Tp53 Expression and Ki-67 Proliferation Index in Surface Epithelial-Stromal Tumors of the Ovary and Their Relationship with the Histopathological Prognostic Parameters

Abstract

Objective: To investigate TP53 and Ki-67 expressions in malignant, borderline and benign epithelial ovarian tumors; correlate results with histopathological parameters; compare TP53 and Ki-67 expressions and discuss ovarian carcinogenesis. Material and Methods: Standard immunohistochemistry was performed in 100 malignant, 27 borderline and 31 benign tumors and 42 non-tumoral ovarian epithelia. Results: TP53 overexpression was higher in malignant (61.0%) than in borderline tumors (40.7%); in malignant cases above 50 years-of-age, with high grade and in undifferentiated and serous subtypes. Carcinomas with solid architecture in serous, high mitosis in non-serous and high pleomorphism in both subtypes; lymph node involvement, and advanced stage also showed higher expressions of TP53 (p<0.05). The mean Ki-67 index was 41.3% in malignant and 17.2% in borderline tumors. Ki-67 index tended to increase with increasing grade, and decrease with lymph node involvement. The coexpression of proteins according to grade, lymph node involvement and stage in different subtypes, showed significant differences and correlations. Conclusion: Our findings support the role of TP53 overexpression in development of “borderline” and malignant epithelial ovarian tumors. The degree of TP53 expression differed in terms of histopathological parameters; and was correlated with Ki-67 index. Especially in early stages, these biological factors could provide additional information to stratify patients for case specific therapies. Turkish Başlık: Overin Yüzey Epitelyal-Stromal Tümörlerinde Tp53 Ekspresyonu ve Ki-67 Proliferasyon İndeksi ve Histopatolojik Prognostik Parametrelerle İlişkileri Anahtar Kelimeler: Over tümörleri, p53, Ki-67 Amaç: Malign, “borderline” ve benign epitelyal over tümörlerinde TP53 ve Ki-67 ekspresyonlarını; karsinomlarda histopatolojik parametrelerle ilişkisini; farklı özelliklerdeki olgu gruplarında TP53 ve Ki-67 ekspresyonlarını araştırmak; overde karsinogenezi tartışmak. Gereç ve Yöntemler: Yüz'ü malign, 27'si “borderline” ve 31'i benign, toplam 158 epitelyal over tümörü ve 42 non-tümöral over dokusunda standart immunohistokimya tekniği kullanıldı. Bulgular: TP53 aşırı-ekspresyonu, “borderline” tümörlere (%40.7) kıyasla malignlerde (%61.0); 50 yaş üstündeki; yüksek dereceli, az/indiferansiye ve seröz; solid yapılanmalı seröz, yüksek pleomorfizm dereceli seröz ve non-seröz, yüksek mitotik indeksli non-seröz subtiplerde; lenf nodu tutulumu gösteren, ileri evredeki karsinomlarda daha yüksekti (p<0.05). Ortalama Ki-67 indeksleri, malignlerde %41.3, “borderline” tümörlerde %17.2 olup; fark anlamlıydı. Karsinomların Ki-67 indeksleri, dereceleri yükseldikçe artarken; lenf nodu tutulumlu olgularda azalma gösterdi. Karsinomların farklı subtiplerinin, derecelerine, lenf nodu tutulumları ve evrelerine göre, TP53 ekspresyonları ve Ki-67 indeksleriyle ilişkilerinde farklılıklar saptandı. Sonuç: TP53 aşırı-ekspresyonunun, malign ve “borderline” over tümörlerinin gelişimindeki rolünü desteklemektedir. Karsinomlarda, TP53 ekspresyonunun derecesi, yaş, histopatolojik subtip, derece, pleomorfizm, yapılanma özelliği, mitotik aktivite, lenf nodu tutulumu ve evre ile ilişkili olarak farklılık; Ki-67 proliferasyon indeksi ile de korelasyon göstermektedir. Malign epitelyal over tümörlerinin bu biyolojik parametrelere göre de ayrılması, gelecekte daha olguya özgün tedavi protokollerinin belirlenmesinde, özellikle erken evrede önemli olabilir.

