Resected Intraductal Papillary Mucinous Neoplasms Research Articles

Abstract 446: Integrated spatial transcriptomics and lipidomics analyses of intraductal papillary mucinous neoplasm identifies enrichment of long chain sulfatide as an early metabolic alteration

Abstract Purpose: To define the metabolic alterations associated with malignant progression of intraductal papillary mucinous neoplasm (IPMN). Experimental Procedures: Matrix-assisted laser desorption/ionization (MALDI)-mass spectrometry (MS) was conducted for spatial characterization of lipid profiles on frozen tissue sections from resected human IPMN patients. The specimen set consisted of either low-grade dysplasia (LG) (n=15), high-grade (HG) dysplasia (n=4), or with an associated pancreatic ductal adenocarcinoma (PDAC) (n=4) as well as 15 PDAC tissues. Utilizing serial sections to the same human IPMN cases analyzed with MALDI-MS imaging, we used the Visium Spatial Gene Expression technology platform to characterize the spatiomolecular underpinnings of LG and HG IPMN. H&E images of the same tissue section used for the Visium workflow, were used to annotate the spots in the dataset covering the epithelial lining of the IPMN lesions (“epilesional” areas) and the spots covering the adjacent microenvironment surrounding the lesion (“perilesiopecific” area). Findings were compared with lipidomic analyses of cystic fluid from 89 IPMN patients. The anti-cancer efficacy of UGT8-IN-1, a selective small molecule inhibitor of ceramide galactosyltransferase (CGT, also known as UGT8), was assessed in vitro and in mutant Kras;Gnas allografts. Results: MALDI/MS-based spatial imaging of human resected IPMN tissues and pancreata from a mutant Kras;Gnas mouse model of IPMN revealed long-chain hydroxylated sulfatides, particularly the C24:0(OH) and C24:1(OH) species, to be selectively enriched in the IPMN and PDAC neoplastic epithelium. Visium spatial transcriptomics data confirmed that the cognate transcripts engaged in sulfatide biosynthesis, including UGT8, Gal3St1, and FA2H, were co-localized with areas of sulfatide enrichment. Lipidomic analyses of cystic fluid from 89 patients with IPMN identified several sulfatide species to be significantly elevated in patients with IPMN/PDAC compared to those with low-grade IPMN. Inhibition of sulfatide metabolism via UGT8-IN-1 reduced viability of Kras;Gnas murine cell lines in vitro and attenuated tumor growth in an allograft IPMN model. UGT8-IN-1 treatment resulted in reduced levels of several sulfatide species, accompanied by a concomitant increase in a subset of quantified sulfatides precursor ceramides, accumulation of mitochondrial mass and reactive oxygen species and time-dependent increases in autophagy/mitophagy markers p62/SQSTM1 and LC-3B, suggesting impaired mitophagy. Conclusion: Enhanced sulfatide metabolism is an early alteration in cystic pre-cancerous lesions of the pancreas that persists through invasive neoplasia. Targeting sulfatide biosynthesis might represent an actionable vulnerability for cancer interception. Citation Format: Yihui Chen, Marta Sans, Fredrik Thege, Rongzhang Dou, Jimin Min, Michele Yip-Schneider, Jianjun Zhang, Ranran Wu, Ehsan Irajizad, Yuki Makino, Kimal Rajapakshe, Mark Hurd, Ricardo León-Letelier, Jody Vykoukal, Jennifer Dennison, Kim-Anh Do, Robert Wolff, Paola Guerrero, Michael Kim, Max Schmidt, Anirban Maitra, Samir Hanash, Johannes Fahrmann. Integrated spatial transcriptomics and lipidomics analyses of intraductal papillary mucinous neoplasm identifies enrichment of long chain sulfatide as an early metabolic alteration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 446.

Intraductal papillary mucinous neoplasms of the pancreas: Cytologic-histologic correlation study and evaluation of the cytologic accuracy in identifying high-grade dysplasia/invasive adenocarcinoma.

