Elsevier

Human Pathology

Volume 42, Issue 1, January 2011, Pages 1-10
Human Pathology

Progress in pathology
Update on the serrated pathway to colorectal carcinoma

https://doi.org/10.1016/j.humpath.2010.06.002Get rights and content

Summary

Adenocarcinoma of the large intestine can no longer be considered one disease but rather a family of diseases with different precursor lesions, different molecular pathways, and different end-stage carcinomas with varying prognoses. Approximately 60% of colorectal carcinomas arise from conventional adenomas via the suppressor pathway leading to microsatellite stable carcinomas. These carcinomas represent the pathway that has been the target of screening and prevention programs to date. However, approximately 35% of carcinomas arise along the serrated pathway developing from the precursor lesion known as the sessile serrated adenoma (also referred to as the sessile serrated polyp). Sessile serrated adenomas/polyps lead to carcinomas with extensive CpG island promoter methylation (CpG island methylated phenotype positive carcinomas), which can be either microsatellite instable high or microsatellite stable. The remaining 5% of carcinomas arise from conventional adenomas in patients with germ line mutations of mismatch repair genes (Lynch syndrome), leading to CpG island methylated phenotype negative microsatellite instable carcinomas. Carcinomas arising from sessile serrated adenomas/polyps are not prevented by removing conventional adenomas and hence may be missed in routine screening programs. In addition, a subset of these lesions may potentially progress rapidly to carcinoma; hence, it is likely that these lesions will require a different screening strategy from that used for conventional adenomas. This article reviews the various pathways to colorectal carcinoma with emphasis on the serrated pathway and evaluates the implications of this pathway for colorectal carcinomas screening programs.

Introduction

Colorectal carcinoma is a major health issue in the United States, representing the second most commonly fatal malignancy after lung. Although it is often assumed that almost all colorectal carcinomas arise from conventional adenomas via the suppressor pathway initiated with a mutation of the APC gene (the Fearon-Vogelstein model), it is now clear that this pathway accounts for only approximately 60% of colon carcinoma [1], [2]. Most of the remaining 40% is accounted for by the more recently described serrated pathway leading to CpG island methylated phenotype (CIMP+) carcinoma (approximately 35%), with the remaining 5% arising via the mutator pathway in Lynch syndrome [2]. Trying to understand the multiplicity of pathways is confused by a plethora of overlapping ways to describe these pathways and cancers. Pathways have been defined by the presumed initiating factor (ie, suppressor [chromosome instability] versus mutator [microsatellite instability] pathways) and by the presumed precursor lesions (ie, conventional adenoma-carcinoma sequence versus the serrated pathway). A commonly utilized subdivision into microsatellite stable (MSS) carcinomas (which represent both suppressor pathway carcinomas arising either sporadically or in familial adenomatous polyposis as well as approximately 60% of CIMP+ carcinomas arising along the serrated pathway) and microsatellite instable high (MSI-H) carcinomas (by convention usually referred to as “MSI” carcinoma without the “high” or “-H” descriptor), which represent all carcinomas in Lynch syndrome arising via the mutator pathway, as well as approximately 40% of sporadic CIMP+ carcinomas, is useful for detecting patients with Lynch syndrome but still represents a phenotypic end stage of differing pathways. All of these different descriptions overlap to some degree. The conventional APC initiated adenoma-carcinoma pathway leads to FAP and sporadic CIMP− colon cancers arising via the suppressor pathway as well as cancers in Lynch syndrome arising along the mutator pathway. The alternate serrated pathway leads to CIMP+ carcinomas either by a mutator pathway (leading to sporadic MSI+CIMP+ carcinomas) or a pathway (details of which are still unknown) that leads to MSS CIMP+ carcinomas. In addition, there remain probable other pathways to colorectal carcinomas that have not yet been well worked out, including MSI-low (MIS-L) carcinomas and carcinomas associated with mutation of the MYH gene, both of which may have some relationship to the serrated pathway. These various pathways and their overlaps are summarized in Fig. 1. Current thinking regarding colorectal pathways was recently summarized in review by the late Jeremy Jass, and this article is recommended reading for anyone wishing to understand the multiple pathways to colorectal carcinoma [2].

Because most screening and intervention programs for colon carcinoma have been directed toward the elimination of conventional adenomas, it would appear that at best a 65% reduction in colorectal carcinoma can be expected by our current approach. Eliminating the other 35% will require a better understanding of the serrated pathway and precursor lesions of the serrated pathway, mainly the lesion known as the sessile serrated adenoma (SSA; AKA sessile serrated polyp) and the less common traditional serrated adenoma (TSA). This review will focus on these lesions and current controversies related to them.

Section snippets

Molecular mechanisms of carcinomas development via the serrated pathway

Developing a management scheme for dealing with serrated lesions requires an understanding of the underlying mechanism of molecular carcinogenesis. The basic mechanism for the suppressor pathway to colon carcinoma begins with a mutation of the APC tumor suppressor gene, which allows unregulated proliferation of epithelial cells with the formation of the a lesion conventionally known as an “adenoma” (these APC-related adenomas will be referred to as “conventional adenomas” throughout this

Precursor lesions of the serrated pathway

As recently as 2003, all of the various serrated lesions were considered hyperplastic or “metaplastic” polyps, and their malignant potential was not well recognized, but it is now generally recognized that these lesions represent a complex family of lesions differing in their specific underlying mutation and degree of methylation [3], [4], [5], [7], [8], [9], [10], [11]. As yet unknown factors lead to alterations in the location of the proliferative zone as well as differences in the anchoring

Terminology and diagnostic criteria

Details of the histological appearance of these lesions have been reviewed extensively elsewhere [7], [8], [9], [10], [11] and will not be repeated here except to provide a brief review and introduction into current issues.

Although the terminology is not perfect because these lesions are not truly “hyperplastic” or “metaplastic,” the term hyperplastic polyp (HP) has been retained for the most indolent form of serrated lesions [11]. These lesions are characterized by variably prominent

The role of SSA/P in carcinogenesis and its effect on management of these lesions

As noted in the introduction, it is now generally recognized that “colon cancer” comprises a family of diseases with various molecular pathways. There is now no question that SSA/P is the immediate precursor lesion to sporadic CIMP+MSI carcinomas. SSA/P is likely the precursor lesion to CIMP+MSS carcinomas as well. Combined, CIMP+MSI and CIMP+MSS carcinomas account for approximately 35% of all colorectal carcinoma; hence, these are very important lesions to recognize and deal with if one wants

Proposed solutions to ongoing issues

As noted above, perhaps the more important issues regarding serrated lesions involve appropriate management, although terminology remains an issue as well. The management issue is amenable to further clinicopathological studies focusing on natural history, not only for the more common SSA/P but also for TSA, since we know the least about that lesion. Additional molecular characterization of specific genetic changes resulting in CIMP+MSS carcinomas and for carcinomas arising in TSA will also be

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