Selected immunohistochemical prognostic factors of endometrial cancer
Authors:
I. Marková; M. Lubušký; M. Procházka; Milan Kudela; M. Dušková; J. Zapletalová; R. Pilka
Authors‘ workplace:
Ústav genetiky a fetální medicíny, LF UP a UP Olomouc, Porodnicko‑gynekologická klinika, LF UP a UP Olomouc, Ústav patologické anatomie, LF UP a UP Olomouc, Ústav lékařské biofyziky, pracoviště biometrie, UP Olomouc
Published in:
Prakt Gyn 2010; 14(1): 14-21
Category:
Original Article
Overview
Objective:
To assess the immunohistochemical expression of p53, bcl- 2, c- erbB- 2, Ki- 67, estrogen (ER) and progesterone (PR) receptors, matrix metalloproteinase- 7 (MMP- 7) and matrix metalloproteinase- 26 (MMP- 26) in endometrial cancer patients. To assess the relation between steroid receptor positivity and other markers. Design: Experimental prospective study. Setting: Department of Obstetrics and Gynecology, Department of Genetics, Department of Pathology, Palacky University Medical School and University Hospital, Olomouc. Methods: We studied 144 cases of primary untreated endometrial carcinoma in which the p53, bcl- 2, c- erbB- 2, Ki- 67, ER, PR, MMP- 7 and MMP- 26 antigens were investigated with the use of immunohistochemical methods. We evaluated the correlations between immunohistochemical staining and the age, FIGO stage, grading, depth of invasion and metastatic spread to lymph nodes. Results: Mean age was 65.7 years (range 34– 90). p53, bcl- 2, c- erbB- 2, Ki- 67, ER, PR were positive in 35 (24.3 %), 100 (69.4 %), 41 (28.4 %), 65 (45.1 %), 115 (79.8 %) and 127 (88.1 %) cases respectively. MMPs were evaluated in a group of 70 patients, MMP- 7 was positive in 33 (47.1 %), MMP- 26 in 40 (57.1 %) cases. MMP- 7 expression decreased with higher patient age. p53 and Ki- 67 overexpression was found to be related to poor differentiation. Immunostaining for bcl- 2 correlated with the positivity of steroid receptors status, while immunostaining for c- erbB- 2 correlated inversely with ER positive group of cases. Conclusion: The overexpression of p53 and Ki- 67 seems to indicate a more malignant phenotype, while bcl- 2 expression in dependence on steroid receptor positivity could contribute to the identification of high‑risk tumors.
Key words:
endometrial cancer – immunohistochemistry – prognostic factors
Sources
1. World Cancer Research Fund/ American Institute for Cancer Research.: Food, Nutrition and the Prevention of Cancer: a Global Perspective. Washington DC: AICR 1997.
2. Ústav zdravotnických informací a statistiky ČR ve spolupráci s Národním onkologickým registrem ČR. Novotvary 2005 ČR.
3. Rose PG. Endometrial carcinoma. N Engl J Med 1996; 335(9): 640– 649.
4. Fader AN, Gibbons HE. Pomáháme ženám s karcinomem endometria žít déle a lépe. Gynekologie po promoci 2008; 8(1): 34– 39.
5. Ascher SM, Reinhold C. Imaging of cancer of the endometrium. Radiol Clin North Am 2002; 40(3): 563– 576.
6. Canavan TP, Doshi NR. Endometrial cancer. Am Fam Physician 1999; 59(11): 3069– 3077.
7. Detailed guide: Endometrial (uterine) cancer. American Cancer Society. Available from: <http:/ / documents.cancer.org/140.00/ 140.00.pdf>.
8. Goodman MT, Hankin JH, Wilkens LR et al. Diet, body size, physical activity, and the risk of endometrial cancer. Cancer Res 1997; 57(22): 5077– 5085.
9. Lu KH, Broaddus RR. Gynecologic cancers in Lynch syndrome/ HNPCC. Fam Cancer 2005; 4(3): 249– 254.
10. Creasman WT. Malignant tumors of the uterine corpus. In: Rock JA, Jones HW (eds). Operative gynecology. Philadelphia: Lippincott Williams & Wilkins 2003; 1445– 1486.
11. Kodama S, Kase H, Tanaka K et al. Multivariate analysis of prognostic factors in patients with endometrial cancer. Int J Gynaecol Obstet 1996; 53(1): 23– 30.
12. Hrachovec P, Pilka R, Dzvinčuk P et al. Rizikové a protektivní faktory karcinomu endometria. Gynekolog 2001; 3: 120– 122.
13. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100(1): 57– 70.
14. Liu FS. Molecular carcinogenesis of endometrial cancer. Taiwan J Obstet Gynecol 2007; 46(1): 26– 32.
15. Salvesen HB, Akslen LA. Molecular pathogenesis and prognostic factors in endometrial carcinoma. APMIS 2002; 110(10): 673– 689.
16. Geisler JP, Wiemann MC, Zhou Z et al. p53 as a prognostic indicator in endometrial cancer. Gynecol Oncol 1996; 61(2): 245– 248.
17. Cherchi PL, Marras V, Capobianco G et al. Prognostic value of p53, c- erb- B2 and MIB- 1 in endometrial carcinoma. Eur J Gynaecol Oncol 2001; 22(6): 451– 453.
18. 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): 551– 558.
19. 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): 353– 359.
20. Erdem O, Erdem M, Dursum A et al. Angiogenesis, p53 and bcl- 2 expression as prognostic indicators in endometrial cancer: Comparison with traditional clinicopathological variables. Int J Gynecol Pathol 2003; 22(3): 254– 260.
21. Sakuragi N, Ohkouchi T, Hareyama H et al. Bcl- 2 expression and prognosis of patients with endometrial carcinoma. Int J Cancer 1998; 79(2): 153– 158.
22. Yamauchi N, Sakamoto A, Uozaki H et al. Imunohistochemical analysis of endometrial adenocarcinoma for bcl- 2 and p53 in relation to expression of sex steroid receptor and proliferative activity. Int J Gynecol Pathol 1996; 15(3): 202– 208.
23. 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): 2380– 2385.
24. Mariani A, Sebo TJ, Webb MJ et al. Molecular and histopathologic predictors of distant failure in endometrial cancer. Cancer Detect Prev 2003; 27(6): 434– 441.
25. 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): 729– 734.
26. Ferrandina G, Ranelletti FO, Gallotta V et al. Expression of cyclooxygenase- 2(COX‑2), receptors for estrogen (ER) and progesteron (PR), p53, Ki- 67, and neu protein in endometrial cancer. Gynecol Oncol 2005; 98(3): 383– 389.
27. Salvesen HB, Iversen OE, Akslen LA. Identification of high‑risk patients by assessment of nuclear Ki- 67 expression in aprospective study of endometrial carcinomas. Clin Cancer Res 1998; 4(11): 2779– 2785.
28. 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): 1382– 1390.
29. 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): 122– 126.
30. Kadar N, Malfetano JH, Homesley HD. Steroid receptor concentrations in endometrial carcinoma: effect on survival in surgically staged patients. Gynecol Oncol 1993; 50(3): 281– 286.
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): 406– 411.
32. Ueno H, Yamashita K, Azumano I et al. Enhanced production and activation of matrix metalloproteinase- 7 (matrilysin) in human endometrial carcinomas. Int J Cancer 1999; 84(5): 470– 477.
33. Pilka R, Norata GD, Domanski H et al. Matrix metalloproteinase- 26 (matrilysin‑2) expression is high in endometrial hyperplasia and decreases with loss of histological differentiation in endometrial cancer. Gynecol Oncol 2004; 94(3): 661– 670.
34. Fitzgibbons PL, Page DL, Weaver D et al. Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 2000; 124(7): 966– 978.
35. Jalava P, Kuopio T, Huovinen R et al. Immunohistochemical staining of estrogen and progesterone receptors: aspects for evaluating positivity and defining the cutpoints. Anticancer Res 2005; 25(3c): 2535– 2542.
36. Ogawa Y, Moriya T, Kato Yet al. Immunohistochemical assessment for estrogen receptor and progesterone receptor status in breast cancer: analysis for a cut‑off point as the predictor for endocrine therapy. Breast Cancer 2004; 11(3): 267– 275.
37. 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): 562– 567.
38. 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): 468– 471.
39. Pijnenborg JM, van de Broek L, Dam de Veen GC et al. TP53 overexpression in recurrent endometrial carcinoma. Gynecol Oncol 2006; 100(2): 397– 404.
40. Tashiro H, Isacson C, Levine R et al. P53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis. Am J Pathol 1997; 150(1): 177– 185.
41. Zheng W, Cao P, Zheng M et al. P53 overexpression and bcl- 2 persistence in endometrial carcinoma: comparison of papillary serous and endometroid subtypes. Gynecol Oncol 1996; 61(2): 167– 174.
