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Kunstman JW, Nagar A, Gibson J, Kunz PL. Modern Management of Gastric Neuroendocrine Neoplasms. Curr Treat Options Oncol 2024; 25:1137-1152. [PMID: 39083164 DOI: 10.1007/s11864-024-01207-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/16/2024] [Indexed: 09/22/2024]
Abstract
OPINION STATEMENT Gastric neuroendocrine neoplasms (G-NENs) are a heterogeneous group of tumors that broadly fall into two groups. The first group, driven by oversecretion of gastrin, are generally multifocal, small, and behave indolently with a low (but non-zero) risk of progression and metastatic spread. They are conventionally categorized into type 1, with endogenous gastric-based overproduction of gastrin, and type 2 G-NEN, with overproduction of gastrin from an extra-gastric gastrin-secreting tumor. The second group, termed type 3 G-NEN, occur spontaneously and are potentially more aggressive, having a clinical course analogous to other neuroendocrine tumors of the gastrointestinal tract. Type 1 G-NEN can be managed with endoscopic surveillance and resection of visible lesions with great success, reserving surgery for the rare high-risk lesion, whereas surgical resection of the causative gastrin-secreting tumor in type 2 G-NEN is usually curative. Type 3 G-NEN is usually managed with formal surgical resection but there is growing evidence that limited surgery or even endoscopic resection in appropriately selected patients with low risk is both safe and effective. A novel subtype of G-NEN, associated with long-term proton pump inhibitor usage, is increasing in incidence. The pathophysiology seems to parallel type 1 G-NEN. In the setting of metastatic disease, which can occur in any subtype but is most common by far in type 3 G-NEN, the lack of trial data unique to G-NEN results in extrapolation of strategies and agents for treatment of non-gastric neuroendocrine disease. The rapid pace of development in this area is likely to benefit the metastatic G-NEN patient as well. As treatment is predicate on type of G-NEN, establishing the etiology of the lesion is crucial but growing knowledge of G-NEN pathophysiology and close collaboration between pathologists, gastroenterologists, radiologists, surgeons, and oncologists have enabled a growing trend towards de-escalation and less-invasive treatment paradigms.
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Affiliation(s)
- John W Kunstman
- Department of Surgery, Division of Surgical Oncology, Yale School of Medicine, New Haven, CT, USA
- VA Connecticut Healthcare System, West Haven, CT, USA
| | - Anil Nagar
- Department of Medicine, Division of Gastroenterology, Yale School of Medicine, New Haven, CT, USA
| | - Joanna Gibson
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | - Pamela L Kunz
- Department of Medicine, Section of Medical Oncology, Yale School of Medicine, 25 York Street, New Haven, CT, 06510, 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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Giusti F, Cioppi F, Fossi C, Marini F, Masi L, Tonelli F, Brandi ML. Secretin Stimulation Test and Early Diagnosis of Gastrinoma in MEN1 Syndrome: Survey on the MEN1 Florentine Database. J Clin Endocrinol Metab 2022; 107:e2110-e2123. [PMID: 34922358 DOI: 10.1210/clinem/dgab903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited endocrine cancer syndrome. Multiple gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) affect 30% to 80% of MEN1 patients, with the most common functioning GEP-NET being gastrinoma. Biochemical identification of hypergastrinemia may help to recognize the presence of gastrinomas before they are detectable by instrumental screening, enabling early diagnosis and start of therapy, preferably before tumor progression and metastases occurrence. OBJECTIVE Evaluate the effectiveness of secretin stimulation test to precociously diagnose the presence of gastrin-secreting tumors. DESIGN Results of secretin stimulation tests, performed between 1991 and February 2020, were retrospectively analyzed, as aggregate, in a cohort of MEN1 patients with GEP-NETs. SETTING Data were extracted from the MEN1 Florentine database. PATIENTS The study included 72 MEN1 patients with GEP-NETs who underwent a secretin stimulation test for the evaluation of gastrin secretion. OUTCOMES A positive secretin stimulation test was assumed with a difference between basal fasting serum gastrin (FSG) and the maximum stimulated value of gastrin over 120 pg/mL. RESULTS The secretin stimulation test showed a secretin-induced hypergastrinemia in 27.8% (20/72) of patients with GEP-NETs, and a positive test in 18 cases. The test allowed the identification of a positively stimulated hypergastrinemia in 75.0% (3/4) of patients who presented a basal FSG within the normal range. CONCLUSIONS Diagnosis of gastrinoma is complex, difficult, and controversial. Results of this study confirm that a positive secretin stimulation test allows early diagnosis of gastrinomas, even in the presence of borderline or normal levels of nonstimulated FSG.
