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Popa SG, Golli AL, Matei CF, Sonei AN, Vere C, Cimpeanu R, Munteanu M, Munteanu A. Pancreatic Neuroendocrine Tumors-Diagnostic Pitfalls of Non-Diabetic Severe Hypoglycemia: Literature Review and Case Report. Diagnostics (Basel) 2025; 15:337. [PMID: 39941267 PMCID: PMC11816404 DOI: 10.3390/diagnostics15030337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/23/2025] [Accepted: 01/27/2025] [Indexed: 02/16/2025] Open
Abstract
Background: Hypoglycemia in the case of persons without diabetes is a rare event, being usually, initially misinterpreted based on the symptoms that can mimic various diseases, especially of a neuro-psychiatric nature. In the case of the identification of insulin-mediated hypoglycemia, the evaluation of pancreatic neuroendocrine tumors, which represent the most common and worrisome causes of non-diabetic insulin-mediated hypoglycemia, must be considered. Case Report: We present the case of a 57-year-old patient, hospitalized for a history of approximately one month of recurrent episodes of symptoms suggestive for severe hypoglycemia. The biological evaluation performed during an episode of hypoglycemia showed a plasma glucose value of 44 mg/dL, insulinemia 16.3 µU/mL, C peptide 3.72 ng/mL, HbA1c 4.99%, absence of urinary ketone bodies and anti-insulin antibodies <0.03 U/mL. The CT and MRI examination showed a 15.3/15 mm rounded tumor in the pancreatic corporeo-caudal region. The pancreatic tumor formation was enucleated and the histopathological and immunohistochemical analysis confirmed the diagnosis of the pancreatic neuroendocrine tumor with a positive reaction for chromogranin A, synaptophysin and insulin, without malignancy features (Ki 67 positive in 1% of the tumor cells). The postoperative evolution was favorable, without episodes of hypoglycemia, the fasting insulinemia one day after surgery being 4.1 µU/mL and HbA1c at three weeks postoperatively being 5.51%. Conclusions: The management of patients with hyperinsulinemic hypoglycemia secondary to insulinoma involves multidisciplinary collaboration with an important role in recognizing symptoms suggestive of hypoglycemia in a person without diabetes, initiating biological and imaging evaluation, establishing the optimal therapeutic option and histopathological confirmation.
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Affiliation(s)
- Simona Georgiana Popa
- Department of Diabetes, Nutrition and Metabolic Diseases, University of Medicine and Pharmacy, 200349 Craiova, Romania;
| | - Andreea Loredana Golli
- Department of Public Health and Healthcare Management, University of Medicine and Pharmacy, 200349 Craiova, Romania
| | - Cristina Florentina Matei
- Department of Diabetes, Nutrition and Metabolic Diseases, Emergency County Hospital, 200642 Craiova, Romania; (C.F.M.); (A.N.S.)
| | - Alexandra Nicoleta Sonei
- Department of Diabetes, Nutrition and Metabolic Diseases, Emergency County Hospital, 200642 Craiova, Romania; (C.F.M.); (A.N.S.)
| | - Cristin Vere
- Department of Gastroenterology, University of Medicine and Pharmacy, 200349 Craiova, Romania; (C.V.); (R.C.)
| | - Radu Cimpeanu
- Department of Gastroenterology, University of Medicine and Pharmacy, 200349 Craiova, Romania; (C.V.); (R.C.)
| | - Marian Munteanu
- Department of Surgery, University of Medicine and Pharmacy, 200349 Craiova, Romania; (M.M.); (A.M.)
| | - Alexandru Munteanu
- Department of Surgery, University of Medicine and Pharmacy, 200349 Craiova, Romania; (M.M.); (A.M.)
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Padmanabhan Nair Sobha R, Jensen CT, Waters R, Calimano-Ramirez LF, Virarkar MK. Appendiceal Neuroendocrine Neoplasms: A Comprehensive Review. J Comput Assist Tomogr 2024; 48:545-562. [PMID: 37574653 DOI: 10.1097/rct.0000000000001528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
ABSTRACT Appendiceal neuroendocrine neoplasm (NEN) is the most common adult appendiceal malignant tumor, constituting 16% of gastrointestinal NENs. They are versatile tumors with varying morphology, immunohistochemistry, secretory properties, and cancer genomics. They are slow growing and clinically silent, to begin with, or present with features of nonspecific vague abdominal pain. Most acute presentations are attributed clinically to appendicitis, with most cases detected incidentally on pathology after an appendectomy. Approximately 40% of them present clinically with features of hormonal excess, which is likened to the functional secretory nature of their parent cell of origin. The symptoms of carcinoid syndrome render their presence clinically evident. However, slow growing and symptomatically silent in its initial stages, high-grade neuroendocrine tumors and neuroendocrine carcinomas of the appendix are aggressive and usually have hepatic and lymph node metastasis at presentation. This review article focuses on imaging characteristics, World Health Organization histopathological classification and grading, American Joint Committee on Cancer/Union or International Cancer Control, European Neuroendocrine Tumor Society staging, European Neuroendocrine Tumor Society standardized guidelines for reporting, data interpretation, early-stage management protocols, and advanced-stage appendiceal NENs. Guidelines are also set for the follow-up and reassessment. The role of targeted radiotherapy, chemotherapy, and high-dose somatostatin analogs in treating advanced disease are discussed, along with types of ablative therapies and liver transplantation for tumor recurrence. The search for newer location-specific biomarkers in NEN is also summarized. Regarding the varying aggressiveness of the tumor, there is a scope for research in the field, with plenty of data yet to be discovered.
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Affiliation(s)
| | - Corey T Jensen
- From the Department of Radiology, University of Texas MD Anderson Cancer Center
| | - Rebecca Waters
- Department of Pathology and Lab Medicine MD Anderson Cancer Center, Houston, TX
| | | | - Mayur K Virarkar
- Department of Radiology, University of Florida College of Medicine, Jacksonville, FL
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3
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Webster AP, Thirlwell C. The Molecular Biology of Midgut Neuroendocrine Neoplasms. Endocr Rev 2024; 45:343-350. [PMID: 38123518 PMCID: PMC11074790 DOI: 10.1210/endrev/bnad034] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 10/12/2023] [Accepted: 11/28/2023] [Indexed: 12/23/2023]
Abstract
Midgut neuroendocrine neoplasms (NENs) are one of the most common subtypes of NEN, and their incidence is rising globally. Despite being the most frequently diagnosed malignancy of the small intestine, little is known about their underlying molecular biology. Their unusually low mutational burden compared to other solid tumors and the unexplained occurrence of multifocal tumors makes the molecular biology of midgut NENs a particularly fascinating field of research. This review provides an overview of recent advances in the understanding of the interplay of the genetic, epigenetic, and transcriptomic landscape in the development of midgut NENs, a topic that is critical to understanding their biology and improving treatment options and outcomes for patients.
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Affiliation(s)
- Amy P Webster
- Department of Clinical and Biomedical Science, University of Exeter College of Medicine and Health, Exeter, EX2 5DW, UK
| | - Chrissie Thirlwell
- Department of Clinical and Biomedical Science, University of Exeter College of Medicine and Health, Exeter, EX2 5DW, UK
- University of Bristol Medical School, University of Bristol, Bristol, BS8 1UD, UK
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4
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Pathak S, Starr JS, Halfdanarson T, Sonbol MB. Understanding the increasing incidence of neuroendocrine tumors. Expert Rev Endocrinol Metab 2023; 18:377-385. [PMID: 37466336 DOI: 10.1080/17446651.2023.2237593] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 07/13/2023] [Indexed: 07/20/2023]
Abstract
INTRODUCTION Neuroendocrine tumors (NETs) are a diverse group of tumors with origins from different primary sites such as gastro-entero-pancreatic, lung and endocrine tissue. Worldwide, their incidence has increased in recent decades. Advances in imaging and better clinical awareness are traditionally attributed to this trend; however, other factors such as genetic and environmental contributors are appreciated as well. AREAS COVERED The purpose of this article is to review the worldwide epidemiologic trends in incidence of NET through the decades and discuss the various factors potentially contributing to the observed changes in incidence trends. EXPERT OPINION Overall, the incidence of NET has increased across the globe over the last few decades. Although multiple genetics and environmental factors have been proposed, the majority of this increase in incidence is secondary to earlier detection. Future studies will help in more accurate assessments and an improved understanding of disease incidence among patients with different grades and differentiation.
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Affiliation(s)
- Surabhi Pathak
- Attending Hematology-Oncology, King's Daughters Medical Center, Ashland, KY, USA
| | - Jason S Starr
- Division of Hematology- Oncology, Mayo Clinic Jacksonville Campus, Jacksonville, FL, USA
| | - Thorvardur Halfdanarson
- Division of Hematology- Oncology, Mayo Clinic, Mayo Clinic Cancer Center, Rochester, MN, USA
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5
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Ghattas S, Hadeer RA, Maalouf H, Al Bitar J, Younes A, Rahban H, El Rassi Z. A Case of Familial Appendiceal Neuroendocrine Tumor. ACG Case Rep J 2023; 10:e01121. [PMID: 37575490 PMCID: PMC10419344 DOI: 10.14309/crj.0000000000001121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 05/24/2023] [Accepted: 07/10/2023] [Indexed: 08/15/2023] Open
Abstract
The risk of developing appendiceal neuroendocrine tumor (aNET) may be attributed to multiple factors. A familial clustering is found in less than 1% of the cases. We report the case of a 25-year-old woman who initially presented with a clinical presentation of acute appendicitis and was subsequently diagnosed with aNET by histopathological examination after an emergency appendectomy. While revealing the result to the patient, she was found to have a positive family history of appendiceal carcinoid tumor. Although rare and only found in 1% of the cases, aNET found in family history should raise the suspicion of neuroendocrine tumors in other family members.
