结直肠锯齿状癌变途径及β-catenin在其中的作用和调控机制

结直肠锯齿状癌变途径是近年来提出的大肠癌发生的一条新的癌变途径,包括增生性息肉、无蒂锯齿状腺瘤、传统锯齿状腺瘤、混合性腺瘤。与传统的腺瘤-癌途径不同,以β-catenin为核心的经典WNT信号通路在锯齿状癌变途径中可能不起主要作用。β-catenin在锯齿状癌变途径中主要起黏附作用。β-catenin粘附和转录功能的调控机制包括翻译后修饰(磷酸化)和构象变化(C端折叠)。     

广基锯齿状病变临床诊断价值及其相关研究现状

结直肠锯齿状病变是一类腺窝上皮呈锯齿状的息肉,其中广基锯齿状病变具有恶变潜能。广基锯齿状病变和传统锯齿状腺瘤的癌变途径代表了15%~30%的结直肠癌发生途径。但广基锯齿状病变,尤其是伴有异型增生的广基锯齿状病变,在内镜检查、病理诊断中均存在相应的难点。本文就广基锯齿状病变的癌变机制、病理特征、流行病学特征、内镜特征等作一归纳和总结。     

无蒂锯齿状腺瘤/息肉(SSA/P)的临床特点及其治疗研究进展

结直肠锯齿状息肉是一种具有锯齿状隐窝结构的息肉类型,根据WHO分类标准,分为增生性息肉(HP)、无蒂锯齿状腺瘤/息肉(SSA/P)和传统锯齿状腺瘤(TSA)三种亚型。目前认为,除了已知的致癌途径,包括腺瘤—癌、炎症—异型增生—癌变、de novo癌途径,锯齿状通路被认为是结直肠癌发病机制的新途径,而SSA/P被认为是锯齿状通路的早期前驱病变。因SSA/P具有独特的组织结构和临床意义,现对其特征、癌变途径以及治疗等方面作一综述。     

锯齿状息肉的研究进展

结直肠癌是一种常见的消化道恶性肿瘤,其癌变途径主要为腺瘤途径(50%~70%)、de novo途径(3%~5%)、锯齿状息肉途径(30%~50%)。目前已有大量研究对锯齿状息肉进行了探讨,但对其癌变机制、内镜特点、治疗策略仍缺乏统一的认识。本文就锯齿状息肉的内镜特征、分子病理特征、治疗策略作一综述。     

结直肠锯齿状病变的癌变机制及内镜诊断研究进展

结直肠锯齿状病变以往被认为是一种良性病变,近10年的研究表明其具有恶性潜能,锯齿状途径被认为是除腺瘤—癌、炎症—异型增生—癌变、de novo癌途径外新的结直肠癌癌变途径。据最新的世界卫生组织分类标准,锯齿状病变分为增生性息肉、无蒂锯齿状病变和传统锯齿状腺瘤3种类型。由于锯齿状病变具有相对特异的癌变途径及内镜下特点,本...     

结直肠锯齿状病变：从组织学形态到分子机制的研究进展

结直肠锯齿状病变是一组上皮呈锯齿状结构的息肉/腺瘤,包括增生性息肉、无蒂锯齿状病变、无蒂锯齿状病变伴异型增生、传统锯齿状腺瘤和未分类的锯齿状腺瘤。无蒂锯齿状病变和传统锯齿状腺瘤是锯齿状病变发展为结直肠癌的前驱病变。锯齿状病变的特征是遗传（BRAF或KRAS基因突变）和表观遗传（CpG岛甲基化表型）的改变,协同驱动结直肠黏膜发生息肉、腺瘤,并恶性转化为结直肠癌。锯齿状病变的复杂性使其诊断困难,易漏诊且恶变率高。本文从内镜特征、病理特征、分子学进展等方面对结直肠锯齿状病变的研究进展作一综述。     

结直肠锯齿状息肉的来源及检测方法的研究进展

结直肠癌(colorectal cancer, CRC)是全球癌症相关死亡的第四大原因。大多数结直肠癌由良性腺瘤和结直肠息肉发展而来。在组织学上,结直肠息肉分为腺瘤,锯齿状息肉和其他罕见息肉。直到2010年,结直肠锯齿状息肉通常被认为是无害的病变,病理学家和胃肠病学家将其报告为增生性息肉(hyperplastic polyps, HPs)。然而,锯齿状息肉中的无柄锯齿状病变(sessile serrated lesion, SSL)作为第二常见的锯齿状病变类型,与传统锯齿状腺瘤(Traditional Serrated Adenoma, TSA)一起被认为是CRC的重要前体病变。而SSL由于其扁平、苍白、被覆黏液而经常被漏诊误诊。因此,本文对锯齿状息肉的来源及检测进行了综述,以期能对其进行更早、更准确的识别,减少CRC的发生。     

