Virchows Archiv

, Volume 424, Issue 1, pp 39–46 | Cite as

Proliferating cell nuclear antigen in breast carcinomas

An immunohistochemical study with correlation to histopathological features and prognostic factors
  • T. Haerslev
  • G. K. Jacobsen
Original Articles

Abstract

Proliferating cell nuclear antigen (PCNA), was examined by immunohistochemistry in 509 breast carcinomas. The immunoreactivity was found to be independent of the length of fixation when the tissue sections were microwaved before incubation with the primary antibody. The PCNA immunoreactivity was assessed by two semi-quantitative methods, which were correlated but not exchangeable. The comedo type of intraductal carcinomas and invasive ductal carcinomas had a higher PCNA score than other types. Lymph node metastases had a significantly higher PCNA score than primary carcinomas. High PCNA immunoreactivity was correlated with the presence of lymph node metastases, absence of tubule formation, numerous mitoses, severe nuclear pleomorphism, high histological grade and absence of progesterone receptors (PgR). PCNA in lymph node positive tumours was correlated with tumour type, especially with ductal carcinomas, absence of tubule formation, high histological grade and absence of PgR, whereas PCNA in lymph node negative tumours was correlated with large tumour size, numerous mitoses, severe nuclear pleomorphism and high histological grade. Number of mitoses and nuclear pleomorphism were the two most important factors in predicting the PCNA score; the absence of PgR and nuclear pleomorphism were important in lymph node negative and positive tumours, respectively. In a univariate analysis high PCNA score was found to be correlated with shorter relapse-free period and poorer over-all survival.

