Molecular and Histologic Considerations in the Assessment of Serrated Polyps.
Genomic and epigenomic alterations that have been shown in the different subtypes of CRC include chromosomal instability, CpG island methylator phenotype (CIMP), microsatellite instability, and activating mutations of key driver genes, including KRAS and BRAF. (11, 12)
In contrast to previous studies that have used limited panels of genomic alterations, genome-wide sequencing and array technologies and large data sets such as the Cancer Genome Atlas Research Network data provide greater molecular details for the recognition of more biologically accurate cancer subgroups. (13)
The early lesion in the conventional pathway of CRC tumorigenesis is the conventional adenoma (tubular or villous adenoma). The conventional CRC molecular pathway involves a predominant pattern of chromosomal instability with a multistep accumulation of genetic aberrations that include mutations in the adenomatous polyposis coli (APC) gene, altered regulation of the Wnt-[beta]-catenin pathway, TP53 gene mutations, and loss of heterozygosity at the 18q chromosome (Figure 1). (3) Progression from conventional adenomas to adenocarcinoma is associated with mutations in genes of the mitogen-activated protein kinase (MAPK) signaling pathway, in particular in KRAS, which was reported in up to 18% of tubular adenomas and 50% of villous adenomas. (3, 14) Activating KRAS and BRAF mutations appear to be mutually exclusive in the MAPK pathway. (15) Kim et al (16) reported approximately half of conventional adenomas to harbor KRAS mutations and none to contain BRAF mutations. Leggett and Whitehall (9) found only a small proportion (up to 9%) of conventional adenomas to contain BRAF mutation. Carcinomas that develop through the conventional pathway are generally CIMP-, are microsatellite stable (MSS), have chromosomal instability, are TP53 mutated, and display loss of heterozygosity at the 18q chromosome (Figure 1). (3)
In contrast to the conventional adenoma-carcinoma pathway, the sessile serrated pathway early lesions are serrated polyps characterized by high incidence of activating BRAF mutations and epigenetic gene silencing mediated via promoter hypermethylation. The resulting sessile serrated adenomas progress through the CIMP and/or the micro- satellite instability pathways, the latter resulting from transcriptional inactivation of the DNA mismatch repair gene MLH1 by promoter methylation (Figure 1). (5, 13-17) An alternative pathway has been proposed in which tubulovillous adenomas are the precursor lesions and are characterized by CIMP-low/MSS and KRAS mutations (Figure 1). (11)
Since the introduction of the term serrated adenoma in 1990 by Longacre and Fenoglio-Preiser, (17) the histologic and molecular features of the distinct types of serrated polyps have become increasingly well recognized, leading to more detailed categorization, treatment approaches, and surveillance recommendations. Currently, 3 types of serrated polyps are acknowledged in the fourth edition (2010) of the World Health Organization (WHO) Classification of Tumors of the Digestive System (18): hyperplastic polyp (HP), sessile serrated adenoma/polyp (SSA/P), and traditional serrated adenoma (TSA). The terms sessile serrated adenoma and sessile serrated polyp are interchangeable. (18) The aim of this review is to integrate the most recent molecular data identified in serrated lesions in the context of their histologic classification and to highlight the role of pathologists in the assessment and reporting of these lesions.
SERRATED LESIONS: EPIDEMIOLOGY AND CLINICAL FEATURES
Because of variations in terminology and detection rates, the prevalence of serrated polyps differs in published reports. (19, 20) In addition, most of the epidemiologic studies of serrated lesions predate the current classification of serrated polyps, limiting their utility. Nonetheless, the prevalence of all serrated lesions was reported to range from 13% to 50% in several autopsy series. (21-24) Serrated lesions may be the precursor to approximately one-third of all colorectal carcinomas. (25) Hyperplastic polyps account for approximately 30% of all colon polyps (26, 27) and comprise the majority (greater than 70%) of serrated polyps. (26-29) Hyperplastic polyps are usually small (1-5 mm), sessile, and most frequently distributed in the distal colon. (30, 31) They are further subclassified into 3 morphologic subtypes with unique histologic and molecular phenotypes as described below. Sessile serrated adenomas/polyps have been reported to be present in 4% to 9% of all patients undergoing screening colonoscopy (26, 32) and comprise up to 4% to 23% of all serrated lesions. (26, 28, 29) The SSA/Ps are slightly larger than HPs (more than 50% are greater than 5 mm in size), are flat, and are preferentially located in the proximal colon. (26, 30, 31, 33) The SSA/Ps tend to occur more frequently in females. (26, 30) Traditional serrated adenoma is the least common of the serrated lesions, representing approximately 1% to 2% of these lesions, (26-28) and typically occurs in the distal colon.
RISK FACTORS FOR SERRATED POLYPS
In sporadic serrated lesions, both proximal and distal serrated lesions have been shown to be associated with cigarette smoking. (34-41) Folate intake and physical activity are inversely associated with the risk of distal serrated lesions. (42) Nonsteroidal anti-inflammatory drug and calcium use, fiber intake, alcohol intake, high body mass index, and family history of CRC have inconsistent associations with distal serrated lesions. (25) Limited epidemiologic data are available on these other factors and their association with proximal serrated lesions. An association between smoking and serrated polyposis syndrome (SPS) has been reported recently. (42, 43)
HISTOLOGIC CRITERIA FOR DIAGNOSIS OF SERRATED LESIONS
The fourth edition (2010) of the WHO Classification of Tumors of the Digestive System (18) provides a recent consensus on the diagnostic framework for the serrated lesions of the colorectum. In the current review, we include additional specific diagnostic features gathered from the recent national and international clinicopathologic consensus reports and critical appraisals since the WHO publication to further refine the definition of these lesions.
Histologically, HPs exhibit elongated crypts extending from the surface to the muscularis mucosa, tapering from a broad luminal opening to a narrowed base. They show variable serration in the upper segments of the crypts and do not have nuclear atypia or dysplasia (Figure 2, A through D). (10, 18, 25) Their proliferation zone is expanded but normally distributed at the bases of the crypts, where mitotic activity can be appreciated. (10, 44) Three subtypes, although currently not recommended for clinical use, are recognized by their slight variation in cytomorphology, distribution in the colon, and molecular characteristics (18): microvesicular HP (MVHP), goblet cell-rich HP (GCHP), and mucin-poor or mucin-depleted HP (Figure 2). Microvesicular HP and GCHP have been studied in further molecular detail in several articles (Table 1; Figure 2).
