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Kenney LM, Hughes M. Surgical Management of Gastroenteropancreatic Neuroendocrine Tumors. Cancers (Basel) 2025; 17:377. [PMID: 39941746 PMCID: PMC11816225 DOI: 10.3390/cancers17030377] [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: 12/14/2024] [Revised: 01/17/2025] [Accepted: 01/22/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND/OBJECTIVES Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from enterochromaffin cells that can arise from the gastrointestinal (GI) tract and pancreas. Surgical management is the cornerstone of treatment, with the optimal approach tailored by tumor grade, size, location, and presence of metastasis. This review discusses the current strategies for the surgical management of NETs of the gastroenteropancreatic tract. METHODS A review of the available literature was conducted to evaluate surgical approaches to NETs. Consensus guidelines were incorporated to synthesize evidence-based recommendations. RESULTS For gastric NETs, surgical approach depends on Rindi Classification, WHO grade, and tumor size, with endoscopic approaches favored for smaller and low-grade lesions. Small bowel NETs can be multifocal and thus often require a surgical approach with careful evaluation of the entire intestine. Pancreatic NETs are categorized as functional or non-functional, with enucleation or formal resection strategies based on size, location, functional status, and risk of malignancy. Colorectal NETs are primarily treated with transanal localized or formal surgical resection, depending on lesion size and depth of invasion or presence of lymph node involvement. Appendiceal NETs are either treated with appendectomy or right hemicolectomy, depending on the size, location, and invasiveness of the lesions. For metastatic NETs, cytoreduction, liver transplantation, and targeted therapies offer symptom relief and possible survival benefits. CONCLUSIONS Surgical resection provides curative potential for localized NETs and symptom control in metastatic cases. Future research is essential to refine guidelines for intermediate-risk lesions and multifocal tumors, ensuring optimal outcomes for patients with gastroenteropancreatic NETs.
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Affiliation(s)
- Lisa M. Kenney
- Department of Surgery, Eastern Virginia Medical School, Macon and Joan Brock Virginia Health Sciences at Old Dominion University, 825 Fairfax Avenue, Suite 610, Norfolk, VA 23507, USA;
| | - Marybeth Hughes
- Department of Surgery, Division of Surgical Oncology, Eastern Virginia Medical School, Macon and Joan Brock Virginia Health Sciences at Old Dominion University, 825 Fairfax Avenue, Suite 610, Norfolk, VA 23507, USA
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Fraker DL. Endocrine Surgery at the NIH: History and Contributions. Ann Surg Oncol 2024; 31:3604-3607. [PMID: 38427159 DOI: 10.1245/s10434-024-15084-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 02/08/2024] [Indexed: 03/02/2024]
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Sheppard BC. The Legacy of Jeff Norton: From Cachexia to the Earlier Detection of Pancreatic Cancer 36 Years of Mentoring a Surgical Scientist. Ann Surg Oncol 2024; 31:3608-3610. [PMID: 38582817 DOI: 10.1245/s10434-024-15218-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 03/09/2024] [Indexed: 04/08/2024]
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Poultsides GA, Kebebew E, Hawn MT. Festschrift for Dr. Jeffrey A. Norton, 12-13 October 2023, Stanford, CA, USA. Ann Surg Oncol 2024; 31:3591-3594. [PMID: 38488895 DOI: 10.1245/s10434-024-15160-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 02/25/2024] [Indexed: 03/17/2024]
Affiliation(s)
- George A Poultsides
- Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
| | - Electron Kebebew
- Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Mary T Hawn
- Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
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Wells SA. Jeffrey A. Norton and the Multiple Endocrine Neoplasia Syndromes. Ann Surg Oncol 2024; 31:3611-3614. [PMID: 38494562 DOI: 10.1245/s10434-024-15079-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 02/08/2024] [Indexed: 03/19/2024]
Abstract
BACKGROUND Jeffrey A. Norton could have been a professional football player but instead he chose to pursue a career in medicine and in the process became an outstanding academic surgeon. This story recounts his ascent from a small town in Massachusetts to the pinnacle of academic surgery. METHODS After graduating from high school in Albany, New York, Jeff continued his education at Dartmouth University, the State University of New York Upstate Medical University at Syracuse (SUNY Upstate Medical University), and the Department of Surgery at the Duke University School of Medicine. When he completed the surgical residency, he spent 10 years at the National Cancer Institute (NCI) where he and his colleagues made significant contributions to the diagnosis and treatment of patients with endocrine tumors. After leaving the NCI, he had highly productive years as a Professor in Departments of Surgery at Washington University, the University of California at San Francisco, and Stanford University. He became a member of every major academic surgical society and won numerous awards for his accomplishments in research. His expertise in educating medical students and surgical residents is legendary. RESULTS In addition to his academic accomplishments, Jeff trained legions of young surgeons who subsequently made significant contributions in surgical investigation and clinical surgery. CONCLUSION It is most fitting that the Stanford University School of Medicine has assembled a group of Jeffrey Norton's colleagues in academic medicine and surgery to pay tribute to his achievements as a surgical scientist.
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Affiliation(s)
- Samuel A Wells
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
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Tran TH, Myung SK, Trinh TTK. Proton pump inhibitors and risk of gastrointestinal cancer: A meta‑analysis of cohort studies. Oncol Lett 2024; 27:28. [PMID: 38073768 PMCID: PMC10698841 DOI: 10.3892/ol.2023.14161] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 10/27/2023] [Indexed: 11/21/2024] Open
Abstract
Although proton pump inhibitors (PPIs) are widely used in the treatment of various acid-related disorders, observational studies have raised concern about an association between PPI use and the risk of gastrointestinal cancer. The present study aimed to investigate the association between them using a meta-analysis of cohort studies. PubMed and Excerpta Medica dataBASE were searched from inception to December 2022 to identify relevant cohort studies. The primary outcome was the risk of gastrointestinal cancer among PPI users, expressed as a pooled odds ratio (OR), relative risk (RR) or hazard ratio (HR) and its 95% CI based on a random-effects model. A total of 25 cohort studies from 23 articles were included in the final analysis. In the meta-analysis of all studies, an increased risk of gastrointestinal cancer following the use of PPIs was observed (OR/RR/HR, 2.09; 95% CI, 1.78-2.46). Subgroup analyses by type of cancer also revealed an association between PPI use and the risk of esophageal, gastric, liver and pancreatic cancer, whereas there was no association for colorectal cancer. The increased risk of gastrointestinal cancer was also observed in individuals who had used PPIs for <1 year (OR/RR/HR, 5.23; 95% CI, 2.96-9.24) as well as individuals who had used PPIs for up to 3 years. The present meta-analysis revealed that the use of PPIs was associated with an increased risk of gastrointestinal cancer.
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Affiliation(s)
- Tien Hoang Tran
- Department of Cancer Control and Population Health, National Cancer Center Graduate School of Cancer Science and Policy, Goyang, Gyeonggi-do 10408, Republic of Korea
| | - Seung-Kwon Myung
- Department of Cancer AI & Digital Health, National Cancer Center Graduate School of Cancer Science and Policy, Goyang, Gyeonggi-do 10408, Republic of Korea
- Cancer Epidemiology Branch, Division of Cancer Data Science, National Cancer Center Research Institute, Goyang, Gyeonggi-do 10408, Republic of Korea
- Department of Family Medicine and Center for Cancer Prevention and Detection, National Cancer Center Hospital, Goyang, Gyeonggi-do 10408, Republic of Korea
| | - Thao Thi Kim Trinh
- Department of Cancer Control and Population Health, National Cancer Center Graduate School of Cancer Science and Policy, Goyang, Gyeonggi-do 10408, Republic of Korea
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Waldum H, Mjønes P. The central role of gastrin in gastric cancer. Front Oncol 2023; 13:1176673. [PMID: 37941554 PMCID: PMC10628637 DOI: 10.3389/fonc.2023.1176673] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 09/19/2023] [Indexed: 11/10/2023] Open
Abstract
The prevalence of gastric cancer has markedly declined, but due to the high mortality rates associated with gastric cancer, it is still a serious disease. The preferred classification of gastric cancer is according to Lauren into either the intestinal type, which has a glandular growth pattern, or the diffuse type, which does not have glandular structures. Both types have been classified as adenocarcinomas, with the latter type based on periodic acid-Schiff (PAS) positivity presumed to reflect mucin. However, the presence of mucin in the diffuse type, in contrast to neuroendocrine/enterochromaffin-like (ECL) cell markers, has not been confirmed by immunohistochemistry and in situ hybridization. The ECL cells are probably prone to becoming cancerous because they do not express E-cadherin. Gastric cancer is unique in that a bacterium, Helicobacter pylori, is thought to be its main cause. H. pylori predisposes infected individuals to cancer only after having caused oxyntic atrophy leading to gastric hypoacidity and hypergastrinemia. No single H. pylori factor has been convincingly proved to be carcinogenic. It is probable that gastrin is the pathogenetic factor for gastric cancer due to H. pylori, autoimmune gastritis, and long-term prolonged inhibition of gastric acid secretion. Hypergastrinemia induces ECL cell hyperplasia, which develops into neuroendocrine tumors (NETs) and then into neuroendocrine carcinomas in rodents, a sequence that has also been described in humans. During carcinogenesis, the tumor cells lose specific traits, requiring that sensitive methods be used to recognize their origin. Gastric cancer occurrence may hopefully be prevented by H. pylori eradication at a young age, and by the reduced use of inhibitors of acid secretion and use of a gastrin antagonist in those with previous long-term H. pylori infection and those with autoimmune gastritis.
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Affiliation(s)
- Helge Waldum
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Patricia Mjønes
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Pathology, St. Olav’s Hospital – Trondheim University Hospital, Trondheim, Norway
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Ito T, Ramos-Alvarez I, Jensen RT. Successful Lifetime/Long-Term Medical Treatment of Acid Hypersecretion in Zollinger-Ellison Syndrome (ZES): Myth or Fact? Insights from an Analysis of Results of NIH Long-Term Prospective Studies of ZES. Cancers (Basel) 2023; 15:1377. [PMID: 36900170 PMCID: PMC10000208 DOI: 10.3390/cancers15051377] [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: 01/13/2023] [Revised: 02/09/2023] [Accepted: 02/15/2023] [Indexed: 02/24/2023] Open
Abstract
Analysis of the efficacy/pharmacology of long-term/lifetime medical treatment of acid hypersecretion in a large cohort of ZES patients in a prospective study. This study includes the results from all 303 patients with established ZES who were prospectively followed and received acid antisecretory treatment with either H2Rs or PPIs, with antisecretory doses individually titrated by the results of regular gastric acid testing. The study includes patients treated for short-term periods (<5 yrs), patients treated long-term (>5 yrs), and patients with lifetime treatment (30%) followed for up to 48 years (mean 14 yrs). Long-term/lifelong acid antisecretory treatment with H2Rs/PPIs can be successfully carried out in all patients with both uncomplicated and complicated ZES (i.e., with MEN1/ZES, previous Billroth 2, severe GERD). This is only possible if drug doses are individually set by assessing acid secretory control to establish proven criteria, with regular reassessments and readjustments. Frequent dose changes both upward and downward are needed, as well as regulation of the dosing frequency, and there is a primary reliance on the use of PPIs. Prognostic factors predicting patients with PPI dose changes are identified, which need to be studied prospectively to develop a useful predictive algorithm that could be clinically useful for tailored long-term/lifetime therapy in these patients.
