Prognostic significance of DNA Topoisomerase II-α (Ki-S 1) immunoexpression in endometrial carcinoma

Objective: In order to determine the significance of proliferative activity (PA) in endometrial carcinomas, we analysed the expression of cell cycle-related antigens in routinely processed tissue.

Materials and methods: Serial sections of 113 endometrial carcinoma specimens were immunostained with the monoclonal antibody DNA Topoisomerase II-alpha (Ki-S1). In addition to Topoisomerase II-alpha (Ki-S1) staining, histologic type, International Federation of Gynecology and Obstetrics (FIGO) stage. FIMO grade, depth of myometrial invasion, tumor size, lymphovascular space invasion, serosal and/or adnexal involvement, lymph node metastasis, age and peritoneal cytology were evaluated as prognostic indicators. The median follow-up time was 23 (range, 1 to 126 ) months.

Results: FIGO stage, FIGO grade, tumor size, lymphovascular space invasion, lymph node metastasis, peritoneal cytology and Topoisomerase II-alpha (Ki-S1) expression all significantly influenced survival in univariate analyses (p < or = 0.05). In the Cox regression analysis, Topoisomerase II-alpha (Ki-S1), serosal and/or adnexal involvement, and lymph node metastasis expression were the only variables with independent prognostic impact (p < or = 0.05), whereas FIGO stage, FIGO grade, histologic type FIGO grade, depth of invasion, tumor size, lymphovascular space invasion, age and peritoneal cytology had no independent influence (p > 0.05). Topoisomerase II-alpha (Ki-S1) staining was significantly elevated in advanced (Stage II, III, IV) as opposed to early (Stage I) carcinomas (p < or = 0.05).

Conclusion: The association with established prognosticators for endometrial carcinomas, and the results of uni- and multivariate analysis indicate that the additional evaluation of DNA Topoisomerase II-alpha (Ki-S1) peptide antibody (PA) is useful for classifying patients into subgroups with low and high risk of relapse which might help to individualize the therapeutic strategy in endometrial carcinomas.

Endometrial carcinoma; Immunohistochemistry; DNA Topoisomerase II-a; Ki-S 1; Prognosis; Monoclonal antibodies

[1] Gassel A. M., Backe J., Krebs S., Schon S., Caffier H., MUilerHermelink H. K.: "Endometrial carcinoma: immunohistochemically detected proliferation index is a prognosticator of long term outcome". J. Clin. Pathol., 1998, 51, 25.

[2] Maneschi M., Maneschi F., Geraci P., Licata M.. D., Serruto A., Attanasio P. et a l.: "Surgical pathological staging of endometrial carcinoma and results of treatment". Eur. J. Gynecol. Oneal., 1992, 13, 30.

[3] Abeler V. M., Kjorstad K. E.: "Endometrial adenocarcinoma with squamous cell differentiation". Cancer, 1992, 69, 488.

[4] Zaino R. J., Karman R. J., Diana K. L., Morrow C. P.: "Pathologic models to predict outcome for women with endometrial adenocarcinoma. The importance of the distinction between surgical stage and clinical stage - A Gynecologic Oncology Group Study" Cancer, 1996, 77, 1115.

[5] Salvesen H. B., Iversen 0. E.,A kslen L.A.: "Prognostic impact of morphometric nuclear grade of endometrial carcinoma". Cancer, 1998,83, 956.

[6] Salvesen H. B., Iversen 0. E., Akslen L. A.: "Prognostic significance of angiogenesis and Ki-67, p53 and p21 expression: A population-based endometrial carcinoma study". J. Clin. Oneal., 1999, 17, 1382.

[71 Fukuda K., Mori M., Uchiyama M., Iwai K., lwasaka T., Sugimon H.: "Prognostic significance of progesterone receptor immunohistochemistry in endometrial carcinoma". Gynecol. Oneal., 1998, 69, 220.

[8] Nordstrom B., Strang P.. Bergstrom R., Nilsson S., Tribukait B.: "A comparison of proliferation markers and their prognostic value for women with endometrial carcinoma. Ki-6, proliferating cell nuclear antigen, and flow cytometric S-phase fraction". Cancer, 1996, 78, 1942.

