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Gastrointestinal Neuroendocrine Tumors: Pancreatic Endocrine Tumors

2008; Elsevier BV; Volume: 135; Issue: 5 Linguagem: Inglês

10.1053/j.gastro.2008.05.047

ISSN

1528-0012

Autores

David C. Metz, Robert T. Jensen,

Tópico(s)

Lung Cancer Research Studies

Resumo

Pancreatic endocrine tumors (PETs) have long fascinated clinicians and investigators despite their relative rarity. Their clinical presentation varies depending on whether the tumor is functional or not, and also according to the specific hormonal syndrome produced. Tumors may be sporadic or inherited, but little is known about their molecular pathology, especially the sporadic forms. Chromogranin A appears to be the most useful serum marker for diagnosis, staging, and monitoring. Initially, therapy should be directed at the hormonal syndrome because this has the major initial impact on the patient's health. Most PETs are relatively indolent but ultimately malignant, except for insulinomas, which predominantly are benign. Surgery is the only modality that offers the possibility of cure, although it generally is noncurative in patients with Zollinger–Ellison syndrome or nonfunctional PETs with multiple endocrine neoplasia-type 1. Preoperative staging of disease extent is necessary to determine the likelihood of complete resection although debulking surgery often is believed to be useful in patients with unresectable tumors. Once metastatic, biotherapy is usually the first modality used because it generally is well tolerated. Systemic or regional therapies generally are reserved until symptoms occur or tumor growth is rapid. Recently, a number of newer agents, as well as receptor-directed radiotherapy, are being evaluated for patients with advanced disease. This review addresses a number of recent advances regarding the molecular pathology, diagnosis, localization, and management of PETs including discussion of peptide-receptor radionuclide therapy and other novel antitumor approaches. We conclude with a discussion of future directions and unsettled problems in the field. Pancreatic endocrine tumors (PETs) have long fascinated clinicians and investigators despite their relative rarity. Their clinical presentation varies depending on whether the tumor is functional or not, and also according to the specific hormonal syndrome produced. Tumors may be sporadic or inherited, but little is known about their molecular pathology, especially the sporadic forms. Chromogranin A appears to be the most useful serum marker for diagnosis, staging, and monitoring. Initially, therapy should be directed at the hormonal syndrome because this has the major initial impact on the patient's health. Most PETs are relatively indolent but ultimately malignant, except for insulinomas, which predominantly are benign. Surgery is the only modality that offers the possibility of cure, although it generally is noncurative in patients with Zollinger–Ellison syndrome or nonfunctional PETs with multiple endocrine neoplasia-type 1. Preoperative staging of disease extent is necessary to determine the likelihood of complete resection although debulking surgery often is believed to be useful in patients with unresectable tumors. Once metastatic, biotherapy is usually the first modality used because it generally is well tolerated. Systemic or regional therapies generally are reserved until symptoms occur or tumor growth is rapid. Recently, a number of newer agents, as well as receptor-directed radiotherapy, are being evaluated for patients with advanced disease. This review addresses a number of recent advances regarding the molecular pathology, diagnosis, localization, and management of PETs including discussion of peptide-receptor radionuclide therapy and other novel antitumor approaches. We conclude with a discussion of future directions and unsettled problems in the field. See Yamagami et al on page 1202 in CGH. See Yamagami et al on page 1202 in CGH. Pancreatic endocrine tumors (PETs) have long fascinated clinicians and investigators because of their unusual and florid symptoms as well as the insights they provide into the actions of gastrointestinal (GI) hormones. PETs share many pathologic and biological features with GI carcinoids, but they have important differences that affect treatment, in addition to having a different pathogenesis,1Duerr E.M. Chung D.C. Molecular genetics of neuroendocrine tumors.Best Pract Res Clin Endocrinol Metab. 