Abstract
Aim: To examine the clinical significance of preoperative urine cytology in patients with low-grade bladder cancer. Patients and Methods: We retrospectively investigated the records of 155 patients diagnosed with primary low-grade (Ta) urothelial carcinoma of the bladder between January 2000 and September 2014. Results: Patients with class III or greater cytology had significantly higher-grade (G2) (p=0.01), larger tumors (≥15 mm, p=0.0009) and significantly shorter recurrence-free survival compared to patients with class II or lower cytology (p<0.0001). However, Cox proportional hazards analysis for recurrence-free survival only identified tumor size (≥15 mm) (hazard ratio=5.97, 95% confidence interval=2.39–17.29; p<0.0001) as a predictor of poor prognosis, although patients with class III or higher preoperative cytology showed a tendency towards frequent intravesical recurrence (hazard ratio=1.98, 95% confidence interval=0.96-4.2; p=0.063). Conclusion: Preoperative urine cytology, in addition to tumor size, might be a useful predictor of intravesical recurrence of bladder cancer.
Non-muscle-invasive bladder cancer (NMIBC) has a high incidence of recurrence. The recurrence rate in a large cohort of patients with NMIBC was 47.8%, based on a median follow-up of 3.9 years, with a median time to first recurrence of 2.7 years (1). Routine, long-term surveillance is therefore necessary to detect recurrence in patients with bladder cancer (BC).
Urine cytology is an important, non-invasive diagnostic procedure for detecting urothelial carcinoma (UC) of the bladder. It is also used to detect recurrence after transurethral resection of bladder tumor (TURBT) or intravesical instillation therapy with chemotherapeutic agents or bacillus Calmette–Guerin in patients with NMIBC. Positive urine cytology generally indicates high-grade UC, such as invasive carcinoma and carcinoma in situ, which have severe cytological atypia (2). In contrast, few patients with low-grade UC demonstrate positive cytology. Although several studies have reported the sensitivity and specificity of urine cytology as a diagnostic marker in BC as a whole (3, 4), its clinical significance in patients with low-grade UC has rarely been reported (5).
In the current study, we investigated the clinical significance of preoperative urine cytology in patients with low-grade UC.
Patients and Methods
We reviewed the clinical and pathological records of 201 consecutive patients who underwent TURBT for primary BC from January 2000 to September 2014, and who were histologically diagnosed with low-grade (Ta) UC at Kyushu University Hospital. Patients with prior /concurrent history of upper urinary tract cancer (n=25), no records of preoperative urine cytology (n=9), no records of tumor number or size (n=6), or no follow-up data after TURBT (n=6) were excluded. A total of 155 patients were therefore included in the final analysis. Histological diagnoses were reviewed based on both the World Health Organization (WHO) classification 2004 (6) and WHO classification 1973 (7). Diagnoses of urine cytology were made according to the Papanicolaou classification system (8).
The relationships between preoperative urine cytology and clinicopathological characteristics including histological grade, tumor size, and tumor number were analyzed. The relationships between urine cytology and clinical outcome in terms of recurrence-free (RFS) and progression-free (PFS) survival were also examined. Tumor recurrence was defined as the identification of a new tumor in the bladder, confirmed by histological examination of consequent TURBT. Tumor progression was defined as intravesical recurrence with confirmed histological muscle invasion or detectable distant metastases.
Clinical characteristics of participating patients.
Statistical analyses were performed with JMP Pro version 11 (SAS Institute, Tokyo, Japan). Actuarial RFS and PFS were calculated by Kaplan–Meier analysis, and univariate comparisons between groups were assessed by log-rank tests. Multivariate analysis was performed using a Cox proportional hazards model to identify the variables that predicted prognostic outcomes. Values of p<0.05 were considered to be statistically significant.
Results
The median age of the patients was 70 years [interquartile range (IQR)=62-75 years] and the median follow-up after TURBT was 30 (IQR=23-68) months. The median size (maximum diameter) of the largest tumor was 15 mm (IQR=10-20 mm). The diagnosis of preoperative urine cytology was class III or less in the majority of patients (130/155, 83.9%). All bladder tumors were histologically diagnosed as low grade according to the 2004 WHO classification, and 129 (83%) were G2, according to the 1973 WHO classification. All the patients underwent complete tumor resection, and 86 patients (55%) were treated with postoperative intravesical chemotherapy. Intravesical recurrence was observed in 36 patients (23%), and one patient (0.6%) experienced progression to muscle-invasive disease (Table I).
Regarding the relationships between preoperative urine cytology and clinicopathological characteristics, patients with class III or higher cytology had significantly higher-grade (G2) (p=0.01) and larger tumors (cut-off value 15 mm, p=0.0009; cut-off value 30 mm, p=0.002), and were significantly older (p=0.048). Similarly, patients with class IV/V cytology had significantly larger tumors (cut-off value 15 mm, p=0.0009; cut-off value 30 mm, p=0.003). There were no significant correlations between any other analyzed features, such as tumor number and sex, and preoperative urine cytology (Table II).
