Terminology, Molecular Features, Epidemiology, and Management of Serrated Colorectal Neoplasia

In addition to the adenoma to carcinoma sequence, colorectal carcinogenesis can occur via the serrated pathway. Studies have focused on clarification of categories and molecular features of serrated polyps, as well as endoscopic detection and risk assessment. Guidelines from the World Health Organization propose assigning serrated polyps to categories of hyperplastic polyps, traditional serrated adenomas, and sessile serrated lesions (SSLs). Traditional serrated adenomas and SSLs are precursors to colorectal cancer. The serrated pathway is characterized by mutations in RAS and RAF, disruptions to the Wnt signaling pathway, and widespread methylation of CpG islands. Epidemiology studies of serrated polyps have been hampered by inconsistencies in terminology and reporting, but the prevalence of serrated class polyps is 20%–40% in average-risk individuals; most serrated polyps detected are hyperplastic. SSLs, the most common premalignant serrated subtype, and are found in up to 15% of average-risk patients by high-detecting endoscopists. Variations in rate of endoscopic detection of serrated polyps indicate the need for careful examination, with adequate bowel preparation and sufficient withdrawal times. Risk factors for SSLs include white race, family history of colorectal cancer, smoking, and alcohol intake. Patients with serrated polyps, particularly SSLs and traditional serrated adenomas, have an increased risk of synchronous and metachronous advanced neoplasia. Surveillance guidelines vary among countries, but SSLs and proximal hyperplastic polyps require special attention in assignment of surveillance interval—especially in light of concerns regarding incomplete detection and resection. In addition to the adenoma to carcinoma sequence, colorectal carcinogenesis can occur via the serrated pathway. Studies have focused on clarification of categories and molecular features of serrated polyps, as well as endoscopic detection and risk assessment. Guidelines from the World Health Organization propose assigning serrated polyps to categories of hyperplastic polyps, traditional serrated adenomas, and sessile serrated lesions (SSLs). Traditional serrated adenomas and SSLs are precursors to colorectal cancer. The serrated pathway is characterized by mutations in RAS and RAF, disruptions to the Wnt signaling pathway, and widespread methylation of CpG islands. Epidemiology studies of serrated polyps have been hampered by inconsistencies in terminology and reporting, but the prevalence of serrated class polyps is 20%–40% in average-risk individuals; most serrated polyps detected are hyperplastic. SSLs, the most common premalignant serrated subtype, and are found in up to 15% of average-risk patients by high-detecting endoscopists. Variations in rate of endoscopic detection of serrated polyps indicate the need for careful examination, with adequate bowel preparation and sufficient withdrawal times. Risk factors for SSLs include white race, family history of colorectal cancer, smoking, and alcohol intake. Patients with serrated polyps, particularly SSLs and traditional serrated adenomas, have an increased risk of synchronous and metachronous advanced neoplasia. Surveillance guidelines vary among countries, but SSLs and proximal hyperplastic polyps require special attention in assignment of surveillance interval—especially in light of concerns regarding incomplete detection and resection. Approximately 25% of sporadic colorectal cancers (CRCs) arise via serrated precursor lesions, but this was not always well recognized. Before 2010, neoplastic serrated lesions were not well detected by endoscopists and were generally interpreted as harmless hyperplastic polyps (HPs) by pathologists, despite histologic evidence for progression in rare cases.1Longacre 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 Google Scholar, 2Goldman H. Ming S. Hickock D.F. Nature and significance of hyperplastic polyps of the human colon.Arch Pathol. 