Absence of a pancreatic microbiome in intraductal papillary mucinous neoplasm.

OBJECTIVE: This study aims to validate the existence of a microbiome within intraductal papillary mucinous neoplasm (IPMN) that can be differentiated from the taxonomically diverse DNA background of next-generation sequencing procedures. DESIGN: We generated 16S rRNA amplicon sequencing data to analyse 338 cyst fluid samples from 190 patients and 19 negative controls, the latter collected directly from sterile syringes in the operating room. A subset of samples (n=20) and blanks (n=5) were spiked with known concentrations of bacterial cells alien to the human microbiome to infer absolute abundances of microbial traces. All cyst fluid samples were obtained intraoperatively and included IPMNs with various degrees of dysplasia as well as other cystic neoplasms. Follow-up culturing experiments were conducted to assess bacterial growth for microbiologically significant signals. RESULTS: Microbiome signatures of cyst fluid samples were inseparable from those of negative controls, with no difference in taxonomic diversity, and microbial community composition. In a patient subgroup that had recently undergone invasive procedures, a bacterial signal was evident. This outlier signal was not characterised by higher taxonomic diversity but by an increased dominance index of a gut-associated microbe, leading to lower taxonomic evenness compared with the background signal. CONCLUSION: The 'microbiome' of IPMNs and other pancreatic cystic neoplasms does not deviate from the background signature of negative controls, supporting the concept of a sterile environment. Outlier signals may appear in a small fraction of patients following recent invasive endoscopic procedures. No associations between microbial patterns and clinical or cyst parameters were apparent.

Risk Factors for Progression in Patients Undergoing Surveillance for Pancreatic Cysts.

OBJECTIVE: To identify risk factors associated with the progression of pancreatic cysts in patients undergoing surveillance. BACKGROUND: Previous studies of intraductal papillary mucinous neoplasms (IPMNs) rely on surgical series to determine malignancy risk and have inconsistently identified characteristics associated with IPMN progression. METHODS: We conducted a retrospective review of 2197 patients presenting with imaging concerning for IPMN from 2010 to 2019 at a single institution. Cyst progression was defined as resection or pancreatic cancer development. RESULTS: The median follow-up time was 84 months from the presentation. The median age was 66 years, and 62% were female. Ten percent had a first-degree relative with pancreatic cancer, and 3.2% had a germline mutation or genetic syndrome associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC). Cumulative incidence of progression was 17.8% and 20.0% at 12 and 60 months postpresentation, respectively. Surgical pathology for 417 resected cases showed noninvasive IPMN in 39% of cases and PDAC with or without associated IPMN in 20%. Only 18 patients developed PDAC after 6 months of surveillance (0.8%). On multivariable analysis, symptomatic disease [hazard ratio (HR)=1.58; 95% CI: 1.25-2.01], current smoker status (HR=1.58; 95% CI: 1.16-2.15), cyst size (HR=1.26; 95% CI: 1.20-1.33), main duct dilation (HR=3.17; 95% CI: 2.44-4.11), and solid components (HR=1.89; 95% CI: 1.34-2.66) were associated with progression. CONCLUSIONS: Worrisome features on imaging at presentation, current smoker status, and symptomatic presentation are associated with IPMN progression. Most patients progressed within the first year of presentation to Memorial Sloan Kettering Cancer Center (MSKCC). Further investigation is necessary to develop personalized cyst surveillance strategies.

Surveillance for Presumed BD-IPMN of the Pancreas: Stability, Size, and Age Identify Targets for Discontinuation.

BACKGROUND & AIMS: Currently, most patients with branch duct intraductal papillary mucinous neoplasms (BD-IPMN) are offered indefinite surveillance, resulting in health care costs with questionable benefits regarding cancer prevention. This study sought to identify patients in whom the risk of cancer is equivalent to an age-matched population, thereby justifying discontinuation of surveillance. METHODS: International multicenter study involving presumed BD-IPMN without worrisome features (WFs) or high-risk stigmata (HRS) at diagnosis who underwent surveillance. Clusters of individuals at risk for cancer development were defined according to cyst size and stability for at least 5 years, and age-matched controls were used for comparison using standardized incidence ratios (SIRs) for pancreatic cancer. RESULTS: Of 3844 patients with presumed BD-IPMN, 775 (20.2%) developed WFs and 68 (1.8%) HRS after a median surveillance of 53 (interquartile range 53) months. Some 164 patients (4.3%) underwent surgery. Of the overall cohort, 1617 patients (42%) remained stable without developing WFs or HRS for at least 5 years. In patients 75 years or older, the SIR was 1.12 (95% CI, 0.23-3.39), and in patients 65 years or older with stable lesions smaller than 15 mm in diameter after 5 years, the SIR was 0.95 (95% CI, 0.11-3.42). The all-cause mortality for patients who did not develop WFs or HRS for at least 5 years was 4.9% (n = 79), and the disease-specific mortality was 0.3% (n = 5). CONCLUSIONS: The risk of developing pancreatic malignancy in presumed BD-IPMN without WFs or HRS after 5 years of surveillance is comparable to that of the general population depending on cyst size and patient age. Surveillance discontinuation could be justified after 5 years of stability in patients older than 75 years with cysts <30 mm, and in patients 65 years or older who have cysts ≤15 mm.

