Side-branch Intraductal Papillary Mucinous Neoplasms Research Articles

Disease progression of side-branch intraductal papillary mucinous neoplasms following solid organ transplant

BackgroundBranch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) are becoming more prevalent with advanced medical imaging and account for most of pancreatic cystic neoplasms (PCNs). Most incidental lesions should be surveyed, with resection reserved for specific, high-risk cases. Solid organ transplantation candidates may be high risk of resection before transplant and will require systemic immunosuppression after transplant, which has been theorized to alter the natural history of the IPMN. We aimed to describe the progression in surveilled cysts after solid organ transplantation. MethodsA prospectively maintained database of PCNs was queried for patients with IPMN. Patients who had received a previous solid organ transplantation and with ≥2 imaging studies >6 months apart after transplantation were included. Clinically relevant (CR) progression was defined as symptoms, worrisome/high-risk stigmata, or invasive carcinoma (IC). Growth ≥5 mm in 2 years is considered CR progression; size ≥3 cm alone is not. ResultsBetween 1997 and 2023, 252 patients received solid organ transplantation (liver, 86; kidney, 113; and lung, 54) and were diagnosed as having an IPMN. This cohort was compared with a set of 770 patients surveilled for IPMN who did not have previous transplantation. Median follow-up period was 3.7 years (IQR, 1.6–6.8). Moreover, 2 transplant patients (0.8%) developed IC, and 4 developed (1.6%) high-grade dysplasia (HGD). Both were less common in transplant patients than the nontransplant population (IC, 3.3%; HGD, 2.9%), although this was not significant on time-to-event analysis (IC, P = .152; HGD, P = .352). The rate of CR progression was high in the transplant cohort (n = 118; 47%). Features of CR progression included size growth (n = 79; 67%), other worrisome/high-risk stigmata (n = 25; 21%), and new main duct involvement (n = 14; 12%). Compared with the nontransplant (n = 128; 17%), transplant patients had a higher rate of CR progression (P < .001), which was mostly explained by a more frequent size growth (31% vs 9%; P < .001). However, no transplant patients with size growth CR progression developed IC. Moreover, 17 (6.7%) required pancreatic surgery for CR progression after transplant vs 58 (7.5%) in the nontransplant population. Furthermore, 6 resected cysts (35%) harbored high-risk pathology after transplant (IC, 2; HGD, 4) vs 40 (69%) in the general population (P < .001; IC, 29; HGD, 11). ConclusionMalignant transformation of BD-IPMNs is rare despite systemic immunosuppression in solid organ transplant patients. This supports transplantation in patients with IPMN without fear of worsening their risk of pancreatic cancer, although it was associated with a higher risk of disease progression. Patients with IPMNs should be surveilled with yearly scans after transplant, with pancreatic resection reserved for only high-risk features as we continue to define the optimal criteria for those with CR progression.

Utility of Radiological Follow Up of Main-Duct Intraductal Papillary Mucinous Neoplasms and Mixed-Type Intraductal Papillary Mucinous Neoplasms.

Intraductal papillary mucinous neoplasms (IPMNs) have the potential to evolve into pancreatic adenocarcinoma (PDAC). While main-duct IPMNs (MD-IPMNs), involving the main pancreatic duct (MPD), are less common than side-branch IPMNs (SB-IPMNs) or mixed-type IPMNs (mixed-IPMNs), their malignant transformation potential is far greater. Controversy exists between different guidelines in terms of recommended management strategies. This study was aimed at assessing the utility of the radiological follow up of MD-IPMNs and mixed-type IPMNs, including prevalence of worrisome radiological findings as well as clinical and laboratory parameters, and their correlation with the development of progression or pancreatic adenocarcinoma. Eighty-four patients with MD-IPMNs or mixed-type IPMNs who underwent at least one magnetic resonance cholangiopancreatography (MRCP) were included. Clinical and laboratory data were obtained retrospectively. A cross-sectional analysis was carried out to establish clinical and laboratory parameters associated with development of PDAC. A retrospective cohort analysis was performed on 44 patients who had at least six months of follow up, trying to identify factors correlating with worrisome radiological features. Nine cases (10.7%) of PDAC were recorded in this cohort. The laboratory and imaging factors associated with cyst size progression greater than 5 mm during follow up were elevated alanine transaminase (ALT) levels, the maximal cyst size, and the MPD diameter. Cross-sectional analysis indicated that PDAC was associated with nausea (p = 0.01), as well as increased levels of aspartate aminotransferase (AST) (p = 0.05), gamma glutamyl transpeptidase (GGT) (p = 0.01), and alkaline phosphatase (ALP) (p = 0.01). Elevated levels of liver enzymes were associated with IPMN progression and, subsequently, the development of PDAC. ALT levels, maximal cyst size, and MPD diameter are associated with the progression of cyst size. These data may aid in risk-stratifying patients when determining the follow up approach for IPMNs.

Consequences of a Surveillance Strategy for Side-branch Intraductal Pancreatic Mucinous Neoplasms: Long-term Follow-up of One Thousand Cysts.