结直肠无蒂锯齿状腺瘤的研究进展

结直肠癌(colorectal cancer,CRC)是世界上第3大常见的恶性肿瘤和第4大癌症死亡原因。根据世界卫生组织(WHO)对消化系统肿瘤的分类,锯齿状息肉（serrated polyposis,SPs）分为无蒂锯齿状腺瘤/息肉(sessile serrated adenoma/polyps,SSA/P)、增生性息肉（hyperplastic polyp,HP）和传统锯齿状腺瘤(traditional serrated adenoma,TSA)。除传统的腺瘤-癌序列途径,TSA和SSA均可通过锯齿状途径导致结CRC,又因TSA较为罕见,故SSA是该途径导致CRC的主要病变。本文总结了SSA/P的相关因素、组织学表现、分子生物学特征、内镜表现及内镜治疗的最新研究进展。     

结直肠锯齿状病变一癌前病变新通路

近年来人们注意到结直肠内存在一系列锯齿状结构病变,统称为锯齿状病变,其与部分散发性大肠癌的发生密切相关。这些病变包括畸形隐窝灶（ACF）、锯齿状息肉（SP）和锯齿状腺癌。本文将重点介绍畸形隐窝灶及锯齿状息肉的形态学、分子生物学研究的现状及进展。     

锯齿状腺瘤研究进展

锯齿状腺瘤（serrated adenoma，SA）是同时具有增生性息肉（hyperplasic polyp，HP）的锯齿状结构和传统腺瘤异型性上皮特征的一种新腺瘤类型。具有锯齿状结构的病变包括HP、HP腺瘤混合性息肉（admixed hyperplasic polyp／adenoma，HP／AD）和SA。近年临床病理学和分子生物学方面的研究认为，HP可能是一种结、直肠癌发生新途径的早期阶段，即“HP—SA-癌”途径。SA组织学发生、形态结构、分子遗传学改变等具特殊性。有研究表明，SA可在2年内发展为进展期大肠癌。因此HP和SA作为一种新的癌前病变值得我们深入研究。     

Serrated pathway in colorectal carcinogenesis

Serrated adenocarcinoma is a recently described subset of colorectal cancer(CRC),which account for about10%of all CRCs and follows an alternative pathway in which serrated polyps replace the traditional adenoma as the precursor lesion to CRC.Serrated polyps form a heterogeneous group of colorectal lesions that includes hyperplastic polyps(HPs),sessile serrated adenoma(SSA),traditional serrated adenoma(TSA)and mixed polyps.HPs are the most common serrated polyp followed by SSA and TSA.This distinct histogenesis is believed to have a major influence in prevention strategies,patient prognosis and therapeutic impact.Genetically,serrated polyps exhibited also a distinct pattern,with KRAS and BRAF having an important contribution to its development.Two other molecular changes that have been implicated in the serrated pathway include microsatellite instability and the CpG island methylator phenotype.In the present review we will address the current knowledge of serrated polyps,clinical pathological features and will update the most recent findings of its molecular pathways.The understanding of their biology and malignancy potential is imperative to implement a surveillance approach in order to prevent colorectal cancer development.     

Sessile serrated adenoma/polyps: Where are we at in 2016?

It is currently known that colorectal cancers(CRC) arise from 3 different pathways: the adenoma to carcinoma chromosomal instability pathway(50%-70%); the mutator "Lynch syndrome" route(3%-5%); and the serrated pathway(30%-35%). The World Health Organization has classified serrated polyps into three types of lesions: hyperplastic polyps(HP),sessile serrated adenomas/polyps(SSA/P) and traditional serrated adenomas(TSA),the latter two strongly associated with development of CRCs. HPs do not cause cancer and TSAs are rare. SSA/P appear to be the responsible precursor lesion for the development of cancers through the serrated pathway. Both HPs and SSA/Ps appear morphologically similar. SSA/P are difficult to detect. The margins are normally inconspicuous. En bloc resection of these polyps can hence be troublesome. A careful examination of borders,submucosal injection of a dye solution(for larger lesions) and resection of a rim of normal tissue around the lesion may ensure total eradication of these lesions.     

