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Serrated colorectal polyps and polyposis
MINI-SYMPOSIUM: PATHOLOGY OF GASTROINTESTINAL POLYPS AND POLYPOSES
Serrated colorectal polyps and polyposis
under-recognition among pathologists. In an attempt to solve these issues, the 4th edition (2010) of the World Health Organisation (WHO) classification defined new histological criteria for all currently recognized subtypes of serrated polyps: hyperplastic polyp (HP), sessile serrated adenoma/polyp (SSA/P) and traditional serrated adenoma (TSA). These criteria should be universally applied to ensure standardized diagnosis and thus the reliable application of surveillance colonoscopy protocols. This review outlines the current knowledge on the histological diagnosis of serrated polyps of the large intestine and addresses the impact of these diagnoses on patient management. We also address the main features of molecular pathways involved in the malignant transformation of serrated polyps. Serrated polyposis is also be discussed with an emphasis on the role of pathologists in the diagnosis of this under-recognized syndrome.
Christophe Rosty Mark Bettington
Abstract Serrated polyps represent a heterogeneous group of lesions, some of which have well-documented malignant potential. The histological classification of serrated polyps has evolved over the last two decades to recognize three major subtypes: hyperplastic polyp, sessile serrated adenoma/polyp and traditional serrated adenoma. Sessile serrated adenoma/ polyp remains under-diagnosed while it represents up to 25% of all serrated polyps and is the precursor lesion to colorectal carcinoma evolving though the serrated neoplasia pathway with BRAF mutation and CpG island methylator phenotype. Pathologists need to be aware of the World Health Organisation criteria to correctly diagnose each entity as patient management guidelines are based upon the use of this classification. Serrated polyposis is an under-recognized syndrome with unknown genetic cause conferring an increased risk of colorectal carcinoma. Pathologists have a pivotal role in identifying these patients who should undergo yearly surveillance colonoscopy.
Histological diagnosis of serrated polyps The common morphological feature of serrated polyps is the ‘saw-tooth’ appearance of the crypts, which occurs due to decreased apoptosis and increased senescence of the epithelial cells. The 4th edition of the WHO classification book published in 20101 subcategorized serrated polyps into three groups: HP, SSA/ P and TSA. The morphological aspects that characterizes each group are the result of differences in the location of the proliferation zones within the colonic crypts.2,3 The main characteristics of each serrated polyp subtype are summarized in Table 1.
Keywords hyperplastic polyp; serrated neoplasia pathway; serrated polyp; serrated polyposis; sessile serrated adenoma; traditional serrated adenoma
Hyperplastic polyps HP is the most common subtype, representing 70e80% of serrated polyps. Forsberg et al. reported that 21% of asymptomatic individuals aged 19e70 years had at least one HP in a Swedish population-based prospective colonoscopy study.4 In HP, the proliferation zone is normally located at the base of the crypts with preserved maturation of epithelial cells symmetrically along the crypts towards the luminal surface. Approximately 75% of HPs are located in the distal colon or rectum as small (<10 mm; usually 1e5 mm) sessile lesions with insignificant malignant potential.5 However, HPs can also be detected in the proximal colon, possibly with increased frequency now that some gastroenterologists use enhanced endoscopic procedures that allow better detection of small sessile polyps compared with white light endoscopy. The possibility that some of these proximal lesions may progress to SSA/P and to malignancy is still unknown and cannot be excluded. The common underlying feature of HP is the normal architecture of elongated and straight crypts with serration restricted to the upper compartment.6 Cytological dysplasia is absent. One caveat to this definition is that the crypt architecture can sometimes appear abnormal displaying dilatation of the bases when mucosal prolapse changes are superimposed (Figure 1). Often, there is a mild thickening of the subepithelial basement membrane compared to the adjacent normal mucosa. Further subdivision of HP into microvesicular HP and goblet cell HP is mostly of academic interest and does not need be included in pathology reports. More importantly, one should consider goblet cell HP when a biopsy of a lesion described as a polyp by endoscopists looks close to normal mucosa on multiple levels. Changes in goblet cell HPs are very mild, characterized by slight crypt elongation with numerous
Introduction The vast majority of colorectal carcinomas (CRC) develop from benign precursor polyps, which can be detected and removed by appropriate screening colonoscopy programs. Colorectal polyps comprise a wide range of neoplastic and non-neoplastic lesions with various risks of malignant transformation. The majority of neoplastic colorectal polyps fall into one the two following categories: conventional adenomas (tubular, tubulo-villous and villous adenomas) and serrated polyps. Over the last 20 years, new subtypes of serrated polyps associated with malignant potential have been recognized from what was collectively known as hyperplastic polyps in the past. As often occurs when new entities are described, this led to confusion, misdiagnosis and
Christophe Rosty MD PhD FRCPA Envoi Pathology, Brisbane, Australia; School of Medicine, University of Queensland, Brisbane, Australia; Cancer and Population Studies Group, Queensland Institute of Medical Research, Brisbane, Australia. Conflicts of interest: none. Mark Bettington BSc MBBS FRCPA The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; School of Medicine, The University of Queensland, Brisbane, QLD, Australia; Envoi Pathology, Brisbane, QLD, Australia. Conflicts of interest: none.
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Summary of pathological and molecular characteristics of serrated polyps Microvesicular HP
Goblet cell HP
TSA
SSA/P
SSA/P with cytological dysplasia
Proportion Predominant colonic location Pathological features
40e50% Distal
20e30% Distal
2e5% Distal
15e25% Proximal
2e5% Proximal
Normal architecture with elongated straight crypts and upper serration Microvesicular mucin, no dysplasia
Normal crypt architecture with subtle surface serration Goblet cell mucin, no dysplasia
Abnormal architecture with dilated crypt base and basal serration Dystrophic goblet cells in crypt base, no dysplasia
SSA/P features with sharp demarcation to dysplasia Conventional intestinal type or serrated type dysplasia
Most common molecular alteration
BRAFV600E mutation (70e80%)
KRAS mutation (50%)
Exophytic (distal) or sessile (proximal) Villiform configuration with ectopic crypt formations Eosinophilic cells with pencillate nuclei Conventional dysplasia can arise BRAFV600E mutation (50%) KRAS mutation (30%)
BRAFV600E mutation (70e80%) CIMP-high
BRAFV600E mutation (80e100%); CIMP-high; MSI or TP53 alteration
HP: Hyperplastic polyp; SSA/P: Sessile serrated adenoma/polyp; TSA: Traditional serrated adenoma; CIMP: CpG island methylator phenotype; MSI: Microsatellite instability.
Table 1
crypt architectural alteration following the shift of the proliferation zone from its normal location at the base to the side of the crypts. This results in asymmetrical maturation of epithelial cells towards both the crypt surface and base.2 The crypts then develop abnormal shapes with dilatation at the bases often in an L-shaped or inverted T-shaped configuration (Figure 3). An expanded proliferation zone is commonly found in the upper part of the crypts and superficial mitoses may sometimes be seen. If cross-sectioned at the level of an active proliferation zone, the appearance may cause misdiagnosis as dysplasia. SSA/P is more frequently found in the proximal colon and tend to be >10 mm in size (Figure 4). However, small SSA/Ps are increasingly recognized and SSA/Ps distal to the transverse colon can also occur.
goblet cells and subtle serration at the surface that can be easily overlooked (Figure 2). The significance of goblet cell HP is unclear; some authors have suggested that it may represent the precursor lesion of TSA.7 On the other hand, the upper serration in microvesicular HP is more obvious and the presence of epithelial cells with microvesicular mucin contrasts with the normal adjacent mucosa. A mucin-poor subtype of HP with reactive cytological atypia has also been described but the significance of this rare lesion is unknown and is likely to represent an injured microvesicular HP.2 Sessile serrated adenoma/polyp The prevalence of SSA/P seems to have increased over the last years as gastroenterologists and pathologists alike became more aware of this entity. In a recent study reviewing the histology of 6340 colorectal polyps from a single pathology practice, SSA/P represented 12.1% of all polyps and 25.3% of serrated polyps.8 However, SSA/P remains under-diagnosed in some pathologist communities due to a lack of awareness of the lesion, when it will be misdiagnosed as HP.9 In contrast to HP, SSA/P displays
Figure 1 Goblet cell hyperplastic polyp with elongated crypts and increased number of goblet cells compared with the normal mucosa on the left part of the image.
