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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.

Cartilage oligomeric matrix protein (COMP) is an emerging regulator of tumor progression. The aim of this study was to evaluate the expression of COMP in periampullary adenocarcinoma with respect to prognostic value for survival and relapse, levels of fibrosis and infiltrating immune cells. COMP expression was evaluated using immunohistochemistry in primary tumors and subsets of paired lymph node metastases in tissue microarrays including 175 patients with periampullary adenocarcinoma. Collagen content was assessed with Sirius Red-Fast Green staining. High COMP levels were detected in cancer cells and in stroma, in 46% and 57% of the patients, respectively. High COMP expression was strongly associated with more aggressive pancreatobiliary-type (PB-type) compared to intestinal-type tumors (p < .0001). Importantly, high expression of COMP correlated with the exclusion of cytotoxic T-cells from the cancer cell compartment of the tumors, particularly in PB-type tumors. Higher levels of fibrosis measured by the density of collagen fibers correlated with high COMP levels in both cancer cells and stroma. This in turn could lead to exclusion of cytotoxic T-cells from accessing the cancer cells, a recognized immunotherapy resistance mechanism. Targeting COMP could therefore be considered as a novel therapeutic strategy in PB-type periampullary adenocarcinoma.

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.

Introduction: The purpose of this study was to associate immunohistochemical expression of β-catenin, EGFR, CK7, CK20, MUC1, MUC2, and CDX2 in ampullary adenocarcinomas with the type of differentiation and prognosis. Methods: Forty-seven patients with ampullary adenocarcinoma who underwent pancreatoduodenectomy with curative intent from 1997 to 2014 were included in this study. Nine patients with perioperative death were included in the association analysis but excluded from survival analysis. All tumors were classified as intestinal or pancreatobiliary type, according to histologic criteria, and immunohistochemically stained against the aforementioned markers. Results: Eighteen carcinomas were classified as intestinal type and 29 carcinomas as pancreatobiliary type. Univariate analysis revealed that CK20 and CDX2 expression correlates with intestinal type, whereas MUC1 positivity indicates pancreatobiliary type. A marginally significant trend was shown for intestinal-type tumors toward larger size and more frequent MUC2 expression. Using multivariate analysis CK20 ( P = .003) and MUC1 ( P = .004) were identified as independent predictors of the intestinal and pancreatobiliary types, respectively. Mean and median survival was 90.3 and 55 months, respectively. Overall 5-year survival rate was 48%. On univariate survival analysis, overall survival was adversely influenced by the number of infiltrated lymph nodes, elevated Ca19-9 serum levels, jaundice, poor differentiation, T4 stage, N1 stage, TNM stage III, and CDX2 immunonegativity. Multivariate analysis identified TNM stage as the only independent prognostic factor in ampullary adenocarcinoma ( P = .048). Conclusions: Immunoreactivity against CK20 and MUC1 in ampullary carcinomas is a useful adjunct to histologic examination in determining histotype. None of the immunohistochemical markers studied had prognostic significance.

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.

Gladhaug I P, Westgaard A, Schjolberg A R, Burum-Auensen E, Pomianowska E & Clausen O P F (2010) Histopathology56, 345–355 Spindle proteins in resected pancreatic head adenocarcinomas: BubR1 is an independent prognostic factor in pancreatobiliary-type tumours 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

BackgroundAdenocarcinoma of the ampulla of Vater (AAV) is standardly treated using a complex operation, a pancreatoduodenectomy (PD), to remove the tumor. However, dicision-making in AAV clinical treatment remains difficult due to the broad range of AAV types, outcomes, and responses to special chemotherapeutics. Thus, this study aimed to explore clinicopathological prognostic factors associated with overall survival, as well as post-chemotherapeutic effects related to curative resection of AAV.MethodsWe retrospectively reviewed data for clinicopathological outcome of 47 patients diagnosed with AAV that had underwent a PD. Overall survival probabilities were obtained using the Kaplan–Meier estimate method and a Cox proportional hazards model.ResultsForty-five patients underwent LPD (laparoscopic pancreatoduodenectomy) and two patients underwent PD. The patient group was composed of 31 males (66%) and 16 females (34%) with a mean age of 65(34–91)years. We selected 45 patients for long-term survival analysis. One- and three-year overall survival rates after resection were 97.6% and 58.9% respectively. The median survival was 37.7 months for the intestinal-type and 26.9 months in pancreatobiliary-type ampullary tumors. Serum carbohydrate antigen (CA) 19-9 greater than 37 U/ml (HR 0.140, P = 0.007), perineural invasion (HR 0.141, P = 0.003), and classification as pancreatobiliary-type (HR 6.633, P = 0.006) were independently associated with poor survival. Serum carcinoembryonic antigen (CEA) greater than 5 µg/ml (P = 0.031), serum CA 19-9 greater than 37 U/ml (P = 0.002), tumor sizes greater than 2.5cm (P=0.002), and positive perineural invasion (P=0.003) were all associated with a poor prognosis in the histopathological subgroup. Serum CA 19-9 greater than 37 U/ml (P=0.002) and positive perineural invasion (P=0.001) were significantly associated with poor survival in of patients with intestinal-type ampullary tumors. Serum CEA greater than 5 µg/ml (P=0.013) and tumor sizes greater than 2.5cm (P=0.002) were significantly associated with poor survival in patients with pancreatobiliary-type ampullary tumors.ConclusionsPancreatobiliary-type ampullary tumors were associated with poor survival. Serum CA 19-9 in the intestinal-type and CEA in the pancreatobiliary-type were significantly associated with poor survival. Ajuvant chemotherapy could not predict the survival of AAV patients.

Ampullary carcinoma is a rare tumor and evidence on the treatment of recurrent metastatic disease is scarce. We report the case of a 60-year-old patient with an R0-resected node-positive adenocarcinoma of the papilla of Vater of an initially diagnosed intestinal subtype who developed pulmonary metastases 2 months after adjuvant gemcitabine chemotherapy and, subsequently, liver metastases. Palliative combination chemotherapy with standard regimens for intestinal-type adenocarcinoma (FOLFOX and FOLFIRI) failed. However, subsequent combination chemotherapy with nanoparticle albumin-bound paclitaxel and gemcitabine, a regimen with proven efficacy in metastatic adenocarcinoma of the pancreas, resulted in a durable, very good partial remission. Treatment was manageable and well tolerated. Primary tumor and metastatic tissue were reassessed by immunohistochemistry and had to be reclassified to a mixed phenotype containing predominant elements of the pancreatobiliary subtype. Our case suggests that combination chemotherapy with nanoparticle albumin-bound paclitaxel and gemcitabine could represent a promising option for the treatment of this rare disease and warrants further investigation within controlled clinical trials. Moreover, thorough characterization of ampullary carcinomas by histomorphology and additional immunohistochemistry should become mandatory in order to start a chemotherapeutic regimen tailored for the definitive subtype.

International audience; BACKGROUND Ampullary adenocarcinoma (AAC) is a rare neoplasm that accounts for only 0.2% of all gastrointestinal cancers. Its incidence rate is lower than 6 cases per million people. Different prognostic factors have been described for AAC and are associated with a wide range of survival rates. However, these studies have been exclusively conducted in patients originating from Asian, European, and North American countries. AIM To evaluate the histopathologic predictors of overall survival (OS) in South American patients with AAC treated with curative pancreaticoduodenectomy (PD). METHODS We analyzed retrospective data from 83 AAC patients who underwent curative (R0) PD at the National Cancer Institute of Peru between January 2010 and October 2020 to identify histopathologic predictors of OS. RESULTS Sixty-nine percent of patients had developed intestinal-type AAC (69%), 23% had pancreatobiliary-type AAC, and 8% had other subtypes. Forty-one percent of patients were classified as Stage I, according to the AJCC 8th Edition. Recurrence occurred primarily in the liver (n = 8), peritoneum (n = 4), and lung (n = 4). Statistical analyses indicated that T3 tumour stage [hazard ratio (HR) of 6.4, 95% confidence interval (CI) of 2.5-16.3, P < 0.001], lymph node metastasis (HR: 4.5, 95%CI: 1.8-11.3, P = 0.001), and pancreatobiliary type (HR: 2.7, 95%CI: 1.2-6.2, P = 0.025) were independent predictors of OS. CONCLUSION Extended tumour stage (T3), pancreatobiliary type, and positive lymph node metastasis represent independent predictors of a lower OS rate in South American AAC patients who underwent curative PD.

