Sessile Serrated Polyps and Colon Cancer Prevention Shahrooz Rashtak1, Rafaela Rego1,2, Seth R

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Review Cancer Prevention Research Sessile Serrated Polyps and Colon Cancer Prevention Shahrooz Rashtak1, Rafaela Rego1,2, Seth R. Sweetser1, and Frank A. Sinicrope1,3

Abstract

Evidence suggests that up to one fifth of colorectal carcinomas that is typically found in the left colon, has a tubulovillous develop from serrated polyps, named for their pattern of colonic architecture, and frequently harbors mutant KRAS.Todate,the crypts, and include the sessile serrated adenoma/polyp (SSA/P) epidemiology of these serrated lesions is poorly understood, that has malignant potential. SSA/Ps are typically located in the and limited observational data suggest a potential chemo- proximal colon and have molecular features of hypermethylation preventive benefitofnonsteroidalanti-inflammatory drugs. of CpG islands in gene promoters and activating point mutations The current primary strategy to reduce the risk of colorectal (V600E) in the BRAF oncogene. Both of these features are seen in carcinoma from serrated polyps is to enhance their detection at sporadic colorectal carcinomas with microsatellite instability colonoscopy and to ensure their complete removal. This review (MSI) which is potentially consistent with an origin of these provides insight into the epidemiologic, clinical, histopatho- cancers from precursor SSA/Ps. Dysplasia is detected in a subset logic, and molecular features of serrated polyps and includes of SSA/Ps with a high risk of progression to carcinoma. An data on their endoscopic detection and chemoprevention. uncommon serrated polyp is the traditional serrated adenoma Cancer Prev Res; 10(5); 1–9. 2017 AACR.

Introduction represent up to 20% of all serrated polyps, are typically sessile or flat lesions, and have a predilection for the right colon (6). In Colorectal cancer is the third most common cancer in the contrast to hyperplastic polyps, SSA/Ps can develop classical United States and the second leading cause of cancer-related dysplasia and are considered precursor lesions of colorectal car- mortality (1). The overall incidence of colorectal carcinoma is cinomas. SSA/Ps are difficult to visualize at endoscopy, as they are decreasing in older adults due, in part, to colonoscopic screening flat and often have overlying, adherent mucus, making them more with removal of adenomatous polyps that are associated with a likely to be overlooked compared with conventional adenomas reduction in mortality from colorectal carcinoma (2). However, (Fig. 1A). SSA/Ps have less distinct borders compared with ade- colonoscopy is an imperfect test with an appreciable rate of nomas and have increased rates of incomplete resection (7). undetected premalignant lesions and less commonly missed SSA/Ps are believed to be an important contributor to interval cancers (3). While adenomatous polyps were traditionally con- colorectal carcinomas, defined as a cancer diagnosed after a screen- sidered to be the sole precursor lesions of colorectal carcinomas, ing or surveillance examination, in which no colorectal carcinoma an important milestone in our understanding of colorectal car- is detected, and before the date of the next recommended exam- cinogenesis has been the recognition of the serrated neoplasia ination (8). Traditional serrated adenomas (TSA) are rare and pathway. Approximately 20% of sporadic colorectal carcinomas represent only 1% of all serrated polyps. TSAs are typically located develop via this pathway with the major precursor lesion being in the left colon, are often pedunculated, and have villous mor- the sessile serrated adenoma/polyp (SSA/P; refs. 4–6). phology with classical dysplasia which confers a malignant poten- The term serrated polyp refers to a lesion with a serrated or tial (9–11). In this article, we review the clinical, endoscopic, and "sawtooth" appearance of the colonic crypts at microscopy. The molecular features of SSA/Ps and their association with colorectal most common serrated polyp is the hyperplastic polyp of the carcinoma. In addition, we discuss quantitative estimates of risk, rectum and sigmoid colon which accounts for 80% of all serrated limited data for chemoprevention, and specific approaches to polyps and lacks malignant potential. SSA/Ps are estimated to improve endoscopic detection and removal.

1Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Histology and molecular features 2 ^ Clinic, Rochester, Minnesota. Department of Pathology, Instituto Portugues de The most recent classification of serrated polyps of the colo- Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal. 3Department of Oncol- rectum by the World Health Organization categorizes them into 2 ogy, Mayo Clinic, Rochester, Minnesota. main groups based on crypt morphology and the presence or Current address for R. Rego: Department of Pathology, Instituto Português de absence of dysplasia. Serrated polyp subtypes include: hyper- Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal. plastic polyp, SSA/P, SSA/P with dysplasia, and TSA (12, 13), Corresponding Author: Frank A. Sinicrope, Mayo Clinic, 200 1st St SW, Roche- and all but hyperplastic polyps are considered precursors of ster, MN 55905. Phone: 507-255-5713; Fax: 507-255-6318; E-mail: colorectal carcinoma (14). This classification is important for [email protected] tailoring surveillance strategies, as each subtype differs in their doi: 10.1158/1940-6207.CAPR-16-0264 malignant potential. Hyperplastic polyps are further subclassified 2017 American Association for Cancer Research. into microvesicular, goblet cell–rich, and mucin-poor variants

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Figure 1. A, SSA/P is seen in the right colon (outlined by arrows) at colonoscopy. Note the typical ﬂat appearance of the lesion and common overlying mucus that can obscure its detection. B, Histopathology of a SSA/P shows the characteristic serrated or "sawtooth" appearance of the colonic crypts that are wide and lateral spreading at the base (arrow) of the polyp. C, SSA/P (down arrow) is seen contiguous with a colonic adenocarcinoma (up arrow). The cancer is poorly differentiated with an area of signet ring cells and was found to have MSI and a BRAF mutation.

(10). The microvesicular hyperplastic polyp (MVHP) is the most in 55 patients (5.8%) were reclassified as SSA/P, 40 of these cases common type and often has mutation in the BRAF oncogene, had no prior diagnosis of high-grade dysplasia (HGD) or colo- suggesting that these polyps may be precursors to SSA/P (15). rectal carcinoma (17). On follow-up, the incidence of subsequent Compared with SSA/Ps, TSAs can carry either KRAS or BRAF colorectal carcinoma was significantly higher in patients with mutations and with either mutation have similar morphologic SSA/P than in those with hyperplastic polyp (12.5% vs. 1.8%). features (ref. 16; Fig. 2). SSA/Ps, like hyperplastic polyps, have Furthermore, approximately 15% of the SSA/Ps initially misdiag- serrated crypts, but SSA/Ps have characteristic crypts that are nosed as hyperplastic polyps were found to evolve into lesions distorted with widened and branching bases (ref. 10; Fig. 1B). with HGD or cancer in the right colon (17). While dysplasia is a Before identification of these unique histopathologic features, universal feature of conventional adenomas, it is not a typical SSA/Ps were interpreted by pathologists as hyperplastic polyps, feature of SSA/Ps although conventional dysplasia may develop and it is likely that under-reading of SSA/Ps continues to occur within an SSA/P indicating neoplastic transformation (10, 18). In today in clinical practice. In a retrospective review of polyps a large retrospective study of SSA/Ps removed at colonoscopy, the initially classified as hyperplastic polyps that were resected overall prevalence of dysplasia was 5% (19). SSA/Ps containing between 1980 and 2001 from a single academic center, 81 polyps dysplastic crypts are classified as SSA/P with dysplasia, which may

Figure 2. The precursor of the ﬁrst pathway (left) is believed to be MVHP, although there is the potential for SSA/P to arise de novo from normal mucosa. This pathway results in BRAF-mutant cancers that are CIMP-high and have MSI-H or are MSS. The second pathway (right) is less well-deﬁned with the potential precursor lesion being the goblet cell hyperplastic polyp leading to the TSA. The end result of this pathway is an MSS and CIMP-low cancer that may have an associated KRAS mutation. Reprinted from ref. 6.

