Clinical Gastroenterology and Hepatology 2015;13:11–26

PERSPECTIVES IN CLINICAL GASTROENTEROLOGYAND HEPATOLOGY

Sessile Serrated Adenomas: An Evidence-BasedGuide to Management

Seth D. Crockett,* Dale C. Snover,‡ Dennis J. Ahnen,§ and John A. Baron*

*Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina;‡Department of Pathology, Fairview Southdale Hospital, Edina, Minnesota; and §Division of Gastroenterology, Department ofVeterans Affairs Eastern Colorado Health Care System and University of Colorado School of Medicine, Denver, Colorado

Abbreviations used in this paper: CI, confidence interval; CIMP, CpGisland methylator phenotype; CRC, colorectal cancer; CT, computedtomography; FIT, fecal immunochemical testing; HP, hyperplastic polyp;MSI, microsatellite instability; MSS, microsatellite stable; MVHP, micro-vesicular hyperplastic polyp; OR, odds ratio; PSP, proximal serrated polyp;SPS, serrated polyposis syndrome; SSA, sessile serrated adenoma; SSAD,sessile serrated adenomas with dysplasia; TSA, traditional serrated ade-noma; WHO, World Health Organization.

© 2015 by the AGA Institute1542-3565/$36.00

The concept of serrated colorectal neoplasia and aserrated pathway to colorectal cancer (CRC) is relativelynew and continuing to evolve, but it has become highlyrelevant to gastroenterologists, pathologist, and oncolo-gists alike. Sessile serrated adenomas (SSA) are nowthought to be the major precursor lesion of serratedpathway cancers, which represent up to one-third of allsporadic CRC cases. However, despite their increasinglyrecognized importance, relatively little is known about theepidemiology and natural history of SSAs, and the molec-ular and epigenetic aspects are incompletely understood.Endoscopists must be aware of the unique features of SSAsso that the practice of colonoscopic screening for CRC caninclude optimized detection, removal, and appropriatesurveillance of SSAs and other serrated precursor lesions.In this review, we discuss the history, epidemiology, andpathologic aspects of SSAs, as well as a recommendedmanagement approach and a discussion of uncertaintiesand opportunities for future research.

Keywords: Sessile Serrated Adenoma; Sessile Serrated Polyp;Serrated Neoplasia; Colorectal Cancer Screening; Colonoscopy;Endoscopic Detection; Polypectomy.

Colorectal cancer (CRC) kills more than 600,000people annually worldwide, and is the second

leading cause of cancer death in the United States.1,2 Untilrecently, adenomatous polyps (now referred to as con-ventional adenomas) were considered the precursorlesions of all cases of sporadic colon cancer, which wasthought to occur via a series of well-defined moleculargenetic steps along the chromosomal instability pathway.3

Recent research has indicated that this paradigmdoes not pertain to all sporadic CRC.4 Previously, allhyperplastic colorectal polyps were regarded as rela-tively harmless lesions without malignant potential. It isnow recognized that these polyps are in fact a hetero-geneous group, now called serrated polyps, characterizedprimarily by a saw-toothed appearance of colonic crypts.This group includes premalignant lesions such as thesessile serrated adenoma (SSA) (also known as thesessile serrated polyp or lesion) and the traditional

serrated adenoma (TSA), in addition to the moreinnocuous hyperplastic polyp (HP).5 SSAs are the pro-totypical precursor lesions of the “serrated pathway” tocolorectal cancer (CRC), now understood to have thepotential to develop into sporadic CRCs via a series ofmolecular alterations including BRAF mutation and CpGisland methylation, with epigenetic inactivation of themismatch repair gene MLH1 resulting in microsatelliteinstability (MSI) (Figure 1).5–9 SSAs are probably theprecursor to CpG island methylator phenotype (CIMP)high microsatellite stable (MSS) carcinomas as well.10

SSAs are a furtive foe for both the gastroenterologistand pathologist. They tend to be proximally located,have subtle endoscopic features, and are susceptible tobeing both overlooked and incompletely resected byendoscopists. To complicate matters further, there re-mains considerable interpathologist variability in thediagnosis of serrated polyp subtypes. These features andtheir potential to progress may explain (at least in part)why colonoscopy offers less protection from right-sidedCRC.11–13 In addition, interval CRCs (ie, those occurringafter a previous colonoscopy) frequently are located inthe proximal colon and have molecular features ofserrated pathway cancers such as CIMP and MSI, sug-gesting that SSAs contribute to this problem as well(Figure 2).13–16 Serrated pathway cancers are thought tobe responsible for 20% to 35% of CRC cases,4,17 whichmakes this CRC subtype a substantial public healthproblem, with an incidence potentially greater than thatof pancreatic, gastric, or esophageal cancer.2

Given their potential public health importance, thisreview focuses on SSAs, with particular attention to

http://dx.doi.org/10.1016/j.cgh.2013.10.035

Figure 1. Proposed serrated pathway to MSI CRC, with characteristic crypt alterations, histologic and endoscopic appear-ance, and epigenetic and genetic alterations. Dotted line between MVHP and SSA indicates a possible but unproven pro-gression step. Regarding crypt alterations, the thickened line indicates a proliferative zone, which is expanded in HPs, andmigrates upward in SSAs. Arrows indicate the direction of maturation. See text for details. MSI-H, high microsatellite instability.Modified with permission from Snover et al.17

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clinical aspects relevant to gastroenterologists. A numberof reviews have been published on the pathologic aspectsof these lesions,6–8,17 and these aspects are covered onlybriefly here.

