Advances in Anatomic Pathology:
Pathologic Features and Biologic Importance of Colorectal Serrated Polyps
Vakiani, Efsevia MD, PhD*; Yantiss, Rhonda K. MD†
*Department of Pathology, Memorial Sloan-Kettering Cancer Center
†Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY
Reprints: Rhonda K. Yantiss, MD, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, 525 East 68th Street, New York 10065, NY (e-mail: email@example.com).
All figures can be viewed online in color at http://www.anatomicpathology.com.
Serrated polyps of the large intestine comprise a heterogeneous group of mucosal lesions that includes nondysplastic polyps, such as hyperplastic polyps and sessile serrated polyps, and polyps that show overt cytologic dysplasia, namely serrated adenomas and mixed hyperplastic/adenomatous polyps. These polyps have received increased recognition over the past 2 decades, as emerging evidence suggests that a subset may be precursors to colorectal carcinomas that lack chromosomal instability. Several investigators have proposed the concept of the “serrated neoplastic pathway” according to which nondysplastic serrated lesions develop progressively severe dysplasia culminating in the development of microsatellite unstable carcinomas that show DNA hypermethylation and BRAF mutations. A subset of hyperplastic polyps and sessile serrated polyps show mutations in the BRAF gene and abnormal DNA methylation, which can, ultimately, affect the promoter regions of key DNA-repair and tumor suppressor genes, such as MLH1 and MGMT, leading to their decreased transcription and microsatellite instability. On the basis of this hypothesis, many authors have proposed that sessile serrated polyps should be treated and surveilled similar to conventional adenomas, although prospective data are lacking. This review describes the clinicopathologic and molecular features of serrated polyps and discusses the current data regarding their biologic significance.
Colorectal carcinoma represents the most frequent type of gastrointestinal malignancy and approximately 150,000 new cases are diagnosed annually.1 Virtually all cases are derived from neoplastic colorectal polyps amenable to endoscopic removal, and, thus, colonoscopy has assumed a major role in colon cancer screening and surveillance. Until recently, colorectal epithelial polyps were divided into 2 broad categories, namely hyperplastic polyps and adenomas. Hyperplastic polyps were defined as nondysplastic lesions composed of crypts with a serrated, or convoluted, growth pattern, whereas adenomas contained dysplastic epithelium with enlarged, hyperchromatic nuclei and showed variable cytologic atypia. However, increasing evidence suggests that serrated colorectal polyps may display morphologic heterogeneity, contain dysplastic epithelium, and, rarely, occur in combination with colonic adenocarcinomas. Serrated polyps also share a constellation of molecular abnormalities, including BRAF or KRAS mutations and DNA hypermethylation at CpG islands within the promoter regions of several genes. The presence of these changes in nondysplastic serrated polyps has led some authors to propose the concept of a “serrated neoplastic pathway,” which implies that these lesions are neoplastic precursors to colonic adenocarcinomas with similar molecular features. The purpose of this review is to discuss the current histologic classification of serrated colorectal polyps, describe their molecular features, and present the available data regarding the biologic importance of these lesions.
MOLECULAR MECHANISMS OF COLORECTAL CARCINOGENESIS
Wnt Signaling and Chromosomal Instability
At least 70% of sporadic colorectal carcinomas harbor biallelic mutations in the APC gene and are probably preceded by tubular or villous (conventional) adenomas that share similar alterations. The APC gene is very large and its protein product plays a pivotal role in Wnt signaling. The APC protein forms a binding complex with β-catenin, glycogen synthase kinase 3 and axin, which results in phosporylation of β-catenin serine and tyrosine residues by glycogen synthase kinase 3, thereby targeting it for ubiquitination and degradation.2 Inactivation of APC disrupts β-catenin degradation and facilitates its translocation to the nucleus where it forms a complex with T-cell factor and lymphoid enhancer factor, leading to transcription of target genes, including c-Myc and cyclin D1.2,3 Colonic neoplasms with APC mutations often show chromosomal instability, which may reflect the combined loss of APC protein-mediated microtubule regulation and defects in genes that regulate sister chromatid cohesion, resulting in abnormal chromosomal segregation and genetic instability.4,5 The APC gene product may also inhibit DNA replication by binding directly to DNA.6 Biallelic inactivation of APC occurs early in the development of conventional adenomas, leading to prolonged cell survival, cell proliferation, progressive chromosomal instability, and loss of heterozygosity.