These polyps represent the most common subtype of HPs. They occur predominantly in the right side of the colon but are more widely distributed than GCHP. (30) Microvesicular HPs show prominent luminal serration and are composed of epithelial cells with small-droplet mucin, with or without interspersed goblet cells. Their nuclear features are bland (Figure 2). (25) Microvesicular HPs exhibit histologic and molecular overlap with SSA/Ps, and may belong at one end of a molecular continuum with SSA/Ps (Table 1). (45) However, MVHPs are distinguished from SSA/Ps by not having the characteristic architectural abnormalities in the deep portion of the crypts. (45)
Goblet Cell-Rich HP
The GCHPs are the second most common subtype of HP and are predominantly located in the distal colon. They are characterized by a bland-appearing, goblet cell-rich epithelium with fewer serrations and a more tubular architecture than MVHPs (Figure 2). (25)
These are the rarest of HPs, display prominent serration, and are composed of mucin-depleted epithelial cells exhibiting mild nuclear atypia characterized by nuclear enlargement and hyperchromasia without pseudostratification. (25) The mucin depletion and nuclear atypia are surmised to represent a reaction to injury and inflammation. (25)
Sessile Serrated Adenoma/Polyp
Similar to HPs, SSA/Ps show elongation of crypts, prominent serration, and no cytologic dysplasia. However, unlike HPs, the architecture at the bases of SSA/Ps is altered, resulting in features such as broad, boot-shaped, L*shaped, inverse T-shaped, or branched crypts, as well as basal serration, which have been referred to as "architectural dysplasia" (Figure 3, A through F). (46) This architectural distortion is believed to be the result of an abnormally located proliferative zone at the side, rather than the base, of crypts, resulting in both upward and downward growth of epithelium. (10, 44)
In SSA/Ps, cells with goblet cell or gastric-foveolar differentiation that are normally present at the luminal surface can become located at the crypt bases, (46) a feature that has been described as inverted maturation or dysmaturation. In addition, the goblet cells can be dystrophic, a feature that refers to free-floating goblet cells in the epithelium with no apical communication to the lumen and may show inversion of the nucleus toward the lumen. The crypts can also herniate through the muscularis mucosa, giving rise to a pseudoinvasive growth pattern, a feature that can occasionally be seen in HPs as well. (25)
The recommendations from the WHO Classification of Tumours of the Digestive System (18) are that "if more than two or three contiguous crypts demonstrate features of SSA/P, the lesion should be classified as SSA/P." More recently, the recommendation from the expert panel consensus by Rex et al (25) is that one unequivocal architecturally distorted crypt base is sufficient to establish the diagnosis of SSA/P. This recommendation is especially important in the differentiation between MVHP and SSA/P, in which one distorted crypt in an overall MVHP-appearing lesion warrants a diagnosis of SSA/P. (25) Crypt abnormalities appear to have overall good interobserver reproducibility if strict criteria for the recognition of SSA-type crypts are followed. (30) Bettington et al (30) further elaborated that any of the following features are diagnostic of SSA-type crypts: (1) any horizontal growth along the muscularis mucosa; (2) dilatation of the crypt base (basal third of the crypt) such that it is wider than the luminal opening; (3) serration extending into the crypt base; or (4) asymmetric proliferation. Applying these criteria to a single crypt for the diagnosis of SSA/P, the proportion of SSA/P to all colorectal polyps increases to 14.7%. (30)
SSA/P With Cytologic Dysplasia
Different types of dysplasia may arise in sessile serrated adenomas during progression to carcinoma, including conventional adenomatous dysplasia and serrated dysplasia (Figures 3, A through F, and 4, A through F). The most common type of dysplasia is that resembling dysplasia of conventional adenomas characterized by elongated pencillate nuclei with hyperchromasia, nuclear pseudostratification, and amphophilic cytoplasm, with frequent loss of expression of MLH1 by immunohistochemistry (Figure 3). (25) The transition between the cytologically dysplastic epithelium and the nondysplastic SSA/P epithelium can be abrupt, appearing as a collision between 2 disparate lesions, leading to their classification as "mixed hyperplastic adenomatous polyps" or "mixed SSA/P-tubular adenoma" in the past. (46, 47) However, morphologic conventional adenomatous dysplasia arising from SSA/Ps exhibits molecular alterations that are distinct from those of conventional adenomas, and therefore the use of the term mixed polyp may not be appropriate. (9) This conventional adenomatous-type dysplasia may range from low grade to high grade. The significance of this stratification in SSA/Ps is not known at this time but is presumably similar to the progression of lesions seen in the conventional adenoma. Another type of dysplasia, termed serrated dysplasia, can also develop in SSA/Ps. It is characterized by cells with a more cuboidal shape and eosinophilic cytoplasm, enlarged vesicular nuclei, and prominent nucleoli (Figure 4). (18) Some SSA/Ps may also show areas exhibiting cytologic dysplastic features of TSA, (25, 46, 48) which will be discussed in more detail below. Serrated dysplasia in SSA/Ps is frequently characterized by areas that include a cribriform complex pattern that correlates with variably lower levels of expression of MLH1 by immunohistochemistry, ranging from a residual dot-expression pattern to complete loss, suggestive of evolving dysplasia (Figure 4).
Traditional Serrated Adenoma
This type of serrated adenomatous polyp shows complex, occasional filiform growth with ectopic crypt formation and exhibits characteristic cytologic features. (44, 46, 49) The hallmark TSA cells are tall with a pencillate nucleus and eosinophilic cytoplasm (Figure 5, A through D). (46) Recently, the defining feature of TSAs has been suggested to be ectopic crypt formation, in which the crypts have detached from the underlying muscularis mucosa, occurring even at the surface of the polyp, and may develop overall protuberant, villiform architecture (Figure 5). (44) These ectopic crypt formations represent the proliferation zones of TSAs. (44) Occasionally,
TSAs may be goblet cell rich and overall contain less eosinophilic morphology. (25) They may develop conventional or serrated dysplasia, which are presumed markers of progression to carcinoma. Although the serrated dysplasia may resemble that seen in a sessile serrated adenoma, the molecular alterations are disparate, as loss of MLH1 is not a characteristic of TSAs or their associated carcinomas (Figure 6, A through D). (25) In one study, a significant proportion (slightly greater than 50%) of TSAs were described to exhibit areas with features of HPs or SSA/Ps and the possibility that HPs and/or SSA/Ps may be precursor lesions to TSAs has been raised. (8, 16, 50)
SERRATED POLYPS UNCLASSIFIABLE
Assessment of serrated polyps can sometimes be limited by tangential sectioning, severe cautery artifact, and/or a superficial biopsy specimen. (18, 25) Additional deeper sections can often resolve the issue of poor orientation and tangential sectioning and enable assessment of the bases of the polyps. However, in a minority of cases, the serrated polyp remains unclassifiable. Another situation when this problem arises is a serrated polyp with prolapse-type changes, which can alter the morphology at the crypt base. (30)
SERRATED POLYPOSIS SYNDROME
Serrated polyposis syndrome was previously known as hyperplastic polyposis syndrome (51); SPS is the elected terminology for this heterogeneous disease condition in the 2010 WHO publication. (18, 52) In the mid-1990s, Torlakovic and Snover (53) described serrated adenomatous polyposis in which adenocarcinoma was found to arise from polyps morphologically resembling sessile serrated adenomas in patients with hyperplastic polyposis. The risk of carcinoma is well recognized in SPS. The rates of synchronous cancer in SPS have been reported to range from 16% to more than 50%. (43, 52, 54-58)
Polyps in SPS are most often sessile and small, are distributed throughout the colon, and comprise predominantly SSA/Ps and MVHPs. Morphologically, conventional adenomatous dysplasia may be present in these polyps, and, when it involves the entire SSA/P, the lesion may resemble a conventional adenoma. SPS is nearly equally distributed among males and females, with a median age of diagnosis between 42 and 66 years. (43, 52, 54, 55, 59)
At least 2 clinical subtypes of serrated polyposis have been identified. (18) Type 1 contains multiple, more proximal, and larger SSA/Ps. In type 2, numerous small HPs are present throughout the colon. Cancer risk is substantial for type 1, but uncertain for type 2, (18) although some studies have reported similar cancer risk for the 2 subtypes. (59)
A set of empirical diagnostic criteria has been devised to capture and identify patients with this syndrome:
1. At least 5 serrated polyps proximal to the sigmoid colon, with 2 or more measuring greater than 10 mm in size.
2. Any serrated polyps proximal to the sigmoid colon in an individual who has a first-degree relative diagnosed with serrated polyposis.
3. More than 20 serrated polyps of any size, distributed throughout the colon. (20)
In a recent large prospective study, 44.1% of patients with serrated polyposis had a first-degree relative with a diagnosis of colorectal carcinoma. (60) Furthermore, a significantly elevated relative risk of colorectal carcinoma in first-degree relatives of patients with SPS of 5.4 was reported. (61)
MOLECULAR MECHANISMS AND PATHWAYS UNDERLYING SERRATED POLYPS AND SERRATED PATHWAY CARCINOMAS
As indicated earlier, 3 main molecular genomic and epigenomic pathways have been identified in CRC and precancerous lesions: microsatellite instability secondary to deficient DNA mismatch repair, CpG island methylator phenotype potentially resulting in transcriptional silencing of hypermethylated genes, and chromosomal instability. (11, 62) Each of the above molecular phenotypes has been shown to correlate with characteristic histologic features of specific subtypes of polyps and CRCs. However, with currently available molecular testing alone, it is not yet possible to accurately predict the individual histopathologic subtype of polyps. Further, it is not possible to accurately predict the array of molecular alterations of an individual polyp or cancer based on morphologic assessment alone. Likely this is because of our incomplete knowledge of all necessary molecular players and possible crossover of pathways during the progression of serrated lesions.
Molecular Pathways Underlying Sessile Serrated Adenomas/Polyps
The SSA/Ps progress through what is currently called the serrated carcinogenesis pathway, frequently show activating mutations in BRAF V600E, and infrequently harbor KRAS mutations (Table 1; Figures 1 and 7). The characteristic serrated phenotype results from abnormal cellular proliferation driven by constitutive activation of the MAPK pathway (Figure 1). (9) The MAPK pathway can be activated by mutations in BRAF and RAS. Additionally, in the absence of mutations in one of the aforementioned genes, activation of epidermal growth factor receptor signaling by ligand binding can also activate the MAPK pathway (Figure 1). (15) In addition, BRAF mutations have been shown to occur early in the development of sporadic hyperplastic aberrant crypt foci in humans. In mice, BRAF oncogene was shown to drive an initial burst of MEK-dependent proliferation, leading to the formation of hyperplastic crypts. (63) In colorectal carcinomas, BRAF V600E mutation also correlates strongly with the CIMP-high epigenomic phenotype (Table 1; Figures 1 and 7). (64) Hypermethylation has been reported in the normal mucosa of hyperplastic polyposis patients, suggesting that aberrant methylation is an initiating event in the serrated carcinogenesis pathway. (65) In normal cells, hyperactivation of the MAPK pathway triggers upregulation of p16INK4a-Rb and p53-p21Waf1, inducing cell cycle arrest. (63, 66-69) Conversely, inactivation of p16INK4a, IGFBP7, and checkpoint-related genes by promoter hypermethylation may promote neoplastic progression in hyperplastic/serrated lesions. (70, 71) Interestingly, BRAF V600E is frequently found in MVHPs but not in GCHPs (Table 1; Figures 1 and 7). Accumulated data show that MVHPs and SSA/Ps reveal nearly overlapping molecular patterns when tested for CIMP, MLH1 methylation, and KRAS and BRAF mutations, consistent with the notion that MVHPs are immediate precursors of SSA/Ps (Table 1; Figures 1 and 7). (9) The SSA/Ps can give rise to both microsatellite unstable (MSIH) or MSS cancers (Figure 1). Epigenetic silencing of DNA mismatch repair gene MLH1 via promoter methylation, which leads to the MSIH phenotype, is detected as variably decreased MLH1 expression in dysplastic areas of SSA/P and as uniform loss of expression in invasive MSIH adenocarcinomas (Figures 3 and 4). (72) It is important to note that although MLH1 methylation is detectable early in SSA/Ps, only reduced or lost expression of the gene, which requires extensive methylation, is associated with dysplasia and heralds the committed progression of the serrated cancer pathway to malignancy. In lesions with loss of MLH1, the PMS2 gene, one partner in the stabilizing mutL heterodimer mismatch repair protein, is also lost. (73)
Molecular Pathways Underlying Traditional Serrated Adenomas
The TSAs are a heterogeneous group of polyps that have been shown to potentially be able to progress through all 3 colorectal carcinoma pathways (Figure 1). A subset of TSAs may be characterized by CIMP-high, BRAF mutation, and MSS, in common with some SSA/Ps. However, in a recent study, TSAs have been shown to be generally distinct from the sessile serrated pathway of colorectal carcinogenesis. (71) Importantly, the DNA mismatch repair proteins are intact in all cases of TSA, including those with cytologic dysplasia and carcinoma (Figure 6). (74)
Colorectal polyps may also progress through an alternative pathway. In this pathway, lesions are characterized by KRAS mutations and silencing of the DNA repair gene methylguanine methyltransferase (MGMT) by promoter hypermethylation, CIMP-low mutation, and MSS. (9) This pathway underlies TSAs as well as some tubulovillous adenomas (Figure 1).
