Do differences in clinical symptoms and referral patterns contribute to the gender gap in bladder cancer?

Authors


Correspondence: Stephan Madersbacher, Department of Urology and Andrology, Donauspital Langobardenstraße 122, A-1220 Vienna, Austria.

e-mail: stephan.madersbacher@wienkav.at

Abstract

What's known on the subject? and What does the study add?

  • Urothelial carcinoma of the bladder (UCB) is more prevalent in men than women; however, in women the tumour stage is generally more advanced at the time of the diagnosis and the prognosis is worse. Possible explanations include anatomical, genetic and socio-economic factors.
  • The study shows that clinical symptoms before the first-time diagnosis of UCB did not differ between the sexes, while primary care and referral patterns did. Women were more likely to receive symptomatic treatment or therapies for alleged UTIs without further investigation or referral to urological evaluation. The study highlights the fact that there may be a diagnostic delay in women which could contribute to the gender-dependent disparities in stage distribution and prognosis of UCB.

Objective

  • To evaluate gender-dependent disparities regarding clinical symptoms, referral patterns or treatments before diagnosis of urothelial carcinoma of the bladder (UCB).

Patients and Methods

  • A consecutive series of patients with newly diagnosed UCB completed a questionnaire at the time of admission for elective transurethral resection of a bladder tumour (TURBT).
  • The questionnaire surveyed the presence of haematuria, dysuria, urgency and bladder pain as well as the number of consultations and treatments before urological evaluation.
  • Tumour characteristics, clinical symptoms, treatments and referrals were compared between men and women in the patient series.

Results

  • In men (n = 130) the distribution of tumour stages was pTa 62.3%, pT1 23.1% and pT ≥ 2 12.3%. The respective percentages in women (n = 38) were pTa 57.9%, pT1 23.7% and pT ≥ 2 18.4% (P > 0.05).
  • The prevalence of clinical symptoms in men vs women was as follows: gross haematuria 65 vs 68%, dysuria 32 vs 44%, urgency 61 vs 47%, and nocturia 57 vs 66%, respectively (P > 0.05).
  • A total of 78% of men vs 55% of women directly consulted a urologist (P < 0.05).
  • Symptomatic treatment for voiding disorders/pain was given without further evaluation to 19% of men vs 47% of women 1 year before the diagnosis of UCB (P < 0.05).
  • A total of 3.8% of men vs 15.8% of women received three or more treatments for urinary tract infections (UTIs) within the same time period (P < 0.05).

Conclusions

  • In the present study there were no gender-related differences in clinical symptoms of UCB, but women were more likely to be treated for voiding complaints or alleged UTIs without further evaluation or referral to urology than men.
  • Gender-dependent disparities in referral patterns exist and might delay definitive diagnosis of UCB in women.
Abbreviations
UCB

urothelial carcinoma of the bladder

TURBT

transurethral resection of a bladder tumour

CIS

carcinoma in situ

Introduction

Urothelial carcinoma of the bladder (UCB) is a tumour entity particularly characterized by its gender-dependent disparities. A higher incidence of UCB in men than in women has long been observed and has been linked to several contributing factors such as increased exposure to carcinogens or the involvement of androgens in bladder carcinogenesis [1]; however, women present with more advanced tumour stages and face a less favourable prognosis [2, 3]. The complex relationship between gender, tumour stage and survival has recently been subject to thought-provoking research. Apparently, disparities in stage distribution do not fully account for the excess mortality in women as differences persist even after adjustment for tumour stage [4-7]. Nevertheless, tumour stage at presentation is a strong predictive factor for prognosis in UCB [8, 9]. Several authors have suggested that the more advanced tumour stages at the time of diagnosis in women might result from the incorrect attribution of early signs of UCB to more common conditions such as UTIs [10-12]. Indeed, a previous investigation showed unequal referral patterns for the urological evaluation of haematuria [13]. To further elucidate this important gender gap, we set up a prospective, questionnaire-based study at three different referral centres that included a consecutive series of patients, with newly diagnosed UCB. Our aim was to establish whether symptoms, referral patterns and treatment regimens before diagnosis differed between the sexes, potentially leading to a deferred diagnosis in women.

Patients and Methods

A consecutive series of patients with newly diagnosed UCB completed a detailed questionnaire at the time of admission for elective transurethral resection of a bladder tumour (TURBT) to one of three participating referral centres in Austria and Italy. In addition to TURBT, further evaluation included urinary cytology at the time of TURBT and evaluation of the upper urinary tract with CT including urography or i.v. urography in all patients.

The entire four-page questionnaire included questions on demographics, smoking habits and professional occupation. The nine specific questions are shown in Fig. 1.

Figure 1.

Questionnaire used in the study.