Mismatch-repair deficiency was originally described in the context of hereditary nonpolyposis colorectal carcinoma (HNPCC) and leads to an accumulation of mutations that result from a failure to correct base pairing errors inherent to DNA replication.7,8 Tumors with mismatch-repair deficiencies commonly show microsatellite instability (MSI) within short nucleotide repeats located in both coding and noncoding DNA regions. MSI is generally evaluated at 5 microsatellite loci and classified as low-frequency (MSI-L), high-frequency (MSI-H), or microsatellite stable depending on the number of loci that demonstrate allelic shifts (1, ≥2, or 0, respectively).9 Patients with HNPCC harbor germline mutations in 1 of 4 mismatch-repair genes: mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), and postmeiotic segregation increased 2 (PMS2), although approximately 90% of cases result from MLH1 or MSH2 mutations.10,11 Sporadic tumors with MSI develop as a result of MLH1 transcriptional inactivation through acquired promoter methylation. They commonly harbor frameshifts in genes with coding mononucleotide repeats (eg, TGFBRII, BAX, MSH3, MSH6, and IGFII) and oncogenic mutations in BRAF, a serine-threonine kinase involved in the ras signal transduction pathway.12 Importantly, many HNPCC-associated colorectal adenomas and cancers harbor mutually exclusive APC or β-catenin abnormalities.13–15 In contrast, disruptions in Wnt signaling are infrequent in sporadic colon cancers with MSI, implying that a nonadenomatous lesion precedes the development of sporadic microsatellite unstable colorectal cancers.16
CpG Island Methylator Phenotype
Although DNA hypermethylation may be limited to the MLH1 promoter, some colonic carcinomas show epigenetic promoter methylation of multiple genes, which is denoted the CpG island methylator phenotype (CIMP).17,18 Promoter methylation represses gene transcription and leads to inactivation of tumor suppressor genes, such as O6-methylguanine-methyltransferase (MGMT), a DNA-repair enzyme, and MLH1, p16, HPP1, and RUNX3.19–21 Carcinomas that show methylation of 2 or more promoters are generally designated as CIMP positive or CIMP high, although the number of genes evaluated and methods used to assess methylation vary widely between different laboratories.22,23 Most studies utilize qualitative assays, such as the methylation-specific polymerase chain reaction, whereas others have used quantitative DNA methylation analysis.18 The CIMP has been linked to a number of clinical and molecular features, including MSI-H, older age, proximal location, female sex, and the presence of V600E point mutations in BRAF.19,20,24–26 The non-neoplastic mucosa associated with these tumors may also show widespread DNA methylation abnormalities, suggesting a role for environmental influences in their genesis.27
Serrated Neoplastic Pathway
The concept of a “serrated neoplastic pathway” has been proposed to explain the development of colon cancers with specific molecular changes, including epigenetic DNA hypermethylation, MSI, and BRAF mutations. This pathway putatively involves several pathogenetically related polyps, namely hyperplastic polyps and sessile serrated polyps, which frequently harbor BRAF mutations and DNA hypermethylation. Presumably, these molecular abnormalities potentiate further genomic hypermethylation that ultimately affects MLH1, MGMT, and other repair genes, culminating in MSI. These later events represent the molecular counterpart to the development of dysplasia in serrated adenomas, mixed hyperplastic/adenomatous polyps, and, ultimately, invasive adenocarcinoma (Fig. 1).
