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BackgroundCancer-associated fibroblasts (CAFs) reportedly enhance the progression of gastrointestinal surgery; however, the role of CAFs in ampullary carcinomas remains poorly examined. This study aimed to investigate the effect of CAFs on the survival of patients with ampullary carcinoma.Materials and methodsA retrospective analysis of 67 patients who underwent pancreatoduodenectomy between January 2000 and December 2021 was performed. CAFs were defined as spindle-shaped cells that expressed α-smooth muscle actin (α-SMA) and fibroblast activation protein (FAP). The impact of CAFs on survival, including recurrence-free (RFS) and disease-specific survival (DSS), as well as prognostic factors associated with survival, was analyzed.ResultsThe high-α-SMA group had significantly worse 5-year RFS (47.6% vs. 82.2%, p = 0.003) and 5-year DSS (67.5% vs. 93.3%, p = 0.01) than the low-α-SMA group. RFS (p = 0.04) and DSS (p = 0.02) in the high-FAP group were significantly worse than those in the low-FAP group. Multivariable analyses found that high α-SMA expression was an independent predictor of RFS [hazard ratio (HR): 3.68; 95% confidence intervals (CI): 1.21–12.4; p = 0.02] and DSS (HR: 8.54; 95% CI: 1.21–170; p = 0.03).ConclusionsCAFs, particularly α-SMA, can be useful predictors of survival in patients undergoing radical resection for ampullary carcinomas.

BACKGROUND: The Naples prognostic score (NPS) is an effective and objective tool to assess the immune–nutritional status of patients with malignant tumors. The aim of this study was to investigate the clinical significance of preoperative NPS on short- and long-term outcomes after pancreatoduodenectomy (PD) for ampullary carcinoma. METHODS: We retrospectively analyzed 404 consecutive patients with ampullary carcinoma who underwent PD between January 2012 and June 2018. Preoperative NPS was calculated from serum albumin and total cholesterol concentrations, and the neutrophil–lymphocyte ratio and lymphocyte-monocyte ratio (LMR). Patients were then divided into three groups according to their NPS. Clinicopathological variables, postoperative outcomes, and survival data were compared between the three groups. Univariate and multivariate Cox analysis of overall survival (OS) and recurrence-free survival (RFS) were also conducted, and time-dependent receiver operating characteristic (ROC) curves were created to evaluate the discriminatory ability of the prognostic scoring systems. RESULTS: Patients with higher NPS had worse prognosis, and significant OS difference (group 0 vs. 1, P=0.02; group 1 vs. 2, P

Objective It is recognised that advanced maternal age is associated with adverse pregnancy outcomes. It is less known what the psychological impact of having a pregnancy in later maternal age is. This study aimed to establish whether women having children over 50 experience challenges with regards to their mental well-being during the pregnancy and thereafter. Study design 17 women delivered aged ≥ 50 at our maternity unit in a central London hospital between 2014 and 2020. Of these, one had died of metastatic ampullary carcinoma two years following delivery, one declined taking part, and two we were unable to get hold of, leaving 13 women in the study. Two validated questionnaires were used to survey the women: (i) Warwick-Edinburgh Mental Well-being Scale (WEMWBS), (ii) Parenting Daily Hassles Scale (PDHS). We analysed the questionnaire data using their individual scoring systems. Results The WEMWBS showed a median score of 60 out of a possible 70 (range: 45–70), indicating a high level of mental well-being among these women. The PDHS results indicated that reported hassles were overall low in both frequency and intensity for the mothers. Conclusion Women giving birth over 50 have often experienced long, emotional and financially-burdensome journeys in order to fall pregnant, usually involving assisted reproductive techniques (ART), with multiple antenatal and delivery complications thereafter. As a result, they are extremely happy and grateful to have the child, and are often in better socioeconomic positions that can help with the stress that comes with child-caring.

Ampullary carcinomas (ACs) represent a rare entity, accounting for approximately 0.2% of all gastrointestinal solid tumors and 20% of all periampullary cancers (PACs). Unfortunately, few data are available regarding the optimal therapeutic strategy for ACs due to their rarity, and physicians frequently encounter significant difficulties in the management of these malignancies. In this review, we will provide an overview of current evidence on AC, especially focusing on biological features, histological characteristics, and available data guiding present and future therapeutic strategies for these rare, and still barely known, tumors.

Background: Ampullary carcinoma is rare with a more favourable prognosis compared to pancreatic ductal adenocarcinoma. The role of histological classification, including pancreatobiliary (PB) and intestinal (INT), on survival and recurrence outcomes in ampullary cancer is still debatable. Methods: 42 patients were identified between 1996-2010. Results: Nineteen classic pancreatoduodenectomies (PD) and 23 pylorus-preserving PDs were performed. Pathological review revealed 23, 18 and 1 patients with the PB, INT and mixed histology, respectively. Adjuvant chemoradiation (ACRT), chemotherapy, and radiation were given to 14 (33.3%), 4 (9.5%) and 2 (4.8%) patients, respectively. Recurrence-free survival (RFS) and overall survival (OS) from time of surgery were higher in the PB histological variant compared to INT (p=0.005 and 0.012, respectively). A landmark (LM) analysis found higher survival in the PB variant patients compared to INT (RFS p=0.023; OS p=0.048). There was no difference in RFS between both histological variants for patients who underwent surgery alone (p=0.42). However, the PB had higher RFS compared to the INT histology for patients who underwent ACRT (p=0.008). Conclusion: Ampullary carcinoma with PB histological variant was associated with significant survival benefit. The PB versus INT survival benefit was seen in the setting of ACRT, but not with surgery alone.

