J Korean Med Sci.  2006 Feb;21(1):35-39. 10.3346/jkms.2006.21.1.35.

Prognostic Value of Immunohistochemical Staining of p53, bcl-2, and Ki-67 in Small Cell Lung Cancer

• Paik KH
• Park YH
• Ryoo BY
• Yang SH
• Lee JC
• Kim CH
• Ki SS
• Kim JM
• Park MJ
• Ahn HJ
• Choi W
• Chung JH

• KMID: 2157779
• DOI: http://doi.org/10.3346/jkms.2006.21.1.35

Abstract

Small cell lung cancer (SCLC) is one of the most fatal cancers in humans and many factors are known to be related to its poor prognosis. Immunohistochemical (IHC) stainings were done on SCLC specimens in order to investigate the prognostic value of the apoptosis-related gene expression and the tumor proliferative maker, and the relationships among these IHC results and patients clinical characteristics, chemoresponsiveness, and survival were analyzed. The medical records of 107 patients were reviewed retrospectively. IHC stainings for p53, bcl-2 and Ki-67 expressions were performed in the 66 paraffin-embedded biopsy samples. Sixty-six out of the 107 patients were evaluable for response rate and survival. The overall response rate was 75% (95% Confidence Interval=74-76%) and the median survival time was 14 months. The median survival time of limited stage was 16 months and that of extensive stage was 10 months. The prevalence of p53, bcl-2 and Ki-67 expression was 62%, 70%, and 49%, respectively. There were no correlations among the immunoreactivities of p53, bcl-2 and Ki-67 with clinical stage, chemoresponsiveness or overall survival. The clinical stage was the only prognostic factor influencing survival. The expression rates of p53, bcl-2, and Ki-67 were relatively high in SCLC without any prognostic significance. The exact clinical role of these markers should be defined through further investigations.

Keyword

Tumor Suppressor Protein p53; bcl-2-Associated X Protein; Ki-67 Antigen; Carcinoma, Small Cell; Tumor Marker, Biological; Prognosis

MeSH Terms

Adult
Aged
Carcinoma, Small Cell/metabolism/*pathology
Female
Humans
Immunohistochemistry
Ki-67 Antigen/analysis
Lung Neoplasms/metabolism/*pathology
Male
Middle Aged
Multivariate Analysis
Prognosis
Proto-Oncogene Proteins c-bcl-2/analysis
Survival Analysis
Tumor Markers, Biological/*analysis
Tumor Suppressor Protein p53/analysis

Figure

• 

  Fig. 1 Survival according to stage.

Reference

1. Ministry of Health and Welfare. 2002 Annual reports of the Korea Central Cancer Center Registry (Published in 2003). 29.

2. Harris CC. Chemical and physical carcinogenesis: advances and perspectives for the 1990s. Cancer Res. 1991. 51:5023S–5044S.

3. McLaren R, Kuzu I, Dunnill M, Harris A, Lane D, Gatter KC. The relationship of p53 immunostaining to survival in carcinoma of the lung. Br J Cancer. 1992. 66:735–738.

4. Lee JS, Yoon A, Kalapurakal SK, Ro JY, Lee JJ, Tu N, Hittleman WN, Hong WK. Expression of p53 oncoprotein in non-small cell lung cancer: a favorable prognostic factor. J Clin Oncol. 1995. 13:1893–1903.

5. Harpole DH, Herndon JE 2nd, Wolf WG, Iglehart JD, Marks JR. A prognostic model of recurrence and death in stage I non-small cell lung cancer utilizing presentation, histopathology and oncoprotein expression. Cancer Res. 1995. 55:51–56.

6. Pezzella F, Turley H, Kuzu I, Tungerkar MF, Dunnil MS, Pierce CB, Harris A, Gatter KC, Mason DY. Bcl-2 protein in non-small cell lung carcinoma. N Engl J Med. 1993. 329:690–694.

7. Fontanini G, Vignati S, Bigini D, Mussi A, Lucchi M, Angeletti CA, Basolo F, Bevilacqua G. Bcl-2 protein: a prognostic factor inversely correlated to p53 in non-small cell lung cancer. Br J Cancer. 1995. 71:1003–1007.

8. Ishida H, Irie K, Itoh T, Furukawa T, Tokunaga O. The prognostic significance of p53 and bcl-2 expression in lung adenocarcinoma and its correlation with Ki-67 growth fraction. Cancer. 1997. 80:1034–1045.

9. van de Vaart PJ, Belderbos J, de Jong D, Sneeuw KC, Majoor D, Bartelink H, Begg AC. DNA-adduct levels as a predictor of outcome for NSCLC patients receiving daily cisplatin and radiotherapy. Int J Cancer. 2000. 89:160–166.

10. Cagini L, Monacelli M, Giustozzi G, Moggi L, Bellezza G, Sidoni A, Bucciarelli E, Darwish S, Ludovini V, Pistola L, Gregorc V, Tonato M. Biological prognostic factors for early stage completely resected non-small cell lung cancer. J Surg Oncol. 2000. 74:53–60.

11. Tungekar MF, Gatter KC, Dunnil MS, Mason DY. Ki-67 immunostaining and survival in operable lung cancer. Histopathology. 1991. 19:545–550.

12. Maitra A, Amirkhan RH, Saboorian MH, Frawley WH, Ashfaq R. Survival in small cell lung carcinoma is independent of Bcl-2 expression. Hum Pathol. 1999. 30:712–717.

13. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij G, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000. 92:205–216.

