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Ito T, Ramos-Alvarez I, Jensen RT. Long-Term Proton Pump Inhibitor-Acid Suppressive Treatment Can Cause Vitamin B 12 Deficiency in Zollinger-Ellison Syndrome (ZES) Patients. Int J Mol Sci 2024; 25:7286. [PMID: 39000391 PMCID: PMC11242121 DOI: 10.3390/ijms25137286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
Whether the long-term treatment of patients with proton pump inhibitors (PPIs) with different diseases [GERD, Zollinger-Ellison syndrome (ZES), etc.] can result in vitamin B12 (VB12) deficiency is controversial. In this study, in 175 patients undergoing long-term ZES treatment with anti-acid therapies, drug-induced control acid secretory rates were correlated with the presence/absence of VB12 deficiency, determined by assessing serum VB12 levels, measurements of VB12 body stores (blood methylmalonic acid (MMA) and total homocysteine[tHYC]), and other features of ZES. After a mean of 10.2 yrs. of any acid treatment (5.6 yrs. with PPIs), 21% had VB12 deficiency with significantly lower serum and body VB12 levels (p < 0.0001). The presence of VB12 deficiency did not correlate with any feature of ZES but was associated with a 12-fold lower acid control rate, a 2-fold higher acid control pH (6.4 vs. 3.7), and acid control secretory rates below those required for the activation of pepsin (pH > 3.5). Over a 5-yr period, the patients with VB12 deficiency had a higher rate of achlorhydria (73% vs. 24%) and a lower rate of normal acid secretion (0% vs. 49%). In conclusion, in ZES patients, chronic long-term PPI treatment results in marked acid hyposecretion, resulting in decreased serum VB12 levels and decreased VB12-body stores, which can result in VB12 deficiency.
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Affiliation(s)
- 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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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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Lee L, Ramos-Alvarez I, Jensen RT. Predictive Factors for Resistant Disease with Medical/Radiologic/Liver-Directed Anti-Tumor Treatments in Patients with Advanced Pancreatic Neuroendocrine Neoplasms: Recent Advances and Controversies. Cancers (Basel) 2022; 14:cancers14051250. [PMID: 35267558 PMCID: PMC8909561 DOI: 10.3390/cancers14051250] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/08/2022] [Accepted: 02/23/2022] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Tumor resistance, both primary and acquired, is leading to increased complexity in the nonsurgical treatment of patients with advanced panNENs, which would be greatly helped by reliable prognostic/predictive factors. The importance in identifying resistance is being contributed to by the increased array of possible treatments available for treating resistant advanced disease; the variable clinical course as well as response to any given treatment approach of patients within one staging or grading system, the advances in imaging which are providing increasing promising results/parameters that correlate with grading/outcome/resistance, the increased understanding of the molecular pathogenesis providing promising prognostic markers, all of which can contribute to selecting the best treatment to overcome resistance disease. Several factors have been identified that have prognostic/predictive value for identifying development resistant disease and affecting overall survival (OS)/PFS with various nonsurgical treatments of patients with advanced panNENs. Prognostic factors identified for patients with advanced panNENs for both OS/PFSs include various clinically-related factors (clinical, laboratory/biological markers, imaging, treatment-related factors), pathological factors (histological, classification, grading) and molecular factors. Particularly important prognostic factors for the different treatment modalities studies are the recent grading systems. Most prognostic factors for each treatment modality for OS/PFS are not specific for a given treatment option. These advances have generated several controversies and new unanswered questions, particularly those related to their possible role in predicting the possible sequence of different anti-tumor treatments in patients with different presentations. Each of these areas is reviewed in this paper. Abstract Purpose: Recent advances in the diagnosis, management and nonsurgical treatment of patients with advanced pancreatic neuroendocrine neoplasms (panNENs) have led to an emerging need for sensitive and useful prognostic factors for predicting responses/survival. Areas covered: The predictive value of a number of reported prognostic factors including clinically-related factors (clinical/laboratory/imaging/treatment-related factors), pathological factors (histological/classification/grading), and molecular factors, on therapeutic outcomes of anti-tumor medical therapies with molecular targeting agents (everolimus/sunitinib/somatostatin analogues), chemotherapy, radiological therapy with peptide receptor radionuclide therapy, or liver-directed therapies (embolization/chemoembolization/radio-embolization (SIRTs)) are reviewed. Recent findings in each of these areas, as well as remaining controversies and uncertainties, are discussed in detail, particularly from the viewpoint of treatment sequencing. Conclusions: The recent increase in the number of available therapeutic agents for the nonsurgical treatment of patients with advanced panNENs have raised the importance of prognostic factors predictive for therapeutic outcomes of each treatment option. The establishment of sensitive and useful prognostic markers will have a significant impact on optimal treatment selection, as well as in tailoring the therapeutic sequence, and for maximizing the survival benefit of each individual patient. In the paper, the progress in this area, as well as the controversies/uncertainties, are reviewed.
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Affiliation(s)
- Lingaku Lee
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
- National Kyushu Cancer Center, Department of Hepato-Biliary-Pancreatology, Fukuoka 811-1395, Japan
| | - Irene Ramos-Alvarez
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
| | - Robert T. Jensen
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
- Correspondence: ; Tel.: +1-301-496-4201
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Muniraj T, Aslanian HR. Pancreatic Neuroendocrine Tumors. GERIATRIC GASTROENTEROLOGY 2021:1933-1951. [DOI: 10.1007/978-3-030-30192-7_81] [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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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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Ahmed M. Gastrointestinal neuroendocrine tumors in 2020. World J Gastrointest Oncol 2020; 12:791-807. [PMID: 32879660 PMCID: PMC7443843 DOI: 10.4251/wjgo.v12.i8.791] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 05/26/2020] [Accepted: 07/19/2020] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal neuroendocrine tumors are rare slow-growing tumors with distinct histological, biological, and clinical characteristics that have increased in incidence and prevalence within the last few decades. They contain chromogranin A, synaptophysin and neuron-specific enolase which are necessary for making a diagnosis of neuroendocrine tumor. Ki-67 index and mitotic index correlate with cellular proliferation. Serum chromogranin A is the most commonly used biomarker to assess the bulk of disease and monitor treatment and is raised in both functioning and non-functioning neuroendocrine tumors. Most of the gastrointestinal neuroendocrine tumors are non-functional. World Health Organization updated the classification of neuroendocrine tumors in 2017 and renamed mixed adenoneuroendocrine carcinoma into mixed neuroendocrine neoplasm. Gastric neuroendocrine tumors arise from enterochromaffin like cells. They are classified into 4 types. Only type I and type II are gastrin dependent. Small intestinal neuroendocrine tumor is the most common small bowel malignancy. More than two-third of them occur in the terminal ileum within 60 cm of ileocecal valve. Patients with small intestinal neuroendrocrine tumors frequently show clinical symptoms and develop distant metastases more often than those with neuroendocrine tumors of other organs. Duodenal and jejuno-ileal neuroendocrine tumors are distinct biologically and clinically. Carcinoid syndrome generally occurs when jejuno-ileal neuroendocrine tumors metastasize to the liver. Appendiceal neuroendocrine tumors are generally detected after appendectomy. Colonic neuroendocrine tumors generally present as a large tumor with local or distant metastasis at the time of diagnosis. Rectal neuroendocrine tumors are increasingly being diagnosed since the implementation of screening colonoscopy in 2000. Gastrointestinal neuroendocrine tumors are diagnosed and staged by endoscopy with biopsy, endoscopic ultrasound, serology of biomarkers, imaging studies and functional somatostatin scans. Various treatment options are available for curative and palliative treatment of gastrointestinal neuroendocrine tumors.