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Affiliation(s)
- Francesca Giusti
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Federica Cioppi
- Azienda Ospedaliero Universitaria Careggi (AOUC), Florence, Italy
| | - Caterina Fossi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Francesca Marini
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
- F.I.R.M.O. Italian Foundation for Research on Bone Diseases, Florence, Italy
| | - Laura Masi
- Azienda Ospedaliero Universitaria Careggi (AOUC), Florence, Italy
| | - Francesco Tonelli
- F.I.R.M.O. Italian Foundation for Research on Bone Diseases, Florence, Italy
| | - Maria Luisa Brandi
- F.I.R.M.O. Italian Foundation for Research on Bone Diseases, Florence, Italy
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4
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Bhattacharya S, Blau JE, Cochran C, Auh S, Weinstein LS, Jensen RT, Wank S. Validity of Secretin Stimulation Testing on Proton Pump Inhibitor Therapy for Diagnosis of Zollinger-Ellison Syndrome. Am J Gastroenterol 2021; 116:2216-2221. [PMID: 34515664 DOI: 10.14309/ajg.0000000000001487] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 08/03/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Zollinger-Ellison syndrome (ZES) is characterized by gastrinoma-induced hypergastrinemia causing excessive gastric acid secretion. Secretin stimulation tests (SSTs) are required for diagnosis in the majority of patients. Two case reports suggest that proton pump inhibitors (PPIs) cause false SST results. Consequently, PPIs are discontinued to allow hyperchlorhydria to recur; however, uncontrolled acidity can cause life-threatening complications in those with underlying undiagnosed ZES. The aim of this study was to determine whether PPIs influence the validity of SSTs for the diagnosis of ZES. METHODS A retrospective chart review was performed. Charts of patients who underwent SSTs were reviewed to determine whether they were performed on or off PPI and the test's accuracy by comparing the results with gold standard tests (diagnostic laboratory testing performed off PPI or surgical pathology consistent with gastrinoma). Sensitivity, specificity, and positive predictive value (PPV) of SST on PPI were calculated and results compared with SST off PPI using noninferiority analyses. RESULTS Twenty-eight patients corresponding to 29 SSTs were performed on PPI, and 70 patients corresponding to 107 SSTs were performed off PPI. Most of them were female and white and had multiple endocrine neoplasia type 1. We found no false-positive or false-negative SSTs on PPI. Sensitivity, specificity, and PPV of SSTs on PPI were determined to be noninferior to SSTs off PPI (P ≤ 0.05 for all). DISCUSSION In our cohort, SSTs on PPI compared with SSTs off PPI were noninferior for sensitivity, specificity, and PPV. These results suggest that PPI withdrawal before SSTs may not be necessary.
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Affiliation(s)
- Sumona Bhattacharya
- Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Jenny E Blau
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
- Early Clinical Development, Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - Craig Cochran
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Sungyoung Auh
- Office of the Clinical Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Lee S Weinstein
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Robert T Jensen
- Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Stephen Wank
- Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Rossi RE, Elvevi A, Citterio D, Coppa J, Invernizzi P, Mazzaferro V, Massironi S. Gastrinoma and Zollinger Ellison syndrome: A roadmap for the management between new and old therapies. World J Gastroenterol 2021; 27:5890-5907. [PMID: 34629807 PMCID: PMC8475006 DOI: 10.3748/wjg.v27.i35.5890] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/29/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Zollinger-Ellison syndrome (ZES) associated with pancreatic or duodenal gastrinoma is characterized by gastric acid hypersecretion, which typically leads to gastroesophageal reflux disease, recurrent peptic ulcers, and chronic diarrhea. As symptoms of ZES are nonspecific and overlap with other gastrointestinal disorders, the diagnosis is often delayed with an average time between the onset of symptoms and final diagnosis longer than 5 years. The critical step for the diagnosis of ZES is represented by the initial clinical suspicion. Hypergastrinemia is the hallmark of ZES; however, hypergastrinemia might recognize several causes, which should be ruled out in order to make a final diagnosis. Gastrin levels > 1000 pg/mL and a gastric pH below 2 are considered to be diagnostic for gastrinoma; some specific tests, including esophageal pH-recording and secretin test, might be useful in selected cases, although they are not widely available. Endoscopic ultrasound is very useful for the diagnosis and the local staging of the primary tumor in patients with ZES, particularly in the setting of multiple endocrine neoplasia type 1. Some controversies about the management of these tumors also exist. For the localized stage, the combination of proton pump inhibitory therapy, which usually resolves symptoms, and surgery, whenever feasible, with curative intent represents the hallmark of gastrinoma treatment. The high expression of somatostatin receptors in gastrinomas makes them highly responsive to somatostatin analogs, supporting their use as anti-proliferative agents in patients not amenable to surgical cure. Other medical options for advanced disease are super-imposable to other neuroendocrine neoplasms, and studies specifically focused on gastrinomas only are scant and often limited to case reports or small retrospective series. The multidisciplinary approach remains the cornerstone for the proper management of this composite disease. Herein, we reviewed available literature about gastrinoma-associated ZES with a specific focus on differential diagnosis, providing potential diagnostic and therapeutic algorithms.