2007; 21: 1-14Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 2Corleto V.D. Delle Fave G. Jensen R.T. Molecular insights into gastrointestinal neuroendocrine tumors: importance and recent advances.Dig Liver Dis. 2002; 34: 668-680Abstract Full Text PDF PubMed Scopus (33) Google Scholar and thus the 2 groups of GI neuroendocrine tumors (NETs) are best considered separately. There have been a number of recent advances in various aspects of PETs including diagnosis, management, insights into molecular changes, tumor localization, and the treatment of advanced disease. This article briefly reviews a number of these advances as well as their current management. This article does not cover all aspects of PETs because many features recently have been covered in reviews or consensus conferences.3Arnold R. Endocrine tumors of the gastrointestinal tract: part 11.Best Practice Res Clin Gastroent. 2005; 19: 659-830Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 4Arnold R. Endocrine tumors of the gastrointestinal tract: part 1.Best Practice Res Clin Gastroent. 2005; 19: 489-656Abstract Full Text Full Text PDF Google Scholar, 5Oberg K. Eriksson B.E. Neuroendocrine tumors.Best Pract Res Clin Endocrinol Metab. 2007; 21: 1-172Abstract Full Text Full Text PDF PubMed Google Scholar, 6de Herder W.W. O'Toole D. Rindi G. et al.ENETS consensus guidelines for the management of patients with digestive neuroendocrine tumors part 1-stomach, duodenum and pancreas.Neuroendocrinology. 2006; 84: 151-216Crossref Scopus (80) Google Scholar, 7Plockinger U. Rindi G. Arnold R. et al.Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS).Neuroendocrinology. 2004; 80: 394-424Crossref PubMed Scopus (278) Google Scholar PETs occur in 0.5%–1.5% of autopsies but are functional or symptomatic in less than 1 in 1000, resulting in a clinical detection rate of 1:100,000 population, which comprises 1%–2% of pancreatic neoplasms.8Oberg K. Eriksson B. Endocrine tumours of the pancreas.Best Pract Res Clin Gastroenterol. 2005; 19: 753-781Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar In older studies, nonfunctional PETs (NF-PETs), insulinomas, and gastrinomas had equal frequency;9Jensen R.T. Endocrine neoplasms of the pancreas.in: Yamada T. Alpers D.H. Kaplowitz N. Textbook of gastroenterology. 5th ed. Blackwell, Oxford2008Crossref Scopus (5) Google Scholar however, in recent studies NF-PETs were twice as frequent.10Ito T. Tanaka M. Sasano H. et al.Preliminary results of a Japanese nationwide survey of neuroendocrine gastrointestinal tumors.J Gastroenterol. 2007; 42: 497-500Crossref PubMed Scopus (53) Google Scholar, 11Panzuto F. Nasoni S. Falconi M. et al.Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization.Endocr Relat Cancer. 2005; 12: 1083-1092Crossref PubMed Scopus (205) Google Scholar The relative frequency of PETs varies in surgical or medical series, but most studies suggest a relative order of: NF-PET > insulinoma > gastrinoma > glucagonoma > VIPomas somatostatinomas > others.9Jensen R.T. Endocrine neoplasms of the pancreas.in: Yamada T. Alpers D.H. Kaplowitz N. Textbook of gastroenterology. 5th ed. Blackwell, Oxford2008Crossref Scopus (5) Google Scholar, 11Panzuto F. Nasoni S. Falconi M. et al.Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization.Endocr Relat Cancer. 2005; 12: 1083-1092Crossref PubMed Scopus (205) Google Scholar Four inherited disorders have an increased incidence of PETs: multiple endocrine neoplasia-type 1 (MEN1), von Hippel–Lindau disease, von Recklinghausen's disease (neurofibromatosis 1), and tuberous sclerosis.12Alexakis N. Connor S. Ghaneh P. et al.Hereditary pancreatic endocrine tumours.Pancreatology. 2004; 4: 417-435Abstract Full Text PDF PubMed Scopus (33) Google Scholar, 13Jensen R.T. Berna M.J. Bingham M.D. et al.Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management and controversies.Cancer. 2008; (in press)PubMed Google Scholar The most important is MEN1 because 80%–100% of these patients develop NF-PETs, 50%–60% develop gastrinomas, 20% develop insulinomas, and 3%–5% develop vasoactive intestinal polypeptide secreting tumor (VIPomas) or glucagonomas with the result that 20%–25% of all gastrinomas and 4% of insulinomas are caused by this syndrome.12Alexakis N. Connor S. Ghaneh P. et al.Hereditary pancreatic endocrine tumours.Pancreatology. 2004; 4: 417-435Abstract Full Text PDF PubMed Scopus (33) Google Scholar, 13Jensen R.T. Berna M.J. Bingham M.D. et al.Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management and controversies.Cancer. 2008; (in press)PubMed Google Scholar PETs (primarily NF-PETs) develop in 10%–17% of von Hippel–Lindau disease patients, in 0% to 10% of neurofibromatosis 1 patients (primarily duodenal somatostatinomas), and in less than 1% of tuberous sclerosis patients (primarily NF-PETs).12Alexakis N. Connor S. Ghaneh P. et al.Hereditary pancreatic endocrine tumours.Pancreatology. 2004; 4: 417-435Abstract Full Text PDF PubMed Scopus (33) Google Scholar, 13Jensen R.T. Berna M.J. Bingham M.D. et al.Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management and controversies.Cancer. 2008; (in press)PubMed Google Scholar PETs are divided clinically into 2 groups: functional and NF-PETs. Functional PETs secrete biologically active peptides causing 1 of 9 well-established syndromes (Table 1). NF-PETs are not associated with a specific hormonal syndrome either because no peptide is secreted or the substance secreted does not cause specific symptoms. Most (>70%) NF-PETs are not truly nonfunctional because they secrete substances such as pancreatic polypeptide, other peptides (neurotensin, ghrelin, and so forth), neuron-specific enolase, chromogranins, or human chorionic-gonadotropin subunits, each of which does not cause specific symptoms9Jensen R.T. Endocrine neoplasms of the pancreas.in: Yamada T. Alpers D.H. Kaplowitz N. Textbook of gastroenterology. 5th ed. Blackwell, Oxford2008Crossref Scopus (5) Google Scholar, 14Kloppel G. Tumour biology and histopathology of neuroendocrine tumours.Best Pract Res Clin Endocrinol Metab. 2007; 21: 15-31Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar (Table 1). In addition to the well-established PET syndromes (Table 1), small numbers of patients are described with PETs producing other biologically active substances and new syndromes have been proposed, although in most cases too few patients have been described to clearly establish this point or its spectrum. GI tumors have been described secreting luteinizing-hormone causing masculinization,15Brignardello E. Manti R. Papotti M. et al.Ectopic secretion of LH by an endocrine pancreatic tumor.J Endocrinol Invest. 2004; 27: 361-365Crossref PubMed Google Scholar secreting renin causing erythrocytosis,16Samyn I. Fontaine C. Van Tussenbroek F. et al.Paraneoplastic syndromes in cancer: case 1 Polycythemia as a result of ectopic erythropoietin production in metastatic pancreatic carcinoid tumor.J Clin Oncol. 2004; 22: 2240-2242Crossref PubMed Scopus (10) Google Scholar and secreting PYY causing constipation (primarily ovarian tumors).17Kawano K. Ushijima K. Fujimoto T. et al.Peptide YY producing strumal carcinoid of the ovary as the cause of severe constipation with contralateral epithelial ovarian cancer.J Obstet Gynaecol Res. 2007; 33: 392-396Crossref PubMed Scopus (8) Google ScholarTable 1Pancreatic Endocrine Tumor SyndromesName of tumor (syndrome)Hormone causing syndromeSigns or symptomsPrimary locationMalignant (%)Gastrinoma (Zollinger–Ellison syndrome)GastrinAbdominal painDiarrheaPancreas: 60%Duodenum: 30%60–90 Esophageal symptomsOther: 10%InsulinomaInsulinHypoglycemic symptomsPancreas: 99%–100%5–15GlucagonomaGlucagonRash, anemiaPancreas: 99%–100%60 Diabetes/glucose intolerance Weight loss Thromboembolic diseaseVIPoma (Verner–Morrison, pancreatic cholera, WDHA)VIPSevere watery diarrheaHypokalemiaPancreas: 90%Other: 10% (neural, adrenal, peri-ganglionic tissue)80SomatostatinomaSomatostatinDiabetes