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Affiliation(s)
- Monjur Ahmed
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA 19107, United States
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Lee L, Ito T, Jensen RT. Prognostic and predictive factors on overall survival and surgical outcomes in pancreatic neuroendocrine tumors: recent advances and controversies. Expert Rev Anticancer Ther 2019; 19:1029-1050. [PMID: 31738624 PMCID: PMC6923565 DOI: 10.1080/14737140.2019.1693893] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/13/2019] [Indexed: 02/06/2023]
Abstract
Introduction: Recent advances in diagnostic modalities and therapeutic agents have raised the importance of prognostic factors in predicting overall survival, as well as predictive factors for surgical outcomes, in tailoring therapeutic strategies of patients with pancreatic neuroendocrine neoplasms (panNENs).Areas covered: Numerous recent studies of panNEN patients report the prognostic values of a number of clinically related factors (clinical, laboratory, imaging, treatment-related factors), pathological factors (histological, classification, grading) and molecular factors on long-term survival. In addition, an increasing number of studies showed the usefulness of various factors, specifically biomarkers and molecular makers, in predicting recurrence and mortality related to surgical treatment. Recent findings (from the last 3 years) in each of these areas, as well as recent controversies, are reviewed.Expert commentary: The clinical importance of prognostic and predictive factors for panNENs is markedly increased for both overall outcome and post resection, as a result of recent advances in all aspects of the diagnosis, management and treatment of panNENs. Despite the proven prognostic utility of routinely used tumor grading/classification and staging systems, further studies are required to establish these novel prognostic factors to support their routine clinical use.
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Affiliation(s)
- Lingaku Lee
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD, 20892-1804, USA
- Department of Hepato-Biliary-Pancreatology, National Kyushu Cancer Center, Fukuoka, 811-1395, Japan
| | - Tetsuhide Ito
- Neuroendocrine Tumor Centre, Fukuoka Sanno Hospital, International University of Health and Welfare, Fukuoka, 814-0001, Japan
| | - Robert T. Jensen
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD, 20892-1804, USA
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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:ijms20205128. [PMID: 31623145 PMCID: PMC6829234 DOI: 10.3390/ijms20205128] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [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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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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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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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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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: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION 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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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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Treatment of Pancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1: Some Clarity But Continued Controversy. Pancreas 2017; 46:589-594. [PMID: 28426491 PMCID: PMC5407310 DOI: 10.1097/mpa.0000000000000825] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Ito T, Jensen RT. Imaging in multiple endocrine neoplasia type 1: recent studies show enhanced sensitivities but increased controversies. INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY 2016; 3:53-66. [PMID: 26834963 DOI: 10.2217/ije.15.29] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
In multiple endocrine neoplasia type 1 (MEN1) patients, a number of recent studies compare the ability of different, new imaging modalities to existing modalities to localize the important neuroendocrine tumors (NETs) that contribute to their decreased life expectancy (pancreatic NETs [pNETs] and thymic carcinoids). These included the use of 68Ga-DOTATOC-PET/CT, endoscopic ultrasound and MRI. The current paper analyzes these results in light of current guidelines and controversies involved in the treatment/management of MEN1 patients. Particular attention is paid to results in these studies with thymic carcinoids and nonfunctional pNETs/gastrinomas, which recent studies show are particularly important in determining long-term survival. These studies show a number of promising imaging results but also raise a number of controversies, which will need to be addressed both in their use initially and for serial studies in these patients.
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Affiliation(s)
- Tetsuhide Ito
- Department of Medicine & Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Robert T Jensen
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20817, USA
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Krampitz GW, Norton JA. WITHDRAWN: Current Problems in Surgery: Pancreatic Neuroendocrine Tumors. Curr Probl Surg 2014. [DOI: 10.1067/j.cpsurg.2013.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Attili F, Capurso G, Vanella G, Fuccio L, Delle Fave G, Costamagna G, Larghi A. Diagnostic and therapeutic role of endoscopy in gastroenteropancreatic neuroendocrine neoplasms. Dig Liver Dis 2014; 46:9-17. [PMID: 23731843 DOI: 10.1016/j.dld.2013.04.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Accepted: 04/20/2013] [Indexed: 02/08/2023]
Abstract
Gastroenteropancreatic neuroendocrine neoplasms have substantially increased over the last decades. Because of the indolent clinical course of the disease even in advance stages and the rise in the incidental diagnosis of small asymptomatic lesions, the prevalence of gastroenteropancreatic neuroendocrine neoplasms is higher than that of pancreatic, gastric and oesophageal adenocarcinomas, making them the second most prevalent cancer type of the gastrointestinal tract. This increase in the overall prevalence of gastroenteropancreatic neuroendocrine neoplasms has been paralleled by a growth in the importance of the endoscopist in the care of these patients, who usually require a multidisciplinary approach. In this manuscript the diagnostic and therapeutic role of endoscopic for gastroenteropancreatic neuroendocrine neoplasms will be reviewed.
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Affiliation(s)
- Fabia Attili
- Digestive Endoscopy Unit, Catholic University, Rome, Italy
| | - Gabriele Capurso
- Division of Digestive and Liver Disease, University La Sapienza, Rome, Italy
| | | | - Lorenzo Fuccio
- Division of Gastroenterology, S. Orsola-Malpighi Hospital, University of Bologna, Italy
| | | | | | - Alberto Larghi
- Digestive Endoscopy Unit, Catholic University, Rome, Italy.
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Abstract
PURPOSE OF REVIEW To review the recent advances and current controversies in patients with Zollinger-Ellison syndrome (ZES). RECENT FINDINGS Recent advances in the management of ZES include: improved understanding of the pathogenesis of gastrinoma and pancreatic neuroendocrine tumors, new prognostic classification systems, new diagnostic algorithms, more sensitive localization studies, new treatment strategies including improved control of gastric acid secretion and role for surgery, and new approaches to patients with advanced disease. Controversies include: the best approach to a patient with hypergastrinemia suspected of possibly having ZES, the appropriate gastrin assay to use, the role of surgery in patients with ZES, especially those with multiple endocrine neoplasia type 1, and the precise order of therapeutic modalities in the treatment of patients with advanced disease. SUMMARY This review updates clinicians regarding important advances and controversies required to optimally diagnose and manage patients with ZES.
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Affiliation(s)
- Tetsuhide Ito
- aDepartment of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan bDigestive Diseases Branch, NIDDK, NIH, Bethesda, Maryland, USA
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De Angelis C, Brizzi RF, Pellicano R. Endoscopic ultrasonography for pancreatic cancer: current and future perspectives. J Gastrointest Oncol 2013; 4:220-30. [PMID: 23730519 DOI: 10.3978/j.issn.2078-6891.2013.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 01/18/2013] [Indexed: 12/13/2022] Open
Abstract
A suspected pancreatic lesion can be a difficult challenge for the clinician. In the last years we have witnessed tumultuous technological improvements of the radiological and nuclear medicine imaging. Taking this into account, we will try to delineate the new role of endoscopic ultrasound (EUS) in pancreatic imaging and to place it in a shareable diagnostic and staging algorithm of pancreatic cancer (PC). To date the most accurate imaging techniques for the PC remain contrast-enhanced computed tomography (CT) and EUS. The latter has the highest accuracy in detecting small lesions, in assessing tumor size and lymph nodes involvement, but helical CT or an up-to-date magnetic resonance imaging (MRI) must be the first choice in patients with a suspected pancreatic lesion. After this first step there is place for EUS as a second diagnostic level in several cases: negative results on CT/MRI scans and persistent strong clinical suspicion of PC, doubtful results on CT/MRI scans or need for cyto-histological confirmation. In the near future there will be great opportunities for the development of diagnostic and therapeutic EUS and pancreatic pathology could be the best testing bench.
