Endocrine Pathology

, Volume 17, Issue 2, pp 119–129 | Cite as

Criteria for malignancy in gastrointestinal endocrine tumors

  • Cesare Bordi
  • Tiziana D'Adda
  • Cinzia Azzoni
  • Silvia Pizzi
  • Lorena Bottarelli
  • Francesca Mormandi
  • Tommaso Antonetti
  • Tu Ving Luong
  • Guido Rindi
European Congress for Pathology Symposium: Criteria for Malignancy in Endocrine Tumors


In contrast with the large amount of data generated from endocrine tumors of the pancreas, sparse and mostly unconfirmed data are available on the criteria for the assessment of malignancy risk and patient outcome in endocrine tumors of the gastrointestinal tract. In these conditions the 2000 WHO classification with its standardized scheme of pathologic report constitutes a framework facilitating the assessment of tumor malignancy and has been regarded as useful for clinical purposes, providing the basis for proper management of the patients and for the design of treatment protocols. The classification is based on a combination of pathological and clinical features with parameters specific for each organ in which the endocrine tumors originate. Three main categories, one further subdivided into two subgroups, are considered: (1) well-differentiated endocrine tumors, further subdivided into tumors with benign and with uncertain behavior; (2) well-differentiated endocrine carcinomas, low grade; and (3) poorly differentiated endocrine carcinomas, high grade. In this review the differential tumor characteristics between the different categories are summarized. Moreover, the relevance of additional features with respect to tumor prognostication, chiefly the Ki-67 proliferation index and malignancy-associated genetic changes, is discussed with emphasis on the discrepancies emerging between tumors of foregut and of midgut origin.

Key Words

WHO classification prognosis well-differentiated endocrine carcinoma poorly differentiated endocrine carcinoma Ki-67 foregut endocrine tumors midgut endocrine tumors 


