Portal de Periódicos da CAPES

Serrated Colon Polyps as Precursors to Colorectal Cancer

2012; Elsevier BV; Volume: 11; Issue: 7 Linguagem: Inglês

10.1016/j.cgh.2012.12.004

1542-7714

Seth Sweetser, Thomas C. Smyrk, Frank A. Sinicrope,

Genetic factors in colorectal cancer

Identification of the serrated neoplasia pathway has improved our understanding of the pathogenesis of colorectal cancer (CRC). Insights include an increased recognition of the malignant potential of different types of serrated polyps such as sessile and traditional serrated adenomas. Sessile serrated adenomas share molecular features with colon tumors that have microsatellite instability and a methylator phenotype, indicating that these lesions are precursors that progress via the serrated neoplasia pathway. These data have important implications for clinical practice and CRC prevention, because hyperplastic polyps were previously regarded as having no malignant potential. There is also evidence that the serrated pathway contributes to interval or missed cancers. Endoscopic detection of serrated polyps is a challenge because they are often inconspicuous with indistinct margins and are frequently covered by adherent mucus. It is important for gastroenterologists to recognize the subtle endoscopic features of serrated polyps to facilitate their detection and removal, and thereby ensure a high-quality colonoscopic examination. Recognition of the role of serrated polyps in colon carcinogenesis has led to the inclusion of these lesions in postpolypectomy surveillance guidelines. However, an enhanced effort is needed to identify and completely remove serrated adenomas, with the goal of increasing the effectiveness of colonoscopy to reduce CRC incidence. Identification of the serrated neoplasia pathway has improved our understanding of the pathogenesis of colorectal cancer (CRC). Insights include an increased recognition of the malignant potential of different types of serrated polyps such as sessile and traditional serrated adenomas. Sessile serrated adenomas share molecular features with colon tumors that have microsatellite instability and a methylator phenotype, indicating that these lesions are precursors that progress via the serrated neoplasia pathway. These data have important implications for clinical practice and CRC prevention, because hyperplastic polyps were previously regarded as having no malignant potential. There is also evidence that the serrated pathway contributes to interval or missed cancers. Endoscopic detection of serrated polyps is a challenge because they are often inconspicuous with indistinct margins and are frequently covered by adherent mucus. It is important for gastroenterologists to recognize the subtle endoscopic features of serrated polyps to facilitate their detection and removal, and thereby ensure a high-quality colonoscopic examination. Recognition of the role of serrated polyps in colon carcinogenesis has led to the inclusion of these lesions in postpolypectomy surveillance guidelines. However, an enhanced effort is needed to identify and completely remove serrated adenomas, with the goal of increasing the effectiveness of colonoscopy to reduce CRC incidence. Colorectal carcinoma (CRC) is the most common gastrointestinal malignancy worldwide,1Jemal A. Bray F. Center M.M. et al.Global cancer statistics.CA Cancer J Clin. 2011; 61: 69-90Crossref PubMed Scopus (30939) Google Scholar and most cases originate from identifiable precursor lesions. Traditionally, epithelial polyps of the colorectum were classified as either hyperplastic or adenomatous, with adenomatous polyps representing the principal precursor to CRCs. However, advances in the molecular understanding of CRC indicate that it is a heterogeneous disorder arising via multiple pathways including the serrated pathway. In this pathway, a distinct subtype of serrated polyps (known as sessile serrated adenomas [SSA/Ps]) has become recognized as an important contributor to CRC incidence.2Huang C.S. Farraye F.A. Yang S. et al.The clinical significance of serrated polyps.Am J Gastroenterol. 