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The Serrated Polyp Comes of Age

2006; Elsevier BV; Volume: 131; Issue: 5 Linguagem: Inglês

10.1053/j.gastro.2006.09.035

1528-0012

Gregory Y. Lauwers, Daniel C. Chung,

Gastric Cancer Management and Outcomes

See "High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy" by Spring KJ, Zhen Zhao Z, Karamatic R, Walsh MD, Whitehall VLJ, Pike T, Simms LA, Young J, James M, Montgomery GW, Appleyard M, Hewett D, Togashi K, Jass JR, and Leggett BA on page 1400. Although there are multiple types of colonic polyps, most of the attention in both clinical practice and basic research has focused on the adenomatous polyp. The precancerous potential of the colonic adenoma is undisputed, but appreciation has steadily grown for the significance of the so-called hyperplastic polyp. The long-held belief that hyperplastic polyps are always benign incidental findings has undergone serious re-evaluation. This stems from the recognition that there is considerable morphologic and molecular heterogeneity within the family of hyperplastic polyps and that certain subtypes do indeed harbor a risk of malignant transformation. Some of the confusion surrounding hyperplastic polyps today revolves around inconsistent terminology and evolving classification schemes. Within the past 10 years, the preferred concept of the "serrated polyp" has emerged, and this reflects the common saw-tooth architectural pattern observed within this entire family of polyps.1Snover D.C. Jass J.R. Fenoglio-Preiser C. Batts K.P. Serrated polyps of the large intestine: a morphologic and molecular review of an evolving concept.Am J Clin Pathol. 2005; 124: 380-391Crossref PubMed Scopus (392) Google Scholar The small, "classic" hyperplastic polyp is the most common type of serrated polyp, and these hyperplastic polyps are now subdivided further into the microvesicular, goblet cell-rich, or mucin-poor subtypes (Figure 1A–C). The less common but clinically more important members of the serrated polyp family include sessile serrated adenomas (SSA), traditional serrated adenomas (TSA), and mixed polyps that contain discrete components of both SSAs and tubular adenomas (Figure 1D, F). Collectively, these have been referred to as either giant hyperplastic polyps, serrated adenomas, hyperplastic-like polyps, or sessile serrated polyps in the past. Although endorsed by a number of pathologists, these new categories have not become utilized widely. One particularly confusing point is that SSAs do not display the cytologic dysplasia that is the hallmark of adenomatous polyps in general. Rather, there are overall architectural features (branching and dilation of the base of the crypts) that are considered dysplastic in SSAs (Figure 1F). Consequently, it has been a challenge to draw meaningful conclusions about the behavior of serrated polyps because of the difficulty in distinguishing the various subtypes as well as the inconsistencies in nomenclature. Although most hyperplastic polyps are diminutive lesions in the rectosigmoid colon with a negligible risk of malignancy, there is growing and compelling evidence that certain serrated polyps (SSAs, TSAs, and mixed polyps) can progress to cancer and some may do so through a unique carcinogenic pathway. The first clues came from those rare individuals who develop numerous large serrated polyps, frequently but not universally of the right colon, and this condition has been loosely designated the hyperplastic polyposis or serrated adenomatous polyposis syndrome. Observational studies have identified synchronous colon cancers in >50% of such individuals.2Torlakovic E. Snover D.C. Serrated adenomatous polyposis in humans.Gastroenterology. 1996; 110: 748-755Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar, 3Leggett B.A. Devereaux B. Biden K. Searle J. Young J. Jass J. Hyperplastic polyposis: association with colorectal cancer.Am J Surg Pathol. 2001; 25: 177-184Crossref PubMed Scopus (164) Google Scholar Furthermore, a histopathologic analysis of 110 unselected TSAs suggested that they can progress to malignancy; dysplasia was identified in 38% of cases and intramucosal carcinoma in 10%.4Longacre T.A. Fenoglio-Preiser C.M. Mixed hyperplastic adenomatous polyps/serrated adenomas A distinct form of colorectal neoplasia.Am J Surg Pathol. 