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Affiliation(s)
- Souad Ghattas
- Department of General Surgery, Saint Georges Hospital University Medical Center, Balamand University, Beirut, Lebanon
| | - Ribal Aby Hadeer
- Department of General Surgery, Saint Georges Hospital University Medical Center, Balamand University, Beirut, Lebanon
| | - Hani Maalouf
- Department of General Surgery, Saint Georges Hospital University Medical Center, Balamand University, Beirut, Lebanon
| | - Jad Al Bitar
- Department of General Surgery, Saint Georges Hospital University Medical Center, Balamand University, Beirut, Lebanon
| | - Ahmad Younes
- Department of General Surgery, Saint Georges Hospital University Medical Center, Balamand University, Beirut, Lebanon
| | - Hind Rahban
- Department of Laboratory Medicine, Lebanese American University Medical Center, Beirut, Lebanon
| | - Ziad El Rassi
- Head of General Surgery Department, Saint George Hospital University Medical Center, Beirut, Lebanon
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6
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Zheng X, Wu M, Li S, Er L, Deng H, Guo S, Liu Z. Clinicopathological characteristics of rectal multiple neuroendocrine neoplasms and literature review. BMC Surg 2023; 23:147. [PMID: 37264328 DOI: 10.1186/s12893-023-02050-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 05/21/2023] [Indexed: 06/03/2023] Open
Abstract
BACKGROUND There are only a few epidemiological reports available for reference. The clinicopathological features are not clear, so there is no consensus on treating rectal multiple neuroendocrine neoplasms. This study aims to summarize the clinicopathological characteristics and preliminarily discuss the clinical diagnosis and treatment of rectal multiple neuroendocrine neoplasms. METHODS This study retrospectively analyzed rectal neuroendocrine neoplasm patients diagnosed and treated at the Fourth Hospital of Hebei Medical University from February 2007 to May 2021. The clinicopathological characteristics of rectal multiple neuroendocrine neoplasms were summarized and analyzed in combination with 14 studies on rectal multiple neuroendocrine neoplasms. RESULTS The incidence of RM-NENs accounted for 3.8% of all R-NENs in this study. The number of tumors varied to some extent, the size of tumors was basically no more than 10 mm, and there were more G1 grade tumors. In the analysis of 46 cases with known lymph node metastasis, the difference in lymph node metastasis rate between the number of tumors < 8 and ≥ 8 was statistically significant (p = 0.002). CONCLUSIONS The incidence of rectal multiple neuroendocrine neoplasms accounted for 3.8% of all rectal neuroendocrine neoplasms. For rectal multiple neuroendocrine neoplasms, the lymph node metastasis rate was higher when the number of tumors was ≥ 8. The influence of the number of tumors on lymph node metastasis should be considered in the selection of treatment.
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Affiliation(s)
- Xiuli Zheng
- Department of Endoscopy, Fourth Hospital of Hebei Medical University, No. 12 Jiankang Road, Chang'an District, Shijiazhuang, 050000, Hebei, China
| | - Mingli Wu
- Department of Endoscopy, Fourth Hospital of Hebei Medical University, No. 12 Jiankang Road, Chang'an District, Shijiazhuang, 050000, Hebei, China.
| | - Shengmian Li
- Department of Gastroenterology, Fourth Hospital of Hebei Medical University, No.12 Jiankang Road, Chang'an District, Shijiazhuang, 050000, Hebei, China
| | - Limian Er
- Department of Endoscopy, Fourth Hospital of Hebei Medical University, No. 12 Jiankang Road, Chang'an District, Shijiazhuang, 050000, Hebei, China
| | - Huiyan Deng
- Department of Pathology, Fourth Hospital of Hebei Medical University, No. 12 Jiankang Road, Chang'an District, Shijiazhuang, 050000, Hebei, China
| | - Shuo Guo
- Department of Endoscopy, Fourth Hospital of Hebei Medical University, No. 12 Jiankang Road, Chang'an District, Shijiazhuang, 050000, Hebei, China
| | - Zhihuan Liu
- Department of Endoscopy, Fourth Hospital of Hebei Medical University, No. 12 Jiankang Road, Chang'an District, Shijiazhuang, 050000, Hebei, China
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7
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Tichanek F, Försti A, Liska V, Hemminki A, Hemminki K. Survival in Colon, Rectal and Small Intestinal Cancers in the Nordic Countries through a Half Century. Cancers (Basel) 2023; 15:cancers15030991. [PMID: 36765946 PMCID: PMC9913304 DOI: 10.3390/cancers15030991] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/08/2023] Open
Abstract
Background: Survival studies in intestinal cancers have generally shown favorable development, but few studies have been able to pinpoint the timing of the changes in survival over an extended period. Here, we compared the relative survival rates for colon, rectal and small intestinal cancers from Denmark (DK), Finland (FI), Norway (NO) and Sweden (SE). Design: Relative 1-, 5- and 5/1-year conditional survival data were obtained from the NORDCAN database for the years 1971-2020. Results: The 50-year survival patterns were country-specific. For colon and rectal cancers, the slopes of survival curves bended upwards for DK, were almost linear for NO and bended downwards for FI and SE; 5-year survival was the highest in DK. Survival in small intestinal cancer was initially below colon and rectal cancers but in FI and NO it caught up toward the end of the follow-up. Conclusions: Relative survival in intestinal cancers has developed well in the Nordic countries, and DK is an example of a country which in 20 years was able to achieve excellent survival rates in colon and rectal cancers. In the other countries, the increase in survival curves for colon and rectal cancer has slowed down, which may be a challenge posed by metastatic cancers.
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Affiliation(s)
- Filip Tichanek
- Biomedical Center, Faculty of Medicine, Charles University Pilsen, 30605 Pilsen, Czech Republic
- Institute of Pathological Physiology, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic
| | - Asta Försti
- Hopp Children’s Cancer Center (KiTZ), 69120 Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69210 Heidelberg, Germany
| | - Vaclav Liska
- Biomedical Center, Faculty of Medicine, Charles University Pilsen, 30605 Pilsen, Czech Republic
- Department of Surgery, School of Medicine in Pilsen, University Hospital, 30605 Pilsen, Czech Republic
| | - Akseli Hemminki
- Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland
- Comprehensive Cancer Center, Helsinki University Hospital, 00290 Helsinki, Finland
| | - Kari Hemminki
- Biomedical Center, Faculty of Medicine, Charles University Pilsen, 30605 Pilsen, Czech Republic
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
- Correspondence:
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8
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Perez K, Kulke MH, Chittenden A, Ukaegbu C, Astone K, Alexander H, Brais L, Zhang J, Garcia J, Esplin ED, Yang S, Da Silva A, Nowak JA, Yurgelun MB, Garber J, Syngal S, Chan J. Clinical Implications of Pathogenic Germline Variants in Small Intestine Neuroendocrine Tumors (SI-NETs). JCO Precis Oncol 2022; 5:808-816. [PMID: 34994613 DOI: 10.1200/po.21.00047] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE An inherited basis for presumed sporadic neuroendocrine tumor (NET) has been suggested by evidence of familial clustering of NET and a higher incidence of second malignancies in patients and families with NET. To further investigate a potential heritable basis for sporadic neuroendocrine tumors, we performed multigene platform germline analysis to determine the frequency of hereditary susceptibility gene variants in a cohort of patients with sporadic small intestine NET (SI-NET). METHODS We performed a multigene platform germline analysis with Invitae's 83-gene, next-generation sequencing panel using DNA from 88 individuals with SI-NET from a clinically annotated database of patients with NET evaluated at Dana-Farber Cancer Institute (DFCI) who are considered high risk for inherited variants. Additionally, we evaluated the prevalence of pathogenic variants in an unselected cohort of patients with SI-NET who underwent testing with Invitae. RESULTS Of the 88 patients in the DFCI cohort, a pathogenic germline variant was identified in eight (9%) patients. In an independent cohort of 120 patients with SI-NET, a pathogenic germline variant was identified in 13 (11%) patients. Pathogenic variants were identified in more than one patient in the following genes: ATM, RAD51C, MUTYH, and BLM. Somatic testing of tumors from the DFCI cohort was suboptimal because of insufficient coverage of all targeted exons, and therefore, analysis was limited. CONCLUSION We demonstrate a 9%-11% incidence of pathogenic germline variants in genes associated with inherited susceptibility for malignancy not previously described in association with SI-NET. The association of these germline variants with neuroendocrine carcinogenesis and risk is uncertain but warrants further characterization.
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Affiliation(s)
- Kimberly Perez
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.,Harvard Medical School, Boston, MA
| | - Matthew H Kulke
- Section of Hematology and Oncology, Boston University and Boston Medical Center, Boston, MA
| | - Anu Chittenden
- Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA
| | - Chinedu Ukaegbu
- Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA
| | - Kristina Astone
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Holly Alexander
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Lauren Brais
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Jinming Zhang
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | | | | | | | - Annacarolina Da Silva
- Harvard Medical School, Boston, MA.,Department of Pathology, Brigham and Women's Hospital, Boston, MA
| | - Jonathan A Nowak
- Harvard Medical School, Boston, MA.,Department of Pathology, Brigham and Women's Hospital, Boston, MA
| | - Matthew B Yurgelun
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.,Harvard Medical School, Boston, MA
| | - Judy Garber
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.,Harvard Medical School, Boston, MA.,Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA
| | - Sapna Syngal
- Harvard Medical School, Boston, MA.,Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA.,Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA
| | - Jennifer Chan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.,Harvard Medical School, Boston, MA
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9
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Aavikko M, Kaasinen E, Andersson N, Pentinmikko N, Sulo P, Donner I, Pihlajamaa P, Kuosmanen A, Bramante S, Katainen R, Sipilä LJ, Martin S, Arola J, Carpén O, Heiskanen I, Mecklin JP, Taipale J, Ristimäki A, Lehti K, Gucciardo E, Katajisto P, Schalin-Jäntti C, Vahteristo P, Aaltonen LA. WNT2 activation through proximal germline deletion predisposes to small intestinal neuroendocrine tumors and intestinal adenocarcinomas. Hum Mol Genet 2021; 30:2429-2440. [PMID: 34274970 PMCID: PMC8643507 DOI: 10.1093/hmg/ddab206] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 07/13/2021] [Accepted: 07/14/2021] [Indexed: 12/13/2022] Open
Abstract
Many hereditary cancer syndromes are associated with an increased risk of small and large intestinal adenocarcinomas. However, conditions bearing a high risk to both adenocarcinomas and neuroendocrine tumors are yet to be described. We studied a family with 16 individuals in four generations affected by a wide spectrum of intestinal tumors, including hyperplastic polyps, adenomas, small intestinal neuroendocrine tumors, and colorectal and small intestinal adenocarcinomas. To assess the genetic susceptibility and understand the novel phenotype, we utilized multiple molecular methods, including whole genome sequencing, RNA sequencing, single cell sequencing, RNA in situ hybridization and organoid culture. We detected a heterozygous deletion at the cystic fibrosis locus (7q31.2) perfectly segregating with the intestinal tumor predisposition in the family. The deletion removes a topologically associating domain border between CFTR and WNT2, aberrantly activating WNT2 in the intestinal epithelium. These consequences suggest that the deletion predisposes to small intestinal neuroendocrine tumors and small and large intestinal adenocarcinomas, and reveals the broad tumorigenic effects of aberrant WNT activation in the human intestine.
