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Histologic classification of ampullary carcinomas as intestinal versus pancreatobiliary is rapidly becoming a part of management algorithms, with immunohistochemical classification schemes also being devised using this classification scheme as their basis. However, data on the reproducibility and prognostic relevance of this classification system are limited. In this study, five observers independently evaluated 232 resected ampullary carcinomas with invasive component >3 mm. Overall interobserver agreement was ‘fair’ ( κ 0.39; P <0.001) with complete agreement in 23%. Using agreement by 3/5 observers as ‘consensus’ 40% of cases were classified as ‘mixed’ pancreatobiliary and intestinal. When observers were asked to provide a final diagnosis based on the predominant pattern in cases initially classified as mixed, there was ‘moderate’ agreement ( κ 0.44; P <0.0001) with 5/5 agreeing in 35%. Cases classified as pancreatobiliary by consensus (including those with pure-pancreatobiliary or mixed-predominantly pancreatobiliary features) had shorter overall (median 41 months) and 5-year survival (38%) than those classified as pure-intestinal/mixed-predominantly intestinal (80 months and 57%, respectively; P =0.026); however, on multivariate analysis this was not independent of established prognostic parameters. Interestingly, when compared with 476 cases of pancreatic ductal adenocarcinomas, the pancreatobiliary-type ampullary carcinomas had better survival (16 versus 41 months, P <0.001), even when matched by size and node status. In conclusion, presumably because of the various cell types comprising the region, ampullary carcinomas frequently show mixed phenotypes and intratumoral heterogeneity, which should be considered when devising management protocols. Caution is especially warranted when applying this histologic classification to biopsies and tissue microarrays. While ampullary carcinomas with more pancreatobiliary morphology have a worse prognosis than intestinal ones this does not appear to be an independent prognostic factor. However, pancreatobiliary-type ampullary carcinomas have a much better prognosis than their pancreatic counterparts.

Background Ampullary adenocarcinoma (AA) originates from either intestinal (INT) or pancreaticobiliary (PB) epithelium. Different prognostic factors of recurrence have been identified in previous studies. Methods In 91 AA patients of the AGEO retrospective multicentre cohort, we evaluated the centrally reviewed morphological classification, panel markers of Ang et al. including CK7, CK20, MUC1, MUC2 and CDX2, the 50-gene panel mutational analysis, and the clinicopathological AGEO prognostic score. Results Forty-three (47%) of the 91 tumours were Ang-INT, 29 (32%) were Ang-PB, 18 (20%) were ambiguous (Ang-AMB) and one could not be classified. Among these 90 tumours, 68.7% of INT tumours were Ang-INT and 78.2% of PB tumours were Ang-PB. MUC5AC expression was detected in 32.5% of the 86 evaluable cases. Among 71 tumours, KRAS, TP53, APC and PIK3CA were the most frequently mutated genes. The KRAS mutation was significantly more frequent in the PB subtype. In multivariate analysis, only AGEO prognostic score and tumour subtype were associated with relapse-free survival. Only AGEO prognostic score was associated with overall survival. Conclusions Mutational analysis and MUC5AC expression provide no additional value in the prognostic evaluation of AA patients. Ang et al. classification and the AGEO prognostic score were confirmed as a strong prognosticator for disease recurrence.

