Skip to main content

Advertisement

SpringerLink
Log in

Historical, current and future perspectives on gastrointestinal and pancreatic endocrine tumors

  • Review Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Gastrointestinal and pancreatic endocrine tumors are neoplasms of which the pathogenesis is not completely understood and of which the clinical behavior is difficult to predict. Originally, Masson suggested that the cell of origin was an endocrine cell derived from the gastrointestinal epithelium. However, Pearse showed that the endocrine cells throughout the body shared various features, among others the amine precursor uptake and decarboxylation (APUD) capacity, and postulated the neural crest as the common origin for all APUD cells, a hypothesis that received support from the scientific community for many years. Now, biologists start to elucidate the various transcription factors that drive gastrointestinal development, and it has become evident that Masson was presumably right. Transcription factors relevant for development may also operate during tumorigenesis, and their expression may determine tumor biology. With other genetic factors, they may play a role in the pathogenesis of gastrointestinal and pancreatic endocrine tumors, and perhaps, their expression will turn out to be of prognostic or therapeutic value. In this review, current knowledge on the development of endocrine cells, hypotheses on the origin of endocrine tumors, genetic alterations, and prognostic factors are discussed. It is suggested that the increasing understanding of the normal development of gastrointestinal and pancreatic endocrine cells, the accumulating data on genetic alterations in endocrine tumors and the reappraisal of the hypotheses on their pathogenesis formulated in the past may help in elucidating their pathogenesis and in more accurately predicting prognosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Ahlgren U, Jonsson J, Edlund H (1996) The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice. Development 122:1409–1416

    PubMed  CAS  Google Scholar 

  2. Apelqvist Å, Li H, Sommer L, Beatus P, Anderson DJ, Honjo T, Hrabe de Angelis M, Lendahl U, Edlund H (1999) Notch signalling controls pancreatic cell differentiation. Nature 400:877–881

    Article  PubMed  CAS  Google Scholar 

  3. Barbareschi M, Roldo C, Zamboni G, Capelli P, Cavazza A, Macri E, Cangi MG, Chilosi M, Doglioni C (2004) CDX-2 homeobox gene product expression in neuroendocrine tumors. Its role as a marker of intestinal neuroendocrine tumors. Am J Surg Pathol 28(9):1169–1176

    Article  PubMed  Google Scholar 

  4. Barghorn A, Komminoth P, Bachmann D, Rutimann K, Saremaslani P, Muletta-Feurer S, Perren A, Roth J, Heitz PU, Speel EJ (2001) Deletion at 3p25.3-p23 is frequently encountered in endocrine pancreatic tumours and is associated with metastatic progression. J Pathol 194:451–548

    Article  PubMed  CAS  Google Scholar 

  5. Barghorn A, Speel EJM, Farspour B, Saremaslani P, Schmid S, Perren A, Roth J, Heitz PU, Komminoth P (2001) Putative tumor suppressor loci at 6q22 and 6q23-q24 are involved in the malignant progression of sporadic endocrine pancreatic tumors. Am J Pathol 158:1903–1911

    PubMed  CAS  Google Scholar 

  6. Beck F (2002) Homeobox genes in gut development. Gut 51:450–454

    Article  PubMed  CAS  Google Scholar 

  7. Beghelli S, Pelosi G, Zamboni G, Falconi M, Iacono C, Bordi C, Scarpa A (1998) Pancreatic endocrine tumours: evidence for a tumour suppressor pathogenesis and for a tumour suppressor gene on chromosome 17p. J Pathol 186:41–50

    Article  PubMed  CAS  Google Scholar 

  8. Bordi C, D'Adda T, Pizzi S, Crafa P, Rindi G (2002) The assessment of malignancy in endocrine tumours of the gastrointestinal tract. Curr Diagn Pathol 8:421–429

    Article  Google Scholar 

  9. Bouwens L, Lu WG, de Krijger RR (1997) Proliferation and differentiation in the human fetal endocrine pancreas. Diabetologia 40:398–404

    Article  PubMed  CAS  Google Scholar 

  10. Capella C, La Rosa S, Solcia E (1997) Criteria for malignancy in pancreatic endocrine tumors. Endocr Pathol 8:87–90

    Article  Google Scholar 

  11. Chakrabarti R, Srivatsan ES, Wood TF, Eubanks PJ, Ebrahimi SA, Gatti RA, Passaro E Jr, Sawicki MP (1998) Deletion mapping of endocrine tumors localizes a second tumor suppressor gene on chromosome band 11q13. Genes Chromosomes Cancer 22:130–137