Intraductal Papillary Mucinous Neoplasms in High-Risk Individuals: Incidence, Growth Rate, and Malignancy Risk.

BACKGROUND AND AIMS: In high-risk individuals (HRIs), we aimed to assess the cumulative incidence of intraductal papillary mucinous neoplasms (IPMNs) and compare IPMN growth, neoplastic progression rate, and the value of growth as predictor for neoplastic progression to these in sporadic IPMNs. METHODS: We performed annual surveillance of Dutch HRIs, involving carriers of germline pathogenic variants (PVs) and PV-negative familial pancreatic cancer kindreds. HRIs with IPMNs were compared with Italian individuals without familial risk under surveillance for sporadic IPMNs. RESULTS: A total of 457 HRIs were followed for 48 (range 2-172) months; the estimated cumulative IPMN incidence was 46% (95% confidence interval, 28%-64%). In comparison with 442 control individuals, IPMNs in HRIs were more likely to grow ≥2.5 mm/y (31% vs 7%; P < .001) and develop worrisome features (32% vs 19%; P = .010). PV carriers with IPMNs more often displayed neoplastic progression (n = 3 [11%] vs n = 6 [1%]; P = .011), while familial pancreatic cancer kindreds did not (n = 0 [0%]; P = 1.000). The malignancy risk in a PV carrier with an IPMN was 23% for growth rates ≥2.5 mm/y (n = 13), 30% for ≥5 mm/y (n = 10), and 60% for ≥10 mm/y (n = 5). CONCLUSIONS: The cumulative incidence of IPMNs in HRIs is higher than previously reported in the general population. Compared with sporadic IPMNs, they have an increased growth rate. PV carriers with IPMNs are suggested to be at a higher malignancy risk. Intensive follow-up should be considered for PV carriers with an IPMN growing ≥2.5 mm/y, and surgical resection for those growing ≥5 mm/y.

Robotic Ultrasound-Guided Central Pancreatectomy with Main Pancreatic Duct Endoscopy Evaluation for High-Risk, Mixed-Type Intraductal Papillary Mucinous Neoplasm.

BACKGROUND: Central pancreatectomy (CP) is a parenchymal-sparing technique indicated for the resection of selected lesions of the neck or proximal body of the pancreas.1,2 The risk of postoperative complications is theoretically doubled because the surgeon has to manage two cut surfaces of the pancreas. The video shows a fully robotic CP to treat a 62-year-old male patient with a mixed-type intraductal papillary mucinous neoplasm (IPMN) of the pancreatic neck, using ultrasound (US) and Wirsung endoscopic evaluation to guide the pancreatic resection and ensure optimal resection margins. MATERIALS AND METHODS: A US-guided robotic CP was carried out, and an intraoperative endoscopic evaluation of the MPD was performed to determine the distal transection level. A transmesocolic, end-to-side, robot-sewn Wirsung-jejunostomy with internal MPD stenting was then created. The procedure was completed with a side-to-side jejunojejunostomy. RESULTS: The operative time was 290 min, with negligible blood loss. During the postoperative course, the patient experienced bleeding from a branch of the gastroduodenal artery with subsequent fluid collection, which was successfully treated with angioembolization and percutaneous drainage. He was discharged home on postoperative day 22. Final pathology revealed a non-invasive IPMN with low-grade dysplasia and free surgical margins. At 12 months of follow-up, the patient was doing well, with no evidence of local recurrence and endocrine or exocrine pancreatic insufficiency. CONCLUSIONS: The combination of robotic surgery with intraoperative US and Wirsungoscopy may offer distinct technical advantages for challenging pancreatectomies that follow the principles of parenchymal-sparing surgery.

Adjuvant chemotherapy for adenocarcinoma arising from intraductal papillary mucinous neoplasia: multicentre ADENO-IPMN study.