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Affiliation(s)
- Roberta Elisa Rossi
- HPB Surgery, Hepatology and Liver Transplantation, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale Tumori (INT, National Cancer Institute), Milan 20133, Italy
- Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy
| | - Alessandra Elvevi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza 20033, Italy
| | - Davide Citterio
- HPB Surgery, Hepatology and Liver Transplantation, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale Tumori (INT, National Cancer Institute), Milan 20133, Italy
| | - Jorgelina Coppa
- HPB Surgery, Hepatology and Liver Transplantation, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale Tumori (INT, National Cancer Institute), Milan 20133, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza 20033, Italy
| | - Vincenzo Mazzaferro
- HPB Surgery, Hepatology and Liver Transplantation, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale Tumori (INT, National Cancer Institute), Milan 20133, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan 20122, Italy
| | - Sara Massironi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza 20033, Italy
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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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7
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Rivillas-Reyes JF, Castro-Avendaño JL, Martínez-Muñoz HF. Zollinger-Ellison syndrome. Case report. CASE REPORTS 2019. [DOI: 10.15446/cr.v5n1.71686] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Introduction: The Zollinger-Ellison syndrome (ZES) is a pathology caused by a neuroendocrine tumor, usually located in the pancreas or the duodenum, which is characterized by elevated levels of gastrin, resulting in an excessive production of gastric acid.Case presentation: A 42-year-old female patient with a history of longstanding peptic ulcer disease, who consulted due to persistent epigastric pain, melena and signs of peritoneal irritation. Perforated peptic ulcer was suspected, requiring emergency surgical intervention. Subsequently, a tumor lesion in the head of the pancreas was documented and managed with Whipple procedure. The pathology results reported a tumor suggestive of neuroendocrine neoplasm.Discussion: The Zollinger-Ellison syndrome occurs in 0.1 to 3 people per 1 000 000 inhabitants worldwide and is predominant in women between 20 and 50 years of age. It usually appears as a refractory acid-peptic disease or as a complication of gastric acid hypersecretion. Medical therapy is the standard management, being proton pump inhibitors (PPI) the most effective option. Surgery is recommended for sporadic ZES.Conclusions: ZES has a low incidence rate. It is rarely considered in the differential diagnosis of chronic epigastric pain and high clinical suspicion is required to achieve adequate management. This article is highly relevant as it presents a confirmed clinical case of ZES in Colombia, highlighting the importance of producing local scientific literature to improve the diagnosis and treatment of this pathology.