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Affiliation(s)
- Tetsuhide Ito
- Neuroendocrine Tumor Centre, Fukuoka Sanno Hospital, International University of Health and Welfare, 3-6-45 Momochihama, Sawara-Ku, Fukuoka 814-0001, Japan
| | | | - Robert T. Jensen
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA
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Robin L, Sauvanet A, Walter T, Najah H, Falconi M, Pattou F, Gaujoux S. Recurrence after surgical resection of nonmetastatic sporadic gastrinoma: Which prognostic factors and surgical procedure? Surgery 2023; 173:1144-1152. [PMID: 36781315 DOI: 10.1016/j.surg.2022.12.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 11/29/2022] [Accepted: 12/30/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND The only curative treatment of gastrinoma is complete resection, but its surgical management remains controversial and prognostic factors of sporadic nonmetastatic gastrinoma are poorly known. METHODS This was a retrospective study including all patients who underwent elective surgery for nonmetastatic sporadic gastrinoma between 2000 and 2020 in 15 hospitals. The primary and secondary outcomes were overall survival and disease-free survival predictive factors. RESULTS In total, 108 patients were included, of which 68 (63%) were duodenal, 19 (18%) pancreatic, and 21 (19%) primary lymph node gastrinomas, with no major difference in clinical presentation. Among the 68 duodenal gastrinomas, 26% (n = 18) underwent pancreaticoduodenectomy (PD) and 74% (n = 50) underwent duodenotomy with the excision of duodenal wall tumors and lymphadenectomy (DUODX + LN). Overall, the median overall survival was 173 months, and the 5-year overall survival was 94%, with no predictive factors identified. The median disease-free survival was 93 months, and the 5-year disease-free survival was 63%. Tumor size >2 cm (P = .00001), grade (P = .00001), and pancreatic tumor location (P = .0001) were predictive factors of recurrence; however, in multivariate analysis, only tumor size >2 cm (P = .005) and grade (P = .013) were independent predictors of recurrence. Age, sex, preoperative gastrin level, lymphadenectomy <10 resected lymph nodes, and metastatic lymph nodes on surgical specimens were not predictors of recurrence. For duodenal gastrinomas, surgical procedures (PD versus DUODX + LN) did not have a significant effect on overall survival and disease-free survival. CONCLUSION Sporadic nonmetastatic gastrinomas had an excellent overall survival. Recurrence is frequent and influenced by tumor size and grade. Regarding sporadic duodenal gastrinoma, duodenotomy with excision of duodenal wall tumors with lymphadenectomy could be considered a valid surgical option, in the absence of clear oncologic superiority of PD.
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Affiliation(s)
- Léa Robin
- Department of General, Visceral, and Endocrine Surgery, Pitié-Salpêtrière Hospital, AP-HP, Paris, France; Department of Hepato-Biliary and Pancreatic Surgery and Liver Transplantation, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; School of Medicine, Sorbonne University, Paris, France
| | - Alain Sauvanet
- Department of Hepato-Biliary and Pancreatic Surgery, Beaujon Hospital, AP-HP, Clichy, France; School of Medicine, Paris University, Paris, France
| | - Thomas Walter
- Service d'Oncologie Médicale et Hépato-gastro-entérologie, Hospices Civil de Lyon, France; School of Medicine, Lyon University, Lyon, France
| | - Haythem Najah
- Department of Digestive and Endocrine Surgery, CHU de Bordeaux, Groupe Hospitalier Sud, Hôpital Haut-Lévêque, Centre Magellan, Pessac, France
| | - Massimo Falconi
- School of Medicine, Vita Salute San Raffaele University, Milan, Italy; Division of Pancreatic Surgery, IRCCS Ospedale San Raffaele, Università Vita-Salute, Milan, Italy; Department of Surgery, Division of Pancreatic Surgery, San Raffaele Scientific Institute, Milan, Italy
| | - François Pattou
- Univ Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1190 Translational Research for Diabetes, European Genomic Institute for Diabetes, Integrated Center of Obesity, France; Department of General and Endocrine Surgery, Lille University Hospital, France
| | - Sébastien Gaujoux
- Department of General, Visceral, and Endocrine Surgery, Pitié-Salpêtrière Hospital, AP-HP, Paris, France; Department of Hepato-Biliary and Pancreatic Surgery and Liver Transplantation, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; School of Medicine, Sorbonne University, Paris, France.
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Marcal LP, Chuang HH, Tran Cao HS, Halperin DM. Pancreatic Neuroendocrine Tumors. ONCOLOGIC IMAGING : A MULTIDISCIPLINARY APPROACH 2023:197-217. [DOI: 10.1016/b978-0-323-69538-1.00014-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Bergquist JR, Shariq OA, Li AY, Worth PJ, Chatzizacharias N, Soonawalla Z, Athanasopoulos P, Toumpanakis C, Hansen P, Parks RW, Connor S, Parker K, Koea J, Srinivasa S, Ielpo B, Lopez EV, Norton JA, Lawrence B, Visser BC. Clinical features and postoperative survival in patients with sporadic versus multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors: An international cohort study. Surgery 2022; 172:723-728. [PMID: 35577612 DOI: 10.1016/j.surg.2022.04.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 02/19/2022] [Accepted: 04/06/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND The optimal surgical management of pancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1 is controversial. This study sought to compare clinicopathologic characteristics and outcomes of multiple endocrine neoplasia type 1-associated and sporadic pancreatic neuroendocrine tumors from a large multi-national database. METHODS A multi-institutional, international database of patients with surgically resected pancreatic neuroendocrine tumors was analyzed. The cohort was divided into 2 groups: those with multiple endocrine neoplasia type 1 versus those with sporadic disease. Clinicopathologic comparisons were made. Overall and disease-free survival were analyzed. Propensity score matching was used to reduce bias. RESULTS Of 651 patients included, 45 (6.9%) had multiple endocrine neoplasia type 1 and 606 sporadic pancreatic neuroendocrine tumors. Multiple endocrine neoplasia type 1-associated pancreatic neuroendocrine tumors were more common in younger patients and associated with multifocal disease at the time of surgery and higher T-stage. Lymph node involvement and the presence of metastasis were similar. Total pancreatectomy rate was 5-fold higher in the multiple endocrine neoplasia type 1 cohort. Median survival did not differ (disease-free survival 126 months multiple endocrine neoplasia type 1 vs 198 months sporadic, P > .5). After matching, survival remained similar (overall survival not reached in either cohort, disease-free survival 126 months multiple endocrine neoplasia type 1 vs 198 months sporadic, P > .5). Equivalence in overall survival and disease-free survival persisted even when patients who underwent subtotal and total pancreatectomy were excluded. CONCLUSION Multiple endocrine neoplasia type 1-associated pancreatic neuroendocrine tumors are more common in younger patients and are associated with multifocality and higher T-stage. Survival for patients with multiple endocrine neoplasia type 1-associated pancreatic neuroendocrine tumors is comparable to those with sporadic pancreatic neuroendocrine tumors, even in the absence of radical pancreatectomy. Consideration should be given to parenchymal-sparing surgery to preserve pancreatic function.
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Affiliation(s)
- John R Bergquist
- Department of Surgery, Stanford University, CA. https://twitter.com/DrJRB
| | - Omair A Shariq
- University of Oxford, UK. https://twitter.com/OmairShariq
| | - Amy Y Li
- Department of Surgery, Stanford University, CA; Department of Surgery, General Surgery Residency Program-Henry Ford Hospital, Detroit, MI
| | | | | | | | | | | | - Paul Hansen
- Providence Portland Cancer Center, Portland, OR
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Abstract
Neurofibromatosis type (NF-1) is an autosomal dominant disorder characterized predominantly by neurocutaneous manifestations. Involvement of the gastrointestinal tract is uncommon but is associated with a significant risk of malignancy. There are a handful of case reports linking NF-1 with pancreatic neuroendocrine tumors; these include gastrin-secreting variants with the attendant Zollinger-Ellison syndrome. We present the case of a 52-year-old lady who presented with recurrent peptic ulceration and diarrhea. Serum gastrin levels were elevated and magnetic resonance imaging demonstrated the presence of a pancreatic lesion with multiple liver metastases. The lesion was moderately fludeoxyglucose avid on positron emission tomography-computed tomography. Endoscopic ultrasonography-guided sampling revealed the presence of synaptophysin positive neuroendocrine cells with positive gastrin immunostaining. A conservative approach was adopted, and the patient's symptoms improved on proton pump inhibitors. Zollinger-Ellison syndrome is an important condition, which should be kept in mind in the patient with NF-1 who presents with recurrent peptic ulceration and diarrhea. The emerging association between these 2 conditions is being examined on a cellular and immunohistochemical level.
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13
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Massironi S, Cavalcoli F, Elvevi A, Quatrini M, Invernizzi P. Somatostatin analogs in patients with Zollinger Ellison syndrome (ZES): an observational study. Endocrine 2022; 75:942-948. [PMID: 34716542 DOI: 10.1007/s12020-021-02915-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 10/07/2021] [Indexed: 02/05/2023]
Abstract
PURPOSE Zollinger Ellison syndrome (ZES) is a rare syndrome caused by gastrin hypersecretion from a gastrinoma. Gastrinoma treatment has two goals: the control of acid hypersecretion and the control of tumor growth. While therapy for the syndrome is univocally based on proton pump inhibitors, the one for disease control is still debated. We here aimed at evaluating the role of somatostatin analogs (SSAs) in the control of tumor progression in a series of ZES patients. METHODS A retrospective analysis of a prospectively collected database of ZES patients, followed and managed from 1990 to 2019, was performed. The patients' clinical, pathological, treatment, and follow-up data were analyzed. Data regarding SSAs therapy start, dosage, duration, and side effects were collected. RESULTS 33 patients with ZES were diagnosed. Fourteen patients (42%) had a grade 1 (G1) neuroendocrine neoplasm (NEN), five had G2 (15%), none had G3. Fifteen patients (45%) had metastatic disease. Overall, 12 (36%) underwent SSAs therapy. The median treatment duration was 36 months. Eight patients (67%) had a sustained response to SSAs, four (33%) showed an early progression, with a significant difference in terms of PFS between the patients with early and late progression (84 vs 2 months, p = 0.004). No differences in terms of OS and PFS were observed between the treated and non-treated patients, despite the proportion of metastatic patients was greater in the SSAs-treated group (75% vs 29% in the non-treated group, p = 0.01). CONCLUSION Present data support the use of SSAs in ZES, considering that gastrinoma is mainly a well-differentiated low-grade tumor (G1 or G2), with a high expression of somatostatin receptors.
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Affiliation(s)
- Sara Massironi
- Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, San Gerardo School of Medicine, Monza, Italy.
| | - Federica Cavalcoli
- Diagnostic and Therapeutic Endoscopy Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
| | - Alessandra Elvevi
- Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, San Gerardo School of Medicine, Monza, Italy
| | - Maurizio Quatrini
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, San Gerardo School of Medicine, Monza, Italy
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Bhattacharya S, Blau JE, Cochran C, Auh S, Weinstein LS, Jensen RT, Wank S. Validity of Secretin Stimulation Testing on Proton Pump Inhibitor Therapy for Diagnosis of Zollinger-Ellison Syndrome. Am J Gastroenterol 2021; 116:2216-2221. [PMID: 34515664 DOI: 10.14309/ajg.0000000000001487] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 08/03/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Zollinger-Ellison syndrome (ZES) is characterized by gastrinoma-induced hypergastrinemia causing excessive gastric acid secretion. Secretin stimulation tests (SSTs) are required for diagnosis in the majority of patients. Two case reports suggest that proton pump inhibitors (PPIs) cause false SST results. Consequently, PPIs are discontinued to allow hyperchlorhydria to recur; however, uncontrolled acidity can cause life-threatening complications in those with underlying undiagnosed ZES. The aim of this study was to determine whether PPIs influence the validity of SSTs for the diagnosis of ZES. METHODS A retrospective chart review was performed. Charts of patients who underwent SSTs were reviewed to determine whether they were performed on or off PPI and the test's accuracy by comparing the results with gold standard tests (diagnostic laboratory testing performed off PPI or surgical pathology consistent with gastrinoma). Sensitivity, specificity, and positive predictive value (PPV) of SST on PPI were calculated and results compared with SST off PPI using noninferiority analyses. RESULTS Twenty-eight patients corresponding to 29 SSTs were performed on PPI, and 70 patients corresponding to 107 SSTs were performed off PPI. Most of them were female and white and had multiple endocrine neoplasia type 1. We found no false-positive or false-negative SSTs on PPI. Sensitivity, specificity, and PPV of SSTs on PPI were determined to be noninferior to SSTs off PPI (P ≤ 0.05 for all). DISCUSSION In our cohort, SSTs on PPI compared with SSTs off PPI were noninferior for sensitivity, specificity, and PPV. These results suggest that PPI withdrawal before SSTs may not be necessary.
