Skip to main content
SpringerLink
Log in

The Endocrine Pancreas

  • Chapter
Book cover Endocrine Pathology

Abstract

The endocrine function of the pancreas was first proposed in 1889 by Von Mering and Minkowsky [1]. A few years later, Laguesse [2] attributed this function to the islets of Langerhans [3]. Diamare identified two islet cell types [4] and, successively, Lane [5] and Bensley [6] named these cells α and β. Just a few years later, other investigators described δ and the fourth type (PP) of islet cells [7,8]. The use of immunohistochemical methods helped in the understanding of the functions and roles of islet cells, correlating the morphological features with the hormonal products. Thus it was demonstrated that β cells produce insulin [9], α cells glucagon [10], δ cells somatostatin [11], and PP cells (F and D1 cells) pancreatic polypeptide [12,13]. Following these pioneer studies, further investigations using new technical approaches, including electron microscopy, in situ hybridization, and molecular biology, have better elucidated the biological role and functions of pancreatic hormones, giving more detailed information about the physiopathology of pancreatic endocrine diseases such as diabetes mellitus and pancreatic endocrine tumors.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Von Mering I, Minkowsky M. Diabetes mellitus nach Pankreasextirpation. Zentral Klin Medizin 1889; 10: 393–394.

    Google Scholar 

  2. Laguesse E. Sur la formation des ilots de Langerhans dans le pancréas. Comptes Rendus des Seances de la Sociéte de Biologie et de Ses Filiales Paris 1894; 46: 819–820.

    Google Scholar 

  3. Langerhans P. Beiträge zur mikroskopischen anatomie der bauchspeicheldrüse. Berlin: Berlin Univ; 1869.

    Google Scholar 

  4. Diamare V. Studi comparativi sulle isole del Langerhans del pancreas. Int Monat Anat Physiol 1899; 16: 155–209.

    Google Scholar 

  5. Lane MA. The cytological characteristics of the areas of Langerhans. Am J Anat 1907; 7: 409–421.

    Article  Google Scholar 

  6. Bensley RR. Studies on the pancreas of the guinea pig. Am J Anat 1911; 12: 297–388.

    Article  Google Scholar 

  7. Bloom W. A new type of granular cell in the islet of Langerhans of man. Anat Rec 1931; 49: 363–371.

    Article  Google Scholar 

  8. Deconinck JF, van Assche FA, Potvliege PR, et al. The ultrastructure of the human pancreatic islets II. The islets of neonates. Diabetologia 1972; 8: 326–333.

    Article  CAS  PubMed  Google Scholar 

  9. Lacy PE, Davies J. Demonstration of insulin in mammalian pancreas by fluorescent antibody method. Stain Technol 1959; 34: 85–89.

    CAS  PubMed  Google Scholar 

  10. Okada N, Takaki R, Kitagawa M. Histological and immunofluorescence studies on the site of origin of glucagon in mammalian pancreas. J Histochem Cytochem 1967; 16: 405–409.

    Article  Google Scholar 

  11. Orci L, Baetens D, Dubois IP, et al. Evidence for D-cell of the pancreas secreting somatostatin. Horm Metabol Res 1975; 7: 400–402.

    Article  CAS  Google Scholar 

  12. Larsson LI, Sundler R, Håkanson R. Pancreatic polypeptide. A postulated new hormone: identiifcation of its cellular storage site by light and electron microscopic immunocytochemistry. Diabetologia 1976; 12: 211–226.

    Article  CAS  PubMed  Google Scholar 

  13. Fiocca R, Sessa F, Tenti P, et al. Pancreatic polypeptide (PP) cells in the PP-rich lobe of the human pancreas are identiifed ultrastructurally and immunocytochemically as F cells. Histochemistry 1983; 77: 511–523.

    Article  CAS  PubMed  Google Scholar 

  14. Liu HM, Potter EL. Development of the human pancreas. Arch Pathol 1962; 74: 439–452.

    CAS  PubMed  Google Scholar 

  15. Upchurch BH, Aponte GW, Leiter AB. Expression of peptide YY in all four islet cell types in the developing mouse pancreas suggests a common peptide YY-producing progenitor. Development 1994; 120: 245–252.

    CAS  PubMed  Google Scholar 

  16. Brand SJ, Fuller PJ. Differential gastrin gene expression in rat gastrointestinal tract and pancreas during neonatal development. J Biol Chem 1988; 263: 5341–5347.

    CAS  PubMed  Google Scholar 

  17. Wheeler MB, Nishitani J, Buchan AMJ, et al. Identiifcation of a transcriptional enhancer important for enteroendocrine and pancreatic islet cell-specific expression of the secretin gene. Mol Cell Biol 1992; 12: 3531–3539.

    CAS  PubMed  Google Scholar 

  18. Conklin JL. Cytogenesis of the human fetal pancreas. Am J Anat 1962; 111: 181–193.

    Article  CAS  PubMed  Google Scholar 

  19. Lackie PM, Zuber C, Roth J. Polysialic acid of neural cell adhesion molecule (N-CAM) is widely expressed during organogenesis in mesodermal and endodermal derivates. Differentiation 1994; 57: 119–131.

    Article  CAS  PubMed  Google Scholar 

  20. Dahl U, Sjodin A, Semb H. Cadherins regulate aggregation of pancreatic beta-cells in vivo. Development 1996; 122: 1895–2902.

    Google Scholar 

  21. Palmiter RD, Behringer RR, Quaife CJ, et al. Cell lineage ablation in transgenic mice by cell-speciifc expression of a toxin gene. Cell 1987;50:435–443. [published erratum Cell 1990; 10: 608.

    Google Scholar 

  22. Evans GA. Dissecting mouse development with toxigenics. Genes Dev 1989; 3: 259–263.

    Article  CAS  PubMed  Google Scholar 

  23. Ohashi PS, Oehen S, Buerki K, et al. Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 1991; 65: 305–317.

    Article  CAS  PubMed  Google Scholar 

  24. Teitelman G, Lee JK, Alpert S. Expression of cell type-specific markers during pancreatic development in the mouse: implications for pancreatic cell lineages. Cell Tissue Res 1987; 250: 435–439.

    Article  CAS  PubMed  Google Scholar 

  25. Teitelman G, Lee JK. Cell lineage analysis of pancreatic islet development: glucagon and insulin cells arise from catecholaminergic precursors in the pancreatic duct. Dev Biol 1987; 121: 454–466.

    Article  CAS  PubMed  Google Scholar 

  26. Teitelman G, Alpert S, Polak JM, et al. Precursor cells of mouse endocrine pancreas coexpress insulin, glucagon and neural proteins tyrosine hydroxylase and neuropeptide Y, but not pancreatic polypeptide. Development 1993; 118: 1031–1039.

    CAS  PubMed  Google Scholar 

  27. Alpert S, Hanahan D, Teitelman G. Hybrid insulin genes reveal a developmental lineage for pancreatic endocrine cells and imply a relationship with neurons. Cell 1988; 53: 295–308.

    Article  CAS  PubMed  Google Scholar 

  28. Madsen OD, Jensen J, Blume N, et al. Pancreatic development and maturation of the islet ß cell. Studies of pluripotent islet culture. Eur J Biochem 1996; 242: 435–445.

    Article  CAS  PubMed  Google Scholar 

  29. Habener JF, Stoffers DA. A newly discovered role of transcription factors involved in pancreas development and the pathogenesis of diabetes mellitus. Proc Assoc Am Physicians 1998; 110: 12–21.

    CAS  PubMed  Google Scholar 

  30. Slack JM. Developmental biology of the pancreas. Development 1995; 121: 1569–1580.

    CAS  PubMed  Google Scholar 

  31. Teitelman G. Cellular and molecular analysis of pancreatic islet cell lineage and differentiation. Recent Prog Hormon Res 1991; 47: 259–294.

    CAS  Google Scholar 

  32. Sander M, German MS. The beta cell transcription factors and development of the pancreas. J Mol Med 1997; 75: 327–340.

    Article  CAS  PubMed  Google Scholar 

  33. Rudnick A, Ling TY, Odagiri H, et al. Pancreatic beta cells express a diverse set of homeobox genes. Proc Natl Acad Sci USA 1994; 91: 12203–12207.

    Article  CAS  PubMed  Google Scholar 

  34. Yamaoka T, Itakura M. Development of pancreatic islets. Int J Mol Med 1999; 3: 247–261.

    CAS  PubMed  Google Scholar 

  35. Pontoglio M, Sreenan S, Rose M, et al. Defective insulin secretion in hepatocyte nuclear factor 1 alpha-deifcient mice. J Clin Invest 1998; 101: 2215–2222.

    Article  CAS  PubMed  Google Scholar 

  36. Pfaff SL, Mendelsohn M, Stewart CL, et al. Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation. Cell 1996; 84: 309–320.

    Article  CAS  PubMed  Google Scholar 

  37. Naya FJ, Huang HP, Qiu Y, et al. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev 1997; 11: 2323–2334.

    Article  CAS  PubMed  Google Scholar 

  38. Sussel L, Kalamaras J, Hartigan-O’Connor DJ, et al. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development 1998; 125: 2213–2221.

    CAS  PubMed  Google Scholar 

  39. Krapp A, Knofler M, Ledermann B, et al. The bHLH protein PTF1- p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. Genes Dev 1998; 12: 3752–3763.

    Article  CAS  PubMed  Google Scholar 

  40. Sosa-Pineda B, Chowdhury K, Torre M, et al. The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature 1997; 386: 399–402.

    Article  CAS  PubMed  Google Scholar 

  41. St-Onge L, Sosa-Pineda B, Chowdhury K, et al. Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas. Nature 1997; 387: 406–409.

    Article  CAS  PubMed  Google Scholar 

  42. Sander M, Neubuser A, Kalamaras J, et al. Genetic analysis reveals that Pax6 is required for normal transcription of pancreatic hormone genes and islet development. Genes Dev 1997; 11: 1662–1673.

    Article  CAS  PubMed  Google Scholar 

  43. Jonsson J, Carlsson L, Edlund T, et al. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 1994; 371: 606–609.

    Article  CAS  PubMed  Google Scholar 

  44. Ahlgren U, Jonsson J, Jonsson L, et al. Beta-cell-speciifc inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev 1998; 12: 1763–1768.

    Article  CAS  PubMed  Google Scholar 

  45. Ravassard P, Chatail F, Mallet J, et al. Relax, a novel rat bHLH transcriptional regulator transiently expressed in the ventricular proliferating zone of the developing central nervous system. J Neurosci Res 1997; 48: 146–158.

    Article  CAS  PubMed  Google Scholar 

  46. Madsen OD, Serup P, Jensen J, et al. A historical and phylogenetic perspective of islet-cell development. In: Habener JF, Hussain MA, eds. Molecular Basis of Pancreas Development and Function. Norwel: Kluwer Academic, 2001: 1–17.

    Chapter  Google Scholar 

  47. Gradwohl G, Dierich A, Le Meur M, et al. Neurogenin 3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci USA 2000; 97: 1607–1611.

    Article  CAS  PubMed  Google Scholar 

  48. Ma Q, Kintner C, Anderson DJ. Identiifcation of neurogenin, a vertebrate neuronal determination gene. Cell 1996; 87: 43–52.

    Article  CAS  PubMed  Google Scholar 

  49. Ma Q, Chen Z, Barrantes I, et al. Neurogenin1 is essential for the determination of neuronal precursors for proximal cranial sensory ganglia. Neuron 1998: 20: 469–482.

    Article  CAS  PubMed  Google Scholar 

  50. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science 1999; 284: 770–776.

    Article  CAS  PubMed  Google Scholar 

  51. De La Pompa JL, Wakeham A, Correia KM, et al. Conservation of the Notch signalling pathway in mammalian neurogenesis. Development 1997; 124: 1139–1148.

    PubMed  Google Scholar 

  52. Jensen J, Pedersen EE, Galante P, et al. Control of endodermal endocrine development by Hes-1. Nature 2000; 24: 36–44.

    CAS  Google Scholar 

  53. Stoffers DA, Zinkin NT, Stanojevic V, et al. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 1997; 15: 106–110.

    Article  CAS  PubMed  Google Scholar 

  54. Wang H, Maechler P, Ritz-Laser B, et al. Pdx1 level deifnes pancreatic gene expression pattern and cell lineage differentiation. J Biol Chem 2001; 276: 25279–25286.

    Article  CAS  PubMed  Google Scholar 

  55. Peshavaria M, Cissell MA, Henderson E, et al. The PDX-1 activation domain provides speciifc functions necessary for transcriptional stimulation in pancreatic ß-cells. Mol Endocrinol 2000; 14: 1907–1917.

    Article  CAS  PubMed  Google Scholar 

  56. Ohlsson H, Karlsson K, Edlund T. IPF1, a homeodomain-containing transactivator of the insulin gene. EMBO J 1993; 12: 4251–4259.

    CAS  PubMed  Google Scholar 

  57. Waeber G, Thompson N, Nicod P, et al. Transcriptional activation of the GLUT2 gene by IPF-1/STF-1/IDX-1 homeobox factor. Mol Endocrinol 1996; 10: 1327–1334.