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Affiliation(s)
- Mervi Aavikko
- Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Sciences (HiLIFE), University of Helsinki, FI-00014 Helsinki, Finland
| | - Eevi Kaasinen
- Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
| | - Noora Andersson
- Department of Pathology, Medicum, University of Helsinki, FI-00014 Helsinki, Finland
| | - Nalle Pentinmikko
- Institute of Biotechnology, Helsinki Institute of Life Sciences (HiLIFE), University of Helsinki, FI-00014 Helsinki, Finland
| | - Päivi Sulo
- Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
| | - Iikki Donner
- Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
| | - Päivi Pihlajamaa
- Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
- Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK
| | - Anna Kuosmanen
- Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
| | - Simona Bramante
- Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
| | - Riku Katainen
- Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
| | - Lauri J Sipilä
- Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
| | - Samantha Martin
- Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
| | - Johanna Arola
- Department of Pathology, HUSLAB, HUS Diagnostic Center, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland
| | - Olli Carpén
- Department of Pathology, HUSLAB, HUS Diagnostic Center, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland
- Research Program in Systems Oncology, University of Helsinki, FI-00014 Helsinki, Finland
| | - Ilkka Heiskanen
- Endocrine Surgery, Abdominal Center, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland
| | - Jukka-Pekka Mecklin
- Department of Surgery, Central Finland Central Hospital, 40620 Jyväskylä, Finland
- Faculty of Sport and Health Sciences, University of Jyväskylä, FI-40014 Jyväskylä, Finland
| | - Jussi Taipale
- Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
- Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK
| | - Ari Ristimäki
- Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
- Department of Pathology, HUSLAB, HUS Diagnostic Center, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland
| | - Kaisa Lehti
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
- Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland
| | - Erika Gucciardo
- Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland
| | - Pekka Katajisto
- Institute of Biotechnology, Helsinki Institute of Life Sciences (HiLIFE), University of Helsinki, FI-00014 Helsinki, Finland
- Department of Biosciences and Nutrition, Karolinska Institutet, 141 83 Huddinge, Sweden
- Faculty of Biological and Environmental Sciences, University of Helsinki, FI-00014 Helsinki, Finland
- Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Camilla Schalin-Jäntti
- Endocrinology, Abdominal Center, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland
| | - Pia Vahteristo
- Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
| | - Lauri A Aaltonen
- Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland
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10
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Alkhayyat M, Saleh MA, Coronado W, Abureesh M, Zmaili M, Qapaja T, Almomani A, Khoudari G, Mansoor E, Cooper G. Epidemiology of neuroendocrine tumors of the appendix in the USA: a population-based national study (2014-2019). Ann Gastroenterol 2021; 34:713-720. [PMID: 34475743 PMCID: PMC8375642 DOI: 10.20524/aog.2021.0643] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 04/05/2021] [Indexed: 12/12/2022] Open
Abstract
Background The appendix is the third most common place for neuroendocrine tumors (NETs) along the digestive tract and NETs are the most common neoplasms of the appendix. However, there are limited population-based data on the epidemiology of this disease. Using a large database, we sought to describe the epidemiology and risk association of NETs of the appendix. Method We queried a multi-institutional database (Explorys Inc., Cleveland, OH, USA), comprising 360 hospitals in the United States (US), for patients with a diagnosis of NETs of the appendix from 2014-2019. Results Of the 30,324,050 individuals in the database, 2020 patients had an appendiceal NET diagnosis (0.007%). The most common presenting symptoms included abdominal pain, nausea, vomiting and diarrhea. Patients with appendiceal NETs were more likely to be female (odds ratio [OR] 1.36, 95% confidence interval [CI] 1.24-1.49), Caucasian (OR 2.71, 95%CI 2.40-3.07), with a history of smoking (OR 1.82, 95%CI 1.65-2.01), family history of primary gastrointestinal malignancy (OR 7.26, 95%CI 6.31-8.33), diagnosis of multiple endocrine tumor type 1 (OR 52.31, 95%CI 23.15-118.23), or neurofibromatosis type 1 (OR 16.37, 95%CI 7.24-37.01). Conclusions In a population-based study in the US, using the Explorys database, we found the overall prevalence of NETs of the appendix to be 7 per 100,000 persons. The incidence in the year January 2019-January 2020 was 0.4 per 100,000 individuals. These rates are higher than previously reported and may be more accurate, given the more comprehensive nature of the Explorys database.
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Affiliation(s)
- Motasem Alkhayyat
- Internal Medicine Department, Cleveland Clinic Foundation, Cleveland, Ohio (Motasem Alkhayyat, Wendy Coronado, Mohammad Zmaili, Thabet Qapaja, Ashraf Almomani)
| | - Mohannad Abou Saleh
- Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic Foundation, Cleveland, Ohio (Mohannad Abou Saleh)
| | - Wendy Coronado
- Internal Medicine Department, Cleveland Clinic Foundation, Cleveland, Ohio (Motasem Alkhayyat, Wendy Coronado, Mohammad Zmaili, Thabet Qapaja, Ashraf Almomani)
| | - Mohammad Abureesh
- Internal Medicine Department, Staten Island University Hospital, Staten Island, NY (Mohammad Abureesh)
| | - Mohammad Zmaili
- Internal Medicine Department, Cleveland Clinic Foundation, Cleveland, Ohio (Motasem Alkhayyat, Wendy Coronado, Mohammad Zmaili, Thabet Qapaja, Ashraf Almomani)
| | - Thabet Qapaja
- Internal Medicine Department, Cleveland Clinic Foundation, Cleveland, Ohio (Motasem Alkhayyat, Wendy Coronado, Mohammad Zmaili, Thabet Qapaja, Ashraf Almomani)
| | - Ashraf Almomani
- Internal Medicine Department, Cleveland Clinic Foundation, Cleveland, Ohio (Motasem Alkhayyat, Wendy Coronado, Mohammad Zmaili, Thabet Qapaja, Ashraf Almomani)
| | - George Khoudari
- Department of Hospital Medicine, Cleveland Clinic Foundation, Cleveland, Ohio (George Khoudari)
| | - Emad Mansoor
- Gastroenterology and Hepatology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (Emad Mansoor, Gregory Cooper), USA
| | - Gregory Cooper
- Gastroenterology and Hepatology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (Emad Mansoor, Gregory Cooper), USA
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11
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Lim JY, Pommier RF. Clinical Features, Management, and Molecular Characteristics of Familial Small Bowel Neuroendocrine Tumors. Front Endocrinol (Lausanne) 2021; 12:622693. [PMID: 33732215 PMCID: PMC7959745 DOI: 10.3389/fendo.2021.622693] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 01/21/2021] [Indexed: 12/14/2022] Open
Abstract
Small bowel neuroendocrine tumors are rare tumors with an increasing incidence over the last several decades. Early detection remains challenging because patients commonly develop symptoms late in the disease course, often after the tumors have metastasized. Although these tumors were thought to arise from sporadic genetic mutations, large epidemiological studies strongly support genetic predisposition and increased risk of disease in affected families. Recent studies of familial small bowel neuroendocrine tumors have identified several novel genetic mutations. Screening for familial small bowel neuroendocrine tumors can lead to earlier diagnosis and improved patient outcomes. This review aims to summarize the current knowledge of molecular changes seen in familial small bowel neuroendocrine tumors, identify clinical features specific to familial disease, and provide strategies for screening and treatment.
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12
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Early life exposures associated with risk of small intestinal neuroendocrine tumors. PLoS One 2020; 15:e0231991. [PMID: 32324813 PMCID: PMC7179894 DOI: 10.1371/journal.pone.0231991] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 04/03/2020] [Indexed: 01/14/2023] Open
Abstract
Small intestinal neuroendocrine tumors (SINT) are rare with incidence increasing over the past 40 years. The purpose of this work is to examine the role of environmental exposures in the rise of SINT incidence using the Utah Population Database, a resource of linked records including life events, cancer diagnoses and residential histories. SINT cases born in Utah were identified through the Utah Cancer Registry with: diagnosis years of 1948 to 2014 and age at diagnosis of 23 to 88 years. Controls were matched to cases 10:1 based on sex, birth year and residence time in Utah. Cases and controls were geocoded to their birth locale. An isotonic spatial scan statistic was used to test for the occurrence and location(s) of SINT clusters. Potential environmental exposures and economic conditions in the birth locales at the time of the birth (1883–1982) were generated using historical references. Conditional logistic regression was used to estimate odd ratios. We report a spatial cluster central to historic coal mining communities, associated with a 2.86 relative risk (p = 0.016) of SINT. Aspatial analyses of industry and mining exposures further suggest elevated risk for early life exposure near areas involved in the construction industry (OR 1.98 p = 0.024). Other exposures approached significance including coal, uranium and hard rock mining during the earliest period (1883–1929) when safety from exposures was not considered. We do observe a lower risk (OR 0.58 p = 0.033) associated with individuals born in rural areas in the most recent period (1945–1982). Environmental exposures early in life, especially those from industries such as mining, may confer an elevated risk of SINT.
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13
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Taggart MW, Foo WC, Lee SM. Tumors of the Gastrointestinal System Including the Pancreas. ONCOLOGICAL SURGICAL PATHOLOGY 2020:691-870. [DOI: 10.1007/978-3-319-96681-6_12] [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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14
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Barry L, McFadden DW. Gastrointestinal Carcinoid Tumors. SHACKELFORD'S SURGERY OF THE ALIMENTARY TRACT, 2 VOLUME SET 2019:939-950. [DOI: 10.1016/b978-0-323-40232-3.00080-7] [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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15
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Genetic heterogeneity of primary lesion and metastasis in small intestine neuroendocrine tumors. Sci Rep 2018; 8:3811. [PMID: 29491456 PMCID: PMC5830878 DOI: 10.1038/s41598-018-22115-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 02/16/2018] [Indexed: 01/01/2023] Open
Abstract
Data on intratumoral heterogeneity of small intestine neuroendocrine tumors (SI-NETs) and related liver metastasis are limited. The aim of this study was to characterize genetic heterogeneity of 5 patients with SI-NETs. Therefore, formalin-fixed, paraffin-embedded tissue samples of primary and metastatic lesions as well as benign liver of five patients with synchronously metastasized, well differentiated SI-NETs were analyzed with whole exome sequencing. For one patient, chip based 850k whole DNA methylome analysis was performed of primary and metastatic tumor tissue as well as control tissue. Thereby, 156 single nucleotide variants (SNVs) in 150 genes were identified and amount of mutations per sample ranged from 9–34 (mean 22). The degree of common (0–94%) and private mutations per sample was strongly varying (6–100%). In all patients, copy number variations (CNV) were found and the degree of intratumoral heterogeneity of CNVs corresponded to SNV analysis. DNA methylation analysis of a patient without common SNVs revealed a large overlap of common methylated CpG sites. In conclusion, SI-NET primary and metastatic lesions show a highly varying degree of intratumoral heterogeneity. Driver events might not be detectable with exome analysis only, and further comprehensive studies including whole genome and epigenetic analyses are warranted.
