The Clinical Significance of Serrated Polyps

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1 CLINICAL AND SYSTEMATIC S nature publishing group 229 CME The Clinical Significance of Serrated Polyps Christopher S. Huang, MD 1, Fr anc is A. Far raye, M D, M S c 1, Sh i Yang, M D 2 and Michael J. O Brien, MD, MPH2 Colorectal cancer (CRC) is a heterogeneous disorder than arises via multiple distinct pathways, such as the serrated pathway, in which serrated polyps (including variants of hyperplastic polyps) are the precursor lesions. Approximately % of all CRCs arise via the serrated pathway, and these serrated carcinomas are clinically, morphologically, and molecularly distinct from conventional CRCs. The prevention of serrated carcinomas represents an important clinical challenge. Gastroenterologists need to recognize and remove potential precursor lesions and implement a postpolypectomy surveillance program when appropriate. This article focuses on the characteristics and significance of clinically relevant serrated polyps and addresses implications for CRC prevention practices. Am J Gastroenterol 2011; 106: ; doi: /ajg ; published online 2 November 2010 INTRODUCTION Th e serrated pathway to adenocarcinoma represents a major challenge to colorectal cancer (CRC) prevention efforts. Although screening and surveillance colonoscopy have been shown to significantly reduce CRC incidence and mortality, this effect appears to be limited mainly to cancers in the distal colon and rectum ( 1 4 ), the majority of which arise via the conventional adenoma carcinoma sequence. Prevention of proximal CRCs has proven more difficult, and interval cancers following a negative or clearing colonoscopy continue to contribute importantly to the overall CRC burden. There is a growing body of evidence that some of these cancers arise via the serrated polyp pathway, and there are many features that distinguish these groups of cancers and their precursors from conventional CRCs. In major contrast to the adenoma carcinoma sequence, the serrated pathway implicates hyperplastic polyps (HPs) as potential precursors to CRC, which contradicts what generations of endoscopists and pathologists have been trained to believe ( 5 9 ). Molecular genetics combined with histological and clinical studies have provided ample evidence, however, that variants of HPs carry the genetic signatures of certain types of CRC, particularly cancers with high levels of microsatellite instability (MSI-H) ( ). In addition to their morphological and molecular differences from conventional CRC, these serrated pathway cancers also have distinct clinical and demographic characteristics: they are more likely to be found in females, located in the proximal colon, and are incident in the mid- to late-70s, a decade later than CRC overall. These characteristics may be linked to the proposed underlying molecular basis for these cancers, a phenomenon called CpG island methylation, a progressive epigenetic process whereby the CpG-rich promoter regions of mutator and suppressor genes become inactivated ( 15 ). This phenomenon finds its greatest expression in proximally located HP-type precursors that typically exhibit BRAF mutation ( 16 ), and this susceptibility may also be related to gender and older age ( 11 ). These serrated polyps are typically flat or sessile lesions and may be readily overlooked unless specifically sought out by the endoscopist. Recognizing that our understanding of this topic is still evolving and that there are many uncertainties that remain, this article will attempt to build upon our previous review on this topic ( 7 ), with an emphasis on the most clinically important subtypes of serrated polyps, and the impact that these lesions may have on the overall CRC burden. The review will also address management and surveillance recommendations and suggest potential changes to our current CRC prevention practices. Readers are encouraged to review Table 1, which provides the definitions of key molecular genetic terms that are central to the discussion of the serrated pathway. CLASSIFICATION OF SERRATED POLYPS Serrated polyps are defined as epithelial lesions, which demonstrate a saw-toothed or serrated appearance on histologic section due to infolding of crypt epithelium. They comprise typical HPs (of which there are at least two main subtypes), atypical HP variants called sessile serrated adenomas (SSAs), and dysplastic serrated polyps, previously known generically as serrated adenomas (SAs). Table 2 shows a proposed classification scheme, which groups serrated polyps into two main categories based on the presence or absence of dysplasia. 1 Department of Medicine, Section of Gastroenterology, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA ; 2 Department of Pathology and Laboratory Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA. Correspondence: Christopher S. Huang, MD, Department of Internal Medicine, Section of Gastroenterology, Boston Medical Center, Boston University School of Medicine, 85 East Concord Street, # 7714, Boston, Massachusetts 02118, USA. christopher.huang@bmc.org Received 4 June 2010; accepted 6 October by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