2011; 106: 229-240Crossref PubMed Scopus (147) Google Scholar Serrated polyps have distinct histopathologic features. Their often subtle appearance at endoscopy poses challenges for endoscopic detection and removal, which are critical for CRC prevention. In this article, we review the classification of serrated polyps, the molecular characteristics of the serrated neoplasia pathway, and the detection and appropriate management of these lesions. Serrated polyps are heterogeneous lesions characterized histologically by glandular serration, ie, a "saw-toothed" infolding of colonic crypt epithelium. This feature is believed to be the result of increased cell turnover combined with delayed migration or failure of apoptosis at the mucosal surface, leading to an accumulation of epithelial cells that are accommodated by infolding (serration) of the epithelial crypt lining.3Torlakovic E. Skovlund E. Snover D.C. et al.Morphologic reappraisal of serrated colorectal polyps.Am J Clin Pathol. 2003; 27: 65-81Google Scholar Historically, polyps with serrated architecture were considered indolent, hyperproliferative, non-neoplastic hyperplastic polyps (HPs). It is now recognized that several distinct subtypes of serrated polyps exist, and a subset may progress to invasive cancer through a serrated neoplasia pathway. Serrated polyp nomenclature is in evolution. The most recent classification by the World Health Organization categorizes them into 2 main groups that are based on the presence or absence of dysplasia (Table 1). This includes serrated polyp subtypes: HP, SSA/P, SSA/P with cytologic dysplasia, and traditional serrated adenoma (TSA).4Snover D.C. Ahnen D. Burt R. et al.Serrated polyps of the colon and rectum and serrated polyposis.in: Bosman F.T. Carneiro F. Hruban R.H. WHO classification of tumours of the digestive system. 4th ed. IARC, Lyon2010Google ScholarTable 1World Health Organization Classification of Serrated Polyps4Snover D.C. Ahnen D. Burt R. et al.Serrated polyps of the colon and rectum and serrated polyposis.in: Bosman F.T. Carneiro F. Hruban R.H. WHO classification of tumours of the digestive system. 4th ed. IARC, Lyon2010Google ScholarNondysplasticDysplasticHPsSSA/P with dysplasia Goblet cell HP Microvesicular HP Mucin-poor HPSSA/PTSA Open table in a new tab The defining histologic feature of HPs is a saw-toothed pattern of epithelial infolding in the upper half of the crypt with a lack of cytologic dysplasia (Figure 1A). HPs are subclassified into microvesicular, goblet cell–rich, and mucin-poor variants.3Torlakovic E. Skovlund E. Snover D.C. et al.Morphologic reappraisal of serrated colorectal polyps.Am J Clin Pathol. 2003; 27: 65-81Google Scholar The microvesicular type is the most frequent type and is characterized by epithelial cells with small droplets of cytoplasmic mucin and decreased goblet cells. There is abundant serration in the upper portion of the crypt, but the crypt base is straight. The microvesicular subtype often has mutation in the BRAF oncogene, suggesting these could be precursors to SSA/P.5Yang S. Farraye F.A. Mack C. et al.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 (262) Google Scholar In contrast, goblet cell–rich HPs have abundant goblet cells, less superficial serration, and lack BRAF mutations. The rare mucin-poor HP, nearly devoid of cytoplasmic mucin, may have increased nuclear atypia. It remains unclear as to whether histologic subtyping of HPs has clinical utility; therefore, current guidelines advise against subtyping in routine clinical practice. SSA/Ps, like HPs, have serrated crypts, but the SSA/P crypts are distorted with widened, branching bases that are a typical feature (Figure 1B).3Torlakovic E. Skovlund E. Snover D.C. et al.Morphologic reappraisal of serrated colorectal polyps.Am J Clin Pathol. 