Improvement of the diagnosis and management of cystic tumors of the pancreas

Sammanfattning: Pancreatic cancer is on its course on becoming the second cause of cancer related mortality. Although improvements have been made in the treatment arsenal, still only a minority of patients are able to receive treatment with curative intention. This can be attributed to the fact that most of the pancreatic cancers are diagnosed at a later stage when curative therapy is no longer possible. Thus, efforts are being made to find pancreatic cancer and its precursor lesions at an earlier stage. Intraductal papillary mucinous neoplasms (IPMN) is the most common type of cystic lesion which has the potential for malignant transformation. Hence, an accurate and early diagnosis of this entity could contribute to reverse the dismal trend of pancreatic cancer. Study I & II Aim: To identify and correlate risk factors for advanced histological findings in IPMN patients. Methods: These were retrospective studies in which patients undergoing resection for IPMN during 2008-2015 (study I) and 2004-2017 (study II) were included. Patients characteristics, radiological and histological data were prospectively collected. Results: One-hundred-fifty-two patients were included in study I and 796 patients in study II. In study I, main pancreatic duct (MPD) dilatation of 6-9.9 mm and >10 mm were associated with an increased risk of advanced IPMN histology, such as high grade dysplasia (HGD) and cancer, at odds of 2.92 (CI 1.38–6.20, p=0.005) and 2.65 (CI 1.12–6.25, p=0.02), respectively. In addition, jaundice and elevated levels of CA 19-9 were also associated with higher risk for HGD/cancer at odds of 15.36 (CI 1.94–121.22, p=0.009) and 4.15 (CI 1.90–9.05, p=0.0003), respectively. These associations remained significant at uni- and multivariable regression analysis. In study II, the results showed MPD-dilatation to be the lone significant variable associated with increased probability of HGD or IPMN-cancer at both uni- and multivariable analysis. MPD dilatation of 5-9.9 mm was associated with odds of 2.74 (CI 1.80–4.16) and 4.42 (CI 2.55–7.66) for HGD and IPMN-cancer respectively. MPD-dilatation over 10 mm was associated with greater odds of 6.57 (CI 3.94–10.98) and 15.07 (CI 8.21–27.65) for HGD and IPMN-cancer, respectively. A 5-7 mm diameter of the MPD was determined as the cut-off value to best discriminate between the lesions with low risk of malignancy to those with a high risk. Conclusions: Even a smaller dilatation of the MPD is associated with increased risk of HGD and IPMN-cancer. Dilatation of the MPD and elevated levels of CA 19-9 are important diagnostic markers of advanced histology, thereby facilitating proper selection of patients most suitable for surgery. Study III & IV Aim: To define and validate the metabolic profile of patients with IPMN and serous cystic neoplasm (SCN) and to correlate the metabolite levels to histology and grade of dysplasia. Methods: Plasma and cyst fluid were prospectively collected from patients undergoing resection for IPMN and SCN. Targeted and untargeted analysis of metabolites and lipids species were performed and correlated to histology and clinical parameters. Results: From a cohort of 35 patients in study III and 57 patients in study IV several metabolites and lipids were identified in both cyst fluid and plasma. In study III, the metabolic profile showed significant alterations in the lipid pathways. An integrated metabolomic and lipidomic analysis model was able to discriminate IPMN from SCN up to 100% accuracy. The results in study IV not only validated the results from study III but also found novel metabolites able to discriminate non-cancerous lesions (low-grade IPMN and SCN) from malignant (HGD and cancer). Furthermore, specific metabolites correlated to presence of bacteria sequences in the cyst fluid. Conclusion: Analysis of the metabolic profile in cyst fluid and plasma from IPMN patients has been able to discriminate IPMN from SCN with high accuracy and also to predict the degree of dysplasia within IPMN. This method has shown potential of clinical application which in turn could improve the diagnosis of pancreatic cystic lesions. Study V Aim: To investigate the rate of new recurrence and progression of known IPMNs in the remnant pancreas after pancreatic surgery and to investigate if the grade of dysplasia at first histology affects the risk of recurrence. Methods: This was a retrospective study in which patients undergoing an elective partial pancreatic resection between 2008 and 2017 were included. Patients who underwent total pancreatectomy and/or had less than 2 years of follow-up were excluded. Patient characteristics and data of radiology, histology and recurrence was collected prospectively. Clinical significant recurrence was defined as findings resulting in a change in the management of the lesion. Results: Overall 224 patients were included in the study. The overall recurrence rate was 44.6% (100/224), whereas the clinical significant recurrence rate was 30.8% (69/224). Patients older than 65 years presented 4.4 odds (CI 1.5-13.1) of recurrence and patients with “known IPMN left in remnant” had 2.6 odds (CI 1.12-5.9) of recurrence. Patients with LGD and HGD at first histology without concomitant PDAC had a clinical significant recurrence rate of 11.1% (15/135). No differences regarding risk of recurrence could be found when comparing patients with LGD to HGD (HR 1.1 [CI 0.5-2.2]). Conclusion: Patients with LGD and HGD at first histology harbor a not negligible risk of future malignant transformation and should not be overlooked. The risk is further increased if the patient is older and/or have a previously known IPMN in the remnant. The overall conclusion of the thesis is that the included studies have increased the knowledge on several aspects in the diagnosis and management of cystic tumors of the pancreas. A known radiological diagnostic marker, the dilatation of the main pancreatic duct, has been studied where the results show that even smaller dilatations over 5 mm may indicate malignancy. An upcoming field in metabolomics has been applied on pancreatic cystic neoplasms and has shown great potential as a future diagnostic method. Lastly, the post-operative management of IPMN patients has been studied where the results highlight the need for continued clinical surveillance due the risk of recurrence even after surgery.