Ampullary carcinoma (AC) is histologically classified as intestinal (In-AC), pancreaticobiliary (Pb-AC) or mixed-AC. The prognostic role of AC subtypes has been debated and remains unclear. The aims of this study were to evaluate outcomes after pancreatoduodenectomy (PD) for each subtype of AC and to compare these with pancreatic ductal adenocarcinoma [PDAC] and distal cholangiocarcinoma [DCC].PDs performed for AC between 2010 and 2018 were retrospectively evaluated. Histological subtype was obtained for all patients. One-year, 3-year and 5-year disease-free-survival (DFS) and overall survival (OS) rates were calculated. Kaplan-Meier survival analysis was performed to compare Pb-AC, In-AC and mixed-AC. Comparison with PDs performed for PDAC and DCC during the same period was also performed.A total of 97 patients undergoing PD for AC were evaluated: 34 (35.1%) In-AC, 54 (55.7%) Pb-AC and 9 mixed-AC (9.3%). DFS and OS rates for Pb-AC were significantly lower compared to In-AC (p 0.05 and p 0.01), but similar to mixed-AC (p = 0.3 and p = 0.4). Adjuvant therapy was not associated with increased survival, regardless of the histological subtype (p 0.05). During the same period, 337 and 53 PDs for PDAC and DCC, respectively, were performed. In-AC was associated with significantly better outcomes compared to PDAC and DCC (p 0.001); DFS and OS rates for Pb-AC and mixed AC were significantly higher compared to PDAC (p 0.001), but similar to DCC (p 0.05).Pb-AC has significantly worse survival compared to In-AC. Moreover, mixed-AC should be considered as Pb-AC. Pb-AC and mixed-AC seem to have better prognosis compared to PDAC, but similar to DCC.

Background Approximately 30-40% of pancreatoduodenectomies for adenocarcinomas result in nonpancreatic periampullary adenocarcinoma as the final diagnosis. Depending on the origin, a distinction is made between four different carcinomas with histomorphological subtypes. Objective Carcinoma location and subtype are of prognostic and therapeutic relevance; however, the preoperative differentiation is often incorrect despite modern diagnostics. Material and methods Overview of the current literature on the classification and preoperative diagnostics of periampullary adenocarcinomas. Results A precise knowledge of the papillary anatomy is necessary for the correct classification of diagnostic findings. Current studies demonstrate diagnostically valuable information from the anamnesis, imaging and endoscopy. Conclusion In ca. 70-80% of cases a correct diagnosis of the type of periampullary adenocarcinoma is possible on the basis of interdisciplinary diagnostics. This potentially enables a correspondingly individualized treatment planning in the preoperative phase.

Die chirurgische Therapie endoskopisch nicht sanierbarer Adenome und von Karzinomen der Papilla duodeni major (Vateri) und Ampulla hepatopancreatica erfordert eine differenzierte Indikationsstellung sowie eine an das Infiltrationsverhalten dieser Tumoren angepasste Operationstechnik. Basierend auf aktuellen wissenschaftlichen Daten und Entwicklungen sollen die Indikationen zur chirurgischen Resektion, chirurgische Strategien und Dissektionstechniken bei Papillentumoren dargestellt werden. Die aktuelle Literatur zur Thematik wurde gesichtet, gemas vorliegender Evidenz gewertet und darauf basierend zu Empfehlungen zusammengefasst. Adenome und Karzinome der Ampullenregion konnen von intestinalen oder pankreatobiliaren Epithelien ausgehen. Bei Ampullenkarzinomen ist die Unterscheidung dieser histopathologischen Subtypen von entscheidender therapeutischer und prognostischer Relevanz. Aufgrund ihrer Entartungstendenz stellen Adenome der Ampullenregion eine Indikation zur Resektion dar. Zur Verfugung stehende Verfahren sind die endoskopische Papillektomie, die chirurgische transduodenale Ampullektomie und die partielle Pankreatoduodenektomie. Die Auswahl des Verfahrens richtet sich nach intraduktaler Tumorausdehnung, Tumorgrose und Dysplasiegrad. Bei klinischem Verdacht auf das Vorliegen eines Ampullenkarzinoms besteht die Indikation zum primar chirurgischen Vorgehen mittels partieller Pankreatoduodenektomie mit systematischer Lymphadenektomie und Level-II-Dissektion des Mesopankreas. Die hinsichtlich onkologischem Gesamtuberleben wesentlichen Prognosefaktoren sind der Lymphknotenstatus und das Vorhandensein einer tumorosen Perineuralscheideninfiltration.

Background: Many studies have confirmed that diabetes was associated with prognosis in many malignant cancer types. However, the impact of diabetes on ampullary carcinoma (AC) has not been investigated. Methods: A total of 266 AC patients in the National Cancer Center of China between January 1998 and December 2020 were retrospectively reviewed. The postoperative complication rate, postoperative recurrence rate, and long-term survival were compared between the diabetes group and the no diabetes group. Results: A total of 32 AC patients (12.03%) were diagnosed with diabetes before surgery. In total, 111 patients (41.73%) had one or more postoperative complications, and there was no perioperative death. There was no statistically significant difference regarding postoperative complications between the diabetes group and the no diabetes group. Altogether, 120 patients (45.11%) experienced postoperative recurrence. Multivariate analysis revealed that diabetes was an independent risk factor for the recurrence (OR: 2.384, 95% CI: 1.065–5.336, p = 0.035), OS (HR: 1.597, 95% CI: 1.005–2.537, p = 0.047), and RFS (HR: 1.768, 95% CI: 1.068–2.925, p = 0.027) in AC patients after curative pancreatoduodenectomy. Conclusions: Diabetes may adversely affect the recurrence of patients with AC after curative pancreaticoduodenectomy, leading to an increased risk of poor prognosis in early-stage patients. Further studies involving a large sample size are needed to validate our results.

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

The ampulla of Vater gives rise to a versatile group of cancers of mixed/hybrid histologic phenotype. Ampullary carcinomas (ACs) are most frequently intestinal or pancreatobiliary adenocarcinomas but other subtypes, such as medullary, mucinous, or signet ring/poorly cohesive cell carcinoma, may be encountered. Ampullary cancer can also be subclassified based on immunohistochemical features, however these classification systems fail to show robust prognostic reliability. More recently, the molecular landscape of AC has been uncovered, and has been shown to have prognostic and predictive significance. In this article, the site-specific, histologic, and genetic characteristics of ampullary carcinoma and its precursor lesions are discussed.

