Elevated Ki-67 (MIB-1) Expression as an Independent Predictor for Poor Prognosis After Radical Cystectomy for Bladder Cancer

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J Urol Oncol. 2017;15(3):152-157

Publication date (electronic) : 2017 December 27

doi : https://doi.org/10.22465/kjuo.2017.15.3.152

Hakmin Lee¹, Dong Hwan Lee¹, Younsoo Chung¹, Ngoc Ha Nguyen², Jong Jin Oh¹, Sangchul Lee¹, Sang Eun Lee¹, Sung Kyu Hong¹, Seok-Soo Byun^,1

¹Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea

²Department of Urology, Cho Ray Hospital, Ho Chi Minh city, Vietnam

Corresponding Author: Seok-Soo Byun Department of Urology, Seoul National University Bundang Hospital, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea E-mail: 65828@snubh.org Tel: +82-31-787-7343, Fax: +82-31-787-4057

Received 2017 October 19; Revised 2017 October 28; Accepted 2017 October 31.

Abstract

INTRODUCTION

Bladder cancer (BCa) is the 9th most common malignancy and approximately 430,000 patients were diagnosed as BCa only in 2012.¹ BCa is also well-known to occur in the under-developed countries and to have strong association with male gender. The risk factors for the having BCa include Schistosoma haematobium infection, tobacco smoking, chemical exposures, and diabetes mellitus treated by pioglitazone.^2–4 The current gold-standard treatment is the radical cystectomy for the patients with muscle invasive BCa (MIBC) or high-risk recurrent nonmuscle invasive BCa (NMIBC).^5,6 However there are no accurate biomarkers to predict the patients’ prognosis after surgery, which is crucial for the patients’ counseling and determining the treatment plan.

The expression of Ki-67 protein is known to be strictly associated with cell proliferation.⁷ The Ki-67 protein is present only in the mitosis stage and absent in the resting stage. This fact makes Ki-67 expression as an excellent biomarker to identify the status of cell proliferation. The fraction of Ki-67 positive cancer cells is often utilized to evaluate the clinical prognosis of the corresponding disease.⁸ However, there had been not many studies to identify the prognostic value of Ki-67 in the BCa cohort. Therefore we tried to evaluate the clinical usefulness of Ki-67 expression in our institutional BCa cohorts which was treated by radical cystectomy for BCa. We tried to evaluate the clinical correlation between the expression of Ki-67 upon postoperative survival outcomes in terms of recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) in our study.

MATERIALS AND METHODS

After the approval of Seoul National University Ethical Review Board (L-2017-1370), we analyzed the data of 29 patients who underwent radical cystectomy from December 2005 to December 2016 at Seoul National University Bundang Hospital. After additional exclusion of patients (preoperative radiotherapy [n=4], other malignancies [n=12], and incomplete information [n=3]), we finally analyzed a total of 230 patients. Patients’ clinical and pathological information were acquired from our database which is prospectively maintained. All surgical specimens were reviewed by senior pathologist who was totally unaware of clinical information about patients. The TNM staging was classified by using the 6th edition of the American Joint Committee cancer guidelines for BCa.⁹ The pathologic results including immunohistochemistry were also collected prospectively but analyzed retrospectively. The postoperative follow-ups were usually performed at 3- to 6-month intervals at the initial 2 years and yearly thereafter. Recurrence of disease was defined as radiologic or pathologic evidence of local recurrence, distant metastasis, or mortalities from BCa. Postoperative evaluations were generally performed by 3 to 6 months intervals for the first 2 years and yearly thereafter but slightly differ between the attending clinicians. Mortality data was acquired from the official database of the Korean National Statistical Office and also validated by reviewing our medical records. The RFS, CSS, and OS were determined from surgery date to progression, any-cause mortality, or cancer-specific mortality, respectively.

RESULTS

The clinical and pathologic characteristics of patients were summarized in Table 1. The median age at surgery was 67.0 years (interquartile range [IQR], 59.8–74.2 years) and median duration of follow up was 26.3 months (IQR, 7.9–60.7 months). There were 186 patients (80.9%) with positive Ki-67 expression and 44 patients (19.1%) without Ki67 expression. The patients with positive Ki-67 expression had significantly worse previous TUR stage (p=0.024) and also pathologic stages (p=0.003). However there were no significant differences in other clinical or pathologic characteristics. The Kaplan-Meier analyses revealed that positive Ki-67 group experienced significantly inferior RFS (p=0.018) and CSS (p=0.019) than the negative Ki-67 group (Fig. 1). The positive Ki-67 group showed high OS than Ki-67 negative group but did not reach the statistical significance. Subsequently, the multivariate Cox proportional analyses showed that the Ki-67 expression was an independent predictor for worse RFS after surgery (HR, 3.142; 95% CI, 1.287–7.671; p=0.012) but not in the OS and CSS (Table 2). The pathologic stage was also revealed as significant prognostic factor for recurrence free survival and OS. Moreover, the patients’ age and neoadjuvant chemotherapy was showed significant results in the multivariate Cox analysis.

