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Zhuravleva E, Lewinska M, O'Rourke CJ, Pea A, Rashid A, Hsing AW, Taranta A, Chang D, Gao YT, Koshiol J, Oliveira RC, Andersen JB. Mutational signatures define immune and Wnt-associated subtypes of ampullary carcinoma. Gut 2025; 74:804-814. [PMID: 39725462 PMCID: PMC12013699 DOI: 10.1136/gutjnl-2024-333368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 11/21/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND AND OBJECTIVE Ampullary carcinoma (AMPAC) taxonomy is based on morphology and immunohistochemistry. This classification lacks prognostic reliability and unique genetic associations. We applied an approach of integrative genomics characterising patients with AMPAC exploring molecular subtypes that may guide personalised treatments. DESIGN We analysed the mutational landscapes of 170 patients with AMPAC. The discovery included 110 tumour/normal pairs and the validation comprised 60 patients. In a tumour subset, we interrogated the transcriptomes and DNA methylomes. Patients were stratified based on mutational signatures and associated with molecular and clinical features. To evaluate tumour and immune cellularity, 22 tumours were independently assessed histomorphologically and by digital pathology. RESULTS We defined three patient clusters by mutational signatures independent of histomorphology. Cluster 1 (C1) was defined by spontaneous deamination of DNA 5-methylcytosine and defective mismatch repair. C2 and C3 were related to the activity of transcription-coupled nucleotide excision repair but C3 was further defined by the polymerase eta mutational process. C1-2 showed enrichment of Wnt pathway alterations, aberrant DNA methylation profiles, immune cell exclusion and patients with poor prognosis. These features were associated with a hypermutator phenotype caused by C>T alterations at CpGs. C3 patients with improved overall survival were associated with activation of immune-related pathways, immune infiltration and elevated expression of immunoinhibitory checkpoint genes. CONCLUSION Immunogenicity and Wnt pathway associations, emphasised by the mutational signatures, defined patients with prospective sensitivity to either immunotherapy or Wnt pathway inhibitors. This emphasises a novel mutational signature-based AMPAC classification with prognostic potential, suggesting prospective implications for subgroup-specific management of patients with AMPAC.
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Affiliation(s)
- Ekaterina Zhuravleva
- Biotech Research and Innovation Center (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Monika Lewinska
- Biotech Research and Innovation Center (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Colm J O'Rourke
- Biotech Research and Innovation Center (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Antonio Pea
- University of Glasgow, Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, Glasgow, UK
- University of Verona, Verona, Italy
| | - Asif Rashid
- Department of Pathology, Division of Pathology/Lab Medicine, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA
| | - Ann W Hsing
- Stanford Cancer Institute and Stanford Prevention Research Center, Department of Medicine, Stanford School of Medicine, Stanford University, Palo Alto, California, USA
| | - Andrzej Taranta
- Biotech Research and Innovation Center (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - David Chang
- University of Glasgow, Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, Glasgow, UK
| | - Yu-Tang Gao
- Department of Epidemiology, Shanghai Cancer Institute, Shanghai, Shanghai, China
| | - Jill Koshiol
- Division of Cancer Epidemiology and Genetics, NIH, Rockville, Maryland, USA
| | | | - Jesper B Andersen
- Biotech Research and Innovation Center (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Ciesielka J, Majewska K, Jabłońska B, Domagała-Haduch M, Liszka Ł, Gisterek-Grocholska I, Mrowiec S. Multimodal treatment for long-term survival in ampullary adenocarcinoma metastatic to the liver. PRZEGLAD GASTROENTEROLOGICZNY 2025; 20:102-106. [PMID: 40191514 PMCID: PMC11966507 DOI: 10.5114/pg.2025.148485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 07/26/2024] [Indexed: 04/09/2025]
Affiliation(s)
- Jakub Ciesielka
- Students’ Scientific Association, Department of Digestive Tract Surgery, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Karolina Majewska
- Department of Digestive Tract Surgery, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Beata Jabłońska
- Department of Digestive Tract Surgery, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Małgorzata Domagała-Haduch
- Department of Oncology and Radiotherapy, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Łukasz Liszka
- Department of Pathomorphology and Molecular Diagnostics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Iwona Gisterek-Grocholska
- Department of Oncology and Radiotherapy, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Sławomir Mrowiec
- Department of Digestive Tract Surgery, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
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Uijterwijk BA, Moekotte A, Boggi U, Mazzola M, Groot Koerkamp B, Dalle Valle R, Koek S, Bolm L, Mazzotta A, Luyer M, Goh BKP, Suarez Muñoz MA, Björnsson B, Kazemier G, Ielpo B, Pessaux P, Kleeff J, Ghorbani P, Mavroeidis VK, Fusai GK, Salvia R, Zerbi A, Roberts KJ, Alseidi A, Al-Sarireh B, Serradilla-Martín M, Vladimirov M, Korkolis D, Soonawalla Z, Gruppo M, Bouwense SAW, Vollmer CM, Behrman SW, Christein JD, Besselink MG, Abu Hilal M. Oncological resection and perioperative outcomes of robotic, laparoscopic and open pancreatoduodenectomy for ampullary adenocarcinoma: a propensity score matched international multicenter cohort study. HPB (Oxford) 2025; 27:318-329. [PMID: 39765373 DOI: 10.1016/j.hpb.2024.11.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 07/28/2024] [Accepted: 11/28/2024] [Indexed: 01/12/2025]
Abstract
BACKGROUND Ampullary adenocarcinoma (AAC) typically presents at an early stage due to biliary obstruction and therefore might be specifically suitable for minimally invasive pancreatoduodenectomy (MIPD). However, studies assessing MIPD specifically for AAC, including the robotic and laparoscopic approach, are limited. The aim of this study is to compare short- and long-term oncological resection and perioperative outcomes of robotic (RPD), laparoscopic (LPD) and open pancreatoduodenectomy (OPD) performed specifically for AAC. METHODS In this multicenter international cohort study, encompassing 35 centers from 11 countries, MIPD versus OPD and subgroup analyses of LPD versus RPD were undertaken. The primary outcomes regarded the oncological resection (R1 resection rate, lymph node yield) and 5-years overall survival. Secondary outcomes were perioperative outcomes (including intra-operative variables, surgical complications and hospital stay). RESULTS In total, patients with AAC who underwent OPD (1721) or MIPD (141) were included. After propensity-score matching, 134 patients per cohort were included. The MIPD group consisted of 53 RPDs and 71 LPDs (50 per group after PSM). There was no difference in overall survival between MIPD and OPD (61.6 % vs 56.2 %, P = 0.215). In the MIPD group, operative time was longer (439 vs 360 min, P < 0.001). Between RPD and LPD, overall survival was not significantly different (75.8 % vs 47.4 %, P = 0.098) and lymph node yield was higher in RPD (21 vs 18, P = 0.014). CONCLUSION In conclusion, patients with AAC seem to have comparable oncological resection and perioperative outcomes from MIPD compared to the traditional OPD. Both RPD as LPD appear to be safe alternatives for patients with AAC, which warrants confirmation by future randomized studies.
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Affiliation(s)
- Bas A Uijterwijk
- Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Amsterdam, the Netherlands; Cancer Center Amsterdam, Amsterdam, the Netherlands.
| | - Alma Moekotte
- Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Amsterdam, the Netherlands; Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Ugo Boggi
- Department of Surgery, Pisa University Hospital, Pisa, Italy
| | - Michele Mazzola
- Division of Oncologic and Mini-invasive General Surgery, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | | | - Sharnice Koek
- Fiona Stanley Hospital, Department of Surgery, Perth, Australia
| | - Louisa Bolm
- Department of Surgery, University Medical Center Schleswig-Holstein, Campus Lübeck, Germany
| | - Alessandro Mazzotta
- Department of Digestive, Oncologic and Metabolic Surgery, Institut Mutualiste Montsouris, Paris, France
| | - Misha Luyer
- Catharina Hospital Eindhoven, Department of Surgery, the Netherlands
| | - Brian K P Goh
- Singapore General Hospital, Department of Hepatopancreatobiliary and Transplant Surgery, Duke-National University of Singapore, Singapore
| | | | - Bergthor Björnsson
- Department of Surgery in Linköping and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Geert Kazemier
- Department of Surgery, Amsterdam UMC, Location VUmc, Amsterdam, the Netherlands
| | | | - Patrick Pessaux
- Hepatobiliary and Pancreatic Surgical Unit, Nouvel Hôpital Civil (NHC), Strasbourg, France
| | - Jorg Kleeff
- Department of Surgery, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Poya Ghorbani
- Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden
| | - Vasileios K Mavroeidis
- Department of Academic Surgery, The Royal Marsden Hospital, London, UK; Department of Hepatobiliary and Pancreatic Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Giuseppe K Fusai
- Department of Surgery, Royal Free London NHS Foundation Trust, London, UK
| | - Roberto Salvia
- Department of General and Pancreatic Surgery, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - Alessandro Zerbi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy; Pancreatic Surgery, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Keith J Roberts
- Faculty of Medicine, University of Birmingham, Birmingham, UK
| | | | | | - Mario Serradilla-Martín
- Instituto de Investigación Sanitaria Aragón, Department of Surgery, Miguel Servet University Hospital, Zaragoza, Spain
| | - Miljana Vladimirov
- Department of General Surgery, Paracelsus Medical University Nürnberg, 90419, Nürnberg, Germany; Department of Abdominal Surgery, University Hospital Lippe, University Bielefeld, Campus Detmold, Germany
| | - Dimitris Korkolis
- Department of Surgery, Hellenic Anticancer Hospital 'Saint Savvas', Athens, Greece
| | - Zahir Soonawalla
- Department of Hepatobiliary and Pancreatic Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Mario Gruppo
- Veneto Institute of Oncology IOV - IRCCS, Unit of Surgical Oncology of the Digestive Tract, Italy
| | - Stefan A W Bouwense
- Department of Surgery, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Charles M Vollmer
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA
| | - Stephen W Behrman
- Department of Surgery, University of Tennessee Health Science Center, Memphis, USA
| | - John D Christein
- Department of Surgery, University of Alabama School of Medicine, Birmingham, USA
| | - Marc G Besselink
- Amsterdam UMC, Location University of Amsterdam, Department of Surgery, Amsterdam, the Netherlands; Cancer Center Amsterdam, Amsterdam, the Netherlands
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Xiao YX, Chen J, Li ZY, Zou YX, Zhou XH, Zhang W, Li HL, Bischof EY, Xiang YB. Global trends in gallbladder cancer survival: A 30-year analysis of cancer registry data. Heliyon 2025; 11:e42853. [PMID: 40070950 PMCID: PMC11894304 DOI: 10.1016/j.heliyon.2025.e42853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 02/17/2025] [Accepted: 02/19/2025] [Indexed: 03/14/2025] Open
Abstract
Background Gallbladder cancer has historically been characterized with a poor prognosis. This study aims to describe the global patterns and temporal trends in gallbladder cancer survival using data from cancer registries. Methods We conducted a systematic review by searching six databases-PubMed, Web of Science, EMBASE, SEER, CNKI, and Wanfang-for using of registry-based data published before January 1, 2024. Survival data were carefully extracted and analyzed from the final set of included studies. Results Among the 55 studies included, more than 320,000 people, suggest that survival improvements for gallbladder cancer have stagnated over the past three decades. No significant improvements in 5-year relative survival rates were observed worldwide. After age standardization, the highest 5-year relative survival rate is 30.6 % (Changzhou, China, 2011-2013 and Korea, 2013-2019), while the lowest is 6.0 % (Austria, 1990). The 5-year relative survival rate for gallbladder cancer was generally higher in Asian populations than in other regions. Survival rates were more favorable in younger individuals, with no differences in survival observed between the sexes. Conclusions Over the past 30 years, the prognosis of patients with gallbladder cancer has not improved significantly worldwide. There is an urgent need for new treatments for gallbladder cancer as well as simple and effective screening methods to improve the survival rate of gallbladder cancer.
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Affiliation(s)
- Yu-Xuan Xiao
- Department of Epidemiology & State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
- School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Jun Chen
- Department of Epidemiology & State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
- School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Zhuo-Ying Li
- Department of Epidemiology & State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
- School of Public Health, Fudan University, Shanghai, 200025, China
| | - Yi-Xin Zou
- Department of Epidemiology & State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
- School of Public Health, Fudan University, Shanghai, 200025, China
| | - Xiao-Hui Zhou
- Department of Epidemiology & State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
- School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Wei Zhang
- Department of Epidemiology & State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Hong-Lan Li
- Department of Epidemiology & State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Evelyne Y. Bischof
- Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China
| | - Yong-Bing Xiang
- Department of Epidemiology & State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
- School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- School of Public Health, Fudan University, Shanghai, 200025, China
- Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China
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Choi JH, Kim WC, Park JK, Lee JK, Lee KT, Lee KH. Bleeding after endoscopic papillectomy and its risk factors: A single center experience of 196 cases. Hepatobiliary Pancreat Dis Int 2024; 23:613-619. [PMID: 38433066 DOI: 10.1016/j.hbpd.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 01/31/2024] [Indexed: 03/05/2024]
Abstract
BACKGROUND Endoscopic papillectomy (EP) is an effective method to remove an ampulla of Vater (AoV) adenoma with minimal invasiveness. We reviewed the clinical outcomes and prognosis of patients undergoing EP, including tumor recurrence and adverse events. METHODS A total of 196 patients who underwent EP from January 2004 to December 2017 were included. Clinical information was collected through electronic medical records, and risk factors to predict post-procedural bleeding were analyzed using a multivariate logistic regression model. RESULTS A total of 93.9% patients (184/196) underwent complete resection. During the follow-up period, 14.7% patients (27/184) experienced tumor recurrence, and two of seven surgically resected tumors were malignant. A total of 45.4% patients (89/196) experienced adverse events related to EP. Delayed bleeding occurred in 16.3% of the patients (32/196), and they were all successfully treated with endoscopic hemostasis and conservative management. The most frequent site of delayed bleeding was the distal end of the papillary orifice, and 56.3% (18/32) patients of delayed bleeding were classified as having mild severity, the others had moderate severity. Familial adenomatous polyposis (FAP) [odds ratio (OR) = 3.80, 95% confidence interval (CI): 1.01-14.29; P < 0.05] and male sex (OR = 2.82, 95% CI: 1.04-7.63; P = 0.04) showed statistical significance in predicting delayed post-EP bleeding. CONCLUSIONS EP for AoV adenoma was a highly effective and safe procedure. The risk of post-EP delayed bleeding was increased in patients with FAP syndrome and male patients, and post-EP bleeding occurred most commonly in the distal part of the AoV.
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Affiliation(s)
- Jin Ho Choi
- Department of Medicine, Division of Gastroenterology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Won Chul Kim
- Department of Medicine, Division of Gastroenterology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Joo Kyung Park
- Department of Medicine, Division of Gastroenterology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Jong Kyun Lee
- Department of Medicine, Division of Gastroenterology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Kyu Taek Lee
- Department of Medicine, Division of Gastroenterology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Kwang Hyuck Lee
- Department of Medicine, Division of Gastroenterology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
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Jiang J, Lv F, Chen C, Jiang W. Effectiveness of endoscopic papillectomy with stent placement in pancreatic and bile ducts for treating duodenal papillary adenoma: a retrospective study. BMC Gastroenterol 2024; 24:379. [PMID: 39448906 PMCID: PMC11515834 DOI: 10.1186/s12876-024-03466-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND Duodenal papillary adenoma, a potentially malignant benign tumor is primarily treated with endoscopic papillectomy. Despite its efficacy, endoscopic papillectomy has a high complication rate. This study investigates whether pancreatic duct and common bile duct stent placement can mitigate these complications. METHODS In a retrospective observational analysis, 79 patients with duodenal papillary adenoma, treated with endoscopic papillectomy at our center, were studied. The cohort included patients who underwent endoscopic papillectomy with no stents placement, common bile duct stent placement alone, pancreatic duct stent placement alone, or stents placement in both ducts. We assessed the outcomes of endoscopic papillectomy, including complete resection rate and recurrence rate as the primary and secondary outcomes respectively. In the meantime, the incidence of complications were also analysed as the safety outcomes. RESULTS Complete resection rates did not significantly differ between patients with or without stent placement (85.7% P group vs. 89.2% N-P group, P = 0.64). Early complication rates were similar across groups. However, significant reduction in common bile duct stenosis was observed in the stenting group (0% B group vs. 10.5% N-B group, P = 0.03). Furthermore, stent placement correlated with lower adenoma recurrence rates during follow-up (2.4% P group vs. 16.2% N-P group, P = 0.03; 2.4% B group vs. 15.8% N-B group, P = 0.04). CONCLUSIONS Pancreatic duct and common bile duct stent placement in endoscopic papillectomy may decrease late complications, particularly common bile duct stenosis, and reduce the recurrence of duodenal papillary adenoma. TRIAL REGISTRATION This study received approval from the Institutional Review Board and Ethics Committee of Beijing Friendship Hospital (Approval No. BFHHZS20230203), and retrospectively registered in www. CLINICALTRIALS gov (NCT06301048, Initial Release date: 02/18/2024, Last Public Release date: 03/03/2024).
