Serrated Lesions and Serrated Polyposis Syndrome Alberto Herreros-De-Tejada1, Carmen González-Lois2 and José Santiago1 Services of 1Digestive Diseases and 2Pathology

REVIEW

Serrated lesions and serrated polyposis syndrome Alberto Herreros-de-Tejada1, Carmen González-Lois2 and José Santiago1 Services of 1Digestive Diseases and 2Pathology. IDIPHIM. Hospital Universitario Puerta de Hierro Majadahonda. Madrid, Spain

ABSTRACT SERRATED PATHWAY CARCINOGENESIS: EPIDEMIOLOGY AND PATHOPHYSIOLOGICAL, The serrated pathway has been shown to be an alternative MOLECULAR AND GENETIC colorectal carcinogenetic route potentially accounting for up to CHARACTERISTICS one third of all CRCs. Serrated lesions, particularly SSPs, have been a focus of research during the past few years. They have well- established histological and molecular characteristics that account for The “serrated” carcinogenesis pathway, which differs their potential carcinogenetic risk through the accumulation BRAF, from the “traditional” one and from the precursor “serrat- KRAS and methylator profile (CpG) mutations. Their endoscopic ed lesions”, accounts for up to 20-30% of all CRCs (4-7). identification and resection represent a challenge because of their The initial description of adenocarcinomas arising from specific characteristics, and the need for an adequate specimen for histological diagnosis. Knowledge of these lesions is key, as is the serrated lesions was reported by Jass and Smith in 1992 adoption of established criteria for their endoscopic description (15), with tobacco exposure defined as a risk factor and no and histological diagnosis. SPS is the maximum expression of conclusive association with ethnic factors (7). The same involvement by serrated lesions, is associated with increased risk for carcinogenetic pathway would result in adenocarcinomas CRC, and requires attentive endoscopic follow-up, as well as family with varying biological behavior, histology and molecular screening. While the exact etiopathogenic mechanism remains unknown, current research will likely provide us with appropriate profiles. answers in the not too distant future. In the serrated pathway, signals are activated within the mitogen-activated protein kinase (MAPK) pathway, also Key words: Colonic polyps. Colorectal cancer. Serrated polyposis known as the RAS-RAF-MAPK cascade, with predom- syndrome. Serrated polyposis. Hyperplastic polyposis syndrome. inant BRAF or KRAS mutations and CpG island meth- Hyperplastic polyps. Sessile serrated polyps. Serrated pathway. ylator phenotype (CIMP), both high-level (CIMP-H) and low level (CIMP-L). The molecular study of adenocarcinomas related to serrated lesions also reveals a smaller INTRODUCTION proportion of CRCs with no BRAF or KRAS mutations. Approximately 30% of CRCs evolve through the serrated Serrated lesions result from alternative carcinogenesis pathway, 10% have BRAF mutations, 15% have KRAS in colorectal cancer (CRC), the so-called “serrated path- mutations, and 5% have both (16). BRAF-mutated CRCs way” (1). These lesions have been the subject of study are found proximally, are CIMP-H, and may exhibit and attention in the last few years, and are considered to microsatellite instability (MSI) o microsatellite stability account for up to one third of all CRCs (2-7). Failure to (MSS). The sessile serrated polyp (SSP) is considered as detect these lesions may possibly result in a significant their precursor lesion, from which dysplasia subsequently number of interval neoplasms for different reasons (chal- develops. KRAS-mutated CRCs are located preferentially lenging identification, predominance in the right colon, in the distal colon, with CIMP-L and MSS. Their precur- incomplete resection from poorly identified lesion mar- sor lesion is thought to be the traditional serrated adenoma gins, etc.) (5,8-11), and indirectly cause a lower effective- (TSA). Serrated-pathway CRCs are usually mucosecre- ness of colonoscopy in the prevention of proximal CRC tory and express MUC2, MUC5B, MUC5A, and MUC6. (12-14). Other typical histological features, most commonly in