2003; 27: 65-81Google Scholar Dysplasia, seen in conventional adenomas, is not a feature of SSA/Ps, but focal dysplasia may develop during tumor progression.3Torlakovic E. Skovlund E. Snover D.C. et al.Morphologic reappraisal of serrated colorectal polyps.Am J Clin Pathol. 2003; 27: 65-81Google Scholar, 6Goldstein N.S. Bhanot P. Odish E. et al.Hyperplastic-like colon polyps that preceded microsatellite-unstable adenocarcinomas.Am J Clin Pathol. 2003; 119: 778-796Crossref PubMed Scopus (263) Google Scholar The presence of typical dysplasia classifies the polyp as SSA/P with dysplasia (Figure 1C), which may represent an intermediary in molecular progression of SSA/P to malignancy.7Li S.C. Burgart L. Histopathology of serrated adenoma, its variants, and differentiation from conventional adenomatous and hyperplastic polyps.Arch Pathol Lab Med. 2007; 131: 440-445Crossref PubMed Google Scholar Colectomy specimens from CRC patients show serrated polyps more frequently, with tumors showing microsatellite instability (MSI).8Hawkins 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 (310) Google Scholar These data were often obtained before recognition of SSA/Ps as a distinct entity, and re-review of the histology has suggested that many of these lesions were SSA/Ps.9Snover D.C. Jass J.R. Fenoglio-Preiser C. et al.Serrated polyps of the large intestine.Am J Clin Pathol. 2005; 124: 380-391Crossref PubMed Scopus (398) Google Scholar When a remnant SSA/P is found adjacent to carcinoma, a transition zone of dysplasia is frequently present.9Snover D.C. Jass J.R. Fenoglio-Preiser C. et al.Serrated polyps of the large intestine.Am J Clin Pathol. 2005; 124: 380-391Crossref PubMed Scopus (398) Google Scholar Molecular profiling of SSA/Ps indicates that dysplastic areas are likely the immediate precursors of CRCs that show MSI.10Leggett B. Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis.Gastroenterology. 2010; 138: 2088-2100Abstract Full Text Full Text PDF PubMed Scopus (759) Google Scholar TSAs are also serrated but have villiform projections lined by hypereosinophilic cells.11Yantiss R.K. Oh K.Y. Chen Y.T. et al.Filiform serrated adenomas: a clinicopathologic and immunophenotypic study of 18 cases.Am J Surg Pathol. 2007; 31: 1238-1245Crossref PubMed Scopus (63) Google Scholar Premature crypt formation perpendicular to the longitudinal axis of the villus is a characteristic histologic feature known as ectopic crypt formation, whereby the crypts have lost anchoring to the underlying muscularis mucosae11Yantiss R.K. Oh K.Y. Chen Y.T. et al.Filiform serrated adenomas: a clinicopathologic and immunophenotypic study of 18 cases.Am J Surg Pathol. 2007; 31: 1238-1245Crossref PubMed Scopus (63) Google Scholar, 12Haramis A.P. Begthel H. van den Born M. et al.De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine.Science. 2004; 303: 1684-1686Crossref PubMed Scopus (633) Google Scholar (Figure 1D). In some TSAs, cytologic dysplasia is present, but in others, pale pink cells with minimal cytologic changes represent metaplastic, nonproliferating, or senescent cells.3Torlakovic E. Skovlund E. Snover D.C. et al.Morphologic reappraisal of serrated colorectal polyps.Am J Clin Pathol. 2003; 27: 65-81Google Scholar, 9Snover D.C. Jass J.R. Fenoglio-Preiser C. et al.Serrated polyps of the large intestine.Am J Clin Pathol. 2005; 124: 380-391Crossref PubMed Scopus (398) Google Scholar The TSA is a poorly understood histologic entity. The molecular characterization of TSAs has shown polyps with either KRAS or BRAF mutations that suggest distinct variants despite overlapping morphologic features.13Fu B. Yachida S. Morgan R. et al.Clinicopathologic and genetic characterization of traditional serrated adenomas of the colon.Am J Clin Pathol. 