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症例は74歳男性．膵頭部腫瘤による閉塞性黄疸で近医に入院し，内視鏡的胆管ドレナージが行われ，当科に紹介となった．造影CT，MRCP，超音波内視鏡検査（EUS）では膵頭部に50mm大の辺縁が造影効果を有し中心部が造影されない腫瘤を認め，嚢胞変性を来した膵内分泌腫瘍の疑いで亜全胃温存膵頭十二指腸切除術を施行した．病理組織診断ではintraductal papillary mucinous neoplasm with an associated carcinoma, pancreatobiliary typeであった．Pancreatobiliary-type intraductal papillary mucinous neoplasmの画像所見に関する報告は少なく，文献的考察を加えて報告する．

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.

Additional file 1: Figure S1 Flowchart of collecting the WSI datasets. Figure S2 Flowchart of collecting the genome sequencing datasets. Figure S3 Performance of the classification model in classifying cholangiocarcinoma and PAC. Table S1 Clinicopathological characteristics of the TCGA dataset. Table S2 Clinicopathological characteristics of the SYSUCC dataset. Table S3 Clinicopathological characteristics of the Zhejiang dataset. Table S4 Identifiers of the cholangiocarcinoma cases used in the TCGA dataset. Table S5 Identifiers of the PAC cases used in the TCGA dataset. Table S6 Clinicopathological characteristics of the SYSUCC AAC dataset for survival analysis.

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.

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 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.

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.

Summary 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.

We experienced a rare case of main duct intraductal papillary mucinous neoplasm (MD-IPMN) without overt mucin production. Histological findings classified the tumor as high-grade dysplasia of pancreatobiliary-type IPMN that has been reported to show high malignant potential with a property to disseminate extensively into pancreatic ducts.

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.

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 mm2/s) was significantly lower than the intestinal-type group ([1.10 ± 0.25] × 10−3 mm2/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. J. Magn. Reson. Imaging 2015.

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.

Introduction: The purpose of this study was to associate immunohistochemical expression of -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.

国際共同研究でintraductal papillary-mucinous neoplasm（以下，IPMNと略記）の組織亜型が示され，胃型と腸型の臨床病理組織学的特徴が判明しつつある．比較的まれなpancreatobiliary type（以下，膵胆型と略記）IPMNの病態の解明を行った．当院で治癒手術を施行したIPMN95例のうち，形態とムチン発現様式に基づき膵胆型と診断された7例について臨床病理組織学的事項を検討した．診断は腺腫1例，IPMN由来浸潤癌6例であった．予後は3例が再発死し，その内2例に肝転移を，1例は肺骨転移を来し，術後生存期間は平均26.4か月であった．その他4例は無再発生存中である．自験例では外科切除時に浸潤癌である率が高く予後不良であった．今後組織亜型の術前診断が治療方針決定に貢献するためにも，症例の蓄積が重要と考えられた.

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.

To differentiate pancreatobiliary-type from intestinal-type periampullary carcinomas using combined magnetic resonance cholangiopancreatography (MRCP), contrast-enhanced MRI, and diffusion-weighted imaging (DWI).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.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.Progressive enhancement and low ADCmin values suggest a pancreatobiliary-type periampullary carcinoma.