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Rudolph JJ, Agyei O, Telvizian T, Ghaneie A. Gastric Neuroendocrine Tumors and Pernicious Anemia: A Case Report and Literature Review. Cureus 2024; 16:e73553. [PMID: 39669826 PMCID: PMC11637537 DOI: 10.7759/cureus.73553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2024] [Indexed: 12/14/2024] Open
Abstract
Gastrointestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, with the gastric (stomach) subtype (G-NETs) representing a significant clinical focus. Type 1 G-NETs are particularly noteworthy due to their relationship with autoimmune atrophic gastritis (AAG) and pernicious anemia (PA), conditions that impact vitamin B12 absorption. This report presents the case of a patient with a type 1 G-NET identified at the initial diagnosis of PA, demonstrating the connection between these conditions. In the literature review, we discuss the general mechanisms underlying PA, including its etiology, pathogenesis, clinical presentations, and diagnostic approaches. Emphasis is placed on the importance of recognizing and diagnosing this condition early, given the treatable nature of the associated gastric neuroendocrine dysregulation. Additionally, the report examines the broad spectrum of G-NETs, with a special emphasis on the characteristics of type 1 tumors. By considering recent developments in the field, we provide an overview of the current understanding of G-NET epidemiology, classification, clinical features, diagnosis, and management strategies.
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Affiliation(s)
| | - Obed Agyei
- Hematology and Medical Oncology, Lankenau Medical Center, Wynnewood, USA
| | - Talar Telvizian
- Hematology and Medical Oncology, Lankenau Medical Center, Wynnewood, USA
| | - Arezoo Ghaneie
- Hematology and Medical Oncology, Lankenau Medical Center, Wynnewood, USA
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Shah SC, Boeder S, Piazuelo MB, Li D. The Stomach Looks Suspicious, But Is It Pernicious? Gastroenterology 2023; 165:1342-1351. [PMID: 37640254 PMCID: PMC11058005 DOI: 10.1053/j.gastro.2023.08.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 08/18/2023] [Accepted: 08/18/2023] [Indexed: 08/31/2023]
Affiliation(s)
- Shailja C Shah
- Gastroenterology Section, Jennifer Moreno Department of Veterans Affairs Medical Center, La Jolla, California; Division of Gastroenterology, University of California, San Diego, La Jolla, California.
| | - Schafer Boeder
- Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California
| | - M Blanca Piazuelo
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Dan Li
- Department of Gastroenterology, Kaiser Permanente Northern California, Santa Clara, California; Division of Research, Kaiser Permanente Northern California, Oakland, California
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Namikawa K, Kamada T, Fujisaki J, Sato Y, Murao T, Chiba T, Kaizaki Y, Ishido K, Ihara Y, Kurahara K, Suga T, Suzuki H, Ito M, Hirakawa K, Maruyama Y, Gotoda T, Hosokawa O, Koike T, Mabe K, Yao T, Inui K, Iishi H, Ogata H, Furuta T, Haruma K. Clinical characteristics and long-term prognosis of type 1 gastric neuroendocrine tumors in a large Japanese national cohort. Dig Endosc 2023; 35:757-766. [PMID: 36721901 DOI: 10.1111/den.14529] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 01/29/2023] [Indexed: 02/02/2023]
Abstract
OBJECTIVES Optimal management of type 1 gastric neuroendocrine tumors (T1-GNETs) remains unknown, with few reports on their long-term prognosis. This study investigated the clinical characteristics and long-term prognosis of T1-GNETs. METHODS We reviewed the medical records of patients diagnosed with T1-GNET during 1991-2019 at 40 institutions in Japan. RESULTS Among 172 patients, endoscopic resection (ER), endoscopic surveillance, and surgery were performed in 84, 61, and 27, respectively, including 27, 77, and 2 patients with pT1a-M, pT1b-SM, and pT2 tumors, respectively. The median tumor diameter was 5 (range 0.8-55) mm. Four (2.9%) patients had lymph node metastasis (LNM); none had liver metastasis. LNM rates were significantly higher in tumors with lymphovascular invasion (LVI) (15.8%; 3/19) than in those without (1.1%; 1/92) (P = 0.016). For tumors <10 mm, LVI and LNM rates were 18.4% (14/76) and 2.2% (2/90), respectively, which were not significantly different from those of tumors 10-20 mm (LVI 13.3%; 2/15, P = 0.211; and LNM 0%; 0/17, P = 1.0). However, these rates were significantly lower than those of tumors >20 mm (LVI 60%; 3/5, P = 0.021; and LNM 40%; 2/5, P = 0.039). No tumor recurrence or cause-specific death occurred during the median follow-up of 10.1 (1-25) years. The 10-year overall survival rate was 97%. CONCLUSIONS Type 1 gastric neuroendocrine tumors showed indolent nature and favorable long-term prognoses. LVI could be useful in indicating the need for additional treatments. ER for risk prediction of LNM should be considered for tumors <10 mm and may be feasible for tumors 10-20 mm. TRIAL REGISTRATION The study protocol was registered in the University Hospital Medical Information Network (UMIN) under the identifier UMIN000029927.
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Affiliation(s)
- Ken Namikawa
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Tomoari Kamada
- Department of Health Care Medicine, Kawasaki Medical School, Okayama, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Junko Fujisaki
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Yuichi Sato
- Department of Gastroenterology, Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Takahisa Murao
- Department of Health Care Medicine, Kawasaki Medical School, Okayama, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Tsutomu Chiba
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Yasuharu Kaizaki
- Department of Pathology, Fukui Prefectural Hospital, Fukui, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Kenji Ishido
- Department of Gastroenterology, Kitasato University School of Medicine, Kanagawa, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Yutaro Ihara
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Koichi Kurahara
- Division of Gastroenterology, Matsuyama Red Cross Hospital, Ehime, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Tomoaki Suga
- Endoscopic Examination Center, Shinshu University, Nagano, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Haruhisa Suzuki
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Masanori Ito
- Department of General Internal Medicine, Hiroshima University Hospital, Hiroshima, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Katsuya Hirakawa
- Division of Gastroenterology, Fukuoka Red Cross Hospital, Fukuoka, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Yasuhiko Maruyama
- Division of Gastroenterology, Fujieda Municipal General Hospital, Shizuoka, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Takuji Gotoda
- Department of Gastroenterology, Nihon University Hospital, Tokyo, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Osamu Hosokawa
- Department of Surgery, Yokohama Sakae Kyosai Hospital, Kanagawa, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Tomohiro Koike
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Miyagi, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Katsuhiro Mabe
- Junpukai Health Maintenance Center - Kurashiki, Okayama, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Kazuo Inui
- Department of Gastroenterology Yamashita Hospital, Aichi, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Hiroyasu Iishi
- Department of Gastroenterology, Itami City Hospital, Hyogo, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Haruhiko Ogata
- Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Tokyo, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Shizuoka, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
| | - Ken Haruma
- Division of Gastroenterology, Department of Internal Medicine 2, Kawasaki Medical School, Okayama, Japan
- Research Group on the Treatment Guidelines for Gastric Carcinoids Associated with Autoimmune Gastritis in Japan, Tokyo, Japan
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Waldum H, Fossmark R. Inflammation and Digestive Cancer. Int J Mol Sci 2023; 24:13503. [PMID: 37686307 PMCID: PMC10487643 DOI: 10.3390/ijms241713503] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 08/25/2023] [Accepted: 08/29/2023] [Indexed: 09/10/2023] Open
Abstract
Chronic inflammation is linked to carcinogenesis, particularly in the digestive organs, i.e., the stomach, colon, and liver. The mechanism of this effect has, however, only partly been focused on. In this review, we focus on different forms of chronic hepatitis, chronic inflammatory bowel disease, and chronic gastritis, conditions predisposing individuals to the development of malignancy. Chronic inflammation may cause malignancy because (1) the cause of the chronic inflammation is itself genotoxic, (2) substances released from the inflammatory cells may be genotoxic, (3) the cell death induced by the inflammation induces a compensatory increase in proliferation with an inherent risk of mutation, (4) changes in cell composition due to inflammation may modify function, resulting in hormonal disturbances affecting cellular proliferation. The present review focuses on chronic gastritis (Helicobacter pylori or autoimmune type) since all four mechanisms may be relevant to this condition. Genotoxicity due to the hepatitis B virus is an important factor in hepatocellular cancer and viral infection can similarly be central in the etiology and malignancy of inflammatory bowel diseases. Helicobacter pylori (H. pylori) is the dominating cause of chronic gastritis and has not been shown to be genotoxic, so its carcinogenic effect is most probably due to the induction of atrophic oxyntic gastritis leading to hypergastrinemia.
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Affiliation(s)
- Helge Waldum
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, 7030 Trondheim, Norway;
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Panzuto F, Ramage J, Pritchard DM, van Velthuysen MLF, Schrader J, Begum N, Sundin A, Falconi M, O'Toole D. European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for gastroduodenal neuroendocrine tumours (NETs) G1-G3. J Neuroendocrinol 2023; 35:e13306. [PMID: 37401795 DOI: 10.1111/jne.13306] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/09/2023] [Accepted: 05/10/2023] [Indexed: 07/05/2023]
Abstract
The aim of the present guidance paper was to update the previous ENETS guidelines on well-differentiated gastric and duodenal neuroendocrine tumours (NETs), providing practical guidance for specialists in the diagnosis and management of gastroduodenal NETs. Type II gastric NETs, neuroendocrine carcinomas (NECs), and functioning duodenal NETs are not covered, since they will be discussed in other ENETS guidance papers.
