Serrated Lesions of the Colorectum: Review and Recommendations From an Expert Panel

Rex, Douglas K.; Ahnen, Dennis J.; Baron, John A.; Batts, Kenneth P.; Burke, Carol A.; Burt, Randall W.; Goldblum, John R.; Guillem, José G.; Kahi, Charles J.; Kalady, Matthew F.; O’Brien, Michael; Odze, Robert D.; Ogino, Shuji; Parry, Susan; Snover, Dale C.; Torlakovic, Emina; Wise, Paul E.; Young, Joanne; Church, James M.

doi:10.1038/ajg.2012.161

Cited by 985 publications

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References 149 publications

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“…10 The diagnosis of traditional serrated adenoma was based on the criteria outlined above and the diagnosis of sessile serrated adenoma was based on previously published criteria. 10,21 …”

Section: Diagnosis and Validation Of Flat Growth Patternmentioning

confidence: 99%

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A clinicopathological and molecular analysis of 200 traditional serrated adenomas

et al. 2015

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The traditional serrated adenoma is the least common colorectal serrated polyp. The clinicopathological features and molecular drivers of these polyps require further investigation. We have prospectively collected a cohort of 200 ordinary and advanced traditional serrated adenomas and performed BRAF and KRAS mutational profiling, CpG island methylator phenotype analysis, and immunohistochemistry for a panel of 7 antibodies (MLH1, b-catenin, p53, p16, Ki67, CK7, and CK20) on all cases. The mean age of the patients was 64 years and 50% were female. Of the polyps, 71% were distal. Advanced histology (overt dysplasia or carcinoma) was present in 19% of cases. BRAF mutation was present in 67% and KRAS mutation in 22%. BRAF mutant traditional serrated adenomas were more frequently proximal (39% versus 2%; Pr0.0001), were exclusively associated with a precursor polyp (57% versus 0%; Pr0.0001), and were more frequently CpG island methylator phenotype high (60% versus 16%; Pr0.0001) than KRAS mutant traditional serrated adenomas. Advanced traditional serrated adenomas retained MLH1 expression in 97%, showed strong p53 staining in 55%, and nuclear b-catenin staining in 40%. P16 staining was lost in the advanced areas of 55% of BRAF mutant traditional serrated adenomas compared with 10% of the advanced areas of KRAS mutant or BRAF/KRAS wildtype traditional serrated adenomas. BRAF and KRAS mutant traditional serrated adenomas are morphologically related but biologically disparate polyps with distinctive clinicopathological and molecular features. The overwhelming majority of traditional serrated adenomas retain mismatch repair enzyme function indicating a microsatellite-stable phenotype. Malignant progression occurs via TP53 mutation and Wnt pathway activation regardless of mutation status. However, CDKN2A (encoding the p16 protein) is silenced nearly exclusively in the advanced areas of the BRAF mutant traditional serrated adenomas. Thus, the BRAF mutant traditional serrated adenoma represents an important precursor of the aggressive BRAF mutant, microsatellite-stable subtype of colorectal carcinoma. The serrated neoplasia pathway accounts for 15 to 35% of colorectal carcinoma. 1-3 Well-established molecular drivers of this pathway are MAP kinase pathway activation, a critical early event resulting from either activating BRAF or KRAS mutation, 4 and the CpG island methylator phenotype, a coordinate methylation of CpG islands in the promoter regions of many genes that results in gene silencing. [4][5][6] The CpG island methylator phenotype is particularly relevant to carcinogenesis when affecting tumorsuppressor genes. 5 MLH1 is the best known of these, with silencing leading to microsatellite instability. This is frequently observed in the malignant transformation of sessile serrated adenomas. However, MLH1 methylation and microsatellite instability are not prerequisites of serrated neoplasia.

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“…10 The diagnosis of traditional serrated adenoma was based on the criteria outlined above and the diagnosis of sessile serrated adenoma was based on previously published criteria. 10,21 …”

Section: Diagnosis and Validation Of Flat Growth Patternmentioning

confidence: 99%

“…16 Diagnosis of a sessile serrated adenoma precursor required the presence of at least one unequivocal sessile serrated adenoma-type crypt. 10,21 A precursor component was diagnosed if there was consensus among all four pathologists.…”

Section: Identification Of a Precursor Componentmentioning

confidence: 99%

A clinicopathological and molecular analysis of 200 traditional serrated adenomas

et al. 2015

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“…Traditional serrated adenoma displays a protuberant growth pattern and is detected more frequently in the left-sided colon, and 29-46% of traditional serrated adenomas harbor KRAS mutation, which rarely occurs in sessile serrated adenoma. 7,10,11 Sessile serrated adenoma is a recognized precursor of colorectal cancer with high levels of microsatellite instability, 1,9 whereas traditional serrated adenoma is more likely to evolve into a colorectal cancer that is microsatellite-stable or has low levels of microsatellite instability. 1,9,11 Furthermore, the Wnt signaling pathway was shown to be activated in a subset of traditional serrated adenoma.…”

mentioning

confidence: 99%

“…7,10,11 Sessile serrated adenoma is a recognized precursor of colorectal cancer with high levels of microsatellite instability, 1,9 whereas traditional serrated adenoma is more likely to evolve into a colorectal cancer that is microsatellite-stable or has low levels of microsatellite instability. 1,9,11 Furthermore, the Wnt signaling pathway was shown to be activated in a subset of traditional serrated adenoma. 12 Thus, traditional serrated adenoma is a heterogeneous entity with partial molecular features of the sessile serrated pathway and the conventional adenoma-carcinoma sequence.…”