To quantify the rate of progression in surveilled cysts and assess what factors should indicate delayed resection. Side-branch intraductal papillary mucinous neoplasms (SB-IPMNs) are increasingly discovered, making it challenging to identify which patients require resection, thus avoiding inappropriate treatment. Most incidental lesions are surveyed, yet the consequences of that decision remain uncertain. A prospectively maintained database of pancreatic cystic neoplasms was queried for patients with SB-IPMN. Patients with ≥2 imaging studies >6 months apart were included. Clinically relevant progression (CR-progression) was defined by symptoms, worrisome/high-risk stigmata, or invasive cancer (IC). Growth ≥5mm in 2 years is considered CR-progression; size ≥3cm alone is not. Between 1997 and 2023, 1337 patients were diagnosed with SB-IPMN. Thirty-seven (2.7%) underwent up-front surgery; 1000 (75.0%) had >6 months of surveillance.The rate of CR-progression was 15.3% (n = 153) based on size increase (n = 63, 6.3%), main-duct involvement (n = 48, 4.8%), symptoms (n = 8, 5.0%), or other criteria (n = 34, 3.4%). At a median follow-up of 6.6 years (interquartile range: 3.0-10.26), 17 patients (1.7%) developed IC. Those with CR-progression developed IC in 11.1% (n = 17) and high-grade dysplasia (HGD) in 6.5% (n = 10). Nearly half of the cancers were not contiguous with the surveyed SB-IPMN.Size ≥3cm was not associated with HGD/IC ( P = 0.232). HGD/IC was least common in CR-progression determined by size growth (6.3%) versus main-duct involvement (24%) or other (43%, P < 0.001)Patients with CR-progression demonstrated improved survival (overall survival) with resection on time-to-event ( P < 0.001) and multivariate Cox regression (hazard ratio = 0.205, 0.096-0.439, P < 0.001) analyses. Overall survival was not improved with resection in all patients ( P = 0.244). CR-progression for SB-IPMNs is uncommon, with the development of cancer anywhere in the pancreas being rare. Initial size should not drive resection. Long-term and consistent nonoperative surveillance is warranted, with surgery currently reserved for CR-progression, knowing that the majority of these still harbor low-grade pathology.

Surveillance Outcome and Genetic Findings in Individuals at High Risk of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate. PDAC surveillance is recommended in high-risk individuals (HRIs) with strong PDAC family history or a pathogenic germline variant (PGV) in a PDAC susceptibility gene. We aimed to explore a potential correlation between genetic status, extent of family history, pancreatic findings, and surveillance implications in heterogeneous PDAC HRIs. A total of 239 HRIs from 202 families were tested genetically and underwent prospective pancreatic surveillance for 6 years. The cohort was divided into 3 groups: familial pancreatic cancer (FPC; 70 individuals, 54 families), familial non-FPC (81 individuals, 73 families), and hereditary pancreatic cancer (PC) (88 individuals, 75 families). PGVs were detected in 37.6% of all families, including 11.1% of FPC families and 9.6% of familial non-FPC families. The hereditary PC group had earlier onset of PDAC compared with the other 2 groups. BRCA2 PGV carriers showed earlier onset of PDAC and pancreatic cysts. Of the 239 HRIs, PDAC was detected in 11 individuals (4.6%), with 73% diagnosed at an early stage; 4 (1.67%) had pancreatic neuroendocrine tumor; 6 (2.5%) had main-duct intraductal papillary neoplasm (IPMN); and 41 (17.15%) had side-branch IPMN. Seventeen individuals were referred to surgery, and 12 were alive at the end of the study. The percentage of PDAC was similar in the 3 groups studied. The hereditary PC group, and particularly BRCA2 PGV carriers, had an earlier age of PDAC onset. PGVs were detected in a significant percentage of HRIs with PC. Surveillance seems effective for detection of early-stage PDAC and precursor lesions.

Optimized surveillance intervals for low-risk side-branch intraductal papillary mucinous neoplasms

Background: Side-branch intraductal papillary mucinous neoplasms (SB-IPMNs) are pre-malignant pancreatic lesions with cumulative malignant transformation (high grade dysplasia [HGD] or pancreatic ductal adenocarcinoma [PDAC]) rates of 5-20%. Surveillance intervals of SB-IPMNs vary depending on cyst and patient-specific features. To better define optimal surveillance intervals, we assessed the incidence of malignant transformation and the development of worrisome features (WFs) or high-risk stigmata (HRS) after initial presentation in SB-IPMNs≤2cm.

Pancreatobiliary manifestations of nonalcoholic fatty liver disease: a retrospective case-control multicenter study.

