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Neuroendocrine Pathology of the Stomach: The Parma Contribution

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Abstract

The current knowledge on gastric neuroendocrine pathology essentially developed in the last four decades. The historical evolution of the concepts and of the relevant clinical implications is described from the perspective of a group actively participating in this research domain. The histamine-producing enterochromaffin-like (ECL) cells have been recognized as the leading cell type involved in the most significant alterations of gastric neuroendocrine cells. The trophic stimulus exerted by circulating gastrin has been demonstrated to have a crucial role on proliferative changes of ECL cells through a sequence of hyperplasia-dysplasia-neoplasia described by Solcia et al. (Digestion 41:185-200,1988). The development of ECL cell tumors in rats treated with toxicological doses of inhibitors of gastric acid secretion prompted appropriate anatomoclinical investigations proving the lack of tumor risk in humans when therapeutic dosages of the drugs are used. Moving from the comprehensive concept of gastric carcinoid, different types of neuroendocrine tumors have been identified in the stomach with substantial variations in prognosis and treatment options. In general, ECL cell tumors developed in hypergastrinemic conditions were found to behave better than those originating outside the setting of hormonal stimulation. Pathological features highly predictive of patient survival have been described. The genetic changes involved in tumor development and progression have revealed substantial overlapping with those of neuroendocrine tumors of other foregut derivatives (i.e., pancreas, duodenum, lung) delineating a family of neuroendocrine tumors genetically distinct from those of the distal parts of the digestive system.

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Abbreviations

CAG-A:

Chronic atrophic gastritis type A

bFGF:

Basic fibroblast growth factor

EC:

Enterochromaffin

ECL:

Enterochromaffin-like

ENETS:

European Neuro-Endocrine Tumor Society

LOH:

Loss of heterozygosity

NEC:

Neuroendocrine carcinoma

NET:

Neuroendocrine tumor

MEN-1:

Multiple endocrine neoplasia type 1

PDEC:

Poorly differentiated endocrine carcinoma

PPI:

Proton pump inhibitor

WHO:

World Health Organization

ZES:

Zollinger-Ellison syndrome

References

  1. Bordi C, Tardini A. Electron microscopy of islet cell tumors. In: Fenoglio CM, Wolff M, (Eds). Progress in surgical pathology. New York: Masson; 1980. p.135–155.

  2. Bordi C, Jemmi G, Banchini E, Costa A (1976) Problemi attuali del carcinoma midollare della tiroide. Recenti Prog Med 60:289-334.

  3. Vassallo G, Capella C, Solcia E (1971) Endocrine cells of the human gastric mucosa. Z Zellforsch Mikrosk Anat 118:49-67.

    Article  CAS  PubMed  Google Scholar 

  4. Pearse AG, Coulling I, Weavers B, Friesen S (1970) The endocrine polypeptide cells of the human stomach, duodenum, and jejunum. Gut 11:649-658.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Håkanson R, Lilja B, Owman C (1969) Cellular localization of histamine and monoamines in the gastric mucosa of man. Histochemie 18:74-86.

    Article  PubMed  Google Scholar 

  6. Solcia E, Capella C, Vassallo G (1970) Endocrine cells of the stomach and pancreas in states of gastric hypersecretion. Rendic R Gastroenterol 2:147-158.

    Google Scholar 

  7. Rubin W (1969) Proliferation of endocrine-like (enterochromaffin) cells in atrophic gastric mucosa. Gastroenterology 57:641-648.

  8. Pearse AG, Bussolati G (1970) Immunofluorescence studies on the distribution of gastrin cells in different clinical states. Gut 11:646-648.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Bordi C, Cocconi G, Togni R, Vezzadini P, Missale G (1974) Gastric endocrine cell proliferation. Association with Zollinger-Ellison syndrome. Arch Pathol 98:274-278.

    CAS  PubMed  Google Scholar 

  10. Bordi C, Costa A, Missale G (1975) ECL cell proliferation and gastrin levels. Gastroenterology 68:205-206.

  11. Håkanson R, Ekelund M, Sundler F. Activation and proliferation of gastric endocrine cells. In: Falkmer S, Håkanson R, Sundler F, (Eds). Evolution and Tumour Pathology of the Neuroendocrine System. Amsterdam: Elsevier; 1984. p.371-398.

  12. Håkanson R, Sundler F (1990) Proposed mechanism of induction of gastric carcinoids: the gastrin hypothesis. Eur J Clin Invest 20:S65-S71.

    Article  PubMed  Google Scholar 

  13. Bordi C, Ravazzola M (1979) Endocrine cells in the intestinal metaplasia of gastric mucosa. Am J Pathol 96:391-398.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Bordi C, Gabrielli M, Missale G (1978) Pathologic changes of endocrine cells in chronic atrophic gastritis. An ultrastructural study on peroral gastric biopsy specimens. Arch Pathol Lab Med 102:129-135.

    CAS  PubMed  Google Scholar 

  15. Bordi C, Ferrari C, D'Adda T, Pilato F, Carfagna G, Bertelé A, Missale G (1986) Ultrastructural characterization of fundic endocrine cell hyperplasia associated with atrophic gastritis and hypergastrinaemia. Virchows Arch A Pathol Anat Histopathol 409:335-347.

    Article  CAS  PubMed  Google Scholar 

  16. Bordi C, Senatore S, Missale G (1976) Gastric carcinoid following gastrojejunostomy. Am J Dig Dis 21:667-671.

    Article  CAS  PubMed  Google Scholar 

  17. Caruso ML, Pilato FP, D'Adda T, Baggi MT, Fucci L, Valentini AM, Lacatena M, Bordi C (1989) Composite carcinoid-adenocarcinoma of the stomach associated with multiple gastric carcinoids and nonantral gastric atrophy. Cancer 64:1534-1539.

    Article  CAS  PubMed  Google Scholar 

  18. D'Adda T, Pilato FP, Sivelli R, Azzoni C, Sianesi M, Bordi C (1994) Gastric carcinoid tumor and its precursor lesions. Ultrastructural study of a case before and after antrectomy. Arch Pathol Lab Med 118:658-663.

    PubMed  Google Scholar 

  19. D'Adda T, Azzoni C, Franzé A, Bordi C (1991) Malignant enterochromaffinlike cell carcinoid of the gastric stump: an ultrastructural study. Ultrastruct Pathol 15:257-265.

    Article  PubMed  Google Scholar 

  20. Solcia E, Bordi C, Creutzfeldt W, Dayal Y, Dayan AD, Falkmer S, Grimelius L, Havu N (1988) Histopathological classification of nonantral gastric endocrine growths in man. Digestion 41:185-200.

    Article  CAS  PubMed  Google Scholar 

  21. D'Adda T, Bertelé A, Pilato FP, Bordi C (1989) Quantitative electron microscopy of endocrine cells in oxyntic mucosa of normal human stomach. Cell Tissue Res 255:41-48.

    Article  PubMed  Google Scholar 

  22. D'Adda T, Corleto V, Pilato FP, Baggi MT, Robutti F, Delle Fave G, Bordi C (1990) Quantitative ultrastructure of endocrine cells of oxyntic mucosa in Zollinger-Ellison syndrome. Correspondence with light microscopic findings. Gastroenterology 99:17-26.

    Google Scholar 

  23. D'Adda T, Pilato FP, Lazzaroni M, Robutti F, Bianchi-Porro G, Bordi C (1991) Ultrastructural morphometry of gastric endocrine cells before and after omeprazole. A study in the oxyntic mucosa of duodenal ulcer patients. Gastroenterology 100:1563-1570.

    Google Scholar 

  24. Havu N (1986) Enterochromaffin-like cell carcinoids of gastric mucosa in rats after life-long inhibition of gastric secretion. Digestion 35:42-55.

    Article  PubMed  Google Scholar 

  25. Bordi C, Annibale B, Azzoni C, Marignani M, Ferraro G, Antonelli G, D'Adda T, D'Ambra G, Delle Fave G (1997) Endocrine cell growths in atrophic body gastritis. Critical evaluation of a histological classification. J Pathol 182:339-346.

    CAS  Google Scholar 

  26. Heitz PU, Kasper M, Klöppel G, Polak JM, Vaitukaitis JL (1983) Glycoprotein-hormone alpha-chain production by pancreatic endocrine tumors: a specific marker for malignancy. Cancer 51:277-282.

  27. Bordi C, Pilato FP, Bertelé A, D'Adda T, Missale G (1988) Expression of glycoprotein hormone alpha-subunit by endocrine cells of the oxyntic mucosa is associated with hypergastrinemia. Hum Pathol 19:580-585.

    Article  CAS  PubMed  Google Scholar 

  28. Bordi C, Falchetti A, Buffa R, Azzoni C, D'Adda T, Caruana P, Rindi G, Brandi ML (1994) Production of basic fibroblast growth factor by gastric carcinoid tumors and their putative cells of origin. Hum Pathol 25:175-180.

    Article  CAS  PubMed  Google Scholar 

  29. Bordi C, D'Adda T, Azzoni C, Ferraro G (1998) Pathogenesis of ECL cell tumors in humans. Yale J Biol Med 71:273-284.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Bordi C, Azzoni C, Ferraro G, Corleto VD, Gibril F, Delle Fave G, Lubensky IA, Venzon DJ, Jensen R T. (2000) Sampling strategies for analysis of enterochromaffin-like cell changes in Zollinger-Ellison syndrome. Am J Clin Pathol 114:419-425.

    CAS  PubMed  Google Scholar 

  31. Peghini PL, Annibale B, Azzoni C, Milione M, Corleto VD, Gibril F, Venzon DJ, Delle Fave G, Bordi C, Jensen RT (2002) Effect of chronic hypergastrinemia on human enterochromaffin-like cells: insights from patients with sporadic gastrinomas. Gastroenterology 123:68-85.

    Article  PubMed  Google Scholar 

  32. Berna MJ, Annibale B, Marignani M, Luong TV, Corleto V, Pace A, Ito T, Liewehr D, Venzon DJ, Delle Fave G, Bordi C, Jensen RT (2008) A prospective study of gastric carcinoids and enterochromaffin-like cell changes in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: identification of risk factors. J Clin Endocrinol Metab 93:1582-1591.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Ojeaburu JV, Ito T, Crafa P, Bordi C, Jensen RT (2011) Mechanism of acid hypersecretion post curative gastrinoma resection. Dig Dis Sci 56:139-154.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Bordi C, Yu JY, Baggi MT, Davoli C, Pilato FP, Baruzzi G, Gardini G, Zamboni G, Franzin G, Papotti M, Bussolati G (1991) Gastric carcinoids and their precursor lesions. A histologic and immunohistochemical study of 23 cases. Cancer 67:663-672.

    Article  CAS  PubMed  Google Scholar 

  35. Rindi G, Luinetti O, Cornaggia M, Capella C, Solcia E (1993) Three subtypes of gastric argyrophil carcinoid and the gastric neuroendocrine carcinoma: a clinicopathologic study. Gastroenterology 104:994-1006.

    CAS  PubMed  Google Scholar 

  36. Solcia E, Capella C, Fiocca R, Rindi G, Rosai J (1990) Gastric argyrophil carcinoidosis in patients with Zollinger-Ellison syndrome due to type 1 multiple endocrine neoplasia. A newly recognized association. Am J Surg Pathol 14:503-513.

    Article  CAS  PubMed  Google Scholar 

  37. Bordi C, Falchetti A, Azzoni C, D'Adda T, Canavese G, Guariglia A, Santini D, Tomassetti P, Brandi ML (1997) Aggressive forms of gastric neuroendocrine tumors in multiple endocrine neoplasia type I. Am J Surg Pathol 21:1075-1082.

    Article  CAS  PubMed  Google Scholar 

  38. Norton JA, Melcher ML, Gibril F, Jensen RT (2004) Gastric carcinoid tumors in multiple endocrine neoplasia-1 patients with Zollinger-Ellison syndrome can be symptomatic, demonstrate aggressive growth, and require surgical treatment. Surgery 136:1267-1274.

    Article  PubMed  Google Scholar 

  39. Bordi C, Azzoni C, D'Adda T, Caruana P, Carlinfante G (1997) Neuroendokrine Tumoren Des Magens: Pathogenese, Klassifikation Und Klinik. Der Pathologe 18:313-321.

    Article  CAS  PubMed  Google Scholar 

  40. Rindi G, Azzoni C, La Rosa S, Klersy C, Paolotti D, Rappel S, Stolte M, Capella C, Bordi C, Solcia E (1999) ECL cell tumor and poorly differentiated endocrine carcinoma of the stomach: prognostic evaluation by pathological analysis. Gastroenterology 116:532-542.

    Article  CAS  PubMed  Google Scholar 

  41. Solcia E, Kloppel G, Sobin LH. Histological Typing of Endocrine Tumours. WHO International Histological Classification of Tumours. Springer: Heidelberg, 2000.

    Book  Google Scholar 

  42. Pape UF, Jann H, Müller-Nordhorn J, Bockelbrink A, Berndt U, Willich SN, Koch M, Röcken C, Rindi G, Wiedenmann B (2008) Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer 113:256-265.

    Article  PubMed  Google Scholar 

  43. Rindi G, Klöppel G, Alhman H, Caplin M, Couvelard A, de Herder WW, Erikssson B, Falchetti A, Falconi M, Komminoth P, Körner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B. (2006) TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 449:395-401.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. La Rosa S, Inzani F, Vanoli A, Klersy C, Dainese L, Rindi G, Capella C, Bordi C, Solcia E (2011) Histologic characterization and improved prognostic evaluation of 209 gastric neuroendocrine neoplasms. Hum Pathol 42:1373-1384.

    Article  PubMed  Google Scholar 

  45. Solcia E, Arnold R, Capella C, Klimstra DS, Klöppel G, Komminoth P, Rindi G. Neuroendocrine Neoplasms Of The Stomach. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, (Eds). WHO Classification of Tumours of the Digestive System. Lyon: IARC Press; 2010. p.64-68.

  46. Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjöld M (1988) Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 332:85-87.

    Article  CAS  PubMed  Google Scholar 

  47. 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  CAS  PubMed  Google Scholar 

  48. 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 79:671-677.

    PubMed  Google Scholar 

  49. D'Adda T, Candidus S, Denk H, Bordi C, Höfler H (1999) Gastric neuroendocrine neoplasms: tumour clonality and malignancy-associated large X-chromosomal deletions. J Pathol 189:394-401.

    Article  PubMed  Google Scholar 

  50. Pizzi S, D'Adda T, Azzoni C, Rindi G, Grigolato P, Pasquali C, Corleto 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.

  51. D'Adda T, Bottarelli L, Azzoni C, Pizzi S, Bongiovanni M, Papotti M, Pelosi G, Maisonneuve P, Antonetti T, Rindi G, Bordi C (2005) Malignancy-associated X chromosome allelic losses in foregut endocrine neoplasms: further evidence from lung tumors. Mod Pathol 18:795-805.

    Article  PubMed  Google Scholar 

  52. Pizzi S, Azzoni C, Bottarelli L, Campanini N, D'Adda T, Pasquali C, Rossi G, Rindi G, Bordi C (2005) RASSF1A promoter methylation and 3p21.3 loss of heterozygosity are features of foregut, but not midgut and hindgut, malignant endocrine tumours. J Pathol 206:409-416.

    Article  CAS  PubMed  Google Scholar 

  53. Toliat MR, Berger W, Ropers HH, Neuhaus P, Wiedenmann B (1997) Mutations in the MEN I gene in sporadic neuroendocrine tumours of gastroenteropancreatic system. Lancet 350:1223.

    CAS  PubMed  Google Scholar 

  54. D'Adda T, Pizzi S, Azzoni C, Bottarelli L, Crafa P, Pasquali C, Davoli C, Corleto VD, Delle Fave G, Bordi C (2002) Different patterns of 11q allelic losses in digestive endocrine tumors. Hum Pathol 33:322-329.

    Article  PubMed  Google Scholar 

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Acknowledgments

The significant contributions of Tiziana D’Adda (electron microscopy and molecular genetics), Cinzia Azzoni (immunohistochemistry and molecular genetics), Silvia Pizzi (molecular genetics) and Lorena Bottarelli (molecular genetics) are gratefully acknowledged.

Moreover, the author sincerely thanks all colleagues and contributors that at various times and to various extent collaborated with him in gastric neuroendocrine research over period of more than 40 years.

Cinzia Azzoni and Lorena Bottarelli collaborated in the preparation of the manuscript.

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  1. Department of Biomedical, Biotechnological and Translational Sciences, Anatomic Pathology Unit, University of Parma, Via Gramsci 14, 43126, Parma, Italy

    Cesare Bordi

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Correspondence to Cesare Bordi.

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Bordi, C. Neuroendocrine Pathology of the Stomach: The Parma Contribution. Endocr Pathol 25, 171–180 (2014). https://doi.org/10.1007/s12022-014-9315-x

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