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confidence: 99%

Traditional serrated adenoma has two pathways of neoplastic progression that are distinct from the sessile serrated pathway of colorectal carcinogenesis

et al. 2014

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Traditional serrated adenoma is one type of colorectal serrated neoplasm and a precursor of colorectal cancer. We evaluated the pathologic and molecular features of 60 traditional serrated adenomas with cytologic dysplasia and/or invasive carcinoma. On the basis of morphological features, 16 cases (27%) were categorized as traditional serrated adenoma with serrated dysplasia and 25 cases (42%) as traditional serrated adenoma with conventional adenomatous dysplasia. In addition, 19 cases (31%) showed an overall tubulovillous adenomatous structure but with focal serrated feature. Traditional serrated adenoma with serrated dysplasia had a significantly higher frequency of BRAF mutation than traditional serrated adenoma with conventional adenomatous dysplasia and tubulovillous adenoma with serrated feature (P ¼ 0.006), whereas traditional serrated adenoma with conventional adenomatous dysplasia and tubulovillous adenoma with serrated feature had higher frequencies of KRAS mutation than traditional serrated adenoma with serrated dysplasia (Po0.0001). Only traditional serrated adenoma with serrated dysplasia showed sessile serrated adenoma-like lesions at the periphery (n ¼ 3) and developed invasive carcinomas when the lesions were o15 mm in size. Abnormal nuclear accumulation of b-catenin was detected in traditional serrated adenoma with conventional adenomatous dysplasia and tubulovillous adenoma with serrated feature but not in traditional serrated adenoma with serrated dysplasia. The frequency of the positive CpG island methylator phenotype was similar among the three dysplastic subtypes, and immunostaining of four mismatch repair proteins in the nucleus was retained in all traditional serrated adenomas and associated invasive malignancies. Traditional serrated adenoma-associated adenocarcinomas (n ¼ 28) displayed distinctive morphological features: oval cell nuclei, serrated glands, infiltrating borders, rare occurrences of necrosis and mucinous differentiation. Overexpression of p53 was detected only in high-grade dysplasia and invasive adenocarcinoma. Our findings indicate that traditional serrated adenoma is a heterogeneous neoplasm with two pathways of neoplastic progression, which are distinct from the sessile serrated pathway of colorectal carcinogenesis.

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“…The serrated neoplastic pathway may contribute to the occurrence of some postcolonoscopy cancers, as some precursor lesions, especially sessile serrated adenomas/polyps (SSA/P), are easily overlooked during colonoscopy (5,6) and are more challenging to remove endoscopically (7). It is generally accepted that large, proximal, or dysplastic (LPD) serrated polyps (SP) purport significant risk for malignant transformation, whereas nondysplastic small distal serrated polyps do not (8)(9)(10)(11). Some studies indicate that 31% of hyperplastic polyps and 27% of nonadenomatous polyps are missed during colonoscopy (12,13), which is consistent with a high variability in serrated polyp detection among endoscopists (i.e., ranging from 8%-32% for all serrated polyps, and from 1%-18% for proximal serrated polyps; refs.…”

Section: Introductionmentioning

confidence: 99%

Simple Clinical Risk Score Identifies Patients with Serrated Polyps in Routine Practice

Bouwens

Winkens

Rondagh

et al. 2013

Cancer Prevention Research

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Large, proximal, or dysplastic (LPD) serrated polyps (SP) need accurate endoscopic recognition and removal as these might progress to colorectal cancer. Herewith, we examined the risk factors for having 1 LPD SP. We developed and validated a simple SP risk score as a potential tool for improving their detection. We reviewed clinical, endoscopic, and histologic features of serrated polyps in a study of patients undergoing elective colonoscopy (derivation cohort). A self-administered questionnaire was obtained. We conducted logistic regression analyses to identify independent risk factors for having 1 LPD SP and incorporated significant variables into a clinical score. We subsequently tested the performance of the SP score in a validation cohort. We examined 2,244 patients in the derivation and 2,402 patients in the validation cohort; 6.3% and 8.2% had 1 LPD SP, respectively. Independent risk factors for LPD SPs were age of more than 50 years [OR 2.2; 95% confidence interval (CI), 1.3-3.8; P ¼ 0.004], personal history of serrated polyps (OR 2.6; 95% CI, 1.3-4.9; P ¼ 0.005), current smoking (OR 2.2; 95% CI, 1.4-3.6; P ¼ 0.001), and nondaily/no aspirin use (OR 1.8; 95% CI, 1.1-3.0; P ¼ 0.016). In the validation cohort, a SP score 5 points was associated with a 3.0-fold increased odds for LPD SPs, compared with patients with a score <5 points. In the present study, age of more than 50 years, a personal history of serrated polyps, current smoking, and nondaily/no aspirin use were independent risk factors for having LPD SPs. The SP score might aid the endoscopist in the detection of such lesions. Cancer Prev Res; 6(8); 855-63. Ó2013 AACR.

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Serrated Lesions of the Colorectum: Review and Recommendations From an Expert Panel

Cited by 985 publications

References 149 publications

A clinicopathological and molecular analysis of 200 traditional serrated adenomas

A clinicopathological and molecular analysis of 200 traditional serrated adenomas

Traditional serrated adenoma has two pathways of neoplastic progression that are distinct from the sessile serrated pathway of colorectal carcinogenesis

Simple Clinical Risk Score Identifies Patients with Serrated Polyps in Routine Practice

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