Nonalcoholic fatty liver disease (NAFLD) has become a major cause of chronic liver disease. Several extrahepatic manifestations have been reported in relation to NAFLD. However, data regarding pancreatobiliary manifestation are scarce. We aimed to explore the association of pancreatobiliary manifestation with NAFLD. A retrospective multicenter study that included all patients who underwent an endoscopic ultrasound performed for hepatobiliary indications and for whom the endosonographer reported on the presence or absence of fatty liver. The endoscopic ultrasound reports were reviewed and all pathological findings were reported. Overall, 545 patients were included in the study, among them, 278 patients had fatty liver (group A) as compared to 267 who did not have (group B). The average age in group A was 64.5 ± 13.5 years vs. 61.2 ± 14.7 years in group B. Male sex constituted 49.6 and 58% in groups A and B, respectively. On multivariate analysis, fatty pancreas [odds ratio (OR) 4.02; P = 0.001], serous cystadenoma (SCA) (OR 5.1; P = 0.0009), mucinous cystadenoma (MCA) (OR 9.7; P = 0.005), side-branch intraductal papillary mucinous neoplasm (IPMN) (OR 2.76; P < 0.0001), mixed-type IPMN (OR 16.4; P = 0.0004), pancreatic neuroendocrine tumor (NET) (OR 8.76; P < 0.0001), gallbladder stones (OR 1.9; P = 0.02) and hilar lymphadenopathy (OR 6.8; P < 0.0001) were significantly higher among patients with NAFLD. After adjustment for fatty pancreas, the association remained significant for SCA (OR 3; P = 0.01), MCA (OR 4.6; P = 0.03), side-branch IPMN (OR 1.7; P = 0.02), mixed-type IPMN (OR 5.5; P = 0.01) and pancreatic NET (OR 4.5; P = 0.001). Pancreatobiliary manifestations are common among patients with NAFLD. Assessment of these coexistent manifestations should be considered in the setting of patients with NAFLD.

Side-branch intraductal papillary mucinous neoplasms of the pancreas: outcome of MR imaging surveillance over a 10 years follow-up

PurposeTo evaluate the outcome of a MR imaging procotol in assessing the evolution of individuals with branch duct - intraductal papillary mucinous neoplasms (BD-IPMN) without worrisome features (WF) and/or high risk stigmata (HRS) at the time of the diagnosis in a follow-up period of at least 10 years. Material and methodsA retrospective revision of a prospectively collected radiological database including a total number of 600 patients who were investigated and diagnosed with “presumed” diagnosis of BD-IPMN at MRI/MRCP at our Department since 2008 was performed. Inclusion criteria were: 1) absence of worrisome features and/or high-risk stigmata at the time of diagnosis (baseline); 2) a radiological follow-up with abdominal MRI/MRCP of at least 10 years. Changes in cysts size, development of WF, HRS and pancreatic cancer, and any other modification during the follow-up were retrospectively analysed by two observers in consensus. ResultsSixty-nine patients fulfilled all the inclusion criteria. During surveillance, the cysts remained dimensionally unchanged or slightly reduced in size in 26.2% and 4.3% of cases respectively, whereas cyst enlargement was demonstrated in 69.5% of cases. Median annual growth rate was of 0.97 ± 0.87 mm/yr (range 0.13-5.0). WF and HRS developed in 10/69 (14.5%) and 3/69 (4.3%) cases, respectively. The incidence of pancreatic cancer in patients with BD-IPMN was 2.9%. ConclusionOur data confirm the low risk of pancreatic cancer development in patients with BD-IPMN, thus justifying an imaging follow-up. Worrisome features and high-risk stigmata were promptly identified during the follow-up, supporting the utility of our surveillance MR imaging protocol.

95 Prevalence of Intrapapillary Mucinous Neoplasm in Patients With Chronic Kidney Disease

INTRODUCTION: The prevalence of intraductal papillary mucinous neoplasm (IPMN) in the general population ranges from 3.3%–9.8%. In patients undergoing liver transplant evaluation, overall prevalence is documented to be 6.6%. So far, the suggested risk factors for IPMN include diabetes, family history of pancreatic adenocarcinoma, and tobacco use. We aim to study the prevalence and risk factors for IPMN formation in patients with chronic kidney disease (CKD). METHODS: We performed a retrospective cross-sectional study of patients with CKD who had MRIs of the abdomen performed between the dates of 1/2018 and 12/2018. Independent chart review was conducted and various demographic, clinical, and imaging metrics were extracted. Overall, the prevalence of IPMN was calculated. A student's t-test and chi-square test were used to compare the IPMN group to non-IPMN group. RESULTS: A total of 400 patients were reviewed. The total prevalence of IPMN in CKD patients was 13.7% (55/400). In 68% of the study patients, the MRI was done for a kidney transplant evaluation. The average age of patients in the study was 58 ± 14 years, 59% were male and 52% patients were on dialysis. Diabetes and Hypertension accounted for 26% and 45% of CKD respectively. In patients with IPMNs, the average size was 10 ± 5.7 mm; 45% were located in the head, 33% in the body and 22% in the tail. Notably, 16% were main duct IPMNs, 80% were side branch IPMNs and 4% patients had mixed (MD + SB) IPMNs. Amongst the patients with IPMNs, 7.5% of patients had associated high-risk features and were referred for endoscopic ultrasound. Comparison of the IPMN group to non-IPMN group is shown in Table 1. IPMNs were most commonly observed in elderly patients. Gender, dialysis status, etiology of CKD, smoking and alcohol intake did not seem to impact the prevalence of IPMN in CKD patients. CONCLUSION: Patients with CKD have a higher prevalence of IPMNs than the general population. We further aim to confirm this interval data with our age and gender matched control group without CKD.

