Benign Intraductal Papillary Mucinous Neoplasms Research Articles

Single-cell RNA sequencing highlights epithelial and microenvironmental heterogeneity in malignant progression of pancreatic ductal adenocarcinoma

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). Single-cell transcriptomics provides a unique perspective for dissecting the epithelial and microenvironmental heterogeneity that accompanies progression from benign IPMNs to invasive PDAC. Single-cell RNA sequencing was performed through droplet-based sequencing on 35 693 cells from three high-grade IPMNs and two IPMN-derived PDACs (all surgically resected). Analysis of single-cell transcriptomes revealed heterogeneous alterations within the epithelium and the tumor microenvironment during the progression of noninvasive dysplasia to invasive cancer. For epithelial cells, we identified acinar–ductal cells and isthmus–pit cells enriched in IPMN lesions and profiled three types of PDAC-unique ductal cells. Notably, a proinflammatory immune component was distinctly observed in IPMNs, comprising CD4+ T cells, CD8+ T cells, and B cells, whereas M2 macrophages were significantly accumulated in PDAC. Through the analysis of cellular communication, the osteopontin gene (SPP1)–CD44 pathway between macrophages and epithelial cells were particularly strengthened in the PDAC group. Further prognostic analysis revealed that SPP1 is a biomarker of IPMN carcinogenesis for surveillance. This study demonstrates the ability to perform high-resolution profiling of single cellular transcriptomes during the progression of high-grade IPMNs to cancer. Notably, single-cell analysis provides an unparalleled insight into both epithelial and microenvironmental heterogeneity associated with early cancer pathogenesis and provides practical markers for surveillance and targets for cancer interception.

Abstract B072: SMAD4 loss allows progression from benign to malignant disease in intraductal papillary mucinous neoplasms

Abstract As increasing numbers of MRIs and other scans are ordered for unrelated diseases, more and more people are being diagnosed with cystic neoplasms of the pancreas. While many or most of these will likely remain benign, intraductal papillary mucinous neoplasms (IPMNs) have a risk of progression to cancer and IPMN is now recognized as another precursor to pancreatic ductal adenocarcinoma. We are investigating the mechanisms by which IPMNs progress from benign to malignant disease in order to identify markers of progression and targets to block that progression. We found that loss of SMAD4 in conjunction with Krasmutation leads to IPMN that quickly becomes invasive in a mouse model. Examining human IPMN tissues, we found that only one in 46 benign IPMN tumors lacked detectable SMAD4 protein. Among 19 cases of invasive IPMNs, the sites of active invasion were SMAD4 negative in 7 cases, nuclear negative/cytoplasm positive in 3 cases (suggesting no active canonical signaling), and a mix of positive and negative cells in 3 cases, implicating complete or partial loss of SMAD-mediated signaling in 68% of actively invading cells. In order to understand how SMAD signaling blocks progression to invasion, we are examining cell lines from a benign mouse model of IPMN. While these lines do not have endogenous TGF beta signaling, they are capable of responding to exogenous TGF beta, suggesting that TGF beta-related ligands may be supplied by the tumor microenvironment rather than the tumor cells themselves. We are currently determining how different TGF beta family members contribute to regulation of growth and invasion in these cells. In summary, loss of the tumor suppressor SMAD4 allows an otherwise benign disease to progress to invasive cancer. Citation Format: Anna L. Means, Hannah Yoo, Quoc-Huy Trinh, Roshini Thiagarajan, Jinghuan Zi, Frank L. Revetta, Marcus C. Tan, Kathleen E. DelGiorno, Mary K. Washington. SMAD4 loss allows progression from benign to malignant disease in intraductal papillary mucinous neoplasms [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B072.

Surgery for intraductal papillary mucinous neoplasms in young patients: High-risk population