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represent an intermediary in the molecular evolution of SSA/P sia. In 16% (5 of 31) of the mice, dysplasia progressed to invasive to cancer (20). When SSA/P tissue is found contiguous with carcinoma, and importantly, nearly 40% (13 of 33) of the BRAF- carcinoma, a transition zone of dysplasia is frequently present mutated serrated adenomas and cancers were MSI-high (MSI-H). (ref. 11; Fig. 1C). Progression to carcinoma was shown to be accelerated by p53 Most colorectal carcinomas develop from conventional ade- mutation or p16Ink4a inactivation. Therefore, overcoming nomas through a pathway characterized by chromosomal insta- p16INK4a and p53 tumor suppressor functions is likely critical for bility (CIN) that is associated with mutations in the APC, TP53, ultimate progression to cancer (28). This study confirms that a SMAD4, PIK3CA, and KRAS genes. In addition, genomic profiling BRAF oncogenic mutation can induce formation of murine revealed other frequently mutated genes (FBXW7, TCF7L2 , NRAS, SSA/Ps with ability to progress to carcinoma. In an model of CTNNB1, SMAD2, FAM123B, and SOX9) in these cancers (21). oncogenic KrasG12D expression driven by a transgenic Villin V600E While BRAF mutations are not found in conventional ade- promoter, epithelial hyperplastic changes were seen but not nomas, they are detected in approximately 8% of colorectal development of TSA or SSA/s. Deletion of Cdkn2a (the locus G12D carcinomas and result in activation of the mitogen-activated encoding p16Ink4a and p19Arf)inKras -expressing mice pre- protein kinase (MAPK) signaling pathway which promote cell vented senescence and led to invasive carcinomas (29, 30). proliferation and survival (22). The other major pathway is that of However, unlike the oncogenic BRAF-driven tumors, these microsatellite instability (MSI) that develops due to deficient tumors neither were MSI-H nor showed WNT pathway activation. DNA mismatch repair (MMR) which is detected in about 15% Using an unsupervised classification strategy involving more of all colorectal carcinomas. MSI is most often sporadic and a than 1,100 colon cancers, established CIN and MSI were identified consequence of epigenetic inactivation of the MLH1 MMR gene in addition to a third subtype that was largely microsatellite stable that occurs in a background of hypermethylation at CpG islands (MSS) and contained relatively more CIMP-positive carcinomas. in the promoter regions of cancer-associated genes that is termed This colon cancer subtype is related to SSA/Ps which show very CIMP (CpG island methylator phenotype) with frequent similar gene expression profiles, including upregulation of genes V600E BRAF mutations. Data indicate that the mutant BRAF onco- involved in matrix remodeling and epithelial–mesenchymal tran- protein functions through the transcriptional repressor MAFG as sition (31). However, factors responsible for driving distinct the pivotal factor required for MLH1 silencing and CIMP in subtypes of colorectal carcinoma are incompletely understood. colorectal carcinomas containing BRAFV600E mutations (23). In In contrast to adenomas where the predominant response to TGFb V600E addition to BRAF , other frequent targets of mutation in MSI was apoptosis, TGFb treatment induced a mesenchymal pheno- tumors include ACVR2A, APC, TGFBR2, MSH3, MSH6, SLC9A9, type in a genetically engineered organoid culture carrying a V600E and TCF7L2 (21). Recently, a consortium was formed to resolve BRAF mutation which represents a model system for inconsistencies among the reported gene expression–based colo- SSA/Ps (32). These data suggest that TGFb signaling may be rectal carcinoma classifications. This effort identified 4 consensus a key factor in directing SSA/Ps to the mesenchymal subtype molecular subtypes (CMS) with distinguishing features: CMS1 of colorectal carcinoma. In another study, RNA sequencing (14%) hypermutated, MSI, and immune activation; CMS2 (RNA-Seq) was performed on 21 SSA/Ps, 10 hyperplastic (37%), epithelial, WNT, and MYC signaling activation; CMS3 polyps, 10 adenomas, 21 uninvolved colon, and 20 control (13%), epithelial, and metabolic dysregulation; and CMS4 colon specimens to define a gene signature of SSA/Ps. This (23%), mesenchymal with TGFb activation, stromal invasion, SSA/P gene signature was then evaluated in colon cancer RNA- and angiogenesis (24). Seq data from The Cancer Genome Atlas (21) to identify a The initiating molecular event in the SSA/Ps to colorectal subtype of colon cancers that may develop from SSA/Ps. A total carcinoma sequence is believed to be mutational activation of 1,422 differentially expressed genes were found in SSA/Ps of the BRAF oncogene, detected in about 80% of these lesions, relative to controls. A 51-gene panel in SSA/P showed similar which is followed by CIMP (5). CIMP is believed to promote expression to a subset of colon cancers with MSI from TCGA. A the transition of MVHPs to SSA/Ps, and hypermethylation of smaller 7-gene panel showed high sensitivity and specificity in MLH1 may be a key event in the development of dysplasia within identifying BRAF-mutant, CIMP-H, and MLH1-silenced colon an SSA/P that may promote progression to cancer (ref. 25; Fig. 2). cancers that are likely to develop through the serrated neoplasia Molecular profiling indicates that dysplastic foci within SSA/Ps are pathway (33). These data suggest that a key event is epigenetic likely to be the immediate precursors of colorectal carcinoma in inactivation of MLH1, often in a background of CIMP, which V600E these lesions (4). Since BRAF mutations and CIMP are confers the MSI-associated subtype. characteristic of sporadic colon cancers with MSI, these data In colectomy specimens from patients with colorectal carcino- suggest that SSA/Ps are precursor lesions of sporadic MSI cancers ma containing serrated polyps, the cancer was more likely to show (26). These findings are supported by a mechanistic animal model MSI-H (34). These data were often obtained before recognition of of SSA/P that was generated by conditional BRAF knock-in mice SSA/Ps as a distinct entity, and re-review of their histology that were crossed to Villin-Cre transgenic mice with restriction of indicates that many of these lesions were SSA/Ps. In a review of the oncogene to small intestinal and colonic epithelia (27). The the pathology database at Mayo Clinic from 2006 to 2012, 2,646 resulting double mutant mice developed serrated polyps that were colorectal carcinomas were identified of which 33 cancers arose characterized by hyperproliferation and activation of ERK and within or contiguous with an SSA/Ps. By histopathology, SSA/Ps WNT signaling pathways. In an age-dependent manner, hyper- that were associated with colon carcinomas contained frequent plasia progressed to dysplasia and TSAs, but not SSA/Ps which the dysplasia (48%). Most of these cancers (94%) had mutated BRAF, authors speculated was due to predilection for polyps in the loss of MLH1 (79%), and were predominantly located in the mouse small intestine, as SSA/Ps in humans are colonic. The proximal colon (6, 35). Taken together, data indicate that SSA/Ps authors referred to the small intestinal lesions as murine serrated are likely the predominant precursor lesion of sporadic colorectal adenomas which showed either low-grade or high-grade dyspla- carcinomas with MSI (36).