    Article  CAS  PubMed  Google Scholar 

  58. Watada H, Kajimoto Y, Kaneto H, et al. Involvement of the homeodomain containing transcription factor PDX-1 in islet amyloid polypeptide gene transcription. Biochem Biophys Res Commun 1996; 229: 746–751.

    Article  CAS  PubMed  Google Scholar 

  59. Ofifeld MF, Jetton TL, Labosky PA, et al. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 1996; 122: 983–985.

    Google Scholar 

  60. Dutta S, Bonner-Weir S, Montminy M, et al. Regulatory factor linked to late-onset diabetes. Nature 1998; 392: 560.

    Article  CAS  PubMed  Google Scholar 

  61. Brink C, Chowdhury K, Gruss P. Pax4 regulatory elements mediate beta cell speciifc expression in the pancreas. Mech Dev 2001; 100: 37–43.

    Article  CAS  PubMed  Google Scholar 

  62. Harrison KA, Thaler J, Pfaff SL, et al. Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deifcient mice. Nat Genet 1999; 23: 71–75.

    CAS  PubMed  Google Scholar 

  63. Li H, Arber S, Jessell TM, et al. Selective agenesis of the dorsal pancreas in mice lacking homeobox gene Hlbx9. Nat Genet 1999; 23: 67–70.

    CAS  PubMed  Google Scholar 

  64. Jensen J, Serup P, Karlsen C, et al. mRNA proifling of rat islet tumors reveals Nkx6.1 as a â-cell speciifc homeodomain transcription factor. J Biol Chem 1996; 271: 18749–18758.

    Article  CAS  PubMed  Google Scholar 

  65. Turque N, Plaza S, Radvanyi F, et al. Pax-QNR/PAX-6, a paired box-and homeobox-containing gene expressed in neurons, is also expressed in pancreatic endocrine cells. Mol Endocrinol 1994; 8: 929–938.

    Article  CAS  PubMed  Google Scholar 

  66. Ahlgren U, Pfaff SL, Jessel TM, et al. Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells. Nature 1997; 385: 257–260.

    Article  CAS  PubMed  Google Scholar 

  67. Dohrmann C, Gruss P, Lemaire L. Pax genes and the differentiation of hormone-producing endocrine cells in the pancreas. Mech Dev 2000; 92: 47–54.

    Article  CAS  PubMed  Google Scholar 

  68. Edlund H. Transcribing pancreas. Diabetes 1998; 47: 1817–1823.

    Article  CAS  PubMed  Google Scholar 

  69. Vinik AJ, Pittenger GL, Pavlic-Renar I. Role of growth factors in pancreatic endocrine cells. Growth and differentiation. Endocr Metab Clin North Am 1993; 22: 875–887.

    CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  71. Finch P, Cunha G, Rubin J, et al. Pattern of keratinocyte growth factor and keratinocyte growth factor receptor expression during mouse foetal development suggests a role in mediating morphogenetic mesenchymal-epithelial interactions. Dev Dynam 1995; 203: 223–240.

    Article  CAS  Google Scholar 

  72. Orr-Urtreger A, Bedford M, Burakowa T, et al. Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2). Dev Biol 1993; 158: 475–486.

    Article  CAS  PubMed  Google Scholar 

  73. Le Bras S, Miralles F, Basmaciogullari A, et al. Fibroblast growth factor 2 promotes pancreatic epithelial cell proliferation via functional fibroblast growth factor receptors during embryonic life. Diabetes 1998; 47: 1236–1242.

    Article  PubMed  Google Scholar 

  74. Le Bras S, Czernichow P, Scharfmann R. A search for tyrosine kinase receptors expressed in the rat embryonic pancreas. Diabetologia 1998; 41: 1474–1481.

    Article  Google Scholar 

  75. Stark KL, McMahon JA, McMahon AP. FGFR-4, a new member of the ifbroblast growth factor receptor family, expressed in the definitive endoderm and skeletal muscle lineages of the mouse. Developmental 1991; 113: 641–651.

    CAS  Google Scholar 

  76. Miralles F, Czernichow P, Ozaki K, et al. Signaling through fibroblast growth factor receptor 2b plays a role in the development of the exocrine pancreas. Proc Natl Acad Sci USA 1999; 96: 6267–6272.

    Article  CAS  PubMed  Google Scholar 

  77. Gonzales AM, Buscaglia M, Ong M, et al. Distribution of basic ifbroblast growth factor in 18-day rat fetus: localization in the basement membranes of diverse tissues. J Cell Biol 1990; 110: 753–765.

    Article  Google Scholar 

  78. Gonzales AM, Hill DJ, Logan A, et al. Distribution of ifbroblast growth factor (FGF)-2 and FGF receptor-1 messenger RNA expression and protein presence in the mid-trimester human fetus. Pediatric Res 1996; 39: 375–385.

    Article  Google Scholar 

  79. Mason I, Fuller-Pace F, Smith R, et al. FGF-7 (keratinocyte growth factor) expression during mouse development suggests roles in myogenesis, forebrain regionalization and epithelial-mesenchymal interactions. Mech Dev 1994; 45: 15–30.

    Article  CAS  PubMed  Google Scholar 

  80. Scharfmann R, Czernichow P. Soluble factors important for pancreatic development. In: Habener JF, Hussain MA, eds. Molecular Basis of Pancreas Development and Function. Norwel: Kluwer Academic, 2001: 165–175.

    Chapter  Google Scholar 

  81. Nguyen HQ, Danilenko DM, Bucay N, et al. Expression of keratinocyte growth factor in embryonic liver of transgenic mice causes changes in epithelial growth and differentiation resulting in poly-cystic kidneys and other organ malformations. Oncogene 1996; 12: 2109–2119.

    CAS  PubMed  Google Scholar 

  82. Celli G, LaRochelle W, Mackem S, et al. Soluble dominant-negative receptor uncovers essential role for ifbroblast growth factors in multi-organ induction and pattering. EMBO J 1998; 17: 1642–1655.

    Article  CAS  PubMed  Google Scholar 

  83. Ishiwata T, Friess H, Büchler MW, et al. Characterization of keratinocyte growth factor and receptor expression in human pancreatic cancer. Am J Pathol 1998; 153: 213–222.

    Article  CAS  PubMed  Google Scholar 

  84. La Rosa S, Uccella S, Erba S, et al. Immunohistochemical detection of ifbroblast growth factor receptors in normal endocrine cells and related tumors of the digestive system. Appl Immunohistochem Mol Morphol 2001; 9: 319–328.

    Article  PubMed  Google Scholar 

  85. Massagué J. The TGFâ family of growth and differentiation factors. Cell 1987; 49: 437–438.

    Article  PubMed  Google Scholar 

  86. Ying SY. Inhibins, activins and follistatin: gonadal proteins modulating the secretion of follicle-stimulating hormone. Endocr Rev 1988; 9: 267–293.

    Article  CAS  PubMed  Google Scholar 

  87. Kim S, Hebrok M, Melton D. Notochord to endoderm signaling is required for pancreas development. Development 1997;124:4243– 4252.

    Google Scholar 

  88. Hebrok M, Kim S, Melton D. Notochord repression of endodermal sonic hedgehog permits pancreas development. Genes Dev 1998; 12: 1705–1713.

    Article  CAS  PubMed  Google Scholar 

  89. Mashima H, Shibata H, Mine T, et al. Formation of insulin-producing cells from pancreatic acinar AR42J cells by hepatocyte growth factor. Endocrinology 1996; 137: 3969–3976.

    Article  CAS  PubMed  Google Scholar 

  90. Mashima H, Yamada S, Tajima T, et al. Genes expressed during the differentiation of pancreatic AR42J cells into insulin-secreting cells. Diabetes 1999; 48: 304–309.

    Article  CAS  PubMed  Google Scholar 

  91. Furkawa M, Eto Y, Kojima I. Expression of immunoreactive activin A in fetal rat pancreas. Endocr J 1995; 42: 63–68.

    Article  Google Scholar 

  92. Ogawa K, Abe K, Kurosawa N, et al. Expression of á, âA and âB subunits of inhibin or activin and follistatin in rat pancreatic islets. FEBS Lett 1993; 319: 217–220.

    Article  CAS  PubMed  Google Scholar 

  93. Yasuda H, Inoue K, Shibata H, et al. Existence of activin A in A- and D-cells of rat pancreatic islet. Endocrinology 1993; 133: 624–630.

    Article  CAS  PubMed  Google Scholar 

  94. Wada M, Shintani Y, Kosaka M, et al. Immunohistochemical localization of activin A and follistatin in human tissues. Endocr J 1996; 43: 375–385.

    Article  CAS  PubMed  Google Scholar 

  95. La Rosa S, Uccella S, Billo P, et al. Immunohistochemical localization of á-and âA-subunits of inhibin/activin in human normal endocrine cells and related tumors of the digestive system. Virchows Arch 1999; 434: 29–36.

    Article  PubMed  Google Scholar 

  96. La Rosa S, Sessa F, Uccella S, et al. Expression of activin/inhibin subunits and follistatin in normal endocrine cells and related tumors of the gut and pancreas. Lab Invest 2001; 81: 77A.

    Article  Google Scholar 

  97. Totsuka Y, Tabuchi M, Kojima I, et al. A novel action of activin A: stimulation of insulin secretion in rat pancreatic islets. Biochem Biophys Res Commun 1988; 156: 335–339.

    Article  CAS  PubMed  Google Scholar 

  98. Yamaoka T, Idehara C, Yano M, et al. Hypoplasia of pancreatic islets in transgenic mice expressing activin receptor mutants. J Clin Invest 1998; 102: 294–301.

    Article  CAS  PubMed  Google Scholar 

  99. Shiozaki S, Tajima T, Zhang YQ, et al. Impaired differentiation of endocrine and exocrine cells of the pancreas in transgenic mouse expressing the truncated type II activin receptor. Biochim Biophys Acta 1999; 1450: 1–11.

    Article  CAS  PubMed  Google Scholar 

  100. Miralles F, Czernichow P, Scharfmann R. Follistatin regulates the relative proportions of endocrine versus exocrine tissue during pancreatic development. Development 1998; 125: 1017–1024.

    CAS  PubMed  Google Scholar 

  101. Ogawa K, Ono K, Kurohmaru M, et al. Effect of streptozocin injection on expression of immunoreactive follistatin and ßA and ßB subunits of inhibin/activin in rat pancreatic islets. Eur J Endocrinol 1995; 132: 363–369.

    Article  CAS  PubMed  Google Scholar 

  102. Miralles F, Battelino T, Czernichow P, et al. TGF-beta plays a role in morphogenesis of the pancreatic islets of Langerhans by controlling the activity of the matrix metalloproteinase MMP-2. J Cell Biol 1998; 143: 827–836.

    Article  CAS  PubMed  Google Scholar 

  103. Sanvito F, Herrera P, Huarte J, et al. TGF-ß1 influences the relative development of the exocrine and endocrine pancreas in vitro. Development 1994; 120: 3451–3462.

    CAS  PubMed  Google Scholar 

  104. Yamanaka Y, Friess H, Büchler M, et al. Synthesis and expression of transforming growth factor ß-1, ß-2, and ß-3 in the endocrine and exocrine pancreas. Diabetes 1993; 42: 746–756.

    Article  CAS  PubMed  Google Scholar 

  105. Wang T, Bonner-Weir S, Oates P, et al. Pancreatic gastrin stimulates islet differentiation of transforming growth factor alpha-induced ductular precursor cells. J Clin Invest 1993; 92: 1349–1356.

    Article  CAS  PubMed  Google Scholar 

  106. Wang RN, Rehfeld JF, Nielsen FC, et al. Expression of gastrin and transforming growth factor-alpha during duct to islet cell differentiation in the pancreas of duct-ligated adult rats. Diabetologia 1997; 40: 887–893.

    Article  CAS  PubMed  Google Scholar 

  107. Erickson S, O’Shea K, Ghaboosi N, et al. ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2- and heregulin-deficient mice. Development 1997; 124: 4999–5011.

    CAS  PubMed  Google Scholar 

  108. Kanana-Gantenbein C, Dicon E, Czernichow P, et al. Presence of nerve growth factor and its receptors in an in vitro model of islet cell development: implication in normal islet morphogenesis. Endocrinology 1995; 136: 3154–3162.

    Article  Google Scholar 

  109. Rooman I, Schuit F, B ouwens L. Effect of vascular endothelial growth factor on growth and differentiation of pancreatic duct epithelium. Lab Invest 1997; 76: 225–232.

    CAS  PubMed  Google Scholar 

  110. Öberg C, Waltenberg J, Claesson-Welsh L, et al. Expression of protein tyrosine kinases in islet cells: possible role of the Flk-1 receptor for ß-cell maturation from duct cells. Growth Factor 1994; 10: 115–126.

    Article  Google Scholar 

  111. Christofori G, Naik P, Hanahan D. Vascular endothelial growth factor and its receptors, flt-1 and flk-1, are expressed in normal pancreatic islets throughout islet cell tumorigenesis. Mol Endocrinol 1995; 9: 1760–1770.

    Article  CAS  PubMed  Google Scholar 

  112. Kuroda M, Oka T, Oka Y, et al. Colocalization of vascular endothelial growth factor (vascular permeability factor) and insulin in pancreatic islet cells. J Clin Endocrinol Metab 1995; 80: 3196–3200.

