Pancreatic Intraductal Papillary Mucinous Neoplasms Research Articles

Dysbiosis Signature of Fecal Microbiota in Patients with Pancreatic Adenocarcinoma and Pancreatic Intraductal Papillary Mucinous Neoplasms

Pancreatic cancer (PC) ranks as the seventh leading cause of cancer-related deaths, with approximately 500,000 new cases reported in 2020. Existing strategies for early PC detection primarily target individuals at high risk of developing the disease. Nevertheless, there is a pressing need to identify innovative clinical approaches and personalized treatments for effective PC management. This study aimed to explore the dysbiosis signature of the fecal microbiota in PC and potential distinctions between its Intraductal papillary mucinous neoplasm (IPMN) and pancreatic ductal adenocarcinoma (PDAC) phenotypes, which could carry diagnostic significance. The study enrolled 33 participants, including 22 diagnosed with PDAC, 11 with IPMN, and 24 healthy controls. Fecal samples were collected and subjected to microbial diversity analysis across various taxonomic levels. The findings revealed elevated abundances of Firmicutes and Proteobacteria in PC patients, whereas healthy controls exhibited higher proportions of Bacteroidota. Both LEfSe and Random Forest analyses indicated the microbiome’s potential to effectively distinguish between PC and healthy control samples but fell short of differentiating between IPMN and PDAC samples. These results contribute to the current understanding of this challenging cancer type and highlight the applications of microbiome research. In essence, the study provides clear evidence of the gut microbiome’s capability to serve as a biomarker for PC detection, emphasizing the steps required for further differentiation among its diverse phenotypes.

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.

Predicting malignancy in pancreatic intraductal papillary mucinous neoplasms: a nomogram applicability study

Predicting malignancy in pancreatic intraductal papillary mucinous neoplasms: a nomogram applicability study

Abstract A028: Multiomic modelling of pancreatic IPMN stroma reveals distinct tertiary lymphoid structure distribution: Mapping the transcriptomic landscape via regional bulk, single-cell and subcellular approaches

Abstract Background Intraductal Papillary Mucinous Neoplasms (IPMN) remain the largest subtype of cystic pancreatic cancer precursors. Cancer risk has been observed to vary between histological grades and histological subtypes. Spatial characterisation has revealed variation in immune cell distribution disease subtypes. Methods A cohort of 14 surgically resected IPMN tumors across a range of histological grades (Low-grade LG, high-grade HG and invasive IPMN cancers IPMN-PDAC) and subtypes (gastric, intestinal, pancreaticobiliary) underwent multimodal spatial interrogation. After expert histopathological annotation; tissue sections underwent regional whole transcriptome analysis with TempO-seq and 10x Visium. Extensive region analysis with NanoString GeoMx employing segmentation using staining for epithelium (PanCK) fibroblast stroma (aSMA) was performed. A tissue microarray was then constructed, and representative cores underwent single-cell and subcellular spatial transcriptomic analysis with NanoString CosMx. Raw count data and digital images were exported and analysed using Seurat, Giotto, SPATA2 and custom R pipelines. Region deconvolution, Harmony integration, Leiden Clustering, Gene Set Enrichment Analysis, Trajectory Mapping, and Moran’s I Analysis were performed. Results TempO-seq revealed up-regulation of canonical oncogene expression in all IPMN-PDAC cases as compared to LG and HG IPMN. There were no statistically significant differences in expression comparing LG and HG IPMN lesions. Visium differential gene expression and clustering models identified cancer epithelium, stroma and lymphatic components that correlated with histopathological annotations. Immune cell rich spots were identified via gene ontology of top 50 marker genes. The spatial trajectory of B-cell expression signatures in IPMN-PDAC showed greater concentration and less variability than HG tumors, Moran’s I -0.34 vs 0.12 (P = 0.021). B-cells in HG IPMN were showed greater concentration and less variability than LG IPMN, Moran’s I -0.15 vs 0.02 (P=0.05). Much of this concentration was in identified lymphoid aggregates or tertiary lymphoid structures. The spatial trajectory of T-cell expression. The spatial trajectory of macrophage expression showed greater concentration and less variability than in LG and HG tumors. GeoMx analysis of stromal regions identified up regulation of B cell signatures in IPMN PDAC and HG IPMN when compared to LG IPMN. Markers associated with TLS formation were found to be significantly upregulated including CXCL13, CXCR5 and LAMP3. Pancreaticobiliary subtypes were found to have the least concentrated B-cell distribution across subtypes. Conclusions Immune cell composition was found to vary across histological grades and subtypes of IPMN. A paradoxical relationship was observed between T-cell infiltrates and B-cell and macrophage populations. The greater proportion of tertiary lymphoid structures, and high levels of TLS specific gene expression, may indicate a propensity for b-cell activation in IPMN tumors which progress to malignancy. Citation Format: Andrew J. Cameron, Assya Legrini, Colin S. Wood, Craig Nourse, Yoana Doncheva, Claire Kennedy Dietrich, Colin Nixon, Jennifer Hay, Fraser Duthie, Pawel Herzyk, Jennifer Morton, Nigel B. Jamieson. Multiomic modelling of pancreatic IPMN stroma reveals distinct tertiary lymphoid structure distribution: Mapping the transcriptomic landscape via regional bulk, single-cell and subcellular approaches [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 A028.