We inquired whether haematuria and symptoms of dysuria and/or bladder pain were present ≤12 months before the first UCB diagnosis and if symptoms of urgency and nocturia were present ≤4 weeks before the diagnosis. Further items concerned consultations and treatments before referral for urological evaluation. The patients were asked how often they had consulted their GP and/or gynaecologist and if they had received symptomatic treatment or treatment for a UTI before they had been referred to a urologist for further evaluation. In addition, we assessed how many urological consultations had been necessary before cystoscopy was performed and whether the bladder tumour was diagnosed at first cystoscopy. Possible answers were ‘never’, ‘once or twice’ and ‘three times or more often’. Information on tumour stage was obtained from the postoperative pathology report at the respective participating referral centre.

For statistical analyses IBM SPSS® Version 19 was used. Comparison between categorical variables was evaluated using the chi-squared test. All tests were two-sided and a P value <0.05 was considered to indicate statistical significance.

Results

Patients

A consecutive series of 200 patients, of whom 152 (76%) were men and 48 (24%) were women, completed the questionnaire at the time of first TURBT for newly diagnosed UCB. In 22 men (14.5%) and 10 women (20.8%) no UCB was found after definitive pathological evaluation of their resection specimen. These 32 patients were excluded from the study leaving 168 patients, of whom 130 (77.4%) were men and 38 (22.6%) were women, for further analysis (Table 1). The mean (range; sd) age of the men was 69.2 (34–91;10.6) years and of the women it was 66.9 (25–92; 13.1) years (P = 0.27; CI −1.8–6.4).

Table 1. Patient and tumour characteristics.
Patient characteristicMenWomenP
Initial no. of patients (n = 200)15248 
Patients with no evidence of bladder tumour (n = 32)2210 
Patients analysed (n = 168)13038 
Mean age, years69.266.90.27
Tumour characteristicMen (n = 130), %Women (n = 38), % 
pTa62.357.90.62
pT123.123.7
pT ≥ 212.318.4
CIS only2.30
Concomitant CIS13.810.50.63
Low grade54.657.90.72
High grade45.442.1

Distribution of Tumour Stages

In the men the distribution of tumour stages was pTa 62.3%, pT1 23.1% and pT ≥ 2 12.3%. Carcinoma in situ (CIS) only was diagnosed in three men (2.3%). The respective percentages in women were pTa 57.9%, pT1 23.7% and pT ≥ 2 18.4%, and there was no solitary CIS (P = 0.62). Concomitant CIS was present in 13.8% of men and 10.5% of women (P = 0.63). UCB was classified as low grade in 54.6% of men and in 57.9% of women, while high grade tumours were found in 45.4% of men and 42.1% of women (P = 0.72). The gender differences did not reach statistical significance in any of the above-mentioned categories.

Clinical Symptoms

Gross haematuria was reported by 65.1% of the men and 68.4% of the women ≤12 months before the first UCB diagnosis (P = 0.71). During the same period, 31.8% of men and 44.4% of women complained of dysuria and/or bladder pain (P = 0.16). A total of 60.6% of men and 47.4% of women noticed urgency (P = 0.15) ≤4 weeks before diagnosis and 56.9% of men and 65.8% of women reported experiencing nocturia (P = 0.33). None of these gender differences reached statistical significance Fig. 2.

Figure 2.

Clinical symptoms 1 to 12 months before diagnosis of UCB.

Consultations and Treatments

A urologist was directly consulted for medical advice by 78.3% of men and by 55.3% of women. By constrast, 14.7% of men and 26.3% of women consulted their GP and/or gynaecologist once or twice, and 7.0% of men and 18.4% of women did so three or more times before being referred to a urologist (P = 0.015). Symptomatic treatment without further evaluation for voiding complaints and/or lower abdominal and bladder pain was given to 16.2% of men and 41.7% of women once or twice, and to 2.9% of men and 5.6% of women three or more times, respectively (P = 0.04). Similarly, 14.6% of men and 26.3% of women received one or two treatments for UTI, and 3.8% of men vs 15.8% of women received three or more treatments ≤1 year before the definite diagnosis of UCB (P = 0.04) (Table 2). In 81.0% of men and 52.8% of women the GP and/or gynaecologist directly referred the patient for urological evaluation (P = 0.04). A cystoscopy was performed at the first consultation with a urologist in 64.7% of men and 58.8% of women (P = 0.54) and in 97.5% of men and 97.4% of women, the bladder tumour was diagnosed at the first cystoscopy (P = 0.97).