BACKGROUND: The clinical impact of adjuvant chemotherapy after resection for adenocarcinoma arising from intraductal papillary mucinous neoplasia is unclear. The aim of this study was to identify factors related to receipt of adjuvant chemotherapy and its impact on recurrence and survival. METHODS: This was a multicentre retrospective study of patients undergoing pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasia between January 2010 and December 2020 at 18 centres. Recurrence and survival outcomes for patients who did and did not receive adjuvant chemotherapy were compared using propensity score matching. RESULTS: Of 459 patients who underwent pancreatic resection, 275 (59.9%) received adjuvant chemotherapy (gemcitabine 51.3%, gemcitabine-capecitabine 21.8%, FOLFIRINOX 8.0%, other 18.9%). Median follow-up was 78 months. The overall recurrence rate was 45.5% and the median time to recurrence was 33 months. In univariable analysis in the matched cohort, adjuvant chemotherapy was not associated with reduced overall (P = 0.713), locoregional (P = 0.283) or systemic (P = 0.592) recurrence, disease-free survival (P = 0.284) or overall survival (P = 0.455). Adjuvant chemotherapy was not associated with reduced site-specific recurrence. In multivariable analysis, there was no association between adjuvant chemotherapy and overall recurrence (HR 0.89, 95% c.i. 0.57 to 1.40), disease-free survival (HR 0.86, 0.59 to 1.30) or overall survival (HR 0.77, 0.50 to 1.20). Adjuvant chemotherapy was not associated with reduced recurrence in any high-risk subgroup (for example, lymph node-positive, higher AJCC stage, poor differentiation). No particular chemotherapy regimen resulted in superior outcomes. CONCLUSION: Chemotherapy following resection of adenocarcinoma arising from intraductal papillary mucinous neoplasia does not appear to influence recurrence rates, recurrence patterns or survival.

Systematic review on surveillance for non-resected branch-duct intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND: The management of branch-duct type intraductal papillary mucinous neoplasms (BD-IPMN) varies in existing guidelines. This study investigated the optimal surveillance protocol and safe discontinuation of surveillance considering natural history in non-resected IPMN, by systematically reviewing the published literature. METHODS: This review was guided by PRISMA. Research questions were framed in PICO format "CQ1-1: Is size criteria helpful to determine surveillance period? CQ1-2: How often should surveillance be carried out? CQ1-3: When should surveillance be discontinued? CQ1-4: Is nomogram predicting malignancy useful during surveillance?". PubMed was searched from January-April 2022. RESULTS: The search generated 2373 citations. After screening, 83 articles were included. Among them, 33 studies were identified for CQ1-1, 19 for CQ1-2, 26 for CQ1-3 and 12 for CQ1-4. Cysts <1.5 or 2 cm without worrisome features (WF) were described as more indolent, and most studies advised an initial period of surveillance. The median growth rate of cysts <2 cm ranged from 0.23 to 0.6 mm/year. Patients with cysts <2 cm showing no morphological changes and no WF after 5-years of surveillance have minimal malignancy risk of 0-2%. Two nomograms created with over 1000 patients had AUCs of around 0.8 and appear to be feasible in a real-world practice. CONCLUSIONS: For patients with suspected BD-IPMN <2 cm and no other WF, less frequent surveillance is recommended. Surveillance may be discontinued for cysts that remain stable during 5-year surveillance, with consideration of patient condition and life expectancy. With this updated surveillance strategy, patients with non-worrisome BD-IPMN should expect more streamlined management and decreased healthcare utilization.

Association of high-risk stigmata and worrisome features with advanced neoplasia in intraductal papillary mucinous neoplasms (IPMN): A systematic review.

BACKGROUND: This systematic review aimed to assess the diagnostic accuracy of the International Consensus Fukuoka Guidelines (ICG2017) in identifying high-risk lesions of Intraductal Papillary Mucinous Neoplasms (IPMNs). METHODS: The ICG2017 revision committee conducted a comprehensive literature review to establish evidence-based statements on IPMNs. The review focused on articles examining the diagnostic value of imaging features (e.g., cyst or main pancreatic duct diameter), clinical symptoms associated with IPMN, and serum biomarkers. Five clinical questions regarding high-risk stigmata (HRS) and worrisome features (WF) in the ICG2017 guidelines were addressed. RESULTS: A total of 210 articles were reviewed. The findings revealed a significant association between the presence of mural nodules ≥5 mm in diameter or solid components with contrast enhancement and the diagnosis of high-grade dysplasia or invasive carcinoma. Contrast-enhanced diagnostic tools, such as CT, MRI, or EUS, demonstrated the highest prediction rate and were recommended. Positive cytology was identified as an HRS, while symptoms like acute pancreatitis and cyst diameter growth ≥2.5 mm per year were considered WFs. The use of nomograms and multiple diagnostic factors was recommended for optimal IPMN management. CONCLUSIONS: This systematic review provides evidence supporting the improved diagnostic accuracy of ICG2017 in identifying high-risk lesions of IPMN. The multidisciplinary incorporation of HRS and WF based on imaging findings and clinical symptoms is crucial. These findings should inform the revision of ICG2017, enhancing the evaluation and management of IPMN patients. By implementing these recommendations, clinicians can make more informed decisions, leading to better diagnosis and treatment outcomes for high-risk IPMN cases.