BACKGROUND The TNM (Tumor, Node, Metastasis) classification of the 8th Union for International Cancer Control and the 6th Japanese classification of biliary tract cancer were made on the premise that the prognostic effect of each regional lymph node station is similar. However, some studies have reported different effects of lymph node metastasis location on post-resection prognosis. This study aimed to investigate outcome following radical resection of ampullary carcinoma according to station of lymph node metastasis. METHODS Patients who underwent surgical resection for ampullary carcinoma between January 2007 and December 2017 at two separate Japanese institutions were included. Regional lymph nodes were subclassified as follows: Pancreatoduodenal lymph nodes (PD) and others (OT). RESULTS Of the 101 patients analyzed, 34 had regional lymph node metastasis. OT metastasis was found in eight patients. Significant differences were found in relapse-free survival (RFS) and overall survival (OS) between the three study groups (no nodal metastasis, only PD metastasis and OT metastasis; P

Endoscopic papillectomy (EP) has been established as a useful endoscopic therapy by the efforts of many pancreatobiliary endoscopists and is presently accepted as a reliable alternative therapy to surgery in patients with ampullary adenoma. Moreover, there have been numerous advancements in EP techniques in recent years. Various approaches and attempts toward expanding the indications of endoscopic resection have been reported. Furthermore, the management and prevention of adverse events (AEs) and endoscopic treatment for remnant or recurrent lesions have also been reported. In the present review, we focus on recent advancements in the EP technique, as well as speculate on the future issues of EP.This review of EP encompasses the indications, preoperative assessments, endoscopic techniques, outcomes, and AEs of EP, post-EP surveillance techniques, and treatments for remnant or recurrence lesions.The ultimate goal of EP is the complete resection of ampullary tumors, regardless of whether they are adenomatous or carcinomatous lesions, without causing any AEs. Therefore, the most important issue is preoperative evaluation, that is, the accurate diagnosis of lesions contraindicated for EP. In addition, further research on the prevention of AEs is also necessary towards establishing EP as a safe endoscopic procedure.

The minimum number of lymph nodes (LNs) that should be resected for accurate nodal staging in patients with ampullary carcinoma (AC) remains controversial. This study aimed to establish a nodal staging score (NSS) to evaluate whether a pathological node-negative AC patient is indeed free of a nodal disease. A total of 2539 AC patients with stages I–III were retrieved from the Surveillance, Epidemiology and End Result database (design cohort [DC], n = 2382) and First Affiliated Hospital of Sun Yat-sen University (validation cohort [VC], n = 157). NSS was developed to represent the probability that a node-negative patient was correctly staged as a function of the number of examined LNs (ELNs) and pathologic T stage with a beta-binomial model. Its prognostic value in node-negative patients was assessed by survival analysis. The probability of missing a metastatic LN decreased as the number of the ELNs increased. NSS was escalated as the number of ELNs increased. For patients with early-stage (T1–T2) and late-stage (T3–T4) tumors, examining 7 and 33 lymph nodes could ensure an NSS of 80.0%, respectively. Multivariate analysis showed that higher NSS was an independent favorable prognostic factor for overall survival in node-negative patients with AC (DC, p

Objectives: Our aim is to investigate the prognostic value and effect on chemotherapy toxicity of pre-treatment sarcopenia determined with positron emission tomography/computerized tomography(PET/CT) in patients with ampullary carcinoma. Methods: Characteristics of patients retrieved retrospectively. Skeletal muscle area(SMA) measurement of the muscle at L3 vertebra level was evaluated for each patient from their PET/CT scan taken at the time of diagnosis. The sex-specific cut-off levels for determining sarcopenia were

Tumors involving the ampulla could be arising primarily in the ampulla or extending from the adjacent. When a neoplasm is centered primarily in the ampulla with or without periampullary mucosal involvement, it is considered a primary ampullary carcinoma. These tumors generally have a better prognosis than duodenal and pancreaticobiliary neoplasms secondarily involving the ampulla. Distinguishing between the two primary types has prognostic implications, as the pancreaticobiliary-type ampullary carcinomas are said to have a poorer prognosis than the intestinal-type. Morphological analysis alone may not suffice in this context. The role of immunohistochemistry has therefore been explored by various groups of workers. The purpose of the present study was to determine the role of morphology and cytokeratin profile in accurate typing of ampullary carcinomas as intestinal and pancreaticobiliary.

BACKGROUND The accuracy of the current staging system for predicting the overall survival (OS) of patients with ampullary carcinoma (AC) is still unsatisfactory, especially in node-negative (N0) patients. We aimed at establishing a nomogram to accurately predict OS in N0 AC. METHODS This study enrolled 697 N0 AC patients from the Surveillance, Epidemiology, and End Results database (design cohort [DC], n = 697) and the First Affiliated Hospital of Sun Yat-sen University (validation cohort [VC], n = 112), who underwent surgical resection. The nomogram was established by using prognostic factors determined by univariate and multivariate regression analyses. RESULTS The nomogram for OS was developed by using four independent prognostic factors, including age, grade, T stage, and a number of examined lymph nodes. The C-index of a nomogram for OS in DC and VC was 0.665 and 0.731, respectively. Calibration curves showed good consistency of the nomogram. The nomogram had a better accuracy in predicting OS compared with conventional staging system (P

Background/aim The platelet-to-lymphocyte ratio (PLR) has recently been suggested as a new predictor of the prognosis in several carcinoma types. However, the clinical impact remains controversial in patients with ampullary carcinoma. Thus, the aim of this study was to investigate other useful biomarkers for identifying poor prognosis in patients with ampullary carcinoma. Patients and methods Forty-one patients with ampullary carcinoma underwent pancreaticoduodenectomy (PD) with curative resection between April 2000 and April 2017. Various clinicopathological findings of the patients and their tumors were evaluated as potential prognostic factors which might enable better stratification of prognosis. Results Platelet-to-lymphocyte ratio, as well as other markers, was found to be a prognostic factor in patients with ampullary carcinoma. The 2-year disease-free survival percentage was significantly higher in the group with low PLR than in the high PLR group (70.2% vs. 28.6%; p=0.005). Combinational analysis of the PLR and conventional TMs enabled us to stratify prognosis of the patients more clearly than by each marker alone. Conclusion PLR was a useful prognostic factor for patients with ampullary cancer. The combination of preoperative PLR and conventional TMs markers may be powerful predictive factors for postoperative prognosis in patients with ampullary carcinoma following PD.