Pancreatic Cyst Size Measurement on Magnetic Resonance Imaging Compared to Pathology.

While multiple cyst features are evaluated for stratifying pancreatic intraductal papillary mucinous neoplasms (IPMN), cyst size is an important factor that can influence treatment strategies. When magnetic resonance imaging (MRI) is used to evaluate IPMNs, no universally accepted sequence provides optimal size measurements. T2-weighted coronal/axial have been suggested as primary measurement sequences; however, it remains unknown how well these and maximum all-sequence diameter measurements correlate with pathology size. This study aims to compare agreement and bias between IPMN long-axis measurements on seven commonly obtained MRI sequences with pathologic size measurements. This retrospective cohort included surgically resected IPMN cases with preoperative MRI exams. Long-axis diameter tumor measurements and the presence of worrisome features and/orhigh-risk stigmata were noted on all seven MRI sequences. MRI size and pathology agreement and MRI inter-observer agreement involved concordance correlation coefficient (CCC) and intraclass correlation coefficient (ICC), respectively. The presence of worrisome features and high-risk stigmata were compared to the tumor grade using kappa analysis. The Bland-Altman analysis assessed the systematic bias between MRI-size and pathology. In 52 patients (age 68 ± 13 years, 22 males), MRI sequences produced mean long-axis tumor measurements from 2.45-2.65 cm. The maximum MRI lesion size had a strong agreement with pathology (CCC = 0.82 (95% CI: 0.71-0.89)). The maximum IPMN size was typically observed on the axial T1 arterial post-contrast and MRCP coronal series and overestimated size versus pathology with bias +0.34 cm. The radiologist interobserver agreement reached ICCs 0.74 to 0.91 on the MRI sequences. The maximum MRI IPMN size strongly correlated with but tended to overestimate the length compared to the pathology, potentially related to formalin tissue shrinkage during tissue processing.

Immunohistochemical FAP Expression Reflects 68Ga-FAPI PET Imaging Properties of Low- and High-Grade Intraductal Papillary Mucinous Neoplasms and Pancreatic Ductal Adenocarcinoma.