NONDYSPLASTIC SERRATED POLYPS
Hyperplastic polyps are small, sessile mucosal lesions that generally span less than 5 mm and occur most commonly in the distal colorectum.28,29 They have an estimated prevalence of 10% to 15% among adult patients in Western populations and constitute approximately one-quarter of all endoscopically removed polyps, but 80% to 90% of all serrated polyps.30–32 Hyperplastic polyps develop nearly a decade earlier than conventional adenomas and affect patients in the fifth and sixth decades of life, but do not show a significant association with increasing age.33,34 These lesions occur more commonly in patients with a history of smoking, alcohol consumption, and low dietary folate, whereas sustained use of nonsteroidal anti-inflammatory drugs may reduce their development.29,33,35
Hyperplastic polyps are composed of crypts with a serrated architecture that increase in diameter as they open onto the surface of the polyp (Fig. 2A). They contain a mixed population of goblet cells and nongoblet mucinous epithelial cells with abundant eosinophilic cytoplasm, and may display a mild degree of cytologic atypia, especially in the lower third of the crypts, but overt dysplasia is lacking. Some hyperplastic polyps contain multinucleated epithelial cells that should not be mistaken for viral cytopathic changes or dysplasia (Fig. 2B).36,37 Hyperplastic polyps that develop in the distal colon may also show epithelial misplacement within the submucosa, similar to adenomas with “pseudoinvasion” (Figs. 2C, D). In one series of 19 polyps with misplaced epithelium, all were located in the rectum or sigmoid colon and measured less than 1 cm. Most (79%) displayed fresh hemorrhage or hemosiderin deposits in the submucosa, suggesting a role for trauma in their pathogenesis.38 Although hyperplastic polyps with misplaced epithelium have been termed “inverted” or “giant” hyperplastic polyps,39 the latter terms should probably be discouraged as they have also been used to describe sessile serrated polyps, as discussed in subsequent sections.40,41
Torlakovic et al32 proposed that hyperplastic polyps could be subclassified based upon their anatomic location, morphologic and cellular features, and epithelial cell proliferation rates. The authors of that study recognized 4 types of nondysplastic serrated polyp: microvesicular hyperplastic polyp, goblet cell type hyperplastic polyp, mucin-poor hyperplastic polyp, and sessile serrated polyp, as described below. Of these, microvesicular hyperplastic polyps are most common. They contain convoluted, serrated crypts lined by tall columnar cells with microvesicular cytoplasm admixed with scattered goblet cells (Figs. 3A, B). Goblet cell type hyperplastic polyps contain elongated, slightly tortuous or dilated crypts with minimal serration and increased numbers of goblet cells (Figs. 3C, D). Mucin-poor hyperplastic polyps have a serrated architecture similar to that of microvesicular hyperplastic polyps, but contain regenerative-appearing epithelial cells with little or no mucin, and are much less common (Figs. 3E, F).
Immunohistochemical and Molecular Features
Although hyperplastic polyps display increased proliferation and mitotic activity compared with normal colonic mucosa, the distribution of Ki-67–labeled epithelium is normal, with positively stained cells being limited to the lower and midcrypt region.30,32,42 Hyperplastic polyps uniformly show strong expression of MUC2, similar to normal colonic goblet cells, but also display aberrant expression of MUC5AC, a gastric foveolar-type mucin.43,44 A subset may also show expression of MUC6, which is normally expressed in gastric pyloric glands: Mochizuka et al45 evaluated a series of hyperplastic polyps and found 27% to express MUC6.
Hyperplastic polyps frequently harbor mutually exclusive mutations in either KRAS or BRAF, both of which are involved in the mitogen-activated protein kinase-signaling pathway. Mutations in KRAS have been described in 4% to 47% of hyperplastic polyps and are more common in goblet cell type hyperplastic polyps of the distal colon, whereas BRAF mutations are detected in at least 70% of microvesicular hyperplastic polyps.34,46–51 O'Brien et al50 evaluated 53 hyperplastic polyps, including 38 microvesicular, 13 goblet cell type, and 2 mucin-poor lesions, and found KRAS mutations to be more frequent in goblet cell type polyps (53.9%) compared with microvesicular (15.8%) and mucin-poor (0%) hyperplastic polyps. Spring et al52 evaluated 54 microvesicular and 66 goblet cell type hyperplastic polyps and found BRAF mutations in 70% of microvesicular, but only 20% of goblet cell type, hyperplastic polyps. These authors also found KRAS mutations to be much less common in the former (11% vs. 50%, respectively).52
