serrated adenoma pathway

Definition: The serrated polyposis syndrome (SPS) is a relatively rare condition characterized by multiple and/or large serrated polyps of the colon. Mutation in BRAF, along with CpG island methylator phenotype, is the molecular marker of "serrated neoplasia pathway" CRC, in which serrated polyps are thought to be the precursor lesions.

In 1999, Iino et al suggested that a proportion of hyperplastic polyps may serve as precursors of some CRC cases.

Now, there is increasing evidence showing that, in some conditions, hyperplastic polyps can be the initial premalignant lesion in the "serrated pathway of carcinogenesis".

Some studies have reported the existence of BRAF mutations in sporadic MSI CRCs which show CIMP suggesting the existence of this alternative pathway.

BRAF mutations and DNA methylation would be early events in this pathway with serrated polyps as precursor lesions.

The lack of adenoma-specific mutations such as APC, KRAS and TP53 in sporadic MSI CRCs, and the fact that BRAF mutation and methylation of CpG islands are exceptional in classic adenomas supports the existence of this pathway.

Tumors following this pathway show some specific characteristics, being more frequent in females and located in the right colon.

Moreover, some preliminary studies suggest that these tumors could be unresponsive to 5-fluorouracil chemotherapy.

Diagnosis

Diagnosis of this disease is made by the fulfillment of any of the World Health Organization’s (WHO) clinical criteria.

SPS exhibits an increased risk of CRC, which occurs on average in subjects aged between 50 to 60 years.

There is a high incidence of synchronous cancers and CRC shows a trend to be located in the proximal colon.

These patients and their relatives should receive strict surveillance strategies because of the high risk of CRC. This review focuses on the SPS, its genetics and management.

Hyperplastic polyps have traditionally been considered not to have malignant potential. New pathological classification of serrated polyps and recent discoveries about the serrated pathway of carcinogenesis have revolutionized the concepts and revitalized the research in this area.

Serrated polyposis syndrome is a relatively rare condition characterized by multiple and/or large serrated polyps of the colon. Clinical characteristics, etiology and relationship of serrated polyposis syndrome to CRC have not been clarified yet.

Patients with this syndrome show a high risk of CRC and both sporadic and hereditary cases have been described. Clinical criteria have been used for diagnosis and frequent colonoscopy surveillance should be performed in order to prevent colorectal cancer.

"Serrated polyposis" syndrome is the paradigm of the "serrated pathway of carcinogenesis" and an excellent and interesting human model for the study of the features that drive progression from hyperplastic polyps (HP) to serrated carcinoma.

These patients show clinical, pathological and molecular features that are very useful for expanding the knowledge of this particular and alternative carcinogenetic pathway.

Clinical synopsis

Characteristics of patients with SPS have been defined mainly based on the publication of series of cases.

There is no sex predominance and the mean age at diagnosis is around 55 years.

SPS has largely been considered a genetic disease, but the pattern of inheritance remains unknown: both autosomal recessive and autosomal dominant patterns have been suggested.

Published case series report that between 10%-50% of patients meeting SPS criteria have a family history of CRC. In this way, Boparai et al. have recently described an increased risk of CRC [relative risk (RR) = 5.4] and SPS (RR = 39) in first-degree relatives of probands diagnosed with SPS compared to the general population.

It is important to point out that conventional adenomas may coexist with serrated polyps in patients with SPS.

Some authors have suggested the existence of various phenotypes within the SPS definition.

Kalady et al described three phenotypic patterns in a series of 115 patients with multiple serrated polyps:
 (1) The patients presented a right-sided phenotype with large sessile serrated adenomas (SSAs) and with a CRC onset in younger individuals (48%);
 (2) Left-sided phenotype with a greater amount of small polyps (16%);
 (3) Mixed phenotype with shared features of the previous phenotypes (37%).

These different patterns should be revised in future studies.

Environmental factors could be partially responsible for the phenotypic differences and model the unknown pattern of inheritance.

Smoking, being overweight and some drugs have been postulated as potential risk factors of HPs.

Samowitz et aldescribed a statistically significant dose-response association between CIMP+ CRC and smoking.

Moreover, Walker et al found a strong association between cigarette smoking and SPS (odds ratio = 8.3; 95% CI: 3.0-22.9) in a case-control study comparing SPS patients with a population-based registry.