To investigate immunohistochemical predictors for intestinal and pancreatobiliary types of adenocarcinoma of ampulla of Vater and identify clinicopathological characteristics associated with the histological types and patient survival. Immunohistochemical markers included MUC1, MUC2, MUC5AC, CDX2, CK7, and CK20. The data were analyzed by univariate and multivariate methods. The two-step cluster method was used to determine the best immunohistochemical markers to discriminate the intestinal from the pancreatobiliary type. This study identified 9 (33.3%) intestinal and 21 (66.7%) pancreatobiliary tumors. CK7 and CDX2 achieved the highest value (= 1) as predictor markers, while CK20, MUC1, and MUC2 showed degrees of importance equal to 0.77, 0.71, and 0.68, respectively. MUC5AC did not reach 0.50 of importance. In the univariate analysis, lymph node involvement, staging (TNM), and angiolymphatic and perineural invasions were associated with histological types. The independent clinicopathological variable in the multivariate model to predict the histological type was angiolymphatic invasion (p = 0.005), OR = 17 (95% CI 2.33 to 123.83). The final model showed positive nodes (N1) associated with shorter survival (HR = 9.5; p = 0.006). Overall survival at 12, 36, and 60 months was 88.5, 67.0, and 47.6%, respectively. CDX2 and CK7 were the immunohistochemical markers that best discriminated the intestinal from the pancreatobiliary type. Lymph node involvement had a high impact on survival and proved to be more frequent in the pancreatobiliary type.

Although several studies have reported that some patients developed metachronous/recurrent intraductal papillary mucinous neoplasms (IPMNs) after partial pancreatectomy, recurrence of IPMN mimicking ampullary cancer is extremely rare. We report the case of a 62-year-old man who developed recurrent IPMN mimicking ampullary cancer. Every 3-6 months, the patient had received surveillance with computed tomography after distal pancreatectomy for IPMN, high-grade, pancreatobiliary type. However, a villous tumor at the major duodenal papilla was found incidentally by upper gastrointestinal endoscopy 2 years and 3 months after initial surgery, and the biopsy result was adenocarcinoma. Endoscopic ultrasonography showed a tumor at the periampullary lesion; however, the origin of the tumor could not be determined definitively. Remnant total pancreatectomy was performed, and the histological diagnosis revealed IPMN, high-grade, pancreatobiliary type. Some patients develop recurrent IPMN mimicking ampullary cancer; thus, careful surveillance for periampullary lesions as well as remnant pancreas should be performed.

Introduction Subclassification of ampullary adenocarcinomas into intestinal and pancreatobiliary type has prognostic and therapeutic implications. Immunohistochemical staining against specific biomarkers has been proven to be a useful adjunct in determining the exact histotype. Furthermore the immunohistochemical profile is suggestive of the molecular pathogenic mechanisms through which the tumor evolved. The aim of this study was to correlate p53, MDM2, CK7, CK20, MUC1, MUC2 and CDX2 expression in ampullary adenocarcinomas with the type of differentiation and patients’ survival. Material and methods Forty-seven radically resected ampullary adenocarcinomas were included in this study. Thirty-eight of them were eligible for survival analysis. Patients’ data were retrospectively collected. All tumors were classified as intestinal or pancreatobiliary type, according to histologic criteria, and immunohistochemically stained against the aforementioned markers. Results There were 18 intestinal and 29 pancreatobiliary type ampullary adenocarcinomas. A trend was found between intestinal type tumors and large tumor size. CK20, MUC2 and CDX2 expression was more prevalent in intestinal type tumors, while MUC1 was more frequently expressed in pancreatobiliary type tumors. Neither p53 nor MDM2 differential expression between the two histotypes reached statistical significance. Multivariate analysis indicated CK20 and MUC1 as independent predictors of the histotype. Mean and median survival was 90.3 and 55 months respectively. Overall 5-year survival rate was 48%. Survival analysis indicated TNM stage as the only independent prognostic factor. Although significant difference in survival rates among the two histotypes was implied based on survival plots, this difference could not gain statistical significance. Conclusion Immunoreactivity against CK20 and MUC1 in ampullary carcinomas is a useful adjunct to histologic examination in determining histotype. None of the immunohistochemical markers studied has prognostic significance. Future studies focused on other signaling pathways should seek further evidence of distinct tumorigenic mechanisms between histotypes of ampullary adenocarcinoma.

Ampullary adenocarcinomas (A-ACs) are rare malignancies with considerable importance because of their high curable resection rate and improved survival rate among periampullary cancers. The RAS-RAF-MAPK pathway is involved in the development of A-ACs and is a potential therapeutic target. However, molecular profiles of A-ACs and their prognostic impact are poorly understood. Peptide nucleic acid-mediated polymerase chain reaction clamping and Mutyper were used to detect KRAS, BRAF, and PIK3CA mutations in 62 paraffinized samples of A-ACs. Of 62 A-ACs, 30.6% had KRAS mutations, but no BRAF mutations and low frequency (1.6%) of PIK3CA mutation were detected. KRAS mutation was correlated with poor tumor differentiation and was a predictor of shorter recurrence-free survival period in overall A-ACs, whereas the prognosis according to the histologic subtypes was not affected by KRAS mutation. Lymph node metastasis was an independent prognostic factor of poor overall survival. Intestinal- and pancreatobiliary-type A-ACs had similar prognosis. Intestinal- and pancreatobiliary-type A-ACs had different prognostic factors; tumor differentiation and lymph node metastasis strongly predicted overall survival and recurrence-free survival in pancreatobiliary-type tumors, respectively, whereas no independent prognostic factors were demonstrated for intestinal-type tumors. Low incidence of KRAS mutations and their strong prognostic value in A-ACs may suggest the potential of survival benefit depending on the epidermal growth factor receptor-targeted therapy. Much lower frequencies of BRAF and PIK3CA mutations may suggest that they do not play a major role in the tumorigenesis of A-ACs. Different therapeutic protocols should be considered for treating pancreatobiliary- and intestinal-type A-ACs.

Background Carcinoma of the ampulla of Vater is uncommon. This study aimed to clarify predictors of survival for ampullary adenocarcinoma and to identify characteristics of its two major pathological subtypes. Methods Medical records were reviewed for 86 patients who underwent curative resection for ampullary adenocarcinoma between 2000 and 2012 at 12 principal hospitals in Kagawa, Japan. Results Resection was most common among 75–79-year-old patients. Actuarial 1-, 3-, and 5-year postoperative survival rates for ampullary adenocarcinoma were 90%, 72.3%, and 69.1%, respectively. Preoperative biliary drainage; serum CA19-9 and total bilirubin levels; pathological grade; perineural, vascular, pancreatic, and duodenal invasion; nodal metastasis; UICC-T stage; and pancreatobiliary subtype were predictors of poor survival. An elevated serum CA19-9 level; an elevated total bilirubin level; lymphatic, vascular, perineural, and pancreatic invasion; and advanced overall tumor stage were more common in patients with pancreatobiliary-type tumors than in patients with intestinal-type tumors. Additionally, pathologic subtype analysis showed that each subtype had distinct prognostic factors. Conclusions Preoperative elevated serum CA19-9 and total bilirubin levels are prognostic factors for ampullary adenocarcinoma, and are both associated with pancreatobiliary-type tumors. Surgeons should be aware of these factors because pancreatobiliary-type adenocarcinoma is aggressively invasive and is associated with poor survival. J. Surg. Oncol. 2014; 110:156–162. © 2014 Wiley Periodicals, Inc.

Adenocarcinoma arising from the ampulla of Vater is a rare disease and has limited data regarding outcome of chemotherapy. The ampulla of Vater is a heterogeneous junctional structure located at the union of the common bile duct, the pancreatic duct, and the small intestine. Thus, ampullary adenocarcinoma is classified as either intestinal type or pancreatobiliary type. We investigated the efficacy of the XELOX (capecitabine plus oxaliplatin) chemotherapy in patients with recurrent or metastatic ampullary adenocarcinoma, and analyzed the histopathologic features and outcomes. From November 2009 to December 2011, 21 patients were treated with XELOX regimen. XELOX was administered in outpatient clinic every 3 weeks according to the following protocol: oral administration of capecitabine 750 mg/m² twice a day on days 1-14 and intravenous injection of oxaliplatin 130 mg/m² on day 1. With follow-up of median 16.6 months, median time to progression (TTP) was 7.6 months (95% confidence interval [CI], 6.7-8.5), and median overall survival was 19.7 months (95% CI, 14.8-23.6). Two patients (9%) achieved complete response and 6 patients (29%) showed partial response. In subgroup analysis with tissue specimens obtained from 17 patients, median TTP was longer among patients with the intestinal-type adenocarcinoma (n = 7), compared to those with the pancreatobiliary type (n = 10) (13.1 vs. 6.4 months, P = 0.038). The most common grade 3-4 adverse event was neutropenia (27%), and most events were mild. XELOX chemotherapy shows favorable efficacy with manageable toxicity for advanced intestinal-type ampullary adenocarcinoma.