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Affiliation(s)
- Sumona Bhattacharya
- Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Jenny E Blau
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
- Early Clinical Development, Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - Craig Cochran
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Sungyoung Auh
- Office of the Clinical Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Lee S Weinstein
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Robert T Jensen
- Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Stephen Wank
- Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
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15
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Yozgat A, Kekilli M, Altay M. Time to give up traditional methods for the management of gastrointestinal neuroendocrine tumours. World J Clin Cases 2021; 9:8627-8646. [PMID: 34734042 PMCID: PMC8546836 DOI: 10.12998/wjcc.v9.i29.8627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 05/19/2021] [Accepted: 08/24/2021] [Indexed: 02/06/2023] Open
Abstract
Neuroendocrine tumors (NETs) are a rare and heterogeneous disease group and constitute 0.5% of all malignancies. The annual incidence of NETs is increasing worldwide. The reason for the increase in the incidence of NETs is the detection of benign lesions, incidental detection due to the highest use of endoscopic and imaging procedures, and higher recognition rates of pathologists. There have been exciting developments regarding NET biology in recent years. Among these, first of all, somatostatin receptors and downstream pathways in neuroendocrine cells have been found to be important regulatory mechanisms for protein synthesis, hormone secretion, and proliferation. Subsequently, activation of the mammalian target of rapamycin pathway was found to be an important mechanism in angiogenesis and tumor survival and cell metabolism. Finally, the importance of proangiogenic factors (platelet-derived growth factor, vascular endothelial growth factor, fibroblastic growth factor, angiopoietin, and semaphorins) in the progression of NET has been determined. Using the combination of biomarkers and imaging methods allows early evaluation of the appropriateness of treatment and response to treatment.
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Affiliation(s)
- Ahmet Yozgat
- Department of Gastroenterology, Ufuk University, Ankara, 06510, Turkey
| | - Murat Kekilli
- Department of Gastroenterology, Gazi University, Ankara 06560, Turkey
| | - Mustafa Altay
- Department of Endocrinology and Metabolism, University of Health Sciences Turkey, Keçiören Health Administration and Research Center, Ankara 06190, Turkey
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Rossi RE, Elvevi A, Citterio D, Coppa J, Invernizzi P, Mazzaferro V, Massironi S. Gastrinoma and Zollinger Ellison syndrome: A roadmap for the management between new and old therapies. World J Gastroenterol 2021; 27:5890-5907. [PMID: 34629807 PMCID: PMC8475006 DOI: 10.3748/wjg.v27.i35.5890] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/29/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Zollinger-Ellison syndrome (ZES) associated with pancreatic or duodenal gastrinoma is characterized by gastric acid hypersecretion, which typically leads to gastroesophageal reflux disease, recurrent peptic ulcers, and chronic diarrhea. As symptoms of ZES are nonspecific and overlap with other gastrointestinal disorders, the diagnosis is often delayed with an average time between the onset of symptoms and final diagnosis longer than 5 years. The critical step for the diagnosis of ZES is represented by the initial clinical suspicion. Hypergastrinemia is the hallmark of ZES; however, hypergastrinemia might recognize several causes, which should be ruled out in order to make a final diagnosis. Gastrin levels > 1000 pg/mL and a gastric pH below 2 are considered to be diagnostic for gastrinoma; some specific tests, including esophageal pH-recording and secretin test, might be useful in selected cases, although they are not widely available. Endoscopic ultrasound is very useful for the diagnosis and the local staging of the primary tumor in patients with ZES, particularly in the setting of multiple endocrine neoplasia type 1. Some controversies about the management of these tumors also exist. For the localized stage, the combination of proton pump inhibitory therapy, which usually resolves symptoms, and surgery, whenever feasible, with curative intent represents the hallmark of gastrinoma treatment. The high expression of somatostatin receptors in gastrinomas makes them highly responsive to somatostatin analogs, supporting their use as anti-proliferative agents in patients not amenable to surgical cure. Other medical options for advanced disease are super-imposable to other neuroendocrine neoplasms, and studies specifically focused on gastrinomas only are scant and often limited to case reports or small retrospective series. The multidisciplinary approach remains the cornerstone for the proper management of this composite disease. Herein, we reviewed available literature about gastrinoma-associated ZES with a specific focus on differential diagnosis, providing potential diagnostic and therapeutic algorithms.
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Affiliation(s)
- Roberta Elisa Rossi
- HPB Surgery, Hepatology and Liver Transplantation, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale Tumori (INT, National Cancer Institute), Milan 20133, Italy
- Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
| | - Alessandra Elvevi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza 20033, Italy
| | - Davide Citterio
- HPB Surgery, Hepatology and Liver Transplantation, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale Tumori (INT, National Cancer Institute), Milan 20133, Italy
| | - Jorgelina Coppa
- HPB Surgery, Hepatology and Liver Transplantation, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale Tumori (INT, National Cancer Institute), Milan 20133, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza 20033, Italy
| | - Vincenzo Mazzaferro
- HPB Surgery, Hepatology and Liver Transplantation, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale Tumori (INT, National Cancer Institute), Milan 20133, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan 20122, Italy
| | - Sara Massironi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza 20033, Italy
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17
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Fujii Y, Tzeng CW, Chiang YJ, Halperin DM, Dasari A, Kim MP, Katz MHG, Lee JE, Ikoma N. Incidence of Lymph Node Metastases and Impact of Radical Surgery for Duodenal Neuroendocrine Tumors. J Surg Res 2021; 268:419-431. [PMID: 34416414 DOI: 10.1016/j.jss.2021.06.085] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 05/25/2021] [Accepted: 06/30/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Despite the high frequency of regional lymph node (LN) metastases associated with duodenal neuroendocrine tumors (D-NETs), the impact of these metastases on survival and the ideal extent of LN dissection are unknown. We used the National Cancer Database (NCDB) to investigate factors associated with survival, including LN metastases and types of surgery, in patients with D-NETs. METHODS All patients with D-NETs recorded in the NCDB between 2004 and 2016 were included in the study. We applied a multivariate Cox regression model to assess the relationship between the clinicopathological characteristics and overall survival (OS). RESULTS We identified 7613 patients, among whom 4886 local excisions and 233 radical surgeries had been performed. Among patients with at least 1 LN pathologically examined, the overall incidence of LN metastasis was 41.2%. For all patients, the median OS was 10.6 years. Univariate analyses showed equivalent OS in N0 and N1 groups (HR,0.83; 95% CI,0.64-1.09) and diminished OS in those who had undergone radical surgery compared with those who had undergone local resection (HR,1.35; 95% CI,1.02-1.8). In multivariable analyses, tumor size >50 mm and having more than 9 positive LNs were associated with diminished OS (HR,1.64 and 5.2; 95% CI,1.25-2.16 and 1.91-14.18), whereas the type of surgery did not remain in the model. CONCLUSION Our study revealed that the presence of regional LN metastases and extent of surgery did not affect OS among patients with D-NETs. Radical resection to clear occult LN metastases for nonfunctioning, sporadic D-NETs was not supported by the current study.
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Affiliation(s)
- Yuki Fujii
- Departments of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Ching-Wei Tzeng
- Departments of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yi-Ju Chiang
- Departments of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Daniel M Halperin
- GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Arvind Dasari
- GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael P Kim
- Departments of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Matthew H G Katz
- Departments of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jeffrey E Lee
- Departments of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Naruhiko Ikoma
- Departments of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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18
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Geslot A, Vialon M, Caron P, Grunenwald S, Vezzosi D. New therapies for patients with multiple endocrine neoplasia type 1. ANNALES D'ENDOCRINOLOGIE 2021; 82:112-120. [PMID: 33839123 DOI: 10.1016/j.ando.2021.03.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 03/18/2021] [Accepted: 03/26/2021] [Indexed: 02/06/2023]
Abstract
In 1953, for the first time, Paul Wermer described a family presenting endocrine gland neoplasms over several generations. The transmission was autosomal dominant and the penetrance was high. Forty years later in 1997, the multiple endocrine neoplasia type 1 (MEN1) gene was sequenced, thus enabling diagnosis and early optimal treatment. Patients carrying the MEN1 gene present endocrine but also non-endocrine tumors. Parathyroid, pancreatic and pituitary impairment are the three main types of endocrine involvement. The present article details therapeutic management of hyperparathyroidism, neuroendocrine pancreatic tumors and pituitary adenomas in patients carrying the MEN1 gene. Significant therapeutic progress has in fact been made in the last few years. As concerns the parathyroid glands, screening of family members and regular monitoring of affected subjects now raise the question of early management of parathyroid lesions and optimal timing of parathyroid surgery. As concerns the duodenum-pancreas, proton-pump inhibitors are able to control gastrin-secreting syndrome, reducing mortality in MEN1 patients. Mortality in MEN1 patients is no longer mainly secondary to uncontrolled hormonal secretion but to metastatic (mainly pancreatic) disease progression. Tumor risk requires regular monitoring of morphological assessment, leading to iterative pancreatic surgery in a large number of patients. Finally, pituitary adenomas in MEN1 patients are traditionally described as aggressive, invasive and resistant to medical treatment. However, regular pituitary screening showed them to be in fact infra-centimetric and non-secreting in the majority of patients. Consequently, it is necessary to regularly monitor MEN1 patients, with regular clinical, biological and morphological work-up. Several studies showed that this regular monitoring impairs quality of life. Building a relationship of trust between patients and care provider is therefore essential. It enables the patient to be referred for psychological or psychiatric care in difficult times, providing long-term support and preventing any breakdown in continuity of care.
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Affiliation(s)
- Aurore Geslot
- Service d'endocrinologie, hôpital Larrey, 24, chemin de Pouvourville, 31029 Toulouse cedex 9, France
| | - Magaly Vialon
- Service d'endocrinologie, hôpital Larrey, 24, chemin de Pouvourville, 31029 Toulouse cedex 9, France
| | - Philippe Caron
- Service d'endocrinologie, hôpital Larrey, 24, chemin de Pouvourville, 31029 Toulouse cedex 9, France
| | - Solange Grunenwald
- Service d'endocrinologie, hôpital Larrey, 24, chemin de Pouvourville, 31029 Toulouse cedex 9, France
| | - Delphine Vezzosi
- Institut CardioMet, Toulouse, France; Service d'endocrinologie, hôpital Larrey, 24, chemin de Pouvourville, 31029 Toulouse cedex 9, France.
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Bennett SA, Law CHL, Assal A, Myrehaug S, Hallet J. Functional Pancreatic Neuroendocrine Tumors. NEUROENDOCRINE TUMORS 2021:137-156. [DOI: 10.1007/978-3-030-62241-1_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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20
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Hanzawa S, Sadamori H, Kagoura M, Monden K, Hioki M, Hyodo T, Omonishi K, Takakura N. Primary hepatic gastrinoma being diagnosed preoperatively: a case report and literature review. Surg Case Rep 2020; 6:290. [PMID: 33206240 PMCID: PMC7674545 DOI: 10.1186/s40792-020-01072-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 11/11/2020] [Indexed: 02/24/2023] Open
Abstract
Background A majority of gastrinomas causing Zollinger–Ellison syndrome are located in the duodenum or pancreas. Primary hepatic gastrinomas are rare and difficult to diagnose. We report a rare case of primary hepatic gastrinoma, which could be diagnosed preoperatively. Case presentation A 29-year-old man with a 55-mm tumor in segments 5 and 6 (S 5/6) of the liver was admitted to our hospital. After thorough investigations, he was treated for a suspected inflammatory pseudotumor and advised to undergo routine follow-up. Two years later, he revisited our hospital with a complaint of abdominal pain, vomiting, and diarrhea. Upper gastrointestinal endoscopy revealed multiple duodenal ulcers. His serum gastrin level was 2350 pg/mL (normal: 37–172 pg/mL), suggesting Zollinger–Ellison syndrome. Abdominal computed tomography showed a 78-mm hypervascular tumor with cystic degeneration in the S 5/6 region of the liver, with a potential to increase over time. The tumor showed hypointensity on T2-weighted and hyperintensity on diffusion-weighted abdominal contrast-enhanced magnetic resonance imaging. Somatostatin receptor scintigraphy (SRS) only detected a hepatic tumor. No tumors in the gastrinoma triangle were detected by endoscopic ultrasonography. Hence, selective arterial calcium injection (SACI) test was performed to determine the location of the gastrinoma. The serum gastrin concentration increased from 4620 pg/mL to 23,600 pg/mL at 20 s after calcium gluconate injection into the proper hepatic artery. Conversely, no effect on serum gastrin level was observed after the injection into any other arteries. Extended right hepatic lobectomy and cholecystectomy were performed after percutaneous transhepatic portal vein embolization. A histopathological examination of the liver tumor revealed a gastrinoma. The patient’s serum gastrin concentration on postoperative day 1 decreased to 65 pg/mL. Conclusion We report a surgical case of primary hepatic gastrinoma correctly diagnosed preoperatively. The patient underwent extended right hepatic lobectomy, resulting in a histological definitive diagnosis of primary hepatic gastrinoma.
