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Background: Ampullary adenocarcinoma (AAC) arises from the ampulla of Vater where the pancreatic duct and bile duct join and empty into the duodenum. It can be classified into intestinal and pancreatobiliary types based on histopathology or immunohistochemistry. However, there are no biomarkers for further classification of pancreatobiliary-type AAC which has important implications for its treatment. We aimed to identify the tumor origin of pancreatobiliary-type AAC by systematically analyzing whole-slide images (WSIs), survival data, and genome sequencing data collected from multiple centers., Methods: This study involved three experiments. First, we extracted quantitative and highly interpretable features from the tumor region in WSIs and constructed a histologic classifier to differentiate between pancreatic adenocarcinoma (PAC) and cholangiocarcinoma. The histologic classifier was then applied to patients with pancreatobiliary-type AAC to infer the tumor origin. Secondly, we compared the overall survival of patients with pancreatobiliary-type AAC stratified by the adjuvant chemotherapy regimens designed for PAC or cholangiocarcinoma. Finally, we compared the mutation landscape of pancreatobiliary-type AAC with those of PAC and cholangiocarcinoma., Results: The histologic classifier accurately classified PAC and cholangiocarcinoma in both the internal and external validation sets (AUC > 0.99). All pancreatobiliary-type AACs (n = 45) were classified as PAC. The patients with pancreatobiliary-type AAC receiving regimens designed for PAC showed more favorable overall survival than those receiving regimens designed for cholangiocarcinoma in a multivariable Cox regression (hazard ratio = 7.24, 95% confidence interval: 1.28-40.78, P = 0.025). The results of mutation analysis showed that the mutation landscape of AAC was very similar to that of PAC but distinct from that of cholangiocarcinoma., Conclusions: This multi-center study provides compelling evidence that pancreatobiliary-type AAC resembles PAC instead of cholangiocarcinoma in different aspects, which can guide the treatment selection and clinical trials planning for pancreatobiliary-type AAC., (© 2022. The Author(s).)

Objective: The magnetic resonance imaging (MRI) features of intestinal-type periampullary carcinoma (IPAC) and pancreatobiliary-type periampullary carcinoma (PPAC) were compared and analyzed to discuss the optimal diagnosis scheme. Method: Preoperative MRI images of 59 patients (32 males, 27 females, aged 37-80 years) diagnosed with periampullary carcinoma (PAC) confirmed by surgery and pathology in Nanjing Drum Tower Hospital from January 2017 to July 2020 were retrospectively analyzed. The patients were divided into 21 cases in the IPAC group (11 males, 10 females) and 38 cases in the PPAC group (21 males, 17 females) according to histopathological results. The conventional MRI plain scan signs included in the analysis include lesion morphology, the largest diameter of the lesion, lesion location, duodenal papilla morphology, plain scan lesion signal (with the normal pancreatic signal as reference), diffusion weighted imaging (DWI) signal. Magnetic resonance cholangiopancreatography (MRCP) image signs include the dilatation of common bile duct and main pancreatic duct and quantitative analysis of their diameter, the presence of a round filling defect in the distal end of the common bile duct, the morphology of common bile duct stenosis, the dilatation of lateral branches around the obstructed pancreatic duct, the ductal sign, the distance from the end of the obstructed common bile duct to the duodenal papilla, the distance from the end of the obstructed pancreatic duct to the duodenal papilla, and the angle of the pancreaticobiliary duct. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic efficacy of single meaningful factors. The MRI features of PAC were summarized according to the significant single factor indicators and were classified into 5 image types. And the diagnostic efficacy of the classification criteria for pathological subtypes of PAC was evaluated by the ROC curve. The DeLong test was used to compare the area under the ROC curve (AUC) of multiple diagnostic methods. Results: In univariate analysis, there were statistically significant differences between IPAC and PPAC in lesion location, duodenal papilla morphology, the circular filling defect in the distal end of the common bile duct, the distance from the obstructed pancreatic duct to the duodenal papilla, the angle of the pancreaticobiliary duct, and lesion signal characteristics on plain T 2 WI fat suppressant images (all P <0.05). Among the 5 types of MRI images, IPAC is mostly manifested as duodenal papillary nodules(15/21,71.4%), while PPAC is more manifested as pancreatic mass type(18/38,47.4%), thickened common bile duct wall type(9/38,23.7%) or ampullary mass type(9/38,23.7%). Both IPAC(2/21,9.5%) and PPAC(0,0) rarely showed the nodular type of common bile duct lumen. In the DeLong test of the significant univariate index(lesion location, duodenal papilla morphology, the circular filling defect in the distal end of the common bile duct, the distance from obstructed pancreatic duct to duodenal papilla, the angle of the pancreaticobiliary duct, and lesion signal characteristics on plain T 2 WI fat suppressant images) and the 5 classification of MRI images, the AUC of the 5 classifications of MRI images was 0.932(95% CI :0.867-0.997), which was higher than that of any of the significant univariate indexes (all P <0.05). In addition, the 5 classifications of MRI images have the same high diagnostic power as the logistic regression analysis model( P >0.05). Conclusions: The 5 classification of MRI images can improve the accuracy of differential diagnosis of IPAC and PPAC before surgery, and the diagnostic efficiency is better than any single factor meaningful index and comparable to that of the logistic regression analysis model.

Aim: To investigate whether computed tomography (CT) radiomics can differentiate pancreatobiliary-type from intestinal-type periampullary carcinomas., Materials and Methods: CT radiomics of 96 patients (54 pancreatobiliary type and 42 intestinal type) with surgically confirmed periampullary carcinoma were assessed retrospectively. Volumes of interest (VOIs) were delineated manually. Radiomic features were extracted from preoperative CT images. A single-phase model and combined-phase model were constructed. Five-fold cross-validation and five machine-learning algorithms were utilised for model construction. The diagnostic performance of the models was evaluated by receiver operating characteristic (ROC) curves, and indicators included area under the curve (AUC), accuracy, sensitivity, specificity, and precision. ROC curves were compared using DeLong's test., Results: A total of 788 features were extracted on each phase. After feature selection using least absolute shrinkage and selection operator (LASSO) algorithm, the number of selected optimal feature was 18 (plain scan), nine (arterial phase), two (venous phase), 23 (delayed phase), 15 (three enhanced phases), and 29 (all phases), respectively. For the single-phase model, the delayed-phase model using the logistic regression (LR) algorithm showed the best prediction performance with AUC, accuracy, sensitivity, specificity, and precision of 0.89, 0.83, 0.80, 0.88, and 0.93, respectively. Two combined-phase models showed better results than the single-phase models. The model of all phases using the LR algorithm showed the best prediction performance with AUC, accuracy, sensitivity, specificity, and precision of 0.96, 0.88, 0.90, 0.93, and 0.92, respectively., Conclusion: Radiomic models based on preoperative CT images can differentiate pancreatobiliary-type from intestinal-type periampullary carcinomas, in particular, the model of all phases using the LR algorithm., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Ampullary cancer may occur as a component of hereditary cancer syndromes. Mutations in inherited cancer susceptibility genes play a therapeutic role and its knowledge in ampullary cancer is lacking., Methods: Thirty-seven cases of ampullary carcinoma were subjected to tumor-normal whole exome sequencing with mean coverage of 100X (blood) and 200X (tumor). Data were analyzed and correlated with intestinal and pancreatobiliary differentiation., Results: There were 22 intestinal, 13 pancreatobiliary and 2 cases of mixed differentiation. One hundred and forty-three germline variations with at least >1 pathogenic germline variants (PGVs) across 83 genes were found in 36 of 37 patients. Twelve genes (14.5 %) showed >3, 20 genes (24.1 %) showed two and 51 genes (61.4 %) showed one PGVs. Intestinal differentiation showed higher PGVs (117 variants, 73 genes) than pancreatobiliary differentiation (85 variants, 62 genes). PGVs in ERCC5, MEN1, MSH3, CHEK1, TP53, APC, FANCA, ERBB2, BRCA1, BRCA2, RTEL1, HNF1A and PTCH1 were seen in >50 % of cases. Nine genes harbored somatic second hits in 14 cases. PGVs in DNA damage-repair, homologous recombination repair, TP53 transcriptional regulation, DNA double stranded breaks, cell cycle and nucleotide excision repair genes were seen in all cases of intestinal and pancreatobiliary differentiation, while DNA mismatch repair genes were found in 81.8 % of intestinal and 84.6 % of pancreatobiliary cancers. Functional pathway analysis showed that DNA damage-repair, double stranded break repair, mismatch repair, homologous recombination repair and TP53 transcriptional regulation genes were altered in both while nucleotide-excision repair was significantly mutated in intestinal type and cell-cycle genes in pancreatobiliary type (p < 0.05)., Conclusion: This study reports spectrum of PGVs in intestinal and pancreatobiliary differentiation of ampullary carcinoma at higher frequency through whole exome sequencing. PGVs were most frequently found in DNA repair genes. Detecting PGVs through tumor-normal sequencing may identify therapeutically actionable and double-hit mutations that can guide towards appropriate management., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