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Figure 2 Microvesicular hyperplastic polyp with mucosal prolapse changes showing more complex crypt serration and distortion than the usual hyperplastic polyp, and smooth muscle in the lamina propria.
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Figure 3 Typical appearance of a sessile serrated adenoma/polyp with contiguous abnormal crypts showing dilatation of the base.
Endoscopically, SSA/P is characterized by the presence of a mucus cap, a rim of debris or bubbles, alteration of the contour of a fold and abnormal mucosal vascular pattern.10 A frequent situation that pathologists encounter is that of a large (>10 mm) serrated polyp in the proximal colon with predominantly straight HP-like appearing crypts and very focal (in some cases, just one) dilated and distorted crypt bases. The focal crypt abnormalities seem to fall short of the WHO definition of SSA/P that requires more than two or three contiguous abnormal crypts. To address this issue, a report following a consensus conference by an expert panel in 2010 recommended that “the presence of at least one unequivocal architecturally distorted, dilated, and/or horizontally branched crypt, particularly if it is associated with inverted maturation, is sufficient for a diagnosis of SSA/P”.11 However, these relaxed criteria for the diagnosis of SSA/P were proposed based on the experience of specialists but lacked clinical-based evidence. Recently, a study by Bettington et al. provided insights for the minimum morphological changes to diagnose SSA/ P and to separate them from HP.8 Sessile polyps with serration displaying at least one abnormal SSA/P-like crypt (Figure 5) showed more frequent proximal colonic location and female predominance similar to that of overt SSA/P and different from the plain HP that do not show any architectural crypt abnormality. The conclusions of this study validated the minimal criteria from the expert panel consensus conference. Dysplasia is not a feature of SSA/P, a controversial issue that led to ongoing debate among pathologists for and against the use
of the term ‘adenoma’ for a lesion that lacks dysplasia. When dysplasia arises in the background of an SSA/P, the polyp is classified as SSA/P with cytological dysplasia.1 The development of dysplasia in SSA/P may portend rapid progression to carcinoma either through methylation of MLH1 or alteration of the TP53 gene.12 Immunohistochemistry for MLH1 could help in identifying the dysplastic component but a normal pattern with retained nuclear stain does not exclude the diagnosis of dysplasia. The dysplastic component may be of two histological types; it may resemble that of conventional adenoma with basophilic cytoplasm and elongated nuclei (Figure 6) or may display a “serrated dysplasia” phenotype with cuboidal cells, eosinophilic cytoplasm, round nuclei with open chromatin and prominent nucleoli (Figure 7). The serrated type of dysplasia can be subtler histologically and may easily be missed. The dysplastic component is usually sharply demarcated from the underlying SSA/P, a feature that led to the term “mixed polyps” or “tubular adenoma mixed with hyperplastic” in the past. This terminology should no longer be used. The separation of dysplasia into high grade and low grade may be difficult and does not need to be reported, as recommended by the WHO classification. Some serrated polyps
Figure 4 Macroscopic appearance of sessile serrated adenoma/polyps (arrows). Note the presence of additional smaller polyps. Scale bar (bottom left) equals to 1 cm.
Figure 6 Sessile serrated adenoma/polyp with cytological dysplasia of conventional intestinal type (left part of the image).
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Figure 5 Low magnification of a sessile serrated adenoma/polyp with predominantly straight hyperplastic polyp-like crypts and only one abnormal dilated crypt base.
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Figure 9 Traditional serrated adenoma with a predominance of goblet cells and an area of high grade dysplasia of conventional intestinal type (left lower part of the image). Figure 7 Sessile serrated adenoma/polyp with cytological dysplasia of serrated type characterized by round nuclei with open chromatin, prominent nucleoli and eosinophilic cytoplasm.
where they tend to have a more sessile appearance. In a study from Korea, up to 20% of TSA were located in the proximal colon.7 The villous projections of TSA are typically lined by tall eosinophilic cells with elongated pencillate nuclei. However, goblet cells may be prominent in some lesions (Figure 9). Conventional dysplasia of intestinal type is also commonly found in TSA that may retain only small foci of eosinophilic cells when dysplasia has overgrown most of the lesion (Figure 10). This may represent a step towards high-grade dysplasia and malignancy. There is an overlap between advanced TSA and tubulo-villous adenoma with serrated morphology. The distinction between these two entities may be difficult and it is currently unknown if these represent polyps with separate malignant potential through different molecular pathways or a spectrum of similar lesions.
demonstrate focal morphological changes of TSA adjacent to a typical SSA/P. It is unclear whether this represents an early form of TSA originating from an SSA/P or the progression of an SSA/P to a more advanced dysplastic lesion. A descriptive report mentioning both components is recommended. Traditional serrated adenoma TSA represents the least common and least understood subtype of serrated polyp. In TSA, the proliferation zone is represented by multiple small ectopic crypt formations from the side of the original crypts and along the newly formed villous projections of the polyp. TSAs are usually exophytic lesions located in the distal colon and rectum with a complex villiform configuration and typical ectopic crypt formations as defined by Torlakovic et al.3 (Figure 8). These ectopic crypts demonstrate normal orientation towards the lumen but the loss of the anchoring of the base in proximity to the muscularis mucosae as in normal mucosa, HP or SSA/P. TSA can also be encountered in the proximal colon
Serrated neoplasia pathway to colorectal carcinoma The concept of pathways to CRC combining pathological, clinical and molecular features has been introduced by Jeremy Jass in his seminal review which defined five types of CRC.13
Figure 8 Typical appearance of a traditional serrated adenoma with a villiform architecture, ectopic crypt formations and tall cells with eosinophilic cytoplasm and pencillate nuclei.
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Figure 10 High grade dysplasia of conventional intestinal type arising in a traditional serrated adenoma.
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Putative different molecular pathways for malignant transformation of serrated polyps
Precursor lesion Predominant location Carcinoma morphology Additional molecular alterations Prognosis compared to adenoma-carcinoma pathway CRC
BRAF MSI serrated pathway
BRAF MSS serrated pathway
KRAS alternate pathway
SSA/P Proximal colon Mucinous, tumour infiltrating lymphocytes CIMP-high; MLH1 methylation; chromosomal stability
SSA/P and TSA Proximal and distal colon Adenocarcinoma NOS, serrated adenocarcinoma CIMP-high; TP53 alteration
Good
Bad
TSA and some TVA Distal colon and rectum Adenocarcinoma NOS, serrated adenocarcinoma MSI and CIMP-low/indeterminate, MGMT methylation; chromosomal instability Bad
MSI: Microsatellite instability; MSS: Microsatellite stable; NOS: Not otherwise specified; CIMP: CpG island methylator phenotype.
