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.     

Serrated colorectal cancer: Molecular classification,prognosis, and response to chemotherapy

Molecular advances support the existence of an alternative pathway of colorectal carcinogenesis that is based on the hypermethylation of specific DNA regions that silences tumor suppressor genes. This alternative pathway has been called the serrated pathway due to the serrated appearance of tumors in histological analysis. New classifications for colorectal cancer(CRC) were proposed recently based on genetic profiles that show four types of molecular alterations: BRAF gene mutations, KRAS gene mutations, microsatellite instability, and hypermethylation of Cp G islands. This review summarizes what is known about the serrated pathway of CRC, including CRC molecular and clinical features, prognosis, and response to chemotherapy.     

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.     

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 lesions: A challenging enemy

The serrated pathway accounts for 30%-35% of colorectal cancer (CRC). Unlike hyperplastic polyps, both sessile serrated lesions (SSLs) and traditional serrated adenomas are premalignant lesions, yet SSLs are considered to be the principal serrated precursor of CRCs. Serrated lesions represent a challenge in detection, classification, and removal–contributing to post-colonoscopy cancer. Therefore, it is of the utmost importance to characterize these lesions properly to ensure complete removal. A retrospective cohort study developed a diagnostic scoring system for SSLs to facilitate their detection endoscopically and subsequent removal. From the study, it can be ascertained that both indistinct border and mucus cap are essential in both recognizing and diagnosing serrated lesions. The proximal colon poses technical challenges for some endoscopists, which is why high-quality colonoscopy plays such an important role. The indistinct border of some SSLs poses another challenge due to difficult complete resection. Overall, it is imperative that gastroenterologists use the key features of mucus cap, indistinct borders, and size of at least five millimeters along with a high-quality colonoscopy and a good bowel preparation to improve the SSL detection rate.     

Reinterpretation of histology of proximal colon polyps called hyperplastic in 2001

AIM： To evaluate how proximal colon polyps interpreted as hyperplastic polyps in 2001 would be interpreted by expert pathologists in 2007.
METHODS： ≥ 5 mm in interpreted pathologists 2007 by 3 GI Forty consecutive proximal colon polyps size, removed in 2001, and originally as hyperplastic polyps by general at Indiana University, were reviewed in pathologists.
CONCLUSION： Many polyps interpreted as hyperplastic in 2001 were considered sessile serrated lesions by GI pathologists in 2007, but there is substantial inter-observer variation amongst GI pathologists.     

Heterogeneity of colorectal adenomas, the serrated adenoma, and implications for screening and surveillance

Current algorithms for screening and surveillance for colon cancer are valuable, but may be limited by the underlying nature of the targeted neoplastic lesions. Although part of the success of adenoma removal relates to interruption of so-called ＂adenoma-carcinoma sequence＂, an alternate serrated pathway to colon cancer may pose difficulties with the ultimate results achieved by traditional colonoscopic methods. The endpoint carcinoma in this unique pathway may be derived from a dysplastic serrated adenoma. These tend to be located primarily in the right colon, especially in females, and are frequently associated with co-existent colon cancer. Unfortunately, however, there are few, if any, other identifiable risk factors, including age or family history of colon polyps or colon cancer. Moreover, this alternate serrated pathway may itself also be quite biologically heterogeneous as reflected in sessile serrated adenomas （SSA） with virtually exclusive molecular signatures defined by the presence of either BRAF or KRAS mutations. Screening algorithms in the future may need to be modified and individualized, depending on new information that likely will emerge on the natural history of these biologically heterogeneous lesions that differs from traditional adenomatous polyps.     

Incidence of colorectal neoplasms among male pilots

AIM: To assess the prevalence of colorectal neoplasms (adenomas, advanced adenomas and colorectal cancers) among Israeli military and commercial airline pilots.METHODS: Initial screening colonoscopy was performed on average-risk (no symptoms and no family history) airline pilots at the Integrated Cancer Prevention Center (ICPC) in the Tel-Aviv Medical Center. Visualized polyps were excised and sent for pathological examination. Advanced adenoma was defined as a lesion >10 mm in diameter, with high-grade dysplasia or villous histology. The results were compared with those of an age- and gender-matched random sample of healthy adults undergoing routine screening at the ICPC.RESULTS: There were 270 pilots (mean age 55.2 ± 7.4 years) and 1150 controls (mean age 55.7 ± 7.8 years). The prevalence of colorectal neoplasms was 15.9% among the pilots and 20.6% among the controls (P = 0.097, χ² test). There were significantly more hyperplastic polyps among pilots (15.5% vs 9.4%, P = 0.004) and a trend towards fewer adenomas (14.8% vs 20.3% P = 0.06). The prevalence of advanced lesions among pilots and control groups was 5.9% and 4.7%, respectively (P = 0.49), and the prevalence of cancer was 0.7% and 0.69%, respectively (P = 0.93).CONCLUSION: There tends to be a lower colorectal adenoma, advanced adenoma and cancer prevalence but a higher hyperplastic polyp prevalence among pilots than the general population.     