Intraductal papillary mucinous neoplasms (IPMNs) may be associated with invasive adenocarcinoma, low-grade dysplasia (LGD), or high-grade dysplasia (HGD). We aimed to review the cytologic-histologic correlation of cases with a histologic diagnosis of IPMN. A database search (January 2010-January 2021) was performed for resected IPMNs with preceding endoscopic ultrasound-guided fine-needle aspiration (FNA). Cytology slides were reviewed for the presence of benign, atypical, or malignant cells, and necrosis. Histologically, IPMNs were classified as benign (LGD) or malignant (HGD or adenocarcinoma). There were 41 patients with IPMN; 24 malignant and 17 benign. Sixteen of the 24 malignant IPMNs were accurately classified as malignant on cytology. There were eight false negatives and one false positive. Cytology yielded a sensitivity of 67% and a specificity of 94%. Among the 16 true positives with FNA diagnosis of adenocarcinoma, seven were IPMNs with HGD, and nine had invasive adenocarcinomas on histology. Cellular morphology and absence or presence of necrosis did not help distinguish HGD from adenocarcinoma on cytology (P > 0.5). Sampling errors and interpretative errors resulted in false-negative cases. Cytology yielded diagnoses related to IPMN in 73% of cases (30/41) and lack of identification of mucinous cells/mucinous background resulted in interpretative errors (9). This study shows that there is a good correlation between cytopathology and surgical pathology diagnoses of IPMNs and that cytology is mostly able to recognize IPMN with HGD/adenocarcinoma. However, heterogeneity in areas of IPMN with HGD/adenocarcinoma may result in sampling errors yielding false-negative cases. Mucinous cells/background should raise the suspicion of IPMN on cytology, even when no neoplastic epithelium is present for the evaluation of dysplasia.

Abstract A011: Proteomic expression using exosomes in intraductal papillary mucinous neoplasms (IPMN) patients to inform risk stratification

Abstract Introduction Intraductal papillary mucinous neoplasm (IPMN), the most common type of pancreatic mucinous cysts, harbor risks of malignant progression of approximately 50% and 5% when found in the main duct (MD) and branch duct (BD), respectively. Surgical resection is standard of care in patients with high-risk stigmata and in some “indeterminate” cases, while surveillance modalities, which may include invasive imaging, are recommended for cases of cysts with “worrisome features”. Given the poor prognosis of late-stage pancreatic cancer, it is critical to accurately risk-stratify patients with IPMNs. We conducted a pilot study to evaluate the association of IPMN features with protein markers using extracellular vesicles (EVs), including exosomes, isolated from the blood of patients with resected IPMNs. Experimental procedure We evaluated 19 patients with IPMNs who underwent surgical resection (Whipple or distal pancreatectomy). Blood was collected before surgery and the EVs were isolated from plasma using an alternating current electrokinetics (ACE) platform. The concentration of 52 EV proteins was measured using a multiplex immunoassay. Surgical explant pathology reports were available and reviewed on all 19 patients. Data are presented as average concentration and 95% CI, and p-values represent the two-tailed t-test. Results Average age was 69 years (range: 47-83) and, of the 19 patients, 12 (63%) were male. Seventeen patients never smoked or were former smokers (quit > 20 years) before sample collection. A total of 14 patients had acute or chronic pancreatitis (7 historical; 7 found in surgical explant) while 4 patients had previously undiagnosed pancreatic intraepithelial neoplasia (PanIN) at the time of surgery. In our EV analysis, we found multiple EV protein biomarkers to be elevated in patients with various IPMN characteristics. Marker A was significantly elevated in patients with high-grade dysplasia (n=10) compared to low-grade dysplasia (n=9) (10.8 [8.4-13.2] vs. 7.5 [5.8 - 9.2] pg/mL, respectively, p = 0.0241), as defined by surgical explant pathology. When examining 13 patients with main-duct or mixed-type IPMNs, markers B, C, and D were elevated compared to the 6 patients with branch-duct or unspecified IPMNs (marker B: 1.9 [1.4-2.3] vs. 1.1 [0.9-1.4] ng/mL, p=0.0099; marker C: 524.3 [400.2-648.4] vs. 318.8 [209.9-427.7] pg/mL, p=0.0102; marker D: 65.8 [43.8-87.7] vs. 39.9 [31.7-48.1] pg/mL, p=0.0281). Conclusions In this pilot study that evaluated 19 patients with IPMNs, we identified multiple EV proteins that are differentially expressed in subgroups of patients. Our findings suggest that these differentially expressed proteomic markers can lead to the development of an algorithm for IPMN risk-stratification and possibly help discern histopathologic grade. Future studies will expand on these preliminary results with the aim of identifying a panel of biomarkers that can risk-stratify IPMNs to guide medical decision-making. Citation Format: Harmeet Dhani, Roberta V. Alexander, Juan Pablo Hinestrosa, Jesus Izaguirre-Carbonell, Dove Keith, Paul R. Billings, Gregory Cote', Rosalie Sears. Proteomic expression using exosomes in intraductal papillary mucinous neoplasms (IPMN) patients to inform risk stratification [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 A011.