[9] Lax S. F.,P izer E. S.,R onnett B. M.,K orman R. J.: "Companson of estrogen and progesterone receptor, Ki-67 and p53 immunohistochemistry in uterine endometrioid carcinoma and endometrioid carcinoma with squamous, mucinous, secretory, and ciliated cell differentiation". Hum. Pathol., 1998, 29, 924.

[10] Mittal K. R., Schwartz P.E., Barwick K.W.: "Architectural (FIGO) grading, nuclear grading and other prognostic indicators in stage I endometrial adenocarcinoma with identification of high risk and low risk groups". Cancer, 1988, 61, 538.

[11] Homesley H. D.. Zaino R.: "Endometrial cancer. Prognostic factors". Sem. Oneal., 1994, 21, 71.

[12] Wang J. C.: "DNA topoisomerases". Annu. Rev. Biochem., 1996, 65, 635

[13] Grue P.. Graer A., Sehested M., Grasser A., Sehested M., Jensen P. B. et al.: "Essential mitotic functions of DNA topoisomerase Ila are not adopted by topoisomerase II􀃂 in human H69 cells". J. Biol Chem., 1998, 273, 33660.

[14] Isaacs R. J., Davies S. L., Sandri M. I.. Redwood C., Wells N. J., Hickson I. D.: "Physiological regulation of eukaryotic topoisomerase 11". Biochim. Biophys. Acta. 1998, 1400, 121.

[15] Watt P. M., Hickson I. D.: "Structure and function of type II DNA topoisomerases. Review article". Biochem. J., 1994, 303, 681.

[16] Jarvinen T. A. H., Holli K., Kuukasjarvi T., Isola J.: "Predictive value of topoisomerase Ila and other prognostic factors for epirubicin chemotherapy in advanced breast cancer". Br. J. Cancer, 1998, 72, 2267.

[17] Rudolph P., Tronnier M., Menzel R., Moller M., Parwaresch R.: "Enhanced expression of Ki-67, topoisomerase Ila, PCNA, p53 and p21WAFI/Cip l reflecting proliferation and repair activity in UV-irradiated melanocytic nevi". Human. Pathol.,1998, 29, 1480.

[18] Rudolph P., MacGrogan G., Bonichon F., Frahm S. 0., de Mascarel I., Trojani M. et al.: "Prognostic significance of Ki-67 and topoisomerase Ila expression in infiltrating ductal carcinoma of the breast. A multivariate analysis of 863 cases". Breast. Cancer Res. Treat., 1999, 55, 61.

[19] Sandri M. I., Hochhauser D., Ayton P., Camplejohn R. C., Whitehowe R.. Turley H. et al.: "Differential expression of the topoisomerase II α and β genes in human breast cancers". Br. J. Cancer, 1996, 73, 1518.

[20] Turley H., Comley M.. Houlbrook S., Nozaki N., Kikuchi A., Hickson I.D., Gatter K. et al.:'The distribution and expression of the two isoforms of DNA topoisomerase II in normal and neoplastic human tissues". Br. J. Cancer, 1997, 75 (9), 1340.

[21] Nielsen A. L.,T homsen H. K.,N yholm H. C.: "Evaluation of the reproducibility of the revised 1988 International Federation of Gynecology and Obstetrics grading system of endometrial cancers with special emphasis on nuclear grading". Cancer, 1991, 68, 2303.

[22] Tornos C., S归E. G., El Naggar A., Burke T. W.: "Aggressive stage I grade I endometrial carcinoma". Cancer, 1992, 70, 790.

[23] Kreipe H., Parwaresch R.: "A closer look at the cell cycle". Virch Arch. A. Pathol. Anal., 1993, 422, 341.

[24] Kreipe H.,H eidebrecht H. J.. Hansen S.,R ohlk W.,K ubbies M., Wacker H.H. et al.: "A new proliferation-associated nuclear antigen detectable in paraffin-embedded tissues by the monoclonal antibody Ki-S l ". Am. J. Pathol., 1993, 142, 3.