The classification of ampullary adenocarcinoma into intestinal and pancreatobiliary sub-types has been found to be important in predicting prognosis and determining therapeutic strategy. Due to considerable inter-observer variability in sub-typing based solely on morphology, higher frequency of poorly differentiated cancers and low incidence of the disease, the histomorphologic classification of ampullary adenocarcinoma remains one of the grey zones in surgical pathology. Pan-IN is a well recognized precursor to pancreatic adenocarcinoma. Three studies have shown concurrent Pan-IN in patients with ampullary carcinoma, but their association with the two sub-types has not yet been reported. Fourteen cases of surgical resection for ampullary adenocarcinoma were retrieved from the archives. The cases were classified into two groups based on the presence or absence of concomitant Pan-IN. All the cases were stained for CK7, CK 20, Villin and CDX 2 and were classified as intestinal or pancreatobiliary types based on the staining pattern. All the 10 cases with Pan-IN stained negative for CDX2 and were classified as pancreatobiliary type (p = 0.01). Of the cases without Pan-IN, 3 were classified as intestinal sub-type based on morphology and CDX2 positivity and 1 was classified as pancreatobiliary type. Concomitant Pan-IN was present in 91% of pancreatobiliary type of ampullary adenocarcinoma. The grade of Pan-IN did not influence the grade or stage of the adenocarcinoma (p > 0.05). The co-occurrence of Pan-IN in a high percentage of the pancreatobiliary sub-type and its complete absence in the intestinal sub-type may serve as a strong differentiator between the two sub-types.

We recently experienced cases of pancreatobiliary-type intraductal papillary mucinous neoplasms (PB-IPMNs) with imaging features resembling pancreatic ductal adenocarcinomas (PDACs), and histologic appearance of purely pancreatobiliary morphology and highly distorted papillary growth, which led to the present study aiming to systematically investigate PB-IPMNs in comparison with PDACs. Surgical cases of PB-IPMNs (n = 31) and PDACs (n = 24) were examined. PB-IPMNs were classified into monotypic tumors (n = 12; 39%) consisting of entirely high-grade pancreatobiliary-type neoplastic cells and polytypic cases (n = 19; 61%) associated with components of low-grade dysplasia and/or other histologic types (eg, gastric, intestinal, or oncocytic types). Clinically, monotypic PB-IPMNs less commonly had dilatation of the ampullary orifice (0% versus 74%) and mucin hypersecretion (17% versus 89%) than did polytypic cases. In most cases of monotypic PB-IPMNs, cystic dilatation of the lesional ducts was less obvious on imaging; therefore, 33% were radiologically diagnosed as PDACs. Histologically, intraductal tumors in monotypic cases showed a highly complex papillary architecture with tubular/cribriform glands and irregular branching, and all these cases were associated with invasive malignancy. GNAS mutations were detected in polytypic PB-IPMNs (6/19; 32%), but there were no GNAS mutations in monotypic cases. The recurrence-free survival of patients with monotypic PB-IPMN or PDAC was similar and significantly worse than that of patients with polytypic PB-IPMN. In conclusion, some cases of monotypic PB-IPMNs lacked the classic characteristics of IPMNs and shared features with PDACs, raising the possibility that these cases may be better classified as a papillary variant of PDACs rather than IPMNs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A 77-year-old woman with mild dilatation (4mm) of the main pancreatic duct was referred to our hospital. Contrast-enhanced computed tomography revealed segmental dilatation of the main pancreatic duct in the pancreatic tail, but no mass was noted in the pancreas. Endoscopic ultrasonography showed low papillary lesions in the dilated pancreatic duct. Cytological analysis of the pancreatic juice revealed adenocarcinoma. Distal pancreatectomy was performed for a diagnosis of main duct-intraductal papillary mucinous cancer (MD-IPMC) of the pancreatic tail. Histological findings indicated pancreatobiliary (PB)-type non-invasive IPMC. Although the patient did not meet the diagnostic criteria for intraductal papillary mucinous neoplasms (IPMNs), her final diagnosis was PB-type non-invasive IPMC. Because PB-type IPMNs display poor mucin production, pancreatic duct dilatation is sometimes mild and requires careful assessment for accurate diagnosis.

Purpose: To differentiate pancreatobiliary-type from intestinal-type periampullary carcinomas using combined magnetic resonance cholangiopancreatography (MRCP), contrast-enhanced MRI, and diffusion-weighted imaging (DWI)., Materials and Methods: MRI (3.0T) results of 41 patients with pathologically confirmed periampullary carcinoma were retrospectively assessed. Two radiologists, blinded to histologic type of each tumor, evaluated image findings independently. MRCP image features, enhancement pattern, and apparent diffusion coefficient (ADC) values were analyzed. Independent-sample t-test, chi-square, or Fisher's exact test were used to determine differential image findings between the pancreatobiliary-type and the intestinal-type group. Cohen's κ statistic or interclass correlation coefficient (ICC) were used to evaluate interobserver agreement between two observers. Univariate and multiple logistic regression analysis were performed to identify MRI features with predictive values., Results: On the basis of hematoxylin-eosin staining, 27 patients were classified as having pancreatobiliary-type carcinomas, and 14 patients the intestinal type. The pancreatobiliary-type carcinomas more commonly showed progressive enhancement than the intestinal type (P = 0.003). The minimum ADC (ADCmin ) value of the pancreatobiliary-type group ([0.95 ± 0.21] × 10(-3) mm(2) /s) was significantly lower than the intestinal-type group ([1.10 ± 0.25] × 10(-3) mm(2) /s) (P = 0.047). For interobserver agreement, the κ values and ICCs for all parameters exceeded 0.8, indicating almost perfect agreement. At multiple logistic regression analysis, the enhancement pattern was the only significant independent predictor (P = 0.011, odds ratio [OR] = 0.105). When the enhancement pattern and ADCmin were used in combination, we could identify 70.4% of pancreatobiliary-type and 78.6% of intestinal-type carcinomas., Conclusion: Progressive enhancement and low ADCmin values suggest a pancreatobiliary-type periampullary carcinoma., (© 2015 Wiley Periodicals, Inc.)