1990; 14: 524-537Crossref PubMed Scopus (603) Google Scholar The transforming pathways recruited by serrated polyps appear to differ from conventional tubular adenomas; more than half of SSAs and TSAs display DNA microsatellite instability (MSI).5Iino H. Jass J.R. Simms L.A. Young J. Leggett B. Ajioka Y. Watanabe H. DNA microsatellite instability in hyperplastic polyps, serrated adenomas, and mixed polyps: a mild mutator pathway for colorectal cancer?.J Clin Pathol. 1999; 52: 5-9Crossref PubMed Scopus (310) Google Scholar In most cases, hypermethylation of the MLH1 DNA repair gene was responsible for the MSI, and this occurred in the setting of global DNA hypermethylation, referred to as the CpG island methylator phenotype (CIMP). When SSAs alone were specifically analyzed, as many as 92% were CIMP positive, and 69% exhibited hypermethylation of MLH1.6O'Brien M.J. Yang S. Clebanoff J.L. Mulcahy E. Farraye F.A. Amorosino M. Swan N. Hyperplastic (serrated) polyps of the colorectum: relationship of CpG island methylator phenotype and K-ras mutation to location and histologic subtype.Am J Surg Pathol. 2004; 28: 423-434Crossref PubMed Scopus (155) Google Scholar Approximately 15% of all sporadic colon cancers also exhibit high levels of MSI (the "MSI-H" phenotype) owing to hypermethylation of the MLH1 gene. The hypothesis that SSAs may be the precursors of these MSI-H colon cancers is supported by their similar distribution in the right colon of elderly women. In addition, individuals with an MSI-H colon cancer are 4 times more likely to harbor a synchronous serrated polyp than those with a microsatellite-stable tumor.7Hawkins N.J. Ward R.L. Sporadic colorectal cancers with microsatellite instability and their possible origin in hyperplastic polyps and serrated adenomas.J Natl Cancer Inst. 2001; 93: 1307-1313Crossref PubMed Scopus (307) Google Scholar Furthermore, a retrospective review of 91 MSI-H colorectal cancers identified SSAs at the same site as the colon cancer on a previous colonoscopic examination, potentially implicating SSAs as precursor lesions in some patients.8Goldstein N.S. Bhanot P. Odish E. Hunter S. Hyperplastic-like colon polyps that preceded microsatellite-unstable adenocarcinomas.Am J Clin Pathol. 2003; 119: 778-796Crossref PubMed Scopus (259) Google Scholar There are additional molecular clues that appear to link SSAs with MSI-H colon cancers. Mutations in either the K-ras or BRAF oncogene are common in colonic neoplasia, and these mutations occur in a mutually exclusive manner. Analyses of SSAs have revealed a frequency of oncogenic BRAF mutations (primarily V600E, formerly known as V599E) as high as 75%–82%.9Kambara T. Simms L.A. Whitehall V.L. Spring K.J. Wynter C.V. Walsh M.D. Barker M.A. Arnold S. McGivern A. Matsubara N. Tanaka N. Higuchi T. Young J. Jass J.R. Leggett B.A. BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum.Gut. 2004; 53: 1137-1144Crossref PubMed Scopus (611) Google Scholar, 10Yang S. Farraye F.A. Mack C. Posnik O. O'Brien M.J. BRAF and KRAS Mutations in hyperplastic polyps and serrated adenomas of the colorectum: relationship to histology and CpG island methylation status.Am J Surg Pathol. 2004; 28: 1452-1459Crossref PubMed Scopus (254) Google Scholar, 11Jass J.R. Baker K. Zlobec I. Higuchi T. Barker M. Buchanan D. Young J. Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a "fusion" pathway to colorectal cancer.Histopathology. 2006; 49: 121-131Crossref PubMed Scopus (230) Google Scholar BRAF mutations are also a hallmark feature of MSI-H cancers (range, 27%–76%9Kambara T. Simms L.A. Whitehall V.L. Spring K.J. Wynter C.V. Walsh M.D. Barker M.A. Arnold S. McGivern A. Matsubara N. Tanaka N. Higuchi T. Young J. Jass J.R. Leggett B.A. BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum.Gut. 2004; 53: 1137-1144Crossref PubMed Scopus (611) Google Scholar, 12Rajagopalan H. Bardelli A. Lengauer C. Kinzler K.W. Vogelstein B. Velculescu V.E. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status.Nature. 