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SSA/Ps and Risk of Colorectal Carcinoma Epidemiology The natural history of SSA/Ps and risk factors for progression to The natural history of SSA/Ps is not well understood and malignancy are poorly understood. SSA/Ps are more commonly estimates of cancer risk remain limited. SSA/Ps may be relatively seen in individuals of advanced age, in women, and in smokers indolent lesions, but a subset may have the potential for rapid (46, 47). In colonoscopy studies and in pathology database progression once dysplasia develops (37). The overall prevalence reviews, women represent up to 65% of individuals with detected of dysplasia in SSA/P is estimated to be 5% on the basis of a large SSA/Ps (22, 46, 48–52). In addition, women have a higher retrospective study of SSA/Ps removed at colonoscopy that were proportion of advanced serrated lesions including SSA/Ps with not associated with cancer (19). A large cross-sectional study low- or high-grade dysplasia and SSA/Ps with invasive adenocar- found that 85% of 2,416 SSA/Ps were nondysplastic, 14% had cinoma (38). A recent analysis of several studies of serrated polyps low- or high-grade dysplasia, and 1% had adenocarcinoma (38). found that risk is associated with different lifestyle factors (53). The frequency of dysplasia in this series, however, may be an When the highest and lowest categories of exposure were com- overestimate, as it may be biased towards larger lesions identified pared, factors found to significantly increase risk for serrated at colonoscopy. Other reports have shown that the prevalence of polyps included tobacco smoking [relative risk (RR), 2.47; 95% SSA/Ps without dysplasia is about 7.4%, whereas the prevalence CI, 2.12–2.87], alcohol intake (RR, 1.33; 95% CI, 1.17–1.52), of SSA/Ps with dysplasia is 0.6%, accounting for total SSA/P high BMI (RR, 1.40; 95% CI, 1.22–1.61), and high intake of fat or prevalence of 8.1% in average risk screening population (39). meat. However, conflicting data exist as to the association of SSA/ The relatively low prevalence of dysplasia in SSA/Ps suggests that Ps with obesity (46, 49, 54), such that this association remains only a small subset of these lesions have the potential for pro- uncertain. Direct associations for smoking and alcohol tended to gression to cancer. This is supported by longitudinal observations be stronger for SSA/Ps than hyperplastic polyps (53). In contrast, on 23 large SSA/Ps found at screening colonoscopy that were left factors found to significantly decrease risks for serrated polyps in situ and did not progress to cancer over a median of 11 years included use of NSAIDs (RR, 0.77; 95% CI, 0.65–0.92) or aspirin (40). In a multicenter study, SSA/Ps that were 1 cm or larger were (RR, 0.81; 95% CI, 0.67–0.99), as well as high intake of folate, significantly associated with a higher risk of developing colorectal calcium, or fiber. No significant associations were detected carcinoma (OR, 4.79). The anatomic location of serrated polyps between serrated polyp risk and physical activity or hormone has been associated with the risk of colorectal carcinoma (41). replacement therapy. The most consistent data are for tobacco as a Recently, a predictive model was developed to identify large, risk factor for SSA/Ps (46, 49, 55), particularly those located proximal, or dysplastic serrated polyps on the basis of clinical in the proximal colon (42, 56). Some (47, 57, 58), but not other factors that include age above 50 years [OR, 2.2; 95% confidence (59, 60), studies found cigarette smoking to be associated with interval (CI), 1.3–3.8], history of serrated polyps (OR, 2.6; 95% MSI-H colorectal carcinomas including a large population-based, CI, 1.3–4.9), current smoking (OR, 2.2; 95% CI, 1.4–3.6), or lack case–control study (61); however, this association may be limited of regular nonsteroidal anti-inflammatory drug (NSAID) use (OR, to tumors showing CIMP, regardless of MSI status (62). In 1.8; 95% CI, 1.1–3.0). An elevated risk score of more than 5 was addition to smoking, other risk factors for serrated lesions with associated with a 3-fold higher chance of detecting a large, CIMP included white race and a history of polyps (63). proximal SSA/P with dysplasia compared with individuals with The gut microbiome is being increasingly recognized as a a lower score (42). This scoring system can potentially alert contributor to colorectal tumorigenesis and evidence suggests endoscopists to be especially vigilant for SSA/Ps in certain groups the role of Fusobacterium nucleatum. The presence of F. nucleatum of patients having a high pretest probability for SSA/Ps. Post- was analyzed in tissues from 343 serrated lesions, 122 non- polypectomy surveillance is recommended after removal of serrated adenomas, and 511 colorectal carcinomas. In this report, SSA/Ps or large and/or proximal hyperplastic polyps. While the the presence of F. nucleatum was similar among SSA/Ps (35%), presence of a hyperplastic polyp is not associated with an TSAs (30%), and non-serrated adenomas (33%) and was signif- increased risk of cancer (43), large (>10 mm) serrated polyps in icantly more frequent in colorectal carcinomas (56%; ref. 64). the proximal or distal colon has been shown to be associated with Interestingly, the investigators found that F. nucleatum was sig- synchronous advanced neoplasia (44). nificantly associated with CIMP-high versus CIMP-low or CIMP- Direct evidence that SSA/Ps can be precursors of colorectal negative premalignant lesions. In a smaller study, the relative carcinoma is shown by the demonstration of an SSA/P contiguous abundance of Fusobacteria in tissue did not differ significantly with a colorectal carcinoma at surgical resection (Fig. 1C). Among between the tubular adenomas and SSA/P groups but was again 33 colon cancers that arose within or contiguous with an SSA/P, higher in the colorectal carcinoma group (65). Another study 16 (48%) were found to contain dysplasia. The presence of focal detected invasive F. nucleatum in the majority of proximal hyper- dysplasia within a contiguous SSA/Ps supports a dysplasia to plastic polyps and SSA/Ps which was significantly higher than carcinoma sequence for these lesions (35). The timing of the found in tubular adenomas (66). Detection of F. nucleatum transition from serrated lesion to cancer is often longer compared showed a predilection for proximal versus distal colorectal car- with adenomas; however, progression of an SSA/P to an early cinomas. These studies suggest that F. nucleatum may play a role in invasive cancer has been documented to occur within 8 months the serrated neoplasia pathway of colon tumorigenesis. Further (37). The presence of dysplasia with a propensity for rapid studies are needed examine microbial composition and metabo- progression may account for the paucity of colon cancers found lites associated with these lesions including their relationship to in association with SSA/Ps at surgical resection because the the tumor immune microenvironment. carcinoma likely overgrows and replaces the SSA/P. In contrast, colorectal carcinomas are more commonly found to contain Association with interval cancers residual adenomatous tissue in endoscopic biopsies and surgical SSA/Ps may contribute disproportionately to interval colon resection specimens (45). cancers which are defined as cancers diagnosed before the next