3013 Fish Mouth Ampulla: Classic Main Duct Intraductal Papillary Mucinous Neoplasm

INTRODUCTION: Intraductal Papillary Mucinous Neoplasms (IPMNs) were first identified in 1982 and there have been increasing rates of diagnosis of IPMNs in recent years with the improvement of imaging modalities. Due to the indolent course of IPMNs, many patients may initially remain asymptomatic for many years. IPMNs should be acted on quickly after diagnosis as they can progress to malignancy. We present a case of a patient who presented with symptoms similar to pancreatitis but was found to have a main duct IPMN with the classic fish mouth appearance of the ampulla. CASE DESCRIPTION/METHODS: A 62-year-old male presented to an outside hospital with epigastric abdominal pain and nausea. RUQ Ultrasound revealed normal liver and gallbladder with heterogenous echotexture within an enlarged pancreas. Abdominal CT Scan revealed a low density heterogenous, contrast enhancing, possibly multicystic lesion at the uncinate process and near the pancreatic head measuring 3.6 × 3.6 cm with dilation of the pancreatic duct. MRCP revealed a dilated pancreatic duct at 6 mm and a cystic appearing pancreatic mass involving uncinate process and portion of the right pancreatic head concerning for intraductal papillary mucinous neoplasm. He was transferred to our facility for formal Gastroenterology evaluation. EGD was performed and revealed a markedly dilated ampulla with mucinous discharge, with classic “fish mouth” appearance. The pancreatic duct was diffusely dilated from the tail to ampulla, up to 17 mm in the head/neck. A cystic lesion measuring 41 × 35 mm adjacent to the main pancreatic duct extending to the uncinate was noted. FNA was performed and pathology confirmed the diagnosis of main duct IPMN. He successfully underwent a Whipple procedure. DISCUSSION: This case illustrates the importance of recognizing a classic endoscopic feature of main duct IPMN: the fish mouth ampulla of Vater. There are three types of IPMNs: main duct, side branch and mixed. MD-IPMNs have the most malignant potential of the three and should be acted on promptly with surgical referral for resection. Approximately 65% of MD-IPMNs are malignant, compared to 20% for side branch IPMNs. Due to the indolent course of IPMNs, many patients will remain asymptomatic for many years. Eventually, patients will present with symptoms similar to pancreatitis. Despite the lack of clear consensus for management of pancreatic cystic lesions between multiple guidelines, all agree that MD-IPMNs should be surgically resected due to the high malignant potential.

Development of a stratification tool to identify pancreatic intraductal papillary mucinous neoplasms at lowest risk of progression.

SummaryBackgroundBecause most pancreatic intraductal papillary mucinous neoplasms (IPMNs) will never become malignant, currently advocated long‐term surveillance is low‐yield for most individuals.AimTo develop a score chart identifying IPMNs at lowest risk of developing worrisome features or high‐risk stigmata.MethodsWe combined prospectively maintained pancreatic cyst surveillance databases of three academic institutions. Patients were included if they had a presumed side‐branch IPMN, without worrisome features or high‐risk stigmata at baseline (as defined by the 2012 international Fukuoka guidelines), and were followed ≥ 12 months. The endpoint was development of one or more worrisome features or high‐risk stigmata during follow‐up. We created a multivariable prediction model using Cox‐proportional logistic regression analysis and performed an internal‐external validation.Results875 patients were included. After a mean follow‐up of 50 months (range 12‐157), 116 (13%) patients developed worrisome features or high‐risk stigmata. The final model included cyst size (HR 1.12, 95% CI 1.09‐1.15), cyst multifocality (HR 1.49, 95% CI 1.01‐2.18), ever having smoked (HR 1.40, 95% CI 0.95‐2.04), history of acute pancreatitis (HR 2.07, 95% CI 1.21‐3.55), and history of extrapancreatic malignancy (HR 1.34, 95% CI 0.91‐1.97). After validation, the model had good discriminative ability (C‐statistic 0.72 in the Mayo cohort, 0.71 in the Columbia cohort, 0.64 in the Erasmus cohort).ConclusionIn presumed side branch IPMNs without worrisome features or high‐risk stigmata at baseline, the Dutch‐American Risk stratification Tool (DART‐1) successfully identifies pancreatic lesions at low risk of developing worrisome features or high‐risk stigmata.