Gastrointestinal cancer precursor risk and mortality in pancreatic intraductal papillary mucinous neoplasms: a nationwide cohort study.

BACKGROUND AND AIMS: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a precursor of pancreatic cancer. While earlier research has shown a high prevalence of synchronous/metachronous extrapancreatic tumors in IPMN patients, these studies have often been small with retrospective data collection. The aim of the study was to examine absolute and relative risks of non-pancreatic gastrointestinal (GI) cancer precursors and mortality in histologically confirmed IPMN. METHODS: Through the nationwide ESPRESSO histopathology cohort, we retrieved data on IPMN between 1965 and 2016. Each index case was matched to ≤5 general population controls. Through Cox regression, we estimated hazard ratios (HRs) for future GI cancer precursors and death. RESULTS: A total of 117 patients with IPMN and 539 age- and sex-matched controls were included. Over a median of 2.1 years of follow up, we confirmed two (1.7%) incident GI cancer precursors in IPMN vs. four (0.7%) in controls, corresponding to an HR of 1.89 (95%CI = 0.34-10.55). By contrast, IPMN patients were at increased risk of death (HR 3.61 (95%CI = 1.79-7.27)). The most common cause of death in IPMN was pancreatic cancer (n = 14; 45.2% of all deaths). CONCLUSIONS: We found no association between IPMN and other GI cancer precursors. This argues against comprehensive routine surveillance for other GI cancer precursors in IPMN patients. Mortality was increased in IPMN with pancreatic cancer being the most common cause of death, indicating the need for lifelong follow up in all resected and non-resected patients with IPMN. However, results should be confirmed in larger cohorts.

Dilated common bile duct is commonly associated with main duct Intraductal Papillary Mucinous Neoplasm of the pancreas.

BACKGROUND: Dilatation of common bile duct (CBD) is mostly pathological and mainly occurs secondary to mechanical causes. We aimed to explore the prevalence of CBD dilatation in Intraductal Papillary Mucinous Neoplasms of the pancreas (IPMN) among patients referred to EUS. METHODS: A retrospective study of all patients who had an EUS diagnosis of IPMN from 2011 to 2019 at Galilee Medical Center were extracted. Control group including patients with other types of pancreatic cysts. RESULTS: Overall, 2400 patients were included in the study, of them 158 patients were diagnosed with pancreatic cysts, 117 patients (74%) diagnosed with IPMN (group A), and 41 patients (26%) diagnosed with other pancreatic cysts (group B). Univariate analysis showed significant association of IPMN (OR 3.8, 95% CI 1.3-11.5), resected gallbladder (GB) (OR 7.75, 95% CI 3.19-18.84), and age (OR 1, 95% CI 1.01-1.08) with CBD dilatation. Classifying IPMN to sub-groups using adjusted multivariate logistic regression analysis, only main duct-IPMN (MD-IPMN) significantly correlated with CBD dilatation compared to branch duct (BD)-IPMN and mixed type-IPMN (OR 19.6, 95% CI 4.57-83.33, OR 16.3, 95% CI 3.02-88.08). CONCLUSION: MD-IPMN was significantly correlated with dilated CBD. Assessment of the pancreas is warranted in encountered cases of dilated CBD without obvious mechanical cause.

Tumor-to-blood pool ratio of 18F-fluorodeoxyglucose-positron emission tomography's standardized uptake value as a useful parameter indicating malignant transformation in pancreatic branch-duct intraductal papillary mucinous neoplasm compared to the international Fukuoka guidelines: a retrospective cohort study from surgical resections.