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Affiliation(s)
- Claudio De Angelis
- Department of Gastroenterology and Hepatology, Endoscopy and Endosonography Center, San Giovanni Battista Hospital (Molinette), University of Turin, Italy
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21
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Ito T, Igarashi H, Uehara H, Berna MJ, Jensen RT. Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/Zollinger-Ellison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors. Medicine (Baltimore) 2013; 92:135-181. [PMID: 23645327 PMCID: PMC3727638 DOI: 10.1097/md.0b013e3182954af1] [Citation(s) in RCA: 138] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is classically characterized by the development of functional or nonfunctional hyperplasia or tumors in endocrine tissues (parathyroid, pancreas, pituitary, adrenal). Because effective treatments have been developed for the hormone excess state, which was a major cause of death in these patients in the past, coupled with the recognition that nonendocrine tumors increasingly develop late in the disease course, the natural history of the disease has changed. An understanding of the current causes of death is important to tailor treatment for these patients and to help identify prognostic factors; however, it is generally lacking.To add to our understanding, we conducted a detailed analysis of the causes of death and prognostic factors from a prospective long-term National Institutes of Health (NIH) study of 106 MEN1 patients with pancreatic endocrine tumors with Zollinger-Ellison syndrome (MEN1/ZES patients) and compared our results to those from the pooled literature data of 227 patients with MEN1 with pancreatic endocrine tumors (MEN1/PET patients) reported in case reports or small series, and to 1386 patients reported in large MEN1 literature series. In the NIH series over a mean follow-up of 24.5 years, 24 (23%) patients died (14 MEN1-related and 10 non-MEN1-related deaths). Comparing the causes of death with the results from the 227 patients in the pooled literature series, we found that no patients died of acute complications due to acid hypersecretion, and 8%-14% died of other hormone excess causes, which is similar to the results in 10 large MEN1 literature series published since 1995. In the 2 series (the NIH and pooled literature series), two-thirds of patients died from an MEN1-related cause and one-third from a non-MEN1-related cause, which agrees with the mean values reported in 10 large MEN1 series in the literature, although in the literature the causes of death varied widely. In the NIH and pooled literature series, the main causes of MEN1-related deaths were due to the malignant nature of the PETs, followed by the malignant nature of thymic carcinoid tumors. These results differ from the results of a number of the literature series, especially those reported before the 1990s. The causes of non-MEN1-related death for the 2 series, in decreasing frequency, were cardiovascular disease, other nonendocrine tumors > lung diseases, cerebrovascular diseases. The most frequent non-MEN1-related tumor deaths were colorectal, renal > lung > breast, oropharyngeal. Although both overall and disease-related survival are better than in the past (30-yr survival of NIH series: 82% overall, 88% disease-related), the mean age at death was 55 years, which is younger than expected for the general population.Detailed analysis of causes of death correlated with clinical, laboratory, and tumor characteristics of patients in the 2 series allowed identification of a number of prognostic factors. Poor prognostic factors included higher fasting gastrin levels, presence of other functional hormonal syndromes, need for >3 parathyroidectomies, presence of liver metastases or distant metastases, aggressive PET growth, large PETs, or the development of new lesions.The results of this study have helped define the causes of death of MEN1 patients at present, and have enabled us to identify a number of prognostic factors that should be helpful in tailoring treatment for these patients for both short- and long-term management, as well as in directing research efforts to better define the natural history of the disease and the most important factors determining long-term survival at present.
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Affiliation(s)
- Tetsuhide Ito
- From the Department of Medicine and Bioregulatory Science (TI, HI), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Digestive Diseases Branch (TI, HI, HU, MJB, RTJ), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and Hôpital Kirchberg (MJB), Luxembourg, Luxembourg
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22
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Abstract
In summary, ZES is a syndrome caused by gastrinoma, usually located within the gastrinoma triangle and associated with symptoms of peptic ulcer disease, GERD, and diarrhea. The diagnosis of ZES is made by measuring fasting levels of serum gastrin, BAO, and the secretin stimulation test. Because of the high association of ZES and MEN1, HPT must be excluded by obtaining a serum calcium and parathyroid hormone level. Treatment of ZES consists of medical control of symptoms with PPIs and evaluation for potentially curative surgical intervention. Noninvasive imaging studies including SRS, CT, and MRI should be performed initially to evaluate for metastases and identify resectable disease. Invasive imaging modalities such as EUS may be performed to further evaluate primary tumors. IOUS, palpation, and duodenotomy are used for intraoperative localization of gastrinomas. In patients with MEN1, surgical resection should be pursued only if there is an identifiable tumor larger than 2 cm and after surgery for the primary hyperparathyroidism (3 1/2-gland parathyroidectomy). All patients with resectable localized sporadic gastrinoma should undergo surgical exploration, even those with biochemical evidence but negative imaging studies. Tumor is most commonly found in the duodenum, and the cure rate is high. In patients with liver metastases, surgery should be considered if all identifiable tumor can be safely removed. A multidisciplinary approach including surgical and nonsurgical therapies should be taken in patients with advanced disease.
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Affiliation(s)
- Geoffrey W Krampitz
- Stanford University School of Medicine, Department of Surgery, 300 Pasteur Drive, H3591, Stanford, CA 94305-5655, USA
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Muniraj T, Vignesh S, Shetty S, Thiruvengadam S, Aslanian HR. Pancreatic neuroendocrine tumors. Dis Mon 2013; 59:5-19. [DOI: 10.1016/j.disamonth.2012.10.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Vinik AI, Gonzales MRC. New and emerging syndromes due to neuroendocrine tumors. Endocrinol Metab Clin North Am 2011; 40:19-63, vii. [PMID: 21349410 DOI: 10.1016/j.ecl.2010.12.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Neuroendocrine tumors (NETs) are rare, slow-growing neoplasms characterized by their ability to store and secrete different peptides and neuroamines. Some of these substances cause specific clinical syndromes whereas others are not associated with specific syndromes or symptom complexes. NETs usually have episodic expression that makes diagnosis difficult, erroneous, and often late. For these reasons a high index of suspicion is needed, and it is important to understand the pathophysiology of each tumor to decide which biochemical markers are more useful and when they should be used.
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Affiliation(s)
- Aaron I Vinik
- Eastern Virginia Medical School, Strelitz Diabetes Center, 855 West Brambleton Avenue, Norfolk, VA 23510, USA.