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recommended screening or surveillance examination. SSA/Ps DNA in feces to identify selected biomarkers and also includes a occur most commonly in the proximal colon which is where quantitative fecal immunohistochemical test (FIT; ref. 79). Stool the majority of interval cancers are detected [21 of 22 (95%); DNA testing was shown to detect 42% of SSA/Ps of at least 1 cm in ref. 67]. A meta-analysis estimated that more than half of size and may, therefore, have the potential to improve the detec- interval cancers are due to undetected lesions and about one tion of SSA/Ps (80). fifth of them are related to incomplete resection. Accordingly, the majority of interval colorectal carcinomas can potentially Serrated polyposis syndrome be prevented by improving colonoscopic detection and resec- Serrated polyposis syndrome (SPS) is characterized by mul- tion techniques (68). Incomplete polyp resection is significant- tiple serrated polyps in the colon of patients who fulfill WHO ly more likely for SSA/Ps compared with adenomas (31.0% vs. criteria and is associated with a high risk of colorectal carcino- 7.2%; RR, 3.7; ref. 7). In a recent study examining colorectal ma. Gene expression profiling indicates that serrated polyps carcinoma with contiguous SSA/P tissue, two thirds of colon from those meeting criteria for the SPS completely overlap with cancer cases [22 of 33 (67%)] were diagnosed between the those found in non-syndromic patients (81). According to recommended colonoscopic screening or surveillance interval American College of Gastroenterology (ACG) clinical guide- (35), thus meeting the definition of interval cancers (69). The lines, genetic testing is not routinely recommended for SPS, as a mean interval from prior colonoscopy to colon cancer diagno- clear genetic etiology has yet to be defined for this condition. sis was 42 months (range, 12–96 months). As shown in prior However, SPS patients with concurrent personal or family studies, SSA/P-associated colon cancers were significantly more history of adenomas can be considered for analysis for MUTYH likely to be MSI-H tumors (6). Compared with colorectal mutations (82). A low frequency of MUTYH mutations has carcinomas diagnosed in patients more than 5 years after been found among patients with multiple adenomatous and colonoscopy or without prior endoscopy, those diagnosed in serrated polyps. This phenotype frequently includes patients patients within 5 years after colonoscopy were more likely to be with serrated polyps, especially when the G396D mutation was characterized by CIMP (multivariate OR, 2.19; 95% CI, 1.14– present. Colonoscopy every 1 to 3 years with attempted remov- 4.21) and MSI (multivariate OR, 2.10; 95% CI, 1.10–4.02; al of all polyps >5 mm diameter for patients with SPS has been ref. 70). These data suggest that a significant proportion of recommended by ACG. Colectomy and ileorectal anastomosis interval cancers may due to overlooked SSA/Ps. is indicated in those who develop cancer or in those where controlling the growth of serrated polyps cannot be achieved Endoscopic detection endoscopically (82). It is important to recognize that newer generation colonoscopes with increased optical resolution permit the detection of subtle Preventive approaches and flat mucosal lesions and likely contribute to the increased Intake of aspirin was found to significantly decrease the risk recognition of SSA/Ps over the past several years. A high-quality of serrated polyps in an analysis of pooled data from 3 ran- bowel preparation with meticulous mucosal inspection is needed domized chemopreventive trials examining the effect of aspirin to optimize the detection of SSA/Ps (71). SSA/Ps commonly have on adenoma recurrence. In this study, daily aspirin intake was an adherent mucus-cap which may be a clue to its presence. associated with a reduced risk of serrated polyps in the right Careful examination of the right colon is critical, as the majority colon (81 mg; RR, 0.56; CI, 0.34–0.91; 325 mg RR, 0.58; 95% of SSA/Ps are proximally located. Colonoscopy has been shown to CI, 0.36–0.95), whereas it had no effect on left-sided or be significantly less effective at detecting as well as reducing advanced lesions compared with placebo (ref. 54; Table 1). mortality from cancers of the right versus left colon (72). Given The study included all types of serrated polyps and of note, a limitations of conventional white light colonoscopy, enhanced family history of polyps or folate intake was each associated endoscopic methods are being studied that include narrow- with an increased risk for serrated polyps diagnosed during band imaging (NBI) and chromoendoscopy that utilizes a each trial's main treatment period of approximately 3 to 4 years mucosal contrast agent (73) for differentiating hyperplastic (54). Another report utilized data from the Prostate, Lung, polyps from SSA/Ps polyps (74). In a study from Japan that Colorectal, and Ovarian Cancer Screening Trial (PLCO) that used magnifying colonoscopy, the type II open-shape pit pat- included 4,017 subjects with a biopsy-proven polyp in the left tern (Type II-O) was reported to be specifictoSSA/PswithBRAF colon or rectum to study the association of NSAIDs (aspirin mutation and CIMP (75). Complete removal of SSA/Ps is and ibuprofen) use with risk of polyp and cancer development. critical to reducing colorectal carcinoma incidence. In a study This study showed that regular use of aspirin was inversely by Pohl and colleagues, 50% of SSA/Ps that were at least 1 cm in associated with adenomas and hyperplastic polyps (OR, 0.8; size were incompletely resected at colonoscopy which under- 95% CI, 0.7–0.9 for both); however, it did not specify the scores the need for proper polypectomy technique (7). Incom- proportion of SSA/P among those with hyperplastic polyps plete polypectomy and lack of adherence to follow-up surveil- (ref. 83; Table 1). Concurrent use of aspirin and ibuprofen was lance are strongly associated with colorectal carcinoma risk associated with even lower risk of developing hyperplastic after colonoscopic polyp detection (76). An expert-panel con- polyps (OR, 0.7; 95% CI, 0.6–0.9), adenomas (OR, 0.8; 95% sensus conference recommends complete removal of all ser- CI, 0.7–0.9), and advanced adenomas (OR, 0.8; 95% CI, 0.7– rated lesions proximal to the sigmoid colon and all serrated 1.0; ref. 83). In a recent meta-analysis that included 43 obser- lesions in the rectosigmoid which are larger than 5 mm in size vational studies, factors found to significantly decrease risk for given their risk of malignancy (77). serrated polyps included use of NSAIDs (RR, 0.77; 95% CI, Multitarget stool DNA testing is an FDA-approved molecular 0.65–0.92) or aspirin (RR, 0.81; 95% CI, 0.67–0.99), with assay that is an available option for colorectal carcinoma screen- suggestionthatthereductioninriskmaybeevenstrongerfor ing in patients at average risk (78). This technology probes shed SSA/Ps (53).

