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Site-specific biology and pathology of gastroenteropancreatic neuroendocrine tumors

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Abstract

The gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are composed of cells with a neuroendocrine phenotype. Well-differentiated tumors, well-differentiated carcinomas, poorly differentiated carcinomas, functioning tumors (with a hormonal syndrome), and nonfunctioning tumors are identified. To predict their clinical behavior, these neuroendocrine tumors are classified on the basis of their clinicopathological features, including size, local invasion, angioinvasion, proliferative activity, histological differentiation, and metastases, into neoplasms with benign, uncertain, low-grade malignant and high-grade malignant behavior. In addition, a tumor/nodes/metastases classification and a grading system are presented. In the light of these criteria, the various GEP-NET entities are reviewed.

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References

  1. Abraham SC, Carney JA, Ooi A, Choti MA, Argani P (2005) Achlorhydria, parietal cell hyperplasia, and multiple gastric carcinoids. A new disorder. Am J Surg Pathol 29:969–975

    PubMed  Google Scholar 

  2. Adrian TE, Uttenthal LO, Williams SJ, Bloom SR (1986) Secretion of pancreatic polypeptide in patients with pancreatic endocrine tumors. N Engl J Med 315:287–291

    Article  PubMed  CAS  Google Scholar 

  3. Akintola-Ogunremi O, Pfeifer JD, Tan BR, Yan Y, Zhu X, Hart J, Goldblum JR, Burgart L, Lauwers GY, Montgomery E, Lewin D, Washington K, Bronner M, Xiao SY, Greenson JK, Lamps L, Lazenby A, Wang HL (2003) Analysis of protein expression and gene mutation of c-kit in colorectal neuroendocrine carcinomas. Am J Surg Pathol 27:1551–1558

    PubMed  Google Scholar 

  4. Anlauf M, Garbrecht N, Henopp T, Schmitt A, Schlenger R, Raffel A, Krausch M, Gimm O, Eisenberger CF, Knoefel WT, Dralle H, Komminoth P, Heitz PU, Perren A, Klöppel G (2006) Sporadic versus hereditary gastrinomas of the duodenum and pancreas: distinct clinico-pathological and epidemiological features. World J Gastroenterol 12:5440–5446

    PubMed  Google Scholar 

  5. Anlauf M, Garbrecht N, Schmitt A, Henopp T, Komminoth P, Heitz PU, Perren A, Klöppel G (2007) Hereditary neuroendocrine tumors of the gastroenteropancreatic system. Virchows Arch (in this issue)

  6. Anlauf M, Perren A, Henopp T, Rudolph T, Garbrecht N, Schmitt A, Raffel A, Gimm O, Weihe E, Knoefel WT, Dralle H, Heitz PU, Komminoth P, Klöppel G (2007) Allelic deletion of the MEN1 gene in duodenal gastrin and somatostatin cell neoplasms and their precursor lesions. Gut 56:637–644

    PubMed  CAS  Google Scholar 

  7. Anlauf M, Perren A, Meyer CL, Schmid S, Saremaslani P, Kruse ML, Weihe E, Komminoth P, Heitz PU, Klöppel G (2005) Endocrine precursor lesions are associated with duodenal gastrinomas in patients suffering from multiple endocrine neoplasia type 1. Virchows Arch 447:169–170

    Google Scholar 

  8. Anlauf M, Schlenger R, Perren A, Bauersfeld J, Koch CA, Dralle H, Raffel A, Knoefel WT, Weihe E, Ruszniewski P, Couvelard A, Komminoth P, Heitz PU, Klöppel G (2006) Microadenomatosis of the endocrine pancreas in patients with and without the multiple endocrine neoplasia type 1 syndrome. Am J Surg Pathol 30:560–574

    PubMed  Google Scholar 

  9. Assadi M, Kubiak R, Kaiser G (2002) Appendiceal carcinoid tumors in children: does size matter? Med Pediatr Oncol 38:65–66

    PubMed  Google Scholar 

  10. Berardi RS (1972) Carcinoid tumors of the colon (exclusive of the rectum): review of the literature. Dis Colon Rectum 15:383–391

    PubMed  CAS  Google Scholar 

  11. Berger G, Trouillas J, Bloch B, Sassolas G, Berger F, Partensky C, Chayvialle JA, Brazeau P, Claustrat B, Lesbros F et al (1984) Multihormonal carcinoid tumor of the pancreas. Secreting growth hormone-releasing factor as a cause of acromegaly. Cancer 54:2097–2108

    PubMed  CAS  Google Scholar 

  12. Blackburn AM, Bryant MG, Adrian TE, Bloom SR (1981) Pancreatic tumours also produce neurotensin. J Clin Endocrinol 52:820–822

    CAS  Google Scholar 

  13. Bonfils S, Landor JH, Mignon M et al (1981) Results of surgical management in 92 consecutive patients with Zollinger–Ellison syndrome. Ann Surg 194:692–697

    PubMed  CAS  Google Scholar 

  14. Bordi C, D’Adda T, Azzoni C, Canavese G, Brandi ML (1998) Gastrointestinal endocrine tumors: recent developments. Endocr Pathol 9:99–115

    Google Scholar 

  15. Bordi C, De Vita O, Pilato FP, Carfagna G, D’Adda T, Missale G, Peracchia A (1987) Multiple islet cell tumors with predominance of glucagon-producing cells and ulcer disease. Am J Clin Pathol 88:153–161

