Colorectal cancer in young adults: improving identification and management of familial gastrointestinal cancer syndromes

Abstract

This thesis evaluates colorectal cancer (CRC) outcomes in young adults and explores various approaches of improving identification and management of individuals with genetic familial gastrointestinal (GI) cancer syndromes such as Lynch syndrome (LS) and familial adenomatous polyposis (FAP). Several research methodologies were utilised to address various hypothesis. Firstly, we evaluated differences in clinicopathological features between early onset CRC (adults less than 40 years of age) and late onset CRC and the prevalence of familial gastrointestinal (GI) cancer syndromes in the young adults with CRC. This thesis demonstrated that 28% of EOCRC had hereditary GI cancer syndromes. The rectum was the most common site of CRC and EOCRC tend to present with poor histological features and advanced disease. Although young age was not an independent prognostic factor, EOCRC had worse diseasefree survival. To improve management of individuals at risk of EOCRC, this thesis explored phenotypic and genotypic factors that can be optimised to improve diagnosis, surveillance and surgical Colorectal Cancer in Young Adults: Improving Identification and Management of Familial Gastrointestinal Cancer Syndromes 4 outcomes in LS and FAP. In FAP, we demonstrated that attenuated FAP is an obsolete term due to observed phenotypic and genotypic variability. We also found that the rate of adenoma of progression in the preoperative colorectum and postoperative rectal remnant was slow (12.5 and 5.5 polyps/year respectively). Therefore, tailored endoscopic surveillance and polypectomy (rectum) are appropriate surveillance strategies. Furthermore, surgical outcomes in individuals undergoing prophylactic surgery for can be improved by ileodistal anastomosis (IDSA), a modification of the conventional ileorectal anastomosis. Finally, this thesis demonstrates that pre-operative screening for LS using mismatch repair immunohistochemistry (MMR IHC) testing on preoperative endoscopic biopsy and metastatic tissue is feasible. In the event of LS CRC, a systematic review and meta-analysis demonstrated that extended colectomy should be considered in young individuals with higher risk MMR pathogenic variant to reduce the risk of metachronous CRC.