BACKGROUND Few studies have compared the oncological benefit of laparoscopic (LPD) and open pancreatoduodenectomy (OPD) for ampullary carcinoma. The aim of this study was to compare the oncological results of these two approaches. METHODS Between 2011 and 2020, 103 patients who underwent PD for ampullary carcinoma, including 31 LPD and 72 OPD, were retrospectively analyzed. Patients were matched on a 1:2 basis for age, sex, body mass index, American Society of Anaesthesiologists score, and preoperative biliary drainage. Short- and long-term outcomes of LPD and OPD were compared. RESULTS The 31 LPD were matched (1:2) to 62 OPD. LPD was associated with a shorter operative time (298 vs. 341 min, p = 0.02) than OPD and similar blood loss (361 vs. 341 mL, p = 0.747), but with more intra- and post-operative transfusions (29 vs. 8%, p = 0.008). There was no significant difference in postoperative mortality (6 vs. 2%), grades B/C postoperative pancreatic fistula (22 vs. 21%), delayed gastric emptying (23 vs. 35%), bleeding (22 vs. 11%), Clavien ≥ III morbidity (22 vs. 19%), or the length of hospital stay (26 vs. 21 days) between LPD and OPD, respectively, but there were more reinterventions (22 vs. 5%, p = 0.009). Pathological characteristics were similar for tumor size (21 vs. 22 mm), well differentiated tumors (41 vs. 38%), the number of harvested (23 vs. 26) or invaded lymph nodes (48 vs. 52%), R0 resection (84 vs. 90%), and other subtypes (T1/2, T3/4, phenotype). With a comparable mean follow-up (41 vs. 37 months, p = 0.59), there was no difference in 1-, 3-, and 5-year overall (p = 0.725) or recurrence-free survival (p = 0.155) which were (93, 74, 67% vs. 97, 79, 76%) and (85, 58, 58% vs. 90, 73, 73%), respectively. CONCLUSION This study showed a similar long-term oncological results between LPD and OPD for ampullary carcinoma. However, the higher morbidity observed with LPD compared to OPD, restricting its use to experienced centers.

Tumor size is still considered a useful prognostic factor in currently available tumor-node-metastasis (TNM) classification staging systems for most solid tumors, but the significance of tumor size on the prognosis of ampullary carcinoma remains controversial. The aim of the current study was to propose a new T-stage classification system for ampullary carcinoma to address the impact of tumor size on the prognostic outcome.Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 1080 patients with ampullary carcinoma who underwent radical surgical resection between 2004 and 2015. Based on the results obtained from analysis of various clinicopathologic factors, a new T-stage classification system was proposed.Among the 1080 patients, 618 were men and 462 were women, with a median tumor size of 2.3 (range 0.1-12) cm. Using the 7th edition of the American Joint Committee on Cancer (AJCC) staging manual, we noticed significant differences in overall survival (OS) between T2 vs. T3 tumors (P0.001) and T3 vs. T4 tumors (P = 0.002), but failed to observe significant differences between T1 vs. T2 tumors (P = 0.498) in our pair-wise comparison. Using the newly developed T-stage classification system, we were able to differentiate significant differences in OS between T1 vs. T2 tumors (P = 0.032), T2 vs. T3 tumors (P0.001) and T3 vs. T4 tumor (P = 0.003) in all pair-wise comparisons. The c-index of the new staging system was 0.653 (95% CI: 0.629-0.677), showing a better discriminatory power than the 0.636 of the 7th AJCC staging system (95% CI: 0.612-0.660).The new T-stage classification system described herein can better differentiate prognostic outcomes after radical resection in patients with ampullary carcinoma by incorporating tumor size and depth of tumor infiltration.

The aim was to study the morphology of the pancreas in embryogenesis and to analyze the immunophenotype of ductal adenocarcinoma (DA) and ampullary carcinoma (AC), taking into account the data obtained. Material and methods . The analysis of operative material of 30 patients with AC and 100 patients with DA was performed. To study the embryogenesis of the pancreas, 14 abortive human embryos were studied. The work used general histological and immunohistochemical methods of investigation. Results. Analyzing the morphology of the pancreas of human embryos at different times of gestational development, we came to the conclusion, that the pancreatobiliary epithelium type is more specialized. Pancreatobiliary tumor immunophenotype was detected in 61% of cases of DA. In 28% of cases (28/100) gastric immunophenotype of DA was detected, which is characterized by expression of mucin 5AC type. Only 11% intestinal immunophenotype of a tumor with isolated expression of mucin type 2 (cytoplasmic reaction) was revealed. In the study of AC, the material was distributed as follows: group with an intestinal phenotype was 60%; with pancreato-biliary type - 33.3%. Conclusion. We believe that for DA with intestinal immunophenotype, it is unacceptable to apply the same treatment regimen as for AC, since this cancer does not have a full intestinal differentiation, but acquires only a similar immunohistochemical profile. In contrast, for AC with pancreatobiliary immunophenotype, the use of standard regimens based on gemcitabine is justified, because these tumors evolve from the hybrid epithelium and retain all the properties of the pancreatobiliary epithelium.