Table 2
Approximately 30% of colorectal carcinoma develops through the serrated neoplasia pathway (Jass types 1 and 2) or the alternate pathway (Jass type 3) (Table 2). Similarities in mucin expression and molecular alterations between SSA/P and a subtype of CRC with high levels of microsatellite instability (MSI) not caused by Lynch syndrome provided the first evidence that this subtype of serrated polyp had malignant potential. This has been complemented by clinical evidence demonstrating a link between SSA/P and CRC from the proximal colon, in particular the frequent occurrence of residual serrated polyps at the edge of a carcinoma demonstrating morphological features of MSI CRC (Figure 11). Nowadays, the serrated neoplasia pathway with SSA/P as the primary precursor polyp is widely accepted. This pathway accounts for 10e15% of all CRC and is primarily defined by BRAF mutation and high levels of CpG island methylator phenotype (CIMP). CIMP describes the coordinate methylation of CpG dinucleotide clusters (CpG islands) in the promoter region of genes, resulting in silencing of gene
expression. This phenotype that segregates with BRAF mutation may target different genes with CpG islands in their promoter regions. When these genes have tumour suppressor properties, the silencing may have important consequences for tumour progression. One of the mismatch repair genes, MLH1, implicated in Lynch syndrome, can become methylated and silenced in about 50% of CRC with BRAF mutation. This event is important for the progression of a proportion of serrated polyps to carcinoma showing MSI, often referred to as sporadic MSI cancer and characterized by a predominance in elderly women, location in the proximal colon, low stage at diagnosis, good outcome and lack of response to 5-Fluorouracil (Jass type 1). On the other hand, BRAF-mutated CRCs that do not develop MSI (microsatellite stable cancer) are often associated with TP53 alteration and demonstrate poor prognosis (Jass type 2).14 The alternate pathway to CRC is not currently widely recognized and further studies are needed to outline the complete clinical, pathological and molecular definition of this subgroup of CRC (Jass type 3). On the molecular level, the alternate pathway combines alterations of the traditional adenoma-carcinoma pathway (Vogelstein progression model) including chromosomal instability and a microsatellite stable phenotype, with a high frequency of mutation in KRAS, an oncogene part of the Mitogen Activated Protein Kinase (MAPK ) pathway upstream BRAF. Additional molecular alterations are the silencing by methylation of the DNA repair gene gene 06-methylguanine DNA methyltransferase (MGMT ), and low/indeterminate levels of CIMP and MSI. In precursor polyps, KRAS mutation has been reported in conventional adenoma with a high villosity, in goblet cell HP and in approximately 30% of TSA. It is possible that some TSAs and tubulo-villous adenomas may progress through the alternate pathway of CRC.
Serrated polyposis Serrated polyposis, previously called hyperplastic polyposis, is a clinically defined syndrome with unknown genetic causes that predisposes affected individuals to an increased risk of CRC. Patients fulfilling one or more of the following criteria are diagnosed with serrated polyposis: (1) at least five serrated polyps
Figure 11 Adenocarcinoma arising from a sessile serrated adenoma/polyp with a transitional zone of dysplasia. The adenocarcinoma is poorly differentiated with prominent tumour infiltrating lymphocytes (inlay), typical of microsatellite instability phenotype.
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polyps. In equivocal cases, screening for germline mutation in MUTYH is recommended. Serrated polyps are not indicative of Lynch syndrome; however there is still confusion among some clinicians who might request mismatch repair protein immunohistochemistry testing for young patients with multiple serrated polyps and a strong family history of CRC. Those patients are very unlikely to have Lynch syndrome but are likely to have serrated polyposis. A family history of CRC is found in approximately 50% of individuals diagnosed with serrated polyposis. Moreover, first-degree relatives are at 5-fold increased risk of CRC compared to the general population.18 CRC in serrated polyposis patients do not necessarily develop through the serrated neoplasia pathway. Only approximately half of CRC harbour a mutation in BRAF and 38% show microsatellite instability though methylation of MLH1.19 These findings emphasize the role of conventional adenomas as precursor lesions to CRC in serrated polyposis. In fact, the most common molecular subtype of cancer in 38 serrated polyposis patients was characterized by an absence of mutation in KRAS or BRAF and a microsatellite stable phenotype, the molecular profile commonly found in CRC developing though the traditional adenoma-carcinoma pathway from conventional adenoma. Importantly, 26% of these patients were diagnosed with synchronous or metachronous CRC. The actual risk for serrated polyposis patients to develop CRC is largely unknown. Published series are often from retrospective studies in selected populations from genetics clinics who were diagnosed with serrated polyposis at the time of CRC. This explains the inflated proportion (up to 60%) of CRC associated with published series of serrated polyposis patients. Until large prospective studies are undertaken in a cohort of patients who benefit from the current surveillance guidelines for serrated polyposis, a figure for the risk of CRC will remain speculative. Recent findings from 109 patients in New Zealand with pancolonic disease followed for a median of 4 years showed that none of patients with polyps only developed CRC when they were managed by 1- to 2-year interval surveillance colonoscopy.20
Current guidelines for colonoscopy surveillance after colonoscopic detection of serrated polyps Polyp subtype
Polyp size
Surveillance interval (years)
Hyperplastic polyp Sessile serrated adenoma/polyp Sessile serrated adenoma/polyp Traditional serrated adenoma Serrated polyposis
Any <10 mm
10 5
10 mm
3
Any
3
Any
1
Table 3
proximal to the sigmoid colon with two or more of these being >10 mm; (2) any number of serrated polyps proximal to the sigmoid colon in an individual who had a first-degree relative with SP; (3) >20 serrated polyps of any size but distributed throughout the colon.1 In practice, criterion 2 is not used on its own. Any subtype of serrated polyp counts for the definition. Moreover, the number of polyps is cumulative over time and the diagnosis of serrated polyposis may require collating the findings of multiple colonoscopy and pathology reports. The prevalence of serrated polyposis has been estimated to be around 0.5% of individuals undergoing a screening colonoscopy following a positive faecal test.15 Individuals with Northern European ancestry are particularly predisposed to this condition with high prevalence in New Zealand, Australia and United Kingdom. However, gastroenterologists and pathologists are often unaware of this syndrome. Serrated polyposis therefore remains largely under-diagnosed. Pathologists have an important role in identifying these patients and should comment on the possibility of this syndrome in their pathology report.16 Serrated polyposis represents a continuum of phenotypes from small numbers of large proximal serrated polyps to numerous distal serrated polyps. Some authors have proposed a classification into two types, reflecting the WHO criteria 1 and 3. Type 1 serrated polyposis is defined by the predominance of large SSA/Ps in the proximal colon while type 2 shows multiple small hyperplastic polyps in the distal colon. Individuals with type 1 polyposis are at greater risk of CRC than individuals with type 2 polyposis. In practice, it is often difficult to clearly categorize a patient with type 1 or 2 and many patients may present with a predominant phenotype at time of diagnosis of the polyposis but often demonstrate an overlap in phenotypes over time with pancolonic disease. The age at diagnosis of this condition is wide, ranging from 17 to 85 years. In up to 80% of cases, conventional adenomas are also present, which may confer an increased risk of CRC compared with patients with serrated polyps only. The admixture of conventional adenomas and serrated polyps can be confusing and raise the possibility of other polyposis syndromes,17 in particular MUTYH-associated polyposis with which serrated polyposis may overlap. Usually, MUTYH-associated polyposis individuals have an excess of conventional adenomas while serrated polyposis individuals have an excess of serrated
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Implication for patient management There are low to moderate levels of evidence on which to base guidelines for colonoscopy surveillance in patients diagnosed with serrated polyps. An important factor that guides colonoscopy surveillance interval is the histological type of polyp detected at the index procedure. It is helpful for pathologists to know the impact of their diagnosis, especially when a definite diagnosis cannot be rendered which may change patient management. Most published guidelines for colonoscopy surveillance after polypectomy agreed that patients with small, distally located hyperplastic polyps do not require specific subsequent surveillance due to the innocuous nature of these lesions. There is growing evidence from a few prospective studies that individuals diagnosed with at least one SSA/P are at increased risk to subsequently develop further SSA/Ps, conventional adenomas and CRC. The current recommendations from the American Gastroenterological Association (AGA)21 are based on the premise that the colonoscopy is of good quality with a high detection rate of serrated lesions and that all serrated lesions are
