A clinicopathological and molecular categorisation of serrated colorectal polyps

Bettington, Mark (2015). A clinicopathological and molecular categorisation of serrated colorectal polyps PhD Thesis, School of Medicine, The University of Queensland. doi:10.14264/uql.2015.871

Attached Files (Some files may be inaccessible until you login with your UQ eSpace credentials)
Name Description MIMEType Size Downloads
s33493440_phd_submission.pdf Thesis (open access) application/pdf 6.60MB 0
Author Bettington, Mark
Thesis Title A clinicopathological and molecular categorisation of serrated colorectal polyps
School, Centre or Institute School of Medicine
Institution The University of Queensland
DOI 10.14264/uql.2015.871
Publication date 2015-08-31
Thesis type PhD Thesis
Supervisor Barbara Leggett
Neal Walker
Vicki Whitehall
Total pages 209
Language eng
Subjects 1112 Oncology and Carcinogenesis
Formatted abstract
Approximately 25% of colorectal carcinomas arise via the serrated neoplasia pathway. These cancers develop in serrated type polyps. Removal of these precursor polyps before the development of malignancy offers a unique opportunity to interrupt neoplastic progression and is the rationale for colonoscopic surveillance.

Serrated colorectal polyps fall into three major subtypes; namely hyperplastic polyps, sessile serrated adenomas and traditional serrated adenomas. Hyperplastic polyps are the most numerous, but have limited, if any malignant potential. Sessile serrated adenomas give rise to the majority of serrated neoplasia pathway malignancies. Although rare, traditional serrated adenomas may be more likely to progress, thus requiring closer surveillance. While both are amenable to colonoscopic removal they present unique challenges when compared to the polyps of the “traditional” colorectal cancer pathway. In particular, sessile serrated adenomas are sessile (hence the name) and difficult to detect by colonoscopy, they are frequently misdiagnosed/under-diagnosed by pathologists, resulting in inadequate surveillance and their molecular biology is incompletely understood. Thus the aims of this PhD were to address issues relating to the diagnostic criteria of serrated colorectal polyps and to better define the clinicopathological and molecular features of these lesions.

To this end several study sets were established. Firstly, a cohort to address issues surrounding the diagnosis of the sessile serrated adenoma was collected. Although recognised as a distinct entity for over ten years, uniform diagnostic criteria for the sessile serrated adenoma have not yet been established. In particular the distinction of this polyp from a closely related entity, the microvesicular hyperplastic polyp, has not been adequately addressed. Thus a central review of a consecutive series of 6340 colorectal polyps was undertaken. During the review, the diagnostic criteria of both the WHO and an expert panel convened by the American College of Gastroenterologists were applied to the diagnoses of all microvesicular hyperplastic polyps and sessile serrated adenomas. A comparison of the clinicopathological features of the patients in these separate groups was then performed. This demonstrated a distinct shift in the clinicopathological features at the diagnostic threshold set by the expert panel but not at the threshold set by the WHO. Thus these findings supported the diagnostic criteria of the expert panel to differentiate microvesicular hyperplastic polyps from sessile serrated adenomas. Furthermore, 14.7% of all colorectal polyps met the expert panel diagnostic criteria for a sessile serrated adenoma.

The second study set comprised 200 rigorously diagnosed traditional serrated adenomas. A detailed clinicopathological and molecular assessment was performed on all cases. It was found that traditional serrated adenomas segregated into two key subtypes based on their BRAF or KRAS mutation status. This important molecular distinction underscored a substantial difference in both the clinicopathological and molecular features of these polyps. In particular BRAF mutated traditional serrated adenomas arose from pre-existing sessile serrated adenomas, were more likely to be located in the proximal colon, were more likely to have a sessile growth pattern, were more likely to demonstrate the CpG island methylator phenotype and were more likely to silence CDKN2A as they progressed to carcinoma. Importantly traditional serrated adenomas of all types retained mismatch repair enzyme function, meaning that the BRAF mutated subtype is an important precursor of the very aggressive BRAF mutated, microsatellite stable subtype of colorectal carcinoma.

The third study set comprised a group of tubulovillous adenomas with serrated architectural features. A detailed clinicopathological and molecular assessment of these polyps was performed and then compared to control sets of traditional serrated adenomas and conventional tubulovillous adenomas. It was found that the serrated tubulovillous adenomas could be reliably diagnosed and had features distinct from both of the control cohorts. Furthermore, they had very high rates of KRAS mutation and thus appear to be an important precursor of the KRAS mutated subtype of colorectal carcinoma.

The final study set comprised 137 sessile serrated adenomas with dysplasia and or carcinoma. These polyps were subjected to a detailed clinicopathological and molecular assessment, with a particular emphasis on the distinction between mismatch repair deficient and mismatch repair proficient cases. This dichotomy underscores the microsatellite instability status of the polyps and has important implications for the prognosis of the resultant carcinomas. It was found that mismatch repair proficient cases had distinct features. In particular they arose more often in males, at a younger age and more often in the distal colon than mismatch repair deficient cases. Furthermore, they were less likely to show the CpG island methylator phenotype and were more likely to harbour a TP53 mutation.

In summary, this thesis has provided evidence to direct the diagnosis of the sessile serrated adenoma, has identified key molecular subtypes of both sessile serrated adenomas and traditional serrated adenomas and has better elucidated the pathways by which these polyps progress to carcinoma. Finally a novel polyp subtype, namely the serrated tubulovillous adenoma has been proposed that appears to have distinctive histological and molecular features. This improved understanding of serrated colorectal polyps will contribute to better pathological diagnosis and to a more scientific basis for colonoscopic surveillance protocols.
Keyword Serrated
Colorectal carcinoma

Document type: Thesis
Collections: UQ Theses (RHD) - Official
UQ Theses (RHD) - Open Access
Version Filter Type
Citation counts: Google Scholar Search Google Scholar
Created: Sat, 15 Aug 2015, 23:38:45 EST by Mark Bettington on behalf of Scholarly Communication and Digitisation Service