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Table 1. Chemoprevention for serrated polyps Chemopreventive Preventive Follow-up strategy effect duration Proposed mechanism Site of action Magnitude Reference Aspirin 81 mg/d Yes 3 y Inhibition of prostaglandins/ Proximal serrated polyps RR, 0.56 (0.34–0.91) (54) eicosanoids Aspirin 325 mg/d Yes 3 y Inhibition of prostaglandins/ Proximal serrated polyps RR, 0.58 (0.36–0.95) eicosanoids Aspirin (> 4 times/mo) Yes 1 y Inhibition of prostaglandins/ Hyperplastic polyps OR, 0.8 (0.7–0.9) (83) eicosanoids Aspirin þ ibuprofen Yes 1 y Inhibition of prostaglandins/ Hyperplastic polyps OR, 0.7 (0.6–0.9) eicosanoids Folic acid, 1 mg/d No 3 y Involved in DNA synthesis Proximal advanceda RR, 2.07 (1.14–3.77) (54, 90) serrated polyps Distal advanceda serrated RR, 0.98 (0.61–1.57) polyp Calcium 1,200 mg/d No 4 y Inhibition of colonic epithelial Serrated polyps (54, 95, 96) proliferation b-Carotene No 4 y Presumed antioxidant effect (54, 92) Vitamin C No Vitamin E No Hormone replacement therapy No 1–9 years Unknown Serrated polyps 1.09 (0.76, 1.57) (49) aAny serrated lesion >1 cm, SSA/P or TSA, or mixed polyps.

