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Human insulinoma: Clinical, cellular, and molecular aspects

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Abstract

Insulinoma is the most frequently encountered functioning endocrine pancreatic tumor in humans. In this overview we summarize morphological and clinical features of insulinomas, report about the proinsulin-insulin conversion in normal and neoplastic B-cells, discuss the new classification, the criteria of malignancy, and the clonal composition of endocrine pancreatic tumors, and outline recent findings on the molecular pathology of these tumors.

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References

  1. Klöppel G, In’t Veld P, Komminoth P, Heitz PU. The endocrine pancreas. In: Kovacs K, SL Asa, eds. Functional endocrine neoplasia. Oxford: Blackwell Scientific Publications 415–487, 1998.

    Google Scholar 

  2. Grimelius L, Hultquist G, Stenquist B. Cytological differentiation of asymptomatic pancreatic islet cell tumors in autopsy material. Virchows Arch [a] Pathol Anat 365:275–288, 1975.

    CAS  Google Scholar 

  3. Roth J, Komminoth P, Klöppel G, Heitz PU. Diabetes and the endocrine pancreas. In: Damjanov I, DT Purtilo, eds. Anderson’s Pathology, 10th Edition. St. Louis, Chicago: Mosby Year Book 2042–2070, 1996.

    Google Scholar 

  4. Le Douarin NM. On the origin of pancreatic endocrine cells. Cell 53:169–171, 1988.

    Article  PubMed  Google Scholar 

  5. Andrew A, Kramer B, Rawdon BB. The origin of gut and pancreatic neuroendocrine (APUD) cells—the last word? [editorial] [In Process Citation]. J Pathol 186:117–118, 1998.

    Article  PubMed  CAS  Google Scholar 

  6. Rindi G, Bishop AE, Murphy D, Solcia E, Hogan B, Polak JM. A morphological analysis of endocrine tumour genesis in pancreas and anterior pituitary of AVP/SV40 transgenic mice. Virchow Arch 412:255–266, 1988.

    Article  CAS  Google Scholar 

  7. Harris S. Hyperinsulinism and dysinsulinism. JAMA 83:729–733, 1924.

    Google Scholar 

  8. Wilder RM, Allan FN, Power MH, Robertson HE. Carcinoma of the islands of the pancreas; hyperinsulinism and hypoglycemia. JAMA 89:348–355, 1927.

    CAS  Google Scholar 

  9. Boden G. Glucagonomas and insulinomas. Gastroenterol Clin North Am 18:831–845, 1989.

    PubMed  CAS  Google Scholar 

  10. Service FJ, McMahon MM, O’Brien PC, Ballard DJ. Functioning insulinoma—incidence, recurrence, and lingterm survival of patients: a 60-year study. Mayo Clin Proc 66:711–719, 1991.

    PubMed  CAS  Google Scholar 

  11. Galbut DL, Markowitz AM. Insulinoma: Diagnosis, surgical management and long-term follow-up. Am J Surg 139:682–690, 1980.

    Article  PubMed  CAS  Google Scholar 

  12. Giercksky KE, Halse J, Mathisen W, Gjone E, Flatmark A. Endocrine tumors of the pancreas. Scand J Gastroenterol 15:129–135, 1980.

    Article  PubMed  CAS  Google Scholar 

  13. Glickman MH, Hart MJ, White TT. Insulinoma in Seattle: 39 cases in 30 years. Am J Surg 140:119–123, 1980.

    Article  PubMed  CAS  Google Scholar 

  14. Le Quesne P, Nabarro JDN, Kurtz A, Zweig S. The management of insulin tumors of the pancreas. Br J Surg 66:373–378, 1979.

    Article  PubMed  Google Scholar 

  15. Stringel G, Dolpe-Scott M, Perelman AH. The occult insulinoma operative localization by quick insulin radioimmunoassay. J Pediatr Surg 20:734–736, 1985.

    Article  PubMed  CAS  Google Scholar 

  16. Danforth DH, Gorden P, Brennan MF. Metastatic insulin secreting carcinoma of the pancreas. Clinical course and the role of surgery. Surgery 96:1027–1037, 1984.

    PubMed  Google Scholar 

  17. Crain EL, Thorn GW. Functioning pancreatic islet cell adenomas: a review of the literature and presentation of two new differential tests. Medicine 28:427–447, 1949.

    Article  PubMed  Google Scholar 

  18. Fajans SS, Vinick AI. Insulin-producing islet cell tumors. Endocrinol Metab Clin North Am 18:45–74, 1989.

    PubMed  CAS  Google Scholar 

  19. Turner RC, Heding LG. Plasma proinsulin, C-peptide and insulin in diagnostic suppresion tests for insulinoma. Diabetologica 13:571–577, 1977.