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.

Serum elastase-1 predicts malignancy in intraductal papillary mucinous neoplasm of the pancreas

BackgroundThe indication for surgical resection of intraductal papillary mucinous neoplasms (IPMNs) is defined by imaging features, such as mural nodules. Although carbohydrate antigen (CA) 19-9 was selected as a parameter for worrisome features, no serum biomarkers were considered when deciding on surgical indications in the latest international consensus guideline. In this study, we assessed whether clinical factors, imaging findings, and serum biomarkers are useful in predicting malignant IPMNs. MethodsA total of 234 resected IPMN cases in Chiba University Hospital from July 2005 to December 2021 were retrospectively analyzed. ResultsAmong the 234 patients with resected IPMNs diagnosed by preoperative imaging, 117 were diagnosed with malignant pathologies (high-grade dysplasia and invasive IPMNs) according to the histological classification. In the multivariate analysis, cyst diameter ≥30 mm; p = 0.035), enhancing mural nodules on multidetector computed tomography (≥5 mm; p = 0.018), and high serum elastase-1 (≥230 ng/dl; p = 0.0007) were identified as independent malignant predictors, while CA19-9 was not. Furthermore, based on the receiver operator characteristic curve analyses, elastase-1 was superior to CA19-9 for predicting malignant IPMNs. Additionally, high serum elastase-1 levels (≥230 ng/dl; p = 0.0093) were identified as independent predictors of malignant IPMNs in patients without mural nodules on multidetector computed tomography (MDCT) in multivariate analysis. ConclusionThe serum elastase-1 level was found to be a potentially useful biomarker for predicting malignant IPMNs.

Integrated Molecular Characterization of Intraductal Papillary Mucinous Neoplasms: An NCI Cancer Moonshot Precancer Atlas Pilot Project.

Integrated molecular analysis of genomic and transcriptomic alterations in the multistep progression of IPMNs, which are bona fide precursors of pancreatic cancer, identifies features associated with progression of low-risk lesions to high-risk lesions and cancer, which might enable patient stratification and cancer interception strategies.

A comparative study between computed tomography and endoscopic ultrasound in the detection of a mural nodule in intraductal papillary mucinous neoplasm –Multicenter observational study in Japan

Background/objectivesThe detection of malignancy is a major concern in the management of intraductal papillary mucinous neoplasm (IPMN). The height of the mural nodule (MN), estimated using endoscopic ultrasound (EUS) and computed tomography (CT), has been considered crucial for predicting malignant IPMN. Currently, whether surveillance using CT or EUS alone is sufficient for detecting MNs remains unclear. This study aimed to compare the ability of CT and EUS to detect MNs in IPMN. MethodsThis multicenter, retrospective observational study was conducted in 11 Japanese tertiary institutions. Patients who underwent surgical resection of IPMN with MN after CT and EUS examinations were eligible to participate. The MN detection rates between CT and EUS were examined. ResultsTwo-hundred-and-forty patients who underwent preoperative EUS and CT had pathologically confirmed MNs. The MN detection rates of EUS and CT were 83% and 53%, respectively (p < 0.001). Additionally, the MN detection rate of EUS was significantly higher than that of CT regardless of morphological type (76% vs. 47% in branch-duct-type IPMN; 90% vs. 54% in mixed IPMN; 98% vs. 56% in main-duct-type IPMN; p < 0.001). Further, pathologically confirmed MNs ≥5 mm were more frequently observed on EUS than on CT (95% vs. 76%, p < 0.001). ConclusionsEUS was superior to CT for the detection of MN in IPMN. EUS surveillance is essential for the detection of MNs.