Keywords

• Ovarian tumors, p53, Ki-67

Overin Yüzey Epitelyal-Stromal Tümörlerinde Tp53 Ekspresyonu ve Ki-67 Proliferasyon İndeksi ve Histopatolojik Prognostik Parametrelerle İlişkileri

Öz

Amaç: Malign, “borderline” ve benign epitelyal over tümörlerinde TP53 ve Ki-67 ekspresyonlarını; karsinomlarda histopatolojik parametrelerle ilişkisini; farklı özelliklerdeki olgu gruplarında TP53 ve Ki-67 ekspresyonlarını araştırmak; overde karsinogenezi tartışmak. Gereç ve Yöntemler: Yüz’ü malign, 27’si “borderline” ve 31’i benign, toplam 158 epitelyal over tümörü ve 42 non-tümöral over dokusunda standart immunohistokimya tekniği kullanıldı. Bulgular: TP53 aşırı-ekspresyonu, “borderline” tümörlere (%40.7) kıyasla malignlerde (%61.0); 50 yaş üstündeki; yüksek dereceli, az/indiferansiye ve seröz; solid yapılanmalı seröz, yüksek pleomorfizm dereceli seröz ve non-seröz, yüksek mitotik indeksli non-seröz subtiplerde; lenf nodu tutulumu gösteren, ileri evredeki karsinomlarda daha yüksekti (p < 0.05). Ortalama Ki-67 indeksleri, malignlerde %41.3, “borderline” tümörlerde %17.2 olup; fark anlamlıydı. Karsinomların Ki-67 indeksleri, dereceleri yükseldikçe artarken; lenf nodu tutulumlu olgularda azalma gösterdi. Karsinomların farklı subtiplerinin, derecelerine, lenf nodu tutulumları ve evrelerine göre, TP53 ekspresyonları ve Ki-67 indeksleriyle ilişkilerinde farklılıklar saptandı. Sonuç: TP53 aşırı-ekspresyonunun, malign ve “borderline” over tümörlerinin gelişimindeki rolünü desteklemektedir. Karsinomlarda, TP53 ekspresyonunun derecesi, yaş, histopatolojik subtip, derece, pleomorfizm, yapılanma özelliği, mitotik aktivite, lenf nodu tutulumu ve evre ile ilişkili olarak farklılık; Ki-67 proliferasyon indeksi ile de korelasyon göstermektedir. Malign epitelyal over tümörlerinin bu biyolojik parametrelere göre de ayrılması, gelecekte daha olguya özgün tedavi protokollerinin belirlenmesinde, özellikle erken evrede önemli olabilir

Anahtar Kelimeler

• Over tümörleri, p53, Ki-67

Kaynakça

1. Tavassoli FA, Deville P. (editors), World Health Organisation Clas- sification of Tumors. Pathology and Genetics of Tumors of the Breast and Female Genital Organs. Lyon, IARC (International Agency for Research on Cancer) Press, 2003: 9-112.
2. Palazzo JP, Monzon F, Burke M, Hyslop T, Dunton C, Barusevicius A, et al. Overexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline ovarian tumors. Hum Pathol 2000;31:698-704. [CrossRef]
3. Santos AM, Sousa H, Pinto D, Portela C, Pereira D, Catarino R, et al. Linking TP53 codon 72 and p21 nt590 genotypes to the development of cervical and ovarian cancer. Eur J Cancer 2006;42:958-63. [CrossRef]
4. Lee H, Park G, Jung JH, Ahn WS, Lee JM, Kim BK, et al. Diagnos- tic approach using the expression profiling of the P53 tumor sup- pressor gene and its related proteins in ovarian epithelial tumors. Int J Gynecol Cancer 2005;15:453-61. [CrossRef]
5. Plisiecka-Hałasa J, Karpinska G, Szymanska T, Ziółkowska I, Madry R, Timorek A, et al. P21WAF1, P27KIP1, TP53 and C-MYC analysis in 204 ovarian carcinomas treated with platinum-based regimens. Ann Oncol 2003;14:1078-85. [CrossRef]
6. Milde-Langosch K, Hagen M, Bamberger AM, Loning T. Expres- sion and prognostic value of the cell-cycle regulatory proteins, Rb, p16MTS1, p21WAF1, p27KIP1, cyclin E, and cyclin D2, in ovarian cancer. Int J Gynecol Pathol 2003;22:168-74. [CrossRef]
7. Dansonka-Mieszkowska A, Ludwig AH, Kraszewska E, Kupryjanczyk J. Geographical variations in TP53 mutational spectrum in ovarian carcinomas. Ann Hum Genet 2006;70:594-604. [CrossRef]
8. Köhler MF, Kerns BJ, Humphrey PA, Marks JR, Bast RC Jr, Ber- chuck A. Mutation and overexpression of p53 in early-stage epi- thelial ovarian cancer. Obstet Gynecol 1993;81:643-50.

9. Milner BJ, Allan LA, Eccles DM, Kitchener HC, Leonard RC, Kelly KF, et al. p53 mutation is a common genetic event in ovarian carcinoma. Cancer Res 1993;53:2128-32.
10. Okamoto A, Sameshima Y, Yokoyama S, Terashima Y, Sugimura T, Terada M, et al. Frequent allelic losses and mutations of the p53 gene in human ovarian cancer. Cancer Res 1991;51:5171-6.
11. Teneriello MG, Ebina M, Linnoila RI, Henry M, Nash JD, Park RC, et al. p53 and Ki-ras gene mutations in epithelial ovarian neo- plasms. Cancer Res 1993;53:3103-8.
12. Cho EY, Choi YL, Chae SW, Sohn JH, Ahn GH. Relationship between p53-associated proteins and estrogen receptor status in ovarian se- rous neoplasms. Int J Gynecol Cancer 2006;16:1000-6. [CrossRef]
13. Psyrri A, Kountourakis P, Yu Z, Papadimitriou C, Markakis S, Camp RL, et al. Analysis of p53 protein expression levels on ovarian can- cer tissue microarray using automated quantitative analysis elu- cidates prognostic patient subsets. Ann Oncol 2007;18:709-15. [CrossRef]
14. Reles A, Wen WH, Schmider A, Gee C, Runnebaum IB, Kilian U, et al. Correlation of p53 mutations with resistance to platinum- based chemotherapy and shortened survival in ovarian cancer. Clin Cancer Res 2001;7:2984-97.
15. Concin N, Hofstetter G, Berger A, Gehmacher A, Reimer D, Watrowski R, et al. Clinical relevance of dominant-negative p73 isoforms for responsiveness to chemotherapy and survival in ovarian cancer: evidence for a crucial p53-p73 cross-talk in vivo. Clin Cancer Res 2005;11:8372-83. [CrossRef]
16. Gadducci A, Di Cristofano C, Zavaglia M, Giusti L, Menicagli M, Cosio S, et al. P53 gene status in patients with advanced serous epithelial ovarian cancer in relation to response to paclitaxel- plus platinum-based chemotherapy and long-term clinical out- come. Anticancer Res 2006;26:687-93.
17. Laframboise S, Chapman W, McLaughlin J, Andrulis IL. p53 mu- tations in epithelial ovarian cancers: possible role in predicting chemoresistance. Cancer J 2000;6:302-8.
18. Shahin MS, Hughes JH, Sood AK, Buller RE. The prognostic sig- nificance of p53 tumor suppressor gene alterations in ovarian carcinoma. Cancer 2000;89:2006-17. [CrossRef]
19. Fallows S, Price J, Atkinson RJ, Johnston PG, Hickey I, Russell SE. P53 mutation does not affect prognosis in ovarian epithelial malignancies. J Pathol 2001;194:68-75. [CrossRef]
20. Wang Y, Helland A, Holm R, Skomedal H, Abeler VM, Danielsen HE, et al. TP53 mutations in early-stage ovarian carcinoma, relation to long-term survival. Br J Cancer 2004;90:678-85. [CrossRef]
21. Goodheart MJ, Ritchie JM, Rose SL, Fruehauf JP, De Young BR, Buller RE. The relationship of molecular markers of p53 function and angiogenesis to prognosis of stage I epithelial ovarian can- cer. Clin Cancer Res 2005;11:3733-42. [CrossRef]
22. Galic V, Willner J, Wollan M, Garg R, Garcia R, Goff BA, et al. Common polymorphisms in TP53 and MDM2 and the relation- ship to TP53 mutations and clinical outcomes in women with ovarian and peritoneal carcinomas. Genes Chromosomes Cancer 2007;46:239-47. [CrossRef]
23. Schindlbeck C, Hantschmann P, Zerzer M, Jahns B, Rjosk D, Janni W, et al. Prognostic impact of Ki-67, p53, human epithelial growth factor receptor 2, topoisomerase IIalpha, epidermal growth fac- tor receptor, and nm23 expression of ovarian carcinomas and dis- seminated tumor cells in the bone marrow. Int J Gynecol Cancer 2007;17:1047-55. [CrossRef]
24. Silverberg SG. Histopathologic grading of ovarian carcinoma: a re- view and proposal. Int J Gynecol Pathol 2000;19:7-15. [CrossRef]
25. Willner J, Wurz K, Allison KH, Galic V, Garcia RL, Goff BA, et al. Al- ternate molecular genetic pathways in ovarian carcinomas of com- mon histological types. Hum Pathol 2007;38:607-13. [CrossRef]
26. Schmider-Ross A, Pirsig O, Gottschalk E, Denkert C, Lichte- negger W, Reles A. Cyclin-dependant kinase inhibitors CIP1 (p21) and KIP1 (p27) in ovarian cancer. J Cancer Res Clin Oncol 2006;132:163-70. [CrossRef]
27. Shimizu M, Nikaido T, Toki T, Shiozawa T, Fujii S. Clear cell car- cinoma has an expression pattern of cell cycle regulatory mol- ecules that is unique among ovarian adenocarcinomas. Cancer 1999;85:669-77. [CrossRef]
28. Geisler HE, Geisler JP, Miller GA, Geisler MJ, Wiemann MC, Zhou Z, et al. p21 and p53 in ovarian carcinoma: their combined stain- ing is more valuable than either alone. Cancer 2001;92:781-6. [CrossRef]
29. Henriksen R, Strang P, Wilander E, Bäckström T, Tribukait B, Oberg K. p53 expression in epithelial ovarian neoplasms: rela- tionship to clinical and pathological parameters, Ki-67 expression and flow cytometry. Gynecol Oncol 1994;53:301-6. [CrossRef]
30. Kerner R, Sabo E, Gershoni-Baruch R, Beck D, Ben-Izhak O. Ex- pression of cell cycle regulatory proteins in ovaries prophylacti- cally removed from Jewish Ashkenazi BRCA1 and BRCA2 mu- tation carriers: correlation with histopathology. Gynecol Oncol 2005;99:367-75. [CrossRef]
31. Kuscu E, Ozdemir BH, Erkanli S, Haberal A. HPV and p53 ex- pression in epithelial ovarian carcinoma. Eur J Gynaecol Oncol 2005;26:642-5.
32. Fauvet R, Dufournet C, Poncelet C, Uzan C, Hugol D, Darai E. Ex- pression of pro-apoptotic (p53, p21, bax, bak and fas) and anti- apoptotic (bcl-2 and bcl-x) proteins in serous versus mucinous bor- derline ovarian tumours. J Surg Oncol 2005;92:337-43. [CrossRef]
33. Dogan E, Saygili U, Tuna B, Gol M, Gürel D, Acar B, et al. p53 and mdm2 as prognostic indicators in patients with epithelial ovar- ian cancer: a multivariate analysis. Gynecol Oncol 2005;97:46-52. [CrossRef]
34. Ozalp SS, Yalcin OT, Basaran GN, Artan S, Kabukcuoglu S, Minsin TH. Prognostic significance of deletion and over-expression of the p53 gene in epithelial ovarian cancer. Eur J Gynaecol Oncol 2000;21:282-6.
35. Ozalp S, Yalcin OT, Minsin TH. Expression of p53 in epithelial ovarian cancer. Int J Gynaecol Obstet 2000;71:277-8. [CrossRef]
36. Berker B, Dunder I, Ensari A, Cengiz SD. Prognostic value of p53 accumulation in epithelial ovarian carcinomas. Arch Gynecol Ob- stet 2002;266:205-9. [CrossRef]
37. Berker B, Dunder I, Ensari A, Cengiz SD, Simsek E. Prognostic sig- nificance of apoptotic index and bcl-2 and p53 expression in epi- thelial ovarian carcinoma. Eur J Gynaecol Oncol 2002;23:505-10.
38. Ayhan A, Tuncer ZS, Ayhan A. p53 expression in ovarian carci- noma with regard to second-look findings. Eur J Gynaecol Oncol 1998;19:501-2.
39. Hartmann LC, Podratz KC, Keeney GL, Kamel NA, Edmonson JH, Grill JP, et al. Prognostic significance of p53 immunostaining in epithelial ovarian cancer. J Clin Oncol 1994;12:64-9.
40. Costa MJ, Hansen CL, Walls JE, Scudder SA. Immunohistochemi- cal markers of cell cycle control applied to ovarian and primary peritoneal surface epithelial neoplasms: p21(WAF1/CIP1) pre- dicts survival and good response to platin-based chemotherapy. Hum Pathol 1999;30:640-7. [CrossRef]
41. Saegusa M, Machida B D, Okayasu I. Possible associations among expression of p14(ARF), p16(INK4a), p21(WAF1/CIP1), p27(KIP1), and p53 accumulation and the balance of apoptosis and cell prolif- eration in ovarian carcinomas. Cancer 2001;92:1177-89. [CrossRef]
42. Ho ES, Lai CR, Hsieh YT, Chen JT, Lin AJ, Hung MH, et al. p53 mutation is infrequent in clear cell carcinoma of the ovary. Gyne- col Oncol 2001;80:189-93. [CrossRef]
43. Eltabbakh GH, Mount SL, Beatty B, Simmons-Arnold L, Cooper K. Clinical and molecular differences between clear cell and pap- illary serous ovarian carcinoma. J Surg Oncol 2006;93:379-86. [CrossRef]
44. Hİgdall EV, Kjaer SK, Blaakaer J, Christensen L, Glud E, Vuust J, et al. P53 mutations in tissue from Danish ovarian cancer pa- tients: from the Danish “MALOVA” ovarian cancer study. Gyne- col Oncol 2006;100:76-82.
45. Agarwal R, Kaye SB. Expression profiling and individualisation of treatment for ovarian cancer. Curr Opin Pharmacol 2006;6:345-9. [CrossRef]
46. Fraser M, Chan SL, Chan SS, Fiscus RR, Tsang BK. Regulation of p53 and suppression of apoptosis by the soluble guanylyl cy- clase/cGMP pathway in human ovarian cancer cells. Oncogene 2006;25:2203-12. [CrossRef]
47. Green JA, Berns EM, Coens C, van Luijk I, Thompson-Hehir J, van Diest P, et al. Alterations in the p53 pathway and progno- sis in advanced ovarian cancer: a multi-factorial analysis of the EORTC Gynaecological Cancer group (study 55865). Eur J Can- cer 2006;42:2539-48. [CrossRef]
48. Yan X, Fraser M, Qiu Q, Tsang BK. Over-expression of PTEN sen- sitizes human ovarian cancer cells to cisplatin-induced apoptosis in a p53-dependent manner. Gynecol Oncol 2006;102:348-55. [CrossRef]
49. Wang Y, Kristensen GB, Bİrresen-Dale AL, Helland A. TP53 muta- tions and codon 72 genotype--impact on survival among ovarian cancer patients. Ann Oncol 2007;18:964-6. [CrossRef]
50. Amikura T, Sekine M, Hirai Y, Fujimoto S, Hatae M, Kobayashi I, et al. Japanese Familial Ovarian Cancer Study Group. Mutational analysis of TP53 and p21 in familial and sporadic ovarian cancer in Japan. Gynecol Oncol 2006;100:365-71. [CrossRef]
51. Righetti SC, Perego P, Carenini N, Zunino F. Cooperation be- tween p53 and p73 in cisplatin-induced apoptosis in ovarian car- cinoma cells. Cancer Lett 2008;263:140-4. [CrossRef]
52. Konstantinidou AE, Korkolopoulou P, Vassilopoulos I, Tsenga A, Thymara I, Agapitos E, et al. Reduced retinoblastoma gene pro- tein to Ki-67 ratio is an adverse prognostic indicator for ovar- ian adenocarcinoma patients. Gynecol Oncol 2003;88:369-78. [CrossRef]
53. Darai E, Walker-Combrouze F, Dauge-Geoffroy MC, Vincent Y, Feldmann G, Madelenat P, et al. Ki 67 expression in 35 border- line ovarian tumours: relations with clinicopathologic parameters and ploidy. Eur J Obstet Gynecol Reprod Biol 1998;76:175-80. [CrossRef]
54. Karaburun S, Karaveli S, Peştereli HE, Simsek T, Sargin CF. Prolif- erating cell nuclear antigen (PCNA) and Ki-67 in epithelial ovarian tumours: correlation with DNA flow cytometric analysis. Adv Clin Path 2001;5:3-9.