BACKGROUND: Identifying malignant transformation in pancreatic branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) remains challenging, but the standardized uptake value (SUV) obtained from 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT has the potential to become a valuable parameter for differentiation. This study aimed to assess the effectiveness of SUV of FDG-PET/CT in distinguishing low-grade dysplasia (LGD), high-grade dysplasia (HGD), and intraductal papillary mucinous carcinoma (IPMC) within BD-IPMNs. METHODS: We assessed 58 patients with confirmed BD-IPMN undergoing surgery between 2008 and 2022. Receiver operating characteristic curves were plotted using the tumor-to-blood pool ratio (TBR) of FDG-PET/CT in two scenarios: one considering HGD + IPMC as positive and the other considering only IPMC as positive. RESULTS: In the cohort of 58 cases, there were 39 females, and the median age was 71 years. The median TBR value was 1.45 (range, 0.35-25.44). The TBRs exhibited a significant correlation with each histopathology (p < 0.001). Furthermore, in the multivariate analysis, TBR was independently significant in both scenarios, with HGD + IPMC defined as malignant (p = 0.001) and with only IPMC defined as malignant (p = 0.024). CONCLUSIONS: TBR might have the potential to serve as a valuable parameter for indicating malignant transformation in pancreatic BD-IPMNs.

[A rare case of intraductal tumor of the pancreas in which an intraductal tubulopapillary neoplasm was mixed with a widely spreading gastric-type intraductal papillary-mucinous neoplasm].

A 70-year-old man receiving treatment for diabetes mellitus presented with a cystic mass in the border area of the pancreatic body and tail on plain computed tomography (CT) due to impaired glucose intolerance. Contrast-enhanced CT showed a faint hyperattenuated nodular mass extending from the dilated main pancreatic duct (MPD) to the branch duct. Endoscopic retrograde cholangiopancreatography revealed a mildly dilated orifice of the papilla of Vater and MPD stenosis with entire upstream and immediate downstream dilatations. The patient underwent distal pancreatectomy due to the suspicion of mixed-type intraductal papillary-mucinous carcinoma. A pathological examination showed an intraductal solid-nodular mass measuring 25mm in length, consisting of two types of neoplasms. One showed tubulopapillary growth with entirely high-grade (HG) atypical cuboidal epithelium, in which immunohistochemical examinations were positive for MUC6 but negative for human gastric mucin (HGM), MUC1, MUC2, and MUC5AC, fitting the concept of intraductal tubulopapillary neoplasm (ITPN). The other showed the same growth of low-grade (LG) atypical columnar cells positive for HGM and MUC5AC and negative for MUC1 and MUC2, which corresponded to gastric-type intraductal papillary-mucinous neoplasm (IPMN) -LG. The tumor had not invaded the duct walls, and no metastatic lymph nodes were observed. The ITPN was adjacent to the IPMN mainly composed of tubular glands mimicking pyloric glands with LG dysplasia that corresponded to the so-called IPMN-pyloric gland variant. Moreover, the proliferation of low-papillary gastric-type IPMN spread around the intraductal tumors. Consequently, the patient was diagnosed with an intraductal tubular neoplasm comprising a noninvasive ITPN and gastric-type IPMN-LG. ITPN is a recently identified intraductal neoplasm of the pancreas proposed by Yamaguchi et al. and is distinguished by intraductal tubulopapillary growth with HG cellular atypia without overt mucin production, in contrast to IPMN. To date, no cases of intraductal nodular tumors comprising ITPN and IPMN have been reported. We report this original case with imaging and pathological observations and discuss potential processes via which ITPN and IPMN may arise adjacent to each other in the same pancreatic duct.

Performance of the 7 th and 8 th Editions of the American Joint Committee on Cancer Staging System in Patients with Intraductal Papillary Mucinous Neoplasm-Associated PDAC : A Multi-institutional Analysis.

OBJECTIVE: To validate the 7 th and 8 th editions of the AJCC staging system for patients with invasive carcinomas arising in association with IPMN (IPMN-associated PDAC). BACKGROUND DATA: Although several studies have validated AJCC systems in patients with conventional PDAC, their applicability to IPMN-associated PDAC has not been assessed. METHODS: Two hundred seventy-five patients who underwent resection for IPMN-associated PDAC between 1996 and 2015 at 3 tertiary centers and had data on the size of the invasive component and lymph node status were identified. Concordance probability estimates (CPE) were calculated and recursive partitioning analysis was employed to identify optimal prognostic cutoffs for T and N. RESULTS: The CPE for the 7 th and 8 th editions of the AJCC schema were relatively good (0.64 for both) and similar for colloid and tubular subtypes (0.64 for both). The 8 th edition introduced T1a sub-staging and a new distinction between N1 and N2. The utility of the former was confirmed, although the latter did not improve prognostic discrimination. The successful validation of the 8th edition of the AJCC criteria in patients with tubular and colloid subtypes allowed us to compare these patients in early vs late T and N stages which showed that with advanced disease, the prognostic superiority of colloid tumors over their tubular counterparts diminishes. CONCLUSIONS: Our findings support the use of the AJCC 8 th edition in the IPMN-associated PDAC population, but suggest that certain cutoffs may need to be revisited. In advanced AJCC stages, patients with colloid vs tubular subtypes have comparable prognosis.