Introduction: Pancreatic surgeries are usually performed for inflammatory conditions and neoplasms. Intraductal Papillary Mucinous Neoplasm (IPMN) account for approximately 5-7% of all pancreatic neoplasms in western literature. To the best of our knowledge, there has been no published literature in Indian subcontinent on IPMN. Aim: To assess the spectrum of different pancreatic pathologies on pancreatic resection specimens. Also, to review and share the experience on the clinicopathological features of IPMNs in our institute. Materials and Methods: This was a 14 year retrospective study of all cases where pancreatic surgeries were done for pancreatic pathology. The slides and blocks of diagnosed cases of IPMNs were retrieved from the department archives, reviewed and a detailed study on the histopathological features was done. Results: Among the 377 pancreatic surgical specimens, pancreatitis was the most common diagnosis followed by exocrine neoplasms and endocrine neoplasms. IPMN constituted 3.2 % of all pancreatic neoplasms. Histologically, the most common type was the gastric foveolar type. Pancreatobiliary type was aggressive and associated with an invasive component and had evidence of metastasis on follow up. Conclusion: IPMNs are rare neoplasms of pancreas with a male predominance. They are usually indolent except for the pancreatobiliary type which may have an aggressive course, often associated with an invasive adenocarcinoma component. Diligent follow up is recommended.

The literature on the clinicopathologic characteristics of tumoral intraepithelial neoplasms (neoplastic polyps) of the gallbladder (GB) is fairly limited, due in part to the variability in definition and terminology. Most reported adenomas (pyloric gland type and others) were microscopic and thus regarded as clinically inconsequential, whereas papillary in situ carcinomas have been largely considered a type of invasive adenocarcinoma under the heading of "papillary adenocarcinomas." In this study, 123 GB cases that have a well-defined exophytic preinvasive neoplasm measuring ≥1 cm were analyzed. The patients were predominantly female (F/M=2:1) with a mean age of 61 y and a median tumor size of 2.2 cm. Half of the patients presented with pain, and in the other half the neoplasm was detected incidentally. Other neoplasms, most being gastrointestinal tract malignancies, were present in 22% of cases. Gallstones were identified in only 20% of cases. Radiologically, almost half were diagnosed as "cancer," roughly half with polypoid tumor, and in 10% the lesion was missed. Pathologic findings: (1) The predominant configuration was papillary in 43%, tubulopapillary in 31%, tubular in 26%. (2) Each case was assigned a final lineage type on the basis of the predominant pattern (>75% of the lesion) on morphology, and supported with specific immunohistochemical cell lineage markers. The predominant cell lineage could be identified as biliary in 50% (66% of which were MUC1), gastric foveolar in 16% (all were MUC5AC), gastric pyloric in 20% (92% MUC6), intestinal in 8% (100% CK20; 75% CDX2; 50%, MUC2), and oncocytic in 6% (17% HepPar and 17% MUC6); however, 90% of cases had some amount of secondary or unclassifiable pattern and hybrid immunophenotypes. (3) Of the cases that would have qualified as "pyloric gland adenoma," 21/24 (88%) had at least focal high-grade dysplasia and 18% had associated invasive carcinoma. Conversely, 8 of 47 "papillary adenocarcinoma"-type cases displayed some foci of low-grade dysplasia, and 15/47 (32%) had no identifiable invasion. (4) Overall, 55% of the cases had an associated invasive carcinoma (pancreatobiliary type, 58; others, 10). Factors associated significantly with invasion were the extent of high-grade dysplasia, cell type (biliary or foveolar), and papilla formation. Among systematically analyzed invasive carcinomas, tumoral intraepithelial neoplasia was detected in 6.4% (39/606). (5) The 3-year actuarial survival was 90% for cases without invasion and 60% for those associated with invasion. In contrast, those associated with invasion had a far better clinical outcome compared with pancreatobiliary-type GB carcinomas (3-yr survival, 27%), and this survival advantage persisted even with stage-matched comparison. Death occurred in long-term follow-up even in a few noninvasive cases (4/55; median 73.5 mo) emphasizing the importance of long-term follow-up. In conclusion, tumoral preinvasive neoplasms (≥1 cm) in the GB are analogous to their pancreatic and biliary counterparts (biliary intraductal papillary neoplasms, pancreatic intraductal papillary mucinous neoplasms, and intraductal tubulopapillary neoplasms). They show variable cellular lineages, a spectrum of dysplasia, and a mixture of papillary or tubular growth patterns, often with significant overlap, warranting their classification under 1 unified parallel category, intracholecystic papillary-tubular neoplasm. Intracholecystic papillary-tubular neoplasms are relatively indolent neoplasia with significantly better prognosis compared with pancreatobiliary-type GB carcinomas. In contrast, even seemingly innocuous examples such as those referred to as "pyloric gland adenomas" can progress to carcinoma and be associated with invasion and fatal outcome.

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.

Most adenomas and carcinomas of small intestine and extrahepatic bile ducts arise in the region of Vater's papilla. In FAP it is the main location for carcinomas after proctocolectomy. In many cases symptoms due to stenosis lead to diagnosis in an early tumor stage. In about 80% curative intended resection is possible. Operability is the most relevant prognostic factor. Inflammatory changes, fibrosis, regeneratory changes after endoscopic manipulation, hyperplasia, preneoplastic lesions close to carcinoma, deeply sited carcinomas under protruded, non-neoplastic duodenal mucosa make the diagnosis difficult on biopsy material. Histologically, intestinal type adenocarcinoma, pancreatobiliary type adenocarcinoma, undifferentiated carcinomas and unusual types can be differentiated. In our own series comprising 45 resected ampullary carcinomas 6 from 10 intestinal type adenocarcinomas, and 4 carcinomas of unusual types expressed the immunohistochemical marker profile of intestinal mucosa (keratin 7-, keratin 20+, MUC2+). 17 from 21 pancreatobiliary type adenocarcinomas, 4 undifferentiated carcinomas, as well as 3 papillary carcinomas showed the immunohistochemical profile of pancreaticobiliary duct mucosa (keratin 7+, keratin 20-, MUC2-). 3 invasive carcinomas which were negative for these markers, showed one of these characteristic marker-combinations in non-invasive adenomatous parts. These findings support the concept of histogenetically different ampullary carcinomas which are developing from the intestinal or from the pancreaticobiliary type mucosa of Vater's papilla. Molecular alterations in ampullary carcinomas are similar to those of colorectal as well as pancreatic carcinomas, although they appear in different frequencies. In future studies molecular alterations in ampullary carcinomas should be correlated closely with the different histologic tumor types. The histologic classification should reflect consequently the histogenesis of ampullary tumors from the two different types of papillary mucosa.

The minor duodenal papilla drains the accessory pancreatic duct of Santorini and lies proximal to the ampulla of Vater. Adenocarcinoma and its precursor lesions arising in the minor papilla are rare. Literature data thus far are limited to a few individual case reports, and the condition is consequently poorly defined. Our study cases were composed of carcinomas fulfilling all of the following criteria: location at 1.5 to 2.5 cm proximal to the major papilla; presence of associated submucosal pancreatobiliary-type ducts with periductal glands or acinar tissue; a predominant submucosal location of the tumor; and lack of an intestinal-type adenoma in the adjacent duodenal mucosa. Tumors were studied morphologically, immunohistochemically, and clinically. Nine cases fulfilling the inclusion criteria were identified. There were 5 men and 4 women with an age range of 50 to 76 years (median, 72 y). The tumor size ranged from 1.2 to 4.4 cm (median, 3 cm). The carcinomas were of colloid type (3 tumors), pancreatobiliary type (4), or nonmucinous intestinal type (2). Five cases were associated with an intraductal papillary mucinous neoplasm (IPMN)-like precursor lesion within the residual structures of the minor papilla in the duodenal submucosa. Immunohistochemically, the intestinal-type and mucinous-type tumors tended to be positive for CK20, CDX2, MUC2, and B72.3, and pancreatobiliary-type tumors tended to be positive for CK7, MUC1, B72.3, and CA125. Loss of DPC4 (Smad4) expression was found in the pancreatobiliary-type carcinomas only. Two tumors showed loss of DNA mismatch-repair protein expression, one losing MLH1 and PMS2 and the other losing MSH6. Both patients were older than 60 years, and neither had germline mutation testing. Follow-up information was available for 6 patients (median follow-up time, 67.5 mo): 3 of the 6 patients died of disease at 60, 75, and 85 months after surgery, respectively, and all 3 patients had an intestinal-type carcinoma (1 colloid and 2 nonmucinous). The patient whose tumor was MSH6 deficient was alive without evidence of disease 51 months after surgery. In conclusion, adenocarcinomas of the minor papilla are rare tumors occurring predominantly in the sixth to seventh decade. Some of them arise from IPMN-like precursors in the residual submucosal minor papilla tissue. Morphologically, immunohistochemically, and clinically they are similar to ampullary or IPMN-associated pancreatic carcinomas and can exhibit either an intestinal, colloid, or pancreaticobiliary phenotype. DNA mismatch-repair deficiency may occur. A careful gross and histologic examination is essential to accurately recognize the site of origin of minor papilla carcinomas.

Carcinoma of the ampulla of Vater is uncommon. This study aimed to clarify predictors of survival for ampullary adenocarcinoma and to identify characteristics of its two major pathological subtypes.Medical records were reviewed for 86 patients who underwent curative resection for ampullary adenocarcinoma between 2000 and 2012 at 12 principal hospitals in Kagawa, Japan.Resection was most common among 75-79-year-old patients. Actuarial 1-, 3-, and 5-year postoperative survival rates for ampullary adenocarcinoma were 90%, 72.3%, and 69.1%, respectively. Preoperative biliary drainage; serum CA19-9 and total bilirubin levels; pathological grade; perineural, vascular, pancreatic, and duodenal invasion; nodal metastasis; UICC-T stage; and pancreatobiliary subtype were predictors of poor survival. An elevated serum CA19-9 level; an elevated total bilirubin level; lymphatic, vascular, perineural, and pancreatic invasion; and advanced overall tumor stage were more common in patients with pancreatobiliary-type tumors than in patients with intestinal-type tumors. Additionally, pathologic subtype analysis showed that each subtype had distinct prognostic factors.Preoperative elevated serum CA19-9 and total bilirubin levels are prognostic factors for ampullary adenocarcinoma, and are both associated with pancreatobiliary-type tumors. Surgeons should be aware of these factors because pancreatobiliary-type adenocarcinoma is aggressively invasive and is associated with poor survival.

Mixed adenoneuroendocrine carcinoma (MANEC) of ampulla is rare, with only 13 cases reported, and the diagnoses were all based on histology mostly after surgery. We describe two new cases with cytological features of signet ring-cell carcinoma mixed with small-cell carcinoma, and intestinal adenocarcinoma mixed with large-cell neuroendocrine carcinoma. Our cases and literature review demonstrate the higher frequency of periampullary-duodenum subtype in MANEC compared with non-MANEC ampullary carcinomas. In accordance, of the 14 MANEC cases with detailed morphology available, the most common glandular components are intestinal-type carcinoma (6/14), followed by goblet carcinoid tumor (3/14), signet ring-cell carcinoma (2/14), pancreatobiliary-type carcinoma (2/14), and pancreatic acinar cell carcinoma (1/14). The intestinal-type carcinoma and goblet carcinoid in MANEC are favorable histological types showing no distant metastasis or mortality (0/9) during 6-36 months follow-up. In contrast, the signet ring cell, pancreatobiliary-type carcinoma, and acinar cell carcinoma are unfavorable with distant metastatic rate and mortality rate of 80% (4/5) during 3-16 months follow-up. The combination of favorable glandular histological types with high-grade neuroendocrine tumors (neuroendocrine carcinoma) has a mortality rate of 0% (0/3), whereas the combination of unfavorable glandular types with low-grade neuroendocrine tumors (e.g., carcinoid, atypical carcinoid) has a mortality rate of 100% (3/3). In addition, younger age (40 years) seems to be associated with high mortality rate of 100% (2/2). Overall, cytology preparations are able to make the diagnosis of MANEC and distinguish the subcomponents. Disease progression is apparently driven by the carcinomatous component of the tumor.

Background & aims Adenocarcinomas of the pancreatobiliary system are currently classified by their primary anatomical location. In particular, the pathological diagnosis of intrahepatic cholangiocarcinoma is still considered as a diagnosis of exclusion of metastatic adenocarcinoma. Periampullary cancers have been previously classified according to the histological type of differentiation (pancreatobiliary, intestinal), but overlapping morphological features hinder their differential diagnosis. We performed an integrative immunohistochemical analysis of pancreato-biliary tumors to improve their diagnosis and prediction of outcome. Methods This was a retrospective observational cohort study on patients with adenocarcinoma of the pancreatobiliary system who underwent diagnostic core needle biopsy or surgical resection at a tertiary referral center. 409 tumor samples were analyzed with up to 27 conventional antibodies used in diagnostic pathology. Immunohistochemical scoring system was the percentage of stained tumor cells. Bioinformatic analysis, internal validation, and survival analysis were performed. Results Hierarchical clustering and differential expression analysis identified three immunohistochemical tumor types (extrahepatic pancreatobiliary, intestinal, and intrahepatic cholangiocarcinoma) and the discriminant markers between them. Among patients who underwent surgical resection of their primary tumor with curative intent, the intestinal type showed an adjusted hazard ratio of 0.19 for overall survival (95% confidence interval 0.05-0.72; p value = 0.014) compared to the extrahepatic pancreatobiliary type. Conclusions Integrative immunohistochemical classification of adenocarcinomas of the pancreatobiliary system results in a characteristic immunohistochemical profile for intrahepatic cholangiocarcinoma and intestinal type adenocarcinoma, which helps in distinguishing them from metastatic and pancreatobiliary type adenocarcinoma, respectively. A diagnostic immunohistochemical panel and additional extended panels of discriminant markers are proposed as guidance for their pathological diagnosis.

The interaction between tumor cells and inflammatory cells has an important role in cancer initiation and progression; however, this interaction has not been systematically investigated in pancreatic neoplasia. In this study, the presence of tumor-infiltrating neutrophils within and/or adjacent to neoplastic cells was investigated in pancreatic neoplasms. Areas with >10 tumor-infiltrating neutrophils/100 epithelial cells were arbitrarily classified as positive. Those with 11–15 tumor-infiltrating neutrophils were considered ‘borderline’ while those with >15 tumor-infiltrating neutrophils were considered ‘significant’. Among 363 invasive ductal carcinomas, 15 showed significant tumor-infiltrating neutrophils (8 were micropapillary carcinomas and 7 were undifferentiated carcinomas). Of 19 mucinous cystic neoplasms with a carcinomatous high-grade papillary component, 11 showed significant tumor-infiltrating neutrophils (mean, 25; range, 14–63 tumor-infiltrating neutrophils). Among intraductal papillary mucinous neoplasms, significant tumor-infiltrating neutrophils were identified in 4/16 pancreatobiliary type, but were uncommon in other types (1/11 oncocytic and 1/23 intestinal types had borderline tumor-infiltrating neutrophils, and 0/10 gastric type had tumor-infiltrating neutrophils). Non-carcinomatous (low-grade and non-papillary) components of these neoplasms did not have tumor-infiltrating neutrophils. Tumor-infiltrating neutrophils were not striking in neuroendocrine tumors (40), serous cystadenomas (18), acinar cell carcinomas (9) or solid-pseudopapillary neoplasms (8). In conclusion, significant tumor-infiltrating neutrophils are uncommon in pancreatic ductal adenocarcinoma, and when they occur it is typically in the micropapillary and undifferentiated types with a known poor prognosis. Among pre-invasive neoplasia, tumor-infiltrating neutrophils show a predilection for papillary in-situ carcinomas of mucinous cystic neoplasms, or less commonly, pancreatobiliary-type intraductal papillary mucinous neoplasms (both of which express cell surface-associated mucin 1 (MUC1)). MUC1 expression by these tumors may have biologic implications, considering its recently established relationship with inflammatory cells in carcinogenesis, and the differential expression of mucins in pancreatic neoplasia. Larger studies are needed to investigate the association between tumor-infiltrating neutrophils and pancreatic neoplasms and their role in their clinical behavior.

The purpose of this study was to examine the expression pattern of MUC5AC and SOX2 in ampulla of vater adenocarcinoma and evaluate the association between expression of these gastric epithelial markers and the histologic phenotype of ampulla of vater carcinoma. Six surgically resected samples of ampulla of vater adenocarcinoma, including four intestinal type carcinomas and two pancreatobiliary type carcinomas, were studied. We performed immunohistochemistry with a monoclonal antibody against MUC5AC and a polyclonal anti-SOX2 antibody. In two of the four intestinal type carcinomas, MUC5AC and SOX2 were focally expressed in the superficial neoplastic mucosa. However, in the centre of the tumour and in other invasive lesions, including vascular invasive lesions and metastatic lymph nodes, neither MUC5AC nor SOX2 was expressed. In contrast, in both pancreatobiliary type carcinomas, expression of MUC5AC and SOX2 was maintained or increased in invasive lesions. Our immunohistochemistry data suggest that MUC5AC and SOX2 are associated with the pancreatobiliary phenotype of ampulla of vater carcinoma and involved in later events in carcinogenesis, such as invasion and metastasis.

This study aimed to determine the clinicopathological features of the subtypes of ampullary carcinoma (AC) to explore the indications for endoscopic papillectomy (EP) in early AC. Fifty-seven patients with AC who underwent curative resection were retrospectively reviewed. The 0/IA stages were significantly more common in the intestinal type (I-type) than in the mixed and pancreatobiliary type (M&PB-type) (90.7% vs 35.7%, P P = 0.002). The tub1 rate was significantly higher in the I-type than in the M&PB-type (81.4% vs 35.7%, P = 0.001). In the I-type, the tub1 rate was significantly higher for Tis/T1a(ampulla) than for T1a tumors limited to the sphincter of Oddi (100% vs 42.9%, P = 0.004). These observations suggest that I-type AC with tub1 is an indication for EP. The concordance rate of pathological subtypes between endoscopic biopsy and resected specimens was high (κ = 0.8053, P

Enteritis cystica profunda (ECP) is an uncommon benign condition arising after mucosal damage. We describe 2 cases of small intestinal adenocarcinomas associated with ECP at the distal ileum, one in a background of active Crohn ileitis (case 1), the other 22 years after pelvic radiation therapy (case 2). Both patients presented with small bowel obstruction and received ileocectomy. Macroscopic examination identified an indurated/strictured area in the distal ileum. Histologically, both cases showed a low-grade tubuloglandular adenocarcinoma arising in a background of chronic ischemic stricture and ECP lined by flat cuboidal cells with mild cytologic atypia resembling pancreatobiliary-type epithelium. There was no conventional dysplasia in the surface or adjacent mucosa. Immunohistochemically, both ECP with metaplasia and invasive carcinomas were diffusely positive for CK7 and CK19, while focally positive for CDX2 or CK20. Both cases showed normal wild-type p53 expression. Case 2 was also mismatch repair protein proficient, with membranous β-catenin staining, and retained nuclear SMAD4 expression. In summary, the 2 cases uniquely exhibits "enteritis-metaplasia-carcinoma" sequence, which has not been reported before. This process appears to bypass conventional dysplasia, be slow and indolent, independent of p53, APC/β-catenin, and SMAD4/TGFβ signaling pathways.

Adenocarcinoma of the ampulla of Vater (AOV) is classified into intestinal type (IT) and pancreatobiliary type (PB); however, the immunological properties of these subtypes remain to be characterized. Here, we evaluated the clinical implications of PD-L1 expression and CD8+ T lymphocyte density in adenocarcinomas of the AOV and their potential association with Yes-associated protein (YAP). We analyzed 123 adenocarcinoma-of-the-AOV patients who underwent surgical resection, and tumors were classified into IT or PB type. Tumor or inflammatory cell PD-L1 expression, CD8+ T lymphocyte density in the cancer cell nest (intratumoral) or in the adjacent stroma, and YAP localization and intensity were analyzed using immunohistochemical staining. PB-type tumors showed higher tumoral PD-L1 expression than IT-type tumors, and tumoral PD-L1 expression was associated with a shorter disease-free survival (DFS) [hazard ratio (HR), 1.77; p = 0.045] and overall survival (OS) (HR 1.99; p = 0.030). Intratumoral CD8+ T lymphocyte density was higher in IT type than in PB type and was associated with a favorable DFS (HR 0.47; p = 0.022). The nuclear staining pattern of YAP in tumor cells, compared to non-nuclear staining patterns, was more frequently associated with PB type and increased tumoral PD-L1 expression. Nuclear YAP staining was a significant prognostic factor for OS (HR 2.21; p = 0.022). These results show that the two subtypes of adenocarcinoma of the AOV exhibit significant differences in tumoral PD-L1 expression and intratumoral CD8+ T lymphocyte density, which might contribute to their distinct clinical features.

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 (pinteraction = 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. Electronic supplementary material The online version of this article (10.1186/s12967-018-1444-4) contains supplementary material, which is available to authorized users.

Hepatocyte growth factor (HGF) and MET are candidates of targeted therapies for cancer patients. Although MET and HGF are commonly expressed in biliary tract cancers, their expression and gene copy number status and their association with KRAS mutations have not been investigated in pancreatobiliary-type ampullary adenocarcinomas (A-ACs), one of the aggressive periampullary cancers. MET and HGF expressions and MET copy number status were examined by performing immunohistochemistry (IHC) and silver in situ hybridization (SISH) in 62 surgically resected, paraffin-embedded tumors, respectively. High MET and HGF protein expressions were detected in 24 (38.7%) and 15 (24.2%) tumors. High MET expression was associated with KRAS mutation. However, there were no associations of high MET/HGF expression alone with other clinicopathological feature or survival. MET SISH positivity was detected in 19 tumors (30.6%), where 84.2% were due to high trisomy or polysomy and only 3 cases (15.8%) were MET gene amplification. The overall MET protein overexpression was well correlated with MET SISH positivity. The concurrent MET SISH positivity and KRAS mutation, not each alone, was an independent poor prognostic factor of disease-free survival only in pancreatobiliary subtype of A-ACs, but not in intestinal subtype. Concurrent MET SISH positivity and KRAS mutation may predict a high risk of recurrence in pancreatobiliary subtype of A-ACs, indicating those markers could be potent candidates for a new therapeutic target in this cancer type. MET IHC can be used as a reliable tool screening for MET copy number status in ampullary cancers.

In the ampulla of Vater, carcinomas with “diffuse-infiltrative”/“signet ring cell” morphology, designated as “poorly cohesive carcinoma” (PCC) in the WHO classification, are very rare and poorly characterized. Nine cases with a classical PCC morphology constituting >50% of the tumor were identified. Mean age was 64.8 years (vs 64.6 in ampullary carcinomas [ACs]) and 6 were males, 3 females. The mean invasive tumor size was 2.5 cm (vs 1.9 in ACs). Other morphologic patterns displayed included cord-like infiltration (n=2), plasmacytoid cells (n=2), and microglandular component (n=4), including goblet cell adenocarcinoma-like foci. None of the cases were associated with dysplasia. By immunohistochemistry, the carcinomas did not show intestinal differentiation (CDX2 0/9, CK20 1/9, MUC2 3/9), MUC1 was positive in 4/9, MUC5AC was positive in 7/8. E-cadherin loss was noted in 4/9. All cases were advanced stage (6/9-pT3, 3/9-pT4) (vs 43% in ACs). Lymph node metastases were identified in 44% (vs 45% in AC). Six patients (67%) died of disease at a median of 25 months, 3 were alive at 13, 15, and 60 months. Overall median survival was significantly worse than that of intestinal-type ACs (26 vs 122 months, P = .006) and trended toward worse than pancreatobiliary type (26 vs 42 months, P = .1). In conclusion, PCCs constitute 2.45% of all ACs. These present as advanced tumors and express upper-gastrointestinal immunoprofile with frequent MUC5AC labeling, which may be helpful in identifying subtle infiltration in the surface mucosa since MUC5AC is not expressed in the ampullary mucosa. Patients have poor prognosis.

Introduction and importance Intraductal papillary neoplasm of the bile duct (IPNB) is known as a precancerous lesion. We herein report a case of IPNB containing adenocarcinoma presenting as multiple pedunculated polyps of the common bile duct with lateral spread of dysplasia at its base. Case presentation A 76-year-old male was admitted to our institution for hematemesis and found to have gastric cancer. Preoperative examinations revealed a tumor in the common bile duct. The patient underwent distal gastrectomy along with bile duct resection. Frozen sections of the resected specimen were checked during the operation and revealed adenocarcinoma. Proximal and distal bile duct margins were also checked and shown to be free of cancer as well as dysplasia. On the resected bile duct, a polypoid lobulated lesion with two heads of 2 cm each growing from a single stalk was located in the common bile duct near the cystic duct confluence, with another 2 cm polypoid lesion on a stalk nearby. The two lesions appeared to be positioned in the common bile duct and cystic duct in a discontinuous manner, but a continuous area of high-grade dysplasia was found to spread at the base of both lesions. Based on the histopathological findings, the tumor was diagnosed as pancreatobiliary type IPNB with carcinoma. Clinical discussion IPNB presents a favorable prognosis after surgical resection but is also known to recur in the residual bile ducts. Surgical resection of the recognizable area of pathology would be the effective treatment option for IPNB with lateral superficial spread and multiple lesions. Conclusion We surgically removed an IPNB presenting as multiple pedunculated polyps with lateral spread of dysplasia at its base. Careful postoperative follow up is imperative in IPNB, since recurrence may occur in the remnant bile ducts.

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

Summary Adenocarcinomas of the ampulla of Vater account for 0.5% of malignant neoplasms of the gastrointestinal tract and 6% to 20% of malignant periampullary neoplasms, with most patients being candidates for elective surgery. Our objective was to evaluate the clinicopathological prognostic factors of ampullary adenocarcinomas after surgical resection in a Mexican population. From the records of the Department of Pathology at the Instituto Nacional de Cancerologia, Mexico, cases diagnosed as adenocarcinomas of the ampulla of Vater were selected over a period of 11 years, from January 2005 to September 2015. Cases with a pancreaticoduodenectomy report were included, and from each case, demographic and pathological data of the surgical specimen were obtained. Univariate and multivariate statistical analyses were performed using the log-rank test and Cox regression. Of 157 cases diagnosed as ampullary adenocarcinomas, 104 patients were excluded as not eligible for surgical treatment at the time of diagnosis. In the remaining 53 patients, a pancreaticoduodenectomy was performed. The mean age of the entire group was 55.4 years, and most were men. Intestinal-type adenocarcinomas were more frequent (77.4%) than pancreatobiliary-type (15.1%), with most being without perineural invasion, well to moderately differentiated, and less than 3 cm in size. Lymph node metastasis and age greater than 65 years had a negative impact on overall survival of the patients. The most convenient classification of malignant epithelial tumors of the Vaterian system is according to the histopathologic phenotype grouped into intestinal-, pancreatobiliary-, and mixed-type adenocarcinomas, as well as uncommon variants.

Background Periampullary adenocarcinomas are a heterogenous group of tumours. Tumour morphology, i.e. intestinal type (I-type) and pancreatobiliary type (PB-type), is a more relevant prognostic factor than anatomical origin. Despite the promising effects of cancer immunotherapy, phase I and II clinical trials have this far been disappointing in pancreas cancer. The aim of this study was to map the spatial distribution of lymphocyte subsets in the tumour microenvironment of periampullary adenocarcinoma, in relation to overall survival (OS) and morphology. Methods Multiplexed immunohistochemistry was performed on tissue microarrays with tumours from a well characterized consecutive cohort of 175 patients with resected periampullary adenocarcinoma. A panel of immune cell markers including CD4, CD8a, FoxP3, CD20, CD45RO and pan-cytokeratin was applied. Results There was no difference in infiltration levels of different lymphocyte populations when taking into account both stromal and tumour compartments, however, in the latter, there were significantly higher levels of activated CD4+ cells (p = 0.027) in PB-type tumors while activated CD8+ cells (p Conclusions These data demonstrate that the composition and clinical impact of immune infiltrates in periampullary adenocarcinoma differ by morphological type as well as localisation. Hence, all these factors should be considered in studies on their prognostic and predictive ability. Legal entity responsible for the study Lund University. Funding Mrs Berta Kamprad Foundation, Skane University Hospital Research Foundation, Lund University Medical Faculty Research grants. Disclosure All authors have declared no conflicts of interest.

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. Electronic supplementary material The online version of this article (doi:10.1186/s12967-017-1256-y) contains supplementary material, which is available to authorized users.

Periampullary adenocarcinomas include four anatomical sites of origin (the pancreatic duct, bile duct, ampulla and duodenum) and most of them fall into two histological subgroups (pancreatobiliary and intestinal). Determining the exact origin of the tumor is sometimes difficult, due to overlapping histopathological characteristics. The prognosis depends on the histological subtype, as well as on the anatomical site of origin, the former being the more important. The molecular basis for these differences in prognosis is poorly understood. Whole‐genome analyses were used to investigate the association between molecular tumor profiles, pathogenesis and prognosis. A total of 85 periampullary adenocarcinomas were characterized by mRNA and miRNA expressions profiling. Molecular profiles of the tumors from the different anatomical sites of origin as well as of the different histological subtypes were compared. Differentially expressed mRNAs and miRNAs between the two histopathological subtypes were linked to specific molecular pathways. Six miRNA families were downregulated and four were upregulated in the pancreatobiliary type as compared to the intestinal type (P

Our objective was to explore alteration of the epidermal growth factor receptor signaling pathway in ampullary carcinoma. Immunohistochemical studies were employed to evaluate expression of amphiregulin as well as expression and activation of epidermal growth factor receptor. A lab developed assay was used to identify mutations in the epidermal growth factor receptor pathway genes, including KRAS, BRAF, PIK3CA, PTEN and AKT1. Fifty two ampullary carcinomas were identified, including 25 intestinal-type and 24 pancreatobiliary-type tumors with the intestinal type being associated with a younger age at diagnosis (p=0.03) and a better prognosis (p

Objective: Ampullary adenocarcinoma is a rare disease entity and little information regarding these tumors is available. The aim of the present study was to clarify the treatment outcome of systemic chemotherapy in patients with advanced ampullary adenocarcinoma. Methods: This study consisted of a retrospective review of data obtained from patients diagnosed as having advanced ampullary adenocarcinoma who received non-surgical treatment at a single institution between 1997 and 2010. Results: We identified 26 patients (15 men, 11 women; median age, 62.0 years) who received treatment for advanced ampullary adenocarcinoma. Twelve patients had Stage IV disease and 14 had recurrences. The chemotherapy regimens consisted of 5-fluorouracil-based regimens (5-fluorouracil þ cisplatin, n ¼ 3; tegafur-uracil þ doxorubicin, n ¼ 5 and tegafur, gimeracil and oteracil potassium, n ¼ 3) and gemcitabine-based regimens (gemcitabine, n ¼ 10 and gemcitabine þ cisplatin, n ¼ 5). The overall response rate was 7.7%. The median progressionfree survival period was 3.2 months (2.5 months in the 5-fluorouracil group vs. 3.5 months in the gemcitabine group), and the median overall survival time was 9.1 months (8.0 months in the 5-fluorouracil group vs. 12.3 months in the gemcitabine group). The median overall survival was significantly longer in stage IV disease than in recurrent disease. The histological phenotype was determined in 10 of the 26 patients. Eight patients had intestinal-type adenocarcinomas and remaining two patients had pancreatobiliary-type adenocarcinomas. Conclusions: The treatment outcome of patients with advanced ampullary adenocarcinoma was poor. Further development of novel treatments is necessary to improve the prognosis.

Aims Ampullary cancer is a relatively uncommon tumour, with a better prognosis than pancreatic cancer. The purpose of this study was to review the recent literature on ampullary adenocarcinoma, focusing on histological types and prognostic factors. Methods and results Using PubMed, we carried out a comprehensive search of the literature, which was extended to April 2013 to retrieve all additional publications. Ampullary cancer comprises two main histological subtypes, the pancreatobiliary type and the intestinal type. These subtypes have different pathogenetic and clinical characteristics. Clinical and histological parameters as well as immunohistochemical markers have been identified as significant prognostic factors in ampullary cancer. Moreover, several immunohistochemical markers have been studied, not only as prognostic factors but as a means of differentiating ampullary from other peri-ampullary tumours, and of identifying the exact histological subtype. Conclusions The considerable differences in the frequencies of the two subtypes of ampullary tumours reported in literature reinforce the necessity to define molecular markers to distinguish them. Until then, the significance of the histological subtype as a prognostic factor should be evaluated cautiously. Future research on the pathogenesis of ampullary cancer will possibly suggest that we should stop treating this type of cancer as a separate entity.

Periampullary carcinoma (PC) is classified into intestinal and pancreatobiliary subtypes using morphology and immunohistochemistry (IHC). Different combinations of markers have been used in the literature. One hundred eight PCs were classified using morphology and IHC (CDX2, mucin [MUC] 2, cytokeratin [CK] 20, CK7, CK17, and MUC1). The expression of these markers was compared with different histologic subtypes, histopathologic prognostic parameters, and patients' survival. There were 38 intestinal and 53 pancreatobiliary subtypes classified on morphology alone. CDX2 showed high sensitivity (89.5%) and specificity (100%) for intestinal type. CK20 and MUC2 showed low sensitivity (50% and 39.5%) but high specificity (86.8% and 96.2%) for intestinal type. CK7 and CK17 showed a sensitivity of 90.5% and 32% and a specificity of 21% and 89.4%, respectively, for pancreatobiliary subtype. MUC1 was 100% sensitive but 0% specific in pancreatobiliary subtype. The overall median survival in morphologic and IHC intestinal type was 45 months versus 20 months in pancreatobiliary type (P = 0.01). Intestinal and pancreatobiliary types of PC were differentiated in 84.2% of cases by morphology alone and in 87.9% cases with IHC. CDX2-positive tumors had a median survival of 44 months versus 22 months in CDX2-negative tumors (P = .03). IHC helped in reclassifying an additional 4 cases of mixed and other types. Among the panel used, CDX2 showed a high sensitivity and specificity for intestinal subtype and was an independent prognostic marker for longer survival. Thus, CDX2 may be used routinely with morphology in subtyping of PC, and a panel of markers may be used in morphologically difficult cases.

We classified resected intraductal papillary mucinous neoplasms (IPMNs) into four subtypes (gastric, intestinal, pancreatobiliary and oncocytic) according to their morphological features and mucin expression, determined their clinicopathological characteristics and investigated the possibility of preoperatively diagnosing these subtypes. Sixty resected tumors, 4 preoperative tumor biopsies and 10 preoperative pancreatic juice cytology specimens were analyzed. The gastric and intestinal types accounted for the majority of IPMNs. Non-gastric type IPMNs were of high-grade malignancy. Many of the pancreatobiliary-type IPMNs were in an advanced stage and were associated with a poor prognosis. The results of mucin immunohistochemical staining of preoperative biopsy and surgically resected specimens were in agreement with each other, and in close agreement with those for pancreatic juice cytology specimens obtained from 10 patients during endoscopic retrograde cholangiopancreatography (ERCP). The immunostaining of preoperative biopsy specimens and ERCP-obtained pancreatic juice cytology specimens may be useful in the differential diagnosis of gastric and intestinal types of IPMN. If such techniques enable the preoperative diagnosis of IPMN subtypes, their use in combination with conventional preoperative imaging modalities may lead to surgical treatment best suited for the biological characteristics of the four subtypes.

Adenocarcinomas of the pancreatobiliary system are currently classified by their primary anatomical location. In particular, the pathological diagnosis of intrahepatic cholangiocarcinoma is still considered as a diagnosis of exclusion of metastatic adenocarcinoma. Periampullary cancers have been previously classified according to the histological type of differentiation (pancreatobiliary, intestinal), but overlapping morphological features hinder their differential diagnosis. We performed an integrative immunohistochemical analysis of pancreato-biliary tumors to improve their diagnosis and prediction of outcome.This was a retrospective observational cohort study on patients with adenocarcinoma of the pancreatobiliary system who underwent diagnostic core needle biopsy or surgical resection at a tertiary referral center. 409 tumor samples were analyzed with up to 27 conventional antibodies used in diagnostic pathology. Immunohistochemical scoring system was the percentage of stained tumor cells. Bioinformatic analysis, internal validation, and survival analysis were performed.Hierarchical clustering and differential expression analysis identified three immunohistochemical tumor types (extrahepatic pancreatobiliary, intestinal, and intrahepatic cholangiocarcinoma) and the discriminant markers between them. Among patients who underwent surgical resection of their primary tumor with curative intent, the intestinal type showed an adjusted hazard ratio of 0.19 for overall survival (95% confidence interval 0.05-0.72; p value = 0.014) compared to the extrahepatic pancreatobiliary type.Integrative immunohistochemical classification of adenocarcinomas of the pancreatobiliary system results in a characteristic immunohistochemical profile for intrahepatic cholangiocarcinoma and intestinal type adenocarcinoma, which helps in distinguishing them from metastatic and pancreatobiliary type adenocarcinoma, respectively. A diagnostic immunohistochemical panel and additional extended panels of discriminant markers are proposed as guidance for their pathological diagnosis.

Background. Malignant neoplasms arising in Meckel’s diverticulum, a vitelline duct remnant, are rare yet well-documented.Case Presentation. A 53-year-old previously healthy female presented with an enlarging midline abdominal wall mass. A computed tomography scan revealed a mass involving the linea alba, bilateral rectus abdominis, and subcutaneous fat. Extensive clinical workup failed to demonstrate other lesions, except local and paratracheal/hilar lymphadenopathy. Histopathologic examination of the resected tumor demonstrated a spectrum of serous neoplasia including serous cystadenoma, papillary serous carcinoma with numerous Psammoma bodies, and a poorly differentiated component. Immunophenotypically, the tumor cells were strongly positive for CK7, CK19, CA19.9, and MUC1 but negative for other lineage markers, findings suggestive of pancreatobiliary type differentiation. The patient died of the disease one year after the initial presentation despite chemotherapy, radiation, and surgery.Conclusion. We present a case of adenocarcinoma arising from the anterior midline abdominal wall, from presumed vitelline duct remnant, with histologic and immunophenotypic features of serous cystadenocarcinoma of pancreatobiliary origin. Though the origin from vitelline duct remnant is difficult to prove in this single case, understanding tumorigenesis of embryonic remnant origin is potentially important to improve the management of cancer of unknown primary.

Background: Natural killer (NK) cells and NK T cells (NKT) are vital parts of tumour immunosurveillance. However, their impact on prognosis and chemotherapy response in periampullary adenocarcinoma, including pancreatic cancer, has not yet been described. Methods: Immune cell-specific expression of CD56, CD3, CD68 and CD1a was analysed by immunohistochemistry on tissue microarrays with tumours from 175 consecutive cases of periampullary adenocarcinoma, 110 of pancreatobiliary type (PB-type) and 65 of intestinal type (Itype) morphology. Kaplan-Meier and Cox regression analysis were applied to determine the impact of CD56+ NK/NKT cells on 5-year overall survival (OS). Results: High density of CD56+ NK/NKT cells correlated with low N-stage and lack of perineural, lymphatic vessel and peripancreatic fat invasion. High density of CD56+ NK/NKT cells was associated with prolonged OS in Kaplan-Meier analysis (p = 0.003), and in adjusted Cox regression analysis (HR = 0.49; 95% CI 0.29-0.86). The prognostic effect of high CD56+ NK/NKT cell infiltration was only evident in cases not receiving adjuvant chemotherapy in PB-type tumours (p for interaction = 0.014). Conclusion: This study demonstrates that abundant infiltration of CD56+ NK/NKT cells is associated with a prolonged survival in periampullary adenocarcinoma. However, the negative interaction with adjuvant treatment is noteworthy. NK cell enhancing strategies may prove to be successful in the management of these cancers. (Less)