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

  18. Bordi C, Ravazzola M, Baetens D, Gorden P, Unger RH, Orci L (1979) A study of glucagonomas by light and electron microscopy and immunofluorescence. Diabetes 28:925–936

    PubMed  CAS  Google Scholar 

  19. Bostwick DG, Quan R, Hoffman AR, Webber RJ, Chang JK, Bensch KG (1984) Growth-hormone-releasing factor immunoreactivity in human endocrine tumors. Am J Pathol 117:167–170

    PubMed  CAS  Google Scholar 

  20. Brenner B, Tang LH, Klimstra DS, Kelsen DP (2004) Small-cell carcinomas of the gastrointestinal tract: a review. J Clin Oncol 22:2730–2739

    PubMed  Google Scholar 

  21. Brenner B, Tang LH, Shia J, Klimstra DS, Kelsen DP (2007) Small cell carcinomas of the gastrointestinal tract: clinicopathological features and treatment approach. Semin Oncol 34:43–50

    PubMed  CAS  Google Scholar 

  22. Broughan TA, Leslie JD, Soto JM, Hermann RE (1986) Pancreatic islet cell tumors. Surgery 99:671–678

    PubMed  CAS  Google Scholar 

  23. Burke AB, Shekitka KM, Sobin LH (1991) Small cell carcinomas of the large intestine. Am J Clin Pathol 95:315–321

    PubMed  CAS  Google Scholar 

  24. Burke AP, Helwig EB (1989) Gangliocytic paraganglioma. Am J Clin Pathol 92:1–9

    PubMed  CAS  Google Scholar 

  25. Burke AP, Sobin LH, Federspiel BH, Shekitka KM, Helwig EB (1990) Carcinoid tumors of the duodenum. A clinicopathologic study of 99 cases. Arch Pathol Lab Med 114:700–704

    PubMed  CAS  Google Scholar 

  26. Burke AP, Thomas RM, Elsayed AM, Sobin LH (1997) Carcinoids of the jejunum and ileum. An immunohistochemical and clinicopathologic study of 167 cases. Cancer 79:1086–1093

    PubMed  CAS  Google Scholar 

  27. Cameron AJ, Hoffman HN (1974) Zollinger–Ellison syndrome. Clinical features and long-time follow-up. Mayo Clin Proc 49:44–51

    PubMed  CAS  Google Scholar 

  28. Capella C, Heitz PU, Höfler H, Solcia E, Klöppel G (1995) Revised classification of neuroendocrine tumours of the lung, pancreas and gut. Virchows Arch 425:547–560

    PubMed  CAS  Google Scholar 

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

    Google Scholar 

  30. Capella C, Polak JM, Buffa R, Tapia FJ, Heitz P, Usellini L, Bloom SR, Solcia E (1983) Morphologic patterns and diagnostic criteria of VIP-producing endocrine tumors. A histologic, histochemical, ultrastructural and biochemical study of 32 cases. Cancer 52:1860–1874

    PubMed  CAS  Google Scholar 

  31. Capella C, Riva C, Rindi G, Sessa F, Usellini L, Chiaravalli A, Carnevali L, Solcia E (1991) Histopathology, hormone products, and clinicopathological profile of endocrine tumors of the upper small intestine: a study of 44 cases. Endocr Pathol 2:92–110

    Article  Google Scholar 

  32. Capella C, Solcia E, Sobin LH, Arnold A (2000) Endocrine tumours of the colon and rectum. In: Hamilton SR, Aaltonen LA (eds) Pathology and genetics. Tumours of the digestive system. WHO classification of tumours. IARC, Lyon, pp 137–139

    Google Scholar 

  33. Capella C, Solcia E, Sobin LH, Arnold A (2000) Endocrine tumours of the small intestine. In: Hamilton SR, Aaltonen LA (eds) Pathology and genetics. Tumours of the digestive system. WHO classification of tumours. IARC, Lyon, pp 77–82

    Google Scholar 

  34. Capella C, Solcia E, Sobin LH, Arnold R (2000) Endocrine tumours of the oesophagus. In: Hamilton SR, Aaltonen LA (eds) Pathology and genetics. Tumours of the digestive system. WHO classification of tumours. IARC, Lyon, pp 26–27

    Google Scholar 

  35. Capella C, Solcia E, Sobin LH, Arnold R (2000) Endocrine tumours of the stomach. In: Hamilton SR, Aaltonen LA (eds) Pathology and genetics. Tumours of the digestive system. WHO classification of tumours. IARC, Lyon, pp 53–57

    Google Scholar 

  36. Chong FK, Graham JH, Madoff IM (1979) Mucin-producing carcinoid (“composite tumor”) of upper third of esophagus. A variant of carcinoid tumor. Cancer 44:1853–1859

    PubMed  CAS  Google Scholar 

  37. Clark ES, Carney JA (1984) Pancreatic islet cell tumor associated with Cushing’s syndrome. Am J Surg Pathol 8:917–924

    PubMed  CAS  Google Scholar 

  38. Crafa P, Milione M, Azzoni C, Pilato FP, Pizzi S, Bordi C (2003) Pleomorph poorly differentiated endocrine carcinoma of the rectum. Virchows Arch 442:605–610