BackgroundIntraductal papillary mucinous neoplasms of the pancreas are uncommon in young individuals. Management of these patients is challenging because the risk of malignancy and recurrence after surgery remains unclear. The aim of the present study was to assess the long-term risk for intraductal papillary mucinous neoplasm recurrence after surgery for intraductal papillary mucinous neoplasms in patients ≤50 years of age. MethodsPerioperative and long-term follow-up data of patients who had undergone surgery for intraductal papillary mucinous neoplasms between 2004 and 2020 were extracted from a prospective unicentric database and retrospectively analyzed. ResultsSeventy-eight patients underwent surgical treatment for benign intraductal papillary mucinous neoplasms (low-grade n = 22 and intermediate-grade n = 21) and malignant intraductal papillary mucinous neoplasms (high-grade n = 16 and intraductal papillary mucinous neoplasm–associated carcinoma n = 19). Severe postoperative morbidity (Clavien–Dindo ≥III) was found in 14 patients (18%). The median length of hospital stay was 10 days. No perioperative mortality was observed. The median length of follow-up was 72 months. Recurrence of intraductal papillary mucinous neoplasm–associated carcinoma was found in 6 patients (19%) with malignant intraductal papillary mucinous neoplasm and 1 patient (3%) with benign intraductal papillary mucinous neoplasm. ConclusionSurgery for intraductal papillary mucinous neoplasm is safe and can be performed with low morbidity and potentially no mortality in young patients. Given the high rate of malignancy (45%), these patients with intraductal papillary mucinous neoplasms represent a high-risk population, and prophylactic surgical treatment should be considered in these patients with long life expectancies. Regular clinical and radiologic follow-up examinations are important to rule out disease recurrence, which is high, especially in patients with intraductal papillary mucinous neoplasm–associated carcinoma.

The effectiveness of endoscopic ultrasonography findings to distinguish benign and malignant intraductal papillary mucinous neoplasm

Background and aimsAccurate evaluation of intraductal papillary mucinous neoplasm (IPMN) is necessary to inform clinical decision-making. But it is still difficult to distinguish benign and malignant IPMN preoperatively. This study aims to evaluate the utility of EUS to predict the pathology of IPMN.MethodsPatients with IPMN who underwent endoscopic ultrasound within 3 months before surgery were collected from six centers. Logistic regression model and random forest model were used to determine risk factors associated with malignant IPMN. In both models, 70% and 30% of patients were randomly assigned to the exploratory group and validation group, respectively. Sensitivity, specificity, and ROC were used in model assessment.ResultsOf the 115 patients, 56 (48.7%) had low-grade dysplasia (LGD), 25 (21.7%) had high-grade dysplasia (HGD), and 34 (29.6%) had invasive cancer (IC). Smoking history (OR = 6.95, 95%CI: 1.98–24.44, p = 0.002), lymphadenopathy (OR = 7.91, 95%CI: 1.60–39.07, p = 0.011), MPD > 7 mm (OR = 4.75, 95%CI: 1.56–14.47, p = 0.006) and mural nodules > 5 mm (OR = 8.79, 95%CI: 2.40–32.24, p = 0.001) were independent risk factors predicting malignant IPMN according to the logistic regression model. The sensitivity, specificity, and AUC were 0.895, 0.571, and 0.795 in the validation group. In the random forest model, the sensitivity, specificity, and AUC were 0.722, 0.823, and 0.773, respectively. In patients with mural nodules, random forest model could reach a sensitivity of 0.905 and a specificity of 0.900.ConclusionsUsing random forest model based on EUS data is effective to differentiate benign and malignant IPMN in this cohort, especially in patients with mural nodules.

DWI Metrics Differentiating Benign Intraductal Papillary Mucinous Neoplasms from Invasive Pancreatic Cancer: A Study in GEM Models.

Simple SummaryIntraductal papillary mucinous neoplasms (IPMN) are common premalignant precursors to pancreatic ductal adenocarcinoma (PDAC). However, current guidelines for clinical management of IPMN are suboptimal and limited to information obtained through anatomical imaging and cytology of biopsy samples. Our results have suggested that diffusion-weighted MRI, an imaging method sensitive to tumor cell density, architecture, and microenvironment is able to differentiate mouse models of IPMN versus PDAC.KPC (KrasG12D:Trp53R172H:Pdx1-Cre) and CKS (KrasG12D:Smad4L/L:Ptf1a-Cre) mice are genetically engineered mouse (GEM) models that capture features of human pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMN), respectively. We compared these autochthonous tumors using quantitative imaging metrics from diffusion-weighted MRI (DW-MRI) and dynamic contrast enhanced (DCE)-MRI in reference to quantitative histological metrics including cell density, fibrosis, and microvasculature density. Our results revealed distinct DW-MRI metrics between the KPC vs. CKS model (mimicking human PDAC vs. IPMN lesion): the apparent diffusion coefficient (ADC) of CKS tumors is significantly higher than that of KPC, with little overlap (mean ± SD vs. , ) despite intratumor and intertumor variability. Kurtosis index (KI) is also distinctively separated in the two models. DW imaging metrics are consistent with growth pattern, cell density, and the cystic nature of the CKS tumors. Coregistration of ex vivo ADC maps with H&E-stained sections allowed for regional comparison and showed a correlation between local cell density and ADC value. In conclusion, studies in GEM models demonstrate the potential utility of diffusion-weighted MRI metrics for distinguishing pancreatic cancer from benign pancreatic cysts such as IPMN.

Static and Dynamic 68Ga-FAPI PET/CT for the Detection of Malignant Transformation of Intraductal Papillary Mucinous Neoplasia of the Pancreas.

Pancreatic ductal adenocarcinoma (PDAC) may arise from intraductal papillary mucinous neoplasms (IPMN) with malignant transformation, but a significant portion of IPMN remains to show benign behavior. Therefore, it is important to differentiate between benign IPMN and IPMN lesions undergoing malignant transformation. However, nonoperative differentiation by ultrasound, CT, MRI, and carbohydrate antigen 19-9 (CA19-9) is still unsatisfactory. Here, we assessed the clinical feasibility of additional assessment of malignancy by PET using 68Ga-labeled fibroblast activation protein inhibitors (68Ga-FAPI PET) in 25 patients with MRI- or CT-proven cystic pancreatic lesions. Methods: Twenty-five patients with cystic pancreatic lesions who were followed up in the European Pancreas Center of Heidelberg University hospital and who were led to surgical resection or fine-needle aspiration due to suspicious clinical, laboratory chemistry, or radiologic findings were examined by static (all patients) and dynamic (20 patients) 68Ga-FAPI PET. Cystic pancreatic lesions were delineated and SUVmax and SUVmean were determined. Time-activity curves and dynamic parameters (time to peak, K 1, k 2, K3, k 4) were extracted from dynamic PET data. Receiver-operating curves of static and dynamic PET parameters were calculated. Results: Eleven of the patients had menacing IPMN (high-grade IPMN with [6 cases] or without [5 cases] progression into PDAC) and 11 low-grade IPMN; 3 patients had other benign entities. Menacing IMPN showed significantly elevated 68Ga-FAPI uptake compared with low-grade IPMN and other benign cystic lesions. In dynamic imaging, menacing IPMN showed increasing time-activity curves followed by slow decrease afterward; time-activity curves of low-grade IPMN showed an immediate peak followed by rapid decrease for about 10 min and slower decrease for the rest of the time. Receiver-operating curves showed high sensitivity and specificity (area under the curve greater than 80%) of static and dynamic PET parameters for the differentiation of IPMN subtypes. Conclusion: 68Ga-FAPI PET is a helpful new tool for the differentiation of menacing and low-grade IPMN and shows the potential to avoid unnecessary surgery for nonmalignant pancreatic IPMN.

The malignant potential of pancreatic intraductal papillary mucinous neoplasm is reflected in expression levels of fucosylated glycans in α1 -acid glycoprotein.

Pancreatic intraductal papillary mucinous neoplasm (IPMN) involves multiple histopathological stages from benign to malignant lesions. Further, a biomarker to diagnose the malignant IPMN (IPMC) is clinically relevant. Recently, we found that serum fucosylated α1 -acid glycoprotein (fAGP) level markedly elevated along with disease progression in large cohorts of patients with various cancers. The fAGP level was retrospectively analyzed in preoperative sera from 109 patients with IPMN, and the clinical relevance of fAGP was compared with currently available predictors as standard. The fAGP level in IPMC was found to be significantly higher than in benign IPMN (P=.0012). At a cutoff value of 27.04 U/μg, its sensitivity, specificity, and accuracy for IPMC were determined to be 83.61%, 65.96%, and 75.93%, respectively. Multivariate analyses revealed that the fAGP level was the only independent risk factor for predicting IPMC. Additionally, a combination of the fAGP level and 18 F-fluorodeoxyglucose uptake on the PET/CT imaging in the lesions seemed to offer the best diagnosis of IPMN. Accordingly, 27 of the 28 patients who were positive in both tests had IPMC, while patients who are negative had benign IPMN. The fAGP level appeared to be a relevant biomarker for malignant potential of IPMN.

Clinical significance of pancreatic calcifications: a 15-year single-center observational study

ObjectivesPancreatic calcifications (PC) are considered specific for chronic pancreatitis (CP), but PC may also be present in non-CP diseases. The aims are to understand the pattern of calcifications in different diseases and to determine they were related to malignant diseases.MethodsA retrospective study was performed including patients with PC or CP undergoing surgery in the Department of General Surgery of Ruijin Hospital from January 2003 to June 2018.ResultsPC were observed in 168 (4.5%) of the 3755 patients with pancreatic lesions treated during the study period. The majority of patients with PC had three kinds of CP (73.2%) while 26.8% had other five kinds of non-CP diseases. In patients with non-CP diseases, the incidence of PC in malignant intraductal papillary mucinous neoplasm (IPMN) was significantly higher than benign IPMN (8.3% vs. 0.7%, p = 0.004). In patients of CP with pancreatic mass (n = 81), PC (Odds ratio = 28.6, p = 0.000), advanced age (> 55 years) and parenchymal atrophy were independent predictors for malignancy. In patients of CP without pancreatic mass (n = 110), there were 82 cases (74.5%) with PC and 5 cases (4.5%) with pancreatic ductal adenocarcinoma. The regression model of risk factors was not successful.ConclusionsThe disease spectrum with PC was very diverse. PC may be related to malignant IPMN in non-CP diseases and is related to malignancy in the patients of CP with pancreatic mass and indications for resection.

Pancreatic resections for benign intraductal papillary mucinous neoplasms: Collateral damages from friendly fire

BackgroundSurgical resection of intraductal papillary mucinous neoplasms is based on preoperative high-risk stigmata/worrisome features, but the risk of overtreatment remains high. The aim of this study was to evaluate surgical indications and perioperative and long-term complications in patients with low-grade intraductal papillary mucinous neoplasms. MethodsPatients who underwent surgical resection between 2009 and 2018 with a final histology of low-grade intraductal papillary mucinous neoplasms were included. Surgical indications, type of surgery, and short- and long-term outcomes were evaluated. ResultsA significant decrease in the rate of patients resected for low-grade intraductal papillary mucinous neoplasms was observed (43.6% in 2009–2012 vs 27.8% in 2013–2018; P = .003), and 133 patients were finally included (62 women, median age: 68 years). Of these, 24.1% had 1 worrisome feature, 39.8% had ≥2 worrisome features, 18.8% had ≥1 high-risk stigmata, and 15.8% had ≥1 worrisome features + 1 high-risk stigmata. Overall surgical morbidity was 55.6%, 15.8% had Clavien-Dindo ≥3 complications, reoperation rate was 3.8%, and 90-day postoperative mortality was 1.5%. After a median follow-up of 60 months, 13 patients (11.5%) had a recurrence of benign intraductal papillary mucinous neoplasm in the pancreatic remnant, and 2 patients (1.8%) developed pancreatic ductal adenocarcinoma. After partial pancreatectomy, 51.3% of patients were taking pancreatic enzyme replacement therapy. Among nondiabetics, 26% developed diabetes after partial pancreatectomy, of which 38% were insulin-dependent. Eighteen patients (13.7%) developed incisional hernia. ConclusionGiven the rates of morbidity and long-term complications after pancreatic resections, surgeons should attentively balance the true risks of intraductal papillary mucinous neoplasm degeneration with the risks of surgical resection in each patient.

Cystic Lesions of the Pancreas: Is Apparent Diffusion Coefficient Value Useful at 3 T Magnetic Resonance Imaging?

The objective of this study is to determine the role of apparent diffusion coefficient (ADC) value at 3T magnetic resonance imaging (MRI) in the characterization of pancreatic cystic lesions. We retrospectively selected a total number of 223 patients with a conclusive diagnosis of pancreatic cystic lesion, previously undergoing MR examination on a 3 T system. The MRI protocol first included axial T1/T2-weighted sequences and magnetic resonance cholangiopancreatography. Diffusion-weighted MRI was performed using a spin-echo echo-planar sequence with multiple b values (0, 150, 500, 1000, and 1500 s/mm2) in all diffusion directions, obtaining an ADC map. Contrast-enhanced T1-weighted sequences were performed during the initial work-up of a pancreatic cystic lesion and when signs of malignancy were suspected during the MRI follow-up. The ADC value of each pancreatic lesion was measured using a monoexponential curve fitting with all the multiple b. The final diagnosis of our study group included the following: serous cystadenomas (n = 42), mucinous cystadenomas (n = 14), intraductal papillary mucinous neoplasms (IPMNs) (n = 121), IPMNs with signs of malignancy at histopathologic examination (n = 24), pseudocysts (n = 9), other cystic lesions (n = 13). A statistically significant difference was observed between the ADC values of malignant IPMNs and those of each other group of pancreatic lesions (P < 0.001). The ADC value of benign IPMN was significantly higher than that of serous cystadenomas (P = 0.024). A statistically significant difference was observed between the ADCs of all mucinous cystic tumors (benign IPMNs together to mucinous cystadenomas) and the ADCs of serous cystadenomas (P = 0.014). Fitted ADC value obtained at 3T MRI may be helpful in the characterization of pancreatic cystic lesions with particular regards of differential diagnosis between mucinous and serous cystic tumors and between malignant and benign IPMNs.

Application of artificial intelligence in diagnosis of pancreatic malignancies by endoscopic ultrasound: a systemic review.

Background:Pancreatic cancer (PC) is a highly fatal malignancy with a global overall 5-year survival of under 10%. Screening of PC is not recommended outside of clinical trials. Endoscopic ultrasonography (EUS) is a very sensitive test to identify PC but lacks specificity and is operator-dependent, especially in the presence of chronic pancreatitis (CP). Artificial Intelligence (AI) is a growing field with a wide range of applications to augment the currently available modalities. This study was undertaken to study the effectiveness of AI with EUS in the diagnosis of PC.Methods:Studies from MEDLINE and EMBASE databases reporting the AI performance applied to EUS imaging for recognizing PC. Data were analyzed using descriptive statistics. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was used to assess the quality of the included studies.Results:A total of 11 articles reported the role of EUS in the diagnosis of PC. The overall accuracy, sensitivity, and specificity of AI in recognizing PC were 80–97.5%, 83–100%, and 50–99%, respectively, with corresponding positive predictive value (PPV) and negative predictive value (NPV) of 75–99% and 57–100%, respectively. Types of AI studied were artificial neural networks (ANNs), convolutional neural networks (CNN), and support vector machine (SVM). Seven studies using other than basic ANN reported a sensitivity and specificity of 88–96% and 83–94% to differentiate PC from CP. Two studies using SVM reported a 94–96% sensitivity, 93%–99% specificity, and 94–98% accuracy to diagnose PC from CP. The reported sensitivity and specificity of detection of malignant from benign Intraductal Papillary Mucinous Neoplasms (IPMNs) was 96% and 92%, respectively.Conclusion:AI reported a high sensitivity with high specificity and accuracy to diagnose PC, differentiate PC from CP, and differentiate benign from malignant IPMN when used with EUS.

Circulating Cytokine Model Allows for Identification of Malignant Intraductal Papillary Mucinous Neoplasms

Introduction: Intraductal papillary mucinous neoplasms (IPMNs) are the precursor lesions of pancreatic cancer. The objective of this study is to assess the discriminatory performance of circulating cytokines containing TNF-α, IL-2R, IL-6 and IL-8, and then build a novel predictive model to improve the diagnostic accuracy. Method: The demographic and clinical characteristics of consecutive patients histologically confirmed as IPMNs between March 2016 and December 2019 were retrospectively collected and analyzed for model establishment. Then, another prospective consecutive cohort was enrolled from March 2020 to January 2021 for further validation. Results: The circulating TNF-α, IL-2R, IL-6 and IL-8 levels were significantly elevated in malignant IPMNs compared to benign IPMNs (p<0.001), and all four circulating cytokines were verified as independent predictors (p<0.05). Then, based on the Logistic algorithm, a novel circulating cytokine score (CCS) was calculated and proved to be an independent predictive indicator (p<0.001). Besides CSS, two high-risk stigmata features containing presence of solid component (PSC) and main pancreatic duct (MPD) dilation ≥ 10 mm were also confirmed as independent indicators for predicting malignant IPMNs. Finally, a novel nomogram incorporating CCS with these two high-risk stigmata features showed a remarkable diagnostic performance both in the training and validation cohorts with AUCs of 0.928 and 0.873, respectively. Conclusion: CCS can be considered as a novel independent predictive indicator for malignant IPMNs, and the formulated nomogram model integrating CCS, PSC and MPD ≥ 10 mm will be a valuable and promising tool for predicting the probability of malignant IPMNs to implement appropriate managements.

The prognostic roles of the prognostic nutritional index in patients with intraductal papillary mucinous neoplasm

The preoperative accurate diagnosis is difficult in the patients with intraductal papillary mucinous neoplasm (IPMN). The aim of the present study was to elucidate the roles of systemic inflammation responses and nutritional status indexes in IPMN. High-grade dysplasia was classified as a malignant neoplasm in the study. We retrospectively reviewed 155 patients who underwent pancreatectomy. The correlation between the clinical factors and several indexes of a systemic inflammation response and nutritional status was analyzed. Among the biomarkers, prognostic nutritional index (PNI) value of malignant IPMN patients was significantly lower than that of benign IPMN patients (P = 0.023), whereas PNI was not significant predictor for malignant IPMN. The multivariate analysis showed that a PNI < 43.5 (odds ratio [OR] 16.1, 95% CI 1.88–138.5, P = 0.011) and a carbohydrate antigen (CA) 19–9 level > 22.5 U/mL (OR 6.64, 95% CI 1.73–25.6, P = 0.006) were significant independent predictors of the presence of lymph node metastasis (LNM). Our scoring system developed based on these two factors. Patients with a score of 0 had no LNM and zero disease-related death. The present study suggested the roles of PNI on the IPMN patients who undergo curative pancreatectomy.

Intraductal papillary mucinous neoplasm of the pancreas: diagnostic performance of the 2017 international consensus guidelines using CT and MRI.

To assess the diagnostic performance of the 2017 international consensus guidelines for intraductal papillary mucinous neoplasm (IPMN) of the pancreas and to compare the diagnostic performance and intermodality agreement between contrast-enhanced CT and MRI. We retrospectively evaluated patients with surgical resection of IPMN of the pancreas who underwent preoperative CT and MRI between 2009 and 2019. Two radiologists evaluated the clinical and imaging features of IPMN of pancreas according to the 2017 international consensus guideline. Univariable and multivariable analyses were performed to identify significant predictors of malignancy in IPMN. The diagnostic abilities of CT and MRI were compared, and their intermodality agreement was determined. Of 175 patients (mean age, 64 years; 116 males), 88 (50.3%) had malignant IPMN. On multivariable analysis, all three high-risk stigmata (main pancreatic duct [MPD] ≥ 10 mm, mural nodule ≥ 5 mm, and obstructive jaundice) and two worrisome features (MPD 5-9 mm and elevated carbohydrate antigen 19-9) were associated with malignant IPMN on CT and MRI (p < 0.05). A mural nodule < 5 mm on MRI was also associated with malignant IPMN (OR 5.3, p = 0.009). The diagnostic accuracy of high-risk stigmata showed no difference between CT and MRI (73.7% vs. 75.4%, p = 0.505), with good to excellent intermodality agreement. Current high-risk stigmata had the strongest association with malignant IPMN on CT and MRI. Although MRI is superior to CT for identifying mural nodules, diagnostic performance for differentiating malignant from benign IPMNs was similar between CT and MRI. • The current high-risk stigmata in the 2017 International Consensus Guidelines had the strongest association with malignant IPMN on CT and MRI. • MRI is better than CT for identifying enhancing mural nodule. • Diagnostic performance for differentiating malignant from benign IPMNs was similar between CT and MRI.

A Scoring System for Predicting Malignancy in Intraductal Papillary Mucinous Neoplasms of the Pancreas: A Multicenter European Validation

Purpose: A preoperative diagnosis of the risk of malignancy for Intraductal Papillary Mucinous Neoplasms (IPMN) is important to choose the treatment. One of the tools currently in use is the Shin score that comprises five variables: age ≥60 years, history of pancreatitis, serum CA 19-9>37 IU/mL, Main Pancreatic Duct diameter ≥6mm and presence of mural nodules. The present study carries out an external validation of Shin score in a European multicenter cohort. Method: European multicenter retrospective study. All patients undergoing surgery for IPMN at 35 hospitals in Europe between 2010-2015 with histological confirmation were included. Results: Data from 567 patients were registered. Serum Ca 19.9, the presence of mural nodules and the MPD diameter were associated with the presence of malignancy (p <0.00001, p = 0.00012, and p = 0.00596 respectively). The score was significantly associated with the presence of malignancy (p <0.00001). In all patients, 64.41% of benign IPMN had a Shin score <3 and 57.34% of those with a diagnosis of malignancy had a score ≥3. The RR with a Shin score of 3 was 1.37 (95% CI: 1.07-1.77), with a sensitivity of 57.09% and specificity of 64.44%. Conclusion: In our series, only the serum Ca 19.9, the mural nodules and the MPD diameter were associated with malignancy. Our data suggest that patients with a Shin score≤1 should be undergo surveillance, while patients with a score≥4 should undergo surgery. Treatment of patients with Shin scores of 2/3 should be individualized.

Sonographic characteristics and follow-up of pancreatic cysts.

To assess sonographic characteristics and outcome of patients with pancreatic cystic lesions seen by ultrasound. From our ultrasound electronic reporting database we identified all patients in which "pancreatic cyst" or "pancreatic cysts" were reported from 1995 to 2018. In patients with more than one sonogram, the first was used for our study. For each case, we recorded sonographic characteristics, maximal diameter, cyst location, and results of follow-up ultrasound, CT or magnetic resonance imaging, as well as patient sex, age, relative clinical history, and endoscopic ultrasound (EUS) or surgical findings when available. Our study included 177 patients of whom 121 were female (68.4%). Mean age at diagnosis was 65 (±16, SD, range 22-99). Ultrasound was the initial diagnostic test in 122 (68.9%). Mean diameter of the index cyst was 13.7 mm (±11.5 mm, SD, range 2-91 mm). Among 177 index cysts, 155 were simple and 22 complex. Three complex cysts were surgically resected, yielding a primary pancreatic malignancy, a metastasis, and an epithelial-lined cyst. One simple cyst was resected, yielding a benign intraductal papillary mucinous neoplasm. Seventeen patients underwent EUS showing six mucinous cysts and 11 nonmucinous cysts. One hundred-eighteen patients had follow-up imaging for a mean time of 5.6 years (±3.8, range 0.25-21 years). One patient was presumed to have primary pancreatic cancer. The overall rate for primary pancreatic malignancy was 1.7% (2/118). Cystic pancreatic lesions seen on ultrasound are most often benign, with a low risk of pancreatic malignancy. Ultrasound is an excellent method to follow-up these cysts.

The diagnostic role of CT, MRI/MRCP, PET/CT, EUS and DWI in the differentiation of benign and malignant IPMN: A meta-analysis

PurposeThe objective of this study was to assess the diagnostic properties of computed tomography (CT), magnetic resonance imaging (MRI/MRCP) /Magnetic Resonance Cholangiopancreatography (MRCP), positron emission tomography/computed tomography (PET/CT), endoscopic ultrasound (EUS) and diffusion-weighted magnetic resonance imaging (DWI) in distinguishing benign and malignant intraductal papillary mucinous neoplasm (IPMN). Materials and methodsEligible databases were searched for eligible studies, published through July 2020 on the diagnostic accuracy of these modalities. Diagnostic accuracy parameters, including sensitivity, specificity, diagnostic odds ratio (DOR), and summary receiver operating characteristic curves (SROC) were calculated. Meta-regression was performed to identify the source of heterogeneity. ResultsIn total, 28 studies were included. Pooled sensitivities for CT, MRI/MRCP, PET/CT, EUS and DWI were 0.7, 0.76, 0.8, 0.6 and 0.72, respectively. Pooled specificities were 0.78, 0.83, 0.9, 0.8 and 0.97. The DORs were 8, 16, 35, 6 and 88. The areas under the curve (AUC) of SROC for CT, MRI/MRCP/MRCP, PET/CT, EUS and DW were 0.8, 0.87, 0.92, 0.79 and 0.82, respectively. ConclusionPET/CT showed the highest AUC and the overall diagnostic accuracy results support the use of MRI/MRCP, PET/CT interchangeably as a first-line examination in the diagnosis of malignant IPMN. With regard to DWI, EUS and CT, each techniques have their advantages and supportive to MRI/MRCP.

CT-Based Radiomics Analysis to Predict Malignancy in Patients with Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas.

Simple SummaryThe management of intraductal papillary mucinous neoplasms of the pancreas (IPMN) remains controversial due to the relatively high rate of unnecessary surgery for low grade dysplasia (LGD) despite the last international recommendations. The aim of our retrospective study was to assess the performance of radiomic analysis on CT in differentiating benign from malignant IPMN. We confirmed in a training cohort (296 patients) and a validation cohort (112 patients) that a total of 85 radiomics features provided valuable additional and independent information for discriminating benign from malignant tumors in the training cohort with an area under the ROC curve (AUC) of 0.84 and an external validation with an AUC of 0.71 with higher performance when implementing clinical variables leading to the indication to surgery. We have demonstrated the capabilities of radiomics models comprising LGD versus high-grade dysplasia (HGD) versus invasive, LGD and HGD, HGD and invasive.To assess the performance of CT-based radiomics analysis in differentiating benign from malignant intraductal papillary mucinous neoplasms of the pancreas (IPMN), preoperative scans of 408 resected patients with IPMN were retrospectively analyzed. IPMNs were classified as benign (low-grade dysplasia, n = 181), or malignant (high grade, n = 128, and invasive, n = 99). Clinicobiological data were reported. Patients were divided into a training cohort (TC) of 296 patients and an external validation cohort (EVC) of 112 patients. After semi-automatic tumor segmentation, PyRadiomics was used to extract radiomics features. A multivariate model was developed using a logistic regression approach. In the training cohort, 85/107 radiomics features were significantly different between patients with benign and malignant IPMNs. Unsupervised clustering analysis revealed four distinct clusters of patients with similar radiomics features patterns with malignancy as the most significant association. The multivariate model differentiated benign from malignant tumors in TC with an area under the ROC curve (AUC) of 0.84, sensitivity (Se) of 0.82, specificity (Spe) of 0.74, and in EVC with an AUC of 0.71, Se of 0.69, Spe of 0.57. This large study confirms the high diagnostic performance of preoperative CT-based radiomics analysis to differentiate between benign from malignant IPMNs.