Endoscopic Ultrasound-guided Needle-based Confocal Laser Endomicroscopy: Appraisal Concerning In-vivo Imaging of Intraductal Papillary Mucinous Neoplasm

Differential diagnosis between benign and potentially malignant cystic pancreatic lesions may be difficult. Previously we have compared cyst fluid serine protease inhibitor Kazal type I (SPINK1) with some traditionally used tumour markers (amylase, CEA, Ca19-9) and found that it may be a new promising maker in the differential diagnosis of cystic pancreatic lesions. In the present study, we focused on cyst fluid SPINK1 levels in benign and potentially malignant cystic pancreatic lesions.Sixty-one patients operated on for cystic pancreatic lesion in Tampere University Hospital, Finland and in Verona University Hospital, Italy, were included. Cyst fluid was aspirated during surgery, stored at −70 °C, and analysed with immunofluorometric assay for SPINK1. The final diagnosis was acute pancreatitis with fluid collection (Acute FC) in 4 patients, chronic pseudocyst (PS) in 17 patients, serous cystadenoma (SCA) in 7 patients, mucinous cystadenoma (MCA) in 21 patients and intraductal papillary-mucinous neoplasm (IPMN) in 12 patients (9 main/mixed duct type and 3 branch duct type).The acute FC patients had high SPINK1 levels. Among chronic cysts, SPINK1 levels were significantly higher in patients with potentially malignant cysts (main/mixed duct IPMN and MCA) than with benign cysts (side branch IPMN and SCA), (median and range, [480 (13–3602) vs. 18 (0.1–278) μg/L]; p < 0.0001). In the subcohort of 24 patients with <3 cm chronic cyst, cyst fluid SPINK 1 levels were significantly lower in SCA or side branch IPMN (3 [2–116] μg/L) than in main duct IPMN or MCA (638 [66–3602] μg/L; p = 0.018). The best sensitivity and specificity to differentiate any size MCA or main/mixed type IPMN from SCA or side branch IPMN were 85% and 84% (AUC 0.94; cut-off value 118 μg/L). The best sensitivity and specificity to differentiate <3 cm MCA or main duct IPMN from SCA or side branch IPMN were 93% and 89% (AUC 0.98; cut-off value 146 μg/L).Cyst fluid SPINK1 may be a possible marker in the differential diagnosis of benign and potentially malignant cystic pancreatic lesions.

New onset diabetes as a predictive factor of focal lesions in the pancreas in a high-risk screening program.

1512 Background: Genetic evolution studies have suggested the existence of a window of opportunity to improve clinical outcomes by intercepting pre-malignant lesions. This study reports the outcomes of Pancreatic Cancer (PC) surveillance in a high risk (HR) cohort followed at The University of Texas MD Anderson Cancer Center (MDA) between 2014 and 2018. Methods: The MDA PC High-Risk Clinic (MDA-PCHRC) performs surveillance based on risk stratification. This study reports 54 months of surveillance. The patients were stratified based on PC family history, personal history of other cancers, and germline mutations ( BRCA1/2, PALB2, STK11, CDKN2A, TP53) with high susceptibility to PC. Low risk patients were not offered surveillance while patients in the moderate or high-risk category were enrolled into a program which included annual screening with blood markers (CA 19-9, fasting glucose, HbA1C, amylase, and lipase) and magnetic resonance imaging/ cholangiopancreatography (MRI/MRCP). High risk patients also had a baseline endoscopic ultrasound (EUS). We evaluated the yield of premalignant lesions detection and our main goal was to detect predictive factors of focal pancreatic lesions and to validate our risk stratification strategy. Results: A total of 206 patients have been referred to our clinic during this time period. From this group, 126 (61%) patients completed at least one cycle of baseline surveillance, for the purposes of the analysis we only focus in the high risk (n=71) and moderate risk group (n=38). We have identified de novo pancreatic focal lesions in 22 patients, 20 from the high risk group (28%) and 2 from the moderate group (5%). Those lesions included 7 patients with simple cysts, 9 with side-branch IPMN, 3 with main duct IPMN, 1 with pseudocyst, 1 with mucinous cyst and 1 with a solid nodule (pancreatic neuroendocrine tumor). We compared demographic information (age, gender, and ethnicity) as well as family and personal medical history between patients with focal pancreatic lesions vs negative or diffuse findings. We found that new onset diabetes was significantly correlated with presence of focal pancreatic lesions 5 (22%) of patients with focal lesions versus patients without non focal lesion 2 (2%) ( P=0.003). Conclusions: Screening at the MDA-PCHRC detect pancreatic premalignant lesions in 20% of the patients in our cohort. We validated our risk stratification methodology and found that new-onset diabetes is predictive of pancreatic lesions, thus suggesting that this factor could be an important biomarker of focal lesions in a HR population.

Testing for Verification Bias in Reported Malignancy Risks for Side-Branch Intraductal Papillary Mucinous Neoplasms: A Simulation Modeling Approach.