Hyperplastic polyps have also been reported to commonly show the CIMP. O'Brien et al53 found 47% of microvesicular polyps, but only 15% of goblet cell type polyps, to show high-frequency DNA methylation, including methylation of the MLH1 (36%) and MGMT (23%) promoters. In a recent study of 48 hyperplastic polyps, 33% showed the CIMP, and promoter methylation of MLH1 and MGMT was detected in 21% and 10% of cases, respectively.22 However, Chan et al54 failed to detect the CIMP in a series of 16 sporadic hyperplastic polyps, and Wynter et al21 found only 5% of distally located hyperplastic polyps to show high-frequency DNA methylation. Earlier reports also suggested that hyperplastic polyps showed abnormalities in DNA-repair mechanisms, but most recent data indicate that these lesions do not show MSI-H and have preserved function of DNA-repair proteins.53,55 Although serrated polyps frequently show partial loss of MLH1 and/or MSH2 immunohistochemical staining in the superficial crypts and surface epithelium, this does not reflect underlying MSI.30,32,44,49,53,56,57
Sessile Serrated Polyp (Sessile Serrated Adenoma)
In the previously cited study, Torlakovic et al32 described a fourth subtype of nondysplastic serrated polyp, which they termed “sessile serrated adenoma.” This lesion shares some overlapping morphologic features with hyperplastic polyps, but tends to be larger and displays evidence of abnormal cellular proliferation, as described below.32 Since that original description, other investigators have proposed that “sessile serrated adenomas” be designated “sessile serrated polyps” or “serrated polyps with abnormal proliferation” until their biologic potential is fully understood, to avoid their confusion with serrated adenomas, which are overtly dysplastic.58 Sessile serrated polyps may occur anywhere in the colorectum, particularly the proximal colon, and show a female predilection. In one study, patients with sessile serrated polyps had increased numbers of nondysplastic serrated polyps and adenomas of the colon, and were more likely to have a family history of colonic carcinoma compared with individuals who lacked these lesions.52 Sessile serrated polyps comprise 2% to 9% of all endoscopically resected polyps, and 7% to 21% of all nondysplastic serrated polyps.30,32,52,59
Sessile serrated polyps are nondysplastic sessile lesions that contain elongated crypts with exaggerated luminal serration. The crypts characteristically display persistent dilation in the deep mucosa (Figs. 4A, B), horizontal branching, or budding above the muscularis mucosae (Figs. 4C, D). Sessile serrated polyps contain a dual population of epithelial cells. Nongoblet epithelial cells are most numerous and display abundant microvesicular cytoplasmic mucin. Nuclear atypia, including nuclear enlargement, irregular nuclear membranes, and prominent nucleoli, may be present in the deeper crypt region, although overt dysplasia is lacking (Fig. 4E). Goblet cells are interspersed among the nongoblet epithelial cells, and may appear “dystrophic,” in that they show a loss of polarity with respect to the basement membrane (Fig. 4F).
Immunohistochemical and Molecular Features
Sessile serrated polyps often display an abnormal proliferation index with aberrant Ki-67 labeling. In a recent study of 29 sessile serrated polyps, Torlakovic et al42 found that Ki-67 immunohistochemical staining of epithelial cells showed striking crypt-to-crypt variation, and labeling within crypts was asymmetrical, leading the authors to hypothesize that irregularity of the proliferative zone in these lesions reflected the presence of abnormal epithelial-mesenchymal interactions. Sessile serrated polyps also show increased immunohistochemical expression of gastric-type mucins, including MUC5A and MUC6.30,44,57 Owens et al57 evaluated a series of 48 hyperplastic polyps and 26 sessile serrated polyps and found partial, or complete, MUC6 staining in the basal crypts in all sessile serrated polyps, but not in hyperplastic polyps. Unfortunately, other investigators have failed to validate these results.45
At least 70% of sessile serrated polyps harbor BRAF mutations, whereas KRAS mutations are detected in less than 10% of cases.44,49,51–53 Spring et al52 evaluated 36 sessile serrated polyps, including 27 that were located in the right colon and 9 that were present in the distal colorectum. They detected BRAF mutations in 85% and 55% of right-sided and left-sided polyps, respectively, but noted KRAS mutations in only 3 polyps, all of which were distally located.52 In another study, Jass et al51 found BRAF mutations in 26/32 (81%) sessile serrated polyps, but only one harbored a KRAS mutation.