    Article  CAS  PubMed  Google Scholar 

  113. La Rosa S, Uccella S, Finzi G, et al. Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: correlation with microvessel density and clinicopathological features. Hum Pathol 2003; 34: 18–27.

    Article  PubMed  CAS  Google Scholar 

  114. Malaisse-Lagae F, Stefan Y, Cox I, et al. Identiifcation of a lobe in the human pancreas rich in pancreatic polypeptide. Diabetologia 1979; 17: 361–365.

    Article  CAS  PubMed  Google Scholar 

  115. Bussolati G, Capella C, Vassallo G, et al. Histochemical and ultra-structural studies of pancreatic A cells. Evidence for glucagon and non-glucagon components of the alpha granule. Diabetologia 1971; 7: 181–188.

    Article  CAS  PubMed  Google Scholar 

  116. Ali Rachedi A, Varndell IM, Adrian TE, et al. Peptide YY (PYY) immunoreactivity is co-stored with glucagon-related immunoreactants in endocrine cells of the gut and pancreas. Histochemistry 1984; 80: 487–491.

    Article  CAS  Google Scholar 

  117. Schmechel D, Marangos PJ, Brightman M. Neuron speciifc enolase is a molecular marker for peripheral and central neuroendocrine cells. Nature 1978; 276: 834–836.

    Article  CAS  PubMed  Google Scholar 

  118. Wilkinson KD, Lee K, Desphande S, et al. The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase. Science 1989; 246: 670–673.

    Article  CAS  PubMed  Google Scholar 

  119. Benjiannet S, Leduc R, Lezure C, et al. GAWK: a novel pituitary peptide: isolation, immunohistochemical localization and complete aminoacid sequence. Biochem Biophys Res Commun 1985; 126: 607–609.

    Google Scholar 

  120. Hsi JL, Seidah NG, De Serves G, et al. Isolation and NH2-terminal sequence of a novel porcine anterior pituitary polypeptide: homology to proinsulin, secretin and Rous sarcoma virus transforming protein TVFV60. Fed Europ Biol Soc Lett 1982; 142: 261–266.

    Article  Google Scholar 

  121. Wiedenmann B, Franke WW. Identification and localization of synaptophysin, an integral membrane glycoprotein of MW 38.000 characteristic of presynaptic vesicles. Cell 1985; 41: 1017–1028.

    Article  CAS  PubMed  Google Scholar 

  122. Ravazzola M, Orci L. Glucagon and glicentin immunoreactivity are topologically segregated in the alpha granule of the human pancreatic A cell. Nature 1980; 286: 66–67.

    Article  Google Scholar 

  123. Solcia E, Fiocca R, Capella C, et al. Glucagon-and PP-related peptides of intestinal L cells and pancreatic/gastric A or PP cells. Possible interrelationships of peptides and cells during evolution, fetal development and tumor growth. Peptides. 1985; 6 (Suppl 3): 223–229.

    Article  CAS  PubMed  Google Scholar 

  124. Goossens A, Heitz PU, Klöppel G. Pancreatic endocrine cells and their non-neoplastic proliferations. In: Dayal Y, ed. Endocrine Pathology of the Gut and Pancreas. Boca Raton: CRC Press, 1991: 69–104.

    Google Scholar 

  125. Misugi K, Howel SL, Greider MH, et al. The pancreatic beta cell. Demonstration with peroxidase-labelled antibody technique. Arch Pathol 1970; 89: 97–102.

    CAS  PubMed  Google Scholar 

  126. Orci L, Ravazzola M, Amherit M, et al. Direct identiifcation of prohormone conversion site in insulin secreting cells. Cell 1985; 42: 671–681.

    Article  CAS  PubMed  Google Scholar 

  127. Westermark P, Wernstedt C, Wilander E, et al. Amyloid ifbrils in human insulinoma and islets of diabetic cats are derived from a neuropeptide-like protein also present in normal islet cells. Proc Natl Acad Sci USA 1987; 84: 3881–3885.

    Article  CAS  PubMed  Google Scholar 

  128. Orci L, Ravazzola M, Storch MJ, et al. Proteolytic maturation is a post-Golgi event which occurs in acidifying clathrin-coated secretory vesicles. Cell 1987; 49: 865–868.

    Article  CAS  PubMed  Google Scholar 

  129. Luft R, Efendic S, Hockfelt T, et al. Immunohistochemical evidence for the localisation of somatostatin-like immunoreactivity in a cell population of pancreatic islets. Med Biol 1974; 52: 428–430.

    CAS  PubMed  Google Scholar 

  130. Like AA. The ultrastructure of the secretory cell of the islets of Langerhans in man. Lab Invest 1967; 16: 937–951.

    CAS  PubMed  Google Scholar 

  131. Grube D, Bohn R. The microanatomy of human islets of Langerhans with special reference to somatostatin (D-) cells. Arch Histol Jpn 1983; 46: 327–353.

    Article  CAS  PubMed  Google Scholar 

  132. La Rosa S, Capella C, Lloyd RV. Localization of myosin XVA in endocrine tumors of the gut and pancreas. Endocr Pathol 2002; 13: 29–37.

    Article  PubMed  Google Scholar 

  133. Alberti KGMN, Zimmet PZ. Deifnition, diagnosis, and classification of diabetes mellitus and its complications. Part 1: diagnosis and classiifcation of diabetes mellitus. Provisional report of a WHO consultation. Diabet Med 1998; 15: 539–553.

    Article  CAS  PubMed  Google Scholar 

  134. American Diabetes Association. Report of the expert committee on the diagnosis and classiifcation of diabetes mellitus. Diabetes Care 1997; 20: 1183–1197.

    Google Scholar 

  135. World Health Organization Expert Committee on diabetes mellitus. 2nd report. Technical report series. Geneva, WHO,1980

    Google Scholar 

  136. Zimet P. Type 2 (non-insulin dependent) diabetes: an epidemiological overview. Diabetologia 1982; 22: 399–411.

    Article  Google Scholar 

  137. Zimet PZ. Diabetes epidemiology as a tool to trigger diabetes research and care. Diabetologia 1999; 42: 499–518.

    Article  Google Scholar 

  138. Unger RH, Foster DW. Diabetes mellitus. In: Wilson JD, Foster DW, Kronenburg HM, Larsen PR, eds. Williams Textbook of Endocrinology, 9th edit. Philadelphia: WB Saunders, 1998: 973–1059.

    Google Scholar 

  139. Masharami U, Karam JH. Pancreatic hormones and diabetes mellitus. In: Greenspan FS, Gardner DG, eds. Basic and Clinical Endocrinology, 6th edit. New York: McGraw-Hill, 2001: 623–698.

    Google Scholar 

  140. Rubenstein AH. Diabetes mellitus, carbohydrate metabolism, and lipid disorders. In: DeGroot LJ, Jamenson JL, eds. Endocrinology, 4th edit. Philadelphia: WB Saunders, 2001: 654–968.

    Google Scholar 

  141. Gepts W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 1965; 14: 619–633.

    CAS  PubMed  Google Scholar 

  142. Foulis AK, Stewart JA. The pancreas in recent-onset type 1 (insulin-dependent) diabetes mellitus: insulin content of islets, insulitis and associated changes in the exocrine acinar tissue. Diabetologia 1984; 26: 456–461.

    Article  CAS  PubMed  Google Scholar 

  143. Klöppel G, Drenck CR, Oberholzer M, et al. Morphometric evidence for a striking B-cell reduction at the clinical onset of type 1 diabetes. Virchows Arch [A] Pathol Anat 1984; 403: 441–452.

    Article  Google Scholar 

  144. Löhr M, Klöppel G. Residual insulin positivity and pancreatic atrophy in relation to duration of chronic type 1 (insulin-dependent) diabetes mellitus and microangiopathy. Diabetologia 1987; 24: 366–371.

    Google Scholar 

  145. Henderson JR, Daniel PM, Fraser PA. The pancreas as a single organ: the influence of the endocrine upon the exocrine part of the gland. Gut 1981; 22: 158–167.

    Article  CAS  PubMed  Google Scholar 

  146. Korc M, Owerbach D, Quinto C, et al. Pancreatic islet-acinar cell interaction: amylase messenger RNA levels are determined by insulin. Science 1981; 213: 351–353.

    Article  CAS  PubMed  Google Scholar 

  147. Gepts W, Le Compte PM. The pancreatic islets in diabetes. Am J Med 1981; 70: 105–115.

    Article  CAS  PubMed  Google Scholar 

  148. Klöppel G, Clemens A. Insulin-dependent diabetes mellitus: islet changes in relation to etiology and pathogenesis. Endocr Pathol 1998; 8: 273–282.

    Article  Google Scholar 

  149. Lernmark A, Klöppel G, Stenger D, et al. Heterogeneity of islet pathology in two infants with recent onset diabetes mellitus. Virchows Arch 1995; 465: 631–640.

    Google Scholar 

  150. Hanninen A, Jalkanen S, Salmi M, et al. Macrophages, T cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulin-dependent diabetes mellitus. J Clin Invest 1992;90:1901– 1910.

    Google Scholar 

  151. Conrad B, Weidmann E, Trucco G, et al. Evidence for superanti-gen involvement in insulin-dependent diabetes mellitus aetiology. Nature 1994; 33: 749–760.

    Google Scholar 

  152. Foulis AK. The pathology of endocrine pancreas in type 1 (insulin-dependent) diabetes mellitus. APMIS 1996; 104: 161–167.

    Article  CAS  PubMed  Google Scholar 

  153. Rahier J, Goebbels RM, Henquin JC. Cellular composition of the human diabetic pancreas. Diabetologia 1983; 24: 336–371.

    Article  Google Scholar 

  154. Junker K, Egeberg J, Kromann H, et al. An autopsy study of the islets of Langerhans in acute-onset juvenile diabetes mellitus. APMIS 1977; 85: 699–706.

    CAS  Google Scholar 

  155. Olgive RF. The endocrine pancreas in human and experimental diabetes. In: Cameron MP, O’Connor M, eds. Ciba Foundation Colloquia on Endocrinology. The Aetiology of Diabetes Mellitus and Its Complications. London: Churchill Livingstone, 1964: 49–74.

    Google Scholar 

  156. Klöppel G. Islet histopathology in diabetes mellitus. In: Klöppel G, Heitz PU, eds. Pancreatic Pathology. Edinburgh: Churchill Livingstone, 1984: 154–192.

    Google Scholar 

  157. Clark A, Charge SBP, Badman MK, et al. Islet amyloid in type 2 (non-insulin-dependent) diabetes. APMIS 1996; 104: 12–18.

    Article  CAS  PubMed  Google Scholar 

  158. Bell ET. Hyalinization of the islets of Langerhans in diabetes mellitus. Diabetes 1952; 1: 341–344.

    CAS  PubMed  Google Scholar 

  159. Johnson KH, O’Brien TD, Betsholtz C, et al. Islet amyloid polypeptide mechanisms of amyloidogenesis in the pancreatic islets and potential roles in diabetes mellitus. Lab Invest 1992; 66: 522–535.

    CAS  PubMed  Google Scholar 

  160. Nishi M, Sanke T, Nagamatsu S, et al. A new beta cell secretory product related to islet amyloid deposits. J Biol Chem 1990;265:4173– 4176.

    Google Scholar 

  161. Lukinius A, Wilander E, Westermark EGT, et al. Co-localization of islet amyloid polypeptide and insulin in the B-cell secretory granules of the human pancreatic islets. Diabetologia 1989; 32: 240–244.

    Article  CAS  PubMed  Google Scholar 

  162. Solcia E, Klöppel G, Capella C. Tumor-like conditions of the endocrine pancreas. In: Rosai J, Sobin LH, eds. Tumors of the Pancreas. Atlas of Tumor Pathology, 3rd edit. Washington, DC: Armed Forces Institute of Pathology, 1997: 237–246.

    Google Scholar 

  163. Ray MB, Zumwalt R. Islet-cell hyperplasia in genetic deficiency of alpha- 1-proteinase inhibitor. Am J Clin Pathol 1986; 85: 681–687.

    CAS  PubMed  Google Scholar 

  164. Weidenhein KM, Hinchey WW, Campbell WG Jr. Hyperinsulinemic hypoglycemia in adults with islet cell hyperplasia and degranulation of exocrine cells of the pancreas. Am J Clin Pathol 1983; 79: 14–24.

    Google Scholar 

  165. Ellison EH, Wilson SD. The Zollinger–Ellison syndrome update. Surg Clin North Am 1967; 47: 1115–1124.

    CAS  PubMed  Google Scholar 

  166. Verner JV, Morrison AB. Endocrine pancreatic islet disease with diarrhea. Report of a case due to diffuse hyperplasia of nonbeta islet tissue with a review of 54 additional cases. Arch Intern Med 1974; 133: 492–499.

    Article  CAS  PubMed  Google Scholar 

  167. Solcia E, Capella C, Buffa R, et al. Antigenic markers of neuroendocrine tumors: their diagnostic and prognostic value. In: Fenoglio CM, Weinstein RS, Kaufman N, eds. New Concepts in Neoplasia as

    Google Scholar 

  168. Applied to Diagnostic Pathology. Baltimore: Williams and Wilkins, 1986:242–261.

    Google Scholar 

  169. Solcia E, Capella C, Riva C, et al. The morphology and neuroendocrine proifle of pancreatic epithelial tumors. Ann NY Acad Sci 1988; 527: 508–517.