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16
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Dumanski JP, Rasi C, Björklund P, Davies H, Ali AS, Grönberg M, Welin S, Sorbye H, Grønbæk H, Cunningham JL, Forsberg LA, Lind L, Ingelsson E, Stålberg P, Hellman P, Tiensuu Janson E. A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors. Endocr Relat Cancer 2017; 24. [PMID: 28634180 PMCID: PMC5527373 DOI: 10.1530/erc-17-0196] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The genetics behind predisposition to small intestinal neuroendocrine tumors (SI-NETs) is largely unknown, but there is growing awareness of a familial form of the disease. We aimed to identify germline mutations involved in the carcinogenesis of SI-NETs. The strategy included next-generation sequencing of exome- and/or whole-genome of blood DNA, and in selected cases, tumor DNA, from 24 patients from 15 families with the history of SI-NETs. We identified seven candidate mutations in six genes that were further studied using 215 sporadic SI-NET patients. The result was compared with the frequency of the candidate mutations in three control cohorts with a total of 35,688 subjects. A heterozygous variant causing an amino acid substitution p.(Gly396Asp) in the MutY DNA glycosylase gene (MUTYH) was significantly enriched in SI-NET patients (minor allele frequencies 0.013 and 0.003 for patients and controls respectively) and resulted in odds ratio of 5.09 (95% confidence interval 1.56-14.74; P value = 0.0038). We also found a statistically significant difference in age at diagnosis between familial and sporadic SI-NETs. MUTYH is involved in the protection of DNA from mutations caused by oxidative stress. The inactivation of this gene leads to specific increase of G:C- > T:A transversions in DNA sequence and has been shown to cause various cancers in humans and experimental animals. Our results suggest that p.(Gly396Asp) in MUTYH, and potentially other mutations in additional members of the same DNA excision-repair pathway (such as the OGG1 gene) might be involved in driving the tumorigenesis leading to familial and sporadic SI-NETs.
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Affiliation(s)
- Jan P Dumanski
- Department of ImmunologyGenetics and Pathology and SciLifeLab, Uppsala University, Uppsala, Sweden
| | - Chiara Rasi
- Department of ImmunologyGenetics and Pathology and SciLifeLab, Uppsala University, Uppsala, Sweden
| | - Peyman Björklund
- Department of Surgical SciencesExperimental Surgery, Uppsala University, Uppsala, Sweden
| | - Hanna Davies
- Department of ImmunologyGenetics and Pathology and SciLifeLab, Uppsala University, Uppsala, Sweden
| | - Abir S Ali
- Department of Medical SciencesEndocrine Oncology, Uppsala University, Uppsala, Sweden
| | - Malin Grönberg
- Department of Medical SciencesEndocrine Oncology, Uppsala University, Uppsala, Sweden
| | - Staffan Welin
- Department of Medical SciencesEndocrine Oncology, Uppsala University, Uppsala, Sweden
| | - Halfdan Sorbye
- Department of OncologyHaukeland University Hospital, Bergen, Norway
- Department of Clinical ScienceUniversity of Bergen, Bergen, Norway
| | - Henning Grønbæk
- Department of Hepatology and GastroenterologyAarhus University Hospital, Aarhus, Denmark
| | | | - Lars A Forsberg
- Department of ImmunologyGenetics and Pathology and SciLifeLab, Uppsala University, Uppsala, Sweden
| | - Lars Lind
- Department of Medical SciencesUppsala University, Uppsala, Sweden
| | - Erik Ingelsson
- Division of Cardiovascular MedicineDepartment of Medicine, Stanford University, San Francisco, California, USA
| | - Peter Stålberg
- Department of Surgical SciencesEndocrine Surgery, Uppsala University, Uppsala, Sweden
| | - Per Hellman
- Department of Surgical SciencesEndocrine Surgery, Uppsala University, Uppsala, Sweden
| | - Eva Tiensuu Janson
- Department of Medical SciencesEndocrine Oncology, Uppsala University, Uppsala, Sweden
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D'Ambrosio D, Tomaselli V, Gargiulo G, Roselli M, Della-Morte D, Abete P. Evans Syndrome Presented with Marginal Zone Lymphoma and Duodenal Neuroendocrine Tumor in an Elderly Woman. INT J GERONTOL 2016. [DOI: 10.1016/j.ijge.2013.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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18
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Pyo JH, Hong SN, Min BH, Lee JH, Chang DK, Rhee PL, Kim JJ, Choi SK, Jung SH, Son HJ, Kim YH. Evaluation of the risk factors associated with rectal neuroendocrine tumors: a big data analytic study from a health screening center. J Gastroenterol 2016; 51:1112-1121. [PMID: 27025841 DOI: 10.1007/s00535-016-1198-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Accepted: 03/14/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Rectal neuroendocrine tumor (NET) is the most common NET in Asia. The risk factors associated with rectal NETs are unclear because of the overall low incidence rate of these tumors and the associated difficulty in conducting large epidemiological studies on rare cases. The aim of this study was to exploit the benefits of big data analytics to assess the risk factors associated with rectal NET. METHODS A retrospective case-control study was conducted, including 102 patients with histologically confirmed rectal NETs and 52,583 healthy controls who underwent screening colonoscopy at the Center for Health Promotion of the Samsung Medical Center in Korea between January 2002 and December 2012. Information on different risk factors was collected and logistic regression analysis applied to identify predictive factors. RESULTS Four factors were significantly associated with rectal NET: higher levels of cholesterol [odds ratio (OR) = 1.007, 95 % confidence interval (CI), 1.001-1.013, p = 0.016] and ferritin (OR = 1.502, 95 % CI, 1.167-1.935, p = 0.002), presence of metabolic syndrome (OR = 1.768, 95 % CI, 1.071-2.918, p = 0.026), and family history of cancer among first-degree relatives (OR = 1.664, 95 % CI, 1.019-2.718, p = 0.042). CONCLUSION The findings of our study demonstrate the benefits of using big data analytics for research and clinical risk factor studies. Specifically, in this study, this analytical method was applied to identify higher levels of serum cholesterol and ferritin, metabolic syndrome, and family history of cancer as factors that may explain the increasing incidence and prevalence of rectal NET.
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Affiliation(s)
- Jeung Hui Pyo
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-dong, Gangnam-gu, Seoul, 135-710, Republic of Korea
| | - Sung Noh Hong
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-dong, Gangnam-gu, Seoul, 135-710, Republic of Korea
| | - Byung-Hoon Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-dong, Gangnam-gu, Seoul, 135-710, Republic of Korea
| | - Jun Haeng Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-dong, Gangnam-gu, Seoul, 135-710, Republic of Korea
| | - Dong Kyung Chang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-dong, Gangnam-gu, Seoul, 135-710, Republic of Korea
| | - Poong-Lyul Rhee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-dong, Gangnam-gu, Seoul, 135-710, Republic of Korea
| | - Jae Jun Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-dong, Gangnam-gu, Seoul, 135-710, Republic of Korea
| | - Sun Kyu Choi
- Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sin-Ho Jung
- Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee Jung Son
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-dong, Gangnam-gu, Seoul, 135-710, Republic of Korea.
| | - Young-Ho Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-dong, Gangnam-gu, Seoul, 135-710, Republic of Korea.
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Ileal “carcinoid” tumors—small size belies deadly intent: high rate of nodal metastasis in tumors ≤1 cm in size. Hum Pathol 2016; 56:123-7. [DOI: 10.1016/j.humpath.2016.05.023] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 05/13/2016] [Accepted: 05/27/2016] [Indexed: 01/13/2023]
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20
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Du Y, Ter-Minassian M, Brais L, Brooks N, Waldron A, Chan JA, Lin X, Kraft P, Christiani DC, Kulke MH. Genetic associations with neuroendocrine tumor risk: results from a genome-wide association study. Endocr Relat Cancer 2016; 23:587-94. [PMID: 27492634 PMCID: PMC6151867 DOI: 10.1530/erc-16-0171] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Accepted: 06/20/2016] [Indexed: 12/13/2022]
Abstract
The etiology of neuroendocrine tumors remains poorly defined. Although neuroendocrine tumors are in some cases associated with inherited genetic syndromes, such syndromes are rare. The majority of neuroendocrine tumors are thought to be sporadic. We performed a genome-wide association study (GWAS) to identify potential genetic risk factors for sporadic neuroendocrine tumors. Using germline DNA from blood specimens, we genotyped 909,622 SNPs using the Affymetrix 6.0 GeneChip, in a cohort comprising 832 neuroendocrine tumor cases from Dana-Farber Cancer Institute and Massachusetts General Hospital and 4542 controls from the Harvard School of Public Health. An additional 241 controls from Dana-Farber Cancer Institute were used for quality control. We assessed risk associations in the overall cohort, and in neuroendocrine tumor subgroups. We identified no potential risk associations in the cohort overall. In the small intestine neuroendocrine tumor subgroup, comprising 293 cases, we identified risk associations with three SNPs on chromosome 12, all in strong LD. The three SNPs are located upstream of ELK3, a transcription factor implicated in angiogenesis. We did not identify clear risk associations in the bronchial or pancreatic neuroendocrine subgroups. This large-scale study provides initial evidence that presumed sporadic small intestine neuroendocrine tumors may have a genetic etiology. Our results provide a basis for further exploring the role of genes implicated in this analysis, and for replication studies to confirm the observed associations. Additional studies to evaluate potential genetic risk factors for sporadic pancreatic and bronchial neuroendocrine tumors are warranted.
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Affiliation(s)
- Yeting Du
- Harvard School of Public HealthBoston, Massachusetts, USA
| | - Monica Ter-Minassian
- Harvard School of Public HealthBoston, Massachusetts, USA Dana-Farber Cancer InstituteBoston, Massachusetts, USA
| | - Lauren Brais
- Dana-Farber Cancer InstituteBoston, Massachusetts, USA
| | | | | | | | - Xihong Lin
- Harvard School of Public HealthBoston, Massachusetts, USA
| | - Peter Kraft
- Harvard School of Public HealthBoston, Massachusetts, USA
| | - David C Christiani
- Harvard School of Public HealthBoston, Massachusetts, USA Massachusetts General HospitalBoston, Massachusetts, USA
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21
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Doi M, Ikawa O, Taniguchi H, Kawamura T, Katsura K. Multiple rectal carcinoid tumors in monozygotic twins. Clin J Gastroenterol 2016; 9:215-21. [PMID: 27334481 DOI: 10.1007/s12328-016-0662-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2015] [Accepted: 05/31/2016] [Indexed: 11/29/2022]
Abstract
We report multiple rectal carcinoid tumors in monozygotic twins who, respectively, had 42 and 36 carcinoid tumors in the lower rectum. This is the first report about carcinoid tumors in monozygotic twins. Both twins developed a similar number of rectal carcinoids with a similar distribution. Investigation of their genetic background may provide information about the origin of these tumors.