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Affiliation(s)
- Francesco Panzuto
- Department of Medical-Surgical Sciences and Translational Medicine, Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
| | - John Ramage
- Department of Gastroenterology, Hampshire Hospitals and ENETS Center, Kings Health Partners London, London, United Kingdom
| | - D Mark Pritchard
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | | | - Joerg Schrader
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nehara Begum
- Department for General-, Visceral-, Thoracic- and Endocrine Surgery, Johannes-Wesling-Klinikum Minden, University Hospital of the Ruhr-University Bochum, Bochum, Germany
| | - Anders Sundin
- Department of Surgical Sciences, Radiology & Molecular Imaging, Uppsala University, Uppsala, Sweden
| | - Massimo Falconi
- Pancreas Translational and Clinical Research Center, Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Dermot O'Toole
- National Centre for Neuroendocrine Tumours, ENETS Centre of Excellence, St. Vincent's University Hospital, Dublin, Ireland
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Shah SC, Piazuelo MB, Kuipers EJ, Li D. AGA Clinical Practice Update on the Diagnosis and Management of Atrophic Gastritis: Expert Review. Gastroenterology 2021; 161:1325-1332.e7. [PMID: 34454714 PMCID: PMC8740554 DOI: 10.1053/j.gastro.2021.06.078] [Citation(s) in RCA: 231] [Impact Index Per Article: 57.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 06/09/2021] [Accepted: 06/28/2021] [Indexed: 02/07/2023]
Abstract
DESCRIPTION The purpose of this Clinical Practice Update Expert Review is to provide clinicians with guidance on the diagnosis and management of atrophic gastritis, a common preneoplastic condition of the stomach, with a primary focus on atrophic gastritis due to chronic Helicobacter pylori infection-the most common etiology-or due to autoimmunity. To date, clinical guidance for best practices related to the diagnosis and management of atrophic gastritis remains very limited in the United States, which leads to poor recognition of this preneoplastic condition and suboptimal risk stratification. In addition, there is heterogeneity in the definitions of atrophic gastritis, autoimmune gastritis, pernicious anemia, and gastric neoplasia in the literature, which has led to confusion in clinical practice and research. Accordingly, the primary objective of this Clinical Practice Update is to provide clinicians with a framework for the diagnosis and management of atrophic gastritis. By focusing on atrophic gastritis, this Clinical Practice Update is intended to complement the 2020 American Gastroenterological Association Institute guidelines on the management of gastric intestinal metaplasia. These recent guidelines did not specifically discuss the diagnosis and management of atrophic gastritis. Providers should recognize, however, that a diagnosis of intestinal metaplasia on gastric histopathology implies the diagnosis of atrophic gastritis because intestinal metaplasia occurs in underlying atrophic mucosa, although this is often not distinctly noted on histopathologic reports. Nevertheless, atrophic gastritis represents an important stage with distinct histopathologic alterations in the multistep cascade of gastric cancer pathogenesis. METHODS The Best Practice Advice statements presented herein were developed from a combination of available evidence from published literature and consensus-based expert opinion. No formal rating of the strength or quality of the evidence was carried out. These statements are meant to provide practical advice to clinicians practicing in the United States. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Atrophic gastritis is defined as the loss of gastric glands, with or without metaplasia, in the setting of chronic inflammation mainly due to Helicobacter pylori infection or autoimmunity. Regardless of the etiology, the diagnosis of atrophic gastritis should be confirmed by histopathology. BEST PRACTICE ADVICE 2: Providers should be aware that the presence of intestinal metaplasia on gastric histology almost invariably implies the diagnosis of atrophic gastritis. There should be a coordinated effort between gastroenterologists and pathologists to improve the consistency of documenting the extent and severity of atrophic gastritis, particularly if marked atrophy is present. BEST PRACTICE ADVICE 3: Providers should recognize typical endoscopic features of atrophic gastritis, which include pale appearance of gastric mucosa, increased visibility of vasculature due to thinning of the gastric mucosa, and loss of gastric folds, and, if with concomitant intestinal metaplasia, light blue crests and white opaque fields. Because these mucosal changes are often subtle, techniques to optimize evaluation of the gastric mucosa should be performed. BEST PRACTICE ADVICE 4: When endoscopic features of atrophic gastritis are present, providers should assess the extent endoscopically. Providers should obtain biopsies from the suspected atrophic/metaplastic areas for histopathological confirmation and risk stratification; at a minimum, biopsies from the body and antrum/incisura should be obtained and placed in separately labeled jars. Targeted biopsies should additionally be obtained from any other mucosal abnormalities. BEST PRACTICE ADVICE 5: In patients with histology compatible with autoimmune gastritis, providers should consider checking antiparietal cell antibodies and anti-intrinsic factor antibodies to assist with the diagnosis. Providers should also evaluate for anemia due to vitamin B-12 and iron deficiencies. BEST PRACTICE ADVICE 6: All individuals with atrophic gastritis should be assessed for H pylori infection. If positive, treatment of H pylori should be administered and successful eradication should be confirmed using nonserological testing modalities. BEST PRACTICE ADVICE 7: The optimal endoscopic surveillance interval for patients with atrophic gastritis is not well-defined and should be decided based on individual risk assessment and shared decision making. A surveillance endoscopy every 3 years should be considered in individuals with advanced atrophic gastritis, defined based on anatomic extent and histologic grade. BEST PRACTICE ADVICE 8: The optimal surveillance interval for individuals with autoimmune gastritis is unclear. Interval endoscopic surveillance should be considered based on individualized assessment and shared decision making. BEST PRACTICE ADVICE 9: Providers should recognize pernicious anemia as a late-stage manifestation of autoimmune gastritis that is characterized by vitamin B-12 deficiency and macrocytic anemia. Patients with a new diagnosis of pernicious anemia who have not had a recent endoscopy should undergo endoscopy with topographical biopsies to confirm corpus-predominant atrophic gastritis for risk stratification and to rule out prevalent gastric neoplasia, including neuroendocrine tumors. BEST PRACTICE ADVICE 10: Individuals with autoimmune gastritis should be screened for type 1 gastric neuroendocrine tumors with upper endoscopy. Small neuroendocrine tumors should be removed endoscopically, followed by surveillance endoscopy every 1-2 years, depending on the burden of neuroendocrine tumors. BEST PRACTICE ADVICE 11: Providers should evaluate for iron and vitamin B-12 deficiencies in patients with atrophic gastritis irrespective of etiology, especially if corpus-predominant. Likewise, in patients with unexplained iron or vitamin B-12 deficiency, atrophic gastritis should be considered in the differential diagnosis and appropriate diagnostic evaluation pursued. BEST PRACTICE ADVICE 12: In patients with autoimmune gastritis, providers should recognize that concomitant autoimmune disorders, particularly autoimmune thyroid disease, are common. Screening for autoimmune thyroid disease should be performed.
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Affiliation(s)
- Shailja C. Shah
- Gastroenterology Section, Veterans Affairs San Diego Healthcare System, La Jolla, California,Division of Gastroenterology, University of California, San Diego, La Jolla, California
| | - M. Blanca Piazuelo
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Ernst J. Kuipers
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Dan Li
- Department of Gastroenterology, Kaiser Permanente Northern California, Santa Clara, California,Division of Research, Kaiser Permanente Northern California, Oakland, California
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Jeong JH, Lee SY, Han HS, Kim JH, Sung IK, Park HS. Five Autoimmune Gastritis Patients with Positive Findings of Serum Anti-parietal Cell Antibodies. THE KOREAN JOURNAL OF HELICOBACTER AND UPPER GASTROINTESTINAL RESEARCH 2021. [DOI: 10.7704/kjhugr.2021.0016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Autoimmune gastritis is a corpus-dominant type of gastritis with positive serum anti-parietal cell antibodies (APCA) and/or anti-intrinsic factor antibodies. Serum APCA and pepsinogen (PG) assays were performed in subjects with corpus-dominant gastritis detected by endoscopy. Serum APCA was positive in five patients. All these patients were postmenopausal women (four Koreans and one Caucasian from the Russian Federation) with a mean age of 59.0±3.2 years. They displayed low PG I levels ranging from 8.1 to 18.8 ng/mL (mean, 11.4±4.8 ng/mL) and low PG I/II ratios ranging from 0.7 to 2.4 (mean, 1.2±0.7). Three of the patients were being treated for autoimmune thyroiditis. Multiple gastric neuroendocrine tumors were observed in two Helicobacter pylori (H. pylori)-naive patients with high serum gastrin levels exceeding 700 pg/mL and serum chromogranin A levels exceeding 1,000 ng/mL. In the remaining three patients, intestinal metaplasia was observed in the biopsied specimens from the antrum, suggesting a history of H. pylori infection. Our findings indicate the value of positive serum APCA findings, low serum PG I levels, and low serum PG I/II ratios in confirming autoimmune gastritis in patients showing corpus-dominant atrophy, regardless of their H. pylori infection status.
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Vitale G, Dicitore A, Barrea L, Sbardella E, Razzore P, Campione S, Faggiano A, Colao A, Albertelli M, Altieri B, Bottiglieri F, De Cicco F, Di Molfetta S, Fanciulli G, Feola T, Ferone D, Ferraù F, Gallo M, Giannetta E, Grillo F, Grossrubatscher E, Guadagno E, Guarnotta V, Isidori AM, Lania A, Lenzi A, Calzo FL, Malandrino P, Messina E, Modica R, Muscogiuri G, Pes L, Pizza G, Pofi R, Puliani G, Rainone C, Rizza L, Rubino M, Ruggieri RM, Sesti F, Venneri MA, Zatelli MC. From microbiota toward gastro-enteropancreatic neuroendocrine neoplasms: Are we on the highway to hell? Rev Endocr Metab Disord 2021; 22:511-525. [PMID: 32935263 PMCID: PMC8346435 DOI: 10.1007/s11154-020-09589-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/04/2020] [Indexed: 02/06/2023]
Abstract
Gut microbiota is represented by different microorganisms that colonize the intestinal tract, mostly the large intestine, such as bacteria, fungi, archaea and viruses. The gut microbial balance has a key role in several functions. It modulates the host's metabolism, maintains the gut barrier integrity, participates in the xenobiotics and drug metabolism, and acts as protection against gastro-intestinal pathogens through the host's immune system modulation. The impaired gut microbiota, called dysbiosis, may be the result of an imbalance in this equilibrium and is linked with different diseases, including cancer. While most of the studies have focused on the association between microbiota and gastrointestinal adenocarcinomas, very little is known about gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). In this review, we provide an overview concerning the complex interplay between gut microbiota and GEP NENs, focusing on the potential role in tumorigenesis and progression in these tumors.
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Affiliation(s)
- Giovanni Vitale
- Istituto Auxologico Italiano IRCCS, Laboratory of Geriatric and Oncologic Neuroendocrinology Research, Cusano Milanino, MI, Italy.
- Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy.
| | - Alessandra Dicitore
- Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy
| | - Luigi Barrea
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Emilia Sbardella
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Paola Razzore
- Endocrinology Unit, A.O. Ordine Mauriziano, Turin, Italy
| | | | | | - Annamaria Colao
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
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Gastritis, Gastric Polyps and Gastric Cancer. Int J Mol Sci 2021; 22:ijms22126548. [PMID: 34207192 PMCID: PMC8234857 DOI: 10.3390/ijms22126548] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 06/08/2021] [Accepted: 06/14/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is still an important disease causing many deaths worldwide, although there has been a marked reduction in prevalence during the last few decades. The decline in gastric cancer prevalence is due to a reduction in Helicobacter pylori infection which has occurred for at least 50 years. The most probable mechanism for the carcinogenic effect of H. pylori is hypergastrinemia since H. pylori infected individuals do not have increased risk of gastric cancer before the development of oxyntic atrophy. When atrophy has developed, the carcinogenic process continues independent of H. pylori. Autoimmune gastritis also induces oxyntic atrophy leading to marked hypergastrinemia and development of ECL cell neoplasia as well as adenocarcinoma. Similarly, long-term treatment with efficient inhibitors of acid secretion like the proton pump inhibitors (PPIs) predisposes to ECL cell neoplasia of a different degree of malignancy. Contrasting the colon where most cancers develop from polyps, most polyps in the stomach have a low malignant potential. Nevertheless, gastric polyps may also give rise to cancer and have some risk factors and mechanisms in common with gastric cancer. In this overview the most common gastric polyps, i.e., hyperplastic polyps, adenomatous polyps and fundic gland polyps will be discussed with respect to etiology and particularly use of PPIs and relation to gastric carcinogenesis.
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Ravizza D, Fiori G. Gastric Neuroendocrine Tumors. NEUROENDOCRINE NEOPLASIA MANAGEMENT 2021:179-190. [DOI: 10.1007/978-3-030-72830-4_13] [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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Towards Understanding of Gastric Cancer Based upon Physiological Role of Gastrin and ECL Cells. Cancers (Basel) 2020; 12:cancers12113477. [PMID: 33266504 PMCID: PMC7700139 DOI: 10.3390/cancers12113477] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/19/2020] [Accepted: 11/21/2020] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Generally, we know that cancers represent genetic changes in tumour cells, but we most often do not know the causes of cancers or how they develop. Our knowledge of the regulation of gastric acid secretion is well known, with the gastric hormone gastrin maintaining gastric acidity by stimulation of the enterochromaffin-like (ECL) cell to release histamine, which subsequently augments acid secretion. Furthermore, it seems to be a general principle that stimulation of function (which, for the ECL cell, is release of histamine) in a parallel way stimulates the proliferation of the same cell. Long-term hyperstimulation of cell division predisposes to genetic changes and, thus, development of tumours. All conditions with reduced gastric acidity result in an increased risk of gastric tumours due to elevated gastrin in order to restore gastric acidity. It is probable that Helicobacter pylori infection (the most important cause of gastric cancer), as well as drugs inhibiting gastric acid secretion induce gastric cancer in the long-term, due to an elevation of gastrin caused by reduced gastric acidity. Gastric carcinomas have been shown to express ECL cell markers, further strengthening this relationship. Abstract The stomach is an ideal organ to study because the gastric juice kills most of the swallowed microbes and, thus, creates rather similar milieu among individuals. Combined with a rather easy access to gastric juice, gastric physiology was among the first areas to be studied. During the last century, a rather complete understanding of the regulation of gastric acidity was obtained, establishing the central role of gastrin and the histamine producing enterochromaffin-like (ECL) cell. Similarly, the close connection between regulation of function and proliferation became evident, and, furthermore, that chronic overstimulation of a cell with the ability to proliferate, results in tumour formation. The ECL cell has long been acknowledged to give rise to neuroendocrine tumours (NETs), but not to play any role in carcinogenesis of gastric adenocarcinomas. However, when examining human gastric adenocarcinomas with the best methods presently available (immunohistochemistry with increased sensitivity and in-situ hybridization), it became clear that many of these cancers expressed neuroendocrine markers, suggesting that some of these tumours were of neuroendocrine, and more specifically, ECL cell origin. Thus, the ECL cell and its main regulator, gastrin, are central in human gastric carcinogenesis, which make new possibilities in prevention, prophylaxis, and treatment of this cancer.
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Trinh VQH, Shi C, Ma C. Gastric neuroendocrine tumours from long-term proton pump inhibitor users are indolent tumours with good prognosis. Histopathology 2020; 77:865-876. [PMID: 32702178 DOI: 10.1111/his.14220] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/07/2020] [Accepted: 07/21/2020] [Indexed: 12/14/2022]
Abstract
AIMS Proton pump inhibitors (PPIs) are among the most widely used medications in the United States. Most PPI users have persistent hypergastrinaemia during treatment. However, gastric neuroendocrine tumours diagnosed in long-term PPI users are rarely reported. Their clinicopathological features and prognosis are not characterised. It remains unclear whether or not they can be classified as Type III sporadic tumours. METHODS AND RESULTS We retrospectively characterised 66 gastric neuroendocrine tumours from patients without atrophic gastritis and gastrinoma from two tertiary care medical centres, including 38 tumours in patients who had used PPIs for at least 1 year and 28 tumours from patients without long-term PPI use (control group, Type III tumours). Compared to controls, tumours from long-term PPI users tended to be in the pT1-2 category (98% versus 79%, P = 0.09) and less often invaded the serosa (3% versus 18%, P = 0.08) or lymphovascular spaces (11% versus 32%, P = 0.06). Using Kaplan-Meier analysis, long-term PPI users had significantly longer overall survival than controls (P = 0.035). While three control patients developed distant metastasis and seven died, long-term PPI users were without distant metastasis (P = 0.06) or death (P = 0.002) during follow-up. However, five long-term PPI users developed additional gastric neuroendocrine tumour(s), while none of the controls did (P = 0.07). CONCLUSIONS Our results show that gastric neuroendocrine tumours of long-term PPI users are probably less aggressive compared to Type III sporadic tumours and have an indolent disease course. Our findings support the classification of gastric neuroendocrine tumours in long-term PPI users as a separate subtype.
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Affiliation(s)
- Vincent Q-H Trinh
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Chanjuan Shi
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Changqing Ma
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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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: 130] [Impact Index Per Article: 26.0] [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: 07/18/2020] [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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Alekberzade AV, Krylov NN, Lipnitskiy EM, Shakhbazov RO, Azari F. [Gastric neuroendocrine tumors]. Khirurgiia (Mosk) 2019:111-120. [PMID: 31825351 DOI: 10.17116/hirurgia2019121111] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Gastrointestinal neuroendocrine tumors are rare neoplasms. Currently, incidence of gastric neuroendocrine tumors (gNETs) is being significantly increased. There are 3 groups of gNETs: types I, II and III. Each type has important features regarding clinical picture, prognosis and treatment strategy. Type I is the most common (70-80%) and associated with chronic atrophic gastritis including autoimmune gastritis and Helicobacter associated atrophic gastritis. Type II (5-6%) is associated with multiple endocrine neoplasia type I and Zollinger-Ellison syndrome (MEN I - ZES). Both types are characterized by hypergastrinemia and small tumor dimension. These neoplasms are multiple and mostly benign. On the contrary, NETs type III (10-15%) is not associated with hypergastrinemia and represented by single large neoplasms. Tumors are malignant as a rule. Therefore, surgical resection and chemotherapy are preferred for these tumors. Endoscopic surgery followed by observation is acceptable for almost all NETS type I and II. At the same time, this approach is advisable only for small and highly differentiated neoplasms type III.
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Affiliation(s)
- A V Alekberzade
- Sechenov First Moscow State Medical University, Moscow, Russia
| | - N N Krylov
- Sechenov First Moscow State Medical University, Moscow, Russia
| | - E M Lipnitskiy
- Sechenov First Moscow State Medical University, Moscow, Russia
| | - R O Shakhbazov
- Department of Surgery, SUNY Upstate Medical University, Syracuse, NY, USA
| | - F Azari
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia PA, USA
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Daskalakis K, Tsoli M, Karapanagioti A, Chrysochoou M, Thomas D, Sougioultzis S, Karoumpalis I, Kaltsas GA, Alexandraki KI. Recurrence and metastatic potential in Type 1 gastric neuroendocrine neoplasms. Clin Endocrinol (Oxf) 2019; 91:534-543. [PMID: 31254407 DOI: 10.1111/cen.14055] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 06/16/2019] [Accepted: 06/27/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND The aim of our study was to assess clinico-pathological and biochemical parameters of Type 1 Gastric Neuroendocrine Neoplasms (GNEN1) with respect to tumours propensity for recurrence and metastasis. METHODS Hospital charts of GNEN1 patients were reviewed at a single tertiary referral centre. RESULTS We included 114 consecutive patients (74 women; age at baseline 54.5 ± 12.7 years [mean ± SD]) with GNEN1. All tumours (n = 114) were well differentiated; Grade 1 (G1) accounted for 56 patients (49%), whereas 46 (40%) were Grade 2 (G2) and 12 (11%) of unknown Grade. Overall follow-up encompassed 45.3 ± 46 (mean ± SD) months in 84 patients who were subjected to annual surveillance; 44 (52%) developed recurrence in the stomach during follow-up with 22 experiencing multiple recurrences; three (2.6%) presented with metastases in locoregional lymph nodes (n = 3) and/or the liver (n = 2); No metastasis or death was reported during follow-up. Median recurrence-free survival (RFS) was 31 months (95% CI: 7.6-54.4). Among clinico-pathological and biochemical parameters investigated, endoscopic intervention compared with surgery (P-value = .009) and higher serum-gastrin levels (s-gastrin) at baseline and first-year follow-up were associated with recurrence (P-value = .022 and .003 respectively) and also shorter RFS (log-rank P = .009 for type of intervention and .014 for s-gastrin, respectively). Receiver Operator Curve analysis of s-gastrin levels at first-year follow-up for recurrence demonstrated an area under the curve of 0.702. CONCLUSION Despite the relatively high prevalence of G2 tumours, endoscopically and/or surgically treated GNEN1 remains an indolent disease with a low metastatic propensity and no disease-specific mortality reported in our series. Many patients though will experience local recurrence, warranting long-term endoscopic surveillance with s-gastrin biomarker being a complementary tool in recurrence prediction.
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Affiliation(s)
- Kosmas Daskalakis
- Endocrine Oncology Unit, 1st Department of Propaupedic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Marina Tsoli
- Endocrine Oncology Unit, 1st Department of Propaupedic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Angeliki Karapanagioti
- Endocrine Oncology Unit, 1st Department of Propaupedic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Chrysochoou
- Endocrine Oncology Unit, 1st Department of Propaupedic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Thomas
- Endocrine Oncology Unit, 1st Department of Propaupedic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Stavros Sougioultzis
- Gastroenterology Division, Department of Pathophysiology, Laikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioannis Karoumpalis
- Department of Gastroenterology, "G. Gennimatas" General Hospital, Athens, Greece
| | - Gregory A Kaltsas
- Endocrine Oncology Unit, 1st Department of Propaupedic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Krystallenia I Alexandraki
- Endocrine Oncology Unit, 1st Department of Propaupedic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
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Waldum HL, Rehfeld JF. Gastric cancer and gastrin: on the interaction of Helicobacter pylori gastritis and acid inhibitory induced hypergastrinemia. Scand J Gastroenterol 2019; 54:1118-1123. [PMID: 31524029 DOI: 10.1080/00365521.2019.1663446] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Gastric cancer, a disease with a reduced frequency for decades, now appears to be on the rise again in young Americans. The epidemiology of gastric cancer differs between tumors in the cardia and those of the more distal parts of the stomach. The tumors are divided into the intestinal type showing glandular growth pattern and the diffuse type with a different pattern. The latter often expresses neuroendocrine and more specifically ECL-cell markers suggesting that they originate from the ECL cell, the target cell for the antral hormone, gastrin. Helicobacter pylori gastritis is accepted as the major cause of gastric cancer, but only after having induced oxyntic atrophy which reduces gastric acid secretion and thus induces hypoacidity leading to hypergastrinemia. Long-term hypergastrinemia is known to induce malignant neoplasia in the stomach of animals as well as man. Recently treatment with proton pump inhibitor after Helicobacter pylori eradication in patients with gastroesophageal reflux disease, has been reported to predispose to gastric cancer. Since profound acid inhibition is a well-known cause of gastric neoplasia, it is to be expected that Helicobacter pylori infection and profound acid inhibition has an additive or possibly potentiating effect on the development of gastric cancer.
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Affiliation(s)
- Helge L Waldum
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology , Trondheim , Norway
| | - Jens F Rehfeld
- Department of Clinical Biochemistry , Rigshospitalet, Copenhagen , Denmark
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The Enterochromaffin-like [ECL] Cell-Central in Gastric Physiology and Pathology. Int J Mol Sci 2019; 20:ijms20102444. [PMID: 31108898 PMCID: PMC6567877 DOI: 10.3390/ijms20102444] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 05/10/2019] [Accepted: 05/13/2019] [Indexed: 12/17/2022] Open
Abstract
Background: Studies on the regulation of gastric and pancreatic secretion began more than 100 years ago. Secretin was the first hormone postulated to exist, initiating the field of endocrinology. Gastrin produced in the antral mucosa was the second postulated hormone, and together with histamine and acetylcholine, represent the three major gastric acid secretagogues known since 1920. For a long time, the mast cell was the only recognized histamine-producing cell in the oxyntic mucosa and, in the mid-1980s, the ECL cell was recognized as the cell producing histamine, taking part in the regulation of gastric acid secretion. Methods: This review is based upon literature research and personal knowledge. Results: The ECL cell carries the gastrin receptor, and gastrin regulates its function (histamine release) as well as proliferation. Long-term hypergastrinemia results in gastric neoplasia of variable malignancies, implying that gastric hypoacidity resulting in increased gastrin release will induce gastric neoplasia, including gastric cancer. Conclusions: The trophic effect of gastrin on the ECL cell has implications to the treatment with inhibitors of acid secretion.
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Abstract
Our group observed the first case of synchronous gastric neuroendocrine tumor (NET) and duodenal gastrinoma with autoimmune chronic atrophic gastritis (CAG), in the absence of Helicobacter pylori infection. Demographic, clinical, endoscopic, and pathologic data were abstracted from the electronic medical record at Mount Sinai Hospital from 2013 to 2015. The patient's anonymity was carefully protected, and informed consent was obtained for publication of protected health information. A 53-year-old woman with hypertension presented to Mount Sinai Hospital in June 2013 for a second opinion for management of gastric and duodenal NETs. After evaluation by gastroenterology and surgery, repeat upper endoscopy with ultrasound and fine-needle aspiration revealed multiple diminutive type I gastric NETs and 2 duodenal NETs, against a background of autoimmune CAG, with biopsy pathology negative for H. pylori. She subsequently underwent a transduodenal resection of the duodenal NETs, confirming low-grade, gastrin-positive, stage T2 duodenal NET. On routine follow-up over the next 2 years, clinical, radiographic, and endoscopic surveillance revealed no recurrent or metastatic gastric or duodenal disease. This first report of synchronous duodenal gastrinoma and gastric NET in the setting of autoimmune CAG can broaden our understanding of gastric NET pathophysiology.
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Waldum HL, Fossmark R. Types of Gastric Carcinomas. Int J Mol Sci 2018; 19:ijms19124109. [PMID: 30567376 PMCID: PMC6321162 DOI: 10.3390/ijms19124109] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 12/15/2018] [Accepted: 12/15/2018] [Indexed: 12/16/2022] Open
Abstract
Gastric cancer has reduced prevalence, but poor prognoses. To improve treatment, better knowledge of carcinogenesis and cells of origin should be sought. Stomach cancers are typically localized to one of the three mucosae; cardial, oxyntic and antral. Moreover, not only the stem cell, but the ECL cell may proliferate and give rise to tumours. According to Laurén, the classification of gastric carcinomas seems to reflect biological important differences and possible different cell of origin since the two subtypes, intestinal and diffuse, do not transform into the other and show different epidemiology. The stem cell probably gives rise to the intestinal type, whereas the ECL cell may be important in the diffuse type. Elevation of gastrin may be the carcinogenic factor for Helicobacter pylori as well as the recently described increased risk of gastric cancer due to proton pump inhibitor treatment. Therefore, it is essential to determine the role of the gastrin target cell, the ECL cell, in gastric carcinogenesis. Clinical trials with gastrin antagonists could improve prognoses in those with gastrin receptor positive tumours. However, further studies on gastric carcinomas applying relative available methods and with the highest sensitivity are warranted to improve our knowledge of gastric carcinogenesis.
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Affiliation(s)
- Helge L Waldum
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, 7006 Trondheim, Norway.
- Department of Gastroenterology and Hepatology, St. Olav's University Hospital, 7006 Trondheim, Norway.
| | - Reidar Fossmark
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, 7006 Trondheim, Norway.
- Department of Gastroenterology and Hepatology, St. Olav's University Hospital, 7006 Trondheim, Norway.
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Abstract
Gastric cancer although occurring in reduced frequency is still an important disease, partly because of the bad prognosis when occurring in western countries. This decline in occurrence may mainly be due to the reduced prevalence of Helicobacter pylori (Hp) infection, which is the most important cause of gastric cancer. There exist many different pathological classifications of gastric carcinomas, but the most useful seems to be the one by Lauren into intestinal and diffuse types since these types seldom transform into the other and also have different epidemiology. During the nearly 30 years that have passed since the groundbreaking description of Hp as the cause of gastritis and gastric cancer, a continuous search for the mechanism by which Hp infection causes gastric cancer has been done. Interestingly, it is mainly atrophic gastritis of the oxyntic mucosa that predisposes to gastric cancer possibly by inducing hypoacidity and hypergastrinemia. There are many arguments in favor of an important role of gastrin and its target cell, the enterochromaffin-like cell, in gastric carcinogenesis. The role of gastrin in gastric carcinogenesis implies caution in the long-term treatment with inhibitors of gastric acid secretion inducing secondary hypergastrinemia, in a common disease like gastroesophageal reflux disease.
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Affiliation(s)
- Helge L. Waldum
- Department of Gastroenterology and Hepatology, St Olav’s Hospital, Trondheim, Norway
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- *Correspondence: Helge L. Waldum,
| | - Liv Sagatun
- Department of Gastroenterology and Hepatology, St Olav’s Hospital, Trondheim, Norway
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Patricia Mjønes
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Pathology, St Olav’s Hospital, Trondheim, Norway
- Department of Laboratory Medicine, Children and Women’s Health, Norwegian University of Science and Technology, Trondheim, Norway
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Ananthamurthy A, Correa M, Patil M. Type 1 Gastric Carcinoid in the Indian Population and Its Association with Multifocal Gastric Atrophy. Euroasian J Hepatogastroenterol 2016; 6:106-110. [PMID: 29201740 PMCID: PMC5578576 DOI: 10.5005/jp-journals-10018-1180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 06/29/2016] [Indexed: 12/21/2022] Open
Abstract
Aim Recent studies have shown an increase in the incidence of gastric neuroendocrine tumors (NETs) (carcinoids). This may be attributable to the frequent employment of endoscopy in clinical practice and the increasing use of proton pump inhibitors. From the literature that is available, it is interesting to note that the profile of patients with gastric carcinoids is different in the Asian population when compared to the western societies. As limited data is available from India, we evaluated retrospectively the clinical profile and pathology of gastric carcinoids presenting to our hospital. Materials and methods A total of 31 patients with gastric carcinoids who presented to our institution from 2006 till 2013 were included in this study. The clinical data were obtained from the case files and the histopathology slides were reviewed. Results Gastric carcinoids constituted about 32% of all gastrointestinal (GI) NETs and were second only to duodenal carcinoids in frequency. Men were more commonly affected (74%) and the majority were of type 1 (90%). Multifocal gastric atrophy with intestinal metaplasia was additional features seen in the majority of cases with type 1 carcinoids. Conclusion This study, one of the largest series reported from India, shows that the frequency and profile of gastric carcinoids is different in this population when compared to the west. It also raises the possibility that Helicobacter pylori induced multifocal gastric atrophy might be a triggering factor for the most common type 1 gastric carcinoid rather than autoimmune gastritis. Clinical significance Eradication of H.pylori may be a potential preventive strategy for the occurrence of gastric carcinoids. How to cite this article Ananthamurthy A, Correa M, Patil M. Type 1 Gastric Carcinoid in the Indian Population and Its Association with Multifocal Gastric Atrophy. Euroasian J Hepato-Gastroenterol 2016;6(2):106-110.
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Affiliation(s)
| | - Marjorie Correa
- Department of Pathology, St. John's Medical College, Bengaluru, Karnataka, India
| | - Mallikarjun Patil
- Department of Gastroenterology, St. John's Medical College, Bengaluru, Karnataka, India
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Waldum HL, Hauso Ø, Sørdal ØF, Fossmark R. Gastrin May Mediate the Carcinogenic Effect of Helicobacter pylori Infection of the Stomach. Dig Dis Sci 2015; 60:1522-7. [PMID: 25480404 DOI: 10.1007/s10620-014-3468-9] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Accepted: 11/26/2014] [Indexed: 12/14/2022]
Abstract
Gastric cancer occurs almost exclusively in patients with gastritis. Since Helicobacter pylori (Hp) was proved to cause gastritis, Hp was also expected to play a role in gastric carcinogenesis. Despite extensive studies, the mechanisms by which Hp cause gastric cancer are still poorly understood. However, there is evidence that the anatomical site of Hp infection is of major importance. Infection confined to the antral mucosa protects against gastric cancer but predisposes to duodenal ulcer, whereas Hp infection of the oxyntic mucosa increases the risk of gastric cancer. Hp infection does not predispose to cancers in the gastric cardia. In patients with atrophic gastritis of the oxyntic mucosa, the intragastric pH is elevated and the concentration of microorganisms in the stomach is increased. This does not lead to increased risk of gastric cancer at all anatomical sites. The site specificity of Hp infection in relation to cancer risk indicates that neither Hp nor the changes in gastric microflora due to gastric hypoacidity are carcinogenic per se. However, reduced gastric acidity also leads to hypergastrinemia, which stimulates the function and proliferation of enterochromaffin-like (ECL) cells located in the oxyntic mucosa. The ECL cell may be more important in human gastric carcinogenesis than previously realized, as every condition causing long-term hypergastrinemia in animals results in the development of neoplasia in the oxyntic mucosa. Patients with hypergastrinemia will far more often develop carcinomas in the gastric corpus. In conclusion, hypergastrinemia may explain the carcinogenic effect of Hp.
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Affiliation(s)
- Helge L Waldum
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Prinsesse Kristinas Gate 1, 7006, Trondheim, Norway,
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Boyce M, Thomsen L. Gastric neuroendocrine tumors: prevalence in Europe, USA, and Japan, and rationale for treatment with a gastrin/CCK2 receptor antagonist. Scand J Gastroenterol 2015; 50:550-9. [PMID: 25665655 DOI: 10.3109/00365521.2015.1009941] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Gastric carcinoids (neuroendocrine tumors) arise from enterochromaffin-like cells in the gastric mucosa. Most are caused by hypergastrinemia. The objectives were to determine if their prevalence in Europe, USA and Japan meets the criteria for an orphan disease and to justify treatment with a gastrin/CCK2 receptor antagonist. METHODS We obtained data from European and USA cancer registries, and searched PubMed. RESULTS Prevalence per 10,000 population obtained from cancer registries was: median 0.32 (range 0.09-0.92) for Europe; and 0.17 for the USA, equivalent to 4812 for the whole population. A PubMed search for gastric carcinoids yielded prevalence for Japan only, which was 0.05 per 10,000 population, equivalent to 665 for the entire population. A further search for gastric carcinoids in patients with pernicious anemia (PA) or autoimmune chronic atrophic gastritis (CAG), two presentations of about 80% of gastric carcinoids, produced prevalence rates of 5.2-11%. Prevalence of PA itself was 0.12-1.9%. Data on CAG epidemiology were sparse. CONCLUSION Prevalence of gastric carcinoids varied widely. All sources probably underestimate prevalence. However, prevalence was below the limits required for recognition by drug regulatory authorities as an orphan disease: 5 per 10,000 population of Europe; 200,000 for the whole population of the USA; and 50,000 for the whole population of Japan. Because gastric carcinoids are an orphan disease, and nonclinical and healthy volunteer studies support treatment with netazepide, a gastrin/CCK2 antagonist, netazepide has been designated an orphan medicinal product in Europe and the USA for development as targeted treatment for gastric carcinoids.
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Affiliation(s)
- Malcolm Boyce
- Hammersmith Medicines Research, Central Middlesex Hospital , London NW10 7NS , England
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Sato Y. Clinical features and management of type I gastric carcinoids. Clin J Gastroenterol 2014; 7:381-6. [PMID: 26184015 DOI: 10.1007/s12328-014-0528-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 09/02/2014] [Indexed: 12/14/2022]
Abstract
Type I gastric carcinoids (TIGCs) are related to chronic atrophic gastritis and are characterized by hypergastrinemia and hyperplasia of enterochromaffin-like cells. TIGCs are the most frequently diagnosed of all gastric carcinoids, accounting for about 70-80 %. Endoscopically, TIGCs are present as small (<10 mm), polypoid lesions or, more frequently, as smooth, rounded submucosal lesions. Histologically, TIGCs arise in the deep mucosa, with some invading the submucosa. Most TIGCs are well-differentiated tumors, with metastasis being rare. Therefore, patients with TIGCs generally have an excellent prognosis. Among the currently available treatment options are total gastrectomy, partial resection, antrectomy, endoscopic resection, and endoscopic surveillance, although no consensus has been reached on their optimal management. Further studies are needed to develop better management options for patients with TIGC.
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Affiliation(s)
- Yuichi Sato
- Department of Gastroenterology, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi-dori, Niigata, 951-8121, Japan,
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Sato Y, Imamura H, Kaizaki Y, Koizumi W, Ishido K, Kurahara K, Suzuki H, Fujisaki J, Hirakawa K, Hosokawa O, Ito M, Kaminishi M, Furuta T, Chiba T, Haruma K. Management and clinical outcomes of type I gastric carcinoid patients: retrospective, multicenter study in Japan. Dig Endosc 2014; 26:377-84. [PMID: 24188531 DOI: 10.1111/den.12197] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Accepted: 09/27/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Type I gastric carcinoids (TIGC) are associated with chronic atrophic gastritis (CAG) with hypergastrinemia and hyperplasia of enterochromaffin-like cells. Several treatment options are currently available for these tumors including total gastrectomy, partial resection, antrectomy, endoscopic resection and endoscopic surveillance. The present study evaluated different treatment approaches and clinical outcomes of patients with TIGC in Japan. METHODS Between 1991 and 2011, 82 patients with TIGC were identified at multicenter institutions in Japan. Patient demographics, tumor size, depth of invasion, vessel involvement, treatment approach, Helicobacter pylori infection, serum gastrin level, recurrence-free survival (RFS) and disease-specific survival (DSS) were analyzed. RESULTS Median age of all patients at the time of diagnosis was 56 years (range, 24-79 years). There were 44 males and 38 females. Patients underwent endoscopic surveillance (n=25), endoscopic resection (n=41) or surgical resection (n=16). Intramucosal invasion was found in 19 patients, submucosal invasion in 44 patients and muscularis propria invasion in one patient. Tumor diameter was ≤ 10 mm in 71 patients, 11-20mm in five patients and ≥ 21 mm in five patients. None of the patients showed rapidly growing tumors, local recurrence or metastasis. The median (range) follow-up period was 7(0-20) years. RFS was 97.6% and DSS was 100% in all the patients. CONCLUSION The prognosis of TIGC patients treated by different modalities in Japan is favorable regardless of the generational change of management for TIGC.
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Affiliation(s)
- Yuichi Sato
- Department of Gastroenterology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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Thomas D, Tsolakis AV, Grozinsky-Glasberg S, Fraenkel M, Alexandraki K, Sougioultzis S, Gross DJ, Kaltsas G. Long-term follow-up of a large series of patients with type 1 gastric carcinoid tumors: data from a multicenter study. Eur J Endocrinol 2013; 168:185-93. [PMID: 23132699 DOI: 10.1530/eje-12-0836] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To study the clinical presentation, diagnostic approach, response to treatment, and the presence of other pathologies in patients with gastric carcinoid type 1 (GC 1) tumors. DESIGN AND METHODS Retrospective analysis of 111 patients from four institutions and a mean follow-up of 76 months. RESULTS The main indications for gastroscopy were upper gastrointestinal tract symptoms. The mean number of lesions, maximum tumoral diameter, and percentage of cells expressing Ki-67 labeling index were 3.6±3.8, 8±12.1 mm and 1.9±2.4% respectively. Serum gastrin and chromogranin A (CgA) levels were elevated in 100/101 and 85/90 patients respectively. Conventional imaging studies demonstrated pathology in 9/111 patients. Scintigraphy with radiolabeled octreotide was positive in 6/60 without revealing any additional lesions. From the 59 patients who had been followed-up without any intervention, five developed tumor progression. Thirty-two patients were treated with long-acting somatostatin analogs (SSAs), leading to a significant reduction of gastrin and CgA levels, number of visible tumors, and CgA immune-reactive tumor cells in 28, 19, 27, and 23 treated patients respectively. Antrectomy and/or gastrectomy were initially performed in 20 patients and a complete response was achieved in 13 patients. The most common comorbidities were vitamin B12 deficiency, thyroiditis, and parathyroid adenomas. CONCLUSIONS Most GCs1 are grade 1 (82.7%) tumors presenting with stage I (73.9%) disease with no mortality after prolonged follow-up. Ocreoscan did not provide further information compared with conventional imaging techniques. Treatment with SSAs proved to be effective for the duration of administration.
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Affiliation(s)
- Dimitrios Thomas
- Department of Pathophysiology, National University of Athens, Mikras Asias 75, 11557 Athens, Greece.
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27
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Jianu CS, Fossmark R, Viset T, Qvigstad G, Sørdal O, Mårvik R, Waldum HL. Gastric carcinoids after long-term use of a proton pump inhibitor. Aliment Pharmacol Ther 2012; 36:644-9. [PMID: 22861200 DOI: 10.1111/apt.12012] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Revised: 05/18/2012] [Accepted: 07/18/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion and give hypergastrinemia secondary to gastric hypoacidity. PPI treatment therefore induces enterochromaffin-like (ECL) cell hyperplasia. Long-term hypergastrinemia in rodents and man also leads to ECL cell neoplasia. Whether long-term PPI treatment will induce ECL cell neoplasia in man has been disputed. AIM To describe gastric carcinoids in two patients with a history of long-term PPI use. RESULTS Two patients had been taking PPI for 12-13 years due to gastro-oesophageal reflux disease. At routine upper gastrointestinal endoscopy a solitary tumour was found in the oxyntic mucosa of both patients. Histology from the tumours showed in both cases a well-differentiated neuroendocrine tumour. Biopsies from flat oxyntic mucosa showed no signs of atrophic gastritis and a normal presence of parietal cells in both cases, but hyperplasia of ECL cells. The tumour in patient 1 was resected endoscopically. After cessation of PPI treatment the tumour regressed in patient 2 and the ECL cell hyperplasia regressed in both patients. In patient 2 serum gastrin and chromogranin A were elevated during PPI treatment, and normalised after cessation of treatment. In patient 1, unfortunately, we had serum only after treatment, and at that time both parameters were normal. CONCLUSION These cases show that hypergastrinemia secondary to proton pump inhibitors treatment, like other causes of hypergastrinemia, may induce enterochromaffin-like cell carcinoids in man.
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Affiliation(s)
- C S Jianu
- Departments of Gastroenterology and Hepatology, St. Olavs Hospital, Trondheim, Norway.
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Duodenal gastrinoma with multiple gastric neuroendocrine tumors secondary to chronic Helicobacter pylori gastritis. Am J Surg Pathol 2012; 36:935-40. [PMID: 22588069 DOI: 10.1097/pas.0b013e31824babc2] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Helicobacter pylori (HP) has been associated with neuroendocrine tumors of the stomach and duodenum. Gastric enterochromaffin-like (ECL) cell tumors and duodenal gastrinomas have also been associated with HP gastritis in separate series but have not been reported together. With other possible causes excluded, we present a patient with HP-associated atrophy of the oxyntic mucosa that ultimately resulted in stimulation and reactive hyperplasia of gastrin-producing cells in both the antrum and proximal duodenum, the latter progressing to formation of a gastrin-producing cell nodule (gastrinoma). Both of these sources of gastrin resulted in ECL hyperplasia in the atrophied oxyntic mucosa with progression to microcarcinoids and well-differentiated neuroendocrine tumors, along with hypertrophy of residual proximal gastric parietal cells. As atrophy tends to spread from the antrum proximally, residual oxyntic mucosa was still infected with HP and offers 1 explanation for the apparent paradox of atrophic gastritis with ECL hyperplasia and neoplasia in the distal oxyntic mucosa, with proximal oxyntic mucosa showing mild hypertrophic changes in a background of typical HP gastritis.
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Antonodimitrakis P, Tsolakis A, Welin S, Kozlovacki G, Öberg K, Granberg D. Gastric carcinoid in a patient infected with Helicobacter pylori: a new entity? World J Gastroenterol 2011; 17:3066-3068. [PMID: 21799655 PMCID: PMC3132260 DOI: 10.3748/wjg.v17.i25.3066] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2010] [Revised: 12/10/2010] [Accepted: 12/17/2010] [Indexed: 02/06/2023] Open
Abstract
There are four types of gastric carcinoid tumors, classified according to their histology and malignant potential. Only a few cases of carcinoid tumors in patients infected with Helicobacter pylori (H. pylori) have been reported so far. We report a patient infected with H. pylori presenting with a small solitary gastric carcinoid tumor with very low proliferative rate and normal gastrin levels. The tumor was endoscopically removed and the patient received an eradication therapy against H. pylori. No signs of metastatic disease have been found so far during more than 3 year of follow-up. Infection with H. pylori may cause chronic gastritis with normal or elevated gastrin levels, leading to the development of gastric carcinoids by mechanisms unrelated to gastrin. Enterochromaffin-like cell tumors related to a chronic H. pylori infection may be considered as a distinct type of gastric carcinoid tumors.
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30
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Mizoshita T, Kataoka H, Kubota E, Shimura T, Mori Y, Wada T, Ogasawara N, Sasaki M, Kamiya T, Sakamoto M, Akamo Y, Joh T. An endocrine cell carcinoma with gastric-and-intestinal mixed phenotype adenocarcinoma component in the stomach. Dig Endosc 2009; 21:258-61. [PMID: 19961526 DOI: 10.1111/j.1443-1661.2009.00903.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A 77-year-old man complained of bodyweight loss, and a Borrmann 3 type lesion was observed endoscopically in the anterior wall of angular region of the stomach. The endocrine cell carcinoma (ECC) having the cytoplasmic staining of chromogranin A (CgA) was detected pathologically in the biopsy samples. The patient underwent distal gastrectomy plus systemic lymph node (LN) dissection (D2 LN dissection), and pathological examination revealed ECC invading the subserosa, and no LN metastasis (pT2N0M0). None of the gastric and intestinal endocrine cell marker expression was apparent in the ECC cells. The lesion also contained a moderately differentiated type tubular adenocarcinoma component, which was judged to be gastric-and-intestinal mixed (GI type) phenotype, using gastric and intestinal exocrine cell markers. After the surgery, he left the hospital and started oral doxifluridine (600 mg/day). The patient now (March 2008, about 19 months since the surgery) continues this chemotherapy with no recurrence. In conclusion, we experienced ECC with a GI type adenocarcinoma component. The ECC cases with the GI type adenocarcinoma component may have a relatively good prognosis, being similar to the results of advanced gastric cancers from the viewpoint of gastric and intestinal phenotypic expression.
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Affiliation(s)
- Tsutomu Mizoshita
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan
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31
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Christopoulos C, Balatsos V, Rotas E, Karoumpalis I, Papavasileiou D, Kontogeorgos G, Dupasquier S, Calender A, Skandalis N, Economopoulos P. The syndrome of gastric carcinoid and hyperparathyroidism: a family study and literature review. Eur J Endocrinol 2009; 160:689-694. [PMID: 19155316 DOI: 10.1530/eje-08-0867] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
OBJECTIVE To present evidence supporting the hypothesis that the coexistence of gastric carcinoids (GCs) and hyperparathyroidism may represent a distinct clinical entity, not related to multiple endocrine neoplasia type 1 (MEN1). METHODS We studied a cohort of five young siblings (age range 26-42 years), one of whom had been found to have GC and hyperparathyroidism. All siblings underwent serial gastroscopies for the assessment of gastric neuroendocrine cell proliferations over a mean follow-up period of 31.2 months. Imaging, biochemical and hormonal as well as molecular genetic investigations were performed in the direction of MEN1 syndrome. The literature was searched for cases with coexistence of GCs and hyperparathyroidism not associated with MEN1. RESULTS Four of the siblings, all male, were found to have GCs in a background of Helicobacter pylori-associated chronic atrophic gastritis and pernicious anaemia, with no serological evidence of gastric autoimmunity. In two of them, asymptomatic hyperparathyroidism was also present. Screening for MEN1 gene mutations or large deletions was negative, and hormone and imaging investigations did not support a diagnosis of familial MEN1 syndrome. A literature search revealed sporadic reports of cases with GC and hyperparathyroidism not attributable to MEN1. CONCLUSIONS The association of GCs and hyperparathyroidism appears to constitute a distinct syndrome that can be encountered in genetically predisposed individuals, and should not be regarded as 'atypical' or 'incomplete' expression of MEN1. Its prevalence and aetiology should be the subject of future studies. Screening for hyperparathyroidism seems to be justified in patients with GC of any type.
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Affiliation(s)
- C Christopoulos
- The Greek MEN-1 Study Group, First Department of Internal Medicine, A. Fleming General Hospital, Athens, Greece.
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Hosoya Y, Satoh K, Hironaka M, Nokubi M, Kurashina K, Shibayama C, Sugimoto H, Sugano K, Nagai H, Yasuda Y. Multiple gastric carcinoids associated with parietal cell hyperplasia: intraoperative detection with a radiolabeled somatostatin analog. Gastric Cancer 2008; 11:123-6. [PMID: 18595020 DOI: 10.1007/s10120-008-0457-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2007] [Accepted: 03/19/2008] [Indexed: 02/07/2023]
Abstract
We describe a 30-year-old man in whom upper endoscopy revealed multiple gastric carcinoids. The peripheral blood gastrin level was 2400 ng/ml (normal range, <200 ng/ml). Mucosal biopsy of the gastric body and fundus showed no atrophy; typical type A chronic atrophic gastritis was thus unlikely. Neither abdominal computed tomography nor selective angiography showed any evidence of tumor in the pancreas or at its periphery. However, the possibility of microgastrinoma could not be ruled out. We performed radioguided surgery with a somatostatin analog, diethylenetriamine pentaacetic acid-D-Phe1-octreotide labeled with (111)In (Octreo Scan). The location of the carcinoids was confirmed. Gastrinoma was ruled out. Total gastrectomy was performed, and the gastrin level decreased to the normal range. Macroscopically, 20 carcinoid tumors, measuring 30 mm in maximum diameter, were confirmed. Microscopic examination showed large numbers of endocrine cell micronests. Hyperplasia of parietal cells was observed, suggesting early-stage type A chronic atrophic gastritis. The antrum contained increased numbers of gastrin-positive cells, which probably caused the preoperative hypergastrinemia.
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Affiliation(s)
- Yoshinori Hosoya
- Department of Surgery, Jichi Medical University, 3311-1 Shimotsuke, Tochigi 329-0498, Japan
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Abstract
BACKGROUND Gastric carcinoid tumours are rare, but are increasing in incidence. AIM To discuss tumour pathogenesis and outline current approaches to patient management. METHODS Review of published articles following a Pubmed search. RESULTS Although interest in gastric carcinoids has increased since it was recognized that they are associated with achlorhydria, to date there is no definite evidence that humans taking long-term acid suppressing medication are at increased risk. Type I tumours are associated with autoimmune atrophic gastritis and hypergastrinaemia, type II are associated with Zollinger-Ellison syndrome, multiple endocrine neoplasia-1 and hypergastrinaemia and sporadic type III carcinoids are gastrin-independent and carry the worst prognosis. Careful investigation of these patients is required, particularly to identify the tumour type, the source of hypergastrinaemia and the presence of metastases. Treatment can be directed at the source of hypergastrinaemia if type I or II tumours are still gastrin responsive and not growing autonomously. Type III tumours should be treated surgically. CONCLUSIONS Advances in our understanding of the pathogenesis of gastric carcinoids have led to recent improvements in investigation and management. Challenges remain in identifying the genetic and environmental factors, in addition to hypergastrinaemia, that are responsible for tumour development in susceptible patients.
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Affiliation(s)
- M D Burkitt
- Division of Gastroenterology, Liverpool University, Liverpool, UK
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34
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Ning PF, Liu HJ, Yuan Y. Dynamic expression of pepsinogen C in gastric cancer, precancerous lesions and Helicobacter pylori associated gastric diseases. World J Gastroenterol 2005; 11:2545-8. [PMID: 15849808 PMCID: PMC4305740 DOI: 10.3748/wjg.v11.i17.2545] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2004] [Revised: 03/20/2004] [Accepted: 04/13/2004] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the relationship between the expression of pepsinogen C (PGC) and gastric cancer, precancerous diseases, and Helicobacter pylori (H pylori) infection. METHODS The expression of PGC was determined by immunohistochemistry method in 430 cases of gastric mucosa. H pylori infection was determined by HE staining, PCR and ELISA in 318 specimens. RESULTS The positive rate of PGC expression in 54 cases of normal gastric mucosa was 100%. The positive rates of PGC expression in superficial gastritis or gastric ulcer or erosion, atrophic gastritis or gastric dysplasia and gastric cancer decreased significantly in sequence (P<0.05; 100%/89.2% vs 14.3%/15.2% vs 2.4%). The over-expression rate of PGC in group of superficial gastritis with H pylori infection was higher than that in group without H pylori infection (P<0.05; chi2= 0.032 28/33 vs 15/25). The positive rate of PGC expression in group of atrophic gastritis with H pylori infection was lower than that in group without H pylori infection (P<0.01; chi2= 0.003 4/61 vs 9/30), and in dysplasia and gastric cancer. CONCLUSION The level of PGC expression has a close relationship with the degree of malignancy of gastric mucosa and development of gastric lesions. There is a relationship between H pylori infection and expression of antigen PGC in gastric mucosa, the positive rate of PGC expression increases in early stage of gastric lesions with H pylori infection such as gastric inflammation and decreases during the late stage such as precancerous diseases and gastric cancer. PGC-negative cases with H pylori-positive gastric lesions should be given special attention.
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Affiliation(s)
- Pei-Fang Ning
- Cancer Institute of the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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35
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Peracchi M, Gebbia C, Basilisco G, Quatrini M, Tarantino C, Vescarelli C, Massironi S, Conte D. Plasma chromogranin A in patients with autoimmune chronic atrophic gastritis, enterochromaffin-like cell lesions and gastric carcinoids. Eur J Endocrinol 2005; 152:443-448. [PMID: 15757862 DOI: 10.1530/eje.1.01862] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVE In atrophic body gastritis (ABG) chronic hypergastrinaemia stimulates enterochromaffin-like (ECL) cell proliferation with development of cell hyperplasia, dysplasia and possibly type-1 gastric carcinoids. As circulating chromogranin A (CgA) levels are a marker of neuroendocrine tumours, we evaluated the clinical usefulness of CgA assay in ABG patients to detect those with carcinoids. DESIGN AND METHODS Plasma CgA levels were measured using a commercial ELISA in 45 healthy volunteers, nine patients with type-1 gastric carcinoids and 43 consecutive ABG patients (21 without and 22 with ECL cell hyperplasia/dysplasia). RESULTS CgA levels were significantly higher in ABG patients with and without gastric carcinoids than in healthy subjects (P < 0.001). The highest values occurred in patients with carcinoids (median (interquartile range): 58.1 (44.5-65.3) U/l) and with ECL cell hyperplasia/dysplasia (35.5 (31.8-48.65) U/l) but there were no significant differences in CgA among the various subgroups of ABG patients classified according to ECL cell status. Nevertheless, in ABG patients without carcinoids CgA values correlated with the presence and severity of ECL cell lesions (r(s) = 0.428, P < 0.01). The sensitivity and specificity of the CgA assay in identifying patients with carcinoids were 100 and 23% respectively. CONCLUSIONS CgA plasma levels reflect the histological degree of ECL cell lesions in patients with ABG but the assay specificity is too low to detect among these patients those with gastric carcinoids.
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Affiliation(s)
- M Peracchi
- Gastroenterology Unit, Department of Medical Sciences, University of Milan, Ospedale Maggiore IRCCS, Padiglione Granelli, Via F Sforza 35, 20122 Milan, Italy.
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36
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Richards ML, Gauger P, Thompson NW, Giordano TJ. Regression of type II gastric carcinoids in multiple endocrine neoplasia type 1 patients with Zollinger-Ellison syndrome after surgical excision of all gastrinomas. World J Surg 2004; 28:652-8. [PMID: 15383867 DOI: 10.1007/s00268-004-7345-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Enterochromaffin-like (ECL) tumors are documented in patients with hypergastrinemia secondary to chronic atrophic gastritis or with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1 (ZES-MEN-1). In patients with ECL tumors and atrophic gastritis, normogastrinemia after antrectomy has resulted in resolution, regression, or stabilization of ECL tumors. The natural history of ECL tumors associated with ZES-MEN-1 following normalization of gastrin levels after gastrinoma resection has not been previously reported. The purpose of this study was to determine the course of ECL tumors in patients with ZES-MEN-1 following normalization of serum gastrin levels after gastrinoma resection. Two patients with ZES-MEN-1 had biopsy-proven ECL tumors on endoscopic evaluation. They then underwent surgical exploration that included distal pancreatectomy, enucleation of pancreatic head tumors, duodenotomy with excision of submucosal tumors, and peripancreatic lymphadenectomy. Gastric ECL tumors larger than 1.0 cm were locally excised. Patients underwent long-term follow-up with biochemical and endoscopic surveillance. Normogastrinemia was achieved and sustained following gastrinoma resection in two patients with ZES-MEN-1. Periodic endoscopic surveillance over a 6-year period showed complete resolution of the ECL tumors. The development of ECL tumors associated with ZES-MEN-1 is multifactorial. Studies identified a genetic influence on tumor growth with loss of heterozygosity at the MEN-1 gene locus in ECL tumors. The resolution of ECL tumors in ZES-MEN-1 patients who are normogastrinemic indicates that an elevated gastrin level is a primary initiator for development of these tumors. Therefore both genetic defects and hypergastrinemia are causative agents. Normalization of serum gastrin levels is critical for the prevention of aggressive forms of ECL tumors.
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Affiliation(s)
- Melanie L Richards
- Department of Surgery, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284, USA.
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37
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Ning PF, Liu HJ, Yuan Y. Expression of pepsinogen C in Helicobacter pylori-associated gastric lesions. Shijie Huaren Xiaohua Zazhi 2004; 12:1089-1091. [DOI: 10.11569/wcjd.v12.i5.1089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of pepsinogen C and its relation with H. pylori infection in gastric cancer and precancerous lesions.
METHODS: The method of immunohistochemistry was used to examine the expression of pepsinogen C in 318 cases of stomach mucosa; the H. pylori infection was determined by H-E stain, PCR and ELISA.
RESULTS: The rate of PGC over-expression in group of superficial gastritis of H. pylori infection was higher than that of non-infection (P < 0.05, 28/33 vs 15/25). The positive rate of PGC in group of atrophic gastritis of H. pylori infection was lower than that of non-infection (P < 0.01, 4/61 vs 9/30) and so were in dysplasia and gastric cancer.
CONCLUSION: There is a relationship between the H. pylori infection and the expression of PGC in gastric mucosa. The expression of PGC increases in superficial gastritis and decreases in atrophic gastritis, dysplasia and gastric cancer with H. pylori infection.
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38
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Waldum H, Berenna E. Discussion on the effect of chronic hypergastrinemia on human enterochromaffin-like cells: insights from patients with sporadic gastrinomas. Gastroenterology 2003; 124:1564-5; author reply 1565. [PMID: 12744241 DOI: 10.1016/s0016-5085(03)00357-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
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Papadimitraki E, Bree ED, Tzardi M, Skordilis P, Kofteridis D, Tsiftsis DD. Gastric Carcinoid in a Young Woman with Systemic Lupus Erythematosus and Atrophic Autoimmune Gastritis. Scand J Gastroenterol 2003; 38:477-481. [PMID: 28443773 DOI: 10.1080/00365520310001734] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Gastric carcinoid is a rare tumour that is associated with chronic atrophic gastritis in the majority of cases. It usually occurs in the 6th or 7th decade of life and is rarely diagnosed in patients under 30 years of age. METHODS We describe a case of multiple gastric carcinoids in a 23-year-old woman with systemic lupus erythematosus and atrophic autoimmune gastritis--an association that has not been reported previously. RESULTS The combination of atrophic autoimmune gastritis and gastric carcinoid with other autoimmune disorders has rarely been reported in the English medical literature. CONCLUSION The fact that it mostly concerns (relatively) young patients may suggest a potential causative relation between those autoimmune disorders and the early development of atrophic gastritis with hypergastrinaemia, which subsequently leads to the occurrence of gastric carcinoid tumours at a young age.
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Affiliation(s)
- E Papadimitraki
- a Depts. of Surgical Oncology, Pathology, Gastroenterology and Internal Medicine University Hospital Medical School of Crete Herakleion Greece
| | - E de Bree
- a Depts. of Surgical Oncology, Pathology, Gastroenterology and Internal Medicine University Hospital Medical School of Crete Herakleion Greece
| | - M Tzardi
- a Depts. of Surgical Oncology, Pathology, Gastroenterology and Internal Medicine University Hospital Medical School of Crete Herakleion Greece
| | - P Skordilis
- a Depts. of Surgical Oncology, Pathology, Gastroenterology and Internal Medicine University Hospital Medical School of Crete Herakleion Greece
| | - D Kofteridis
- a Depts. of Surgical Oncology, Pathology, Gastroenterology and Internal Medicine University Hospital Medical School of Crete Herakleion Greece
| | - D D Tsiftsis
- a Depts. of Surgical Oncology, Pathology, Gastroenterology and Internal Medicine University Hospital Medical School of Crete Herakleion Greece
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Ren JM, Zou QM, Wang FK, He Q, Chen W, Zen WK. PELA microspheres loaded H. pylori lysates and their mucosal immune response. World J Gastroenterol 2002; 8:1098-102. [PMID: 12439933 PMCID: PMC4656388 DOI: 10.3748/wjg.v8.i6.1098] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To prepare poly (D,L-lactide)-polyethylene glycol copolymer (PELA) microspheres loaded H.pylori lysates or Cystografin and observe their targeting in gastrointestinal mucous membrane or analyze the mucosal immune responses by oral administration.
METHODS: PELA microspheres loaded H.pylori lysates or Cystografin were prepared by double emulsion evaporation method. Their distribution in gastrointestinal mucous membrane was observed by CT.Balb/c mice orally immunized in mucosal immune responses, whose antibody production in salivary and gut washing and antibody secreting cells in Peyer’s patches (PP) were estimated by ELISA and ELISPOT, respectively. The microspheres’ physical properties, such as particle size, protein level and morphology were investigated.
RESULTS: All prepared microspheres were found to have a smooth surface morphology from 3.20-4.05 μm in diameter and high encapsulation efficiency from 74.9%-82.2%. No significant correlation in their physical properties was shown, depending on their molecular weight at the similar composition ratio. Immunization with all types of PELA-Hp microspheres elevated the saliva sIgA level at week 3 by approximately 3-4 times that with soluble antigen, which was greatly enhanced after boosting. At one week after last immunization with all types of PELA-Hp microspheres (week 8), the specific sIgA-ASCs, IgG-ASCs and sIgA in salivary rose obviously. In intestinal Peyer’s patches, the specific sIgA-ASCs were 5.92-6.98 × 104/mL cell and IgG-ASCs were 3.47-4.02 × 104/mL cell, about 5-9 times higher than those with soluble antigen (P < 0.01). ASCs in intestine were more than those in stomach and the majority of the ASCs were sIgA-ASCs. The sIgA in gut washing fluid was 1.62-1.85 OD, about 3-6 times tthat of those with soluble antigen. There were significant differences of the ASCs and sIgA in gut washing fluid as compared with those of PBS and MS-0 (P < 0.05). There appeared to be good correlation between sIgA level in gut washing fluid and sIgA-ASCs in intestinal Peyer’s patches.
CONCLUSION: PELA microspheres may be used as vehicle to delivery antigen and adjuvant in designing oral vaccination.
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Affiliation(s)
- Jian-Min Ren
- Faculty of Medical Laboratory Science, Third Military Medical University, Chongqing 400038, China.
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