PROGNOSTİC VALUE OF Kİ67 İN BORDERLİNE MUCİNOUS OVARİAN TUMORS

Öz

Objective Ovarian borderline tumors (OBTs) are an intermediate type of ovarian neoplasm. Ovarian mucinous borderline tumors (MBT) are the second most common subtype of OBT. Because of their uncertain pathogenesis and biological behaviour they cannot be classified clearly into benign and malign categories. There is a need to identify a parameter that provides more prog- nostic information about the clinical course and can be evaluated easily in routine practice. Ki67 is a routinely used immunohistochemical marker that is strongly associated with cellular proliferation, including tumor cells. We aimed in this study to evaluate the prognostic significance and to determine prognostic cut-off value of Ki67 counting in the MBTs and to investigate its relationship with clinicopathologic features, recurrence, and long term survival status and also to provide more information to the literature. Material and Method A total of 20 cases diagnosed with ovarian mucinous borderline tumors were identified. Immunohistochemical studies were performed on the most representative sample of the tumor. Positive signal was nuclear and it was evaluated by two pathologists. Results Ki67 proliferating index (P.I) value with a median of 15%(1-47%) and a mean of 16% Ki67 P.I. reached statistically significance at 20% cut-off value with progression and at 30% cut-off value with 5-year OS. (p=0.021 and p=0.032, respectively). Although the Ki67 P.I. tended to increase with age, there was no statistical association between Kİ67 P.I. and other clinicopathological parameters including tumor size, laterality, capsule integrity, intraepithelial carcinoma and focal atypia. Conclusion In our study, recurrence was more frequent when Ki67 was greater than 20%, and 5-year survival was lower when Ki67 was greater than 30%, suggesting that the Ki67 index was associated with a more aggressive course and death. Therefore, we predicted that Ki 67 would be useful in determining the frequency of follow-up of patients and predicting their prognosis. However, we think that this result should be supported by larger series.

Anahtar Kelimeler

• Borderline
• Mucinous
• Ovary
• Tumor
• Ki67

BORDERLİNE MÜSİNÖZ OVER TÜMÖRLERİNDE Kİ67'NİN PROGNOSTİK DEĞERİ

Öz

Amaç Overin müsinöz borderline tümörleri (MBT), borderline over tümörlerinin en sık görülen ikinci alt tipidir. Belirsiz patogenezleri ve biyolojik davranışları nedeniyle, benign veya malign kategorilere açıkça sınıflandırılamadıkları için klinik seyir hakkında daha prognostik bilgi sağlayan ve rutin pratikte kolaylıkla değerlendirilebilecek bir parametrenin belirlenmesine ihtiyaç vardır. Ki67, tümör hücreleri de dahil olmak üzere hücresel proliferasyonla güçlü bir şekilde ilişkili olan ve rutin olarak kullanılan bir immünohistokimyasal belirteçtir. Bu çalışmada MBT'lerde Ki67 sayımının prognostik önemini değerlendirmeyi ve prognostik eşik değerini belirlemeyi ve klinikopatolojik özellikleri, nüks ve uzun süreli sağkalım durumu ile ilişkisini araştırmayı ve ayrıca literatüre daha fazla bilgi sağlamayı amaçladık. Gereç ve Yöntem Müsinöz borderline over tümörü tanısı koyulan toplam 20 vaka çalışmaya alındı. Tümörü en iyi temsil eden örnek üzerinde immünohistokimyasal çalışmalar yapıldı. Nükleer boyanma pozitif kabul edildi ve iki patolog tarafından değerlendirildi Bulgular Ki67 proliferasyon indeksi (P.I) medyan %15 (1-47% ve ortalama %16'dır. Ki67 P.I. progresyonla %20 eşik değerinde ve 5 yıllık OS ile %30 eşik değerinde istatistiksel olarak anlamlılığa ulaştı. (sırasıyla p=0.021 ve p=0.032). Ki67 P.I. yaşla birlikte artma eğilimindeydi. Kİ67 P.I. ile tümör boyutu, lateralite, kapsül bütünlüğü, intraepitelyal karsinom ve fokal atipi dahil olmak üzere diğer klinikopatolojik parametreler arasında istatistiksel bir ilişki yoktu. Sonuç Çalışmamızda Ki67 %20'den yüksek olduğunda nüksün daha sık oluşu, Ki67 %30'dan yüksek olduğunda 5 yıllık sağkalımın daha düşük oluşu Ki67 indeksinin daha agresif seyir ve ölüm ile ilişkili olduğunu düşündürdü. Bu nedenle Ki 67'nin hastaların takip sıklığını belirlemede ve prognozlarını tahmin etmede faydalı olacağını öngördük. Ancak bu sonucun daha geniş seriler ile desteklenmesi gerektiğini düşünüyoruz.