mellitusPancreas: 56%60 CholelithiasesDuodenum/jejunum: 44% Diarrhea SteatorrheaGRFomaGrowth hormone releasing factorAcromegalyPancreas: 30%Lung: 54%30Jejunum: 7%Other: 13% (adrenal foregut, retro-peritoneum)ACTHoma (Cushing's syndrome)ACTHCushing's syndromePancreas: 4%–16% all ectopic Cushing's>90PET causing the carcinoid syndrome (carcinoid syndrome)Serotonin tachykinins prostaglandinsDiarrheaFlushingPancreas: 100%68–88PET causing hypercalcemiaPTH-RPSymptoms due to increased calciumPancreas: 100%80–90Nonfunctioning (PPoma, nonfunctional)None (PP, CgA, NSE, and so forthaNo symptoms were caused by product hypersecretion; other peptides not causing symptoms include ghrelin, neurotensin, calcitonin, subunits of human chorionic gonadotropin, and so forth.)Weight loss, hepatomegalyAbdominal massOccasionally asymptomaticPancreas: 100%60–90ACTH, adrenocorticotropic hormone; CgA, chromogranin A; PTH-RP, parathormone-related peptide; NSE, neuron-specific enolase; PPoma, pancreatic polypeptide; WDHA, watery diarrhea, hypokalemia, achlorhydria.a No symptoms were caused by product hypersecretion; other peptides not causing symptoms include ghrelin, neurotensin, calcitonin, subunits of human chorionic gonadotropin, and so forth. Open table in a new tab ACTH, adrenocorticotropic hormone; CgA, chromogranin A; PTH-RP, parathormone-related peptide; NSE, neuron-specific enolase; PPoma, pancreatic polypeptide; WDHA, watery diarrhea, hypokalemia, achlorhydria. PETs share pathologic features with carcinoids: both are considered to arise from the diffuse neuroendocrine cell system; uncommonly show mitotic figures; commonly show electron-dense granules containing various peptides, chromogranins, neuron-specific enolase, and synaptophysin; and they have many similarities in biological behavior.14Kloppel G. Tumour biology and histopathology of neuroendocrine tumours.Best Pract Res Clin Endocrinol Metab. 2007; 21: 15-31Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 18Kloppel G. Anlauf M. Epidemiology, tumour biology and histopathological classification of neuroendocrine tumours of the gastrointestinal tract.Best Pract Res Clin Gastroenterol. 2005; 19: 507-517Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar The latter properties, particularly the presence of chromogranin, are widely used to identify GI NETs.14Kloppel G. Tumour biology and histopathology of neuroendocrine tumours.Best Pract Res Clin Endocrinol Metab. 2007; 21: 15-31Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 18Kloppel G. Anlauf M. Epidemiology, tumour biology and histopathological classification of neuroendocrine tumours of the gastrointestinal tract.Best Pract Res Clin Gastroenterol. 2005; 19: 507-517Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Both functional and NF-PETs frequently (>50%) synthesize more than one peptide.14Kloppel G. Tumour biology and histopathology of neuroendocrine tumours.Best Pract Res Clin Endocrinol Metab. 2007; 21: 15-31Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 18Kloppel G. Anlauf M. Epidemiology, tumour biology and histopathological classification of neuroendocrine tumours of the gastrointestinal tract.Best Pract Res Clin Gastroenterol. 2005; 19: 507-517Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar However, in most cases, these multiple peptides are not associated with specific syndromes. For this reason the diagnosis of a functional syndrome (Table 1) depends not on immunocytochemistry, but is diagnosed clinically.9Jensen R.T. Endocrine neoplasms of the pancreas.in: Yamada T. Alpers D.H. Kaplowitz N. Textbook of gastroenterology. 5th ed. Blackwell, Oxford2008Crossref Scopus (5) Google Scholar, 14Kloppel G. Tumour biology and histopathology of neuroendocrine tumours.Best Pract Res Clin Endocrinol Metab. 2007; 21: 15-31Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 18Kloppel G. Anlauf M. Epidemiology, tumour biology and histopathological classification of neuroendocrine tumours of the gastrointestinal tract.Best Pract Res Clin Gastroenterol. 