2002; 418: 934Crossref PubMed Scopus (1059) Google Scholar, 13Koinuma K. Shitoh K. Miyakura Y. Furukawa T. Yamashita Y. Ota J. Ohki R. Choi Y.L. Wada T. Konishi F. Nagai H. Mano H. Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas.Int J Cancer. 2004; 108: 237-242Crossref PubMed Scopus (114) Google Scholar, 14Lubomierski N. Plotz G. Wormek M. Engels K. Kriener S. Trojan J. Jungling B. Zeuzem S. Raedle J. BRAF mutations in colorectal carcinoma suggest two entities of microsatellite-unstable tumors.Cancer. 2005; 104: 952-961Crossref PubMed Scopus (61) Google Scholar, 15Wang L. Cunningham J.M. Winters J.L. Guenther J.C. French A.J. Boardman L.A. Burgart L.J. McDonnell S.K. Schaid D.J. Thibodeau S.N. BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair.Cancer Res. 2003; 63: 5209-5212PubMed Google Scholar, 16Deng G. Bell I. Crawley S. Gum J. Terdiman J.P. Allen B.A. Truta B. Sleisenger M.H. Kim Y.S. BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer.Clin Cancer Res. 2004; 10: 191-195Crossref PubMed Scopus (332) Google Scholar), but are rarely observed in microsatellite-stable colon cancers (range, 2%–12%12Rajagopalan H. Bardelli A. Lengauer C. Kinzler K.W. Vogelstein B. Velculescu V.E. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status.Nature. 2002; 418: 934Crossref PubMed Scopus (1059) Google Scholar, 13Koinuma K. Shitoh K. Miyakura Y. Furukawa T. Yamashita Y. Ota J. Ohki R. Choi Y.L. Wada T. Konishi F. Nagai H. Mano H. Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas.Int J Cancer. 2004; 108: 237-242Crossref PubMed Scopus (114) Google Scholar, 14Lubomierski N. Plotz G. Wormek M. Engels K. Kriener S. Trojan J. Jungling B. Zeuzem S. Raedle J. BRAF mutations in colorectal carcinoma suggest two entities of microsatellite-unstable tumors.Cancer. 2005; 104: 952-961Crossref PubMed Scopus (61) Google Scholar, 15Wang L. Cunningham J.M. Winters J.L. Guenther J.C. French A.J. Boardman L.A. Burgart L.J. McDonnell S.K. Schaid D.J. Thibodeau S.N. BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair.Cancer Res. 2003; 63: 5209-5212PubMed Google Scholar, 16Deng G. Bell I. Crawley S. Gum J. Terdiman J.P. Allen B.A. Truta B. Sleisenger M.H. Kim Y.S. BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer.Clin Cancer Res. 2004; 10: 191-195Crossref PubMed Scopus (332) Google Scholar), suggesting a molecular ontogeny with the sessile serrated adenoma. Furthermore, the finding that BRAF mutations are very uncommon (range, 0%–5%9Kambara T. Simms L.A. Whitehall V.L. Spring K.J. Wynter C.V. Walsh M.D. Barker M.A. Arnold S. McGivern A. Matsubara N. Tanaka N. Higuchi T. Young J. Jass J.R. Leggett B.A. BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum.Gut. 2004; 53: 1137-1144Crossref PubMed Scopus (611) Google Scholar, 11Jass J.R. Baker K. Zlobec I. Higuchi T. Barker M. Buchanan D. Young J. Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a "fusion" pathway to colorectal cancer.Histopathology. 2006; 49: 121-131Crossref PubMed Scopus (230) Google Scholar) in traditional tubular adenomas also argues against their role as a precursor lesion for MSI-H cancers. Although not definitive, these findings collectively point to a risk of malignant transformation in SSAs through a novel pathway that involves DNA MSI and mutations in BRAF. The overall impact of SSAs on cancer risk in the population has been uncertain because their true prevalence is unknown. This is due, in part, to the difficulty in identifying these lesions endoscopically; they are easily missed because of their flat growth pattern and pale appearance (Figure 1E). In this issue of Gastroenterology, Spring et al17Spring K.J. Zhen Z.Z. Karamtic R. Walsh M.D. Whitehall V.L. Pike T. Simms L.A. Young J. James M. Montgomery G.W. Appleyard M. Hewett D. Togashi K. Jass J.R. Leggett B.A. High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy.Gastroenterology. 