Expression of p53, Ki-67, bcl-2, c-erb-2, estrogen, and progesterone receptors in endometrial cancer

Česká verzia

Authors: R. Pilka; I. Míčková ¹; M. Lubušký ²; M. Dušková ¹; M. Říčánková ³; Milan Kudela ^{1 1}
Authors place of work: Porodnicko gynekologická klinika, LF UP a UP, Olomouc ¹; Ústav lékařské genetiky, LF UP a FN Olomouc ²; Ústav patologické anatomie, LF UP a FN Olomouc ³
Published in the journal: Ceska Gynekol 2008; 73(4): 222-227

Summary

Objective:
To assess the immunohistochemical expression of p53, bcl-2, c-erb-2, Ki-67, estrogen and progesterone receptors in endometrial cancer patients.

Design:
Experimental study.

Setting:
Department of Obstetrics and Gynecology, Institute of Human Genetics, Department of Pathology, Palacky University Medical School and University Hospital, Olomouc.

Methods:
We studied 103 cases of primary untreated endometrial carcinoma in which the p53, bcl-2, c-erb-2, Ki-67, estrogen and progesterone receptor antigens were investigated by an immunohistochemical method. We evaluated the correlations among the immunohistochemical staining assessed by histoscore, and the age, grading, depth of invasion, stage of the neoplasia and extrauterine disease.

Results:
Mean age was 67 years (range 35-90). p53, bcl-2, c-erb-2, Ki-67, estrogen and progesterone receptors were positive in 49 (48%), 81 (79%). 18 (17%), 99 (96%), 73 (70%) and 87 (84%) patients respectively. There was no clear association between immunohistochemical parameters and the age of patients. p53 and Ki-67 overexpression was found to be related to poor grade of differentiation, deeper myometrial invasion, advanced stage of neoplasia and extrauterine spread of disease. Immunostaining for bcl-2 correlated inversely with FIGO stage, while c-erb-2 was overexpressed in tumors with deeper myometrial invasion. Estrogen and progesterone receptor positive tumors showed a statistically significant association with clinicopathological parameters of better clinical outcome.

Conclusion:
The overexpression of p53 and Ki-67 seems to indicate more malignant phenotype, while bcl‑2 and c-erb-2 may have a limited role in the identification of high-risk tumors.

Key words:
endometrial cancer, immunohistochemistry, prognostic factors.

Zdroje

1. Backe, J., Gassel, AM., Krebs, S., et al. Immunohistochemically detected HER-2/neu-expression and prognosis in endometrial carcinoma. Arch Gynecol Obstet, 1997, 259, 4, p. 189-195.

2. Candiani, GB., Belloni, C., Maggi, R., et al. Evaluation of different surgical approaches in the treatment of endometrial cancer at FIGO stage I. Gynecol Oncol, 1990, 37, 1, p. 6-8.

3. Corn, BW., Lanciano, RM., Greven, KM., et al. Impact of improved irradiation technique, age, and lymph node sampling on the severe complication rate of surgically staged endometrial cancer patients: a multivariate analysis. J Clin Oncol, 1994, 12, 3, p. 510-515.

4. Coronado, PJ., Vidart, JA., Lopez-asenjo, JA., et al. P53 overexpression predicts endometrial carcinoma recurrence better than HER-2/neu overexpression. Eur J Obstet Gynecol Reprod Biol, 2001, 98, 1, p. 103-108.

5. Creasman, WT. Prognostic significance of hormone receptors in endometrial cancer. Cancer, 1993, 71, 4, Suppl., p. 1467-1470.

6. Creutzberg, CL., van Putten, WL., Koper, PC., et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet, 2000, 355, 9213, p. 1404-1411.

7. Czerwenka, K., Lu, Y., Heuss, F. Amplification and expression of the c-erbB-2 oncogene in normal, hyperplastic, and malignant endometria. Int J Gynecol Pathol, 1995, 14, 2, p. 98-106.

8. Erdem, O., Erdem, M., Dursun, A., et al. Angiogenesis, p53, and bcl-2 expression as prognostic indicators in endometrial cancer: comparison with traditional clinicopathologic variables. Int J Gynecol Pathol, 2003, 22, 3, p. 254-260.

9. Fukuda, K., Mori, M., Uchiyama, M., et al. Prognostic significance of progesterone receptor immunohistochemistry in endometrial carcinoma. Gynecol Oncol, 1998, 69, 3, p. 220-225.

10. Gassel, AM., Backe, J., Krebs, S., et al. Endometrial carcinoma: immunohistochemically detected proliferation index is a prognosticator of long-term outcome. J Clin Pathol, 1998, 51, 1, p. 25-29.

11. Geisler, JP., Geisler, HE., Miller, GA., et al. MIB-1 in endometrial carcinoma: prognostic significance with 5-year follow-up. Gynecol Oncol, 1999, 75, 3. p. 432-436.