Key words

Proliferating cell nuclear antigen Immunohistochemistry Breast carcinomas 

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References

  1. Andersen KW, Mouridsen HT, Castberg T, Fischerman K, Andersen J, Hou-Jensen K, Brincker H, Johansen H, Henriksen E, Rorth M, Rossing N (1981) Organization of the Danish adjuvant trials in breast cancer. Danish Med Bull 28:102–106Google Scholar
  2. Armitage P, Berry G (1987) Statistical methods in medical research. Blackwell, Oxford, pp. 121Google Scholar
  3. Battersby S, Andersson TJ (1990) Correlation of proliferative activity in breast tissue using PCNA/cyclin. Hum Pathol 21:781Google Scholar
  4. Bellamy COC, McDonald C, Salter DM, Chetty U, Anderson TJ (1993) Noninvasive ductal carcinoma of the breast: the relevance of histologic categorization. Hum Pathol 24:16–23Google Scholar
  5. Bloom HJG, Richardson WW (1957) Histological grading and prognosis in breast cancer. Br J Cancer 11:359–377Google Scholar
  6. Bravo R (1986) Synthesis of the nuclear protein cyclin (PCNA) and its relationship with DNA replication Exp Cell Res 163:287–293Google Scholar
  7. Bravo R, Macdonald-Bravo H (1984) Induction of the nuclear protein “cyclin” in quiescent mouse 3T3 cells stimulated by serum and growth factors: correlation with DNA synthesis. EMBO J 3:3177–3184Google Scholar
  8. Bravo R, Macdonald-Bravo H (1985) Changes in the nuclear distribution of cyclin (PCNA) but not its synthesis depend on DNA replication. EMBO J 4:655–661Google Scholar
  9. Bravo R, Macdonald-Bravo H (1987) Existence of two populations of cyclin/proliferating cell nuclear antigen during the cell cycle: association with DNA replication sites. J Cell Biol 105:1549–1554Google Scholar
  10. Bravo R, Frank R, Blundell PA, Macdonald-Bravo H (1987) Cyclin/PCNA is the auxiliary protein of DNA polymerase alpha. Nature 326:515–517Google Scholar
  11. Celis JE, Bravo R, Larsen PM, Fey SJ (1984) Cyclin: a nuclear protein whose level correlates directly with the proliferative state of normal as well as transformed cells. Leuk Res 8:143–147Google Scholar
  12. Clayton F (1991) Pathologic correlates of survival in 378 lymph node-negative infiltrating ductal carcinomas: mitotic count is the best single predictor. Cancer 68:1309–1317Google Scholar
  13. Cox DR, Oakes D (1984) Analysis of survival data. Chapman and Hall, LondonGoogle Scholar
  14. Dawson AE, Norton JA, Weinberg DS (1990) Comparative assessment of proliferation and DNA content in breast carcinoma by image analysis and flow cytometry. Am J Pathol 136:1115–1124Google Scholar
  15. Dervan PA, Magee HM, Buckley C, Carney DN (1992) Proliferating cell nuclear antigen count in formalin-fixed paraffin-embedded tissue correlate with Ki-67 in fresh tissue. Am J Clin Pathol 97:S21–28Google Scholar
  16. Donhuijsen K, Schmidt U, Hirche H, van Beuningen D, Budach V (1990) Changes in mitotic rate and cell cycle fractions caused by delayed fixation. Hum Pathol 21:709–714Google Scholar
  17. Garcia RL, Coltera MD, Gown AM (1989) Analysis of proliferative grade using anti-PCNA/cyclin monoclonal antibodies in fixed, embedded tissues. Am J Pathol 134:733–739Google Scholar
  18. Gasparini S, Meli S, Pozza S, Cazzavillan S, Beliacqua P (1992) PC-10 antibody to proliferating cell nuclear antigen (PCNA) is not related to prognosis in human breast carcinomas. Growth Reg 2:145–150Google Scholar
  19. Gerdes J, Lemke H, Baisch H, Wacker H-H, Schwab U, Stein H (1984) Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 133:1710–1715Google Scholar
  20. Graem N, Helweg-Larsen K (1979) Mitotic activity and delay in fixation of tissues. Acta Pathol Microbiol Scand [A] 87:375–378Google Scholar
  21. Hall PA, Levison DA (1990) Review: assessment of cell proliferation in histological material. J Clin Pathol 43:184–192Google Scholar
  22. Kallioniemi O-P (1988) Comparison of fresh and paraffin-embedded tissue as starting material for DNA flow cytometry and evaluation of intratumoural heterogenicity. Cytometry 9:164–169Google Scholar
  23. Kallioniemi O-P, Viskolpi T, Holli K, Heikkinen A, Isola J, Koivula T (1991) Improved prognostic impact of S-phase values from paraffin embedded breast and prostate carcinomas after correcting for nuclear slicing. Cytometry 12:413–421Google Scholar
  24. Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481Google Scholar
  25. Kurki P, Vanderlaan M, Dolbeare F, Gray J, Tan EM (1986) Expression of proliferating cell nuclear antigen (PCNA)/cyclin during the cell cycle. Exp Cell Res 166:209–219Google Scholar
  26. Leong AS-Y, Milios J, Tang SK (1993) Is immunolocalisation of proliferating cell nuclear antigen (PCNA) in paraffin sections a valid index of cell proliferation. Appl Immunohistochem 12:127–135Google Scholar
  27. Macdonald-Bravo H, Bravo R (1985) Induction of the nuclear protein cyclin in serum-stimulated quiescent 3T3 cells is independent of DNA synthesis. Exp Cell Res 156:455Google Scholar
  28. Mango WB, Hirschfield L, Bhuiya T, Harrison G, Mir R (1992) Correlation of proliferating cell nuclear antigen (PCNA reactivity and Ki-67 reactivity) in primary breast carcinoma with hormone, and diease-free survival. Conn Med 56:667–669Google Scholar
  29. Mathews MB, Bernstein RM, Franza BR, Garrels JI (1984) Identity of the proliferating cell nuclear antigen and cyclin. Nature 303:374–376Google Scholar
  30. McGuire WL (1987) Prognostic factors for recurrence and survival in human breast cancer. Breast Cancer Res Treat 10:5–9Google Scholar
  31. Meyer JS, McDivitt RW, Stone KR, Prey MU, Bauer WC (1984) Practical breast carcinoma cell kinetics: a review and update. Breast Cancer Res Treat 4:79–88Google Scholar
  32. Page DL, Anderson TJ, Rogers LW (1987) Carcinoma in situ (CIS). In: Page DL, Anderson TJ (eds) Diagnostic histopathology of the breast. Churchill Livingstone, Edinburgh, pp 157–192Google Scholar
  33. Prelich G, Tan C-K, Kostura M, Mathews MB, So AG, Downey KM, Stillman B (1987) Functional identity of proliferating cells nuclear antigen and a DNA polymerase-δ auxiliary protein. Nature 326:517–520Google Scholar
  34. Sabatti E, Gerdes J, Gherlinzoni F, Poggi S, Zucchini L, Melilli G, Grigioni F, Del Vecchio MT, Leoncini L, Falini B, Pileri SA (1993) Comparison between the monoclonal antibodies Ki-67 and PC10 in 125 malignant lymphomas. J Pathol 169:397–403Google Scholar
  35. Siitonen SM, Isola JJ, Rantala IS, Helin HJ (1993a) Intratumor variation in cell proliferation in breast carcinoma as determined by anti-PCNA monoclonal antibody and automated image analysis. Am J Clin Pathol 99:226–231Google Scholar
  36. Siitonen SM, Kallioniemi O-P, Isola JJ (1993b) Proliferating cell nuclear antigen immunohistochemistry using monoclonal antibody 19A2 and a new antigen retrieval technique has prognostic impact in archival paraffin-embedded node-negative breast cancer. Am J Pathol 142:1081–1089Google Scholar
  37. Suzuki K, Katoh R, Kawaoki A (1992) Immnohistochemical demonstration of proliferating cell nuclear antigen (PCNA) in formalin-fixed, paraffin-embedded sections from rat and human tissues. Acta Histochem Cytochem 25:13–21Google Scholar
  38. Tahan SR, Neuberg DS, Dieffenbach A, Yacoub L (1993) Prediction of early relapse and shortened survival in patients with breast cancer by proliferating cell nuclear antigen score. Cancer 71:3552–3559Google Scholar
  39. Tubiana M, Courdi A (1989) Cell proliferation kinetics in human solid tumours: relation to probability of metastatic, dissemination and long-term survival. Radiother Oncol 15:1–18Google Scholar
  40. Tubiana M, Pejovic MH, Koscielny S, Chvaudra N, Malaise E (1989) Growth rate, kinetics of tumour cell proliferation and long-term outcome in human breast cancer. Int J Cancer 44:17–22Google Scholar
  41. World Health Organization Histological typing of breast tumours (1968) World Health Organization, GenevaGoogle Scholar
  42. Yu CC-W, Woods AL, Levison DA (1992) The assessment of cellular proliferation by immunohistochemistry: a review of currently available methods and their applications. Histochemical J 24:121–131Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • T. Haerslev
    • 1
  • G. K. Jacobsen
    • 1
  1. 1.Department of Pathology, Gentofte HospitalUniversity of CopenhagenHellerupDenmark

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