Skip to main content
SpringerLink
Log in

Proliferative activity in pancreatic endocrine tumors: Association with function, metastases, and survival

  • Clinical Research
  • Published:
Endocrine Pathology Aims and scope Submit manuscript

Abstract

Endocrine tumors of the pancreas are slow-growing lesions, yet one-third to one-half will metastasize. It is generally accepted that histopathologic features do not reliably predict metastatic potential or outcome. We investigated whether proliferative activity, as determined by MIB-1 labeling, correlated with tumor type, metastasis, or patient survival. Formalin-fixed sections of pancreatic endocrine tumors were immunohistochemically stained for the MIB-1 antibody against Ki-67 using the avidin-biotin complex technique. Labeling index (LI) was determined by counting 1000 consecutive tumor cells in an area of greatest staining intensity at ×400 and expressed as a percentage. The study group included 37 patients, including 10 gastrinomas, 9 insulinomas, 4 glucagonomas, 2 VIPomas, and 12 nonfunctioning tumors. Twenty-one patients had metastases, primarily to regional lymph nodes and the liver. Five patients had MEN I. MIB-1 LI was significantly greater in the nonfunctioning tumors (mean 20.9%) than in the functioning tumors (mean 5.1%) (p = 0.01). LI for functional tumors (insulinomas 6.4%, glucagonoma 4.4%, gastrinomas 3.2%, VIPomas 3.2%) were similar to each other. MIB-1 was significantly higher in those tumors that metastasized (mean 15.6%) compared to those that did not (mean 3.1%), (p = 0.04). All tumors with MIB-1 LI≥10% developed metastases. Logistic regression showed that MIB-1 was a significant predictor of metastases (p = 0.003) after adjusting for functional status. MIB-1 LI also correlated with outcome in that those patients with MIB-1 LI ≥10% had a mean survival of 19 mo compared to 72 mo for those with levels <10% (p = 0.0001). Results of the proportional hazards model showed that MIB-1 remained a significant (p = 0.03) and independent predictor of survival times after adjustment for tumor size and functional status. Higher MIB-1 LI values, were significantly associated with shorter survival times. In conclusion, MIB-1 LI appears to be a useful indicator of metastatic potential and is predictive of outcome in PET.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Larsson L-I. Endocrine pancreatic tumors. Hum Pathol 9:401–416, 1978.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Heitz PhU, Kloppel G. Endocrine tumors of the pancreas and duodenum. Verh Dtch Ges Pathol 71:202–221, 1987.

    CAS  Google Scholar 

  4. Kloppel G, Delling G, Knipper A, Heitz PU. Immunocytochemical mapping of pancreatic apudomas in multiple endocrine adenomatosis with primary hyperparathyroidism. Acta Endocrinol 87(Suppl 215):57,58, 1978.

    Google Scholar 

  5. Eckhauser FE, Cheung PS, Vinik AI, Strodel WE, Lloyd RV, Thompson NW. Nonfunctioning malignant neuroendocrine tumors of the pancreas. Surg 100:978–987, 1986.

    CAS  Google Scholar 

  6. White TJ, Edney JA, Thompson JS, Karrer FW, Moor BJ. Is there a prognostic difference between functional and nonfunctional islet cell tumors? Am J Surg 168:627–630, 1994.

    Article  PubMed  CAS  Google Scholar 

  7. Compton CC. Diseases of the pancreas. In Weidner N., ed. The difficult diagnosis in surgical pathology. Philadelphia: Saunders, 1996;270–272.

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  10. Heitz PU, von Herbay G, Kloppel G, Komminoth P, Kasoer M, Hofler H, Muller K-M, Oberholzer M. The expression of subunits of human chorionic gonadotropin (hCG) by nontrophoblastic, nonendocrine, and endocrine tumors. Am J Clin Pathol 88:467–472, 1987.

    PubMed  CAS  Google Scholar 

  11. Viale G, Doglioni C, Gamgacorta M, Zamboni G, Coggi G, Bordi C. Progesterone receptor immunoreactivity in pancreatic endocrine tumors. An immunocytochemical study of 156 neuroendocrine tumors of the pancreas, gastrointestinal and respiratory tracts, and skin. Cancer 70:2268–2277, 1992.

    Article  PubMed  CAS  Google Scholar 

  12. Hofler H, Ruhri C, Putz B, Wirnsberger G, Hauser H. Oncogene expression in endocrine pancreatic tumors. Virchows Arch B Cell Pathol 55:355–361, 1988.

    CAS  Google Scholar 

  13. Graeme-Cook F, Bell DA, Flotte I-J, Preffer F, Pastel-Levy C, Nardi G, Compton C. Aneuploidy in pancreatic insulinomas does not predict malignancy. Cancer 66:2365–2368, 1990.