12. Geisler, JP., Geisler, HE., Wiemann, MC., et al. p53 expression as a prognostic indicator of 5-year survival in endometrial cancer. Gynecol Oncol, 1999, 74, 3, p. 468-471.

13. Geisler, JP., Wiemann, MC., Zhou, Z., et al. p53 as a prognostic indicator in endometrial cancer. Gynecol Oncol, 1996, 61, 2, p. 245-248.

14. Goodman, MT., Hankin, JH., Wilkens, LR., et al. Diet, body size, physical activity, and the risk of endometrial cancer. Cancer Res 1997, 57, 22, p. 5077-5085.

15. Gossett, DR., Alo, P., Bristow, RE., et al. Inability of immunohistochemistry to predict clinical outcomes of endometrial cancer patients. Int J Gynecol Cancer, 2004, 14, 1, p. 145-151.

16. Halperin, R., Zehavi, S., Habler, L., et al. Comparative immunohistochemical study of endometrioid and serous papillary carcinoma of endometrium. Eur J Gynaecol Oncol, 2001, 22, 2, p. 122-126.

17. Hanahan, D., Weinberg, RA. The hallmarks of cancer. Cell, 2000, 100, 1, p. 57-70.

18. Heinze, T., Jonas, S., Karsten, A., et al. Determination of the oncogenes p53 and C-erb B2 in the tumour cytosols of advanced hepatocellular carcinoma (HCC) and correlation to survival time. Anticancer Res, 1999, 19, (4A), p. 2501-2503.

19. Hrachovec, P, Pilka, R., Dzvinčuk, P., Kudela, M. Rizikové a protektivní faktory karcinomu endometria. Gynekolog, 2001, 3, s. 120-122.

20. Chen, Y., Sato, M., Fujimura, S., et al. Expression of Bcl-2, Bax, and p53 proteins in carcinogenesis of squamous cell lung cancer. Anticancer Res, 1999, 19, (2B), p. 1351-1356.

21. Choi, KC., Kang, SK., Tai, CJ., et al. Estradiol up-regulates antiapoptotic Bcl-2 messenger ribonucleic acid and protein in tumorigenic ovarian surface epithelium cells. Endocrinology, 2001, 142, 6, p. 2351-2360.

22. Ito, K., Sasano, H., Matsunaga, G., et al. Correlations between p21 expression and clinicopathological findings, p53 gene and protein alterations, and survival in patients with endometrial carcinoma. J Pathol, 1997, 183, 3, p. 318-324.

23. Kadar, N., Malfetano, JH., Homesley, HD. Steroid receptor concentrations in endometrial carcinoma: effect on survival in surgically staged patients. Gynecol Oncol, 1993, 50, 3, p. 281-286.

24. Kakar, S., Puangsuvan, N., Stevens, JM., et al. HER-2/neu assessment in breast cancer by immunohistochemistry and fluorescence in situ hybridization: comparison of results and correlation with survival. Mol Diagn, 2000, 5, 3, p. 199-207.

25. Kleine, W., Maier, T., Geyer, H., et al. Estrogen and progesterone receptors in endometrial cancer and their prognostic relevance. Gynecol Oncol, 1990, 38, 1, p. 59-65.

26. Kudela, M., Pilka, R. Is there a real risk in patients with endometrial carcinoma undergoing diagnostic hysteroscopy (HSC)? Eur J Gynaecol Oncol, 2001, 22, 5, p. 342-344.

27. Lax, SF., Pizer, ES., Ronnett, BM., et al. Clear cell carcinoma of the endometrium is characterized by a distinctive profile of p53, Ki-67, estrogen, and progesterone receptor expression. Hum Pathol, 1998, 29, 6, p. 551-558.

28. Liu, G., Schwartz, JA Brooks, SC. p53 down-regulates ER-responsive genes by interfering with the binding of ER to ERE. Biochem Biophys Res Commun, 1999, 264, 2, p. 359-364.

29. Lukes, AS., Kohler, MF., Pieper, CF., et al. Multivariable analysis of DNA ploidy, p53, and HER-2/neu as prognostic factors in endometrial cancer. Cancer, 1994, 73, 9, p. 2380-2385.

30. Martin-Hirsch, PL., Lilford, RJ., Jarvis, GJ. Adjuvant progestagen therapy for the treatment of endometrial cancer: review and meta-analyses of published randomised controlled trials. Eur J Obstet Gynecol Reprod Biol, 1996, 65, 2, p. 201-207.

31. Morris, PC., Anderson, JR., Anderson, B., et al. Steroid hormone receptor content and lymph node status in endometrial cancer. Gynecol Oncol, 1995, 56, 3, p. 406-411.

32. Morrow, CP., Bundy, BN., Kurman, RJ., et al. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol, 1991, 40, 1, p. 55-65.

33. Nordstrom, B., Strang, P., Lindgren, A., et al. Endometrial carcinoma: the prognostic impact of papillary serous carcinoma (UPSC) in relation to nuclear grade, DNA ploidy and p53 expression. Anticancer Res, 1996, 16, 2, p. 899-904.

