2010-04-12 19:24:26 UTC

The Serrated Polyp Pathway to Colorectal Cancer: Implications for the Clinician

April 12, 2010

Dennis J. Ahnen, MD

Dennis J. Ahnen, MD

Denver Department of Veterans Affairs Medical Center, Colorado Professor of Medicine, University of Colorado Denver School of Medicine  


The recognition of a putative serrated polyp pathway to colorectal cancer (CRC) has challenged the fundamental view that colon adenocarcinomas arise only from conventional adenomas. How did this happen, how strong is the data that a serrated polyp pathway actually exists and what are the clinical implications of such a pathway to cancer?

Until the late 1990s, colorectal polyps were generally divided into two major subtypes: hyperplastic polyps (HPs) and adenomatous polyps, and the consensus opinion was that adenomatous polyps were the precursor of CRC, while HPs were considered to have little or no clinical significance. This changed dramatically as pathologists described a spectrum of polyps that had some architectural similarities to HPs, but also had some cytologic and biologic features that were similar to classic adenomas. It was the molecular biologists, however, who convincingly showed that a serrated polyp pathway to cancer that was distinct from the classic adenoma-carcinoma sequence existed.

Longacre and Fenoglio-Preiser1 first used the term “serrated adenoma” to describe polyps that had sawtooth-shaped infoldings (serrations) of the surface, crypt epithelium and a rather uniform dysplastic cytology. In 2003, Torlakovic et al.2 suggested that serrated polyps be further divided into two groups: traditional serrated adenomas (TSAs) for those described by Longacre et al. and sessile serrated adenomas (SSAs) for lesions that had a serrated architecture, which typically extended the full length of the glands and were associated with dilated crypts that were often L- or flask-shaped, but did not necessarily have classic cytologic dysplasia. Some SSAs, however, do develop distinct foci of unequivocal dysplasia and these are sometimes referred to as mixed polyps (MPs). HPs, TSAs, SSAs and MPs are all classified as serrated polyps and it is thought that many of these lesions had been previously reported as HPs by most pathologists. TSAs are rare and their role as a CRC precursor is not well defined, but there is both histologic and molecular evidence supporting an HP-SSA-MP pathway to CRC.

Histologic evidence

The finding that some colonic adenocarcinomas (up to 15 percent of proximal CRCs) have a distinct serrated mucosal surface similar to that seen in serrated polyps suggests the possibility of a pathogenic relationship. More convincing, however, is the evidence of serrated cancers with residual SSA or MP at their periphery and the finding of MPs containing areas of high-grade dysplasia or focally invasive cancer.3, 4 The frequent finding of serrated polyps nearby microsatellite unstable CRCs suggested a possible link between the serrated polyp and the microsatellite unstable subset of CRCs. Finally, the description of a familial syndrome (hyperplastic polyposis or serrated adenomatous polyposis), characterized by numerous serrated polyps and a markedly increased cancer risk, suggests that serrated polyps5 can be the precursor to CRC in a manner analogous to the link between familial adenomatous polyposis and the classic adenoma-carcinoma sequence. Large HPs, SSAs and microsatellite unstable CRCs are all more common in the proximal than in the distal colon. These regional and histologic associations have been cited to support the concept that large HPs, SSAs and MPs could be the precursor of some CRCs, particularly those of the proximal colon.

Molecular evidence

About 85 percent of sporadic CRCs originate through what is called the chromosomal instability (CIN) pathway described by Vogelstein et al.6 that gives rise to aneuploid, microsatellite stable CRCs. About 15 percent of sporadic CRCs appear to arise from a distinct molecular pathway, which gives rise to diploid microsatellite unstable CRCs. Molecular analyses of microsatellite unstable CRCs have provided strong evidence that the precursor of these cancers cannot be the classic adenoma and is likely to be the serrated polyp.

Microsatellite instability (MSI)

MSI is due to failure of DNA mismatch repair and was originally described in families with Lynch syndrome, which is due to a germline mutation in one of the DNA mismatch repair genes. It is now known that most microsatellite unstable CRCs occur sporadically and are due to defective DNA mismatch repair induced by epigenetic hypermethylation of CpG islands in the promoter region of one of the DNA mismatch repair genes MLH1. MSI is not a feature of either classic adenomas, HPs or SSAs, but can be seen in the dysplastic foci of MPs.4, 7, 8

CpG island methylator phenotype (CIMP)

The finding that MSI in sporadic CRCs is due to hypermethylation of MLH1 linked these tumors to an epigenetic process of gene silencing termed CIMP.3, 4 CIMP refers to non-random hypermethylation of promoter regions of numerous cancer-related genes, including MLH1. CIMP can be seen in both HPs and classic adenomas, but is much more frequently seen in SSAs and MPs.7, 8

BRAF mutations

Mutations in the BRAF kinase are found in about 75 percent of MSI CRCs, but in less than 10 percent of microsatellite stable CRCs. This is of interest because the BRAF protein is immediately downstream from KRAS in a kinase pathway known to be important for growth factor signaling, and the KRAS gene is one of the most commonly mutated oncogenes in the classic CIN pathway to CRC. Conceptually, mutational activation of both KRAS and BRAF would be redundant as they would both activate the same signaling system. In fact, mutations in these two genes appear to be mutually exclusive in colonic neoplasia. Classic colonic adenomas commonly have KRAS mutations, but rarely have BRAF mutations, suggesting that the colonic adenoma is not likely to be the precursor of sporadic MSI CRCs. The large majority (60 percent to 80 percent) of microvesicular HPs, SSAs and MPs have BRAF mutations, suggesting that these serrated polyps are the precursors of sporadic MSI CRCs.7, 8

Thus, both histologic and molecular data strongly suggests that some HPs may give rise to SSA and MPs, which are the precursors of most MSI CRCs. The data does not suggest that all HPs are at risk for progression to cancer, but that large and right-sided HPs as well as SSAs and MPs should be viewed as a putative cancer precursor.