The objective of our study was to test for the possibility that published malignancy risks for side-branch intraductal papillary mucinous neoplasms (IPMNs) are overestimates, likely due to verification bias. We tested for possible verification bias using simulation modeling techniques. First, in age-defined hypothetical cohorts of 10 million persons, we projected the frequency of pancreatic ductal adenocarcinoma (PDAC) arising from side-branch IPMNs over 5 years using published estimates of their prevalence (4.4%) and rate of malignant transformation (1.9%). Second, we projected the total number of PDAC cases in corresponding cohorts over the same time horizon using national cancer registry data. For each cohort, we determined whether the percentage of all PDAC cases that arose from side-branch IPMNs (i.e., side-branch IPMN-associated PDAC cases) was clinically plausible using an upper limit of 10% to define plausibility, as estimated from the literature. Model assumptions and parameter uncertainty were evaluated in sensitivity analysis. Across all cohorts, percentages of side-branch IPMN-associated PDACs greatly exceeded 10%. In the base case (mean age = 55.7 years), 80% of PDAC cases arose from side-branch IPMNs (7877/9786). In the oldest cohort evaluated (mean age = 75 years), this estimate was 76% (14,227/18,714). In a secondary analysis, we found that if an upper limit threshold of 10% for side-branch IPMN-associated PDAC was imposed, the model-predicted rate of malignancy for side-branch IPMNs would be less than 0.24% over a 5-year time horizon, substantially lower than most literature-based estimates. Our results suggest that reported malignancy risks associated with side-branch IPMNs are likely to be overestimates and imply the presence of verification bias.

Pancreatoscopy-guided laser dissection and ablation for treatment of benign and neoplastic pancreatic disorders: an initial report (with videos)

Per-oral pancreatoscopy (POP) permits direct evaluation of the pancreatic duct for the visualization and sampling of neoplastic lesions and treatment of pancreatic duct stones by using intraductal lithotripsy techniques. Pancreatic laser endotherapy of mucosa has been described in animal models for tumor ablation, but human experience is lacking. We describe 3 unique and challenging clinical situations that benefited from pancreatic laser dissection and ablation. Case 1 was a 75-year-old woman with presumed divisum-associated chronic pancreatitis who had recurrent acute pancreatitis despite minor papilla sphincterotomy and therapeutic stent placement. POP showed a side-branch intraductal papillary mucinous neoplasm within the neck of the pancreas. POP-guided holmium laser ablation of neoplastic tissue was performed, followed by pancreatic stent placement every 6 months, with no further hospitalizations at 20 months of follow-up. Case 2 was a 69-year-old woman with divisum-associated chronic calcific pancreatitis and recalcitrant mid-body stenosis. Previous attempts at balloon dilation and stent placement failed to resolve the stenosis. POP-guided holmium laser dissection of the stenosis was pursued, with immediate radiographic resolution. Case 3 was a 65-year-old woman with chronic calcific pancreatitis and a large stone burden who underwent POP-guided electrohydraulic lithotripsy and partial stone extraction followed by stent placement. Unfortunately, the stent fractured during the subsequent removal attempt because the fragment was impacted in the pancreatic body. POP-guided laser dissection and lithotripsy were used to debulk dense fibrous tissue and stones surrounding the stent fragment, respectively, followed by removal. Pancreatoscopy-guided laser endotherapy is a novel and potentially useful technique to manage difficult benign and neoplastic pancreatic disorders.

Imaging Follow-up of Low-Risk Incidental Pancreas and Kidney Findings: Effects of Patient Age and Comorbidity on Projected Life Expectancy.

Purpose To determine the effects of patient age and comorbidity level on life expectancy (LE) benefits associated with imaging follow-up of Bosniak IIF renal cysts and pancreatic side-branch (SB) intraductal papillary mucinous neoplasms (IPMNs). Materials and Methods A decision-analytic Markov model to evaluate LE benefits was developed. Hypothetical cohorts with varied age (60-80 years) and comorbidities (none, mild, moderate, or severe) were evaluated. For each finding, LE projections from two strategies were compared: imaging follow-up and no imaging follow-up. Under follow-up, it was assumed that cancers associated with the incidental finding were successfully treated before they spread. For patients without follow-up, mortality risks from Bosniak IIF cysts (renal cell carcinoma) and SBIPMNs (pancreatic ductal adenocarcinoma) were incorporated. Model assumptions and parameter uncertainty were evaluated in sensitivity analysis. Results In the youngest, healthiest cohorts (age, 60 years; no comorbidities), projected LE benefits from follow-up were as follows: Bosniak IIF cyst, 6.5 months (women) and 5.8 months (men); SBIPMN, 6.4 months (women) and 5.3 months (men). Follow-up of Bosniak IIF cysts in 60-year-old women with severe comorbidities yielded a LE benefit of 3.9 months; in 80-year-old women with no comorbidities, the benefit was 2.8 months, and with severe comorbidities the benefit was 1.5 months. Similar trends were observed in men and for SBIPMN. Results were sensitive to the performance of follow-up for cancer detection; malignancy risks; and stage at presentation of malignant, unfollowed Bosniak IIF cysts. Conclusion With progression of age and comorbidity level, follow-up of low-risk incidental findings yields increasingly limited benefits for patients. © RSNA, 2018 Online supplemental material is available for this article.

Prevalence and outcomes of pancreatic cystic neoplasms in liver transplant recipients.