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Affiliation(s)
- Momoko Doi
- Department of Surgery, Yawata Chuo Hospital, Yawata, Japan. .,Department of Surgery, Kyoto Second Red Cross Hospital, Kyoto, Japan.
| | - Osamu Ikawa
- Department of Surgery, Kyoto Second Red Cross Hospital, Kyoto, Japan
| | - Hiroki Taniguchi
- Department of Surgery, Kyoto Second Red Cross Hospital, Kyoto, Japan
| | - Takuji Kawamura
- Department of Gastroenterology, Kyoto Second Red Cross Hospital, Kyoto, Japan
| | - Kanade Katsura
- Department of Histopathology and Cytology, Kyoto Second Red Cross Hospital, Kyoto, Japan
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22
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Neklason DW, VanDerslice J, Curtin K, Cannon-Albright LA. Evidence for a heritable contribution to neuroendocrine tumors of the small intestine. Endocr Relat Cancer 2016; 23:93-100. [PMID: 26604321 PMCID: PMC4684974 DOI: 10.1530/erc-15-0442] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 11/23/2015] [Indexed: 12/20/2022]
Abstract
Small intestinal neuroendocrine tumors (SI-NETs) are rare tumors arising from the enterochromaffin cells of the gut. Having a first-degree relative with a SI-NET has been shown to confer a substantial risk arising from shared environment and genetics. Heritable risk was examined using a computerized genealogy linked to historical statewide cancer data. A population-based analysis of the observed familial clustering of SI-NETs was performed to assess the genetic risk in distant relatives. A test for significant excess relatedness of 384 individuals with genealogy data and histologically confirmed SI-NETs was performed by comparing pairwise relatedness of cases to 1000 sets of matched controls. Overall significant excess pairwise relatedness was found for the 384 cases (P<0.001) and was still observed when closer than first cousin relationships were ignored (P=0.041). Relative risks (RRs) for SI-NETs were estimated as a ratio of observed to expected number of SI-NET cases among each relationship class. Siblings have a 13.4-fold (P<0.0001) and parents have a 6.5-fold (P=0.143) RR, suggesting both genetic and environmental influences. The risk extends out to third-degree relatives with a 2.3-fold RR (P=0.008). Metachronous cancers were also reported in 26% of the SI-NET cases demonstrating an increased RR of colon, bladder, non-Hodgkin lymphoma, melanoma, and prostate cancers. Although SI-NETs are rare, relatives of these cases are at a significantly elevated risk of developing a SI-NET due to heritable genetic factors. Definition of the genetic risk factors will be an important tool for earlier diagnosis and better outcomes for SI-NETs.
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Affiliation(s)
- Deborah W Neklason
- Division of Genetic EpidemiologyDepartment of Internal Medicine, University of Utah, Salt Lake City, Utah, USAHuntsman Cancer InstituteUniversity of Utah, 2000 Circle of Hope, Room 3265, Salt Lake City, Utah 84112-5550, USADivision of Public HealthDepartment of Family and Preventive Medicine, University of Utah, Salt Lake City, Utah, USAGeorge E. Wahlen Department of Veterans Affairs Medical CenterSalt Lake City, Utah, USA Division of Genetic EpidemiologyDepartment of Internal Medicine, University of Utah, Salt Lake City, Utah, USAHuntsman Cancer InstituteUniversity of Utah, 2000 Circle of Hope, Room 3265, Salt Lake City, Utah 84112-5550, USADivision of Public HealthDepartment of Family and Preventive Medicine, University of Utah, Salt Lake City, Utah, USAGeorge E. Wahlen Department of Veterans Affairs Medical CenterSalt Lake City, Utah, USA
| | - James VanDerslice
- Division of Genetic EpidemiologyDepartment of Internal Medicine, University of Utah, Salt Lake City, Utah, USAHuntsman Cancer InstituteUniversity of Utah, 2000 Circle of Hope, Room 3265, Salt Lake City, Utah 84112-5550, USADivision of Public HealthDepartment of Family and Preventive Medicine, University of Utah, Salt Lake City, Utah, USAGeorge E. Wahlen Department of Veterans Affairs Medical CenterSalt Lake City, Utah, USA
| | - Karen Curtin
- Division of Genetic EpidemiologyDepartment of Internal Medicine, University of Utah, Salt Lake City, Utah, USAHuntsman Cancer InstituteUniversity of Utah, 2000 Circle of Hope, Room 3265, Salt Lake City, Utah 84112-5550, USADivision of Public HealthDepartment of Family and Preventive Medicine, University of Utah, Salt Lake City, Utah, USAGeorge E. Wahlen Department of Veterans Affairs Medical CenterSalt Lake City, Utah, USA Division of Genetic EpidemiologyDepartment of Internal Medicine, University of Utah, Salt Lake City, Utah, USAHuntsman Cancer InstituteUniversity of Utah, 2000 Circle of Hope, Room 3265, Salt Lake City, Utah 84112-5550, USADivision of Public HealthDepartment of Family and Preventive Medicine, University of Utah, Salt Lake City, Utah, USAGeorge E. Wahlen Department of Veterans Affairs Medical CenterSalt Lake City, Utah, USA
| | - Lisa A Cannon-Albright
- Division of Genetic EpidemiologyDepartment of Internal Medicine, University of Utah, Salt Lake City, Utah, USAHuntsman Cancer InstituteUniversity of Utah, 2000 Circle of Hope, Room 3265, Salt Lake City, Utah 84112-5550, USADivision of Public HealthDepartment of Family and Preventive Medicine, University of Utah, Salt Lake City, Utah, USAGeorge E. Wahlen Department of Veterans Affairs Medical CenterSalt Lake City, Utah, USA Division of Genetic EpidemiologyDepartment of Internal Medicine, University of Utah, Salt Lake City, Utah, USAHuntsman Cancer InstituteUniversity of Utah, 2000 Circle of Hope, Room 3265, Salt Lake City, Utah 84112-5550, USADivision of Public HealthDepartment of Family and Preventive Medicine, University of Utah, Salt Lake City, Utah, USAGeorge E. Wahlen Department of Veterans Affairs Medical CenterSalt Lake City, Utah, USA Division of Genetic EpidemiologyDepartment of Internal Medicine, University of Utah, Salt Lake City, Utah, USAHuntsman Cancer InstituteUniversity of Utah, 2000 Circle of Hope, Room 3265, Salt Lake City, Utah 84112-5550, USADivision of Public HealthDepartment of Family and Preventive Medicine, University of Utah, Salt Lake City, Utah, USAGeorge E. Wahlen Department of Veterans Affairs Medical CenterSalt Lake City, Utah, USA
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Leoncini E, Carioli G, La Vecchia C, Boccia S, Rindi G. Risk factors for neuroendocrine neoplasms: a systematic review and meta-analysis. Ann Oncol 2015; 27:68-81. [PMID: 26487581 DOI: 10.1093/annonc/mdv505] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Accepted: 10/12/2015] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Neuroendocrine neoplasms (NENs) are rare cancers mainly of lung and digestive tract. Little is known on risk factors. The aim of this work is to define the risk factors for NEN development by extensive review and meta-analysis of published data. METHODS The search was conducted on Medline, Scopus, and Web of Science following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The Newcastle-Ottawa scale was used for study quality. Meta-analyses were conducted by primary site. Odds ratio (OR), hazard ratio, risk ratio, standardized incidence ratio, and associated 95% confidence intervals (CIs) were abstracted. Data were combined and analyses carried out for risk factors considered by at least two studies. Random-effects model was adopted for study variation. RESULTS Of 1535 extracted articles, 24 were enrolled. Meta-analyses were possible for pancreas, small intestine, and rectum. Risk for NEN associated with: (i) family history of cancer at all investigated sites (lung, stomach, pancreas, small intestine, appendix, and colon; OR 2.12 [95% CI 1.40-3.22, I(2) = 0.0%, P = 0.681] at meta-analysis in pancreas); (ii) body mass index (BMI) or diabetes (stomach, pancreas, and small intestine; OR of 2.76 [95% CI 1.65-4.64, I(2) = 58.5%, P = 0.090] for diabetes at meta-analysis in pancreas); (iii) cigarette smoking (lung, stomach, pancreas, and small intestine; OR of 1.34 [95% CI 1.10-1.63, I(2) = 0.0%, P = 0.780] and of 1.59 [95% CI 1.07-2.37, I(2) = 32.9%, P = 0.225] for smokers versus never-smokers at meta-analysis for pancreas and small intestine); (iv) alcohol consumption (pancreas and rectum; OR of 2.44 [95% CI 1.07-5.59, I(2) = 65.8%, P = 0.054] and of 1.53 [95% CI 0.99-2.35, I(2) = 0.0%, P = 0.630] for heavy drinkers versus never-drinkers at meta-analysis for pancreas and rectum). CONCLUSIONS Family history of cancer is the most relevant risk factor for NEN development at all investigated sites, followed by BMI and diabetes. Cigarette smoking and alcohol consumption are potential risk factors for selected anatomical sites.
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Affiliation(s)
- E Leoncini
- Section of Hygiene, Institute of Public Health, Università Cattolica del Sacro Cuore, Rome
| | - G Carioli
- Department of Clinical Sciences and Community Health, University of Milan, Milan
| | - C La Vecchia
- Department of Clinical Sciences and Community Health, University of Milan, Milan
| | - S Boccia
- Section of Hygiene, Institute of Public Health, Università Cattolica del Sacro Cuore, Rome
| | - G Rindi
- Institute of Anatomic Pathology, Università Cattolica del Sacro Cuore, Rome, Italy
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Hughes MS, Azoury SC, Assadipour Y, Straughan DM, Trivedi AN, Lim RM, Joy G, Voellinger MT, Tang DM, Venkatesan AM, Chen CC, Louie A, Quezado MM, Forbes J, Wank SA. Prospective evaluation and treatment of familial carcinoid small intestine neuroendocrine tumors (SI-NETs). Surgery 2015; 159:350-6. [PMID: 26454678 DOI: 10.1016/j.surg.2015.05.041] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Revised: 04/22/2015] [Accepted: 05/13/2015] [Indexed: 01/17/2023]
Abstract
BACKGROUND The aim of this study was to prospectively screen patients with a positive family history of carcinoid small intestine neuroendocrine tumors (SI-NETs) to elucidate the benefits of early detection and operative intervention. METHODS A single-center, prospective trial was conducted from 2008 to 2014 that evaluated patients with 2 or more blood relatives with carcinoid SI-NETs. All eligible patients were screened with urine/serum biochemistries and various imaging modalities. Operative intervention was elected in patients found to have at least 1 positive diagnostic study. RESULTS Twenty-nine patients from 13 families had occult carcinoid SI-NETs (15 female, 14 male). Twenty-four of the 29 patients (83%) had multifocal disease found in either the distal jejunum or ileum. On average, 75.9 cm (range, 13-195) of bowel was resected in 1 segment. Three patients were found to have stage IV disease at operation. All stage I-IIIB patients who had R0 resections have remained disease-free, with a median follow-up of 35 months. CONCLUSION Familial carcinoid SI-NETs often are asymptomatic and can be diagnosed with aggressive screening. With early detection, there may be a window of opportunity for operative resection to change the natural history of this disease and even prove to be curative.
