistent feature of mucinous adenocarcinoma. Nuclear accumulations of beta-catenin and p53 were observed in 50% (6 of 12) and 41.7% (5 of 12) of SSANs, respectively, and were exclusively present in HGD/carcinoma areas. By contrast, neither nuclear beta-catenin nor p53 expressions were seen in HPs or SSAs (P < 0.0001). BRAF mutations (V600E) were observed in 45.8% (11 of 24) of HPs, 60.9% (14 of 23) of SSAs, and 63.6% (7 of 11) of SSANs, and were equally found in both SSA and carcinoma/HGD areas of the individual SSANs. KRAS exon 1 mutations were uncommon in all 3 groups (4.2%, 4.4%, and 0%, respectively). No mutations of PIK3CA exon 9 or exon 20 were found in any cases that were examined. These findings suggest that BRAF mutations may be associated with the pathogenesis of SSA, but progression to HGD or early invasive carcinoma may be associated with other factors, such as alterations of p53 and beta-catenin. In addition, our histologic observations suggest a possible close association between SSAN and mucinous adenocarcinoma.