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Affiliation(s)
- Shunya Hanzawa
- Department of Surgery, Fukuyama City Hospital, 5-23-1 Zao-cho, Fukuyama, Hiroshima, 721-8511, Japan.
| | - Hiroshi Sadamori
- Department of Surgery, Fukuyama City Hospital, 5-23-1 Zao-cho, Fukuyama, Hiroshima, 721-8511, Japan
| | - Masaaki Kagoura
- Department of Surgery, Fukuyama City Hospital, 5-23-1 Zao-cho, Fukuyama, Hiroshima, 721-8511, Japan
| | - Kazuteru Monden
- Department of Surgery, Fukuyama City Hospital, 5-23-1 Zao-cho, Fukuyama, Hiroshima, 721-8511, Japan
| | - Masayoshi Hioki
- Department of Surgery, Fukuyama City Hospital, 5-23-1 Zao-cho, Fukuyama, Hiroshima, 721-8511, Japan
| | - Tsuyoshi Hyodo
- Department of Radiology, Fukuyama City Hospital, 5-23-1 Zao-cho, Fukuyama, Hiroshima, 721-8511, Japan
| | - Kunihiro Omonishi
- Department of Pathology, Fukuyama City Hospital, 5-23-1 Zao-cho, Fukuyama, Hiroshima, 721-8511, Japan
| | - Norihisa Takakura
- Department of Surgery, Fukuyama City Hospital, 5-23-1 Zao-cho, Fukuyama, Hiroshima, 721-8511, Japan
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21
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Ito T, Jensen RT. Perspectives on the current pharmacotherapeutic strategies for management of functional neuroendocrine tumor syndromes. Expert Opin Pharmacother 2020; 22:685-693. [PMID: 33131345 DOI: 10.1080/14656566.2020.1845651] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Introduction: In the past, controlling the hormone-excess-state was the main determinant of survival in Functional-Neuroendocrine-Neoplasm-syndromes (F-NENs). This was difficult because the pharmacological-armamentarium available was limited. Recently, new therapeutic strategies have increased but it also generated controversies/uncertainties.Areas covered: The authors briefly review: established/proposed F-NENs; the rationale for treatments; the recommended initial-pharmacotherapeutic-approach to controlling F-NENs hormone-excess-state; the secondary-approaches if the initial approach fails or resistance develops; and the approach to deal with the malignant nature of the NEN. Also discussed are controversies/uncertainties related to new treatments.Expert opinion: Unfortunately, except for patients with insulinomas (>90-95%), gastrinomas (<20-40%), a minority with the other F-panNENs and 0-<1% with Carcinoid-syndrome is curative-surgery possible. Except for insulinomas, gastrinomas, and ACTHomas, long-acting somatostatin-analogs are the initial-pharmacological-treatments for hormone-excess-state. For insulinomas prior to surgery/malignancy, diazoxide is the initial drug-treatment; for gastrinomas, oral PPIs; and for ACTHomas, steroidogenesis inhibitors. There are now several secondary pharmacotherapeutic treatments. Surgery and liver-directed therapies also have a role in selected patients. Particularly promising is the recent results with PRRT for the hormone-excess-state, independent of its anti-growth effect. The sequence to use various agents and the approach to syndrome diagnosis while taking various agents remains unclear/controversial in many cases.
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Affiliation(s)
- Tetsuhide Ito
- Neuroendocrine Tumor Centre, Fukuoka Sanno Hospital, International University of Health and Welfare, Fukuoka, Japan
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22
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Noda H, Masuda K, Kanbara M, Maeda H, Kobayashi TK, Yutani C. Cytopathological evaluation of potential malignancy of duodenal gastrinoma using aspiration smears from two patients' resected tumors (NET G1, NET G2): A case report. Mol Clin Oncol 2020; 12:592-596. [PMID: 32337043 DOI: 10.3892/mco.2020.2030] [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: 10/23/2019] [Accepted: 02/21/2020] [Indexed: 11/06/2022] Open
Abstract
Sporadic gastrin-producing neuroendocrine tumors (NETs) of the duodenum present with either Zollinger-Ellison syndrome or unspecific syndromes. Ki-67 scoring in cytopathology is an alternative approach for establishing the gastrinoma grade. Although the majority of NETs, including gastrinomas, occur in the duodenum, most research regarding the Ki-67 index is focused on tumors of pancreatic origin. To the best of our knowledge, there is no study on the Ki-67 index for cytological analysis of duodenal gastrinoma. The current report presents two cases of a 56-year-old man and a 66-year-old woman with NET G1 and G2 gastrinoma, respectively, arising in the duodenal bulb. The present report focused on the differences in nuclear pleomorphism and Ki-67 index between these two cases.
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Affiliation(s)
- Hirotaka Noda
- Department of Pathology, Amagasaki Chuo Hospital, Amagasaki, Hyogo 661-0976, Japan.,Department of Clinical Laboratory, Amagasaki Chuo Hospital, Amagasaki, Hyogo 661-0976, Japan
| | - Kazuyoshi Masuda
- Department of Pathology, Amagasaki Chuo Hospital, Amagasaki, Hyogo 661-0976, Japan
| | - Masami Kanbara
- Department of Clinical Laboratory, Amagasaki Chuo Hospital, Amagasaki, Hyogo 661-0976, Japan
| | - Hiromi Maeda
- Department of Clinical Laboratory, Amagasaki Chuo Hospital, Amagasaki, Hyogo 661-0976, Japan
| | - Tadao K Kobayashi
- Division of Health Sciences, Cancer Education and Research Center, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Chikao Yutani
- Department of Pathology, Amagasaki Chuo Hospital, Amagasaki, Hyogo 661-0976, Japan
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Hayashi R, Minami I, Sasahara Y, Izumiyama H, Yoshimoto T, Kishino M, Kudo A, Tateishi U, Tanabe M, Yamada T. Diagnostic accuracy of selective arterial calcium injection test for localization of gastrinoma. Endocr J 2020; 67:305-315. [PMID: 31813923 DOI: 10.1507/endocrj.ej19-0413] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The appropriate localization of gastrinoma is still difficult. We aimed to evaluate the diagnostic accuracy of selective arterial calcium injection (SACI) for localization of gastrinomas including multiple lesions. This retrospective study included ten patients with surgically proven gastrinomas (gastrinoma group) and six patients without any findings suggesting Zollinger-Ellison syndrome (non-gastrinoma group). For SACI, calcium gluconate was injected into the arteries supplying pancreas, duodenum, and liver. Blood samples from the hepatic vein were obtained before and 30, 60, and 120 seconds after each injection. The results were considered positive when the increase in serum immunoreactive gastrin (IRG) levels within 60 seconds of calcium gluconate injection were more than 80 pg/mL and more than 20% from baseline. We evaluated the efficacy of SACI by comparing the SACI responses with definitive locations diagnosed by clinical and histopathological findings. In the gastrinoma group, false-positive responses were confirmed in seven of the ten patients. False-negative response was observed in one of the feeding arteries of one patient with gastrinomas in multiple locations. Conversely, the greatest increase in serum gastrin levels from baseline at 30 seconds indicated the true-positive responses in all patients with gastrinomas. In the non-gastrinoma group, calcium gluconate injection into gastroduodenal artery evoked positive responses in five of the six patients. In conclusion, our data suggest the strongest gastrin response evoked by SACI indicates the definitive location in patients with gastrinomas. In contrast, SACI could not accurately locate multiple gastrin-secreting lesions due to poor specificity.
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Affiliation(s)
- Ruriko Hayashi
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Endocrinology and Metabolism, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan
| | - Isao Minami
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Endocrinology, Yokohama City Minato Red Cross Hospital, Kanagawa, Japan
| | - Yuriko Sasahara
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Endocrinology and Metabolism, Soka Municipal Hospital, Saitama, Japan
| | - Hajime Izumiyama
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takanobu Yoshimoto
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Diabetes and Endocrinology, Tokyo Metropolitan Hiroo Hospital, Tokyo, Japan
| | - Mitsuhiro Kishino
- Department of Diagnostic Radiology and Nuclear Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Atsushi Kudo
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ukihide Tateishi
- Department of Diagnostic Radiology and Nuclear Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Minoru Tanabe
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tetsuya Yamada
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
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24
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Alkhushaym N, Almutairi AR, Althagafi A, Fallatah SB, Oh M, Martin JR, Babiker HM, McBride A, Abraham I. Exposure to proton pump inhibitors and risk of pancreatic cancer: a meta-analysis. Expert Opin Drug Saf 2020; 19:327-334. [PMID: 31928106 DOI: 10.1080/14740338.2020.1715939] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 01/10/2020] [Indexed: 02/07/2023]
Abstract
Objectives: To estimate the pancreatic cancer risk among subjects exposed versus not exposed to proton pump inhibitors.Methods: The authors searched PubMed, EMBASE, Scopus, Cochrane Library, and clinicaltrials.gov to identify relevant studies. The authors quantified pancreatic cancer risk among subjects exposed versus not exposed to PPIs, expressed as the pooled (adjusted) odds ratio (OR/aOR) and 95% confidence interval (95%CI) in overall and sensitivity analyses.Results: One randomized trial, two cohort, four case-control, and five nested case-control studies with 700,178 subjects (73,985 cases; 626,193 controls) were retained. PPI exposure was associated with pancreatic cancer risk (OR = 1.75, 95%CI = 1.12-2.72, I2 = 99%); confirmed in sensitivity analyses for high-quality studies, observational studies, case-control studies, studies with pancreatic cancer as the primary outcome, and in sensitivity analyses for diabetes and obesity but not for pancreatitis and smoking. This association was independent of the duration and Defined Daily Dose of PPI exposure. Rabeprazole had a singular significant association with pancreatic cancer (OR = 5.40, 95%CI = 1.98-14.703, I2 = 87.9%).Conclusion: The class of PPIs is associated with a 1.75-fold increase in pancreatic cancer risk, confirmed in sensitivity analyses.