Long-term (10-year) outcomes and prognostic factors in resected intraductal papillary mucinous neoplasm tumors in Finland: A nationwide retrospective study

BackgroundThe degree of dysplasia is the most important prognostic factor for patients with resected intraductal papillary mucinous neoplasms. Intraductal papillary mucinous neoplasms are predominantly premalignant conditions; in most cases, surveillance is an adequate treatment. If worrisome features are present, surgery should be considered. However, there is limited data on the long-term prognosis of resected intraductal papillary mucinous neoplasms. We aimed to ascertain the nationwide survival of patients with resected intraductal papillary mucinous neoplasms and identify factors associated with survival. MethodsThis is a retrospective nationwide cohort study. All intraductal papillary mucinous neoplasms operated on in Finland between 2000 and 2008 were identified. Patient records were evaluated, and original radiologic data and histologic samples were re-evaluated. Survival data were collected after a 10-year follow-up period. ResultsOut of 2,024 pancreatic resections, 88 were performed for intraductal papillary mucinous neoplasm. The median age of the patients was 65 years. Histologic diagnoses were main duct intraductal papillary mucinous neoplasm 47/88 (53,4%), mixed-type intraductal papillary mucinous neoplasm 27/88 (30.7%), and branchduct intraductal papillary mucinous neoplasm 14/88 (15.9%). Of the tumors, 40/88 (45.5%) were low-grade dysplasia, 9/88 (10.2%) high-grade, and 39/88 (44.3%) were invasive cancer. The median survival was 121 (range 0–252) months. Ten-year survival was 72.5%, 66.7%, and 23.1% in the low-grade dysplasia, high-grade dysplasia, invasive cancer groups, respectively. Ten-year mortality for pancreatic cancer was 5%, 9.1%, and 71.8% in the low-grade dysplasia, high-grade dysplasia, invasive cancer groups, respectively. ConclusionOverall, 44.3% of the patients had a malignant tumor, and three-quarters (74.5%) of the main duct intraductal papillary mucinous neoplasms were malignant or high-grade dysplasia at the time of surgery. Ten-year survival was significantly better in patients operated on at the stage of a premalignant tumor (low-grade dysplasia + high-grade dysplasia) than in patients operated on at the stage of a malignant tumor.

IPMN-LEARN: A linear support vector machine learning model for predicting low-grade intraductal papillary mucinous neoplasms.

We aimed to build a machine learning tool to help predict low-grade intraductal papillary mucinous neoplasms (IPMNs) in order to avoid unnecessary surgical resection. IPMNs are precursors to pancreatic cancer. Surgical resection remains the only recognized treatment for IPMNs yet carries some risks of morbidity and potential mortality. Existing clinical guidelines are imperfect in distinguishing low-risk cysts from high-risk cysts that warrant resection. We built a linear support vector machine (SVM) learning model using a prospectively maintained surgical database of patients with resected IPMNs. Input variables included 18 demographic, clinical, and imaging characteristics. The outcome variable was the presence of low-grade or high-grade IPMN based on post-operative pathology results. Data were divided into a training/validation set and a testing set at a ratio of 4:1. Receiver operating characteristics analysis was used to assess classification performance. A total of 575 patients with resected IPMNs were identified. Of them, 53.4% had low-grade disease on final pathology. After classifier training and testing, a linear SVM-based model (IPMN-LEARN) was applied on the validation set. It achieved an accuracy of 77.4%, with a positive predictive value of 83%, a specificity of 72%, and a sensitivity of 83% in predicting low-grade disease in patients with IPMN. The model predicted low-grade lesions with an area under the curve of 0.82. A linear SVM learning model can identify low-grade IPMNs with good sensitivity and specificity. It may be used as a complement to existing guidelines to identify patients who could avoid unnecessary surgical resection.