    Article  PubMed  CAS  Google Scholar 

  12. Chen YJ, Vortmeyer A, Zhuang Z, Gibril F, Jensen RT (2004) X-chromosome loss of heterozygosity frequently occurs in gastrinomas and is correlated with aggressive tumor growth. Cancer 100:1379–1387

    Article  PubMed  Google Scholar 

  13. Cheng H, Leblond CP (1974) Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian theory of the origin of the four epithelial cell types. Am J Anat 141:537–562

    Article  PubMed  CAS  Google Scholar 

  14. Chung DC, Smith AP, Louis DN, Graeme-Cook F, Warshaw AL, Arnold A (1997) Analysis of the retinoblastoma tumour suppressor gene in pancreatic endocrine tumours. Clin Endocrinol 47:523–528

    Article  CAS  Google Scholar 

  15. Chung DC, Smith AP, Louis DN, Graeme-Cook F, Warshaw AL, Arnold A (1997) A novel pancreatic endocrine tumor suppressor gene locus on chromosome 3p with clinical prognostic implications. J Clin Invest 100(2):404–410

    PubMed  CAS  Google Scholar 

  16. D'Adda T, Keller G, Bordi C, Höfler H (1999) Loss of heterozygosity in 11q13-14 regions in gastric neuroendocrine tumors not associated with multiple endocrine neoplasia type 1 syndrome. Lab Invest 79(6):671–677

    PubMed  Google Scholar 

  17. D'Adda T, Pizzi S, Azzoni C, Bottarelli L, Crafa P, Pasquali C, Davoli C, Corletto VD, Delle Fave G, Bordi C (2002) Different patterns of 11q allelic losses in digestive endocrine tumors. Human Pathol 3:322–329

    Article  Google Scholar 

  18. Debelenko LV, Emmert-Buck MR, Zhuang Z, Epshteyn E, Moskaluk CA, Jensen RT, Liotta LA, Lubensky IA (1997) The multiple endocrine neoplasia type I gene locus is involved in the pathogenesis of type II gastric carcinoids. Gastroenterology 113:773–781

    Article  PubMed  CAS  Google Scholar 

  19. Deshpande V, Fernandez-del Castillo C, Muzikansky A, Deshpande A, Zukerberg L, Warshaw AL, Lauwers GY (2004) Cytokeratin 19 is a powerful predictor of survival in pancreatic endocrine tumors. Am J Surg Pathol 28:1145–1153

    Article  PubMed  Google Scholar 

  20. Feyrter F (1938) Über diffuse endocrine epitheliale Organe. Leipzig Zentr Inn Med 29:545–571

    Google Scholar 

  21. Feyrter F (1956) Zur Lehre von den periferen endokrinen (parakrinen) Drüsen des Menschen. Neue Erkenntnisse. Wien Med Wochenschr 106(23):515–516

    PubMed  CAS  Google Scholar 

  22. Fontaine J, Le Douarin NM (1977) Analysis of endoderm formation in the avian blastoderm by the use of quail-chick chimaeras. The problem of the neuroectodermal origin of the cells of the APUD series. J Embryol Exp Morphol 41:209–222

    PubMed  CAS  Google Scholar 

  23. Graphin-Button A, Majithia AR, Melton DA (2001) Key events of pancreas formation are triggered in gut endoderm by ectopic expression of pancreatic regulatory genes. Genes Dev 15:444–454

    Article  Google Scholar 

  24. Hald J, Hjort P, German MS, Madsen OD, Serup P, Jensen J (2003) Activated Notch1 prevents differentiation of pancreatic acinar cells and attenuate endocrine development. Dev Biol 260:426–437

    Article  PubMed  CAS  Google Scholar 

  25. Hamilton SR, Aaltonen LA (eds) (2000) World Health Organization international classification of tumours. Pathology and genetics of tumours of the digestive system. IARC Press, Lyon

    Google Scholar 

  26. Heitz PU, Komminoth P, Perren A, Klimstra DS, Dayal Y, Bordi C, Lechago J, Centeno BA, Klöppel G (2004) Pancreatic endocrine tumours: introduction. In: De Lellis RA, Lloyd RV, Heitz PU, Eng C (eds) World Health Organization international classification of tumours. Pathology and genetics of tumours of endocrine organs. IARC Press, Lyon, pp 177–182