History

The understanding of serrated polyps has beenevolving over the past 30 years. Originally, all such lesionswere classified as HPs, and considered benign, non-neoplastic colorectal polyps, in contrast to adenomatouspolyps (ie, conventional adenomas). Occasional reports inthe 1970s and 1980s challenged the convention that HPslacked malignant potential,18–21 but it was not until the1990s when the term “serrated adenoma” was coined byLongacre and Fenoglio-Presier22 to describe a polyp withcrypt serration resembling that of HPs, but also withcytologic dysplasia not characteristic of HPs. A number ofthese serrated adenomas (which would be classified asTSAs using contemporary terminology) had foci of

intramucosal carcinoma, establishing a risk of neoplastictransformation, and thus this report served to codify thepremalignant potential of some serrated lesions. In 1996,Torlakovic and Snover23 analyzed polyps from personswith HPs (now known as serrated polyposis, definedlater), and identified a previously unrecognized serratedpolyp characterized by large size and proximal location,and histologically by architectural distortion resultingfrom abnormalities in proliferation (Figure 1). This isgenerally considered the first description of the SSA,although this nomenclature was not generally acknowl-edged until a 2003 report that described TSAs and SSAs asseparate entities.24 Subsequent reports have helped torefine the pathologic andmolecular features of SSAs.8,25,26

Taxonomy and Nomenclature

The World Health Organization (WHO) now recog-nizes 3 categories of serrated polyps, all characterized byserration of the glandular epithelium: HPs, SSAs, andTSAs (Supplementary Figure 1).27

Figure 2. SSAs likelycontribute to theproblemofinterval (or postcolono-scopy) cancers for 3 chiefreasons: (1) SSAs can bedifficult to detect duringcolonoscopy and are com-monly missed; (2) it isthought that SSAs have thepotential for rapid progres-sion owing to the develop-ment of MSI, especiallyafter dysplasia develops;and (3) incomplete poly-pectomy is common withSSAs. Hollow arrowsrepresent potential targetsfor combating this problem.

January 2015 Sessile Serrated Adenomas 13

Hyperplastic Polyps

HPs are typically small (�5 mm), and roughly 70%are located in the distal colon and rectum.28,29 Endo-scopically, or whitish color, sessile or flat morphology,and have a type II asteroid, stellate, or papillary Kudo pitpattern when examined with chromoendoscopy ornarrow-band imaging.30 Histologically, HPs have cryptserration involving the upper segment of colonic crypts,with normal proliferation and no nuclear atypia ordysplasia.26 HPs are the most common type of serratedpolyp, representing 29% to 40% of all polyps, and 80%to 95% of all serrated polyps.24,31,32 There are severalsubtypes of HPs including the most common micro-vesicular hyperplastic polyp (MVHP), the goblet cell–richHP, and the mucin-poor HP (Supplementary Figure 1).Although HPs as a group do not directly progress tomalignancy, some MVHPs do contain a BRAFV600E muta-tion, which disrupts normal apoptosis of epithelial cells.33

MVHPs also have a higher incidence of CIMP, especially in

the proximal colon, a trait it shares with SSAs.33 For thesereasons, it has been proposed that MVHPs may progressto SSAs, but this has not been proven.34

Sessile Serrated Adenomas

SSAs are significantly less common than HPs.Depending on the series, SSAs represent up to one fifthof all serrated polyps.32,35–37 There remains consider-able controversy as to the best name for this lesion(Table 1). Some investigators prefer the term sessileserrated polyp to differentiate it from conventional ad-enomas, whereas other investigators (particularly inEurope) prefer the term sessile serrated lesion becauseSSAs can be nonpolypoid and flat. Although SSA (andTSA) contain the word “adenoma,” it is important torecognize that these lesions are quite distinct fromconventional adenomas with respect to histologyand molecular biology. Conventional adenomas bydefinition contain dysplasia, but SSAs typically are

Table 1. Nomenclature Issues of SSA

Proposed term Pros Cons

SSA Term adenoma connotes premalignantpotential

Term differentiates SSAs from HPs

Creates confusion with conventional adenomas for providersand patients

Some argue that the term adenoma should apply only todysplastic lesions

Sessile serrated polyp Avoids confusion with conventional adenomasDoes not imply dysplasia is present

Some SSAs are flat and nonpolypoid by Paris classificationHPs also are polyps that are sessile and serratedFails to convey the premalignant potential of these lesionsMay cause problems with insurance coverage for repeat

endoscopySessile serrated lesion Avoids confusion with conventional adenomas

Does not imply dysplasia is presentTerm is inclusive of nonpolypoid (eg, flat)

lesionsPreferred term of some European groups

The term lesion does not necessarily imply neoplasiaHPs also are lesions that are sessile and serratedFails to convey the premalignant potential of these lesionsMay cause problems with insurance coverage for repeat

endoscopySSA/P Hybrid term of SSA and sessile serrated

polyp indicates that both terms applyto same lesion

Most inclusive term

CumbersomeCons of both terms apply

Serrated adenoma Congruent with terminology of otherpremalignant colon polyps (eg, tubularadenomas, villous adenomas)

Nonspecific term could include both SSAs and TSAsCreates confusion with conventional adenomas for providers

and patientsSome argue that the term adenoma should apply only to

dysplastic lesionsUse of this term is discouraged

Serrated polyp with abnormalproliferation

Indicates that lesions have abnormalproliferation even in absence of truedysplasia

Nonspecific term could include both SSAs and TSAsCumbersomeNot frequently used

Giant HP Historical importance (first term usedby Jass)124

Indicates large sizeDifferentiates from diminutive HPs

Does not differentiate from HP apart from sizeDoes not connote premalignant potentialSome SSAs are smallUse of this term is discouraged

Variant HP Differentiates from typical HPs Suggests SSAs are a subset of HPsDoes not connote premalignant potentialUse of this term is discouraged

SSA/P, sessile serrated adenoma or polyp.

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nondysplastic.24 The characteristic histology, molecularfeatures, epidemiology, and endoscopic appearance ofSSAs will be described further later.

Traditional Serrated Adenomas

TSAs are the least common serrated lesions, repre-senting only 1% of these polyps.31 TSAs tend to be leftsided, protuberant, and/or pedunculated, and a signifi-cant proportion harbor conventional dysplasia.22 Histo-logically, TSAs have villiform features and cells withelongated nuclei and eosinophilic cytoplasm along withectopic crypts.8,26 Given their rarity, these polyps andtheir behavior are not as well characterized as HPs andSSAs. Although TSAs also have malignant potential,22

their pathway to cancer involves different steps thanSSAs, and is not as well understood. In contrast to SSAs,TSAs more commonly are KRAS-mutated (vs BRAF-mutated),38 may show epigenetic inactivation ofother DNA repair genes such as O6-methylguanine-DNAmethyl-transferase (MGMT), and likely give rise to

MSS cancers.6 Furthermore, because TSAs have an endo-scopic appearance similar to conventional adenomas andtypically are located distally,39,40 they do not present thesame challenges as SSAs with respect to endoscopicdetection, and are unlikely to be overlooked. TSAs are alsoless likely to be misclassified pathologically as HPs.41

Serrated Polyposis Syndrome

Serrated polyposis syndrome (SPS) (formerly knownas hyperplastic polyposis) is a condition of multiplicity ofserrated polyps. The serrated polyps found in patientswith SPS include mainly SSAs, but HPs also often arepresent, in addition to occasional TSAs.42 Conventionaladenomas also can co-exist with serrated lesions in SPSand the presence of adenomas may portend anincreased CRC risk in syndromic patients.42 The meanage at presentation is approximately 55 years, andmales and females are affected equally.43 Althoughsome cases may be heritable, the exact genetic defectassociated with SPS has not yet been identified, and the

January 2015 Sessile Serrated Adenomas 15

pattern of inheritance is uncertain.43,44 Therefore, thediagnosis currently is based on meeting somewhatarbitrary clinical criteria. According to the WHO, per-sons may be diagnosed with SPS if they have thefollowing findings on a single colonoscopic screeningexamination: (1) at least 5 serrated polyps proximal tothe sigmoid colon, 2 of which are greater than 10 mm indiameter; (2) any number of serrated polyps occurringproximal to the sigmoid colon in an individual who has afirst-degree relative with serrated polyposis; or (3)more than 20 serrated polyps of any size distributedthroughout the colon.27 Patients with SPS generally areconsidered to be at increased risk of CRC. Case series ofpatients with SPS have reported that between 25% and70% of SPS patients have CRC at the time of initial diag-nosis or during follow-up evaluation.42,45 However, suchstudies are prone to referral bias, and some studies reportno associated cancer risk,46 and therefore the actual riskof malignancy associated with SPS is unknown.

Histopathology

SSAs are characterized by distorted crypt bases andcrypt dilation caused by migration of the proliferativezone to the side of the crypt.26 These features distin-guish SSAs from HPs, which have a normal basal pro-liferative zone and straight (although serrated) crypts(Figure 1).17 Unlike conventional adenomas, SSAs donot typically have overt cytologic dysplasia, althoughdysplasia does develop in some lesions as they prog-ress.31 It is important to note that the dysplasia found inSSAs has different molecular features than the dysplasiaseen in conventional adenomas, and hence SSAs withcytologic dysplasia are not simply a combined SSA/tubular adenoma.17 SSAs also can have foci of intra-mucosal carcinoma and/or adjacent invasiveCRC.31,47,48

Genetics and Epigenetics

The pathway by which conventional adenomas giverise to CRC has been well studied and involves mutationsin APC, KRAS, and p53 among others,3 whereas the mo-lecular alterations associated with SSAs include BRAFmutation, and CIMP, which can lead to epigenetic silencingof MLH1, a mismatch repair gene, resulting in MSI(Figure 1).5,17,35 In contrast, BRAF mutations areextremely rare in conventional adenomas.49 There isheterogeneity among serrated lesions, however; someCIMP-positive serrated lesions lead to MSS cancers,possibly owing to methylation of MGMT, tumor suppres-sors, or apoptosis genes.4,8 In line with their distinct ge-netic and epigenetic profile is a corresponding differencein behavior of SSAs compared with conventional ade-nomas. Because serrated pathway cancers can involveMSI, it is thought that they have the potential for rapidgrowth once cytologic dysplasia has developed,47

although this is difficult to prove definitively. However,the clinical consequences of specific epigenetic alterationsfound in SSAs are largely unstudied.

Epidemiology

The understanding of the epidemiology of SSAs is inevolution. Most studies of the epidemiology of serratedpolyps predate the contemporary understanding ofserrated neoplasia. The early investigations of HPs arereally studies of what we now know to be serrated polypsin general, which may have included some SSAs. Never-theless, more recent studies have begun to focus on riskfactors of significant serrated polyps (eg, large and/orright-sided polyps) and SSAs specifically.

Prevalence

Approximately 20% to 40% of adults have at least 1serrated polyp, including distal HPs.50,51 SSAs represent3% to 22% of serrated lesions, and 75% to 90% of SSAsare right sided.31,32,35,36,52 In average-risk screening pa-tients, the reported SSA prevalence ranges from 2% to7%.37,53 A study that used high-resolution magnifyingchromoendoscopy to optimize detection and includedsome high-risk patients (ie, personal or family history ofCRC or polyps) reported the prevalence of SSAs was ashigh as 14%.32 Other investigators using surrogate def-initions for significant serrated lesions (eg, large orproximally located serrated polyps) have reportedprevalence estimates in the 2% to 20% range in average-risk screening populations.54–57 A number of pathologyseries focused on serrated lesions also have been re-ported in which, typically, colorectal polypectomy spec-imens from a particular pathology laboratory arereviewed using current pathologic criteria.31,35,36 Fromthese series, it is estimated that SSAs represent 1% to9% of all resected colorectal polyps. Multiplicity ofserrated polyps is common. A recent study of more than1000 patients with serrated polyps (including HPs, SSAs,and TSAs) reported that 44% of patients with serratedpolyps had more than 1 serrated polyp, including 21%with 2 serrated polyps, 10% with 3 serrated polyps, 5%with 4 serrated polyps, and 8% with 5 or more serratedpolyps.54

Risk Factors

A number of studies have examined the epidemiologyand risk factors of HPs as a group, but because smalldistal HPs represent the majority of serrated polyps, thesignificance of these findings with respect to SSAs isquestionable. Although the risk factors for SSAs and HPslikely overlap to some degree, it is important to under-stand factors that predispose persons to develop SSAsspecifically. As a surrogate for SSAs, some investigatorshave examined the epidemiology of proximally located or

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large (typically 1 cm or larger) serrated polyps. Proximalserrated polyps (PSP) have been associated with tobaccouse in some studies,58,59 but not others.60 Nonsteroidalanti-inflammatory drug use also has been associatedwith a decreased risk of PSPs.59,60

With regard to SSAs specifically, the publishedresearch on risk factors is limited. Several studies haveidentified tobacco as a risk factor for SSAs.61–63 Therehave been mixed results with respect to obesity becauseone study did find an association between increasedbody mass index and SSAs,61 however, 2 other studiesdid not.60,62 Although conventional adenomas areconsistently more common in men, this does not appearto be true of SSAs. Colonoscopic series have reportedthat SSAs are at least as common in women as they are inmen, with women representing 50% to 63% of thosewith detected SSAs.37,62 Similarly, pathology seriesreport that 49% to 65% of those with removed SSAs arewomen.31,32,36,37,61,64,65 Interestingly, one study reportedthat women comprised progressively higher proportionsof those with more advanced serrated lesions (womenrepresented 53%, 57%, 69%, and 76% of those withnondysplastic SSAs, SSAs with low- and high-gradedysplasia, and SSAs with invasive adenocarcinoma,respectively).31 One US study reported an associationbetween higher levels of education and SSAs.62 Furtherresearch is needed to clarify whether other factors suchas race, alcohol intake, other socioeconomic factors, anddiet are potentially significant risk factors for thedevelopment of SSAs. Identifying predisposing factors forthese important CRC precursors is important for pre-vention and diagnostic efforts.

Recently, a risk score for identifying large, proximal,or dysplastic serrated polyps has been reported.59 Thisrisk score was based on associated factors identified in across-sectional analysis of individuals undergoing elec-tive colonoscopy at a single Dutch hospital. The identifiedpredictive factors based on multivariate analysisincluded age older than 50 (odds ratio [OR], 2.2; 95%confidence interval [CI], 1.3–3.8), history of serratedpolyps (OR, 2.6; 95% CI, 1.3–4.9), current smoking (OR,2.2; 95% CI, 1.4–3.6), and lack of regular nonsteroidalanti-inflammatory drug use (OR, 1.8; 95% CI, 1.1–3.0). Itremains to be seen whether this score will be useful inclinical practice, but it does serve to emphasize that therisk profile for SSAs differs somewhat from that of con-ventional adenomas (eg, lack of association with malesex), and endoscopists should be especially vigilant forSSAs in certain groups of patients (eg, smokers and thosewith a history of SSAs).

Natural History

Risk of Dysplasia and Progression

The risk and rate of progression of SSAs is not welldocumented. Some investigators have postulated that

SSAs arise from serrated aberrant crypt foci and/orprecursor HPs (namely MVHP), but it also is possible thatthey arise de novo (Figure 1).5,17,66,67 As mentionedearlier, cytologic dysplasia is not common in SSAs,although they do have malignant potential. In one largecross-sectional study of 2416 SSAs, 85% were nondys-plastic, 14% had low- or high-grade dysplasia, and 1%had adenocarcinoma.31 In addition, there have been casereports of rapid progression of SSAs to cancer in lessthan 1 year.47

Synchronous Neoplasia

Although the risk of synchronous neoplasia for SSAsspecifically has not been well studied, there is some ev-idence that proximal and large serrated polyps areassociated with an increased risk of synchronousadvanced neoplasia and cancer.54,58,64,68,69 Furthermore,persons with concomitant SSAs and conventional ade-nomas appear to be at high risk of synchronous CRC.64

Persons with SSAs also frequently have synchronousserrated polyps.70

Metachronous Neoplasia

A few studies have suggested that SSAs and large HPsmay be associated with an increased risk of metachro-nous polyps,58,65,71 but these studies generally usedoutdated pathologic criteria to define the serrated le-sions, were not confined specifically to SSAs, or werelimited by small sample size and variable follow-up pe-riods. Further research is needed to better quantify therisk of synchronous and metachronous neoplasia asso-ciated with SSAs specifically.

Detection and Removal

Endoscopic Appearance

Characteristic features of SSAs include proximallocation (>75%),32,36 sessile or flat morphology(>90%),39,72 a resemblance to prominent folds (37%),72

pale color (75%),39 indistinct borders (73%),73 andmucus capping (64%–100%)72,74 (Figure 3). All of thesefeatures contribute to a subtle endoscopic appearance,and thus without careful attention from the endoscopist,even large SSAs can escape detection. In 20% to 50% ofSSAs, a rim of bubbles or debris is present that can helpdelineate the lesions and serve as an identification aid.72

On chromoendoscopy or narrow-band imaging, SSAstypically have a type II-O or open Kudo pit pattern on amagnified view.40 Several Japanese studies have re-ported this pit pattern has good sensitivity and speci-ficity for identifying SSAs (84%–97% and 66%–86%,respectively), but this technique is highly operator-dependent.73,75,76

Figure 3. Endoscopic images of SSA larger than 1 cm from 3 different patients featuring sessile or flat morphology and palecolor (all), mucus/debris covering (all), resemblance to prominent folds (A and C), and indistinct borders (A and B). Some SSAsare located behind folds and are best visualized (and removed) from a retroflexed position (B).

January 2015 Sessile Serrated Adenomas 17

Procedural Factors

Bowel preparation. It is well established that inade-quate bowel preparation negatively impacts adenomadetection, particularly for smaller lesions.77 SSAs arelikely even more vulnerable to underdetection in personswith suboptimal preparations. There are multiple rea-sons for this problem: (1) flat morphology makes SSAsmore vulnerable to being obscured by adherent stool andintestinal fluids; (2) SSAs more commonly are located inthe right colon, which is more susceptible to imperfectcleansing; and (3) the mucus cap and ring of debrissurrounding SSAs often facilitates identification in well-prepared colons, so poor preparations (and water jetirrigation needed to combat them) may eliminate thisidentification tool. Better bowel preparation is associatedwith improved detection of flat lesions in general,78 butone recent study did not find a statistically significantassociation between bowel preparation and PSP detec-tion.56 However, the effects of bowel preparation ondetection of SSAs specifically has not been well studied.

Endoscopic technique. Different investigators havereported various techniques to optimize the detection ofproximally located polyps including intensive inspectionor second looks in the right colon, examination withnarrow-band imaging, routine retroflexion in theascending colon, cap-fitted colonoscopy, and spraychromoendoscopy.79–83 However, data that these tech-niques improve detection of SSAs specifically are lacking.Nevertheless, it makes intuitive sense that more carefuland thorough examination of the right colon will help tooptimize SSA detection. In addition, high rates of SSAdetection have been reported with high-resolutionmagnified chromoendoscopy and use of pit-patternrecognition as mentioned earlier.32 However, there issignificant variability in endoscopists’ abilities to accu-rately identify pit patterns, neither routine chromoendo-scopy nor endoscopic magnification is in widespread usecurrently in the United States, and the cost effectiveness ofthese techniques in average-risk screening populations isquestionable.84

Withdrawal time. Longer withdrawal time duringcolonoscopic screening has been linked with higherdetection rates of conventional adenomas.85 However,

the existing data linking withdrawal times to serratedpolyp detection are relatively sparse. One retrospectiveUS study of more than 18,000 colonoscopies reported astrong relationship between withdrawal time and overallserrated polyp detection.86 More recently, a prospectiveDutch study found that longer withdrawal time wasassociated with significantly better PSP detection (OR,1.12; 95% CI, 1.10–1.16).56 However, these studies werelimited by the small number of endoscopists, and furtherresearch is needed on this topic.

Endoscopic Detection Rates

Several studies have documented a wide variability inendoscopists’ detection of PSPs and SSAs specifically.37,55

Hetzel et al37 reported results from a single-centerretrospective cohort study of 7192 patients undergoingaverage-risk CRC screening colonoscopies by 13 differentendoscopists. In this study, SSA detection ranged from0% in the lowest detector to 2.2% in the highest detec-tor. Interestingly, this same study reported that overallSSA detection improved substantially over time, from0.2% in 2006 to 1.1% in 2008, suggesting eitherincreased recognition by endoscopists, pathologists, orboth, over this time period. Kahi et al55 also investigatedendoscopic detection of serrated lesions in a single-center retrospective study of 6681 patients undergoingaverage-risk CRC screening by 15 different endoscopists.In this study, detection of PSPs ranged from 1% to 18%for individual endoscopists. In a prospective study of1426 people undergoing colonoscopic screening, deWijkerslooth et al56 reported that the PSP detection rateranged from 6% to 22% among 5 different experiencedendoscopists. Another single-center (and single endo-scopist) study reported detection of PSPs and/or SSAs in23% of screening colonoscopies after using specializedlesion-recognition training, cap-fitted colonoscopy,rigorous cleansing, and intensive inspection.83 Several ofthese studies reported that SSA (or PSP) detectiongenerally correlated with adenoma detection rates.37,55 Itis clear from these data that when performed skillfully,endoscopy can identify important serrated lesions quitecommonly. Distressingly, these data also highlight thefact that some endoscopists do not identify SSAs

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commonly enough, a situation that likely is fairlypervasive throughout the gastroenterology profession.Individual and practice improvement strategies areneeded to reduce this variation and improve the detec-tion and removal of important serrated precursor lesionson an individual and systematic level.

Detection of Sessile Serrated Adenomas byOther Methods

Although colonoscopy certainly is imperfect, itlikely is superior to alternative CRC screening methodsfor the detection of SSAs. Little has been published inthis area, but it is known that computed tomography(CT) colonography has difficulty detecting flat andsessile lesions because of its reliance on morphology,and absence of information on surface characteristics(color, vascular pattern, and so forth).87,88 There arescant data on the detection of lesions other than con-ventional adenomas by CT colonography, but what hasbeen published suggests that this technique lacksadequate sensitivity for these lesions.89 With respect tofecal occult blood testing and fecal immunochemicaltesting (FIT), serrated polyps are thought to be lesslikely to hemorrhage than conventional adenomas, soscreening tests that rely on the detection of blood areunlikely to be very effective.90,91 The recent develop-ment of stool DNA tests for CRC largely have focusedon markers based on the traditional adenoma-carcinoma sequence (ie, APC, KRAS), but these testsoffer some promise of serrated polyp detection,particularly if methylated or other markers of theserrated pathway are included.91,92 However, there is apaucity of published data on SSA detection with fecaloccult blood testing, FIT, and stool DNA panelsbecause, for the most part, serrated lesions have beenignored in CRC screening trials. Therefore, with all ofits limitations, colonoscopy likely represents our bestchance of addressing and removing serrated pathwayprecursor lesions such as SSAs.

Endoscopic Removal

Few published studies have addressed the issue ofoptimal SSA polypectomy technique. In one recent study,resections of 346 polyps (including 42 SSAs) wereexamined for completeness using standardized post-polypectomy biopsy specimens from the resected mar-gins.93 This study found that 31% of SSAs were resectedincompletely, compared with 7% of other polyps. Morestrikingly, nearly half (48%) of the large SSAs (between 1and 2 cm) were resected incompletely. This alarminglyhigh rate of incomplete resection of SSAs highlights theneed for extra care when resecting large flat polyps inthe right colon to avoid residual polyp tissue. Incompleteresection of polyps is a likely explanation for some in-terval cancers (Figure 2).94

Pathologic Interpretation

Because serrated neoplasia is a recent concept,pathologic interpretation also is inconsistent. One reportfrom a single academic center with 12 different pathol-ogists reported that the SSA classification prevalencevaried from 0% to 4% of patients depending on thepathologist.55 Other studies of tandem pathologistreadings have shown variable interobserver agreementbetween pathologists, ranging from poor to good(k ¼ 0.16–0.66), with a substantial number of polypsread as an SSA by one pathologist, and as an HP byanother.41,70,95 Further evidence of pathologic misclas-sification was provided by a recent Canadian study inwhich previously reported HPs were re-reviewed from acity-wide sample by 2 gastrointestinal pathologists ac-cording to current criteria.52 In this study, 17% ofproximal HPs and 20% of HPs greater than 5 mm werereclassified as SSAs. For these reasons, some in-vestigators advocate treating all right-sided and larger(�1 cm) HPs the same as SSAs with respect to surveil-lance recommendations.96 However, gastrointestinal pa-thologists generally have higher reported SSAclassification rates than nonspecialists,37,52 and a recentEuropean study showed excellent agreement amongexpert pathologists (k >0.8) regarding serrated le-sions.97 In addition, there is evidence that pathologicdiagnoses of SSAs have increased steadily in recentyears.98 Taken together, these studies indicate thatvariation in pathologist interpretation may be reducedas the concept of serrated neoplasia becomes betterunderstood and disseminated.

Proposed Management

Over the past several decades, colonoscopicscreening in the United States has been tailored to thedetection, removal, and surveillance of conventionaladenomas. SSAs have received considerably less atten-tion until recently. The problem of serrated neoplasiaand SSAs specifically highlights many of the weaknessesof our current colonoscopy screening approach to CRCprevention (Figure 4). Indeed, there are data that priorcolonoscopy offers little or no protection from SSAs, incontrast to advanced adenomas.99 From a public healthstandpoint, gastroenterologists must direct their atten-tion to the optimal detection, removal, and appropriatesurveillance of SSAs to effectively prevent sporadic CRC.From a patient-care standpoint, endoscopists must beaware of the existence, importance, and identifyingfeatures of SSAs to optimize the management of pa-tients harboring these premalignant lesions. Ongoingprofessional education is important in this regardbecause this is a burgeoning area of research, andsuggested management likely will be in evolution forthe foreseeable future. Specific recommendations areprovided later.

Figure 4. The issue of serrated neoplasia magnifies many of the flaws of CRC screening programs, and colonoscopyscreening specifically. (1) Risk factors for SSAs are poorly understood. Current risk-based screening recommendations (eg,screen between ages 50–75) may not optimize prevention of serrated pathway cancers. (2) SSAs are less likely to be detectedby CT colonography (because of flat appearance) or flexible sigmoidoscopy (because of proximal location). Prevention ofserrated pathway cancers may be more difficult in individuals who choose noncolonoscopy screening modalities. (3) SSAshave a subtle endoscopic appearance and can be missed during colonoscopy. There is significant variability in endoscopicdetection of SSAs. Poor preparation quality (especially in the right colon) may further impair the detection of SSAs. (4) Becauseof flat/sessile morphology, size, and proximal location, removal of SSAs requires more polypectomy time and skill, and in-volves more risk. Incomplete resection is common with SSAs. (5) Pathologic understanding of serrated neoplasia is in evo-lution, with variability in interpretation and terminology used. SSAs may be read as HPs by some pathologists. (6) Surveillancerecommendations are based largely on expert opinion and conjecture, not data. Some guidelines do not make specificmanagement recommendations for serrated polyps. (7) Because of issues 3, 4, 5, and 6, individuals harboring SSAs may notundergo surveillance colonoscopy at appropriate intervals. f/u, follow up; prep, preparation.

January 2015 Sessile Serrated Adenomas 19

Educate Your Patients AboutBowel Preparation

As discussed earlier, adequate purgative preparationbefore colonoscopy is critical to providing high-qualityendoscopic screening for adenomas, flat lesions, and(likely) SSAs. There are now good data to support the useof split-dose preparation regimens, which are associatedwith better patient satisfaction, better colonic cleansing(particularly of the right colon), and improved adenomaand total polyp detection rates.100,101 Therefore, wecurrently recommend using split-dose preparation regi-mens for optimization of both conventional adenoma andserrated polyp detection.

Know Your Sessile Serrated Adenoma orProximal Serrated Polyp Detection Rate

Given the known variation in endoscopic detection ofSSAs, endoscopists should be aware of their SSA (or PSP)detection rate. Although there are data that SSA/PSPdetection rates and adenoma detection rates are corre-lated,37,55,57 these are not equivalent; the endoscopistswith the highest adenoma detection rates do not alwayshave the highest SSA or PSP detection rates.37,56 More-over, greater endoscopy experience does not necessarilyimply a high PSP detection rate.56 Recognizing SSAs andother nonpolypoid and flat neoplastic lesions requires anoverlapping yet distinct skill set than that required to

detect polypoid adenomas.102,103 Nevertheless, it goeswithout saying that all endoscopists should strive tomeet and exceed published standards for conventionaladenoma detection rates.104 One group has suggested atarget PSP detection rate of at least 5% for average-riskscreening colonoscopies.57 Although optimal or bench-mark SSA detection rates have not yet been firmlyestablished, existing data suggest that SSAs should beidentified in at least 1% of screening colonoscopies.105

The true prevalence of SSAs is probably significantlyhigher than this figure, so even endoscopists meetingthese arbitrary metrics likely can improve their detectionrates. Some groups have reported use of standardizededucation modules or training programs to optimize thedetection of flat and subtle lesions.102 Suboptimal SSAdetection, especially if out of proportion to PSP detection,also may indicate discordance between local pathologistinterpretation and current pathology recommenda-tions,24,27,96 and should prompt a discussion regardingthe classification of serrated polyps with the interpretingpathologist.

Perform Attentive Colonoscopy

Meticulous colonoscopy technique is needed to opti-mize SSA detection. In particular, assiduous examinationof the right colon is important given that the majorityof SSAs are proximally located. The endoscopistmust perform careful examination of colonic folds and

20 Crockett et al Clinical Gastroenterology and Hepatology Vol. 13, No. 1

mucus-covered areas for associated mucosal abnormal-ities. In our own practice, we recommend that endo-scopists learn to retroflex the endoscope and use thistechnique in the ascending colon to better visualize thebacks of folds in the right colon. This practice has beenshown to be safe and effective in experienced hands.80

Examination of the right colon more than once also isrecommended by some experts, and this practice hasbeen shown to improve proximal polyp detection.79,106

When suspicious lesions or mucosal abnormalities arefound it is important to accurately record their size andlocation so that the site can be re-assessed at a later dateif needed. The use of narrow-band imaging or chro-moendoscopy techniques may facilitate the identificationand delineation of SSAs, especially if the endoscopist istrained in pit-pattern recognition.75,84 When a suspectedSSA is found, heightened attention throughout theremainder of the examination is warranted because ofthe significant risk of synchronous serrated and con-ventional adenomas, and an increased risk ofCRC.58,68,70,107

Resect Carefully

As with any neoplastic colorectal polyp, completeresection is important to reduce the risk of dysplastic orcancerous tissue left in situ, and to avoid regrowth ofneoplastic tissue at the polypectomy site. As discussedearlier, incomplete resection of SSAs, even in experi-enced hands, is relatively common.93 Most SSAs aresmaller than 2 cm (average size, 5–7 mm)24,35 and can beresected safely and effectively at the time of a screeningor surveillance colonoscopy. Optimal technique variesdepending on the individual characteristics of the SSA.For flat lesions, submucosal injection often is useful toprovide a cushion for resection, and to allow for bettervisualization and seating of the polypectomy snare.Chromoendoscopy and/or including a dye (eg, indigocarmine) in the submucosal injection fluid also can helpbetter define the margins of the polyp and assist com-plete resection. In light of the data showing an inordi-nately high incomplete resection rate for SSAs largerthan 1 cm, it seems reasonable to tattoo such lesions andrepeat an endoscopy in 3 to 6 months to assess the siteand remove any residual polyp.

An expanded armamentarium is required forremoving SSAs; certain snares may be more effective forremoval of these types of polyps including stiffer snares,or spiral or crescent/duckbill-shaped snares.106 If theendoscopist is inexperienced in performing endoscopicmucosal resection, or is uncomfortable removing a sus-pected SSA because of its morphology (eg, flat or laterallyspreading), size (eg, >2 cm), or location (behind a fold,abutting the ileocecal valve, and so forth), referral to acolleague or center with appropriate advanced endos-copy expertise in complex polypectomies is recom-mended.108,109 The need for surgical resection of SSAs is

rare, and reserved for very large and/or dysplastic SSAs,multiple SSAs, or those located in difficult locations (eg,appendiceal orifice).109

Talk With Your Pathologist Colleagues

As discussed earlier, there is known variation inpathologic interpretation of serrated polyps. Before theunique histopathologic features of SSAs were identified,these lesions generally were read by pathologists asHPs. It is likely that some systematic under-reading ofSSAs continues to occur today. Gastroenterologistsshould have a discussion with their pathology col-leagues regarding the concept of serrated neoplasia andshould partner to discuss cases in which the endoscopicand pathologic determinations differ (eg, a large right-sided sessile polyp with typical endoscopic features ofan SSA read as a HP). Providing relevant clinical infor-mation, en bloc resections, and properly orientatedspecimens also helps pathologists to interpret polypsaccurately.110 If this is performed, the pathologistshould be able to determine if the margins of the polypare free of residual neoplasia and that information canaid in follow-up recommendations.

Be Aware of Surveillance Guidelines

A key question with respect to the management ofpatients with SSAs pertains to the recommended intervalfor surveillance colonoscopy. Several investigators andgroups have published recommendations on surveillanceof individuals with serrated polyps (Table 2). Mostrecently, the US Multisociety Task Force guidelines forsurveillance after colonoscopic polypectomy recom-mended 1 to 5 years of follow-up evaluation of SSAs,depending on the number and size of lesions found, andthe presence or absence of dysplasia.111 These guidelineslargely mirror those for conventional adenomas. Aconsensus panel of international experts on serratedneoplasia also recently published similar, but moredetailed, recommendations.96 Individual investigatorsalso have made various recommendations regardingsurveillance of these lesions that vary from 6 months to10 years.5,17,64,91,112,113 Some current colonoscopy andCRC screening guidelines do not make any specific rec-ommendations regarding surveillance intervals for thosewith serrated lesions, or recommend that managementbe analogous to that of conventional adenomas.114–116

We favor the consensus panel guidelines, given theirmore detailed management recommendations,96 but it isimportant to recognize that surveillance recommenda-tions for SSAs likely will be in evolution as our under-standing of the behavior and significance of these lesionsimproves. One area of ambiguity relates to SSAs withdysplasia (SSAD), for which the consensus panel guide-lines recommend a 1- to 3-year surveillance interval.Although a 3-year surveillance examination seems

Table 2. Published Recommendations for Endoscopic Surveillance in Persons Harboring SSAs

Author, year Recommended surveillance for SSAs

Groups/guidelinesUS consensus panel, 201296 <3 SSA, all <10 mm: 5 y

�3 SSAs: 3 ySSA �10 mm: 3 y�2 SSAs �10 mm: 1–3 ySSAD: 1–3 y

US Multi-society Task Force, 2012111 SSA <10 mm: 5 ySSA �10 mm: 3 ySSAD: 3 y

Australian Guidelines, 2011115 No specific recommendationBritish Society of Gastroenterology Guidelines, 2010114 No specific recommendationEuropean Union Guidelines, 2010116 No specific recommendation

Individual authorsHuang, 20115 <3 SSAs, all <10 mm: 5 y

�3 SSAs: 3 ySSA �10 mm: 3 ySSAD: 3 y

Vu, 201164 <3 SSA: 5–10 ySSA <10 mm: 5–10 y�3 SSAs: 3 ySSA �10 mm: 3 ySSAD: 3 y

Snover, 201117 �2 SSAs �10 mm: 1 yTerdiman, 2010112 Proximal SSA/HP: 3 y

Distal SSA/HP <10 mm: 10 ySSA/HP �10 mm: 3 ySSAD: 3 y

Groff, 2008113 <3 SSA: 5 y�3 SSAs: 3 ySSAD: 3 y

East, 200891 SSA �10 mm: 3 y�3 SSAs: 3 y�3 Proximal HP: 5 yProximal HP �10 mm: 5 y

January 2015 Sessile Serrated Adenomas 21

appropriate for patients with SSADs if complete resec-tion was achieved, endoscopists should have a lowthreshold to perform repeat colonoscopy at a short in-terval (3–6 mo) for assessment of an SSAD polypectomysite when piecemeal resection was performed, or whenresidual polyp tissue is suspected on the basis of endo-scopic appearance or pathology evaluation.

An important consideration is patients with sus-pected SPS, for whom the recommended surveillanceinterval is 1 year. It is worth noting that WHO criteria1 and 3 for SPS (see earlier) are the most common phe-notypes,42 and given that multiplicity of serrated polyps iscommon,54 both scenarios can be underdiagnosed, leadingto inappropriately long (ie, >1 y) surveillance recom-mendations in such patients.117 Interestingly, in patientswith a history of SSAs, some investigators recommendconsidering optimizing surveillance detection by use ofchromoendoscopy.91 Furthermore, extending colono-scopic surveillance beyond the traditional cut-off point of75 years of age also has been recommended because of thepresumed potential for rapid neoplastic growth.91 How-ever, evidence to support the benefit of these recommen-dations currently is lacking.

Uncertainties and Future Directions

Pathogenesis

The understanding of serrated neoplasia continues toadvance, but many uncertainties remain. Furtherresearch is needed in the area of pathogenesis ofserrated neoplasia, so the genetic and epigenetic stepsalong the serrated pathway to CRC (particularly forCIMP-MSS carcinomas) can be better delineated. Dis-covery of the fundamental cause of CIMP and uniformityin its definition would help clarify this important featureof the serrated pathway. In addition, further study ofpatients with SPS and its phenotypes and inheritancepatterns offers the opportunity to identify the geneticbasis of this hereditary syndrome. It is likely that thesegenes also would be relevant to sporadic serratedneoplasia and SSAs specifically. It also is possible that thecurrent diagnostic criteria for SPS may become mean-ingless if the rate of recognition of SSAs continues toincrease, and/or if more meaningful phenotypic patternsemerge.

22 Crockett et al Clinical Gastroenterology and Hepatology Vol. 13, No. 1

Epidemiology and Natural History

Despite growing recognition of the problem ofserrated neoplasia, as described earlier, the epidemi-ology and natural history of SSAs remain poorly under-stood. A better understanding of the risk factors for SSAsmay help to determine not only which populations havethe highest risk of harboring these lesions, but also couldhelp inform studies of pathogenesis. There have beenlimited longitudinal studies of these lesions, and little isknown about the dwell time, features associated withrapid growth or recurrence, and the true prognosticsignificance of finding SSAs on colonoscopy. As such, thecurrent guidelines for the management of serratedlesions96,111 are based more on expert opinion ratherthan a substantial evidence base. Additional prospectivestudies are necessary to better inform clinical decisionmaking and surveillance recommendations. Along thoselines, some investigators have recommended random-ized trials of SSA polypectomy and surveillance vswatchful waiting or serial biopsies to generate evidenceregarding the benefits and harms of different manage-ment strategies.118 Furthermore, the clinical implicationsof genetic and epigenetic alterations of SSAs largely areunknown. It is possible that a more comprehensivesemimolecular classification of colorectal polyps willhelp better risk-stratify patients in the future.17

Detection and Resection

Because variable detection (and underdetection spe-cifically) is so pervasive, it seems that initial effortsshould be directed at improving endoscopic detectionand removal with existing technologies, personnel, andinfrastructure. However, because the detection of SSAs isaffected disproportionately by the inherent technicallimitations of visual inspection with standard white-lightcolonoscopy, novel or adjunctive approaches may beneeded. Several existing endoscopic tools offer the po-tential to improve SSA detection including magnificationchromoendoscopy,32 cap-fitted colonoscopy,82 andretroflexion in ascending colon80 as detailed earlier. Inaddition, emerging technologies such as wide-angle co-lonoscopy,119 use of the third eye retroscope,120 andothers also are promising in this regard. However, moreresearch is needed to determine whether these devicesand techniques (alone or in combination) are effective,easily learned, practical, and cost effective with respectto improving SSA detection. As mentioned earlier, stoolDNA tests do offer some promise of serrated lesiondetection, particularly if serrated pathway markers areincluded. Endomicroscopy, spectroscopy, and molecularimaging also are intriguing developments that potentiallycould impact SSA detection in the future.121–123

Furthermore, better quantitative estimates of SSAdetection by alternative screening methods (eg, FIT, CTcolonography, flexible sigmoidoscopy) are needed to

fully understand the implications of SSAs for screeningguidelines and test selection.

Because resection of SSAs often is inadequate,93

further research is needed to optimize complete resec-tion of these lesions to mitigate the risk of polypregrowth and interval cancers (Figure 2). It is worthnoting that the currently available tools for polypectomy(eg, standard oval snares) largely were developed withpolypoid adenomas in mind, and other snare shapes andpolypectomy tools may need to be appropriated ordeveloped to optimize resection of SSAs and other largeand/or flat colonic lesions.

Conclusions

SSAs represent a new type of combatant in the waragainst CRC, and it is important for clinicians and re-searchers to understand their importance. These lesionsundoubtedly play a role in interval cancer development(Figure 2). It is clear that unless gastroenterologistsdirect their attention to the detection, removal, andappropriate surveillance of SSAs, optimal prevention ofsporadic CRC will not be possible. The current CRCscreening approach also must adapt to address serratedneoplasia (Figure 4). Additional research is needed inthis area, particularly with regard to pathogenesis,epidemiology, behavior, and endoscopic management ofthese important CRC precursors.

Supplementary Material

Note: To access the supplementary material accom-panying this article, visit the online version of ClinicalGastroenterology and Hepatology at www.cghjournal.org,and at http://dx.doi.org/10.1016/j.cgh.2013.10.035.

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Reprint requestsAddress requests for reprints to: Seth D. Crockett, MD, MPH, AssistantProfessor, Division of Gastroenterology and Hepatology, University of NorthCarolina,CB7080,ChapelHill, NorthCarolina27599. e-mail: sethc@med.unc.edu;fax: (919) 966-6842.

Conflicts of interestThe authors disclose no conflicts.

FundingThis project was supported, in part, by an American College of Gastroenter-ology Junior Faculty Development Award (ACG-JR-000-2012).

Supplementary Figure 1.WHO taxonomy of serratedpolyps.

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