Serrated Colon Polyps as Precursors to Colorectal Cancer

doi:10.1016/j.cgh.2012.12.004

Clinical Gastroenterology and Hepatology

Volume 11, Issue 7, July 2013, Pages 760-767

https://doi.org/10.1016/j.cgh.2012.12.004 Get rights and content

Identification of the serrated neoplasia pathway has improved our understanding of the pathogenesis of colorectal cancer (CRC). Insights include an increased recognition of the malignant potential of different types of serrated polyps such as sessile and traditional serrated adenomas. Sessile serrated adenomas share molecular features with colon tumors that have microsatellite instability and a methylator phenotype, indicating that these lesions are precursors that progress via the serrated neoplasia pathway. These data have important implications for clinical practice and CRC prevention, because hyperplastic polyps were previously regarded as having no malignant potential. There is also evidence that the serrated pathway contributes to interval or missed cancers. Endoscopic detection of serrated polyps is a challenge because they are often inconspicuous with indistinct margins and are frequently covered by adherent mucus. It is important for gastroenterologists to recognize the subtle endoscopic features of serrated polyps to facilitate their detection and removal, and thereby ensure a high-quality colonoscopic examination. Recognition of the role of serrated polyps in colon carcinogenesis has led to the inclusion of these lesions in postpolypectomy surveillance guidelines. However, an enhanced effort is needed to identify and completely remove serrated adenomas, with the goal of increasing the effectiveness of colonoscopy to reduce CRC incidence.

Section snippets

Classification

Serrated polyps are heterogeneous lesions characterized histologically by glandular serration, ie, a “saw-toothed” infolding of colonic crypt epithelium. This feature is believed to be the result of increased cell turnover combined with delayed migration or failure of apoptosis at the mucosal surface, leading to an accumulation of epithelial cells that are accommodated by infolding (serration) of the epithelial crypt lining.³ Historically, polyps with serrated architecture were considered

Molecular Features of the Serrated Neoplasia Pathway

Most CRCs develop from conventional adenomas through a molecular pathway characterized by chromosomal instability. However, approximately 15% of CRCs develop through an alternate pathway characterized by defective DNA mismatch repair (MMR) that gives rise to high-frequency MSI (MSI-H). MSI was first described in association with Lynch syndrome (hereditary nonpolyposis colorectal cancer) caused by germline mutations in MMR genes. In sporadic CRCs, MSI is a consequence of defective MMR caused by

Epidemiology of Serrated Polyps

By far, the most common serrated polyp is the conventional HP, which accounts for 70%–95% of all serrated polyps30, 31 and most frequently occurs in the rectosigmoid colon.³¹ SSA/Ps account for 5%–25% of serrated polyps and occur predominantly in the proximal colon.30, 31, 32, 33 Although the prevalence of SSA/Ps varies depending on the clinical study, the overall prevalence varies from 2%–9%.30, 31, 32, 33 However, a recent study evaluating the prevalence of serrated polyps in the proximal

Serrated Polyposis Syndrome

The recently modified World Health Organization clinical criteria for the diagnosis of serrated polyposis include any one of the following: (1) at least 5 histologically diagnosed serrated polyps proximal to the sigmoid colon, 2 of which are greater than 1 cm in diameter, (2) any number of serrated polyps occurring proximal to the sigmoid colon in an individual with a first-degree relative with serrated polyposis, or (3) more than 20 serrated polyps of any size but distributed throughout the

Clinical Implications

The recognition of a serrated neoplasia pathway to CRC has important clinical implications for detection, surveillance, and treatment. Although management of colonic serrated neoplasia should be based on the natural history and malignant potential of the various subtypes of serrated polyps, such data are limited because studies were performed before the distinction among serrated polyp subtypes. A critical yet unanswered question is whether certain serrated polyp subtypes, especially SSA/Ps,

Detection of Serrated Polyps

Serrated polyps are less likely than conventional adenomas to bleed, so fecal occult blood testing may not detect these lesions.⁶¹ Although there are no data regarding the sensitivity and specificity of computed tomographic colonography to detect serrated polyps, the sessile and flat morphology of these lesions suggests that that this modality would perform poorly. Optical colonoscopy appears to be the best of the current screening methods to detect serrated polyps⁶¹; however, significant

