Stavropoulos Nikolaos E, Filiadis Ioannis, Ioachim Elli, Hastazeris Konstantinos, Tsimaris Ioannis, Kalogeras Demetrios, Stefanaki Stella, Agnantis Nicki J
Department of Urology, G. Hatzikosta General Hospital, Makriyianni Ave., 45001 Ioannina, Greece.
Anticancer Res. 2002 Nov-Dec;22(6B):3759-64.
Although tumor grade and stage are the most accurate prognostic factors in the evaluation of transitional cell bladder cancer, they cannot always predict the true tumor biological potential since superficial tumors of the same stage and grade may have completely different clinical courses. This study was performed in order to examine whether p53, bcl-2 and Ki-67 have any validity in predicting the course of superficial bladder tumors, with high risk for recurrence or progression, over the traditional prognostic factors that are currently used. Furthermore, we investigated whether any one of these markers maintains its prognostic capability after one course of intravesical instillations of IFN gamma.
The immunohistochemical evaluation of bladder tumor specimens, that were obtained transurethrally for the expression of p53, bcl-2 and Ki-67, was performed in 58 patients. After meticulous selection of cut-off values for the expression of the aforementioned markers, twenty-eight patients were treated only with transurethral resection (TURBT only group) while 30 patients received adjuvantly intravesical instillations of interferon gamma. The times to first recurrence and progression were recorded during the follow-up period which ranged from 3 to 36 months (mean 11.7 months). The prognostic significance of tumor stage, grade, presence of CIS, p53, bcl-2 and Ki-67 in determining the risk for recurrence, was studied with both univariate (log-rank test) and multivariate (Cox regression) methods of analysis, separately for the TURBT only group of patients and for those who received instillations. The same analysis was employed for the risk of progression in the overall number of progressed patients.
According to both uni- and multivariate analysis of the prognostic significance for tumor stage (T), grade (G), presence of CIS, p53, Ki-67 and bcl-2 in each group of patients, the Ki-67 index was the only independent prognostic factor for recurrence in patients treated with TURBT only (p = 0.0044 univariate, p = 0.031 multivariate). None of the factors which were studied proved to have prognostic significance for recurrence in the group of patients who received adjuvant intravesical instillation with the immunomodulating agent. Although in the univariate analysis all the studied parameters except tumor stage seem to be associated in a statistically significant manner with higher risk for progression, the multivariate analysis did not yield any independent significant prognosticator. The same evaluation was performed only for the patients with grade 2 disease (28) and yielded statistically significantly higher risk for recurrence, both in uni- (p = 0.0081) and in multivariate analysis (p = 0.044) only in the patients with overexpression of Ki-67 who were treated with TURBT alone.
The Ki-67 proliferative index has an independent validity in predicting those patients with high risk superficial bladder tumors who may recur in a short follow-up period. A similar relationship of Ki-67 overexpression to progression was not detected. The expression of p53 and bcl-2 does not seem to offer any prognostic information in predicting either recurrence or progression over the prognostic factors that are currently used in clinical practice.
尽管肿瘤分级和分期是评估移行细胞膀胱癌最准确的预后因素，但由于相同分期和分级的浅表性肿瘤可能具有完全不同的临床病程，它们并不总能预测肿瘤的真正生物学潜能。进行本研究是为了检验与目前使用的传统预后因素相比，p53、bcl-2和Ki-67在预测具有高复发或进展风险的浅表性膀胱肿瘤病程方面是否具有任何有效性。此外，我们研究了在进行一个疗程的膀胱内干扰素γ灌注后，这些标志物中的任何一个是否仍保持其预后能力。
对58例经尿道获取的膀胱肿瘤标本进行免疫组化评估，以检测p53、bcl-2和Ki-67的表达。在精心选择上述标志物表达的临界值后，28例患者仅接受经尿道切除术（仅TURBT组），而30例患者接受辅助性膀胱内干扰素γ灌注。在3至36个月（平均11.7个月）的随访期内记录首次复发和进展的时间。分别对仅TURBT组患者和接受灌注的患者，采用单因素（对数秩检验）和多因素（Cox回归）分析方法，研究肿瘤分期、分级、CIS的存在、p53、bcl-2和Ki-67在确定复发风险方面的预后意义。对所有进展患者的进展风险进行同样的分析。
根据对每组患者中肿瘤分期（T）、分级（G）、CIS的存在、p53、Ki-67和bcl-2预后意义的单因素和多因素分析，Ki-67指数是仅接受TURBT治疗患者复发的唯一独立预后因素（单因素p = 0.0044，多因素p = 0.031）。在所研究的因素中，没有一个被证明对接受免疫调节剂辅助膀胱内灌注的患者组的复发具有预后意义。尽管在单因素分析中，除肿瘤分期外，所有研究参数似乎都与较高进展风险有统计学显著关联，但多因素分析未产生任何独立的显著预后指标。仅对2级疾病患者（28例）进行了同样的评估，结果显示仅在单独接受TURBT治疗且Ki-67过表达的患者中，复发风险在单因素分析（p = 0.0081）和多因素分析（p = 0.044）中均有统计学显著升高。
Ki-67增殖指数在预测那些在短期随访期内可能复发的高风险浅表性膀胱肿瘤患者方面具有独立有效性。未检测到Ki-67过表达与进展之间的类似关系。在预测复发或进展方面，与目前临床实践中使用的预后因素相比，p53和bcl-2的表达似乎未提供任何预后信息。