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Affiliation(s)
- Nasser Alkhushaym
- Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, The University of Arizona, Tucson, AZ, USA
- Department of Clinical Pharmacy, Royal Commission Health Services Program, Jubail, Saudi Arabia
| | - Abdulaali R Almutairi
- Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, The University of Arizona, Tucson, AZ, USA
- SFD-Drug sector, Saudi Food and Drug Authority, Riyadh, Saudi Arabia
| | - Abdulhamid Althagafi
- Clinical Pharmacy Department, College of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Saad B Fallatah
- Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, The University of Arizona, Tucson, AZ, USA
- Clinical and Hospital Pharmacy Department, College of Pharmacy, Taibah University, Medina, Saudi Arabia
| | - Mok Oh
- Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, The University of Arizona, Tucson, AZ, USA
| | - Jennifer R Martin
- Arizona Health Sciences Library, The University of Arizona, Tucson, AZ, USA
- Department of Pharmacy Practice and Science, College of Pharmacy, The University of Arizona, Tucson, AZ, USA
| | - Hani M Babiker
- Department of Hematology & Oncology, College of Medicine, The University of Arizona, Tucson, AZ, USA
- Department of Pharmacy Practice and Science, College of Pharmacy, The University of Arizona, Tucson, AZ, USA
| | - Ali McBride
- Department of Pharmacy Practice and Science, College of Pharmacy, The University of Arizona, Tucson, AZ, USA
- Department of Pharmacy Practice and Science, College of Pharmacy, The University of Arizona, Tucson, AZ, USA
- University of Arizona Cancer Center, Tucson, AZ, USA
| | - Ivo Abraham
- Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, The University of Arizona, Tucson, AZ, USA
- Department of Pharmacy Practice and Science, College of Pharmacy, The University of Arizona, Tucson, AZ, USA
- Department of Pharmacy Practice and Science, College of Pharmacy, The University of Arizona, Tucson, AZ, USA
- Department of Family and Community Medicine, College of Medicine, The University of Arizona, Tucson, AZ, USA
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Chen YJ, Ojeaburu JV, Vortmeyer A, Yu S, Jensen RT. Alterations of chromosome 3p in 24 cases of gastrinomas and their correlations with clinicopathological and prognostic features. JOURNAL OF PANCREATOLOGY 2020; 3:42-49. [DOI: 10.1097/jp9.0000000000000034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Abstract
Purpose:
The pathogenesis of gastrinomas is largely unknown, and there is a lack of reliable genetic determinants that are useful to distinguish malignant and benign forms of this tumor or predict the prognosis of patients with this disease. Loss of heterozygosity (LOH) on chromosome 3p is reported to occur in pancreatic neuroendocrine tumors (PNETs) as well as in non-PNETs and its presence is reported to correlate with tumor prognosis in non-endocrine tumors. However, little data are available from prospective studies on gastrinomas.
Experimental design:
We assessed occurrence of 3p LOH in 24 gastrinomas and correlated its presence with tumor biological behavior and other clinicopathological features of gastrinomas.
Results:
Either 3p LOH or microsatellite instability involving 3p occurred in 11 of 24 tumors (46%). Seven (29%) gastrinomas had 3p LOH. Of the 7 gastrinomas with 3p LOH, 5 (71%) had 3p12 LOH with the marker D3S2406, which was the shortest region of highest overlap (SRO). Chromosome 3p LOH was not associated with aggressive biological behavior of gastrinomas or with poor prognosis of patients with gastrinoma. Similarly, 3p12 LOH (SRO) was not correlated with aggressive growth of tumors and/or liver metastases.
Conclusion:
Gastrinomas have a relative high frequency of 3p12 LOH suggesting this area may harbor putative tumor suppressor gene(s), which may play a role in the tumorigenesis, but not aggressiveness, of a subset of these tumors.
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Affiliation(s)
- Yuan-Jia Chen
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases
| | - Jeremiah V. Ojeaburu
- Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases
| | - Alexander Vortmeyer
- Molecular Pathogenesis Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
| | - Shuang Yu
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Robert T. Jensen
- Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases
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Asban A, Patel AJ, Reddy S, Wang T, Balentine CJ, Chen H. Cancer of the Endocrine System. ABELOFF'S CLINICAL ONCOLOGY 2020:1074-1107.e11. [DOI: 10.1016/b978-0-323-47674-4.00068-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Howe JR, Merchant NB, Conrad C, Keutgen XM, Hallet J, Drebin JA, Minter RM, Lairmore TC, Tseng JF, Zeh HJ, Libutti SK, Singh G, Lee JE, Hope TA, Kim MK, Menda Y, Halfdanarson TR, Chan JA, Pommier RF. The North American Neuroendocrine Tumor Society Consensus Paper on the Surgical Management of Pancreatic Neuroendocrine Tumors. Pancreas 2020; 49:1-33. [PMID: 31856076 PMCID: PMC7029300 DOI: 10.1097/mpa.0000000000001454] [Citation(s) in RCA: 259] [Impact Index Per Article: 51.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the surgical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The group reviewed a series of questions of specific interest to surgeons taking care of patients with pancreatic neuroendocrine tumors, and for each, the available literature was reviewed. What follows are these reviews for each question followed by recommendations of the panel.
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Affiliation(s)
- James R. Howe
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA
| | | | - Claudius Conrad
- Department of Surgery, St. Elizabeth Medical Center, Tufts University School of Medicine, Boston, MA
| | | | - Julie Hallet
- Department of Surgery, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Canada
| | - Jeffrey A. Drebin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Rebecca M. Minter
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | | | | | - Herbert J. Zeh
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX
| | - Steven K. Libutti
- §§ Department of Surgery, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ
| | - Gagandeep Singh
- Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, CA
| | - Jeffrey E. Lee
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Thomas A. Hope
- Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA
| | - Michelle K. Kim
- Department of Medicine, Mt. Sinai Medical Center, New York, NY
| | - Yusuf Menda
- Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, IA
| | | | - Jennifer A. Chan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Rodney F. Pommier
- Department of Surgery, Oregon Health & Sciences University, Portland, OR
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Ishida H, Lam AKY. Pancreatic neuroendocrine neoplasms: The latest surgical and medical treatment strategies based on the current World Health Organization classification. Crit Rev Oncol Hematol 2020; 145:102835. [DOI: 10.1016/j.critrevonc.2019.102835] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 11/06/2019] [Accepted: 11/11/2019] [Indexed: 12/15/2022] Open
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Eusebi LH, Thorburn D, Toumpanakis C, Frazzoni L, Johnson G, Vessal S, Luong TV, Caplin M, Pereira SP. Endoscopic ultrasound-guided fine-needle aspiration vs fine-needle biopsy for the diagnosis of pancreatic neuroendocrine tumors. Endosc Int Open 2019; 7:E1393-E1399. [PMID: 31673610 PMCID: PMC6805236 DOI: 10.1055/a-0967-4684] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 06/03/2019] [Indexed: 02/07/2023] Open
Abstract
Background and study aims Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) as a method of obtaining preoperative diagnosis of pancreatic neuroendocrine tumors (PanNETs) has been reported in several series. Fine-needle biopsies (FNB) are increasingly employed to obtain core specimens during EUS. However, the differences in efficacy between these sampling methods in the diagnosis of PanNETs still needs to be defined. Patients and methods Over a 13-year period, all patients who underwent EUS-guided tissue sampling of suspicious pancreatic lesions with clinical, endoscopic and pathologic details were entered into an electronic database. Lesions underwent EUS-FNA or FNB sampling, or a combination of the two. The accuracy and safety of different EUS-guided sampling methods for confirmed PanNETs were investigated. Results A total of 91 patients (M/F: 42/49, median age: 57 years), who underwent 102 EUS procedures had a final diagnosis of PanNET. Both EUS-guided sampling modalities were used in 28 procedures, EUS-FNA alone was used in 61 cases, while EUS-FNB alone in 13 cases. Diagnostic yield of EUS-FNA and EUS-FNB alone, including the inadequate specimens, was 77.5 % (95 %CI: 68.9 - 86.2 %) and 85.4 % (95 %CI: 74.6 - 96.2 %), respectively. The combination of both sampling modalities established the diagnosis in 96.4 % of cases (27/28) (95 %CI: 89.6 - 100 %), significantly superior to EUS-FNA alone ( P = 0.023). Diagnostic sensitivity among the adequate samples for EUS-FNA, EUS-FNB and for the combination of the two methods was 88.4 % (95 %CI: 80.9 - 96.0 %), 94.3 % (95 %CI: 86.6 - 100 %) and 100 % (95 %CI: 100 - 100 %). There was one reported complication, a post-FNA bleeding, treated conservatively. Conclusions EUS-FNB improves diagnostic sensitivity and confers additional information to cytological assessment of PanNETs.
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Affiliation(s)
- Leonardo H. Eusebi
- HPB endoscopy unit, Royal Free Hospital NHS Trust, London, UK,Department of Medical and Surgical Sciences, University of Bologna, Italy
| | | | - Christos Toumpanakis
- Neuroendocrine Tumour Unit, Centre for Gastroenterology, Royal Free Hospital NHS Trust, London, UK
| | - Leonardo Frazzoni
- Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Gavin Johnson
- HPB endoscopy unit, Royal Free Hospital NHS Trust, London, UK,Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Sheida Vessal
- HPB endoscopy unit, Royal Free Hospital NHS Trust, London, UK
| | - Tu Vinh Luong
- Department of Cellular Pathology, Royal Free London NHS Foundation, London, UK
| | - Martyn Caplin
- Neuroendocrine Tumour Unit, Centre for Gastroenterology, Royal Free Hospital NHS Trust, London, UK
| | - Stephen P. Pereira
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK,Institute for Liver & Digestive Health, University College London, UK,Corresponding author Prof. Stephen P. Pereira The UCL Institute for Liver & Digestive HealthNW3 2PFUK+4407729632540
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Lee L, Ramos-Alvarez I, Ito T, Jensen RT. Insights into Effects/Risks of Chronic Hypergastrinemia and Lifelong PPI Treatment in Man Based on Studies of Patients with Zollinger-Ellison Syndrome. Int J Mol Sci 2019; 20:5128. [PMID: 31623145 PMCID: PMC6829234 DOI: 10.3390/ijms20205128] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/08/2019] [Accepted: 10/13/2019] [Indexed: 02/07/2023] Open
Abstract
The use of proton pump inhibitors (PPIs) over the last 30 years has rapidly increased both in the United States and worldwide. PPIs are not only very widely used both for approved indications (peptic ulcer disease, gastroesophageal reflux disease (GERD), Helicobacter pylori eradication regimens, stress ulcer prevention), but are also one of the most frequently off-label used drugs (25-70% of total). An increasing number of patients with moderate to advanced gastroesophageal reflux disease are remaining on PPI indefinitely. Whereas numerous studies show PPIs remain effective and safe, most of these studies are <5 years of duration and little data exist for >10 years of treatment. Recently, based primarily on observational/epidemiological studies, there have been an increasing number of reports raising issues about safety and side-effects with very long-term chronic treatment. Some of these safety issues are related to the possible long-term effects of chronic hypergastrinemia, which occurs in all patients taking chronic PPIs, others are related to the hypo-/achlorhydria that frequently occurs with chronic PPI treatment, and in others the mechanisms are unclear. These issues have raised considerable controversy in large part because of lack of long-term PPI treatment data (>10-20 years). Zollinger-Ellison syndrome (ZES) is caused by ectopic secretion of gastrin from a neuroendocrine tumor resulting in severe acid hypersecretion requiring life-long antisecretory treatment with PPIs, which are the drugs of choice. Because in <30% of patients with ZES, a long-term cure is not possible, these patients have life-long hypergastrinemia and require life-long treatment with PPIs. Therefore, ZES patients have been proposed as a good model of the long-term effects of hypergastrinemia in man as well as the effects/side-effects of very long-term PPI treatment. In this article, the insights from studies on ZES into these controversial issues with pertinence to chronic PPI use in non-ZES patients is reviewed, primarily concentrating on data from the prospective long-term studies of ZES patients at NIH.
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Affiliation(s)
- Lingaku Lee
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA.
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
| | | | - Tetsuhide Ito
- Neuroendocrine Tumor Centra, Fukuoka Sanno Hospital, International University of Health and Welfare 3-6-45 Momochihama, Sawara-Ku, Fukuoka 814-0001, Japan.
| | - Robert T Jensen
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA.
