Update on the serrated pathway to colorectal carcinoma - Anatomia ...

Human Pathology (2010) xx, xxx–xxxwww.elsevier.com/locate/humpathProgress in pathology<strong>Update</strong> on the serrated pathway to colorectal carcinomaDale C. Snover MD ⁎Department of Pathology, Fairview Southdale Hospital, Hibbing, MN 55746, USADepartment of Laboratory Medicine and Pathology, The University of Minnesota Medical School, Edina, MN 55435, USAReceived 7 May 2010; revised 11 June 2010; accepted 16 June 2010Keywords:Colon adenocarcinoma;Serrated pathway;Sessile serrated adenoma;Traditional serratedadenoma;Hyperplastic polypSummary Adenocarcinoma of the large intestine can no longer be considered one disease but rather afamily of diseases with different precursor lesions, different molecular pathways, and different end-stagecarcinomas with varying prognoses. Approximately 60% of colorectal carcinomas arise fromconventional adenomas via the suppressor pathway leading to microsatellite stable carcinomas. Thesecarcinomas represent the pathway that has been the target of screening and prevention programs to date.However, approximately 35% of carcinomas arise along the serrated pathway developing from theprecursor lesion known as the sessile serrated adenoma (also referred to as the sessile serrated polyp).Sessile serrated adenomas/polyps lead to carcinomas with extensive CpG island promoter methylation(CpG island methylated phenotype positive carcinomas), which can be either microsatellite instable highor microsatellite stable. The remaining 5% of carcinomas arise from conventional adenomas in patientswith germ line mutations of mismatch repair genes (Lynch syndrome), leading to CpG islandmethylated phenotype negative microsatellite instable carcinomas. Carcinomas arising from sessileserrated adenomas/polyps are not prevented by removing conventional adenomas and hence may bemissed in routine screening programs. In addition, a subset of these lesions may potentially progressrapidly to carcinoma; hence, it is likely that these lesions will require a different screening strategy fromthat used for conventional adenomas. This article reviews the various pathways to colorectal carcinomawith emphasis on the serrated pathway and evaluates the implications of this pathway for colorectalcarcinomas screening programs.© 2010 Published by Elsevier Inc.1. IntroductionColorectal carcinoma is a major health issue in the UnitedStates, representing the second most commonly fatalmalignancy after lung. Although it is often assumed thatalmost all colorectal carcinomas arise from conventionaladenomas via the suppressor pathway initiated with amutation of the APC gene (the Fearon-Vogelstein model),it is now clear that this pathway accounts for onlyapproximately 60% of colon carcinoma [1,2]. Most of the⁎ Department of Pathology, Fairview Southdale Hospital.E-mail address: snoverd@umn.edu.remaining 40% is accounted for by the more recentlydescribed serrated pathway leading to CpG island methylatedphenotype (CIMP+) carcinoma (approximately 35%), withthe remaining 5% arising via the mutator pathway in Lynchsyndrome [2]. Trying to understand the multiplicity ofpathways is confused by a plethora of overlapping ways todescribe these pathways and cancers. Pathways have beendefined by the presumed initiating factor (ie, suppressor[chromosome instability] versus mutator [microsatelliteinstability] pathways) and by the presumed precursor lesions(ie, conventional adenoma-carcinoma sequence versus theserrated pathway). A commonly utilized subdivision intomicrosatellite stable (MSS) carcinomas (which represent bothsuppressor pathway carcinomas arising either sporadically or0046-8177/$ – see front matter © 2010 Published by Elsevier Inc.doi:10.1016/j.humpath.2010.06.002

6 D. C. SnoverFig. 4 Microvesicular hyperplastic polyp. Note that the crypts arerelatively straight with narrow bases (40). Also, see Fig. 3A.are found almost exclusively in the left colon andcommonly demonstrate Kras mutations, whereas MVHP,which is still predominantly left-sided but with more rightsidedlesions than GCHP, tends to be BRAF mutated [4].MPHP appears to represent a damaged MVHP with reactivechange, but this category is rare and has not been wellstudied. It has been suggested that MVHP may act as aprecursor to the more advanced and clearly premalignantSSA/P, in large part because they share the BRAF mutationand a propensity to methylation, although this has not beenproven and perhaps is of more theoretical than practicalsignificance. Very rarely will one encounter a MVHP thatdemonstrates cytological dysplasia resembling conventionaladenoma, and hence, it is possible that MVHP mayoccasionally become methylated at a gene critical forcarcinogenesis, as occurs in SSA/P, and hence may progressto malignancy without an intervening SSA/P.Perhaps the most persistent and perplexing issueregarding serrated lesions is the fact that there remains noconsensus on the best terminology for the lesion knownvariably in the literature as sessile serrated adenoma (SSA),sessile serrated polyp (SSP), or serrated polyp with abnormalproliferation . The term SSA was the first term used for thislesion, and a majority of the current literature is written usingthe term SSA; however, there is a second large group whoprefers SSP. The term serrated polyp with abnormalproliferation is rapidly losing favor. The rationale for theuse of “polyp” rather than “adenoma” for this lesion revolvesaround a concern that use of “adenoma” will cause confusionwith conventional adenomas arising via the APC mutationpathway, despite the fact that most authors in the field acceptthat these lesions are functionally premalignant and hence“neoplastic.” In the practice of this author, who has used theterm SSA since 1996, confusion with conventional adenomashas not been an issue with our gastroenterologists, who seemto have no difficulty understanding the difference betweenSSA, tubular adenoma, tubulovillous adenoma, and villousadenoma once they are familiar with the concept. Manyauthors believe that SSA is the best term because it reflectsthe premalignant potential of this lesion in the serratedpathway and is likely to lead to more appropriatemanagement that other more noncommittal terms. Nonetheless,consensus has not been reached, and the upcomingfourth edition of the WHO classification of tumors of thedigestive trace will reflect that at the current time either termis acceptable as long as it is recognized that SSA and SSP arereferring to the same lesion [11]. For clarity sake, SSA/P willbe used throughout this article. Unfortunately, there are stillsome pathologists who continue to use the term hyperplasticpolyp or variant hyperplastic polyp for these lesions, a mostunfortunate fact given the considerable management differencesbetween HP and SSA/Ps. The use of the “hyperplasticpolyp” for these lesions should be avoided.SSA/P is characterized mechanistically by movement ofthe proliferative zone away from its usual location in the baseof the crypts, resulting in maturation, which may developtoward the base of the crypts leading to distortion of the cryptarchitecture, commonly with dilated, L, inverted T, or anchorshapedcrypts with mature cells where the proliferative zonenormally is located (as evidenced by mucinous differentiationas well as marking for cytokeratin 20 (Figs. 3B and 5) [10]).The crypts still retain their “attachment” or orientation towardto the muscularis mucosae, however, and are arrangedperpendicular to the muscularis mucosae. SSA/P in itsearliest stage does not manifest dysplasia resemblingconventional adenoma, although with progression towardcarcinomas, such dysplasia develops.There has been variation regarding the best term forlesions that combine the features of SSA/P with areas offrank cytological dysplasia that resemble conventionaladenomas (Fig. 6). These lesions have in most of the olderFig. 5 SSA/P without cytological dysplasia. Compared to theHP, the overall architecture is distorted with variably shaped cryptsand mature cells at the base of the crypts (40). Also, see Fig. 3B.

Serrated pathway to colorectal carcinomaFig. 6 SSA/P with cytological dysplasia. This lesion hascharacteristics of an SSA/P on the right, but on the left, theepithelium is cytologically dysplastic demonstrating hyperchromaticelongated nuclei with pseudostratification. This may indicateconversion to a MSI state. There is an underlying invasiveadenocarcinoma as well (40).literature been called mixed HP-TA, and with the recognitionof SSA/P, it turned out that the serrated portion of most ofthese mixed lesions was in reality SSA/P, leading to the useof the term mixed SSA/P-TA for these lesions [7]. However,it is currently felt that this term is misleading because thecytologically dysplastic part of these polyps is not aconventional TA from a molecular perspective and probablyhas a more aggressive course than conventional TA. Asnoted above, conventional TA is a lesion that starts with anAPC mutation, acquires addition mutations over time, andeventually, in a small number of cases and generally over thecourse of 10 years or more, becomes malignant. SSA/P withcytological dysplasia, on the other hand, in some cases (ie, inthe case of lesions developing into MSI carcinomas)represents the development of microsatellite instability inthe lesion and hence is creating a lesion with a propensity todevelop into carcinoma with high frequency and rapidity (seeFig. 2 and discussion above). These lesions are not APCmutated and probably require considerably more aggressivefollow-up than conventional adenomas. Hence, “SSA/P withcytological dysplasia” is the preferred term for this lesion,and the term mixed SSA/P-TA or HP-TA is no longerconsidered acceptable.The other term that has had some controversy is that of the“traditional” serrated adenoma (TSA). This lesion is one ofseveral forms of serrated lesions that fit the definition of“serrated adenoma” proposed in the seminal article byLongacre and Fenoglio-Prieser in 1990 [12]. The definitionprovided initially for “serrated adenoma” was that a “serratedadenoma” was a lesion with dysplasia (and hence “adenoma”by conventional criteria in use at the time) but which showedan overall serrated configuration. Unfortunately, this definitionis overly broad and can be used to describe what are nowknown to be 3 or possibly 4 different lesions (SSA/P, SSA/Pwith cytological dysplasia, TSA, and conventional APCadenomas with a serrated growth pattern). Recognizing this,in 2003, it was suggested that the most unique of this group,and the one member of this group which did not have a bettername, should be recognized as a separate entity, and the termtraditional serrated adenoma was recommended (because itwas thought that this lesion was the one member of thisgroup that was most easily recognized by most pathologists,and the one that at the time was probably most commonlybeing called “serrated adenoma,” in large part because at thetime SSA/P was still being called HP by most pathologists,and SSA/P with cytological dysplasia was being calledmixed HP-TA.) [3]. It is of some interest along these linesthat a recent reproducibility study identified this lesion as theone with the best kappa statistic of the various serratedlesions, supporting our contention that most pathologistsalready know how to recognize this lesion [13].There does continue to be some variation in the diagnosisof TSA, however, in large part because of recent suggestionsfor expansion of the diagnostic criteria [10]. The originaldefinition of TSA was a very simplistic one, with the mostnotable feature being the presence of a peculiar type ofatypical cell characterized by relatively abundant eosinophiliccytoplasm resembling that of an oncocyte, withelongated nuclei (typically not hyperchromatic) often locatedin the mid portion of the cell and with little or nopseudostratification and with little proliferative activity asdetermined by mitotic count or Ki67 immunoreactivity[3,7,10]. This cell was considered by many as being“dysplastic” and therefore was often equated with the“dysplasia” of conventional adenomas. Given the lack ofproliferative activity (as well as the lack of APC mutations)in these cells, they are not likely to have the same neoplasticpotential as conventional dysplasia and are better consideredFig. 7 TSA. This lesion is characterized by an overall somewhatvilliform configuration with a very complex overall architecture(40). Also, see Fig. 3C.7

8 D. C. SnoverTable 2Proposal for a semimolecular classification of colorectal polypsTraditional terminology(pre-2003)Recently revised terminology(post-2003)Proposed semimolecular terminologyAdenoma Conventional adenoma APC-related neoplastic polypsTubular adenoma Tubular adenoma Nonserrated neoplastic polyp without villous componentTubulovillous adenoma Tubulovillous adenomas Nonserrated neoplastic polyp with villous componentVillous adenoma Villous adenomaSerrated adenomaHyperplastic polyp Serrated adenomas CIMP-adenomas, BRAF typeHyperplastic polyp SSA/P without cytological dysplasia Sessile serrated neoplastic polyp without cytological dysplasiaSSA/P with cytological dysplasia Sessile serrated neoplastic polyp with cytological dysplasiaCIMP-adenomas, KRAS typeTSA without conventional dysplasia Filiform serrated neoplastic polyp without conventional dysplasiaTSA with conventional dysplasia Filiform serrated neoplastic polyp with conventional dysplasiaHyperplastic polypsHyperplastic polyp, BRAF typeMicrovesicular HPMicrovesicular HPHyperplastic polyp, Kras typeGCHPGCHPHyperplastic polyp, otherMucin poor HPMucin poor HPa metaplastic or possibly senescent cell. Although this celltype was original considered a sine qua non for the diagnosisof TSA, it is now apparent that this cell type can be seen in avariety of circumstances including in small areas ofotherwise typical SSA/P, in some conventional adenomas(APC-related) and sometimes even in reactive mucosa. Animmunohistochemical analysis of proliferation and maturationin serrated lesions has pointed out that a more likelydiagnostic abnormality in TSA is the presence of smallectopic crypts created by apparent loss of anchoring of theFig. 8 TSA with conventional dysplasia. This TSA hascytological dysplasia similar to that seen in conventional adenomasin the right portion of the photo. In this particular case, the dysplasiais high grade with a cribriform pattern of growth. There wasinvasive carcinoma elsewhere in this polyp (40).crypt bases to the muscularis mucosae [10] (Figs. 3C and 7).These ectopic crypts demonstrated strong CK20 staining inthe luminal portions and Ki67 staining in the deeper aspects,hence recapitulating small crypts except that the base of thecrypts was free floating in the lamina propria of villi ratherthan sitting on (or being “anchored to”) the muscularismucosae. We now feel that these ectopic crypts are probablythe best defining feature of TSA, although most TSAs willalso have the atypical eosinophilic cell noted above. Theseectopic crypts are not present in all areas of all TSAs butshould be present at least focally. Often TSA will have largeareas with the metaplastic eosinophilic cells described above,but using these diagnostic criteria, a TSA can also becomposed mainly of goblet cells. Whether these different celltypes have any molecular or prognostic implications is alsonot known. The lesion described as “filiform” serratedadenoma is probably synonymous with TSA or represents asubset of TSA and may provide less confusing terminology(see Table 2) [14].Although eosinophilic metaplastic cells often make up aconsiderable portion of TSAs, atypical cells with many ofthe morphological attributes of conventional dysplasia (ie,hyperchromasia, pseudostratification and increased proliferativeactivity) do occur in TSA, probably as part ofconversion toward malignancy (Fig. 8). The molecularcharacteristics of these cells (eg, mutation and methylationstatus) have not been well characterized, however, and therehas been essentially no discussion of the terminology of thisconverted lesion in the literature. Trying to be analogous toSSA/P, it would probably be appropriate to refer to theselesions as “TSA with conventional cytological dysplasia,”despite the fact that this is somewhat cumbersome. Thespecific mechanism of carcinogenesis in TSA is currentlynot well known and is discussed briefly above under

Serrated pathway to colorectal carcinoma“molecular mechanisms of carcinomas development via theserrated pathway.”5. The role of SSA/P in carcinogenesis and itseffect on management of these lesionsAs noted in the introduction, it is now generallyrecognized that “colon cancer” comprises a family ofdiseases with various molecular pathways. There is now noquestion that SSA/P is the immediate precursor lesion tosporadic CIMP+MSI carcinomas. SSA/P is likely theprecursor lesion to CIMP+MSS carcinomas as well.Combined, CIMP+MSI and CIMP+MSS carcinomas accountfor approximately 35% of all colorectal carcinoma;hence, these are very important lesions to recognize anddeal with if one wants to reduce the risk of colon carcinomathrough screening. Unfortunately, we are still somewhatimpaired in our understanding of the natural history ofserrated lesions because of a lack of longitudinal studies,and current recommendations for management are based inlarge part on our understanding of the molecular mechanismsof the pathway and on observational studies includingrecent data on the frequency of serrated pathway–associated carcinomas presenting as interval cancers inscreening programs.One important difference in screening for serratedlesions (as opposed to screening for conventional adenomas)results from the fact that the CIMP+MSI pathwaymay be a rapidly progressive pathway, much more rapidthan carcinogenesis via the conventional APC pathway, asdescribed above. Recent analysis of “interval carcinomas”occurring in screening populations has indicated that thesecancers are disproportionally MSI [15]. One possiblereason for this is that some of these lesions may becomemalignant very rapidly, with their entire lifespan fitting inthe 5 or 10 years between screening examinations. Anotherpotential reason that should not be overlooked, however, isthat SSA/P is a very subtle lesion and may be difficult toidentify on endoscopic examination, especially for anendoscopist who is not experienced with recognizing thesubtle changes that might indicate the presence of a lesion(especially adherent stool or mucin that must be washed offto visualize the lesion). Therefore, interval MSI cancersmight also occur because SSA/Ps are being missed. It turnsout that interval cancers are not only disproportionallyCIMP+MSI, but they are also disproportionally CIMP+MSS [16]. Because there is no a priori reason to suspectthat CIMP+MSS development has the same potential rapidprogression as seen with CIMP+MSI carcinoma, thisfinding would bolster the theory that some of the issuerelated to interval cancers involves failure to identify theunderlying lesion. Regardless of the reason, this apparentenhancement of interval cancers with CIMP+ carcinomasarising via the serrated pathway has significant implicationson the appropriate interval for rescreening patients with aknown SSA/P.Our past recommendations had suggested that the mostworrisome lesions of this group, and the lesion with the mostpressing need for close surveillance, were the SSA/Ps withcytological dysplasia, since these lesions have the potentialto rapidly progress to carcinoma [7,8]. We still maintain thatany lesion with this histology should be removed entirely bywhatever means necessary and that the patient undergorepeat endoscopy no longer than a year after initial excision(if the endoscopist is comfortable that the lesion has beenentirely removed) or sooner if there is any question aboutadequacy of excision. TSAs, either with or without changesof conventional dysplasia, are probably best treated asconventional adenomas because they do not lead to thedevelopment of MSI carcinomas, and hence, there is noreason to suspect that they might be more aggressive thanother lesions. In addition, because they tend to occur in therectosigmoid region and are usually well-circumscribedprotruding lesions, surveillance and removal tend to beeasier. The real management issue is for SSA/P withoutcytological dysplasia because these are the most commonlesions and are the ones that are most difficult to visualizeand remove.Our original recommendations were relatively leisurelyregarding this group, with recommendations to remove thelesion if possible or, if the lesion was not easily resected viathe endoscopy, to do surveillance at annual intervals toliberally biopsy the lesion and look for cytological dysplasiathat would then accelerate the need to remove the lesion[7,8]. If the lesion was completely removed, then wesuggested reversion to “standard” adenoma surveillanceintervals. Given the recent data regarding CIMP+ andinterval cancers, however, this may not be an adequatestrategy. Personal observations by myself and others(Kenneth Batts, MD, personal communications) wouldindicate that often patients with one SSA/P will harborothers, either synchronously or metachronously. This seemsespecially true for large lesions found in the right colon.When the criteria for “serrated polyposis” (formerly knownas “hyperplastic polyposis”) are met ([1] at least 5 serratedpolyps proximal to the sigmoid colon with 2 or more ofthem larger than 10 mm, [2] any number of serrated polypsproximal to the sigmoid colon in an individual who has afirst-degree relative with serrated polyposis, or [3] morethan 20 serrated polyps of any size, but distributedthroughout the colon ), the situation is more defined, andclose surveillance with possible colectomy is considered[11]. However, the criteria for serrated polyposis are at thispoint still entirely arbitrary, and therefore, it is possible ifnot probable that the finding of multiple SSA/Ps of any sizeor location may be adequate to recommend more frequentsurveillance. As noted above, the issue with SSA/P may be2-fold—potential rapid progression to carcinoma andincomplete removal. To prevent interval cancers, therefore,shortened interval surveillance may be appropriate.9

10 D. C. SnoverReasonable risk factors suggesting the need for shortinterval reendoscopy would include size of lesions (lesionssmaller than 1 cm may not be as important), location oflesions (right sided lesions may be more important), and age(older patients being more prone to SSA/P as well as tosporadic MSI carcinomas), in addition to number of lesions.A reasonable strategy, and one we are currently recommending,would be to repeat surveillance at 1 year foranyone with 2 or more completely removed SSA/Ps greaterthan 1 cm and determine future screening based on thesefindings. If there is any significant risk that a lesion was notcompletely removed, repeat endoscopy at a shorter intervalmay well be indicated. If additional SSA/Ps are identified at1 year, annual surveillance (at least until there is a negativecolonoscopy) would seem reasonable. If screening at 1 yearis clear of lesions, then extension of the interval to 2 to 3years would seem appropriate.6. Proposed solutions to ongoing issuesAs noted above, perhaps the more important issuesregarding serrated lesions involve appropriate management,although terminology remains an issue as well. Themanagement issue is amenable to further clinicopathologicalstudies focusing on natural history, not only for the morecommon SSA/P but also for TSA, since we know the leastabout that lesion. Additional molecular characterization ofspecific genetic changes resulting in CIMP+MSS carcinomasand for carcinomas arising in TSA will also be valuablein this regard, since this information may help determine thebest surveillance and prevention strategies.Regarding the terminology issues, at the current time, thereappears to be a stalemate between the proponents of SSA andthose for SSP. Much of this problem exists because of thetraditional use of the term adenoma not as a generic family oflesions (ie, polyps with premalignant potential) but rather for aspecific subset of adenomas, that is, adenomas predominantlyarising along the suppressor pathway initiated with APCmutations. Perhaps it is time for gastrointestinal pathologists toconsider reclassification of adenomas on a semimolecularbasis, realizing that it is not practical to perform moleculartesting on all lesions removed as adenomas. We could,however, alter our terminology to indicate the likely molecularaspects of adenomas, something that would point out thepotential molecular difference and would at a minimum havean educational effect if not a direct management effect. It mightalso be advisable to eliminate the term adenoma fromterminology given the long history of using this word onlyfor precursor lesions to non-CIMP carcinomas (ie, APCrelatedcarcinomas arising via the suppressor pathway and MSIcarcinomas arising via MMR mutations in Lynch syndrome);however, finding a convenient shorthand substitute will bedifficult. Nonetheless, as a starting point, a suggestion for asemimolecular classification is proposed in Table 2.References[1] Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis.Cell 1990;61:759-67.[2] Jass JR. Classification of colorectal cancer based on correlation ofclinical, morphological and molecular features. Histopathology2007;50:113-30.[3] Torlakovic E, Skovland E, Snover DC, et al. Morphologicreappraisal of serrated colorectal polyps. Am J Surg Pathol2003;27:65-81.[4] O'Brien MJ, Yang S, Mack C, et al. Comparison of microsatelliteinstability, CpG island methylation phenotype, BRAF and KRASstatus in serrated polyps and traditional adenomas indicates separatepathways to distinct colorectal carcinoma end points. Am J Surg Pathol2006;30:1491-501.[5] Yachida S, Mudali S, Martin SA, Montgomery EA, Iacobuzio-DonahueCA. Beta-catenin nuclear labeling is a common feature of sessileserrated adenomas and correlates with early neoplastic progression afterBRAF activation. Am J Surg Pathol 2009;33:1823-32.[6] Boparai KS, Dekker E, Van Eeden S, et al. Hyperplastic polyps andsessile serrated adenomas as a phenotypic expression of MYHassociatedpolyposis. Gastroenterology 2008;135:2014-8.[7] Snover DC, Jass JR, Fenoglio-Preiser C, Batts KP. Serrated polyps ofthe large intestine: a morphologic and molecular review of an evolvingconcept. Am J Clin Pathol 2005;124:380-91.[8] Snover DC. Serrated polyps of the large intestine. Sem Diag Pathol2005;22:301-8.[9] East JE, Saunders BP, Jass JR. Sporadic and syndromic hyperplasticpolyps and serrated adenomas of the colon: classification, moleculargenetics, natural history, and clinical management. Gastroenterol ClinNorth Am 2008;37:25-46.[10] Torlakovic EE, Gomez JD, Driman DK, et al. Sessile serrated adenoma(SSA) vs. traditional serrated adenoma (TSA). Am J Surg Pathol2008;32:21-9.[11] Snover DC, Ahnen DJ, Burt RW, Odze RD. Serrated polyps of thecolon and rectum and serrated (“hyperplastic”) polyposis. In: BozmanFT, Carneiro F, Hruban RH, Theise N, editors. WHO classification oftumours. Pathology and genetics. Tumours of the digestive system.Berlin: Springer-Verlag (4th ed. [in press]).[12] Longacre TA, Fenoglio-Preiser CF. Mixed hyperplastic adenomatouspolyps/serrated adenomas. A distinct form of colorectal neoplasia. AmJ Surg Pathol 1990;14:524-37.[13] Farris AB, Misdraji J, Srivastava A, et al. Sessile serrated adenoma:challenging discrimination from other serrated colonic polyps. Am JSurg Pathol 2008;32:30-5.[14] Yantiss RK, Oh KY, Chen YT, et al. Filiform serrated adenomas: aclinicopathologic and immunophenotypic study of 18 cases. Am JSurg Pathol 2007;31:1238-45.[15] Sawhney MS, Farrar WD, Gudiseva S, et al. Microsatellite instabilityin interval colon cancers. Gastroenterology 2006;131:1700-5.[16] Arain MA, Sawhney M, Sheikh S, et al. CIMP status of interval coloncancers: another piece to the puzzle. Am J Gastroenterol 2010;105:1189-95.