Periampullary adenocarcinomas can be of two histological subtypes, intestinal or pancreatobiliary. The latter is more frequent and aggressive, and characterized by a prominent desmoplastic stroma, which is tightly related to the biology of the cancer, including its poor response to chemotherapy. Whereas miRNAs are known to regulate various cellular processes and interactions between cells, their exact role in periampullary carcinoma remains to be characterized, especially with respect to the prominent stromal component of pancreatobiliary type cancers. The present study aimed at elucidating this role by miRNA expression profiling of the carcinomatous and stromal component in twenty periampullary adenocarcinomas of pancreatobiliary type. miRNA expression profiles were compared between carcinoma cells, stromal cells and normal tissue samples. A total of 43 miRNAs were found to be differentially expressed between carcinoma and stroma of which 11 belong to three miRNA families (miR-17, miR-15 and miR-515). The levels of expression of miRNAs miR-17, miR-20a, miR-20b, miR-223, miR-10b, miR-2964a and miR-342 were observed to be higher and miR-519e to be lower in the stromal component compared to the carcinomatous and normal components. They follow a trend where expression in stroma is highest followed by carcinoma and then normal tissue. Pathway analysis revealed that pathways regulating tumor-stroma interactions such as ECM interaction remodeling, epithelial-mesenchymal transition, focal adhesion pathway, TGF-beta, MAPK signaling, axon guidance and endocytosis were differently regulated. The miRNA-mRNA mediated interactions between carcinoma and stromal cells add new knowledge regarding tumor-stroma interactions., (Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Background: The clinico-oncological outcomes of precursor epithelial subtypes of adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMN) are limited to small cohort studies. Differences in recurrence patterns and response to adjuvant chemotherapy between A-IPMN subtypes are unknown., Methods: Clincopathological features, recurrence patterns and long-term outcomes of patients undergoing pancreatic resection (2010-2020) for A-IPMN were reported from 18 academic pancreatic centres worldwide. Precursor epithelial subtype groups were compared using uni- and multivariate analysis., Results: In total, 297 patients were included (median age, 70 years; male, 78.9%), including 54 (18.2%) gastric, 111 (37.3%) pancreatobiliary, 80 (26.9%) intestinal and 52 (17.5%) mixed subtypes. Gastric, pancreaticobiliary and mixed subtypes had comparable clinicopathological features, yet the outcomes were significantly less favourable than the intestinal subtype. The median time to recurrence in gastric, pancreatobiliary, intestinal and mixed subtypes were 32, 30, 61 and 33 months. Gastric and pancreatobiliary subtypes had worse overall recurrence (p = 0.048 and p = 0.049, respectively) compared with the intestinal subtype but gastric and pancreatobiliary subtypes had comparable outcomes. Adjuvant chemotherapy was associated with improved survival in the pancreatobiliary subtype (p = 0.049) but not gastric (p = 0.992), intestinal (p = 0.852) or mixed subtypes (p = 0.723). In multivariate survival analysis, adjuvant chemotherapy was associated with a lower likelihood of death in pancreatobiliary subtype, albeit with borderline significance [hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.31-1.01; p = 0.058]., Conclusions: Gastric, pancreatobiliary and mixed subtypes have comparable recurrence and survival outcomes, which are inferior to the more indolent intestinal subtype. Pancreatobiliary subtype may respond to adjuvant chemotherapy and further research is warranted to determine the most appropriate adjuvant chemotherapy regimens for each subtype., (© 2024. The Author(s).)

Background: Ampullary carcinomas typically have either intestinal or pancreatobiliary type of differentiation, histopathologically resembling carcinomas of its adjacent tissues (duodenum, bile duct, or pancreas). We evaluated whether the histologic type itself is more important for long-term survival than the fact that the tumor originated in the ampulla., Methods: Microscopic slides from 207 consecutive pancreatoduodenectomies were reviewed (72 pancreatic, 46 biliary, 61 ampullary, and 28 duodenal adenocarcinomas; 76 intestinal type, 131 pancreatobiliary type). Tumor size, nodal involvement, margin involvement, degree of differentiation, vascular involvement, and perineural growth, as well as overall survival, were compared between different origins of the same histologic type., Results: Intestinal-type ampullary adenocarcinomas had similar frequency of poor histopathologic factors compared to duodenal adenocarcinomas, and pancreatobiliary-type ampullary adenocarcinomas had similar frequency of poor histopathologic factors compared to pancreatobiliary-type biliary and pancreatic adenocarcinomas. Adjusting for tumor size and nodal involvement, there was no difference in long-term survival between patients with intestinal-type ampullary, duodenal, or biliary and pancreatic tumors (p = 0.79), and there was no difference in long-term survival between patients with pancreatobiliary-type ampullary, biliary, or pancreatic tumors (p = 0.41)., Conclusions: Long-term survival for patients with ampullary carcinomas equals pancreatic, biliary, and duodenal carcinomas when the same histologic type is compared. It can be questioned whether ampullary carcinomas should be regarded as a separate entity in classification of solid tumors. Clinical trials on adjuvant treatments for periampullary carcinomas should stratify by pancreatobiliary type versus intestinal type of histologic differentiation.

Objectives: Intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas are classified into 4 types--gastric, intestinal, pancreatobiliary, and oncocytic--on the basis of their morphology and immunohistochemistry. We classified IPMNs at our institute and used this classification to determine the clinicopathological features, prognosis, and malignant potential of the 4 types., Methods: Sixty-one patients with IPMN who underwent surgery between 2000 and 2007 were evaluated retrospectively., Results: There were 24 tumors of the gastric type, 22 intestinal, 12 pancreatobiliary, and 3 oncocytic. Patients with the intestinal or gastric type had a better prognosis than those with the pancreatobiliary type. The intestinal and pancreatobiliary types had almost the same frequencies of carcinoma, but the intestinal type tended to have a lower frequency of invasive carcinoma than the pancreatobiliary type. Patients with invasive carcinomas derived from intestinal-type IPMNs tended to have a better prognosis than those whose invasive carcinomas were derived from the pancreatobiliary type., Conclusions: Intraductal papillary-mucinous neoplasm of the gastric and intestinal types may have less malignant potential than that of the pancreatobiliary type. Invasive carcinomas derived from intestinal-type IPMNs may be less invasive and slower growing than those derived from the pancreatobiliary type.

Aims: Spindle proteins such as Aurora A, Mad2 and BubR1 are important for chromosome segregation during mitosis. Dysfunction of these proteins is implicated in the development of many cancers. The aim was to examine their possible prognostic impact in resected adenocarcinomas in the pancreatic head., Methods and Results: Two hundred and eighteen consecutively resected pancreatobiliary-type (n=145) and intestinal-type (n=73) adenocarcinomas involving the pancreatic head were examined for expression of Aurora A, Mad2 and BubR1 by immunohistochemistry on tissue microarrays. Aurora A (P<0.001) and Mad2 (P=0.003) were expressed more often and at higher levels in intestinal-type compared with pancreatobiliary-type tumours, whereas BubR1 was equally expressed in both histological types. Expression of BubR1, Aurora A and Mad2 was not associated with ploidy status. None of the spindle proteins was significantly associated with prognosis in intestinal-type tumours. In pancreatobiliary-type tumours, any BubR1 expression was sufficient to predict poor prognosis (P=0.006), whereas Aurora A and Mad2 expression was not significantly associated with prognosis (P=0.86 and P= 0.87, respectively). On adjusted Cox regression analysis, BubR1 expression independently predicted poor prognosis [P=0.002; hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.26, 2.79)], particularly in small tumours (P=0.001; HR 2.93, 95% CI 1.53, 5.62)., Conclusion: BubR1 expression is a novel, independent adverse prognostic factor after pancreatoduodenectomy of pancreatobiliary-type adenocarcinomas.