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31
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Norton JA, Foster DS, Blumgart LH, Poultsides GA, Visser BC, Fraker DL, Alexander HR, Jensen RT. Incidence and Prognosis of Primary Gastrinomas in the Hepatobiliary Tract. JAMA Surg 2019; 153:e175083. [PMID: 29365025 DOI: 10.1001/jamasurg.2017.5083] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
| | - Deshka S. Foster
- Department of Surgery, Stanford University, Stanford, California
| | - Leslie H. Blumgart
- Department of Surgery, Memorial Sloan Kettering Cancer Institute, New York, New York
| | | | | | | | | | - Robert T. Jensen
- Digestive Diseases Branch, National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland
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Shao QQ, Zhao BB, Dong LB, Cao HT, Wang WB. Surgical management of Zollinger-Ellison syndrome: Classical considerations and current controversies. World J Gastroenterol 2019; 25:4673-4681. [PMID: 31528093 PMCID: PMC6718045 DOI: 10.3748/wjg.v25.i32.4673] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 04/29/2019] [Accepted: 05/03/2019] [Indexed: 02/06/2023] Open
Abstract
Zollinger-Ellison syndrome (ZES) is characterized by gastric acid hypersecretion causing severe recurrent acid-related peptic disease. Excessive secretion of gastrin can now be effectively controlled with powerful proton pump inhibitors, but surgical management to control gastrinoma itself remains controversial. Based on a thorough literature review, we design a surgical algorithm for ZES and list some significant consensus findings and recommendations: (1) For sporadic ZES, surgery should be routinely undertaken as early as possible not only for patients with a precisely localized diagnosis but also for those with negative imaging findings. The surgical approach for sporadic ZES depends on the lesion location (including the duodenum, pancreas, lymph nodes, hepatobiliary tract, stomach, and some extremely rare sites such as the ovaries, heart, omentum, and jejunum). Intraoperative liver exploration and lymphadenectomy should be routinely performed; (2) For multiple endocrine neoplasia type 1-related ZES (MEN1/ZES), surgery should not be performed routinely except for lesions > 2 cm. An attempt to perform radical resection (pancreaticoduodenectomy followed by lymphadenectomy) can be made. The ameliorating effect of parathyroid surgery should be considered, and parathyroidectomy should be performed first before any abdominal surgery for ZES; and (3) For hepatic metastatic disease, hepatic resection should be routinely performed. Currently, liver transplantation is still considered an investigational therapeutic approach for ZES. Well-designed prospective studies are desperately needed to further verify and modify the current considerations.
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Affiliation(s)
- Qian-Qian Shao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China
| | - Bang-Bo Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China
| | - Liang-Bo Dong
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China
| | - Hong-Tao Cao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China
| | - Wei-Bin Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China
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Management of MEN1 Related Nonfunctioning Pancreatic NETs: A Shifting Paradigm: Results From the DutchMEN1 Study Group. Ann Surg 2019; 267:1155-1160. [PMID: 28257328 DOI: 10.1097/sla.0000000000002183] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
OBJECTIVE To assess if surgery for Multiple Endocrine Neoplasia type 1 (MEN1) related nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs) is effective for improving overall survival and preventing liver metastasis. BACKGROUND MEN1 leads to multiple early-onset NF-pNETs. The evidence base for guiding the difficult decision who and when to operate is meager. METHODS MEN1 patients diagnosed with NF-pNETs between 1990 and 2014 were selected from the DutchMEN1 Study Group database, including > 90% of the Dutch MEN1 population. The effect of surgery was estimated using time-dependent Cox analysis with propensity score restriction and adjustment. RESULTS Of the 152 patients, 53 underwent surgery and 99 were managed by watchful waiting. In the surgery group, tumors were larger and faster-growing, patients were younger, more often male, and were more often treated in centers that operated more frequently. Surgery for NF-pNETs was not associated with a significantly lower risk of liver metastases or death, [adjusted hazard ratio (HR) = 0.73 (0.25-2.11)]. Adjusted HR's after stratification by tumor size were: NF-pNETs <2 cm = 2.04 (0.31-13.59) and NF-pNETs 2-3 cm = 1.38 (0.09-20.31). Five out of the 6 patients with NF-pNETs >3 cm managed by watchful waiting developed liver metastases or died compared with 6 out of the 16 patients who underwent surgery. CONCLUSIONS MEN1 patients with NF-pNETs <2 cm can be managed by watchful waiting, hereby avoiding major surgery without loss of oncological safety. The beneficial effect of a surgery in NF-pNETs 2 to 3 cm requires further research. In patients with NF-pNETs >3 cm, watchful waiting seems not advisable.
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34
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Surgical Management of Multiple Endocrine Neoplasia 1 and Multiple Endocrine Neoplasia 2. Surg Clin North Am 2019; 99:693-709. [DOI: 10.1016/j.suc.2019.04.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Buicko JL, Finnerty BM, Zhang T, Kim BJ, Fahey TJ, Nancy Du YC. Insights into the biology and treatment strategies of pancreatic neuroendocrine tumors. ACTA ACUST UNITED AC 2019; 2. [PMID: 31535089 DOI: 10.21037/apc.2019.06.02] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pancreatic neuroendocrine tumors (PNETs) are the second most common primary pancreatic neoplasms after pancreatic ductal adenocarcinoma. PNETs present with widely various clinical manifestation and unfavorable survival rate. The recent advances in next generation sequencing have significantly increased our understanding of the molecular landscape of PNETs and help guide the development of targeted therapies. This review intends to outline a holistic picture of the tumors by discussing current understanding of clinical presentations, up-to-date treatment strategies, novel mouse models, and molecular biology of PNETs. Furthermore, we will provide insight into the future development of more effective targeted therapies that are necessary to manage PNETs.
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Affiliation(s)
- Jessica L Buicko
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
| | | | - Tiantian Zhang
- Department of Pathology & Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Bu Jung Kim
- Department of Pathology & Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Thomas J Fahey
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
| | - Yi-Chieh Nancy Du
- Department of Pathology & Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
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36
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Clinicopathological features and surgical outcomes of resected functional pancreatic neuroendocrine tumors: a single institution experience. JOURNAL OF PANCREATOLOGY 2019. [DOI: 10.1097/jp9.0000000000000018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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Abstract
OBJECTIVE To determine the role of reoperation in patients with persistent or recurrent Zollinger-Ellison Syndrome (ZES). BACKGROUND Approximately, 0% to 60% of ZES patients are disease-free (DF) after an initial operation, but the tumor may recur. METHODS A prospective database was queried. RESULTS A total of 223 patients had an initial operation for possible cure of ZES and then were subsequently evaluated serially with cross sectional imaging-computed tomography, magnetic resonance imaging, ultrasound, more recently octreoscan-and functional studies for ZES activity. The mean age at first surgery was 49 years and with an 11-year mean follow-up 52 patients (23%) underwent reoperation when ZES recurred with imageable disease. Results in this group are analyzed in the current report. Reoperation occurred on a mean of 6 years after the initial surgery with a mean number of reoperations of 1 (range 1-5). After reoperation 18/52 patients were initially DF (35%); and after a mean follow-up of 8 years, 13/52 remained DF (25%). During follow-up, 9/52 reoperated patients (17%) died, of whom 7 patients died a disease-related death (13%). The overall survival from first surgery was 84% at 20 years and 68% at 30 years. Multiple endocrine neoplasia type 1 status did not affect survival, but DF interval and liver metastases did. CONCLUSIONS These results demonstrate that a significant proportion of patients with ZES will develop resectable persistent or recurrent disease after an initial operation. These patients generally have prolonged survival after reoperation and 25% can be cured with repeat surgery, suggesting all ZES patients postresection should have systematic imaging, and if tumor recurs, advise repeat operation.
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Kamilaris CDC, Stratakis CA. Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis. Front Endocrinol (Lausanne) 2019; 10:339. [PMID: 31263451 PMCID: PMC6584804 DOI: 10.3389/fendo.2019.00339] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 05/10/2019] [Indexed: 12/21/2022] Open
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary tumor syndrome inherited in an autosomal dominant manner and characterized by a predisposition to a multitude of endocrine neoplasms primarily of parathyroid, enteropancreatic, and anterior pituitary origin, as well as nonendocrine neoplasms. Other endocrine tumors in MEN1 include foregut carcinoid tumors, adrenocortical tumors, and rarely pheochromocytoma. Nonendocrine manifestations include meningiomas and ependymomas, lipomas, angiofibromas, collagenomas, and leiomyomas. MEN1 is caused by inactivating mutations of the tumor suppressor gene MEN1 which encodes the protein menin. This syndrome can affect all age groups, with 17% of patients developing MEN1-associated tumors before 21 years of age. Despite advances in the diagnosis and treatment of MEN1-associated tumors, patients with MEN1 continue to have decreased life expectancy primarily due to malignant neuroendocrine tumors. The most recent clinical practice guidelines for MEN1, published in 2012, highlight the need for early genetic and clinical diagnosis of MEN1 and recommend an intensive surveillance approach for both patients with this syndrome and asymptomatic carriers starting at the age of 5 years with the goal of timely detection and management of MEN1-associated neoplasms and ultimately decreased disease-specific morbidity and mortality. Unfortunately, there is no clear genotype-phenotype correlation and individual mutation-dependent surveillance is not possible currently.
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Jensen RT, Bodei L, Capdevila J, Couvelard A, Falconi M, Glasberg S, Kloppel G, Lamberts S, Peeters M, Rindi G, Rinke A, Rothmund M, Sundin A, Welin S, Fazio N. Unmet Needs in Functional and Nonfunctional Pancreatic Neuroendocrine Neoplasms. Neuroendocrinology 2018; 108:26-36. [PMID: 30282083 DOI: 10.1159/000494258] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 09/26/2018] [Indexed: 12/17/2022]
Abstract
Recently, the European Neuroendocrine Tumor Society (ENETS) held working sessions composed of members of the advisory board and other neuroendocrine neoplasm (NEN) experts to attempt to identify unmet needs in NENs in different locations or with advanced/poorly differentiated NENs. This report briefly summarizes the main proposed areas of unmet needs in patients with functional and nonfunctional pancreatic NENs.
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Affiliation(s)
- Robert T Jensen
- Cell Biology Section, NIDDK, National Institutes of Health, Bethesda, Maryland,
| | - Lisa Bodei
- Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Jaume Capdevila
- Department of Medical Oncology, Vall d'Hebron University Hospital, Vall Hebron Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | - Massimo Falconi
- Chirurgia del Pancreas, Università Vita e Salute, San Raffaele Hospital IRCCS, Milan, Italy
| | - Simona Glasberg
- Neuroendocrine Unit, Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Günter Kloppel
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - Steven Lamberts
- Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Marc Peeters
- Department of Oncology, Antwerp University Hospital, Edegem, Belgium
| | - Guido Rindi
- Institute of Anatomic Pathology, Policlinico A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Anja Rinke
- Department of Gastroenterology, UKGM Marburg and Philipps University, Marburg, Germany
| | | | - Anders Sundin
- Department of Radiology, Institute of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Staffan Welin
- Endocrine Oncology Unit, Department of Medical Sciences, University Hospital, Uppsala, Sweden
| | - Nicola Fazio
- Gastrointestinal and Neuroendocrine Oncology Unit, European Institute of Oncology (IEO), Milan, Italy
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Massironi S, Campana D, Partelli S, Panzuto F, Rossi RE, Faggiano A, Brighi N, Falconi M, Rinzivillo M, Delle Fave G, Colao AM, Conte D. Heterogeneity of Duodenal Neuroendocrine Tumors: An Italian Multi-center Experience. Ann Surg Oncol 2018; 25:3200-3206. [PMID: 30054824 DOI: 10.1245/s10434-018-6673-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND The optimal management of duodenal neuroendocrine neoplasms (dNENs) is unclear, and endoscopic resection is increasingly performed instead of surgery. METHODS This is a retrospective analysis of patients with histologically confirmed diagnosis of dNENs, managed at five Italian tertiary referral Centers in Italy. RESULTS From 2000 to 2017, 108 patients (69 males, 39 females, median age 59.5 years) were included in this study. Seventy-one patients had G1, 21 G2, 4 G3 dNENs (12 Ki-67 not available). Fifty-four patients showed metastases at diagnosis, and 20 patients developed metachronous metastases. Thirty patients had a functioning dNEN (14 metastatic). Fifty-seven patients had the dNEN surgically resected, 16 endoscopically, 23 metastatic, received medical therapy + surgery or endoscopy. Seven patients underwent liver-directed therapies, and one patient had PRRT. Median OS was 187 months. During a median follow-up of 76 months, 20 patients died (19 of disease-related causes). At Cox's multivariate proportional hazard regression, grading and age were the only variables independently related to OS. Median PFS was 170 months. Grading and staging at the initial diagnosis were independently related to PFS. No differences in terms of OS and PFS were observed between patients treated surgically or endoscopically. CONCLUSIONS dNENs prognosis may be highly variable. These tumors can be metastatic in up to 50% of cases at the time of first diagnosis and can develop metastases thereafter. Functioning neoplasms express high metastatic potential. Nuclear imaging should be performed to exclude distant metastases in all dNENs. Endoscopy and surgery play a primary role in the management of the disease. Further prospective studies are needed.