Furthermore, EGFR activation and mutations in the PIK3/ AKT/mTOR pathway can promote polyp progression through either the sessile serrated pathway or the alternative pathway. (75) Specifically, mutations in PIK3CA exon 20 and PTEN have been shown to significantly associate with the sessile-serrated pathway including MSIH, CIMP-high, and BRAF mutations, whereas PIK3CA exon 9 mutations are overrepresented in MSS/CIMP-low/KRAS mutant cancers. (75, 76) Day et al (75) showed PIK3CA and PTEN mutations in approximately 12% and 6% of colon cancers, respectively, and showed that alterations in PI3K pathway signaling are common in proximal colon cancers. Further, Whitehall et al reported that among polyps, PIK3CA mutations were exclusively seen in tubulovillous adenomas. (76)
GUIDELINES FOR SURVEILLANCE OF SERRATED POLYPS
Screening guidelines for colorectal carcinoma based on the risk stratification of conventional adenomas are well accepted in clinical practice. However, recommendations have only recently been established for serrated lesions. (25, 77)
Patients with conventional adenomas are risk stratified based on the number, size, grade of dysplasia, and presence of significant villous architecture of the polyps. In the most current (2012) consensus update on colorectal carcinoma by the US Multi-Society Task Force, (77) patients with low-risk adenomas (fewer than 3 tubular adenomas, each less than 10 mm in diameter, and exhibiting low-grade dysplasia only) are surveyed at a 5- to 10-year interval, whereas patients with high-risk adenomas (3 or more adenomas, any adenoma of size 10 mm or larger, any adenoma exhibiting areas of high-grade dysplasia, or any adenoma exhibiting significant villous histology) are surveyed at 3-year intervals. An even shorter surveillance interval is recommended for patients with more than 10 adenomas. (77)
As the classification, recognition, and detection of serrated lesions are still being refined, limited prospective data are available for surveillance of serrated polyps and prevention of colorectal carcinoma. Currently, the level of evidence for these recommendations is only low to moderate, as determined by expert consensus. (25, 77)
The association of serrated polyps with risk of cancer has come from studies showing that proximal and large serrated polyps are associated with synchronous neoplasia at screening colonoscopy and with interval neoplasia at follow-up colonoscopy. (37,78) O'Brien et al (6) showed that the molecular features of carcinomas arising from serrated lesions overlapped, in a study wherein the residual serrated adenoma was compared with the adjacent invasive adenocarcinoma ("serrated carcinoma"), with some cases in which both the serrated adenoma and the adenocarcinoma were MSIH with matching loss of MLH1 by immunohistochemistry and other cases with a pattern of negative microsatellite instability in both the cancer and serrated polyp. Several independent investigators reported that detection of serrated polyps 10 mm or greater in size at screening colonoscopy were associated with an increased risk for synchronous carcinoma or high-grade adenoma elsewhere in the colon. (37, 78-80) Histology corresponding to a sessile serrated adenoma, proximal location, and presence of cytologic dysplasia are further listed as factors associated with higher risk of colorectal carcinoma. (77)
The consensus update on colorectal carcinoma by the US Multi-Society Task Force recommends treating a sessile serrated polyp of size 10 mm or greater and a sessile serrated polyp with cytologic dysplasia as high-risk adenoma (77) and managing serrated polyps that are smaller than 10 mm without cytologic dysplasia as low-risk adenoma (Table 2). (77) Because of interobserver variation, some expert pathologists maintain that proximal colon serrated lesions larger than 10 mm should be diagnosed as sessile serrated polyps, even when the histology resembles that of an HP. (74) As discussed previously, the risk of developing carcinoma is significant in patients with SPS. It is recommended that patients with the diagnosis of SPS undergo annual surveillance colonoscopy (Tables 2 and 3). (77)
A separate set of recommendations from an expert panel regarding the postpolypectomy surveillance of serrated lesions was published in 2012 by Rex et al. (25) In addition to the intervals proposed by the US Multi-Society Task Force, this panel of experts advocates for even closer surveillance of serrated polyps meeting certain conditions (Table 3). Hyperplastic polyps larger than 5 mm and/or greater than 3 in number proximal to the sigmoid colon are to be managed as the same as low-risk adenoma; sessile serrated adenomas greater than 2 in number are to be managed as high-risk adenoma. (27) Furthermore, 2 or more large sessile serrated adenomas and sessile serrated adenomas with cytologic dysplasia can be followed more closely than the 3-year interval prescribed for high-risk adenomas. (25) In their recommendations, the surveillance intervals for traditional serrated adenoma are the same as those for sessile serrated adenoma. A 5-year surveillance interval for first-degree relatives of patients with SPS is also delineated. The consensus opinion is for the complete removal of all serrated lesions except for diminutive (less than 5 mm) rectal sigmoid serrated polyps. (25)
In light of the molecular features that characterize serrated lesions (Table 4), immunohistochemistry for MLH1 may be useful to support the diagnosis of SSA/P with cytologic dysplasia. The majority of SSA/Ps with foci of dysplasia will show loss of expression of MLH1, indicating development of MSIH. In our practice we stain for PMS2 in parallel, because there is concomitant loss of PMS2 in true loss of expression of MLH1. BRAF V600E mutation is supportive of a diagnosis of sessile serrated adenoma but is not independently diagnostic. The standard levels and extension of methylation that correlate with expression of MLH1 have not yet been established in serrated lesions (Table 1).
Critical review of literature and compilation of data reveal intricate interactions among the key molecular players in the serrated polyps. Although our understanding of the molecular pathways of serrated lesions continues to evolve, a combination of histologic assessment, immunohistochemistry, and epi/genomic studies allows for the classification, diagnosis, and prognostication of these entities.
(1.) Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer I Clin. 2014; 64(2):104-117.
(2.) Markowitz SD, Bertagnolli MM. Molecular origins of cancer: molecular basis of colorectal cancer. N Engl I Med. 2009; 361(25):2449-2460.
(3.) Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990; 61(5):759-767.
(4.) Makinen MJ. Colorectal serrated adenocarcinoma. Histopathology. 2007; 50(1):131-150.
(5.) Noffsinger AE. Serrated polyps and colorectal cancer: new pathway to malignancy. Annu Rev Pathol. 2009; 4:343-364.
(6.) O'Brien MJ, Yang S, Mack C, et al. Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points. Am I Surg Pathol. 2006; 30(12):1491-1501.
(7.) O'Brien MJ. Hyperplastic and serrated polyps of the colorectum. Gastroenterol Clin North Am. 2007; 36(4):947-968, viii.
(8.) Groff RJ, Nash R, Ahnen DJ. Significance of serrated polyps of the colon. Curr Gastroenterol Rep. 2008; 10(5):490-498.
(9.) Leggett B, Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology. 2010; 138(6):2088-2100.
(10.) Snover DC. Update on the serrated pathway to colorectal carcinoma. Hum Pathol. 2011; 42(1):1-10.
(11.) Pancione M, Remo A, Colantuoni V. Genetic and epigenetic events generate multiple pathways in colorectal cancer progression. Pathol Res Int. 2012; 2012:509348.
(12.) Simons CC, Hughes LA, Smits KM, et al. A novel classification of colorectal tumors based on microsatellite instability, the CpG island methylator phenotype and chromosomal instability: implications for prognosis. Ann Oncol. 2013; 24(8): 2048-2056.