Pancreatic intraductal papillary mucinous neoplasms (IPMNs) are grossly visible (typically > 5 mm) intraductal epithelial neoplasms of mucin-producing cells, arising in the main pancreatic duct or its branches. According to the current 2-tiered grading scheme, these lesions are categorized as having either low-grade (LG) dysplasia, which has a benign prognosis, or high-grade (HG) dysplasia, which formally represents a carcinoma in situ and thus can transform to pancreatic ductal adenocarcinoma (PDAC). Because both entities require different treatments according to their risk of becoming malignant, a precise pretherapeutic diagnostic differentiation is inevitable for adequate patient management. Recently, our group has demonstrated that 68Ga-fibroblast activation protein (FAP) inhibitor (FAPI) PET/CT shows great potential for the differentiation of LG IPMNs, HG IPMNs, and PDAC according to marked differences in signal intensity and tracer dynamics. The purpose of this study was to biologically validate FAP as a target for PET imaging by analyzing immunohistochemical FAP expression in LG IPMNs, HG IPMNs, and PDAC and comparing with SUV and time to peak (TTP) measured in our prior study. Methods: To evaluate the correlation of the expression level of FAP and α-smooth muscle actin (αSMA) in neoplasm-associated stroma depending on the degree of dysplasia in IPMNs, 98 patients with a diagnosis of LG IPMN, HG IPMN, PDAC with associated HG IPMN, or PDAC who underwent pancreatic surgery at the University Hospital Heidelberg between 2017 and 2023 were identified using the database of the Institute of Pathology, University Hospital Heidelberg. In a reevaluation of hematoxylin- and eosin-stained tissue sections of formalin-fixed and paraffin-embedded resection material from the archive, which was originally generated for histopathologic routine diagnostics, a regrading of IPMNs was performed by a pathologist according to the current 2-tiered grading scheme, consequently eliminating the former diagnosis of "IPMN with intermediate-grade dysplasia." For each case, semithin tissue sections of 3 paraffin blocks containing neoplasm were immunohistologically stained with antibodies directed against FAP and αSMA. In a masked approach, a semiquantitative analysis of the immunohistochemically stained slides was finally performed by a pathologist by adapting the immunoreactive score (IRS) and human epidermal growth factor receptor 2 (Her2)/neu score to determine the intensity and percentage of FAP- and αSMA-positive cells. Afterward, the IRS of 14 patients who underwent 68Ga-FAPI-74 PET/CT in our previous study was compared with their SUVmax, SUVmean, and TTP for result validation. Results: From 98 patients, 294 specimens (3 replicates per patient) were immunohistochemically stained for FAP and αSMA. Twenty-three patients had LG IPMNs, 11 had HG IPMNs, 10 had HG IPMNs plus PDAC, and 54 had PDAC. The tumor stroma was in all cases variably positive for FAP. The staining intensity, percentage of FAP-positive stroma, IRS, and Her2/neu score increased with higher malignancy. αSMA expression could be shown in normal pancreatic stroma as well as within peri- and intraneoplastic desmoplastic reaction. No homogeneous increase in intensity, percentage, IRS, and Her2/neu score with higher malignancy was observed for αSMA. The comparison of the mean IRS of FAP with the mean SUVmax, SUVmean, and TTP of 68Ga-GAPI-74 PET/CT showed a matching value increasing with higher malignancy in 68Ga-FAPI-74 PET imaging and immunohistochemical FAP expression. Conclusion: The immunohistochemical staining of IPMNs and PDAC validates FAP as a biology-based stromal target for invivo imaging. Increasing expression of FAP in lesions with a higher degree of malignancy matches the expectation of a stronger FAP expression in PDAC and HG IPMNs than in LG IPMNs and corroborates our previous findings of higher SUVs and a longer TTP in PDAC and HG IPMNs than in LG IPMNs.

The tumoral microbiome of pancreatic intraductal papillary mucinous neoplasm: A single-center retrospective cohort study.

Pancreatic intraductal papillary mucinous neoplasm (IPMN) is one of the most common precancerous lesions of pancreatic carcinoma. Studies have found that the tumoral microbiome has an important influence on pancreatic carcinoma. However, the tumoral microbiome of IPMNs has rarely been explored. Tumoral microbiome gene sequencing was carried out using 16 specimens of IPMN and 45 specimens of IPMN with associated invasive carcinoma (IPMN-IC) by 2bRAD sequencing for microbiome. The profile of the tumoral microbiome was summarized. Associations of the tumoral microbiome with disease grade, histological subtype, and prognosis were analyzed. A total of 598 species of microbes were identified, comprising 228 genera, 109 families, 60 orders, 29 classes, 14 phyla, and 2 kingdoms. The genus Pseudomonas was detected more frequently and had higher relative abundance in IPMN-ICs; Alcaligenes faecalis was detected with higher relative abundance in IPMNs. Bifidobacterium pseudolongum had a higher relative abundance in the IPMN-IC group, regardless of histological subtype. Moreover, among patients with IPMN-ICs, those with a high relative abundance of B.pseudolongum had better overall survival than those with a low relative abundance. Patients who were positive for Staphylococcus aureus or Mycolicibacillus koreensis had shorter survival. The presence of S.aureus was an independent risk factor for poor prognosis. There are enriching tumoral microbes in IPMN. The tumoral microbiome of IPMN is different from that of IPMN-IC.