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Affiliation(s)
- Jiani Jiang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, P.R. China
| | - Fujing Lv
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, P.R. China.
| | - Chuyan Chen
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, P.R. China
| | - Wei Jiang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, P.R. China
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Zhang JZ, Zhang ZW, Guo XY, Zhu DS, Huang XR, Cai M, Guo T, Yu YH. Comparison of clinical characteristics and prognostic factors in two site-specific categories of ampullary cancer. World J Gastroenterol 2024; 30:4281-4294. [PMID: 39492830 PMCID: PMC11525854 DOI: 10.3748/wjg.v30.i39.4281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 09/13/2024] [Accepted: 09/20/2024] [Indexed: 10/12/2024] Open
Abstract
BACKGROUND Ampullary cancer is a relatively rare malignant tumor in the digestive system. Its incidence has increased in recent years. As for now, its biological characteristics have not been fully clarified. Recent studies have primarily focused on the histological classification and genetic changes, but there are fewer investigations into the differences among site-specific subgroups. The clinicopathological characteristics of ampullary cancer occurring in different positions have not been elucidated. Furthermore, the role of adjuvant therapy in the treatment of patients with ampullary cancer remains controversial. AIM To study the clinicopathological features of the two site-specific subgroups of ampullary cancer and explore the factors affecting prognosis. METHODS A total of 356 patients who met the inclusion and exclusion criteria were enrolled. Patients were divided into ampulla of Vater cancer (AVC) and duodenal papilla cancer (DPC) based on the gross and microscopic findings. Baseline data, admission examination results, and perioperative outcomes were collected and analyzed. The Kaplan-Meier curve was used for survival analysis. Univariate and multivariate analysis was performed to explore the independent risk factors affecting the overall survival (OS) of both groups. RESULTS The preoperative total bilirubin level in patients with AVC was significantly higher than those with DPC (P = 0.04). The OS for patients with DPC was 58.90 ± 38.74 months, significantly longer than 44.31 ± 35.90 months for patients with AVC (P < 0.01). The independent risk factors affecting the OS of AVC included: Preoperative albumin level (P = 0.009), total bilirubin level (P = 0.017), and number of positive lymph nodes (P = 0.005). For DPC, risk factors included: Age (P = 0.004), tumor size (P = 0.023), number of positive lymph nodes (P = 0.010) and adjuvant treatment (P = 0.020). Adjuvant therapy significantly improved the OS rate of patients with DPC, but not for those with AVC. CONCLUSION Patients with AVC had a shorter OS compared to those with DPC. The prognosis factors and the role of adjuvant therapy of two groups were different.
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Affiliation(s)
- Jing-Zhao Zhang
- Department of Biliopancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Zhi-Wei Zhang
- Department of Biliopancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Xin-Yi Guo
- Department of Biliopancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Deng-Sheng Zhu
- Department of Biliopancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Xiao-Rui Huang
- Department of Biliopancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Ming Cai
- Department of Biliopancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Tong Guo
- Department of Biliopancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Ya-Hong Yu
- Department of Biliopancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
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Stornello C, Cristofori C, Checchin D, de Palo MG, Grillo S, Peserico G, Quintini D, Gruppo M, De Simoni O, Fantin A. The Role of Endoscopic Ultrasound in Ampullary Lesion Management. Diagnostics (Basel) 2024; 14:1855. [PMID: 39272640 PMCID: PMC11394035 DOI: 10.3390/diagnostics14171855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 07/07/2024] [Accepted: 08/21/2024] [Indexed: 09/15/2024] Open
Abstract
Ampullary lesions, neoplasms originating in the papilla of Vater, represent a rare yet clinically significant group of tumors with diverse etiologies and management challenges. This comprehensive review aims to elucidate the pivotal role of endoscopic ultrasound (EUS) in the diagnosis, staging, and management of ampullary lesions. This review begins by providing an overview of ampullary lesions, their epidemiology, and associated risk factors. We delve into their clinical presentation, emphasizing the importance of early and accurate diagnosis. Furthermore, we explore the limitations of traditional diagnostic modalities and highlight the growing relevance of EUS in ampullary lesion evaluation. We discuss the superior spatial resolution of EUS in comparison with other imaging methods, and we present an in-depth analysis of EUS-guided sampling and its pivotal role in obtaining histological samples for accurate diagnosis. In addition to diagnosis, we examine the indispensable role of EUS in ampullary lesion staging and its clinical implications. Furthermore, we discuss the potential of EUS in the surveillance and follow-up of ampullary lesions, ensuring timely detection of recurrence and monitoring treatment response in sporadic cases and in the context of familial syndromes, such as familial adenomatous polyposis (FAP). In conclusion, this review underscores the indispensable role of endoscopic ultrasound in the multifaceted approach to ampullary lesion evaluation. EUS not only enhances diagnostic accuracy but also informs treatment decisions and minimally invasive therapeutic interventions. As our understanding of ampullary lesions continues to evolve, EUS remains an invaluable tool for the improvement of patient outcomes and quality of life.
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Affiliation(s)
- Caterina Stornello
- Gastroenterology Unit, Veneto Institute of Oncology IOV-IRCCS, 35100 Padua, Italy
| | - Chiara Cristofori
- Gastroenterology Unit, Veneto Institute of Oncology IOV-IRCCS, 35100 Padua, Italy
| | - Davide Checchin
- Gastroenterology Unit, Dell'Angelo Hospital, 30174 Venice, Italy
| | - Maria Grazia de Palo
- Gastroenterology Unit, Veneto Institute of Oncology IOV-IRCCS, 35100 Padua, Italy
| | - Sabina Grillo
- Gastroenterology Unit, Veneto Institute of Oncology IOV-IRCCS, 35100 Padua, Italy
| | - Giulia Peserico
- Gastroenterology Unit, Veneto Institute of Oncology IOV-IRCCS, 35100 Padua, Italy
| | - Dario Quintini
- Gastroenterology Unit, Veneto Institute of Oncology IOV-IRCCS, 35100 Padua, Italy
| | - Mario Gruppo
- Unit of Surgical Oncology of Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, 35100 Padua, Italy
| | - Ottavia De Simoni
- Unit of Surgical Oncology of Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, 35100 Padua, Italy
| | - Alberto Fantin
- Gastroenterology Unit, Veneto Institute of Oncology IOV-IRCCS, 35100 Padua, Italy
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Yoon SJ, Hong SS, Jang KT, Yoon SK, Kim H, Shin SH, Heo JS, Kang CM, Kim KS, Hwang HK, Han IW. Predicting lymph node metastasis using preoperative parameters in patients with T1 ampulla of vater cancer. BMC Cancer 2024; 24:935. [PMID: 39090569 PMCID: PMC11293034 DOI: 10.1186/s12885-024-12311-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 04/25/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Lymph node (LN) metastasis is an established prognostic factor for patients with surgically resected ampulla of Vater (AoV) cancer. The standard procedure for radical resection, including removal of regional LNs, is pancreaticoduodenectomy (PD); however, local excision has been considered as an alternative option for patients in the early stage cancer with significant comorbidities. In the present study, we elucidated the preoperative factors associated with LN metastasis to determine the appropriate surgical extent for T1 AoV cancer. METHODS We included patients who underwent surgery for T1 AoV cancer at Samsung Medical Center and Severance Hospital between 2000 and 2019. Risk factors were analyzed to identify the preoperative parameters associated with LN metastasis or regional LN recurrence during follow-up. Finally, using the identified risk factors, a prediction model was constructed. RESULTS Among 342 patients, 311 patients underwent PD, whereas 31 patients underwent transduodenal ampullectomy. Fourty-eight patients had LN metastasis according to pathology report, and two patients presented with regional LN recurrence. Age, carbohydrate antigen 19 - 9 (CA 19 - 9), and tumor differentiation were identified as factors associated with the increased risk of LN metastasis or regional LN recurrence. The area under the curve of the prediction model with these three factors was 0.728. CONCLUSION Our newly developed prediction model using age, CA 19 - 9, and tumor differentiation can help select patients who require PD over local excision. Nevertheless, additional in-depth analysis is warranted to select appropriate surgical extent for patients with presumed T1 AoV cancer.
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Affiliation(s)
- So Jeong Yoon
- Division of Hepatobiliary-Pancreatic Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, Korea
| | - Seung Soo Hong
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, Korea
| | - Kee-Taek Jang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - So Kyung Yoon
- Department of Surgery, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Hongbeom Kim
- Division of Hepatobiliary-Pancreatic Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, Korea
| | - Sang Hyun Shin
- Division of Hepatobiliary-Pancreatic Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, Korea
| | - Jin Seok Heo
- Division of Hepatobiliary-Pancreatic Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, Korea
| | - Chang Moo Kang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, Korea
| | - Kyung Sik Kim
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, Korea
| | - Ho Kyoung Hwang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, Korea.
| | - In Woong Han
- Division of Hepatobiliary-Pancreatic Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, Korea.
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10
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Zhang Y, Xu S, Xu J, Wu S, Yao W, Lu S, Zhang G, Chen T. Iodine-125 brachytherapy in inoperable duodenal papilla carcinoma: a case report series. Front Oncol 2024; 14:1394178. [PMID: 39050575 PMCID: PMC11266157 DOI: 10.3389/fonc.2024.1394178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 06/28/2024] [Indexed: 07/27/2024] Open
Abstract
Background Duodenal papilla carcinoma (DPC) is a rare malignancy often diagnosed at an advanced stage. When surgery is not feasible in localized disease due to advanced age or comorbidities, there remains no consensus on optimal management for these patients. Case summary This case series details the therapeutic outcomes of 125I seed implantation in two elderly patients with DPC. A notable tumor reduction was achieved within two months after implantation. Furthermore, both patients demonstrated radiological tumor response and survived for over six months following the initial 125I seed treatment, marking the first reported instance of 125I seed implantation to effectively control DPC. Conclusion The anti-tumor activity of 125I seed implantation in the reported two cases of DPC underscores its potential as a viable treatment option for inoperable localized DPC.
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Affiliation(s)
- Yue Zhang
- Department of Interventional Oncology, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shangbin Xu
- Department of Interventional Oncology, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Xu
- Department of Interventional Oncology, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shen Wu
- Department of Interventional Oncology, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenyi Yao
- Department of Interventional Oncology, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shengying Lu
- Department of Interventional Oncology, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guangtao Zhang
- Department of Interventional Oncology, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tingsong Chen
- Department of Interventional Oncology, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
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11
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Lee J, Park YB, Han SY, Joo DC, Hong SM, Yi K, Kim DU. New Method of Papillectomy May Decrease Recurrence: Anchoring Method versus Conventional Method. J Clin Med 2024; 13:3226. [PMID: 38892937 PMCID: PMC11172506 DOI: 10.3390/jcm13113226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 05/16/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Background/Objectives: Endoscopic papillectomy (EP) is the preferred treatment for ampullary tumors because it has fewer side effects than surgical removal. This study retrospectively compared a new anchoring EP method (A-EP) with the conventional (C-EP) approach. Methods: Ninety-nine patients who underwent EP at a single medical institution between 2009 and 2021 were retrospectively reviewed. In all patients, the indications for EP were pathological adenoma with <10 mm of biliary invasion and a tumor diameter <30 mm on endoscopic ultrasonography. The exclusion criteria were antiplatelet/anticoagulant use, previous upper GI surgery, or prior biliary/pancreatic endoscopic therapy. One expert endoscopist performed the two types of EPs, A-EP and C-EP. Results: Sixty-two patients underwent A-EP, and 37 underwent C-EP. There were no significant differences in baseline characteristics, such as sex, age, tumor size, and ductal invasion on endoscopic ultrasound. The A-EP group had higher en bloc resection rates (95.2% vs. 78.4%, p = 0.010). Although the difference was not statistically significant, it tended towards fewer incidences of pancreatitis (p = 0.081) and duct stricture (p = 0.081). The recurrence rate was lower in the A-EP group (8.1% vs. 37.8%, p = 0.000). There were no significant differences between the two groups regarding the follow-up period (A-EP vs. C-EP, 725 vs. 1045 days, p = 0.109) or the days of recurrence (A-EP vs. C-EP, 341 vs. 562 days, p = 0.551). Conclusions: A-EP showed better outcomes than C-EP in terms of en bloc resection and recurrence rates, providing evidence for the efficacy of this novel EP method.
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Affiliation(s)
- Jonghyun Lee
- Division of Gastroenterology, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea; (J.L.); (Y.B.P.); (S.Y.H.); (D.C.J.); (S.M.H.); (K.Y.)
- Department of Internal Medicine, College of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Yong Bo Park
- Division of Gastroenterology, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea; (J.L.); (Y.B.P.); (S.Y.H.); (D.C.J.); (S.M.H.); (K.Y.)
| | - Sung Yong Han
- Division of Gastroenterology, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea; (J.L.); (Y.B.P.); (S.Y.H.); (D.C.J.); (S.M.H.); (K.Y.)
- Department of Internal Medicine, College of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Dong Chan Joo
- Division of Gastroenterology, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea; (J.L.); (Y.B.P.); (S.Y.H.); (D.C.J.); (S.M.H.); (K.Y.)
- Department of Internal Medicine, College of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Seung Min Hong
- Division of Gastroenterology, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea; (J.L.); (Y.B.P.); (S.Y.H.); (D.C.J.); (S.M.H.); (K.Y.)
- Department of Internal Medicine, College of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Kiyoun Yi
- Division of Gastroenterology, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea; (J.L.); (Y.B.P.); (S.Y.H.); (D.C.J.); (S.M.H.); (K.Y.)
- Department of Internal Medicine, College of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Dong Uk Kim
- Department of Internal Medicine, CHA Gumi Medical Center, CHA University, Gumi-si 39295, Republic of Korea
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12
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Cui TT, Guo XX, Li BR, Wang ZK, Xiao NJ, Liu F, Wang XD, Li W. The role of EUS-guided iodine-125 seed implantation in patients with unresectable ampullary cancer after relief of obstructive jaundice. J Contemp Brachytherapy 2024; 16:121-127. [PMID: 38808212 PMCID: PMC11129651 DOI: 10.5114/jcb.2024.139279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 04/09/2024] [Indexed: 05/30/2024] Open
Abstract
Purpose Few studies have focused on the management of inoperable ampullary carcinoma (AC), and patients with jaundice suffer from biliary stents replacement frequently. Iodine-125 (125I) brachytherapy has been used in the treatment of malignant tumors owing to its curative effect, minimal surgical trauma, and tolerable complications. The aim of the study was to investigate the role of 125I seed implantation in patients with unresectable ampullary carcinoma after relief of obstructive jaundice. Material and methods A total of 44 patients with obstructive jaundice resulting from unresectable ampullary carcinoma from January 1, 2010 to October 31, 2020 were enrolled in the study. Eleven patients underwent implantation of 125I seeds under endoscopic ultrasound (EUS) after receiving biliary stent placement via endoscopic retrograde cholangiopancreatography (ERCP) (treatment group), and 33 patients received a stent alone via ERCP (control group). Cox regression model was applied in this single-center retrospective comparison study. Results The median maximum intervention interval for biliary obstruction was 381 days (interquartile range [IQR]: 204-419 days) in the treatment group and 175 days (IQR: 126-274 days) in the control group (p < 0.05). Stent occlusion rates at 90 and 180 days in the control group were 12.9% and 51.6%, respectively. No stent occlusion occurred in the treatment group. Patients in the treatment group obtained longer survival time (median, 26 vs. 13 months; p < 0.01) and prolonged duodenal obstruction (median, 20.5 vs. 11 months; p < 0.05). No brachytherapy-related grade 3 or 4 adverse events were observed. Conclusions Longer intervention interval for biliary obstruction and survival as well as better stent patency and prolonged time to duodenal obstruction could be achieved by implanting 125I seeds combined with biliary stent in patients with unresectable ampullary cancer.