34. Nyholm, HC., Christensen, IJ Nielsen, AL. Progesterone receptor levels independently predict survival in endometrial adenocarcinoma. Gynecol Oncol, 1995, 59, 3, p. 347-351.

35. Ohkouchi, T., Sakuragi, N., Watari, H., et al. Prognostic significance of Bcl-2, p53 overexpression, and lymph node metastasis in surgically staged endometrial carcinoma. Am J Obstet Gynecol, 2002, 187, 2, p. 353-359.

36. Owen, P., Duncan, ID. Is there any value in the long term follow up of women treated for endometrial cancer? Br J Obstet Gynaecol, 1996, 103, 7, p. 710-713.

37. Pansare, V., Munkarah, AR., Schimp, V., et al. Increased expression of hypoxia-inducible factor 1alpha in type I and type II endometrial carcinomas. Mod Pathol, 2007, 20, 1, p. 35-43.

38. Pijnenborg, JM., van de Broek, L., Dam de Veen, GC., et al. TP53 overexpression in recurrent endometrial carcinoma. Gynecol Oncol, 2006, 100, 2, p. 397-404.

39. Pike, MC., Peters, RK., Cozen, W., et al. Estrogen-progestin replacement therapy and endometrial cancer. J Natl Cancer Inst, 1997, 89, 15, p. 1110-1116.

40. Pisani, AL., Barbuto, DA., Chen, D., et al. HER-2/neu, p53, and DNA analyses as prognosticators for survival in endometrial carcinoma. Obstet Gynecol, 1995, 85, (5 Pt 1) p. 729-734.

41. Podczaski, E., Kaminski, P., Gurski, K., et al. Detection and patterns of treatment failure in 300 consecutive cases of „early“ endometrial cancer after primary surgery. Gynecol Oncol, 1992, 47, 3, p. 323-327.

42. Potischman, N., Hoover, RN., Brinton, LA., et al. Case-control study of endogenous steroid hormones and endometrial cancer. J Natl Cancer Inst, 1996, 88, 16, p. 1127-1135.

43. Prat, J. Prognostic parameters of endometrial carcinoma. Hum Pathol, 2004, 35, 6, p. 649-662.

44. Reinartz, JJ., George, E., Lindgren, BR., et al. Expression of p53, transforming growth factor alpha, epidermal growth factor receptor, and c-erbB-2 in endometrial carcinoma and correlation with survival and known predictors of survival. Hum Pathol, 1994, 25, 10, p. 1075-1083.

45. Rolitsky, CD., Theil, KS., McGaughy, VR., et al. HER-2/neu amplification and overexpression in endometrial carcinoma. Int J Gynecol Pathol, 1999, 18, 2, p. 138-143.

46. Rose, PG. Endometrial carcinoma. N Engl J Med, 1996, 335, 9, p. 640-649.

47. Sakuragi, N., Ohkouchi, T., Hareyama, H., et al. Bcl-2 expression and prognosis of patients with endometrial carcinoma. Int J Cancer, 1998, 79, 2, p. 153-158.

48. Salvesen, HB., Iversen, OE, Akslen, LA. Identification of high-risk patients by assessment of nuclear Ki-67 expression in a prospective study of endometrial carcinomas. Clin Cancer Res, 1998, 4, 11, p. 2779-2785.

49. Salvesen, HB., Iversen, OE, Akslen, LA. Prognostic significance of angiogenesis and Ki-67, p53, and p21 expression: a population-based endometrial carcinoma study. J Clin Oncol, 1999, 17, 5, p. 1382-1390.

50. Soong, R., Knowles, S., Williams, KE., et al. Overexpression of p53 protein is an independent prognostic indicator in human endometrial carcinoma. Br J Cancer, 1996, 74, 4, p. 562-537.

51. Stattin, P., Damber, JE., Karlberg, L., et al. Bcl-2 immunoreactivity in prostate tumorigenesis in relation to prostatic intraepithelial neoplasia, grade, hormonal status, metastatic growth and survival. Urol Res, 1996, 24, 5, p. 257-264.

52. Svoboda, B. Guidelines efektivní léčebné péče. Zhoubné nádory těla děložního. In Onkologie v gynekologii a mammologii, Sborník přednášek. Brno, 1999; s. 59-64.

53. Trimble, EL., Kosary, C., Park, RC. Lymph node sampling and survival in endometrial cancer. Gynecol Oncol, 1998, 71, 3, p. 340-343.

54. ÚZIS. Zdravotnická statistika, Národní onkologický registr. In Praha, 2000, s. 51.

55. Wang, D., Konishi, I., Koshiyama, M., et al. Expression of c-erbB-2 protein and epidermal growth receptor in endometrial carcinomas. Correlation with clinicopathologic and sex steroid receptor status. Cancer, 1993, 72, 9, p. 2628-2637.

56. Watson, P., Vasen, HF., Mecklin, JP., et al. The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer. Am J Med, 1994, 96, 6, p. 516-520.