Surveillance of sellected patients of main duct-involved and mixed-type of pancreatic intraductal papillary mucinous neoplasm without resection at diagnosis

Surveillance of sellected patients of main duct-involved and mixed-type of pancreatic intraductal papillary mucinous neoplasm without resection at diagnosis

Radiomics model versus 2017 revised international consensus guidelines for predicting malignant intraductal papillary mucinous neoplasms.

To evaluate a CT-based radiomics model for identifying malignant pancreatic intraductal papillary mucinous neoplasms (IPMNs) and compare its performance with the 2017 international consensus guidelines (ICGs). We retrospectively included 194 consecutive patients who underwent surgical resection of pancreatic IPMNs between January 2008 and December 2020. Surgical histopathology was the reference standard for diagnosing malignancy. Using radiomics features from preoperative contrast-enhanced CT, a radiomics model was built with the least absolute shrinkage and selection operator by a five-fold cross-validation. CT and MR images were independently reviewed based on the 2017 ICGs by two abdominal radiologists, and the performances of the 2017 ICGs and radiomics model were compared. The areas under the curve (AUCs) were compared using the DeLong method. A total of 194 patients with pancreatic IPMNs (benign, 83 [43%]; malignant, 111 [57%]) were chronologically divided into training (n = 141; age, 65 ± 8.6years; 88 males) and validation sets (n = 53; age, 66 ± 9.7years; 31 males). There was no statistically significant difference in the diagnostic performance of the 2017 ICGs between CT and MRI (AUC, 0.71 vs. 0.71; p = 0.93) with excellent intermodality agreement (k = 0.86). In the validation set, the CT radiomics model had higher AUC (0.85 vs. 0.71; p = 0.038), specificity (84.6% vs. 61.5%; p = 0.041), and positive predictive value (84.0% vs. 66.7%; p = 0.044) than the 2017 ICGs. The CT radiomics model exhibited better diagnostic performance than the 2017 ICGs in classifying malignant IPMNs. Compared with the radiologists' evaluation based on the 2017 international consensus guidelines, the CT radiomics model exhibited better diagnostic performance in classifying malignant intraductal papillary mucinous neoplasms. • There is a paucity of comparisons between the 2017 international consensus guidelines (ICGs) and radiomics models for malignant intraductal papillary mucinous neoplasms (IPMNs). • The CT radiomics model developed in this study exhibited better diagnostic performance than the 2017 ICGs in classifying malignant IPMNs. • The radiomics model may serve as a valuable complementary tool to the 2017 ICGs, potentially allowing a more quantitative assessment of IPMNs.

Squamous cell carcinoma of the pancreas with a pancreatic intraductal papillary mucinous neoplasm: a case report

Squamous cell carcinoma (SCC) of the pancreas is very rare. No reports have described SCC accompanied by intraductal papillary mucinous neoplasm (IPMN) of the pancreas. This report presents the first known case of SCC with IPMN of the pancreas in a 71-year-old man, with a focus on radiologic findings. Here, the imaging features of SCC with IPMN of the pancreas were similar to those of IPMN of the pancreas with high-risk stigmata features.

Hepatic Steatosis After Partial Pancreatectomy in a Cohort of Patients with Intraductal Papillary Mucinous Neoplasm