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25
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Ojeaburu JV, Ito T, Crafa P, Bordi C, Jensen RT. Mechanism of acid hypersecretion post curative gastrinoma resection. Dig Dis Sci 2011; 56:139-54. [PMID: 20725788 PMCID: PMC2990801 DOI: 10.1007/s10620-010-1234-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2010] [Accepted: 03/30/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND Some patients with Zollinger-Ellison syndrome post curative gastrinoma resection continue to show gastric acid hypersecretion; however, the mechanism is unknown. AIM The aim of this study was to prospectively study acid secretion following curative gastrinoma resection and analyze factors contributing in patients with Zollinger-Ellison syndrome. METHODS Fifty patients cured post gastrinoma resection were studied with serial assessments of acid secretory status, cure status and ECL-cell status/activity (with serial biopsies, CgA, urinary N-MIAA). Correlative analysis was performed to determine predictive factors. RESULTS Hypersecretion occurred in 31 patients (62%) and 14 had extreme-hypersecretion. There was an initial decline (3-6 months) in BAO/MAO, which then remained stable for eight years. Preoperative BAO correlated with the postoperative secretion, but not other clinical, tumoral, laboratory variables, the degree of postoperative acid suppression or type of antisecretory drug needed. Hypersecretors had greater postoperative ECL changes (P=0.005), serum CGA (P=0.009) and 24-h urinary N-MIAA (P=0.0038). CONCLUSIONS Post curative resection, gastric hypersecretion persists long term (mean 8 years) in 62% of patients and in 28% it is extreme, despite normogastrinemia. No preoperative variable except BAO correlates with postresection hypersecretion. The persistent increased ECL-cell extent post curative resection suggests prolonged hypergastrinemia can lead to changes in ECL-cells that are either irreversible in humans or sustained by unknown mechanisms not involving fasting hypergastrinemia and which can result in hypersecretion, in a proportion of which it can be extreme. Whether similar findings may occur in patients with idiopathic GERD treated for prolonged periods (>10 years) with PPIs, at present, is unknown.
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Affiliation(s)
- Jeremiah V. Ojeaburu
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1804
| | - Tetsuhide Ito
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan
| | - Pellegrino Crafa
- Department of Pathology and Laboratory Medicine, Section of Pathological Anatomy University of Parma, Parma, Italy
| | - Cesare Bordi
- Department of Pathology and Laboratory Medicine, Section of Pathological Anatomy University of Parma, Parma, Italy
| | - Robert T. Jensen
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1804
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26
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Kulke MH, Anthony LB, Bushnell DL, de Herder WW, Goldsmith SJ, Klimstra DS, Marx SJ, Pasieka JL, Pommier RF, Yao JC, Jensen RT. NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas 2010; 39:735-52. [PMID: 20664472 PMCID: PMC3100728 DOI: 10.1097/mpa.0b013e3181ebb168] [Citation(s) in RCA: 378] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Well-differentiated neuroendocrine tumors (NETs) of the stomach and pancreas represent 2 major subtypes of gastrointestinal NETs. Historically, there has been little consensus on the classification and management of patients with these tumor subtypes. We provide an overview of well-differentiated NETs of the stomach and pancreas and describe consensus guidelines for the treatment of patients with these malignancies.
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Affiliation(s)
- Matthew H Kulke
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston MA 02115, USA.
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28
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Abstract
It is clear that a properly performed initial operation is the key to success in the management of a patient with ZES. However, reoperation is frequently a consideration in the management of patients with ZES because high rates of persistent and recurrent disease are manifest even with modern imaging and surgical approaches. In carefully selected patients, reoperation can result in durable biochemical cure and improved survival and should be considered. A thorough knowledge of the natural history of the sporadic form of ZES and ZES in the context of MEN-1, patterns of presentation, and sites of metastases are necessary to achieve the best outcome in patients with this unusual disease.
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Affiliation(s)
- Stephen R Grobmyer
- Division of Surgical Oncology, Department of Surgery, University of Florida, 1600 SW Archer Road, Room 6165, P.O. Box 100109, Gainesville, FL 32610, USA.
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29
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30
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Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology 2008; 135:1469-92. [PMID: 18703061 PMCID: PMC2612755 DOI: 10.1053/j.gastro.2008.05.047] [Citation(s) in RCA: 535] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2008] [Revised: 03/25/2008] [Accepted: 05/12/2008] [Indexed: 12/14/2022]
Abstract
Pancreatic endocrine tumors (PETs) have long fascinated clinicians and investigators despite their relative rarity. Their clinical presentation varies depending on whether the tumor is functional or not, and also according to the specific hormonal syndrome produced. Tumors may be sporadic or inherited, but little is known about their molecular pathology, especially the sporadic forms. Chromogranin A appears to be the most useful serum marker for diagnosis, staging, and monitoring. Initially, therapy should be directed at the hormonal syndrome because this has the major initial impact on the patient's health. Most PETs are relatively indolent but ultimately malignant, except for insulinomas, which predominantly are benign. Surgery is the only modality that offers the possibility of cure, although it generally is noncurative in patients with Zollinger-Ellison syndrome or nonfunctional PETs with multiple endocrine neoplasia-type 1. Preoperative staging of disease extent is necessary to determine the likelihood of complete resection although debulking surgery often is believed to be useful in patients with unresectable tumors. Once metastatic, biotherapy is usually the first modality used because it generally is well tolerated. Systemic or regional therapies generally are reserved until symptoms occur or tumor growth is rapid. Recently, a number of newer agents, as well as receptor-directed radiotherapy, are being evaluated for patients with advanced disease. This review addresses a number of recent advances regarding the molecular pathology, diagnosis, localization, and management of PETs including discussion of peptide-receptor radionuclide therapy and other novel antitumor approaches. We conclude with a discussion of future directions and unsettled problems in the field.
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Affiliation(s)
- David C Metz
- Division of Gastroenterology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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31
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Banasch M, Schmitz F. Diagnosis and treatment of gastrinoma in the era of proton pump inhibitors. Wien Klin Wochenschr 2008; 119:573-8. [PMID: 17985090 DOI: 10.1007/s00508-007-0884-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The Zollinger-Ellison syndrome is characterized pathophysiologically by a significant hypergastrinemia derived from a gastrin-secreting neuroendocrine tumor with a primary location in the pancreas or duodenum. Chronic hypergastrinemia in turn triggers gastric acid hypersecretion yielding in chronic or recurrent or refractory peptic ulcer disease and/or chronic diarrhea. One half of patients with ZES will have distant metastases in the liver by the time the diagnosis is established and one half of all patients with ZES will experience chronic diarrhea as chief complaint rather than peptic ulcer-related symptoms and signs. Gastrinomas have been reported to either manifest sporadically or to occur in conjunction with the genetic background of the MEN-I syndrome. Diagnosis is based on the patients history which is typically characterized by recurrent episodes of peptic ulcer disease or by severe reflux esophagitis and/or diarrhea or by acid-related symptoms which fail to respond to standard treatment regimens. Upper gastrointestinal tract endoscopy will provide evidence for peptic ulcer disease in anatomical regions located aborally the duodenal bulb within the descending part of the duodenum or even farther distally within the jejunum. Peptic ulcers frequently occur in groups indicating some substantial acid hypersecretion. A gastric pH > 2 is mutually exclusive for ZES. Increased serum gastrin levels confirm the diagnosis biochemically. Gastrin secretion can be determined in the basal state or following stimulation with secretin or calcium. High sensitivity and specificity for the diagnosis of ZES is provided by determining the ratio of basal versus pentagastrin-stimulated gastric acid secretion: The ratio of BAO / MAO > 0.6 is highly specific for gastrinoma. To localize the gastrin-secreting tumor computer-assisted tomography, endoscopic ultrasound, and somatostatin receptor scintigraphy provide useful help but most recently, endoscopic ultrasound with high resolution transducers appear to improve preoperative site localization. If modern imaging techniques fail to elucidate the site of the tumor, intraoperative diaphany may help to detect gastrinomas within the duodenal wall. Definitive treatment will only be achieved by total surgical resection of the gastrin-producing tumor in the pancreas or duodenum including dissection of the regional lymph nodes. Control of symptoms will have to be achieved by administration of highly potent proton pump inhibitors in up to 2-3-fold increased standard doses to inhibit gastric acid hypersecretion. Elevation of gastric pH > 4 will be the therapeutic target to protect the mucosa of the upper gastrointestinal tract. Basal acid output should be reduced to less than 10 mEq H(+) per hour which requires administration of highly potent proton pump inhibitors with a recommended starting dose of 60 mg omeprazole equivalents per day.