2012; 138: 356-366Crossref PubMed Scopus (52) Google Scholar Most CRCs develop from conventional adenomas through a molecular pathway characterized by chromosomal instability. However, approximately 15% of CRCs develop through an alternate pathway characterized by defective DNA mismatch repair (MMR) that gives rise to high-frequency MSI (MSI-H). MSI was first described in association with Lynch syndrome (hereditary nonpolyposis colorectal cancer) caused by germline mutations in MMR genes. In sporadic CRCs, MSI is a consequence of defective MMR caused by hypermethylation of the MLH1 MMR gene that frequently occurs in a background of increased methylation of CpG islands in gene promoter regions known as the CpG island-methylator phenotype (CIMP).14Toyota M. Ahuja N. Ohe-Toyota M. et al.CpG island methylator phenotype in colorectal cancer.Proc Natl Acad Sci U S A. 1999; 96: 8681-8686Crossref PubMed Scopus (2178) Google Scholar, 15Ogino S. Nosho K. Irahara N. et al.Prognostic significance and molecular associations of 18q loss of heterozygosity: a cohort study of microsatellite stable colorectal cancers.J Clin Oncol. 2009; 27: 4591-4598Crossref PubMed Scopus (99) Google Scholar, 16Rajagopalan H. Bardelli A. Lengauer C. et al.Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status.Nature. 2002; 418: 934Crossref PubMed Scopus (1088) Google Scholar CIMP is not exclusive to MSI tumors because it is infrequently found in tumors lacking MLH1 methylation or MSI.17Samowitz W.S. Albertsen H. Herrick J. et al.Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer.Gastroenterology. 2005; 129: 837-845Abstract Full Text Full Text PDF PubMed Scopus (495) Google Scholar Thus, CIMP CRCs include almost all sporadic cases with MSI and a proportion of CRCs that are microsatellite stable.15Ogino S. Nosho K. Irahara N. et al.Prognostic significance and molecular associations of 18q loss of heterozygosity: a cohort study of microsatellite stable colorectal cancers.J Clin Oncol. 2009; 27: 4591-4598Crossref PubMed Scopus (99) Google Scholar, 17Samowitz W.S. Albertsen H. Herrick J. et al.Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer.Gastroenterology. 2005; 129: 837-845Abstract Full Text Full Text PDF PubMed Scopus (495) Google Scholar, 18Weisenberger D.J. Siegmund K.D. Campan M. et al.CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.Nat Genet. 2006; 38: 787-793Crossref PubMed Scopus (1582) Google Scholar About 40% of CRCs with MSI and MLH1 hypermethylation carry hot-spot mutations (V600E) in codon 15 of the BRAF oncogene.17Samowitz W.S. Albertsen H. Herrick J. et al.Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer.Gastroenterology. 2005; 129: 837-845Abstract Full Text Full Text PDF PubMed Scopus (495) Google Scholar, 19Domingo E. Laiho P. Ollikainen M. et al.BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing.J Med Genet. 2004; 41: 664-668Crossref PubMed Scopus (300) Google Scholar Mutations in BRAF result in activation of the mitogen-activated protein kinase pathway that promotes cell proliferation and survival. The improved histologic classification of serrated polyps has enabled a comparison of molecular features that is based on polyp subtype. It is believed that most CRCs with the CIMP phenotype evolve through the serrated neoplasia pathway.20Arain M.A. Sawhney M. Sheikh S. et al.CIMP status of interval colon cancers: another piece to the puzzle.Am J Gastroenterol. 2010; 105: 1189-1195Crossref PubMed Scopus (286) Google Scholar, 21Jass J.R. Serrated adenoma of the colorectum and the DNA-methylator phenotype.Nat Clin Pract Oncol. 2005; 2: 398-405Crossref PubMed Scopus (166) Google Scholar A clear link has been found between serrated polyps, especially SSA/Ps, and sporadic CRCs showing MSI and CIMP.18Weisenberger D.J. Siegmund K.D. Campan M. et al.CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.Nat Genet. 2006; 38: 787-793Crossref PubMed Scopus (1582) Google Scholar By using a specific marker panel,18Weisenberger D.J. Siegmund K.D. Campan M. et al.CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.Nat Genet. 2006; 38: 787-793Crossref PubMed Scopus (1582) Google Scholar CIMP was detected in 7% of microvesicular HPs and in 48% of advanced serrated polyps.22Fernando W.D. Whitehall V.L. Leggett B.A. et al.SLC5A8 methlyation: CIMP and BRAF mutation in serrated polyps of the colorectum.J Gastroenterol Hepatol. 