Nonalcoholic fatty liver disease (NAFLD) has been observed in patients after partial pancreatectomy. Previous studies have been performed on oncologic patients who underwent partial pancreatectomy and received adjuvant chemotherapy. By studying a cohort of patients with intraductal papillary mucinous neoplasms (IPMNs) who did not receive chemotherapy, the authors investigate the isolated effect of partial pancreatectomy on the development of fatty liver. A retrospective search for patients with pancreatic IPMNs who underwent partial pancreatectomy at an academic center from 2006 to 2014 identified 63 patients, including 42 who had pancreaticoduodenectomy (PD) and 21 who had distal pancreatectomy (DP). Fourteen patients with preoperative hepatic steatosis, diabetes, obesity, on steroid therapy, history of malignancy, or incomplete data were excluded. No patient received chemotherapy. Liver fat signal fraction (LFSF) was computed by the Dixon method using pre- and postoperative in- and out-of-phase MRI. Of the 49 patients included in the study, 29 (59%) underwent PD and 20 (41%) underwent DP. A total of 17 patients (34%) developed fatty liver after surgery. The entire cohort developed significant weight loss, 72.1 versus69.4kg (P<0.01). Postoperatively, there was significant increase in LFSF, 1.3% versus 9.6% following PD (P<0.01), and 2.1% versus 9.4% following DP (P=0.01). Partial pancreatectomy increases the risk of NAFLD independent of chemotherapy-induced hepatotoxicity. The underlying mechanism remains unclear and possibly related to pancreatic exocrine insufficiency and malnutrition.

Computed high-b-value high-resolution DWI improves solid lesion detection in IPMN of the pancreas

ObjectivesTo examine the effect of high-b-value computed diffusion-weighted imaging (cDWI) on solid lesion detection and classification in pancreatic intraductal papillary mucinous neoplasm (IPMN), using endoscopic ultrasound (EUS) and histopathology as a standard of reference.MethodsEighty-two patients with known or suspected IPMN were retrospectively enrolled. Computed high-b-value images at b = 1000 s/mm2 were calculated from standard (b = 0, 50, 300, and 600 s/mm2) DWI images for conventional full field-of-view (fFOV, 3 × 3 × 4 mm3 voxel size) DWI. A subset of 39 patients received additional high-resolution reduced-field-of-view (rFOV, 2.5 × 2.5 × 3 mm3 voxel size) DWI. In this cohort, rFOV cDWI was compared against fFOV cDWI additionally. Two experienced radiologists evaluated (Likert scale 1–4) image quality (overall image quality, lesion detection and delineation, fluid suppression within the lesion). In addition, quantitative image parameters (apparent signal-to-noise ratio (aSNR), apparent contrast-to-noise ratio (aCNR), contrast ratio (CR)) were assessed. Diagnostic confidence regarding the presence/absence of diffusion-restricted solid nodules was assessed in an additional reader study.ResultsHigh-b-value cDWI at b = 1000 s/mm2 outperformed acquired DWI at b = 600 s/mm2 regarding lesion detection, fluid suppression, aCNR, CR, and lesion classification (p =  < .001–.002). Comparing cDWI from fFOV and rFOV revealed higher image quality in high-resolution rFOV-DWI compared to conventional fFOV-DWI (p ≤ .001–.018). High-b-value cDWI images were rated non-inferior to directly acquired high-b-value DWI images (p = .095–.655).ConclusionsHigh-b-value cDWI may improve the detection and classification of solid lesions in IPMN. Combining high-resolution imaging and high-b-value cDWI may further increase diagnostic precision.Clinical relevance statementThis study shows the potential of computed high-resolution high-sensitivity diffusion-weighted magnetic resonance imaging for solid lesion detection in pancreatic intraductal papillary mucinous neoplasia (IPMN). The technique may enable early cancer detection in patients under surveillance.Key Points• Computed high-b-value diffusion-weighted imaging (cDWI) may improve the detection and classification of intraductal papillary mucinous neoplasms (IPMN) of the pancreas.• cDWI calculated from high-resolution imaging increases diagnostic precision compared to cDWI calculated from conventional-resolution imaging.• cDWI has the potential to strengthen the role of MRI for screening and surveillance of IPMN, particularly in view of the rising incidence of IPMNs combined with now more conservative therapeutic approaches.

Pancreatic Intraductal Papillary Mucinous Neoplasms: A Narrative Review.