The CIMP is also a frequent feature of sessile serrated polyps.21,22,49,53,54 O'Brien et al53 assessed 29 sessile serrated polyps and found that 76% displayed the CIMP, compared with 47% of microvesicular hyperplastic polyps. A more recent series of 32 sessile serrated polyps reported a somewhat lower frequency (44%) of CIMP, which was similar to that seen in microvesicular hyperplastic polyps (41%).22
Approximately 25% of sessile serrated polyps show complete loss of MGMT immunohistochemical expression, but up to 40% display aberrant methylation of the MGMT promoter.21,30,51,53 Loss of MLH1 immunostaining has been described in 0% to 81% of sessile serrated polyps, and reports describe 28% to 72% of these lesions to show MLH1 promoter methylation.30,32,56,60,61 However, loss of immunostaining for DNA-repair proteins in these lesions is uniformly limited to the superficial colonic mucosa, and the functional implications of promoter methylation are unclear: most investigators have not confirmed the presence of defective DNA-repair mechanisms in sessile serrated polyps.30,59 O'Brien et al53 failed to identify MSI-H in any of the 29 sessile serrated polyps they analyzed. Similarly, Yantiss et al62 evaluated a series of 33 nondysplastic serrated polyps of the appendix, including 15 sessile serrated polyps, for evidence of defective DNA-repair mechanisms. Although they found partial loss of MLH1 immunohistochemical expression in 52% of nondysplastic serrated polyps, this finding did not correlate with the presence of MSI in any of the cases.62 Thus, it is likely that decreased immunohistochemical expression of these markers reflects the proliferative characteristics of nondysplastic serrated polyps, rather than the presence of defective DNA-repair mechanisms.
Pathologic Distinction Between Subtypes of Nondysplastic Serrated Polyp
The pathologic distinction between microvesicular hyperplastic polyps and sessile serrated polyps is extremely problematic, and interobserver variability may be as high as 40%, even among expert pathologists.59,63 Farris et al64 recently performed a correlation study, in which they asked 5 pathologists with specific interest in colorectal polyps to classify 185 serrated polyps as hyperplastic polyps, sessile serrated polyps, and serrated adenomas. Notably, the authors excluded small polyps (≤5 mm diameter) and cases with poorly oriented tissue sections, but still found only moderate interobserver agreement with respect to the diagnoses of hyperplastic polyp and sessile serrated polyp. They also noted that agreement did not improve when pathologists were informed of the anatomic site and size of the polyp.64 It is likely that diagnostic difficulties arise from the frequent occurrence of nondysplastic serrated polyps that show some, but not all, of the morphologic features typical of sessile serrated polyps. Chung et al44 performed a focused study on nondysplastic serrated polyps with features “intermediate” between those of hyperplastic polyps and sessile serrated polyps. They evaluated 31 serrated polyps, all of which spanned less than 1 cm, displayed at least 4 morphologic features typical of sessile serrated polyp, and were evenly distributed throughout the colorectum; and compared their molecular features with those of 6 proximally located sessile serrated polyps. They found that polyps with “intermediate” features showed MUC5AC expression (52%) and BRAF mutations (83%) at rates comparable with those of sessile serrated polyps (50% and 100%, respectively); and concluded that many hyperplastic polyps cannot be reliably distinguished from sessile serrated polyps based on available molecular techniques and morphologic features.44
DYSPLASTIC SERRATED POLYPS
The term “serrated adenoma” was first proposed by Longacre and Fenoglio-Preiser31 to describe dysplastic polyps characterized by prominent glandular serration and cytologic dysplasia. Serrated adenomas are relatively uncommon, but show a predilection for the distal colorectum. Longacre and Fenoglio-Preiser found serrated adenomas to account for less than 0.6% of polyps in their review of more than 18,000 cases.31 Subsequent studies have estimated that serrated adenomas comprise 0.7% to 1.9% of all endoscopically resected polyps, 2% to 7% of all serrated polyps, and 1% to 3% of all adenomas.30,52
Serrated adenomas show a protuberant growth pattern and contain convoluted, serrated crypts lined by overtly dysplastic epithelial cells (Fig. 5A). The neoplastic epithelial cells contain abundant eosinophilic cytoplasm and elongated pencillate nuclei with small, but conspicuous nucleoli and smooth nuclear contours (Fig. 5B). Generally, these lesions show a lesser degree of nuclear atypia than conventional adenomas. Large serrated adenomas of the distal colorectum may display prominent finger-like, bulbous projections lined by epithelium with a serrated contour, and have been referred to as filiform serrated adenomas (Fig. 5C).38 Serrated adenomas with this unusual pattern of growth often show evidence of mucosal trauma, including lamina propria edema, erosions, or ulceration (Fig. 5D). Despite their unusual morphologic features, filiform serrated adenomas share similar molecular characteristics with serrated adenomas, as discussed below.