2 230 Huang et al. Table 1. Definition of key molecular genetic terms pertinent to the serrated pathway BRAF-mut CpG island methylation Epigenetic KRAS-mut Microsatellite instability A mutation of the BRAF oncogene at the V600E locus results in its activation and consequent persistent signaling of an intracellular growth control pathway called mitogen-activated protein kinase (MAPK). This mutation has high sensitivity and specificity for the serrated polyp pathway and is found in most MVSPs, SSAs, and sporadic CIMP-H CRC, and rarely, if ever, in the conventional adenoma carcinoma sequence. Dense clusters of cytosine nucleotides followed by a guanine nucleotide, referred to as CpG islands, occur selectively in the promotor (transcription control) regions of many genes, including growth suppressor and DNA repair genes. CpG island methylation refers to the addition of methyl groups to cytosine in such locations, where it can cause silencing of the genes and lead to neoplastic growth. Gene panel assays have been developed that reliably identify CRCs that have high levels of CpG island methylation ( CIMP-high ); these cancers are very strongly associated with BRAF mutation, both with and without MSI. A lower level of aberrant gene methylation, best revealed by alternative assay panels, is referred to as CIMP-low. This pattern appears to be associated with KRAS-mut carcinomas, both serrated and conventional. Methylation of cytosine in the CpG island regions of DNA is a molecular change that is transmissible to cell progeny, but it does not alter the nucleotide sequence of the DNA and thus is referred to as epigenetic as distinct from a genetic change. KRAS is an oncogene that, when activated, signals in tandem with BRAF in the MAPK cell signaling pathway. Activating mutations of KRAS (usually at codon 12 or 13) are prevalent in tubulovillous and villous adenomas of the conventional adenoma carcinoma sequence. They are also frequently found in serrated polyps, including the hyperplastic polyp subtype GCSP and dysplastic serrated polyps that have a traditional serrated adenoma phenotype. Microsatellites are repeat nucleotide sequences of variable length that are distributed throughout the genome including the coding regions of many growth control genes. During cell replication, errors in copying these sequences are prevented by a series of DNA repair proteins produced by the mismatch repair genes. Inactivation of both alleles of one of these genes results in myriad mutations in microsatellites, a status referred to as microsatellite instability. This can be found in about 15 % of all colorectal cancers. Inactivation of the mismatch repair gene hmlh1, as a result of CPG island methylation of its promoter region, accounts for ~ 75 % of MSI CRC and most of the remainder are associated with the inherited mutations of Lynch syndrome (hereditary non-polyposis colon cancer syndrome). CIMP, CpG island methylation phenotype; CRC, colorectal cancer; MSI, microsatellite instability; MVSPs, microvesicular serrated polyps; SSA, sessile serrated adenoma. Table 2. Classification of serrated polyps Non-dysplastic Hyperplastic polyps Goblet cell serrated polyp (GCSP) Microvesicular serrated polyp (MVSP) Sessile serrated adenoma (SSA, also known as sessile serrated polyp, sessile serrated lesion and serrated polyp with abnormal proliferation) Dysplastic Sessile serrated adenoma, dysplastic (SSAD) Traditional serrated adenoma (TSA) A persistent area of contention with respect to the nomenclature of these polyps has been use of the term SSA, in that by convention colorectal adenomas are dysplastic, whereas SSAs lack cytological dysplasia, although compared with HPs they manifest both disordered proliferation and disordered crypt architecture ( 17 ). The most recent edition of a major gastrointestinal pathology reference textbook opts for the term sessile serrated polyp ( 18 ), and recent consensus European publications have used the term sessile serrated lesion in preference to SSA ( 19 ). In this review, we are not presuming to adjudicate the matter but use the term SSA in deference, at this point, to its growing acceptance in clinical practice and its more widespread use in the literature. Hyperplastic polyps Typical HPs, as a group, are highly prevalent, diminutive sessile polyps that are most commonly located in the distal colon and rectum ( ). Endoscopically, HPs are usually readily identifiable by their smooth, symmetrical, pale appearance, as well as their tendency to flatten when the colon is insufflated with air ( 26,27 ). Image-enhanced endoscopy techniques reveal that HPs exhibit two distinct surface patterns: one shows large and regular stellate pit openings; the second shows enlarged round crypts with an expanded (relative to normal) pericryptal zone. These two surface patterns correspond to the two histological subtypes ( Figure 1 ): microvesicular serrated polyps (MVSPs) and goblet cell serrated polyps (GCSPs) ( 17 ). Not surprisingly, these two distinct HP phenotypes also differ in their molecular profiles. MVSPs frequently have the same molecular genetic abnormalities found in more advanced serrated lesions (SSAs), namely BRAF V600E mutation (BRAF -mut) and an increased level of susceptibility to aberrant methylation at promoter regions (CpG island methylation phenotype (CIMP)) ( 8,11,12,28 ). It would appear, therefore, that MVSPs may progress to SSAs, particularly when located in the proximal colon. The GCSP variant, in contrast, is likely to have a KRAS mutation (KRAS - mut), a molecular genetic change that is mutually exclusive with BRAF- mut and infrequently found in SSAs ( 28 ). Whether GCSPs progress to more advanced lesions is not known with certainty, but there is some evidence that large GCSPs mimic SSAs and are potentially the precursors of KRAS- mut dysplastic serrated polyps ( 29 ). At this time, classifying HPs as either MVSPs or GCSPs is of no clinical importance, except perhaps in The American Journal of GASTROENTEROLOGY VOLUME 106 FEBRUARY