    Article  CAS  PubMed  Google Scholar 

  170. Kahn E, Anderson WM, Greco MA, et al. Pancreatic disorders in pediatric acquired immunodeficiency syndrome. Hum Pathol 1995; 26: 765–770.

    Article  CAS  PubMed  Google Scholar 

  171. Verloes A Massart B, Dehlleux I, et al. Clinical overlap of Beckwith– Wiedemann, Perlman and Simpson-Golabi-Behmel syndromes: a diagnostic pitfall. Clin Genet 1995; 47: 257–262.

    Article  CAS  PubMed  Google Scholar 

  172. Hardwick DF, Dimmick JE. Metabolic cirrhosis of infancy and early childhood. In: Rosenberg HS, Bolande RP, eds. Perspectives in Pediatric Pathology, Vol. 3. Chicago, Year Book, 1976:103– 144.

    Google Scholar 

  173. Zellweger H. Cerebro-hepato-renal syndrome. In: Bergsma D, ed. Birth Defects Compendium, 2nd edit. New York: Alan R. Liss, 1979: 178–196.

    Google Scholar 

  174. Rosemberg AM, Hawort JC, DeGroot W, et al. A case of leprechaunism with severe hyperinsulinemia. Am J Dis Child 1980; 134: 170–175.

    Google Scholar 

  175. Stefan Y, Bordi C, Grasso S, et al. Beckwith–Wiedemann syndrome: a quantitative, immunohistochemical study of the pancreatic islet cell populations. Diabetologia 1985; 28: 914–919.

    Article  CAS  PubMed  Google Scholar 

  176. Laidlaw GF. Nesioblastoma, the islet tumor of the pancreas. Am J Pathol 1938; 2: 125–134.

    Google Scholar 

  177. Aynsley-Green A, Polak JM, Bloom SR, et al. Nesidioblastosis of the pancreas: definition of the syndrome and the management of the severe neonatal hyperinsulinemic hypoglycemia. Arch Dis Child 1981; 56: 469–508.

    Article  Google Scholar 

  178. Stanley CA, Baker L. The causes of neonatal hypoglycemia. N Engl J Med 1999; 340: 1200–1201.

    Article  CAS  PubMed  Google Scholar 

  179. Thornton PS, Alter CA, Katz LE, et al. Short-and long-term use of octreotide in the treatment of congenital hyperinsulinism. J Pediatr 1993; 123: 637–643.

    Article  CAS  PubMed  Google Scholar 

  180. De Lonlay-Debeney P, Poggi-Travert F, Fournet JC, et al. Clinical features of 52 neonates with hyperinsulinism. N Engl J Med 1999; 340: 1169–1175.

    Article  Google Scholar 

  181. Shilyansky J, Fisher S, Cutz E, et al. Is 95% pancreatectomy the procedure of choice for treatment of persistent hyperinsulinemic hypoglycemia of the neonate? J Pediatr Sur 1997; 32: 342–346.

    Article  CAS  Google Scholar 

  182. Reinecke-Lüthge A, Koschoreck F, Klöppel G. The molecular basis of persistent hyperinsulinemic hypoglycemia of infancy and its pathologic substrates. Virchows Arch 2000; 436: 1–5.

    Article  PubMed  Google Scholar 

  183. Dunne MJ, Kane C, Shephered RM, et al. Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor. N Engl J Med 1997; 336: 703–706.

    Article  CAS  PubMed  Google Scholar 

  184. Nestorowicz A, Inagaki N, Gonoi T, et al. A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism. Diabetes 1997; 46: 1743–1748.

    Article  CAS  PubMed  Google Scholar 

  185. Thomas PM, Cote GJ, Wohlik N, et al. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 1995; 268: 426–429.

    Article  CAS  PubMed  Google Scholar 

  186. De Lonlay P, Fournet JC, Rahier J, et al. Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy. J Clin Invest 1997; 100: 802–807.

    Article  PubMed  Google Scholar 

  187. Meissner T, Beinbrech B, Mayatepek E. Congenital hyperinsulinism: molecular basis of a heterogeneous disease. Hum Mutat 1999; 13: 351–361.

    Article  CAS  PubMed  Google Scholar 

  188. Jaffe R, Hashida Y, Yunis EJ. Pancreatic pathology in hyperinsulinemic hypoglycemia of infancy. Lab Invest 1980; 42: 356–365.

    CAS  PubMed  Google Scholar 

  189. Goossens A, Gepts W, Saudubray JM, et al. Diffuse and focal nesidioblastosis: a clinicopathological study of 24 patients with persistent neonatal hyperinsulinemic hypoglycemia. Am J Surg Pathol 1989; 13: 766–775.

    Article  CAS  PubMed  Google Scholar 

  190. Witte DP, Greider MH, Deschryver-Kecskement K, et al. The juvenile human endocrine pancreas: normal vs idiopathic hyperinsulinemic hypoglycemia. Semin Diagn Pathol 1984; 1: 30–42.

    CAS  PubMed  Google Scholar 

  191. Sampoux C, Guiot Y, Lefevre A, et al. Neonatal hyperinsulinemic hypoglycemia: heterogeneity of the syndrome and keys for differential diagnosis. J Clin Endocrinol Metab 1998; 83: 1455–1461.

    Article  Google Scholar 

  192. Lyonnet S, B onnefont JP, Saudubray JM, et al. Localization of focal lesion permitting partial pancreatectomy in infants. Lancet 1989; 2: 671.

    Article  CAS  PubMed  Google Scholar 

  193. Falkmer S, Askensten U. Disturbed growth of the endocrine pancreas. In: Levebre PJ, Pipeleers DG, eds. The Pathology of the Endocrine Pancreas in Diabetes. Berlin: Springer-Verlag, 1988: 125–140.

    Chapter  Google Scholar 

  194. Dahms BB, Landing BH, Blastovics M, et al. Nesidioblastosis and other islet cell abnormalities in hyperinsulinemic hypoglycemia of childhood. Hum Pathol 1980; 11: 641–649.

    Article  CAS  PubMed  Google Scholar 

  195. Gould VE, Memoli VA, Dardi LE, et al. Nesidiodysplasia and nesidioblastosis of infancy: structural and functional correlation with the syndrome of hyperinsulinemic hypoglycemia. Pediatr Pathol 1983; 1: 7–31.

    Article  CAS  PubMed  Google Scholar 

  196. Rahier J, Falt K, Muntefering H, et al. The basis structural lesion of persistent neonatal hypoglycemia with hyperinsulinism: deficiency of pancreatic D-cells or hyperactivity of B-cells? Diabetologia 1984; 26: 282–289.

    Article  CAS  PubMed  Google Scholar 

  197. Sampoux C, Guiot Y, Dubois D, et al. Pancreatic B-cell proliferation in persistent hyperinsulinemic hypoglycemia of infancy: an immunohistochemical study of 18 cases. Mod Pathol 1998; 11: 444–449.

    Google Scholar 

  198. Kollee LA, Monnens LA, Cejka V, et al. Persistent neonatal hypoglycemia due to glucagon deifciency. Arch Dis Child 1978; 53: 422–424.

    Article  CAS  PubMed  Google Scholar 

  199. Keller A, Stone AM, Valderrama E, et al. Pancreatic nesidioblastosis in adults. Am J Surg 1983; 145: 412–416.

    Article  CAS  PubMed  Google Scholar 

  200. Burman WJ, McDermott MT, Bornemann M. Familial hyperinsulinism presenting in adults. Arch Intern Med 1992; 152: 2125–2127.

    Article  CAS  PubMed  Google Scholar 

  201. Kim HK, Shong YK, Cho Y, et al. Nesidioblastosis in an adult with hyperinsulinemic hypoglycemia. Endocr J 1996; 43: 163–167.

    Article  CAS  PubMed  Google Scholar 

  202. Veda Y, Kurihara K, Kondoh T, et al. Islet-cell hyperplasia causing hyperinsulinemic hypoglycemia in an adult. J Gastroenterol 1998; 33: 125–128.

    Article  Google Scholar 

  203. Eriguchi N, Aoyagi S, Hara M, et al. Nesidioblastosis with hyperinsulinemic hypoglycemia in adults: report of two cases. Surg Today 1999; 29: 361–363.

    Article  CAS  PubMed  Google Scholar 

  204. Weinstock G, Margulies P, Kahn E, et al. Islet cell hyperplasia: an unusual cause of hypoglycemia in an adult. Metabolism 1986; 35: 11–117.

    Article  Google Scholar 

  205. Kim YW, Park YK, Park JH, et al. Islet cell hyperplasia of the pancreas presenting as hyperinsulinemic hypoglycemia in an adult. Yon-sei Med J 2000; 41: 426–429.

    CAS  Google Scholar 

  206. Witteles RM, Strayss FH, Sugg SL, et al. Adult-onset nesidioblastosis causing hypoglycemia. An important clinical entity and continuing treatment dilemma. Arch Surg 2001; 136: 656–663.

    Article  CAS  PubMed  Google Scholar 

  207. Service FJ, Natt N, Thompson GB, et al. Noninsulinoma pancreatogenous hypoglycemia: a novel syndrome of hyperinsulinemic hypoglycemia in adults independent of mutations in Kir6.2 and SUR1 genes. J Clin Endocrinol Metab 1999; 84: 1582–1589.

    Article  CAS  PubMed  Google Scholar 

  208. Klöppel G, Willemer S, Stamm B, et al. Pancreatic lesions and hormonal proifle of pancreatic tumors in multiple endocrine neoplasia type I. An immunocytochemical study of nine patients. Cancer 1986; 57: 1824–1832.

    Article  PubMed  Google Scholar 

  209. Rindi G, Terenghi G, Westermark G, et al. Islet amyloid polypeptide (IAPP) in proliferating pancreatic B cells during development, hyperplasia and neoplasia in man and mouse. Am J Pathol 1991; 138: 1321–1334.

    CAS  PubMed  Google Scholar 

  210. Rindi G, Bishop AE, Murphy D, et al. Morphological analysis of endocrine tumour genesis in pancreas and anterior pituitary of AVP/ SV40 transgenic mice. Virchows Arch [A] 1988; 412: 255–266.

    Article  CAS  Google Scholar 

  211. Rindi G, Grant SGN, Yiangou Y, et al. Development of neuroendocrine tumours in the gastrointestinal tract of transgenic mice: heterogeneity of hormone expression. Am J Pathol 1990; 136: 1349–1363.

    CAS  PubMed  Google Scholar 

  212. Rindi G, Efrat S, Gathei MA, et al. Glucagonomas of transgenic mice express a wide range of general neuroendocrine markers and bioactive peptides. Virchows Arch [A] 1991; 419: 115–129.

    Article  CAS  Google Scholar 

  213. Bonner-Weir S, Baxter LA, Schuppin GT, Smith FE. A second pathway for regeneration of adult exocrine and endocrine pancreas. Diabetes 1993; 42: 1715–1720.

    Article  CAS  PubMed  Google Scholar 

  214. Smith FE, Rosen KM, Villa-Komaroff L, et al. Enhanced insulin-like growth factor I gene expression in regenerating rat pancreas. Proc Natl Acad Sci USA 1991; 6152–6156.

    Google Scholar 

  215. Porta EA, Stein AA, Patterson P. Ultrastructural changes of the pancreas and liver in cystic ifbrosis. Am J Clin Pathol 1964; 42: 451–465.

    CAS  PubMed  Google Scholar 

  216. Cubilla AL, Fitzgerald PJ. Tumors of the exocrine pancreas. Atlas of Tumor Pathology. Washington, DC: Armed Forces Institute of Pathology, 1984.

    Google Scholar 

  217. Bockman DE, Boydston WR, Anderson WC. Origin of tubular complexes in human chronic pancreatitis. Am J Surg 1982; 144: 243–249.

    Article  CAS  PubMed  Google Scholar 

  218. Goodswaard WB, Houthoff HJ, Koudstaal J, et al. Nesidioblastosis and endocrine hyperplasia of the pancreas: a secondary phenomenon. Hum Pathol 1986; 17: 46–54.

    Article  Google Scholar 

  219. Rindi G. Transgenic models of endocrine tumors. In: Polak JM, ed. Diagnostic Histopathology of Neuroendocrine Tumors. Edinburgh: Churchill-Livingstone, 1993: 67–89.

    Google Scholar 

  220. Solcia E, Sessa F, Rindi G, et al. Pancreatic endocrine tumors: nonfunctioning tumors and tumors with uncommon function. In: Dayal Y, ed. Endocrine Pathology of the Gut and Pancreas. Boca Raton: CRC Press, 1991: 105–132.

    Google Scholar 

  221. Solcia E, Klöppel G, Capella C. Tumors of the endocrine pancreas. In: Rosai J, Sobin LH, eds. Tumors of the Pancreas. Atlas of Tumor Pathology, 3rd edit. Washington, DC: Armed Forces Institute of Pathology, 1997: 145–209.

    Google Scholar 

  222. Crabtree JS, Scacheri PC, Ward JM, et al. A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. Proc Natl Acad Sci USA 2001; 98: 118–123.