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  40. Dayal Y, Lin HD, Tallberg K, Reichlin S, DeLellis RA, Wolfe HJ (1986) Immunocytochemical demonstration of growth hormone-releasing factor in gastrointestinal and pancreatic endocrine tumors. Am J Clin Pathol 85:13–20

    PubMed  CAS  Google Scholar 

  41. Dayal Y, Tallberg KA, Nunnemacher G, DeLellis RA, Wolfe HJ (1986) Duodenal carcinoids in patients with and without neurofibromatosis. A comparative study. Am J Surg Pathol 10:348–357

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  43. Donow C, Pipeleers-Marichal M, Schröder S, Stamm B, Heitz PU, Klöppel G (1991) Surgical pathology of gastrinoma. Site, size, multicentricity, association with multiple endocrine neoplasia type 1, and malignancy. Cancer 68:1329–1334

    PubMed  CAS  Google Scholar 

  44. Drucker DJ, Asa SL, Henderson J, Goltzman D (1989) The parathyroid hormone-like peptide gene is expressed in the normal and neoplastic human endocrine pancreas. Mol Endocrinol 3:1589–1595

    PubMed  CAS  Google Scholar 

  45. Eissele R, Anlauf M, Schäfer MKH, Eiden LE, Arnold R, Weihe E (1999) Expression of vesicular monoamine transporters in endocrine hyperplasia and endocrine tumors of the oxyntic stomach. Digestion 60:428–439

    PubMed  CAS  Google Scholar 

  46. Federspiel BH, Burke AP, Sobin LH, Shekitka KM (1990) Rectal and colonic carcinoids. A clinicopathologic study of 84 cases. Cancer 65:135–140

    PubMed  CAS  Google Scholar 

  47. Fiocca R, Rindi G, Capella C, Grimelius L, Polak JM, Schwartz TW, Yanaihara N, Solcia E (1987) Glucagon, glicentin, proglucagon, PYY, PP and proPP-icosapeptide immunoreactivities of rectal carcinoid tumors and related non-tumor cells. Regul Pept 17:9–29

    PubMed  CAS  Google Scholar 

  48. Fung JW, Lam KS (1995) Neurofibromatosis and insulinoma. Postgrad Med J 71:485–486

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  50. Garbrecht N, Anlauf M, Schmitt A, Heitz PU, Moch H, Komminoth P, Perren A, Klöppel G (2007) Duodenal somatostatin-producing neuroendocrine tumors (SOM-NETs): frequency, types, biological behavior, functional activity and association with hereditary syndromes (Abstract). Pathol Res Pract 203:383

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  53. Godwin JD2 (1975) Carcinoid tumors. An analysis of 2,837 cases. Cancer 36:560–569

    PubMed  Google Scholar 

  54. Grimelius L, Hultquist GT, Stenkvist B (1975) Cytological differentiation of asymptomatic pancreatic islet cell tumours in autopsy material. Virchows Arch A Pathol Anat 365:275–288

    CAS  Google Scholar 

  55. Hamid QA, Bishop AE, Sikri KL, Varndell IM, Bloom SR, Polak JM (1986) Immunocytochemical characterization of 10 pancreatic tumours, associated with the glucagonoma syndrome, using antibodies to separate regions of the pro-glucagon molecule and other neuroendocrine markers. Histopathology 10:119–133

    PubMed  CAS  Google Scholar 

  56. Heitz PU (1984) Pancreatic endocrine tumors. In: Klöppel G, Heitz PU (eds) Pancreatic pathology. Churchill Livingstone, Edinburgh, pp 206–232

    Google Scholar 

  57. Heitz PU, Klöppel G, Polak JM, Staub JJ (1981) Ectopic hormone production by endocrine tumors: localization of hormones at the cellular level by immunocytochemistry. Cancer 48:2029–2037

    PubMed  CAS  Google Scholar 

  58. Heitz PU, Komminoth P, Perren A, Klimstra DS, Dayal Y, Bordi C, LeChago J, Centeno BA, Klöppel G (2004) Pancreatic endocrine tumours: introduction. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C (eds) Pathology and genetics: tumours of endocrine organs. WHO classification of tumors. IARC, Lyon, pp 177–182

    Google Scholar 

  59. Hemminki K, Li X (2001) Incidence trends and risk factors of carcinoid tumors. A nationwide epidemiologic study from Sweden. Cancer 92:2204–2210

    PubMed  CAS  Google Scholar 

  60. Higgins GA, Recant L, Fischman AB (1979) The glucagonoma syndrome: surgically curable diabetes. Am J Surg 137:142–148

    PubMed  CAS  Google Scholar 

  61. Hoang MP, Hobbs CM, Sobin LH, Albores-Saavedra J (2002) Carcinoid tumor of the esophagus: a clinicopathologic study of four cases. Am J Surg Pathol 26:517–522

    PubMed  Google Scholar 

  62. Hochwald SN, Zee S, Conlon KC, Colleoni R, Louie O, Brennan MF, Klimstra DS (2002) Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. J Clin Oncol 20:2633–2642

    PubMed  Google Scholar 

  63. Hock YL, Scott KW, Grace RH (1993) Mixed adenocarcinoma/carcinoid tumour of large bowel in a patient with Crohn’s disease. J Clin Pathol 46:183–185

    PubMed  CAS  Google Scholar 

  64. Horenstein MG, Erlandson RA, Gonzalez-Cueto DM, Rosai J (1998) Presacral carcinoid tumors. Report of three cases and review of the literature. Am J Surg Pathol 22:251–255

