Subtypes Of Intraductal Papillary Mucinous Neoplasm Research Articles

O77: Invasive intraductal oncocytic papillary neoplasms (IOPN) and adenocarcinomas arising from Intraductal papillary mucinous neoplasms (IPMN): adjuvant chemotherapy, patterns of recurrence and survival

Abstract Introduction Invasive intraductal oncocytic papillary neoplasms (IOPNs) are extremely rare and are increasingly being recognised as their own entity, distinct from intraductal papilliary mucinous neoplasism subtypes (IPMN). Their clinicopathologic behaviour, recurrence patterns, response to adjuvant chemotherapy and long-term survival outcomes are unknown compared to adenocarcinomas arising from IPMN but were investigated in the present study. Methods Patients undergoing pancreatic resection between 2010-2020 for invasive IOPNs and adenocarcinoma arising from IPMNs were identified retrospectively from 18 academic pancreatic centers worldwide. Survival analyses were conducted to compare outcome measures between IOPNs and IPMN precursor epithelial subtypes and invasive components. Results Of the 459 patients with invasive IOPN/IPMNs, 20 patients had an invasive IOPN (median age,69; male,n=11), the majority of which were in the pancreatic head (75%) and underwent either a Whipples procedure (40%) or PPPD (35%). After a median follow-up of 6 years, 45% of invasive IOPNs developed recurrence (1-year,30.0%; 5-year,69.2%) and 40% survived follow-up (2-year survival 55.0%, 5-year survival, 30.8%). Recurrence rates and survival of invasive IOPNs were higher than colloid IPMNs (n=64) (p=0.031 and p=0.007) and comparable with ductal IPMNs (n=331) as well as gastric (n=54) and pancreatobiliary (n=111) IPMN subtypes. Invasive IOPN had significantly lower cancer-specific survival compared to colloid carcinomas (p<0.001). Adjuvant chemotherapy did not improve rates of recurrence in invasive IOPN and IPMN subtypes (p>0.05). Conclusions Invasive IOPNs are more aggressive than previously suspected and should be regarded as their own entity. Adjuvant chemotherapy does not reduce rates of recurrence regardless of neoplasm type.

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.

Lactate dehydrogenase isoform expressions differing impacts on gastrointestinal carcinogenesis

In cancer cells, metabolic alterations support tumor growth, survival, and progression. This study aims to examine the effects of lactate metabolism on the carcinogenesis of gastrointestinal subtypes. Hence, signatures relevant to lactate metabolism were gathered from the molecular signatures database and investigated in the genome-wide expression profiles of gastrointestinal cancer cohorts' using gene sets-based pathway activation scoring analysis. The results of this study represent that the lactate metabolism signatures are significantly expressed across gastrointestinal subtype tumors such as intestinal histopathological subtype of gastric tumor, intraductal papillary mucinous neoplasm (IPMN) subtype of pancreatic cancer, and hepatocellular carcinoma (HCC) stage of liver tumors, respectively. As a result, these metabolisms were dysregulated across subtypes of gastrointestinal carcinogenesis. The identified dysregulation was further reconfirmed by examining corresponding metabolic gene expression patterns across various subtypes encompassing single-cell RNA sequence profiles. These outcomes also reassured that lactate dehydrogenase isoform genes such as LDHA, LDHC, and its transporter gene SLC16A1 are highly enriched in intestinal, IPMN, and HCC subtypes' tumors, respectively. In contrast, LDHB and LDHD genes are vastly elevated in non-tumorous tissues than in gastrointestinal cancer. Furthermore, overall survival plots also reconfirmed that these gene expressions were associated with poor survival in the corresponding subtype's patient cohorts. All of these findings demonstrate the existence of lactate metabolic rewiring and involvement in gastrointestinal carcinogenesis. These results may help develop therapeutic target therapies for malignancies of the gastrointestinal subtype.

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.

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.