Pre-emptive resection for intraductal papillary mucinous neoplasia – Long-term outcome is similar between non-invasive and early invasive lesions in a tertiary single center

BackgroundPre-emptive resection for intraductal papillary mucinous neoplasm (IPMN) aims to reduce the risk before invasive transformation has taken place. Pancreatic resections are highly associated with major morbidity and mortality. Long-term overall survival (OS) after resection for invasive IPMN (inv-IPMN) in early stages is favorable. Comparison of long-term OS for resected non-invasive IPMN and early staged inv-IPMN is poorly delineated. This study aims to compare outcomes for resected non-invasive IPMN and T1-staged inv-IPMN. MethodsAll patients ≥18 years of age resected for IPMN up to stage T1 at Karolinska University Hospital between 2008 and 2020 were included. Two-year OS were compared between groups by chi-squared test, and 5-year OS was estimated using Kaplan-Meier method. Covariates associated with death was assessed in multivariable Cox regression model. ResultsWe included 284 patients, 264 (93%) non-invasive IPMN and 20 (7%) T1-staged inv-IPMN. Dysplasia of low grade (LGD) and high grade, i.e., tumor in situ (Tis) were present in 190 (67%) and 75 (26%) patients respectively. The 2-year OS for the entire cohort was 96%, and there were no differences between non-invasive and inv-IPMN (96% vs 92%, p = 0.203), nor between IPMN with LGD and Tis-T1b-staged IPMN (96% vs 95%, p = 0.734). ConclusionTwo thirds of the specimen from pre-emptive resections were of LGD and did not involve superior OS than in situ or early cancer. Due to high complication burden, efforts should be made to avoid resection when LGD is probable and rather identify more accurate predictors for surgery.

Digital spatial profiling of intraductal papillary mucinous neoplasms: Toward a molecular framework for risk stratification

The histopathologic heterogeneity of intraductal papillary mucinous neoplasms (IPMN) complicates the prediction of pancreatic ductal adenocarcinoma (PDAC) risk. Intratumoral regions of pancreaticobiliary (PB), intestinal (INT), and gastric foveolar (GF) epithelium may occur with either low-grade dysplasia (LGD) or high-grade dysplasia (HGD). We used digital spatial RNA profiling of dysplastic epithelium (83 regions) from surgically resected IPMN tissues (12 patients) to differentiate subtypes and predict genes associated with malignancy. The expression patterns of PB and GF lesions diverged from INT, suggesting that PB and GF arise from a common lineage. Transcriptional dysregulation within PB lesions mirrored that of PDAC, whereas INT and GF foci did not. Tumor necrosis factor/nuclear factor κB (TNF-NFκB) and cell cycle (cycling S and cycling G2-M) programs occurred with relative prominence in PB and INT subtypes, respectively. Together, this study delineates markers of high-risk IPMN and insights into malignant progression.

A model for predicting degree of malignancy in patients with intraductal papillary mucinous neoplasm.

There is no predictive model available to address early stage malignant intraductal papillary mucinous neoplasm (IPMN) including high grade dysplasia (HGD) and pT1a (invasive component≤0.5 cm). The aim of this study was to establish an objective and sufficient model to predict the degree of malignancy in patients with IPMN, which can be easily applied in daily practice and adopted for any type of lesion. A retrospective cohort study of 309 patients who underwent surgical resection for IPMN was performed. Members of the cohort were randomly allocated to the training or testing set. A detection tree model and random forest model were used for a 3-class classification to distinguish low grade dysplasia (LGD), HGD/pT1a IPMN, and invasive intraductal papillary mucinous cancer (I-IPMC) beyond pT1a. Of the 309 patients, 54 (17.4%) had early stage malignancy (19 HGD, 35 pT1a), 49 (15.9%) had I-IPMC beyond pT1a, and 206 (66.7%) had LGD IPMN. We proposed a 3-class classification model using a random forest algorithm, and the model had an accuracy of 99.5% with the training set, and displayed an accuracy of 96.0% with the testing set. We used SHAP for interpretation of the model and showed the top five factors (mural nodule size, main pancreatic duct diameter, CA19-9 levels, lesion edge and common bile duct dilation) were most likely to influence the 3-class classification results in terms of interpretation of the random forest model. This predictive model will help assess an individual's risk for different stages of IPMN malignancy and may help identify patients with IPMN who require surgery.

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.

Peak density of immature nerve cells occurs with high-grade dysplasia in intraductal papillary mucinous neoplasms of the pancreas.