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Affiliation(s)
- Sara Massironi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
| | - Davide Campana
- Department of Medical and Surgical Sciences, Bologna University St. Orsola-Malpighi Polyclinic Hospital, Bologna, Italy
| | - Stefano Partelli
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy
| | - Francesco Panzuto
- Digestive and Liver Diseases Department, University "La Sapienza" of Rome Sant'Andrea Hospital, Rome, Italy
| | - Roberta Elisa Rossi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Antongiulio Faggiano
- Division of Endocrinology, Department of Clinical Medicine and Surgery, University "Federico II" of Naples, Naples, Italy
| | - Nicole Brighi
- Department of Medical and Surgical Sciences, Bologna University St. Orsola-Malpighi Polyclinic Hospital, Bologna, Italy
| | - Massimo Falconi
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy
| | - Maria Rinzivillo
- Digestive and Liver Diseases Department, University "La Sapienza" of Rome Sant'Andrea Hospital, Rome, Italy
| | - Gianfranco Delle Fave
- Digestive and Liver Diseases Department, University "La Sapienza" of Rome Sant'Andrea Hospital, Rome, Italy
| | - Anna Maria Colao
- Division of Endocrinology, Department of Clinical Medicine and Surgery, University "Federico II" of Naples, Naples, Italy
| | - Dario Conte
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
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Polenta V, Slater EP, Kann PH, Albers MB, Manoharan J, Ramaswamy A, Mahnken AH, Bartsch DK. Preoperative Imaging Overestimates the Tumor Size in Pancreatic Neuroendocrine Neoplasms Associated with Multiple Endocrine Neoplasia Type 1. World J Surg 2018; 42:1440-1447. [PMID: 29075857 DOI: 10.1007/s00268-017-4317-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND Radiological tumor size of non-functioning pancreatic neuroendocrine neoplasms (Nf-pNENs) associated with multiple endocrine neoplasia type 1 (MEN1) is a crucial parameter to indicate surgery. The aim of this study was to compare radiological size (RS) and pathologic size (PS) of MEN1 associated with pNENs. METHODS Prospectively collected data of MEN1 patients who underwent pancreatic resections for pNENs were retrospectively analyzed. RS was defined as the largest tumor diameter measured on endoscopic ultrasound (EUS), magnetic resonance imaging (MRI) or computed tomography (CT). PS was defined as the largest tumor diameter on pathological analysis. Student's t test and linear regression analysis were used to compare the median RS and PS. p < 0.05 was considered significant. RESULTS Forty-four patients with a median age of 37 (range 10-68) years underwent primary pancreatic resections for pNENs. Overall, the median RS (20 mm, range 3-100 mm) was significantly larger than the PS (13 mm, range 4-110 mm) (p = 0.001). In patients with pNENs < 20 mm (n = 27), the size difference (median RS 15 mm vs PS 12 mm) was also significant (p = 0.003). However, the only modality that significantly overestimated the PS was EUS (median RS 14 mm vs 11 mm; p = 0.0002). RS overestimated the PS in 21 patients (21 of 27 patients, 78%). Five of 11 patients (12%) with a Nf-pNEN and a RS > 20 mm had in reality a PS < 20 mm. MRI was the imaging technique that best correlated with PS in the total cohort (r = 0.8; p < 0.0001), whereas EUS was the best correlating imaging tool in pNENs < 20 mm (r = 0.5; p = 0.0001). CONCLUSION Preoperative imaging, especially EUS, frequently overestimates the size of MEN1-pNENs, especially those with a PS < 20 mm. This should be considered when indicating surgery in MEN1 patients with small Nf-pNENs.
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Affiliation(s)
- V Polenta
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany. .,Department of General Surgery, Ospedali Riuniti Ancona, Conca 71, Torrette, 60020, Ancona, Italy.
| | - E P Slater
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany
| | - P H Kann
- Division Endocrinology, Philipps-University Marburg, Marburg, Germany
| | - M B Albers
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany
| | - J Manoharan
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany
| | - A Ramaswamy
- Institute of Pathology, Philipps-University Marburg, Marburg, Germany
| | - A H Mahnken
- Department of Radiology, Philipps-University Marburg, Marburg, Germany
| | - D K Bartsch
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany
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Abstract
This article reviews the role of surgical and medical management in patients with Zollinger-Ellison syndrome (ZES) due to a gastrin-secreting neuroendocrine tumor (gastrinoma). It concentrates on the status at present but also briefly reviews the changes over time in treatment approaches. Generally, surgical and medical therapy are complementary today; however, in some cases, such as patients with ZES and multiple endocrine neoplasia type 1, the treatment approach remains controversial.
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Affiliation(s)
- Jeffrey A Norton
- Department of Surgery, Stanford University School of Medicine, 291 campus Drive, Stanford, CA 94305-5101, USA
| | - Deshka S Foster
- Department of Surgery, Stanford University School of Medicine, 291 campus Drive, Stanford, CA 94305-5101, USA
| | - Tetsuhide Ito
- Neuroendocrine Tumor Centra, Fukuoka Sanno Hospital, International University of Health and Welfare, 3-6-45 Momochihama, Sawara-Ku, Fukuoka 814-0001, Japan
| | - Robert T Jensen
- Digestive Diseases Branch, NIDDK, National Institutes of Health, Building 10, Room 9C-103, Bethesda, MD 20892-1804, USA.
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43
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Lee L, Ito T, Jensen RT. Imaging of pancreatic neuroendocrine tumors: recent advances, current status, and controversies. Expert Rev Anticancer Ther 2018; 18:837-860. [PMID: 29973077 PMCID: PMC6283410 DOI: 10.1080/14737140.2018.1496822] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Recently, there have been a number of advances in imaging pancreatic neuroendocrine tumors (panNETs), as well as other neuroendocrine tumors (NETs), which have had a profound effect on the management and treatment of these patients, but in some cases are also associated with controversies. Areas covered: These advances are the result of numerous studies attempting to better define the roles of both cross-sectional imaging, endoscopic ultrasound, with or without fine-needle aspiration, and molecular imaging in both sporadic and inherited panNET syndromes; the increased attempt to develop imaging parameters that correlate with tumor classification or have prognostic value; the rapidly increasing use of molecular imaging in these tumors and the attempt to develop imaging parameters that correlate with treatment/outcome results. Each of these areas and the associated controversies are reviewed. Expert commentary: There have been numerous advances in all aspects of the imaging of panNETs, as well as other NETs, in the last few years. The advances are leading to expanded roles of imaging in the management of these patients and the results being seen in panNETs/GI-NETs with these newer techniques are already being used in more common tumors.
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Affiliation(s)
- Lingaku Lee
- a Department of Medicine and Bioregulatory Science , Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan
- b Digestive Diseases Branch , NIDDK, NIH , Bethesda , MD , USA
| | - Tetsuhide Ito
- c Neuroendocrine Tumor Centra, Fukuoka Sanno Hospital International University of Health and Welfare 3-6-45 Momochihama , Sawara-Ku, Fukuoka , Japan
| | - Robert T Jensen
- b Digestive Diseases Branch , NIDDK, NIH , Bethesda , MD , USA
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Rossi RE, Rausa E, Cavalcoli F, Conte D, Massironi S. Duodenal neuroendocrine neoplasms: a still poorly recognized clinical entity. Scand J Gastroenterol 2018; 53:835-842. [PMID: 29726295 DOI: 10.1080/00365521.2018.1468479] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 04/16/2018] [Accepted: 04/16/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Duodenal neuroendocrine neoplasms (dNENs) are rare tumors, which usually show good prognosis. The optimal management of these tumors is still far from being clearly understood because of their rarity and the poor level of knowledge about their natural history. Herein, we have reviewed the literature on dNENs to collect and analyze the current data on epidemiology, diagnosis and management of these rare tumors. METHODS Bibliographical searches were performed in PubMed, using the following keywords: duodenal neuroendocrine neoplasm; duodenum; gastrinoma; diagnosis; therapy; guidelines. We searched for all relevant articles published over the last 15 years. Non-English language papers were excluded. RESULTS We reviewed the pertinent articles about dNENs. Upper gastrointestinal endoscopy with biopsy is the cornerstone of the dNENs diagnostic process. Endoscopic ultrasound with fine-needle aspiration/biopsy should be performed in order to locally stage the disease and in all cases of non-diagnostic endoscopy. Endoscopic or complete surgical removal of the primary lesion is the recommended treatment and is generally achievable for the majority of the patients. A less aggressive approach may be suggested for well-differentiated low-stage tumors. After NEN removal, patients should be closely followed-up especially during the first 3 years by endoscopic examination, imaging tests and CgA measurements. CONCLUSIONS The multi-disciplinary approach and the preservation of the quality of life of the patients play a key role in the therapeutic process for dNENs. Further studies are needed to better define standardized guidelines specific to dNENs, including optimal management approaches and follow-up intervals.
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Affiliation(s)
- Roberta Elisa Rossi
- a Department of Gastroenterology and Endoscopy , Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico , Milan , Italy
- b Department of Pathophysiology and Organ Transplant , Università degli Studi di Milano , Milan , Italy
| | - Emanuele Rausa
- c General and Emergency Surgery Department , ASST Trauma Center "Papa Giovanni XXIII" Hospital , Bergamo , Italy
| | - Federica Cavalcoli
- a Department of Gastroenterology and Endoscopy , Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico , Milan , Italy
- b Department of Pathophysiology and Organ Transplant , Università degli Studi di Milano , Milan , Italy
| | - Dario Conte
- a Department of Gastroenterology and Endoscopy , Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico , Milan , Italy
- b Department of Pathophysiology and Organ Transplant , Università degli Studi di Milano , Milan , Italy
| | - Sara Massironi
- a Department of Gastroenterology and Endoscopy , Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico , Milan , Italy
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Albertario S, Forti P, Bianchi C, Morone G, Tinozzi FP, Moglia P, Abelli M, Benedetti M, Aprile C. Radioguided Surgery for Gastrinoma: A Case Report. TUMORI JOURNAL 2018; 88:S41-3. [PMID: 12365386 DOI: 10.1177/030089160208800338] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Aims and Background Gastrinomas are the most common neuroendocrine tumors of the duodenopancreatic region. Surgical resection is the primary type of radical treatment. Methods and Study Design At the Institute of General, Gastrointestinal and Breast Surgery we treated a patient with a duodenal gastrinoma that was diagnosed and localized by means of selective celiacmesenteric angiography and labeled octreotide scintigraphy. Surgery was performed using a radioguided technique; in this way we easily detected the small tumor and discovered another tracer-uptaking lesion that turned out to be a metastatic lymph node. Results Surgical resection is the ideal treatment for sporadic gastrinoma: it improves quality of life, prolongs survival, and reduces the incidence of metastases, with a modest percentage of complications and practically zero mortality. Meanwhile, medical treatment is being revaluated, particulary in the case of metastatic disease or polyendocrine MEN1 syndrome. A fundamental aspect in the management of gastrinomas is tumor localization. Endoscopic ultrasonography and labeled octreotide scintigraphy (Octreoscan) proved to be more effective than the usual imaging modalities. Intraoperative ultrasonography, gastroscopy for duodenal transillumination and repeated measurement of blood gastrin levels should be performed intraoperatively in the surgical treatment of gastrinomas. Conclusions The clinical application of radioguided surgery for tracer-uptaking endocrine tumors is still controversial. In our case the decision to use this method was influenced by the fear that the patient's obesity and the effects of previous surgery could hamper the identification of the small tumor.