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5 Spring KJ, Zhao ZZ, Karamatic R, et al. High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy. Gastroenterology 2006; 131: 1400e7. 6 Torlakovic E, Skovlund E, Snover DC, Torlakovic G, Nesland JM. Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol 2003; 27: 65e81. 7 Kim KM, Lee EJ, Kim YH, Chang DK, Odze RD. KRAS mutations in traditional serrated adenomas from Korea herald an aggressive phenotype. Am J Surg Pathol 2010; 34: 667e75. 8 Bettington M, Walker N, Rosty C et al. Critical appraisal of the diagnosis of the sessile serrated adenoma. Am J Surg Pathol. In press. 9 Dada M, Wang LM, Chetty R. Incidence and review of sessile serrated polyp reporting in a district general hospital in the UK. Virchows Arch 2013; 463: 633e6. 10 Rosty C, Hewett DG, Brown IS, Leggett BA, Whitehall VL. Serrated polyps of the large intestine: current understanding of diagnosis, pathogenesis, and clinical management. J Gastroenterol 2013; 48: 287e302. 11 Rex DK, Ahnen DJ, Baron JA, et al. Serrated lesions of the colorectum: review and recommendations from an expert panel. Am J Gastroenterol 2012; 107: 1315e29. 12 Sheridan TB, Fenton H, Lewin MR, et al. Sessile serrated adenomas with low- and high-grade dysplasia and early carcinomas: an immunohistochemical study of serrated lesions “caught in the act”. Am J Clin Pathol 2006; 126: 564e71. 13 Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 2007; 50: 113e30. 14 Lochhead P, Kuchiba A, Imamura Y, et al. Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. J Natl Cancer Inst 2013; 105: 1151e6. 15 Biswas S, Ellis AJ, Guy R, Savage H, Madronal K, East JE. High prevalence of hyperplastic polyposis syndrome (serrated polyposis) in the NHS bowel cancer screening programme. Gut 2013; 62: 475. 16 Crowder CD, Sweet K, Lehman A, Frankel WL. Serrated polyposis is an underdiagnosed and unclear syndrome: the surgical pathologist has a role in improving detection. Am J Surg Pathol 2012; 36: 1178e85. 17 Rosty C, Buchanan DD, Walsh MD, et al. Phenotype and polyp landscape in serrated polyposis syndrome: a series of 100 patients from genetics clinics. Am J Surg Pathol 2012; 36: 876e82. 18 Boparai KS, Reitsma JB, Lemmens V, et al. Increased colorectal cancer risk in first-degree relatives of patients with hyperplastic polyposis syndrome. Gut 2010; 59: 1222e5. 19 Rosty C, Walsh MD, Walters RJ, et al. Multiplicity and molecular heterogeneity of colorectal carcinomas in individuals with serrated polyposis. Am J Surg Pathol 2013; 37: 434e42. 20 Parry S, Woodall S, Arnold J, et al. Serrated polyposis syndrome: monitoring a cohort with colonoscopic surveillance in a tertiary setting continues to prove safe. Fam Cancer 2013; 12: S60. 21 Lieberman DA, Rex DK, Winawer SJ, Giardiello FM, Johnson DA, Levin TR. Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-society task force on colorectal cancer. Gastroenterology 2012; 143: 844e57. 22 Toon CW, Walsh MD, Chou A, et al. BRAFV600E immunohistochemistry facilitates universal screening of colorectal cancers for Lynch syndrome. Am J Surg Pathol 2013; 37: 1592e602.
fully resected except for the most diminutive hyperplastic polyps in the distal bowel (Table 3). They are also based on the premise that the polyps are classified according to the most recent WHO guidelines as described in this review. If gastroenterologists have any doubt about the histological diagnosis, a conservative position is often taken that considers all proximal serrated lesions >10 mm to be SSA/P even if they are reported as HP. According to the AGA guidelines, all serrated lesions should be removed at colonoscopy, except for diminutive rectosigmoid hyperplastic polyps, which should be randomly sampled for histology. A follow-up colonoscopy at 3e6 months is warranted after piecemeal resection of large serrated polyps given the risks of incomplete resection and reports of early interval cancer. The surveillance interval for patients who fulfil the criteria for serrated polyposis is 1 year and a screening colonoscopy is recommended in first-degree relatives aged 40 years or aged 10 years younger than the age of diagnosis of the youngest relatives.
Conclusions In summary, the terminology for the diagnosis serrated polyps has evolved over the last 20 years to recognize subtypes with well-documented malignant potential. Pathologists need to be aware of the histological criteria to diagnose SSA/P which represents up to 25% of all serrated polyps. The histological classification of serrated polyps according of the latest WHO criteria is one of the premises for the current patient surveillance guidelines. Serrated polyposis may be more prevalent than initially thought and pathologists should be aware of the clinical criteria to identify these patients. The recent availability of an antibody that reliably detects BRAF mutation by immunohistochemistry shows promise in helping to identify and further characterize serrated polyps and move towards a more molecularly based classification.22 The issue of inter-observer agreement among pathologists, including gastrointestinal pathologists, to reproducibly diagnose serrated polyps has been reported by several authors. In most studies, a poor to moderate level of agreement was observed with kappa values ranging from 0.14 to 0.55 to diagnose SSA/P.23,24 However, with pathologist becoming increasingly aware of the 2010 WHO criteria, it is expected that the reproducibility of serrated polyp diagnosis will improve over time.25 A
REFERENCES 1 Snover DC, Ahnen DJ, Burt RW, Odze RD. Serrated polyps of the colon and rectum and serrated polyposis. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO classification of tumours of the digestive system. Lyon, France: IARC Press, 2010; 160e5. 2 Snover DC. Update on the serrated pathway to colorectal carcinoma. Hum Pathol 2011; 42: 1e10. 3 Torlakovic EE, Gomez JD, Driman DK, et al. Sessile serrated adenoma (SSA) vs. traditional serrated adenoma (TSA). Am J Surg Pathol 2008; 32: 21e9. 4 Forsberg AM, Kjellstrom L, Agreus L, et al. Prevalence of colonic neoplasia and advanced lesions in the normal population: a prospective population-based colonoscopy study. Scand J Gastroenterol 2012; 47: 184e90.
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23 Wong NA, Hunt LP, Novelli MR, Shepherd NA, Warren BF. Observer agreement in the diagnosis of serrated polyps of the large bowel. Histopathology 2009; 55: 63e6. 24 Farris AB, Misdraji J, Srivastava A, et al. Sessile serrated adenoma: challenging discrimination from other serrated colonic polyps. Am J Surg Pathol 2008; 32: 30e5. 25 Ensari A, Bilezikci B, Carneiro F, et al. Serrated polyps of the colon: how reproducible is their classification? Virchows Arch 2012; 461: 495e504.
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TSA can demonstrate a predominance of goblet cells and can be overgrown by superimposed conventional dysplasia of intestinal type Pathologists should be aware of the criteria for serrated polyposis and comment on the possibility of this under-diagnosed syndrome that prompts specific management
Research directions Practice points C C
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The 2010 WHO criteria for the histological diagnosis of serrated polyps must be universally used by pathologists Up to 25% of serrated polyps are SSA/P and may have malignant potential The presence of only one unequivocal abnormal SSA/P-like crypt is sufficient for the diagnosis of SSA/P A dysplastic component in an SSA/P may portend the rapid step for malignant progression and should be carefully looked for
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C C
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Large prospective studies are required to better understand the significance of SSA/P and TSA for more evidence-based guidelines of surveillance The malignant potential of distal SSA/P is unclear TSA is a heterogeneous group that would require a molecularbased classification with the possible aid of BRAF immunohistochemistry The risk of cancer in serrated polyposis patients in relation to various phenotypic presentations over long term surveillance needs to be defined
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Serrated colorectal polyps and polyposis
under-recognition among pathologists. In an attempt to solve these issues, the 4th edition (2010) of the World Health Organisation (WHO) classification defined new histological criteria for all currently recognized subtypes of serrated polyps: hyperplastic polyp (HP), sessile serrated adenoma/polyp (SSA/P) and traditional serrated adenoma (TSA). These criteria should be universally applied to ensure standardized diagnosis and thus the reliable application of surveillance colonoscopy protocols. This review outlines the current knowledge on the histological diagnosis of serrated polyps of the large intestine and addresses the impact of these diagnoses on patient management. We also address the main features of molecular pathways involved in the malignant transformation of serrated polyps. Serrated polyposis is also be discussed with an emphasis on the role of pathologists in the diagnosis of this under-recognized syndrome.
Christophe Rosty Mark Bettington
Abstract Serrated polyps represent a heterogeneous group of lesions, some of which have well-documented malignant potential. The histological classification of serrated polyps has evolved over the last two decades to recognize three major subtypes: hyperplastic polyp, sessile serrated adenoma/polyp and traditional serrated adenoma. Sessile serrated adenoma/ polyp remains under-diagnosed while it represents up to 25% of all serrated polyps and is the precursor lesion to colorectal carcinoma evolving though the serrated neoplasia pathway with BRAF mutation and CpG island methylator phenotype. Pathologists need to be aware of the World Health Organisation criteria to correctly diagnose each entity as patient management guidelines are based upon the use of this classification. Serrated polyposis is an under-recognized syndrome with unknown genetic cause conferring an increased risk of colorectal carcinoma. Pathologists have a pivotal role in identifying these patients who should undergo yearly surveillance colonoscopy.
Histological diagnosis of serrated polyps The common morphological feature of serrated polyps is the ‘saw-tooth’ appearance of the crypts, which occurs due to decreased apoptosis and increased senescence of the epithelial cells. The 4th edition of the WHO classification book published in 20101 subcategorized serrated polyps into three groups: HP, SSA/ P and TSA. The morphological aspects that characterizes each group are the result of differences in the location of the proliferation zones within the colonic crypts.2,3 The main characteristics of each serrated polyp subtype are summarized in Table 1.
Keywords hyperplastic polyp; serrated neoplasia pathway; serrated polyp; serrated polyposis; sessile serrated adenoma; traditional serrated adenoma
Hyperplastic polyps HP is the most common subtype, representing 70e80% of serrated polyps. Forsberg et al. reported that 21% of asymptomatic individuals aged 19e70 years had at least one HP in a Swedish population-based prospective colonoscopy study.4 In HP, the proliferation zone is normally located at the base of the crypts with preserved maturation of epithelial cells symmetrically along the crypts towards the luminal surface. Approximately 75% of HPs are located in the distal colon or rectum as small (<10 mm; usually 1e5 mm) sessile lesions with insignificant malignant potential.5 However, HPs can also be detected in the proximal colon, possibly with increased frequency now that some gastroenterologists use enhanced endoscopic procedures that allow better detection of small sessile polyps compared with white light endoscopy. The possibility that some of these proximal lesions may progress to SSA/P and to malignancy is still unknown and cannot be excluded. The common underlying feature of HP is the normal architecture of elongated and straight crypts with serration restricted to the upper compartment.6 Cytological dysplasia is absent. One caveat to this definition is that the crypt architecture can sometimes appear abnormal displaying dilatation of the bases when mucosal prolapse changes are superimposed (Figure 1). Often, there is a mild thickening of the subepithelial basement membrane compared to the adjacent normal mucosa. Further subdivision of HP into microvesicular HP and goblet cell HP is mostly of academic interest and does not need be included in pathology reports. More importantly, one should consider goblet cell HP when a biopsy of a lesion described as a polyp by endoscopists looks close to normal mucosa on multiple levels. Changes in goblet cell HPs are very mild, characterized by slight crypt elongation with numerous
Introduction The vast majority of colorectal carcinomas (CRC) develop from benign precursor polyps, which can be detected and removed by appropriate screening colonoscopy programs. Colorectal polyps comprise a wide range of neoplastic and non-neoplastic lesions with various risks of malignant transformation. The majority of neoplastic colorectal polyps fall into one the two following categories: conventional adenomas (tubular, tubulo-villous and villous adenomas) and serrated polyps. Over the last 20 years, new subtypes of serrated polyps associated with malignant potential have been recognized from what was collectively known as hyperplastic polyps in the past. As often occurs when new entities are described, this led to confusion, misdiagnosis and
Christophe Rosty MD PhD FRCPA Envoi Pathology, Brisbane, Australia; School of Medicine, University of Queensland, Brisbane, Australia; Cancer and Population Studies Group, Queensland Institute of Medical Research, Brisbane, Australia. Conflicts of interest: none. Mark Bettington BSc MBBS FRCPA The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; School of Medicine, The University of Queensland, Brisbane, QLD, Australia; Envoi Pathology, Brisbane, QLD, Australia. Conflicts of interest: none.
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Summary of pathological and molecular characteristics of serrated polyps Microvesicular HP
Goblet cell HP
TSA
SSA/P
SSA/P with cytological dysplasia
Proportion Predominant colonic location Pathological features
40e50% Distal
20e30% Distal
2e5% Distal
15e25% Proximal
2e5% Proximal
Normal architecture with elongated straight crypts and upper serration Microvesicular mucin, no dysplasia
Normal crypt architecture with subtle surface serration Goblet cell mucin, no dysplasia
Abnormal architecture with dilated crypt base and basal serration Dystrophic goblet cells in crypt base, no dysplasia
SSA/P features with sharp demarcation to dysplasia Conventional intestinal type or serrated type dysplasia
Most common molecular alteration
BRAFV600E mutation (70e80%)
KRAS mutation (50%)
Exophytic (distal) or sessile (proximal) Villiform configuration with ectopic crypt formations Eosinophilic cells with pencillate nuclei Conventional dysplasia can arise BRAFV600E mutation (50%) KRAS mutation (30%)
BRAFV600E mutation (70e80%) CIMP-high
BRAFV600E mutation (80e100%); CIMP-high; MSI or TP53 alteration
HP: Hyperplastic polyp; SSA/P: Sessile serrated adenoma/polyp; TSA: Traditional serrated adenoma; CIMP: CpG island methylator phenotype; MSI: Microsatellite instability.
Table 1
crypt architectural alteration following the shift of the proliferation zone from its normal location at the base to the side of the crypts. This results in asymmetrical maturation of epithelial cells towards both the crypt surface and base.2 The crypts then develop abnormal shapes with dilatation at the bases often in an L-shaped or inverted T-shaped configuration (Figure 3). An expanded proliferation zone is commonly found in the upper part of the crypts and superficial mitoses may sometimes be seen. If cross-sectioned at the level of an active proliferation zone, the appearance may cause misdiagnosis as dysplasia. SSA/P is more frequently found in the proximal colon and tend to be >10 mm in size (Figure 4). However, small SSA/Ps are increasingly recognized and SSA/Ps distal to the transverse colon can also occur.
goblet cells and subtle serration at the surface that can be easily overlooked (Figure 2). The significance of goblet cell HP is unclear; some authors have suggested that it may represent the precursor lesion of TSA.7 On the other hand, the upper serration in microvesicular HP is more obvious and the presence of epithelial cells with microvesicular mucin contrasts with the normal adjacent mucosa. A mucin-poor subtype of HP with reactive cytological atypia has also been described but the significance of this rare lesion is unknown and is likely to represent an injured microvesicular HP.2 Sessile serrated adenoma/polyp The prevalence of SSA/P seems to have increased over the last years as gastroenterologists and pathologists alike became more aware of this entity. In a recent study reviewing the histology of 6340 colorectal polyps from a single pathology practice, SSA/P represented 12.1% of all polyps and 25.3% of serrated polyps.8 However, SSA/P remains under-diagnosed in some pathologist communities due to a lack of awareness of the lesion, when it will be misdiagnosed as HP.9 In contrast to HP, SSA/P displays
Figure 1 Goblet cell hyperplastic polyp with elongated crypts and increased number of goblet cells compared with the normal mucosa on the left part of the image.
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Figure 2 Microvesicular hyperplastic polyp with mucosal prolapse changes showing more complex crypt serration and distortion than the usual hyperplastic polyp, and smooth muscle in the lamina propria.
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Figure 3 Typical appearance of a sessile serrated adenoma/polyp with contiguous abnormal crypts showing dilatation of the base.
Endoscopically, SSA/P is characterized by the presence of a mucus cap, a rim of debris or bubbles, alteration of the contour of a fold and abnormal mucosal vascular pattern.10 A frequent situation that pathologists encounter is that of a large (>10 mm) serrated polyp in the proximal colon with predominantly straight HP-like appearing crypts and very focal (in some cases, just one) dilated and distorted crypt bases. The focal crypt abnormalities seem to fall short of the WHO definition of SSA/P that requires more than two or three contiguous abnormal crypts. To address this issue, a report following a consensus conference by an expert panel in 2010 recommended that “the presence of at least one unequivocal architecturally distorted, dilated, and/or horizontally branched crypt, particularly if it is associated with inverted maturation, is sufficient for a diagnosis of SSA/P”.11 However, these relaxed criteria for the diagnosis of SSA/P were proposed based on the experience of specialists but lacked clinical-based evidence. Recently, a study by Bettington et al. provided insights for the minimum morphological changes to diagnose SSA/ P and to separate them from HP.8 Sessile polyps with serration displaying at least one abnormal SSA/P-like crypt (Figure 5) showed more frequent proximal colonic location and female predominance similar to that of overt SSA/P and different from the plain HP that do not show any architectural crypt abnormality. The conclusions of this study validated the minimal criteria from the expert panel consensus conference. Dysplasia is not a feature of SSA/P, a controversial issue that led to ongoing debate among pathologists for and against the use
of the term ‘adenoma’ for a lesion that lacks dysplasia. When dysplasia arises in the background of an SSA/P, the polyp is classified as SSA/P with cytological dysplasia.1 The development of dysplasia in SSA/P may portend rapid progression to carcinoma either through methylation of MLH1 or alteration of the TP53 gene.12 Immunohistochemistry for MLH1 could help in identifying the dysplastic component but a normal pattern with retained nuclear stain does not exclude the diagnosis of dysplasia. The dysplastic component may be of two histological types; it may resemble that of conventional adenoma with basophilic cytoplasm and elongated nuclei (Figure 6) or may display a “serrated dysplasia” phenotype with cuboidal cells, eosinophilic cytoplasm, round nuclei with open chromatin and prominent nucleoli (Figure 7). The serrated type of dysplasia can be subtler histologically and may easily be missed. The dysplastic component is usually sharply demarcated from the underlying SSA/P, a feature that led to the term “mixed polyps” or “tubular adenoma mixed with hyperplastic” in the past. This terminology should no longer be used. The separation of dysplasia into high grade and low grade may be difficult and does not need to be reported, as recommended by the WHO classification. Some serrated polyps
Figure 4 Macroscopic appearance of sessile serrated adenoma/polyps (arrows). Note the presence of additional smaller polyps. Scale bar (bottom left) equals to 1 cm.
Figure 6 Sessile serrated adenoma/polyp with cytological dysplasia of conventional intestinal type (left part of the image).
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Figure 5 Low magnification of a sessile serrated adenoma/polyp with predominantly straight hyperplastic polyp-like crypts and only one abnormal dilated crypt base.
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Figure 9 Traditional serrated adenoma with a predominance of goblet cells and an area of high grade dysplasia of conventional intestinal type (left lower part of the image). Figure 7 Sessile serrated adenoma/polyp with cytological dysplasia of serrated type characterized by round nuclei with open chromatin, prominent nucleoli and eosinophilic cytoplasm.
where they tend to have a more sessile appearance. In a study from Korea, up to 20% of TSA were located in the proximal colon.7 The villous projections of TSA are typically lined by tall eosinophilic cells with elongated pencillate nuclei. However, goblet cells may be prominent in some lesions (Figure 9). Conventional dysplasia of intestinal type is also commonly found in TSA that may retain only small foci of eosinophilic cells when dysplasia has overgrown most of the lesion (Figure 10). This may represent a step towards high-grade dysplasia and malignancy. There is an overlap between advanced TSA and tubulo-villous adenoma with serrated morphology. The distinction between these two entities may be difficult and it is currently unknown if these represent polyps with separate malignant potential through different molecular pathways or a spectrum of similar lesions.
demonstrate focal morphological changes of TSA adjacent to a typical SSA/P. It is unclear whether this represents an early form of TSA originating from an SSA/P or the progression of an SSA/P to a more advanced dysplastic lesion. A descriptive report mentioning both components is recommended. Traditional serrated adenoma TSA represents the least common and least understood subtype of serrated polyp. In TSA, the proliferation zone is represented by multiple small ectopic crypt formations from the side of the original crypts and along the newly formed villous projections of the polyp. TSAs are usually exophytic lesions located in the distal colon and rectum with a complex villiform configuration and typical ectopic crypt formations as defined by Torlakovic et al.3 (Figure 8). These ectopic crypts demonstrate normal orientation towards the lumen but the loss of the anchoring of the base in proximity to the muscularis mucosae as in normal mucosa, HP or SSA/P. TSA can also be encountered in the proximal colon
Serrated neoplasia pathway to colorectal carcinoma The concept of pathways to CRC combining pathological, clinical and molecular features has been introduced by Jeremy Jass in his seminal review which defined five types of CRC.13
Figure 8 Typical appearance of a traditional serrated adenoma with a villiform architecture, ectopic crypt formations and tall cells with eosinophilic cytoplasm and pencillate nuclei.
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Figure 10 High grade dysplasia of conventional intestinal type arising in a traditional serrated adenoma.
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Putative different molecular pathways for malignant transformation of serrated polyps
Precursor lesion Predominant location Carcinoma morphology Additional molecular alterations Prognosis compared to adenoma-carcinoma pathway CRC
BRAF MSI serrated pathway
BRAF MSS serrated pathway
KRAS alternate pathway
SSA/P Proximal colon Mucinous, tumour infiltrating lymphocytes CIMP-high; MLH1 methylation; chromosomal stability
SSA/P and TSA Proximal and distal colon Adenocarcinoma NOS, serrated adenocarcinoma CIMP-high; TP53 alteration
Good
Bad
TSA and some TVA Distal colon and rectum Adenocarcinoma NOS, serrated adenocarcinoma MSI and CIMP-low/indeterminate, MGMT methylation; chromosomal instability Bad
MSI: Microsatellite instability; MSS: Microsatellite stable; NOS: Not otherwise specified; CIMP: CpG island methylator phenotype.
Table 2
Approximately 30% of colorectal carcinoma develops through the serrated neoplasia pathway (Jass types 1 and 2) or the alternate pathway (Jass type 3) (Table 2). Similarities in mucin expression and molecular alterations between SSA/P and a subtype of CRC with high levels of microsatellite instability (MSI) not caused by Lynch syndrome provided the first evidence that this subtype of serrated polyp had malignant potential. This has been complemented by clinical evidence demonstrating a link between SSA/P and CRC from the proximal colon, in particular the frequent occurrence of residual serrated polyps at the edge of a carcinoma demonstrating morphological features of MSI CRC (Figure 11). Nowadays, the serrated neoplasia pathway with SSA/P as the primary precursor polyp is widely accepted. This pathway accounts for 10e15% of all CRC and is primarily defined by BRAF mutation and high levels of CpG island methylator phenotype (CIMP). CIMP describes the coordinate methylation of CpG dinucleotide clusters (CpG islands) in the promoter region of genes, resulting in silencing of gene
expression. This phenotype that segregates with BRAF mutation may target different genes with CpG islands in their promoter regions. When these genes have tumour suppressor properties, the silencing may have important consequences for tumour progression. One of the mismatch repair genes, MLH1, implicated in Lynch syndrome, can become methylated and silenced in about 50% of CRC with BRAF mutation. This event is important for the progression of a proportion of serrated polyps to carcinoma showing MSI, often referred to as sporadic MSI cancer and characterized by a predominance in elderly women, location in the proximal colon, low stage at diagnosis, good outcome and lack of response to 5-Fluorouracil (Jass type 1). On the other hand, BRAF-mutated CRCs that do not develop MSI (microsatellite stable cancer) are often associated with TP53 alteration and demonstrate poor prognosis (Jass type 2).14 The alternate pathway to CRC is not currently widely recognized and further studies are needed to outline the complete clinical, pathological and molecular definition of this subgroup of CRC (Jass type 3). On the molecular level, the alternate pathway combines alterations of the traditional adenoma-carcinoma pathway (Vogelstein progression model) including chromosomal instability and a microsatellite stable phenotype, with a high frequency of mutation in KRAS, an oncogene part of the Mitogen Activated Protein Kinase (MAPK ) pathway upstream BRAF. Additional molecular alterations are the silencing by methylation of the DNA repair gene gene 06-methylguanine DNA methyltransferase (MGMT ), and low/indeterminate levels of CIMP and MSI. In precursor polyps, KRAS mutation has been reported in conventional adenoma with a high villosity, in goblet cell HP and in approximately 30% of TSA. It is possible that some TSAs and tubulo-villous adenomas may progress through the alternate pathway of CRC.
Serrated polyposis Serrated polyposis, previously called hyperplastic polyposis, is a clinically defined syndrome with unknown genetic causes that predisposes affected individuals to an increased risk of CRC. Patients fulfilling one or more of the following criteria are diagnosed with serrated polyposis: (1) at least five serrated polyps
Figure 11 Adenocarcinoma arising from a sessile serrated adenoma/polyp with a transitional zone of dysplasia. The adenocarcinoma is poorly differentiated with prominent tumour infiltrating lymphocytes (inlay), typical of microsatellite instability phenotype.
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polyps. In equivocal cases, screening for germline mutation in MUTYH is recommended. Serrated polyps are not indicative of Lynch syndrome; however there is still confusion among some clinicians who might request mismatch repair protein immunohistochemistry testing for young patients with multiple serrated polyps and a strong family history of CRC. Those patients are very unlikely to have Lynch syndrome but are likely to have serrated polyposis. A family history of CRC is found in approximately 50% of individuals diagnosed with serrated polyposis. Moreover, first-degree relatives are at 5-fold increased risk of CRC compared to the general population.18 CRC in serrated polyposis patients do not necessarily develop through the serrated neoplasia pathway. Only approximately half of CRC harbour a mutation in BRAF and 38% show microsatellite instability though methylation of MLH1.19 These findings emphasize the role of conventional adenomas as precursor lesions to CRC in serrated polyposis. In fact, the most common molecular subtype of cancer in 38 serrated polyposis patients was characterized by an absence of mutation in KRAS or BRAF and a microsatellite stable phenotype, the molecular profile commonly found in CRC developing though the traditional adenoma-carcinoma pathway from conventional adenoma. Importantly, 26% of these patients were diagnosed with synchronous or metachronous CRC. The actual risk for serrated polyposis patients to develop CRC is largely unknown. Published series are often from retrospective studies in selected populations from genetics clinics who were diagnosed with serrated polyposis at the time of CRC. This explains the inflated proportion (up to 60%) of CRC associated with published series of serrated polyposis patients. Until large prospective studies are undertaken in a cohort of patients who benefit from the current surveillance guidelines for serrated polyposis, a figure for the risk of CRC will remain speculative. Recent findings from 109 patients in New Zealand with pancolonic disease followed for a median of 4 years showed that none of patients with polyps only developed CRC when they were managed by 1- to 2-year interval surveillance colonoscopy.20
Current guidelines for colonoscopy surveillance after colonoscopic detection of serrated polyps Polyp subtype
Polyp size
Surveillance interval (years)
Hyperplastic polyp Sessile serrated adenoma/polyp Sessile serrated adenoma/polyp Traditional serrated adenoma Serrated polyposis
Any <10 mm
10 5
10 mm
3
Any
3
Any
1
Table 3
proximal to the sigmoid colon with two or more of these being >10 mm; (2) any number of serrated polyps proximal to the sigmoid colon in an individual who had a first-degree relative with SP; (3) >20 serrated polyps of any size but distributed throughout the colon.1 In practice, criterion 2 is not used on its own. Any subtype of serrated polyp counts for the definition. Moreover, the number of polyps is cumulative over time and the diagnosis of serrated polyposis may require collating the findings of multiple colonoscopy and pathology reports. The prevalence of serrated polyposis has been estimated to be around 0.5% of individuals undergoing a screening colonoscopy following a positive faecal test.15 Individuals with Northern European ancestry are particularly predisposed to this condition with high prevalence in New Zealand, Australia and United Kingdom. However, gastroenterologists and pathologists are often unaware of this syndrome. Serrated polyposis therefore remains largely under-diagnosed. Pathologists have an important role in identifying these patients and should comment on the possibility of this syndrome in their pathology report.16 Serrated polyposis represents a continuum of phenotypes from small numbers of large proximal serrated polyps to numerous distal serrated polyps. Some authors have proposed a classification into two types, reflecting the WHO criteria 1 and 3. Type 1 serrated polyposis is defined by the predominance of large SSA/Ps in the proximal colon while type 2 shows multiple small hyperplastic polyps in the distal colon. Individuals with type 1 polyposis are at greater risk of CRC than individuals with type 2 polyposis. In practice, it is often difficult to clearly categorize a patient with type 1 or 2 and many patients may present with a predominant phenotype at time of diagnosis of the polyposis but often demonstrate an overlap in phenotypes over time with pancolonic disease. The age at diagnosis of this condition is wide, ranging from 17 to 85 years. In up to 80% of cases, conventional adenomas are also present, which may confer an increased risk of CRC compared with patients with serrated polyps only. The admixture of conventional adenomas and serrated polyps can be confusing and raise the possibility of other polyposis syndromes,17 in particular MUTYH-associated polyposis with which serrated polyposis may overlap. Usually, MUTYH-associated polyposis individuals have an excess of conventional adenomas while serrated polyposis individuals have an excess of serrated