Colorectal cancer： Pathways,pathology and practice： From the editor

This review explores the chief genetic and epigenetic events that promote pathological progression in colorectal carcinogenesis. This article discusses the molecular and pathological basis for classifying colorectal neoplasia into suppressor, mutator and methylator pathways. These differing mechanisms of genomic instability are associated with specific cancer characteristics, and may provide the opportunity for more effective prevention and surveillance strategies in the future. This is the first review in a series of five topics outlining important and developing aspects of colorectal cancer.     

Issues related to colorectal cancer and colorectal cancer screening practices in women

Studies have shown that colorectal cancer (CRC) incidence is equal between men and women. However, several studies have demonstrated lower adenoma detection rates in women than in men. Many questions arise about differences in adenomas, CRC, and screening practices between men and women: should screening be the same for both sexes, are there differences in risk factors in the formation of colon cancer, should special groups of women be screened differently from the general population, are colonoscopies tolerated differently in women and why, and what determines if a woman will undergo colonoscopy? This article reviews these issues.     

Endoscopic management of colorectal polyps: From benign to malignant polyps

Colorectal cancer(CRC) is the third most common cancer worldwide and the second leading cause of cancer related death in the world. The early detection and removal of CRC precursor lesions has been shown to reduce the incidence of CRC and cancer-related mortality. Endoscopic resection has become the first-line treatment for the removal of most precursor benign colorectal lesions and selected malignant polyps. Detailed lesion assessment is the first critical step in the evaluation and management of colorectal polyps. Polyp size, location and both macro-and micro-features provide important information regarding histological grade and endoscopic resectability. Benign polyps and even malignant polyps with superficial submucosal invasion and favorable histological features can be adequately removed endoscopically. When compared to surgery, endoscopic resection is associated with lower morbidity, mortality, and higher patient quality of life. Conversely, malignant polyps with deep submucosal invasion and/or high risk for lymph node metastasis will require surgery. From a practical standpoint,the most appropriate strategy for each patient will need to be individualized,based not only on polyp-and patient-related characteristics, but also on local resources and expertise availability. In this review, we provide a broad overview and present a potential decision tree algorithm for the evaluation and management of colorectal polyps that can be widely adopted into clinical practice.     

Risk of cancer in small and diminutive colorectal polyps

The prevalence of cancer in small and diminutive polyps is relevant to “resect and discard” and CT colonography reporting recommendations.We evaluated a prospectively collected colonoscopy polyp database to identify polyps <10 mm and those with cancer or advanced histology (high-grade dysplasia or villous elements).Of 32,790 colonoscopies, 15,558 colonoscopies detected 42,630 polyps <10 mm in size. A total of 4790 lesions were excluded as they were not conventional adenomas or serrated class lesions.There were 23,524 conventional adenomas <10 mm of which 22,952 were tubular adenomas. There were 14,316 serrated class lesions of which 13,589 were hyperplastic polyps and the remainder were sessile serrated polyps. Of all conventional adenomas, 96 had high-grade dysplasia including 0.3% of adenomas ≤5 mm in size and 0.8% of adenomas 6–9 mm in size. Of all conventional adenomas, 2.1% of those ≤5 mm in size and 5.6% of those 6–9 mm in size were advanced. Among 36,107 polyps ≤5 mm in size and 6523 polyps 6–9 mm in size, there were no cancers.These results support the safety of resect and discard as well as current CT colonography reporting recommendations for small and diminutive polyps.     

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...     

How to avoid overtreatment of benign colorectal lesions: Rationale for an evidence-based management

Implementing population-based screening programs for colorectal cancer has led to an increase in the detection of large but benign histological lesions. Currently, endoscopic mucosal resection can be considered the standard technique for the removal of benign lesions of the colon due to its excellent safety profile and good clinical results. However, several studies from different geographic areas agree that many benign colon lesions are still referred for surgery. Moreover, the referral rate to surgery is not decreasing over the years, despite the theoretical improvement of endoscopic resection techniques. This article will review the leading causes for benign colorectal lesions to be referred for surgery and the influence of the endoscopist experience on the referral rate. It will also describe how to categorize a polyp as complex for resection and consider an endoscopist as an expert in endoscopic resection. And finally, we will propose a framework for the accurate and evidence-based treatment of complex benign colorectal lesions.     

SDC2基因甲基化对结直肠癌诊断价值的Meta分析

目的 通过Meta分析方法评价多配体蛋白聚糖2(Syndecan-2,SDC2)基因甲基化作为生物标志物诊断结直肠癌(colorectal cancer,CRC)的价值.方法 计算机检索PubMed、Cochrane Library、Embase、Web of Science、CBM、万方、知网、维普数据库,查找建库至...     