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Affiliation(s)
- Ting-ting Cui
- Department of Gastroenterology and Hepatology, Air Force Medical Center, Beijing, China
- Department of Gastroenterology and Hepatology, Medical School of Chinese PLA, Beijing, China
| | - Xin-xiang Guo
- Physical Examination Center, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China
| | - Bai-rong Li
- Department of Gastroenterology and Hepatology, Air Force Medical Center, Beijing, China
| | - Zi-kai Wang
- Department of Gastroenterology and Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Nian-jun Xiao
- Department of Gastroenterology and Hepatology, Air Force Medical Center, Beijing, China
- Department of Gastroenterology and Hepatology, Medical School of Chinese PLA, Beijing, China
| | - Fang Liu
- Department of Gastroenterology and Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xiang-dong Wang
- Department of Gastroenterology and Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Wen Li
- Department of Gastroenterology and Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, China
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13
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Peirce V, Paskow M, Qin L, Dadzie R, Rapoport M, Prince S, Johal S. A Systematised Literature Review of Real-World Treatment Patterns and Outcomes in Unresectable Advanced or Metastatic Biliary Tract Cancer. Target Oncol 2023; 18:837-852. [PMID: 37751011 PMCID: PMC10663194 DOI: 10.1007/s11523-023-01000-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/08/2023] [Indexed: 09/27/2023]
Abstract
BACKGROUND Biliary tract cancers are rare aggressive malignancies typically diagnosed when the disease is metastatic or unresectable, precluding curative treatment. OBJECTIVE We aimed to identify treatment guidelines, real-world treatment patterns, and outcomes for unresectable advanced or metastatic biliary tract cancers in adult patients. METHODS Databases (MEDLINE, Embase, Cochrane Database of Systematic Reviews) were systematically searched between 1 January, 2000 and 25 November, 2021, and supplemented by hand searches. Eligible records were (1) treatment guidelines and (2) observational studies reporting real-world treatment outcomes, for unresectable advanced or metastatic biliary tract cancers. Only studies performed in the UK, Germany, France, Australia, Canada and South Korea were extracted, to moderate the number of records for synthesis while maintaining representation of a wide range of biliary tract cancer incidences. RESULTS A total of 66 relevant unique full-text records were extracted, including 16 treatment guidelines and 50 observational studies. Among guidelines, chemotherapies were most strongly recommended at first line (1L); the combination of gemcitabine and cisplatin (GEMCIS) was recommended as the standard of care in 1L. Recommendations for systemic chemotherapy in the second line (2L) conflicted because of uncertainties around survival benefit. Guidelines on further lines of treatment included a range of locoregional modalities and stenting or best supportive care without providing clear recommendations because of data paucity. Fifty observational studies reporting real-world treatment outcomes were extracted, of which 25 (50%) and 9 (18%) reported outcomes in 1L and 2L, respectively; 22 (44%) reported outcomes for treatments described as 'palliative'. In 1L, outcomes for systemic chemotherapy were most frequently described (23/25 studies), and GEMCIS was the most common systemic chemotherapy used (10/23 studies) in line with guidelines. Median overall survival with 1L systemic chemotherapy was < 12 months in most studies (16/23; range 4.7-22.3 months). Most 2L studies (10/11) described outcomes for systemic chemotherapy, most commonly for fluoropyrimidine-based regimen (5/10 studies). Median overall survival with 2L systemic chemotherapy was < 12 months in 5/10 studies (range 4.9-21.5 months). Median progression-free survival was reported more rarely than median overall survival. Some studies with small sample sizes or specifically selected patient populations (e.g. higher performance status, or patients who had already responded to treatment) achieved higher median overall survival. CONCLUSIONS At the time of this review, treatment options for unresectable advanced or metastatic biliary tract cancers confer poor real-world survival. For over a decade, GEMCIS remained the 1L standard of care, highlighting the lack of therapeutic innovation in this indication and the urgent unmet need for novel treatments with improved outcomes in this aggressive condition. Additional observational studies are needed to further understand the effectiveness of currently available treatments, as well as newly available therapies including the addition of immunotherapy in the evolving treatment landscape.
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Affiliation(s)
- Vivian Peirce
- AstraZeneca, Academy House, 132-136 Hills Road, Cambridge, CB2 8PA, UK.
| | | | - Lei Qin
- AstraZeneca, Gaithersburg, MD, USA
| | | | | | | | - Sukhvinder Johal
- AstraZeneca, Academy House, 132-136 Hills Road, Cambridge, CB2 8PA, UK
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14
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Walter D, Schnitzbauer AA, Schulze F, Trojan J. The Diagnosis and Treatment of Ampullary Carcinoma. DEUTSCHES ARZTEBLATT INTERNATIONAL 2023; 120:729-735. [PMID: 37656482 DOI: 10.3238/arztebl.m2023.0195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 08/09/2023] [Accepted: 08/09/2023] [Indexed: 09/02/2023]
Abstract
BACKGROUND Ampullary or papillary carcinoma is a malignant tumor arising from the mucosa in the region of the major duodenal papilla, also known as the ampulla of Vater. Uniform treatment recommendations are lacking both for the adjuvant situation and for palliative care. METHODS A selective literature search was carried out in PubMed in order to identify the most informative publications concerning the epidemiology, clinico-pathological background, and surgical and medical treatment of this condition. RESULTS Ampullary carcinoma has an incidence of 0.5 to 0.9 per 100 000 persons and a poor prognosis, with a 5-year survival rate of 41% to 45% for locally confined and 4% to 7% for metastatic disease. Most such tumors are of an intestinal or a pan - creaticobiliary immunohistochemical subtype; the latter has a worse prognosis (median survival, 72-80 vs. 33-41 months). Targeted treatment is not yet available for either subtype, nor is there enough scientific evidence available for the formulation of specific therapeutic recommendations in either the adjuvant or the palliative situation. The treatment of choice for ampullary carcinoma is radical oncological resection of the head of the pancreas with systematic lymphadenectomy. Five-year overall survival is between 10% and 75% depending on the stage. No definitive recommendation for adjuvant therapy can be given. Palliative therapy can be oriented to the published treatment strategies for cancer of the colon, pancreas, and bile duct. CONCLUSION The current state of the evidence on the treatment of ampullary carcinoma is poor. Therapeutic decisions should be discussed in an interdisciplinary tumor board and should, in our opinion, take the histological subtype into account.
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Affiliation(s)
- Dirk Walter
- Department of Internal Medicine, J.W. Goethe University Hospital, Frankfurt/Main; Department of General, Visceral, Transplant- and Thoracic Surgery, J.W. Goethe University Hospital, Frankfurt/Main; Dr. Senckenberg Institute for Pathology, University Hospital Frankfurt, Goethe University Frankfurt am Main
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15
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Zhang XJ, Fei H, Guo CG, Sun CY, Li ZF, Li Z, Chen YT, Che X, Zhao DB. Analysis of textbook outcomes for ampullary carcinoma patients following pancreaticoduodenectomy. World J Gastrointest Surg 2023; 15:2259-2271. [PMID: 37969713 PMCID: PMC10642474 DOI: 10.4240/wjgs.v15.i10.2259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 09/01/2023] [Accepted: 09/07/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND Textbook outcomes (TOs) have been used to assess the quality of surgical treatment for many digestive tumours but not ampullary carcinoma (AC). AIM To discuss the factors associated with achieving a TO and further explore the prognostic value of a TO for AC patients undergoing curative pancreaticoduodenectomy (PD). METHODS Patients who underwent PD at the China National Cancer Center between 1998 and 2020 were identified. A TO was defined by R0 resection, examination of ≥ 12 Lymph nodes, no prolonged hospitalization, no intensive care unit treatment, no postoperative complications, and no 30-day readmission or mortality. Cox regression analysis was used to identify the prognostic value of a TO for overall survival (OS) and recurrence-free survival (RFS). Logistic regression was used to identify predictors of a TO. The rate of a TO and of each indicator were compared in patients who underwent surgery before and after 2010. RESULTS Ultimately, only 24.3% of 272 AC patients achieved a TO. A TO was independently associated with improved OS [hazard ratio (HR): 0.443, 95% confidence interval (95%CI): 0.276-0.711, P = 0.001] and RFS (HR: 0.379, 95%CI: 0.228-0.629, P < 0.001) in the Cox regression analysis. Factors independently associated with a TO included a year of surgery between 2010 and 2020 (OR: 4.549, 95%CI: 2.064-10.028, P < 0.001) and N1 stage disease (OR: 2.251, 95%CI: 1.023-4.954, P = 0.044). In addition, the TO rate was significantly higher in patients who underwent surgery after 2010 (P < 0.001) than in those who underwent surgery before 2010. CONCLUSION Only approximately a quarter (24.3%) of AC patients achieved a TO following PD. A TO was independently related to favourable oncological outcomes in AC and should be considered as an outcome measure for the quality of surgery. Further multicentre research is warranted to better elucidate its impact.
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Affiliation(s)
- Xiao-Jie Zhang
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - He Fei
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Chun-Guang Guo
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Chong-Yuan Sun
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ze-Feng Li
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zheng Li
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ying-Tai Chen
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xu Che
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China
| | - Dong-Bing Zhao
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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16
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Maselli R, de Sire R, Fugazza A, Spadaccini M, Colombo M, Capogreco A, Beyna T, Repici A. Updates on the Management of Ampullary Neoplastic Lesions. Diagnostics (Basel) 2023; 13:3138. [PMID: 37835881 PMCID: PMC10572979 DOI: 10.3390/diagnostics13193138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/03/2023] [Accepted: 10/04/2023] [Indexed: 10/15/2023] Open
Abstract
Ampullary neoplastic lesions (ANLs) represent a rare cancer, accounting for about 0.6-0.8% of all gastrointestinal malignancies, and about 6-17% of periampullary tumors. They can be sporadic or occur in the setting of a hereditary predisposition syndrome, mainly familial adenomatous polyposis (FAP). Usually, noninvasive ANLs are asymptomatic and detected accidentally during esophagogastroduodenoscopy (EGD). When symptomatic, ANLs can manifest differently with jaundice, pain, pancreatitis, cholangitis, and melaena. Endoscopy with a side-viewing duodenoscopy, endoscopic ultrasound (EUS), and magnetic resonance cholangiopancreatography (MRCP) play a crucial role in the ANL evaluation, providing an accurate assessment of the size, location, and characteristics of the lesions, including the staging of the depth of tumor invasion into the surrounding tissues and the involvement of local lymph nodes. Endoscopic papillectomy (EP) has been recognized as an effective treatment for ANLs in selected patients, providing an alternative to traditional surgical methods. Originally, EP was recommended for benign lesions and patients unfit for surgery. However, advancements in endoscopic techniques have broadened its indications to comprise early ampullary carcinoma, giant laterally spreading lesions, and ANLs with intraductal extension. In this paper, we review the existing evidence on endoscopic diagnosis and treatment of ampullary neoplastic lesions.
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Affiliation(s)
- Roberta Maselli
- Gastroenterology, Endoscopy Unit, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (R.M.); (A.F.); (M.S.); (M.C.); (A.C.); (A.R.)
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy
| | - Roberto de Sire
- Gastroenterology, Endoscopy Unit, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (R.M.); (A.F.); (M.S.); (M.C.); (A.C.); (A.R.)
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, University Federico II of Naples, 80126 Naples, Italy
| | - Alessandro Fugazza
- Gastroenterology, Endoscopy Unit, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (R.M.); (A.F.); (M.S.); (M.C.); (A.C.); (A.R.)
| | - Marco Spadaccini
- Gastroenterology, Endoscopy Unit, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (R.M.); (A.F.); (M.S.); (M.C.); (A.C.); (A.R.)
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy
| | - Matteo Colombo
- Gastroenterology, Endoscopy Unit, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (R.M.); (A.F.); (M.S.); (M.C.); (A.C.); (A.R.)
| | - Antonio Capogreco
- Gastroenterology, Endoscopy Unit, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (R.M.); (A.F.); (M.S.); (M.C.); (A.C.); (A.R.)
| | - Torsten Beyna
- Department of General Internal Medicine and Gastroenterology, Evangelisches Krankenhaus, 40217 Düsseldorf, Germany;
| | - Alessandro Repici
- Gastroenterology, Endoscopy Unit, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (R.M.); (A.F.); (M.S.); (M.C.); (A.C.); (A.R.)
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy
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17
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Guo Q, Ding X, Lv F, Xiao D, Wang J, Ji G. Diagnostic value of endoscopic ultrasonography in periampullary duodenal tumours. J Minim Access Surg 2023; 19:540-543. [PMID: 37861647 PMCID: PMC10695309 DOI: 10.4103/jmas.jmas_240_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/28/2022] [Accepted: 05/03/2023] [Indexed: 10/21/2023] Open
Abstract
Introduction The objective of this study was to investigate the diagnostic value of endoscopic ultrasonography (EUS) for tumours around the duodenal ampullary. Patients and Methods A retrospective analysis was performed on cases diagnosed and treated in our hospital from October 2016 to August 2021 due to the lesions around the duodenal ampulla. All patients received EUS, abdominal enhanced computed tomography (CT) and magnetic resonance imaging combined with magnetic resonance cholangiopancreatography (MRI-MRCP). Pathological diagnosis was used to verify the accuracy of the imaging findings. The detection rates of periampullary tumours by EUS, abdominal enhanced CT and MRI-MRCP were determined and compared. Results A total of 86 patients were included in this study. According to the pathological diagnosis, the detection rate of EUS was 87% (36/41) for periampullary tumour lesions with a tumour diameter <1 cm, which was significantly higher than that of MRI-MRCP (59%, 24/41) (P = 0.003) and CT (44%, 18/41) (P < 0.001). For periampullary tumour lesions with a tumour diameter ≥1 cm, the detection rate of MRI-MRCP was 93% (42/45), which was significantly higher than that of EUS (78%, 35/45) (P = 0.036) and CT (76%, 34/45) (P = 0.02). Conclusions EUS can accurately detect tumour lesions around the ampullary part of the duodenum with minimal gas interference. For periampullary tumour lesions <1 cm, EUS has better diagnostic accuracy than abdominal-enhanced CT and MRI-MRCP. In addition, a biopsy of the lesion can be performed at the same time during the EUS examination. Therefore, EUS has an important clinical significance and value in the diagnosis of duodenal periampullary tumours.