3 Serrated Polyps Review 231 Figure 1. Histologic features of the two major subtypes of typical hyperplastic polyps. Goblet cell serrated polyps ( a ) have enlarged crypts with an abundance of mature goblet cells in the upper crypts, prominent tufting of the surface epithelium and inconspicuous serration. Microvesicular serrated polyps ( b ) are characterized by elongated funnel-shaped crypts with orderly maturation from crypt base to surface. The cells of the upper crypt show small cytoplasmic vacuoles (microvesicular); serration is present in the upper and mid crypt. the context of evaluating patients with multiple serrated polyps. The same cannot be said, however, of distinguishing these HPs from SSAs, which although non-dysplastic are of paramount clinical interest. Sessile serrated adenoma The prevalence, characteristics, and significance of SSAs as sporadic lesions were not widely appreciated until 2003, when their histologic features were formally analyzed ( 17 ), and they were specifically identified as the probable precursors to MSI-H cancers (30 ). There is now emerging scientific consensus that the SSA is the precursor whose detection is at the root of preventing serrated pathway cancers. Epidemiology Based on recent studies, SSAs are present in 1 4 % of the general population ( 31,32 ), and represent approximately 1 9 % of all polyps ( 31,33 35 ). The median age of patients with SSAs in one large cross-sectional analysis of resected polyps was approximately 61 years ( 36 ), and there is a trend toward a female gender bias ( 35 ). Characteristics SSAs are the likely successor lesions of pre-existing MVSPs and hyperplastic aberrant crypt foci, although some have argued that they manifest their characteristic abnormal growth patterns ab initio ( 35 ). Histologically, SSAs are distinguished from typical HPs by the presence of crypt architectural alterations that reflect disordered growth, or dysmaturation ( Figure 2 ) ( 17,30 ). The most characteristic and recognizable of these include the presence of inverted T- or L-shaped crypt bases. Other features include dilated crypts and serration extending into the lower third of the crypt. Focal nuclear stratification, mild nuclear atypia, or dystrophic goblet cells may be seen in the crypt bases, but overt cytologic dysplasia, as has been emphasized, is not a feature of SSAs ( 17 ). SSAs have two defining molecular genetic characteristics that indicate their relationship to MVSPs as well as to sporadic MSI-H CRCs, namely, BRAF -mut and high levels of CpG Figure 2. Histologic features of sessile serrated adenomas. This hyperplastic polyp (HP) variant resembles microvesicular serrated polyps (MVSPs) in its upper part but the lower crypts show architectural disorder with the formation of irregular crypt bases with inverted T or L shapes (arrow). Other typical features represented here are dilated and serrated crypt bases. island methylation (CIMP-H) ( 12,35,37 ). The large columnar vacuolated cells of the upper crypts of the MVSP and SSA are a manifestation of cell senescence. This cellular change is thought to be an adaptive response to oncogenic signaling from the mutated BRAF gene ( 38 ). Senescent cells have switched off cell division, and it is hypothesized that induction of cell senescence accounts for HPs being at very low risk for further neoplastic progression. SSAs on the other hand can progress to dysplasia and malignancy, and this propensity has been linked to short circuiting of the senescence response in the crypt cells by CpG island methylation-induced inactivation of growth control genes ( 11,12,39,40 ). Endoscopically, SSAs are usually larger than 5 mm, flat, sessile or superficially elevated in morphology, malleable, and frequently covered by a thin layer of yellowish mucus ( 19,41 44 ). They tend to be larger than typical HPs and are more commonly located in the proximal colon ( 17,33,35 ). Their surface is generally smooth or granular, and they often have poorly defined, irregular borders, at times resembling a prominent fold of redundant mucosa ( Figure 3 ). These endoscopic characteristics may make SSAs difficult to detect and resect in entirety. The use of image-enhanced 2011 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

4 232 Huang et al. Figure 3. Endoscopic features of sessile serrated adenomas. These lesions are frequently subtle and fl at, and may resemble a redundant mucosal fold ( a ) with an adherent layer of mucus on the surface ( b ). They typically have a smooth surface seen on white light endoscopy ( c ) and a weak / normal vascular pattern intensity seen using narrow-band imaging ( d ). endoscopy techniques such as high-resolution / magnification chromoendoscopy and narrow-band imaging reveals that the majority of SSAs have a type II (stellate / asteroid) pit pattern and weak or normal vascular pattern intensity ( 45 ). Clinical significance The significance of SSAs lies in their malignant potential. The SSA was first specifically identified as the potential precursor to CRC in a histologic analysis of a series of patients with hyperplastic polyposis ( 46 ). Subsequent studies identified links between proximal serrated polyps (originally diagnosed as HPs) and the development of MSI-H CRCs ( 30,47 ). Although SSAs are at the outset non-dysplastic, dysplasia can and does arise within SSAs, giving rise to dysplastic serrated polyps. There is some evidence that aberrant Wnt signaling leading to β -catenin translocation to the nucleus, by mechanisms different from those in conventional adenomas, may drive this transition ( 48 ). Yachida et al. (49 ) have recently reported abnormal nuclear labeling of β -catenin in 29 % of SSAs lacking dysplasia compared with 100 % of SSAs with dysplasia. Whatever the underlying mechanism, that development of dysplasia is a necessary step for progression to malignancy is supported by several histological studies that have demonstrated a transitional zone of dysplasia, often showing a conventional tubular or tubulovillous appearance, intervening between characteristic SSA and invasive carcinoma in early serrated carcinomas (12,50 52). Development of dysplasia can sometimes be appreciated at endoscopy with the emergence of a mixture of type IIIL or IV pit patterns within the SSA ( 19,43 45 ). An estimate of the risk for progression of SSA is provided by a recent study, which found that among 2,139 patients with at least one SSA, 12, 2, and 1 % of patients harbored SSAs with low-grade dysplasia, high-grade dysplasia, and adenocarcinoma, respectively ( 36 ). Therefore, there is cogent morphological as well as molecular genetic evidence linking SSAs to dysplasia and CRC, mandating that gastroenterologists recognize and manage these lesions appropriately. Dysplastic serrated polyps Dysplastic serrated polyps, also known generically as SAs, are defined as polyps that share two histological features: (i) a serrated gland component and (ii) the presence of cytologic dysplasia. The current convention appears to be to further divide dysplastic serrated polyps into two main categories: (i) SSA with dysplasia (SSAD), which exhibits SSA morphologic characteristics (e.g., inverted T- and L-shaped crypt bases, crypt branching and dilatation, presence of mature goblet cells in the crypt bases) or shows SSA contiguous to an area of serrated or conventional dysplasia ( Figure 4 ) and (ii) traditional serrated adenoma (TSA), which lacks SSA patterns and more closely resembles conventional adenoma ( Figure 5 ) ( 53 ). Features more frequently associated with TSAs than with SSADs include distal location, polypoid as distinct from sessile growth pattern, tubulovillous architecture, and marked cytoplasmic eosinophilia ( 33,43,44,54 58 ). Recently, Torlakovic et al. ( 54 ) have proposed that ectopic crypt formation is the essential histological feature that distinguishes TSAs from The American Journal of GASTROENTEROLOGY VOLUME 106 FEBRUARY

5 Serrated Polyps Review 233 Figure 4. Endoscopic appearance and histology of a sessile serrated adenoma with dysplasia. Endoscopically ( a ), the polyp has a sessile, lobulated appearance. Histology ( b ) demonstrates a protruding nodule of adenomatous low- and high-grade dysplasia (black arrow) arising within a non-dysplastic sessile serrated adenoma (SSA) on the left of the image, identifi ed by serration and marked irregularity of the crypt architecture. called these polyps fusion pathway polyps, the term referring to their combination of serrated pathway features such as CpG island methylation and characteristics of the conventional pathway (adenoma carcinoma sequence) such as chromosomal deletions and p53 mutation. The most prudent approach to dysplastic serrated polyps, whether SSAD or TSA, may be to implement a surveillance program similar to that for advanced conventional adenomas once the polyp has been judged, with a high level of confidence, to have completely removed. Figure 5. Histologic features of a traditional serrated adenoma. This example, which has a KRAS mutation and is microsatellite stable (MSS), shows cytoplasmic eosinophilia, an exophytic tubulovillous architecture, and prominence of ectopic crypt formation (arrows). SSAs. This term refers to new crypt formation in which orientation of the crypt base to the muscularis mucosae is lost, in contrast to SSAs in which anchorage of new crypts to muscularis mucosae is generally maintained. On a molecular genetic level, the majority of SSADs are BRAF -mut; TSAs are frequently KRAS-mut (49 ) but are also found in a proportion of cases to be both KRAS wild type and BRAF wild type, and in some cases to be BRAF -mut, defying histological predictors ( 59 ). So-called mixed polyps can be incorporated within the SSAD and TSA categories. Other types of dysplastic serrated polyps that have been proposed, that are beyond the scope of this discussion, include conventional adenoma with serrated architecture, which refers to a conventional adenoma with focal and ill-defined serrated features ( 60 ). Dysplastic serrated polyps as a group are much less common than conventional adenomas or HPs, representing only 0.6 % of over 18,000 polyps analyzed in the original report by Longacre and Fenoglio-Preiser ( 61 ). Data from more recent studies demonstrate that TSAs and SSADs may each represent 1 2 % of all polyps (31,33,35,62 ). Some authorities have expressed the view that SSADs are at greater risk of progressing to CRC than TSAs ( 54 ), warranting more aggressive surveillance. However, a recent Korean study has reported a high frequency of high-grade dysplasia or intramucosal carcinoma in KRAS- mut TSAs ( 59 ). Jass et al. (62 ) have THE CLINICAL SIGNIFICANCE OF END POINT CARCINOMAS OF THE SERRATED PATHWAY Although most cases of CRC arise via the conventional adenoma carcinoma sequence ( 63 ), it has become evident that several alternative pathways exist, culminating in end point cancers with specific genetic signatures and distinctive clinical and morphological profiles ( 10 ). It is estimated that up to 20 % of all CRCs originate from serrated polyps ( 10 ), amounting to nearly 30,000 cases annually based on 2009 statistics ( 64 ). Recognition of the heterogeneity of serrated polyps and end point serrated cancers has led to the hypothesis that there are two parallel serrated pathways: one characterized by BRAF -mut and the other by KRAS-mut (Figure 6 ) (8,9,12,28,62 ). The predominant, BRAF -mut serrated pathway culminates in end point cancers which demonstrate high levels of CpG island methylation (CIMP-H). They include the majority of sporadic (non-syndromic) MSI-H CRCs and represent ~12 15 % of all CRCs. Epigenetic silencing of the DNA mismatch repair gene hmlh1 by promoter methylation is a key event in this arm, leading to MSI-H which is thought to drive progression from low-grade dysplasia, to high-grade dysplasia, and ultimately to invasive cancer ( 12 ). A proportion of BRAF -mut, CIMP-H cancers are micro satellite stable (MSS) and frequently have a p53 mutation, and, perhaps for this reason, tend to exhibit more aggressive clinical behavior and poorer prognosis than their MSI counterparts ( 65 ). Distinguishing clinical features of all CIMP-H CRCs include their over-representation in women and predilection for location in the proximal colon. Morphologically, they frequently demonstrate glandular serration, mucinous differentiation, poorly differentiated glands or none (as in undifferentiated or medullary carcinoma), 2011 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

6 234 Huang et al. HP - MVSP subtype Sessile serrated adenoma SSA+D SSA+HGD Serrated carcinoma ACF-H CpG island methylation Microsatellite instability Proximal predominance MSI-H Loss of hmlh1 BRAF mutation Normal KRAS mutation ACF-H? Precursor lesion Serrated adenoma (TSA) SA+HGD CpG island methylation Serrated carcinoma Distal predominance MSI-L/MSS Chromosomal instability Chromosomal instability Figure 6. Schematic illustration of the postulated serrated pathways to colorectal cancer. ACF-H, aberrant crypt foci-hyperplastic type; HP-MVSP, hyperplastic polyp, microvesicular serrated polyp subtype; MSI-H, microsatellite instability-high; MSI-L, microsatellite instability-low; MSS, microsatellite stable; SA + HGD, serrated adenoma with high-grade dysplasia; SSA + D, sessile serrated adenoma with dysplasia; SSA + HGD, sessile serrated adenoma with high-grade dysplasia; TSA, traditional serrated adenoma. increased intratumoral lymphocytes, and Crohn s-like nodular peritumoral lymphocytic infiltrates (66 68 ). The KRAS -mut arm of the serrated polyp pathway culminates in end point carcinomas that demonstrate lower levels of CIMP (CIMP-L). The measurement and significance of low levels of CpG island methylation is controversial ( 14 ). In contrast to the BRAF -mut arm, hmlh1 is not inactivated in these cancers and they are invariably MSS. Mutation of suppressor genes and p53, rather than aberrant methylation, appears to be the main driving force for their evolution. Some authors have suggested that KRASmut serrated cancers account for ~ 5 % of all CRC ( 10 ), but it is difficult to make a precise estimate because KRAS, unlike BRAF, is also found in up to 50 % of conventional CRCs. Perhaps, the best current evidence that these cancers represent a distinct entity is the finding of KRAS -mut dysplastic serrated polyps in continuity with high-grade dysplasia and or early invasive carcinoma, a finding most frequently encountered in the distal colon. The problem of right-sided and interval cancers Recent studies have demonstrated that the age-adjusted incidence and mortality rates from right-sided CRCs have not decreased in recent years despite the more widespread use of screening colonoscopy ( 1,4 ). Possible explanations for this phenomenon include missed lesions in the proximal colon due to incomplete examination, suboptimal bowel preparation, incomplete polyp removal, or unrecognized abnormalities (e.g., SSAs), as well as differing biologic behaviors of proximal vs. distal precursor lesions. Although this hypothesis has not been directly studied, serrated pathway cancers are likely a major contributor to the rising ratio of proximal-to-distal CRCs ( 69 ). A recent population-based study found that right-sided CRCs were significantly associated with female gender and advancing age ( 70 ), features that are disproportionately represented among patients with MSI-H CRCs arising via the serrated pathway. Interval cancers, typically defined as cancers that are diagnosed within 5 years of a complete / clearing colonoscopy, represent ~2 6 % of all CRCs (71 74 ). Several studies have shown that interval cancers, compared with non-interval cancers, are much more likely to occur in the proximal colon, demonstrate CIMP and MSI-H ( 71,73,75,76 ), features that are suggestive of a BRAF-mut serrated origin. It is therefore plausible that a significant proportion of interval cancers arise from prevalent SSAs that go unrecognized or are incompletely resected, which ultimately transform into invasive cancers. Risk and rate of progression to malignancy Although the malignant progression of serrated polyps has been clearly documented, the natural history and rate of progression of serrated polyps are less well established. There has been a The American Journal of GASTROENTEROLOGY VOLUME 106 FEBRUARY

7 Serrated Polyps Review 235 concern that BRAF -mut dysplastic serrated polyps will progress rapidly to carcinoma upon the acquisition of MSI-H status, akin to the behavior of adenomas in the hereditary non-polyposis colon cancer syndrome. In the original report on SAs, 37 % had foci of significant dysplasia and 11 % contained intramucosal carcinoma ( 61 ). Subsequent studies have reported a 3 16 % prevalence rate of high-grade dysplasia or intramucosal carcinoma in SAs ( 56,58,77 81 ). As mentioned above, a recent study on patients with SSAs reported prevalence rates of 12 and 2 % for low-grade dysplasia and high-grade dysplasia, respectively ( 36 ). It has been estimated that ~ 6 % of SSAs develop into MSI- H CRCs, based on the assumptions that the prevalence rate of SSAs is 12 % ( 82 ), and the expected lifetime risk of MSI-H CRCs is 0.75 % ( 83 ). The rate at which serrated polyps progress to CRC is uncertain and likely is variable, depending on if, or when, MSI-H status is acquired. The observation that serrated cancers are more prevalent than dysplastic serrated polyps would suggest rapid transformation to CRC ( 9,33,52,84 ). Clearly, the possibility of rapid transformation exists, as evidenced in a recent case report describing progression from SSA to early carcinoma within 8 months ( 85 ). However, not all the available data suggest a frequent or rapid progression to CRC down the serrated pathway. One large cross-sectional analysis reported that the median age of patients with SSAs, SSADs, and SSAs with carcinoma were 61, 66, and 76 years, respectively, suggesting a progression that occurs over a period of 15 years ( 36 ). In addition, data from one of the first studies to specifically identify SSAs as the precursors to MSI-H cancer suggested a slow progression, with an interval between the CRC and the SSAs that preceded them of over 3 years in 90 % of cases, and over 6 years in 55 % ( 30 ). Furthermore, several studies have shown that the malignant potential of dysplastic serrated polyps is similar to, if not lower than that of conventional adenomas ( 77,81,86,87 ). Therefore, at this time, no firm conclusions regarding the true frequency and rate of progression from SSA or dysplastic serrated polyp to CRC can be drawn. This uncertainty notwithstanding, the malignant potential of these lesions is beyond doubt, and they represent the precursors to an important proportion of the overall CRC burden. As such, these lesions should be regarded as important targets of our CRC prevention strategies. Risk of metachronous and synchronous neoplasia in patients with serrated polyps There are limited data on the risk of metachronous and synchronous neoplasia in patients with clinically important serrated polyps, specifically dysplastic serrated polyps and SSAs. In a retrospective study of 239 subjects with HPs, SAs or conventional adenomas at index examination, metachronous serrated CRC was diagnosed after a mean of 14 years in 5 % of patients with SAs removed during index examination ( 88 ). This study also found that the presence of SA on index examination predicted the presence of metachronous SAs, but not conventional adenomas: in patients with index SAs, 75 % of metachronous polyps were SAs, whereas only 6 % were conventional adenomas, suggesting that the effect of genetic and environmental factors in determining the predominant type of polyp is constant ( 88 ). A recent study by Pai et al. ( 89 ) reported that the finding of one SSA was frequently associated with synchronous serrated polyps in non-syndromic patients, suggesting a strong field phenomenon predisposing patients to multiple serrated polyps. This group has also reported that patients with SSAs frequently are found to have histologically distinctive conventional adenomas that exhibit low levels of CIMP ( 60 ). More recently, several studies have highlighted the association between serrated polyps and conventional adenomas and advanced colorectal neoplasia ( ). In a study of 4,714 asymptomatic subjects undergoing screening colonoscopy, Li et al. (92 ) found that large serrated polyps ( 1 cm) were strongly and independently associated with synchronous advanced neoplasia defined as invasive carcinoma, tubular adenoma 1 cm, or adenoma with any villous histology or high-grade dysplasia. Nearly 25 % of subjects with large serrated polyps had synchronous advanced colorectal neoplasia, compared with ~10 % of subjects without large serrated polyps. This association between large serrated polyps and advanced colorectal neoplasia, particularly CRC, was confirmed in a large, multi-center observational study of over 10,000 subjects who underwent first-time colonoscopy for a variety of indications ( 91 ). CRC was present in 708 subjects (6.9 % ), and on multivariate analysis, the presence of large serrated polyps was the strongest risk factor for CRC, particularly for proximal CRCs. Finally, Schreiner et al. ( 93 ) have also demonstrated the significant association between proximal or large non-dysplastic serrated polyps and the presence of synchronous advanced neoplasia. Furthermore, they found that individuals with proximal non-dysplastic serrated polyps at baseline were at increased risk of having three or more synchronous small tubular adenomas at baseline, as well as any non-advanced adenomas detected during surveillance colonoscopy. Altogether, the weight of the available evidence suggests that large serrated polyps should be considered a marker for synchronous advanced colorectal neoplasia, including CRC, and that certain serrated polyps (proximal or dysplastic) increase the risk of metachronous serrated and / or conventional adenomas. Risk factors for serrated neoplasia Few epidemiologic studies have specific investigated risk factors for serrated polyps. Serrated polyps tend to be less common in African Americans and Hispanics compared to Caucasians ( 22,94 ). Studies on various dietary and lifestyle factors have not revealed consistent effects on the risk of serrated polyps, and a recent study suggested that the risk profile for distal serrated polyps actually differs from that of proximal serrated polyps ( 94 ). This study found that obesity, cigarette smoking, dietary fat, total energy intake, and red meat intake were associated with an increased risk of distal (but not proximal) serrated polyps. In contrast, others have demonstrated an increased risk of rightsided serrated polyps associated with smoking ( 93 ). Cigarette smoking is a known risk factor for serrated polyps and is also associated with MSI in sporadic CRCs ( 22,95 97 ). Furthermore, smoking has also been shown to be associated with an increased risk of CRCs with BRAF -mut and / or CIMP ( 98 ), features that 2011 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

8 236 Huang et al. are characteristic of proximally located serrated polyps. Female gender, multiplicity of serrated polyps, larger polyp size, and polyp location in the proximal colon have also been identified as risk factors for SSAs as well as CIMP and BRAF -mutated CRCs ( 35,99,100 ). Higher BMI is associated with an increased risk of large serrated polyps ( 92 ), and as mentioned above, may have a particular influence on the risk of serrated polyps in the left colon ( 94 ). Finally, a family history of CRC or polyps may increase the risk of SSAs and right-sided serrated polyps ( 35,93,94 ). Hyperplastic polyposis syndrome: a precancerous condition Hyperplastic polyposis syndrome is an uncommon and heterogeneous condition characterized by the presence of multiple and / or large serrated polyps. Following its description as a condition with little or no malignant potential by Williams et al. ( 101 ) in 1980, several reports of CRC arising in patients with this syndrome have been published, providing some of the earliest evidence of a link between serrated polyps and CRC ( ). Although the true risk of CRC in hyperplastic polyposis is not known, based on available data from case reports and case series, the incidence of CRC appears to range from 40 to 50 % ( ). The World Health Organization has established the following criteria for the diagnosis of hyperplastic polyposis ( 112 ): (i) at least five HPs located proximal to the sigmoid colon, two of which are larger than 10 mm in diameter; (ii) any number of HPs located proximal to the sigmoid colon in an individual who has a first-degree relative with hyperplastic polyposis; or (iii) > 30 HPs of any size, distributed throughout the colon. Appreciated to be a genetically and phenotypically heterogeneous condition, it has been proposed that there are two distinct types of hyperplastic polyposis ( 113,114 ): type I hyperplastic polyposis (serrated adenomatous polyposis) is characterized by multiple (five or more), large, proximally located SSAs (coexisting with TSAs, mixed polyps, and conventional adenomas) and is associated with a significant risk for CRC ( 46 ). In this syndrome, there is a high frequency of concordant BRAF- mut and CIMP-H in serrated lesions, and aberrant methylation can be demonstrated even in normal mucosa, suggesting a field defect in epigenetic regulation ( 115 ). Type II hyperplastic polyposis, a more heterogeneous condition, is characterized by numerous ( 30), small HPs distributed throughout the colon, and is believed to have a significantly weaker association with CRC ( 101,116 ). Further studies are needed to validate the distinction between the proposed types of hyperplastic polyposis syndrome, characterize their clinical and molecular features and natural history, and determine appropriate clinical management. Only 50 % of patients with hyperplastic polyposis have a family history of colon cancer and the syndrome has no proven hereditary basis, but there is substantial evidence in support of a genetic etiology. This evidence includes examples of familial hyperplastic polyposis, early age of onset, polyp multiplicity, high level of risk for CRC, and ethnic associations in population studies ( 115,117 ). Young and Jass ( 115 ) proposed that a field susceptibility to CpG island methylation is the most likely basis for the genetic predisposition in type I hyperplastic polyposis. Hyperplastic polyposis with multiple KRAS -mut serrated polyps has also been described in association with bi-allelic germline mutations of MUTYH ( 29 ). IMPLICATIONS FOR CRC PREVENTION PRACTICES There are currently no formal guidelines on the management of serrated polyps other than small rectal HPs, which can be regarded as inconsequential and do not require complete resection or surveillance. The most recent consensus statement by the United States Multi-Society Task Force on CRC, American Cancer Society, and American College of Radiology addressed the issue of SAs and SSAs, but concluded that there was insufficient data to formulate surveillance guidelines for these lesions ( 118 ). Therefore, the recommendations presented in this article are based on expert opinion, shaped by current knowledge regarding the malignant potential of these serrated polyps. Recognition and resection of serrated lesions In order to prevent serrated pathway cancers, the precursor lesions need to be recognized and resected in their entirety. Given what we know about the gross morphology of SSAs as well as their predilection for the proximal colon, colonoscopy is the preferred method for detecting these lesions ( 83 ). Endoscopists need to be particularly aware of the subtle appearance of SSAs, and recognize clues such as an adherent mucus coating. A recent study performed at our institution found that there is significant variation in detection rates of patients with SSAs among experienced gastroenterologists using white light endoscopy, ranging from 0 to 2.2 % (119 ). Image-enhanced endoscopy techniques such as chromoendoscopy may improve detection of serrated polyps ( 35,43, ), but they are not yet recommended for routine use in screening procedures ( 123 ). Chromoendoscopy using a contrast dye, either sprayed on the surface or injected submucosally, may also facilitate complete resection of sessile lesions by delineating the margins of the polyp ( Figure 7 ). The techniques used to resect serrated polyps are the same as those used for conventional adenomas, and can be selected according to the size, location, and gross morphology of the polyp. Cold snare polypectomy can be safely performed for diminutive sessile polyps ( ) and avoids the potential for cautery artifact interfering with histologic examination of the specimen. In the authors experience, inject-and-cut endoscopic mucosal resection is the preferred technique ( 127,128 ) for resecting large, sessile /superficially elevated, or poorly defined serrated lesions. Follow-up examination in 3 months and then in 1 year should be performed in these circumstances to examine the polypectomy site and ensure a clean colon before entering the patient into a longterm surveillance program. Post-polypectomy surveillance Although surveillance following removal of isolated typical HPs is not necessary, surveillance after resection of SSAs and dysplastic serrated polyps is recommended ( Table 3 ). Polyps diagnosed as The American Journal of GASTROENTEROLOGY VOLUME 106 FEBRUARY