Serrated polyps of the colon and rectum: Remove or not?

In recent years, the serrated neoplasia pathway where serrated polyps arise as a colorectal cancer has gained considerable attention as a new carcinogenic pathway. Colorectal serrated polyps are histopathologically classified into hyperplastic polyps(HPs), sessile serrated lesions, and traditional serrated adenomas; in the serrated neoplasia pathway, the latter two are considered to be premalignant. In western countries, all colorectal polyps, including serrated polyps, apart from diminutive rectosigmoid HPs are removed. However, in Asian countries, the treatment strategy for colorectal serrated polyps has remained unestablished. Therefore, in this review, we described the clinicopathological features of colorectal serrated polyps and proposed to remove HPs and sessile serrated lesions ≥ 6 mm in size, and traditional serrated adenomas of any size.     

Clinicopathological characteristics of serrated polyps as precursors to colorectal cancer: Current status and management

Serrated polyps have long been thought to lack malignant potential in the human colorectum. However, identification of the serrated pathway to colorectal cancer based on molecular biology has improved our understanding of the pathogenesis of colorectal cancers. Accordingly, serrated polyps such as traditional serrated adenoma and sessile serrated adenoma/polyps (SSA/P) are now considered to be precursor lesions of the serrated pathway. Recently, serrated polyps were classified into three subtypes, consisting of hyperplastic polyp, SSA/P, and traditional serrated adenoma, according to the World Health Organization classification. It has been suggested that SSA/P in the proximal colon are a precursor lesion of pathogenesis of colorectal cancer and are characterized by BRAF mutation and a CpG island methylator phenotype with or without microsatellite instability. However, SSA/P is more challenging to detect by colonoscopy and is likely to account for some interval cancers, particularly in the proximal colon because it presents flat or sessile, isochroous appearance, and occasionally has a mucous cap. Furthermore, the possibility has been raised that pathologists misclassify SSA/P as hyperplastic polyp. It is important for gastroenterologists to recognize the endoscopic features of serrated polyps to facilitate their detection and removal and also to establish postpolypectomy surveillance guidelines. In this review, we discuss the recent classification of serrated polyps; the molecular characteristics of the serrated pathway; appropriate diagnostic methods using endoscopy, including a new image‐enhanced endoscopic technique; and management of these lesions.     

Serrated polyposis syndrome: molecular, pathological and clinical aspects

Hyperplastic polyps have traditionally been considered not to have malignant potential. New pathological classification of serrated polyps and recent discoveries about the serrated pathway of carcinogenesis have revolutionized the concepts and revitalized the research in this area. Until recently, it has been thought that most colorectal cancers arise from conventional adenomas via the traditional tumor suppressor pathway initiated by a mutation of the APC gene, but it has been found that this pathway accounts for only approximately 70%-80% of colorectal cancer (CRC) cases. The majority of the remaining colorectal cancer cases follow an alternative pathway leading to CpG island methylator phenotype carcinoma with BRAF mutation and with or without microsatellite instability. The mechanism of carcinomas arising from this alternative pathway seems to begin with an activating mutation of the BRAF oncogene. Serrated polyposis syndrome is a relatively rare condition characterized by multiple and/or large serrated polyps of the colon. Clinical characteristics, etiology and relationship of serrated polyposis syndrome to CRC have not been clarified yet. Patients with this syndrome show a high risk of CRC and both sporadic and hereditary cases have been described. Clinical criteria have been used for diagnosis and frequent colonoscopy surveillance should be performed in order to prevent colorectal cancer. In this review, we try to gather new insights into the molecular pathogenesis of serrated polyps in order to understand their possible clinical implications and to make an approach to the management of this syndrome.     

Sessile serrated adenoma/polyp showed rapid malignant transformation in the final 13 months

Based on the concept of the adenoma-carcinoma sequence, most colorectal cancers are considered to arise from conventional adenomas. However, recent studies suggested that a subset of colorectal cancers develop through the serrated neoplastic pathway. It has also been documented that serrated polyps can rapidly transform into invasive cancers even when they are small in size. We now describe a case of a sessile serrated adenoma/polyp which had been followed up for 4 years but eventually showed rapid transformation into an advanced cancer accompanied by a remarkable morphological change within only 13 months. Retrospective genetic and epigenetic analyses showed microsatellite instability, CpG island methylator phenotype-positive, and BRAF mutation in the lesion, suggesting the tumor had developed through the serrated neoplastic pathway. This case may provide valuable information about the natural history of sessile serrated adenoma/polyps which eventually progress to advanced cancers.     