42. Inoue M. Current molecular aspects of the carcinogenesis of the uterine endometrium. Int J Gynecol Cancer 2001; 11(5): 339– 348.
43. 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): 1351– 1356.
44. 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): 257– 264.
45. Geisler JP, Geisler HE, Wiemann MC et al. Lack of bcl- 2 persistence: an independent prognostic indicator of poor prognosis in endometrial carcinoma. Gynecol Oncol 1998; 71(2): 305– 307.
46. 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): 359– 364.
47. Appel ML, Edelweiss MI, Fleck J et al. p53 and bcl- 2 as prognostic markers in endometrial carcinoma. Pathol Oncol Res 2008; 14(1): 23– 30.
48. 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): 432– 436.
49. Nordström B, Strang P, Bergström R et al. A comparison of proliferation markers and their prognostic value for women with endometrial carcinoma. Ki- 67, proliferating cell nuclear antigen, and flow cytometric S- phase fraction. Cancer 1996; 78(9): 1942– 1951.
50. 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): 35– 43.
51. 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): 199– 207.
52. Ioffe OB, Papadimitriou JC, Drachenberg CB et al. Correlation of proliferation indices, apoptosis and related oncogene expression (bcl- 2 and c- erbB- 2) and p53 in proliferative, hyperplastic and malignant endometrium. Hum Pathol 1998; 29(10): 1150– 1159.
53. Khalifa MA, Mannel RS, Haraway SD et al. Expression of EGRF, HER- 2/ neu, p53 and PCNA in endometrioid, serous papillary and clear cell endometrial adenocarcinomas. Gynecol Oncol 1994; 53(1): 84– 92.
54. Matias- Guiu X, Catasus L, Bussaglia E et al. Molecular pathology of endometrial hyperplasia and carcinoma. Hum Pathol 2001; 32(6): 569– 577.
55. Williams JA jr, Wang ZR, Parrish RS et al. Fluorescence in situ hybridisation analysis of HER- 2/ neu, c- myc and p53 in endometrial cancer. Exp Mol Pathol 1999; 67(3): 135– 143.
56. 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): 103– 108.
57. 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): 98– 106.
58. Morrison C, Zanagnolo V, Ramirez N et al. HER- 2 is an independent prognostic factor in endometrial cancer: association with outcome in a large cohort of surgically staged patients. J Clin Oncol 2006; 24(15): 2376– 2385.
59. Jazaeri AA, Nunes KJ, Dalton MS et al. Well‑differentiated endometrial adenocarcinomas and poorly differentiated mixed mullerian tumors have altered ER and PR isoform expression. Oncogene 2001; 20(47): 6965– 6969.
60. Nyholm HC, Christensen IJ, Nielsen AL. Progesterone receptor levels independently predict survival in endometrial adenocarcinoma. Gynecol Oncol 1995; 59(3): 347– 351.
61. Fukuda K, Mori M, Uchiyama M et al. Prognostic significance of progesterone receptor immunohistochemistry in endometrial carcinoma. Gynecol Oncol. 1998; 69(3): 220– 225.
62. Nagase H, Woessner JF jr. Matrix metalloproteinases. J Biol Chem. 1999; 274(31): 21491– 21494.
63. Graesslin O, Cortez A, Uzan C et al. Endometrial tumor invasiveness is related to metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 expressions. Int J Gynecol Cancer 2006; 16(5): 1911– 1917.
64. Wang FQ, So J, Reierstad S et al. Matrilysin (MMP- 7) promotes invasion of ovarian cancer cells by activation of progelatinase. Int J Cancer 2005; 114(1): 19– 31.
65. Isaka K, Nishi H, Nakai H et al. Matrix metalloproteinase- 26 is expressed in human endometrium but not in endometrial cancer. Cancer 2003; 97(1): 79– 89.
66. Tunuguntla R, Ripley D, Sang QX et al. Expression of matrix metalloproteinase- 26 and tissue inhibitors of metalloproteinases TIMP- 3 and- 4 in benign endometrium and endometrial cancer. Gynecol Oncol 2003; 89(3): 453– 459.
Labels
Paediatric gynaecology Gynaecology and obstetrics Reproduction medicineArticle was published in
Practical Gynecology
2010 Issue 1
Most read in this issue
- Margin status of conizations with histological finding carcinoma in situ
- ICTP marker and breast cancer with bone metastases – our experience
- Intrahepatic cholestasis of pregnancy – selected perinatal outcomes.
- Therapeutic options for assisted reproduction in patients with impaired ovarian reserve