2008; 23: A218Crossref PubMed Scopus (98) Google Scholar CIMP positivity is frequent in proximal SSA/Ps,9Snover D.C. Jass J.R. Fenoglio-Preiser C. et al.Serrated polyps of the large intestine.Am J Clin Pathol. 2005; 124: 380-391Crossref PubMed Scopus (398) Google Scholar and SSA/P histology has been seen at the margins of MSI CRCs.9Snover D.C. Jass J.R. Fenoglio-Preiser C. et al.Serrated polyps of the large intestine.Am J Clin Pathol. 2005; 124: 380-391Crossref PubMed Scopus (398) Google Scholar, 23Mäkinen M.J. George S.M. Jernvall P. et al.Colorectal carcinoma associated with serrated adenoma: prevalence, histological features, and prognosis.J Pathol. 2001; 193: 286-294Crossref PubMed Scopus (221) Google Scholar If hypermethylation inactivates MLH1 early in the serrated pathway, then a MSI-H CRC will result. BRAF and KRAS mutations are early molecular alterations in serrated lesions24Beach R. Chan A.O. Wu T.T. et al.BRAF mutations in aberrant crypt foci and hyperplastic polyposis.Am J Pathol. 2005; 166: 1069-1075Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar and are mutually exclusive in colorectal neoplasms.16Rajagopalan H. Bardelli A. Lengauer C. et al.Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status.Nature. 2002; 418: 934Crossref PubMed Scopus (1088) Google Scholar A simplified diagram of these 2 serrated pathways is shown in Figure 2. CIMP has been shown to be strongly associated with point mutations in BRAF.25Kambara T. Simms L.A. Whitehall V.L. et al.BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum.Gut. 2004; 53: 1137-1144Crossref PubMed Scopus (633) Google Scholar BRAF V600E mutation is an early event in the serrated pathway that is detected frequently in microvesicular HPs and in most SSA/Ps that also display a high level of CIMP.5Yang S. Farraye F.A. Mack C. et al.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 (262) Google Scholar In contrast, BRAF mutations are not found in conventional adenomas.25Kambara T. Simms L.A. Whitehall V.L. et al.BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum.Gut. 2004; 53: 1137-1144Crossref PubMed Scopus (633) Google Scholar Importantly, neither BRAF mutations nor CIMP are found in CRCs with germline MMR mutations that result in Lynch syndrome, thereby highlighting their association with the serrated pathway. Taken together, these findings support the notion that SSA/Ps are the precursor lesions of sporadic MSI CRC. Although this end point does intersect with the end point in Lynch syndrome, it is important to remember that the major precursor lesion of CRCs in Lynch syndrome is the adenoma, not a serrated polyp. Compelling evidence supports a serrated neoplasia pathway, with SSA/Ps bearing BRAF mutations as precursors of high-frequency MSI and/or CIMP-high CRCs.5Yang S. Farraye F.A. Mack C. et al.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 (262) Google Scholar, 25Kambara T. Simms L.A. Whitehall V.L. et al.BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum.Gut. 2004; 53: 1137-1144Crossref PubMed Scopus (633) Google Scholar A second pathway involves CIMP-low and microsatellite stable cancers that are associated with KRAS mutations. A precursor lesion of this second pathway may be the TSA. An additional feature of this second putative serrated pathway is silencing of the DNA repair gene methylguanine methyltransferase by promoter hypermethylation, which has been associated with KRAS mutation and CIMP-low status.26Whitehall V.L. Walsh M.D. Young J. et al.Methylation of O–6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability.Cancer Res. 2001; 61: 827-830PubMed Google Scholar, 27Ogino S. Kawasaki T. Ogawa A. et al.TGFBR2 mutation is correlated with CpG island methylator phenotype in microsatellite instability-high colorectal cancer.Hum Pathol. 2007; 38: 614-620Crossref PubMed Scopus (43) Google Scholar Further support for at least 2 serrated neoplasia pathways is the finding that KRAS and BRAF mutations segregate with lesion type, ie, polypoid vs flat, respectively.28Yamagata S. Muto T. Uchida Y. et al.Polypoid growth and K-ras codon 12 mutation in colorectal cancer.Cancer. 