结直肠息肉癌变的内镜下表现、治疗及癌变因素分析

目的探讨结直肠息肉癌变的内镜下表现,分析癌变相关因素和治疗策略。方法回顾性分析经电子结肠镜检查或治疗的77例结直肠癌变息肉患者的临床、内镜及病理资料,探讨影响结直肠息肉癌变的相关因素及其内镜下治疗策略。结果77例癌变结直肠息肉中,9例伴发结肠癌。60例有临床症状,症状发生率为77．9％（60／77）。息肉癌变主要分布在乙状结肠,多发生于年龄超过60岁的老年患者,绒毛状腺瘤癌变率最高。行电子结肠镜电切法切除44例,其中完全切除38例。结论年龄〉60岁患者和乙状结肠息肉癌变发生率明显增高,选择性对属于原位癌或早期浸润癌的癌变息肉行电子结肠镜下切除是安全有效的。     

The role of cell-free DNA in predicting colorectal cancer prognosis

Introduction: Colorectal cancer is a cancer of the digestive system with poor prognosis. Cell-free DNA has received much attention with its unique predominance, especially in colorectal cancer.

Areas covered: This study has summarized recent advancements and challenges regarding cell-free DNA in predicting CRC prognosis. Furthermore, the authors make predictions on the potential developments concerning cell-free DNA in future prognosis prediction techniques.

Expert commentary: Cell-free DNA has the value of predicting CRC prognosis as an important biomarke. Further clinical trials should be performed to promote translating cell-free DNA into clinical applications.     

Pretreatment serum levels of hematopoietic cytokines in patients with colorectal adenomas and cancer

Background and aim Hematopoietic cytokines (HCs) regulate the proliferation and differentiation of hematopoietic progenitor cells, and it was proved that HCs can promote cancer growth. The aim of this study is to determine whether HCs might be useful in the diagnosis of colorectal cancer.Materials and methods We compared the serum levels of stem cell factor (SCF), interleukin 3 (IL-3), granulocyte–macrophage colony-stimulating factor (GM-CSF), and macrophage colony-stimulating factor (M-CSF) in 97 colorectal cancer patients with those in 35 patients with colorectal adenomas and 65 healthy subjects (control group). Additionally, we investigated commonly accepted tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). HCs were determined using enzyme linked immunosorbent assay (ELISA). CEA and CA 19-9 were measured by microparticle enzyme immunoassay.Results Serum levels of GM-CSF, M-CSF, and tumor markers were significantly higher in cancer patients as compared to the control group and adenomas patients. Of these, hematopoietic cytokines were found elevated in the higher proportion of patients than CEA and CA 19-9. The sensitivity of SCF was higher than the sensitivity of other cytokines, but diagnostic specificity and predictive value were highest for M-CSF. Moreover, the M-CSF area under the receiver operating characteristic curve was larger than the areas of other cytokines. The highest values of diagnostic parameters were observed for the combined use of M-CSF with CEA.Conclusion The obtained data support the M-CSF usefulness as a tumor marker for colorectal cancer, especially in combination with CEA.     

Vitamin supplements among women with adenomatous polyps and cancer of the colon

Chemoprevention of various epithelial cancers with vitamins or minerals has been the subject of multiple intervention trials to assess the impact of supplementation. These include several trials in patients with adenomatous polyps of the colon, a precursor lesion for colon cancer. The authors interviewed 255 women who underwent colonoscopy at Columbia Presbyterian Medical Center between 1983 and 1985 with a telephone-administered structured questionnaire. Eleven interviews were excluded for various reasons. Overall, 57.7 percent of the 244 interviewees used vitamin pills on a regular basis (at least once a week for a year); 6.6 percent of the interviewees used vitamin A, 20.7 percent used vitamin C, and 16.2 percent used vitamin E. There were no statistically significant differences in vitamin usage among women with adenomatous polyps of the colon (105 cases), women with colon cancer (56 cases), and women without colonic neoplasia (83 cases). Despite widespread use of supplementary vitamins, this study failed to demonstrate major benefits in preventing colon polyps or cancer. Read in part at the Tenth Meeting of the American Society for Preventive Oncology, Bethesda, Maryland, March 7, 1986. Supported by NCI Grant No.CA37196, an American Cancer Society Junior Faculty Fellowship (AIN), a grant from the Andrew Mellon Foundation, and an internship from the Health Research Training Program of the NYC Department of Health (CMJ).     

SEPT9在结直肠癌早期检测中的研究进展

SEPT9是13个Septin同源基因家族之一,参与调控众多过程,包括细胞分裂、细胞极化、细胞迁移以及线粒体分裂等。研究表明在众多肿瘤中,SEPT9都发挥着作用,尤其在结直肠肿瘤研究领域,外周血SEPT9基因甲基化检测更是研究热点,其检测的敏感度和特异度相对于其他糖蛋白肿瘤标志物、粪便隐血试验和粪便免疫化学测试等更具有优势,相对于结直肠镜等侵入性检查更节约成本,同时有着更好的依从性。本文对SEPT9的功能、与结直肠癌之间的关系以及对结直肠肿瘤的筛查及诊断价值做一综述。