Intraductal papillary mucinous neoplasms (IPMNs) are the most frequent cystic pancreatic neoplasm. They derive from the main pancreatic duct or branch ducts. This narrative review aims to present and compare the current guidelines on the management of IPMNs. We reviewed the most important scientific literature on the management of IPMNs. The clinical presentation of IPMNs is usually nonspecific; common symptoms are abdominal pain, weight loss, and jaundice. There are no sex differences, and the incidence increases with age. It is considered a premalignant lesion associated with synchronous or metachronous carcinomas. Multifocal sites within the pancreas and the presence of solid components, like mural nodules, are predictive factors for developing malignancy. Magnetic resonance imaging (MRI) is the imaging technique of choice. However, computed tomography (CT) and endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) can also contribute to the diagnosis. Resection is the optimal treatment for IPMNs that arise from the main duct, while several indications are suggested for the surgery on IPMNs of branch ducts. The decision on surgery is not always a simple task and should be based on high-risk features of the neoplasm. In any case, re-examination and follow-up are highly recommended.

Serine/Threonine Kinase 11 Plays a Canonical Role in Malignant Progression of KRAS -Mutant and GNAS -Wild-Type Intraductal Papillary Mucinous Neoplasms of the Pancreas.

We aimed to elucidate the clinicopathobiological significance of Serine/Threonine Kinase 11 (STK11) in pancreatic intraductal papillary mucinous neoplasms (IPMNs). STK11 is a tumor suppressor involved in certain IPMNs; however, its significance is not well known. In 184 IPMNs without Peutz-Jeghers syndrome, we analyzed expression of STK11 and phosphorylated-AMPKa in all cases, and p16, p53, SMAD4, and β-catenin in 140 cases by immunohistochemistry; and we analyzed mutations in 37 genes, including whole coding exons of STK11, CDKN2A, TP53, and SMAD4, and hotspots of KRAS, BRAF, and GNAS in 64 cases by targeted sequencing. KRAS and GNAS were additionally analyzed in 86 STK11-normal IPMNs using digital-PCR. Consistent loss or reduction of STK11 expression was observed in 26 of 184 (14%) IPMNs. These STK11-aberrant IPMNs were 17 of 45 (38%) pancreatobiliary, 8 of 27 (30%) oncocytic, 1 of 54 (2%) gastric, and 0 of 58 (0%) intestinal subtypes ( P = 8.5E-11), and 20 of 66 (30%) invasive, 6 of 74 (8%) high-grade, and 0 of 44 (0%) low-grade ( P = 3.9E-06). Sixteen somatic STK11 mutations (5 frameshift, 6 nonsense, 1 splicing, and 4 missense) were detected in 15/26 STK11-aberrant IPMNs ( P = 4.1E-06). All STK11-aberrantIPMNs were GNAS -wild-type and 96% of them were KRAS or BRAF -mutant.Morphologically, STK11-aberrant IPMNs presented "fern-like" arborizing papillae with thin fibrovascular core. Phosphorylated-AMPKa was down-regulated in STK11-aberrant IPMNs (92%, P = 6.8E-11). Patients with STK11-aberrant IPMNs showed poorer survival than patients with STK11-normal IPMNs ( P = 3.6E-04 overall; P = 6.1E-04 disease-free). STK11 may play a canonical role in malignant progression and poor survival of patients with IPMNs. Aberrant STK11-driven phosphorylated AMPK downregulation may provide therapeutic opportunities with mTOR inhibitors/AMPK activators.

Pancreatic intraductal papillary mucinous neoplasm evolving into adenocarcinoma. Continual follow-up necessary.

We report a 62-year-old female with chronic pancreatitis after three episodes of severe acute pancreatitis. In 2008, an uneven main pancreatic duct (MPD) of 16 mm was found during an abdominal ultrasound. The follow-up was not continued until 2020, when a dilation of 27 mm of the MPD was discovered at magnetic resonance imaging (MRI). In 2022, another radiological test was carried out showing a dilation of the MPD of 40 mm with an intraductal tumoral lesion of 30 mm at the head of the pancreas). An echo-endoscopy was carried out and a pancreatic-duodenal tumour with a mixed pattern was discovered. Atypic cells were observed at the fine needle punction. A total duodenopancreatectomy was successfully carried out. In the anatomopathological macroscopic study a 14 cm-multi-cystic neoformation was seen and a solid tumour was discovered at the head of the pancreas that infiltrated the wall of the duodenum. In the longitudinal cross-section of the pancreatic body the MPD was seen to be severely dilated. A focal adenocarcinoma in a intraductal papillary mucinous neoplasm (IPMN) was finally diagnosed. Pancreatic lesions are usually asymptomatic and are detected by chance during other imaging tests. The IPMN rates of malignancy have been reported of between 19 to 30%. The management of pancreatic cystic lesions still represents a clinical challenge. As always, the multi-disciplinary management is mandatory in this type of tumour.