// Tommaso Mazza 1 , Massimiliano Copetti 2 , Daniele Capocefalo 1, 8 , Caterina Fusilli 1 , Tommaso Biagini 1 , Massimo Carella 3 , Antonio De Bonis 4 , Nicola Mastrodonato 4 , Ada Piepoli 5 , Valerio Pazienza 5 , Evaristo Maiello 6 , Fabio Francesco di Mola 7 , Pierluigi di Sebastiano 7 , Angelo Andriulli 5 and Francesca Tavano 5 1 Unit of Bioinformatics, Research Hospital, San Giovanni Rotondo 71013, Italy 2 Unit of Biostatistics, Research Hospital, San Giovanni Rotondo 71013, Italy 3 Medical Genetics Unit, Research Hospital, San Giovanni Rotondo 71013, Italy 4 Department of Surgery, Research Hospital, San Giovanni Rotondo 71013, Italy 5 Division of Gastroenterology and Research Laboratory, San Giovanni Rotondo 71013, Italy 6 Department of Oncology IRCCS “Casa Sollievo della Sofferenza”, Research Hospital, San Giovanni Rotondo 71013, Italy 7 Division of Surgical Oncology “SS Annunziata” Hospital, Chieti 66100, Italy 8 Department of Cellular Biotechnologies and Haematology, Sapienza University of Rome, Rome 00161, Italy Correspondence to: Francesca Tavano, email: f.tavano@operapadrepio.it Keywords: microRNA; pancrearic ductal adenocarcinoma; ampullary carcinoma Received: December 06, 2016 Accepted: July 11, 2017 Published: October 31, 2017 ABSTRACT MiRNA expression abnormalities in adenocarcinoma arising from pancreatic ductal system (PDAC) and Vater’s papilla (PVAC) could be associated with distinctive pathologic features and clinical cancer behaviours. Our previous miRNA expression profiling data on PDAC (n=9) and PVAC (n=4) were revaluated to define differences/similarities in miRNA expression patterns. Afterwards, in order to uncover target genes and core signalling pathways regulated by specific miRNAs in these two tumour entities, miRNA interaction networks were wired for each tumour entity, and experimentally validated target genes underwent pathways enrichment analysis. One hundred and one miRNAs were altered, mainly over-expressed, in PDAC samples. Twenty-six miRNAs were deregulated in PVAC samples, where more miRNAs were down-expressed in tumours compared to normal tissues. Four miRNAs were significantly altered in both subgroups of patients, while 27 miRNAs were differentially expressed between PDAC and PVAC. Although miRNA interaction networks were more complex and dense in PDAC than in PVAC, pathways enrichment analysis uncovered a functional overlapping between PDAC and PVAC. However, shared signalling events were influenced by different miRNA and/or genes in the two tumour entities. Overall, specific miRNA expression patterns were involved in the regulation of a limited core signalling pathways in the biology landscape of PDAC and PVAC.

Background There is currently ample consensus about the safety and feasibility of robotic pancreaticoduodenectomy (RPD). However, few studies are available on the long-term oncological outcomes of this procedure. We present a long-term survival analysis (up to 10 years) of our series of RPD carried out for ductal and ampullary adenocarcinoma. Methods A retrospective analysis of a prospectively collected approved database was carried out including 39 patients who underwent RPD for pancreatic ductal and ampullary adenocarcinomas. Results The 5-year overall survival for ductal and ampullary carcinoma was 41% with an estimated median and mean survival of 27 and 52 months. The ampullary group had significantly longer 5-year survival (68%) than the ductal group (30%). Conclusion Our data show, within the limitations of their retrospective nature, that robotic pancreaticoduodenectomy provides similar short- and long-term survival outcomes compared to open technique in the treatment of pancreatic ductal and ampullary adenocarcinoma.

Background Clinical evidence of intraductal dissemination through the pancreatic duct has been rare. We herein describe a case of ampullary carcinoma that disseminated in the remnant pancreas through the pancreatic duct. Case presentation A 68-year-old woman underwent SSPPD for ampullary carcinoma. The tumor was diagnosed as adenocarcinoma without lymph node metastasis (T2N0M0, stage IB). Computed tomography (CT) performed 3 years later revealed a 14-mm tumor near the site of the pancreaticojejunal anastomosis. Endoscopic ultrasound-guided fine needle aspiration showed adenocarcinoma that was morphologically similar to the specimen from the first surgery. We diagnosed recurrence of ampullary carcinoma in the remnant pancreas. A total remnant pancreatectomy was performed. We found a white solid tumor at the 20-mm distal side of pancreaticojejunal anastomosis. The tumor was morphologically similar and immunostaining showed a pattern identical to that of the original tumor, suggesting that the two tumors were of the same origin. Conclusion The recurrent lesion was most likely the result of tumor cells leaving the tumor and implanting in the remnant pancreatic duct epithelium. Intraductal dissemination of adenocarcinoma is thought to be a cause of remnant recurrence after SSPPD in cases of obstruction of the pancreatic duct or an iatrogenic procedure.

Ampullary cancer represents approximately 6% of the malignant periampullary tumors. An early occurrence of symptoms leads to a 5-year survival rate after curative surgery of 30 to 67%. In addition to the tumor stage, the immunohistological subtypes appear to be important for postoperative prognosis. The aim of this study was to analyze the different subtypes regarding their prognostic relevance. A total of 170 patients with ampullary cancer were retrospectively analyzed between 1999 until 2016 after pancreatic resection. Patients were grouped according to their pathohistological subtype of ampullary cancer (pancreatobiliary, intestinal, mixed). Characteristics among the groups were analyzed using univariate and multivariate models. Survival probability was analyzed by the Kaplan-Meier method. An exact subtyping was possible in 119 patients. A pancreatobiliary subtype was diagnosed in 69 patients (58%), intestinal in 41 patients (34.5%), and a mixed subtype in 9 patients (7.6%). Survival analysis showed a significantly worse 5-year survival rate for the pancreatobiliary subtype compared with the intestinal subtype (27.5% versus 61%, p p