Objective The aim of this study was to investigate the clinical relevance of the 8th edition of the Union for International Cancer Control classification of TNM staging for ampulla of Vater carcinoma (AC). Methods A total of 104 consecutive patients who underwent macroscopic curative resection for AC between January 2002 and September 2017 were investigated. Results Significant differences in recurrence-free survival (RFS) were found between T1a and T1b ( p  = 0.0030), but not between T1b and T2 ( p  = 0.9319), T2 and T3a ( p  = 0.0732), or T3a and T3b ( p  = 0.2118). The prognostic impact of the depth of duodenal invasion and pancreatic invasion, which define the T category, were evaluated. With regard to duodenal invasion, significant differences in RFS were found between the negative and submucosa classifications ( p  = 0.0012) and the muscularis propria and serosa classifications ( p  = 0.0131), but not between the submucosa and muscularis propria classifications ( p  = 0.6390). With regard to pancreatic invasion, significant differences in RFS were found between the negative and ≤ 0.5 cm classifications ( p  = 0.0001), and ≤ 0.5 cm and > 0.5 cm classifications ( p  = 0.0062). A Cox proportional hazard analysis for RFS revealed that duodenal invasion (submucosa or muscularis propria/negative, hazard ratio [HR] 5.08; serosa/negative, HR 7.42), and pancreatic invasion (≤ 0.5 cm/negative, HR 8.23; > 0.5 cm/negative, HR 9.81) were independent prognostic factors. An alternative new T category was proposed, based on the HRs, as follows: T1, tumor limited to the ampulla of Vater or sphincter of Oddi; T2, duodenal invasion (submucosa or muscularis propria); T3, pancreatic invasion (≤ 0.5 cm) or duodenal invasion (serosa); and T4, pancreatic invasion (> 0.5 cm). This alternative T category can well classify each subgroup with prognostic differences. Conclusions Reconsideration of the T category based on the prognostic impact of TNM factors, including the depth of duodenal and pancreatic invasion, are required in the 8th edition T category.

Importance The lack of multidisciplinary workflow guidelines and clear definitions and classifications for neoplasms in and around the ampulla of Vater results in inconsistencies affecting patient care and research. Objective The PERIPAN international multidisciplinary consensus group aimed to standardize the multidisciplinary diagnostic workflow and achieve consensus on definitions and classifications in order to ensure proper classification and optimal diagnostic assessment and consequently to improve patient care and future research. Design An international team of 43 experts (pathologists, surgeons, radiologists, gastroenterologists, oncologists) from 12 countries identified knowledge gaps, reviewed 37061 articles, and proposed recommendations using the Scottish Intercollegiate Guidelines Network methodology (SIGN), including the Delphi methodology and the AGREEII tool for quality assessment and external validation. Results The 38 consensus questions and 51 recommendations provide guidance on the following key aspects: I. More specific anatomic criteria for the definition of what qualifies as “ampullary” neoplasms, their distinction from duodenal and common bile duct tumors, and clinicopathologic characteristics of anatomic subsets; II. Avoidance of the confusing term “periampullary” for final classification; III. Refined definitions of intestinal, pancreatobiliary and mixed subtypes, and introduction of rare histologic subtypes; IV. The use and limitations of immunohistochemical and molecular profiling; V. Biopsy acquisition; VI. Clinical information required for accurate pathology assessment of biopsies and ampullectomy specimens; VII. Key items to be included in pathology reports of endoscopic specimens. Conclusions and Relevance Recognition of the Brescia PERIPAN guidelines will allow a more accurate classification of true ampullary cancers and their differentiation from other “periampullary” tumors. This will have significant implications for endoscopic interpretation and management, staging, pathologic diagnosis and therapeutic evaluation as well as oncologic treatment of various anatomic and histologic subsets of ampullary tumors. This will enhance the quality of both clinical care and future research in this complex medical field.

The benefit of adjuvant chemotherapy for resected pancreatic ductal adenocarcinoma (PDAC) has been confirmed in randomized controlled trials. For nonpancreatic periampullary cancers (NPPC) originating from the distal bile duct, duodenum, ampulla, or papilla of Vater, the role of adjuvant therapy remains largely unclear. This review describes methods for distinguishing PDAC from NPPC by means of readily available and recently developed molecular diagnostic methods. The difficulties of reliably determining the exact origin of these cancers pathologically also is discussed. The review also considers the possibility of unintentional inclusion of NPPC in the most important adjuvant trials on PDAC and the subsequent implications for interpretation of the results. The authors conclude that correct determination of the origin of periampullary cancers is essential for clinical management and should therefore be systematically incorporated into clinical practice and future studies.