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Affiliation(s)
- S Albertario
- Istituto di Chirurgia Generale e dei Trapianti d'Organo, Università degli Studi di Pavia, Italy
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Abstract
Pancreatic neuroendocrine tumours (PNETs) might occur as a non-familial isolated endocrinopathy or as part of a complex hereditary syndrome, such as multiple endocrine neoplasia type 1 (MEN1). MEN1 is an autosomal dominant disorder characterized by the combined occurrence of PNETs with tumours of the parathyroids and anterior pituitary. Treatments for primary PNETs include surgery. Treatments for non-resectable PNETs and metastases include biotherapy (for example, somatostatin analogues, inhibitors of receptors and monoclonal antibodies), chemotherapy and radiological therapy. All these treatments are effective for PNETs in patients without MEN1; however, there is a scarcity of clinical trials reporting the efficacy of the same treatments of PNETs in patients with MEN1. Treatment of PNETs in patients with MEN1 is challenging owing to the concomitant development of other tumours, which might have metastasized. In recent years, preclinical studies have identified potential new therapeutic targets for treating MEN1-associated neuroendocrine tumours (including PNETs), and these include epigenetic modification, the β-catenin-wingless (WNT) pathway, Hedgehog signalling, somatostatin receptors and MEN1 gene replacement therapy. This Review discusses these advances.
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Affiliation(s)
- Morten Frost
- Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, OX3 7LJ. United Kingdom
- Endocrine Research Unit, University of Southern Denmark, Odense, 5000, Denmark
| | - Kate E Lines
- Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, OX3 7LJ. United Kingdom
| | - Rajesh V Thakker
- Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, OX3 7LJ. United Kingdom
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47
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Guarnotta V, Martini C, Davì MV, Pizza G, Colao A, Faggiano A. The Zollinger-Ellison syndrome: is there a role for somatostatin analogues in the treatment of the gastrinoma? Endocrine 2018; 60:15-27. [PMID: 29019150 DOI: 10.1007/s12020-017-1420-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 09/02/2017] [Indexed: 12/17/2022]
Abstract
PURPOSE Analyze the role of somatostatin analogues (SSAs) in the treatment of sporadic and MEN1-related gastrinomas, trying to define whether recent trials have changed the landscape of gastrinoma therapy. METHODS We evaluate the rationale of SSA use in the treatment of gastrinomas, summarize the current literature concerning the effect of SSAs on the control of Zollinger-Ellison syndrome (ZES) and gastrinomas tumor progression and discuss their role in the most recent guidelines. RESULTS The medical treatment of gastrinoma and related ZES is aimed at controlling acid hypersecretion and tumor progression, in inoperable patients. The use of proton pump inhibitors (PPIs) to control the syndrome is a cornerstone in the ZES therapy. SSAs are not usually indicated for antisecretory purpose, because PPIs are considered the treatment of choice, due to their long lasting high efficacy and oral availability. The antiproliferative effect of SSAs has been established by two placebo-controlled trials that have clearly demonstrated a significant increase in progression free survival in patients affected by non-functioning well-differentiated advanced neuroendocrine tumors (NETs). The recent ENETS guidelines recommend the use of SSAs in advanced well differentiated NETs as antiproliferative agents. CONCLUSIONS The high sstr-expression in gastrinomas make them highly responsive to SSAs and support the use of such drugs to counteract the tumour growth in patients not amenable to surgical cure. Unfortunately, limited data, mainly case reports or small series, support the use of SSAs in advanced gastrinomas, therefore, it is difficult to quantify their ability to control tumour growth and disease progression.
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Affiliation(s)
- Valentina Guarnotta
- Biomedical Department of Internal and Specialist Medicine (DIBIMIS), Section of Endocrine-Metabolic Diseases, University of Palermo, Palermo, Italy
| | - Chiara Martini
- Clinica Medica 3^, Department of Medicine, DIMED, University of Padova, Padova, Italy.
| | - Maria Vittoria Davì
- Section of Endocrinology, Medicina Generale e Malattie Aterotrombotiche e Degenerative, Department of Medicine, University of Verona, Verona, Italy
| | - Genoveffa Pizza
- Department of Clinical Medicine and Surgery, "Federico II" University of Naples, Naples, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and Surgery, "Federico II" University of Naples, Naples, Italy
| | - Antongiulio Faggiano
- Thyroid and Parathyroid Surgery Unit, Istituto Nazionale per lo studio e la cura dei tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy
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Tariq H, Kamal MU, Vootla V, ElZaeedi M, Niazi M, Gilchrist B, Ihimoyan A, Dev A, Chilimuri S. A Rare Cause of Abdominal Pain and Mass in an 18-Year-Old Patient: A Diagnostic Dilemma. Gastroenterology Res 2018; 11:75-78. [PMID: 29511413 PMCID: PMC5827909 DOI: 10.14740/gr955w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Accepted: 01/23/2018] [Indexed: 01/10/2023] Open
Abstract
We present a case of an 18-year-old male who presented with complains of abdominal pain, nausea and vomiting for 2 years. An esophagogastroduodenoscopy (EGD) revealed a 3 mm nodule on the lesser curvature of the stomach and prominent gastric folds. Biopsy of the nodule revealed a well-differentiated neuroendocrine tumor (NET) in lamina prop with focal extension into muscularis mucosa consistent with a gastric carcinoid. Tumor cells stained with neuron-specific enolase (NSE), chromogranin and synaptophysin only. The prominent gastric fold biopsy revealed gastric fundic mucosa with mucosal edema and focal mild chronic inflammation. Serum gastrin level was found to be 2,083 pg/mL. Abdomen CT and endoscopic ultrasound (EUS) revealed a mass near the pancreatic neck. These findings were consistent with a functional gastrin producing well-differentiated grade 1 neuroendocrine neoplasm (gastrinoma). The patient underwent exploratory laparotomy with resection of the mass and resulting in normalization of gastrin levels.
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Affiliation(s)
- Hassan Tariq
- Department of Medicine, Bronx Lebanon Hospital Center, Bronx, NY 10457, USA
| | | | - Vamshidhar Vootla
- Department of Medicine, Bronx Lebanon Hospital Center, Bronx, NY 10457, USA
| | - Mohamed ElZaeedi
- Department of Surgery, Bronx Lebanon Hospital Center, Bronx, NY 10457, USA
| | - Masooma Niazi
- Department of Pathology, Bronx Lebanon Hospital Center, Bronx, NY 10457, USA
| | - Brian Gilchrist
- Department of Surgery, Bronx Lebanon Hospital Center, Bronx, NY 10457, USA
| | - Ariyo Ihimoyan
- Department of Medicine, Bronx Lebanon Hospital Center, Bronx, NY 10457, USA
| | - Anil Dev
- Department of Medicine, Bronx Lebanon Hospital Center, Bronx, NY 10457, USA
| | - Sridhar Chilimuri
- Department of Medicine, Bronx Lebanon Hospital Center, Bronx, NY 10457, USA
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Affiliation(s)
- Deepak Atri
- From the Department of Medicine, Johns Hopkins Hospital and Johns Hopkins University School of Medicine, Baltimore (D.A., D.F., R.M.); and the Department of Medicine, University of California, San Francisco, and the Medical Service, San Francisco Veterans Affairs Medical Center - both in San Francisco (G.D., K.R.F.)
| | - David Furfaro
- From the Department of Medicine, Johns Hopkins Hospital and Johns Hopkins University School of Medicine, Baltimore (D.A., D.F., R.M.); and the Department of Medicine, University of California, San Francisco, and the Medical Service, San Francisco Veterans Affairs Medical Center - both in San Francisco (G.D., K.R.F.)
| | - Gurpreet Dhaliwal
- From the Department of Medicine, Johns Hopkins Hospital and Johns Hopkins University School of Medicine, Baltimore (D.A., D.F., R.M.); and the Department of Medicine, University of California, San Francisco, and the Medical Service, San Francisco Veterans Affairs Medical Center - both in San Francisco (G.D., K.R.F.)
| | - Kenneth R Feingold
- From the Department of Medicine, Johns Hopkins Hospital and Johns Hopkins University School of Medicine, Baltimore (D.A., D.F., R.M.); and the Department of Medicine, University of California, San Francisco, and the Medical Service, San Francisco Veterans Affairs Medical Center - both in San Francisco (G.D., K.R.F.)
| | - Reza Manesh
- From the Department of Medicine, Johns Hopkins Hospital and Johns Hopkins University School of Medicine, Baltimore (D.A., D.F., R.M.); and the Department of Medicine, University of California, San Francisco, and the Medical Service, San Francisco Veterans Affairs Medical Center - both in San Francisco (G.D., K.R.F.)
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Hagi T, Hosoda Y, Komoto I, Uemoto S, Hijioka S, Taki Y, Nishiyama K, Imamura M. A primary hepatic gastrinoma accompanied by hyperplasia of multi-nodular Brunner's glands. Surg Case Rep 2017; 3:118. [PMID: 29181825 PMCID: PMC5704026 DOI: 10.1186/s40792-017-0392-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 11/09/2017] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND Primary hepatic gastrinoma causing severe ulcerogenic syndrome is extremely rare. Herein, we report a case of primary hepatic gastrinoma accompanied by hyperplasia of multi-nodular Brunner's glands in a patient who instead, preoperatively, was suspected of having multiple duodenal gastrinomas and hepatic metastasis. CASE PRESENTATION A 57-year-old woman consulted a clinic complaining of melena, intermittent abdominal pain, diarrhea, and vomiting which had persisted for about 3 years. Six months before her presentation, she underwent segmental resection of the jejunum for acute peritonitis due to the spontaneous jejunal perforation. A blood test revealed that her serum immunoreactive gastrin (IRG) level was 12,037 pg/mL. Subsequently, she was transferred to our hospital. On computed tomography (CT), a hypervascular tumor of 23 mm in the segment 5 (S5) region of the liver was visualized. A selective arterial secretagogue injection test (SASI test) was performed twice. The first SASI test revealed that the hepatic tumor was a gastrinoma, and there was no gastrinoma in the duodeno-pancreatic region. Additionally, somatostatin receptor scintigraphy only visualized the tumor in the liver. However, the second SASI test, which was performed during the administration of a proton pump inhibitor and a somatostatin analog (octreotide acetate), revealed that there may have been gastrinomas existing not only in the liver but also in the upper part of the duodenum or the head of the pancreas. Duodenal endoscopy revealed multiple submucosal tumors in the first and the second portion of the duodenum, although a pathological examination of biopsied specimens obtained from the duodenal lesions was negative for malignant cells. Multiple endocrine neoplasia type 1 (MEN1) was excluded from her family history, and serum levels of both intact parathyroid hormone (iPTH) and calcium were within normal ranges. An anterior segmentectomy of the liver and pancreas-preserving total duodenectomy were performed on September 9, 2013. Postoperatively, her serum immunoreactive gastrin level decreased to less than 50 pg/mL. Pathological study of the resected specimens revealed a gastrinoma in the liver, but no gastrinoma in the duodenum. Interestingly, the duodenal submucosal tumor-like lesions were hyperplastic Brunner's glands. Postoperatively, she has been well without recurrence of hypergastrinemia for 4 years. CONCLUSION We report a case of primary hepatic gastrinoma in a patient who has been cured for 4 years postoperatively. The diagnosis was somewhat difficult due to the coexisting, multiple hyperplastic Brunner's glands of the duodenum mimicking the submucosal neuroendocrine tumors, which might have developed due to long-term hypergastrinemia.
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Affiliation(s)
- Takaomi Hagi
- Department of Gastroenterological Surgery, Kansai Electric Power Hospital, 2-1-7 Fukushima, Fukushima-ku, Osaka, 553-0003, Japan.,Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yohei Hosoda
- Department of Gastroenterological Surgery, Kansai Electric Power Hospital, 2-1-7 Fukushima, Fukushima-ku, Osaka, 553-0003, Japan
| | - Izumi Komoto
- Department of Gastroenterological Surgery, Kansai Electric Power Hospital, 2-1-7 Fukushima, Fukushima-ku, Osaka, 553-0003, Japan.
| | - Shinji Uemoto
- Department of Hepato-Biliary-Pancreatic and Transplantation Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Susumu Hijioka
- Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Yoshiro Taki
- Department of Gastroenterological Surgery, Kansai Electric Power Hospital, 2-1-7 Fukushima, Fukushima-ku, Osaka, 553-0003, Japan
| | - Kazuhiro Nishiyama
- Department of Gastroenterological Surgery, Kansai Electric Power Hospital, 2-1-7 Fukushima, Fukushima-ku, Osaka, 553-0003, Japan
| | - Masayuki Imamura
- Department of Gastroenterological Surgery, Kansai Electric Power Hospital, 2-1-7 Fukushima, Fukushima-ku, Osaka, 553-0003, Japan
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