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Affiliation(s)
- Qiuxia Guo
- Department of Gastroenterology, Wuhan Fourth Hospital, Wuhan, Hubei Province, China
| | - Xiangwu Ding
- Department of Gastroenterology, Wuhan Fourth Hospital, Wuhan, Hubei Province, China
| | - Fei Lv
- Department of Gastroenterology, Wuhan Fourth Hospital, Wuhan, Hubei Province, China
| | - Ding Xiao
- Department of Gastroenterology, Wuhan Fourth Hospital, Wuhan, Hubei Province, China
| | - Jing Wang
- Department of Gastroenterology, Wuhan Fourth Hospital, Wuhan, Hubei Province, China
| | - Guibao Ji
- Department of Gastroenterology, Wuhan Fourth Hospital, Wuhan, Hubei Province, China
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Oflas D, Canaz F, Özer İ, Demir L, Çolak E. Significance of High-Mobility Group A Protein 2 Expression in Pancreatic Ductal Adenocarcinoma and Ampullary Adenocarcinoma. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2023; 34:1014-1024. [PMID: 37787719 PMCID: PMC10645280 DOI: 10.5152/tjg.2023.22881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 09/03/2023] [Indexed: 10/04/2023]
Abstract
BACKGROUND/AIMS Pancreatic and ampullary adenocarcinoma (AAC) are quite resistant to chemotherapy with high metastasis potential. Our study aimed to interpret high-mobility group A protein 2 (HMGA2) expression in benign and precursor pancreatic lesions and pancreatic and ampullary carcinoma and to evaluate its relationship with epithelial-mesenchymal transition (EMT) and clinicopathological parameters. MATERIALS AND METHODS In this study, normal-appearing pancreas, chronic pancreatitis (CP), low- (L) and high (H)-grade pancreatic intraepithelial neoplasia (PanIN), pancreatic ductal adenocarcinoma (PDAC), and AAC were evaluated with the immunohistochemical marker of HMGA2. Vimentin and E-cadherin immunohistochemical stains were applied in PDAC and AAC. RESULTS The HMGA2 expression was not detected in normal-appearing pancreas, CP, and L-PanIN. A statistically significant expression was observed in PDAC and H-PanIN (P < .001). A statistically significant correlation was found between loss of membranous E-cadherin expression and vimentin positivity and HMGA2 expression (P > .05). The HMGA2 expression was observed to increase the risk of diseaserelated death and decrease overall survival (OS) in AAC and the neoplasia group (P = .002 and P = .016, respectively). There was no significant difference in OS and risk of death in PDAC (P > .05) with respect to HMGA2 positivity. CONCLUSION High-mobility group A protein 2 is a helpful immunohistochemical marker in differentiating CP from PDAC. It also plays a role in EMT and may serve as a potential new prognostic agent and therapeutic target in tumors of the periampullary region, especially AAC.
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Affiliation(s)
- Damla Oflas
- Department of Pathology, Osmangazi University Faculty of Medicine, Eskişehir, Turkey
| | - Funda Canaz
- Department of Pathology, Osmangazi University Faculty of Medicine, Eskişehir, Turkey
| | - İlter Özer
- Department of General Surgery, Osmangazi University Faculty of Medicine, Eskişehir, Turkey
| | - Lütfiye Demir
- Department of Medical Oncology, Osmangazi University Faculty of Medicine, Eskişehir, Turkey
| | - Ertuğrul Çolak
- Department of Biostatistics, Osmangazi University Faculty of Medicine, Eskişehir, Turkey
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19
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Jun SY, Lee EJ, Kim SI, An S. Tumor Microenvironment Prognostic Risk and Its Association With MUC5AC in Ampullary Carcinoma. Arch Pathol Lab Med 2023; 147:1060-1074. [PMID: 36445719 DOI: 10.5858/arpa.2022-0131-oa] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/05/2022] [Indexed: 09/01/2023]
Abstract
CONTEXT.— The tumor-host interaction in the tumor microenvironment (TME) affects the prognosis of patients with malignant tumors. TME assessed via tumor budding (BD) and tumor-infiltrating lymphocyte (TIL) had a prognostic impact in patients with nonampullary small intestinal and colorectal carcinomas. In ampullary carcinoma (AC), MUC5AC was recently revealed as a significant prognosticator, but studies about the TME have not been conducted. OBJECTIVE.— To assess TME-based prognostic risk in AC. DESIGN.— We generated a collective TME risk index based on high-grade BD at the invasive front (BD3) and high density of stromal-TIL (>5%) in 64 surgically resected ACs. We evaluated its predictive values for overall survival (OS) and recurrence-free survival (RFS). We also investigated the relationship of TME to MUC5AC expression. RESULTS.— TME prognostic risk index was classified into low-risk (BDLow/TILHigh; 26 of 64; 41%), intermediate-risk (BDLow/TILLow or BDHigh/TILHigh; 23; 36%), and high-risk (BDHigh/TILLow; 15; 23%) groups. Higher TME prognostic risk was associated with higher tumor grade (P = .03), lymphovascular invasion (P = .05), and MUC5AC immunopositivity (P = .02). TME prognostic risk index displayed better predictive ability for both OS (53.9 versus 46.1 versus 42.2) and RFS (24.8 versus 16.9 versus 15.3) than BD or TIL alone. In multivariate analysis, TME prognostic risk index was an independent prognosticator for OS (P = .003) and RFS (P = .03). CONCLUSIONS.— TME risk index in combination with BD and TIL was a stronger predictor of prognostic risk stratification than either BD or TIL alone for both OS and RFS in patients with AC. MUC5AC may modulate the interaction between tumor cells and immunity toward enhancing invasiveness in TME.
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Affiliation(s)
- Sun-Young Jun
- From the Department of Pathology (Jun, Kim, An), Incheon St Mary�s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eui-Jin Lee
- The Clinical Research Center (Lee), Incheon St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sang-Il Kim
- From the Department of Pathology (Jun, Kim, An), Incheon St Mary�s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Soyeon An
- From the Department of Pathology (Jun, Kim, An), Incheon St Mary�s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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20
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Gonçalves M, Rebelo A, Costa R, Ferreira A. Endoscopic ampullectomy of a giant pedunculated ampullary adenoma. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2023; 115:467-468. [PMID: 36426861 DOI: 10.17235/reed.2022.9316/2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/05/2023]
Abstract
The authors present a case of a 72-year-old woman with a personal history of arterial hypertension, dyslipidemia and gallstones. For suspected choledocholithiasis, a MR-Cholangiopancreatography was performed, which revealed the presence of an endoluminal polypoid structure in the third duodenal portion.
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Affiliation(s)
| | | | - Rita Costa
- Gastrenterology, Braga Hospital, Portugal
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21
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Facer BD, Cloyd JM, Manne A, Pitter KL, Diaz DA, Bazan JG, Miller ED. Treatment Patterns and Outcomes for Patients with Ampullary Carcinoma Who Do Not Undergo Surgery. Cancers (Basel) 2023; 15:3727. [PMID: 37509388 PMCID: PMC10378072 DOI: 10.3390/cancers15143727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/18/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
Abstract
Surgical resection is the standard of care for ampullary adenocarcinoma (AC). Many patients are ineligible due to comorbidities/advanced disease. Evidence for the optimal non-operative management of localized AC is lacking. We hypothesize that patients treated with chemotherapy (CT) and definitive radiation (DRT) will have superior survival (OS) compared to those treated with CT alone. We performed a retrospective review of the National Cancer Database from 2004 to 2017 to identify patients with non-metastatic AC and no surgical intervention. Patients were categorized as having received no treatment, palliative radiotherapy (PRT) alone, CT alone, CT + PRT, DRT alone, or CT + DRT. We utilized Kaplan-Meier analysis to determine OS and the log-rank test to compare survival curves. Among 2176 patients, treatment groups were: No treatment (71.2%), PRT alone (1.9%), CT alone (13.1%), CT + PRT (1.6%), DRT alone (2.4%), and CT + DRT (9.7%). One-year OS varied by treatment group, ranging from 35.1% (PRT alone) to 59.4% (CT + DRT). The one-year OS in a matched cohort was not significantly different between CT alone and CT + DRT (HR 0.87, 95% CI 0.69-1.10, p = 0.87). Most patients with non-metastatic AC not treated with surgery do not receive any treatment. There is no difference in one-year OS between those undergoing CT alone and CT + DRT.
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Affiliation(s)
- Benjin D Facer
- Department of Radiation Oncology, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Jordan M Cloyd
- Division of Surgical Oncology, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Ashish Manne
- Department of Internal Medicine, Division of Medical Oncology, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Kenneth L Pitter
- Department of Radiation Oncology, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Dayssy A Diaz
- Department of Radiation Oncology, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Jose G Bazan
- Department of Radiation Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Eric D Miller
- Department of Radiation Oncology, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
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22
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Nishio K, Kimura K, Murata A, Ohira G, Shinkawa H, Kodai S, Amano R, Tanaka S, Shimizu S, Takemura S, Kanazawa A, Kubo S, Ishizawa T. Comparison of clinicopathological characteristics between resected ampullary carcinoma and carcinoma of the second portion of the duodenum. World J Gastrointest Surg 2022; 14:1219-1229. [PMID: 36504514 PMCID: PMC9727577 DOI: 10.4240/wjgs.v14.i11.1219] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 10/10/2022] [Accepted: 10/20/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Few studies compared the oncological and biological characteristics between ampullary carcinoma (AC) and cancer of the second portion of the duodenum (DC-II), although both tumors arise from anatomically close locations.
AIM To elucidate differences in clinicopathological characteristics, especially the patterns of lymph node metastasis (LNM), between AC and DC-II.
METHODS This was a retrospective cohort study of 80 patients with AC and 27 patients with DC-II who underwent pancreaticoduodenectomy between January 1998 and December 2018 in two institutions. Clinicopathological factors, LNM patterns, and prognosis were compared between the two groups.
RESULTS The patients with AC and DC-II did not exhibit significant differences in 5-year overall survival (66.0% and 67.1%, respectively) and 5-year relapse-free survival (63.5% and 62.2%, respectively). Compared to the patients with DC-II, the rate of preoperative biliary drainage was higher (P = 0.042) and the rates of digestive symptoms (P = 0.0158), ulcerative-type cancer (P < 0.0001), large tumor diameter (P < 0.0001), and advanced tumor stage (P = 0.0019) were lower in the patients with AC. The LNM rates were 27.5% and 40.7% in patients with AC and DC-II, respectively, without significant difference (P = 0.23). The rates of LNM to hepatic nodes (N-He) and pyloric nodes (N-Py) were significantly higher in patients with DC-II than in those with AC (metastasis to N-HE: 18.5% and 5% in patients with DC-II and AC, respectively; P = 0.0432; metastasis to N-Py: 11.1% and 0% in patients with DC-II and AC, respectively; P = 0.0186)
CONCLUSION Although there were no significant differences in the prognosis and recurrence rates between the two groups, metastases to N-He and N-Py were more frequent in patients with DC-II than in those with AC.
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Affiliation(s)
- Kohei Nishio
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University, Osaka 5458585, Japan
| | - Kenjiro Kimura
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University, Osaka 5458585, Japan
| | - Akihiro Murata
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka City General Hospital, Osaka 5340021, Japan
| | - Go Ohira
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University, Osaka 5458585, Japan
| | - Hiroji Shinkawa
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University, Osaka 5458585, Japan
| | - Shintaro Kodai
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka City General Hospital, Osaka 5340021, Japan
| | - Ryosuke Amano
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University, Osaka 5458585, Japan
| | - Shogo Tanaka
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University, Osaka 5458585, Japan
| | - Sadatoshi Shimizu
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka City General Hospital, Osaka 5340021, Japan
| | - Shigekazu Takemura
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University, Osaka 5458585, Japan
| | - Akishige Kanazawa
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka City General Hospital, Osaka 5340021, Japan
| | - Shoji Kubo
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University, Osaka 5458585, Japan
| | - Takeaki Ishizawa
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University, Osaka 5458585, Japan
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23
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Zaccari P, Archibugi L, Belfiori G, Nista E, dell'Anna G, Crippa S, Schepis T, Tacelli M, Aleotti F, Petrone MC, Mariani A, Costamagna G, Gasbarrini A, Larghi A, Falconi M, Arcidiacono PG, Capurso G. Risk factors for the occurrence of ampullary tumors: A case-control study. United European Gastroenterol J 2022; 10:730-735. [PMID: 35894762 PMCID: PMC9486500 DOI: 10.1002/ueg2.12281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 06/28/2022] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The incidence of ampullary tumors is increasing but data on association with an increased exposure to certain risk factors are scanty. OBJECTIVE To investigate risk and protective factors associated with the occurrence of ampullary tumors and whether these factors differ between ampullary tumors of the intestinal and pancreatobiliary subtypes or between adenomas and carcinomas. METHODS The association between a large set of exposome features and ampullary tumors occurrence was investigated in a bi-centric case-control study after ethic committee approval and power calculation. RESULTS In 223 histologically confirmed patients and 446 controls, previous cholecystectomy (odd ratio [OR] = 2.07; 95% confidence interval [CI] = 1.34-3.20) and proton pump inhibitors use (OR = 1.66; 95% CI = 1.16-2.37) were associated with increased risk of ampullary tumors, aspirin use (OR = 0.57; 95% CI = 0.36-0.90) and light alcohol intake (OR = 0.54; 95% CI = 0.38-0.76) with reduced risk. A previous cholecystectomy was also associated with tumors of intestinal subtype and with both adenomas and carcinomas, and proton pump inhibitors use with adenomas only. Smoking, body mass index, family history of cancers, previous ulcer, diabetes and use of statins, insulin and metformin were not significant factors. CONCLUSION This is the first case-control study specifically highlighting factors associated with the occurrence of ampullary tumors. We report factors that are novel and plausible, in keeping with mechanisms described for other gastrointestinal tumors and with potential clinical relevance.
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Affiliation(s)
- Piera Zaccari
- Pancreato‐biliary Endoscopy and Endoscopic UltrasoundPancreas Translational and Clinical Research CenterSan Raffaele Scientific Institute IRCCSMilanItaly
| | - Livia Archibugi
- Pancreato‐biliary Endoscopy and Endoscopic UltrasoundPancreas Translational and Clinical Research CenterSan Raffaele Scientific Institute IRCCSMilanItaly
| | - Giulio Belfiori
- Pancreatic Surgery DivisionsPancreas Translational and Clinical Research CenterSan Raffaele Scientific Institute IRCCSMilanItaly
| | - Enrico Nista
- Department of Medical and Surgical SciencesFondazione Policlinico Universitario A. Gemelli IRCCSRomeItaly
| | - Giuseppe dell'Anna
- Pancreato‐biliary Endoscopy and Endoscopic UltrasoundPancreas Translational and Clinical Research CenterSan Raffaele Scientific Institute IRCCSMilanItaly
| | - Stefano Crippa
- Pancreatic Surgery DivisionsPancreas Translational and Clinical Research CenterSan Raffaele Scientific Institute IRCCSMilanItaly
| | - Tommaso Schepis
- Department of Medical and Surgical SciencesFondazione Policlinico Universitario A. Gemelli IRCCSRomeItaly
| | - Matteo Tacelli
- Pancreato‐biliary Endoscopy and Endoscopic UltrasoundPancreas Translational and Clinical Research CenterSan Raffaele Scientific Institute IRCCSMilanItaly
| | - Francesca Aleotti
- Pancreatic Surgery DivisionsPancreas Translational and Clinical Research CenterSan Raffaele Scientific Institute IRCCSMilanItaly
| | - Maria Chiara Petrone
- Pancreato‐biliary Endoscopy and Endoscopic UltrasoundPancreas Translational and Clinical Research CenterSan Raffaele Scientific Institute IRCCSMilanItaly
| | - Alberto Mariani
- Pancreato‐biliary Endoscopy and Endoscopic UltrasoundPancreas Translational and Clinical Research CenterSan Raffaele Scientific Institute IRCCSMilanItaly
| | - Guido Costamagna
- Digestive Endoscopy UnitFondazione Policlinico Universitario A. Gemelli IRCCSRomeItaly
| | - Antonio Gasbarrini
- Department of Medical and Surgical SciencesFondazione Policlinico Universitario A. Gemelli IRCCSRomeItaly
| | - Alberto Larghi
- Digestive Endoscopy UnitFondazione Policlinico Universitario A. Gemelli IRCCSRomeItaly
| | - Massimo Falconi
- Pancreatic Surgery DivisionsPancreas Translational and Clinical Research CenterSan Raffaele Scientific Institute IRCCSMilanItaly
| | - Paolo Giorgio Arcidiacono
- Pancreato‐biliary Endoscopy and Endoscopic UltrasoundPancreas Translational and Clinical Research CenterSan Raffaele Scientific Institute IRCCSMilanItaly
| | - Gabriele Capurso
- Pancreato‐biliary Endoscopy and Endoscopic UltrasoundPancreas Translational and Clinical Research CenterSan Raffaele Scientific Institute IRCCSMilanItaly
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24
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Abstract
Most ampullary lesions (ALs) are sporadic, involve the major papilla, and are premalignant (adenomas). They are often diagnosed as an incidental finding during endoscopy or imaging procedures. Diagnosis and staging of ALs include endoscopic, histologic, and radiological evaluations. Currently, endoscopic papillectomy is the preferred treatment for ALs in most situations. In this article, we will describe the diagnostic work-up and focus on the endoscopic treatment, including indications, technique, outcomes, complications, and follow-up.