Relevance of gene mutations and methylation to the growth of pancreatic intraductal papillary mucinous neoplasms based on pyrosequencing

We aimed to assess some of the potential genetic pathways for cancer development from non-malignant intraductal papillary mucinous neoplasm (IPMN) by evaluating genetic mutations and methylation. In total, 46 dissected regions in 33 IPMN cases were analyzed and compared between malignant-potential and benign cases, or between malignant-potential and benign tissue dissected regions including low-grade IPMN dissected regions accompanied by malignant-potential regions. Several gene mutations, gene methylations, and proteins were assessed by pyrosequencing and immunohistochemical analysis. RASSF1A methylation was more frequent in malignant-potential dissected regions (p = 0.0329). LINE-1 methylation was inversely correlated with GNAS mutation (r = − 0.3739, p = 0.0105). In cases with malignant-potential dissected regions, GNAS mutation was associated with less frequent perivascular invasion (p = 0.0128), perineural invasion (p = 0.0377), and lymph node metastasis (p = 0.0377) but significantly longer overall survival, compared to malignant-potential cases without GNAS mutation (p = 0.0419). The presence of concordant KRAS and GNAS mutations in the malignant-potential and benign dissected regions were more frequent among branch-duct IPMN cases than among the other types (p = 0.0319). Methylation of RASSF1A, CDKN2A, and LINE-1 and GNAS mutation may be relevant to cancer development, IPMN subtypes, and cancer prognosis.

Carbohydrate Antigen 19-9 Is an Invasive Malignancy Preoperative Prognostic Factor for Intraductal Papillary Mucinous Neoplasms

Introduction: This study aimed to determine the preoperative clinicophysiological and postoperative clinicopathological predictors of malignancy in patients with intraductal papillary mucinous neoplasm (IPMN). Methods: This was a retrospective observational study. We included 121 patients (73 men and 48 women; mean age: 68.7 years) who had undergone pancreatic resection for IPMN between 2007 and 2018. These patients were grouped into invasive carcinoma (IPMN-INV, N = 21) and low/high-grade IPMN (IPMN-LG/HG, N = 100) groups. Univariate and multivariate analyses of clinicophysiological parameters were carried out. These parameters were also compared between the IPMN-INV/HG (N = 53) and IPMN-LG (N = 68) groups. Survival analyses according to macroscopic type and IPMN subtypes were performed. Results: On univariate analysis, age (p = 0.038), carbohydrate antigen (CA) 19-9 (p < 0.001), IPMN macroscopic type (p = 0.001), IPMN subtype (p < 0.001), pancreatic duct diameter (p < 0.001), and mural nodule (p = 0.042), between IPMN-INV and IPMN-LG/HG were found to be significant prognostic factors of malignancy. CA 19-9 was found to be an independent prognostic factor of IPMN malignancy on multivariate analysis (p = 0.035). The 1-, 3-, and 5-year overall survival (OS) rates of the IPMN-INV and IPMN-LG/HG groups were 94.4/100%, 94.4/100%, and 67.2/100%, respectively. The OS rate in the IPMN-LG/HG group was significantly higher than that in the IPMN-INV group (p < 0.001). On univariate analysis, platelet (p = 0.043), CA 19-9 (p = 0.039), prognostic nutritional index (p = 0.034), platelet/lymphocyte ratio (p = 0.01), IPMN macroscopic type (p < 0.001), IPMN subtype (p < 0.001), pancreatic duct diameter (p = 0.036), and mural nodule (p = 0.032) between IPMN-INV/HG and IPMN-LG were found to be significant prognostic factors of malignancy. On multivariate analysis, CA 19-9 was found to be an independent prognostic factor (p = 0.042) between IPMN-INV/HG and IPMN-LG of malignancy. The 1-, 3-, and 5-year OS rates of the IPMN-INV/HG and IPMN-LG groups were 97.9/100%, 97.9/100%, and 82.6/100%, respectively. The OS rate was significantly higher in the IPMN-LG group than in the IPMN-INV/HG group (p = 0.03). No significant differences in survival were observed in patients with macroscopic tumors (p= 0.544). Conclusion: CA 19-9 is an independent invasive malignancy predictor of IPMN.