Table 2. Treatments for UTI and symptomatic treatments for voiding complaints and/or lower abdominal and bladder pain.
 Men, %Women, %P
Treatments for UTI   
None81.557.90.04
1 or 214.626.3
 ≥33.815.8
Symptomatic treatments   
 None81.052.80.04
1 or 216.241.7
≥32.95.6

Discussion

Tumour stage is a well-established predictive factor for progression in non-muscle-invasive UCB and for survival in carcinoma invading bladder muscle [8, 9, 14]. Several studies have shown that women present with more advanced tumour stages. In an analysis of the Surveillance, Epidemiology and End Results database, women were more likely to present with muscle-invasive disease than men (22% of males vs 25% of females in Caucasian and 30% of males vs 43% of females in African-American patients, P < 0.001) [2]. The same study showed a greater hazard ratio in bladder-cancer-specific mortality for women vs men ≤4 years after diagnosis when the majority of cancer deaths occur. Interestingly, these findings are not consistent throughout the published data. In an Austrian mono-centre series of 1269 patients, treated between 1969 and 1997, women had less invasive and less aggressive tumours at time of diagnosis [15]. By contrast, another survey of >20 000 patients from the Netherlands Cancer Registry reported a higher share of early stages of bladder cancer in men than in women (71 vs 63%, respectively, for pTa, CIS and pT1). This difference diminished with advanced tumour stages (7% in men vs. 9% in women for pT4, N+ and M+) [3]. In the present study, the distribution of tumour stages between both sexes showed a similar pattern with a lower percentage of non-muscle-invasive and a higher percentage of muscle-invasive tumours in women compared with men; however, the difference was not significant, most likely because of the limited sample size.

The unequal stage distribution of UCB has been linked to gender differences, such as different pelvic anatomy, vascular and lymphatic drainage, or involvement of androgens in carcinogenesis and progression [1, 11, 12]. Alternatively, one could hypothesize that the disparities seen in UCB represent a gender gap that relates to a delay in diagnosis because of differing clinical symptoms and evaluations before definitive diagnosis or variable referral patterns. This raises the question of whether women have less explicit warning signs of UCB or whether those signs do not raise red flags for the treating healthcare professional.

Gender-specific data on clinical presentation of UCB is scarce. To our knowledge, no detailed analysis of gender-specific differences in UCB symptoms has yet been undertaken. In the present study, there were no gender-related disparities in any of the afore-mentioned symptom categories, but referral patterns did differ substantially. It has been shown previously that gender inequalities in specialist evaluation of haematuria exist. The analysis of insurance records of 926 healthcare plan participants showed a 65% higher likelihood for men to be referred to specialized evaluation of primary or first recurrent episode of haematuria [13]. Further surveys based on questionnaires sent to primary healthcare providers showed a certain reluctance among them to refer patients with gross or significant microscopic haematuria to urology [16, 17]. In addition, a review of medical records from 343 patients with a diagnosis of bladder cancer showed a time-delay from primary consultation to first referral and, later on, to definite diagnosis of bladder cancer in women [18].

The present multicentre study was conducted in the setting of two healthcare systems (in Austria and Italy) in which patients have direct access to specialized medical care without having to consult a primary healthcare provider previously; however, only about half of the women compared with 78% of the men directly consulted a urologist. When GPs and/or gynaecologists were consulted, women had to do so more often than men before being referred to specialized care. Similarly, women were treated for UTI and given symptomatic treatment without further clinical evaluation more often than men before being referred to a urologist. Most notably, treatment for alleged UTI was given three or more times to 15% of women compared with only ∼4% of men, and symptomatic treatment for dysuria and/or bladder pain was given, without prior evaluation, to 19 and 47% of men and women, respectively. One might presume that, in some of these cases, possible symptoms of UCB might have been incorrectly attributed to the much more common bladder infections in women.

Once with the urologist, diagnosis was usually made without further delay since the majority of cystoscopies were performed at first consultation and most tumours were diagnosed at first cystoscopy.

The present study has several limitations. Firstly, the data are derived from non-validated questionnaires and might be subject to recall bias; however, this was unavoidable because, before the diagnosis of UCB, the patients included in the series had access to a wide range of different healthcare providers such as different hospitals, outpatient clinics or independent GPs, gynaecologists and urologists. Patient records of these independent sources are neither fully accessible nor controllable and they are not incorporated in any centralized database. Relying on any outside records might therefore create an incomplete dataset even more prone to bias. Furthermore, we regarded it safe to assume that any recall bias would be equally distributed between the genders. Secondly, we investigated referral patterns and frequencies of consultations, so we cannot provide the exact period of time between the first onset of a given symptom and the definite diagnosis of UCB. Nevertheless, it can be assumed that differing referral patterns would result in a diagnostic delay. Thirdly, as there were no long-term follow-up data on the patient cohort we cannot correlate a potentially worse prognosis to those patients who had a referral delay. In spite of the limited sample size we consider our data representative as patients were recruited from three centres in different regions of two different countries.

Clearly, differences in stage distribution at first diagnosis of UCB do not directly translate into worse survival rates for women. A series of other gender- related factors, such as socio-demographic characteristics and inequalities in healthcare, response to and acceptance of UCB therapy, hormonal and anatomical differences have to be taken into account; however, the differing referral patterns we observed might delay a timely diagnosis of UCB in women and potentially lead to a more advanced tumour stage and thus a worse prognosis. In our opinion, these findings underline the importance of highlighting for primary healthcare providers the issue of female bladder cancer and of further emphasizing the role of the urologist as the specialist for bladder complaints in both men and women.

Conflict of Interest

None declared.

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