    Google Scholar 

  27. Hessman O, Lindberg D, Einarsson A, Lillhager P, Carling T, Grimelius L, Eriksson B, Åkerström G, Westin G, Skogseid B (1999) Genetic alterations on 3p, 11q13, and 18q in nonfamilial and MEN I-associated pancreatic endocrine tumors. Genes Chromosomes Cancer 26:258–264

    Article  PubMed  CAS  Google Scholar 

  28. Jenny M, Uhl C, Roche C, Duluc I, Guillermin V, Guillemot F, Jensen J, Kedinger M, Gradwohl G (2002) Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium. EMBO 21(23):6338–6347

    Article  CAS  Google Scholar 

  29. Jensen J, Engholm Pedersen E, Galante P, Hald J, Heller RS, Ishibashi M, Kagayama R, Guillemot F, Serup P, Madsen OD (2000) Control of endodermal endocrine development by Hes-1. Nat Genet 24:36–44

    Article  PubMed  CAS  Google Scholar 

  30. Klimstra DS, Rosai J, Heffess CS (1994) Mixed acinar–endocrine carcinomas of the pancreas. Am J Surg Pathol 18(8):765–778

    Article  PubMed  CAS  Google Scholar 

  31. Klöppel G, Heitz PU, Capella C, Solcia E (2000) Endocrine tumours of the pancreas. In: Solcia E, Klöppel G, Sobin LH (eds) World Health Organization international histological classification of tumours. Histological typing of endocrine tumours, 2nd edn. Springer, Berlin Heidelberg New York, pp 56–60

    Google Scholar 

  32. Kytölä S, Höög A, Nord B, Cedermark B, Frisk T, Larsson C, Kjellman M (2001) Comparative genomic hybridization identifies loss of 18q22-qter as an early and specific event in tumorigenesis of midgut carcinoids. Am J Pathol 158(5):1803–1808

    PubMed  Google Scholar 

  33. La Rosa S, Rigoli E, Uccella S, Chiaravalli AM, Capella C (2004) CDX2 as a marker of intestinal EC-cells and related well-differentiated endocrine tumors. Virchows Arch 445(3):248–254

    Article  PubMed  CAS  Google Scholar 

  34. Leonard JH, Cook AL, Van Gele M, Boyle GM, Inglis KJ, Speleman F, Sturm RA (2002) Proneural and proneuroendocrine transcription factor expression in cutaneous mechanoreceptor (Merkel) cells and Merkel cell carcinoma. Int J Cancer 101(2):103–110

    Article  PubMed  CAS  Google Scholar 

  35. Leotlela PD, Jauch A, Holtgreve-Grez H, Thakker RV (2003) Genetics of neuroendocrine and carcinoid tumors. Endocr-Relat Cancer 10:437–450

    Article  PubMed  CAS  Google Scholar 

  36. Leow CC, Romero MS, Ross S, Polakis P, Gao WQ (2004) Hath1, Down-regulated in colon adenocarcinomas, inhibits proliferation and tumorigenesis of colon cancer cells. Cancer Res 64:6050–6057

    Article  PubMed  CAS  Google Scholar 

  37. Lewis BC, Klimstra DS, Varmus HE (2003) The c-myc and PyMT oncogenes induce different tumor types in a somatic mouse model for pancreatic cancer. Genes Dev 17:3127–3138

    Article  PubMed  CAS  Google Scholar 

  38. Lubensky IA, Pack S, Ault D, Vortmeyer AO, Libutti SK, Choyke PL, Walther MM, Linehan WM, Zhuang Z (1998) Multiple neuroendocrine tumors of the pancreas in von Hippel–Lindau disease patients. Histopathological and molecular genetic analysis. Am J Pathol 153(1):223–231

    PubMed  CAS  Google Scholar 

  39. Lubomierski N, Kersting M, Bert T, Muench K, Wulbrand U, Schuermann M, Bartsch D, Simon B (2001) Tumor suppressor genes in the 9p21 gene cluster are selective targets of inactivation in neuroendocrine gastroenteropancreatic tumors. Cancer Res 61:5905–5910

    PubMed  CAS  Google Scholar 

  40. Löllgen RM, Hessman O, Szabo E, Westin G, Åkerström G (2001) Chromosome 18 deletions are common events in classical midgut carcinoid tumors. Int J Cancer 92:812–815

    Article  PubMed  Google Scholar 

  41. Madsen OD, Jensen J, Petersen HV, Pedersen EE, Oster A, Andersen FG, Jorgensen MC, Jensen PB, Larsson LI, Serup P (1997) Transcription factors contributing to the pancreatic beta-cell phenotype. Horm Metab Res 29(6):265–270

    Article  PubMed  CAS  Google Scholar 

  42. Masson P (1928) Carcinoids (argentaffin-cell tumors) and nerve hyperplasia of the appendicular mucosa. Am J Pathol IV(3):181–211

    Google Scholar 

  43. Masson P (1951) La malignité des carcinoids du tube digestif. Mikroskopie 6:133–146

    PubMed  CAS  Google Scholar 

  44. Masson P (1956) Tumeurs humaines. Histologie. Diagnostics Et Techniques, 2nd edn. Libraire Maloine, Paris, pp 530–539

    Google Scholar 

  45. Modlin IM, Shapiro MD, Kidd M (2004) Siegfried Oberndorfer: origins and perspectives of carcinoid tumors. Human Pathol 35(12):1440–1451

    Article  Google Scholar 

  46. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD (2005) Current status of gastrointestinal carcinoids. Gastroenterology 128(6):1717–1751

    Google Scholar 

  47. Muscarella P, Melvin WS, Fisher WE, Foor J, Ellison EC, Herman JC, Schirmer WJ, Hitchcock CL, DeYoung BR, Weghorst CM (1998) Genetic alterations in gastrinomas and non-functioning pancreatic neuroendocrine tumors: an analysis of p16/MTS1 tumor suppressor gene inactivation. Cancer Res 58:237–240

    PubMed  CAS  Google Scholar 

  48. Naya FJ, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, Tsai MJ (1997) Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/NeuroD-deficient mice. Genes Dev 11:2323–2334

    Google Scholar 

  49. Ohike N, Jürgensen A, Pipeleers-Marichal M, Klöppel G (2003) Mixed ductal–endocrine carcinomas of the pancreas and ductal adenocarcinomas with scattered endocrine cells: characterization of the endocrine cells. Virchows Arch 442:258–265

    Google Scholar 

  50. Paraskevakou H, Saetta A, Skandalis K, Tseleni S, Athanassiadis A, Davaris PS (1999) Morphological–histochemical study of intestinal carcinoids and K-ras mutation analysis in appendiceal carcinoids. Pathol Oncol Res 5(3):205–210

    Article  PubMed  CAS  Google Scholar 

  51. Pavelić K, Hrašćan R, Kapitanovic S, Karapandza N, Vranes Z, Belicza M, Kruslin B, Cabrijan T (1995) Multiple genetic alterations in malignant metastatic insulinomas. J Pathol 177:395–400

    Article  PubMed  Google Scholar 

  52. Pearse AGE (1969) The cytochemistry and ultrastructure of polypeptide hormone-producing cells of the APUD series and the embryologic, physiologic and pathologic implications of the concept. J Histochem Cytochem 17(5):303–313

    PubMed  CAS  Google Scholar 

  53. Peters J, Jürgensen A, Klöppel G (2000) Ontogeny, differentiation and growth of the endocrine pancreas. Virchows Arch 436:527–538

    Article  PubMed  CAS  Google Scholar 

  54. Peters K, Panienka R, Li J, Klöppel G, Wang R (2005) Expression of stem cell markers and transcription factors during the remodeling of the rat pancreas after duct ligation. Virchows Arch 446:56–63

    Article  PubMed  CAS  Google Scholar 

  55. Perren A, Saremaslani P, Schmid S, Bonvin C, Locher T, Roth J, Heitz PU, Komminoth P (2003) DPC4/Smad4: no mutations, rare allelic imbalances, and retained protein expression in pancreatic endocrine tumors. Diagn Mol Pathol 12(4):181–186

    Article  PubMed  CAS  Google Scholar 

  56. Pizzi S, D'Adda T, Azzoni C, Rindi G, Grigolato P, Pasquali C, Corletto VD, Delle Fave G, Bordi C (2002) Malignancy-associated allelic losses on the X-chromosome in foregut but not in midgut endocrine tumours. J Pathol 196:401–407

    Article  PubMed  Google Scholar 

  57. Pizzi S, Azzoni C, Bassi D, Bottarelli L, Milione M, Bordi C (2003) Genetic alterations in poorly differentiated endocrine carcinomas of the gastrointestinal tract. Cancer 98:1273–1282

    Article  PubMed  CAS  Google Scholar 

  58. Ramnani DM, Wistuba II, Behrens C, Gazdar AF, Sobin LH, Albores-Saavedra J (1999) K-ras and p53 mutations in the pathogenesis of classical and goblet cell carcinoids of the appendix. Cancer 86:14–21

    Article  PubMed  CAS  Google Scholar 

  59. Schonhoff SE, Giel-Moloney M, Leiter AB (2004) Neurogenin 3-expressing progenitor cells in the gastrointestinal tract differentiate into both endocrine and non-endocrine cell types. Dev Biol 270:443–454

    Article  PubMed  CAS  Google Scholar 

  60. Schonhoff SE, Giel-Moloney M, Leiter AB (2004) Development and differentiation of gut endocrine cells. Endocrinology 145(6):2639–2644

    Article  PubMed  CAS  Google Scholar 

  61. Schwitzgebel VM, Scheel DW, Conners JR, Kalamaras J, Lee JE, Anderson DJ, Sussel L, Johnson JD, German MS (2000) Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development 127:3533–3542

    PubMed  CAS  Google Scholar 

  62. Schwitzgebel VM (2001) Programming of the pancreas. Mol Cell Endocrinol 185:99–108

    Article  PubMed  CAS  Google Scholar 

  63. Silberg DG, Swain GP, Suh ER, Traber PG (2000) Cdx1 and Cdx2 expression during intestinal development. Gastroenterology 119:961–971

    Article  PubMed  CAS  Google Scholar 

  64. Skipper M, Lewis J (2000) Getting to the guts of enteroendocrine differentiation. Nat Genet 24:3–4

    Article  PubMed  CAS  Google Scholar 

  65. Solcia E, Capella C, Klöppel G, Heitz PU, Sobin LH, Rosai J (2000) Endocrine tumours of the gastrointestinal tract. In: Solcia E, Klöppel G, Sobin LH (eds) World Health Organization international histological classification of tumours. Histological typing of endocrine tumours, 2nd edn. Springer, Berlin Heidelberg New York, pp 61–68

    Google Scholar 

  66. Speel EJM, Richter J, Moch H, Egenter C, Saremaslani P, Rutimann K, Zhao J, Barghorn A, Roth J, Heitz PU, Komminoth P (1999) Genetic differences in endocrine pancreatic tumor subtypes detected by comparative genomic hybridization. Am J Pathol 155(6):1787–1794

    PubMed  CAS  Google Scholar 

  67. Stenhouse G, Fyfe N, King G, Chapman A, Kerr KM (2004) Thyroid transcription factor 1 in pulmonary adenocarcinoma. J Clin Pathol 57:383–387

    Article  PubMed  CAS  Google Scholar 

  68. Stumpf E, Aalto Y, Höög A, Kjellman M, Otonkoski T, Knuutila S, Andersson LC (2000) Chromosomal alterations in human pancreatic endocrine tumors. Genes Chromosomes Cancer 29:83–87

    Article  PubMed  CAS  Google Scholar 

  69. Vortmeyer AO, Huang S, Lubensky I, Zhuang Z (2004) Non-islet origin of pancreatic islet cell tumors. J Clin Endocrinol Metab 89(4):1934–1938

    Article  PubMed  CAS  Google Scholar 

  70. Warner RRP (2005) Enteroendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology 128:1668–1684

    Article  PubMed  Google Scholar 

  71. Werling RW, Yaziji H, Bacchi CE, Gown AM (2003) CDX2, a highly sensitive and specific marker of adenocarcinomas of intestinal origin: an immunohistochemical survey of 476 primary and metastatic carcinomas. Am J Surg Pathol 27(3):303–310

    Article  PubMed  Google Scholar 

  72. Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY (2001) Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294(5549):2155–2158

    Article  PubMed  CAS  Google Scholar 

  73. Zhao J, de Krijger RR, Meier D, Speel EJ, Saremaslani P, Muletta-Feurer S, Matter C, Roth J, Heitz PU, Komminoth P (2000) Genomic alterations in well-differentiated gastrointestinal and bronchial neuroendocrine tumors (carcinoids). Marked differences indicating diversity in molecular pathogenesis. Am J Pathol 157(5):1431–1438

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors are indebted to Professor G. Klöppel for critically reading the manuscript and for his suggestions.

Author information

Authors and Affiliations

  1. Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105, Amsterdam, The Netherlands

    Susanne van Eeden & G. Johan A. Offerhaus

Authors
  1. Susanne van Eeden
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Johan A. Offerhaus
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susanne van Eeden.

Rights and permissions

Reprints and permissions

About this article

Cite this article

van Eeden, S., Offerhaus, G.J.A. Historical, current and future perspectives on gastrointestinal and pancreatic endocrine tumors. Virchows Arch 448, 1–6 (2006). https://doi.org/10.1007/s00428-005-0082-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-005-0082-4

Keywords

Search

Navigation