The development of neural structures within tumors is now considered vital for carcinogenesis. However, the time course of this development in human pre-invasive neoplasia has been incompletely described. Therefore, we performed a detailed analysis of nerves across the neoplastic spectrum in resected intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Histology and multiplexed immunochemistry demonstrated that nerve density increased from low-grade (LG) to high-grade dysplasia (HG) but did not further increase once invasive IPMN (INV IPMN) was present. Higher nerve density correlated with increasing expression of nerve growth factor (NGF) by the tumor cells. Intra-tumoral nerves were immature and lacked markers of sympathetic, parasympathetic, and sensory lineages. Here, we show for the first time the presence of neural precursor cells (NPCs) within the stroma of pancreatic tumors. The density of these doublecortin (DCX)-positive NPCs increased from LG to HG, but not from HG to INV IPMN. We conclude that peak neural density of tumors is reached in high-grade dysplasia (often termed carcinoma in situ) rather than after invasion. These findings suggest that nerve-tumor interactions are important in IPMN progression and may serve as the basis for future mechanistic studies and novel therapeutic modalities. © 2022 The Pathological Society of Great Britain and Ireland.

Multidimensional Immunophenotyping of Intraductal Papillary Mucinous Neoplasms Reveals Novel T Cell and Macrophage Signature.

Intraductal papillary mucinous neoplasms (IPMN) are the only radiographically identifiable precursor to pancreatic adenocarcinoma, yet little is known about how these lesions progress to cancer. Inflammation has been associated with dysplastic progression; however, the cause and composition of this inflammation remains poorly characterized. We sought to comprehensively profile immune cell infiltration using parallel spatial transcriptomic and flow cytometric techniques. Twelve patients with resected IPMN exhibiting both high-grade dysplasia (HGD) and low-grade dysplasia (LGD) were selected for spatial transcriptomics (NanoString GeoMx). Immune (CD45+), epithelial (PanCK+), and stromal (SMA+) compartments were analyzed separately using the GeoMx NGS Pipeline. An additional 11 patients resected for IPMN of varying degrees of dysplasia underwent immunophenotyping using flow cytometry (DURAClone IM). Spatial transcriptomics revealed that T cells represent the dominant immune cell within IPMN stroma, which was confirmed by flow cytometry (56%). Spatial profiling found that the T-cell infiltrate was significantly higher in regions of LGD compared with HGD (62% vs. 50%, p = 0.038). Macrophages were the only other immune cell type with > 10% abundance, yet conversely, were generally more abundant in regions of HGD compared to LGD (19% vs. 11%, p = 0.058). Correspondingly, immune cells within regions of HGD demonstrated transcriptional upregulation of genes associated with macrophage activity including secretion (CXCL1) and phagocytosis (C1QA, C1S, C4B). IPMN immune infiltrate is primarily composed of T cells and macrophages. Regions of HGD appear to be relatively deplete of T cells and show a trend toward macrophage enrichment compared with regions of LGD.

Preoperative Predictive Features of Invasive Carcinoma Among Intraductal Papillary Mucinous Neoplasm of the Pancreas.

Noninvasive intraductal papillary mucinous neoplasms (IPMNs) theoretically do not metastasize. The purpose of this study is to preoperatively distinguish invasive carcinomas associated with IPMN from noninvasive IPMN. A total of 131 patients who underwent surgical resection for IPMN were retrospectively analyzed to identify the predictors of invasive carcinoma, based on the International Association of Pancreatology Consensus Guidelines. Of the 131 patients, 29 (22%) had invasive carcinomas and 102 (78%) had noninvasive IPMN. An enhancing mural nodule (MN) greater than or equal to 5 mm, obstructive jaundice, an abrupt change in the caliber of the pancreatic duct (PD) with distal pancreatic atrophy, and lymphadenopathy were the significant predictors of invasive carcinoma in univariate analysis. The optimal cutoff value for the size of the enhancing MN to differentiate invasive carcinoma was 13 mm. In multivariate analysis, enhancing MN greater than or equal to 13 mm, obstructive jaundice, and an abrupt change in the PD caliber were the independent predictors. When all these factors were absent, only 17% were invasive carcinomas. Enhancing MN greater than or equal to 13 mm, obstructive jaundice, and an abrupt change in the PD caliber were predictive factors for invasive carcinoma. Systematic lymph node dissection may be omitted when a high-risk patient has none of these factors.