2005; 19: 507-517Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar A recent standard World Health Organization classification has proposed GI NETs be assigned to 1 of 3 categories (well-differentiated tumor, well-differentiated carcinoma, and poorly differentiated carcinoma) based on histology, size, and proliferative indices.14Kloppel G. Tumour biology and histopathology of neuroendocrine tumours.Best Pract Res Clin Endocrinol Metab. 2007; 21: 15-31Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar In general, histologic classifications of PETs have failed to predict growth patterns for a given tumor. However, this classification will allow a more standardized comparison of results of different studies. A TNM classification for PETs also has been proposed19Rindi G. Kloppel G. Alhman H. et al.TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system.Virchows Arch. 2006; 449: 395-401Crossref PubMed Scopus (670) Google Scholar that is based on the World Health Organization classification of GI NETs and that may provide a more standardized assessment of patients and have important prognostic clinical value. Little is known about the molecular pathogenesis of PETs.1Duerr E.M. Chung D.C. Molecular genetics of neuroendocrine tumors.Best Pract Res Clin Endocrinol Metab. 2007; 21: 1-14Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 2Corleto V.D. Delle Fave G. Jensen R.T. Molecular insights into gastrointestinal neuroendocrine tumors: importance and recent advances.Dig Liver Dis. 2002; 34: 668-680Abstract Full Text PDF PubMed Scopus (33) Google Scholar, 8Oberg K. Eriksson B. Endocrine tumours of the pancreas.Best Pract Res Clin Gastroenterol. 2005; 19: 753-781Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar This has occurred in part because alterations in common oncogenes (fos, jun, myc, k-ras, and so forth) or common tumor-suppressor genes (p53, retinoblastoma, and so forth) are not generally implicated in their pathogenesis.1Duerr E.M. Chung D.C. Molecular genetics of neuroendocrine tumors.Best Pract Res Clin Endocrinol Metab. 2007; 21: 1-14Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 2Corleto V.D. Delle Fave G. Jensen R.T. Molecular insights into gastrointestinal neuroendocrine tumors: importance and recent advances.Dig Liver Dis. 2002; 34: 668-680Abstract Full Text PDF PubMed Scopus (33) Google Scholar, 8Oberg K. Eriksson B. Endocrine tumours of the pancreas.Best Pract Res Clin Gastroenterol. 2005; 19: 753-781Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar Some of the most important insights have come from studies of inherited PET syndromes.1Duerr E.M. Chung D.C. Molecular genetics of neuroendocrine tumors.Best Pract Res Clin Endocrinol Metab. 2007; 21: 1-14Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 2Corleto V.D. Delle Fave G. Jensen R.T. Molecular insights into gastrointestinal neuroendocrine tumors: importance and recent advances.Dig Liver Dis. 2002; 34: 668-680Abstract Full Text PDF PubMed Scopus (33) Google Scholar, 8Oberg K. Eriksson B. Endocrine tumours of the pancreas.Best Pract Res Clin Gastroenterol. 2005; 19: 753-781Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 20Rindi G. Bordi C. Aetiology, molecular pathogenesis and genetics.Best Pract Res Clin Gastroenterol. 2005; 19: 519-534Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Altered genes causing these syndromes are important in some cases of sporadic PETs (ie, nonfamilial cases).1Duerr E.M. Chung D.C. Molecular genetics of neuroendocrine tumors.Best Pract Res Clin Endocrinol Metab. 2007; 21: 1-14Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 2Corleto V.D. Delle Fave G. Jensen R.T. Molecular insights into gastrointestinal neuroendocrine tumors: importance and recent advances.Dig Liver Dis. 2002; 34: 668-680Abstract Full Text PDF PubMed Scopus (33) Google Scholar, 8Oberg K. Eriksson B. Endocrine tumours of the pancreas.Best Pract Res Clin Gastroenterol. 2005; 19: 753-781Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 20Rindi G. Bordi C. Aetiology, molecular pathogenesis and genetics.Best Pract Res Clin Gastroenterol. 