    PubMed  CAS  Google Scholar 

  65. Howard TJ, Zinner MJ, Stabile BE, Passaro E Jr (1990) Gastrinoma excision for cure. A prospective analysis. Ann Surg 211:9–14

    PubMed  CAS  Google Scholar 

  66. Huncharek M, Muscat J (1995) Small cell carcinoma of the esophagus. The Massachusetts General Hospital experience, 1978 to 1993. Chest 107:179–181

    PubMed  CAS  Google Scholar 

  67. Inai K, Kobuke T, Yonehara S, Tokuoka S (1989) Duodenal gangliocytic paraganglioma with lymph node metastasis in a 17-year-old boy. Cancer 63:2540–2545

    PubMed  CAS  Google Scholar 

  68. Isolauri J, Mattila J, Kallioniemi OP (1991) Primary undifferentiated small cell carcinoma of the esophagus: clinicopathological and flow cytometric evaluation of eight cases. J Surg Oncol 46:174–177

    PubMed  CAS  Google Scholar 

  69. Jensen RT, Gardner JD (1991) Zollinger–Ellison syndrome: clinical presentation, pathology, diagnosis and treatement. In: Dannenberg A, Zakim D (eds) Peptic ulcer and other acid-related diseases. Spectrum, New York, pp 117–211

    Google Scholar 

  70. Jensen RT, Gardner JD (1993) Gastrinoma. In: Go VLW, DiMagno EP, Gardner JD, Lebenthal E, Reber HA, Scheele GA (eds) The pancreas: biology, pathobiology and disease. Raven, New York, pp 931–978

    Google Scholar 

  71. Kao PC, Klee GG, Taylor RL, Heath H3d (1990) Parathyroid hormone-related peptide in plasma of patients with hypercalcemia and malignant lesions [see comments]. Mayo Clin Proc 65:1399–1407

    PubMed  CAS  Google Scholar 

  72. Kapran Y, Bauersfeld J, Anlauf M, Sipos B, Klöppel G (2006) Multihormonality and entrapment of islets in pancreatic endocrine tumors. Virchows Arch 448:394–398

    PubMed  CAS  Google Scholar 

  73. Kent RB3, van Heerden JA, Weiland LH (1981) Nonfunctioning islet cell tumours. Ann Surg 193:185–190

    PubMed  Google Scholar 

  74. Kimura W, Kuroda A, Morioka Y (1991) Clinical pathology of endocrine tumors of the pancreas. Analysis of autopsy cases. Dig Dis Sci 36:933–942

    PubMed  CAS  Google Scholar 

  75. Klöppel G, Clemens A (1996) The biological relevance of gastric neuroendocrine tumors. Yale J Biol Med 69:69–74

    PubMed  Google Scholar 

  76. Klöppel G, Heitz PU (1988) Pancreatic endocrine tumors. Pathol Res Pract 183:155–168

    PubMed  Google Scholar 

  77. Klöppel G, Heitz PU (2007) Tumors of the endocrine pancreas. In: Fletcher CD (ed) Diagnostic histopathology of tumors, vol. 2. 3rd edn. Churchill Livingstone, Philadelphia, pp 1123–1137

    Google Scholar 

  78. Klöppel G, Höfler H, Heitz PU (1993) Pancreatic endocrine tumours in man. In: Polak JM (ed) Diagnostic histopathology of neuroendocrine tumours, chapter 5. Churchill Livingstone, Edinburgh, pp 91–121

    Google Scholar 

  79. Klöppel G, In’t Veld PA, Komminoth P, Heitz PU (1998) The endocrine pancreas. In: Kovacs K, Asa SL (eds) Functional endocrine pathology, 2nd edn. Blackwell, Boston, pp 415–487

    Google Scholar 

  80. Krejs GJ, Orci L, Conlon JM, Ravazzola M, Davis GR, Raskin P, Collins SM, McCarthy DM, Baetens D, Rubenstein A, Aldor TA, Unger RH (1979) Somatostatinoma syndrome. Biochemical, morphologic and clinical features. N Engl J Med 301:285–292

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  82. Larsson LI, Hirsch MA, Holst JJ, Ingemansson S, Kuhl C, Jensen SL, Lundquist G, Rehfeld JF, Schwartz TW (1977) Pancreatic somatostatinoma. Clinical features and physiological implications. Lancet i:666–668

    Google Scholar 

  83. Law SY, Fok M, Lam KY, Loke SL, Ma LT, Wong J (1994) Small cell carcinoma of the esophagus. Cancer 73:2894–2899

    PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  85. Levi F, Te VC, Randimbison L, Rindi G, La Vecchia C (2000) Epidemiology of carcinoid neoplasms in Vaud, Switzerland, 1974–1997. Br J Cancer 83:952–955

    PubMed  CAS  Google Scholar 

  86. Ligneau B, Lombard-Bohas C, Partensky C, Valette PJ, Calender A, Dumortier J, Gouysse G, Boulez J, Napoleon B, Berger F, Chayvialle JA, Scoazec JY (2001) Cystic endocrine tumors of the pancreas: clinical, radiologic, and histopathologic features in 13 cases. Am J Surg Pathol 25:760