Anahtar Kelimeler

• Borderline
• Ki67
• Müsinöz
• Over
• Tümör

Kaynakça

1. 1. Longacre TA, Gilks CB. Surface Epithelial Stromal Tumors of the Ovary. In: Gynecologic Pathology. 1st Ed. London: Elsevier; 2009.
2. 2. Vang R, Khunamornpong S, Köbel M, Longacre TA, Ramalingam P. Who Classification of Tumours of Female Reproductive Organs. Lyon: IARC; 2020.
3. 3. Hauptmann S, Friedrich K, Redline R, Avril S. Ovarian borderline tumors in the 2014 WHO classification: evolving concepts and diagnostic criteria. Virchows Arch. 2017;470(2):125–142. doi:10.1007/s00428-016-2040-8
4. 4. Kurman RJ, Carcangiu ML, Harrington CS, Young RH. WHO classification of tumours of female reproductive organs. Lyon: IARC; 2014.
5. 5. Rodríguez IM, Prat J. Mucinous tumors of the ovary: A clinicopathologic analysis of 75 borderline tumors (of intestinal type) and carcinomas. Am J Surg Pathol. 2002;26(2):139-52. doi:10.1097/00000478-200202000-00001
6. 6. Cadron I, Leunen K, Van Gorp T, Amant F, Neven P, Vergote I. Management of borderline ovarian neoplasms. J Clin Oncol. 2007;25(20):2928-37. doi:10.1200/JCO.2007.10.8076
7. 7. Tinelli R, Tinelli A, Tinelli FG, Cicinelli E, Malvasi A. Conservative surgery for borderline ovarian tumors: A review. Gynecol Oncol. 2006;100(1):185-191. doi:10.1016/j.ygyno.2005.09.021
8. 8. Giurgea LN, Ungureanu C, Mihailovici MS. The immunohistochemical expression of p53 and Ki67 in ovarian epithelialborderline tumors. Correlation with clinicopathological factors. Rom J Morphol Embryol. 2012;53(4):967–973

9. 9. Malpica A, Longacre TA. Prognostic indicators in ovarian serous borderline tumours. Pathology. 2018;50(2):205-213. doi: 10.1016/j.pathol.2017.12.001
10. 10. Klöppel G, La Rosa S. Ki67 labeling index: assessment and prognostic role in gastroenteropancreatic neuroendocrine neoplasms. Virchows Arch. 2018;472(3):341-349. doi:10.1007/s00428-017-2258-0
11. 11. Rindi G, Arnold R, Bosman F. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: WHO Classification of Tumors of the Digestive System. 4th Ed. Lyon: IARC; 2010.
12. 12. Guadagno E, Pignatiello S, Borrelli G, et al. Ovarian borderline tumors, a subtype of neoplasm with controversial behavior. Role of Ki67 as a prognostic factor. Pathol Res Pract. 2019;215(11):152633. doi:10.1016/j.prp.2019.152633
13. 13. Riopel MA, Ronnett BM, Kurman RJ. Evaluation of diagnostic criteria and behavior of ovarian intestinal- type mucinous tumors: Atypical proliferative (borderline) tumors and intraepithelial, microinvasive, invasive, and metastatic carcinomas. Am J Surg Pathol. 1999;23(6):617-35. doi:10.1097/00000478- 199906000-00001
14. 14. Khunamornpong S, Settakorn J, Sukpan K, Suprasert P, Siriaunkgul S. Mucinous tumor of low malignant potential (“borderline” or “atypical proliferative” tumor) of the ovary: A study of 171 cases with the assessment of intraepithelial carcinoma and microinvasion. Int J Gynecol Pathol. 2011;30(3):218-30. doi:10.1097/PGP.0b013e3181fcf01a
15. 15. Kim KR, Lee HI, Lee SK, Ro JY, Robboy SJ. Is stromal microinvasion in primary mucinous ovarian tumors with “mucin granuloma” true invasion? Am J Surg Pathol. 2007;31(4):546-54. doi:10.1097/01.pas.0000213430.68998.2c
16. 16. Lee KR, Scully RE. Mucinous tumors of the ovary: A clinicopathologic study of 196 borderline tumors (of intestinal type) and carcinomas, including an evaluation of 11 cases with “pseudomyxoma peritonei.” Am J Surg Pathol. 2000;24(11):1447-64. doi:10.1097/00000478-200011000-00001
17. 17. Garzetti GG, Ciavattini A, Goteri G, et al. Ki67 antigen immunostaining (MIB 1 monoclonal antibody) in serous ovarian tumors: Index of proliferative activity with prognostic significance. Gynecol Oncol. 1995;56(2):169-74. doi:10.1006/gyno.1995.1026
18. 18. Halperin R, Zehavi S, Dar P, et al. Clinical and molecular comparison between borderline serous ovarian tumors and advanced serous papillary ovarian carcinomas. Eur J Gynaecol Oncol. 2001;22(4):292-6.
19. 19. Münstedt K, Von Georgi R, Franke FE. Correlation between MIB1-determined tumor growth fraction and incidence of tumor recurrence in early ovarian carcinomas. Cancer Invest. 2004;22(2):185-94. doi:10.1081/CNV-120030206
20. 20. Heeran MC, Høgdall CK, Kjaer SK, et al. Prognostic value of tissue protein expression levels of MIB-1 (Ki-67) in Danish ovarian cancer patients: From the “MALOVA” ovarian cancer study. APMIS. 2013;121(12):1177-86. doi:10.1111/apm.12071