[25] Geisler J. P.,G eisler H. E.,M iller G. A.,W iemann M. C.,Z hou Z., Crabtree W.: "MIB-1 in endometrial carcinoma: Prognostic significance with 5-year follow-up". Gynecol. Oneal., 1999. 75, 432.

[26] Cattoretti G.. Becker M. H., Key G., Duchrow M., Schluter C., Galle J. et al.:'"Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB I and MIB 3) detect proliferating cells in microwave processed formalin-fixed paraffin sections". J. Pathol., 1992, 168, 357.

[27] Rudolp P., Lappe T., Schubert C., Schmidt D., Parwaresch R. M., Christophers E.: "Diagnostic assessment of two novel proliferation-specific antigens in benign and malignant melanocytic lesions". Am. J. Pathol.,1 995. 147, 1615.

[28] Rudolph P.,K ellner U.,C hassevent A.,C ollin F.,B onichon F.,P arwaresch R. et al.: "Prognostic relevance of a novel proliferation marker, Ki-S 11, for soft tissue sarcoma: A multivariate study". Am. J. Pathol., 1997., 150, 1997.

[29] Boege F.,A ndersen A.,J ensen S.,Z eidler R.,K reipe H.:''Proliferation-associated nuclear antigen Ki-S 1 is identical with topoisomerase Ila: Delineation of a carboxy-terminal epitope with peptide antibodies". Am. J. Pathol., 1995, 146, 1302.

[30] Kellner U., Heidebrecht H. J., Rudolph P., Biersack H., Buck F., Dakowski T. et al.: "Detection of human topoisomerase Ila in cell lines and tissues: Characterization of five novel monoclonal anti bodies". J. Histochem., 1997, 45, 251.

[31] Gerdes J., Li L., Schlueter C., Duchrow M ., Wohlenberg C.. Gerlach C. et al.: "Immunobiochemical and molecular biologic characterization of cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67". Am. J. Pathol., 1991, 138, 867.

[32] Gerdes J., Lemke H., Baisch H., Wacker H. H., Schwab U., Stem H.: "Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67". J Immunol., 1984, 133, 1710.

[33] Yabuki N.,S sano H.,K ato K.. Ohara S.,To yota T.,N agura H. et al.: "Immunohistochemical study of DNA topoisomerase in human gastric disorders". Am. J. Pathol., 1996, 149, 997.

[34] Schneider E., Hsianh Y. H., Liu L. F.: "DNA topoisomerases as anticancer drug targets". Adv. P harmacol., 1990, 21. 149.

[35] Nitiss J. L., Liu Y. X., Harbury P., Jannatipour R., Wasserman R., Wang J. C.: "Amsacrine and etoposide hypersentivity of yeast cells overexpressing DNA topoisomerase II". Cancer Res., 1992, 52, 4467.

[36] Salvesen H. B., Iversen O. E., Akslen L. A.: "Prognostic significance of angiogenesis and Ki-67, p53, and p2 l expression: A population-based endometrial carcinoma study". J. Clin. Oneal., 1999, 17, 1382.

[37] Backe J.,G assel A. M.,M uller T.,S chon S.,K aesemann H.: "Rate of proliferation as a prognostic criterion in endometrial carcinomaan immunohistochemical analysis with the monoclonal antibody Ki-SI". Zentrtalbl. Gyniikol., 1997, 119, 334.

[38] Bonatz G.,L iittes J.,H amann S.,M ettler L.,J onat W.,P arwaresch R.: "I mmunohistochemical assessment of p 170 provides prognostic information in endometrial carcinoma". Hum. Pathol., 1999, 34, 43.

[39] Bonatz G., Liittges J., Hedderich J., Inform D., Jonat W., Rudolph P.,P arwaresch R.: "Prognostic significance of a novel proliferation marker, anti-repp 86, for endometrial carcinoma: A multivariate study". Human. Pathol., 1999, 30, 949.

[40] Hao Y. J., Natsume A., Mizuno M., Taniguchi K.,Wakabayashi T., Yoshida J.: "Correlation between DNA topoisomerase Ila expression and sensitivity to etoposide in human glioma cell lines". Gan To Kagaku Ryoho, 2000, 27, 1403 (abstract)