(13.) Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012; 487(7407):330-337.
(14.) Jass JR, Baker K, Zlobec I, et al. Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a "fusion" pathway to colorectal cancer. Histopathology. 2006; 49(2):121-131.
(15.) Bongers G, Muniz LR, Pacer ME, et al. A role for the epidermal growth factor receptor signaling in development of intestinal serrated polyps in mice and humans. Gastroenterology. 2012; 143(3):730-740.
(16.) Kim MJ, Lee EJ, Suh JP, et al. Traditional serrated adenoma of the colorectum: clinicopathologic implications and endoscopic findings of the precursor lesions. Am I Clin Pathol. 2013; 140(6):898-911.
(17.) Longacre TA, Fenoglio-Preiser CM. Mixed hyperplastic adenomatous polyps/serrated adenomas: a distinct form of colorectal neoplasia. Am I Surg Pathol. 1990; 14(6):524-537.
(18.) Snover D, 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. 4th ed. Lyon, France: IARC Press; 2010:160-165. World Health Organization Classification of Tumours; vol 3.
(19.) Payne SR, Church TR, Wandell M, et al. Endoscopic detection of proximal serrated lesions and pathologic identification of sessile serrated adenomas/polyps vary on the basis of center. Clin Gastroenterol Hepatol. 2014; 12(7):1119-1126.
(20.) Tadros M, Anderson JC. Serrated polyps: clinical implications and future directions. Curr Gastroenterol Rep. 2013; 15(9):342.
(21.) Clark JC, Collan Y, Eide TJ, et al. Prevalence of polyps in an autopsy series from areas with varying incidence of large-bowel cancer. Int I Cancer. 1985; 36(2):179-186.
(22.) Vatn MH, Stalsberg H. The prevalence of polyps of the large intestine in Oslo: an autopsy study. Cancer. 1982; 49(4):819-825.
(23.) Johannsen LG, Momsen O, Jacobsen NO. Polyps of the large intestine in Aarhus, Denmark: an autopsy study. Scand I Gastroenterol. 1989; 24(7):799-806.
(24.) Williams AR, Balasooriya BA, Day DW. Polyps and cancer of the large bowel: a necropsy study in Liverpool. Gut. 1982; 23(10):835-842.
(25.) Rex DK, Ahnen DJ, Baron JA, et al. Serrated lesions of the colorectum: review and recommendations from an expert panel. Am I Gastroenterol. 2012; 107(9):1315-1329; quiz 1314, 1330.
(26.) 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(5):1400-1407.
(27.) Carr NJ, Mahajan H, Tan KL, Hawkins NJ, Ward RL. Serrated and non-serrated polyps of the colorectum: their prevalence in an unselected case series and correlation of BRAF mutation analysis with the diagnosis of sessile serrated adenoma. I Clin Pathol. 2009; 62(6):516-518.
(28.) Lu FI, van Niekerk de W, Owen D, Tha SP, Turbin DA, Webber DL. Longitudinal outcome study of sessile serrated adenomas of the colorectum: an increased risk for subsequent right-sided colorectal carcinoma. Am I Surg Pathol. 2010; 34(7):927-934.
(29.) Higuchi T, Sugihara K, Jass JR. Demographic and pathological characteristics of serrated polyps of colorectum. Histopathology. 2005; 47(1):32-40.
(30.) Bettington M, Walker N, Rosty C, et al. Critical appraisal of the diagnosis of the sessile serrated adenoma. Am I Surg Pathol. 2014; 38(2):158-166.
(31.) Torlakovic E, Skovlund E, Snover DC, Torlakovic G, Nesland JM. Morphologic reappraisal of serrated colorectal polyps. Am I Surg Pathol. 2003; 27(1):65-81.
(32.) Pai RK, Hart J, Noffsinger AE. Sessile serrated adenomas strongly predispose to synchronous serrated polyps in non-syndromic patients. Histopathology. 2010; 56(5):581-588.
(33.) Lash RH, Genta RM, Schuler CM. Sessile serrated adenomas: prevalence of dysplasia and carcinoma in 2139 patients. I Clin Pathol. 2010; 63(8):681-686.
(34.) Ji BT, Weissfeld JL, Chow WH, Huang WY, Schoen RE, Hayes RB. Tobacco smoking and colorectal hyperplastic and adenomatous polyps. Cancer Epidemiol Biomarkers Prev. 2006; 15(5):897-901.
(35.) Paskett ED, Reeves KW, Pineau B, et al. The association between cigarette smoking and colorectal polyp recurrence (United States). Cancer Causes Control. 2005; 16(9):1021-1033.
(36.) Wallace K, Grau MV, Ahnen D, et al. The association of lifestyle and dietary factors with the risk for serrated polyps of the colorectum. Cancer Epidemiol Biomarkers Prev. 2009; 18(8):2310-2317.
(37.) Schreiner MA, Weiss DG, Lieberman DA. Proximal and large hyperplastic and nondysplastic serrated polyps detected by colonoscopy are associated with neoplasia. Gastroenterology. 2010; 139(5):1497-1502.
(38.) Anderson JC, Rangasamy P, Rustagi T, et al. Risk factors for sessile serrated adenomas. J Clin Gastroenterol. 2011; 45(8):694-699.
(39.) Shrubsole MJ, Wu H, Ness RM, Shyr Y, Smalley WE, Zheng W. Alcohol drinking, cigarette smoking, and risk of colorectal adenomatous and hyperplastic polyps. Am J Epidemiol. 2008; 167(9):1050-1058.
(40.) Morimoto LM, Newcomb PA, Ulrich CM, Bostick RM, Lais CJ, Potter JD. Risk factors for hyperplastic and adenomatous polyps: evidence for malignant potential? Cancer Epidemiol Biomarkers Prev. 2002; 11(10, pt 1):1012-101 8.
(41.) Rustagi T, Rangasamy P, Myers M, et al. Sessile serrated adenomas in the proximal colon are likely to be flat, large and occur in smokers. World J Gastroenterol. 2013; 19(32):5271-5277.
(42.) Martinez ME, McPherson RS, Levin B, Glober GA. A case-control study of dietary intake and other lifestyle risk factors for hyperplastic polyps. Gastroenterology. 1997; 113(2):423-429.
(43.) Jasperson KW, Kanth P, Kirchhoff AC, et al. Serrated polyposis: colonic phenotype, extracolonic features, and familial risk in a large cohort. Dis Colon Rectum. 2013; 56(11):1211-1216.
(44.) Torlakovic EE, Gomez JD, Driman DK, et al. Sessile serrated adenoma (SSA) vs. traditional serrated adenoma (TSA). Am J Surg Pathol. 2008; 32(1): 21-29.
(45.) Mesteri I, Bayer G, Meyer J, et al. Improved molecular classification of serrated lesions of the colon by immunohistochemical detection of BRAF V600E. Mod Pathol. 2014; 27(1):135-144.
(46.) Snover DC, Jass JR, Fenoglio-Preiser C, Batts KP. Serrated polyps of the large intestine: a morphologic and molecular review of an evolving concept. Am J Clin Pathol. 2005; 124(3):380-391.
(47.) Urbanski SJ, Kossakowska AE, Marcon N, Bruce WR. Mixed hyperplastic adenomatous polyps--an underdiagnosed entity: report of a case of adenocarcinoma arising within a mixed hyperplastic adenomatous polyp. Am J Surg Pathol. 1984; 8(7):551-556.
(48.) 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(3):287-302.
(49.) Yantiss RK, Oh KY, Chen YT, Redston M, Odze RD. Filiform serrated adenomas: a clinicopathologic and immunophenotypic study of 18 cases. Am J Surg Pathol. 2007; 31(8):1238-1245.
(50.) 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(5):667-675.
(51.) Young J, Jass JR. The case for a genetic predisposition to serrated neoplasia in the colorectum: hypothesis and review of the literature. Cancer Epidemiol Biomarkers Prev. 2006; 15(10):1778-1784.
(52.) 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(3):434-442.
(53.) Torlakovic E, Snover DC. Serrated adenomatous polyposis in humans. Gastroenterology. 1996; 110(3):748-755.
(54.) Miwata T, Hiyama T, Oka S, et al. Clinicopathologic features of hyperplastic/serrated polyposis syndrome in Japan. J Gastroenterol Hepatol. 2013; 28(11):1693-1698.
(55.) Boparai KS, Mathus-Vliegen EM, Koornstra JJ, et al. Increased colorectal cancer risk during follow-up in patients with hyperplastic polyposis syndrome: a multicentre cohort study. Gut. 2010; 59(8):1094-1100.
(56.) Rubio CA, Stemme S, Jaramillo E, Lindblom A. Hyperplastic polyposis coli syndrome and colorectal carcinoma. Endoscopy. 2006; 38(3):266-270.
(57.) Hyman NH, Anderson P, Blasyk H. Hyperplastic polyposis and the risk of colorectal cancer. Dis Colon Rectum. 2004; 47(12):2101-2104.
(58.) Leggett BA, Devereaux B, Biden K, Searle J, Young J, Jass J. Hyperplastic polyposis: association with colorectal cancer. Am J Surg Pathol. 2001; 25(2):177-184.
(59.) Kalady MF, Jarrar A, Leach B, et al. Defining phenotypes and cancer risk in hyperplastic polyposis syndrome. Dis Colon Rectum. 2011; 54(2):164-170.
(60.) Oquinena S, Guerra A, Pueyo A, et al. Serrated polyposis: prospective study of first-degree relatives. Eur J Gastroenterol Hepatol. 2013; 25(1):28-32.
(61.) Boparai KS, ReitsmaJB, Lemmens V, et al. Increased colorectal cancer risk in first-degree relatives of patients with hyperplastic polyposis syndrome. Gut. 2010; 59(9):1222-1225.
(62.) Leedham S, East JE, Chetty R. Diagnosis of sessile serrated polyps/ adenomas: what does this mean for the pathologist, gastroenterologist and patient? J Clin Pathol. 2013; 66(4):265-268.
(63.) Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev. 2010; 24(22):2463-2479.
(64.) Rosenberg DW, Yang S, Pleau DC, et al. Mutations in BRAF and KRAS differentially distinguish serrated versus non-serrated hyperplastic aberrant crypt foci in humans. Cancer Res. 2007; 67(8):3551-3554.
(65.) Minoo P, Baker K, Goswami R, et al. Extensive DNA methylation in normal colorectal mucosa in hyperplastic polyposis. Gut. 2006; 55(10):1467-1474.
(66.) Carragher LA, Snell KR, Giblett SM, et al. V600EBraf induces gastrointestinal crypt senescence and promotes tumour progression through enhanced CpG methylation of p16INK4a. EMBO Mol Med. 2010; 2(11):458-471.
(67.) Feng Y, Bommer GT, Zhao J, et al. Mutant KRAS promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool. Gastroenterology. 2011; 141(3):1003-1013.e1-e10.
(68.) Bennecke M, Kriegl L, Bajbouj M, et al. Ink4a/Arf and oncogene-induced senescence prevent tumor progression during alternative colorectal tumorigenesis. Cancer Cell. 2010; 18(2):135-146.
(69.) Haigis KM, Kendall KR, Wang Y, et al. Differential effects of oncogenic K- Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat Genet. 2008; 40(5):600-608.
(70.) Minoo P, Jass JR. Senescence and serration: a new twist to an old tale. J Pathol. 2006; 210(2):137-140.
(71.) Hinoue T, Weisenberger DJ, Pan F, et al. Analysis of the association between CIMP and BRAF in colorectal cancer by DNA methylation profiling. PLoS One. 2009; 4(12):e8357.
(72.) 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(4):564571.
(73.) Gologan A, Sepulveda AR. Microsatellite instability and DNA mismatch repair deficiency testing in hereditary and sporadic gastrointestinal cancers. Clin Lab Med. 2005; 25(1):179-196.
(74.) Tsai JH, Liau JY, Lin YL, et al. Traditional serrated adenoma has two pathways of neoplastic progression that are distinct from the sessile serrated pathway of colorectal carcinogenesis. Mod Pathol. 2014; 27(10):1375-1385.
(75.) Day FL, Jorissen RN, Lipton L, et al. PIK3CA and PTEN gene and exon mutation-specific clinicopathologic and molecular associations in colorectal cancer. Clin Cancer Res. 2013; 19(12):3285-3296.
(76.) Whitehall VL, Rickman C, Bond CE, et al. Oncogenic PIK3CA mutations in colorectal cancers and polyps. Int J Cancer. 2012; 131(4):813-820.
(77.) Lieberman DA, Rex DK, Winawer SJ, et al. Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2012; 143(3): 844-857.
(78.) Hiraoka S, Kato J, Fujiki S, et al. The presence of large serrated polyps increases risk for colorectal cancer. Gastroenterology. 2010; 139(5):1503-1510, 1510.e1-1510.e3.
(79.) Li D, Jin C, McCulloch C, et al. Association of large serrated polyps with synchronous advanced colorectal neoplasia. Am J Gastroenterol. 2009; 104(3): 695-702.
(80.) Alvarez C, Andreu M, Castells A, et al. Relationship of colonoscopy- detected serrated polyps with synchronous advanced neoplasia in average-risk individuals. Gastrointest Endosc. 2013; 78(2):333-341.e1.
(81.) Sandmeier D, Benhattar J, Martin P, Bouzourene H. Serrated polyps of the large intestine: a molecular study comparing sessile serrated adenomas and hyperplastic polyps. Histopathology. 2009; 55(2):206-213.
(82.) Kambara T, Simms LA, Whitehall VL, et al. BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut. 2004; 53(8):1137-1144.
(83.) Kim KM, Lee EJ, Ha S, et al. Molecular features of colorectal hyperplastic polyps and sessile serrated adenoma/polyps from Korea. Am J Surg Pathol. 2011; 35(9):1274-1286.
(84.) Kim YH, Kakar S, Cun L, Deng G, Kim YS. Distinct CpG island methylation profiles and BRAF mutation status in serrated and adenomatous colorectal polyps. Int J Cancer. 2008; 123(11):2587-2593.
(85.) Yang S, Farraye FA, Mack C, Posnik O, O'Brien MJ. BRAF and KRAS mutations in hyperplastic polyps and serrated adenomas of the colorectum: relationship to histology and CpG island methylation status. Am J Surg Pathol. 2004; 28(11):1452-1459.
Hui-Min Yang, MD; James M. Mitchell, MD; Jorge L. Sepulveda, MD, PhD; Antonia R. Sepulveda, MD, PhD
Accepted for publication November 7, 2014.
From the Department of Pathology and Cell Biology, Columbia University, New York, New York.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Antonia R. Sepulveda, MD, PhD, Department of Pathology and Cell Biology, Columbia University Medical Center, 630 W 168th St, VC-14 RM 212, New York, NY 10032 (e-mail: email@example.com).
Caption: Figure 1. Diagram representing the main pathways and molecular alterations of sessile serrated neoplasia, conventional adenomatous pathway, and alternative pathway. Abbreviations: APCm, mutated APC gene; BRAFm, mutated BRAF gene; BRAFwt, BRAF wild type; CIMP, CpG island methylator phenotype; CIMPH, CIMP high; CIMPL, CIMP low; CIMP-, CIMP negative; CIN, chromosomal instability; DNMT3, DNA methyltransferase-3; [IGFBP.sup.CG], IGFBP methylation; KRASm, mutated KRAS gene; [MGMT.sup.CG], MGMT methylation; [MLH1.sup.CG], MLH1 methylation; MSIH, microsatellite unstable; MSS, microsatellite stable; MVHP, microvesicular hyperplastic polyp; [P16.sup.CG], P16 methylation; SSA/P, sessile serrated adenoma/polyp; TA, tubular adenoma; TSA, traditional serrated adenoma; TVA, tubulovillous adenoma.
Caption: Figure 2. Cytomorphologic and architectural features of microvesicular hyperplastic polyp (A and B) and goblet cell hyperplastic polyp (C and D) (hematoxylin-eosin, original magnification3200 [A through D]).
Caption: Figure 3. Cytomorphologic and architectural features that characterize sessile serrated adenoma/polyp (SSA/P) (A through C). Focus of conventional dysplasia arising in SSA/P (D). Immunohistochemistry for MLH1 shows preserved expression in a nondysplastic area of SSA/P (E) and a focus of adenomatous type dysplasia with complete loss of MLH1 expression (F) (hematoxylin-eosin, original magnification X200 [A through D]; immunohistochemical stain for MLH1, original magnification X200 [E and F]).
Caption: Figure 4. Dysplasia in sessile serrated adenoma/polyp. Cytomorphologic and architectural features that characterize serrated dysplasia (A and B) or adenomatous type dysplasia (D and E), with loss of expression of MLH1 in the dysplastic epithelium (E). Immunohistochemistry for MLH1 shows progressive loss of expression in a focus of serrated dysplasia (C) with residual expression in a dot pattern shown at high power in (F) (hematoxylineosin, original magnification X200 [A, B, and D]; immunohistochemical stain for MLH1, original magnification X200 [C, E, and F]).
Caption: Figure 5. Cytomorphologic and architectural features that characterize traditional serrated adenomas. Epithelial lining characterized by columnar cells with a pencillate nucleus and eosinophilic cytoplasm are typical of traditional serrated adenomas (A, C, and D). Ectopic crypt formation, in which the crypts have detached from the underlying muscularis mucosa, are seen here as short crypt structures along the surface of the polyp (B) (hematoxylin-eosin, original magnification X200 [A through D]).
Caption: Figure 6. Progressive dysplasia in a traditional serrated adenoma (TSA). Typical TSA epithelium (A), foci of low- and high-grade adenomatous dysplasia elsewhere in the polyp (B), and invasive adenocarcinoma arising from this TSA (C). Preserved expression of MLH1 in dysplastic areas of the polyp (D) (hematoxylin-eosin, original magnification X200 [A through C]; immunohistochemical stain for MLH1, original magnification X200 [D]).
Caption: Figure 7. Frequency of molecular alterations in hyperplastic polyps (goblet cell hyperplastic polyps [GCHP], and microvesicular hyperplastic polyps [MVHP]), sessile serrated adenoma/polyps (SSA) and traditional serrated adenomas (TSA). Data were collected from the published literature (Table 1) where the sessile serrated adenoma/polyp terminology was used. Weighted averages of frequency of each molecular alteration were calculated to generate the graph. Abbreviations: CIMP-H, CpG island methylator phenotype high; CIMP-L, CpG island methylator phenotype low.
Please Note: Illustration(s) are not available due to copyright restrictions.