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Affiliation(s)
- Matthias Banasch
- Department of Medicine I, St. Josef-Hospital, University of Bochum, Bochum, Germany
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Abstract
Surgery has been demonstrated to offer potential for cure in patients who have sporadic ZES and improved tumor-related survival in all patients who have ZES with gastrinomas larger than 2.5 cm. Techniques such as preoperative localization with SRS and intraoperative localization with duodenotomy have improved the effectiveness of surgical intervention for ZES. Future directions for investigation should include better defining the role of preoperative EUS and developing new, more sensitive techniques for preoperative localization. More research also is needed to define the appropriate indications for pancreaticoduodenectomy in ZES and to determine whether proximal vagotomy should be performed at the time of surgical exploration.
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Norton JA, Jensen RT. Role of surgery in Zollinger-Ellison syndrome. J Am Coll Surg 2007; 205:S34-7. [PMID: 17916516 DOI: 10.1016/j.jamcollsurg.2007.06.320] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2007] [Accepted: 06/13/2007] [Indexed: 12/15/2022]
Affiliation(s)
- Jeffrey A Norton
- Surgical Oncology, Department of Surgery, Stanford University, Palo Alto, California, USA.
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Fendrich V, Langer P, Waldmann J, Bartsch DK, Rothmund M. Management of sporadic and multiple endocrine neoplasia type 1 gastrinomas. Br J Surg 2007; 94:1331-41. [PMID: 17939142 DOI: 10.1002/bjs.5987] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Gastrinomas are functional endocrine duodenopancreatic tumours and are responsible for Zollinger-Ellison syndrome (ZES). Clinical presentation, localization techniques and operative management were reviewed. METHODS An electronic search of the Medline database was undertaken for articles published in English between January 1987 and May 2007. This timeframe was chosen because of the fundamental changes in operative strategy, antisecretory therapy and localization techniques during this period. RESULTS AND CONCLUSION Most gastrinomas are located in the 'gastrinoma triangle', comprising the head of the pancreas, and the first and second parts of the duodenum. Some 20 per cent of gastrinomas occur in association with multiple endocrine neoplasia type 1 (MEN1) and 50-60 per cent of tumours are malignant at the time of diagnosis. Biochemical evidence justifies operation of which duodenotomy is an essential part. Only complete tumour resection allows 5- and 10-year survival rates of 90 per cent. Pylorus-preserving pancreaticoduodenectomy may be the procedure of choice for MEN1-ZES.
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Affiliation(s)
- V Fendrich
- Department of Surgery, Philipps University Marburg, Marburg, Bielefeld, Germany.
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35
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Abstract
Incidental, nonfunctional pancreatic endocrine tumors (PET) are observed with increasing frequency. Most are insulinomas. Endoscopic ultrasound with fine-needle aspiration plays a significant role in the localization and tissue diagnosis of PET. Establishing PET behavior as aggressive or indolent remains challenging especially preoperatively. Newer techniques including DNA and micro-RNA analysis may play a role in this arena. Small benign PET may be enucleated or removed laparoscopically. Surgery is the mainstay of treating advanced disease including those with metastases and Zollinger-Ellison syndrome. The management of multiple endocrine neoplasia type 1 continues to be a challenge, including treating symptoms, targeted resections, and close observation. Diagnosis, management, and prognostication of PET are under evolution and a number of changes in these fronts are anticipated.
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Affiliation(s)
- Niraj Jani
- The Department of Medicine, The University of Pittsburgh Medical Center, 200 Lothrop Street, Mezz Level C, PUH, Pittsburgh, PA, USA
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36
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Berna MJ, Hoffmann KM, Long SH, Serrano J, Gibril F, Jensen RT. Serum gastrin in Zollinger-Ellison syndrome: II. Prospective study of gastrin provocative testing in 293 patients from the National Institutes of Health and comparison with 537 cases from the literature. evaluation of diagnostic criteria, proposal of new criteria, and correlations with clinical and tumoral features. Medicine (Baltimore) 2006; 85:331-364. [PMID: 17108779 PMCID: PMC9817094 DOI: 10.1097/md.0b013e31802b518c] [Citation(s) in RCA: 150] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
In two-thirds of patients with Zollinger-Ellison syndrome (ZES), fasting serum gastrin (FSG) levels overlap with values seen in other conditions. In these patients, gastrin provocative tests are needed to establish the diagnosis of ZES. Whereas numerous gastrin provocative tests have been proposed, only the secretin, calcium, and meal tests are widely used today. Many studies have analyzed gastrin provocative test results in ZES, but they are limited by small patient numbers and methodologic differences. To address this issue, we report the results of a prospective National Institutes of Health (NIH) study of gastrin provocative tests in 293 patients with ZES and compare these data with those from 537 ZES and 462 non-ZES patients from the literature. In 97%-99% of gastrinoma patients, an increase in serum gastrin post secretin (Delta secretin) or post calcium (Delta calcium) occurred. In NIH ZES patients with <10-fold increase in FSG, the sensitivity/specificity of the widely used criteria were as follows: Delta secretin > or =200 pg/mL (83%/100%), Delta secretin >50% (86%/93%), Delta calcium > or =395 pg/mL (54%/100%), and Delta calcium >50% (78%/83%). A systematic analysis of the sensitivity and specificity of other possible criteria for a positive secretin or calcium test allowed us to identify a new criterion for secretin testing (Delta > or =120 pg/mL) with the highest sensitivity/specificity (94%/100%) and to confirm the commonly used criterion for calcium tests (Delta > or =395 pg/mL) (62%/100%). This analysis further showed that the secretin test was more sensitive than the calcium test (94% vs. 62%). Our results suggest that secretin stimulation should be used as the first-line provocative test because of its greater sensitivity and simplicity and lack of side effects. In ZES patients with a negative secretin test, 38%-50% have a positive calcium test. Therefore the calcium test should be considered in patients with a strong clinical suspicion of ZES but a negative secretin test. Furthermore, we found that some clinical (diarrhea, duration of medical treatment), laboratory (basal acid output), and tumoral (size, extent) characteristics correlate with the serum gastrin increase post secretin and post calcium. However, using the proposed criteria, the result of these provocative tests (that is, positive or negative) is minimally influenced by these factors, so secretin and calcium provocative tests are reliable in patients with different clinical, laboratory, and tumor characteristics. A systematic analysis of meal testing showed that 54%-77% of ZES patients have a <50% postprandial serum gastrin increase. However, 9%-20% of ZES patients had a >100% increase post meal, causing significant overlap with antral syndromes. Furthermore, we could not confirm the usefulness of meal tests for localization of duodenal gastrinomas. We conclude that the secretin test is a crucial element in the diagnosis of most ZES patients, the calcium test may be useful in selected patients, but the meal test is not helpful in the management of ZES. For secretin testing, the criterion with the highest sensitivity and specificity is an increase of > or =120 pg/mL, which should replace other criteria commonly used today.