Segmental Versus Diffuse Main Duct Intraductal Papillary Mucinous Neoplasm: Examination of Main Pancreatic Duct Morphology and Implications for Malignancy Risk and Extent of Surgical Resection.

OBJECTIVE: To determine whether the morphologic features of the main pancreatic duct (MPD) of main-duct-involved-intraductal papillary mucinous neoplasm (IPMN) (ie, main duct or mixed main duct/side branch) have implications for the risk of malignancy and extent of resection. BACKGROUND: International consensus guidelines acknowledge the presence of various MPD morphologies (ie, diffuse vs segmental main-duct-involved-IPMN) without a precise definition of each entity and with limited data to guide treatment strategy. METHODS: All consecutive main-duct-involved-IPMN patients (2005-2019) with a MPD diameter ≥5 mm by cross-sectional imaging were reviewed from a prospective institutional database. Morphologic features of the MPD were correlated with the identification of high-grade dysplasia or pancreatic ductal adenocarcinoma (HGD/PDAC) by logistic regression modeling. In patients who underwent partial pancreatectomy, preoperative MPD morphologic features were correlated with the future development of HGD/PDAC in the pancreatic remnant by Cox hazards modeling. RESULTS: In a cohort of 214 main-duct-involved-IPMN patients, the overall rate of HGD/PDAC was 54.2%. MPD morphologic characteristics associated with HGD/PDAC included: maximal MPD diameter (5-10 mm: 29.8%; 10-14 mm: 59.0%; 15-19 mm: 78.6%; ≥20 mm: 95.8%; P <0.001), segmental extent of maximal dilation (<25%: 28.2%; 25%-49%: 54.9%; 50%-74%: 63.1%; ≥75%: 67.9%; P =0.002), and nonsegmental MPD diameter (<5 mm: 21.5% vs ≥5 mm: 78.5%, P <0.001). Diffuse MPD dilation involving ≥90% extent was rare (5.6%). After a median follow-up of 50 months, 7 (7.2%) patients who underwent partial pancreatectomy for IPMN without associated PDAC developed HGD/PDAC in the pancreatic remnant. Maximal MPD diameter, segmental extent of maximal dilation, or nonsegmental MPD diameter were not associated with the development of HGD/PDAC in the pancreatic remnant. However, a mural nodule on preoperative imaging was associated with the development of HGD/PDAC in the pancreatic remnant. CONCLUSIONS: "Diffuse" involvement with homogenous dilation of the MPD was rare. For the majority of patients with segmental main-duct-involved-IPMN, the MPD morphology conferred malignancy risk. Duct morphology was not predictive for the development of HGD or invasive disease in the pancreatic remnant, implying the safety of limited pancreatic resection for initial surgical management.

Clinical Outcomes of Intraductal Papillary Mucinous Neoplasms With Dilatation of the Main Pancreatic Duct.

BACKGROUND & AIMS: Dilatation of the main pancreatic duct (MPD) has been a surgical indication for intraductal papillary mucinous neoplasms (IPMNs). Few studies have investigated long-term outcomes of IPMNs with MPD dilatation. METHODS: Among 3610 patients diagnosed with pancreatic cysts between 1994 and 2021, we identified 2829 IPMN patients, including 282 patients with MPD ≥5 mm, and examined short-term (≤6 months) and long-term risks of pancreatic carcinoma. Utilizing competing risks proportional hazards models, we estimated subdistribution hazard ratios for incidence of pancreatic carcinoma with adjustment for potential confounders. RESULTS: In analyses of short-term outcomes of the 282 patients with MPD dilatation, 72 (26%) patients were diagnosed with pancreatic carcinoma based on surgical or nonsurgical exploration. During long-term follow-up of 168 patients, we documented 24 (14%) patients diagnosed with pancreatic carcinoma (18 with IPMN-derived carcinoma and 6 with concomitant ductal adenocarcinoma). The patients with the MPD = 5-9.9 mm had cumulative incidence rates of pancreatic carcinoma diagnosis of 8.1% (95% confidence interval [CI], 4.3%-13.5%) and 10.0% (95% CI, 5.5%-15.9%) at 2 and 5 years, respectively; and the patients with the MPD ≥10 mm had the corresponding rates of 16.0% (95% CI, 3.6-36.5%) and 33.3% (95% CI, 10.3%-58.8%). The multivariable subdistribution hazard ratios were 2.78 (95% CI, 1.57-4.90) and 7.00 (95% CI, 2.58-19.0) for the MPD = 5-9.9 mm and ≥10 mm (vs <5 mm), respectively. CONCLUSIONS: IPMNs with MPD dilatation at baseline were associated with higher prevalence and incidence of pancreatic carcinoma compared with IPMNs with no MPD dilatation.

Pancreatic Cancer Screening for At-Risk Individuals (Pancreas Scan Study): Yield, Harms, and Outcomes From a Prospective Multicenter Study.

INTRODUCTION: Guidelines endorse pancreatic cancer screening in genetically susceptible individuals. We conducted a prospective, multicenter study to determine yield, harms, and outcomes of pancreatic cancer screening. METHODS: All high-risk individuals undergoing pancreatic cancer screening at 5 centers from 2020 to 2022 were prospectively enrolled. Pancreas findings were designated as low-risk (fatty or chronic pancreatitis-like changes), intermediate-risk (neuroendocrine tumor [NET] <2 cm or branch-duct intraductal papillary mucinous neoplasm [IPMN]), or high-risk lesions (high-grade pancreatic intraepithelial neoplasia/dysplasia, main-duct IPMN, NET >2 cm, or pancreatic cancer). Harms from screening included adverse events during screening or undergoing low-yield pancreatic surgery. Annual screening was performed using endoscopic ultrasound and or magnetic resonance cholangiopancreatography. Annual screening for new-onset diabetes using fasting blood sugar was also performed ( ClinicalTrials.gov : NCT05006131). RESULTS: During the study period, 252 patients underwent pancreatic cancer screening. Mean age was 59.9 years, 69% were female, and 79.4% were White. Common indications were BRCA 1/2 (36.9%), familial pancreatic cancer syndrome kindred (31.7%), ataxia telangiectasia mutated (3.5%), Lynch syndrome (6.7%), Peutz-Jeghers (4.3%), and familial atypical multiple mole melanoma (3.5%). Low-risk lesions were noted in 23.4% and intermediate-risk lesions in 31.7%, almost all of which were branch-duct IPMN without worrisome features. High-risk lesions were noted in 2 patients (0.8%), who were diagnosed with pancreas cancer at stages T2N1M0 and T2N1M1. Prediabetes was noted in 18.2% and new-onset diabetes in 1.7%. Abnormal fasting blood sugar was not associated with pancreatic lesions. There were no adverse events from screening tests, and no patient underwent low-yield pancreatic surgery. DISCUSSION: Pancreatic cancer screening detected high-risk lesions with lower frequency than previously reported. No harms from screening were noted.

Expression of PD-L1 and VISTA in Intraductal Papillary Mucinous Neoplasm With Associated Invasive Carcinoma of the Pancreas.

Early detection and treatment of invasive carcinoma arising in association with intraductal papillary mucinous neoplasm (IPMN), which is biologically and (epi)genetically distinct from conventional pancreatic ductal adenocarcinoma, provide an opportunity to improve the prognosis of this lethal disease. Despite the successful application of programmed death (ligand) 1 (PD-[L]1)-blocking strategies in numerous cancers, the immune microenvironment of IPMN with associated invasive carcinoma remains elusive. Here, we investigated CD8+ T cells, CD68+ macrophages, PD-L1, and V-domain immunoglobulin suppressor of T-cell activation (VISTA) in 60 patients with IPMN with associated invasive carcinoma using immunohistochemistry, explored their correlations with clinicopathologic variables and prognosis, and compared them with those in 76 patients with IPMN without invasive carcinoma (60 low-grade and 16 high-grade lesions). Using antibodies against CD8, CD68, and VISTA, we evaluated tumor-infiltrating immune cells in 5 high-power fields (×400) and calculated the corresponding mean counts. PD-L1 with a combined positive score of ≥1 was regarded as positive, and VISTA expression on tumor cells (TCs) was deemed positive when ≥1% of TCs showed membranous/cytoplasmic staining. A reduction of CD8+ T cells and an increase of macrophages were observed during carcinogenesis. Positive PD-L1 combined positive score and VISTA expression on TCs were 13% and 11% in the intraductal component of IPMN with associated invasive carcinoma, 15% and 12% in the associated invasive carcinoma, and 6% and 4% in IPMN without an invasive carcinoma, respectively. Interestingly, the PD-L1 positivity rate was the highest in a subset of associated invasive carcinomas (predominantly gastric-type-derived) and was associated with higher counts of CD8+ T cells, macrophages, and VISTA+ immune cells. Accumulation of VISTA+ immune cells was observed in the intraductal component of IPMN with associated invasive carcinoma compared with that of low-grade IPMN, whereas in intestinal-type IPMN with associated invasive carcinoma, the number of these cells decreased during the transition from the intraductal component to the associated invasive carcinoma. Survival analysis revealed that a higher number of macrophages predicted poorer prognosis. In conclusion, our results might help in individualized immunotherapeutic strategies for these patients.