Table 1. Frequency of Molecular Alterations in Serrated Lesions (a) Serrated Source, y No. of KRAS BRAF Lesion Cases HP Sandmeier et al, (81) 2009 12 17 83 Kim et al, (16) 2013 20 20 50 Kambara et al, (82) 2004 27 30 19 Jass et al, (14) 2006 49 4 67 GCHP Kim et al, (83) 201 1 11 73 0 Kim et al, (84) 2008 12 8 75 Yang et al, (85) 2004 13 46 23 O'Brien et al, (6) 2006 14 43 21 Spring et al, (26) 2006 66 50 20 MVHP Kim et al, (83) 2011 30 17 67 Kim et al, (84) 2008 32 6 88 Yang et al, (85) 2004 38 13 76 O'Brien et al, (6) 2006 38 13 76 Spring et al, (26) 2006 54 11 70 SSA/P Kambara et al, (82) 2004 16 0 75 Sandmeier et al, (81) 2009 16 25 63 Kim et al, (83) 2011 20 10 50 O'Brien et al, (6) 2006 29 7 83 Jass et al, (14) 2006 32 3 81 Kim et al, (84) 2008 32 8 81 Spring et al, (26) 2006 36 8 78 Yang et al, (85) 2004 104 19 67 TSA Jass et al, (14) 2006 15 27 33 Kim et al, (16) 2013 23 44 44 O'Brien et al, (6) 2006 29 24 62 Spring et al, (26) 2006 3 0 66 Kim et al, (84) 2008 30 17 76 Kambara et al, (82) 2004 5 20 20 MDHP/MPHP Kim et al, (83) 2011 4 25 25 Spring et al, (26) 2006 7 43 57 SSA/D Kim et al, (83) 2011 34 15 68 TSA/D Kim et al, (16) 2013 84 31 58 Serrated Source, y CIMP-L CIMP-H Lesion HP Sandmeier et al, (81) 2009 Kim et al, (16) 2013 Kambara et al, (82) 2004 Jass et al, (14) 2006 GCHP Kim et al, (83) 201 1 73 18 Kim et al, (84) 2008 75 8 Yang et al, (85) 2004 31 15 O'Brien et al, (6) 2006 14 Spring et al, (26) 2006 MVHP Kim et al, (83) 2011 20 73 Kim et al, (84) 2008 41 41 Yang et al, (85) 2004 21 47 O'Brien et al, (6) 2006 47 Spring et al, (26) 2006 SSA/P Kambara et al, (82) 2004 Sandmeier et al, (81) 2009 Kim et al, (83) 2011 20 75 O'Brien et al, (6) 2006 76 Jass et al, (14) 2006 Kim et al, (84) 2008 47 44 Spring et al, (26) 2006 Yang et al, (85) 2004 19 59 TSA Jass et al, (14) 2006 Kim et al, (16) 2013 O'Brien et al, (6) 2006 79 Spring et al, (26) 2006 Kim et al, (84) 2008 47 43 Kambara et al, (82) 2004 MDHP/MPHP Kim et al, (83) 2011 25 75 Spring et al, (26) 2006 SSA/D Kim et al, (83) 2011 18 77 TSA/D Kim et al, (16) 2013 Serrated Source, y MLH1 Lesion Methylation HP Sandmeier et al, (81) 2009 8 Kim et al, (16) 2013 Kambara et al, (82) 2004 Jass et al, (14) 2006 GCHP Kim et al, (83) 201 1 46 Kim et al, (84) 2008 8 Yang et al, (85) 2004 O'Brien et al, (6) 2006 14 Spring et al, (26) 2006 MVHP Kim et al, (83) 2011 77 Kim et al, (84) 2008 28 Yang et al, (85) 2004 O'Brien et al, (6) 2006 40 Spring et al, (26) 2006 SSA/P Kambara et al, (82) 2004 Sandmeier et al, (81) 2009 38 Kim et al, (83) 2011 75 O'Brien et al, (6) 2006 72 Jass et al, (14) 2006 Kim et al, (84) 2008 16 Spring et al, (26) 2006 Yang et al, (85) 2004 TSA Jass et al, (14) 2006 Kim et al, (16) 2013 O'Brien et al, (6) 2006 48 Spring et al, (26) 2006 Kim et al, (84) 2008 3 Kambara et al, (82) 2004 MDHP/MPHP Kim et al, (83) 2011 25 Spring et al, (26) 2006 SSA/D Kim et al, (83) 2011 74 TSA/D Kim et al, (16) 2013 Abbreviations: CIMP-H, CpG island methylator phenotype high; CIMP-L, CpG island methylator phenotype low; GCHP, goblet cell-rich HP; HP, hyperplastic polyp; MDHP/MPHP, mucin-depleted/mucin-poor HP; MVHP, microvesicular HP; SSA/D, SSA/P with dysplasia; SSA/P sessile serrated adenoma/polyp; TSA, traditional serrated adenoma; TSA/D, TSA with dysplasia. (a) Weighted averages represented as percentage of cases showing alterations: KRAS or BRAF mutations; CIMP-L or CIMP-H; MLH1 gene CpG methylation. Empty cells indicate not tested. Only left-sided HPs and SSA/Ps had KRAS mutation. (81) Immunohistochemistry did not show loss of MLH1 in any HPs, SSA/Ps, or TSAs. (84) In TSAs and HPs both BRAF and KRAS mutations were negative in 11% and 30% of cases, respectively. (16) The frequency of KRAS or BRAF mutation in TSA with conventional dysplasia was not significantly different from those without conventional dysplasia. (16) Table 2. Recommendations for Surveillance Intervals in Patients With Serrated Lesions in the Colon and Rectum, Based on the Consensus Update by the US Multi-Society Task Force on Colorectal Cancer (a) Baseline Colonoscopy Interval, y No Polyps 10 Small (<10 mm) HPs in rectosigmoid 10 SSA/P <10 mm and without dysplasia 5 SSA/P [greater than or equal to] 10 mm 3 SSA/P with dysplasia 3 TSA 3 SPS 1 Abbreviations: HP, hyperplastic polyp;SPS, serrated polyposis syndrome;SSA/P, sessile serrated adenoma/polyp;TSA, traditional serrated adenoma. (a) Reprinted with permission from Elsevier from Lieberman DA, Rex DK, Winawer SJ, et al. (77) Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology, 2012;143(3)844-857. Table 3. Recommendations for Surveillance Intervals in Patients With Serrated Lesions in the Colon and Rectum, Based on the Review and Recommendations From an Expert Panel (a) Polyp Type Size Number HP <10 mm Any [less than or equal [less than or to] 5 mm equal to] 3 Any >3 >5 mm >1 SSA/P or TSA <10 mm [less than or equal to] 2 [greater than or 1 equal to] 10 mm <10 mm >2 [greater than or [greater than or equal to] 10 mm equal to] 2 SSA/P with dysplasia Any Any SPS (b) Polyp Type Location Interval, y HP Rectosigmoid 10 Proximal to sigmoid 10 5 5 SSA/P or TSA Any 5 3 3 1-3 SSA/P with dysplasia 1-3 SPS (b) 1 Abbreviations: HP, hyperplastic polyp;SPS, serrated polyposis syndrome;SSA/P, sessile serrated adenoma/polyp;TSA, traditional serrated adenoma. (a) Reprinted from Rex et al, (25) Am J Gastroenterol, 2012, by permission from Macmillan Publishers Ltd. (b) Patients with SPS are recommended to have annual surveillance. First-degree relatives of patients with SPS should start surveillance colonoscopy at age 40 or 10 years younger than the age of diagnosis of the affected relative, at an interval of every 5 years. Table 4. Molecular Features of Serrated Adenomas (a) Lesion CIMP-H MLH1 MSI/MLH1 BRAF KRAS Methylation Loss Mutation Mutation SSA/P 3+ 2+ - 3+ - SSA/P with 3+ 2+ 2+ 3+ - cytologic dysplasia TSA 2+ 1 + - 1+ 1+ Abbreviations: CIMP-H, CpG island methylator phenotype high; MSI, microsatellite instability; SSA/P, sessile serrated adenoma/polyp; TSA, traditional serrated adenoma. (a) Frequency of molecular alteration: 3+, extensively present; 2+, generally present; 1+, present in a subset; -, not typically present. Modified from Rex et al, 25 Am J Gastroenterol, 2012, by permission from Macmillan Publishers Ltd.
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|Author:||Yang, Hui-Min; Mitchell, James M.; Sepulveda, Jorge L.; Sepulveda, Antonia R.|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Jun 1, 2015|
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