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Affiliation(s)
- Marc J Berna
- From Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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37
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Berna MJ, Hoffmann KM, Serrano J, Gibril F, Jensen RT. Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature. Medicine (Baltimore) 2006; 85:295-330. [PMID: 17108778 PMCID: PMC9806863 DOI: 10.1097/01.md.0000236956.74128.76] [Citation(s) in RCA: 164] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
The assessment of fasting serum gastrin (FSG) is essential for the diagnosis and management of patients with the Zollinger-Ellison syndrome (ZES). Although many studies have analyzed FSG levels in patients with gastrinoma, limited information has resulted from these studies because of their small size, different methodologies, and lack of correlations of FSG levels with clinical, laboratory, or tumor features in ZES patients. To address this issue, we report the results of a prospective National Institutes of Health (NIH) study of 309 patients with ZES and compare our results with those of 2229 ZES patients in 513 small series and case reports in the literature. In the NIH and literature ZES patients, normal FSG values were uncommon (0.3%-3%), as were very high FSG levels >100-fold normal (4.9%-9%). Two-thirds of gastrinoma patients had FSG values <10-fold normal that overlap with gastrin levels seen in more common conditions, like Helicobacter pylori infection or antral G-cell hyperplasia/hyperfunction. In these patients, FSG levels are not diagnostic of ZES, and gastrin provocative tests are needed to establish the diagnosis. Most clinical variables (multiple endocrine neoplasia type 1 status, presence or absence of the most common symptoms, prior medical treatment) are not correlated with FSG levels, while a good correlation of FSG values was found with other clinical features (prior gastric surgery, diarrhea, duration from onset to diagnosis). Increasing basal acid output, but not maximal acid output correlated closely with increasing FSG. Numerous tumoral features correlated with the magnitude of FSG in our study, including tumor location (pancreatic > duodenal), primary size (larger > smaller) and extent (liver metastases > local disease). In conclusion, this detailed analysis of FSG in a large number of patients with ZES allowed us to identify important clinical guidelines that should contribute to improved diagnosis and management of patients with ZES.
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Affiliation(s)
- Marc J Berna
- From Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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Norton JA, Fraker DL, Alexander HR, Gibril F, Liewehr DJ, Venzon DJ, Jensen RT. Surgery increases survival in patients with gastrinoma. Ann Surg 2006; 244:410-9. [PMID: 16926567 PMCID: PMC1856542 DOI: 10.1097/01.sla.0000234802.44320.a5] [Citation(s) in RCA: 140] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To determine whether the routine use of surgical exploration for gastrinoma resection/cure in 160 patients with Zollinger-Ellison syndrome (ZES) altered survival compared with 35 ZES patients who did not undergo surgery. SUMMARY BACKGROUND DATA The role of routine surgical exploration for resection/cure in patients with ZES has been controversial since the original description of this disease in 1955. This controversy continues today, not only because medical therapy for acid hypersecretion is so effective, but also in large part because no studies have shown an effect of tumor resection on survival. METHODS Long-term follow-up of 160 ZES patients who underwent routine surgery for gastrinoma/resection/cure was compared with 35 patients who had similar disease but did not undergo surgery for a variety of reasons. All patients had preoperative CT, MRI, ultrasound; if unclear, angiography and somatostatin receptor scintigraphy since 1994 to determine resectability. At surgery, all had the same standard ZES operation. All patients were evaluated yearly with imaging studies and disease activity studies. RESULTS The 35 nonsurgical patients did not differ from the 160 operated in clinical, laboratory, or tumor imaging results. The 2 groups did not differ in follow-up time since initial evaluation (range, 11.8-12 years). At surgery, 94% had a tumor removed, 51% were cured immediately, and 41% at last follow-up. Significantly more unoperated patients developed liver metastases (29% vs. 5%, P = 0.0002), died of any cause (54 vs. 21%, P = 0.0002), or died a disease-related death (23 vs. 1%, P < 0.00001). Survival plots showed operated patients had a better disease-related survival (P = 0.0012); however, there was no difference in non-disease-related survival. Fifteen-year disease-related survival was 98% for operated and 74% for unoperated (P = 0.0002). CONCLUSIONS These results demonstrate that routine surgical exploration increases survival in patients with ZES by increasing disease-related survival and decreasing the development of advanced disease. Routine surgical exploration should be performed in ZES patients.
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Affiliation(s)
- Jeffrey A Norton
- Department of Surgery, Stanford University Medical Center, Stanford, CA 94305-5641, USA.
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Mittendorf EA, Shifrin AL, Inabnet WB, Libutti SK, McHenry CR, Demeure MJ. Islet Cell Tumors. Curr Probl Surg 2006; 43:685-765. [PMID: 17055796 DOI: 10.1067/j.cpsurg.2006.07.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Millikan KW, Hollinger EF. Carcinoid Tumors. Surg Oncol 2006. [DOI: 10.1007/0-387-21701-0_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Jensen RT, Niederle B, Mitry E, Ramage JK, Steinmuller T, Lewington V, Scarpa A, Sundin A, Perren A, Gross D, O'Connor JM, Pauwels S, Kloppel G. Gastrinoma (duodenal and pancreatic). Neuroendocrinology 2006; 84:173-82. [PMID: 17312377 DOI: 10.1159/000098009] [Citation(s) in RCA: 163] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Abstract
Endocrine pancreatic tumours (EPTs) are uncommon tumours occurring in approximately 1 in 100,000 of the population, representing 1-2% of all pancreatic neoplasms. Some of the tumours may be part of multiple endocrine neoplasia type one (MEN-1) syndrome or von Hippel-Lindau (vHL) disease. EPTs are classified as functioning or non-functioning tumours on the basis of their clinical manifestation. The biochemical diagnosis of EPT is based on hormones and amines released. Besides specific markers such as insulin, there are also general tumour markers such as chromogranin A, which is the most valuable marker and has been reported to be increased in plasma in 50-80% of patients with EPTs and correlates with tumour burden. The location of endocrine tumours of the pancreas includes different techniques, from endoscopic investigations to scintigraphy (e.g. somatostatin receptor scintigraphy) and positron emission tomography. The medical treatment of endocrine pancreatic tumours consists of chemotherapy, somatostatin analogues and alpha-interferon. None of these can cure a patient with malignant disease. In future, therapy will be custom-made and based on current knowledge of tumour biology and molecular genetics.
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Affiliation(s)
- Kjell Oberg
- Department of Medical Sciences, University Hospital, 751 85 Uppsala, Sweden.
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Abstract
It has become increasingly clear that duodenal gastrinomas are the most common cause of Zollinger-Ellison syndrome (ZES). However, attempts to find these tumors before and during surgery for ZES have had limited success until duodenotomy (opening the duodenum) was described. The routine use of duodenotomy in patients with non-familial gastrinoma increases the number of duodenal tumors found, and the immediate and long-term cure-rate. The increase in cure-rate appears to be secondary to increased detection of small, previously undetectable duodenal gastrinomas. Duodenotomy detects small tumors (<1 cm) in the proximal duodenum. It does not detect more duodenal gastrinomas per patient, nor does it detect tumors in unusual duodenal locations. Duodenotomy decreases the death-rate associated with these tumors. However, it has not affected the rate of development of liver metastases. Duodenotomy is a critical method to find duodenal gastrinomas. It should be routinely performed in all surgery to find and remove gastrinoma for cure of ZES.