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Implication for patient management There are low to moderate levels of evidence on which to base guidelines for colonoscopy surveillance in patients diagnosed with serrated polyps. An important factor that guides colonoscopy surveillance interval is the histological type of polyp detected at the index procedure. It is helpful for pathologists to know the impact of their diagnosis, especially when a definite diagnosis cannot be rendered which may change patient management. Most published guidelines for colonoscopy surveillance after polypectomy agreed that patients with small, distally located hyperplastic polyps do not require specific subsequent surveillance due to the innocuous nature of these lesions. There is growing evidence from a few prospective studies that individuals diagnosed with at least one SSA/P are at increased risk to subsequently develop further SSA/Ps, conventional adenomas and CRC. The current recommendations from the American Gastroenterological Association (AGA)21 are based on the premise that the colonoscopy is of good quality with a high detection rate of serrated lesions and that all serrated lesions are
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5 Spring KJ, Zhao ZZ, Karamatic R, et al. High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy. Gastroenterology 2006; 131: 1400e7. 6 Torlakovic E, Skovlund E, Snover DC, Torlakovic G, Nesland JM. Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol 2003; 27: 65e81. 7 Kim KM, Lee EJ, Kim YH, Chang DK, Odze RD. KRAS mutations in traditional serrated adenomas from Korea herald an aggressive phenotype. Am J Surg Pathol 2010; 34: 667e75. 8 Bettington M, Walker N, Rosty C et al. Critical appraisal of the diagnosis of the sessile serrated adenoma. Am J Surg Pathol. In press. 9 Dada M, Wang LM, Chetty R. Incidence and review of sessile serrated polyp reporting in a district general hospital in the UK. Virchows Arch 2013; 463: 633e6. 10 Rosty C, Hewett DG, Brown IS, Leggett BA, Whitehall VL. Serrated polyps of the large intestine: current understanding of diagnosis, pathogenesis, and clinical management. J Gastroenterol 2013; 48: 287e302. 11 Rex DK, Ahnen DJ, Baron JA, et al. Serrated lesions of the colorectum: review and recommendations from an expert panel. Am J Gastroenterol 2012; 107: 1315e29. 12 Sheridan TB, Fenton H, Lewin MR, et al. Sessile serrated adenomas with low- and high-grade dysplasia and early carcinomas: an immunohistochemical study of serrated lesions “caught in the act”. Am J Clin Pathol 2006; 126: 564e71. 13 Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 2007; 50: 113e30. 14 Lochhead P, Kuchiba A, Imamura Y, et al. Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. J Natl Cancer Inst 2013; 105: 1151e6. 15 Biswas S, Ellis AJ, Guy R, Savage H, Madronal K, East JE. High prevalence of hyperplastic polyposis syndrome (serrated polyposis) in the NHS bowel cancer screening programme. Gut 2013; 62: 475. 16 Crowder CD, Sweet K, Lehman A, Frankel WL. Serrated polyposis is an underdiagnosed and unclear syndrome: the surgical pathologist has a role in improving detection. Am J Surg Pathol 2012; 36: 1178e85. 17 Rosty C, Buchanan DD, Walsh MD, et al. Phenotype and polyp landscape in serrated polyposis syndrome: a series of 100 patients from genetics clinics. Am J Surg Pathol 2012; 36: 876e82. 18 Boparai KS, Reitsma JB, Lemmens V, et al. Increased colorectal cancer risk in first-degree relatives of patients with hyperplastic polyposis syndrome. Gut 2010; 59: 1222e5. 19 Rosty C, Walsh MD, Walters RJ, et al. Multiplicity and molecular heterogeneity of colorectal carcinomas in individuals with serrated polyposis. Am J Surg Pathol 2013; 37: 434e42. 20 Parry S, Woodall S, Arnold J, et al. Serrated polyposis syndrome: monitoring a cohort with colonoscopic surveillance in a tertiary setting continues to prove safe. Fam Cancer 2013; 12: S60. 21 Lieberman DA, Rex DK, Winawer SJ, Giardiello FM, Johnson DA, Levin TR. Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-society task force on colorectal cancer. Gastroenterology 2012; 143: 844e57. 22 Toon CW, Walsh MD, Chou A, et al. BRAFV600E immunohistochemistry facilitates universal screening of colorectal cancers for Lynch syndrome. Am J Surg Pathol 2013; 37: 1592e602.
fully resected except for the most diminutive hyperplastic polyps in the distal bowel (Table 3). They are also based on the premise that the polyps are classified according to the most recent WHO guidelines as described in this review. If gastroenterologists have any doubt about the histological diagnosis, a conservative position is often taken that considers all proximal serrated lesions >10 mm to be SSA/P even if they are reported as HP. According to the AGA guidelines, all serrated lesions should be removed at colonoscopy, except for diminutive rectosigmoid hyperplastic polyps, which should be randomly sampled for histology. A follow-up colonoscopy at 3e6 months is warranted after piecemeal resection of large serrated polyps given the risks of incomplete resection and reports of early interval cancer. The surveillance interval for patients who fulfil the criteria for serrated polyposis is 1 year and a screening colonoscopy is recommended in first-degree relatives aged 40 years or aged 10 years younger than the age of diagnosis of the youngest relatives.
Conclusions In summary, the terminology for the diagnosis serrated polyps has evolved over the last 20 years to recognize subtypes with well-documented malignant potential. Pathologists need to be aware of the histological criteria to diagnose SSA/P which represents up to 25% of all serrated polyps. The histological classification of serrated polyps according of the latest WHO criteria is one of the premises for the current patient surveillance guidelines. Serrated polyposis may be more prevalent than initially thought and pathologists should be aware of the clinical criteria to identify these patients. The recent availability of an antibody that reliably detects BRAF mutation by immunohistochemistry shows promise in helping to identify and further characterize serrated polyps and move towards a more molecularly based classification.22 The issue of inter-observer agreement among pathologists, including gastrointestinal pathologists, to reproducibly diagnose serrated polyps has been reported by several authors. In most studies, a poor to moderate level of agreement was observed with kappa values ranging from 0.14 to 0.55 to diagnose SSA/P.23,24 However, with pathologist becoming increasingly aware of the 2010 WHO criteria, it is expected that the reproducibility of serrated polyp diagnosis will improve over time.25 A
REFERENCES 1 Snover DC, Ahnen DJ, Burt RW, Odze RD. Serrated polyps of the colon and rectum and serrated polyposis. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO classification of tumours of the digestive system. Lyon, France: IARC Press, 2010; 160e5. 2 Snover DC. Update on the serrated pathway to colorectal carcinoma. Hum Pathol 2011; 42: 1e10. 3 Torlakovic EE, Gomez JD, Driman DK, et al. Sessile serrated adenoma (SSA) vs. traditional serrated adenoma (TSA). Am J Surg Pathol 2008; 32: 21e9. 4 Forsberg AM, Kjellstrom L, Agreus L, et al. Prevalence of colonic neoplasia and advanced lesions in the normal population: a prospective population-based colonoscopy study. Scand J Gastroenterol 2012; 47: 184e90.
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23 Wong NA, Hunt LP, Novelli MR, Shepherd NA, Warren BF. Observer agreement in the diagnosis of serrated polyps of the large bowel. Histopathology 2009; 55: 63e6. 24 Farris AB, Misdraji J, Srivastava A, et al. Sessile serrated adenoma: challenging discrimination from other serrated colonic polyps. Am J Surg Pathol 2008; 32: 30e5. 25 Ensari A, Bilezikci B, Carneiro F, et al. Serrated polyps of the colon: how reproducible is their classification? Virchows Arch 2012; 461: 495e504.
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TSA can demonstrate a predominance of goblet cells and can be overgrown by superimposed conventional dysplasia of intestinal type Pathologists should be aware of the criteria for serrated polyposis and comment on the possibility of this under-diagnosed syndrome that prompts specific management
Research directions Practice points C C
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The 2010 WHO criteria for the histological diagnosis of serrated polyps must be universally used by pathologists Up to 25% of serrated polyps are SSA/P and may have malignant potential The presence of only one unequivocal abnormal SSA/P-like crypt is sufficient for the diagnosis of SSA/P A dysplastic component in an SSA/P may portend the rapid step for malignant progression and should be carefully looked for
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Large prospective studies are required to better understand the significance of SSA/P and TSA for more evidence-based guidelines of surveillance The malignant potential of distal SSA/P is unclear TSA is a heterogeneous group that would require a molecularbased classification with the possible aid of BRAF immunohistochemistry The risk of cancer in serrated polyposis patients in relation to various phenotypic presentations over long term surveillance needs to be defined
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