1995; 75: 953-957Crossref PubMed Scopus (87) Google Scholar KRAS mutations are common in rectal and polypoid TSAs29Torlakovic E.E. Gomez J.D. Driman D.K. et al.Sessile serrated adenoma (SSA) vs traditional serrated adenoma (TSA).Am J Clin Pathol. 2008; 32: 21-29Google Scholar but are rare in SSA/Ps.25Kambara T. Simms L.A. Whitehall V.L. et al.BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum.Gut. 2004; 53: 1137-1144Crossref PubMed Scopus (633) Google Scholar In aggregate, data suggest that approximately 30% of colonic adenocarcinomas derive from the serrated neoplasia pathway.10Leggett B. Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis.Gastroenterology. 2010; 138: 2088-2100Abstract Full Text Full Text PDF PubMed Scopus (759) Google Scholar By far, the most common serrated polyp is the conventional HP, which accounts for 70%–95% of all serrated polyps30Carr N.J. Mahajan H. Tan K.L. et al.Serrated and non-serrated polyps of the colorectum: their prevalence in an unselected case series and correlation of BRAF mutation analysis with the diagnosis of sessile serrated adenoma.J Clin Pathol. 2009; 62: 516-518Crossref PubMed Scopus (180) Google Scholar, 31Spring K.J. Zhao Z.Z. Karamatic R. et al.High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy.Gastroenterology. 2006; 131: 1400-1407Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar and most frequently occurs in the rectosigmoid colon.31Spring K.J. Zhao Z.Z. Karamatic R. et al.High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy.Gastroenterology. 2006; 131: 1400-1407Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar SSA/Ps account for 5%–25% of serrated polyps and occur predominantly in the proximal colon.30Carr N.J. Mahajan H. Tan K.L. et al.Serrated and non-serrated polyps of the colorectum: their prevalence in an unselected case series and correlation of BRAF mutation analysis with the diagnosis of sessile serrated adenoma.J Clin Pathol. 2009; 62: 516-518Crossref PubMed Scopus (180) Google Scholar, 31Spring K.J. Zhao Z.Z. Karamatic R. et al.High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy.Gastroenterology. 2006; 131: 1400-1407Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar, 32Lash R.H. Genta R.M. Schuler C.M. Sessile serrated adenomas: prevalence of dysplasia and carcinoma in 2139 patients.J Clin Pathol. 2010; 63: 681-686Crossref PubMed Scopus (249) Google Scholar, 33Hetzel J.T. Huang C.S. Coukos J.A. et al.Variation in the detection of serrated polyps in an average risk colorectal cancer screening cohort.Am J Gastroenterol. 2010; 105: 2656-2664Crossref PubMed Scopus (279) Google Scholar Although the prevalence of SSA/Ps varies depending on the clinical study, the overall prevalence varies from 2%–9%.30Carr N.J. Mahajan H. Tan K.L. et al.Serrated and non-serrated polyps of the colorectum: their prevalence in an unselected case series and correlation of BRAF mutation analysis with the diagnosis of sessile serrated adenoma.J Clin Pathol. 2009; 62: 516-518Crossref PubMed Scopus (180) Google Scholar, 31Spring K.J. Zhao Z.Z. Karamatic R. et al.High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy.Gastroenterology. 2006; 131: 1400-1407Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar, 32Lash R.H. Genta R.M. Schuler C.M. Sessile serrated adenomas: prevalence of dysplasia and carcinoma in 2139 patients.J Clin Pathol. 2010; 63: 681-686Crossref PubMed Scopus (249) Google Scholar, 33Hetzel J.T. Huang C.S. Coukos J.A. et al.Variation in the detection of serrated polyps in an average risk colorectal cancer screening cohort.Am J Gastroenterol. 2010; 105: 2656-2664Crossref PubMed Scopus (279) Google Scholar However, a recent study evaluating the prevalence of serrated polyps in the proximal colon in average-risk individuals undergoing screening colonoscopy found the prevalence of SSA/Ps to be as high as 20%.34Kahi C.J. Li X. Eckert G.J. et al.High colonoscopic prevalence of proximal colon serrated polyps in average-risk men and women.Gastrointest Endosc. 