AimsKnowledge regarding the genetic features of ampullary carcinoma (AC) in European patients is limited. The utility of tumour markers for the establishment of a malignant diagnosis in biopsies from the ampullary region has not been fully elucidated. We aimed to describe the clinical, pathological, immunohistochemical (IHC) and genetic features of a Danish series of surgically resected ACs.MethodsSurgically resected ACs (n=59) were examined regarding (1) clinicopathological features, (2) histological subtypes, (3) expression of IMP3, maspin, MUC5AC and S100P and (4) next-generation sequencing using a hybrid capture-based platform (Illumina HiSeq2500), including 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer. Tumour mutational burden (TMB) and microsatellite instability (MSI) were also evaluated.ResultsPancreatobiliary adenocarcinomas (PB-AC), intestinal adenocarcinomas (INT-AC), other ampullary tumours and mixed adenocarcinomas represented 45.8%, 23.7%, 16.9% and 13.6%. The proportion of IHC-positive ACs (score ≥2) was: Maspin (94.9%), IMP3 (67.8%), S100P (39.0%) and MUC5AC (18.6%). Most frequently altered genes were TP53 (59.3%), KRAS (40.7%), APC (27.8%), SMAD4 (20.4%), CDKN2A (16.7%) and ARID2/PIK3CA (each 11.1%). MUC5AC and S100P were frequently expressed in PB-AC, APC alterations frequent in INT-AC, SOX9 alterations were exclusive in INT-AC and MDM2 and FRS2 alterations in PB-AC. Four of 49 ACs (8.2%) were TMB-high/MSI-high and showed loss of MLH1 and PMS2.ConclusionsPB-AC was the most frequent histological subtype of AC. Maspin and IMP3 were the IHC tumour markers with the highest sensitivity. Adenocarcinoma subtypes differed regarding several genetic alterations, whose predictive value remains to be evaluated.

Background: Ampullary carcinoma (AC) is a rare gastrointestinal cancer with few effective standard treatment options. For patients with unresectable diseases, the response rates for radiotherapy, chemotherapy, and chemoradiotherapy are low. Evaluation of the actionable mutations through genomic profiling will enable patients to enroll in matched clinical trials. Methods: To characterize actionable targets in 27 Chinese AC patients, a 500-gene next-generation sequencing panel was applied to assess the mutational status of their tumor tissues, including SNV, insertions/deletions, CNV and re-arrangements. Also, paired genomic DNA sample was extracted and analyzed by a 93-gene NGS panel to characterize germline variants. Results: Recurrent somatic mutated genes were KRAS (63%), TP53 (59%), APC (26%), SMAD4 (19%), CDKN2A (15%), ELF3 (11%), ERBB2 (11%), ERBB3 (11%) and MAP2K4 (11%). Consistent with previous studies, all mutations in AC driver gene ELF3 (n =3) were inactivating (three indels and one in splicing-site). The median tumor mutation burden (TMB) of our cohort was 1.6 (0-6.1) mutations/Mb and none of our patients had high microsatellite instability (MSI-H). Overall, we observed a wide spectrum of hotspot mutations in cancer driver genes including ERBB3 (n =2), FBXW7 (n =2), U2AF1 (n =2), BRAF (n =1), ERBB2/HER2 (n =1) and PIK3CA (n =1). The HER2 R678Q mutation, located in the transmembrane domain (TMD), activated HER2 signaling by improving the active dimer interface or stabilizing an activating conformation of HER2. Interestingly, both ERBB3 mutations (G284R and D297Y) were located in the extracellular domain (ECD) and their oncogenic activity also depended on the kinase-activity of ERBB2. These three mutations, together with one case of ERBB2 amplification, can be targeted by anti-HER2 antibodies and small-molecule HER2 kinase inhibitors. The BRAF N581I mutation is resistant to BRAF inhibitor vemurafenib but sensitive to MEK inhibitor trametinib. The PIK3CA N1044K mutation is oncogenic but its sensitivity to PIK3CA inhibitor alpelisib is unknown. Additionally, one patient had high level of FGFR2 amplification which may be suitable for the clinical trials of FGFR2 inhibitors pemigatnib and erdafitnib. Furthermore, two patients carried loss-of-function germline mutations in DNA repair genes PALB2 and CHEK2 which may confer synthetic lethality with PARP inhibitors. Taken together, at least eight (29.6%) patients in our cohort had actionable therapeutic targets. Conclusions: Through comprehensive genomic characterization of Chinese AC patients, we identified multiple actionable mutations in multiple signaling pathways. Our findings indicated that molecular profiling can provide clinical benefits to a significant portion of AC patients. Citation Format: Fei Wang, Si Liu, Xiaomo Li, Zhiming Zhao, Tonghui Ma, Hongling Yuan, Rong Liu. Evaluation of somatic and germline mutations in ampullary carcinoma reveals actionable targets in multiple signaling pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2182.

Background: The purpose of our study was to examine the relationship between clinicopathologic variables and morphologic subtypes in ampullary carcinoma, with an emphasis on the expression of SMAD4 tumor suppressor gene. Methods: Sixty-three cases of ampullary carcinomas resected between 2000–2011 were included in this study. Clinical characteristics and outcome data were recorded. Tumors were classified as pancreatobiliary or intestinal type based on morphology, and immunohistochemical (IHC) studies for cytokeratin 7 (CK7), cytokeratin 20 (CK20), cytokeratin 17 (CK17), and SMAD4 were performed. Results: Forty-nine percent of the ampullary tumors were pancreatobiliary, 29% were intestinal, and 22% were other variants. Tumors with pancreatobiliary morphology showed worse overall survival than those with intestinal morphology or other variants (P=0.03). A trend for higher stage, recurrence and less survival was seen in cases with negative SMAD4 expression. In multivariate analysis, age group (≤60 vs . >60 years) and expression of CK17 were the most prognostic of survival. Conclusions: Ampullary tumors with pancreatobiliary morphology have a worse overall survival, while negative SMAD4 expression is associated with a trend of less survival.

Ampullary carcinoma (AC) is a relatively rare entity often managed as a biliopancreatic carcinoma. AC has a better prognosis than peri ampullary tumors after resection, but more than a third of patients relapse. Factors predictive of recurrence are controversial, mainly because the relevant studies are very small or also included non AC tumors. There are no guidelines on the use of adjuvant or neoadjuvant chemotherapy. The aim of this study was to identify prognostic factors for recurrence after AC resection in a large multicentric cohort, and to establish a simple, practical, predictive score for recurrence in order to guide multidisciplinary decisions.We included 152 consecutive patients who underwent Whipple's pancreaticoduodenectomy for ampullary carcinoma from January 2000 to December 2010 in 10 gastrointestinal oncology departments.The estimated overall 5-year disease-free survival rate (DFS) was 47.1%. In multivariate analysis, age≥ 75 years at diagnosis (p0.0001), poor general condition (p = 0.01), poorly (p = 0.005) or moderately differentiated tumors (p = 0.01) and TNM stage IIb or III (p = 0.05) were associated with poor DFS. Based on this multivariate analysis, we developed a prognostic score with three levels of risk: DFS at 5 years was 73.5% in the low-risk group and 20.1% in the high-risk group.This simple score based on age, general condition, tumor differentiation and TNM stage can classify patients into subgroups with different risks of recurrence and could help with therapeutic decisionmaking.

