title: An investigation into the role of faecal calprotectin assessment in the diagnosis and management of colorectal neoplasia
Creators: name: Ross, Fiona A.
Publisher: name: University of Glasgow
Year: 2022

description: Colorectal cancer is the 2nd most common cause of cancer death in the United Kingdom and globally. Although staging and prognosis is based on the tumour, nodes, metastases assessment the role of both local colonic inflammation and systemic inflammation is now recognised as an important component of determining cancer progression and survival. Faecal calprotectin (FC), a measure of colonic inflammation, represents another assessment of inflammation. Whether colonic inflammation measured by FC has a role in development or progression of colorectal cancer (CRC) is not known. Furthermore, it is unclear whether existing measures of local and systemic inflammation relate to colonic inflammation measured by FC. The work presented in this thesis investigates the correlation with faecal calprotectin and colorectal neoplasia, systemic inflammation and the tumour microenvironment. I hypothesised that faecal calprotectin levels are associated with presence of colorectal neoplasia and a diagnosis of colorectal cancer, correlating with advancing disease stage and the presence of local peritumoural inflammation. In chapter 3, a systematic review of the published literature demonstrated that the role of FC in the diagnosis of CRC has not been defined. There is a lack of evidence supporting an association between FC and adenoma/advanced adenomas. However my review confirmed an association between FC and CRC where median FC was higher in CRC, in comparison to healthy subjects in fifteen of the sixteen studies and a 5-fold increased likelihood than controls to have an elevated FC (OR 5.19, 95% CI 3.12-8.62, P&lt;0.001 with a heterogeneity (I2=27%)). In chapter 4, I studied the role of FC in a large, well defined cohort of faecal occult blood test (FOBT) positive patients as part of a screened population. In this study, FC was strongly associated with CRC (sensitivity 92.8% for CRC, at 50μg/g) but lacked specificity. FC also failed to show sufficient sensitivity and specificity for the detection of non-cancer neoplasia. In chapter 5 within this screening cohort, I evaluated the relationships between FC and systemic markers of inflammation, but found no evidence of a strong link between a systemic inflammatory response (SIR) and presence of CRC and no significant relationship between FC and SIR. In chapter 6, a larger cohort of CRC patients in whom FC measurement was performed, advanced disease stage had a possible non-significant association with higher levels of FC, with T4 tumours having the highest median FC (321μg/g), with 67% having a FC ≥200μg/g. 29% of those with T1 tumours had a FC ≥200μg/g. Patients with nodal or metastatic disease had higher median FC, compared to those without. Patients with peritoneal involvement had significantly higher median FC, compared to those without, median FC (405μg/g vs 164μg/g), p &lt;0.05. 89% of patients with peritoneal involvement had FC ≥200μg/g, compared to 44% in those without peritoneal involvement (p&lt;0.05). Poorly differentiated tumours had a higher median FC (281.5μg/g) than well/moderate differentiated tumours (169μg/g), but not significantly. Patients with larger tumours had higher FC levels, tumours ≥3.5cm had a higher median FC 251.5μg/g, and 67% had a FC ≥200μg/g, in comparison to those with a tumour &lt;3.5cm (median 164 μg/g, and 48% FC ≥200μg/g). To summarise larger, more advanced tumours were more likely to have higher levels of FC. In chapter 7, in the context of a pilot study, I assessed whether there was an association between FC and markers of the local inflammatory response. I found that both Klintrup-Mäkinen (KM) and tumour stroma percentage (TSP) have higher FC levels in high grade KM and TSP, in comparison to low grade. As a preliminary study these results, suggest that there may be an association between FC, KM and TSP, which warrants further study. In summary, this thesis has confirmed an association between FC and CRC and potentially in larger, more advanced tumours in CRC. There may be an association between FC and local peritumoural inflammation in the tumour microenvironment in CRC. More work is required to clarify if FC can safely be used in the prioritisation of patients requiring CRC diagnostic investigations and in the staging of CRC as a marker of more advanced disease and a marker of the local inflammatory response.