Human Cripto-1, a membrane-bound protein, plays an important role during early embryogenesis and has oncogenic properties, including cell transformation and enhancement of invasion. Cripto-1 is up-regulated in various malignant tissues and premalignant lesions. However, Cripto-1 expression in intraductal papillary mucinous neoplasms (IPMNs) has yet to be reported. This study aimed to investigate Cripto-1 expression in IPMNs and evaluate the expression patterns according to the histological grade or phenotypic subclassification. Cripto-1 expression was evaluated by immunohistochemistry using 37 IPMN tissue samples and real-time RT-PCR analysis of seven frozen samples. Cripto-1 was up-regulated in 59.5% of IPMNs. Cripto-1 was positively stained in 3 of 4 (75%) adenomas, 12 of 19 (63.2%) borderline neoplasms, 5 of 11 (45.5%) non-invasive carcinomas and 2 of 3 (66.7%) invasive carcinomas. There was no correlation between Cripto-1 overexpression and the histological grade (P>0.05). Cripto-1 expression was significantly increased in pancreatobiliary- (4/5, 80%) and gastric-type (13/19, 68.4.2%) IPMNs compared with those of the intestinal type (2/10, 20%; P<0.01). Cripto-1 mRNA expression was higher in gastric- and pancreatobiliary-type IPMNs than in intestinal ones, supporting the immunohistochemical results. It is concluded that Cripto-1 overexpression is involved in the tumorigenesis of gastric- and pancreatobiliary-type IPMNs.

Because of the distinct and complex anatomy of the ampullary region, the exact origin of the periampullary tumors was often difficult to ascertain. In this study, we evaluated 78 patient samples, including 26 small intestinal adenocarcinomas, 35 pancreatic ductal adenocarcinomas, and 17 cholangiocarcinomas by immunohistochemical detection of cadherin-17 (CDH17), CDX2, CK20, and CK19 protein expression. The result showed that CDH17 and CDX2 expression was higher in small intestinal adenocarcinoma (73.1% and 65.4%) than in pancreatic (14.3% and 2.9%) and bile duct (41.2% and 23.5%) cancers, respectively. CK20 expression was low in 78 tumor tissues, but relatively high in small intestinal adenocarcinoma (42.3%). CK19 showed a strong positive expression in all 78 adenocarcinoma tissues. The CDH17-high/CDX2-high pattern was predominantly expressed in small intestinal cancer tissues (75%), whereas the CDH17-low/CDX2-low pattern was observed in pancreatic cancers (63.8%) and bile duct cancers (20.9%). The study concluded that CDH17-high/CDX2-high adenocarcinomas more likely originated from small intestine versus pancreas or bile duct, whereas CDH17-low/CDX2-low ones are more likely of pancreatic origin. The combined use of CDH17 and CDX2 could be helpful in providing support for the histologic origin of periampullary adenocarcinoma., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Small intestinal adenomas are uncommon. Majority of these occur in the region of the ampulla of Vater. Adenomas of the ampulla can be further subdivided into two types-intestinal and pancreatobiliary. While intestinal adenomas are more frequent, pancreatobiliary adenomas are rare. There is limited literature regarding the role of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in the diagnosis of ampullary/peri-ampullary neoplasms. Here, we describe the cytologic features of a pancreatobiliary neoplasm of the duodenum that was sampled by EUS-FNA. The aspirate was cellular and revealed cells with moderately abundant oncocytic cytoplasm. The nuclei were round with fine chromatin and focally prominent nucleoli. Although the concurrent biopsy showed no high-grade dysplasia or invasive carcinoma, the EUS and imaging findings were highly suspicious for invasion. A broad differential diagnosis is under consideration for a duodenal mass that encompasses neoplasms of the biliary tract, pancreas, duodenum, and ampulla of Vater. To our knowledge, cytologic features of a pancreatobiliary neoplasm of the duodenum have not been previously reported. Our case highlights the features seen on cytology with histologic correlation in the hopes of elucidating features to better characterize these lesions., (© 2019 Wiley Periodicals, Inc.)

Although many genes and miRNAs have been reported for various cancers, pancreatic cancer's specific genes or miRNAs have not been studied precisely yet. Therefore, we have analyzed the gene and miRNA expression profile of pancreatic cancer data in the gene expression omnibus (GEO) database. The microarray-derived miRNAs and mRNAs were annotated by gene ontology (GO) and signaling pathway analysis. We also recognized mRNAs that were targeted by miRNA through the mirDIP database. An integrated analysis of the microarray revealed that only 6 out of 43 common miRNAs had significant differences in their expression profiles between the tumor and normal groups (P value < 0.05 and |log Fold Changes (logFC)|> 1). The hsa-miR-210 had upregulation, whereas hsa-miR-375, hsa-miR-216a, hsa-miR-217, hsa-miR-216b and hsa-miR-634 had downregulation in pancreatic cancer (PC). The analysis results also revealed 109 common mRNAs by microarray and mirDIP 4.1 databases. Pathway analysis showed that amoebiasis, axon guidance, PI3K-Akt signaling pathway, absorption and focal adhesion, adherens junction, platelet activation, protein digestion, human papillomavirus infection, extracellular matrix (ECM) receptor interaction, and riboflavin metabolism played important roles in pancreatic cancer. GO analysis revealed the significant enrichment in the three terms of biological process, cellular component, and molecular function, which were identified as the most important processes associated strongly with pancreatic cancer. In conclusion, DTL, CDH11, COL5A1, ITGA2, KIF14, SMC4, VCAN, hsa-mir-210, hsa-mir-217, hsa-mir-216a, hsa-mir-216b, hsa-mir-375 and hsa-mir-634 can be reported as the novel diagnostic or even therapeutic markers for the future studies. Also, the hsa-mir-107 and hsa-mir-125a-5p with COL5A1, CDH11 and TGFBR1 genes can be introduced as major miRNA and genes on the miRNA-drug-mRNA network. The new regulatory network created in our study could give a deeper knowledge of the pancreatic cancer., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Periampullary neoplasms are a heterogeneous group of different tumor entities arising from the periampullary region, of which pancreatic ductal adenocarcinoma (PDAC) is the most common subgroup with 60-70%. As typical for pancreatic adenocarcinomas, periampullary pancreatic cancer is characterized by an aggressive growth and early systemic progression. Due to the anatomical location in close relationship to the papilla of Vater symptoms occur at an earlier stage of the disease, so that treatment options and prognosis are overall more favorable compared to pancreatic carcinomas at other locations. Nevertheless, the principles of treatment for periampullary pancreatic cancer are not substantially different from the standards for pancreatic cancer at other locations. A potentially curative approach for non-metastatic periampullary pancreatic cancer is a multimodal therapy concept, which includes partial pancreatoduodenectomy as a radical oncological resection in combination with a systemic adjuvant chemotherapy. As a result, long-term survival can be achieved in patients with favorable prognostic factors. In addition, with the continous development of surgery and systemic treatment potentially curative treatment concepts for advanced initially nonresectable tumors were also established, after completion of neoadjuvant treatment. This article presents the current surgical principles of a radical oncological resection for periampullary pancreatic cancer in the context of a multimodal treatment concept with an outlook for future developments of treatment., (© 2021. The Author(s).)

Background: The role of neoadjuvant therapy (NT) for ampullary carcinoma (AC) has not been clearly established., Methods: Patients who underwent pancreatoduodenectomy for AC between 2004 and 2016 were identified in the National Cancer Database. Overall survival (OS) was compared between those who received NT before resection and those who underwent surgery first (SF). Propensity score matching (PSM) was performed using age, pathologic T and N stage, and tumor differentiation., Results: Among 8688 patients with AC, 175 (2.0%) received NT before surgery. While patients who received NT were younger (p = .022) and more likely to have nodal metastasis (43.3% vs. 35.1%, p < .001), there was no difference in OS on univariate (43 vs. 33 months; hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.88-1.37, p = .401) or multivariate (HR: 1.09, 95% CI: 0.88-1.36, p = .416) analysis between groups. After PSM, there remained no difference in OS between NT or SF groups on univariate (37 vs. 32 months; HR: 1.20, 95% CI: 0.87-1.64, p = .350) or multivariate (HR: 0.99, 95% CI: 0.71-1.38, p = .943) analysis., Conclusion: NT followed by surgery was not associated with improved survival outcomes compared with SF among patients with localized AC. While NT is an acceptable alternative for patients with advanced disease, SF should remain the standard of care., (© 2021 Wiley Periodicals LLC.)