    Google Scholar 

  87. Lindberg GM, Molberg KH, Vuitch MF, Albores-Saavedra J (1997) Atypical carcinoid of the esophagus. A case report and review of the literature. Cancer 79:1476–1481

    PubMed  CAS  Google Scholar 

  88. Lloyd RV (2003) Practical markers used in the diagnosis of neuroendocrine tumors. Endocr Pathol 14:293–301

    PubMed  CAS  Google Scholar 

  89. Lloyd RV, Mervak T, Schmidt K, Warner TF, Wilson BS (1984) Immunohistochemical detection of chromogranin and neuron-specific enolase in pancreatic endocrine neoplasms. Am J Surg Pathol 8:607–614

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  91. MacGillivray DC, Heaton RB, Rushin JM, Cruess DF (1992) Distant metastasis from a carcinoid tumor of the appendix less than one centimeter in size. Surgery 111:466–471

    PubMed  CAS  Google Scholar 

  92. Maggard MA, O’Connell JB, Ko CY (2004) Updated population-based review of carcinoid tumors. Ann Surg 240:117–122

    PubMed  Google Scholar 

  93. Martin EN, Potet F (1974) Pathology of endocrine tumors of the GI tract. Clin Gastroenterol 3:511–532

    Google Scholar 

  94. Matsumoto T, Jo Y, Mibu R, Hirahashi M, Yao T, Iida M (2003) Multiple microcarcinoids in a patient with long standing ulcerative colitis. J Clin Pathol 56:963–965

    PubMed  CAS  Google Scholar 

  95. McGory ML, Maggard MA, Kang H, O’Connell JB, Ko CY (2005) Malignancies of the appendix: beyond case series reports. Dis Colon Rectum 48:2264–2271

    PubMed  Google Scholar 

  96. Melmed S, Yamashita S, Kovacs K, Ong J, Rosenblatt S, Braunstein G (1987) Cushing’s syndrome due to ectopic proopiomelanocortin gene expression by islet cell carcinoma of the pancreas. Cancer 59:772–778

    PubMed  CAS  Google Scholar 

  97. Merchant SH, VanderJagt T, Lathrop S, Amin MB (2006) Sporadic duodenal bulb gastrin-cell tumors: association with Helicobacter pylori gastritis and long-term use of proton pump inhibitors. Am J Surg Pathol 30:1581–1587

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  99. Modlin IM, Lye KD, Kidd M (2003) A 5-decade analysis of 13,715 carcinoid tumors. Cancer 97:934–959

    PubMed  Google Scholar 

  100. Modlin IM, Sandor A (1997) An analysis of 8305 cases of carcinoid tumors. Cancer 79:813–829

    PubMed  CAS  Google Scholar 

  101. Moldow RE, Connelly RR (1968) Epidemiology of pancreatic cancer in Connecticut. Gastroenterology 55:677–686

    PubMed  CAS  Google Scholar 

  102. Moyana TN (1989) Carcinoid tumors arising from Meckel’s diverticulum. A clinical, morphologic, and immunohistochemical study. Am J Clin Pathol 91:52–56

    PubMed  CAS  Google Scholar 

  103. Nascimbeni R, Villanacci V, Di Fabio F, Gavazzi E, Fellegara G, Rindi G (2005) Solitary microcarcinoid of the rectal stump in ulcerative colitis. Neuroendocrinology 81:400–404

    PubMed  CAS  Google Scholar 

  104. Nassar H, Albores-Saavedra J, Klimstra DS (2005) High-grade neuroendocrine carcinoma of the ampulla of Vater. A clinicopathologic and immunohistochemical analysis of 14 cases. Am J Surg Pathol 29:588–594

    PubMed  Google Scholar 

  105. Norton JA, Doppman JL, Collen MJ, Harmon JW, Maton PN, Gardner JD, Jensen RT (1986) Prospective study of gastrinoma localization and resection in patients with Zollinger–Ellison syndrome. Ann Surg 204:468–479

    PubMed  CAS  Google Scholar 

  106. Norton JA, Doppman JL, Jensen RT (1992) Curative resection in Zollinger–Ellison syndrome. Results of a 10-year prospective study. Ann Surg 215:8–18

    PubMed  CAS  Google Scholar 

  107. Norton JA, Fraker DL, Alexander HR, Venzon DJ, Doppman JL, Serrano J, Goebel SU, Peghini PL, Roy PK, Gibril F, Jensen RT (1999) Surgery to cure the Zollinger–Ellison syndrome. N Engl J Med 341:635–644

    PubMed  CAS  Google Scholar 

  108. O’Dorisio TM, Ellison EC, Johnson JA, Mazzaferri EL (1993) Multiple endocrine neoplasia and gastrinoma. In: Mazzaferri EL, Samaan NA (eds) Endocrine tumors. Blackwell, Boston, pp 484–496

    Google Scholar 

  109. Oberhelman HA Jr, Nelsen TS (1964) Surgical consideration in the management of ulcerogenic tumors of the pancreas and duodenum. Am J Surg 108:132–141

    PubMed  Google Scholar 

  110. Oberndorfer S (1907) Karzinoide tumoren des dünndarms. Frankf Z Pathol 1:425–432

    Google Scholar 

  111. Ooi A, Kameya T, Tsumuraya M, Yamaguchi K, Abe K, Shimosato Y, Yanaihara N (1985) Pancreatic endocrine tumours associated with WDHA syndrome. An immunohistochemical and electron microscopic study. Virchows Arch A Pathol Anat 405:311–323