AIMTo determine the prevalence, characteristics and clinical course of pancreatic cystic neoplasms (PCNs) in liver transplantation (LT) recipients.METHODSWe retrospectively studied consecutive patients who underwent LT between January 1998 to April 2016. Clinical and laboratory data were obtained from patient medical records. Imaging findings on computed tomography and magnetic resonance cholangiopancreatography were reviewed by two radiologists.RESULTSDuring the study period, 872 patients underwent cadaveric LT. Pancreatic cysts were identified in 53/872 (6.1%) and 31/53 (58.5%) were PCNs [28 intraductal papillary mucinous neoplasm (IPMN), 2 mucinous cystic neoplasm (MCN), 1 serous cystadenoma]. Patients with PCNs exhibited less male predominance (55% vs 73%, P = 0.03) compared to patients without pancreatic cysts. Thirteen patients (42%) were diagnosed with PCN pre-LT while 18 patients (58%) developed PCN post-LT. The median size of PCNs was 13mm [interquartile range (IQR) 10-20 mm]. All IPMNs were side-branch type. Most PCNs were found in the head and body of pancreas (37% each), followed by the tail (25%). Five patients underwent further evaluation with endoscopic ultrasound. Progress imaging was performed on 81% of patients. PCNs remained stable in size and number in all but 2 patients. During a median follow up of 39 mo (IQR 26-58 mo), the 2 (6%) patients with MCN underwent pancreatectomy. No PCN patient developed pancreatic adenocarcinoma, while 5 died from illnesses unrelated to the PCN. Among patients without PCN, 1/841 (0.1%) developed pancreatic adenocarcinoma.CONCLUSIONThe prevalence of PCNs in LT recipients was similar to the general population (3.6%, 31/872). Side-branch IPMNs do not appear to have accelerated malignant potential in post-LT patients, indicating the current surveillance guidelines are applicable to this group.

Itʼs in Her DNA: A Case Highlighting the Role of DNA Molecular Analysis in Intraductal Papillary Mucinous Neoplasm

Intraductal papillary mucinous neoplasms (IPMN) are premalignant and require either surgical resection or long-term surveillance. We present a case highlighting the role of DNA molecular analysis in diagnosing another premalignant lesion in a woman initially thought to have only IPMN. A 76-year-old woman was referred for a pancreatic mass noted on abdominal ultrasound. Imaging was performed as a “screening” modality, given maternal history of pancreatic cancer. The patient denied weight loss. She was well appearing without jaundice. Her abdomen was soft. Liver associated enzymes and bilirubin were normal. CT scan showed several hypodense tubular structures in the head and uncinate process of the pancreas communicating with several ectatic side branches. Endoscopic ultrasonography (EUS) of the pancreas revealed anechoic cystic dilation of a side branch measuring 2.6 cm x 1.9 cm, consistent with a side branch IPMN not meeting Sendai criteria for surgical resection. Fine needle aspiration (FNA) showed a thick mucinous aspirate. Cytology revealed extracellular mucin with no evidence of high-grade dysplasia or malignancy. Carcinoembryonic antigen (CEA) was 241 ng/mL. DNA molecular analysis revealed low clonality KRAS mutation and no loss of heterozygosity, classified as likely benign. Because of the KRAS mutation, the patient was referred to surgery and underwent a Whipple procedure. Surgical pathology revealed IPMN, gastric type (intermediate grade). No high-grade dysplasia or carcinoma was noted within the cysts. However, the adjacent pancreas exhibited pancreatic intraepithelial neoplasia, intermediate grade (PanIN-2). DNA molecular analysis examines the mutation status of certain genes, notably KRAS. Studies have shown that DNA analysis increases the sensitivity of detecting mucinous cysts to 73-84% when combined with CEA and cytology, a rate higher than with EUS, cytology, and tumor markers alone. Our case demonstrates a unique instance where imaging did not meet Sendai or the revised Fukuoka criteria for surgical resection of IPMN, but DNA molecular analysis led to a decision for resection. This ultimately led to finding PanIN, thought to be the most common precursor to pancreatic ductal adenocarcinoma. Thus, DNA analysis not only helped diagnose IPMN but also proved crucial in discovering a second premalignant neoplasm. The role of DNA molecular analysis in PanIN and the association between IPMN and PanIN are areas for further research.Figure: The largest hypodense tubular structure in the uncinate process and head measures approximately 1.9 x 1.3 cm.Figure: Associated, several hypodense tubular structures in uncinate process and head which appear to communicate with ectatic side branches.Figure: EUS images showing IPMN with FNA performed.

Pancreatic Cancer Screening.

This review describes the rationale for pancreatic cancer screening, outlines groups that are at elevated risk for pancreatic cancer, and summarizes the relative risk in each setting. We also review the methods available for performing pancreatic cancer screening and the recommended screening intervals. Several genetic mutations have been identified that increase the risk for pancreatic cancer. Most are rare, however, and at-risk individuals are most often those with a strong family history of pancreatic cancer (with multiple family members affected) but no identifiable genetic mutation. Known genetic syndromes that increase the risk for pancreatic cancer include hereditary pancreatitis, familial atypical mole and multiple melanoma, Peutz-Jeghers syndrome, Lynch syndrome, BRCA mutations, and Li-Fraumeni syndrome. Genetic testing should be performed in conjunction with genetic counseling, and testing of an affected family member is preferred if possible.The goal of pancreatic cancer screening is to identify pancreatic cancer at an early, curable stage or, ideally, to identify precancerous lesions that can be resected to prevent the development of cancer. Imaging can be performed with either endoscopic ultrasound (EUS) or magnetic resonance cholangiopancreatography (MRCP). These techniques are generally considered to be complementary, although an advantage of EUS is that cysts or solid lesions can be sampled at the time of the procedure. Published results of small cohorts of high-risk patients in pancreatic cancer screening programs have demonstrated a high prevalence of small cystic lesions identified on EUS or MRCP, which often represent side-branch intraductal papillary mucinous neoplasms (IPMN). Knowledge of conditions and syndromes that increase pancreatic cancer risk allows one to identify those patients that may benefit from pancreatic cancer screening. As we gather evidence from large, international, multicenter cohorts of patients at high-risk for pancreatic cancer who are undergoing screening and as our understanding of the genetic underpinnings of pancreatic cancer improve, recommendations on screening will continue to be refined.