Conclusion

Recognition of the serrated neoplasia pathway represents an important advance in understanding CRC carcinogenesis with opportunities for prevention. Serrated colorectal polyps are clinically and molecularly diverse lesions that share common crypt luminal morphology characterized by glandular serration. Evidence indicates that subtypes of serrated polyps, particularly TSA, SSA/P, and SSA/P with dysplasia, may progress to adenocarcinoma through a serrated neoplasia pathway. Furthermore, data

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Impact of the Sessile Serrated Polyp Pathway on Predicted Colorectal Cancer Outcomes
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Approximately 20%–30% of colorectal cancers (CRCs) arise from the serrated polyp pathway. CRC screening options have differential sensitivity to detect sessile serrated polyps (SSPs). We used the Colorectal Cancer and Adenoma Incidence and Mortality Microsimulation Model (CRC-AIM) to assess how the detection of SSPs impacts predicted life years gained (LYG), CRC incidence, and CRC mortality with multitarget stool DNA (mt-sDNA) or fecal immunochemical test (FIT) screening.
A simulated cohort of average-risk US individuals underwent triennial mt-sDNA or annual FIT screening between ages 45–75 years. SSP-attributed CRCs were modeled at 0% (base case), 14.3%, 20%, and 30%, in combination with 4 adherence & attendance scenarios: S1: 100% stool-screening adherence/100% follow-up colonoscopy attendance after a positive stool test; S2: reported stool-screening adherence (mt-sDNA = 71%; FIT = 43%)/100% follow-up colonoscopy attendance; S3: reported stool-screening adherence/reported follow-up colonoscopy attendance (mt-sDNA = 72%; FIT = 47%); and S4: reported stool-screening adherence/72% follow-up colonoscopy attendance. Outcomes were per 1000 individuals. Sensitivity analyses used ranges of stool-screening adherence or follow-up attendance.
At S1, S2, S3, and S4, LYG with FIT at the base case (0% SSP-attributed CRC) was 346.7, 279.3, 126.6, and 196.1, respectively, and with mt-sDNA was 324.6, 311.8, 215.8, and 215.8, respectively. Among the 4 adherence/attendance scenarios, modeling SSP-attributed CRCs decreased LYG by 4.9–20.9 with FIT and 2.0–5.1 with mt-sDNA. At S3 and 30% SSP-attributable CRCs, mt-sDNA had 95.1 more LYG, 21.5% greater CRC incidence reduction, and 22.2% greater CRC mortality reduction than FIT.
Incorporating SSPs and real-world adherence into the CRC-AIM modeling analyses yielded more practice-relevant estimates of CRC screening outcomes and should be applied in future studies to afford more appropriate assessment of comparative effectiveness estimates between guideline-endorsed screening options.
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In our multisetting practice, more than 50% of patients overall (and 80% of those with any neoplasm) were found to have proximal CRN at colonoscopy to evaluate positive mt-sDNA.45 This high yield of proximal neoplasms is likely due to the infrequency of hemorrhage among these flat lesions48 and the more continuous exfoliation of DNA markers during ongoing cellular turnover.35 These data are consistent with a prior head-to-head observation that mt-sDNA is more sensitive than FIT for the detection of screen-relevant neoplasms proximal to the splenic flexure.37
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Additionally, like in several other modeling studies,10 the serrated pathway was not included in our analyses. Considering that colonoscopy is less effective in detecting serrated lesions,44 a slightly higher overall prevalence of adenomas, a slightly lower transition rate from adenoma to cancer, and slightly smaller effects of screening colonoscopy in reducing CRC deaths or YPLL might be expected when the serrated pathway is incorporated. Third, in this analysis, people with adenoma removed were moved backward to the no-neoplasm state and were considered in the same way as those without colonoscopy findings in subsequent years based on the assumption that their excess risk could be compensated through surveillance colonoscopies.
Recent guidelines on colorectal cancer (CRC) screening recommend starting screening earlier than before. We performed a simulation study to examine and compare the optimal ages to have once-only screening colonoscopy and repeated colonoscopies.
A Markov model was set up using data from the German national screening colonoscopy registry to simulate the natural history of the adenoma-carcinoma process. CRC deaths and years of potential life lost (YPLL) for a hypothetical unscreened 50-year-old German population were estimated for a single screening colonoscopy or 2 or 3 screening colonoscopies with 10-year intervals at various ages.
One single screening colonoscopy performed between 50 and 65 years of age was expected to reduce CRC death by 49% to 69% and YPLL by 51% to 68%. An inverted U-shaped association was found between screening age and proportion of CRC deaths or YPLL prevented. The optimal age for once-only colonoscopy that yielded the highest reductions in YPLL was around 54 years for men and 56 years for women. Estimates were approximately 6 to 8 years higher when proportions of CRC deaths prevented were examined. For 2 or 3 screening colonoscopies, the optimal starting age fell to around 50 years or even younger for both genders.
Based on the YPLL estimates, in a high CRC incidence and high life expectancy country like Germany, the optimal age for once-only screening colonoscopy is around 55 years and possibly slightly younger for men than for women. When 2 or more screening colonoscopies are offered with 10-year intervals, screening should start at age 50 at the latest or possibly even younger for both genders.
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: This article has an accompanying continuing medical education activity on page e55. Learning Objectives—At the end of this activity, the successful learner will be able to explain the key molecular alterations of serrated polyps, identify their subtle endoscopic features, and construct an appropriate surveillance plan for the various types of serrated polyps.