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Affiliation(s)
- Sara Teles de Campos
- Department of Gastroenterology, Digestive Unit, Champalimaud Foundation, Avenida de Brasília, Lisbon 1400-038, Portugal
| | - Marco J Bruno
- Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Dr. Molewaterplein 40, Rotterdam 3015 GD, the Netherlands.
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25
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Duan Z, Zhang Y, Tang Y, Gao R, Bao J, Liang B. Adjuvant therapy for periampullary carcinoma and the significance of histopathological typing: A systematic review. Transl Oncol 2022; 20:101414. [PMID: 35397420 PMCID: PMC9006738 DOI: 10.1016/j.tranon.2022.101414] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 03/24/2022] [Accepted: 03/30/2022] [Indexed: 12/19/2022] Open
Abstract
The efficacy of adjuvant therapy for periampullary carcinoma is controversial. There is a trend of classification periampullary carcinoma into PB-type and IN-type, and the prognosis of different subtypes may be significantly different. The PB-type patients who accepted gemcitabine based chemotherapy and IN-type patients who accepted 5-FU based chemotherapy, maybe improved the prognosis. Chemoradiotherapy appears to be more effective in patients with advanced stages. There are few related studies on targeted therapy and immunotherapy, and further research is needed. Objective This review investigates the role of adjuvant therapy (AT) and the importance of histopathological typing in periampullary carcinoma (PAC) treatment. Background PAC is a relatively rare gastrointestinal malignancy. The regimen and effect of AT in PAC are still controversial. However, there is a treatment based on histopathological types (pancreaticobiliary-type, PB-type or intestinal-type, IN-type), but there are no clear guidelines indicating that typing can be used to guide the selection of AT drugs. Methods A literature search of PubMed and Web of Science databases was conducted for studies published from January 2001 to August 2021 on the use of AT in PAC. Results A total of 75 studies were included in this review. According to existing studies, AT for PAC is mostly based on 5-FU or gemcitabine, but the effect is unknown. However, when PAC is classified into different histopathological types, AT with gemcitabine is beneficial for patients with the PB-type of PAC, while 5-FU-based AT is beneficial for patients with the IN-type of PAC. In addition, the benefits of AT are more pronounced in patients with a high-risk disease, such as patients with stage II/III, T3/T4 tumors, or positive lymph node involvement. There are few studies on targeted therapy and immunotherapy for PAC. Conclusions This review suggests that AT has potential survival benefits, especially when based on the histopathologic type that helps the choice of drugs during AT in PAC patients.
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Affiliation(s)
- Zhiqing Duan
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yinuo Zhang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yajie Tang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ruqing Gao
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jing Bao
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Bo Liang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
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26
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Zubair AB, Khan Sherwani IAR, Ahmad M, Tahir MA, Khalil MI, Bukhari MM, Sabir M, Bhatti AA, Afzal N, Kaneez M. The Spectrum of Postoperative Complications and Outcomes After Pancreaticoduodenectomy: A Retrospective Outlook From a Developing Country. Cureus 2022; 14:e22218. [PMID: 35340487 PMCID: PMC8930489 DOI: 10.7759/cureus.22218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2022] [Indexed: 12/03/2022] Open
Abstract
Background Pancreaticoduodenectomy is an extremely complex surgical procedure that mandates aggressive postoperative management. Unfortunately, in developing countries, the limited resources and poor postoperative care lead to multiple complications and abysmal outcomes. Therefore, our study aimed to evaluate the spectrum of postoperative complications and outcomes among patients undergoing pancreaticoduodenectomy. Methods This retrospective study involved a total of 97 patients who underwent pancreaticoduodenectomy for ampullary, periampullary, or pancreatic tumors. Patients with advanced metastasis and unresectable tumors were excluded from the study. Patients were studied for various parameters including the demographic details, postoperative outcomes, characteristics of the tumor, and postoperative complications. Results Out of 97 patients, 59 (60.8%) patients were males. The mean age of the study participants was 53.43 ± 17.89 years. Jaundice and abdominal pain were the most common presenting symptoms among the study participants. Of the 97 patients, 58 (59.8%) had malignant tumors. A total of 49 patients developed various postoperative complications including surgical site infections (10.3%), anastomosis leakage (9.27%), pancreatic fistula (9.27%), cholangitis (7.2%), and biliary leakage (4.1%). A total of 29 (29.9%) patients expired due to postoperative complications. Conclusions Surgical site infections, anastomosis leakage, pancreatic fistula, cholangitis, and biliary leakage are common but preventable postoperative complications after pancreaticoduodenectomy. These lead to morbidity and mortality, especially in the setting of a resource-deprived developing country. Aggressive postoperative management, improved surgical technique, better intraoperative hemostasis management, and a multi-disciplinary approach for the management of such patients can help in preventing postoperative complications and improving the postoperative outcomes.
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Scroggie DL, Mavroeidis VK. Surgical ampullectomy: A comprehensive review. World J Gastrointest Surg 2021; 13:1338-1350. [PMID: 34950424 PMCID: PMC8649570 DOI: 10.4240/wjgs.v13.i11.1338] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/29/2021] [Accepted: 10/14/2021] [Indexed: 02/06/2023] Open
Abstract
Tumours of the ampulla of Vater are relatively uncommon lesions of the digestive system. They are typically diagnosed at an earlier stage than other types of tumours in this region, due to their tendency to invoke symptoms by obstructing the bile duct or pancreatic duct. Consequently, many are potentially curable by excision. Surgical ampullectomy (SA) (or transduodenal ampullectomy) for an ampullary tumour was first described in 1899, but was soon surpassed by pancreatoduodenectomy (PD), which offered a more extensive resection resulting in a lower risk of recurrence. Ongoing innovation in endoscopic techniques over recent decades has led to the popularization of endoscopic papillectomy (EP), particularly for adenomas and even early cancers. The vast majority of resectable ampullary tumours are now treated using either PD or EP. However, SA continues to play a role in specific circumstances. Many authors have suggested specific indications for SA based on their own data, practices, or interpretations of the literature. However, certain issues have attracted controversy, such as its use for early ampullary cancers. Consequently, there has been a lack of clarity regarding indications for SA, and no evidence-based consensus guidelines have been produced. All studies reporting SA have employed observational designs, and have been heterogeneous in their methodologies. Accordingly, characteristics of patients and their tumours have differed substantially across treatment groups. Therefore, meaningful comparisons of clinical outcomes between SA, PD and EP have been elusive. Nevertheless, it appears that suitably selected cases of ampullary tumours subjected to SA may benefit from favourable peri-operative and long-term outcomes with very low mortality and significantly long survival, hence its role in this setting warrants further clarification, while it can also be useful in the management of specific benign entities. Whilst the commissioning of a randomised controlled trial seems unlikely, well-designed observational studies incorporating adjustments for confounding variables may become the best available comparative evidence for SA, potentially informing the eventual development of consensus guidelines. In this comprehensive review, we explore the role of SA in the modern management of ampullary lesions.
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Affiliation(s)
- Darren L Scroggie
- Department of Population Health Sciences, Bristol Centre for Surgical Research, Bristol Medical School, Bristol BS8 2PS, United Kingdom
| | - Vasileios K Mavroeidis
- Department of HPB Surgery, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom
- Department of Surgery, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, United Kingdom
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Rare Orbital Metastasis Originating from Ampullary Adenocarcinoma. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:medicina57111238. [PMID: 34833456 PMCID: PMC8624159 DOI: 10.3390/medicina57111238] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 11/12/2021] [Indexed: 12/13/2022]
Abstract
Background: Orbital metastasis from ampullary carcinoma is rare, with no previously reported cases. Case presentation: We report the case of a 60-year-old man who complained of a right-sided headache, blurred vision, progressive proptosis, ptosis, and right eye pain for 3 months. His past medical history included an ampullary adenocarcinoma stage IIIA treated via the Whipple procedure and adjuvant chemoradiotherapy 1 year ago. However, he was lost to follow-up. Computed tomography of the orbit showed a soft tissue lesion in the right orbital fossa measuring 3.3 × 2 × 2 cm. An orbital mass biopsy demonstrated an intestinal-type adenocarcinoma that tested positive for cytokeratins 7 and 20 and CDX2 on immunohistochemical staining. The pathologic diagnosis was metastatic adenocarcinoma from the ampulla of Vater. Despite oncological treatment, the patient’s illness progressed. He received palliative treatment and died 1 month later. Conclusions: We presented a rare case of orbital metastasis from ampullary adenocarcinoma. This should be considered in the differential diagnosis of patients with a history of ampullary adenocarcinoma who present with symptoms referring to the relevant locations.
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Abstract
OPINION STATEMENT ACs are rare tumors, and thus, there is a lack of prospective trials supporting treatment decisions. Moreover, although anatomically uniform, ACs comprise of biologically distinct entities, depending on what cell type they arise from. This makes the interpretation of limited data even more challenging. Overall, the clinical outcomes of patients with AC are better than those with pancreatic cancer. However, recurrence rates remain high after curative resection. Despite the absence of definitive evidence, we believe that these high recurrence rates are a rational justification for consideration of adjuvant therapy in resected disease, and therapy selection should take tumor biology, stage, resection margins, as well as patient comorbidities and performance status into account. Largely extrapolating from pancreas cancer, we recommend consideration of adjuvant chemotherapy with 6 months of dose-modified FOLFIRINOX in fit patients with pancreatobiliary subtype tumors. Alternative regimens include gemcitabine in combination with capecitabine. If chemoradiotherapy is being added, 6 weeks of radiotherapy in conjunction with 5-FU or capecitabine can be considered. For intestinal subtypes, we recommend 3-6 months of adjuvant FOLFOX. Future studies are needed to evaluate the role of contemporary, multi-agent chemotherapy and chemoradiotherapy in patients with resected and advanced ampullary adenocarcinoma. However, the logistics of performing large randomized trials in patients with a rare cancer is challenging, and the data collection, even in a carefully designed study, would likely take many years. As such, relying on data from basket trials and retrospective analysis will likely serve as guidance for treatment decisions in the near future. Treatment of metastatic disease should employ regimens that are typically used to treat pancreas cancer for tumors of pancreatobiliary subtype and 5-FU-based regimens for intestinal subtypes. Studies specific for patients with advanced AC are much needed. Molecular testing using next-generation sequencing and testing for microsatellite instability (MSI) should be performed on all tumors. We now have disease agnostic options based on these results. Pembrolizumab is approved for MSI-H tumors and tumors with high tumor mutational burden regardless of the primary site. Larotrectinib is approved for tumors with NTRK fusions. At a time when numerous therapeutic agents are in development, for example, those targeting specific K-RAS alterations or NRG fusions, identifying molecular aberrations can significantly impact patient outcomes as well as provide further insights into the biology of disease. In addition, based on recent data suggesting a significant prevalence of germline alterations in patients with ampullary tumors, referral to genetics counselors and germline testing is warranted in a significant proportion of patients with AC.
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Lemmers DHL, Cherri S, van Etten-Jamaludin FS, Noventa S, Zaniboni A, Wilmink JW, Besselink MG, Abu Hilal M. Adjuvant chemotherapy following curative-intent resection for ampullary adenocarcinoma. Hippokratia 2021. [DOI: 10.1002/14651858.cd014749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Daniel HL Lemmers
- Department of Surgery, Hepato-Biliary and Pancreatic Unit; Instituto Fondazione Poliambulanza; Brescia Italy
- Department of Surgery; Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam; Amsterdam Netherlands
| | - Sara Cherri
- Department of Medical Oncology; Instituto Fondazione Poliambulanza; Brescia Italy
| | | | - Silvia Noventa
- Department of Medical Oncology; Instituto Fondazione Poliambulanza; Brescia Italy
| | - Alberto Zaniboni
- Department of Medical Oncology; Instituto Fondazione Poliambulanza; Brescia Italy
| | - Johanna W Wilmink
- Department of Medical Oncology; Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam; Amsterdam Netherlands
| | - Marc G Besselink
- Department of Surgery; Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam; Amsterdam Netherlands
| | - Mohammed Abu Hilal
- Department of Surgery, Hepato-Biliary and Pancreatic Unit; Instituto Fondazione Poliambulanza; Brescia Italy
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Hayata Y, Nakagawa H, Kurosaki S, Kawamura S, Matsushita Y, Hayakawa Y, Suzuki N, Hata M, Tsuboi M, Kinoshita H, Miyabayashi K, Mizutani H, Nakagomi R, Ikenoue T, Hirata Y, Arita J, Hasegawa K, Tateishi K, Koike K. Axin2 + Peribiliary Glands in the Periampullary Region Generate Biliary Epithelial Stem Cells That Give Rise to Ampullary Carcinoma. Gastroenterology 2021; 160:2133-2148.e6. [PMID: 33465373 DOI: 10.1053/j.gastro.2021.01.028] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 01/11/2021] [Accepted: 01/11/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Peribiliary glands (PBGs), clusters of epithelial cells residing in the submucosal compartment of extrahepatic bile ducts, have been suggested as biliary epithelial stem/progenitor cell niche; however, evidence to support this claim is limited because of a lack of PBG-specific markers. We therefore sought to identify PBG-specific markers to investigate the potential role of PBGs as stem/progenitor cell niches, as well as an origin of cancer. METHODS We examined the expression pattern of the Wnt target gene Axin2 in extrahepatic bile ducts. We then applied lineage tracing to investigate whether Axin2-expressing cells from PBGs contribute to biliary regeneration and carcinogenesis using Axin2-CreERT mice. RESULTS Wnt signaling activation, marked by Axin2, was limited to PBGs located in the periampullary region. Lineage tracing showed that Axin2-expressing periampullary PBG cells are capable of self-renewal and supplying new biliary epithelial cells (BECs) to the luminal surface. Additionally, the expression pattern of Axin2 and the mature ductal cell marker CK19 were mutually exclusive in periampullary region, and fate tracing of CK19+ luminal surface BECs showed gradual replacement by CK19- cells, further supporting the continuous replenishment of new BECs from PBGs to the luminal surface. We also found that Wnt signal enhancer R-spondin3 secreted from Myh11-expressing stromal cells, corresponding to human sphincter of Oddi, maintained the periampullary Wnt signal-activating niche. Notably, introduction of PTEN deletion into Axin2+ PBG cells, but not CK19+ luminal surface BECs, induced ampullary carcinoma whose development was suppressed by Wnt inhibitor. CONCLUSION A specific cell population receiving Wnt-activating signal in periampullary PBGs functions as biliary epithelial stem/progenitor cells and also the cellular origin of ampullary carcinoma.
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Affiliation(s)
- Yuki Hayata
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Hayato Nakagawa
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan.
| | | | - Satoshi Kawamura
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Yuki Matsushita
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Nobumi Suzuki
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Masahiro Hata
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Mayo Tsuboi
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Hiroto Kinoshita
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan; Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Chuo-ku, Tokyo, Japan
| | - Koji Miyabayashi
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Hiroya Mizutani
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Ryo Nakagomi
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Tsuneo Ikenoue
- Division of Clinical Genome Research, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yoshihiro Hirata
- Division of Advanced Genome Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Junichi Arita
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Keisuke Tateishi
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
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Kim D, Konyn P, Cholankeril G, Bonham CA, Ahmed A. Trends in the Mortality of Biliary Tract Cancers Based on Their Anatomical Site in the United States From 2009 to 2018. Am J Gastroenterol 2021; 116:1053-1062. [PMID: 33929380 DOI: 10.14309/ajg.0000000000001151] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 12/14/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Recent trends in the incidence and mortality of biliary tract cancers are unknown. We estimated the trends in biliary tract cancers-related incidence and mortality stratified by anatomical site, age, sex, and race/ethnicity in the US adults. METHODS We performed a population-based trend analysis using the US national incidence (2009-2017) and mortality records (2009-2018). We identified age-standardized incidence and mortality from intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma, gallbladder cancer, and ampulla of Vater cancer using appropriate ICD-10 code. Temporal mortality was calculated by joinpoint trend analysis with estimates of annual percentage change (APC) described as each trend segment. RESULTS The incidence rates of ICC increased linearly (APC 8.9%, 95% confidence interval [CI] 7.8%-10.0%) while gallbladder cancer-related incidence rates remained stable early and decreased significantly later in the study (APC -2.8%, 95% CI -5.5% to -0.0% [2014-2017]). Age-standardized mortality from biliary tract cancers steadily increased with an annual increase of 2.0% (95% CI 1.6%-2.3%). Although there was a linear increase in the ICC-related mortality (APC 3.5%, 95% CI 3.1%-3.8%), extrahepatic cholangiocarcinoma-related mortality tended to remain stable earlier and increased later (APC 7.0%, 95% CI 4.6%-9.5% [2013-2018]). By contrast, gallbladder cancer-related mortality steadily decreased over 10 years (APC -1.6%, 95% CI -2.1% to -1.1%). Significant differences in mortality and changes in trends over time were observed in non-Hispanic blacks, Hispanics, and non-Hispanic Asians. DISCUSSION In this analysis of nationally representative data, changing mortality trends in various biliary tract cancers was noted with a disproportionately higher burden of fatality in minorities.