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Affiliation(s)
- Jeffrey A Norton
- Department of Surgery, Stanford University Medical Center, 300 Pasteur Drive, Room H3651, Stanford, CA 94305-5641, USA.
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Norton JA, Jensen RT. Resolved and unresolved controversies in the surgical management of patients with Zollinger-Ellison syndrome. Ann Surg 2004; 240:757-73. [PMID: 15492556 PMCID: PMC1356480 DOI: 10.1097/01.sla.0000143252.02142.3e] [Citation(s) in RCA: 149] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVE Highlight unresolved controversies in the management of Zollinger-Ellison syndrome (ZES). SUMMARY BACKGROUND DATA Recent studies have resolved some of the previous controversies including the surgical cure rate in patients with and without Multiple Endocrine Neoplasia-type1 (MEN1), the biological behavior of duodenal and pancreatic gastrinomas, role of imaging studies to localize tumor, and gastrectomy to manage acid output. METHODS Review of the literature based on computer searches in Index Medicus, Pubmed and Ovid. RESULTS Current controversies as identified in the literature include the role of endoscopic ultrasound (EUS), surgery in ZES patients with MEN1, pancreaticoduodenectomy (Whipple procedure), lymph node primary gastrinoma, parietal cell vagotomy, reoperation and surgery for metastatic tumor, and the use of minimally invasive surgical techniques to localize and remove gastrinoma. CONCLUSIONS It is hoped that future studies will focus on these issues to improve the surgical management of ZES patients.
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Affiliation(s)
- Jeffrey A Norton
- Department of Surgery, Stanford University Medical Center, Stanford, California 94305-5641, USA.
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Norton JA, Alexander HR, Fraker DL, Venzon DJ, Gibril F, Jensen RT. Does the use of routine duodenotomy (DUODX) affect rate of cure, development of liver metastases, or survival in patients with Zollinger-Ellison syndrome? Ann Surg 2004; 239:617-25; discussion 626. [PMID: 15082965 PMCID: PMC1356269 DOI: 10.1097/01.sla.0000124290.05524.5e] [Citation(s) in RCA: 114] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To determine whether routine use of duodenotomy (DUODX) alters cure rate, survival, or development of liver metastases in 143 patients (162 operations) with Zollinger-Ellison syndrome (ZES) without MEN1. SUMMARY BACKGROUND DATA DUODX has been shown to increase the detection of duodenal gastrinomas, but it is unknown if it alters rate of cure, liver metastases, or survival. Data from our prospective studies of surgery in ZES allow us to address this issue because DUODX was not performed before 1987, whereas it was routinely done after 1987. METHODS All patients with sporadic ZES (non-MEN1) undergoing surgery for possible cure without a prior DUODX from November 1980 to June 2003 were included. Patients had preoperative computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound; if unclear, angiography and somatostatin receptor scintigraphy since 1994. At surgery, all had the same standard ZES operation and were assessed immediately postoperatively, at 3 to 6 months, and yearly for cure (fasting gastrin, secretin test. and imaging studies). RESULTS A DUODX was performed in 79 patients (94 operations), and no DUODX was performed in 64 patients (68 operations), with 10 patients having both (no DUODX, then a DUODX later). Gastrinoma was found in 98% with DUODX compared with 76% with no DUODX (P < 0.00001). Duodenal gastrinomas were found more frequently with DUODX (62% vs. 18%; P < 0.00001), whereas pancreatic, lymph node, and other primary gastrinomas occurred similarly. Six of the 10 patients with 2 operations had a duodenal tumor found with DUODX during a second operation that was missed in the first operation without DUODX. Both the immediate postoperative cure rate (65% vs. 44%; P = 0.010) and long-term cure rate at last follow-up (8.8 +/- 0.4 years; range, 0.1 to 21.5) (52% vs. 26%; P = 0.0012) were significantly greater with a DUODX than without. In patients without pancreatic tumors or liver metastases at surgery, both the rate of developing liver metastases (6% vs. 9.5%) and the disease-related death rate (0% vs. 2%) were low and not significantly different in patients with or without a DUODX. CONCLUSIONS These results demonstrate that routine use of DUODX increases the short-term and long-term cure rate due to the detection of more duodenal gastrinomas. The rate of development of hepatic metastases and/or disease-related mortality in patients without pancreatic tumors is low, and no effect of DUODX on these parameters was seen. Duodenotomy (DUODX) should be routinely performed during all operations for cure of sporadic ZES.
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Affiliation(s)
- Jeffrey A Norton
- Surgical Oncology, Department of Surgery, Stanford University Medical Center, Room H-3591, 300 Pasteur Drive, Stanford, CA 94305-5641, USA.
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Gibril F, Schumann M, Pace A, Jensen RT. Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature. Medicine (Baltimore) 2004; 83:43-83. [PMID: 14747767 DOI: 10.1097/01.md.0000112297.72510.32] [Citation(s) in RCA: 195] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
In patients with multiple endocrine neoplasia type 1 (MEN1), the most common functional pancreatic endocrine tumor (PET) syndrome is Zollinger-Ellison syndrome (ZES). ZES has been well studied in its sporadic form (that is, without MEN1); however, there are limited data on patients with MEN1 and ZES (MEN1/ZES), and the long-term natural history is largely unknown. To address this issue we report the results of a prospective long-term National Institutes of Health (NIH) study of 107 MEN1/ZES patients and compare our results with those of 1009 MEN1/ZES patients in 278 case reports and small series in the literature. Patients were clinically, radiologically, and biochemically evaluated yearly for all MEN1 manifestations (mean follow-up, 10 yr; range, 0.1-31 yr). Compared with patients from the literature, the NIH MEN1/ZES patients more frequently had pituitary (60%) and adrenal (45%) disease and carcinoid tumors (30%), but had equal frequency of hyperparathyroidism (94%), thyroid disease (6%), or lipomas (5%). Twenty-five percent of both the NIH and the literature patients lacked a family history of MEN1; ZES was the initial clinical manifestation of MEN1 in 40%. ZES onset preceded the diagnosis of hyperparathyroidism in 45%. However, ZES was rarely (8%) the only initial manifestation of MEN1 if careful testing was done. ZES occurred before age 40 years in 50%-60% of the current patients, in contrast to older studies. The diagnosis of ZES is delayed 3-5 years from its onset and is delayed as long as in sporadic ZES cases. Pituitary disease and carcinoid tumors (gastric > bronchial, thymic) are more frequent than generally reported, whereas a second functional PET is uncommon. In patients with MEN1/ZES without a family history of MEN1, the MEN1 manifestations are not as severe. This study shows that MEN1/ZES patients differ in many aspects from those commonly reported in older studies involving few MEN1/ZES patients. In this study we have identified a number of important clinical and laboratory features of MEN1/ZES that were not previously appreciated, which should contribute to earlier diagnosis and improve both short- and long-term management.