    Article  Google Scholar 

  223. Nicholls AG. Simple adenoma of the pancreas arising from an island of Langerhans. J Med Res 1902; 8: 385–395.

    CAS  PubMed  Google Scholar 

  224. Heitz PU. Pancreatic endocrine tumors. In: Klöppel G, Heitz PU, eds. Pancreatic Pathology. Edinburgh: Churchill-Livingstone, 1984: 206–232.

    Google Scholar 

  225. Capella C, Heitz PU, Höfler H, et al. Revised classiifcation of neuro-endocrine tumours of the lung, pancreas and gut. Virchows Arch 1995; 425: 547–560.

    Article  CAS  PubMed  Google Scholar 

  226. Kimura N, Miura W, Noshiro T, et al. Ki-67 is an indicator of progression of neuroendocrine tumors. Endocr Pathol 1994; 5: 223–228.

    Article  Google Scholar 

  227. DeLellis RA. Does the evaluation of proliferative activity predict malignancy or prognosis in endocrine tumors? Hum Pathol 1995; 26: 131–133.

    Article  CAS  PubMed  Google Scholar 

  228. Lloyd RV. Proliferative markers in the study of endocrine diseases. Endocr Pathol 1995; 6: 83–86.

    Article  Google Scholar 

  229. Pelosi G, Zamboni G. Proliferation markers and their uses in the study of endocrine tumors. Endocr Pathol 1996; 7: 103–119.

    Article  PubMed  Google Scholar 

  230. Pelosi G, Zamboni G, Doglioni C, et al. Immunodetection of proliferating cell nuclear antigen assesses the growth fraction and predicts malignancy in endocrine tumors of the pancreas. Am J Surg Pathol 1992; 16: 1215–1225.

    Article  CAS  PubMed  Google Scholar 

  231. La Rosa S, Sessa F, Capella C, et al. Prognostic criteria in nonfunctioning pancreatic endocrine tumors. Virchows Arch 1996; 429: 323–333.

    Article  PubMed  Google Scholar 

  232. Lloyd RV. Utility of Ki-67 as a prognostic marker in pancreatic endocrine neoplasms. Am J Clin Pathol 1998; 109: 245–247.

    CAS  PubMed  Google Scholar 

  233. Chaudhry A, Öberg K, Wilander E. A study of biological behavior based on the expression of a proliferating antigen in neuroendocrine tumors of the digestive system. Tumor Biol 1992; 13: 27–35.

    Article  CAS  Google Scholar 

  234. Pelosi G, Bresaola E, Bogina G, et al. Endocrine tumors of the pancreas: Ki-67 immunoreactivity on parafifn sections is an independent predictor for malignancy. A comparative study with proliferating-cell nuclear antigen and progesterone receptor protein immunostaining, mitotic index, and other clinicopathologic variable. Hum Pathol 1996; 27: 1124–1134.

    Article  CAS  PubMed  Google Scholar 

  235. Pelosi G, Pasini F, Bresaola E, et al. High-afifnity monomeric 67-kD laminin receptors and prognosis in pancreatic endocrine tumors. J Pathol 1997; 183: 62–69.

    Article  CAS  PubMed  Google Scholar 

  236. Clarke MR, Baker EV, Weyant RJ, et al. Proliferative activity in pancreatic endocrine tumors: association with function, metastases, and survival. Endocr Pathol 1997; 8: 181–187.

    Article  PubMed  Google Scholar 

  237. Gentil Perret AG, Mosnier JF, Buono JP, et al. The relationship between MIB-1 proliferation index and outcome in pancreatic neuroendocrine tumors. Am J Clin Pathol 1998; 109: 286–293.

    Google Scholar 

  238. Chang HJ, Batts KP, Lloyd RV, et al. Prognostic signiifcance of p27, Ki-67, and topoisomerase IIa expression in clinically nonfunctioning pancreatic endocrine tumors. Endocr Pathol 2000;11:229– 241.

    Google Scholar 

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

    Article  Google Scholar 

  240. Solcia E, Klöppel G, Sobin LH, et al. Histological typing of endocrine tumours. WHO International Histological Classiifcation of Tumours, 2nd edit. Berlin: Springer, 2000.

    Book  Google Scholar 

  241. Heymann MF, Joubert M, Nemeth J, et al. Prognostic and immunohistochemical validation of the Capella classiifcation of pancreatic neuroendocrine tumours: an analysis of 82 sporadic cases. Histopathology 2000; 36: 421–432.

    Article  CAS  PubMed  Google Scholar 

  242. Schindl M, Kaczirek K, Kaserer K, et al. Is the new classification of neuroendocrine pancreatic tumors of clinical help? World J Surg 2000; 24: 1312–1318.

    Article  CAS  PubMed  Google Scholar 

  243. Morohoshi T, Kanda M, Horie A, et al. Immunocytochemical markers of uncommon pancreatic tumors. Acinar cell carcinoma, pancreatoblastoma and solid-cystic (papillary-cystic) tumor. Cancer 1987; 59: 739–747.

    Article  CAS  PubMed  Google Scholar 

  244. Klimstra DS, Heffess CS, Oertel JE, et al. Acinar cell carcinoma of the pancreas. A clinicopathologic study of 28 cases. Am J Surg Pathol 1992; 16: 815–837.

    Article  CAS  PubMed  Google Scholar 

  245. Klimstra DS, Wenig BM, Adair CF, et al. Pancreatoblastoma. A clinicopathologic study and review of the literature. Am J Surg Pathol 1995; 19: 1371–1389.

    Article  CAS  PubMed  Google Scholar 

  246. Lam KY, Lo CY. Pancreatic endocrine tumour: a 22-year clinico-pathological experience with morphological, immunohistochemical observation and review of the literature. Eur J Surg Oncol 1997; 23: 36–42.

    Article  CAS  PubMed  Google Scholar 

  247. Broughan TA, Leslie JD, Soto JM, et al. Pancreatic islet cell tumours. Surgery 1986; 99: 671–678.

    CAS  PubMed  Google Scholar 

  248. Klöppel G, Heitz PU. Pancreatic endocrine tumors. Path Res Pract 1988; 183: 155–168.

    Article  PubMed  Google Scholar 

  249. Koolie H, Whitte TT. Pancreatic islet beta cell tumors and hyperplasia: experience in 14 Seattle hospitals. Ann Surg 1972;175:326– 335.

    Google Scholar 

  250. Howard JN, Moss NH, Rhoads JE. Hyperinsulinism and islet cell tumors of the pancreas with 398 recorded tumors. Surg Gynecol Obstet 1950; 90: 417–455.

    CAS  Google Scholar 

  251. Stefanini P, Carboni M, Patrassi N. Beta islet cell tumours of the pancreas, results of a statistical study on 1067 cases collected. Surgery 1974; 75: 597–609.

    CAS  PubMed  Google Scholar 

  252. Lo CY, Lam KY, Kung AWC, et al. Pancreatic insulinomas. A 15 years experience. Arch Surg 1997; 132: 926–930.

    Article  CAS  PubMed  Google Scholar 

  253. Grant CS. Gastrointestinal endocrine tumours. Insulinoma. Ballieres Clin Gastroenterol 1996; 10: 645–671.

    Article  CAS  Google Scholar 

  254. Boden G. Insulinoma and glucagonoma. Semin Oncol 1987; 14: 253–262.

    CAS  PubMed  Google Scholar 

  255. Rothmund M, Angelini L, Breust M, et al. Surgery for benign insulinoma: an international review. World J Surg 1990; 14: 398–399.

    Article  Google Scholar 

  256. Le Bodic MF, Heymann MF, Lecomte M, et al. Immunohistochemical study of 100 pancreatic tumors in 28 patients with multiple endocrine neoplasia type I. Am J Surg Pathol 1996; 20: 1378–1384.

    Article  PubMed  Google Scholar 

  257. Toshimori H, Narita R, Nakazato M, et al. Islet amyloid polypeptide in insulinoma and islets of the pancreas of non-diabetic and diabetic subjects. Virchows Arch [A] 1991; 418: 411–417.

    Article  CAS  Google Scholar 

  258. Lin TH, Tseng HC, Zhu Y, et al. Insulinoma. An immunohistochemical and morphologic analysis of 95 cases. Cancer 1985;56:1420– 1429.

    Google Scholar 

  259. Mukai K, Grotting JC, Greider MH, et al. Retrospective study of 77 pancreatic endocrine tumors using the immunoperoxidase method. Am J Surg Pathol 1982; 6: 387–399.

    Article  CAS  PubMed  Google Scholar 

  260. Klöppel G, Höfler H, Heitz PU. Pancreatic endocrine tumors in man. In: Polak JM, ed. Diagnostic Histopathology of Neuroendocrine Tumors. Edinburgh: Churchill-Livingstone, 1993: 91–121.

    Google Scholar 

  261. Azzoni C, D’Adda T, Tamburrano G, et al. Functioning human insulinomas. An immunohistochemical analysis of intracellular insulin processing. Virchows Arch 1998; 433: 495–504.

    Article  CAS  PubMed  Google Scholar 

  262. Pavelic K, Hrascani R, Kapitanovic S, et al. Molecular genetics of malignant insulinoma. Anticancer Res 1996; 16: 1707–1718.

    CAS  PubMed  Google Scholar 

  263. Berger M, Bordi C, Cupper HY, et al. Functional and morphologic characterization of human insulinomas. Diabetes 1983; 32: 921–931.

    Article  CAS  PubMed  Google Scholar 

  264. Creutzfeldt W, Arnold R, Creutzfeldt C, et al. Biochemical and morphological investigations of 30 human insulinomas. Correlation between the tumor content of insulin and proinsulin-like components and the histological and ultrastructural appearance. Diabetologia 1973; 9: 217–231.

    Article  CAS  PubMed  Google Scholar 

  265. Ruttmann E, Klöppel G, Klehn M, et al. Pancreatic glucagonoma with and without the syndrome. Immunocytochemical study of 5 tumor cases and review the literature. Virchows Arch A 1980; 388: 51–67.

    Google Scholar 

  266. Soga J, Yakuwa Y. Glucagonoma/diabetico-dermatogenic syndrome (DDS): a statistical evaluation of 407 reported cases. J Hepatobiliary Pancreat Surg 1998; 5: 312–319.

    Article  CAS  PubMed  Google Scholar 

  267. Hamid QA, Bishop AE, Sikri KL, et al. Immunocytochemical characterization of 10 pancreatic tumours, associated with the glucagonoma syndrome, using antibodies to separate regions of the proglucagon molecule and other neuroendocrine markers. Histopathology 1986; 10: 119–133.

    Article  CAS  PubMed  Google Scholar 

  268. Polak JM, Bloom SR. Glucagon-producing tumors and the glucagonoma syndrome. In: Dayal Y, ed. Endocrine Pathology of the Gut and Pancreas. Boca Raton: CRC Press, 1991: 227–240.

    Google Scholar 

  269. Bordi C, Ravazzola M, Baetens D, et al. A study of glucagonomas by light and electron microscopy and immunofluorescence. Diabetes 1979; 28: 925–936.

    Article  CAS  PubMed  Google Scholar 

  270. Creutzfeldt W. Endocrine tumors of the pancreas. In: Volk BW, Wellman KF, eds. The Diabetic Pancreas. New York: Plenum, 1977: 551–590.

    Chapter  Google Scholar 

  271. Mullan MH, Gauger PG, Thompson NW. Endocrine tumours of the pancreas: review and recent advances. ANZ J Surg 2001; 71: 475–482.

    Article  CAS  PubMed  Google Scholar 

  272. Wynick D, Williams SJ, Bloom SR. Symptomatic secondary hormone syndromes in patients with established malignant pancreatic endocrine tumors. N Engl J Med 1988; 319: 605–607.

    Article  CAS  PubMed  Google Scholar 

  273. Vinik AI, Strodel WE, Eckauser FE, et al. Somatostatinoma, PPoma, neurotensinoma. Semin Oncol 1987; 14: 263–281.

    CAS  PubMed  Google Scholar 

  274. De Nutte N, Somers G, Gepts W, et al. Pancreatic hormone release in tumor-associated hypersomatostatinemia. Diabetologia 1978; 15: 227.

    Google Scholar 

  275. Harris GJ, Tio F, Cruz AB. Somatostatinoma: a case report and review of the literature. J Surg Oncol 1987; 36: 8–16.

    Article  CAS  PubMed  Google Scholar 

  276. Saurenmann P, Binswanger R, Maurer R, et al. Somatostatin produzierender endokrinen pankreastumor bei neurofibromatose von Recklinghausen. Shweiz Med Wschr 1987; 117: 1134–1139.

    CAS  Google Scholar 

  277. Goshev E, Krustev Z, Baev S, et al. A case of somatostatinoma of the pancreas. Vutr Boles 1988; 27: 127–130.

    CAS  PubMed  Google Scholar 

  278. Levi S, Bjarnnason I, Swinson CM, et al. Malignant pancreatic somatostatinoma in a patient with dermatitis herpetiformis and coeliac disease. Digestion 1988; 39: 1–6.

    Article  CAS  PubMed  Google Scholar 

  279. Willicox PA, Immelman EJ, Barron JL, et al. Pancreatic somatostatinoma: presentation with recurrent episodes of severe hyperglycemia and ketoacidosis. Q J Med 1988; 68: 559–571.