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Affiliation(s)
- Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
| | - Peter Konyn
- Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - George Cholankeril
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
| | - Clark Andrew Bonham
- Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
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Geerdes EE, Sideras K, Aziz MH, van Eijck CH, Bruno MJ, Sprengers D, Boor PPC, Kwekkeboom J. Cancer Cell B7-H3 Expression Is More Prevalent in the Pancreato-Biliary Subtype of Ampullary Cancer Than in Pancreatic Cancer. Front Oncol 2021; 11:615691. [PMID: 33996541 PMCID: PMC8117087 DOI: 10.3389/fonc.2021.615691] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 03/30/2021] [Indexed: 11/29/2022] Open
Abstract
B7-H3 is an immunomodulatory member of the B7-superfamily with limited expression in normal tissues, but overexpression in several types of cancer. Therefore it is currently being explored as a potential target for cancer immunotherapy. The biological relevance of B7-H3 expression in pancreatic cancer is unclear, while there are no data on B7-H3 expression in ampullary cancer. We aimed to compare intra-tumoral B7-H3 expression between these two closely related cancer types and analyze its association with post-surgical disease course. B7-H3 expression levels were determined by immunohistochemistry in tissue microarrays of resected tumors of 137 pancreatic cancer patients and 83 patients with ampullary cancer of the pancreato-biliary subtype. B7-H3 was more frequently expressed in cancer cells of ampullary cancer patients compared to pancreatic cancer patients (51% versus 21%; p< 0.001). In ampullary cancer patients, but not in pancreatic cancer patients, B7-H3 cancer cell expression was associated with longer disease-free survival and patient survival. However, the prognostic value of B7-H3 was lost upon adjustment for CA19-9 levels. The frequencies of B7-H3 expression in tumor stroma did not differ between the two types of cancer (66% versus 63%). In both cancer types, stromal B7-H3 expression was not associated with post-surgical disease course. Compared to pancreatic cancer, B7-H3 is more frequently expressed in cancer cells of patients with the pancreato-biliary subtype of ampullary cancer. These data suggest that B7-H3 may represent an interesting potential target for immunotherapy in ampullary cancer rather than in pancreatic cancer.
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Affiliation(s)
- Emma E Geerdes
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Kostandinos Sideras
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands.,Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - M Hosein Aziz
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Casper H van Eijck
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Marco J Bruno
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Dave Sprengers
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Patrick P C Boor
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Jaap Kwekkeboom
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
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Vanbiervliet G, Strijker M, Arvanitakis M, Aelvoet A, Arnelo U, Beyna T, Busch O, Deprez PH, Kunovsky L, Larghi A, Manes G, Moss A, Napoleon B, Nayar M, Pérez-Cuadrado-Robles E, Seewald S, Barthet M, van Hooft JE. Endoscopic management of ampullary tumors: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 2021; 53:429-448. [PMID: 33728632 DOI: 10.1055/a-1397-3198] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
1: ESGE recommends against diagnostic/therapeutic papillectomy when adenoma is not proven.Strong recommendation, low quality evidence. 2: ESGE recommends endoscopic ultrasound and abdominal magnetic resonance cholangiopancreatography (MRCP) for staging of ampullary tumors.Strong recommendation, low quality evidence. 3: ESGE recommends endoscopic papillectomy in patients with ampullary adenoma without intraductal extension, because of good results regarding outcome (technical and clinical success, morbidity, and recurrence).Strong recommendation, moderate quality evidence. 4: ESGE recommends en bloc resection of ampullary adenomas up to 20-30 mm in diameter to achieve R0 resection, for optimizing the complete resection rate, providing optimal histopathology, and reduction of the recurrence rate after endoscopic papillectomy.Strong recommendation, low quality evidence. 5: ESGE suggests considering surgical treatment of ampullary adenomas when endoscopic resection is not feasible for technical reasons (e. g. diverticulum, size > 4 cm), and in the case of intraductal involvement (of > 20 mm). Surveillance thereafter is still mandatory.Weak recommendation, low quality evidence. 6: ESGE recommends direct snare resection without submucosal injection for endoscopic papillectomy.Strong recommendation, moderate quality evidence. 7: ESGE recommends prophylactic pancreatic duct stenting to reduce the risk of pancreatitis after endoscopic papillectomy.Strong recommendation, moderate quality evidence. 8: ESGE recommends long-term monitoring of patients after endoscopic papillectomy or surgical ampullectomy, based on duodenoscopy with biopsies of the scar and of any abnormal area, within the first 3 months, at 6 and 12 months, and thereafter yearly for at least 5 years.Strong recommendation, low quality evidence.
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Affiliation(s)
- Geoffroy Vanbiervliet
- Department of Digestive Endoscopy, Centre Hospitalier Universitaire de Nice, Nice, France
| | - Marin Strijker
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Marianna Arvanitakis
- Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Arthur Aelvoet
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Urban Arnelo
- Department of Surgery, Centre for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Torsten Beyna
- Department of Gastroenterology, Evangelisches Krankenhaus Düsseldorf, Dusseldorf, Nordrhein-Westfalen, Germany
| | - Olivier Busch
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Pierre H Deprez
- Gastroenterology and Hepatology Department, Cliniques universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Lumir Kunovsky
- Department of Gastroenterology and Internal Medicine, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Department of Surgery, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Alberto Larghi
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gianpiero Manes
- Aziende Socio Sanitaria Territoriale Rhodense, Gastroenterology, Garbagnate Milanese, Italy
| | - Alan Moss
- Department of Endoscopic Services, Western Health, Melbourne, Australia
- Department of Medicine, Western Health, Melbourne Medical School, University of Melbourne, Victoria, Australia
| | - Bertrand Napoleon
- Service de Gastroentérologie, Hôpital Privé Jean Mermoz, Ramsay Générale de Santé, Lyon, France
| | - Manu Nayar
- Department of Gastroenterology, Freeman Hospital, Newcastle upon Tyne, UK
| | - Enrique Pérez-Cuadrado-Robles
- Department of Gastroenterology, Georges-Pompidou European Hospital, AP-HP Centre - Université de Paris, Paris, France
| | - Stefan Seewald
- Gastroenterology Center, Klinik Hirslanden, Zurich, Switzerland
| | - Marc Barthet
- Department of Gastroenterology, Hôpital Nord, Assistance publique des hôpitaux de Marseille, Marseille, France
| | - Jeanin E van Hooft
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, The Netherlands
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de Jong EJM, Geurts SME, van der Geest LG, Besselink MG, Bouwense SAW, Buijsen J, Dejong CHC, Heij LR, Koerkamp BG, de Hingh IHJT, Hoge C, Kazemier G, van Laarhoven HWM, de Meijer VE, Mohammad NH, Strijker M, Timmermans KCAA, Valkenburg-van Iersel LBJ, Wilmink JW, Tjan-Heijnen VCG, de Vos-Geelen J. A population-based study on incidence, treatment, and survival in ampullary cancer in the Netherlands. Eur J Surg Oncol 2021; 47:1742-1749. [PMID: 33712346 DOI: 10.1016/j.ejso.2021.02.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/11/2021] [Accepted: 02/23/2021] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Ampullary cancer is rare and as a result epidemiological data are scarce. The aim of this population-based study was to determine the trends in incidence, treatment and overall survival (OS) in patients with ampullary adenocarcinoma in the Netherlands between 1989 and 2016. METHODS Patients diagnosed with ampullary adenocarcinoma were identified from the Netherlands Cancer Registry. Incidence rates were age-adjusted to the European standard population. Trends in treatment and OS were studied over (7 years) period of diagnosis, using Kaplan-Meier and Cox regression analyses for OS and stratified by the presence of metastatic disease. RESULTS In total, 3840 patients with ampullary adenocarcinoma were diagnosed of whom, 55.0% were male and 87.1% had non-metastatic disease. The incidence increased from 0.59 per 100,000 in 1989-1995 to 0.68 per 100,000in 2010-2016. In non-metastatic disease, the resection rate increased from 49.5% in 1989-1995 to 63.9% in 2010-2016 (p < 0.001). The rate of adjuvant therapy increased from 3.1% to 7.9%. In non-metastatic disease, five-year OS (95% CI) increased from 19.8% (16.9-22.8) in 1989-1995 to 29.1% (26.0-31.2) in 2010-2016 (logrank p < 0.001). In patients with metastatic disease, median OS did not significantly improve (from 4.4 months (3.6-5.0) to 5.9 months (4.7-7.1); logrank p = 0.06). Cancer treatment was an independent prognostic factor for OS among all patients. CONCLUSION Both incidence and OS of ampullary cancer increased from 1989 to 2016 which is most likely related to the observed increased resection rates and use of adjuvant therapy.
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Affiliation(s)
- Evelien J M de Jong
- Department of Internal Medicine, Division of Medical Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, 6202 AZ, the Netherlands
| | - Sandra M E Geurts
- Department of Internal Medicine, Division of Medical Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, 6202 AZ, the Netherlands
| | - Lydia G van der Geest
- Department of Research, Netherlands Comprehensive Cancer Organization (IKNL), Eindhoven, 5612 HZ, the Netherlands
| | - Marc G Besselink
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, 1105 AZ, the Netherlands
| | - Stefan A W Bouwense
- Department of Surgery, Maastricht University Medical Center, Maastricht, 6202 AZ, the Netherlands
| | - Jeroen Buijsen
- Department of Radiation Oncology (Maastro), GROW School for Oncology, Maastricht University Medical Center, Maastricht, 6202 AZ, the Netherlands
| | - Cornelis H C Dejong
- Department of Surgery, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, 6202 AZ, the Netherlands
| | - Lara R Heij
- Department of Surgery, Maastricht University Medical Center, Maastricht, 6202 AZ, the Netherlands; Surgery Aachen: Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, Aachen, 52062, Germany; Institute of Pathology, RWTH Aachen University, Aachen, 52062, Germany
| | - Bas Groot Koerkamp
- Department of Surgery, Division of Oncology, Erasmus Medical Center, Rotterdam, 3015 GD, the Netherlands
| | - Ignace H J T de Hingh
- Department of Surgery, Catharina Cancer Institute, Eindhoven, 5623 EJ, the Netherlands
| | - Chantal Hoge
- Department of Internal Medicine, Division of Gastroenterology, Maastricht University Medical Center, Maastricht, 6202 AZ, the Netherlands
| | - Geert Kazemier
- Department of Surgery, Cancer Amsterdam, Amsterdam UMC, VU Amsterdam, Amsterdam, 1081 HV, the Netherlands
| | - Hanneke W M van Laarhoven
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, 1105 AZ, the Netherlands
| | - Vincent E de Meijer
- Department of Surgery, University of Groningen and University Medical Center Groningen, Groningen, 9713 GZ, the Netherlands
| | - Nadia Haj Mohammad
- Department Medical Oncology Medicine, Division of Radiology and Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, 3584 CX, the Netherlands
| | - Marin Strijker
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, 1105 AZ, the Netherlands
| | - Karin C A A Timmermans
- Department of Research, Netherlands Comprehensive Cancer Organization (IKNL), Eindhoven, 5612 HZ, the Netherlands
| | - Liselot B J Valkenburg-van Iersel
- Department of Internal Medicine, Division of Medical Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, 6202 AZ, the Netherlands
| | - Johanna W Wilmink
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, 1105 AZ, the Netherlands
| | - Vivianne C G Tjan-Heijnen
- Department of Internal Medicine, Division of Medical Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, 6202 AZ, the Netherlands
| | - Judith de Vos-Geelen
- Department of Internal Medicine, Division of Medical Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, 6202 AZ, the Netherlands.
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Moekotte AL, Lof S, Van Roessel S, Fontana M, Dreyer S, Shablak A, Casciani F, Mavroeidis VK, Robinson S, Khalil K, Gradinariu G, Mowbray N, Al-Sarireh B, Fusai GK, Roberts K, White S, Soonawalla Z, Jamieson NB, Salvia R, Besselink MG, Abu Hilal M. Histopathologic Predictors of Survival and Recurrence in Resected Ampullary Adenocarcinoma: International Multicenter Cohort Study. Ann Surg 2020; 272:1086-1093. [PMID: 30628913 DOI: 10.1097/sla.0000000000003177] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The aim of the study was to define histopathologic characteristics that independently predict overall survival (OS) and disease-free survival (DFS), in patients who underwent resection of an ampullary adenocarcinoma with curative intent. SUMMARY BACKGROUND DATA A broad range of survival rates have been described for adenocarcinoma of the ampulla of Vater, presumably due to morphological heterogeneity which is a result of the different epitheliums ampullary adenocarcinoma can arise from (intestinal or pancreaticobiliary). Large series with homogenous patient selection are scarce. METHODS A retrospective multicenter cohort analysis of patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma in 9 European tertiary referral centers between February 2006 and December 2017 was performed. Collected data included demographics, histopathologic details, survival, and recurrence. OS and DFS analyses were performed using Kaplan-Meier curves and Cox proportional hazard models. RESULTS Overall, 887 patients were included, with a mean age of 66 ± 10 years. The median OS was 64 months with 1-, 3-, 5-, and 10-year OS rates of 89%, 63%, 52%, and 37%, respectively. Histopathologic subtype, differentiation grade, lymphovascular invasion, perineural invasion, T-stage, N-stage, resection margin, and adjuvant chemotherapy were correlated with OS and DFS. N-stage (HR = 3.30 [2.09-5.21]), perineural invasion (HR = 1.50 [1.01-2.23]), and adjuvant chemotherapy (HR = 0.69 [0.48-0.97]) were independent predictors of OS in multivariable analysis, whereas DFS was only adversely predicted by N-stage (HR = 2.65 [1.65-4.27]). CONCLUSIONS Independent predictors of OS in resected ampullary cancer were N-stage, perineural invasion, and adjuvant chemotherapy. N-stage was the only predictor of DFS. These findings improve predicting survival and recurrence after resection of ampullary adenocarcinoma.
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Affiliation(s)
- Alma L Moekotte
- Department of Surgery, University Hospital of Southampton NHS Foundation Trust, Southampton, UK
| | - Sanne Lof
- Department of Surgery, University Hospital of Southampton NHS Foundation Trust, Southampton, UK
| | - Stijn Van Roessel
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Martina Fontana
- Department of Surgery, University Hospital of Verona, Verona, Italy
| | - Stephan Dreyer
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK
| | - Alaaeldin Shablak
- Department of Oncology, University Hospital of Southampton NHS Foundation Trust, Southampton, UK
| | - Fabio Casciani
- Department of Surgery, University Hospital of Verona, Verona, Italy
| | - Vasileios K Mavroeidis
- Department of Hepatobiliary and Pancreatic Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Stuart Robinson
- Department of Surgery, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
| | - Khalid Khalil
- Faculty of Medicine, University of Birmingham, Birmingham, UK
| | - George Gradinariu
- Department of Surgery, Royal Free London NHS Foundation Trust, London, UK
| | | | | | | | - Keith Roberts
- Faculty of Medicine, University of Birmingham, Birmingham, UK
| | - Steve White
- Department of Surgery, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
| | - Zahir Soonawalla
- Department of Hepatobiliary and Pancreatic Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Nigel B Jamieson
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK
| | - Roberto Salvia
- Department of Surgery, University Hospital of Verona, Verona, Italy
| | - Marc G Besselink
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Mohammed Abu Hilal
- Department of Surgery, University Hospital of Southampton NHS Foundation Trust, Southampton, UK
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Vining CC, Schuitevoerder D, Turaga KK. Ampullary adenocarcinoma: the current state of adjuvant therapies. Hepatobiliary Surg Nutr 2020; 9:647-649. [PMID: 33163515 DOI: 10.21037/hbsn.2019.11.37] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Charles C Vining
- Section of General Surgery/Surgical Oncology, The University of Chicago Medicine, Chicago, USA
| | - Darryl Schuitevoerder
- Section of General Surgery/Surgical Oncology, The University of Chicago Medicine, Chicago, USA
| | - Kiran K Turaga
- Section of General Surgery/Surgical Oncology, The University of Chicago Medicine, Chicago, USA
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Han S, Jang KT, Choi DW, Choi SH, Heo JS, Han IW, Park D, Ryu Y. Prognostic Impact of Intra-Ampullary Papillary-Tubular Neoplasm versus Flat Dysplasia as Precursor Lesions of Ampullary Adenocarcinoma. Dig Surg 2020; 37:505-514. [PMID: 33080609 DOI: 10.1159/000510961] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 08/17/2020] [Indexed: 12/10/2022]
Abstract
BACKGROUND The aim of this study is to compare the prognostic impact of 2 precursor lesions of ampullary adenocarcinoma, intra-ampullary papillary-tubular neoplasm (IAPN) and flat dysplasia (FD). METHODS From December 1994 to December 2012, a total of 359 patients underwent curative surgery for ampullary adenocarcinoma. RESULTS The precursor lesions were IAPNs in 134 (37.3%) patients and FD in the other 225 (62.7%) patients. The FD group had more aggressive tumor biology with advanced T stage (p = 0.002), nodal involvement (p < 0.001), poor differentiation (p < 0.001), perineural and lymphovascular invasion (p < 0.001), and pancreatobiliary or mixed subtype (p < 0.001). Five-year overall survival rates were 71.1% in the IAPN group and 51.4% in the FD group (p = 0.002), respectively. Five-year disease-free survival rates were 69.7% in the IAPN group and 49.6% in the FD group (p < 0.001), respectively. The recurrence rate was also higher in the FD group (49.8 vs. 30.6%; p < 0.001). On multivariate analysis, higher levels of tumor markers including CEA and CA19-9, lymph node metastasis, poorly differentiated histology, and perineural invasion were negative predictive factors for survival. Higher levels of CEA and CA19-9, lymphovascular invasion, and FD were independent prognostic factors for recurrence. CONCLUSION FD was significantly associated with worse prognosis and a greater tendency toward advanced disease. Further studies are needed to clarify the impacts of these precursor lesions.
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Affiliation(s)
- Sunjong Han
- Department of Surgery, Chungnam National University Sejong Hospital, Sejong, Republic of Korea
| | - Kee-Taek Jang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Wook Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea,
| | - Seong Ho Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jin Seok Heo
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - In Woong Han
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - DaeJoon Park
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Youngju Ryu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Moekotte AL, van Roessel S, Malleo G, Rajak R, Ecker BL, Fontana M, Han HS, Rabie M, Roberts KJ, Khalil K, White SA, Robinson S, Halimi A, Zarantonello L, Fusai GK, Gradinariu G, Alseidi A, Bonds M, Dreyer S, Jamieson NB, Mowbray N, Al-Sarireh B, Mavroeidis VK, Soonawalla Z, Napoli N, Boggi U, Kent TS, Fisher WE, Tang CN, Bolm L, House MG, Dillhoff ME, Behrman SW, Nakamura M, Ball CG, Berger AC, Christein JD, Zureikat AH, Salem RR, Vollmer CM, Salvia R, Besselink MG, Abu Hilal M, Aljarrah R, Barrows C, Cagigas MN, Lai ECH, Wellner U, Aversa J, Dickson PV, Ohtsuka T, Dixon E, Zheng R, Kowalski S, Freedman-Weiss M. Development and external validation of a prediction model for survival in patients with resected ampullary adenocarcinoma. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2020; 46:1717-1726. [PMID: 32624291 DOI: 10.1016/j.ejso.2020.04.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/26/2020] [Accepted: 04/09/2020] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Ampullary adenocarcinoma (AAC) is a rare malignancy with great morphological heterogeneity, which complicates the prediction of survival and, therefore, clinical decision-making. The aim of this study was to develop and externally validate a prediction model for survival after resection of AAC. MATERIALS AND METHODS An international multicenter cohort study was conducted, including patients who underwent pancreatoduodenectomy for AAC (2006-2017) from 27 centers in 10 countries spanning three continents. A derivation and validation cohort were separately collected. Predictors were selected from the derivation cohort using a LASSO Cox proportional hazards model. A nomogram was created based on shrunk coefficients. Model performance was assessed in the derivation cohort and subsequently in the validation cohort, by calibration plots and Uno's C-statistic. Four risk groups were created based on quartiles of the nomogram score. RESULTS Overall, 1007 patients were available for development of the model. Predictors in the final Cox model included age, resection margin, tumor differentiation, pathological T stage and N stage (8th AJCC edition). Internal cross-validation demonstrated a C-statistic of 0.75 (95% CI 0.73-0.77). External validation in a cohort of 462 patients demonstrated a C-statistic of 0.77 (95% CI 0.73-0.81). A nomogram for the prediction of 3- and 5-year survival was created. The four risk groups showed significantly different 5-year survival rates (81%, 57%, 22% and 14%, p < 0.001). Only in the very-high risk group was adjuvant chemotherapy associated with an improved overall survival. CONCLUSION A prediction model for survival after curative resection of AAC was developed and externally validated. The model is easily available online via www.pancreascalculator.com.
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Affiliation(s)
- Alma L Moekotte
- Department of Surgery, University Hospital of Southampton NHS Foundation Trust, Southampton, UK; Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands.
| | - Stijn van Roessel
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Giuseppe Malleo
- Department of Surgery, University Hospital of Verona, Verona, Italy
| | - Rushda Rajak
- Department of Histopathology, University Hospital of Southampton NHS Foundation Trust, Southampton, UK
| | - Brett L Ecker
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA
| | - Martina Fontana
- Department of Surgery, University Hospital of Verona, Verona, Italy
| | - Ho-Seong Han
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University, College of Medicine, South Korea
| | - Mohamed Rabie
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University, College of Medicine, South Korea
| | - Keith J Roberts
- Faculty of Medicine, University of Birmingham, Birmingham, UK
| | - Khalid Khalil
- Faculty of Medicine, University of Birmingham, Birmingham, UK
| | - Steven A White
- Department of Surgery, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
| | - Stuart Robinson
- Department of Surgery, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
| | - Asif Halimi
- Pancreatic Surgery Unit, Division of Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Laura Zarantonello
- Pancreatic Surgery Unit, Division of Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Giuseppe K Fusai
- Department of Surgery, Royal Free Hospital NHS Foundation Trust, London, UK
| | - George Gradinariu
- Department of Surgery, Royal Free Hospital NHS Foundation Trust, London, UK
| | - Adnan Alseidi
- Department of Surgery, Virginia Mason Medical Center, Seattle, USA
| | - Morgan Bonds
- Department of Surgery, Virginia Mason Medical Center, Seattle, USA
| | - Stephan Dreyer
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK
| | - Nigel B Jamieson
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK
| | | | | | - Vasileios K Mavroeidis
- Department of Hepatobiliary and Pancreatic Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Zahir Soonawalla
- Department of Hepatobiliary and Pancreatic Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Niccolò Napoli
- Department of Surgery, Pisa University Hospital, Pisa, Italy
| | - Ugo Boggi
- Department of Surgery, Pisa University Hospital, Pisa, Italy
| | - Tara S Kent
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | | | - Chung N Tang
- Department of Surgery, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China
| | - Louisa Bolm
- Department of Surgery, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Michael G House
- Department of Surgery, Indiana University School of Medicine, Indianapolis, USA
| | - Mary E Dillhoff
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, USA
| | - Stephen W Behrman
- Department of Surgery, University of Tennessee Health Science Center, Memphis, USA
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Chad G Ball
- Department of Surgery, University of Calgary, Calgary, Alberta, Canada
| | - Adam C Berger
- Department of Surgery, Jefferson Medical College, Philadelphia, USA
| | - John D Christein
- Department of Surgery, University of Alabama School of Medicine, Birmingham, USA
| | - Amer H Zureikat
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, USA
| | - Ronald R Salem
- Department of Surgery, Yale School of Medicine, New Haven, USA
| | - Charles M Vollmer
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA
| | - Roberto Salvia
- Department of Surgery, University Hospital of Verona, Verona, Italy
| | - Marc G Besselink
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Mohammed Abu Hilal
- Department of Surgery, University Hospital of Southampton NHS Foundation Trust, Southampton, UK; Department of Surgery, Istituto Fondazione Poliambulanza, Brescia, Italy.
| | - Ra'ed Aljarrah
- Department of Surgery, University Hospital of Southampton NHS Foundation Trust, Southampton, UK
| | - Courtney Barrows
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | | | - Eric C H Lai
- Department of Surgery, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China
| | - Ulrich Wellner
- Department of Surgery, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China
| | - John Aversa
- Department of Surgery, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Paxton V Dickson
- Department of Surgery, University of Tennessee Health Science Center, Memphis, USA
| | - Takao Ohtsuka
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Elijah Dixon
- Department of Surgery, University of Calgary, Calgary, Alberta, Canada
| | - Richard Zheng
- Department of Surgery, Jefferson Medical College, Philadelphia, USA
| | - Stacy Kowalski
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, USA
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Lwin KM, Linn YH, Dee YKS. Ampullary Adenocarcinoma: a Mini-Review and a Case Report of a Clinically Stable Disease Patient Treated with Herbal Supplements. J Gastrointest Cancer 2020; 52:750-758. [PMID: 32860204 DOI: 10.1007/s12029-020-00501-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Khin Maung Lwin
- FAME Pharmaceuticals Industry Co., Ltd., FAME Clinic, Yangon, Myanmar
| | - Ye Htut Linn
- Research and Development Department, FAME Pharmaceuticals Industry Co., Ltd., Yangon, Myanmar.
| | - Yamin Kyaw Swar Dee
- Research and Development Department, FAME Pharmaceuticals Industry Co., Ltd., Yangon, Myanmar
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Increased expression of secreted frizzled related protein 1 (SFRP1) predicts ampullary adenocarcinoma recurrence. Sci Rep 2020; 10:13255. [PMID: 32764696 PMCID: PMC7413269 DOI: 10.1038/s41598-020-69899-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 07/20/2020] [Indexed: 12/20/2022] Open
Abstract
Ampullary adenocarcinoma is a rare gastrointestinal cancer in which WNT signalling dysregulation has been previously reported. Secreted frizzled related protein 1 (SFRP1) is one of the extracellular ligands of WNT signalling. We performed bioinformatics analyses of SFRP1 expression in human cancer. Microarray analysis of SFRP1 in periampullary adenocarcinoma was obtained from the Gene Expression Omnibus GSE39409 dataset. SFRP1 expression in ampullary adenocarcinoma was detected by immunohistochemistry staining and correlated with patients’ clinical outcomes. Our results showed that SFRP1 expression had different clinical applications in all types of human cancer. No detected alteration of SFPR1 gene and SFRP1 expression in ampullary adenocarcinoma was lower than that in other periampullary adenocarcinomas. However, high expression levels of SFRP1 protein were correlated with cancer recurrence, peritoneal carcinomatosis and poor patient prognosis. Gene set enrichment analysis showed downregulation of multiple WNT-related genes in primary culture cells from ampullary adenocarcinoma, but SFRP1 expression was increased. We found an interaction between WNT, bone morphogenetic protein and hedgehog signalling with SFRP1. Furthermore, a high expression of SFRP1 predicted poor prognosis for ampullary adenocarcinoma patients. Because it is a multifunctional protein, SFRP1 targeting serves as a potential therapy for ampullary adenocarcinoma patients.
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Moekotte AL, Malleo G, van Roessel S, Bonds M, Halimi A, Zarantonello L, Napoli N, Dreyer SB, Wellner UF, Bolm L, Mavroeidis VK, Robinson S, Khalil K, Ferraro D, Mortimer MC, Harris S, Al-Sarireh B, Fusai GK, Roberts KJ, Fontana M, White SA, Soonawalla Z, Jamieson NB, Boggi U, Alseidi A, Shablak A, Wilmink JW, Primrose JN, Salvia R, Bassi C, Besselink MG, Abu Hilal M. Gemcitabine-based adjuvant chemotherapy in subtypes of ampullary adenocarcinoma: international propensity score-matched cohort study. Br J Surg 2020; 107:1171-1182. [PMID: 32259295 DOI: 10.1002/bjs.11555] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 12/14/2019] [Accepted: 01/23/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND Whether patients who undergo resection of ampullary adenocarcinoma have a survival benefit from adjuvant chemotherapy is currently unknown. The aim of this study was to compare survival between patients with and without adjuvant chemotherapy after resection of ampullary adenocarcinoma in a propensity score-matched analysis. METHODS An international multicentre cohort study was conducted, including patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma between 2006 and 2017, in 13 centres in six countries. Propensity scores were used to match patients who received adjuvant chemotherapy with those who did not, in the entire cohort and in two subgroups (pancreatobiliary/mixed and intestinal subtypes). Survival was assessed using the Kaplan-Meier method and Cox regression analyses. RESULTS Overall, 1163 patients underwent pancreatoduodenectomy for ampullary adenocarcinoma. After excluding 187 patients, median survival in the remaining 976 patients was 67 (95 per cent c.i. 56 to 78) months. A total of 520 patients (53·3 per cent) received adjuvant chemotherapy. In a propensity score-matched cohort (194 patients in each group), survival was better among patients who received adjuvant chemotherapy than in those who did not (median survival not reached versus 60 months respectively; P = 0·051). A survival benefit was seen in patients with the pancreatobiliary/mixed subtype; median survival was not reached in patients receiving adjuvant chemotherapy and 32 months in the group without chemotherapy (P = 0·020). Patients with the intestinal subtype did not show any survival benefit from adjuvant chemotherapy. CONCLUSION Patients with resected ampullary adenocarcinoma may benefit from gemcitabine-based adjuvant chemotherapy, but this effect may be reserved for those with the pancreatobiliary and/or mixed subtype.