Immunohistochemical and Molecular Features
Serrated adenomas show a lower proliferation rate than conventional adenomas, but increased proliferation compared with sessile serrated polyps, in that they often contain epithelial cells that express Ki-67 in the upper crypt region.30,65 The proliferating cells are distributed irregularly within the crypts and may be most abundant in “ectopic crypt foci,” which are defined as abnormal crypts that show loss of orientation with respect to the muscularis mucosae.42 Most serrated adenomas express colonic and gastric-foveolar–type mucins, but not MUC6.30,45,57
The molecular relationships between serrated and conventional adenomas remain unclear, and many data reported in the literature are conflicting. For example, Dehari66 and Hiyama et al67 performed 2 separate studies, after which they independently concluded that serrated adenomas are genetically different from conventional adenomas based on infrequent detection of APC mutations and regular observation of p53 mutations in the former (3.8% and 47%, respectively) compared with the latter (66.7% and 0%, respectively). However, Fogt et al48 evaluated the molecular characteristics of 46 serrated adenomas and 32 conventional adenomas, and found loss of heterozygosity of APC, p53, p16, and 3p at comparable rates in both groups, suggesting that they are genetically similar.48
Most serrated adenomas harbor abnormalities in the mitogen-activated protein kinase pathway, although, in contrast to sessile serrated polyps, a greater proportion (up to 28%) of these lesions contain KRAS mutations.34,47,51,68–70 In their study of 15 serrated adenomas, Jass et al51 found 27% and 33% to harbor KRAS and BRAF mutations, respectively. A higher frequency (77%) of BRAF mutations was reported by Lee et al,69 however, 13 of 35 “serrated adenomas” included in that study were mixed hyperplastic/adenomatous polyps, as defined below.
The majority of serrated adenomas exhibit the CIMP. Park et al71 evaluated the methylation status of 22 serrated adenomas and 34 conventional adenomas, and reported concordant methylation of 2 or more gene promoter sites in 68% of serrated adenomas compared with only 18% of conventional adenomas. O'Brien et al53 performed a similar study of 29 cases, in which they found 79% of serrated adenomas to show high-frequency DNA methylation, compared with only 26% of conventional adenomas.
Abnormal function of DNA-repair proteins is likely infrequent among serrated adenomas. Partial loss of MGMT immunohistochemical expression has been reported in 13% to 28% of serrated adenomas, and similar numbers (20% to 45%) show aberrant MGMT promoter methylation.22,30,51,53,56,70,72 Methylation of the MLH1 promoter has been reported in 3% to 48% of cases, and most studies have demonstrated preserved immunohistochemical expression of MLH1.22,30,53,56,57,60,62,68,73 O'Brien et al failed to detect MSI-H in any of 29 serrated adenomas evaluated,53 but noted that adjacent adenocarcinomas frequently showed MSI-H, leading them to conclude that MSI is a late event in the serrated neoplastic pathway.
MIXED HYPERPLASTIC/ADENOMATOUS POLYPS (SESSILE SERRATED POLYPS WITH DYSPLASIA)
Mixed hyperplastic/adenomatous polyps contain discrete areas of dysplastic (adenomatous epithelium), admixed with nondysplastic crypts that show a serrated architecture. These lesions are relatively uncommon, representing 0.8% to 1.7% of all endoscopically removed polyps and 4% to 16% of serrated polyps.30,52,56
Mixed hyperplastic/adenomatous polyps contain dysplastic crypts that may assume a tubular, villous, or serrated appearance, admixed with nondysplastic serrated crypts reminiscent of hyperplastic polyps or sessile serrated polyps (Figs. 6A, B). Unfortunately, these lesions have not been well characterized to date: most studies have either excluded them from evaluation, or combined them with serrated adenomas for purposes of analysis.