Decision of Surgical Indication of Pancreatic Intraductal Papillary Mucinous Neoplasm by 18F-Fluorodeoxyglucose Positron Emission Tomography with Computed Tomography

Decision of Surgical Indication of Pancreatic Intraductal Papillary Mucinous Neoplasm by 18F-Fluorodeoxyglucose Positron Emission Tomography with Computed Tomography

Negative correlation between the nuclear size and nuclear Lamina component Lamin A in intraductal papillary mucinous neoplasms of the pancreas.

Background: The nuclear laminar protein Lamin A and inner nuclear membrane protein Emerin plays important role in sustaining nuclear structure. However, They have not investigated the significance of these proteins for development of pancreatic intraductal papillary mucinous neoplasm (IPMN). Methods: We examined pancreatic IPMN specimens for nuclear morphology and nuclear protein expression pattern of Lamin A and Emerin. Forty-two IPMN specimens were included, with 30 classified as intraductal papillary mucinous adenoma (IPMA) and 12 as intraductal papillary mucinous carcinoma (IPMC). Results: Classification according to histological subtype revealed that 26 specimens were of the gastric subtype (1 IPMC case), 8 were pancreatobiliary (6 IPMC cases), 6 were intestinal (3 IPMC cases), and 2 were oncocytic (all cases were IPMC). The frequency of IPMN subtypes in this study seemed to agree with those in previous reports. We analyzed Feulgen staining sections for nuclear morphological analysis using computer-assisted image analysis. Nuclear area and perimeter were significantly larger in IPMC than in IPMA. Finally, we examined the positive ratios of Lamin A and Emerin in immunohistochemical staining sections by image analysis. We found a negative correlation between the nuclear size and Lamin A-positive ratio, which was significantly lower in IPMC than that in IPMA. However, no significant correlation was observed between nuclear size and Emerin expression was observed, and no differences were found in the Emerin-positive ratio between IPMA and IPMC. Conclusion: Our results suggest that a decreased Lamin A positive ratio induces nuclear enlargement in adenomas, which thereby induce promotion to carcinomas. Furthermore, Lamin A expression can be a reliable biomarker for distinguishing between IPMC and IPMA.

A pilot study to evaluate tissue- and plasma-based DNA driver mutations in a cohort of patients with pancreatic intraductal papillary mucinous neoplasms.

Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions to pancreatic ductal adenocarcinoma that are challenging to manage due to limited imaging, cytologic, and molecular markers that accurately classify lesions, grade of dysplasia, or focus of invasion preoperatively. The objective of this pilot study was to determine the frequency and type of DNA mutations in a cohort of surgically resected, pathologically confirmed IPMN, and to determine if concordant mutations are detectable in paired pretreatment plasma samples. Formalin-fixed paraffin-embedded (FFPE) tissue from 46 surgically resected IPMNs (31 low-grade, 15 high-grade) and paired plasma from a subset of 15 IPMN cases (10 low-grade, 5 high-grade) were subjected to targeted mutation analysis using a QIAseq Targeted DNA Custom Panel. Common driver mutations were detected in FFPE from 44 of 46 (95.6%) IPMN cases spanning all grades; the most common DNA mutations included: KRAS (80%), RNF43 (24%), and GNAS (43%). Of note, we observed a significant increase in the frequency of RNF43 mutations from low-grade to high-grade IPMNs associated or concomitant with invasive carcinoma (trend test, P = 0.01). Among the subset of cases with paired plasma, driver mutations identified in the IPMNs were not detected in circulation. Overall, our results indicate that mutational burden for IPMNs is a common occurrence, even in low-grade IPMNs. Furthermore, although blood-based biopsies are an attractive, noninvasive method for detecting somatic DNA mutations, the QIAseq panel was not sensitive enough to detect driver mutations that existed in IPMN tissue using paired plasma in the volume we were able to retrieve for this retrospective study.