: Conflicts of interest The authors disclose no conflicts.

: Funding F. A. Sinicrope is a recipient of a Senior Scientist Award (K05CA-142885) from the U.S. National Cancer Institute.

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Perspectives in clinical gastroenterology and hepatologySerrated Colon Polyps as Precursors to Colorectal Cancer

Section snippets

Classification

Molecular Features of the Serrated Neoplasia Pathway

Epidemiology of Serrated Polyps

Serrated Polyposis Syndrome

Clinical Implications

Detection of Serrated Polyps

Conclusion

Gastroenterology

Gastroenterology

Am J Pathol

Hum Pathol

Gastroenterology

Gastrointest Endosc

Gastroenterology

Gastroenterology

Gastrointest Endosc

Am J Pathol

Am J Pathol

Gastroenterology

Hum Pathol

Gastroenterology

Gastroenterol Clin North Am

Clin Gastroenterol Hepatol

Gastrointest Endosc

Gastrointest Endosc

Gastrointest Endosc

Gastrointest Endosc

Clin Gastroenterol Hepatol

Gastrointest Endosc

Gastrointest Endosc

Gastroenterology

Gastroenterology

Gastroenterology

Global cancer statistics

CA Cancer J Clin

The clinical significance of serrated polyps

Am J Gastroenterol

Morphologic reappraisal of serrated colorectal polyps

Am J Clin Pathol

Serrated polyps of the colon and rectum and serrated polyposis

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

Hyperplastic-like colon polyps that preceded microsatellite-unstable adenocarcinomas

Am J Clin Pathol

Histopathology of serrated adenoma, its variants, and differentiation from conventional adenomatous and hyperplastic polyps

Arch Pathol Lab Med

Sporadic colorectal cancers with microsatellite instability and their possible origin in hyperplastic polyps and serrated adenomas

J Natl Cancer Inst

Serrated polyps of the large intestine

Am J Clin Pathol

Filiform serrated adenomas: a clinicopathologic and immunophenotypic study of 18 cases

Am J Surg Pathol

De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine

Science

Clinicopathologic and genetic characterization of traditional serrated adenomas of the colon

Am J Clin Pathol

CpG island methylator phenotype in colorectal cancer

Proc Natl Acad Sci U S A

Prognostic significance and molecular associations of 18q loss of heterozygosity: a cohort study of microsatellite stable colorectal cancers

J Clin Oncol

Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status

Nature

CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer

Nat Genet

Perspectives in clinical gastroenterology and hepatology
Serrated Colon Polyps as Precursors to Colorectal Cancer