    CAS  Google Scholar 

  112. Ooi A, Ota M, Katsuda S, Nakanishi I, Sugawara H, Takahashi I (1995) An unusual case of multiple gastric carcinoids associated with diffuse endocrine cell hyperplasia and parietal cell hypertrophy. Endocr Pathol 6:229–237

    PubMed  Google Scholar 

  113. Ordóñez NG, Manning JT Jr, Raymond AK (1985) Argentaffin endocrine carcinoma (carcinoid) of the pancreas with concomitant breast metastasis: an immunohistochemical and electron microscopic study. Human Pathol 16:746–751

    Google Scholar 

  114. Parkes SE, Muir KR, al Sheyyab M, Cameron AH, Pincott JR, Raafat F, Mann JR (1993) Carcinoid tumours of the appendix in children 1957–1986: incidence, treatment and outcome. Br J Surg 80:502–504

    PubMed  CAS  Google Scholar 

  115. Partensky C, Chayvialle JA, Berger F, Souquet JC, Moulinier B (1993) Five-year survival after transhiatal resection of esophageal carcinoid tumor with a lymph node metastasis. Cancer 72:2320–2322

    PubMed  CAS  Google Scholar 

  116. Peck JJ, Shields AB, Boyden AM, Dworkin LA, Nadal JW (1983) Carcinoid tumors of the ileum. Am J Surg 146:124–132

    PubMed  CAS  Google Scholar 

  117. Perren A, Anlauf M, Komminoth P (2007) Molecular profiles of gastroenteropancreatic endocrine tumors. Virchows Arch (in this issue)

  118. Pipeleers-Marichal M, Donow C, Heitz PU, Klöppel G (1993) Pathologic aspects of gastrinomas in patients with Zollinger–Ellison syndrome with and without multiple endocrine neoplasia type I. World J Surg 17:481–488

    PubMed  CAS  Google Scholar 

  119. Pipeleers-Marichal M, Somers G, Willems G, Foulis A, Imrie C, Bishop AE, Polak JM, Häcki WH, Stamm B, Heitz PU, Klöppel G (1990) Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type 1 and the Zollinger–Ellison syndrome. N Engl J Med 322:723–727

    Article  PubMed  CAS  Google Scholar 

  120. Pipeleers D, Couturier E, Gepts W, Reynders J, Somers G (1983) Five cases of somatostatinoma: clinical heterogeneity and diagnostic usefulness of basal and tolbutamide-induced hypersomatostatinemia. J Clin Endocrinol Metab 56:1236–1242

    Article  PubMed  CAS  Google Scholar 

  121. Prinz RA, Dorsch TR, Lawrence AM (1981) Clinical aspects of glucagon-producing islet cell tumors. Am J Gastroenterol 76:125–131

    PubMed  CAS  Google Scholar 

  122. Pulitzer M, Xu R, Suriawinata AA, Waye JD, Harpaz N (2006) Microcarcinoids in large intestinal adenomas. Am J Surg Pathol 30:1531–1536

    PubMed  Google Scholar 

  123. Qualtrough D, Hinoi T, Fearon E, Paraskeva C (2002) Expression of CDX2 in normal and neoplastic human colon tissue and during differentiation of an in vitro model system. Gut 51:184–190

    PubMed  CAS  Google Scholar 

  124. Rappel S, Altendorf-Hofmann A, Stolte M (1995) Prognosis of gastric carcinoid tumours. Digestion 56:455–462

    Article  PubMed  CAS  Google Scholar 

  125. Reed RJ, Daroca PJ Jr, Harkin JC (1977) Gangliocytic paraganglioma. Am J Surg Pathol 1:207–216

    Article  PubMed  CAS  Google Scholar 

  126. Regan PT, Malagelada JR (1978) A reappraisal of clinical, roentgenographic and endoscopic features of Zollinger–Ellison syndrome. Mayo Clin Proc 53:19–23

    PubMed  CAS  Google Scholar 

  127. Rindi G, Klöppel G, Ahlman H, Caplin M, Couvelard A, de Herder WW, Eriksson B, Falchetti A, Falconi M, Komminoth P, Körner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B, and all other Frascati Consensus Conference participants (2006) TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 449:395–401

    PubMed  CAS  Google Scholar 

  128. Rindi G, Klöppel G, Couvelard A, Komminoth P, Koerner M, Lopes J, McNicol AM, Nilsson O, Perren A, Scarpa A, Frascati Consensus Conference participants (2007) TNM staging of midgut and hindgut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch (in press)

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

    PubMed  CAS  Google Scholar 

  130. Rindi G, Paolotti D, Fiocca R, Wiedenmann B, Henry JP, Solcia E (2000) Vesicular monoamine transporter 2 as a marker of gastric enterochromaffin-like cell tumors. Virchows Arch 436:217–223

    PubMed  CAS  Google Scholar 

  131. Roggli VL, Judge DM, McGavran MH (1979) Duodenal glucagonoma: a case report. Human Pathol 10:350–353

    CAS  Google Scholar 

  132. Rosenberg JM, Welch JP (1985) Carcinoid tumors of the colon. A study of 72 patients. Am J Surg 149:775–779

    PubMed  CAS  Google Scholar 

  133. Rossi G, Bertolini F, Sartori G, Bigiani N, Cavazza A, Foroni M, Valli R, Rindi G, De Gaetani C, Luppi G (2004) Primary mixed adenocarcinoma and small cell carcinoma of the appendix. A clinicopathologic, immunohistochemical, and molecular study of a hitherto unreported tumor. Am J Surg Pathol 28:1233–1239