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  1. 1.
    Rindi G, Leiter AB, Kopin AS, Bordi C, Solcia E. The “normal” endocrine cell of the gut: changing concepts and new evidences. Ann N Y Acad Sci 1014:1–12, 2004.PubMedCrossRefGoogle Scholar
  2. 2.
    Capella C, Heitz PU, Höfler H, Solcia E, Klöppel G. Revised classification of neuroendocrine tumours of the lung, pancreas and gut. Virchows Arch 425:547–560, 1995.PubMedCrossRefGoogle Scholar
  3. 3.
    Solcia E, Klöppel G, Sobin LH. Histological typing of endocrine tumours. 2nd ed. Berlin: Springer, 2000.Google Scholar
  4. 4.
    Rossi G, Valli R, Bertolini F, et al. 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, 2003.PubMedCrossRefGoogle Scholar
  5. 5.
    Plöckinger U, Rindi G, Arnold R, et al. Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours—a consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS). Neuroendocrinology 80:394–424, 2004.PubMedCrossRefGoogle Scholar
  6. 6.
    Wiedemann B, Jensen RT, Mignon M, et al. Preoperative diagnosis and surgical management of neuroendocrine gastroenteropancreatic tumors: General recommendations by a consensus workshop. World J Surg 22:309–318, 1998.CrossRefGoogle Scholar
  7. 7.
    Öberg K. State of the art and future prospects in the management of neuroendocrine tumors. Quart J Nucl Med 44:3–12, 2000.Google Scholar
  8. 8.
    Reubi JC, Kappeler A, Waser B, Laissue J, Hipkin RW, Schonbrunn A. Immunohistochemical localization of somatostatin receptor sst2A in human tumors. Am J Pathol 153:233–245, 1998.PubMedGoogle Scholar
  9. 9.
    Soga J, Tazawa K. Pathologic analysis of carcinoids. Histologic reevaluation of 62 cases. Cancer 28:990–998, 1971.PubMedCrossRefGoogle Scholar
  10. 10.
    Rindi G, Villanacci V, Ubiali A, Scarpa A. Endocrine tumors of the digestive tract and pancreas: histogenesis, diagnosis and molecular basis. Expert Rev Mol Diagn 1:323–333, 2001.PubMedCrossRefGoogle Scholar
  11. 11.
    Canavese G, Azzoni C, Pizzi S, et al. p27: A potential main inhibitor of cell proliferation in digestive endocrine tumors but not a marker of benign behavior. Hum Pathol 32:1094–1101, 2001.PubMedCrossRefGoogle Scholar
  12. 12.
    La Rosa S, Sessa F, Capella C, et al. Prognostic criteria in nonfunctioning pancreatic endocrine tumours. Virchows Arch 429:323–333, 1996.PubMedCrossRefGoogle Scholar
  13. 13.
    Pizzi S, Azzoni C, Bassi D, Bottarelli L, Milione M, Bordi C. Genetic alterations in poorly differentiated endocrine carcinomas of the gastrointestinal tract. Cancer 98:1273–1282, 2003.PubMedCrossRefGoogle Scholar
  14. 14.
    Furlan D, Cerutti R, Uccella S, et al. Different molecular profiles characterize well-differentiated endocrine tumors and poorly differentiated endocrine carcinomas of the gastroenteropancreatic tract. Clin Canc Res 10:947–957, 2004.CrossRefGoogle Scholar
  15. 15.
    Furlan D, Bernasconi B, Uccella S, Cerutti R, Carnevali I, Capella C. Allelotypes and fluorescence in situ hybridization profiles of poorly differentiated endocrine carcinomas of different sites. Clin Canc Res 11:1765–1775, 2005.CrossRefGoogle Scholar
  16. 16.
    Bordi C, D'Adda T, Azzoni C, Canavese G, Brandi ML. Gastrointestinal endocrine tumors: recent developments. Endocr Pathol 9:99–115, 1998.Google Scholar
  17. 17.
    Pelosi G, Bresaola E, Bogina G, et al. Endocrine tumors of the pancreas: Ki-67 immunoreactivity on paraffin 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 variables. Hum Pathol 27:1124–1134, 1996.PubMedCrossRefGoogle Scholar
  18. 18.
    Hochwald SN, Zee S, Conlon KC, et al. 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, 2002.PubMedCrossRefGoogle Scholar
  19. 19.
    Nakasu S, Li DH, Okabe H, Nakajima M, Matsuda M. Significance of MIB-1 staining indices in meningiomas. Comparison of two counting methods. Am J Surg Pathol 25:472–478, 2001.PubMedCrossRefGoogle Scholar