14. Kastan MB, Canman CE, Leonard CJ. P53, cell cycle control and apoptosis: implications for cancer. Cancer Metastasis Rev. 1995. 14:3–15.

15. Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994. 54:4855–4878.

16. Quinlan DC, Davidson AG, Summers CL, Warden HE, Doshi HM. Accumulation of p53 protein correlates with a poor prognosis in human lung cancer. Cancer Res. 1992. 52:4828–4831.

17. Laudanski J, Burzykowski T, Niklinska W, Chyczewski K, Furman M, Niklinski J. Prognostic value of serum p53 antibodies in patients with resected non-small cell lung cancer. Lung Cancer. 1998. 22:191–200.

18. Mitsudomi T, Suzuki S, Yatabe Y, Nishio M, Kuwabara M, Gotoh K, Hatooka S, Shinoda M, Suyama M, Ogawa M, Takahashi T, Ariyoshi Y, Takahashi T. Clinical implications of p53 autoantibodies in the sera of patients with non-small cell lung cancer. J Natl Cancer Inst. 1998. 90:1563–1568.

19. Bergqvist M, Brattstrom D, Larsson A, Holmertz J, Hesselius P, Losenberg L, Wagenius G, Brodin O. P53 auto-antibodies in non-small cell lung cancer patients can predict increased life expectancy after radiotherapy. Anticancer Res. 1998. 18:1999–2002.

20. Rosenfeld MR, Malats N, Schramm L, Graus F, Cardenal F, Vinolas N, Rosell R, Tora M, Real FX, Posner JB, Dalmau J. Serum anti-p53 antibodies and prognosis of patients with small cell lung cancer. J Natl Cancer Inst. 1997. 89:381–385.

21. Zalcman G, Tredaniel J, Schlichtholz B, Urban T, Milleron B, Lubin R, Meignin V, Couderc LJ, Hirsch A, Soussi T. Prognostic significance of serum p53 antibodies in patients with limited stage small cell lung cancer. Int J Cancer. 2000. 89:81–86.

22. Rodriguez-Salas N, Palacios J, Moreno G, de Castro J, Gonzalez-Baron M, Gamallo C. Correlation of p53 oncoprotein expression with chemotherapy response in small cell lung carcinomas. Lung Cancer. 2001. 34:67–74.

23. Gemba K, Ueoka H, Kiura K, Tabata M, Harada M. Immunohistochemical detection of mutant p53 protein in small cell lung cancer: relationship to treatment outcome. Lung Cancer. 2000. 29:23–31.

24. de Jong D, Prins FA, Mason DY, Reed JC, van Ommen GB, Kluin PM. Subcellular localization of the bcl-2 protein in malignant and normal lymphoid cells. Cancer Res. 1994. 54:256–260.

25. Reed JC. Bcl-2 family proteins. Oncogene. 1998. 17:3225–3236.

26. Cleary ML, Sklar J. Nucleotide sequence of a t (14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18. Proc Natl Acad Sci USA. 1985. 82:7439–7443.

27. Harris AL. What does bcl-2 mean in solid tumors-friend or foe? Ann Oncol. 1994. 5:388–390.

28. Reed JC, Kitada S, Takayama S, Miyashita T. Regulation of chemoresistance by the bcl-2 oncoprotein in non-Hodgkin's lymphoma and lymphocytic leukemia cell lines. Ann Oncol. 1994. 5:Suppl 1. 61–65.

29. Korsmeyer SJ. Bcl-2 initiates a new category of oncogenes: regulators of cell death. Blood. 1992. 80:879–886.

30. Gaffney EF, O'Neil AJ, Staunton MJ. Bcl-2 and prognosis in non-small-cell lung carcinoma. N Engl J Med. 1994. 330:1757–1758.

31. Kim YC, Park KO, Kim HJ, Choi IS, Park CS, Juhng SW. DNA ploidy and proliferative activity in bcl-2 expressed non-small cell lung cancer. Korean J Intern Med. 1996. 11:101–107.

32. Mathews MB, Bernstein RM, Franza BR Jr, Garrels JI. Identity of the proliferating cell nuclear antigen and cyclin. Nature. 1984. 309:374–376.

33. Landberg G, Ross G. Proliferating cell nuclear antigen and Ki-67 antigen expression in human hematopoietic cells during growth stimulation and differentiation. Cell Prolif. 1993. 26:427–437.

34. Wilson GD, Saunders MI, Dische S, Daley FM, Robinson BM, Martindale CA, Joiner B, Richman PI. Direct comparison of bromodeoxyuridine and Ki-67 labelling indices in human tumours. Cell Prolif. 1996. 29:141–152.

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

36. Tubiana M, Courdi A. Cell proliferation kinetics in human solid tumors: relation to probability of metastatic dissemination and long-term survival. Radiother Oncol. 1989. 15:1–18.

37. Scagliotti GV, Micela M, Gubetta L, Leonardo E, Cappia S, Borasio P, Pozzi E. Prognostic significance of Ki-67 labelling in resected non small cell lung cancer. Eur J Cancer. 1993. 29:363–365.

38. Wang DG, Johnston CF, Sloan JM, Buchanan KD. Expression of Bcl-2 in lung neuroendocrine tumors: comparison with p53. J Pathol. 1998. 184:247–251.

39. Mizera-Nyczak E, Dyszkiewicz W, Heider KH, Zeromski J. Isoform expression of CD44 adhesion molecules, Bcl-2, p53 and Ki-67 proteins in lung cancer. Tumour Biol. 2001. 22:45–53.