BACKGROUND AND AIM Endoscopic papillectomy (EP) has been attempted not only for benign lesions but also for early ampullary carcinoma (AC). However, there is still no sufficient evidence or consensus regarding the effectiveness of EP for early AC. Herein, we evaluated the expanding indication of EP for early AC. METHODS Between May 1999 and December 2016, 177 patients were diagnosed with ampullary tumor before undergoing EP, and their clinical and histopathological data were analyzed retrospectively. RESULTS There were 27 Tis-T1a AC patients and four T1b AC patients who underwent EP. Mean tumor size was 14.1 mm for Tis-T1a AC and 17.0 mm for T1b AC. For the histological grade, 50% (2/4) of T1b AC were moderately differentiated, whereas 96.3% (26/27) of Tis-T1a AC were well differentiated and papillary. For lymphovascular invasion, one (25%) occurred in T1b AC but none occurred in Tis-T1a AC. There was no AC recurrence from the date of EP until a maximum of 5 years (Tis-T1a: mean period 48.5 months [5-60]; T1b: mean period 26.5 months [3-60]). CONCLUSIONS Endoscopic papillectomy is useful and reliable for the curative treatment of T1a AC. Large-scale prospective studies with long-term follow up are needed.

Aim To investigate the utility of local resection (LR) for T1 duodenal carcinoma and T1 ampullary carcinoma. Patients and methods Between June 2002 and November 2014, a total of 64 patients with pathological T1 (pT1) ampullary carcinoma (25 patients) and pT1 duodenal carcinoma (39 patients) were treated. Of these, 33 patients underwent local resection (LR group), while the other 31 patients underwent pancreatoduodenectomy (PD group). Results The LR group had 31 patients with pT1a and 2 patients with pT1b. PD group had 18 patients with pT1a and 13 patients with pT1b. One patient with pT1b duodenal carcinoma (20.0%) and one patient with pT1b ampullary carcinoma (10.0%) developed lymph node metastasis, while none of the patients with pT1a disease developed metastases. Conclusion LR may be considered in the patients preoperatively diagnosed with T1a duodenal carcinoma and T1a ampullary carcinoma.

Recently, immunohistochemistry-based classifications of ampullary carcinomas have been proposed (Ang and colleagues [PMID: 24832159]; Chang and colleagues [PMID: 23439753]). In this study, the prognostic value of Ang/Chang panel markers (CK20, MUC1, MUC2, CDX2) as well as other markers (CK7, MUC5AC, and MUC6) were tested on full-faced sections of 136 ampullary carcinoma resections with substantial (>5 mm) invasion. Immunohistochemistry was correlated with both histologic classification (intestinal [INT], pancreatobiliary [PB], or nontubular based on ≥3/5 observer agreement) and clinical outcome. No prognostic correlation was found with MUC1, CDX2, MUC2 or CK20 despite testing with different quantitative cutoffs. CK7 and CK20 were nonspecific. Ang classification had reasonable correlation with histologic subclassification of tubular cases as INT versus PB with high specificity but low sensitivity and ambiguous category was large (29%) and included also some classical cases. Prognostically, Ang classification approached but did not reach statistical significance, even when their large "ambiguous" group was eliminated and only tubular cases were analyzed (Ang-INT vs. Ang-PB; P=0.08). The Chang panel, in which the definition of the INT subcategory is not clearly defined, only marginally reached prognostic significance when tested as MUC1+/CDX2- versus MUC1-/CDX2+ and only by Wilcoxon test (P=0.0485) but 31% of the cases were "unclassifiable." The only individual marker that was found to have direct and strong correlation with the clinical outcome was MUC5AC (not used in the Ang or Chang panels), with statistically significant survival differences found with various cutoffs tested (for 20% cutoff, 5-y survival, 68% vs. 31%; P=0.0002). In addition, MUC5AC significantly stratified the histologically PB and INT cases (P=0.01 and 0.03, respectively), as well as Ang's ambiguous and Chang's unclassified cases (P=0.006 and 0.007, respectively). In conclusion, the widely used putative lineage markers, MUC1/MUC2/CK7/CK20/CDX2, do not seem to have direct/significant prognostic correlation either individually or in combination of Ang and Chang panels. Ang panel is helpful as an adjunct in determining the cell lineage with a few caveats. MUC5AC proves to be a significant independent prognosticator and should be incorporated into evaluation of ampullary carcinomas.

Indispensable key to successful diagnosis and treatment of cancer, including ampullary carcinoma is operating properly cut material for further histological examination. In this paper we present a modern algorithm for morphological study remote organocomplexes, which is designed to achieve the maximum objective morphological data at ampullary carcinomas.

Context.—In ampullary carcinoma staging, T1 is defined as a tumor limited to the ampulla of Vater or the sphincter of Oddi, and T2 is defined as invasion into the duodenal wall. However, the definition of duodenal wall invasion is vague. Ampullary carcinoma that invades beyond the sphincteric of Oddi (perisphincteric invasion) or into the duodenal submucosa could be considered pT1b because submucosal invasion is classified as pT1b in gastrointestinal tract tumors. However, there are no data regarding T subclassifications for ampullary carcinoma with perisphincteric or duodenal submucosa invasion. Objectives.—To determine the T subclassification of ampullary carcinoma that invades into perisphincteric or duodenal submucosa. Design.—Pathologically proven ampullary carcinomas with T1 or T2 were reviewed (n = 105). We reclassified tumors as pT1a that were limited to within the sphincter of Oddi (n = 40; 38%), as pT1b for tumors that invaded beyond the sphincter of Oddi or into the duodenal submucosa (n = 25; 24%), and as pT2 for tumors that invaded into duodenal proper muscle (n = 40; 38%). Results.—Lymph node metastasis and recurrence were absent in ampullary carcinoma with pT1a, whereas nodal metastasis were noted in 24% (6 of 25) and 40% (16 of 40) of the ampullary carcinomas with pT1b and pT2, respectively. Tumor recurrence/metastasis rate of ampullary carcinoma with pT1b and pT2 was 44% (11 of 25) and 40% (16 of 40), respectively. The 5-year disease-free-survival rates from ampullary carcinoma with pT1a, pT1b, and pT2 were 95% (38 of 40), 56% (14 of 25), and 58% (23 of 40), respectively (P = .003). The 5-year overall survival from ampullary carcinoma with pT1a, pT1b, and pT2 was 98% (39 of 40), 72% (18 of 25), and 60% (24 of 40), respectively. Conclusions.—The clinicopathologic outcome of ampullary carcinoma with a pT1b subclassification was worse than it was for T1a and approached the outcome for pT2.

The distal common bile duct (CBD) and ampulla are extremely difficult sites to evaluate on CT. This article seeks to provide the reader with a framework and algorithmic approach to the evaluation of abnormalities involving the distal CBD and ampulla, including an emphasis on the use of multiplanar reformations and 3D imaging, the morphologic features on CT that suggest the presence of malignancy, and a differential diagnosis for abnormalities in this location.In our experience, both the distal CBD and ampulla are common sites of missed diagnoses for radiologists. Avoiding mistakes in interpreting imaging findings in this location requires a systematic approach especially in the setting of unexplained biliary ductal dilatation. Rather than simply suggesting that MRCP or ERCP be performed for the ultimate diagnosis, radiologists can perform a careful CT evaluation using multiplanar reformations and 3D imaging to determine the correct diagnosis prospectively. A timely and correct diagnosis is imperative because lesions in the ampulla and CBD can be very aggressive despite their small size.

Ampullary carcinoma is a rare tumor. There are neither sufficient available data related to management after resection of the neoplasm of the ampulla of Vater, nor any international recommendations. The aim of this study was to identify factors associated with recurrence and survival after curative resection.A retrospective follow-up study was conducted including patients with ampullary carcinoma who underwent resection with curative intent in 12 French surgical centers between January 1990 and November 2011.In this study, 319 patients underwent surgical resection for an ampullary neoplasm. Disease recurred in 120 patients (37.6%), and the 5- and 10-year disease-free survival rates were 48.9% and 40.4%, respectively. In multivariable Cox regression, preoperative bilirubin, T stage, pancreaticobiliary histology subtype, and lymph node involvement were each significantly associated with the risk of recurrence.Ampullary carcinomas are a heterogeneous group that can be classified as intestinal and pancreaticobiliary subtypes. Our findings indicate that pancreaticobiliary differentiation, advanced stage, and lymph node involvement are predictors of both poor disease-free and poor overall survival. It is still unclear what adjuvant treatment after curative resection of ampullary carcinoma is optimal. It would be informative to evaluate adjuvant therapy according to histological subtype.

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

Aim: In cases of ampullary carcinoma, lymph node involvement affects the selection of treatment strategies. This study aimed to identify clinicopathologic features of ampullary carcinoma with lymph node metastases. Methods: The records of 74 consecutive patients with ampullary adenocarcinoma who underwent pancreaticoduodenectomy (PD) with regional lymph node dissection were retrospectively analyzed. Results: Twenty-two patients (30%) with lymph node metastasis had significantly worse survival after resection than those without lymph node metastasis (p = 0.017). Univariate analyses revealed that preoperative biliary drainage; elevated serum carbohydrate antigen 19-9 (≥36 U/ml); moderate-to-poor pathologic grade (G2/3); perineural, vascular, lymphatic, pancreas, and duodenal invasion; and T category were significantly associated with lymph node metastasis. In multivariate analysis, only pathologic grade (G2/3) remained significantly associated with lymph node metastasis (hazard ratio, 6.51; p = 0.035). In sub-classified analysis for T category, lymph node metastasis was found in 5 of 22 cases (22.7%) of T1 tumors. Four of five cases with lymph node metastases had a dominant G2/3 component, whereas only 2 of 17 cases without lymph node metastases had a G2/3 component in T1 tumors (p = 0.0036). Conclusions: Pathologic grade (G2/3) was significantly and independently associated with lymph node metastasis and was also a significant predictor in T1 tumor cases.

Background & Aims The epidemiology of biliary tract cancers (BTC) varies between geographical regions and has changed over time globally. We investigated the incidence and mortality trends of patients diagnosed with BTC over a 20-year period in Austria. Methods Patients diagnosed with intrahepatic (iCCC)/extrahepatic cholangiocarcinoma (eCCC), ampullary carcinoma, gall bladder carcinoma (GBC), overlapping lesions or unspecified carcinomas of the biliary tract and liver were included. Data on age-adjusted incidence were obtained from the Austrian National Cancer Registry which compiles data on all newly diagnosed cancers. Data on age-adjusted mortality were obtained from the national death registry (Statistics Austria). Results Between 1990 and 2009, 15201 patients were diagnosed with BTC (m/f=42/58%; mean age, 73 years). The median survival of all patients with BTC was 4.8 months with a 1-/5-year survival rate of 31%/10%. In iCCC, the incidence and mortality rates increased from 1990 to 2009 in both men and women while in eCCC, the incidence and mortality rates decreased over time in both sexes. In ampullary carcinoma, the incidence slightly decreased in men and remained stable in women. The mortality rate remained stable in both sexes. In GBC, the age-adjusted incidence and mortality rates dramatically decreased in both sexes. Conclusions GBC and iCCC were the most common entities amongst BTC. While incidence and mortality rates of iCCC increased in men and women over time, incidence and mortality rates of eCCC and GBC decreased in both sexes. Other carcinomas of the biliary tract i.e. ampullary carcinoma were rarely diagnosed.