  20. 20.
    Rindi G, Azzoni C, La Rosa S, et al. ECL cell tumor and poorly differentiated endocrine carcinoma of the stomach: prognostic evaluation by pathological analysis. Gastroenterology 116:532–542, 1999.PubMedCrossRefGoogle Scholar
  21. 21.
    Deshpande V, Fernandez del Castillo C, Muzikansky A, et al. Cytokeratin 19 is a powerful predictor of survival in pancreatic endocrine tumors. Am J Surg Pathol 28:1145–1153, 2004.PubMedCrossRefGoogle Scholar
  22. 22.
    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 13:27–35; 1992.CrossRefGoogle Scholar
  23. 23.
    Heitz PU, Kasper M, Klöppel G, Polak JM, Vaitukaitis JL. Glycoprotein-hormone alpha-chain production by pancreatic endocrine tumors: a specific marker for malignancy. Immunocytochemical analysis of tumors of 155 patients. Cancer 51:277–282, 1983.PubMedCrossRefGoogle Scholar
  24. 24.
    Bordi C, Pilato FP, D'Adda T. Comparative study of seven neuroendocrine markers in pancreatic endocrine tumours. Virchows Arch A 413:387–398, 1988.CrossRefGoogle Scholar
  25. 25.
    Graeme-Cook F, Nardi G, Compton C. Immunocytochemical staining for human chorionic gonadotropin subunits does not predict malignancy in insulinomas. Am J Clin Pathol 93:273–276, 1990.PubMedGoogle Scholar
  26. 26.
    Donow C, Baisch H, Heitz PU, Klöppel G. Nuclear DNA content in 27 pancreatic endocrine tumours. Correlation with malignancy, survival and expression of glycoprotein hormone alpha chain. Virchows Arch (Path Anat) 419:463–468, 1991.Google Scholar
  27. 27.
    Bordi C, Pilato FP, Bertelé A, D'Adda T, Missale G. Expression of glycoprotein hormone alpha-subunit by endocrine cells of the oxyntic mucosa is associated with hypergastrinemia. Hum Pathol 19:580–585, 1988.PubMedCrossRefGoogle Scholar
  28. 28.
    Bordi C, D'Adda T, Azzoni C, Pilato FP, Caruana P. Hypergastrinemia and gastric enterochromaffin-like cells. Am J Surg Pathol 19 (suppl 1):S8-S19, 1995PubMedGoogle Scholar
  29. 29.
    Bordi C, D'Adda T, Azzoni C, Ferraro G, Pathogenesis of ECL cell tumors in humans. Yale J Biol Med 71:273–284, 1998.PubMedGoogle Scholar
  30. 30.
    Fukayama M, Hayashi Y, Shiozawa Y, Okabe S, Koike M. Human chorionic gonadotropin alpha-subunit in rectal carcinoids. Its mode of presence and the change of granule morphology. Am J Pathol 135:1065–1072, 1989.PubMedGoogle Scholar
  31. 31.
    Carlinfante G, Lampugnani R, Azzoni C, Aprile MR, Brandi ML, Bordi C. Expression of the α- and β-subunits of human chorionic gonadotropin by subsets of parathyroid cells in states of hyperparathyroidism. J Pathol 185:389–393, 1998.PubMedCrossRefGoogle Scholar
  32. 32.
    Goto A, Niki T, Terado Y, Fukushima J, Fukayama M. Prevalence of CD99 protein expression in pancreatic endocrine tumours (PETs). Histopathology 45:384–392, 2004.PubMedCrossRefGoogle Scholar
  33. 33.
    Rigaud G, Missiaglia E, Moore PS, et al. High resolution allelotype of nonfunctional pancreatic endocrine tumors: identification of two molecular subgroups with clinical implications. Cancer Res 61;285–292, 2001.PubMedGoogle Scholar
  34. 34.
    Pizzi S, D'Adda T, Azzoni C, et al. Malignancy-associated allelic losses on X chromosome in foregut but not in midgut endocrine tumours. J Pathol 196:401–407, 2002.PubMedCrossRefGoogle Scholar
  35. 35.
    Pizzi S, Azzoni C, Bottarelli L, et al. RASSF1A promoter methylation and 3p21.3 LOH label foregut, but not midgut and hindgut, malignant endocrine tumours. J Pathol 206:409–416, 2005.PubMedCrossRefGoogle Scholar
  36. 36.
    Leotlela PD, Jauch A, Holtgreve Grez H, Thakker RV. Genetics of neuroendocrine and carcinoid tumours. Endoc Relat Cancer 10:437–450, 2003.CrossRefGoogle Scholar
  37. 37.