The aim of the study was to compare histological features, postoperative outcomes, and long-term prognostic factors after pancreaticoduodenectomy for distal cholangiocarcinoma and pancreatic ductal adenocarcinoma. From 2005 to 2017, 188 pancreaticoduodenectomies (pancreatic ductal adenocarcinoma n = 151, distal cholangiocarcinoma n = 37) were included. Postoperative outcomes were compared after matching on pancreatic gland texture and main pancreatic duct size. Matching according to tumor size, lymph node invasion and resection margin was used to compare overall and disease-free survival. Distal cholangiocarcinoma patients had more often "soft" pancreatic gland (P = 0.002) and small size main pancreatic duct (P = 0.001). Pancreatic ductal adenocarcinoma patients had larger tumors (P = 0.009), and higher lymph node ratio (P = 0.017). Severe morbidity (P = 0.023) and clinically relevant pancreatic fistula (P = 0.018) were higher in distal cholangiocarcinoma patients. After matching on gland texture and main pancreatic duct diameter, clinically relevant postoperative pancreatic fistula was still more frequent in distal cholangiocarcinoma patients (P = 0.007). Tumor size > 20 mm was predictive of impaired overall survival (P = 0.024) and disease-free survival (P = 0.003), tumor differentiation (P = 0.027) was predictive of impaired overall survival. Survival outcomes for distal cholangiocarcinoma and pancreatic ductal cholangiocarcinoma were similar after matching patients according to tumor size, lymph node invasion and resection margin. Long-term outcomes after pancreaticoduodenectomy for distal cholangiocarcinoma and pancreatic ductal adenocarcinoma patients are similar. Postoperative course is more complicated after pancreaticoduodenectomy for distal cholangiocarcinoma than pancreatic ductal adenocarcinoma. After pancreaticoduodenectomy, patients with distal cholangiocarcinoma and pancreatic ductal adenocarcinoma have similar long-term oncological outcomes.

Aims: Intraductal papillary mucinous neoplasms (IPMNs) differentiate in several histological directions, which are related to their clinical behaviour. Differentiation of IPMNs to the gastric foveolar epithelium/pyloric gland (PG) is well known. However, no study has been conducted regarding fundic gland (FG) differentiation. The aim of this study was to determine the frequency of FG differentiation and its relationship with the clinicopathological features of IPMNs, by studying 48 surgically resected IPMN cases consisting of 17 gastric IPMNs, 15 intestinal IPMNs, 10 pancreatobiliary IPMNs, and six oncocytic IPMNs., Methods and Results: Clinicopathological data, including histological tumour grade, immunohistochemical data for mucins (MUCs), pepsinogen I, pepsinogen II, and H,K-ATPase, and GNAS/KRAS status, were analysed. Pepsinogen I and H,K-ATPase were used to assess FG differentiation, and pepsinogen II and MUC6 were used to identify the equivalent cell type of the normal FG. Reverse transcription polymerase chain reaction (RT-PCR) for PGA5/PGC (pepsinogen I and pepsinogen II mRNA, respectively) and quantitative real-time RT-PCR (qRT-PCR) for PGA5 were performed to confirm the immunohistochemistry results. Pepsinogen I expression was detected in 12.5% (6/48) of total IPMNs, of which 66.7% (4/6) of oncocytic IPMNs and 20.0% (2/10) of pancreatobiliary IPMNs were pepsinogen I-positive. No H,K-ATPase-positive cases were detected. Three oncocytic IPMNs with pepsinogen I expression showed similar histology to normal FG. RT-PCR and qRT-PCR confirmed the immunohistochemical results. All IPMNs with FG differentiation were of the oncocytic or pancreatobiliary subtype, were of histologically high grade, and were without GNAS mutation., Conclusions: The differentiation of IPMNs to gastric FG is related to oncocytic and pancreatobiliary subtypes, and to high grade. This is the first report to describe differentiation of IPMNs to the FG, and to reveal its relationship with the clinicopathological features of IPMNs., (© 2016 John Wiley & Sons Ltd.)

This report describes a unique case of intraductal tubulopapillary neoplasm (ITPN) of the pancreas in order to clarify its oncogenesis and more precisely classify pancreatic intraductal neoplasms. A 74-year-old man visited our institution for follow-up of acute pancreatitis. Imaging examinations revealed a hypovascular intraductal mass in the head of the pancreas with progressive dilation of the pancreatic duct, atrophy of the pancreatic parenchyma, and a non-mucinous appearance. A pancreatoduodenectomy was performed to identify this pancreatic intraductal neoplasm. Macroscopically, the tumor was a solid nodular mass with no visibly secreted mucin obstructing the dilated ducts. Histologically, it had a homogeneous appearance with nodules of back-to-back tubular glands and occasional papillary elements, and there were no apparent transitions to areas with less marked cytoarchitectural atypia. Although the intraductal neoplastic growth corresponded to an ITPN, immunohistochemical staining revealed partial positivity for MUC5AC, for which ITPNs are characteristically negative. Somatic mutations in KRAS, GNAS, BRAF, and PIK3CA were not detected. A loss of MUC5AC expression and mutations in KRAS and GNAS are key elements in the diagnosis of ITPN. Thus, it was difficult to distinguish the present case as a pancreatobiliary-type (PB-type) intraductal papillary mucinous neoplasm (IPMN) or a phenotypic variant of ITPN. As it is possible that some cases of PB-type IPMN and ITPN overlap, the precise classification of these rare lesions may require re-evaluation., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Background: Standard lymphadenectomy for pancreatoduodenectomy is defined for pancreatic ductal adenocarcinoma and adopted for patients with non-pancreatic periampullary cancer (NPPC), ampullary adenocarcinoma (AAC), distal cholangiocarcinoma (dCCA), or duodenal adenocarcinoma (DAC). This study aimed to compare the patterns of lymph node metastases among the different NPPCs in a large series and in a systematic review to guide the discussion on surgical lymphadenectomy and pathology assessment., Methods: This retrospective cohort study included patients after pancreatoduodenectomy for NPPC with at least one lymph node metastasis (2010-2021) from 24 centers in nine countries. The primary outcome was identification of lymph node stations affected in case of a lymph node metastasis per NPPC. A separate systematic review included studies on lymph node metastases patterns of AAC, dCCA, and DAC., Results: The study included 2367 patients, of whom 1535 had AAC, 616 had dCCA, and 216 had DAC. More patients with pancreatobiliary type AAC had one or more lymph node metastasis (67.2% vs 44.8%; P < 0.001) compared with intestinal-type, but no differences in metastasis pattern were observed. Stations 13 and 17 were most frequently involved (95%, 94%, and 90%). Whereas dCCA metastasized more frequently to station 12 (13.0% vs 6.4% and 7.0%, P = 0.005), DAC metastasized more frequently to stations 6 (5.0% vs 0% and 2.7%; P < 0.001) and 14 (17.0% vs 8.4% and 11.7%, P = 0.015)., Conclusion: This study is the first to comprehensively demonstrate the differences and similarities in lymph node metastases spread among NPPCs, to identify the existing research gaps, and to underscore the importance of standardized lymphadenectomy and pathologic assessment for AAC, dCCA, and DAC., (© 2024. The Author(s).)