1970; 89: 349-354PubMed Google Scholar There is still a great deal of misunderstanding surrounding serrated polyps with respect to terminology, classification, and risk assessment. In part, this is due to confusing nomenclature, varied and changing pathology criteria, and uncertainties about prognosis. Additionally, knowledge about the importance of serrated neoplasia in CRC prevention has been disseminated relatively slowly to pathologists and gastroenterologists. Serrated polyps is an umbrella term that encompasses HPs, sessile serrated lesions (SSLs), and traditional serrated adenomas (TSAs) (Figure 1A). HPs are the most common, comprising approximately 75% all serrated polyps. SSLs (previously called sessile serrated adenomas or sessile serrated polyps) account for approximately 25% of serrated polyps. In general, SSLs are characterized by a larger size (Supplementary Figure 1A), location in the proximal colon, and a distinct endoscopic appearance compared with HPs. TSAs are the least-common type of serrated polyp, and are typically polypoid lesions found in the distal colorectum. SSLs and TSAs are each considered precursor lesions for CRC.3World Health OrganisationClassification of Tumours of the Digestive Tract. IARC Press, Lyon2019Google Scholar We review what we have learned about serrated lesions, the recently updated World Health Organization (WHO) criteria for management of serrated neoplasias, and their molecular features. We discuss the epidemiology of serrated polyps, detection of premalignant serrated polyps by various CRC screening tests (particularly SSLs), and surveillance recommendations for patients with serrated polyps. Our increased insight into the development of serrated polyps is reflected in the increasing complexity of the different subtypes identified. Through the 1990s, most polyps with serrated architecture were classified as metaplastic or HPs, but there are now at least 3 well-described serrated polyp entities. With every new edition of the WHO classification system, changes in definitions cause changes in reported distributions and clinical impact (Figure 1B). HPs are identified by exclusion—if in a well-oriented tissue section, the architectural criteria for SSL are not met.3World Health OrganisationClassification of Tumours of the Digestive Tract. IARC Press, Lyon2019Google Scholar Because the characteristics of SSLs are mainly observed in the deeper parts of the crypts, the orientation of biopsies is essential for an adequate diagnosis. The overall architecture of HP is unchanged compared with the normal colonic mucosa, and crypts remain evenly spaced. The superficial epithelium shows serration, which might cover the upper two-thirds of the crypts (Figure 1A). Two variants of HPs are the microvesicular type and the goblet cell–rich hyperplastic polyps. Goblet cell–rich hyperplastic polyps have subtle morphologic alterations, such as surface tufting and increased numbers of goblet cells, resulting in small polyps. Microvesicular hyperplastic polyp are easily recognized and characterized by microvesicular epithelial cells with abundant cytoplasm, with clear stellate lumina in cross-sectioned crypts. A third subtype was described (the mucin-poor type), but it is no longer considered a separate subtype—these lesions are caused by regenerative changes in damaged microvesicular hyperplastic polyps.3World Health OrganisationClassification of Tumours of the Digestive Tract. IARC Press, Lyon2019Google Scholar The WHO recommends use of the term sessile serrated lesion vs other terms, such as sessile serrated adenoma, sessile serrated polyp, or sessile serrated adenoma/polyp.3World Health OrganisationClassification of Tumours of the Digestive Tract. IARC Press, Lyon2019Google Scholar The major feature that distinguishes SSLs from HPs is architectural distortion, which is most likely a result of alterations in the proliferative zone of the crypts. According to the updated WHO criteria, the presence of a single unequivocally distorted crypt is considered diagnostic for SSL.3World Health OrganisationClassification of Tumours of the Digestive Tract. IARC Press, Lyon2019Google Scholar Crypt distortion can be present in different forms, such as horizontal crypts, dilated crypts (basal