Immunohistochemical and Molecular Features
Mixed hyperplastic/adenomatous polyps probably do not represent “collision” lesions composed of adenomatous and hyperplastic elements. Rather, emerging evidence suggests that the different components share similar molecular features, indicating that these lesions likely represent hyperplastic or sessile serrated polyps with dysplasia. Iino et al74 evaluated 12 mixed polyps and found MSI-H and MSI-L in 25% and 58% of cases, respectively. Importantly, they also detected similar molecular changes in both the nondysplastic and dysplastic components when separately analyzed.74 Similar genetic abnormalities in the hyperplastic and adenomatous components were also observed in another series of 13 mixed polyps, which found MSI-L and MSI-H in 38% and 8% of cases, respectively.68
Sheridan et al75 described the molecular features of 11 sessile serrated polyps that contained foci of low-grade dysplasia, high-grade dysplasia, and/or early invasive adenocarcinoma, and found that loss of MLH1 immunoexpression was limited to foci of dysplasia and carcinoma. In another study of 8 sessile serrated polyps with dysplasia, Goldstein76 found MSI-H in overtly dysplastic epithelium, but not in the nondysplastic serrated components of the polyps. Although few studies have specifically evaluated other molecular features of “mixed” polyps, they appear to harbor BRAF or KRAS mutations with near equal frequency.51,52
Distinction Between Subtypes of Dysplastic Serrated Polyp
The molecular evaluation of dysplastic serrated polyps has been hampered by inclusion of morphologically distinct polyps in the same diagnostic category. For example, although O'Brien et al53 reported BRAF mutations and the CIMP in 62% and 79% of serrated adenomas, these authors used the term “serrated adenoma” to encompass both serrated adenomas and mixed hyperplastic/adenomatous polyps.77 In another study, Jass et al51 evaluated the molecular features of 25 dysplastic serrated polyps, which they classified as resembling either sessile serrated polyps with dysplasia or conventional adenomas. They found that 63% of the former harbored BRAF mutations, whereas KRAS mutations were detected in 56% of the latter.51 It is likely that conflicting data regarding the molecular features of dysplastic serrated polyps reflect the application of inconsistent diagnostic criteria to the classification of these lesions.
HYPERPLASTIC (SERRATED) POLYPOSIS
Some patients may develop an unusual polyposis disorder termed “hyperplastic polyposis” characterized by the adult-onset of multiple serrated polyps throughout the colon. The disease is generally asymptomatic, although larger polyps or malignancies may produce bleeding. Defining features of hyperplastic polyposis include the presence of any one of the following criteria: (1) greater than 30 serrated polyps of any size distributed throughout the colon, (2) 5 or more serrated polyps located proximal to the sigmoid colon, 2 of which span at least 1 cm, and (3) any number of serrated polyps located proximal to the sigmoid colon in a first-degree relative of a patient with this disorder.78
Several authors have suggested that hyperplastic polyposis represents a heterogenous condition and have proposed that 2 forms of the disease exist.79,80 The first is characterized by multiple (≥30), small (<1 cm) hyperplastic polyps distributed throughout the colorectum, many of which harbor KRAS mutations, and does not appear to be associated with increased cancer risk.81 Patients with the second form of the disease typically have 5 or more polyps located proximal to the sigmoid colon, at least one of which spans 1 cm or more.82,83 Patients in the latter group develop a variety of different types of nondysplastic and dysplastic serrated polyps and also nonserrated dysplastic polyps (conventional adenomas). Polyps from these patients show frequent BRAF mutations and CIMP, but lack KRAS mutations. Moreover, different types of polyps from the same patient often show similar methylation abnormalities, and extensive DNA methylation is present in apparently normal colorectal mucosa, indicating that patients with this disorder may have a constitutional abnormality in DNA methylation.54,84,85 Importantly, patients with multiple large serrated polyps are at increased risk for the development of colonic cancer. The severity of cancer risk has not been established, but several small series have reported the presence of carcinoma in 50% to 70% of patients with hyperplastic/serrated polyposis.83,86,87
SERRATED POLYPS IN INFLAMMATORY BOWEL DISEASE
Patients with inflammatory bowel disease may develop nondysplastic and dysplastic serrated polyps of the colorectum, although their frequency and distribution have not been examined in large studies.88–91 The mechanisms underlying epithelial serration in the context of inflammatory bowel disease are not well understood. Odze et al89 studied 39 ulcerative colitis patients who developed hyperplastic polyps in areas of colitis. They found that colitis-associated hyperplastic polyps harbored KRAS mutations (19%) and displayed loss of heterozygosity of APC (21%), 3p (40%), p53 (27%), and p16 (20%) at rates comparable with those observed in sporadic hyperplastic polyps.89
Rubio et al91 evaluated a series of 50 colectomy specimens from patients with inflammatory bowel disease who developed dysplasia and/or carcinoma. They found that 43% of adenomas adjacent to invasive carcinomas contained neoplastic crypts with a serrated architecture, compared with only 7% of the adenomas adjacent carcinomas that developed in patients without inflammatory bowel disease.91 In another study, Kilgore et al92 noted the presence of mucosal hyperplasia in 33% of patients with Crohn disease and adenocarcinoma, compared with 10% of patients with Crohn disease who underwent surgery for medical indications, suggesting that mucosal hyperplasia may represent an unusual form of dysplasia in the patients with inflammatory bowel disease.92