Background We assessed the expression of cytokeratin (CK) and apomucin (MUC) in ampullary carcinoma (AC) to develop a system for the classification of ACs on the basis of their clinical significance. Method We studied the expressions of CK7, CK20, MUC1, MUC2, MUC5AC, and MUC6 in 43 patients with ACs. Clinical data were obtained retrospectively by examining surgically resected ACs of the patients. Results We classified the cases into 3 groups: tumors expressing CK20 and lacking MUC1 (intestinal type [I-type], 26%), tumors expressing MUC1 and lacking CK20 (pancreatobiliary type [PB-type], 35%), and those expressing or lacking both CK20 and MUC1 (other type [O-type], 39%). Eight (73%) of 11 I-type carcinomas, 3 (20%) of 15 PB-type carcinomas, and 4 (24%) of 17 O-type carcinomas were classified as pT1. The number of I-type carcinomas in the early tumor stages was significantly higher than the number of PB- and O-type carcinomas (p = 0.014 and p = 0.018, respectively). The 5-year survival rates for pT1, pT2, and pT3 tumors were 76%, 33%, and 22%, respectively (p < 0.001). Rates of MUC5AC and MUC6 coexpression for I-type, PB-type, and O-type tumors were 18%, 13%, and 53%, respectively. There was a significant correlation between MUC5AC and MUC6 coexpression and O-type characteristics (p = 0.031). The five-year survival rates for O-type ACs with and without MUC5AC and MUC6 coexpression were 71% and 17%, respectively (p = 0.048). Conclusions The immunohistochemical subtypes based on CK and MUC expression correlated with tumor progression. Gastric MUC5AC and MUC6 coexpression correlated with better prognosis for O-type ACs.

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.

Objectives The purpose of this investigation was to assess the prognostic importance of the combination of preoperative hemoglobin (Hb) levels and Geriatric Nutritional Risk Index (GNRI) in forecasting postoperative survival outcomes for patients undergoing pancreaticoduodenectomy (PD) due to Vater ampulla carcinoma (VPC). Methods The GNRI nutritional screening was conducted for all patients, and patient outcomes, including overall survival (OS), were subsequently monitored. An H‐ GNRI scoring system was established using the optimal critical values of 125.5 g/L for Hb and 91.72 for GNRI, as determined by X‐tile software. According to the H‐GNRI score, the patients were categorized into three groups, namely low H‐GNRI group (H‐GNRI score = 0, n = 47) with Hb < 125.5 g/L and GNRI < 91.72; medium H‐GNRI group (H‐GNRI score = 1, n = 77) with Hb < 125.5 g/L and GNRI ≥ 91.72, or Hb ≥ 125.5 g/L and GNR < 91.72; and high H‐GNRI group (H‐GNRI score = 2, n = 51) with Hb ≥ 125.5 g/L and GNRI ≥ 91.72. The Kaplan–Meier analysis and log‐rank tests were employed to evaluate the OS rate and compare survival disparities among various groups. Additionally, both univariate and multivariate analyses were conducted utilizing the Cox regression model, with p < 0.05 considered statistically significant. Finally, to evaluate the predictive effectiveness of Hb, GNRI, and H‐GNRI, a receiver operating characteristic (ROC) curve was constructed to compare the area under curve (AUC) values. Results The OS rate was higher in patients with high Hb levels (≥ 125.5 g/L) compared to those with low Hb levels (< 125.5 g/L). Likewise, patients in the high GNRI group (≥ 91.72) exhibited significantly superior OS compared to those in the low GNRI group (< 91.72). Compared with both the medium and low H‐GNRI groups, the high H‐GNRI group demonstrated a notably higher OS rate. The T stage (HR = 2.523, 95% CI: 1.694–3.757, p < 0.001), N stage (HR = 2.018, 95% CI: 1.255–3.246, p = 0.004), and the H‐GNRI score (H‐GNRI score of 2 used as the baseline; H‐GNRI score of 0: HR = 2.569, 95% CI: 1.499–4.402, p < 0.001; H‐GNRI score of 1: HR = 1.835, 95% CI: 1.118–3.014, p = 0.016), after adjusting for gender, were determined to be independent significant predictors affecting the OS of patients with VPC. The AUC of H‐GNRI was 0.677, exceeding that of Hb levels (0.631) and GNRI (0.615). Conclusions The combination of preoperative Hb levels and GNRI demonstrates superior predictive efficacy for VPC patients undergoing PD, compared with either Hb levels or GNRI score alone. Therefore, the H‐GNRI score can be utilized to promptly identify high‐risk patients, establish comprehensive nutritional pre‐rehabilitation plans through interdisciplinary collaboration, and inform decisions regarding additional adjunctive therapies.