    Google Scholar 

  280. Pinsard D, Chadenas D. Somatostatinomas. Diabetes Metab 1988; 14: 43–59.

    CAS  Google Scholar 

  281. Konomi K, Chjiiwa K, Katsuta T, et al. Pancreatic somatostatinoma: a case report and review of the literature. J Surg Oncol 1990;43:259– 265.

    Google Scholar 

  282. Ohasawa H, Kanatsuka A, Tokuyama Y, et al. Amyloid protein in somatostatinoma differs from human islet amyloid polypeptide. Acta Endocrinol 1991; 124: 45–53.

    Google Scholar 

  283. Stavri GT, Pritchard GA, Williams EJ, et al. Somatostatinoma of the pancreas with hypercalcemia. A case report. Eur J Surg Oncol 1992; 18: 298–300.

    CAS  PubMed  Google Scholar 

  284. Roy J, Pompilio M, Yvin JL. Somatostatinoma pancréatique. Une nouvelle observation. La Presse Médicale 1993; 22: 1012.

    CAS  PubMed  Google Scholar 

  285. Dominioni L, Dionigi R, Benevento A, et al. Very late recurrence of a somatostatin-cell tumor of the head of the pancreas. Pancreas 1995; 10: 417–419.

    Article  CAS  PubMed  Google Scholar 

  286. Maki M, Kaneko Y, Ohta Y, et al. Somatostatinoma of the pancreas associated with von Hippel-Lindau disease. Intern Med 1995; 34: 661–665.

    Article  CAS  PubMed  Google Scholar 

  287. Anene C, Thompson JS, Saigh J, et al. Somatostatinoma; atypical presentation of a rare pancreatic tumor. Am J Gastroenterol 1995; 90: 819–821.

    CAS  PubMed  Google Scholar 

  288. Barbato A, Roviello F, De Stefano A, et al. A case of pancreatic somatostatinoma. Minerva Chir 1996; 51: 475–479.

    CAS  PubMed  Google Scholar 

  289. Roy J, PompilioM, Samana G. Pancreatic somatostatinoma andMEN1. Apropos of a case. Review of the literature. Am Endocrinol 1996; 57: 71–76.

    CAS  Google Scholar 

  290. Sessa F, Arcidiacono M, Valenti L, et al. Metastatic psammomatous somatostatinoma of the pancreas causing severe ketoacidotic diabetes cured by surgery. Endocr Pathol 1998; 8: 327–333.

    Article  Google Scholar 

  291. Sugimoto F, Sekiya T, Saito M, et al. Calcitonin-producing pancreatic somatostatinoma: report of a case. Surg Today 1998;28:1279– 1282.

    Google Scholar 

  292. Cantor AM, Rigby CC, Beck PR, et al. Neuroifbromatosis, pheochromocytomas, and somatostatinoma. Br J Med 1982;185:1618– 1619.

    Google Scholar 

  293. La Rosa S, Sessa F, Leone BE, et al. Clinico-pathologic proifle of duodenal and pancreatic somatostatin-cell tumors. Mod Pathol 1997; 10: 50A.

    Google Scholar 

  294. Soga J, Yakuwa Y. Vipoma/diarrheogenic syndrome: a statistical evaluation of 241 reported cases. J Exp Clin Cancer Res 1998; 17: 389–400.

    CAS  PubMed  Google Scholar 

  295. Capella C, Polak JM, Buffa R, et al. Morphologic patterns and diagnostic criteria of VIP-producing endocrine tumors. A histologic, histochemical, ultrastructural and biochemical study of 32 cases. Cancer 1983; 52: 1860–1874.

    Article  CAS  PubMed  Google Scholar 

  296. Morrison AB. Islet cell tumors and the diarrheogenic syndrome. In: Fitzgerald PJ, Morrison AB, eds. The Pancreas. Baltimore: Williams and Wilkins, 1978: 185–207.

    Google Scholar 

  297. Solcia E, Capella C, Riva C, et al. The morphology and neuroendocrine proifle of pancreatic epithelial VIPomas and extrapancreatic, VIP-producing, neurogenic tumors. Ann NY Acad Sci 1988; 527: 508–517.

    Article  CAS  PubMed  Google Scholar 

  298. Maton PN, O’Dorisio TM, O’Dorisio MS, et al. Successful therapy of pancreatic cholera with the long-acting somatostatin analogue SMS 201–995: relation between plasma concentration of drug and clinical and biochemical responses. Scand J Gastroenterol 1986; 21 (Suppl 119): 181–186.

    Article  Google Scholar 

  299. Fox PS, Hoffmann JW, Wilson SD, et al. Surgical management of the Zollinger–Ellison syndrome. Surg Clin North Am 1974; 54: 395–407.

    CAS  PubMed  Google Scholar 

  300. Buchanan KD, Johnson CF, O’Hare M, et al. Neuroendocrine tumors. A European view. Am J Med 1986; 81 (Suppl 6B): 14–22.

    Article  CAS  PubMed  Google Scholar 

  301. Stamm B, Hacki WH, Klöppel G, et al. Gastrin-producing tumors and the Zollinger-Ellison syndrome. In: Dayal Y, ed. Endocrine Tumors of the Gut and Pancreas. Boca Raton: CRC Press, 1991: 155–194.

    Google Scholar 

  302. Jensen RT, Doppman JL, Gardner JD. Gastrinoma. In: Go VL, Gardner JD, Brooks FP, Lebenthal E, Di Magno EP, Scheele GA, eds. The Exocrine Pancreas: Biology, Pathobiology, and Disease. New York: Raven Press, 1986: 727–744.

    Google Scholar 

  303. Stabile BE, Morrow DJ, Passaro E Jr. The gastrinoma triangle: operative implications. Am J Surg 1984; 147: 25–31.

    Article  CAS  PubMed  Google Scholar 

  304. Creutzfeldt W, Arnold R, Creutzfeldt C, et al. Pathomorphologic, biochemical, and diagnostic aspects of gastrinomas (Zollinger–Ellison syndrome). Hum Pathol 1975; 6: 47–76.

    Article  CAS  PubMed  Google Scholar 

  305. Solcia E, Capella C, Buffa R, et al. Pathology of the Zollinger– Ellison syndrome. Prog Surg Pathol 1980; 1: 119–133.

    Google Scholar 

  306. Weber HC, Venzon DY, Lin TY, et al. Determinants of survival in patients with Zollinger–Ellison syndrome: a prospective long-term study. Gastroenterology 1995; 108: 1637–1649.

    Article  CAS  PubMed  Google Scholar 

  307. Mao C, el Attar A, Domenico DR, et al. Carcinoid tumors of the pancreas. Status report based on two cases and review of the world’s literature. Int J Pancreatol 1998; 23: 153–164.

    Article  CAS  PubMed  Google Scholar 

  308. Dollinger MR, Ratner LH, Shamoian CA, et al. Carcinoid syndrome associated with pancreatic tumors. Arch Intern Med 1967;120:575– 580.

    Google Scholar 

  309. Patchefsky AS, Solit R, Phillips LD, et al. Hydroxyindole-producing tumors of the pancreas-carcinoid islet cell tumor and oat cell carcinoma. Ann Intern Med 1972; 77: 53–61.

    CAS  PubMed  Google Scholar 

  310. Van Der Sluys Veer J, Choufoer JC, et al. Metastasizing islet-cell tumour of the pancreas associated with hypoglycemia and carcinoid syndrome. Lancet 1964; 1: 1416–1419.

    Article  Google Scholar 

  311. Dayal Y, Lin HD, Tallberg K, et al. Immunocytochemical demonstration of growth hormone–releasing factor in gastrointestinal and pancreatic endocrine tumors. Am J Clin Pathol 1986;85:13–20–20.

    Google Scholar 

  312. Asa SL, Kovacs K, Thoner MD, et al. Immunohistochemical localization of growth-hormone-releasing hormone in human tumors. J Clin Endocrinol Metab 1985; 60: 423–427.

    Article  CAS  PubMed  Google Scholar 

  313. Bostwick DG, Quan R, Hoffman AR, et al. Growth-hormone-releasing factor immunoreactivity in human endocrine tumors. Am J Pathol 1984; 117: 167–170.

    CAS  PubMed  Google Scholar 

  314. Sanno N, Teramoto A, Osamura RY, et al. A growth hormone-releasing hormone-producing pancreatic islet cell tumor metastasized to the pituitary is associated with pituitary somatotroph hyperplasia and acromegaly. J Clin Endocrinol Metab 1997; 82: 2731–2737.

    Article  CAS  PubMed  Google Scholar 

  315. Caplan RH, Koob L, Abellera RM, et al. Cure of acromegaly by operative removal of an islet tumor of the pancreas. Am J Med 1978; 64: 874–882.

    Article  CAS  PubMed  Google Scholar 

  316. Saeger W, Shulte HM, Klöppel G. Morphology of a GHRH producing pancreatic islet cell tumor causing acromegaly. Virchows Arch [A] 1986; 409: 547–554.

    Article  CAS  Google Scholar 

  317. Sano T, Yamasaki R, Saito H, et al. Growth hormone-releasing hormone (GHRH)-secreting pancreatic tumor in a patient with multiple endocrine neoplasia type 1. Am J Surg Pathol 1987;11:810– 819.

    Google Scholar 

  318. Wilson DM, Ceda GP, Bostwick DG, et al. Acromegaly and Zollinger–Ellison syndrome secondary to an islet cell tumor: characterization and quantiifcation of plasm and tumor human growth hormone-releasing factor. J Clin Endocrinol Metab 1984;59:1002– 1005.

    Google Scholar 

  319. Berger G, Trouillas J, Bloch B, et al. Multihormonal carcinoid tumor of the pancreas. Secreting growth hormone-releasing factor as a cause of acromegaly. Cancer 1984; 54: 2097–2108.

    Article  CAS  PubMed  Google Scholar 

  320. Ezzat S, Ezrin C, Yamashita S, et al. Recurrent acromegaly resulting from ectopic growth hormone gene expression by a metastatic pancreatic tumor. Cancer 1993; 71: 66–70.

    Article  CAS  PubMed  Google Scholar 

  321. Clark ES, Carney JA. Pancreatic islet cell tumor associated with Cushing syndrome. Am J Surg Pathol 1984; 8: 917–924.

    Article  CAS  PubMed  Google Scholar 

  322. Heitz PU, Klöppel G, Polak JM, et al. Ectopic hormone production by endocrine tumors: localization of hormones at the cellular level by immunocytochemistry. Cancer 1981; 48: 2029–2037.

    Article  CAS  PubMed  Google Scholar 

  323. Liddle GW, Givens JR, Nicholson WE, et al. The ectopic ACTH syndrome. Cancer Res 1965; 25: 1057–1061.

    CAS  PubMed  Google Scholar 

  324. Torriani F, Uske A, Temier E, et al. Pancreatic insuloma causing Cushing’s syndrome. J Endocrinol Invest 1989; 12: 313–319.

    CAS  PubMed  Google Scholar 

  325. Styne DM, Isaac R, Miller WL. Endocrine, histological, and biochemical studies of adrenocorticotropin-producing islet cell carcinoma of the pancreas in childhood with characterization of proopiomelanocortin. J Clin Endocrinol Metab 1983; 57: 723–731.

    Article  CAS  PubMed  Google Scholar 

  326. Lyons DF, Eisen BR, Clark ME, et al. Concurrent Cushing’s and Zollinger–Ellison syndromes in a patient with islet cell carcinoma. Case report and review of the literature. Am J Med 1984; 76: 729–733.

    Article  CAS  PubMed  Google Scholar 

  327. Corrin B, Gilby ED, Jones NF, et al. Oat cell carcinoma of the pancreas with ectopic ACTH secretion. Cancer 1973; 31: 1523–1527.

    Article  CAS  PubMed  Google Scholar 

  328. Arps H, Dietel M Schulz A, et al. Pancreatic endocrine carcinoma with ectopic PTH-production and paraneoplastic hypercalcemia. Virchows Arch [A] 1986; 408: 497–503.

    Google Scholar 

  329. Ratcliffe WA, Bowden SJ, Dunne FP, et al. Expressing and processing of parathyroid hormone related protein in a pancreatic endocrine cell tumour associated with hypercalcemia. Clin Endocrinol 1994; 40: 679–686.

    Article  CAS  Google Scholar 

  330. Tarver DS, Birch SJ. Case report: life-threating hypercalcemia secondary to pancreatic tumour secreting parathyroid hormone-related protein. Successful control by hepatic arterial embolization. Clin Radiol 1992; 46: 204–205.

    Article  CAS  PubMed  Google Scholar 

  331. Miraliakbari BA, Asa SL, Boudreau SF. Parathyroid hormone-like peptide in pancreatic endocrine carcinoma and adenocarcinoma associated with hypercalcemia. Hum Pathol 1992; 23: 884–887.

    Article  CAS  PubMed  Google Scholar 

  332. Mitlak BH, Hutchinson JS, Kaufman SD, et al. Parathyroid hormone-related peptide mediates hypercalcemia in an islet cell tumor of the pancreas. Horm Metab Res 1991; 23: 344–346.