The mechanism underlying the potential chemopreventive decreasing the risk of serrated polyps that did not achieve statis- efficacyofNSAIDsagainstdevelopmentofserratedpolypsis tical significance (92). With regard to hormone replacement unclear. NSAIDs inhibit cyclooxygenase enzymes that regulate therapy, usage failed to reduce the risk of serrated polyps, includ- the synthesis of prostaglandins and related eicosanoids. Com- ing SSA/Ps (49). pared to adenomas, SSA/Ps have been shown to infrequently overexpress COX2; however, COX2 overexpression is more Conclusion frequent with neoplastic progression (84). Data from observational studies suggest that regular aspirin use was not associated Recognition of the serrated neoplasia pathway provides an with a decreased risk of BRAF-mutated colorectal carcinomas opportunity to further reduce the incidence of colorectal carci- (85) which may arise via the serrated pathway. Of note, aspirin noma. The SSA/P is a colonic polyp with malignant potential, and intake (600 mg/d for a mean of 25 months) was shown to a subset shows classical dysplasia indicating the potential to significantly reduce the incidence of colorectal carcinoma in progress via a dysplasia-to-carcinoma sequence. While uncom- Lynch Syndrome gene mutation carriers (86) whose tumors mon among serrated polyps, TSAs are known to have malignant lack BRAF mutations (87). Prospectively conducted, random- potential. Interobserver variability remains an issue in the histo- ized trials are needed to further examine the ability of NSAIDs pathologic diagnosis of SSA/Ps (93), although pathologists with to prevent SSA/Ps, and as of this writing, there remains insuf- gastrointestinal subspecialty training and those who have gained ficient evidence to recommend use of aspirin or other NSAIDs familiarity with these lesions through the literature were shown to for the prevention of these lesions. be more likely to make an accurate diagnosis (94). Given inter- Calcium supplementation was not associated with a reduced observer variation in pathologic interpretation, guidelines of the risk of developing serrated polyps (ref. 54; Table 1). Folic acid is an American Gastroenterological Association recommend that all essential micronutrient in the process of DNA synthesis, and a low proximal colon serrated lesions 10 mm in size should be folate-containing diet has been associated with an increased risk considered sessile serrated polyps, even if the pathologic inter- of colorectal carcinoma (88). In a large observational cohort pretation is hyperplastic polyp (82). (Nurses' Health Study), supplemental folic acid was significantly Given limited data, large-scale genomic analysis is needed to associated with a lower risk of colorectal carcinoma (RR, 0.25; further molecularly characterize SSA/Ps including the subset with 95% CI, 0.13–0.51) that was apparent only after 15 years of intake dysplasia and/or carcinoma. As with adenomas, it is likely that (89). In contrast, a randomized controlled trial revealed that 1 only a subset of serrated polyps will ever progress to develop mg/d of supplemental folic acid was associated with higher risk of dysplasia, yet factors governing such progression remain developing colorectal adenomas and advanced proximal serrated unknown. SSA/Ps have molecular features of BRAF mutations polyps (RR, 2.07; 95% CI, 1.14–3.77) with failure to reduce the and CIMP that also characterize sporadic colorectal carcinomas risk of colorectal carcinoma (refs. 90, 91; Table 1). A pooled with MSI which supports the origin of these cancers from pre- analysis of 3 large chemoprevention studies found that folate cursor SSA/Ps. However, gene expression profiling data suggest treatment was associated with an increased risk for right-sided that SSA/Ps may also be precursors of a mesenchymal subtype of serrated polyps diagnosed during each trial's main treatment colorectal carcinoma that have a poor prognosis (24). The iden- period of 3 to 4 years (54). In these studies, serrated polyps were tification of patients at risk of serrated polyps including lifestyle broadly defined and subsets were not specifically examined. factors that influence this risk remain an important unmet need. A Pooled data from a randomized trial showed a modest effect of greater insight into the epidemiology of serrated polyps has the supplemental antioxidant vitamins C and E and b-carotene in potential to enhance primary and secondary prevention strategies.

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While limited data suggest that NSAIDs may protect against Authors' Contributions serrated polyps, further studies are needed to conﬁrm this ﬁnding Conception and design: S. Rashtak, S.R. Sweetser, F.A. Sinicrope and to provide mechanistic insight. Evidence indicates that SSA/ Acquisition of data (provided animals, acquired and managed patients, Ps may be important contributors to interval colorectal carcino- provided facilities, etc.): F.A. Sinicrope Analysis and interpretation of data (e.g., statistical analysis, biostatistics, mas, especially in the right colon. Accordingly, efforts to enhance computational analysis): R. Rego, F.A. Sinicrope the endoscopic detection of SSA/Ps and ensure their complete Writing, review, and/or revision of the manuscript: S. Rashtak, R. Rego, removal are an immediate need and important for reducing S.R. Sweetser, F.A. Sinicrope colorectal carcinoma incidence. Guidelines for the management Administrative, technical, or material support (i.e., reporting or organizing of patients with serrated polyps are based upon consensus opin- data, constructing databases): F.A. Sinicrope ion and are expected to continue to evolve. Study supervision: F.A. Sinicrope

Disclosure of Potential Conﬂicts of Interest Received October 14, 2016; revised November 21, 2016; accepted March 15, No potential conﬂicts of interest were disclosed. 2017; published OnlineFirst March 21, 2017.

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