    PubMed  Google Scholar 

  134. Rossi G, Valli R, Bertolini F, Sighinolfi P, Losi L, Cavazza A, Rivasi F, Luppi G (2003) Does mesoappendix infiltration predict a worse prognosis in incidental neuroendocrine tumors of the appendix? A clinicopathologic and immunohistochemical study of 15 cases. Am J Clin Pathol 120:706–711

    PubMed  Google Scholar 

  135. Roth J, Komminoth P, Klöppel G, Heitz PU (1996) Diabetes and the endocrine pancreas. In: Damjanov I, Purtilo DT (eds) Anderson’s pathology. Mosby, Chicago, pp 2041–2070

    Google Scholar 

  136. Ruttman E, Klöppel G, Bommer G, Kiehn M, Heitz PU (1980) Pancreatic glucagonoma with and without syndrome. Immunocytochemical study of 5 tumour cases and review of the literature. Virchows Arch A Pathol Anat 388:51–67

    CAS  Google Scholar 

  137. Sakhuja P, Malhotra V, Gondal R, Dutt N, Choudhary A (2001) Periampullary gangliocytic paraganglioma. J Clin Gastroenterol 33:154–156

    PubMed  CAS  Google Scholar 

  138. Sano T, Asa SL, Kovacs K (1988) Growth hormone-releasing hormone-producing tumors: clinical, biochemical, and morphological manifestations. Endocr Rev 9:357–373

    PubMed  CAS  Google Scholar 

  139. Schmitt AM, Anlauf M, Rousson V, Schmid S, Kofler A, Riniker F, Bauersfeld J, Barghorn A, Probst N, Moch H, Heitz PU, Klöppel G, Komminoth P, Perren A (2007) WHO 2004 criteria and CK19 are reliable prognostic markers in pancreatic endocrine tumors. Am J Surg Pathol (in press)

  140. Service FJ, Dale AJ, Elveback LR, Jiang NS (1976) Insulinoma: clinical and diagnostic features of 60 consecutive cases. Mayo Clin Proc 51:417–429

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  142. Sessa F, Arcidiaco M, Valenti L, Solcia M, Di Maggio E, Solcia E (1998) Metastatic psammomatous somatostatinoma of the pancreas causing severe ketoacedotic diabetes cured by surgery. Endocr Pathol 8:327–333

    Google Scholar 

  143. Shorter NA, Glick RD, Klimstra DS, Brennan MF, Laquaglia MP (2002) Malignant pancreatic tumors in childhood and adolescence: the Memorial Sloan-Kettering experience, 1967 to present. J Pediatr Surg 37:887–892

    PubMed  Google Scholar 

  144. Soga J (1997) Carcinoids of the rectum: an evaluation of 1271 reported cases. Surg Today 27:112–119

    PubMed  CAS  Google Scholar 

  145. Soga J (1998) Carcinoids of the colon and ileocecal region: a statistical evaluation of 363 cases collected from the literature. J Exp Clin Cancer Res 17:139–148

    PubMed  CAS  Google Scholar 

  146. Soga J (2005) Early-stage carcinoids of the gastrointestinal tract: an analysis of 1914 reported cases. Cancer 103:1587–1595

    PubMed  Google Scholar 

  147. Soga J, Tazawa K (1971) Pathologic analysis of carcinoids. Histologic reevaluation of 62 cases. Cancer 28:990–998

    PubMed  CAS  Google Scholar 

  148. Soga J, Yakuwa Y, Osaka M (1998) Insulinoma/hypoglycemic syndrome: a statistical evaluation of 1085 reported cases of a Japanese series. J Exp Clin Cancer Res 17:379–388

    PubMed  CAS  Google Scholar 

  149. Solcia E, Capella C, Fiocca R, Cornaggia M, Bosi F (1989) The gastroenteropancreatic endocrine system and related tumors. Gastroenterol Clin North Am 18:671–693

    PubMed  CAS  Google Scholar 

  150. Solcia E, Capella C, Fiocca R, Sessa F, La Rosa S, Rindi G (1998) Disorders of the endocrine system. In: Ming SC, Goldman H (eds) Pathology of the gastrointestinal tract. Williams and Wilkins, Philadelphia, pp 295–322

    Google Scholar 

  151. Solcia E, Capella C, Klöppel G (1997) Tumors of the pancreas. AFIP Atlas of tumor pathology, third series, fascicle 20. Armed Forces Institute of Pathology, Washington, DC

    Google Scholar 

  152. Solcia E, Klöppel G, Sobin LH, (In collaboration with 9 pathologists from 4 countries) (2000) Histological typing of endocrine tumours, 2nd edn. WHO international histological classification of tumours. Springer, Berlin

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  154. Stage JG, Stadil R (1979) The clinical diagnosis of Zollinger–Ellison syndrome. Scand J Gastroenterol 14(Suppl 53):79–91

    Google Scholar 

  155. Stamm B, Häcki WH, Klöppel G, Heitz PU (1991) Gastrin-producing tumors and the Zollinger–Ellison syndrome. In: Dayal Y (ed) Endocrine pathology of the gut and pancreas. CRC, Boca Raton, pp 155–194