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Affiliation(s)
- Fathia Gibril
- From Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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Norton JA, Jensen RT. Current surgical management of Zollinger-Ellison syndrome (ZES) in patients without multiple endocrine neoplasia-type 1 (MEN1). Surg Oncol 2003; 12:145-51. [PMID: 12946485 DOI: 10.1016/s0960-7404(03)00035-5] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The role of surgery in the management of patients with sporadic (not part of multiple endocrine neoplasia type 1) Zollinger-Ellison syndrome (ZES) is controversial. In this setting, 60-90% of gastrinomas are malignant and medical therapy can control the gastric acid hypersecretion in virtually every patient. Therefore, the progression of tumor is the major determinant of survival. Surgery will cure approximately one-third of patients with sporadic ZES. It will decrease the development of liver metastases and may improve survival. Somatostatin receptor scintigraphy is the best preoperative localization study. Its results are as good as all other imaging studies combined. Operative techniques should always include duodenotomy (opening the duodenum) and meticulous dissection of lymph nodes in the gastrinoma triangle, because duodenal primary tumors are often missed and lymph node primary tumors or metastases are common. Postoperative evaluation should include secretin test because it is the most sensitive method to document cure and detect tumor recurrence.
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Affiliation(s)
- Jeffrey A Norton
- Department of Surgery, University of California San Francisco, 533 Parnassus Avenue, Room U-372, San Francisco, CA 94143-0790, USA
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Zogakis TG, Gibril F, Libutti SK, Norton JA, White DE, Jensen RT, Alexander HR. Management and outcome of patients with sporadic gastrinoma arising in the duodenum. Ann Surg 2003; 238:42-8. [PMID: 12832964 PMCID: PMC1422657 DOI: 10.1097/01.sla.0000074963.87688.31] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND Primary duodenal gastrinomas are now recognized as a common etiology for patients with sporadic Zollinger Ellison Syndrome (ZES); however, the clinical and pathologic features of this condition and long-term outcome after operation are not well characterized. METHODS Between November 1982 and September 2000, 63 patients diagnosed with sporadic ZES underwent resection of a primary duodenal gastrinoma and regional nodal metastases with curative intent. Data from a prospectively maintained database were reviewed for clinical and pathologic parameters relating to primary tumor size, location, frequency of lymph node metastases, and disease-specific and disease-free survival. RESULTS There were 41 males and 22 females (mean age, 48.6 years). The majority of duodenal gastrinomas were in the first or second portions of the duodenum (83%). Tumor size ranged from 0.2 to 2.0 cm with 62% measuring less than 1.0 cm. Sixty percent of individuals had regional lymph node metastases identified primarily in proximity to the primary tumor. At a median 10-year follow-up, the overall disease-specific and disease-free survivals were 100% and 60%, respectively. Actuarial 10-year disease-free survival was significantly higher for patients without lymph node metastases versus those with lymph node metastases (78% versus 48%, P = 0.0137). CONCLUSIONS Duodenal gastrinomas in patients with sporadic ZES are frequently small, most commonly located in the proximal duodenum, and associated with regional lymph node metastases in 60%. Disease-free survival is lower for patients with regional lymph node metastases suggesting that a more systematic lymphadenectomy to extirpate occult disease may be indicated in this group.
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Affiliation(s)
- Theresa G Zogakis
- Surgery Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, Building 10, Room 2B07, 10 Center Drive, Bethesda, MD 20892-1502, USA
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Norton JA, Alexander HR, Fraker DL, Venzon DJ, Gibril F, Jensen RT. Possible primary lymph node gastrinoma: occurrence, natural history, and predictive factors: a prospective study. Ann Surg 2003; 237:650-7; discussion 657-9. [PMID: 12724631 PMCID: PMC1514510 DOI: 10.1097/01.sla.0000064375.51939.48] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To analyze the results of a prospective study of 176 patients with Zollinger-Ellison syndrome (ZES) (138 sporadic, 38 MEN1) undergoing 207 operations over a 17-year period. SUMMARY BACKGROUND DATA The existence of lymph node (LN) primary gastrinoma causing ZES is controversial. METHODS Three groups of patients were compared: LN only resected, cured, and no relapse (likely LN primary); same criteria but relapse (unlikely LN primary); and duodenal primary and LN metastases (Duo-LN). RESULTS Forty-five (26%) had only LN(s) as the initial tumor found. Twenty-six of the 45 (58%) fit the definition of a likely LN primary because they were apparently cured postresection. At 10.4 +/- 1.2 years, 69% of the 26 patients with likely LN primary tumors have remained cured and have LN primaries. In the 8 of 26 with recurrent ZES, it occurred at 5 +/- 1 years, and 3 had duodenal gastrinoma that had been missed. Ten percent (13/138) of all patients with sporadic ZES and 0% (0/38) with ZES and MEN1 remained cured with only a LN tumor removed. In patients with sporadic gastrinomas no clinical, laboratory, or radiographic localization feature differed among patients with likely LN primary (n = 16) and those with unlikely LN primary (n = 6) or those with Duo-LN (n = 37). In the likely LN primary group, the largest LN was 2.2 +/- 0.2 cm, the number of LNs removed was 1.3 +/- 0.1 (25% > or =1 LN), and 78% were in the gastrinoma triangle, which also did not differ from the other 2 groups. Disease-free survival was similar in the likely LN primary group, patients with Duo-LN, and those with pancreatic primaries. CONCLUSIONS These results support the conclusion that primary LN gastrinomas occur and are not rare (approximately 10% of sporadic cases). These results suggest that a proportion (25%) of these tumors are either multiple or malignant. Because no clinical, laboratory, or tumoral characteristic distinguishes patients with LN primary tumors, all patients with ZES undergoing surgery should have an extensive exploration to exclude duodenal or pancreatic tumors and routine removal of lymph nodes in the gastrinoma triangle.
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Affiliation(s)
- Jeffrey A Norton
- Department of Surgery, University of California San Francisco, 533 Parnassus Avenue, U-371, Box 0790, San Francisco, CA 94143, USA.
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Abstract
With current treatment, survival of greater than 1 year should be anticipated for many patients with pancreatic cancer. Cure rates (5-year survival) of greater than 10% have been achieved even for unresectable disease. Obstructive jaundice is managed successfully with endoscopic placement of a plastic stent early in the evaluation of a patient with suspected regional pancreatic cancer, and a metal wall stent is reserved for patients with known 1997 AJCC stage IVB carcinoma or nonoperative patients. Relief of biliary obstruction allows improvement in liver function and more time to evaluate tumor stage accurately to determine initial treatment (see Fig. 1). A cost-effective algorithm to determine accurate stage and treatment can start with the size of the mass on initial imaging studies. EUS-guided FNA represents a significant improvement over CT scan-guided FNA to make a tissue diagnosis. Small pancreatic masses that would be resected regardless of whether an FNA is positive or negative require only an EUS evaluation to establish an early resectable stage. Tumors reliably staged as unresectable by nonoperative imaging methods including EUS are treated with chemotherapy with or without concurrent radiotherapy because median survival of these patients is 2 years in some series. Tumors can be resected after neoadjuvant chemoradiotherapy. For chronic pain or gastric outlet obstruction not responding or treatable by chemoradiotherapy, endoscopically guided celiac plexus nerve block and stenting improve the quality of life for patients with pancreatic cancer. A team approach is required to achieve the objectives of improved quality of life, prolonged survival, and possible cure for pancreatic cancer. The optimal combination and sequencing of staging methods, including EUS, specialized CT scan, MR imaging, intraoperative findings, and pathologic evaluations, would improve selection of patients for potential curative resection. Interpretations of disease stage based on each of these methods may overlap but are not identical and are operator dependent. Rather than reliance on any single standard, clinical judgment and communication among the team are paramount to providing optimal care for patients with a pancreatic neoplasm.
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Affiliation(s)
- Harry Snady
- Pancreatobiliary Treatment Group, EUS Imaging, 22 East 88th Street, New York, NY 10128, USA. www.eusimaging.com
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