9 Serrated Polyps Review 237 Figure 7. Endoscopic appearance of a large sessile serrated adenoma and the use of chromoendoscopy to facilitate polyp delineation and resection. ( a ) This lesion, which demonstrates the characteristic mucus covering and smooth surface, was initially biopsied but not resected by the referring gastroenterologist, and the adjacent mucosa was tattooed. ( b ) Follow-up examination revealed this to be a large lesion with a redundant, fold-like morphology and poorly defined margins. ( c ) Chromoendoscopy using topical application of 0.2 % indigo carmine clearly delineated the margins of the polyp. ( d ) Submucosal injection of 0.2 % indigo carmine further highlighted the extent of the polyp and simultaneously provided a cushion for endoscopic mucosal resection. Table 3. Surveillance recommendations after resection of serrated polyps Category Typical hyperplastic polyp Sessile serrated adenoma (non-dysplastic) Sessile serrated adenoma with dysplasia (SSAD) Traditional serrated adenoma (TSA) Suspected type I hyperplastic polyposis (serrated adenomatous polyposis) Recommended surveillance interval No surveillance recommended, unless multiple, large and proximally located 5 Years if < 3 lesions, all < 1 cm size; 3 Years if 3 lesions, or any 1 cm size 3 Years, after ensuring complete resection (see text) 1 3 Years, with resection of polyps > 5 mm HPs may also warrant surveillance if there are attendant risk factors such as multiplicity, large size, proximal location, or family history of CRC. Gastroenterologists should appreciate that accurate and reproducible categorization of serrated polyps by pathologists can be challenging in clinical practice ( 34,53,54,119,129,130 ). As the distinction between HP and SSA represents a continuum of histological abnormality without sharp boundaries, particularly in smaller early SSAs (130 ), gastroenterologists need to be aware of the possibility of misclassification, and take into account clinical and endoscopic factors when deciding how to manage a particular patient diagnosed with a HP. The optimal surveillance interval after resection of these serrated lesions is unknown, given uncertainty regarding their natural history and risk of recurrent / metachronous neoplasia. Until further data are available, it would be reasonable to follow SSAs without cytologic dysplasia as per the current surveillance guidelines for conventional adenomas, stratified according to polyp size and number ( 8,83 ). Dysplastic serrated polyps, both SSADs and TSAs, may warrant more intensive surveillance, similar to that performed for advanced conventional adenomas. Accordingly, surveillance colonoscopy in 3 years would be reasonable after ensuring complete resection. Finally, the presence of multiple (5 + ), large ( > 1 cm), proximally located serrated polyps may be a manifestation of type I hyperplastic polyposis syndrome ( 114 ). Although data on screening and surveillance in this condition are severely lacking, given its frequent association with CRC, we would recommend colono scopy every 1 3 years with resection of all lesions larger than 5 mm ( 83,116 ). Colectomy may be justified in patients with an extremely high polyp burden, concomitant dysplastic serrated polyps, or multiple advanced adenomas. Colonoscopic screening of first-degree relatives should be considered starting at age 40 years, or 10 years earlier than the earliest age at diagnosis in the family ( 131 ). SUMMARY CRC is a heterogeneous disorder that arises via multiple distinct pathways. In one such pathway, serrated polyps, including variants 2011 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

10 238 Huang et al. of HPs, are the precursor lesions. Approximately % of all CRCs arise via this serrated pathway; most are proximally located and are characterized by a molecular genetic profile of BRAF-mut and CIMP-H. Serrated polyps that are KRAS -mut also contribute to serrated pathway carcinomas and these, in contrast, are generally distally located, CIMP-L and MSS. There is growing evidence that end point cancers of the serrated pathway, particularly when proximally located, are major contributors to occurrences of interval cancer following negative colonoscopy. Gastroenterologists need to be able to recognize and remove potential precursor lesions and implement a post-polypectomy surveillance program in order to prevent these cancers. Further investigation is needed to improve our ability to detect important serrated polyps, clarify their natural history, and determine their optimal management. ACKNOWLEDGMENTS We thank John O Hara for his assistance in preparing the histology images used in this article. CONFLICT OF INTEREST Guarantor of the article : Christopher S. Huang, MD. Specific author contributions: Drafted and revised the manuscript and approved the final version: Christopher S. Huang; initiated the plan to write this article, edited the manuscript, and approved the final version: Francis A. Farraye; edited the manuscript and approved the final version: Shi Yang; provided his expertise on the molecular genetic and pathology aspects of the topic, helped draft and revise the manuscript, and approved the final version: Michael J. O Brien. Financial support : None. Potential competing interests : None. REFERENCES 1. B ax te r N N, G ol dwass e r M A, Pas z at L F et al. Association of colonoscopy and death from colorectal cancer. Ann Intern Med 2009 ; 150 : L a koff J, Pas z at L F, S ask in R et al. 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