Clinical implications

The existence of a serrated polyp pathway doesn’t fundamentally alter the approach to CRC prevention with colonoscopy, but it does highlight the importance of several of the current guidelines for high-quality colonoscopy.

Perform careful colonoscopy

Undetected lesions have been cited as the most common cause of interval advanced adenomas and cancers in patients undergoing surveillance colonoscopy.9 Miss rates may be higher for large HPs and SSAs than for adenomas since they are more often flat, right sided and are sometimes covered with mucus, making them difficult to distinguish from the surrounding normal mucosa. Thus, good quality patient preparation, particularly of the right colon, and careful visualization during white light colonoscopy are essential for the identification and characterization of these lesions. The routine use of a split prep and monitoring of cecal intubation rates, adenoma detection rates and withdrawal times seem like reasonable measures that might decrease miss rates of all types of colonic polyps.

Remove all colonic polyps completely whenever feasible

The Multi-Society Task Force on Colorectal Cancer recommends that all polyps identified during colonoscopy should be completely removed (multiple diminutive hyperplastic-appearing polyps in the rectosigmoid are an exception, which may be sampled).10 Assurance of complete polypectomy may be more difficult for large HPs and SSAs since their borders may be less distinct than those of classic adenomas. The availability of chromoendoscopy, narrow band imaging or similar technologies may be helpful to define the surface characteristics and borders of serrated polyps.11 Complete excision may also be aided by the routine use of a snare technique with care to include a margin of normal mucosa in the polypectomy specimen for even small polyps, rather than the use of multiple pinch biopsies. As is recommended for large adenomas, the adequacy of the polypectomy margin should be reviewed for large serrated polyps, and repeat colonoscopic evaluation of the larger (>2 cm) polypectomy sites is recommended.10 Just as occasionally required for complete removal of conventional adenomas, surgical resection should be considered for removal of large proximal serrated polyps if repeat attempts at colonoscopic polypectomy fail.

Base surveillance on histology  of the removed polyp(s)

The presence of only diminutive HPs in the rectosigmoid is not thought to predict an increased subsequent risk of CRC, so screening and surveillance intervals should not be changed by this finding. Although recommendations may change as we learn more about the other types of colonic serrated polyps, it seems reasonable now to follow these lesions in a manner similar to traditional adenomatous polyps.12 Surveillance intervals for completely removed large HPs and SSAs without dysplasia can be similar to those for small tubular adenomas (five years to 10 years), although five-year intervals seem prudent initially since the natural history of these lesions is unclear. Recommended surveillance intervals after completely removed serrated adenomas with dysplasia (MPs and TSAs) or for more than two SSAs or large HPs are similar to those for advanced adenomas (three years).         


Both histologic and molecular evidence indicates that the serrated polyp-carcinoma sequence appears to be a genuine pathway to CRC. The polyps of this pathway, which have the potential of developing into sporadic MSI carcinomas, should be identified and treated with careful colonoscopy (good patient prep, sufficient withdrawal times and complete polypectomy). Until better natural history information is available, it seems reasonable to follow SSAs, MPs, TSAs and even large right-sided HPs in a manner similar to the current follow-up of conventional adenomas.


  1. Longacre T, Fenoglio-Preiser C, Mixed hyperplastic adenomatous polyps/serrated adenomas. A distinct form of colorectal neoplasia. Am J Surg Pathol 1990; 14:524-37.
  2. Torlakovic E, Skovlund E, Snover D, et al., Morphologic reappraisal of serrated colorectal polyps. J Surg Pathol 2003;27:65-81.
  3. Makinen M, Gearge S, Jernvall P, et al., Colorectal carcinoma associated with serrated adenoma--prevalance, histological features, and prognosis. J Pathol 2001; 193:286-294.                                        
  4. Huang S, Obrien M, Hyperplastic polyps, serrated adenomas, and the serrated polyp neoplasia pathway. Am J Gastroenterol 2004;99:2242-2255.
  5. Jass J, Lino H, Ruszkiewicz A, et al., Neoplastic progression occurs through mutator pathways in hyperplastic polyposis of the colorectum. Gut 2000;47:43-49.
  6. Vogelstein B, Fearon E, Hamilton S, et al., Genetic alterations during colorectal-tumor development. NEJM 1988;319:525-32.
  7. O’Brien M, Yang S, Mack C, et al., Comparison of micorsatellite 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 J Surg Pathol 2006;30:1291-1501.
  8. East J, Saunders B, Jass J, Sporadic and syndromic hyperplastic polyps and serrated adenomas of the colon: classification, molecular genetics, natural history, and clinical management. Gastroenterol Clin North Am 2008.;37:25-46.
  9. Pabby A, Schoen R, Weissfeld J, et al., Analysis of colorectal cancer occurrence during surveillance colonoscopy in the dietary polyp prevention trial. Gastrointest Endosc 2005;61:385-91.
  10. Rex D, Bond J, Winawer S, et al., Quality in the technical performance of colonoscopy and the continuous quality improvement process for colonoscopy: recommendations of the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol 2002;97:1296-308.
  11. Soetikno R, Kaltenbach T, Rouse R, et al., Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA 2008;299:1027-1035.
  12. Snover D, Jass J, Fenoglio-Preiser C, et al., Serrated polyps of the large intestine: a morphological and molecular review of an evolving concept. Am J Clin Pathol 2005;124:380-391.




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