Endoscopic ultrasonography findings of pancreatic parenchyma for predicting subtypes of intraductal papillary mucinous neoplasms

Background and aimsThe subtypes of intraductal papillary mucinous neoplasms (IPMNs) are closely associated with the clinicopathological behavior and recurrence after surgical resection. However, there are no established non-invasive methods to confirm the subtypes of IPMNs without surgery. The aim of this study is to predict the subtypes of IPMNs using the findings of endoscopic ultrasonography (EUS). MethodsSixty-two consecutive patients with IPMNs who underwent EUS before surgery were retrospectively reviewed. The following EUS findings were analyzed and their relationship with the subtypes was evaluated: diameter of the main pancreatic duct, cyst size, number of cysts, height of mural nodule, early chronic pancreatitis (CP) finding, fatty parenchyma and atrophic parenchyma. ResultsThe subtypes of IPMNs were as follows: gastric (G)-type 38 (61%), intestinal (I) -type 14 (23%) and pancreatobiliary (PB) -type 10 (16%). Fatty parenchyma was significantly associated with G-type (P < 0.0001). Early CP findings ≥2 and atrophic parenchyma were significantly correlated with I-type (P < 0.0001). PB-type was significantly associated with pancreatic parenchyma without early CP findings or fatty degeneration in comparison to the other subtypes (P < 0.0001). Using the above characteristic EUS findings, the sensitivity, specificity, and accuracy were as follows: 63%, 92% and 74%, respectively, in G-type, 57%, 96% and 87% in I-type, and 90%, 94% and 94% in PB-type. ConclusionsThe evaluation of EUS findings, especially focused on the pancreatic parenchyma, has the potential to predict the subtypes of IPMN.

Hyalinized stroma is a characteristic feature of pancreatic intraductal oncocytic papillary neoplasm: An immunohistochemical study

Hyalinized stroma (HS) is a dense, eosinophilic, and amorphous extracellular material in the stroma. HS is observed in several tumors; however, it has not been comprehensively studied in pancreatic intraductal papillary mucinous neoplasm (IPMN) or intraductal oncocytic papillary neoplasm (IOPN). Here, we aimed to evaluate the immunohistochemical and microscopic characteristics of HS in IPMN and IOPN. The prevalence of HS was determined in 168 cases of IPMN, including intestinal type (IPMN-I), gastric type (IPMN-G), and pancreatobiliary type (IPMN-PB), as well as in 11 cases of IOPN. Immunohistochemical staining for laminin and collagen (types I, II, III, IV, and V), as well as Congo red staining were performed in IPMN and IOPN cases containing HS. The prevalence of HS among the IPMN and IOPN specimens was 1.2% (2/168 cases) and 45.5% (5/11 cases), respectively. The prevalence rates of HS in each IPMN subtype were as follows: 2.2% (2/91 cases) in IPMN-G, and 0% in IPMN-PB and IPMN-I. All seven HS cases were positive for collagen I, III, IV, and V but were negative for Congo red staining. Most cases showed negative, focal, or weak expression of laminin and type II collagen. These findings indicate that HS is associated with IOPN and is primarily composed of collagen fibers.

CD117 Is a Specific Marker of Intraductal Papillary Mucinous Neoplasms (IPMN) of the Pancreas, Oncocytic Subtype.