Literature on non-ampullary–duodenal carcinomas is limited. We analyzed 47 resected non-ampullary–duodenal carcinomas. Histologically, 78% were tubular-type adenocarcinomas mostly gastro-pancreatobiliary type and only 19% pure intestinal. Immunohistochemistry (n=38) revealed commonness of ‘gastro-pancreatobiliary markers’ (CK7 55, MUC1 50, MUC5AC 50, and MUC6 34%), whereas ‘intestinal markers’ were relatively less common (MUC2 36, CK20 42, and CDX2 44%). Squamous and mucinous differentiation were rare (in five each); previously, unrecognized adenocarcinoma patterns were noted (three microcystic/vacuolated, two cribriform, one of comedo-like, oncocytic papillary, and goblet-cell-carcinoid-like). An adenoma component common in ampullary–duodenal cancers was noted in only about a third. Most had plaque-like or ulcerating growth. Mismatch repair protein alterations were detected in 13% (all with plaque-like growth and pushing-border infiltration). When compared with ampullary (n=355) and pancreatic ductal (n=227) carcinomas, non-ampullary–duodenal carcinomas had intermediary pathologic features with mean invasive size of 2.9 cm (vs 1.9, and 3.3) and 59% nodal metastasis (vs 45, and 77%). Its survival (3-, 5-year rates of 57 and 57%) was similar to that of ampullary–duodenal carcinomas (59 and 52%; P=0.78), but was significantly better than the ampullary ductal (41 and 29%, P

Context.—There are virtually no data in the literature regarding the incidence, patterns, and clinicopathologic characteristics of mucinous carcinomas (MCs) of the gallbladder (GB).Objective.—To determine the incidence of mucinous differentiation in invasive GB carcinomas and the clinicopathologic characteristics of those that qualify as MC.Design.—Primary invasive GB carcinomas (n = 606) were reviewed for mucinous differentiation. Some degree of mucin production was identified in 40 cases (6.6%); however, only 15 (2.5%) were qualified for the World Health Organization definition of MC (stromal mucin deposition constituting >50% of the tumor).Results.—The mean age was 65 years, and the female to male ratio was 1.1 (versus 3.9 for conventional pancreatobiliary-type GB adenocarcinomas; P = .04). A significant proportion of the cases (8 of 12, 67%) presented with the clinical picture and intraoperative findings that were interpreted as acute cholecystitis. Mean and median tumor sizes were larger than those of conventional adenocarcinomas (4.8 and 3.4 cm versus 2.9 and 2.5 cm, respectively; P = .01). Most (13 of 15, 87%) cases presented with pT3 tumors (versus 48% for ordinary GB carcinomas; P = .01). Two cases had almost an exclusive colloid pattern (>90% composed of well-defined stromal mucin nodules that contained scanty carcinoma cells, most of which were floating within the mucin). Eight cases were of mixed-mucinous type, showing a mixture of colloid and noncolloid patterns. Five others had prominent signet-ring cells, both floating within the mucin (which constituted >50% of the tumor by definition) and infiltrating into the stroma as individual signet-ring cells in some areas. Immunohistochemical analysis performed on the 7 cases that had available tissue revealed CK7 in 4 of 7 (57%), CK20 in 2 of 7 (29%), MUC1 in 4 of 7 (57%), MUC2 in 6 of 7 (86%), CDX2 in 1 of 7 (14%), MUC5AC in 6 of 7 (86%), MUC6 in 0 of 7 (0%), and loss of E-cadherin in 6 of 7 (86%). The MLH1 and MSH2 were retained in 6 of 7 cases (100%). Follow-up information was available for 13 cases: 11 (85%) died of disease (1–37 months) and 2 (15%) were alive (23 months and 1 month). Overall survival of MCs was significantly worse than that of conventional adenocarcinomas (13 versus 26 months; P = .01); however, that did not seem to be independent of stage.Conclusions.—Mucinous carcinomas constitute 2.5% of GB carcinomas. They present with an acute cholecystitis-type picture. Most MCs are a mixed-mucinous, not pure colloid, type. They are typically large and advanced tumors at the time of diagnosis and thus exhibit more-aggressive behavior than do ordinary GB carcinomas. Immunophenotypically, they differ from conventional GB adenocarcinomas by MUC2 positivity, from intestinal carcinomas by an often inverse CK7/20 profile, from pancreatic mucinous carcinomas by CDX2 negativity, and from mammary colloid carcinomas by a lack of MUC6. Unlike gastrointestinal MCs, they appear to be microsatellite stable.

Westgaard A, Clausen OPF, Gladhaug IP. Survival estimates after pancreatoduodenectomy skewed by non-standardized histopathology reports. APMIS 2011; 119: 689–700. Survival estimates may be biased if quality control on histopathology is insufficient. We evaluated the effects of standardizing histopathology for pancreatoduodenectomy specimens and compared survival estimates based on standardized vs non-standardized histopathological evaluation. Microscopic slides and histopathological reports from 311 consecutive pancreatoduodenectomies (1980–2004) were reviewed, including 104 adenocarcinomas (1980–1997) resected before and 123 adenocarcinomas (1998–2004) resected after standardizing histopathology. Histopathological factors were re-evaluated for all primary adenocarcinomas (n = 227). The most frequent histological types were pancreatobiliary-type (n = 145) and intestinal-type (n = 73). Standardized histopathology was associated with sampling more blocks and nodes (p

Objective The clinicopathological significance of four morphological types of intraductal papillary mucinous neoplasms of the pancreas (IPMNs; gastric, intestinal, pancreatobiliary and oncocytic) was assessed. Design Retrospective multicentre analysis of 283 surgically resected IPMNs. Results Of the 283 IPMNs, 139 were of the gastric type, 101 were intestinal, 19 were pancreatobiliary and 24 were oncocytic. These types were significantly associated with clinicopathological factors including sex (p=0.0032), age (p=0.00924), ectatic duct size (p=0.0245), detection of mural nodules (p=4.09×10 −6 ), histological grade (p −16 ), macroscopic types with differential involvement of the pancreatic duct system (p=3.91×10 −5 ), invasive phenotypes (p=3.34×10 −12 ), stage (p −16 ) and recurrence (p=0.00574). Kaplan–Meier analysis showed significant differences in patient survival by morphological type (p=5.24×10 −6 ). Survival rates at 5 and 10 years, respectively, were 0.937 (95% CI 0.892 to 0.984) for patients with gastric-type IPMNs; 0.886 (95% CI 0.813 to 0.965) and 0.685 (95% CI 0.553 to 0.849) for those with intestinal-type IPMNs; 0.839 (95% CI 0.684 to 1.000) and 0.734 (95% CI 0.526 to 1.000) for those with oncocytic-type IPMNs; and 0.520 (95% CI 0.298 to 0.909) and undetermined for those with pancreatobiliary-type IPMNs. Analysis by the Cox proportional hazards model comparing prognostic risks determined by stage and the morphological and macroscopic types indicated that staging was the most significant predictor of survival (p=3.68×10 −8 ) followed by the morphological type (p=0.0435). Furthermore, the morphological type remained a significant predictor in a subcohort of invasive cases (p=0.0089). Conclusion In this multicentre retrospective analysis, the morphological type of IPMN appears to be an independent predictor of patient prognosis.

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are classified into the following four histopathologic subtypes: gastric, intestinal, pancreatobiliary, and oncocytic. However, the clinicopatholgic characteristics of IPMN subtypes have not been fully clarified. Recently, a subgroup classification of minimally invasive intraductal papillary mucinous carcinomas (MI-IPMCs) was suggested in contrast to overt invasive carcinoma from IPMCs (IC-IPMCs). The purpose of this study was to determine whether or not the pathologic subtype classification can predict prognosis and to validate the usefulness of the newly proposed diagnostic criteria of MI-IPMCs. We reviewed the clinicopathologic characteristics of 142 surgically resected cases of IPMNs. There were 54, 56, 30, and two cases of the gastric, intestinal, pancreatobiliary, and oncocytic types of IPMNs, respectively. The intestinal and pancreatobiliary types were more likely to have a main duct type. All gastric type tumors were adenomas or moderate dysplasia, whereas greater than one half of the intestinal and pancreatobiliary types were carcinomas in situ or invasive carcinomas. A significant difference in recurrence and death rate was noted for invasive carcinoma between the intestinal and pancreatobiliary types. The majority of MI-IPMCs were the intestinal type, whereas the majority of IC-IPMCs were the pancreatobiliary type. The IC-IPMC group showed a decreased recurrence-free and overall survival with statistically significance (p < 0.001 and p = 0.001, respectively). Our results suggest that the pathologic subtype classification and the newly proposed diagnostic criteria for minimal invasion may also be useful to predict prognosis of IPMNs of the pancreas.