2006; : 131Google Scholar report on 189 patients who underwent colonoscopic high-magnification chromoendoscopy with indigo carmine for routine diagnostic indications or surveillance because of a personal or family history of polyps and cancer. None of the examinations was performed as routine screening in average-risk individuals. Among the most salient findings was the high prevalence of SSAs. Of all polyps identified, SSAs comprised 9%, whereas only 1.7% were mixed serrated/adenomatous polyps and 5 mm, 75% were located in the proximal colon, and 65% of all patients with SSAs were women. Those with SSAs were more likely to have multiple polyps than those without SSAs, but there was no correlation with age or personal or family history of polyps or cancer. On a molecular level, 78% of SSAs harbored a BRAF mutation, whereas an oncogenic K-ras mutation was only identified in 8%. Among the 248 tubular or tubulovillous adenomas analyzed from the same patients, only 1 had a BRAF mutation. These findings are consistent with previous reports that indicate a close link between BRAF mutations and SSAs. Perhaps more intriguing is the observation that BRAF mutations were much more common in the microvesicular subtype of hyperplastic polyp (70%) than the goblet cell-rich subtype (20%), raising the possibility that the microvesicular hyperplastic polyp may be a precursor lesion for the sessile serrated adenoma. The high proportion of SSAs in this population serves as a reminder that this is not a rare lesion and that conventional colonoscopy may be inadequate to detect the majority of them. It remains to be defined whether there is a similarly high prevalence of SSAs in the average risk population. Regardless, magnification chromoendoscopy is not a widely available option. However, chromoendoscopy alone may be available in many centers, and it would be of interest to determine the detection rate for this technique alone as well as in combination with magnification. Ultimately, any such specialized screening would be targeted to individuals at higher risk, but a convincing profile of the high-risk patient has yet to be defined. The serrated polyp, and the SSA in particular, has come front and center, but where do we go from here? On a molecular level, it would be of interest to define why polyps with BRAF and K-ras mutations behave so differently. From a clinical perspective, the precise risk of malignant transformation in SSAs needs to be defined, as well as if and at what rate microvesicular hyperplastic polyps develop into SSAs. In addition, it is not yet clear whether SSAs must progress through an intermediate stage as a tubular adenoma before the final transformation into cancer. The appropriate follow-up after resection of a sessile serrated adenoma has not been standardized. If these polyps are indeed precursors of MSI-H colon cancers, the possibility of a more rapid progression to cancer should be considered, because MSI tumors that arise in the setting of the hereditary nonpolyposis colorectal cancer/Lynch syndrome can exhibit rapid tumor progression, even within 1–2 years.19Jo W.S. Chung D.C. Genetics of hereditary colorectal cancer.Semin Oncol. 2005; 32: 11-23Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 20Chung D.C. Rustgi A.K. The hereditary nonpolyposis colorectal cancer syndrome: genetics and clinical implications.Ann Intern Med. 2003; 138: 560-570Crossref PubMed Scopus (248) Google Scholar Until more data are available, it would be prudent to recommend complete resection of SSAs and surveillance examinations at least as frequent as the intervals established for adenomatous polyps. An essential prerequisite for all future studies is the standardization of nomenclature for serrated polyps, and the terminology proposed by the Rodger C. Haggitt Gastrointestinal Pathology Society (Figure 1) is an important step in that direction.1Snover D.C. Jass J.R. Fenoglio-Preiser C. Batts K.P. Serrated polyps of the large intestine: a morphologic and molecular review of an evolving concept.Am J Clin Pathol. 2005; 124: 380-391Crossref PubMed Scopus (392) Google Scholar Although there may be additional modifications in the future, it is critical to embrace these guidelines now to facilitate meaningful lines of investigation and the development of rational clinical recommendations. Our understanding of the biology of the serrated polyp is far from complete. Nevertheless, serrated polyps have indeed come of age, and now is the time for gastroenterologists and pathologists alike to recognize their diversity as well as their importance.