Emerging concepts in colorectal neoplasia

An understanding of the mechanisms that explain the initiation and early evolution of colorectal cancer should facilitate the development of new approaches to effective prevention and intervention. This review highlights deficiencies in the current model for colorectal neoplasia in which APC mutation is placed at the point of initiation. Other genes implicated in the regulation of apoptosis and DNA repair may underlie the early development of colorectal cancer. Inactivation of these genes may occur not by mutation or loss but through silencing mediated by methylation of the gene's promoter region. hMLH1 and MGMT are examples of DNA repair genes that are silenced by methylation. Loss of expression of hMLH1 and MGMT protein has been demonstrated immunohistochemically in serrated polyps. Multiple lines of evidence point to a "serrated" pathway of neoplasia that is driven by inhibition of apoptosis and the subsequent inactivation of DNA repair genes by promoter methylation. The earliest lesions in this pathway are aberrant crypt foci (ACF). These may develop into hyperplastic polyps or transform while still of microscopic size into admixed polyps, serrated adenomas, or traditional adenomas. Cancers developing from these lesions may show high- or low-level microsatellite instability (MSI-H and MSI-L, respectively) or may be microsatellite stable (MSS). The suggested clinical model for this alternative pathway is the condition hyperplastic polyposis. If colorectal cancer is a heterogeneous disease comprising discrete subsets that evolve through different pathways, it is evident that these subsets will need to be studied individually in the future.     

Hyperplastic polyps of the colorectum—Innocent or guilty?

Hyperplastic polyps have traditionally been regarded as nonneoplastic polyps lacking malignant potential. The demonstration of genetic alterations within these lesions indicates an underlying neoplastic cause. There is evidence that hyperplastic polyps are heterogeneous. Most are innocuous, but subsets may have malignant potential. Risk factors for neoplastic progression include multiple, large, and proximally located polyps. Aberrant methylation resulting in the silencing of cancer genes may be an important underlying mechanism, particularly in pathways progessing to tumors with DNA microsatellite instability. Lesions intermediate between hyperplastic polyp and cancer include admixed polyps and serrated adenomas. Currently, pathologists have different thresholds for diagnosing serrated adenomas, including the distinction from large hyperplastic polyps. Reasons for over looking this pathway in the past may include rapid tumor progression and the fact that proximally located hyperplastic polyps may be flat and not especially numerous. Management of the serrated pathway of colorectal neoplasia may require novel approaches to screening, early detection, and prevention.     

Emerging concepts in colorectal serrated polyps

Colorectal serrated polyps are heterogeneous epithelial lesions characterized by a serrated architecture. They include the classical hyperplastic polyps and the much rarer serrated adenomas and mixed polyps. Whereas serrated adenomas are composed of an unequivocal adenomatous epithelium with architectural serrated, mixed polyps include two separate hyperplastic and adenomatous components. During the past few years, another type of serrated polyp with only very subtle proliferation abnormalities has been described. These atypical serrated polyps may occur either sporadically or in the context of colorectal polyposis. Despite their close resemblance to traditional hyperplastic polyps, some authors argued that they should be regarded as authentically neoplastic lesions and have proposed to call them "sessile serrated adenomas". Their malignant potential requires their removal when discovered during colonoscopy. This article reviews the histological features, the endoscopic appearance, the natural history and the molecular phenotype of the different categories of serrated polyps and introduces the concept of "serrated neoplastic pathway" in the development of colorectal cancer.     

Evolution of colorectal cancer: change of pace and change of direction

This review compiles evidence for an alternative to the classical adenoma-carcinoma sequence in the evolution of colorectal cancer. It is suggested that between 30 and 50 of colorectal cancers are not initiated by mutation of the tumor suppressor gene APC, but through the epigenetic silencing of genes implicated in the control of differentiation, cell cycle control and DNA repair proficiency. The precursor polyps are often characterized by a serrated architecture, and include hyperplastic polyps, admixed polyps and serrated adenomas. The alternative pathway is heterogeneous and may culminate in cancers showing low or high level DNA microsatellite instability (MSI-L and MSI-H, respectively), and in cancers that are microsatellite stable (MSS). Cancers showing DNA MSI may be characterized by an accelerated evolution. Cancers in hereditary non-polyposis colorectal cancer show features of both classical (adenoma and APC mutation) and alternative pathways (rapid evolution, MSI-H and lack of chromosomal instability).