Keane, Margaret Geraldine; (2025) The development of novel diagnostic markers and treatments for cystic lesions of the pancreas. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Pancreatic cysts are an increasingly common clinical finding, present in 13-49% of patients undergoing magnetic resonance imaging for non-pancreatic reasons. They have a wide differential diagnosis, which includes a small proportion that will ultimately progress to invasive cancer. Pancreatic ductal adenocarcinoma is the third leading cause of cancer death in Europe. In the UK approximately 10,000 people are diagnosed with the disease annually. In most cases curative surgical resection is not possible, and this is largely attributed to late diagnosis. Approximately 15% of pancreatic cancers arise from precancerous pancreatic cysts (Intraductal Papillary Mucinous Neoplasms or Mucinous Cystic Neoplasms), offering a unique opportunity for early detection and curative intervention, in a disease with a dismal prognosis and five-year survival of less than 7%. The natural history of pancreatic cystic lesions (PCL) remains poorly understood. Chapter 2 summarizes the surveillance and surgical outcomes from a large UK cohort. Growing numbers of patients are being followed annually. Chapter 3 demonstrates through a questionnaire-based study, that surveillance for PCL with low malignant potential is anxiety provoking and worrisome for patients. In patients referred for surgical resection, only a third are found to have invasive cancer. Better diagnostic tests are therefore needed to more accurately diagnose invasive cancer preoperatively. Chapter 4 provides a systematic review of biomarkers for pancreatic cancer. Chapter 5 evaluates novel cell cycle biomarkers in cyst fluid, for the identification of high-risk lesions. Chapter 6 summarises the results of a phase II study of the safety and utility of endoscopic ultrasound guided needle based confocal endomicroscopy (EUS nCLE) for detection of high-risk PCL. Although improved sensitivity and diagnostic accuracy was demonstrated, this was not significantly better than cyst fluid cytology, which is the current standard of care. Chapter 7 explores if fluoroscopic labeled biomarkers could differentiate high risk PCL and discusses if ultimately these biomarkers could be used to improve the EUS nCLE technique. Overtreatment remains a concern in patients with PCL, sent for surgical resection. Chapter 2 highlights less than a third of patients are ultimately diagnosed with invasive cancer. Pancreatic surgery, even when performed in high volume centres, is associated with significant morbidity (up to 40%) and mortality (0-4%). Minimally invasive ablative techniques are an attractive alternative to surveillance in low-risk lesions and for high-risk lesions in those unfit for surgery or who refuse surgery. Chapter 9 summarises the results from a phase II study of the safety and utility of endoscopic ultrasound guided radiofrequency ablation in the treatment of premalignant PCL.

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