    Google Scholar 

  156. Stamm B, Hedinger CE, Saremaslani P (1986) Duodenal and ampullary carcinoid tumors. A report of 12 cases with pathological characteristics, polypeptide content and relation to the MEN 1 syndrome and von Recklingshausen’s disease (neurofibromatosis). Virchows Arch A Pathol Anat 408:475–489

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  158. Stinner B, Kisker O, Zielke A, Rothmund M (1996) Surgical management for carcinoid tumors of small bowel, appendix, colon, and rectum. World J Surg 20:183–188

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  160. Taccagni GL, Carlucci M, Sironi M, Cantaboni A, Di Carlo V (1986) Duodenal somatostatinoma with psammoma bodies: an immunohistochemical and ultrastructural study. Am J Gastroenterol 81:33–37

    PubMed  CAS  Google Scholar 

  161. Theunissen P, Fickers M, Goei R (2001) Primary large cell neuroendocrine carcinoma of the presacral region. J Clin Pathol 54:880–882

    PubMed  CAS  Google Scholar 

  162. Thompson JC, Lewis BG, Wiener I, Townsend CM Jr (1983) The role of surgery in the Zollinger–Ellison syndrome. Ann Surg 197:594–607

    Article  PubMed  CAS  Google Scholar 

  163. Thompson NW, Vinik AI, Eckhauser FE (1989) Microgastrinomas of the duodenum. A cause of failed operations for the Zollinger–Ellison syndrome. Ann Surg 209:396–404

    PubMed  CAS  Google Scholar 

  164. Ubiali A, Benetti A, Papotti M, Villanacci V, Rindi G (2001) Genetic alterations in poorly differentiated endocrine colon carcinomas developing in tubulo-villous adenomas: a report of two cases. Virchows Arch 439:776–781

    PubMed  CAS  Google Scholar 

  165. van Heerden JA, Edis AJ, Service FJ (1979) The surgical aspects of insulinomas. Ann Surg 189:677–682

    PubMed  Google Scholar 

  166. Vinik AI, Strodel WE, Eckhauser FE, Moattari AR, Lloyd R (1987) Somatostatinomas, PPomas, neurotensinomas. Semin Oncol 14:263–281

    PubMed  CAS  Google Scholar 

  167. Volante M, Rindi G, Papotti M (2006) The grey zone between pure (neuro)endocrine and non-(neuro)endocrine tumors: a comment on concepts and classification of mixed exocrine-endocrine neoplasms. Virchows Arch 449:499–506

    PubMed  Google Scholar 

  168. Vortmeyer AO, Lubensky IA, Merino MJ, Wang CY, Pham T, Furth EE, Zhuang Z (1997) Concordance of genetic alterations in poorly differentiated colorectal neuroendocrine carcinomas and associated adenocarcinomas. J Natl Cancer Inst 89:1448–1453

    PubMed  CAS  Google Scholar 

  169. Watson KJ, Shulkes A, Smallwood RA, Douglas MC, Hurley R, Kalnins R, Moran L (1985) Watery diarrhea-hypokalemia-achlorhydria syndrome and carcinoma of the esophagus. Gastroenterology 88:798–803

    PubMed  CAS  Google Scholar 

  170. Weber HC, Venzon DJ, Lin JT, Fishbein VA, Orbuch M, Strader DB, Gibril F, Metz DC, Fraker DL, Norton JA, Jensen RT (1995) Determinants of metastatic rate and survival in patients with Zollinger–Ellison syndrome: a prospective long-term study. Gastroenterology 108:1637–1649

    PubMed  CAS  Google Scholar 

  171. Wilander E, El-Salhy M, Willén T, Grimelius L (1981) Immunocytochemistry and electron microscopy of an argentaffin endocrine tumor of the pancreas. Virchows Arch A Pathol Anat 392:263–269

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  173. Williams ED, Sandler M (1963) The classification of carcinoid tumours. Lancet I:238–239

    Google Scholar 

  174. Yagihashi S, Yagihashi N, Nagai K (1992) Cystic pancreatic glucagonoma in contact with insulinoma found in a hypoglycemic patient. Pathol Res Pract 188:751–756

    PubMed  CAS  Google Scholar 

  175. Yantiss RK, Odze RD, Farraye FA, Rosenberg AE (2003) Solitary versus multiple carcinoid tumors of the ileum. A clinical and pathologic review of 68 cases. Am J Surg Pathol 27:811–817

    PubMed  Google Scholar 

  176. Zollinger RM, Ellison EH (1955) Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg 142:709–723

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, University of Kiel, Michaelisstr. 11, 24105, Kiel, Germany

    Günter Klöppel & Martin Anlauf

  2. Department of Pathology, University of Parma, Parma, Italy

    Guido Rindi

  3. Department of Pathology, Technical University of Munich, Munich, Germany

    Aurel Perren

  4. Institute of Pathology, Stadtspital Triemli, Zurich, Switzerland

    Paul Komminoth

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  1. Günter Klöppel
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Correspondence to Günter Klöppel.

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Klöppel, G., Rindi, G., Anlauf, M. et al. Site-specific biology and pathology of gastroenteropancreatic neuroendocrine tumors. Virchows Arch 451 (Suppl 1), 9–27 (2007). https://doi.org/10.1007/s00428-007-0461-0

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