Background: Outcomes for ampullary adenocarcinomas are heterogeneous, and numerous methods of categorisation exist. A histomolecular phenotype based on histology, caudal-type homeodomain transcription factor 2 (CDX2) staining and Mucin 1 (MUC1) staining has recently been tested and validated in two cohorts. We attempt to validate this classification in a large patient population. Methods: Tissue samples from 163 patients with resected ampullary adenocarcinoma were classified based on histology and immunohistochemical expression of CDX2 and MUC1. A pancreaticobiliary histomolecular classification (PB) was defined as a sample with pancreaticobiliary histology, positive MUC1 and negative CDX2 expression. Results: There were 82 deaths; median follow-up of 32.4 months; and median overall survival of 87.7 (95% CI 42.9–109.5) months. PB comprised 28.2% of the cases. Factors associated with overall survival were histological subtype ( P =0.0340); T1/2 vs T3/4 ( P =0.001); perineural ( P <0.0001) and lymphovascular ( P =0.0203) invasion; and histomolecular intestinal histomolecular phenotype (INT) vs PB phenotype (106.4 vs 21.2 months, P <0.0001). Neither MUC1 nor CDX2 was statistically significant, although MUC1 positivity defined as ⩾10% staining was significant ( P =0.0023). In multivariate analysis, age (HR 1.03), PB phenotype (HR 2.26) and perineural invasion (PNI; HR 2.26) were associated with poor survival. Conclusions: The prognostic ability of histomolecular phenotype has been validated in an independent cohort of ampullary adenocarcinoma patients.

Determination of the primary tumor in periampullary region carcinomas can be difficult, and the pathological assessment and clinicopathological characteristics remain elusive. In this study, we investigated the current recognition and practices for periampullary region adenocarcinoma with an indeterminable origin among expert pathologists through a cognitive survey. Simultaneously, we analyzed a prospective collection of cases with an indeterminable primary tumor diagnosed from 2008 to 2018 to elucidate their clinicopathological features. All cases with pathological indeterminable primary tumors were reported and discussed in a clinicopathological conference to elucidate if it was possible to distinguish the primary tumor clinically and pathologically. From the cognitive survey, over 85% of the pathologists had experienced cases with indeterminable primary tumors; however, 70% of the cases was reported as pancreatic cancer without definitive grounds. Interpretation of the main tumor mass varied, and no standardized method was developed to determine the primary tumor. During a prospective study, 42 of the 392 periampullary carcinoma cases (10.7%) were considered as tumors with a pathological indeterminable origin. After the clinicopathological conferences, 21 (5.4%) remained indeterminable and were considered final indeterminable cases. Histological studies showed that the tumors spread along both the bile duct and main pancreatic duct; this was the most representative finding of the final indeterminable cases. This study is the first to elucidate and recognize the current clinicopathological features of periampullary region adenocarcinomas with an indeterminable origin. Adequate assessment of primary tumors in periampullary region carcinomas will help to optimize epidemiological data of pancreatic and bile duct cancer. This study is the first to elucidate and recognize the current clinicopathological features of periampullary region adenocarcinomas with an indeterminable origin.