2005; 19: 519-534Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar MEN1 is caused by mutations in the MEN1 gene on chromosome 11q13, which encodes for a 610 amino acid protein, menin, a nuclear protein that binds to numerous transcription factors.13Jensen R.T. Berna M.J. Bingham M.D. et al.Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management and controversies.Cancer. 2008; (in press)PubMed Google Scholar, 21Chandrasekharappa S.C. Guru S.C. Manickam P. et al.Positional cloning of the gene for multiple endocrine neoplasia—-type 1.Science. 1997; 276: 404-407Crossref PubMed Scopus (1264) Google Scholar, 22Busygina V. Bale A.E. Multiple endocrine neoplasia type 1 (MEN1) as a cancer predisposition syndrome: clues into the mechanisms of MEN1-related carcinogenesis.Yale J Biol Med. 2006; 79: 105-114PubMed Google Scholar However, the exact mechanism leading to the development of PETs still remains unclear. Sporadic PETs show an acquired loss of heterozygosity at this locus in 20%–90%, and 27%–39% have a mutation.1Duerr E.M. Chung D.C. Molecular genetics of neuroendocrine tumors.Best Pract Res Clin Endocrinol Metab. 2007; 21: 1-14Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 2Corleto V.D. Delle Fave G. Jensen R.T. Molecular insights into gastrointestinal neuroendocrine tumors: importance and recent advances.Dig Liver Dis. 2002; 34: 668-680Abstract Full Text PDF PubMed Scopus (33) Google Scholar, 8Oberg K. Eriksson B. Endocrine tumours of the pancreas.Best Pract Res Clin Gastroenterol. 2005; 19: 753-781Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 23Goebel S.U. Heppner C. Burns A.D. et al.Genotype/phenotype correlations of MEN1 gene mutations in sporadic gastrinoma.J Clin Endocrinol Metab. 2000; 85: 116-123Crossref PubMed Scopus (75) Google Scholar, 24Debelenko L.V. Zhuang Z.P. Emmert-Buck M.R. et al.Allelic deletions on chromosome 11q13 in multiple endocrine neoplasia type-I-associated sporadic gastrinomas and pancreatic endocrine tumors.Cancer Res. 1997; 57: 2238-2243PubMed Google Scholar In addition, recent studies have shown alterations in the p16/MTS1 tumor-suppressor gene, the DP64/SMAD4 gene, amplification of the HER-2/neu proto-oncogene, and loss of an unknown tumor-suppressor gene on chromosome 1 or 3p also could be important in the molecular pathogenesis of PETs.1Duerr E.M. Chung D.C. Molecular genetics of neuroendocrine tumors.Best Pract Res Clin Endocrinol Metab. 2007; 21: 1-14Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 2Corleto V.D. Delle Fave G. Jensen R.T. Molecular insights into gastrointestinal neuroendocrine tumors: importance and recent advances.Dig Liver Dis. 2002; 34: 668-680Abstract Full Text PDF PubMed Scopus (33) Google Scholar, 8Oberg K. Eriksson B. Endocrine tumours of the pancreas.Best Pract Res Clin Gastroenterol. 2005; 19: 753-781Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 20Rindi G. Bordi C. Aetiology, molecular pathogenesis and genetics.Best Pract Res Clin Gastroenterol. 2005; 19: 519-534Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Genome-wide allelotyping and comparative genomic hybridization show that chromosomal gains (especially 7q, 17q, 17p, and 20q) and losses (especially 1p, 3p, 3, 6p, 22q) frequently occur in PETs and carcinoids; however, their frequency varies markedly in these 2 GI NETs, providing evidence that they have a different pathogenesis.1Duerr E.M. Chung D.C. Molecular genetics of neuroendocrine tumors.Best Pract Res Clin Endocrinol Metab. 2007; 21: 1-14Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 2Corleto V.D. Delle Fave G. Jensen R.T. Molecular insights into gastrointestinal neuroendocrine tumors: importance and recent advances.Dig Liver Dis. 2002; 34: 668-680Abstract Full Text PDF PubMed Scopus (33) Google Scholar, 8Oberg K. Eriksson B. Endocrine tumours of the pancreas.Best Pract Res Clin Gastroenterol. 2005; 19: 753-781Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 20Rindi G. Bordi C. Aetiology, molecular pathogenesis and genetics.Best Pract Res Clin Gastroenterol. 2005; 19: 519-534Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 25Perren A. Komminoth P. Heitz P.U. Molecular genetics of gastroenteropancreatic endocrine tumors.Ann N Y Acad Sci. 2004; 1014: 199-208Crossref PubMed Scopus (22) Google Scholar Gene expression profiling using microarray analysis recently has identified in PETs numerous additional altered genes.26Capurso G. Lattimore S. Crnogorac-Jurcevic T. et al.Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets.Endocr Relat Cancer. 2006; 13: 541-558Crossref PubMed Scopus (61) Google Scholar, 27Dilley W.G. Kalyanaraman S. Verma S. et al.Global gene expression in neuroendocrine tumors from patients with the MEN1 syndrome.Mol Cancer. 2005; 4: 9Crossref PubMed Scopus (37) Google Scholar, 28Hansel D.E. Rahman A. House M. et al.Met proto-oncogene and insulin-like growth factor binding protein 3 overexpression correlates with metastatic ability in well-differentiated pancreatic endocrine neoplasms.Clin Cancer Res. 2004; 10: 6152-6158Crossref PubMed Scopus (73) Google Scholar, 29Maitra A. Hansel D.E. Argani P. et al.Global expression analysis of well-differentiated pancreatic endocrine neoplasms using oligonucleotide microarrays.Clin Cancer Res. 2003; 9: 5988-5995PubMed Google Scholar In comparison with normal islets in one study,29Maitra A. Hansel D.E. Argani P. et al.Global expression analysis of well-differentiated pancreatic endocrine neoplasms using oligonucleotide microarrays.Clin Cancer Res. 2003; 9: 5988-5995PubMed Google Scholar 66 genes were overexpressed (particularly genes for some growth factors [IFGFBP3], cell migration/adhesion molecules [fibronectin], and putative oncogenes [MLLT 10/AF10]), and 119 were underexpressed (particularly genes involved in cell-cycle regulation [p21cip1], transcription factors [JunD], and a putative metastasis suppressor gene [NME3]). In a second study,26Capurso G. Lattimore S. Crnogorac-Jurcevic T. et al.Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets.Endocr Relat Cancer. 2006; 13: 541-558Crossref PubMed Scopus (61) Google Scholar when gene expression patterns in NF-PETs were compared with normal islets and 3 neuroendocrine tumor cell lines, 667 genes were up-regulated (particularly SERPINA10, BIN1, LCK, and BST2) and 323 were down-regulated. At present, a clear concordance among studies is still lacking, but this approach is leading to the identification of numerous new candidate genes that may prove important in the pathogenesis of PETs or in determining growth behavior, which may have prognostic implications. PETs differ in their malignant potential and location (Table 1). Some PETs (insulinomas, glucagonomas, and VIPomas in adults) are found almost entirely within the pancreas, whereas others, although still referred to as PETs, actually occur in extrapancreatic locations (duodenal gastrinomas [60%–80%],30Hoffmann K.M. Furukawa M. Jensen R.T. Duodenal neuroendocrine tumors: classification, functional syndromes, diagnosis and medical treatment.Best Pract Res Clin Gastroenterol. 2005; 19: 675-697Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 31Jensen R.T. Niederle B. Mitry E. et al.Gastrinoma (duodenal and pancreatic).Neuroendocrinology. 2006; 84: 173-182Crossref PubMed Scopus (113) Google Scholar, 32Thom A.K. Norton J.A. Axiotis C.A. et al.Location, incidence and malignant potential of duodenal gastrinomas.Surgery. 1991; 110: 1086-1093PubMed Google Scholar small intestinal somatostatinomas [40%–50%], and growth hormone-releasing factor secreting tumor (GRFomas) primarily in the lung [>70%]) (Table 1). Insulinomas are malignant in 5%–15%, whereas the other PETs are malignant in 50%–90%, with metastases usually developing initially in regional lymph nodes, later in the liver, and subsequently in distant sites such as bone.6de Herder W.W. O'Toole D. Rindi G. et al.ENETS consensus guidelines for the management of patients with digestive neuroendocrine tumors part 1-stomach, duodenum and pancreas.Neuroendocrinology. 2006; 84: 151-216Crossref Scopus (80) Google Scholar, 8Oberg K. Eriksson B. Endocrine tumours of the pancreas.Best Pract Res Clin Gastroenterol. 2005; 19: 753-781Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 14Kloppel G. Tumour biology and histopathology of neuroendocrine tumours.Best Pract Res Clin Endocrinol Metab. 2007; 21: 15-31Abstract Full Text

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