Loss of Trefoil Factor 2 From Pancreatic Duct Glands Promotes Formation of Intraductal Papillary Mucinous Neoplasms in Mice

Little is known about the origin of pancreatic intraductal papillary mucinous neoplasms (IPMN). Pancreatic duct glands (PDGs) are gland-like outpouches budding off the main pancreatic ducts that function as a progenitor niche for the ductal epithelium; they express gastric mucins and have characteristics of side-branch IPMNs. We investigated whether PDGs are a precursor compartment for IPMNs and the role of Trefoil factor family 2 (TFF2)-a protein expressed by PDGs and the gastric mucosa that are involved in epithelial repair and tumor suppression. We obtained pancreatectomy specimens from 20 patients with chronic pancreatitis, 13 with low-grade side-branch IPMNs, and 15 patients with PDAC; histologically normal pancreata were used as controls (n= 18). Samples were analyzed by immunohistochemistry to detect TFF1 and TFF2 and cell proliferation. We performed mitochondrial DNA mutational mapping studies to determine the cell lineage and fate of PDG cells. Pdx1-Cre;LSL-KRASG12D (KC) mice were bred with TFF2-knockout mice to generate KC/Tff2-/- and KC/Tff2+/- mice. Pancreata were collected and histologically analyzed for formation of IPMN, pancreatic intraepithelial neoplasias, and PDAC, in addition to proliferation and protein expression. Human pancreatic ductal epithelial cells and PDAC cell lines were transfected with vectors to overexpress or knock down TFF2 or SMAD4. Histologic analysis of human samples revealed gastric-type IPMN to comprise 2 molecularly distinct layers: a basal crypt segment that expressed TFF2 and overlying papillary projections. Proliferation occurred predominantly in the PDG-containing basal segments. Mitochondrial mutation mapping revealed a 97% match between the profiles of proliferating PDG cells and their overlying nonproliferative IPMN cells. In contrast to KC mice, 2-month-old KC/Tff2+/- and KC/Tff2-/- mice developed prominent papillary structures in the duct epithelium with cystic metaplasia of the PDG, which resembled human IPMN; these expressed gastric mucins (MUC5AC and MUC6), but not the intestinal mucin MUC2. KC/TFF2-knockout mice developed a greater number and higher grade of pancreatic intraepithelial neoplasias than KC mice, and 1 mouse developed an invasive adenocarcinoma. Expression of TFF2 reduced proliferation of PDAC cells 3-fold; this effect required up-regulation and activation of SMAD4. We found expression of TFF2 to be down-regulated in human PDAC by hypermethylation of its promoter. In histologic analyses of human IPMNs, we found PDGs to form the basal segment and possibly serve as a progenitor compartment. TFF2 has tumor-suppressor activity in the mouse pancreas and prevents formation of mucinous neoplasms.

Efficacy of Endoscopic Minor Papilla Sphincterotomy for Symptomatic Santorinicele.

Santorinicele, a rare focal cystic dilation of the distal portion of the dorsal pancreatic duct at the minor papilla, can be a cause of recurrent acute pancreatitis (RAP). Endoscopic minor papilla sphincterotomy (EMPS) has been evaluated as a treatment in case reports but never systematically investigated. We performed a retrospective analysis of the efficacy of EMPS in reducing episodes of pancreatitis. We collected data on 30 patients with santorinicele and RAP who underwent EMPS from June 2009 through April 2015 at University Hospital of Verona in Italy. The mean follow-up period was 43.8 months. The average number of pancreatitis episodes per year before EMPS was 1.59 vs 0.18 episodes after EMPS; the average number of pancreatitis cases that occurred during a comparable timeperiod before EMPS was 2.63 vs 0.67 cases after EMPS (P < .0001). Complete responses toEMPS (no recurrence of pancreatitis) were reported for 80% of patients. Six patients relapsed after amean time of 16 months. Five patients were found to have a potential cause of RAP beyond santorinicele (2 patients had post-sphincterotomy stenosis, 1 patient was a chronic consumer of alcohol, 1 patient had a mutation in the CFTR gene, and 1 patient had a side-branch intraductal papillary mucinous neoplasm). EMPS is effective in reducing the incidence of pancreatitis in patients with santorinicele.