Srivastava et al93 reported the development of serrated polyposis in 3 patients with inflammatory bowel disease, including 2 ulcerative colitis patients and 1 patient with Crohn disease. They noted that most of the lesions were hyperplastic polyps and sessile serrated polyps, although 2 patients had concomitant serrated adenomas and 1 had a conventional adenoma. The authors analyzed multiple polyps obtained from each of the patients, and found that all showed retention of MLH1 immunohistochemical expression, but KRAS mutations were present in 45% of the polyps. Interestingly, none of the examined polyps harbored detectable BRAF mutations.93
Despite recent advances in our understanding of the mechanisms underlying the development of serrated colorectal polyps, very few prospective data regarding the natural history of these lesions are available, particularly with respect to the biologic behavior of sessile serrated polyps. The biologic risk of distally located nondysplastic serrated polyps is probably quite low, as the putative endpoint of the serrated neoplastic pathway, namely, the colonic carcinoma that displays MSI-H, CIMP, and BRAF mutations, typically occurs proximal to the sigmoid colon. Historical data also indicate the risk of distal nondysplastic serrated polyps to be minimal and, thus, surveillance after their removal is not currently recommended.94 In contrast, the biologic potential of nondysplastic serrated polyps that develop in the proximal colon is not known, and there are no data regarding potential biologic differences between proximally located hyperplastic polyps and sessile serrated polyps. Earlier studies proposed that these lesions should be aggressively treated and surveilled, although most investigators now suggest that they be completely resected endoscopically, if possible, and carefully followed if complete removal is not possible. However, it is clear that patients with serrated polyposis are at increased risk for cancer development and, thus, should undergo close clinical surveillance.77,95
Although some investigators have suggested that dysplastic serrated polyps, such as serrated adenomas and mixed hyperplastic/adenomatous polyps, should be completely resected and surveilled in a fashion similar to “advanced” conventional adenomas (ie, adenomas that span at least 1 cm, show high-grade dysplasia, or display a villous architecture), most pathologists consider these lesions to have a biologic risk similar to that of conventional adenomas of comparable size.59,96 Recommendations for more aggressive management and surveillance are based on early data suggesting that dysplastic serrated polyps progressed to carcinoma more rapidly than nonserrated conventional adenomas.31 However, subsequent studies have reported that the rates of intramucosal carcinoma and high-grade dysplasia detection in serrated adenomas are comparable with those of conventional adenomas. In a study of 38 patients with serrated adenomas and 138 patients with conventional adenomas, Lazarus et al found the risk of cancer development to be similar.97
The biologic significance of serrated polyps that develop in association with inflammatory bowel disease is not clear, and the currently used dysplasia classification scheme does not consider these lesions, as it is based on criteria used to evaluate conventional cytologic dysplasia typical of tubular and villous adenomas. Some investigators have suggested that nondysplastic serrated polyps, such as sessile serrated polyps, be managed in a fashion similar to that of adenoma-like polypoid dysplastic lesions, whereas others choose to consider such lesions to be “indefinite” for dysplasia.93
SUMMARY AND CONCLUSIONS
Serrated colorectal polyps have been implicated in the development of colonic carcinoma through the “serrated neoplastic pathway,” which is characterized by early BRAF mutations, progressive DNA hypermethylation, and the late development of high-frequency MSI. Morphologic and molecular observations have provided support for the belief that sessile serrated polyps may be biologically important, particularly when they are large, multiple, and located in the proximal colon. However, a number of serious issues have become evident as data regarding serrated polyps have become available. It is quite clear that nondysplastic serrated polyps show overlapping morphologic and molecular features, such that the distinction between hyperplastic polyps and sessile serrated polyps is not possible in many cases. Data regarding the molecular features of serrated polyps are also conflicting, reflecting inconsistent diagnostic criteria and inappropriate histopathologic classification of polyps in many cases. In addition, reported methods for assessing DNA methylation and protein function are not standardized or universally accepted, resulting in significant interpretative errors, particularly with respect to the evaluation of DNA-repair protein expression. Future studies should address these issues and prospectively evaluate the biologic potential of serrated polyps to aid clinicians in the management of these lesions.
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hyperplastic polyp; serrated adenoma; mixed polyp; BRAF; KRAS; microsatellite instability; DNA hypermethylation
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