Table 1.

Summarization of clinical and pathologic characteristics of entire patients

Fig. 1.

Kaplan-Meier analyses for recurrence-free (A), overall (B), and cancer-specific survivals (C) after radical cystectomy in patients with bladder cancer.

Table 2.

Multivariate analyses using Cox proportional hazard model on recurrence-free, overall, and cancer-specific survivals after surgery

DISCUSSION

In this study, we observed that the high Ki-67 was significantly related with the worse survival outcomes after radical cystectomy in patients with BCa in terms of RFS and CSS. Moreover the expression of Ki-67 was revealed to be independent predictor of worse RFS from the multivariate Cox analysis. Even though the Ki-67 expression did not show significant association with CSS and OS in the multivariate analyses, we think that the statistical insignificance of our results is due to our study's small number of cohort. Therefore we believe that the Ki-67 expression should be re-evaluated in the further prospectively organized studies with more large number of subjects.

The Ki-67 protein is not a novel biomarker and it's appearance is go back to 1980's. Gerdes et al.¹⁰ first demonstrated the Ki-67 and initial prototype monoclonal antibody, which was produced by tumor cells of Hodgkin lymphoma cell from mouse. As the Ki-67 expression can be observed in the all pro-liferating cells (normal and tumor cells), the Ki-67 expression was utilized as a biomarker which can represent the status of cell proliferation. Subsequently, numerous studies tried to evaluate the prognostic value of Ki-67 in the various types of cancers.¹¹ Drach et al.¹¹ reported that the expression of Ki-67 is well-correlated with the course of the disease and has further strength in distinguishing multiple myeloma from other monoclonal gammopathy. Huuhtanen et al.¹² analyzed 123 patients with soft tissue sarcoma and concluded that the Ki-67 score was strong predictor for predicting the metastasis-free survival and CSS. Several group also showed that the Ki-67 expression can have excellent power in predicting the patients’ prognosis in prostate cancer.^13–15 Bai et al.¹³ analyzed small cohorts of 39 patients and found that the Ki-67 expression have prognostic information from their multivariate analyses. Moul et al.¹⁵ performed the immunohistochemistry staining using the pathologic specimens from 162 patients with localized prostate cancer and reported that Ki-67, p53, and bcl-2 have significant correlation with biochemical recurrence after surgery.

Preceding the present study, there had been several studies which tried to elucidate the clinical usefulness of Ki-67 in the patients with BCa.¹⁶ Margulis et al.¹⁶ analyzed the data of 226 patients with BCa. The Ki-67 expression was found in the 42.5% of cystectomy specimens and in 54% of metastatic lymph nodes. The Ki-67 was also significantly aassociated with the advanced pathologic stage (p=0.001), higher grade (p=0.040), and lymph node invasion (p=0.036) in their study. More recently, Wang et al.¹⁷ also analyzed the small cohort of 103 patients who were treated with radical cystectomy for BCa in single institution in china. They reported that there was significant association between the Ki-67 expression and CSS in the female BCa patients. Apart from the MIBC, Ding et al.¹⁸ evaluate the association of Ki-67 and disease prognosis in patients with NMIBC. After analyzing the clinical data of 332 patients after transurethral resection, the Ki-67 expression was significantly associated with high European Organization for Research and Treatment of Cancer risk scores for tumor recurrence and progression. Furthermore, multivariates analyses revealed that Ki-67 was independent risk factor for tumor recurrence and progression of disease.

Our study is limited by its retrospective design though our database was managed prospectively. We also admit the possibility of selection bias since only patients who underwent radical cystectomy were included in our study. Moreover, the indication for neoadjuvant chemotherapy was not controlled and varies according to the physicians and time periods, which may significantly impact the outcomes of our study. However, our study is the first study which tried to evaluate the clinical significance of Ki-67 in Korean population. Further study with prospective design and large number of subjects are needed to evaluate the true clinical usefulness of Ki-67 expression in BCa patients.

CONCLUSIONS

The expression of Ki-67 was significantly associated with worse pathologic and survival outcomes in patients with localized prostate cancer. These findings may help the future clinicians to predict the PCa prognosis more exactly and to choose the optimal treatments.

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