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Affiliation(s)
- Marybeth S Hughes
- Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
| | - Saïd C Azoury
- Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Yasmine Assadipour
- Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - David M Straughan
- Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Apurva N Trivedi
- Digestive Diseases Branch, National Institute of Diabetes, Kidney and Digestive Diseases, National Institutes of Health, Bethesda, MD
| | - Ramona M Lim
- Digestive Diseases Branch, National Institute of Diabetes, Kidney and Digestive Diseases, National Institutes of Health, Bethesda, MD
| | - Grishma Joy
- Digestive Diseases Branch, National Institute of Diabetes, Kidney and Digestive Diseases, National Institutes of Health, Bethesda, MD
| | - Mark T Voellinger
- Digestive Diseases Branch, National Institute of Diabetes, Kidney and Digestive Diseases, National Institutes of Health, Bethesda, MD
| | - Derek M Tang
- Digestive Diseases Branch, National Institute of Diabetes, Kidney and Digestive Diseases, National Institutes of Health, Bethesda, MD
| | | | - Clara C Chen
- Radiology and Imaging Sciences, National Institutes of Health, Bethesda, MD
| | - Adeline Louie
- Radiology and Imaging Sciences, National Institutes of Health, Bethesda, MD
| | - Martha M Quezado
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Joanne Forbes
- Digestive Diseases Branch, National Institute of Diabetes, Kidney and Digestive Diseases, National Institutes of Health, Bethesda, MD
| | - Stephen A Wank
- Digestive Diseases Branch, National Institute of Diabetes, Kidney and Digestive Diseases, National Institutes of Health, Bethesda, MD
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Bruno W, Fornarini G, Ghiorzo P. Signs and genetics of rare cancer syndromes with gastroenterological features. World J Gastroenterol 2015; 21:8985-8993. [PMID: 26290627 PMCID: PMC4533032 DOI: 10.3748/wjg.v21.i30.8985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Revised: 05/26/2015] [Accepted: 07/15/2015] [Indexed: 02/07/2023] Open
Abstract
Although the genetic bases of most hereditary cancer syndromes are known, and genetic tests are available for them, the incidence of the most rare of these syndromes is likely underestimated, partially because the clinical expression is neither fully understood nor easily diagnosed due to the variable and complex expressivity. The clinical features of a small pool of rare cancer syndromes include gastroenterological signs, though not necessarily tumors, that could require the intervention of a gastroenterologist during any of the phases of the clinical management. Herein we will attempt to spread the knowledge on these rare syndromes by summarizing the phenotype and genetic basis, and revising the peculiar gastroenterological signs whose underlying role in these rare hereditary cancer syndromes is often neglected. Close collaboration between geneticists and gastroenterologists could facilitate both the early identification of patients or relatives at-risk and the planning of multidisciplinary and tailored management of these subjects.
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26
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Kidd M, Modlin IM, Bodei L, Drozdov I. Decoding the Molecular and Mutational Ambiguities of Gastroenteropancreatic Neuroendocrine Neoplasm Pathobiology. Cell Mol Gastroenterol Hepatol 2015; 1:131-153. [PMID: 28210673 PMCID: PMC5301133 DOI: 10.1016/j.jcmgh.2014.12.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 12/19/2014] [Indexed: 02/08/2023]
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), considered a heterogeneous neoplasia, exhibit ill-defined pathobiology and protean symptomatology and are ubiquitous in location. They are difficult to diagnose, challenging to manage, and outcome depends on cell type, secretory product, histopathologic grading, and organ of origin. A morphologic and molecular genomic review of these lesions highlights tumor characteristics that can be used clinically, such as somatostatin-receptor expression, and confirms features that set them outside the standard neoplasia paradigm. Their unique pathobiology is useful for developing diagnostics using somatostatin-receptor targeted imaging or uptake of radiolabeled amino acids specific to secretory products or metabolism. Therapy has evolved via targeting of protein kinase B signaling or somatostatin receptors with drugs or isotopes (peptide-receptor radiotherapy). With DNA sequencing, rarely identified activating mutations confirm that tumor suppressor genes are relevant. Genomic approaches focusing on cancer-associated genes and signaling pathways likely will remain uninformative. Their uniquely dissimilar molecular profiles mean individual tumors are unlikely to be easily or uniformly targeted by therapeutics currently linked to standard cancer genetic paradigms. The prevalence of menin mutations in pancreatic NEN and P27KIP1 mutations in small intestinal NEN represents initial steps to identifying a regulatory commonality in GEP-NEN. Transcriptional profiling and network-based analyses may define the cellular toolkit. Multianalyte diagnostic tools facilitate more accurate molecular pathologic delineations of NEN for assessing prognosis and identifying strategies for individualized patient treatment. GEP-NEN remain unique, poorly understood entities, and insight into their pathobiology and molecular mechanisms of growth and metastasis will help identify the diagnostic and therapeutic weaknesses of this neoplasia.
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Key Words
- 5-HT, serotonin, 5-hydroxytryptamine
- Akt, protein kinase B
- BRAF, gene encoding serine/threonine-protein kinase B-Raf
- Blood
- CGH, comparative genomic hybridization
- CREB, cAMP response element-binding protein
- Carcinoid
- CgA, chromogranin A
- D cell, somatostatin
- DAG, diacylglycerol
- EC, enterochromaffin
- ECL, enterochromaffin-like
- EGFR, epidermal growth factor receptor
- ERK, extracellular-signal-regulated kinase
- G cell, gastrin
- GABA, γ-aminobutyric acid
- GEP-NEN, gastroenteropancreatic neuroendocrine neoplasms
- GPCR, G-protein coupled receptor
- Gastroenteropancreatic Neuroendocrine Neoplasms
- IGF-I, insulin-like growth factor-I
- ISG, immature secretory vesicles
- Ki-67
- LOH, loss of heterozygosity
- MAPK, mitogen-activated protein kinase
- MEN-1/MEN1, multiple endocrine neoplasia type 1
- MSI, microsatellite instability
- MTA, metastasis associated-1
- NEN, neuroendocrine neoplasms
- NFκB, nuclear factor κB
- PET, positron emission tomography
- PI3, phosphoinositide-3
- PI3K, phosphoinositide-3 kinase
- PKA, protein kinase A
- PKC, protein kinase C
- PTEN, phosphatase and tensin homolog deleted on chromosome 10
- Proliferation
- SD-208, 2-(5-chloro-2-fluorophenyl)-4-[(4-pyridyl)amino]p-teridine
- SNV, single-nucleotide variant
- SSA, somatostatin analog
- SST, somatostatin
- Somatostatin
- TGF, transforming growth factor
- TGN, trans-Golgi network
- TSC2, tuberous sclerosis complex 2 (tuberin)
- Transcriptome
- VMAT, vesicular monoamine transporters
- X/A-like cells, ghrelin
- cAMP, adenosine 3′,5′-cyclic monophosphate
- mTOR, mammalian target of rapamycin
- miR/miRNA, micro-RNA
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Affiliation(s)
| | - Irvin M. Modlin
- Correspondence Address correspondence to: Irvin M. Modlin, MD, PhD, The Gnostic Consortium, Wren Laboratories, 35 NE Industrial Road, Branford, Connecticut, 06405.
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WHO Grade 2 Neuroendocrine Tumor in a 15-Year-Old Male: A Case Report and Literature Review. Case Rep Pathol 2014; 2014:426161. [PMID: 25525544 PMCID: PMC4266762 DOI: 10.1155/2014/426161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 11/07/2014] [Accepted: 11/09/2014] [Indexed: 12/01/2022] Open
Abstract
Neuroendocrine tumors, distinguished from adenocarcinomas by their neuroendocrine differentiation, are the most common pediatric epithelial malignancy that most often occurs in the appendix. In 2010, the WHO classified neuroendocrine neoplasms into three grades based on morphology, mitotic count, and Ki67 proliferation index. A 15-year-old male with a history of anemia and failure to thrive was diagnosed with a well-differentiated neuroendocrine tumor in the jejunum that invaded into the subserosal soft tissue and metastasized to four lymph nodes. Pediatric neuroendocrine tumors frequently arise within hereditary tumor syndromes with pancreatic neuroendocrine tumors being the most common. Several studies also indicate an elevated risk of small intestinal neuroendocrine tumors in which children born to a parent with a history of neuroendocrine tumors in the small intestine have a significant increased risk of developing one.
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Halfdanarson TR, Bamlet WR, McWilliams RR, Hobday TJ, Burch PA, Rabe KG, Petersen GM. Risk factors for pancreatic neuroendocrine tumors: a clinic-based case-control study. Pancreas 2014; 43:1219-22. [PMID: 25291526 PMCID: PMC4267883 DOI: 10.1097/mpa.0000000000000234] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Pancreatic neuroendocrine tumors (PNETs) are uncommon, and little is known about their risk factors and association with other cancers. We evaluated whether the following risk factors known to be associated with pancreatic adenocarcinoma are also associated with PNETs: smoking, alcohol use, family history of PNET, and other cancers, and personal history of diabetes as potential risk factors. METHODS Patients with PNETs seen at Mayo Clinic Rochester between 2000 and 2011 were compared with controls seen for a general medical evaluation. Patients and controls completed the same questionnaires. After excluding insulinoma and high-grade PNETs, 355 cases were evaluated, and 309 were matched to 602 controls (2:1) on age, sex, and region of residence. RESULTS Personal smoking history was not associated with PNETs. Alcohol use was less common among cases (54% vs 67%, P < 0.001). Cases were more likely to report a family member with sarcoma (P = 0.02), PNET (P = 0.02), gallbladder cancer (P = 0.02), ovarian cancer (P = 0.04), and gastric cancer (P = 0.01). There was no association with other cancers in family members. Diabetes was more commonly reported by cases than controls (19% vs 11%, P < 0.001). CONCLUSIONS With the exception of diabetes, risk factors that are associated with pancreatic adenocarcinoma are not risk factors for PNETs.
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Affiliation(s)
| | - William R. Bamlet
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Robert R McWilliams
- Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Timothy J. Hobday
- Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Patrick A. Burch
- Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Kari G. Rabe
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Gloria M. Petersen
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota
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Landerholm K, Falkmer U, Persson R, Wall N, Hallert C, Järhult J. Overrepresentation of HLA-DQ2 in small intestinal neuroendocrine tumor patients. J Gastrointest Cancer 2014; 45:472-5. [PMID: 25257389 DOI: 10.1007/s12029-014-9651-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
PURPOSE To investigate whether celiac disease risk haplotypes HLA-DQ2 and DQ8 also increase the risk for developing small intestinal neuroendocrine tumor (SI-NET). METHODS Thirty-five patients with serotonin-producing jejunal and ileal SI-NET were examined with HLA-DQ genotyping and serology for IgA anti-tissue transglutaminase (tTG) antibodies. RESULTS Twenty-one patients (60 %) carried HLA-DQ2 or DQ8, twice the frequency of the general population (P < 0.001). In particular DQ2 was overrepresented (P = 0.013). Gender, age, disease stage, histopathological grade, or multifocality of primary tumor did not differ between patients with DQ2 or DQ8 and patients with other HLA-DQ haplotypes. No patient in the study was diagnosed with celiac disease (latent or symptomatic) as anti-tTG antibodies were negative in all 35. CONCLUSION HLA-DQ haplotypes associated with celiac disease are overrepresented also in patients with SI-NET, in particular HLA-DQ2.
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Affiliation(s)
- Kalle Landerholm
- Department of Surgery, Ryhov County Hospital, SE-551 85, Jönköping, Sweden,
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30
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Familial risk of small intestinal carcinoid and adenocarcinoma. Clin Gastroenterol Hepatol 2013; 11:944-9. [PMID: 23500615 DOI: 10.1016/j.cgh.2013.02.025] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Revised: 02/07/2013] [Accepted: 02/15/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Small intestinal cancer (SIC) is rare, and its etiology is poorly understood. We compared clusters of families with SICs of different histologic subtypes. METHODS By using the nationwide family cancer data sets of Sweden and Finland, we identified a cohort of 9964 first-degree relatives of 1799 patients with SIC, diagnosed from 1961 through 2009. Data were collected from time periods as long as 47 years (mean, 35.4 y), and cancer incidence was determined. Standardized incidence ratios (SIRs) were calculated and stratified by sex, age, time period, and cancer type, using the incidence rates for the entire national population as the reference. RESULTS Among the 1799 SIC cases, 1.1% had a sibling with SIC, so the SIR was 11.8 (95% confidence interval [CI], 7.2-18.2); 1.1% had a parent or child with SIC (SIR, 3.5; 95% CI, 2.0-5.6). The SIR of concordant carcinoid histology of SIC among siblings was 28.4 (95% CI, 14.7-49.6; n = 12) and in parent-child pairs was 9.9 (95% CI, 5.4-16.6; n = 14). The familial risk of concordant histologic subtypes increased for siblings diagnosed with adenocarcinoma, but only 2 familial cases were identified. In family members of patients with SIC of the adenocarcinoma subtype, risks of colorectal and bladder cancer were modestly but significantly increased compared with the general population. Family members of patients with SIC of the carcinoid subtype had an increased risk for kidney cancer and polycythemia vera. CONCLUSIONS Based on data from our population-based study, first-degree relatives of patients with small intestinal carcinoid tumors have developed these tumors with high incidence. Because of the rareness of this tumor, the absolute risk remains moderate even within families. Gastroenterologists could inform patients with small intestinal carcinoids about the familial risk and encourage counseling for their first-degree relatives. Studies are needed to identify genetic factors that affect susceptibility to SIC.
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31
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Taylor WSJ, Vaughan P, Trotter S, Rajesh PB. A Rare Association of Pulmonary Carcinoid, Lymphoma, and Sjögren Syndrome. Ann Thorac Surg 2013; 95:1086-7. [DOI: 10.1016/j.athoracsur.2012.06.051] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Revised: 05/22/2012] [Accepted: 06/25/2012] [Indexed: 02/07/2023]
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Kaasinen E, Aavikko M, Vahteristo P, Patama T, Li Y, Saarinen S, Kilpivaara O, Pitkänen E, Knekt P, Laaksonen M, Artama M, Lehtonen R, Aaltonen LA, Pukkala E. Nationwide registry-based analysis of cancer clustering detects strong familial occurrence of Kaposi sarcoma. PLoS One 2013; 8:e55209. [PMID: 23365693 PMCID: PMC3554690 DOI: 10.1371/journal.pone.0055209] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Accepted: 12/23/2012] [Indexed: 11/18/2022] Open
Abstract
Many cancer predisposition syndromes are rare or have incomplete penetrance, and traditional epidemiological tools are not well suited for their detection. Here we have used an approach that employs the entire population based data in the Finnish Cancer Registry (FCR) for analyzing familial aggregation of all types of cancer, in order to find evidence for previously unrecognized cancer susceptibility conditions. We performed a systematic clustering of 878,593 patients in FCR based on family name at birth, municipality of birth, and tumor type, diagnosed between years 1952 and 2011. We also estimated the familial occurrence of the tumor types using cluster score that reflects the proportion of patients belonging to the most significant clusters compared to all patients in Finland. The clustering effort identified 25,910 birth name-municipality based clusters representing 183 different tumor types characterized by topography and morphology. We produced information about familial occurrence of hundreds of tumor types, and many of the tumor types with high cluster score represented known cancer syndromes. Unexpectedly, Kaposi sarcoma (KS) also produced a very high score (cluster score 1.91, p-value <0.0001). We verified from population records that many of the KS patients forming the clusters were indeed close relatives, and identified one family with five affected individuals in two generations and several families with two first degree relatives. Our approach is unique in enabling systematic examination of a national epidemiological database to derive evidence of aberrant familial aggregation of all tumor types, both common and rare. It allowed effortless identification of families displaying features of both known as well as potentially novel cancer predisposition conditions, including striking familial aggregation of KS. Further work with high-throughput methods should elucidate the molecular basis of the potentially novel predisposition conditions found in this study.
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Affiliation(s)
- Eevi Kaasinen
- Genome-Scale Biology Research Program, and Department of Medical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Mervi Aavikko
- Genome-Scale Biology Research Program, and Department of Medical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Pia Vahteristo
- Genome-Scale Biology Research Program, and Department of Medical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Toni Patama
- Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland
| | - Yilong Li
- Genome-Scale Biology Research Program, and Department of Medical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Silva Saarinen
- Genome-Scale Biology Research Program, and Department of Medical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Outi Kilpivaara
- Genome-Scale Biology Research Program, and Department of Medical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Esa Pitkänen
- Genome-Scale Biology Research Program, and Department of Medical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Paul Knekt
- National Institute of Health and Welfare, Helsinki, Finland
| | | | - Miia Artama
- Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland
| | - Rainer Lehtonen
- Genome-Scale Biology Research Program, and Department of Medical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Lauri A. Aaltonen
- Genome-Scale Biology Research Program, and Department of Medical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Eero Pukkala
- Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland
- School of Health Sciences, University of Tampere, Tampere, Finland
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Abstract
UNLABELLED Identification of common molecular mechanisms is needed to facilitate the development of new treatment options for patients with ileal carcinoids. PURPOSE OF REVIEW Recent profiling studies on ileal carcinoids were examined to obtain a comprehensive view of risk factors, genetic aberrations, and transcriptional alterations. Special attention was paid to mechanisms that could provide novel targets for therapy. RESULTS Genome-wide association studies have shown that single nucleotide polymorphisms (SNPs) at IL12A and DAD1 are associated with an increased risk of ileal carcinoids. Genomic profiling revealed distinct patterns of copy-number alterations in ileal carcinoids. Two groups of carcinoids could be identified by hierarchical clustering. A major group of tumors was characterized by loss on chromosome 18 followed by additional losses on chromosomes 3p, 11q, and 13. Three minimal common regions of deletions were identified at 18q21.1-q21.31, 18q22.1-q22.2, and 18q22.3-q23. A minor group of tumors was characterized by clustered gains on chromosomes 4, 5, 7, 14, and 20. Expression profiling identified three groups of ileal carcinoids by principal component analysis. Tumor progression was associated with changes in gene expression including downregulation of MIR133A. Candidate genes for targeted therapy included ERBB2/HER2, DAD1, PRKCA, RYBP, CASP1, CASP4, CASP5, VMAT1, RET, APLP1, OR51E1, GPR112, SPOCK1, RUNX1, and MIR133A. CONCLUSION Profiling of ileal carcinoids has revealed recurrent genetic alterations and distinct patterns of gene expression. Frequent alterations in cellular pathways and genes were identified, suggesting novel targets for therapy. Translational studies are needed to validate suggested molecular targets.
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Affiliation(s)
- Ola Nilsson
- Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.
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Gao L, Lipka S, Hurtado-Cordovi J, Avezbakiyev B, Zuretti A, Rizvon K, Mustacchia P. Synchronous Duodenal Carcinoid and Adenocarcinoma of the Colon. World J Oncol 2012; 3:239-242. [PMID: 29147314 PMCID: PMC5649904 DOI: 10.4021/wjon554w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2012] [Indexed: 01/11/2023] Open
Abstract
Carcinoid tumors are a histological subtype of well differentiated, low to intermediate grade, slow-growing neuroendocrine malignancies capable of secreting bioactive peptides, such as 5-hydroxytryptamine (5-HT, serotonin), chromogranin-A and chromogranin-C. Here we present a case of a duodenal carcinoid that simultaneously occurred with adenocarcinoma of the colon. A 59-year-old male with a past medical history of hepatitis C and hypertension presented complaining of worsening abdominal pain associated with 2 - 3 episodes per week of bright red blood per rectum for the past month. He also reported a 20 pounds weight loss in the last 6 months. Social history was significant for a 15 pack year history. Vitals on admission were within normal limits. Physical exam was significant for right upper quadrant tenderness without guarding, rebound, or organomegaly. Rectal exam revealed no blood or masses. Laboratory results showed iron deficiency anemia with hemoglobin of 9.6 K/mm3. Esophagogastroduodenoscopy revealed a 4 mm duodenal polyp. Colonoscopy was terminated early secondary to a large circumferential obstructing mass found in the descending colon. Immunohistochemistry of the duodenal biopsy was positive for synaptophysin and chromogranin-A; consistent with the diagnosis of stage I carcinoid tumor. Biopsy results of the colonic mass showed a stage I well-differentiated adenocarcinoma. The patient underwent a left colectomy and partial duodenectomy; he remains in remission after 2 year of close follow up. When the diagnosis of small bowel carcinoid is made, further screening for other primary neoplasms should be sought to prevent potential late stage diagnosis of synchronous malignancies. This is crucial because patients’ demise usually result from the associate tumor and not the carcinoid component. Finally, we would like to raise clinician’s awareness regarding the incidence of this entity since some of the studies suggest that it is more common than it was previously thought.
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Affiliation(s)
- Limin Gao
- Department of Internal Medicine, Associated with North Shore- Long Island Jewish Health Care System, Nassau University Medical Center 2201 Hempstead Turnpike, East Meadow NY 11554, USA
| | - Seth Lipka
- Department of Internal Medicine, Associated with North Shore- Long Island Jewish Health Care System, Nassau University Medical Center 2201 Hempstead Turnpike, East Meadow NY 11554, USA
| | - Jorge Hurtado-Cordovi
- Department of Internal Medicine, Associated with North Shore- Long Island Jewish Health Care System, Nassau University Medical Center 2201 Hempstead Turnpike, East Meadow NY 11554, USA
| | - Boris Avezbakiyev
- Department of Internal Medicine, division of Hematology/Oncology, Associated with North Shore- Long Island Jewish Health Care System. Nassau University Medical Center 2201 Hempstead Turnpike, East Meadow NY 11554, USA
| | - Alejandro Zuretti
- Department of Pathology, Associated with North Shore- Long Island Jewish Health Care System, Nassau University Medical Center 2201 Hempstead Turnpike, East Meadow NY 11554, USA
| | - Kaleem Rizvon
- Department of Internal Medicine, division of Gastroenterology, Associated with North Shore- Long Island Jewish Health Care System, Nassau University Medical Center 2201 Hempstead Turnpike, East Meadow NY 11554, USA
| | - Paul Mustacchia
- Department of Internal Medicine, division of Gastroenterology, Associated with North Shore- Long Island Jewish Health Care System, Nassau University Medical Center 2201 Hempstead Turnpike, East Meadow NY 11554, USA
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Multifocal colorectal adenocarcinoma with a synchronous multifocal carcinoid of the small intestine--case report and literature review. POLISH JOURNAL OF SURGERY 2012; 83:562-7. [PMID: 22189284 DOI: 10.2478/v10035-011-0089-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
The paper presents a case report of coexisting multifocal colorectal cancer and multifocal carcinoid of the small intestine. Our literature review did not demonstrate any report of such case. We emphasize necessity of careful inspection of abdominal cavity during any surgical procedure since small lesions, in particular in the small intestine, may be omitted--as was the case during the initial colectomy in our case. Current epidemiological data are also presented and standards of management for diagnosis and treatment of gastrointestinal carcinoid.