    Article  CAS  PubMed  Google Scholar 

  333. Rizzoli R, Sappino AP, Bonjour JP. Parathyroid hormone-related protein and hypercalcemia in pancreatic neuroendocrine tumors. Int J Cancer 1990; 46: 394–398.

    Article  CAS  PubMed  Google Scholar 

  334. Rasbach DA, Hammond JM. Pancreatic islet cell carcinoma with hypercalcemia. Primary hyperparathyroidism or humoral hypercalcemia of malignancy. Am J Med 1985; 78: 337–342.

    Article  CAS  PubMed  Google Scholar 

  335. Druker DJ, Asa SL, Henderson J, et al. The parathyroid hormone-like peptide gene is expressed in the normal and neoplastic human endocrine pancreas. Mol Endocrinol 1989; 3: 1589–1595.

    Article  Google Scholar 

  336. Kim DG, Chejifec G, Prinz RA. Islet cell carcinoma of the pancreas. Am Surg 1989; 55: 325–332.

    CAS  PubMed  Google Scholar 

  337. Thompson GB, van Heerden JA, Grant CS, et al. Islet cell carcinomas of the pancreas: a twenty-year experience. Surgery 1988; 104: 1011–1017.

    CAS  PubMed  Google Scholar 

  338. Venkatesh S, Ordonez NG, Ajani J, et al. Islet cell carcinoma of the pancreas. A study of 98 patients. Cancer 1990; 65: 354–357.

    Article  CAS  PubMed  Google Scholar 

  339. Grimelius L, Hultquist GT, Stenkvist B. Cytological differentiation of asymptomatic pancreatic islet cell tumors in autopsy material. Virchows Arch [A] 1975; 365: 275–288.

    Article  CAS  Google Scholar 

  340. Kimura W, Kuroda A, Morioka Y. Clinical pathology of endocrine tumors of the pancreas: analysis of autopsy cases. Dig Dis Sci 1991; 36: 933–942.

    Article  CAS  PubMed  Google Scholar 

  341. Eckhauser FE, Cheung PS, Vinik AI, et al. Nonfunctioning malignant neuroendocrine tumors of the pancreas. Surgery 1986; 100: 978–988.

    CAS  PubMed  Google Scholar 

  342. Evans DB, Skibber JM, Lee JE, et al. Nonfunctioning islet cell carcinoma of the pancreas. Surgery 1993; 114: 1175–1182.

    CAS  PubMed  Google Scholar 

  343. Kent RB, van Heerden JA, Weiland LH. Nonfunctioning islet cell tumors. Ann Surg 1981; 193: 185–190.

    Article  PubMed  Google Scholar 

  344. Cubilla AL, Hajdu SI. Islet cell carcinoma of the pancreas. Arch Pathol 1975; 99: 204–207.

    CAS  PubMed  Google Scholar 

  345. La Rosa S, Sessa F, Uccella S, et al. Histological and immunohistochemical study of calcitonin-cell tumors of the pancreas. Digestion 1997; 58 (Suppl 2): 19.

    Google Scholar 

  346. Fleury A, Fléjou JF, Sauvanet A, et al. Calcitonin-secreting tumors of the pancreas: about six cases. Pancreas 1998; 16: 545–550.

    Article  CAS  PubMed  Google Scholar 

  347. Polak JM, Bloom SR, Adrian TE, et al. Pancreatic polypeptide in insulinomas, gastrinomas, VIPomas and glucagonomas. Lancet 1976; 1: 328–330.

    Article  CAS  PubMed  Google Scholar 

  348. Adrian TE, Uttenthal LO, Williams SJ, et al. Secretion of pancreatic polypeptide in patients with pancreatic endocrine tumors. N Engl J Med 1986; 315: 287–291.

    Article  CAS  PubMed  Google Scholar 

  349. Tomita T, Friesen SR, Pollok HG. PP-producing tumors (PPomas). In: Dayal Y, ed. Endocrine Tumors of the Gut and Pancreas. Boca Raton: CRC Press, 1991: 279–304.

    Google Scholar 

  350. O’Connor TP, Wade TP, Sunwoo YC, et al. Small cell undifferentiated carcinoma of the pancreas. Report of a patient with tumor marker studies. Cancer 1992; 70: 1514–1519.

    Article  PubMed  Google Scholar 

  351. Reyes CV, Wang T. Undifferentiated small cell carcinoma of the pancreas: report of five cases. Cancer 1981; 47: 2500–2502.

    Article  CAS  PubMed  Google Scholar 

  352. Sessa F, Bonato M, Frigerio B, et al. Ductal cancers of the pancreas frequently express markers of gastrointestinal epithelial cells. Gastroenterology 1990; 98: 1655–1665.

    CAS  PubMed  Google Scholar 

  353. Kaufmann O, Dietel M. Expression of thyroid transcription factor-1 in pulmonary and extrapulmonary small cell carcinomas and other neuroendocrine carcinomas of various primary sites. Histopathology 2000; 36: 415–420.

    Article  CAS  PubMed  Google Scholar 

  354. Klöppel G. Mixed exocrine–endocrine tumors of the pancreas. Semin Diagn Pathol 2000; 17: 104–108.

    PubMed  Google Scholar 

  355. Üstün MÖ, Tugyan N, Tunakan M. Coexistence of an endocrine tumour in a serous cystadenoma (microcystic adenoma) of the pancreas, an unusual association J Clin Pathol 2000; 53: 800–802.

    Google Scholar 

  356. Keel SB, Zukerberg L, Graeme-Cook F, et al. A pancreatic endocrine tumor arising within a serous cystadenoma of the pancreas. Am J Surg Pathol 1996; 20: 471–475.

    Article  CAS  PubMed  Google Scholar 

  357. Leteurtre E, Brami F, Kerr-Conte J, et al. Mixed ductal-endocrine carcinoma of the pancreas. A case study with mixed ductal-endocrine metastasis double labeled for cytokeratin 19 and synaptophysin. Arch Pathol Lab Med 2000; 124: 284–286.

    CAS  PubMed  Google Scholar 

  358. Klimstra DS, Rosai J, Heffess CS. Mixed acinar-endocrine carcinomas of the pancreas. Am J Surg Pathol 1994; 18: 765–778.

    Article  CAS  PubMed  Google Scholar 

  359. Schron DS, Mendelsohn G. Pancreatic carcinoma with duct, endocrine, and acinar differentiation. A histological, immunocytochemical, and ultrastructural study. Cancer 1984; 54: 1766–1770.

    Article  CAS  PubMed  Google Scholar 

  360. Burgess JR, Greenaway TM, Shepherd JJ. Expression of the MEN-1 gene in a large kindred with multiple endocrine neoplasia type 1. J Inter Med 1998; 243: 465–470.

    Article  CAS  Google Scholar 

  361. Jensen RT. Pancreatic endocrine tumors: Recent advances. Ann Oncol 1999; 10: S170–S176.

    Article  Google Scholar 

  362. Lubensky IA, Debelenko LV, Zhuang Z, et al. Allelic deletions on chromosome 1 1q13 in multiple tumors from individual MEN1 patients. Cancer Res 1996; 56: 5272–5278.

    CAS  PubMed  Google Scholar 

  363. Emmert-Buck MR, Lubensky IA, Dong Q, et al. Localization of the multiple endocrine neoplasia type 1 (MEN1) gene based on tumor loss of heterozygosity analysis. Cancer Res 1997;57:1855– 1858.

    Google Scholar 

  364. Chandrasekharappa SC, Guru SC, Manickam, et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997; 276: 404–407.

    Article  CAS  PubMed  Google Scholar 

  365. Guo SS, Sawaicki MP Molecular and genetic mechanisms of tumorigenesis in multiple endocrine neoplasia type 1. Mol Endocrinol 2001; 15: 1653–1664.

    Article  CAS  PubMed  Google Scholar 

  366. Calender A, Vercherat C, Gaudray P, et al. Deregulation of genetic pathways in neuroendocrine tumors. Ann Oncol 2001;12:S3– S11.

    Google Scholar 

  367. Guru SC, Crabtree JS, Brown KD, et al. Isolation, genomic organization, and expression analysis of Men1, the murine homolog of the MEN1 gene. Mamm Genome 1999; 10: 592–596.

    Article  CAS  PubMed  Google Scholar 

  368. Khodaei S, O’Brien KP, Dumanski J, et al. Characterization of the MEN1 ortholog in zebrafish. Biochem Biophys Res Commun 1999; 264: 404–408.

    Article  CAS  PubMed  Google Scholar 

  369. Maruyama K, Tsukada T, Honda M, et al. Complementary DNA structure and genomic organization of Drosophila menin. Mol Cell Endocrinol 2000; 168: 135–140.

    Article  CAS  PubMed  Google Scholar 

  370. Agarwal S, Kester MB, Debelenko LV, et al. Germline mutations of the MEN1 gene in familial MEN1 and related states. Hum Mol Genet 1997; 6: 1169–1175.

    Article  CAS  PubMed  Google Scholar 

  371. Shimizu S, Tsukada T, Futami H, et al. Germline mutations of the MEN1 gene in Japanese kindred with multiple endocrine neoplasia type 1. Jpn J Cancer 1997; 88: 1029–1032.

    Article  CAS  Google Scholar 

  372. Bassett JHD, Forbes SA, Pannett AAJ, et al. Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet 1998; 62: 232–244.

    Article  CAS  PubMed  Google Scholar 

  373. Giraud S, Zhang CX, Serova-Sinilnikova O, et al. Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Am J Hum Genet 1998; 63: 455–467.

    Article  CAS  PubMed  Google Scholar 

  374. Teh BT, Kytöla S, Farnebo F, et al. Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. J Clin Endocrinol Metab 1998; 83: 2621–2626.

    Article  CAS  PubMed  Google Scholar 

  375. Poncin J, Abs R, Velkeniers B, et al. Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases. Hum Mutat 1999; 13: 54–60.

    Article  CAS  PubMed  Google Scholar 

  376. Teth BT, McArdle J, Parameswaran V, et al. Sporadic primary hyperparathyroidism in the setting of multiple endocrine neoplasia type 1. Arch Surg 1996; 131: 1230–1232.

    Article  Google Scholar 

  377. Stock JL, Warth MR, Teh BT, et al. A kindred with a variant of multiple endocrine neoplasia type 1 demonstrating frequent expression of pituitary tumors but not linked to the multiple endocrine type 1 locus at chromosome region 11q13. J Clin Endocrinol Metab 1997; 82: 486–492.

    Article  CAS  PubMed  Google Scholar 

  378. Khodaei-O’Brien S, Zablewska B, Fromaget M, et al. Heterogeneity at the 5’ end of MEN1 transcripts. Biochem Biophys Res Commun 2000; 276: 508–514.

    Article  PubMed  CAS  Google Scholar 

  379. Crabtree JS, Scacheri PC, Ward JM, et al. A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. Proc Natl Acad Sci USA 2001; 98: 1118–1123.

    Article  CAS  PubMed  Google Scholar 

  380. Guru SC, Goldsmith PK, Burns AL, et al. Menin, the product of the MEN1 gene, is a nuclear protein. Proc Natl Acad Sci USA 1998; 95: 1630–1634.

    Article  CAS  PubMed  Google Scholar 

  381. Kaji H, Canaff K, Goltzman D, et al. Cell cycle regulation of MENIN expression. Cancer Res 1999; 59: 5097–5101.

    CAS  PubMed  Google Scholar 

  382. Kaji H, Canaff L, Lebrun JJ, et al. Inactivation of menin, a Smad3- interacting protein, blocks transforming growth factor type ß signaling. Proc Natl Acad Sci USA 2001; 98: 3837–3842.

    Article  CAS  PubMed  Google Scholar 

  383. Scappaticci S, Maraschio P, Del Ciotto N, et al. Chromosome abnormalities in lymphocytes and fibroblasts of subjects with multiple endocrine neoplasia type 1. Cancer Genet Cytogenet 1991; 52: 85–92.

    Article  CAS  PubMed  Google Scholar 

  384. Tomassetti P, Cometa G, Del Vecchio E, et al. Chromosomal instability in multiple endocrine neoplasia type 1. Cytogenetic evaluation with DEB test. Cancer Genet Cytogenet 1995; 9: 123–126.

    Article  Google Scholar 

  385. Sakurai A, Katai M, Itakura Y, et al. Premature centromere division in patients with multiple endocrine neoplasia type 1. Cancer Genet Cytogenet 1999; 109: 138–140.

    Article  CAS  PubMed  Google Scholar 

  386. Hessman O, Skogseid B, Westin G, et al. Multiple allelic deletions and intratumoral genetic heterogeneity in men1 pancreatic tumors. J Clin Endocrinol Metab 2001; 86: 1355–1361.

    Article  CAS  PubMed  Google Scholar 

  387. Richard S, Giraud S, Beround C, et al. Von Hippel–Lindau disease: recent genetic progress and patient management. Ann Endocrinol 1998; 59: 452–458.

    CAS  Google Scholar 

  388. Neumann HPH, Dinkel E, Brambs H, et al. Pancreatic lesions in the von Hippel–Lindau syndrome. Gastroenterology 1991; 101: 465–471.

    CAS  PubMed  Google Scholar 

  389. Lubensky IA, Pack S, Ault D, et al. Multiple neuroendocrine tumors of the pancreas in von Hippel–Lindau disease patients: histopathological and molecular genetic analysis. Am J Pathol 1998; 153: 223–231.