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8
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Guarnotta V, Martini C, Davì MV, Pizza G, Colao A, Faggiano A. The Zollinger-Ellison syndrome: is there a role for somatostatin analogues in the treatment of the gastrinoma? Endocrine 2018; 60:15-27. [PMID: 29019150 DOI: 10.1007/s12020-017-1420-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 09/02/2017] [Indexed: 12/17/2022]
Abstract
PURPOSE Analyze the role of somatostatin analogues (SSAs) in the treatment of sporadic and MEN1-related gastrinomas, trying to define whether recent trials have changed the landscape of gastrinoma therapy. METHODS We evaluate the rationale of SSA use in the treatment of gastrinomas, summarize the current literature concerning the effect of SSAs on the control of Zollinger-Ellison syndrome (ZES) and gastrinomas tumor progression and discuss their role in the most recent guidelines. RESULTS The medical treatment of gastrinoma and related ZES is aimed at controlling acid hypersecretion and tumor progression, in inoperable patients. The use of proton pump inhibitors (PPIs) to control the syndrome is a cornerstone in the ZES therapy. SSAs are not usually indicated for antisecretory purpose, because PPIs are considered the treatment of choice, due to their long lasting high efficacy and oral availability. The antiproliferative effect of SSAs has been established by two placebo-controlled trials that have clearly demonstrated a significant increase in progression free survival in patients affected by non-functioning well-differentiated advanced neuroendocrine tumors (NETs). The recent ENETS guidelines recommend the use of SSAs in advanced well differentiated NETs as antiproliferative agents. CONCLUSIONS The high sstr-expression in gastrinomas make them highly responsive to SSAs and support the use of such drugs to counteract the tumour growth in patients not amenable to surgical cure. Unfortunately, limited data, mainly case reports or small series, support the use of SSAs in advanced gastrinomas, therefore, it is difficult to quantify their ability to control tumour growth and disease progression.
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Affiliation(s)
- Valentina Guarnotta
- Biomedical Department of Internal and Specialist Medicine (DIBIMIS), Section of Endocrine-Metabolic Diseases, University of Palermo, Palermo, Italy
| | - Chiara Martini
- Clinica Medica 3^, Department of Medicine, DIMED, University of Padova, Padova, Italy.
| | - Maria Vittoria Davì
- Section of Endocrinology, Medicina Generale e Malattie Aterotrombotiche e Degenerative, Department of Medicine, University of Verona, Verona, Italy
| | - Genoveffa Pizza
- Department of Clinical Medicine and Surgery, "Federico II" University of Naples, Naples, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and Surgery, "Federico II" University of Naples, Naples, Italy
| | - Antongiulio Faggiano
- Thyroid and Parathyroid Surgery Unit, Istituto Nazionale per lo studio e la cura dei tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy
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9
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Sundaresan S, Meininger CA, Kang AJ, Photenhauer AL, Hayes MM, Sahoo N, Grembecka J, Cierpicki T, Ding L, Giordano TJ, Else T, Madrigal DJ, Low MJ, Campbell F, Baker AM, Xu H, Wright NA, Merchant JL. Gastrin Induces Nuclear Export and Proteasome Degradation of Menin in Enteric Glial Cells. Gastroenterology 2017; 153:1555-1567.e15. [PMID: 28859856 PMCID: PMC5705278 DOI: 10.1053/j.gastro.2017.08.038] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 07/31/2017] [Accepted: 08/13/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS The multiple endocrine neoplasia, type 1 (MEN1) locus encodes the nuclear protein and tumor suppressor menin. MEN1 mutations frequently cause neuroendocrine tumors such as gastrinomas, characterized by their predominant duodenal location and local metastasis at time of diagnosis. Diffuse gastrin cell hyperplasia precedes the appearance of MEN1 gastrinomas, which develop within submucosal Brunner's glands. We investigated how menin regulates expression of the gastrin gene and induces generation of submucosal gastrin-expressing cell hyperplasia. METHODS Primary enteric glial cultures were generated from the VillinCre:Men1FL/FL:Sst-/- mice or C57BL/6 mice (controls), with or without inhibition of gastric acid by omeprazole. Primary enteric glial cells from C57BL/6 mice were incubated with gastrin and separated into nuclear and cytoplasmic fractions. Cells were incubated with forskolin and H89 to activate or inhibit protein kinase A (a family of enzymes whose activity depends on cellular levels of cyclic AMP). Gastrin was measured in blood, tissue, and cell cultures using an ELISA. Immunoprecipitation with menin or ubiquitin was used to demonstrate post-translational modification of menin. Primary glial cells were incubated with leptomycin b and MG132 to block nuclear export and proteasome activity, respectively. We obtained human duodenal, lymph node, and pancreatic gastrinoma samples, collected from patients who underwent surgery from 1996 through 2007 in the United States or the United Kingdom. RESULTS Enteric glial cells that stained positive for glial fibrillary acidic protein (GFAP+) expressed gastrin de novo through a mechanism that required PKA. Gastrin-induced nuclear export of menin via cholecystokinin B receptor (CCKBR)-mediated activation of PKA. Once exported from the nucleus, menin was ubiquitinated and degraded by the proteasome. GFAP and other markers of enteric glial cells (eg, p75 and S100B), colocalized with gastrin in human duodenal gastrinomas. CONCLUSIONS MEN1-associated gastrinomas, which develop in the submucosa, might arise from enteric glial cells through hormone-dependent PKA signaling. This pathway disrupts nuclear menin function, leading to hypergastrinemia and associated sequelae.
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Affiliation(s)
- Sinju Sundaresan
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan
| | - Cameron A Meininger
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan
| | - Anthony J Kang
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan
| | - Amanda L Photenhauer
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan
| | - Michael M Hayes
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan
| | - Nirakar Sahoo
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan
| | - Jolanta Grembecka
- Department of Pathology, University of Michigan, Ann Arbor, Michigan
| | - Tomasz Cierpicki
- Department of Pathology, University of Michigan, Ann Arbor, Michigan
| | - Lin Ding
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan
| | - Thomas J Giordano
- Department of Pathology, University of Michigan, Ann Arbor, Michigan
| | - Tobias Else
- Division of Metabolism Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan
| | - David J Madrigal
- Endocrine Oncology Program, University of Michigan, Ann Arbor, Michigan
| | - Malcolm J Low
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Fiona Campbell
- Department of Pathology, Royal Liverpool University Hospital, Liverpool, United Kingdom
| | - Ann-Marie Baker
- Center for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Haoxing Xu
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan
| | - Nicholas A Wright
- Center for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Juanita L Merchant
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
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10
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Metz DC, Cadiot G, Poitras P, Ito T, Jensen RT. Diagnosis of Zollinger-Ellison syndrome in the era of PPIs, faulty gastrin assays, sensitive imaging and limited access to acid secretory testing. INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY 2017; 4:167-185. [PMID: 29326808 PMCID: PMC5757869 DOI: 10.2217/ije-2017-0018] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 09/14/2017] [Indexed: 12/12/2022] Open
Abstract
In recent years the diagnosis of Zollinger-Ellison syndrome (ZES) has become increasingly controversial with several new approaches and criteria proposed, differing from the classical biochemical criterion of inappropriate hypergastrinemia (i.e., hypergastrinemia in the presence of hyperchlorhydria) (Table 1). These changes have come about because of the difficulty and potential dangers of stopping proton pump inhibitors (PPIs) for gastric acid analysis; the recognition than many of the current assays used to assess gastrin concentrations are unreliable; the development of sensitive imaging modalities that detect neuroendocrine tumors (NETs) including an increasing number of the primary gastrinomas; the increased use of percutaneous or endoscopic ultrasound (EUS)-directed biopsies/cytology and the general lack of availability of acid secretory testing. In this article we will discuss the basis for these controversies, review the proposed changes in diagnostic approaches and make recommendations for supporting the diagnosis of ZES in the modern era.
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Affiliation(s)
- David C Metz
- Division of Gastroenterology, Hospital of the University of Pennsylvania, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, PA, 19104, USA
| | - Guillaume Cadiot
- Service d"Hepato-Gastroenterologie, Centre Hospitalier Universitaire de Reims, Hopital Robert Debre, F-51092, Reims, France
| | - Pierre Poitras
- Department of Gastroenterology, CHUM, Université de Montréal, Montreal, Canada
| | - 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, Maryland, 20817, USA
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Catching the Zebra: Clinical Pearls and Pitfalls for the Successful Diagnosis of Zollinger-Ellison Syndrome. Dig Dis Sci 2017; 62:2258-2265. [PMID: 28776139 DOI: 10.1007/s10620-017-4695-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 07/26/2017] [Indexed: 12/11/2022]
Abstract
Zollinger-Ellison syndrome (ZES) results from an ectopic gastrin-secreting tumor leading to peptic ulcer disease, reflux, and chronic diarrhea. While early recognition portends an excellent prognosis with >80% survival at 15 years, symptoms are often nonspecific making the diagnosis difficult to establish. Diagnosis involves a series of tests, including fasting gastrin, gastric pH, chromogranin A, and secretin stimulation. Performing these tests in the correct sequence and at the proper time is essential to avoid inaccurate results. Tumor localization is equally nuanced. Although providers have classically used 111indium-radiolabeled octreotide with somatostatin receptor scintigraphy to evaluate tumor size and metastases, recent studies have shown superior results with newer imaging modalities. In particular, 68gallium (68Ga)-labeled somatostatin radiotracers (i.e., 68Ga-DOTATOC, 68Ga-DOTANOC and 68Ga-DOTATATE) used with positron emission tomography/computed tomography can provide excellent results. Endoscopic ultrasound is another useful modality, particularly in patients with ZES in the setting of multiple endocrine neoplasia type 1. This review aims to provide clinicians with an overview of ZES with a focus on both clinical presentation and the proper utilization of the various biochemical and imaging tests available.
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Minalyan A, Benhammou JN, Artashesyan A, Lewis MS, Pisegna JR. Autoimmune atrophic gastritis: current perspectives. Clin Exp Gastroenterol 2017; 10:19-27. [PMID: 28223833 PMCID: PMC5304992 DOI: 10.2147/ceg.s109123] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
At present there is no universally accepted classification for gastritis. The first successful classification (The Sydney System) that is still commonly used by medical professionals was first introduced by Misiewicz et al in Sydney in 1990. In fact, it was the first detailed classification after the discovery of Helicobacter pylori by Warren and Marshall in 1982. In 1994, the Updated Sydney System was proposed during the International Workshop on the Histopathology of Gastritis followed by the publication in The American Journal of Surgical Pathology by Dixon et al. Using the new classification, distinction between atrophic and nonatrophic gastritis was revised, and the visual scale grading was incorporated. According to the Updated Sydney System Classification, atrophic gastritis is categorized into multifocal (H. pylori, environmental factors, specific diet) and corpus-predominant (autoimmune). Since metaplasia is a key histological characteristic in patients with atrophic gastritis, it has been recommended to use the word "metaplastic" in both variants of atrophic gastritis: autoimmune metaplastic atrophic gastritis (AMAG) and environmental metaplastic atrophic gastritis. Although there are many overlaps in the course of the disease and distinction between those two entities may be challenging, the aim of this review article was to describe the etiology, epidemiology, pathogenesis, diagnosis, clinical manifestations and treatment in patients with AMAG. However, it is important to mention that H. pylori is the most common etiologic factor for the development of gastritis in the world.
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Affiliation(s)
- Artem Minalyan
- Division of Gastroenterology, Hepatology and Parenteral Nutrition
| | | | - Aida Artashesyan
- Division of Gastroenterology, Hepatology and Parenteral Nutrition
| | - Michael S Lewis
- Department of Pathology and Laboratory Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Joseph R Pisegna
- Division of Gastroenterology, Hepatology and Parenteral Nutrition
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Parnall T, Caldwell K, Noel JM, Russell J, Reyes C. Hypertrophic pyloric stenosis in a 15-year-old male. JOURNAL OF PEDIATRIC SURGERY CASE REPORTS 2016. [DOI: 10.1016/j.epsc.2016.09.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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Falconi M, Eriksson B, Kaltsas G, Bartsch DK, Capdevila J, Caplin M, Kos-Kudla B, Kwekkeboom D, Rindi G, Klöppel G, Reed N, Kianmanesh R, Jensen RT. ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. Neuroendocrinology 2016; 103:153-171. [PMID: 26742109 PMCID: PMC4849884 DOI: 10.1159/000443171] [Citation(s) in RCA: 979] [Impact Index Per Article: 108.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Abstract
PURPOSE OF REVIEW This review summarizes the past year's literature regarding the neural, paracrine, hormonal, and intracellular regulation of gastric acid secretion. RECENT FINDINGS Gastric acid facilitates the digestion of protein as well as the absorption of iron, calcium, vitamin B12, and certain medications. High gastric acidity, in combination with pepsin and lipase, kills ingested microorganisms and may play a role in preventing bacterial overgrowth, enteric infection, and possibly spontaneous bacterial peritonitis, community-acquired pneumonia, and infection with Mycobacterium tuberculosis. Stimulants of acid secretion include histamine, gastrin, acetylcholine, and ghrelin. Inhibitors include somatostatin, gastric inhibitory polypeptide, calcitonin gene-related peptide, and adrenomedullin. Helicobacter pylori stimulates or inhibits depending upon the time course of infection and the area of the stomach predominantly infected. Proteins implicated in H-K-ATPase membrane trafficking include myosin IIB, F-actin, ezrin, and Rab GTPases. SUMMARY Our understanding of the regulation of gastric acid secretion continues to advance. Such knowledge is crucial for the management of acid-peptic disorders and the development of novel medications, such as cholecystokinin-2 receptor antagonists.
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