    Article  CAS  Google Scholar 

  20. Comi RJ, Gorden P, Doppman JL. Insulinoma. In: Go VLW, EP Di Magno, JD Gardner, E Lebenthal, HA Reber, GA Scheele, eds. The pancreas: biology, pathobiology and disease. New York: Raven Press 979–996, 1993.

    Google Scholar 

  21. Lehnert T. Liver transplantation for metastatic neuroendocrine carcinoma: an analysis of 103 patients. Transplantation 66:1307–1312, 1998.

    Article  PubMed  CAS  Google Scholar 

  22. Oberg K, Eriksson B. The role of interferons in the management of carcinoid tumors. Acta Oncol 30:519–522, 1991.

    PubMed  CAS  Google Scholar 

  23. Perry RR, Vinik AI. Diagnosis and management of functioning islet cell tumors. J Clin Endocr Metabol 80:2237–2278, 1995.

    Google Scholar 

  24. Krentz AJ, Hale PJ, Baddeley RM. Intraoperative blood glucose and serum insulin concentrations in the surgical management of insulinoma. Postgrad Med J 66:24–27, 1990.

    PubMed  CAS  Google Scholar 

  25. Stefanini P, Carboni M, Patrassi N, Basoli A. Beta-islet cell tumors of the pancreas: results of a study on 1’067 cases. Surgery 75:597–609, 1974.

    PubMed  CAS  Google Scholar 

  26. Filipi CJ, Higgins GA. Diagnosis and management of insulinoma. Am J Surg 125:231–239, 1975.

    Article  Google Scholar 

  27. Howard TJ, Stabile BE, Zinner MJ, Chang S, Bhagavan BS, Passaro EJ. Anatomic distribution of pancreatic endocrine tumors. Am J Surg 159:258–264, 1990.

    Article  PubMed  CAS  Google Scholar 

  28. Moss NH, Rhoades JE. Hyperinsulinism and islet cell tumors of the pancreas. In: Howard JM, GL Jordan, eds. Surgical diseases of the pancreas. Philadelphia: Lippincott, 1960; 321–441.

    Google Scholar 

  29. Komminoth P, Heitz PU, Klöppel G. Pathology of MEN-1: Morphology, clinicopathologic correlations and tumor development. Int J Med 243:455–464, 1997.

    Article  Google Scholar 

  30. Berger M, Bordi C, Cuppers HJ, Berchtold P, Gries FA, Munterfering H, Sailer R, Zimmermann H, Orci L. Functional and morphologic characterization of human insulinomas. Diabetes 32:921–931, 1983.

    Article  PubMed  CAS  Google Scholar 

  31. Creutzfeldt C, Track NS, Creutzfeldt W. In vitro studies of the rate of proinsulin and insulin turnover in seven human insulinomas. Eur J Clin Invest 3:371–384, 1973.

    PubMed  CAS  Google Scholar 

  32. Heitz PU. Pancreatic endocrine tumours. In: Klöppel G, PU Heitz, eds. Pancreatic pathology. Edinburgh, London, Melbourne, New York: Churchill Livingstone, 1984; 206–239.

    Google Scholar 

  33. Williams AJ, Coates PJ, Lowe DG, McLean C, Gale EA. Immunochemical investigation of insulinomas for islet amyloid polypeptide and insulin: evidence for differential synthesis and storage. Histopathology 21:215–223, 1992.

    Article  PubMed  CAS  Google Scholar 

  34. Roth J, Komminoth P, Heitz PU. Topographic abnormalities of proinsulin to insulin conversion in functioning human insulinomas. Comparison of immunoelectron microscopic and clinical data. Am J Pathol 147:489–502, 1995.

    PubMed  CAS  Google Scholar 

  35. Roth J, Klöppel G, Madsen OD, Storch MJ, Heitz PU. Distribution patterns of proinsulin and insulin in human insulinomas: an immunohistochemical analysis in 76 tumors. Virchows Arch B 63:51–61, 1992.

    PubMed  CAS  Google Scholar 

  36. Azzoni C, D’Adda T, Tamburrano G, Coscelli C, Madsen OD, Scopsi L, Bordi C. Functioning human insulinomas. An immunohistochemical analysis of intracellular insulin processing. Virchows Arch 433:495–504, 1998.

    Article  PubMed  CAS  Google Scholar 

  37. Capella C, Heitz PU, Hofler H, Solcia E, Kloppel G. Revised classification of neuroendocrine tumors of the lung, pancreas and gut. Digestion 55 (suppl 3):11–23, 1994.

    PubMed  Google Scholar 

  38. Klöppel G. Classification of neuroendocrine tumors. Verh Dtsch Ges Path 81:111–117, 1997.

    Google Scholar 

  39. Rindi G, Capella C, Solcia E. Cell biology, clinicopathological profile, and classification of gastro-enteropancreatic endocrine tumors. J Mol Med 76:413–420, 1998.

    Article  PubMed  CAS  Google Scholar 

  40. Klöppel G, Höfler H, Heitz PU. Pancreatic endocrine tumours in man. In: Polak JM, eds. Diagnostic histopathology of neuroendocrine tumours. Edinburgh: Churchill Livingstone 91–121, 1993.

    Google Scholar 

  41. La Rosa S, Sessa F, Capella C, Riva C, Leone BE, Klersy C, Rindi G, Solcia E. Prognostic criteria in nonfunctioning pancreatic endocrine tumours. Virchows Arch 429:323–333, 1996.

    Article  PubMed  Google Scholar 

  42. Seelentag WKF, Li WP, Hsu-Schmitz SF, Heitz PU, Roth J. The prognostic value of β1,6-branched oligosaccharides in human colorectal carcinoma. Cancer Res. 58:5559–5564, 1998.

    PubMed  CAS  Google Scholar 

  43. Li WP, Komminoth P, Zuber C, Klöppel G, Heitz PU, Roth J. Can malignancy in insulinoma be predicted by the expression patterns of beta 1,6 branching of asparagine-linked oligosaccharides and polysialic acid of the neural cell adhesion molecule? Virchows Arch 429:197–204, 1996.

    Article  PubMed  CAS  Google Scholar 

  44. Komminoth P, Seelentag WK, Saremaslani P, Heitz PU, Roth J. CD44 isoform expression in the diffuse neuroendocrine system. II. Benign and malignant tumors. Histochem Cell Biol 106:551–62, 1996.

    PubMed  CAS  Google Scholar 

  45. Perren A, Roth J, Muletta-Feurer S, Saremaslani P, Speel EJM, Heitz PU, Komminoth P. Clonal analysis of sporadic pancreatic endocrine tumours. J Pathol 186:363–371, 1998.

    Article  PubMed  CAS  Google Scholar 

  46. Chandrasekharappa SC, Guru SC, Manickam P, Olufemi S, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Rester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL, Marx SJ. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276:404–406, 1997.

    Article  PubMed  CAS  Google Scholar 

  47. Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene (see comments). Science 260:1317–20, 1993.

    Article  PubMed  CAS  Google Scholar 

  48. Lohmann DR, Funk A, Niedermeyer HP, Haupel S, Hofler H. Identification of p53 gene mutations in gastrointestinal and pancreatic carcinoids by nonradioisotopic SSCA. Virchows Arch B Cell Pathol Incl Mol Pathol 64:293–6, 1993.

    Article  PubMed  CAS  Google Scholar 

  49. Höfler H, Ruhri C, Pütz B, Winsberger G, Hauser H. Oncogene expression in endocrine pancreatic tumors. Virchows Arch B 55:355–361, 1988.

    PubMed  Google Scholar 

  50. Iwamura Y, Futagawa T, Kaneko M, Nakagawa K, Kawai K, Yamashita K, Nakamura T, Hayashi H. Co-deletions of the retinoblastoma gene and Wilms’ tumor gene and rearrangement of the Krev-1 gene in a human insulinoma. Jpn J Clin Oncol 22:6–9, 1992.

    PubMed  CAS  Google Scholar 

  51. Sawicki MP, Wan YJ, Johnson CL, Berenson J, Gatti R, Passaro EJ. Loss of heterozygosity on chromosome 11 in sporadic gastrinomas. Hum Genet 89:445–449, 1992.

    Article  PubMed  CAS  Google Scholar 

  52. Komminoth P, Roth J, Muletta FS, Saremaslani P, Seelentag WK, Heitz PU. RET proto-oncogene point mutations in sporadic neuroendocrine tumors. J Clin Endocrinol Metab 81:2041–2046, 1996.

    Article  PubMed  CAS  Google Scholar 

  53. Zhuang Z, Vortmeyer AO, Pack S, Huang S, Pham TA, Wang C, Park WS, Agarwal SK, Debelenko LV, Kester M, Guru SC, Manickam P, Olufemi SE, Yu F, Heppner C, Crabtree JS, Skarulis MC, Venzon DJ, Emmert BM, Spiegel AM, Chandrasekharappa SC, Collins FS, Burns AL, Marx SJ, Lubensky IA, et al. Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas. Cancer Res 57:4682–4686, 1997.