    Article  CAS  PubMed  Google Scholar 

  390. Hammel P, Vilgrain V, Terris B, et al. Pancreatic involvement in Von Hippel–Lindau disease. Gastroenterology 2000; 119: 1087–1095.

    Article  CAS  PubMed  Google Scholar 

  391. Hoang MP, Hruban RH, Albores-Saavedra J. Clear cell endocrine pancreatic tumor mimicking renal cell carcinoma: a distinctive neoplasm of von Hippel–Lindau disease. Am J Surg Pathol 200; 125: 602–609.

    Google Scholar 

  392. Libutti SK, Choyke PL, Bartlett DL, et al. Pancreatic neuroendocrine tumors associated with von Hippel–Lindau disease: diagnostic and management recommendations. Surgery 1998; 124: 1153–1159.

    Article  CAS  PubMed  Google Scholar 

  393. Lott ST, Chandler DS, Curley SA, et al. High frequency loss of heterozygosity in von Hippel–Lindau (VHL)-associated and sporadic pancreatic islet cell tumors: evidence for a stepwise mechanism for malignant conversion in VHL tumorigenesis. Cancer Res 2002; 62: 1952–1955.

    CAS  PubMed  Google Scholar 

  394. Latif F, Tory K, Gnarra J, et al. Identiifcation of the von Hippel– Lindau disease tumor suppressor gene. Science 1993; 260: 1317–1320.

    Article  CAS  PubMed  Google Scholar 

  395. Gnarra JR, Zhou S, Merrill MJ, et al. Post-trascriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc Natl Acad Sci USA 1996; 93: 10589–10594.

    Article  CAS  PubMed  Google Scholar 

  396. Lisztwan J, Imbert G, Wirbelauer C, et al. The von Hippel–Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity. Genes Dev 1999; 13: 1822–1833.

    Article  CAS  PubMed  Google Scholar 

  397. Pause A, Lee S, Lonergan KM, et al. The von Hippel–Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. Proc Natl Acad Sci USA 1998; 95: 993–998.

    Article  CAS  PubMed  Google Scholar 

  398. Zbar B, Kishida T, Chen F, et al. Germline mutations in the Von Hippel–Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat 1996; 8: 348–357.

    Article  CAS  PubMed  Google Scholar 

  399. Prowse AH, Webster AR, Richard FM, et al. Somatic inactivation of the VHL gene in von Hippel–Lindau disease tumors. Am J Hum Genet 1997; 60: 765–771.

    CAS  PubMed  Google Scholar 

  400. Aubert-Petit G, Baudin E, Cauilleaux AF, et al. Neuroendocrine tumors and von Hippel–Lindau disease-3 cases. Presse Med 1999; 28: 1231–1234.

    CAS  PubMed  Google Scholar 

  401. Hessman O, Lindberg D, Skogscid B, et al. Mutation of the multiple endocrine neoplasia type 1 gene in nonfamilial, malignant tumors of the endocrine pancreas. Cancer Res 1998; 58: 377–379.

    CAS  PubMed  Google Scholar 

  402. Shan L, Nakamura M, Yokoi T, et al. Somatic mutations of multiple endocrine neoplasia type 1 gene in the sporadic endocrine tumors. Lab Invest 1998; 78: 471–475.

    CAS  PubMed  Google Scholar 

  403. Moore PS, Missiaglia E, Antonello D, et al. Role of disease-causing genes in sporadic pancreatic endocrine tumors: MEN1 and VHL. Genes Chromosome Cancer 2001; 32: 177–181.

    Article  CAS  Google Scholar 

  404. Zhuang Z, Vortmeyer AO, Pack S, et al. Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas. Cancer Res 1997; 57: 4682–4686.

    CAS  PubMed  Google Scholar 

  405. Debelenko LV, Zhuang Z, Emmert-Buck MR, et al. Allelic deletions on chromosome 11q13 in multiple endocrine neoplasia type 1-associated and sporadic gastrinomas and pancreatic endocrine tumors. Cancer Res 1997; 57: 2238–2243.

    CAS  PubMed  Google Scholar 

  406. Cupisti K, Hoppner W, Dotzenrath C, et al. Lack of Men1 gene mutations in 27 sporadic insulinomas. Eur J Clin Invest 2000; 30: 325–329.

    Article  CAS  PubMed  Google Scholar 

  407. Gortz B, Roth J, Krahenmann A, et al. Mutations 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 1999; 154: 429–436.

    Article  CAS  PubMed  Google Scholar 

  408. Wang EH, Ebrahimi SA, Wu AY, et al. Mutation of the MENIN gene in sporadic pancreatic endocrine tumors. Cancer Res 1998; 58: 4417–4420.

    CAS  PubMed  Google Scholar 

  409. Mailman MD, Muscarella P, Schirmer WJ, et al. Identiifcation of MEN1 mutations in sporadic enteropancreatic neuroendocrine tumors by analysis of parafifn-embedded tissue. Clin Chem 1999; 45: 29–34.

    CAS  PubMed  Google Scholar 

  410. Rigaud G, Missiaglia E, Moore PS, et al. High resolution allelotype of nonfunctional pancreatic endocrine tumors: identiifcation of two molecular subgroups with clinical implications. Cancer Res 2001; 61: 285–292.

    CAS  PubMed  Google Scholar 

  411. Chung DC, Smith AP, Louis DN, et al. A novel pancreatic endocrine tumor suppressor gene locus on chromosome 3p with clinical prognostic implications. J Clin Invest 1997; 100: 404–410.

    Article  CAS  PubMed  Google Scholar 

  412. Nikiforova MN, Nikiforov YE, Biddinger P, et al. Frequent loss of heterozygosity at chromosome 3p14.2–3p21 in human pancreatic islet cell tumors. Clin Endocrinol 1999; 51: 27–33.

    Article  CAS  Google Scholar 

  413. Barghorn A, Komminoth P, Bachmann D, et al. Deletion at 3p25.3– p23 is frequently encountered in endocrine pancreatic tumors and is associated with metastatic progression. J Pathol 2001; 194: 451–458.

    Article  CAS  PubMed  Google Scholar 

  414. Pellegata NS, Sessa F, Renault B, et al. K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions. Cancer Res 1994; 54: 1556–1560.

    CAS  PubMed  Google Scholar 

  415. Beghelli S, Pelosi G, Zamboni G, et al. Pancreatic endocrine tumors: evidence for a tumor suppressor pathogenesis and for a tumor suppressor gene on chromosome 17p. J Pathol 1998; 186: 41–50.

    Article  CAS  PubMed  Google Scholar 

  416. Lohmann DR, Funk A, Niedermeyer HP, et al. Identiifcation of p53 gene mutations in gastrointestinal and pancreatic carcinoids by non-radioisotopic SSCA. Virchows Arch B Cell Pathol 1993; 64: 293–296.

    Article  CAS  Google Scholar 

  417. Bartsch D, Hahn SA, Danichevski KD, et al. Mutations of the DPC4/ Smad4 gene in neuroendocrine pancreatic tumors. Oncogene 1999; 18: 2367–2371.

    Article  CAS  PubMed  Google Scholar 

  418. Hessman O, Lindberg D, Einarsson A, et al. Genetic alterations on 3p, 1 1q13 and 18q in nonfamilial and MEN1-association pancreatic endocrine tumors. Genes Chromosomes Cancer 1999; 26: 258–264.

    Article  CAS  PubMed  Google Scholar 

  419. Perren A, Hivolimann S, Saremadani P, et al. DPC4/SMAD4 expression is lost in a subset of duodenal adenocarcinomas of the pancreas but not in endocrine pancreatic tumors and chronic pancreatitis. Lab Invest 2002; 82: 119A.

    Google Scholar 

  420. Muscarella P, Melvin WS, Fisher WE, et al. Genetic alterations in gastrinomas and nonfunctioning pancreatic neuroendocrine tumors: an analysis of p16/MTS 1 tumor suppressor gene inactivation. Cancer Res 1998; 58: 237–240.

    CAS  PubMed  Google Scholar 

  421. Lubomierski N, Kersting M, Bert T, et al. Tumor suppressor genes in the 9p21 gene cluster are selective targets of inactivation in neuroendocrine gastroenteropancreatic tumors. Cancer Res 2001; 61: 5905–5910.

    CAS  PubMed  Google Scholar 

  422. Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 2000; 16: 168–174.

    Article  CAS  PubMed  Google Scholar 

  423. Chung DC, Smith AP, Luis DN, et al. Analysis of the retinoblastoma tumor suppressor gene in pancreatic endocrine tumors. Clin Endocrinol 1997; 47: 523–528.

    Article  CAS  Google Scholar 

  424. Perren A, Komminoth P, Saremaslani P, et al. Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal islet cells. Am J Pathol 2000; 157: 1097–1103.

    Article  CAS  PubMed  Google Scholar 

  425. Pearce SHS, Trump D, Wooding C, et al. Loss of heterozygosity studies at the retinoblastoma and breast cancer susceptibility (BRCA2) loci in pituitary, parathyroid, pancreatic and carcinoid tumors. Clin Endocrinol 1996; 45: 195–200.

    Article  CAS  Google Scholar 

  426. Roncalli M, Coggi G. Oncogenes and neuroendocrine tumors. In: Polak JM, ed. Diagnostic Histopathology of Neuroendocrine Tumors. London: Churchill-Livingstone, 1993: 41–66.

    Google Scholar 

  427. Speel EJM, Richter J, Moch H, et al. Genetic differences in endocrine pancreatic tumor subtype detect by comparative genomic hybridization. Am J Pathol 1999; 155: 1787–1794.

    Article  CAS  PubMed  Google Scholar 

  428. Zhao J, Moch H, Scheidweiler F, et al. Genomic imbalances in the progression of endocrine pancreatic tumors. Genes Chromosome Cancer 2001; 32: 364–372.

    Article  CAS  Google Scholar 

  429. Tonnies H, Toliar MR, Ramel C, et al. Analysis of sporadic neuroendocrine tumors of the enteropancreatic system by comparative genomic hybridisation. Gut 2001; 48: 536–541.

    Article  CAS  PubMed  Google Scholar 

  430. Ebrahimi SA, Wang EH, Wu A, et al. Deletion of chromosome 1 predicts prognosis in pancreatic endocrine tumors. Cancer Res 1999; 59: 311–315.

    CAS  PubMed  Google Scholar 

  431. Pizzi S, D’Adda T, Azzoni C, et al. Malignancy-associated allelic losses on the X-chromosome in foregut but not midgut endocrine tumors. J Pathol 2002; 196: 401–407.

    Article  PubMed  Google Scholar 

  432. Barghorn A, Speel EJ, Farspour B, et al. Putative tumor suppressor loci at 6q22 and 6q23–q24 are involved in the malignant progression of sporadic endocrine pancreatic tumors. Am J Pathol 2001; 158: 1903–1911.

    Article  CAS  PubMed  Google Scholar 

  433. Driman DK, Kobrin MS, Kudlow JE, et al. Transforming growth factor-(x in normal and neoplastic human endocrine tissues. Hum Pathol 1992; 23: 1360–1365.

    Article  CAS  PubMed  Google Scholar 

  434. Srivastava A, Alexander J, Lomakin I, et al. Immunohistochemical expression of transforming growth factor a and epidermal growth factor receptor in pancreatic endocrine tumors. Hum Pathol 2001; 32: 1184–1189.

    Article  CAS  PubMed  Google Scholar 

  435. La Rosa S, Uccella S, Capella C, et al. Localization of hepatocyte growth factor and its receptor met in endocrine cells and related tumors of the gut and pancreas: an immunohistochemical study. Endocr Pathol 2000; 11: 315–329.

    Article  PubMed  Google Scholar 

  436. Wulbrand U, Wied M, Zöfel P, et al. Growth factor receptor expression in human gastroenteropancreatic neuroendocrine tumours. Eur J Clin Invest 1998; 28: 1038–1049.

    Article  CAS  PubMed  Google Scholar 

  437. Terris B, Scoazec Y, Rubbia L, et al. Expresion of vascular endothelial growth factor in digestive neuroendocrine tumors. Histopathology 1998; 32: 133–138.

    Article  CAS  PubMed  Google Scholar 

  438. Chaudhry A, Papanicolaou V, Öberg K, et al. Expression of platelet-derived growth factor and its receptors in neuroendocrine tumors of the digestive system. Cancer Res 1992; 52: 1006–1012.

    CAS  PubMed  Google Scholar 

  439. Höög A, Kjellman M, Sandberg Nordqvist AC, et al. Insulin-like growth factor-II in pancreatic endocrine tumours. APMIS 2001; 109: 127–140.

    Article  PubMed  Google Scholar 

Download references

Authors
  1. Stefano La Rosa MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniela Furlan BscD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fausto Sessa MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carlo Capella MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Pathology, Mayo Clinic, Rochester, MN, USA

    Ricardo V. Lloyd MD, PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Springer Science+Business Media New York

About this chapter

Cite this chapter

La Rosa, S., Furlan, D., Sessa, F., Capella, C. (2004). The Endocrine Pancreas. In: Lloyd, R.V. (eds) Endocrine Pathology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-403-0_16

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-403-0_16

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-423-4

  • Online ISBN: 978-1-59259-403-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation