Prognostic Significance of Ploidy and DNA Index in Patients with Epithelial Ovarian Carcinoma

Abstract

Objective: To explore the significance of DNA ploidy and DNA index cutt off value to overall survival, and their potential value as independent prognostic factors. Material and Methods: Paraffin-embedded tissue from sixty-one ovarian epithelial cancers were analyzed by histology and flow cytometry. The results of DNA analysis were correlated with clinicopathologic data. For univariate survival analysis we used the Kaplan-Meier model and log-rank test to assess the differences between the groups. For multivariate analysis, Cox proportional hazard regression model was used to examine several parameters simultaneously. Results: Aneuploidy was significantly associated with advanced clinical stage, menopausal status, high grade, serous histological type and vascular invasion. Univariate analysis showed that aneuploidy (p = 0.001) and DNA index > 1.4 (p = 0.007) were associated with shorter overall survival. Multivariate analysis showed only vascular invasion as an independent prognostic factor (p < 0.001). Conclusions: Although abnormal DNA content was associated with traditional clinicopathological characteristics for aggressive tumors and shorter overall survival, aneuploidy and high DNA index had no independent prognostic value in our study.

Zusammenfassung

Zielsetzung: Feststellung der Signifikanz der DNS-Ploidie und der DNS-Indizes für das Überleben von Ovarialkarzinom-Patientinnen und der potenziellen Bedeutung dieser Indizes als unabhängige prognostische Faktoren. Material und Methoden: Paraffiniertes Gewebe von 61 Ovarialkarzinomen wurde histologisch und mittels Durchflusszytometrie analysiert. Die Ergebnisse der DNS-Analysen wurden mit den klinisch-pathologischen Daten verglichen. Die Kaplan-Meier-Methode und der Log-Rank-Test wurden zur Bewertung der Überlebensanalyse und der Unterschiede zwischen den einzelnen Gruppen angewendet. Zur Multivarianzanalyse verwendeten wir das Cox'sche proportionale Zufalls-Regressionsmodell, um mehrere Parameter gleichzeitig messen zu können. Ergebnisse: Eine Aneuploidie bestand signifikant bei fortgeschrittenem klinischem Status, Menopause, bei hochgradiger Serohistologie und bei vaskulärer Tumorinvasion. Die Univarianzanalyse ergab, dass bei Aneuploidie (p = 0,001) und einem DNS-Index ≥1,4 (p = 0,007) die allgemeine Überlebensrate kürzer war. Die Multivarianzanalyse ergab lediglich die vaskuläre Tumorinvasion als unabhängigen Prognosefaktor (p < 0,001). Schlussfolgerung: Obwohl sich ein anormaler DNS-Gehalt als klinopathologisch charakteristisch für das Vorhandensein aggressiver Tumoren und eine kürzere Überlebenszeit erwies, ergaben sowohl Aneuploidie als auch ein hoher DNS-Index keinen unabhängigen prognostischen Wert im Rahmen unserer Untersuchung.

Key words

DNA Index - flow cytometry - ovarian cancer - ploidy

Schlüsselwörter

DNA‐Index - Flow‐Zytometrie - Ovarialkarzinom - Ploidie

References

• 1 Baak J P, Chan K K, Stolk J G, Kenemans P. Prognostic factors in borderline and invasive ovarian tumors of the common epithelial type.  Pathol Res Pract. 1987;  182 755-774
• 2 Bell D A. Ovarian surface epithelial-stromal tumors.  Hum Pathol. 1991;  22 750-762
• 3 Benedet J L, Bender H, Jones I IIH, Ngan H YS, Pecorelli S. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers.  Obstet Gynecol. 2000;  70 209-262
• 4 Bernabei V M, Miller D S, Bauer K D, Murad T M, Rademaker A W, Lurain J R. Flow cytometric evaluation of epithelial ovarian cancer.  Am J Obstet Gynecol. 1990;  162 1584-1590
• 5 Brescia R J, Barakat R A, Beller U, Frederickson G, Suhrland M J, Dubin N, Demopoulos R I. The prognostic significance of nuclear DNA content in malignant epithelial tumors of the ovary.  Cancer. 1990;  65 141-147
• 6 Cox D R. Statistics.  J R Statist Soc. 1972;  B34 187-220
• 7 Curling M, Stenning S, Hudson C N, Watson J V. Multivariate analyses of DNA index, p62^c-myc, and clinicopathological status of patients with ovarian cancer.  J Clin Pathol. 1998;  51 455-461
• 8 Erba E, Ubezio P, Pep S, Vaghi M, Marsoni S, Torri W, Mangioni C, Landoni F, Dincalci M. Flow cytometric analysis of DNA content in human ovarian cancers.  Br J Cancer. 1989;  60 45-50
• 9 Geisler J P, Geisler H E. Tumor markers and molecular biological markers in gynecologic malignancies.  Curr Opin Obstet Gynecol. 2001;  13 31-39
• 10 Hedley D W, Friedlander M L, Taylor I W, Rugg C A, Musgrove E A. Method for analysis of cellular DNA-content of paraffin-embedded pathological material using flow cytometry.  J Histochem Cytochem. 1983;  31 1333-1335
• 11 Hiddemann W, Schuman J, Andreef M, Barlogie B, Herman C J, Leif R C, Mayall B H, Murphy R F, Sandberg A A. Conventione on nomenclature for DNA cytometry. Committee on nomenclature, society for analytical cytology.  Cancer genet cytogenet. 1984;  13 181-183
• 12 Holschneider C H, Berek J S. Ovarian cancer: epidemiology, biology, and prognostic factors.  Semin Surg Oncol. 2000;  19 3-10
• 13 Kaern J, Trope C G, Kristensen G B, Pettersem E O. Flow cytometric DNA ploidy and S-phase heterogeneity in advanced ovarian carcinoma.  Cancer. 1994;  73 1870-1877
• 14 Kaplan E L, Meier P. Nonparametric estimation from incomplete observations.  J Am Stat Assoc. 1958;  53 457-481
• 15 Kimmig R, Wimberger P, Hillemanns P, Kapsner T, Caspari C, Hepp H. Multivariate analysis of the prognostic significance of DNA ploidy and S-phase fraction in ovarian cancer determined by flow cytometry following detection of cytokeratin-labeled tumor cells.  Gynecol Oncol. 2002;  84 21-31
• 16 Klemi P J, Joensuu H, Maenpaa J, Kiilholma P. Influence of cellular DNA content on survival in ovarian carcinoma.  Obstet Gynecol. 1989;  170 200-204
• 17 Khoo S K, Hurst T, Kearsley G D, Dickie G, Free K, Parsons P G, Whitaker S, Ward B. Prognostic significance of tumor ploidy in patients with advanced ovarian cancer.  Gynecol Oncol. 1990;  39 284-288
• 18 Lai C H, Hsueh S, Tsao K C, Chen S M. DNA aneuploidy in benign tumors and normal tissues of the female genital tract.  Int J Gynecol Pathol. 1996;  15 63-68
• 19 Resnik E, Trujillo Y P, Taxy J B. Long-term survival and DNA ploidy in advanced epithelial ovarian cancer.  J Surg Oncol. 1997;  64 299-303
• 20 Schueler J A, Trimbos J B, Burg M VD, Cornelisse C J, Hermans J, Fleuren G J. DNA index reflects the biological behavior of ovarian carcinoma stage I-IIa.  Gynecol Oncol. 1996;  62 59-66
• 21 Seidman I D, Norris H J, Griffin Jl, Hitchcock C L. DNA flow cytometric analysis of serous ovarian tumors of low malignant potential.  Cancer. 1993;  71 3947-3951
• 22 Shackney S E, Shankey T V. Common patterns of genetic evolution in human solid tumors.  Cytometry. 1997;  29 1-27
• 23 Shankey T V, Rabinovitch P S, Bagwell B, Bauer K D, Duque R E, Hedley D W, Mayall B H, Wheeless L, Cox C. Guidelines for implementation of clinical DNA cytometry. International society for analytical cytology.  Cytometry. 1993;  14 472-477
• 24 Silverberg S G. Histopathologic grading of ovarian carcinoma: a review and proposal.  Int J Gynecol Pathol. 2000;  19 7-15
• 25 Tomić S, Ilić Forko J, Babić D, Šundov D, Kuret S, Anđelinović Š. C-erb-2, p53, and nm23 proteins as prognostic factors in patients with epithelial ovarian carcinoma.  Croat Med J. 2003;  44 429-434
• 26 Van Dam J. Ploidy in ovarian cancer and prognosis. Leake R, Gore M, Ward RH The biology of gynaecological cancer. London; RCOG Press 1995: 258-273
• 27 Valverde J J, Martin M, Garcia-Asenjo J A, Casado A, Vidart J A, Diaz-Rubio E. Prognostic value of DNA quantification in early epithelial ovarian carcinoma.  Obstet Gynecol. 2001;  97 409-416
• 28 WHO histological classification of tumors of the ovary. Tavassoli FA, Devilee P Pathology and genetics of tumors of the breast and femal genital organs. Lyon; IARC press 2003: 114-115
• 29 Zanetta G, Keeney G L, Cha S S, Wieand H S, Katzmann J A, Podratz K C. DNA index by flow cytometric analysis: an additional prognostic factor in advanced ovarian carcinoma without residual disease after primary operation.  Gynecol Oncol. 1996;  62 208-212