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Affiliation(s)
- A L Moekotte
- Departments of Surgery, Southampton, UK
- Department of Surgery, Cancer Centre Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - G Malleo
- Department of Surgery, University Hospital of Verona, Verona, Italy
| | - S van Roessel
- Department of Surgery, Cancer Centre Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - M Bonds
- Department of Surgery, Virginia Mason Medical Center, Seattle, Washington, USA
| | - A Halimi
- Pancreatic Surgery Unit, Division of Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - L Zarantonello
- Pancreatic Surgery Unit, Division of Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - N Napoli
- Department of Surgery, Pisa University Hospital, Pisa, Italy
| | - S B Dreyer
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK
| | - U F Wellner
- Department of Surgery, University Medical Centre Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - L Bolm
- Department of Surgery, University Medical Centre Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - V K Mavroeidis
- Department of Hepatobiliary and Pancreatic Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - S Robinson
- Department of Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - K Khalil
- Faculty of Medicine, University of Birmingham, Birmingham, UK
| | - D Ferraro
- Department of Surgery, Royal Free London NHS Foundation Trust, London, UK
| | - M C Mortimer
- Department of Surgery, Morriston Hospital, Swansea, UK
| | - S Harris
- Medical Statistics, Faculty of Medicine, University of Southampton, Southampton, UK
| | - B Al-Sarireh
- Department of Surgery, Morriston Hospital, Swansea, UK
| | - G K Fusai
- Department of Surgery, Royal Free London NHS Foundation Trust, London, UK
| | - K J Roberts
- Faculty of Medicine, University of Birmingham, Birmingham, UK
| | - M Fontana
- Department of Surgery, University Hospital of Verona, Verona, Italy
| | - S A White
- Department of Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Z Soonawalla
- Department of Hepatobiliary and Pancreatic Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - N B Jamieson
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK
| | - U Boggi
- Department of Surgery, Pisa University Hospital, Pisa, Italy
| | - A Alseidi
- Department of Surgery, Virginia Mason Medical Center, Seattle, Washington, USA
| | - A Shablak
- Departments of Medical Oncology, University Hospital of Southampton NHS Foundation Trust, Southampton, UK
| | - J W Wilmink
- Department of Medical Oncology, Cancer Centre Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands
| | | | - R Salvia
- Department of Surgery, University Hospital of Verona, Verona, Italy
| | - C Bassi
- Department of Surgery, University Hospital of Verona, Verona, Italy
| | - M G Besselink
- Department of Surgery, Cancer Centre Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - M Abu Hilal
- Departments of Surgery, Southampton, UK
- Department of Surgery, Istituto Fondazione Poliambulanza, Brescia, Italy
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43
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Can pathologists reliably establish ampulla of Vater carcinoma histologic subtype on H&E alone? Concordance of subtype and comparison to immunohistochemistry-established subtype. JOURNAL OF PANCREATOLOGY 2019. [DOI: 10.1097/jp9.0000000000000032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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44
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Walsh MF, Sacca R, Wildman T, Amoroso K, Kennedy J, Zhang L, Birsoy O, Mandelker D, Steinsnyder Z, Latham A, Carlo MI, Cadoo K, Kemel Y, Robson M, Stadler ZK, Offit K. Pathogenic Loss-of-Function Germline TERT Mutations in Patients With Solid Tumors. JCO Precis Oncol 2019; 3:PO.19.00230. [PMID: 32923861 PMCID: PMC7446479 DOI: 10.1200/po.19.00230] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/12/2019] [Indexed: 11/20/2022] Open
Affiliation(s)
- Michael F. Walsh
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Rosalba Sacca
- Memorial Sloan Kettering Cancer Center, New York, NY
| | | | | | | | - Liying Zhang
- Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ozge Birsoy
- Memorial Sloan Kettering Cancer Center, New York, NY
| | | | | | - Alicia Latham
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Maria I. Carlo
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Karen Cadoo
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Yelena Kemel
- Memorial Sloan Kettering Cancer Center, New York, NY
| | - Mark Robson
- Memorial Sloan Kettering Cancer Center, New York, NY
| | - Zsofia K. Stadler
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Kenneth Offit
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
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Regalla DKR, Jacob R, Manne A, Paluri RK. Therapeutic options for ampullary carcinomas. A review. Oncol Rev 2019; 13:440. [PMID: 31565197 PMCID: PMC6747019 DOI: 10.4081/oncol.2019.440] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 08/28/2019] [Indexed: 02/08/2023] Open
Abstract
Ampullary Carcinoma arises from a histologically heterogeneous region where three different epithelia converge. Even though Ampullary Carcinoma has a superior prognosis compared to pancreatic and biliary ductal neoplasms, at least half of the patients turn up at an advanced stage that limits the treatment prospects. In addition to surgery for early-stage disease, several studies have shown that chemoradiotherapy confers additional benefits in the management of Ampullary Carcinoma. Analogously, chemotherapy plays a crucial role in treating advanced Ampullary Carcinoma with distant metastasis/recurrences. Although, stage of the disease, lymph node status, and histo-morphology are three critical prognostic variables, recently much attention is being placed on the genetic landscape of Ampullary Carcinoma. In this review, we have discussed various studies describing the role of chemoradiation and chemotherapy in the treatment of early and advanced stage Ampullary Carcinoma. Also, we have summarized the molecular landscape of Ampullary Carcinoma and the novel therapeutic strategies which could possibly target the genetic alterations involving the tumor cells.
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Affiliation(s)
| | - Rojymon Jacob
- Radiation Oncology, University of Alabama at Birmingham Hospital, Birmingham, AL
| | - Ashish Manne
- Medical Oncology, University of South Alabama Hospital, Mobile, AL
| | - Ravi Kumar Paluri
- Hematology-Oncology, University of Alabama at Birmingham Hospital, Birmingham, AL, USA
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Li W, Martinez-Useros J, Garcia-Carbonero N, Fernandez-Aceñero MJ, Ortega-Medina L, Garcia-Botella S, Perez-Aguirre E, Diez-Valladares L, Garcia-Foncillas J. The Prognosis Value of PIWIL1 and PIWIL2 Expression in Pancreatic Cancer. J Clin Med 2019; 8:1275. [PMID: 31443431 PMCID: PMC6780139 DOI: 10.3390/jcm8091275] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Revised: 08/12/2019] [Accepted: 08/21/2019] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer is a highly aggressive manifestation of cancer, and currently presents poor clinical outcome due to its late diagnosis with metastasic disease. Surgery is the only approach with a curative intend; however, the survival rates seen in this type of patient are still low. After surgery, there is a lack of predictive prognosis biomarkers to predict treatment response and survival to establish a personalized medicine. Human P-element-induced wimpy testis 1 (PIWIL1) and P-element-induced wimpy testis 2 (PIWIL2) proteins act as protectors of germline, and their aberrant expression has been described in several types of tumors. In this study, we aimed to assess an association between PIWIL1 and PIWIL2 expression and the prognosis of biliopancreatic cancer patients. For this, we analyzed protein expression in complete resected tumor samples, and found a significant association between PIWIL2 expression and both progression-free and overall survival (p = 0.036 and p = 0.012, respectively). However, PIWIL2 expression was significantly associated with progression-free survival (p = 0.029), and overall survival (p = 0.025) of such tumors originated in the pancreas, but not in the bile duct or ampulla of Vater. Further analysis revealed that PIWIL1 and PIWIL2, at both mRNA and protein expression levels, correlated positively with factors associated to the progenitor molecular subtype of pancreatic cancer. Based on these findings, PIWIL1 and PIWIL2 expression may be considered a potential prognostic biomarker for resectable pancreatic cancer and may serve to guide subsequent adjuvant treatment decisions.
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Affiliation(s)
- Weiyao Li
- Translational Oncology Division, OncoHealth Institute, Fundacion Jimenez Diaz University Hospital, Av. Reyes Católicos 2, 28040 Madrid, Spain
| | - Javier Martinez-Useros
- Translational Oncology Division, OncoHealth Institute, Fundacion Jimenez Diaz University Hospital, Av. Reyes Católicos 2, 28040 Madrid, Spain.
| | - Nuria Garcia-Carbonero
- Translational Oncology Division, OncoHealth Institute, Fundacion Jimenez Diaz University Hospital, Av. Reyes Católicos 2, 28040 Madrid, Spain
| | - Maria J Fernandez-Aceñero
- Pathology Department, University Hospital Gregorio Marañon, C/del Dr. Esquerdo 46, 28007 Madrid, Spain
| | - Luis Ortega-Medina
- Pathology Department, Clinico San Carlos University Hospital, C/Profesor Martin Lagos, 28040 Madrid, Spain
| | - Sandra Garcia-Botella
- Surgery Department (Pancreatobiliary Unit), Hospital Clínico San Carlos, C/Profesor Martin Lagos, 28040 Madrid, Spain
| | - Elia Perez-Aguirre
- Surgery Department (Pancreatobiliary Unit), Hospital Clínico San Carlos, C/Profesor Martin Lagos, 28040 Madrid, Spain
| | - Luis Diez-Valladares
- Surgery Department (Pancreatobiliary Unit), Hospital Clínico San Carlos, C/Profesor Martin Lagos, 28040 Madrid, Spain
| | - Jesus Garcia-Foncillas
- Translational Oncology Division, OncoHealth Institute, Fundacion Jimenez Diaz University Hospital, Av. Reyes Católicos 2, 28040 Madrid, Spain.
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Harthimmer MR, Stolborg U, Pfeiffer P, Mortensen MB, Fristrup C, Detlefsen S. Mutational profiling and immunohistochemical analysis of a surgical series of ampullary carcinomas. J Clin Pathol 2019; 72:762-770. [DOI: 10.1136/jclinpath-2019-205912] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 06/08/2019] [Accepted: 06/10/2019] [Indexed: 12/20/2022]
Abstract
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.
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Ferchichi M, Jouini R, Koubaa W, Khanchel F, Helal I, Hadad D, Bibani N, Chadli-Debbiche A, BenBrahim E. Ampullary and pancreatic adenocarcinoma-a comparative study. J Gastrointest Oncol 2019; 10:270-275. [PMID: 31032094 DOI: 10.21037/jgo.2018.09.09] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) and ampullary adenocarcinoma (AAC) are 2 gastrointestinal cancers that share overlapping symptoms. Although some studies have proposed the hypothesis of differences in pathogenesis and prognosis in these 2 cancers; they remain treated similarly. The classification of AAC into three subtypes [pancreatobiliary (PB), intestinal (IT) and mixed (M)] is especially crucial for the 3 axes of patients management (diagnosis, prognosis and therapy). Some studies suggest that PB subtype pathogenesis is comparable to PDAC. The objective of this study was to conduct a comparative analysis between PDAC and AAC; notably PB subtype; via mutational status analysis of 3 oncogenes (KRAS, NRAS and BRAF) hoping to consolidate AAC biology understanding. Methods Nine hot spot mutation sites of KRAS, NRAS and BRAF were analysed using pyrosequencing in 39 PDAC and 21 AAC from Tunisian patients. Comparative study was performed using SPSS software. Results Mutations in oncogenes were detected in almost 43% of AAC, especially in PB (47%) and 95% of PDAC. KRAS was the most mutated oncogene. There were statistical significant differences between PDAC and AAC in tumor differentiation (P<0.001), perineural invasion (P<0.001), vascular emboli (P=0.001), T stage (P=0.007), N stage (P=0.001) and mutational status (P<0.001). When comparing PDAC and PB subtype, there were also significant differences in tumor size (P=0.001), tumor differentiation (P<0.001), perineural invasion (P<0.001), vascular emboli (P=0.001), T stage (P=0.033), N stage (P<0.001) and mutational status (P<0.001). Conclusions AAC even PB subtype is different from PDAC. We think that these different tumor types require highly individualized therapy guided by their histomolecular characteristics and that we should stop diagnosing and treating them as a unique entity.
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Affiliation(s)
- Marwa Ferchichi
- University of Sciences, Farhat Hached Campus, Tunis El Manar, Tunis, Tunisia.,Pathology Department, Habib Thameur Hospital, University of Medicine, Tunis, Tunisia
| | - Raja Jouini
- Pathology Department, Habib Thameur Hospital, University of Medicine, Tunis, Tunisia
| | - Wafa Koubaa
- Pathology Department, Habib Thameur Hospital, University of Medicine, Tunis, Tunisia
| | - Fatma Khanchel
- Pathology Department, Habib Thameur Hospital, University of Medicine, Tunis, Tunisia
| | - Imen Helal
- Pathology Department, Habib Thameur Hospital, University of Medicine, Tunis, Tunisia
| | - Dhafer Hadad
- Surgery Department, Habib Thameur Hospital, Tunis, Tunisia
| | - Norsaf Bibani
- Gastroenterology Department, Habib Thameur Hospital, Tunis, Tunisia
| | | | - Ehsen BenBrahim
- Pathology Department, Habib Thameur Hospital, University of Medicine, Tunis, Tunisia
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Fernández Aceñero MJ, Martínez Useros J, Díez-Valladares L, Ortega-Medina L, Pérez Aguirre E, de la Serna Esteban S, García Botella S, Díaz Del Arco C. [Prognostic factors in adenocarcinoma of the ampulla of Vater]. REVISTA ESPANOLA DE PATOLOGIA : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE ANATOMIA PATOLOGICA Y DE LA SOCIEDAD ESPANOLA DE CITOLOGIA 2018; 51:210-215. [PMID: 30269771 DOI: 10.1016/j.patol.2018.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 02/26/2018] [Accepted: 03/07/2018] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Ampullary adenocarcinoma seems less aggressive than other pancreato-biliary neoplasms. The aim of this study is to define determining prognostic factors. MATERIAL AND METHODS Retrospective case series from a large tertiary Hospital including all patients diagnosed with ampullary adenocarcinoma who underwent cephalic pancreatoduodenectomy with curative intent. Outcome variables have been progression free survival and overall survival. RESULTS 24 patients were included. 54.2% were females and the mean age was 72.5 (45-85). Most cases were of intestinal type (50%), followed by pancreatobiliary (37.5%) and mucinous. Only 8.3% were high histopathological grade. Vessel invasion was detected in 31.8% of the cases and perineural infiltration in 20.8%. A large percentage of cases showed no lymph node involvement at the time of diagnosis (54.1%). Most cases were stage T1 or T3 (39.1 y 43.5%, respectively). 34.8% of the patients recurred, mainly in regional lymph nodes (62.5% of the recurrences) and they all died of tumor, mainly during the first year after diagnosis. Multivariate analysis with Cox regression model revealed that only lymph node involvement was independently associated to a shorter disease free progression interval and overall survival. CONCLUSIONS Lymph node involvement was the most important predictive factor for ampullary adenocarcinoma in this series.
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Affiliation(s)
- M Jesús Fernández Aceñero
- Departamentos de Anatomía Patológica y Cirugía General, Hospital Clínico San Carlos, Madrid, España; Unidad de Oncología Fundación Jiménez Díaz, Madrid, España.
| | | | - Luis Díez-Valladares
- Departamentos de Anatomía Patológica y Cirugía General, Hospital Clínico San Carlos, Madrid, España
| | - Luis Ortega-Medina
- Departamentos de Anatomía Patológica y Cirugía General, Hospital Clínico San Carlos, Madrid, España
| | - Elia Pérez Aguirre
- Departamentos de Anatomía Patológica y Cirugía General, Hospital Clínico San Carlos, Madrid, España
| | | | - Sandra García Botella
- Departamentos de Anatomía Patológica y Cirugía General, Hospital Clínico San Carlos, Madrid, España
| | - Cristina Díaz Del Arco
- Departamentos de Anatomía Patológica y Cirugía General, Hospital Clínico San Carlos, Madrid, España
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Bahl B, Vadlamudi R, Yedla P, Smalligan RD. 'Bleeding Dilemma': The Story of a Periampullary Mass. Cureus 2018; 10:e3035. [PMID: 30254824 PMCID: PMC6150752 DOI: 10.7759/cureus.3035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 07/22/2018] [Indexed: 11/29/2022] Open
Abstract
Periampullary malignancies arise in the vicinity of the ampulla of Vater, a common passage for biliary and pancreatic secretions. Determining the anatomical origin of these tumors represents a diagnostic challenge. This is especially true for large tumors due to the transitional nature of this region, proximity to different structures, anatomical variations, and overlapping features among constituting structures. This determination has significant prognostic and therapeutic implications. Among them, primary ampullary adenocarcinoma is a rare malignancy that has the best overall prognosis with high rates of potentially curative resection and possible survival even in advanced disease. Due to its rarity, it is also a vague territory with no definitive guidelines regarding management and surveillance currently available. Acute gastrointestinal hemorrhage is a rare presentation of ampullary carcinoma that occurs secondary to tumor ulceration. We report an elderly male with a previously known large, initially asymptomatic periampullary mass who came for evaluation of melena and was noted to be hypotensive secondary to acute blood loss from the large tumor, later determined to be adenocarcinoma of the ampulla of Vater.
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Affiliation(s)
- Bhavyaa Bahl
- UAB Internal Medicine, Huntsville Regional Medical Campus, Huntsville Hospital, Huntsville, USA
| | - Rohith Vadlamudi
- UAB School of Medicine, Huntsville Regional Medical Campus, Huntsville Hospital, Huntsville, USA
| | - Parekha Yedla
- UAB Internal Medicine, Huntsville Regional Medical Campus, Huntsville Hospital, Huntsville , USA
| | - Roger D Smalligan
- UAB Medicine, Huntsville Regional Medical Campus, Huntsville Hospital, Huntsville, USA
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