Circulating extracellular vesicle-encapsulated microRNA as screening biomarkers for intraductal papillary mucinous neoplasm.

Since intraductal papillary mucinous neoplasms (IPMNs) occasionally contain pancreatic malignancies, it is vital to develop a screening program that can detect IPMNs in the general population and that can identify IPMNs with high malignant potential. The present study investigated whether microRNAs (miRNAs/miRs) in the blood may be diagnostic markers for IPMN screening. Initially, extracellular vesicle-encapsulated miRNAs (EV-miRNAs) in the serum with altered expression between IPMN, IPMN-derived carcinoma (IPMC) and control samples, were identified using microarray analysis. To validate the microarray results, the expression levels of selected EV-miRNAs were detected. Briefly, serum EV-miRNAs were extracted from 38 patients with IPMN (11 patients with IPMC and 27 patients with benign IPMN) and 21 non-tumor controls. The results of the microarray analysis revealed that the expression levels of EV-miR-22-3p, EV-miR-4539 and EV-miR-6132 were higher in the IPMN and IPMC serum samples compared with those in the control samples. With regards to discriminating IPMNs from controls, only miR-4539 exhibited a significant difference (P=0.004). In the comparison between IPMN and IPMC, carcinogenic antigen 19-9 (CA19-9) and EV-miR-6132 exhibited significant differences (P=0.01 and P=0.007, respectively). Receiver operating characteristic (ROC) curve analysis demonstrated that EV-miR-4539 could discriminate patients with IPMNs from control patients, with an area under the curve (AUC) of 0.72. Additionally, ROC analysis indicated that the markers could discriminate patients with IPMC from benign IPMN, with AUC values of 0.77 for EV-miR-6132 and 0.74 for CA19-9. In conclusion, the present study suggested that EV-miRNAs may be used as diagnostic markers for the detection of IPMNs in the general population as well as for identifying IPMNs with high malignant potential.

S1487 Simultaneous Pancreatico-Enteric Fistulae: A Complication of Pancreatic Intraductal Papillary Mucinous Neoplasm

INTRODUCTION: Intraductal papillary mucinous neoplasms (IPMN) are mucin producing tumors which arise from epithelial cells of the pancreatic duct. They present with varying degrees of dysplasia, possess the potential for malignant transformation and require definitive surgical management. IPMNS have been reported to fistulize into the surrounding organs. We present a case in which an IPMN fistulized into both the gastric body and the duodenum. CASE DESCRIPTION/METHODS: A 67-year-old female with a PMH of CAD, HTN, CKD, aortic stenosis, sick sinus syndrome s/p AICD presented with abdominal pain and unintentional weight loss. CT scan of the abdomen revealed diffuse enlargement of the pancreas with marked dilatation of the pancreatic duct, which measured up to 3.8 cm. She underwent diagnostic ERCP/EUS at which time a bulging ampulla with classical “fish eye” appearance was identified (Figure 1). A pathology specimen was collected and the patient was diagnosed with IPMN. While awaiting surgical intervention the patient re-presented with symptomatic anemia and melenic stools, indicating UGIB. Upper endoscopy was performed, revealing a large gastropancreatic fistula along the greater curvature of the proximal gastric body with mucin protruding (Figure 2). Biopsies taken from the gastric fistulous tract and mucin specimen cytology confirmed pancreatic IPMN. The patient was not amenable to complete pancreatectomy and partial pancreatectomy was attempted.It was however aborted intraoperatively due to prominent and undisecteble pancreatic vasculature,due to copious underlying adhesions. The patient instead underwent repair of the gastropancreatic and colopancreatic fistulae with partial omentectomy, as per patient preference. Post-op course was uneventful, and the patient was discharged with outpatient follow up and plan for conservative care. DISCUSSION: Pancreatic IPMNs progress from benign neoplasms to invasive neoplasms in an average span of 5-6 years. However, both IPMNs possess potential for fistula formation into a surrounding structure as fistula formation may occur from direct invasion or secondary to inflammation.In this case, we observed the unusual presentation of a benign IPMN forming simultaneous fistulous tracts to the gastric and duodenal lumens.Figure 1.: Upper GI endoscopy showing gastric body with mucin protruding.Figure 2.: Upper GI endoscopy showing gastric body with mucin protruding.