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Teerlink CC, Albright FS, Lins L, Cannon-Albright LA. A comprehensive survey of cancer risks in extended families. Genet Med 2012; 14:107-14. [PMID: 22237439 DOI: 10.1038/gim.2011.2] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
PURPOSE Cancer is familial; yet known cancer predisposition genes, as well as recognized environmental factors, explain only a small percentage of familial cancer clusters. This population-based description of cancer clustering describes patterns of cancer coaggregation suggestive of a genetic predisposition. METHODS Using a computerized genealogy of Utah families linked to a statewide cancer registry, we estimated the relative risks for 36 different cancer sites in first-, second-, and third-degree relatives of cancer cases, for each cancer site individually, and between cancer sites. We estimated the sex- and birth-year-specific rates for cancer using 1 million individuals in the resource. We applied these rates to groups of cases or relatives and compared the observed and expected numbers of cancers to estimate relative risks. RESULTS Many cancer sites show significantly elevated relative risks among distant relatives for cancer of the same site, strongly supporting a heritable contribution. Multiple combinations of cancer sites were observed among first-, second-, and third-degree relatives, suggesting the existence of heritable syndromes involving more than one cancer site. CONCLUSION This complete description of coaggregation of cancer by site in a well-defined population provides a set of observations supporting heritable cancer predispositions and may support the existence of genetic factors for many different cancers.
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Affiliation(s)
- Craig C Teerlink
- Division of Genetic Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
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Ter-Minassian M, Wang Z, Asomaning K, Wu MC, Liu CY, Paulus JK, Liu G, Bradbury PA, Zhai R, Su L, Frauenhoffer CS, Hooshmand SM, De Vivo I, Lin X, Christiani DC, Kulke MH. Genetic associations with sporadic neuroendocrine tumor risk. Carcinogenesis 2011; 32:1216-22. [PMID: 21606320 PMCID: PMC3149206 DOI: 10.1093/carcin/bgr095] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2011] [Revised: 05/04/2011] [Accepted: 05/17/2011] [Indexed: 12/13/2022] Open
Abstract
Genetic risk factors for sporadic neuroendocrine tumors (NET) are poorly understood. We tested risk associations in patients with sporadic NET and non-cancer controls, using a custom array containing 1536 single-nucleotide polymorphisms (SNPs) in 355 candidate genes. We identified 18 SNPs associated with NET risk at a P-value <0.01 in a discovery set of 261 cases and 319 controls. Two of these SNPs were found to be significantly associated with NET risk in an independent replication set of 235 cases and 113 controls, at a P value ≤0.05. An SNP in interleukin 12A (IL12A rs2243123), a gene implicated in inflammatory response, replicated with an adjusted odds ratio (95% confidence interval) (aOR) = 1.47 (1.03, 2.11) P-trend = 0.04. A second SNP in defender against cell death, (DAD1 rs8005354), a gene that modulates apoptosis, replicated at aOR = 1.43 (1.02, 2.02) P-trend = 0.04. Consistent with our observations, a pathway analysis, performed in the discovery set, suggested that genetic variation in inflammatory pathways or apoptosis pathways is associated with NET risk. Our findings support further investigation of the potential role of IL12A and DAD1 in the etiology of NET.
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Affiliation(s)
- Monica Ter-Minassian
- Environmental and Occupational Medicine and Epidemiology Program, Department of Environmental Health, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA.
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Abstract
PURPOSE OF REVIEW Neuroendocrine tumors, particularly small intestinal tumors, also grouped as 'carcinoids', are defined by an increasing incidence and prevalence, a poor response to current therapies, and confusion regarding appropriate models for drug development. Despite these issues, approximately 350 studies were published in the last year. RECENT FINDINGS Two sources of confusion are clearly apparent. First, pharmacotherapeutic studies using pancreatic tumor cell lines as models for small intestinal or 'carcinoid' tumor biology are considered appropriate. Second, there is continued inclusion and analysis of pancreatic endocrine tumors with small intestinal neuroendocrine tumors in clinical studies. One highlight of this year is additional data confirming the significant differences between pancreatic tumor cell lines and small intestinal cell lines, the different gene expressions, for example, PAX8, between these two tumor types, and the observations that these two tumors respond differently in clinical trials, for example, to mammalian target of rapamycin (mTOR) inhibitors. Other highlights include delineating the role of the tumor microenvironment in the development of fibrosis and developing a minimum pathology dataset and a prognostic nomogram that may have utility in stratifying patients for clinical studies. SUMMARY A number of interesting studies have been published during 2009-2010, but critical areas remain that require resolution. Current data, for the most part, reflect amplification of previously held concepts with modest advances in novel information.
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39
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Schimmack S, Svejda B, Lawrence B, Kidd M, Modlin IM. The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors. Langenbecks Arch Surg 2011; 396:273-98. [DOI: 10.1007/s00423-011-0739-1] [Citation(s) in RCA: 112] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2011] [Accepted: 01/07/2011] [Indexed: 02/07/2023]
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40
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Abstract
Current treatment of endocrine cancers relies primarily on surgical resection, which is generally effective only for localized disease. Radioactive iodine treatment is an important modality for those thyroid cancers that maintain the ability to take up iodine. For endocrine cancers that are no longer localized, current modes of therapy, including various combinations of chemotherapy and radiation, are inadequate, posing a major challenge to ongoing research to develop more effective methods for diagnosis and treatment. In this article, we offer some predictions of future trends in the diagnosis and treatment of endocrine cancers. Following a general introduction, we focus on thyroid cancer as a paradigm for what we may expect in future developments, and then add selected comments relevant to parathyroid, adrenocortical, and gastrointestinal and pancreatic neuroendocrine tumors. Rapid, inexpensive whole genome sequencing of both germline and tumor DNA, novel molecular and functional imaging, as well as new biomarkers are expected to enable more precise diagnosis, targeted therapy, and possibly prevention. Translating the coming wave of data on the molecular pathogenesis of endocrine cancers into practical diagnostic and treatment modalities will require new forms of collaboration between investigators, clinicians, and industry.
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Affiliation(s)
- Allen M Spiegel
- Department of Medicine, and Montefiore-Einstein Center for Cancer Care, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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Scherübl H, Jensen RT, Cadiot G, Stölzel U, Klöppel G. Neuroendocrine tumors of the small bowels are on the rise: Early aspects and management. World J Gastrointest Endosc 2010; 2:325-34. [PMID: 21160582 PMCID: PMC2998818 DOI: 10.4253/wjge.v2.i10.325] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2010] [Revised: 08/02/2010] [Accepted: 08/09/2010] [Indexed: 02/05/2023] Open
Abstract
Neuroendocrine tumors of the small bowel are on the rise. In the US they have increased by 300%-500% in the last 35 years. At the same time their prognosis is much improved. Today, most neuroendocrine tumors (NETs) of the duodenum are detected "incidentally" and therefore recognized at an early stage. Duodenal NETs which are well differentiated, not larger than 10 mm and limited to the mucosa/submucosa can be endoscopically resected. The management of duodenal NETs ranging between 10 and 20 mm needs an interdisciplinary discussion. Endoscopic ultrasound is the method of choice to determine tumor size and depth of infiltration. Surgery is recommended for well-differentiated duodenal NET tumors greater than 20 mm, for localized sporadic gastrinomas (of any size) and for localized poorly differentiated NE cancers. Surgery is recommended for any ileal NET. Advanced ileal NETs with a carcinoid syndrome are treated with long-acting somatostatin analogs. This treatment significantly improves (progression-free) survival in patients with metastatic NETs of the ileum. For optimal NET management, tumor biology, type, localization and stage of the neoplasm, as well as the patient's individual circumstances have to be taken into account.
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Affiliation(s)
- Hans Scherübl
- Hans Scherübl, Departments of Gastroenterology and Gastrointestinal Oncology, Vivantes Klinikum Am Urban, Berlin 10967, Germany
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Boudreaux JP, Klimstra DS, Hassan MM, Woltering EA, Jensen RT, Goldsmith SJ, Nutting C, Bushnell DL, Caplin ME, Yao JC. The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the Jejunum, Ileum, Appendix, and Cecum. Pancreas 2010; 39:753-766. [PMID: 20664473 DOI: 10.1097/mpa.0b013e3181ebb2a5] [Citation(s) in RCA: 373] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Well-differentiated neuroendocrine tumors (NETs) of the jejunum, ileum, and appendix are also collectively known as midgut carcinoids. Similar to NETs in general, the diagnosed incidence of the midgut NETs is on the rise. Their presenting symptoms vary depending on stage and primary site. Local-regional NETs often present with vague and nonspecific symptoms. Classic carcinoid syndrome is more likely to appear in patients with advanced disease. Local-regional NETs of the small bowel should be resected whenever possible. With the exception of small well-differentiated NETs of the appendix, NETs of the midgut have substantial risk of relapse after resection and need to be followed for at least 7 years.Metastatic/advanced NETs of the midgut are incurable. Optimal management requires a multidisciplinary approach. Somatostatin analogs are effective in the management of carcinoid syndrome. Octreotide long-acting release has also recently been shown to delay disease progression. Liver-directed therapy and surgical debulking can improve quality of life in selected patients. Pivotal phase 3 studies with bevacizumab targeting vascular endothelial growth factor and everolimus targeting mTOR (mammalian target of rapamycin) are ongoing and may lead to improved outcome. Further studies of novel approaches such as peptide receptor radiotherapy are also warranted.
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Affiliation(s)
- J Philip Boudreaux
- Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, LA, USA
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Coexistence of tumorlet and marginal zone B-cell lymphoma in the lung. Pathol Res Pract 2010; 206:508-10. [DOI: 10.1016/j.prp.2010.01.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2009] [Revised: 01/06/2010] [Accepted: 01/19/2010] [Indexed: 11/20/2022]
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