The intraductal oncocytic papillary neoplasm (IOPN) of the pancreas has been recognized by WHO classification as a unique intraductal papillary mucinous neoplasm (IPMN) category. IOPN is composed of oxyphil cells, usually expressing MUC5AC, MUC6, and Hep Par-1, and harboring PRKACA/B fusion genes as their genetic hallmark. Although IOPNs are associated with an infiltrative adenocarcinoma in up to 30% of cases, the survival rate after surgical resection approaches 100%. This highlights the importance of the correct IOPN diagnosis, above all in cases with an associated invasive component. In this study, the immunohistochemical expression of CD117 was investigated in 111 IPMNs, including 17 oncocytic, 45 gastric, 20 pancreatico-biliary, and 29 intestinal IPMNs. We also tested the expression of MUC5AC, MUC6, and Hep Par-1 in the IOPN cohort. CD117 positivity was significantly more frequent in IOPNs compared to the other IPMN subtypes (p < 0.0001). Furthermore, within IOPN, a lower or absent CD117, MUC5AC, MUC6, and Hep Par-1 expression tended to be associated with the presence of an infiltrative component. Our findings shed light into the biology of these complex lesions, which are confirmed to be a distinctive IPMN subtype; notably, CD117 emerged as a potential, additional tool in the differential diagnosis of IPMNs.

Abstract C46: Establishing a living biobank of patient-derived organoids of intraductal papillary mucinous neoplasms

Abstract Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. There is an unmet need to develop strategies to detect pancreatic cancer at an early, operable stage and prevent its progression. Intraductal papillary mucinous neoplasms (IPMNs) are cystic pancreatic cancer precursors that comprise nearly 50% of pancreatic cysts detected incidentally via computed tomography (CT) scans. Since IPMNs can progress from low- and moderate-grade dysplasia and invasion, the study of these lesions offers a prime opportunity to develop early detection and prevention strategies. Organoids are an ideal preclinical platform to study IPMNs, and the objective of the current investigation was to establish the first living biobank of IPMN tumor organoids. IPMN tumors and adjacent normal pancreatic tissues were harvested from 15 patients undergoing pancreatic surgical resection at Moffitt Cancer Center &amp; Research Institute (Tampa, FL) between 2017 and 2019. Following immunohistopathologic analysis of primary tissues, organoid cultures were generated, expanded, and cryopreserved. Furthermore, organoid cultures were generated from cryopreserved tissues as well. Count and size of the organoids over time was determined via the Image-Pro Premier 3D Version digital platform. Genomic characterization of the organoids was performed through DNA fingerprinting, and a subset of cases were sequenced. The success rates of organoid generation from IPMN tumor and adjacent normal pancreatic tissues were 81% and 87%, respectively. IPMN organoids derived from different IPMN subtypes tissues showed different morphologies in vitro, with the low- and moderate-grade pancreatobiliary subtypes showing the highest proliferation rates. This model has potential to provide new opportunities to unveil mechanisms of IPMN progression to invasion and to shed insight into novel biomarkers for detection and targets for chemoprevention. Citation Format: Dayana Reverón, Francisca Beato, Gina DeNicola, Antonio Ortiz, Barbara Centeno, Kun Jiang, Daniel Jeong, Mokenge Malafa, Pamela Hodul, Kaleena Deszi, Jennifer Permuth, Jason Fleming. Establishing a living biobank of patient-derived organoids of intraductal papillary mucinous neoplasms [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C46.

Intraductal oncocytic papillary neoplasm of the pancreas: A systematic review

BackgroundIntraductal oncocytic papillary neoplasm of the pancreas (IOPN–P) is a rare subtype of intraductal papillary mucinous neoplasm (IPMN). This study was performed to summarize the clinicopathological features and management of IOPN-P. MethodsEnglish-language articles were searched from MEDLINE and EMBASE from the first report of IOPN-P in 1996 until 1 May 2019 following the methodology in the PRISMA guidelines. ResultsIn total, 66 patients from 24 full articles were included in the final data analysis. The patients’ average age was 61 years, and the male/female ratio was 1. Most lesions were large (average size, 5.50 cm), located in the pancreatic head, and found either incidentally or by uncharacteristic abdominal symptoms. IOPN-P was usually a cystic and solid lesion with or without mural nodules on radiological examination. A definitive diagnosis was often acquired from fine needle aspiration biopsy or postoperative pathology. All tumors were diagnosed as carcinoma in situ or minimally invasive carcinoma, necessitating surgical resection. The prognosis of IOPN-P was better than that of other IPMN subtypes, even when metastasis occurred. Recurrence after surgical resection of IOPN-P was rare. ConclusionsIOPN-P is rare among IPMN subtypes with unique pathological characteristics. Because of the nontypical symptoms and radiological findings, a definitive preoperative diagnosis usually depends on multimodal examinations. Management and surveillance of IOPN-P after surgical resection should be differentiated from those of other pancreatic benign cystic lesions because of its relative malignancy, but IOPN-P should also be differentiated from other IPMN subtypes and malignant cystic tumors because of its favorable prognosis.