The Landmark Series: Intraductal Papillary Mucinous Neoplasms of the Pancreas-From Prevalence to Early Cancer Detection.

Modern series report a prevalence of pancreatic cysts in the general population of up to 50% in prospective studies. Of these, about half will be pancreatic cystic neoplasms (PCNs) that have varying degrees of malignant potential. Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are the most common PCNs and are known predecessors of pancreatic adenocarcinoma. Critically, they are one of the only radiographically identifiable precursors of pancreatic cancer and thus provide an opportunity for early cancer detection and surgical resection with curative intent. The combination of high prevalence and potential for malignant degeneration underscore the relevance of discussing the best management of IPMNs and improving the existing standard of care. Landmark data on IPMN prevalence, guidelines, surveillance, biomarkers, and immune landscape are highlighted.

Surveillance after resection of non-invasive intraductal papillary mucinous neoplasms (IPMN). A systematic review.

BACKGROUND: The ideal surveillance strategy after partial pancreatectomy for non-invasive IPMN remains undefined and existing guidelines provide conflicting recommendations. The present study was developed in anticipation of the joint meeting of the International Association of Pancreatology (IAP) and the Japan Pancreas Society (JPS) held in Kyoto in July 2022. METHODS: An international team of experts developed the four clinical questions (CQ) to operationalize issues pertaining to surveillance of patients in this context. A systematic review was designed following the PRISMA guidelines and registered in PROSPERO. The search strategy was executed in PubMed/Medline (Ovid), Embase, the Cochrane Library and Web of Science databases. Four investigators individually extracted data from the selected studies and drafted recommendations for each CQ. These were subsequently discussed and agreed upon that the IAP/JPS meeting. RESULTS: From a total of 1098 studies identified through the initial search, 41 studies were included in the review and informed the recommendations. No studies providing level one data were identified in this systematic review, all studies included were cohort or case-control studies. CONCLUSIONS: There is a lack of level 1 data addressing the issue of surveillance of patients following partial pancreatectomy for non-invasive IPMN. The definition of remnant pancreatic lesion in this setting is largely heterogeneous across all studies evaluated. Herein we propose an inclusive definition of remnant pancreatic lesions to guide future prospective efforts for reporting the natural history and long-term outcomes of these patients.

Pancreatic duct epithelial malignancy suggested by large focal pancreatic parenchymal atrophy in cystic diseases of the pancreas.

BACKGROUND: /Objectives: A cystic lesion is common in the pancreas. Focal pancreatic parenchymal atrophy (FPPA) has been reported as a sign of high-grade pancreatic intraepithelial neoplasia/carcinoma in situ (HGP/CIS). Some cystic lesions accompany FPPA. However, the relationship between a cystic lesion, FPPA, and the histopathological background of the pancreatic duct is unknown. METHODS: We retrospectively evaluated the data of 98 patients with a cystic lesion who underwent serial pancreatic juice aspiration cytologic examination (SPACE) because of accompanying FPPA, increased size of the cystic lesion, and pancreatic duct stricture at the base. RESULTS: The clinical diagnosis of a cystic lesion was intraductal papillary mucinous neoplasia (IPMN) and cysts in 72 (73.5%) and 26 (26.5%) patients, respectively. Ninety of the 98 patients (91.8%) had FPPA. Positive results (adenocarcinoma and suspicion) on SPACE were observed in 56 of all cases (57.1%), 48 of IPMN (66.7%), 8 of cysts (30.8%), and 54 of FPPA (59.3%), and were significantly associated with IPMN (p = 0.002) and the large FPPA (>269.79 mm2,p = 0.0001); moreover, these disorders are considerably related (p = 0.0003). Fifty patients (51.0%) with positive results on SPACE underwent surgery, with the histopathological diagnosis of epithelial malignancy in 42 patients (42.9%, 42/50, 84%). Many cystic lesions clinically diagnosed as IPMN were dilated branches covered by pancreatic intraepithelial neoplasia. CONCLUSIONS: Positive results on SPACE were significantly associated with the clinical diagnosis of IPMN and the large FPPA. Moreover, these disorders are significantly related. Surgery owing to positive results could lead to the histopathological diagnosis of HGP/CIS.