Number of Worrisome Features and Risk of Malignancy in Intraductal Papillary Mucinous Neoplasm.

The 2017 revised International Association of Pancreatology guidelines for management of intraductal papillary mucinous neoplasm (IPMN) describe worrisome features (WF) and high-risk stigmata (HRS), recommending resection in the latter and further work-up and close surveillance for patients with WF. The effect of multiple WF on the likelihood of malignancy has not been evaluated. Eight hundred ten patients who underwent pancreatic resection for IPMN in 2 tertiary referral centers were identified from prospective institutional databases. Patients were retrospectively categorized into subgroups according to the number of WF or HRS and presence of malignancy, defined as high-grade dysplasia (HGD) or invasive cancer on final pathology. Three hundred seventy-nine (47%) patients had HRS, 370 (46%) had 1 or more WF, and 61 patients (7%) had neither. Malignancy was present in 70% (n = 267) of patients with HRS and in 30% (n = 127) of those with WF. Only 3 of 61 patients without WF/HRS had malignancy, and all only in the form of HGD. The risk of malignancy increased in a stepwise fashion with the number of WF, to 22%, 34%, and 59% with 1, 2, and 3 WF, respectively (p = 0.001), and reached 100% in patients with 4 or more WF. Although the relative risks differed for particular WF, the areas under the curve were not statistically different. We confirm that presence of HRS in IPMN is associated with a very high likelihood of malignancy. The presence of a single WF has a malignancy risk of 22%, and additional WF increase this risk significantly. When 3 or more WF are present, the risk is similar to that of HRS.

Development and external validation of a nomogram with inflammatory markers for predicting invasiveness of intraductal papillary mucinous neoplasm of pancreas.

Recent studies have reported that inflammatory markers, such as neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and advanced lung cancer inflammation index, are associated with invasiveness of intraductal papillary mucinous neoplasm (IPMN). This study aimed to develop and validate a new nomogram that includes inflammatory markers for predicting the invasiveness of IPMN.The data of 365 patients who underwent surgical resection for IPMN at 4 centers between 1995 and 2016 were retrospectively reviewed to develop a new nomogram. For external validation, a separate patient cohort was used. The predictive ability of the nomogram was evaluated using the area under the receiver operating characteristic curve.The new nomogram was developed using the following variables which were identified as risk factors for invasive IPMN: body mass index, preoperative serum bilirubin level, carbohydrate antigen 19-9, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, advanced lung cancer inflammation index, main duct type, presence of solid portion, and tumor size. After external validation, the area under the curve value was 0.649 (95% CI: 0.578-0.720, P < .001).To the best of our knowledge, this study is the first to predict and externally validate the invasiveness in IPMN using inflammatory markers. Further research is necessary to improve predictability of the model for selecting patients for surgical resection.

Epidemiological Factors Associated With Intraductal Papillary Mucinous Neoplasm of the Pancreas: A Dual Center Case-Control Study.

The present study aimed to identify epidemiological factors associated with the development of intraductal papillary mucinous neoplasms (IPMN) of the pancreas comparing patients after IPMN resection with population-based controls. Preoperative data of 811 patients undergoing pancreatic resection for IPMN were matched in a 1:1 ratio with a random sample of volunteers from the Study of Health in Pomerania, which showed no pancreatic cyst greater than 2 mm in magnetic resonance cholangiopancreaticography. A total of 811 controls with a mean age of 61.9 years (standard deviation, 8.4 years) were matched to cases with a mean age of 66.1 years (standard deviation, 9.3 years). A previous history of pancreatitis, endocrine pancreatic insufficiency was significantly more frequent in IPMN patients compared with controls (P = 0.001). Moreover, adjusted data revealed that urogenital cancer (P = 0.034), colorectal cancer (P = 0.021), as well as first-degree family history of colorectal cancer (P = 0.001) were significantly more frequent in IPMN patients. A history of urogenital and colorectal cancer often coincides with IPMN, which have an indication for surgery and are associated with preoperative episodes of pancreatitis and with endocrine insufficiency. Prospective studies are needed to investigate the role of these factors in IPMN development.