Wallace et al, using the data of multicenter chemoprevention trials, came upon the association of some environmental factors with an increased risk of colonic serrated polyps (not necessary SPS criteria).

On the one hand, in the left colon, obesity, smoking, increased dietary fat and red meat intake were linked with serrated polyps.

On the other hand, in the right colon, the risk factors were folate intake and family history of polyps, whereas aspirin treatment was shown as a protective factor.

Diagnostic criteria

Diagnostic criteria of SPS were first defined by Burt and Jass in 2000 for the WHO. These criteria have been recently redefined and this entity is now called "Serrated Polyposis".

A patient is diagnosed with SPS if at least one of the following criteria is met:
 (1) At least five serrated polyps proximal to the sigmoid colon, two of which are greater than 10 mm in diameter;
 (2) Any number of serrated polyps occurring proximal to the sigmoid colon in an individual who has a first-degree relative with serrated polyposis;
 (3) More than 20 serrated polyps of any size distributed throughout the colon.

This arbitrary definition has been considered over the years somewhat restrictive. Moreover, SPS probably comprises a heterogeneous group of patients that includes several phenotypes of serrated polyposis. However, until the molecular basis of this syndrome is better understood, this clinical definition is applicable.

The "serrated pathway of colorectal carcinogenesis"

Colorectal cancer (CRC) is a common and lethal disease. It is a major health issue in western countries where it represents the second most common fatal malignancy after lung cancer.

Until recently, it has been thought that most CRCs arise from conventional adenomas via the traditional tumor suppressor pathway initiated with a mutation of the APC gene, but it has been found that this pathway accounts for only approximately 70%-80% of CRC cases.

The majority of the remaining CRC cases (20%-30%) follow an alternative pathway leading to CpG island methylator phenotype (CIMP+) carcinoma with BRAF mutation and with or without microsatellite instability.

This pathway is called the "serrated pathway of colorectal carcinogenesis".

The mechanism of carcinomas arising from this alternative pathway seems to begin with an activating mutation of the BRAF oncogene. This BRAF mutation provokes the development of serrated lesions that are mainly microvesicular hyperplastic polyps or sessile serrated polyps.

These lesions are prone to methylation of CpG islands in the promoter regions of genes resulting in their epigenetic silencing.

The best characterized gene silenced by this mechanism is MLH1. This gene is one of the mismatch repair genes and its epigenetic silencing results in sporadic tumors with microsatellite instability (MSI).

However, other genes such as P16, MGMT, or IGFBP7 may also be epigenetically inactivated.

Genetics

Until recently, it has been thought that most colorectal cancers arise from conventional adenomas via the traditional tumor suppressor pathway initiated by a mutation of the APC gene, but it has been found that this pathway accounts for only approximately 70%-80% of colorectal cancer (CRC) cases.

The majority of the remaining colorectal cancer cases follow an alternative pathway leading to CpG island methylator phenotype carcinoma with BRAF mutation and with or without microsatellite instability.

The mechanism of carcinomas arising from this alternative pathway seems to begin with an activating mutation of the BRAF oncogene.

The serrated neoplasia pathway is thought to give rise to the majority of sporadic microsatellite instability-high (MSI-H) colon cancer.

Tubular and tubulovillous adenomas with features of the serrated neoplasia pathway have been described, and unlike "sessile serrated adenomas", these lesions lack BRAF mutations.

Histological analysis of the precursor adenomas to sporadic MSI-H colon cancer demonstrated a high frequency of "crypt serrations" compared with MSS colon cancer (93 vs 36%, P

<0.001).>

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References

 Multiplicity and Molecular Heterogeneity of Colorectal Carcinomas in Individuals With Serrated Polyposis. Rosty C, Walsh MD, Walters RJ, Clendenning M, Pearson SA, Jenkins MA, Win AK, Hopper JL, Sweet K, Frankel WL, Aronson M, Gallinger S, Goldblatt J, Tucker K, Greening S, Gattas MR, Woodall S, Arnold J, Walker NI, Parry S, Young JP, Buchanan DD. Am J Surg Pathol. 2012 Dec 1. PMID: #23211288#

 Proximal colon cancers and the serrated pathway: a systematic analysis of precursor histology and BRAF mutation status. Patil DT, Shadrach BL, Rybicki LA, Leach BH, Pai RK. Mod Pathol. 2012 Jun 8. PMID: #22684223#