Clinical-relevant model of intraductal papillary mucinous neoplasm induced by ARID1A loss.

e14696 Background: Intraductal papillary mucinous neoplasm (IPMN) constitutes a precursor lesion for malignancy of pancreas. Genes encoding subunits of SWI/SNF chromatin-remodeling complexes like ARID1A are collectively mutated in a significant proportion of patients with pancreatic neoplasm. In the present study, we characterize the role of ARID1A in pancreatic tumorigenesis using genetic engineering mouse models. Methods: Various mouse strains were interbred to obtain pancreas-specific Arid1aflox, KrasLSL-G12D/+; Arid1aflox, KrasLSL-G12D/+; Tgfbr2flox; Arid1aflox, and various littermate control animals. Tissue microarrays were used to determine the expression of ARID1A in human pancreatic ductal adenocarcinoma and IPMN. Results: Arid1a loss in pancreas of mice incurred pancreatic duct dilation and development of cystic lesions. Concomitant Kras mutation and Arid1a inactivation accelerated formation of cystic neoplasm resembling human IPMN. These lesions were reminiscent of specific subtype of IPMN given their morphology and expression pattern of mucin proteins. Histological examination further revealed the step-wise progression of these neoplasm from low-grade to high-grade dysplasia and even invasive carcinoma. TGFBR2 deletion promoted the malignant transformation of IPMN to invasive carcinoma in the background of Kras and Arid1a alterations. Analysis of human tissues consistently showed negative or low expression of ARID1A in over half of IPMN patients. Moreover, patients with pancreatic adenocarcinoma also exhibited downregulated ARID1A expression, and reduced expression correlated with worse prognosis. Conclusions: We have established a preclinical mouse model of pancreatic cystic tumor closely resembling human IPMN. This is helpful for the further understanding of biology of IPMN and highlight therapeutic niches for patient tailored treatment in those with altered SWI/SNF function.

Clinical assessment of the GNAS mutation status in patients with intraductal papillary mucinous neoplasm of the pancreas.

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is characterized by cystic dilation of the pancreatic duct, caused by mucin hypersecretion, with slow progression via the adenoma-carcinoma sequence mechanism. Mutation of GNAS at codon 201 is found exclusively in IPMNs, occurring at a rate of 41-75%. Recent advances in molecular biological techniques have demonstrated that GNAS mutation might play a role in the transformation of IPMNs after the appearance of neoplastic cells, rather than in the tumorigenesis of IPMNs. GNAS mutation is observed frequently in the intestinal subtype of IPMNs with MUC2 expression, and less frequently in IPMNs with concomitant pancreatic ductal adenocarcinoma (PDAC). Research has focused on assessing GNAS mutation status in clinical practice using various samples. In this review, we discuss the clinical application of GNAS mutation assessment to differentiate invasive IPMNs from concomitant PDAC, examine the clonality of recurrent IPMNs in the remnant pancreas using resected specimens, and differentiate pancreatic cystic lesions using cystic fluid collected by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), duodenal fluid, and serum liquid biopsy samples.

Pancreatic Intraductal Papillary Mucinous Neoplasm With Elevated Pre-Operative Cystic Carcinoembryonic Antigen Level: A Histopathologic Correlation.

BackgroundTo study the relationship between carcinoembryonic antigen (CEA) level, intraductal papillary mucinous neoplasm (IPMN) subtype, and the presence of invasive carcinoma.MethodsCystic CEA level and the following pathologic variables: subtypes of IPMN, size of cystic lesion, presence of dysplasia or carcinoma, and main or branch duct involvement from 45 IPMN cases were analyzed.ResultsThere was a significant correlation between pre-operative cystic fluid CEA level and the intensity of luminal CEA staining. However, there was no correlation between CEA level and cystic mucinous secretions or mucinous epithelial cytoplasm CEA staining, mucin glycoprotein expression, size of lesion, grade of dysplasia or presence of invasive carcinoma. CEA level was neither sensitive nor specific for the presence of invasive carcinoma.ConclusionsCystic CEA level may not be a reliable determinant of the presence or absence of invasive carcinoma in IPMNs, and its use to assess risk of malignancy may be limited.

Clinical features and surgical indications and malignant risk factors analysis of intraductal papillary mucinous neoplasms of the pancreas

Objective To investigate the clinical features and surgical indications of subtypes of intraductal papillary mucinous neoplasm (IPMN) of the pancreas, and analyze its malignant risk factors. Methods The retrospective case-control study was conducted. The clinicopathological data of 77 patients with IPMN of the pancreas who were admitted to the First Hospital of Peking University from January 2008 to December 2016 were collected. The subtypes of IPMN of the pancreas detected by preoperative imaging examination included main-duct type (MD-IPMN) in 46 patients, branch-duct type (BD-IPMN) in 12 patients, mixed type (MT-IPMN) in 19 patients. The surgical indications were consulted from the Guideline for the diagnosis and treatment of pancreatic cystic lesions composed by the Pancreatic Surgery Group of Surgery Branch of China Medical Association. Surgical procedure was selected according to the location and size of the IPMN. Four to 6 cycles of chemotherapy with S-1 and/or Gemcitabine were conducted for patients with malignant IPMN according to the tolerance and baseline characteristics. Observation indicators included: (1) comparison of the clinical features MD-IPMN, MT-IPMN and BD-IPMN; (2) surgical and postoperative conditions; (3) results of postoperative pathological examination and malignant risk factors analysis; (4) accuracy evaluation of Sendai and Fukuoka guidelines for the diagnosis of malignant IPMN of the pancreas; (5) follow-up results and survival. Patients were followed up by outpatient examination and telephone interview till December 2016. The postoperative adjuvant therapy, tumor recurrence and metastasis of malignant IPMN patients and postoperative survival condition of all the patients were collected. Measurement data with normal distribution were expressed as ±s or average (range), and pairwise comparison was analyzed by t test. Measurement data with skewed distribution were expressed by median (range). Comparison between count data and univariate analysis were done by chi-square test. Multiple factors analysis was done by Logistic regression model. The survival curve was drawn and the survival rate were calculated by Kaplan-Meier method. The comparison of survival was done by Log-rank test. Results (1) Comparison of clinical features between MD-IPMN, MT-IPMN and BD-IPMN: The numbers of patients with symptoms, jaundice, those complicated with diabetes and elevated CA19-9 were 55, 20, 43 and 28 in MD-IPMN and MT-IPMN, and 6 , 0, 3 and 1 in BD-IPMN, with statistically significant difference (χ2=5.421, 3.516, 5.525, 3.834, P 0.05), while significant difference in the specificity between the 2 guidelines were detected (χ2=12.500, P<0.05). (5) Follow-up and survival: Seventy of 77 patients were followed up, including 42 with benign IPMN and 28 with malignant IPMN. The median survival time was 35.0 months (range, 6.0-94.0 months). All the malignant IPMN patients received adjuvant therapy. The 1-, 3-, 5-year overall survival rates of 47 patient with benign IPMN were 100.0%, 96.2% and 96.2%, respectively, and 1 patient died of cardiac infarction. The 1-, 3-, 5-year overall survival rates of 30 patients with malignant IPMN were 96.6%, 81.8%, 38.6%, respectively, and 11 patients died of tumor recurrence or metastasis with median time of tumor recurrence or metastasis of 20.5 months (6.0-61.6 months). The 1-, 3-, 5-year overall survival rates of 17 patients with negative lymph node metastasis were 100.0%, 100.0% and 60.0%, respectively, and the 1-, 3-, 5-year overall survival rates of 13 patients with positive lymph node metastasis were 91.7%, 57.1% and 0, respectively. There was statistically significant difference between patients with benign and malignant IPMN (χ2=12.530, P<0.05). There was statistically significant difference between patients with negative lymph node metastasis and those with positive lymph node metastasis (χ2=16.977, P<0.05). Conclusions Patients with MD-IPMN or MT-IPMN are more vulnerable to be complicated with diabetes, jaundice, elevated CA19-9 and high malignancy, and thus surgery is recommended. Jaundice, elevated CEA and CA19-9, tumor diameter≥3.0 cm, MD-IPMN are the independent risk factors influencing the malignancy of IPMN. Key words: Intraductal papillary mucinous neoplasms of the pancreas; Classification; Surgical procedures, operative; Prognosis

Clinicopathological features of intraductal papillary neoplasms of the bile duct: a comparison with intraductal papillary mucinous neoplasm of the pancreas with reference to subtypes.

Intraductal papillary epithelial neoplasms of the pancreatobiliary system (intraductal papillary neoplasm of the bile duct (IPNB) and intraductal papillary mucinous neoplasm (IPMN)) seem to share many clinicopathological features; however, IPNB has not been fully characterized. In order to understand the clinicopathological/immunohistochemical features of IPNB better, we compared 52 cases of IPNB with 42 cases of IPMNs with mural nodules. The IPNB cases were divided into two groups according to their histological similarity and according to five key histological findings. All IPNB and IPMN cases mainly affected middle-aged to elderly people, predominantly men. Mucin hypersecretion was less frequent in IPNB compared to IPMN. Group 2 IPNB more frequently had a higher histopathological grade and more extensive stromal invasion than IPMN. Group 1 IPNB and IPMN were further classified into four subtypes (gastric, intestinal, pancreatobiliary, and oncocytic). Although each subtype of IPNB and IPMN showed similar histology, the immunohistochemical results were different. The gastric type of IPNB was less frequently positive for CDX2, and intestinal IPNB was more frequently positive for MUC1 and less frequently positive for MUC2, MUC5AC, and CDX2 compared to each subtype of IPMN, respectively. In conclusion, IPNB and IPMN have some clinicopathological features in common, but mucin hypersecretion was less frequent both in IPNBs than in IPMN. Group 2 IPNB differed from IPMN in several parameters of tumor aggressiveness. Additional clinicopathological and molecular studies should be performed with respect to the subtypes of IPNB and IPMN.

Diversity of Precursor Lesions For Pancreatic Cancer: The Genetics and Biology of Intraductal Papillary Mucinous Neoplasm.

Pancreatic ductal adenocarcinoma (PDA), one of the most lethal cancers worldwide, is associated with two main types of morphologically distinct precursors—pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). Although the progression of PanIN into invasive cancer has been well characterized, there remains an urgent need to understand the biology of IPMNs, which are larger radiographically detectable cystic tumors. IPMNs comprise a number of subtypes with heterogeneous histopathologic and clinical features. Although frequently remaining benign, a significant proportion exhibits malignant progression. Unfortunately, there are presently no accurate prognosticators for assessing cancer risk in individuals with IPMN. Moreover, the fundamental mechanisms differentiating PanIN and IPMN remain largely obscure, as do those that distinguish IPMN subtypes. Recent studies, however, have identified distinct genetic profiles between PanIN and IPMN, providing a framework to better understand the diversity of the precursors for PDA. Here, we review the clinical, biological, and genetic properties of IPMN and discuss various models for progression of these tumors to invasive PDA.

The Evolving Role of Pathology in New Developments, Classification, Terminology, and Diagnosis of Pancreatobiliary Neoplasms.

Pancreatobiliary tract lesions are increasingly being discovered because of more sensitive imaging modalities. Magnetic resonance imaging has identified incidental pancreatic cysts in 13.5% of patients of progressively increasing age. Pancreatobiliary tissue is more accessible through endoscopic ultrasound and magnetic resonance imaging-guided biopsy procedures, and is now an integral part of pathologists' routine practice. Accordingly, several new tumor categories have been recently recognized, including intraductal tubulopapillary neoplasm, a new addition to tumoral intraepithelial neoplasms. Other entities have been reclassified, including the recent transition to 2-tiered grading of preinvasive neoplasms, as well as new perspectives on the distinctive biologic behavior of oncocytic intraductal papillary mucinous neoplasms (IPMNs) compared with other IPMN subtypes. This has led to proposals for revised staging of virtually every segment of the pancreatobiliary tree, with theranostic markers becoming an integral part of workup. Ki-67 is now an integral part of the classification of neuroendocrine tumors, with new definitions of "high-grade neuroendocrine carcinoma." Although bile duct brushings have opened new avenues for diagnosis, their sensitivity remains low and often requires concomitant fluorescent in situ hybridization to better define ambiguous cases. Various molecular pathways have been elucidated for pancreatic cysts, including KRAS for ductal neoplasia, GNAS for intestinal IPMNs, RNF3 for mucinous cysts, and VHL for serous cystic neoplasms, all key players in diagnostic workup. Integration of these updates into our understanding of pancreatobiliary disease requires active engagement of pathologists for appropriate specimen triage, judicious interpretation of results, and incorporation into reporting and staging. They also provide exciting opportunities for targeted therapy.

Interobserver variability in intraductal papillary mucinous neoplasm subtypes and application of their mucin immunoprofiles

AbstractIntraductal papillary mucinous neoplasm is considered a precursor lesion to pancreatic adenocarcinoma. These are further classified into four histologic subtypes: gastric, intestinal, pancreatobiliary, and oncocytic. The first aim of this study was to assess the interobserver variability among five gastrointestinal pathologists in diagnosing intraductal papillary mucinous neoplasm subtypes by morphology alone. The second aim of the study was to compare intraductal papillary mucinous neoplasm subtypes, which received consensus diagnoses (≥80% agreement) with their respective mucin immunoprofiles (MUC1, MUC2, MUC5AC, MUC6, and CDX2). A consensus histologic subtype was reached in 58% of cases (29/50) among the five gastrointestinal pathologists. Overall there was moderate agreement (κ=0.41, P<0.01) in subtyping intraductal papillary mucinous neoplasms without the use of immunohistochemistry. The histologic subtype with the best interobserver agreement was intestinal type (κ=0.56, P<0.01) followed by pancreatobiliary, gastric, mixed, and oncocytic types (κ=0.43, P<0.01; κ=0.38, P<0.01; κ=0.17, P<0.01; κ=0.08, P<0.04, respectively). Both kappa values for mixed and oncocytic subtypes were likely artificially low due to the underrepresentation of these subtypes in this study and not a true indication of poor interobserver agreement. Following an intradepartmental consensus meeting between two gastrointestinal pathologists, 68% of cases (34/50) received a consensus intraductal papillary mucinous neoplasm subtype. Sixty-nine percent of cases (11/16) that did not receive a consensus intraductal papillary mucinous neoplasm subtype could be classified based on their respective immunoprofiles. Standardizing the use of immunohistochemistry with a mucin immunopanel (MUC1, MUC2, MUC5AC, and MUC6) may improve the agreement of diagnosing intraductal papillary mucinous neoplasm histologic subtypes.