2012; 75: 515-520Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar TSAs are much less common than SSA/Ps and account for only <1% of all colorectal polyps.30Carr N.J. Mahajan H. Tan K.L. et al.Serrated and non-serrated polyps of the colorectum: their prevalence in an unselected case series and correlation of BRAF mutation analysis with the diagnosis of sessile serrated adenoma.J Clin Pathol. 2009; 62: 516-518Crossref PubMed Scopus (180) Google Scholar, 31Spring K.J. Zhao Z.Z. Karamatic R. et al.High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy.Gastroenterology. 2006; 131: 1400-1407Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar TSAs typically occur in the distal colon and rectum and tend to have a pedunculated or broad-based polypoid growth pattern when compared with SSA/P.29Torlakovic E.E. Gomez J.D. Driman D.K. et al.Sessile serrated adenoma (SSA) vs traditional serrated adenoma (TSA).Am J Clin Pathol. 2008; 32: 21-29Google Scholar Although uncommon, TSAs are likely precursor lesions to some CRCs, as suggested by Longacre and Fenoglio-Preiser,35Longacre 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 (620) Google Scholar who showed that 11% of TSAs contain intramucosal carcinoma. The primary risk factors for serrated neoplasia are common to subjects with conventional adenomas and include the combined effects of inherited (genetic) susceptibility and environmental factors. Environmental factors that increase the risk for serrated neoplasia include lifestyle and diet. In a study by Wallace et al,36Wallace K. Grau M.V. Ahnen D. et al.The association of lifestyle and dietary factors with the risk for serrated polyps of the colorectum.Cancer Epidemiol Biomarkers Prev. 2009; 18: 2310-2317Crossref PubMed Scopus (131) Google Scholar obesity, dietary fat, cigarette smoking, total energy intake, and red meat were associated with an increased risk of serrated polyps in the left colon, whereas a family history of polyps and folate supplementation were associated with an increased risk of serrated polyps in the proximal colon. Cigarette smoking is associated with an increased risk of conventional adenomas and CRC. Studies examining the association of cigarette smoking and incident CRC have found that smokers have a significantly higher risk of tumors with MSI, CIMP, and BRAF mutations.37Limsui D. Vierkant R.A. Tillmans L.S. et al.Cigarette smoking and colorectal cancer risk by molecularly defined subtypes.J Natl Cancer Inst. 2010; 102: 1012-1022Crossref PubMed Scopus (234) Google Scholar These molecular features, characteristic of SSA/Ps, suggest that cigarette smoking increases CRC risk via the serrated neoplasia pathway. Jeevaratnam et al38Jeevaratnam P. Cottier D.S. Browett P.J. et al.Familial giant hyperplastic polyposis predisposing to colorectal cancer: a new hereditary bowel cancer syndrome.J Pathol. 1996; 179: 20-25Crossref PubMed Scopus (152) Google Scholar first described the possibility of a familial serrated polyposis syndrome (SPS) in 1996. Subsequently, cases of hyperplastic polyposis with synchronous adenocarcinoma were reported, and it is now recognized that individuals with hyperplastic polyposis may present with synchronous cancers of the colorectum in up to 25% or more cases.26Whitehall V.L. Walsh M.D. Young J. et al.Methylation of O–6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability.Cancer Res. 2001; 61: 827-830PubMed Google Scholar, 39Boparai K.S. Reitsma J.B. Lemmens V. et al.Increased colorectal cancer risk in first-degree relatives of patients with hyperplastic polyposis syndrome.Gut. 2010; 59: 1222-1225Crossref PubMed Scopus (109) Google Scholar, 40Kalady M.F. Jarrar A. Leach B. et al.Defining phenotypes and cancer risk in hyperplastic polyposis syndrome.Dis Colon Rectum. 2011; 54: 164-170Crossref PubMed Scopus (101) Google Scholar, 41Chow E. Lipton L. Lynch E. et al.Hyperplastic polyposis syndrome: phenot