    Bordi C, D'Adda T, Pizzi S, Crafa P, Rindi G, The assessment of malignancy in endocrine tumours of the gastrointestinal tract. Curr Diagn Pathol 8:421–429, 2002.CrossRefGoogle Scholar
  38. 38.
    Ebrahimi SA, Wang EH, Wu A, Schreck RR, Passaro E, Sawicki MP. Deletion of chromosome 1 predicts prognosis in pancreatic endocrine tumors. Cancer Res 59:311–315, 1999.PubMedGoogle Scholar
  39. 39.
    Speel EJM, Richter J, Moch H, et al. Genetic differences in endocrine pancreatic tumorsubtypes detected by comparative genomic hybridization. Am J Pathol 155:1787–1794, 1999.PubMedGoogle Scholar
  40. 40.
    Chung DC, Smith AP, Louis DN, Graeme-Cook F, Warshaw AL, Arnold A. A novel pancreatic endocrine tumor suppressor gene locus on chromosome 3p with clinical prognostic implications. J Clin Invest 100:404–410, 1997.PubMedCrossRefGoogle Scholar
  41. 41.
    Hessman O, Lindberg D, Einarsson A, et al. Genetic alterations on 3p, 11q13, and 18q in nonfamilial and MEN 1-associated pancreatic endocrine tumors. Gene Chromosome Canc 26:258–264, 1999.CrossRefGoogle Scholar
  42. 42.
    Barghorn A, Komminoth P, Bachmann D, et al. Deletion at 3p25.3-p.23 is frequently encountered in endocrine pancreatic tumours and is associated with metastatic progression. J Pathol 194:451–458, 2001.PubMedCrossRefGoogle Scholar
  43. 43.
    Zhao JM, Moch H, Scheidweiler AF, et al. Genomic imbalances in the progression of endocrine pancreatic tumors. Gene Chromosome Canc 32:364–372, 2001.CrossRefGoogle Scholar
  44. 44.
    Kytola S, Hoog A, Nord B, et al. Comparative genomic hybridization identifies loss of 18q22-qter as an early and specific event in tumorigenesis of midgut carcinoids. Am J Pathol 158:1803–1808, 2001.PubMedGoogle Scholar
  45. 45.
    Barghorn A, Speel EJM, Farspour B, et al. Putative tumor suppressor loci at 6q22 and 6q23-q24 are involved in the malignant progression of sporadic endocrine pancretic tumors. Am J Pathol 158:1903–1911, 2001.PubMedGoogle Scholar
  46. 46.
    Beghelli S, Pelosi G, Zamboni G, et al. Pancreatic endocrine tumours: evidence for a tumour suppressor pathogenesis and for a tumour suppressor gene on chromosome 17p. J Pathol 186:41–50, 1998.PubMedCrossRefGoogle Scholar
  47. 47.
    Rindi G, Alberizzi P, Candusso M, La Rosa S, Capella C, Solcia E. Loss of heterozygosity for chromosome 17p,P53 gene, and chromosome 18q, DCC gene, in aggressive endocrine tumors of the stomach, Gastroenterology 116:G2156 (Abstract), 1999.CrossRefGoogle Scholar
  48. 48.
    Vortmeyer AO, Lubensky IA, Merino MJ, et al. Concordance of genetic alterations in poorly differentiated colorectal neuroendocrine carcinomas and associated adenocarcinomas. N Natl Cancer Inst 89:1448–1453, 1997.CrossRefGoogle Scholar
  49. 49.
    D'Adda T, Candidus S, Bordi C, Hoffler H. Gastric neuroendocrine neoplasms: tumor clonality and malignancy associated large X-chromosomal deletions. J Pathol 189:394–401, 1999.PubMedCrossRefGoogle Scholar
  50. 50.
    Missiaglia E, Moore PS, Williamson J, et al. Sex chromosome anomalies in pancreatic endocrine tumors. Int J Cancer 98:532–538, 2002.PubMedCrossRefGoogle Scholar
  51. 51.
    Brandi ML, Bordi C, Falchetti A, Tonelli F, Marx SJ. Multiple endocrine neoplasia type 1. In: Brandi ML, Bordi C, Falchetti A, Tonelli F, Marx SJ, eds. Principles of Bone Biology. San Diego: Academic Press, 1996; 783–797.Google Scholar

Copyright information

© Humana Press Inc. 2006

Authors and Affiliations

  • Cesare Bordi
    • 1
  • Tiziana D'Adda
    • 1
  • Cinzia Azzoni
    • 1
  • Silvia Pizzi
    • 1
  • Lorena Bottarelli
    • 1
  • Francesca Mormandi
    • 1
  • Tommaso Antonetti
    • 1
  • Tu Ving Luong
    • 1
  • Guido Rindi
    • 1
  1. 1.Dipartimento di Patologia e Medicina di Laboratorio, Sezione di Anatomia PatologicaUniversità degli StudiParmaItaly

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