Context.—: Tumoral (grossly visible) intraductal neoplasms of the bile ducts are still being characterized., Objective.—: To investigate their morphologic, immunohistochemical, and molecular features., Design.—: Forty-one cases were classified as gastric-, intestinal-, pancreatobiliary-type intraductal papillary neoplasm (IPN), intraductal oncocytic papillary neoplasm (IOPN), or intraductal tubulopapillary neoplasm (ITPN) on the basis of histology. All neoplasms were subjected to targeted next-generation sequencing., Results.—: The mean age at diagnosis was 69 years (42-81 years); male to female ratio was 1.3. Most neoplasms (n = 23, 56%) were extrahepatic/large (mean size, 4.6 cm). The majority (n = 32, 78%) contained high-grade dysplasia, and 68% (n = 28) revealed invasion. All gastric-type IPNs (n = 9) and most ITPNs/IOPNs showed consistent colabeling for CK7/MUC6, which was less common among others (P = .004). Intestinal-type IPNs (n = 5) showed higher rates of CK20 expression than others (P < .001). Overall, the most commonly mutated genes included TP53 and APC, while copy number variants affected ELF3 and CDKN2A/B. All gastric-type IPNs contained an alteration affecting the Wnt signaling pathway; 7 of 9 (78%) showed aberrations in the MAPK pathway. Mutations in APC and KRAS were common in gastric-type IPNs as compared with others (P = .01 for both). SMAD4 was more frequently mutated in intestinal-type IPNs (P = .02). Pancreatobiliary-type IPNs (n = 14) exhibited frequent alterations in tumor suppressor genes including TP53, CDKN2A/B, and ARID2 (P = .04, P = .01 and P = .002, respectively). Of 6 IOPNs analyzed, 3 (50%) revealed ATP1B1-PRKACB fusion. ITPNs (n = 6) showed relatively few recurrent genetic aberrations. Follow-up information was available for 38 patients (median, 58.5 months). The ratio of disease-related deaths was higher for the cases with invasion (56% versus 10%)., Conclusions.—: Tumoral intraductal neoplasms of the bile ducts, similar to their counterparts in the pancreas, are morphologically and genetically heterogeneous., (© 2023 College of American Pathologists.)

Background: Pancreatic medullary carcinoma (PMC) is a rare pancreatic tumor, usually showing the presence of microsatellite instability, mostly MLH1 silencing, and a wild-type KRAS mutation status. We report here a PMC arising from a Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN), both having KRAS and TP53 mutations., Case Presentation: We report the case of a 73-year-old woman presenting with right iliac fossa pain. MRI revealed a 16 mm diameter mass in the pancreas, leading to a pancreatic duct stricture and upstream a dilatation of the distal pancreatic duct of Wirsung. A fine needle aspiration was performed, and pathology analysis revealed malignant glandular cells. The patient underwent distal pancreatectomy. Gross examination revealed an12 mm indurated white lesion, adjacent to a cystic lesion extending into the rest of the pancreatic body. Microscopically, the cystic area represented a mixed (gastric-type and pancreatobiliary-type) IPMN, involving the main and secondary pancreatic ducts with low-grade and high-grade dysplasia. In the periphery of this IPMN, a 14mm associated invasive carcinoma was observed, characterized by focal gland formation and by poorly differentiated cells with a syncytial appearance, associated with a dense lymphoplasmocytic and neutrophilic infiltrate. Immunohistochemical analyses showed loss of MSH2 and MSH6 expression. Microsatellite instability was confirmed by molecular test. Molecular analysis was performed both on the invasive carcinoma and on the high-grade dysplasia IPMN, revealing the same mutation profile with KRAS and TP53 mutations. The proposed diagnosis was mixed IPMN with associated invasive medullary carcinoma that presented loss of MSH2 and MSH6 expression., Conclusions: The present case reports for the first time, at the best of our knowledge, the coexistence of IPMN lesions and PMC, both having the same molecular alterations. It also describes the second case of PMC with microsatellite instability, MSH2 and MSH6 silenced., (© 2021. The Author(s).)

Background/objectives: According to the revised international intraductal papillary mucinous neoplasm (IPMN) guidelines (2017), the indication for surgery is based on risk classification. However, some IPMNs with high-risk stigmata (HRS) can be observed for long periods without resection. Hence, we need to reconsider the risk stratification, and this study aimed to propose a novel risk stratification for HRS-IPMNs., Methods: We enrolled 328 patients diagnosed with IPMN using endoscopic ultrasound between 2012 and 2019. We compared clinicopathological features between HRS and worrisome features (WF) and evaluated outcomes of HRS-IPMN., Results: Fifty-three patients (HRS 38, WF 15) underwent resection at initial diagnosis and 275 patients were observed. Following observation for 30 months, 22 patients (17 HRS, 5 WF) underwent resection. Analysis of resected IPMNs (n = 75) revealed that HRS had dominantly pancreatobiliary mucin subtype. Pancreatobiliary-type IPMN had larger nodule sizes and lymphatic invasion and high recurrence with poor prognosis. Seventy-four patients were diagnosed with HRS, 55 underwent resection, and 19 continue to be observed. The resected group had larger nodule sizes (median 8 mm vs. 5 mm; P = 0.060), whereas the observed group had more main pancreatic duct (MPD) dilation (median 10 mm vs. 5 mm; P = 0.005). In the resected HRS group, only patients with MPD dilation ≥10 mm (n = 10) had no recurrence but had a favorable prognosis compared with those nodule size ≥5 mm (n = 45)., Conclusions: Large nodule size may be associated with pancreatobiliary subtype and poor prognosis; however, patients with MPD dilation ≥10 mm with nodule size <5 mm did not require resection., Competing Interests: Declaration of competing interest The authors have no conflict of interest in this report., (Copyright © 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: The clinical management of pancreatic and other periampullary neoplasms remains challenging. In contrast to other cancer types, immunotherapies are largely ineffective, and the reason for the deprived immune response and the immune inhibiting cellular composition is only fragmentarily understood. The aim of this study was to comprehensively map the abundance, topographic distribution and spatial interaction of innate and innate-like immune cells in the tumor microenvironment of periampullary adenocarcinoma., Methods: Multiplexed immunofluorescent imaging was performed on tissue microarrays with tumors from a consecutive cohort of 175 patients with resected periampullary adenocarcinoma. To obtain a detailed spatial analysis of immune cell infiltration, two multiplex immune panels including antibodies against CD3, NKp46, CD56, CD68, CD163 and CD1a, CD208, CD123, CD15, CD68 and pan-cytokeratin were applied., Results: The infiltration of natural killer (NK) and NK-like T (NKT) cells was lower in malignant compared to benign tissue. NKT cells were more abundant in intestinal type compared to pancreatobiliary type tumors, and were associated with more favorable clinicopathological features and a prolonged survival. The interaction of NKp46 + NKT cells with macrophages was also associated with a prolonged survival., Conclusions: This study provides a comprehensive map of the innate immune landscape in periampullary adenocarcinoma. NK cells, and even more so NKT cells, are revealed to be central players in the local immune response in a clinically relevant context., (Copyright © 2020 Lundgren, Micke, Elebro, Heby, Hrynchyk, Nodin, Leandersson, Mezheyeuski and Jirström.)

Metachronous development of intraductal papillary mucinous neoplasms in the remnant pancreas following resection is a significant clinical burden. Our aim was to characterize the clinicopathological and molecular features of the patients with metachronous tumor development to identify predictive factors and the possible route(s) of dissemination. Seventy-four patients who underwent resection of intraductal papillary mucinous neoplasms with no invasive compartment or associated carcinoma were retrospectively analyzed. In patients with metachronous tumor development, targeted sequencing of 18 genes associated with pancreatic tumorigenesis and immunohistochemical detection of four proteins (p53, SMAD4, p16, and β-catenin) were performed on both primary and metachronous tumors. The distributions of microscopic neoplastic lesions were examined at surgical margins and in apparently normal tissue apart from the primary tumor. During the median follow-up period of 52 months, 9 patients (12%) developed metachronous tumors in the remnant pancreas. Primary tumors located in the body/tail of the pancreas (odds ratio, 15; 95% confidence interval, 1.6-131) and of the pancreatobiliary type (odds ratio, 6.1; 95% confidence interval, 1.1-35.7) were identified as significant risk factors for subsequent metachronous tumor development. Eight of the nine patients shared molecular aberrations between their primary and metachronous tumors, suggesting migrations from the primary tumor to the pancreatic duct as the cause of metachronous tumor development. Our data suggest that these post-resection metachronous tumors develop by skip dissemination of the primary tumor, potentially via the pancreatic duct. The development of strategies to better predict and prevent this form of tumor progression is necessary.

Background: The purpose of the current study was to investigate the immunohistochemical (IHC) profile of liver metastases (LM) in patients with pancreatic ductal adenocarcinoma (PDAC)., Methods: Expression of 15 IHC markers in liver biopsies from 77 patients with PDAC, who were diagnosed between 2010 and 2014, were evaluated. In a separate subgroup analysis (n = 12), paired samples (LM and primary tumor) from the same patient were investigated for IHC profile differences., Results: LM samples were classified as pancreatobiliary-type (PB-type) in 72 patients (93.5%), intestinal-type (INT-type) in four patients (5.2%), and squamous in one patient (1.3%). There was no significant difference in overall survival (OS) between LM of the PB-type or INT-type (p = 0.097). In a multivariate analysis, age <70 years (p = 0.047), absence of SMAD4 mutation (p = 0.026), absence of CDX2 expression (p = 0.003), and well to moderate differentiation were significant prognostic factors for better OS in patients with LM (p = 0.031). Analysis of paired tissue samples from LM and the primary tumor revealed a difference in CDX2 (50% increase, p = 0.125) and SMAD4 (33% loss of SMAD4, p = 0.375)., Conclusions: CDX2 expression and SMAD4 mutation indicate a poor outcome in patients with LM of PDAC. Matched-pair analysis revealed differences in distinct IHC marker expression., (Copyright © 2019 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Introduction In recent years, the widespread utilisation of advanced imaging modalities has led to a surge in the detection rate of pancreatic cystic lesions, particularly intraductal papillary mucinous neoplasms (IPMN). Consequently, this review aims to provide a comprehensive examination of IPMN, focusing on elucidating its intricate facets including definition, epidemiology, pathogenesis, classification, imaging modalities for diagnosis, analysis of pancreatic cyst fluid, evaluation of malignant potential, and identification of pertinent features. Brief Overview of Current Knowledge: IPMN represents a diagnostic conundrum owing to its variable biological behaviour encompassing both benign and malignant spectra, necessitating meticulous evaluation and risk stratification. Various imaging techniques such as MRI, CT, EUS and abdominal ultrasonography serve pivotal roles in the diagnostic algorithm and risk assessment of IPMN. Additionally, the analysis of pancreatic cyst fluid, incorporating biomarkers and the string sign test, assumes a critical role in discerning mucinous from non-mucinous cysts and gauging malignant potential. Discriminating high-risk stigmata and worrisome features serve as a compass for clinical decision-making regarding the imperative of surgical intervention versus vigilant surveillance. Summary Despite persistent challenges, the ongoing evolution of diagnostic modalities and risk assessment methodologies augur well for refining therapeutic strategies and enhancing clinical outcomes in managing IPMN. This review underscores the imperative of sustained research endeavours in the realm of pancreatic oncology to enrich our comprehension of IPMN pathophysiology and to optimise clinical care paradigms. [ABSTRACT FROM AUTHOR]

Objective: Periampullary carcinomas are a group of neoplasms with variable histopathology that originate from the anatomical junction of different epithelial types including the bile duct, pancreatic duct, and duodenal mucosa. This study was performed to determine whether the histopathologic type of these tumors should be considered an independent prognostic factor., Methods: We analyzed the specimen histopathology of 37 patients who underwent radical cephalic pancreatoduodenectomy for carcinoma of the ampulla of Vater during a 5-year period. We excluded patients with other tumors with an indication for Whipple's procedure and those in whom R0 resection was not achieved., Results: The carcinomas of the hepatopancreatic ampulla were intestinal in 23 (62%) patients, pancreatobiliary in 13 (35%), and mixed type in 1 (3%). The analysis demonstrated significantly more advanced local tumor spread, a more aggressive lymph node metastasizing pattern, and more frequent lymphatic and perineural invasion in patients with pancreatobiliary than intestinal and mixed type tumors., Conclusion: Pancreatobiliary type of ampullary carcinoma is associated with a poorer prognosis than intestinal and mixed types because of its more aggressive behavior. Histopathology should be regarded as an independent predictor of survival and may have therapeutic and prognostic implications for patients.

Intraductal papillary mucinous neoplasms of the pancreas (IPMN) are among the most important precancerous lesions in the pancreas. V‑Ki‑ras 2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most important genes involved in pancreatic neoplasms, and exhibits a high mutation rate in pancreatic ductal adenocarcinomas and pancreatic intraepithelial neoplasia. The present study aimed to further elucidate the associations among IPMN subtypes (gastric, intestinal, pancreatobiliary and oncocytic), pathological classifications [low‑grade, intermediate‑grade, and high‑grade IPMN, and associated minimally invasive carcinoma (invasive depth ≤0.5 cm) and advanced invasive carcinoma (invasive depth >0.5 cm)]. A total of 56 cases of IPMN were studied using scorpion amplified refractory mutation system analysis of KRAS mutations, pathological features and prognosis. KRAS mutations were identified in 50% (28/56 cases). The frequency was 60% (9/15 cases) in gastric‑type, 52.6% (10/19 cases) in intestinal‑type, 47.3% (9/19 cases) in pancreatobiliary‑type and zero (0/3 cases) in oncocytic‑type IPMN. Except for oncocytic type IPMN, the frequencies of KRAS mutations in IPMN with low, intermediate and high grade, and IPMN‑associated carcinoma were 58.3% (7/12 cases), 27.3% (3/11 cases), 80% (4/5 cases) and 56% (14/25 cases), respectively. With more advanced dysplasia and invasion, the prevalence of KRAS mutations in intestinal‑type IPMN increased (P=0.012). The Kaplan‑Meier survival curve demonstrated that survival rate was not associated with KRAS mutation (log‑rank test; P=0.308). The prevalence of KRAS mutations was lowest in intestinal‑type IPMN, and was in proportion to the degree of dysplasia and invasion. Therefore, KRAS mutation in IPMN does not correlate with histological subtype, dysplasia grade, depth of invasion or survival.

Background: Periampullary adenocarcinomas, including pancreatic cancer, are a heterogeneous group of tumors with poor prognosis, where classification into intestinal type (I-type) or pancreatobiliary type (PB-type) is a relevant prognostic factor. The clinical significance of deficient mismatch repair (dMMR) in periampullary adenocarcinoma is comparatively unexplored. Herein, we examined the associations of MMR immunophenotype with long-term survival in patients with resected periampullary adenocarcinoma, with particular reference to morphology and adjuvant treatment response., Methods: MMR protein expression was assessed by immunohistochemistry on tissue microarrays with primary tumors from a retrospective cohort of 175 patients with periampullary adenocarcinoma treated with pancreaticoduodenectomy during 2001-2011 in Malmö and Lund University Hospitals, Sweden. Cox proportional hazards models were applied to calculate hazard ratios (HR) and 95% confidence intervals (CI)., Results: After a mean follow-up of 46.5 (1.9-185.1) months, 35 patients (20.3%) were alive, 24 with I-type and 11 with PB-type tumors. MMR protein expression could be evaluated in 172 cases, in which dMMR was denoted in 20 (11.6%) cases, 13/63 (20.6%) in I-type and 7/109 (6.4%) in PB-type tumors. dMMR was associated with a significantly prolonged overall survival in the entire cohort (HR = 0.28, 95% CI 0.13-0.57), and in I-type tumors (HR = 0.20, 95% CI 0.06-0.68), however not independent of conventional prognostic factors. In PB-type tumors, dMMR was not prognostic, but there was a significant negative interaction between dMMR and adjuvant treatment (p interaction  = 0.015)., Conclusions: dMMR is more frequent in I-type compared to PB-type periampullary adenocarcinoma, and is a prognostic factor for long-term survival only in the former. The finding of the small number of PB-type tumors with dMMR potentially lacking benefit from adjuvant chemotherapy is however noteworthy and merits further validation.

As the most common and most important cancer of the pancreas, with rapid mortality and now also as the third leading cause of cancer-related deaths in the United States, pancreatic ductal adenocarcinoma (PDAC) has become synonymous with "pancreas cancer". PDAC is also the prototype of the "pancreatobiliary-type" adenocarcinomas, along the biliary tract, ampullary and gallbladder cancers with the similar morphology and behavior. Recent molecular profiling studies have identified distinct subsets of PDAC, potentially with different behaviors and targetability. Moreover, while PDAC is by far the most common cancer of the pancreas, there are various other types that occur in this organ and are erroneously classified together with PDAC. Many of these have different molecular and biologic characteristics that warrant their management separately although they are also technically "pancreatic cancers". While some are closely related to PDAC and have as aggressive behavior (such as adenosquamous carcinomas which are recently recognized under "basal" like category in profiling studies, which are actually even worse prognostically than PDACs), in the meantime, others such as colloid carcinoma has a much better behavior than PDAC, and as a carcinoma with intestinal lineage (MUC2/CDX2) colloid carcinoma may require an entirely different treatment approach as well. Similarly, medullary carcinomas also appear to have different biology. Additionally, non-ductal cancers such as acinar, neuroendocrine, solid-pseudopapillary neoplasms and pancreatoblastoma have their respective clinicopathologic and molecular associations and warrant careful elimination in the management and study protocols. Another very problematic aspect in the classification of "pancreas cancer" is its delineation from the cancers of neighboring organs, in particular, ampullary/duodenal and common bile duct (CBD) cancers, for which recently more refined criteria have been provided. Additionally, the possibility of metastasis from another site and lymphomas also need to be considered. In summary, there is a whole host of cancers that occur in the pancreas that ought to be considered carefully before a case is classified as an ordinary "pancreas cancer" (PDAC).

Background: Dendritic cells (DC) and tumour-associated macrophages (TAM) are essential in linking the innate and adaptive immune response against tumour cells and tumour progression. These cells are also potential target for immunotherapy as well as providing a handle to investigate immune status in the tumour microenvironment. The aim of the present study was to examine their impact on prognosis and chemotherapy response in periampullary adenocarcinoma, including pancreatic cancer, with particular reference to morphological subtype., Methods: The density of tolerogenic immature CD1a + dendritic cells (DC), and MARCO + , CD68 + and CD163 + tissue-associated macrophages (TAM) was analysed by immunohistochemistry in tissue micro arrays with tumours from 175 consecutive cases of periampullary adenocarcinoma who had undergone pancreaticoduodenectomy, 110 with pancreatobiliary type (PB-type) and 65 with intestinal type (I-type) morphology. Kaplan-Meier and Cox regression analyses were applied to determine the impact of immune cell infiltration on 5-year overall survival (OS)., Results: High density of CD1a + DCs was an independent prognostic factor for a reduced OS in PB-type but not in I-type tumours (adjusted HR = 2.35; 95% CI 1.13-4.87). High density of CD68 + and CD163 + TAM was significantly associated with poor OS in the whole cohort, however only in unadjusted analysis (HR = 1.67; 95% CI 1.06-2.63, and HR = 1.84; 95% CI 1.09-3.09, respectively) and not in strata according to morphological subtype. High density of MARCO + macrophages was significantly associated with poor prognosis in I-type but not in PB-type tumours (HR = 2.14 95% CI 1.03-4.44), and this association was only evident in patients treated with adjuvant chemotherapy. The prognostic value of the other investigated immune cells did not differ significantly in strata according to adjuvant chemotherapy., Conclusions: The results from this study demonstrate that high infiltration of tolerogenic immature DCs independently predicts a shorter survival in patients with PB-type periampullary adenocarcinoma, and that high density of the MARCO + subtype of TAMs predicts a shorter survival in patients with I-type tumours. These results emphasise the importance of taking morphological subtype into account in biomarker studies related to periampullary cancer, and indicate that therapies targeting dendritic cells may be of value in the treatment of PB-type tumours, which are associated with the worst prognosis.

The patient was a 60-year-old man without any particular complaints, but he underwent abdominal computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) due to a fatty liver, which revealed two similar cystic lesions regarded as branch duct-type intraductal papillary mucinous neoplasm (BD-IPMN) in the pancreatic body [BD-IPMN (b), 16 mm in size] and tail [BD-IPMN (t), 13 mm in size] without a "high-risk stigmata" or "worrisome features". He subsequently received follow-up by MRCP every 6 months. Two years later, MRCP showed prominent dilation of the main pancreatic duct (MPD) and mural nodule formation within the dilated MPD adjacent to the BD-IPMN (b). Distal pancreatectomy specimens revealed that the BD-IPMN (b) was lined by low-papillary gastric mucinous epithelium with low-to-intermediate-grade dysplasia and involved the MPD, forming a malignant mural nodule showing pancreatobiliary-type IPMN. In contrast, the BD-IPMN (t) was lined by flat, monolayer columnar gastric mucinous epithelium without atypia, which suggested the possibility of a "simple mucinous cyst". A genetic analysis showed KRAS mutation only in BD-IPMN (b). Differences in the histological and genetic findings between two similar BD-IPMNs in the present case may suggest what kinds of examinations should be performed in patients with BD-IPMNs without any worrisome features.

Distal common bile duct carcinoma is a poorly characterized entity for reasons such as variable terminology and difficulty in determining site of origin of intrapancreatic lesions. We compared clinicopathologic features of pancreatobiliary-type adenocarcinomas within the pancreas, but arising from the distal common bile duct, with those of pancreatic and ampullary origin. Upon careful review of 1017 pancreatoduodenectomy specimens with primary adenocarcinoma, 52 (5%) qualified as intrapancreatic distal common bile duct carcinoma. Five associated with an intraductal papillary neoplasm were excluded; the remaining 47 were compared to 109 pancreatic ductal adenocarcinomas and 133 ampullary carcinomas. Distal common bile duct carcinoma patients had a younger median age (58 years) than pancreatic ductal adenocarcinoma patients (65 years) and ampullary carcinoma patients (68 years). Distal common bile duct carcinoma was intermediate between pancreatic ductal adenocarcinoma and ampullary carcinoma with regard to tumor size and rates of node metastases and margin positivity. Median survival was better than for pancreatic ductal adenocarcinoma (P=0.0010) but worse than for ampullary carcinoma (P=0.0006). Distal common bile duct carcinoma often formed an even band around the common bile duct and commonly showed intraglandular neutrophil-rich debris and a small tubular pattern. Poor prognostic indicators included node metastasis (P=0.0010), lymphovascular invasion (P=0.0299), and margin positivity (P=0.0069). Categorizing the tumors based on size also had prognostic relevance (P=0.0096), unlike categorization based on anatomic structures invaded. Primary distal common bile duct carcinoma is seen in younger patients than pancreatic ductal adenocarcinoma or ampullary carcinoma. Its prognosis is significantly better than pancreatic ductal adenocarcinoma and worse than ampullary carcinoma, at least partly because of differences in clinical presentation. Use of size-based criteria for staging appears to improve its prognostic relevance. Invasive pancreatobiliary-type distal common bile duct carcinomas are uncommon in the West and have substantial clinicopathologic differences from carcinomas arising from the pancreas and ampulla.