Peritoneal Metastases After Intraductal Papillary Mucinous Neoplasm Resection: How Common are They?

IntroductionPeritoneal metastases (PMs) following resection of pancreatic intraductal papillary mucinous neoplasms (IPMNs) are rare. Consequently, prevalence, risk factors, and prognosis are not well known. We reviewed our institution’s experience and published literature to further characterize the scope of this phenomenon. MethodsAll pancreatectomy cases (556 patients) performed at a tertiary care center between 2010 and 2020 were reviewed to identify IPMN diagnoses. Patients with adenocarcinoma not arising from IPMN, or a history of other malignancies were excluded. ResultsSeventy-eight patients underwent pancreatectomy with IPMN on final pathology at our institution; 51 met inclusion criteria. Of these, there were five cases of PMs (4:1 females:males). Four had invasive carcinoma arising from IPMN and one had high-grade dysplasia at the index operation. Female sex and invasive histology were significantly associated with PM (P < 0.05). PM rates by sex were 3% (95% confidence interval [CI]: 0.5-15) in males and 22% (95% CI: 9-45) in females. Rates by histology were 2.9% (95% CI: 0.5-15) for noninvasive IPMN, and 23.5% (95% CI: 9.5-47) for invasive carcinoma arising from IPMN. Median interval from surgery to PMs was 7 mo (range: 3-13). ConclusionsPMs following IPMN resection are rare but may be more common in patients with invasive histology. Although rare, PMs can arise in patients with noninvasive IPMNs. Further studies on pathophysiology and risk factors of PM following IPMN resection are needed and may reinforce adherence to guidelines recommending long-term surveillance.

Two Cases of Duodenal Neuroendocrine (Carcinoid) Tumor Concurrent with Invasive Gastric Adenocarcinoma and Pancreatic Intraductal Papillary Mucinous Neoplasm

Abstract Introduction/Objective Neuroendocrine (carcinoid) tumors of the duodenum are extremely rare and account for only 2-4% of gastrointestinal tract neuroendocrine tumors. We report two cases of incidentally discovered duodenal neuroendocrine tumor which respectively occurred in a patient with invasive gastric adenocarcinoma and in a patient with pancreatic intraductal papillary mucinous neoplasm (IPMN). Methods/Case Report The first case involved a 60-year old male who presented with melena and symptomatic anemia and was found on EGD to have a large circumferential mass at the gastric antrum/pylorus, which was revealed to be an invasive gastric adenocarcinoma on biopsy. At the time of distal gastrectomy for this malignancy, a concurrent, 0.6 cm-sized, low grade neuroendocrine tumor was incidentally discovered at the duodenal margin. The duodenal tumor consisted of nests and trabeculae of monotonous cells with ovoid/round nuclei, finely speckled “salt and pepper” chromatin, and low mitotic rate (&amp;lt; 2 mitoses/2 mm2), and invaded only into submucosa. The tumor cells were strongly and diffusely positive for neuroendocrine markers chromogranin, synaptophysin, and CD56, positive for CK7 and CDX2, negative for CK20, and with low Ki67 proliferation index (&amp;lt; 3%). The second case involved a 69-year old female who presented with epigastric pain and was found on abdominal CT to have a 4 cm-sized cystic mass in the pancreatic head. While biopsy of the pancreatic mass revealed an IPMN, a separate biopsy of an incidentally discovered, 1 cm-deep ulcer in the duodenum bulb revealed a low-grade neuroendocrine tumor with similar morphologic features, mitotic rate, and immunohistochemical staining pattern as the prior case while also negative for IMP3 stain. The patient had normal serum gastrin and urine HIAA levels, but elevated serum chromogranin-A levels. Results (if a Case Study enter NA) NA. Conclusion Duodenal carcinoids are rare (1-3% of primary duodenal tumors) and are mostly non-functional and unifocal. The duodenum is also the least common site (2-4%) for GI tract neuroendocrine tumors. The pathophysiology of these tumors is still poorly understood, with the majority occurring sporadically and a minority in the setting of hereditary cancer syndromes. This report documents two very rare instances of duodenal neuroendocrine tumor incidentally discovered with invasive gastric adenocarcinoma and pancreatic IPMN.