    PubMed  CAS  Google Scholar 

  54. Görtz B, Roth J, Krähenmann A, de Krijger RR, Muletta-Feurer S, Rütimann K, Saremaslani P, Speel EJM, Heitz PU, Komminoth P. Murations and allelic deletions of the MEN1 gene are associated with a subset of sporadic endocrine pancreatic and neuroendocrine tumors and not restricted to foregut neoplasms. Am J Pathol 154:429–436, 1999.

    PubMed  Google Scholar 

  55. Görtz B, Roth J, Speel EJM, Krähenmann A, De Krijger RR, Matias-Guiu X, Muletta-Feurer S, Rütimann K, Saremaslani P, Heitz PU, Komminoth P. MEN1 gene mutation analysis of sporadic adrenocortical lesions. Int J Cancer 80:373–379, 1999.

    Article  PubMed  Google Scholar 

  56. Görtz B, Muletta-Feurer S, De Krijger RR, Rütimann K, Speel EJM, Saremaslani P, Roth J, Heitz PU, Komminoth P. MEN-1 gene mutations in sporadic neuroendocrine and adrenocortical tumors. Path Res Pract 194:277 (Abstract), 1998.

    Google Scholar 

  57. Dietrich WF, Radany EH, Smith JS, Bishop JM, Hanahan D, Lander ES. Genome-wide search for loss of heterozygosity in transgenic mouse tumors reveals candidate tumor suppressor genes on chromosomes 9 and 16. Proc Natl Acad Sci U S A 91:9451–5, 1994.

    Article  PubMed  CAS  Google Scholar 

  58. Barghorn A, Rütimann K, Saremaslani P, Muletta S, Speel EJM, Roth J, Heitz PU, Komminoth P. Loss of heterozygosity von 3p25 in sporadischen neuroendokrinen Pankreastumoren: ein Malignitätsmarker? Schweiz Med Wochenschr 128:1870 (Abstract 13), 1998.

    Google Scholar 

  59. Chung DC, Smith AP, Louis DN, GraemeCook F, Warshaw AL, Arnold a. A novel pancreatic endocrine tumor suppressor gene locus on chromosome 3p with clinical prognostic implications. J Clin Invest 100:404–410, 1997.

    Article  PubMed  CAS  Google Scholar 

  60. Radford DM, Ashley SW, Wells SJ, Gerhard DS. Loss of heterozygosity of markers on chromosome 11 in tumors from patients with multiple endocrine neoplasia syndrome type 1. Cancer Res 50:6529–6533, 1990.

    PubMed  CAS  Google Scholar 

  61. Ding SF, Habib NA, Delhanty JD, Bowles L, Greco L, Wood C, Williamson RC, Dooley JS. Loss of heterozygosity on chromosomes 1 and 11 in carcinoma of the pancreas. Br J Cancer 65:809–812, 1992.

    PubMed  CAS  Google Scholar 

  62. Shi YP, Naik P, Dietrich WF, Gray JW, Hanahan D, Pinkel D. DNA copy number changes associated with characteristic LOH in islet cell carcinomas of transgenic mice. Genes Chromosomes Cancer 19:104–111, 1997.

    Article  PubMed  CAS  Google Scholar 

  63. Long PP, Hruban RH, Lo R, Yeo CJ, Morsberger LA, Griffin CA. Chromosome analysis of nine endocrine neoplasms of the pancreas. Cancer Genet Cytogenet 77:55–59, 1994.

    Article  PubMed  CAS  Google Scholar 

  64. Speel EJM, Richter J, Moch H, Egenter C, Roth J, Saremaslani P, Rüttiman K, Barghorn A, Barghorn A, Heitz PU, Komminoth P. Comparative genomic hybridization analysis of sporadic endocrine pancreatic tumors. Am J Pathol 153:1600 (Abstract ST7), 1998.

    Google Scholar 

  65. Speel EJM, Richter J, Moch H, Roth J, Egenter C, Saremaslani P, Rütimann K, Zhao J, Barghorn A, Heitz PU, Komminoth P. Genetic differences in endocrine pancreatic tumors subtypes detected by comparative genomic hybridization. Am J Pathol in press.

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Authors and Affiliations

  1. Department of Pathology, University of Zurich, Schmelzbergstrasse 12, CH-8091, Zürich, Switzerland

    Paul Komminoth MD, Philipp U. Heitz MD & Jürgen Roth MD, PhD

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  1. Paul Komminoth MD
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  2. Philipp U. Heitz MD
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Correspondence to Paul Komminoth MD.

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Komminoth, P., Heitz, P.U. & Roth, J. Human insulinoma: Clinical, cellular, and molecular aspects. Endocr Pathol 10, 269–281 (1999). https://doi.org/10.1007/BF02739769

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