    Article  PubMed  CAS  Google Scholar 

  14. Donow C, Baisch H, Heitz PU, Kloppel G. Nuclear DNA content in 27 pancreatic endocrine tumors: correlation with malignancy, survival and expression of glycoprotein hormone alpha chain. Virchows Arch 419:463–468, 1991.

    Article  CAS  Google Scholar 

  15. Kenny BD, Sloan JM, Hamilton PW, Watt PCH, Johnston CF, Buchanan KD. The role of morphometry in predicting prognosis in pancreatic islet cell tumors. Cancer 64:460–465, 1989.

    Article  PubMed  CAS  Google Scholar 

  16. Ruschoff I, Willemer S, Brunzel M, Trautmann ME, Frank M, Arnold R, Kloppel G. Nucleolar organizer regions and glycoprotein-hormone α-chain reaction as markers of malignancy in endocrine tumours of the pancreas. Histopathol 22:51–57, 1993.

    Article  CAS  Google Scholar 

  17. Pelosi G, Zamboni G, Doglioni C, Rodella S, Bresaola E, Iacono C, Serio G, Iannucci A, Scarpa A. Immunodetection of proliferating cell nuclear antigen assesses the growth fraction and predicts malignant in endocrine tumors of the pancreas. Am J Surg Pathol 16:1215–1225, 1992.

    Article  PubMed  CAS  Google Scholar 

  18. Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H. Cell cycle analysis of a cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67. J Immunol 133:1710–1715, 1984.

    PubMed  CAS  Google Scholar 

  19. Rose DSC, Maddox PH, Brown DC. Which proliferation markers for routine immunohistology: a comparison of five antibodies. J Clin Pathol 47:1010–1014, 1994.

    Article  PubMed  CAS  Google Scholar 

  20. McCormick D, Chong H, Hobbs C, Datta C, Hall PA. Detection of the Ki-67 antigen in fixed and wax-embedded sections with the monoclonal antibody M1B1. Histopathol 22: 355–360, 1993.

    Article  CAS  Google Scholar 

  21. Linden MD, Torres FX, Kubus J, Zarbo RJ. Clinical application of morphologic and immunocytochemical assessments of cell proliferation. Am J Clin Pathol 97(Suppl):S4-S13, 1992.

    PubMed  CAS  Google Scholar 

  22. Keshgegian M, Cnaan A. Proliferation markers in breast carcinoma. Am J Clin Pathol 104:42–49, 1995.

    PubMed  CAS  Google Scholar 

  23. Pinder SE, Wencyk P, Sibbering DM, Bell JA, Elston CW, Nicholson R, Robertson JFR, Blamey RW, Ellis IO. Assessment of the new proliferation marker MIB1 in breast carcinoma using image analysis: associations with other prognostic factors and survival. Br J Cancer 71:146–149, 1995.

    PubMed  CAS  Google Scholar 

  24. Ng IOL, Na J, Lai ECS, Fan ST, Ng M. Ki-67 antigen expression in hepatocellular carcinoma using monoclonal antibody MIB1. A comparison with proliferating cell nuclear antigen. Am J Clin Pathol 104:313–318, 1995.

    PubMed  CAS  Google Scholar 

  25. Goldblum JR, Shannon R, Kaldjian EP, Thiny M, Davenport R, Thompson N, Lloyd RV. Immunohistochemical assessment of proliferative activity in adrenocortical neoplasms. Mod Pathol 6:663–668, 1993.

    PubMed  CAS  Google Scholar 

  26. Clarke MR, Weyant RJ, Watson CG, Carty SE. MIB-1, bcl-2, cathepsin B, cathepsin D, FGF, c-met and type IV collagenase in benign and malignant pheochromocytomas. Mod Pathol 9:47A, 1996.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, University of Pittshurgh School of Medicine, Pittsburgh, PA

    Martha R. Clarke MD, Evan E. Baker MD & Lisa Hill BA

  2. Department of Surgery, University of Pittshurgh School of Medicine, Pittsburgh, PA

    Sally E. Carty MD

  3. School of Dental Health, Pittsburgh, PA

    Robert J. Weyant DMD, Drph

Authors
  1. Martha R. Clarke MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Evan E. Baker MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert J. Weyant DMD, Drph
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lisa Hill BA
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sally E. Carty MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martha R. Clarke MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clarke, M.R., Baker, E.E., Weyant, R.J. et al. Proliferative activity in pancreatic endocrine tumors: Association with function, metastases, and survival. Endocr Pathol 8, 181–187 (1997). https://doi.org/10.1007/BF02738784

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02738784

Key Words

Search

Navigation