Received: 26-10-2015 Accepted: 13-09-2016

Correspondence: Alberto Herreros de Tejada Echanojáuregui. Service of Herreros-de-Tejada A, González-Lois C, Santiago J. Serrated lesions and ser- Digestive Diseases. IDIPHIM. Hospital Universitario Puerta de Hierro Maja- rated polyposis syndrome. Rev Esp Enferm Dig 2016;109(7):516-526. dahonda. C/ Manuel de Falla, 1. 28222 Majadahonda. Madrid, Spain DOI: 10.17235/reed.2017.4065/2015 e-mail: [email protected] 2017, Vol. 109, N.º 7 SERRATED LESIONS AND SERRATED POLYPOSIS SYNDROME 517

CRCs with MSI, include poor differentiation, intratumoral association with inhibited cell exfoliation and inhibited lymphocytosis, and a peritumoral Crohn-like inflamma- apoptosis (25). tory response (16). Histologic diagnosis of serrated lesions is challenging, Histological subtype definitions have been described with low inter-observer concordance, which has been clas- for this pathway (serrated adenocarcinoma, medullary sically attributed to two major issues: carcinoma); however, despite their recognition as variants – The histological differential diagnosis between in the WHO classification (17), no direct correspondence hyperplastic polyp (HP) and SSP without dysplasia with specific molecular profiles can be found. Hence, the is challenging in endoscopic biopsy samples, limited sole histological feature useful for the diagnosis of serrat- by deficient orientation or fragmentation. ed-pathway CRC is its continuity with a precursor lesion – Different guidelines provide different terminologies (Fig. 1A). and minimal diagnostic criteria (6,13,17). A major goal in order to advance in the study of these lesions is a homogeneous terminology and clearly defined SERRATED LESIONS: HISTOLOGIC TYPES minimal diagnostic criteria. In this regard, recently report- AND ENDOSCOPIC CHARACTERISTICS ed diagnostic guidelines recommend a simplified classification system (6): Serrated lesions represent approximately one third of 1. Hyperplastic polyp (HP). all colonic polyps (18,19), with a prevalence of 20-35% 2. Sessile serrated polyp (SSP) (without/with dyspla- among the general population (20,21). Serrated lesions sia). show hystopathological features unlike conventional 3. Traditional serrated adenoma (TSA). adenomas, and endoscopic appearance partly correlate 4. Mixed polyp: this category, still unrecognized by the to histological subtype (22). The term “serrated adeno- WHO classification, is included in these guidelines ma” was first used by Longacre and Fenoglio-Preiser for lesions with HP-like diagnostic characteristics in 1990 (23) to describe lesions sharing hyperplastic and “classic” adenoma features in the left colon. polyp (HP) and adenoma features. Later, Torlakovic When described in the right colon, most lesions are and Snover used the term “sessile serrated adenoma” SSP with dysplasia. In any case, the diagnosis of in the setting of hyperplastic polyposis syndrome (24). these lesions is controversial, with no complete con- The “sawtoothed” appearance of the crypt epithelium sensus in the literature. is the most typical morphologic feature. It results from In this review we primarily consider the lesions recog- expansion of the mid- or upper-crypt proliferative area in nized by the WHO, which are discussed in detail below.

A B

Fig. 1. A. Histologic image of serrated adenocarcinoma on a sessile serrated polyp (hematoxylin-eosin stain, x25). The image shows a transition area in a sessile serrated polyp, with characteristically inverted (dilated at the base) crypts on the left. A transitional dysplasia area may be seen in the middle of the image. To the right, an infiltrating adenocarcinoma with associated Crohn-like inflammation is shown. B. Immunohistochemical pattern from the same adenocarcinoma (immunohistochemical stain with diaminobenzidine for MLH1 [x25]). Loss of nuclear DNA repair gene MLH1-coded protein expression in the adenocarcinoma and dysplasia areas (negative, blue nuclei), which is otherwise preserved in the dysplasia-free sessile serrated polyp area (positive, brown nuclei).

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Hyperplastic polyp potentially neoplastic, with a prevalence of high-grade dysplasia at 10-13% (22,23,29), particularly when larger These lesions make up the most numerous group of than 10 mm (32). serrated lesions (85%) (26,27). They are about 5 mm in They are characterized by sessile or a flat morpholo- size, pale or mucosa-like in color, and most are located gy (0-Is /0-II), pale color similar to the normal mucosa, in the sigma and rectum (6,22). Their mucosal pattern fuzzy vascular pattern, and poorly delineated limits, and with star-shaped crypts (Kudo II pattern with magnifica- are usually covered by a yellowish mucus layer that may tion endoscopy) is characteristic (Fig. 2A). Histologically, hide them from sight in the presence of adhered fecaloid glands exhibit a saw-toothed profile without dysplasia or remnants (13,26,33,34) (Fig. 2C). One third of cases may histologic features, preventing them being categorized as exhibit an erythematous surface, and the mean size is SSPs (17). above 10 mm (22,33). Most (> 80%) are located proxi- Three morphological patterns exist: mally to the descending colon (34). Their superficial crypt 1. Microvesicular HP: mucosecretory epithelial cells pattern may be similar to that of HPs, but a Kudo II open and reduced goblet-cell density (Fig. 2B). They usu- shape (II-O) has been specifically described, with larger ally have BRAF mutations. oval crypts (Fig. 2E). This pattern is highly predictive of 2. HP rich in goblet cells: usually associated with SSP, with a specificity of 97.3% (34,35) and limited sensi- KRAS mutations. tivity at < 66% (36). However, the II-O pattern seems to be 3. HP poor in mucin: scarce, similar to microvesicular, a marker for the CpG methylator phenotype and microsat- less mucin. ellite instability, which would define a premalignant status High grade dysplasia in HP is exceptional, and the risk (35). Another interesting characteristic that has been stud- for CRC is negligible for smaller lesions in the left colon (6). ied with NBI + magnification is the presence of “varicose” vasculature (varicose microvascular vessels), defined as tortuous vascular structures larger than mucosal vessels in Sessile serrated polyp (SSP) diameter, which seemingly are highly specific (88%) (33). In the literature the terms sessile serrated adenoma and These lesions are a minor subgroup among ser- sessile serrated polyp are often used interchangeably. The rated lesions, with an overall prevalence of 2-13% WHO has attempted to unify both terms with the desig- (5,11,18,19,26-31); however, they are considered to be nation “sessile serrated adenoma/polyp” (SSA/P) (6,17).

A B C D

E F G H

Fig. 2. A. Endoscopic image of a 3-mm hyperplastic polyp in the sigma, after staining with 0.4% indigo carmine. It exhibits a Kudo II superficial pattern with stellate crypts. B. Histologic image of microvesicular hyperplastic polyp (hematoxylin-eosin, x50). Glands exhibit a “serrated” profile only in their upper portion, not at the bottom, and are not dilated (in contrast to sessile serrated polyps). C. Endoscopic image of a 15-mm sessile serrated polyp (SSP) in the ascending colon, after staining with 0.4% indigo carmine. Typical features include: pale color, vague borders, blurred vascular pattern, glossy mucus coating, and fecaloid remnants. D. Histologic image of sessile serrated polyp (hematoxylin-eosin, x25). The panoramic image shows the diagnostic characteristics of a SSP: irregular crypt distribution, serrated profile down to the gland bottom, and dilated crypts at the bottom, at times with horizontal crypt extension (T or L) or branching. The lesion meets the WHO criteria (at least three crypts or two consecutive crypts with these features). E. Endoscopic image of a 25-mm SSP with 0-IIa morphology in the sigma, after staining with 0.4% indigo carmine. A Kudo type O-II crypt pattern may be seen at the center (arrowhead). F. Histologic close-up image of a sessile serrated polyp (hematoxylin-eosin, x100). Detail view of the dilated, serrated crypts at the base. G. White light endoscopic image of an 8-mm traditional serrated adenoma in the rectum. “Pinecone”-like 0-Is morphology. H. Histologic image of the above (hematoxylin-eosin, x25; detail inset x200) revealing a villous lesion with eosinophilic cells and dysplasia. Typical ectopic crypts may be seen on the villus sides. Inset: close-up of ectopic crypts.

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However, the recently reported British guidelines on ser- plasm in the colon and rectum, histologically recognized rated lesions recommend that only SSP be used (6), since in classic adenomas. Dysplasia, according to the WHO the term adenoma implies the presence of dysplasia, which classification, may be high-grade or low-grade (6,17). In does not occur in all SSPs. The morphological features dis- this context, dysplasia is commonly associated with the tinguishing them from HPs are listed in figures 2D and F. absence of the DNA repair protein hMLH-1 within the The current guidelines differ regarding minimal diag- carcinogenic pathway including BRAF mutations and dif- nostic criteria: fuse DNA methylation (CIMP-H) (Fig. 1B). In comparison – The WHO establishes a minimum of three crypts, or with adenomas, dysplasia is also more common in lesions two adjacent crypts with the typical morphological > 10 mm (29). Data remain inconclusive on SSP-associated features, in any single lesion (17). risk for CRC. It is mostly accepted that larger lesions with – The American Gastroenterology Society recommends dysplasia represent the highest risk for progression (6). only one crypt with one or more characteristic features (13). Histological and endoscopic differentiation between HP Traditional serrated adenoma (TSA) and SSP depends on a variable agreement rate and is a controversial topic in daily clinical practice (37). A recent These are uncommon lesions with an estimated preva- study with NBI and magnification showed a high diag- lence < 1% among the general population (18,27). Their nostic yield for three combined characteristics (varicose morphology is often protusive (0-Ip) and exophytic, with vascular pattern, size > 10 mm, and location in the right a mean size greater than 10 mm, the surface color is ery- colon) when distinguishing SSPs from HPs larger than 6 thematous, and they are distributed in the entire colon but mm (33). Despite efforts to establish diagnostic criteria they are most commonly distal (22,41,44,45). Their typical in the past few years, both the endoscopist and pathol- macroscopic shape is referred to as “pinecone”-like (Fig. ogist must have a high suspicion index, particularly for 2G) or double elevation (22,46), although shapes similar SSP (38). According to the WHO criteria, a continuous to those of classic adenomas are also common (47). Under spectrum persists between microvesicular HP and SSP. magnification, characteristic crypt Kudo patterns include SSPs are usually larger than 10 mm, and almost certainly the IIIL “stellar”, III-H “fern-like” (22,46), and IV-S “saw- will meet such minimal criteria, preferably in complete, toothed” types (34,35), but their actual diagnostic yield has well-oriented, non-fragmented resections. There are inde- been questioned. Given the nature of these lesions, some terminate lesions that do not meet WHO minimal criteria, cases exhibit a melting pot appearance including several usually as they are smaller, but do contain some crypts patterns (II, IIIs, IIIL) (47). with characteristic features. Diagnostic correlation increas- The incidence of high-grade dysplasia is lower than es when lesion location and size is known (39). 2% (22). Fifty per cent of cases are said to be associated SSP identification during endoscopy is particularly with a HP or SSP component in the same lesion, or with a challenging, and detection rates among endoscopists (23- tubular or tubulovillous adenoma in their vicinity (44,45). 65%) (19,28,30,40) are highly variable, much more so than The association with HP or SSP within the same lesion for adenomas (19), which likely indicates that a signif- correlates with a colonic location, similar to the way these icant number of lesions remain undiagnosed in clinical two lesions present in clinical practice (48). practice (13). An experienced endoscopist may identify an Characteristically, cells have an eosinophilic cytoplasm SSP in the right colon in up to 20% of procedures (31,40). with long nuclei (Fig. 2H). Their serrated appearance Therefore, such lesions must be proactively searched for results from a combination of undulated crypt epithelium with an adequate withdrawal time and systematic, careful and crypt budding (ectopic crypts). Sessile serrated pol- examination (40). The challenging nature of endoscopic yps have no budding. They are characterized by disrupted SSP diagnosis, and its likely relationship with interval cell control and programmed cell death signaling path- CRC, have led some authors to suggest a 5-10% minimal ways, which results in enhanced cell proliferation. Such detection rate for these lesions as quality criterion with increased cell proliferation leads to the accumulation of a high discriminating power in the mid-risk population somatic mutations, which may account for the faster devel- (28,31,36,40,41), although no evidence similar to that sup- opment of traditional serrated adenomas when compared porting the role of adenoma detection rates in reducing to conventional adenomas (6). CRC incidence and CRC-related mortality is available yet (42,43). Miscellanea: special situations where serration may develop SSP with dysplasia Serrated glands have been shown to develop in chronic This is a well-established class among SSPs. Dysplasia inflammatory bowel disease, with or without dysplasia, is defined as the morphologic aspect of intraepithelial neo- and in association with stromal lesions (neurofibromas,

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perineuromas, fibroblastic polyps, submucosal lipomas) 2. Any number of serrated lesions proximal to the sig- (6). Whether this is due simply to comorbidity or second- ma in an individual with a first-degree relative diag- ary serration has not be determined. nosed with SPS. 3. Over 20 serrated lesions spread along the whole colon, regardless of size. General recommendations from a histological Clinically, three disease phenotypes may be distin- viewpoint guished, which might even translate to different etiopathogenic substrates. Phenotype 1 represents the most common The desirable goal in the diagnosis of serrated lesions subtype (50% of cases) and is characterized by a reduced is increased histological recognition and inter-observer number of large serrated polyps in the right colon. In con- agreement, which requires: trast, phenotype 2 is characterized by a high number of – Differentiating SSPs and HPs by applying the criteria smaller serrated lesions in the left colon. Lastly, phenotype established in diagnostic guidelines. 3 (30% of cases) represents a mixture of the other two – Obtaining a fine lesion en-bloc resection (preferable phenotypes (49). to endoscopic biopsy) for improved orientation and assessment of completeness. – Obtaining a good correlation with endoscopic data Epidemiology and risk factors to assess lesion risk, particularly regarding size and location. The prevalence of SPS is poorly understood, but a – Using the nomenclature recommended by guidelines greater awareness of endoscopists and pathologists of (WHO) to increase consistency and improve data col- these conditions, together with diagnostic advancements, lection for the study of these lesions. has clearly increased the recognition of serrated lesions – Assessing dysplasia in this context according to the and, consequently, SPS (50). Overall, its prevalence seems already established dysplasia criteria for “classic” lower than 0.09% in colonoscopy-based CRC screening adenomas. programs (51), but is considerably higher in preselected (positive fecal occult blood test) populations, with esti- mates of 0.34-0.66% (52,53). SPS prevalence is higher SERRATED POLYPOSIS SYNDROME (SPS) than for other polyposis syndromes, including familial adenomatous polyposis (54). The mean age at diagnosis is Serrated polyposis syndrome (SPS) is characterized by 55 years, with no differences between genders (49,55,56). multiple serrated lesions (SSP/HP) (Fig. 3), and defined Clear demographic, histopathologic, or molecular differ- by one or more than three WHO-defined criteria (17,25): ences do not exist between phenotypes, and a greater pro- 1. Presence of at least five serrated lesions proximal portion was only shown among first-degree relatives with to the sigma, with at least two of them larger than CRC for phenotype 2 (numerous smaller lesions mainly in 10 mm. the left colon) (57). Several studies have associated smoking and being overweight with the development of serrated lesions and SPS (56,58,59).

Diagnosis and etiopathogenesis

This is a highly heterogeneous clinical condition with a poorly understood etiopathogenesis and natural histo- ry. While most SPS cases are sporadic, evidence suggests that this syndrome exhibits a genetic component at least occasionally. The higher prevalence of CRC and SPS in first-degree relatives (FDRs) as compared to the general population supports this theory (49,55,56,60-68), although the genetic basis and its heritance pattern is not fully understood yet (60,66). The action of various environmental factors on an unknown genetic predisposition will likely condition specific disease expression (49). The exclusive use of clinical diagnostic criteria, which Fig. 3. White light endoscopy image of the transverse colon in a 50-year- may somehow be considered to be both arbitrary and old patient diagnosed with SPS. Multiple serrated lesions (0-IIa mor- restrictive, largely results from unfamiliarity with the phology) may be seen on folds, with characteristics suggestive of SSP condition itself. Thus, difficulties in the endoscopic rec- (arrows), in a short colonic segment.

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ognition of serrated lesions, together with the challenges er risk profile (absence of SSPs proximal to the splenic often entailed by their correct histological characterization, angle, with high-grade dysplasia) where monitoring could commonly results in under-diagnosis. be performed less frequently than 3-year intervals (56). In cases not amenable to endoscopic control because of the number or characteristics of serrated lesions, or when Molecular characteristics of serrated polyps in SPS a CRC is identified, a surgical approach is recommended (subtotal/total colectomy) (13). The prevalence of KRAS and BRAF mutations in It is currently recommended that all first-degree relatives serrated polyps is 64-75% (66,69). Those mutations are undergo screening colonoscopy starting at 35-40 years of more common in serrated polyps from patients with age, or ten years earlier than the age of SPS diagnosis when SPS than in sporadic serrated polyps, hence they could diagnosed at a younger age. Recommended subsequent be used as a criterion supporting the diagnosis of SPS monitoring should be at 5-year intervals, except when (57,66). Interestingly, dysplasia develops more common- lesions are present (13,55,64). ly in lesions with BRAF and KRAS mutations (69). In fact, almost 90% of CRCs with the CpG island methylator phenotype (CIMP+) characteristic of the serrated pathway ENDOSCOPIC TECHNICAL ASPECTS FOR THE have BRAF and/or KRAS mutations (70). This fact may IDENTIFICATION OF SERRATED LESIONS indicate a higher risk for the development of dysplasia foci in serrated polyps in the SPS setting. Withdrawal time

As seen for adenoma identification (74), withdrawal Increased risk for CRC time is key for the identification of serrated lesions, particularly of SSPs (28,40). Recently, an important study The association of SPS and increased CRC prev- highlighted the relevance of lengthening withdrawal time alence/incidence (25-70%) is a classic description to nine minutes in order to obtain 30% higher recognition (55,60,68,71,72). Recent studies seem to reduce the esti- rates for serrated lesions (SSPs and HPs) as compared to mated risk by about 15% (56), with a cumulative risk for six minutes (28). interval cancer at five years of 2-7% (8,56,65) regardless of the phenotype (56,57). The presence of at least two SSPs proximal to the splenic angle, or of high-grade dysplasia Preparation in any SSP, seems to be a factor associated with increased risk for CRC development (56). Although numerous studies have shown that adequate preparation correlates to higher adenoma detection rates (75,76), this relationship could not be specifically and SPS and first-degree relatives unequivocally established for serrated lesions (40,77). However, indirect evidence suggests that suboptimal It has been shown that over 30% of first-degree rela- preparation is associated with lower detection rates for tives of patients meeting SPS diagnostic criteria are them- non-polypoid lesions (78), among which serrated lesions selves diagnosed with SPS during screening colonoscopy may be reasonably expected. (55,56,60-64), mainly using the WHO’s second criterion (64). An association of CRC has been reported for up to 10-50% of FDRs, and the risk for CRC in FDRs is estimat- Indigo carmine chromoendoscopy ed to be 5-fold that of the general population (49,55,65- 68). In contrast to other hereditary syndromes, evidence Indigo carmine panchromoendoscopy has indirectly for an increased incidence of extracolonic neoplasms in proven effective for detecting serrated lesions in a number patients with SPS or their FDRs has been insufficiently of studies (79,81). However, its usefulness has not been proven (49,73). shown consistently (47,82), and SPS is likely the sole sce- nario where it may be recommended for routine use until further studies are available (82). Endoscopic follow-up and screening for families

Current clinical guidelines recommend that these Narrow band imaging (NBI) chromoendoscopy patients be monitored annually with colonoscopy, attempt- ing to resect at least all serrated lesions > 3-5 mm, with The application of the characteristics included in special emphasis in the right colon (13). However, recent the NICE (NBI International Colorectal Endoscopic studies seem to suggest a subgroup of patients with a low- Classification) (83) has been specifically studied for the

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characterization of SSP-like serrated lesions starting with margins should be excised with biopsy forceps or treated four endoscopic features: cloud-like surface, borders indis- with argon plasma (47). Flat morphology (0-II), poorly tinguishable from the normal mucosa, surface dark spots, defined borders, extension to colonic folds, and preferen- and irregular borders (50). The promising results initially tial location at the proximal colon (26,33,34) are probably obtained in the ex vivo study (50) could not be replicated factors leading to significant rates of incomplete resec- in clinical practice (84), hence no definitive conclusions tion as seen in some studies for serrated lesions > 10 mm may be drawn. (> 30%) (89), which makes endoscopic follow-up at 3-6 months advisable according to some authors (38). Virtual chromoendoscopy (NBI), either superficial or submucosal, ENDOSCOPIC MANAGEMENT AND must be attempted with the indigo carmine stain to aid bor- FOLLOW-UP FOR SERRATED LESIONS der definition prior to EMR (13,38,47), emphasizing the importance of safe surgical margins. Furthermore, serrated As a general recommendation, serrated lesions smaller lesions are usually soft, slippery growths commonly seen than 5 mm, with hyperplastic appearance, located in the on folds, which require a stiff or monofilament snares to sigma and rectum should not be systematically resected firmly grab the lesion and adjacent normal mucosa (38,41). (13,41) given that their malignant potential is extremely All endoscopists should not overlook the importance of rare, and are considered as a normal finding by post-colo- specimen preparation to facilitate its pathological study. noscopy follow-up guidelines (85). Real-time endoscopic Extension and fixation on a flat surface, be it blotting paper assessment with NBI has proven a high-yield strategy for or a harder material (rubber, cork) for larger lesions, is the differentiation of HPs from adenomatous lesions (86). strongly recommended (90,91). Adequate serrated lesion Some authors recommend endoscopic resection for all ser- preparation and extension has been shown to significantly rated lesions that are proximal to the sigma, particularly increase the SSP-related diagnostic rate and inter-pathol- those with endoscopic characteristics suggestive of SSP ogist agreement (90). or TSA (13,41). However, the resection of lesions > 3 mm Resection with biopsy forceps (1-3 mm) or the cold will likely be insufficient to provide a protective effect of snare technique (> 3 mm) is acceptable for smaller lesions colonoscopy for CRC (87). (< 6-8 mm) (13,92,93). The technique of choice for larg- As a general approach, virtually the same principles er lesions is hot-snare EMR (47). Various studies have regarding polypectomy and endoscopic mucosal resection specifically addressed hot-snare EMR for SSPs > 20 mm, (EMR) for adenomatous lesions apply to serrated lesions, with resection rates > 95% and complication rates < 15% with the following peculiarities. Complete, en-bloc resec- (94). Nonetheless, late recurrence is a limitation of frag- tion should be attempted for serrated lesions whenever mented EMR for these lesions, with rates approaching possible (88). When unfeasible, residual tissue at resection 20% (95). More extensive studies including adenomatous

Table I. Follow-up recommendations for serrated lesions and SPS, adapted from Rex et al. (13), Castells et al. (100), East et al. (41) and Carballal et al. (56) Histology/syndrome Number Size Location Colonoscopy interval Any < 10 mm Rectum and sigmoid colon 10 years ≤ 3 < 5 mm Proximal to sigmoid colon HP >3 Any size Proximal to sigmoid colon 5 years ≥ 1 > 5 mm < 3 < 10 mm Any 5 years ≥ 3 Any size Any 3 years 1 ≥ 10 mm SSP ≥ 2 ≥ 10 mm ≥ 1 > 20 mm Any 1-3 years ≥ 1 w/dysplasia Any size ≤ 2 Any size Distal to splenic angle 2-3 years SPS > 2 Any size Proximal to splenic angle 1 year ≥ 1 with HGD Any size Proximal to splenic angle 1 year HP: Hyperplastic polyp; SSP: Sessile serrated polyp; SPS: Serrated polyposis syndrome (WHO criteria); HGD: High-grade dysplasia.

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and serrated lesions > 20-40 mm using fragmented EMR 14. Singh H, Turner D, Xue L, et al. Risk of developing colorectal cancer have shown success rates above 90%, albeit with a persist- following a negative colonoscopy examination: Evidence for a 10-year interval between colonoscopies. JAMA 2006;295(20):2366-73. DOI: ing relapse risk, particularly for lesions > 40 mm (96,97). 10.1001/jama.295.20.2366 A recently used technique for large serrated lesions is 15. Jass JR, Smith M. Sialic acid and epithelial differentiation in colorectal endoscopic submucosal dissection, which allows en-bloc polyps and cancer - A morphological, mucin and lectin histochemical study. Pathol 1992;24(4):233-42. DOI: 10.3109/ 00313029209068874 resection with no size limitations for colorectal lesions 16. O’Brien MJ, Zhao Q, Yang S. Colorectal serrated pathway cancers (98). and precursors. Histopathol 2015;66(1):49-65. DOI: 10.1111/his.12564 While consensus guidelines have been recently report- 17. 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