Relationships between recurrence-free survival and preoperative urine cytology. A: Patients with class III or higher cytology more frequently experienced recurrence than did patients with class I or II cytology (p=0.008). B: There was no significant difference in recurrence-free survival between patients with class IV or higher cytology and patients with class III or lower cytology (p=0.28). TURBT, Transurethral resection of bladder tumor.
Univariate analysis for RFS showed that patients with class III or higher preoperative urine cytology had a significantly shorter RFS compared with patients with class II or lower cytology (p=0.008) (Figure 1A). There was no significant difference in RFS between patients with class IV/V and those with class III or lower urine cytology (p= 0.28) (Figure 1B).
Multivariate analysis of tumor size (≥15 mm), tumor number, preoperative urine cytology (≥class III), histological grade (including G2 element) and postoperative intravesical chemotherapy using a Cox proportional hazards model for RFS identified only tumor size (≥15 mm) (p<0.0001) as an independent predictor of poor prognosis. Although preoperative cytology class III or higher tended to be associated with poor prognosis, the result was not significant (p=0.06) (Table III).
Relationships between preoperative urine cytology and clinicopathological features of bladder cancer.
Univariate and multivariate analyses for intravesical recurrence of bladder cancer.
Discussion
Urine cytology is a non-invasive procedure performed as part of the essential screening and follow-up examinations in patients with BC (1, 3-5). Cytological diagnosis depends mainly on cytological atypia, and patients with high-grade carcinomas, such as muscle-invasive UC or carcinoma in situ, thus frequently have positive cytology, while patients with low-grade UC rarely do. Cytological diagnosis for BC generally has a high specificity and low sensitivity, and a systematic review reported a specificity of 94% [95% confidence interval (CI)=90-96%] and sensitivity of 55% (95% CI=48-62%) (3). The sensitivity depends on the histological grade, which accounts for the difference in sensitivities between high-grade (≥70%) and low-grade (30-40%) UC (9-12).
These previous results suggest that urine cytology provides less valuable clinical information in patients with low-grade UC. However, although numerous reports have described the clinical characteristics of urine cytology in bladder UC overall, few have addressed its significance in patients with low-grade UC. In the current study, we therefore examined the relationships between preoperative urine cytology and clinicopathological features in 155 patients with primary low-grade UC, and showed that urine cytology of class III or higher was significantly correlated with higher grade (containing G2 element) and larger size (≥15 mm) in low-grade UCs. These results thus depend on both the cytological grade and number of carcinoma cells in the urine.
Regarding the relationship between urine cytology and prognosis, 36 patients (23%) experienced intravesical recurrence and one patient showed progression to muscle-invasive disease during the median 30-month follow-up period. Although univariate analysis identified a tumor size 15 mm or more (p<0.0001) and cytology class III or higher (p=0.008) as being significantly correlated with intravesical recurrence, multivariate analysis only identified a correlation with tumor size ≥15 mm [hazard ratio (HR)=5.8, 95% CI=2.4-17.3; p<0.0001). Meanwhile, preoperative cytology of class III or higher tended to be associated with frequent intravesical recurrence (HR=1.98, 95% CI=0.96-4.2; p=0.063). However, cytology of class IV or higher showed no significant correlation with intravesical recurrence. These results indicate that preoperative urine cytology of class III or higher might predict a higher risk of intravesical recurrence, even in patients with low-grade UCs. Only 25 (16%) patients in the current study demonstrated preoperative cytology of class IV or higher, which may have contributed to the apparent lack of any significant correlation with intravesical recurrence.
Jackson et al. reported the relationships between preoperative urine cytology, classified as positive, suspicious, atypical or negative, and clinicopathological characteristics and clinical outcomes in 87 patients with low-grade UCs (5). In the current study, we classified urine cytology according to the Papanicolaou classification (13), and considered that class I/II, class III, and class IV/V were equivalent to negative, atypical, and suspicious/positive, respectively, in the study by Jackson et al. Jackson et al. reported that patients with positive/suspicious cytology experienced significantly more frequent progression to high-grade UC compared with those with atypical/negative cytology (p=0.009), but found no correlation between cytology and intravesical recurrence (p=0.11). In the current study, we were unable to analyze the correlation between cytology and progression to high-grade UC because only two patients showed progression, while 36 patients experienced intravesical recurrence. However, patients with class III or higher cytology had a poorer prognosis in terms of intravesical recurrence according to the univariate analysis. This apparent discrepancy may be attributable to the different diagnostic classifications used and different cohorts studied. However, despite the limitations of being retrospective studies with relatively small sample sizes, both the current study and the one of Jackson et al. (5) highlight the possible clinical significance of urine cytology in patients with low-grade UC.
Acknowledgements
This study was supported in part by the National Cancer Center Research and Development Fund (H24-A-4) and by a Grant-in-Aid for Clinical Cancer Research (H22-Clinical Cancer-026, Project ID: 1010387) from the Ministry of Health, Labour and Welfare of Japan.
- Received November 15, 2015.
- Revision received December 9, 2015.
- Accepted December 14, 2015.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