third of the crypt), and/or crypts that have serrations extending in the crypt base. Branching crypts are no longer considered diagnostic of SSL, although these frequently occur in combination with other crypt abnormalities. Clinical features, such as size, location, and endoscopic appearance can support identification of SSL, but are not sufficient for identification. Other features that support identification are the presence of mucosal prolapse or stromal proliferations. Mucosal prolapse is also known as herniation through the muscularis mucosa, pseudoinvasion, epithelial misplacement, or inverted crypts. It is rare in patients with HP.4Hu K. Shen S. Zhang L. Herniation of crypts in hyperplastic polyp and sessile serrated adenoma: a prospective study.Am J Cancer Res. 2018; 8: 144-153PubMed Google Scholar The exact etiology is unknown, so this phenomenon has not been given a name yet. Stromal proliferation includes perineural proliferation as well as lipomatosis. More than 6% of SSLs have perineural-like stromal proliferations that can be detected during histology analysis5Pai R.K. Mojtahed A. Rouse R.V. et al.Histologic and molecular analyses of colonic perineurial-like proliferations in serrated polyps: perineurial-like stromal proliferations are seen in sessile serrated adenomas.Am J Surg Pathol. 2011; 35: 1373-1380Crossref PubMed Scopus (0) Google Scholar and do not share the BRAF mutations present in the epithelial component.6Erlenbach-Wunsch K. Bihl M. Hartmann A. et al.Serrated epithelial colorectal polyps (hyperplastic polyps, sessile serrated adenomas) with perineurial stroma: clinicopathological and molecular analysis of a new series.Ann Diagn Pathol. 2018; 35: 48-52Crossref PubMed Scopus (2) Google Scholar The clinical implications of these minor histologic features are not clear. Progression of SSLs into SSLs with dysplasia (SSL-D) is not frequent—approximately 4%–8% of SSLs contain dysplasia.7Yang J.F. Tang S.J. Lash R.H. et al.Anatomic distribution of sessile serrated adenoma/polyp with and without cytologic dysplasia.Arch Pathol Lab Med. 2015; 139: 388-393Crossref PubMed Scopus (21) Google Scholar, 8Abdeljawad K. Vemulapalli K.C. Kahi C.J. et al.Sessile serrated polyp prevalence determined by a colonoscopist with a high lesion detection rate and an experienced pathologist.Gastrointest Endosc. 2015; 81: 517-524Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar At least 3 different morphologic types of dysplasia have been described in SSL-D,9Liu C. Walker N.I. Leggett B.A. et al.Sessile serrated adenomas with dysplasia: morphological patterns and correlations with MLH1 immunohistochemistry.Mod Pathol. 2017; 30: 1728-1738Crossref PubMed Scopus (24) Google Scholar, 10Cenaj O. Gibson J. Odze R.D. Clinicopathologic and outcome study of sessile serrated adenomas/polyps with serrated versus intestinal dysplasia.Mod Pathol. 2018; 31: 633-642Crossref PubMed Scopus (6) Google Scholar which often occur within the same lesion. Intestinal dysplasia is similar to the dysplasia observed in conventional adenomas, and is relatively rare. There is no loss of MLH1 staining, and there seems to be no progression to CRC in these lesions, especially when there is low-grade dysplasia.9Liu C. Walker N.I. Leggett B.A. et al.Sessile serrated adenomas with dysplasia: morphological patterns and correlations with MLH1 immunohistochemistry.Mod Pathol. 2017; 30: 1728-1738Crossref PubMed Scopus (24) Google Scholar, 10Cenaj O. Gibson J. Odze R.D. Clinicopathologic and outcome study of sessile serrated adenomas/polyps with serrated versus intestinal dysplasia.Mod Pathol. 2018; 31: 633-642Crossref PubMed Scopus (6) Google Scholar Serrated dysplasia is more common and is characterized by eosinophilic cytoplasm and tightly packed small glands, and its presence can be considered to represent progression to a TSA.11Bettington M.L. Walker N.I. Rosty C. et al.A clinicopathological and molecular analysis of 200 traditional serrated adenomas.Mod Pathol. 2015; 28: 414-427Crossref PubMed Google Scholar Nuclear atypia and mitotic activity are pronounced, and loss of MLH1 staining is infrequent. The third pattern is the minimal deviation dysplasia, with limited changes compared to SSL, and characteristic loss of MLH1. Most SSL-Ds, however, have an undefined pattern of dysplasia, with loss of MLH1 expression in up to 80% of cases.9Liu C. Walker N.I. Leggett B.A. et al.Sessile serrated adenomas with dysplasia: morphological patterns and correlations with MLH1 immunohistochemistry.Mod Pathol. 2017; 30: 1728-1738Crossref PubMed Scopus (24) Google Scholar Immunohistochemical analysis for MLH1 is important for determining the presence of clinically important dysplasia in SSLs—loss of MLH1 staining confirms the presence of dysplasia. However, the normal staining pattern can be retained in some cases of evident dysplasia. The different types of dysplasia have limited diagnostic value, but are increasingly studied in research into progression of SSLs, in combination with their molecular features. It is important to be aware of these different SSL-D in clinical practice. TSAs are villous polyps with cells that contain prominent eosinophilic cytoplasm and pencillate nuclei. The pattern of serration is different from that of SSLs or HPs, and features narrow slits (Figure 1A). Ectopic crypts, a diagnostic features of TSAs, are found mainly in larger, distally located lesions.11Bettington M.L. Walker N.I. Rosty C. et al.A clinicopathological and molecular analysis of 200 traditional serrated adenomas.Mod Pathol. 2015; 28: 414-427Crossref PubMed Google Scholar Ectopic crypts develop orthogonally to the crypt axis and therefore have no connection to the muscularis mucosae. They contain actively proliferating cells that have aberrant expression of GREM1. Variants in the GREM1 gene have been associated with hereditary mixed polyposis syndrome.12Davis H. Irshad S. Bansal M. et al.Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche.Nat Med. 2015; 21: 62-70Crossref PubMed Scopus (111) Google Scholar Lesions with characteristics of SSLs and TSAs should be classified as TSAs. Older clinical specimens and studies included serrated polyps that were misidentified, compared with modern criteria. Studies have evaluated the effects of reviewing these specimens, to establish the accuracy of identification based on histologic features, and mainly focused on the distinction between HP and SSL. This distinction is a significant challenge—multiple studies have reported considerable inter-observer variability in identification of HPs, and of SSLs in particular.13Ensari A. Bilezikci B. Carneiro F. et al.Serrated polyps of the colon: how reproducible is their classification?.Virchows Arch. 2012; 461: 495-504Crossref PubMed Scopus (0) Google Scholar, 14Rau T.T. Agaimy A. Gehoff A. et al.Defined morphological criteria allow reliable diagnosis of colorectal serrated polyps and predict polyp genetics.Virchows Arch. 2014; 464: 663-672Crossref PubMed Scopus (24) Google Scholar, 15Wong N.A. Hunt L.P. Novelli M.R. et al.Observer agreement in the diagnosis of serrated polyps of the large bowel.Histopathology. 2009; 55: 63-66Crossref PubMed Scopus (0) Google Scholar See Figure 1 for the variations in identification attributable to modifications in WHO definitions. Revision of cases performed from 2000 to 2010 indicate the increasing recognition of SSLs. One study during this time period reviewed more than 1400 HPs, and reclassified 6% of HPs as SSLs.16Lu F.I. van Niekerk de W. Owen D. et al.Longitudinal outcome study of sessile serrated adenomas of the colorectum: an increased risk for subsequent right-sided colorectal carcinoma.Am J Surg Pathol. 2010; 34: 927-934Crossref PubMed Scopus (131) Google Scholar After SSLs (then called SSA/Ps) were included in the WHO classification of 2010, 8%–19% of HPs were reclassified as SSLs.17Schramm C. Kaiser M. Drebber U. et al.Factors associated with reclassification of hyperplastic polyps after pathological reassessment from screening and surveillance colonoscopies.Int J Colorectal Dis. 2016; 31: 319-325Crossref PubMed Scopus (8) Google Scholar, 18Singh H. Bay D. Ip S. et al.Pathological reassessment of hyperplastic colon polyps in a city-wide pathology practice: implications for polyp surveillance recommendations.Gastrointest Endosc. 2012; 76: 1003-1008Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 19Lin Y.C. Chiu H.M. Lee Y.C. et al.Hyperplastic polyps identified during screening endoscopy: reevaluated by histological examinations and genetic alterations.J Formos Med Assoc. 2014; 113: 417-421Crossref PubMed Google Scholar When only larger HPs were taken into account, the proportion of reclassified HPs was as high as 28%.20Tinmouth J. Henry P. Hsieh E. et al.Sessile serrated polyps at screening colonoscopy: have they been under diagnosed?.Am J Gastroenterol. 2014; 109: 1698-1704Crossref PubMed Scopus (23) Google Scholar, 21Kim S.W. Cha J.M. Lee J.I. et al.A significant number of sessile serrated adenomas might not be accurately diagnosed in daily practice.Gut Liver. 2010; 4: 498-502Crossref PubMed Scopus (15) Google Scholar Application of the 1 crypt rule, per the recent revised WHO criteria, likely increases the sensitivity of detection of SSLs further. Bettington et al22Bettington M. Walker N. Rosty C. et al.Critical appraisal of the diagnosis of the sessile serrated adenoma.Am J Surg Pathol. 2014; 38: 158-166Crossref PubMed Scopus (55) Google Scholar reported that the application of this criterion resulted in a 7% increase in the proportion of serrated polyps classified as SSLs. An additional benefit of this new definition is improved inter-observer agreement compared with the 4th edition WHO criteria.23Snover D.C. Ahnen D. Burt R. Odze R.D. Serrated Polyps of the Colon and Rectum and Serrated Polyposis.WHO Classification of Tumours of the Digestive System. 4th ed. IARC Press, Lyon, France2010Google Scholar, 24Kolb J.M. Morales S.J. Rouse N.A. et al.Does better specimen orientation and a simplified grading system promote more reliable histologic interpretation of serrated colon polyps in the community practice setting? Results of a nationwide study.J Clin Gastroenterol. 2016; 50: 233-238Crossref PubMed Scopus (7) Google Scholar Inter-observer agreement can be further improved by better orientation of polyps25Morales S.J. Bodian C.A. Kornacki S. et al.A simple tissue-handling technique performed in the endoscopy suite improves histologic section quality and diagnostic accuracy for serrated polyps.Endoscopy. 2013; 45: 897-905Crossref PubMed Scopus (0) Google Scholar and by training.26IJspeert J.E.G. Madani A. Overbeek L.I. et al.Implementation of an e-learning module improves consistency in the histopathological diagnosis of sessile serrated lesions within a nationwide population screening programme.Histopathology. 2017; 70: 929-937Crossref PubMed Scopus (9) Google Scholar To acknowledge ongoing research, the category “serrated adenoma not classified” has been introduced by the WHO. This category should only be used for lesions that cannot be classified as TSAs or SSLs. In analogy to serrated precursor lesions, serrated adenocarcinoma is increasingly recognized as a distinct CRC subtype. Studies found that 10%–15% of colorectal tumors could be classified as serrated adenocarcinomas, based on histologic features.27Garcia-Solano J. Perez-Guillermo M. Conesa-Zamora P. et al.Clinicopathologic study of 85 colorectal serrated adenocarcinomas: further insights into the full recognition of a new subset of colorectal carcinoma.Hum Pathol. 2010; 41 (1359–168)Crossref PubMed Scopus (53) Google Scholar These tumors have glandular serration, with or without mucinous areas. Based on molecular features, researchers proposed that approximately 25% of colorectal tumors develop along the serrated pathway, although these tumors do not all necessarily have serrated morphology. The serrated pathway is characterized by a sequence of genetic and epigenetic changes that accompany polyp progression, tracked by histologic features (Figure 2A). In most serrated polyps, the first step of the pathway is believed to be acquisition of a mutation in a gene that regulates mitogen-activated protein kinase pathway (such as in KRAS or in most cases BRAF).28O'Brien M.J. Yang S. Clebanoff J.L. et al.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 (145) Google Scholar Activating mutations in BRAF result in widespread methylation of CpG islands, called the a CpG island methylator phenotype (CIMP).29Bond C.E. Liu C. Kawamata F. et al.Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal neoplasia.Epigenetics. 2018; 13: 40-48Crossref PubMed Scopus (18) Google Scholar, 30Weisenberger 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 (1313) Google Scholar CIMP results in silencing of many genes, including some tumor suppressor genes. Hypermethylation of CDKN2A (which encodes P16) occurs more frequently in TSAs than SSLs, in particular in the advanced lesions with BRAF mutations.11Bettington M.L. Walker N.I. Rosty C. et al.A clinicopathological and molecular analysis of 200 traditional serrated adenomas.Mod Pathol. 2015; 28: 414-427Crossref PubMed Google Scholar Hypermethylation of the promoter of the MLH1 occurs only in SSLs and is associated with specific polymorphisms in MLH1 (MLH1-93AA).31Fennell L.J. Jamieson S. McKeone D. et al.MLH1-93 G/a polymorphism is associated with MLH1 promoter methylation and protein loss in dysplastic sessile serrated adenomas with BRAF(V600E) mutation.BMC Cancer. 2018; 18: 35Crossref PubMed Scopus (0) Google Scholar Approximately 75% of SSL-D32Bettington M. Walker N. Rosty C. et al.Clinicopathological and molecular features of sessile serrated adenomas with dysplasia or carcinoma.Gut. 2017; 66: 97-106Crossref PubMed Google Scholar have microsatellite instability (MSI), resulting from this specific hypermethylation. Thus, immunostaining for MLH1 protein can identify dysplasia.9Liu C. Walker N.I. Leggett B.A. et al.Sessile serrated adenomas with dysplasia: morphological patterns and correlations with MLH1 immunohistochemistry.Mod Pathol. 2017; 30: 1728-1738Crossref PubMed Scopus (24) Google Scholar Progression of serrated polyps is associated with activation of the WNT signaling pathway (Figure 2B). The development of conventional adenomas also involves activation of the WNT pathway, which is usually an early step in carcinogenesis. Truncating mutations in APC gene are found in >90% of adenomas. In contrast, similar APC mutations are found in only 10%–15% of SSL-D and 36% of TSAs.33Borowsky J. Dumenil T. Bettington M. et al.The role of APC in WNT pathway activation in serrated neoplasia.Mod Pathol. 2018; 31: 495-504Crossref PubMed Scopus (14) Google Scholar Activation of the WNT pathway in SSLs is caused mainly by mutations in the RNF43–ZNRF3 complex34Hashimoto T. Yamashita S. Yoshida H. et al.WNT pathway gene mutations are associated with the presence of dysplasia in colorectal sessile serrated adenoma/polyps.Am J Surg Pathol. 2017; 41: 1188-1197Crossref PubMed Scopus (19) Google Scholar, 35Yan H.H.N. Lai J.C.W. Ho S.L. et al.RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation.Gut. 2017; 66: 1645-1656Crossref PubMed Scopus (54) Google Scholar; these can be as frequent as 86% in cases with MLH1 promoter hypermethylation. Mutations in this receptor prevent normal regulation of WNT by RNF43-mediated stimulation of endocytosis of the frizzled–LRP5–LRP6 complex.36Koo B.K. Spit M. Jordens I. et al.Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors.Nature. 2012; 488: 665-669Crossref PubMed Scopus (405) Google Scholar Alternatively, approximately 30% of TSAs have fusions of genes in the R-spondin family (RSPO fusions), resulting in R-spondin overexpression, and down-regulation of RNF43.37Sekine S. Ogawa R. Hashimoto T. et al.Comprehensive characterization of RSPO fusions in colorectal traditional serrated adenomas.Histopathology. 2017; 71: 601-609Crossref PubMed Scopus (13) Google Scholar, 38de Lau W. Peng W.C. Gros P. et al.The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength.Genes Dev. 2014; 28: 305-316Crossref PubMed Scopus (237) Google Scholar This occurs more frequently in KRAS-mutated TSAs. Colorectal tumors arising from serrated lesions can exhibit different molecular features, likely dependent on the precursor polyps and pathways. There are at least 3 subgroups of CRCs, based on molecular features (Figure 2). CRCs with BRAF mutations have high levels of CpG island methylation (CIMP-high), MSI, and are mainly found in the right colon.39Phipps A.I. Limburg P.J. Baron J.A. et al.Association between molecular subtypes of colorectal cancer and patient survival.Gastroenterology. 2015; 148: 77-87 e2Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 40Domingo E. Camps C. Kaisaki P.J. et al.Mutation burden and other molecular markers of prognosis in colorectal cancer treated with curative intent: results from the QUASAR 2 clinical trial and an Australian community-based series.Lancet Gastroenterol Hepatol. 2018; 3: 635-643Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 41Taieb J. Le Malicot K. Shi Q. et al.Prognostic value of BRAF and KRAS mutations in MSI and MSS stage III colon cancer.j Natl Cancer Inst. 2017; 109Crossref PubMed Scopus (43) Google Scholar, 42Murcia O. Juarez M. Rodriguez-Soler M. et al.Colorectal cancer molecular classification using BRAF, KRAS, microsatellite instability and CIMP status: prognostic implications and response to chemotherapy.PLoS One. 2018; 13e0203051Crossref PubMed Scopus (1) Google Scholar MSI is found in conventional adenomas only in patients with Lynch syndrome (Dabir et al, unpublished data), so it is reasonable to assume that CRCs with BRAF mutations (3%–8% of CRCs)39Phipps A.I. Limburg P.J. Baron J.A. et al.Association between molecular subtypes of colorectal cancer and patient survival.Gastroenterology. 2015; 148: 77-87 e2Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 40Domingo E. Camps C. Kaisaki P.J. et al.Mutation burden and other molecular markers of prognosis in colorectal cancer treated with curative intent: results from the QUASAR 2 clinical trial and an Australian community-based series.Lancet Gastroenterol Hepatol. 2018; 3: 635-643Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 41Taieb J. Le Malicot K. Shi Q. et al.Prognostic value of BRAF and KRAS mutations in MSI and MSS stage III colon cancer.j Natl Cancer Inst. 2017; 109Crossref PubMed Scopus (43) Google Scholar, 42Murcia O. Juarez M. Rodriguez-Soler M. et al.Colorectal cancer molecular classification using BRAF, KRAS, microsatellite instability and CIMP status: prognostic implications and response to chemotherapy.PLoS One. 2018; 13e0203051Crossref PubMed Scopus (1) Google Scholar are of only serrated origin, and are derived from SSLs. Morphologically, medullary, mucinous, and signet ring cell carcinomas are overrepresented in this tumor group.43Kim J.H. Bae J.M. Cho N.Y. et al.Distinct features between MLH1-methylated and unmethylated colorectal carcinomas with the CpG island methylator phenotype: implications in the serrated neoplasia pathway.Oncotarget. 2016; 7: 14095-14111PubMed Google Scholar These tumors are called CMS1 in the common molecular subtype classifications of CRC,44Guinney J. Dienstmann R. Wang X. et al.The consensus molecular subtypes of colorectal cancer.Nat Med. 2015; 21: 1350-1356Crossref PubMed Scopus (1182) Google Scholar and are characterized by a hypermutator phenotype and favorable patient outcomes. A second group of colorectal tumors, which is more rare (account for 2%–6%), have mutations in BRAF, are CIMP high, but are microsatellite stable (MSS).39Phipps A.I. Limburg P.J. Baron J.A. et al.Association between molecular subtypes of colorectal cancer and patient survival.Gastroenterology. 2015; 148: 77-87 e2Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 40Domingo E. Camps C. Kaisaki P.J. et al.Mutation burden and other molecular markers of prognosis in colorectal cancer treated with curative intent: results from the QUASAR 2 clinical trial and an Australian community-based series.Lancet Gastroenterol Hepatol. 2018; 3: 635-643Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 41Taieb J. Le Malicot K. Shi Q. et al.Prognostic value of BRAF and KRAS mutations in MSI and MSS stage III colon cancer.j Natl Cancer Inst. 2017; 109Crossref PubMed Scopus (43) Google Scholar, 42Murcia O. Juarez M. Rodriguez-Soler M. et al.Colorectal cancer molecular classification using BRAF, KRAS, microsatellite instability and CIMP status: prognostic implications and response to chemotherapy.PLoS One. 2018; 13e0203051Crossref PubMed Scopus (1) Google Scholar BRAF mutations are rare in conventional adenomas,45Spring K.J. Zhao Z.Z. Karamatic R. et al.High prevalence of sessile se