Muscle-invasive and Metastatic Bladder Cancer


3.1. Epidemiology

Bladder cancer is the 7th most commonly diagnosed cancer in males, whilst it drops to 10th position when both genders are considered [7]. The worldwide age-standardised incidence rate (per 100,000 person/years) is 9.5 for men and 2.4 for women [7]. In the European Union, the age-standardised incidence rate is 20 for men and 4.6 for women [7]. In Europe, the highest age-standardised incidence rate has been reported in Belgium (31 in men and 6.2 in women) and the lowest in Finland (18.1 in men and 4.3 in women) [7].

Worldwide, the BC age-standardised mortality rate (per 100,000 person/years) was 3.3 for men vs. 0.86 for women in 2012 [7]. Bladder cancer incidence and mortality rates vary across countries due to differences in risk factors, detection and diagnostic practices, and availability of treatments. The variations are, however, also partly caused by the different methodologies used in the studies and the quality of data collection [8,9]. The incidence and mortality of BC has decreased in some registries, possibly reflecting the decreased impact of causative agents [10,11].

Approximately 75% of patients with BC present with disease confined to the mucosa (stage Ta, carcinoma in situ [CIS]) or submucosa (stage T1). In younger patients (< 40 years) this percentage is even higher [12]. Patients with TaT1 and CIS have a high prevalence due to long-term survival in many cases and lower risk of cancer-specific mortality (CSM) compared to T2-4 tumours [7,8].

3.2. Aetiology

3.2.1. Tobacco smoking

Tobacco smoking is the most well-established risk factor for BC, causing 50–65% of male cases and 20–30% of female cases [13,14]. A causal relationship has been established between exposure to tobacco and cancer in studies in which chance, bias and confounding can be discounted with reasonable confidence [15].

The incidence of BC is directly related to the duration of smoking and the number of cigarettes smoked per day [16]. A meta-analysis looked at 216 observational studies on cigarette smoking and cancer published between 1961 and 2003, and the pooled risk estimates for BC demonstrated a significant association for both current and former smokers [17]. Recently, an increase in risk estimates for current smokers relative to never smokers has been described suggesting this could be due to changes in cigarette composition [13]. Starting to smoke at a younger age increased the risk of death from BC [18]. An immediate decrease in the risk of BC was observed in those who stopped smoking. The reduction was about 40% within one to four years of quitting smoking and 60% after 25 years of cessation [16]. A meta-analysis of nine studies, not distinguishing between MIBC and NMIBC, suggested that smokers who decide to quit during the diagnostic work-up or upon bladder cancer diagnosis do not have a better prognosis than those who continue to smoke [19]. Nethertheless, encouraging people to stop smoking would result in the incidence of BC decreasing equally in men and women [13].

3.2.2. Occupational exposure to chemicals

Occupational exposure is the second-most important risk factor for BC. Work-related cases accounted for 20–25% of all BC cases in several series and it is likely to occur in occupations in which dyes (with the exception of hair dyes [20]), rubbers, textiles, paints, leathers, and chemicals are used [21,22]. The risk of BC due to occupational exposure to carcinogenic aromatic amines is significantly greater after ten years or more of exposure; the mean latency period usually exceeds 30 years [23,24]. Population-based studies established the occupational attribution for BC in men to be 7.1%, while no such attribution was discernible for women [8,25].

3.2.3. Radiotherapy

Increased rates of secondary bladder malignancies have been reported after external-beam radiotherapy (EBRT) for gynaecological malignancies, with relative risks (RR) of 2–4 [22]. In a population-based cohort study, the standardised incidence ratios for BC developing after radical prostatectomy (RP), EBRT, brachytherapy, and EBRT-brachytherapy were 0.99, 1.42, 1.10, and 1.39, respectively, in comparison with the general U.S. population [26].

It has recently been proposed that patients who have received radiotherapy (RT) for prostate cancer with modern modalities such as intensity-modulated RT (IMRT) may have lower rates of in-field bladder- and rectal secondary malignancies [27]. Nevertheless, since longer follow-up data are not yet available, and as BC requires a long period to develop, patients treated with radiation and with a long life expectancy are at a higher risk of developing BC [27].

3.2.4. Dietary factors

Several dietary factors have been related to BC; however, the links remain controversial. The European Prospective Investigation into Cancer and Nutrition (EPIC) study is an on-going multicentre cohort study designed to examine the association between diet, lifestyle, environmental factors and cancer. They found no links between BC and fluid intake, red meat, vegetable and fruit consumption and only recently an inverse association between dietary intake of flavonoids and lignans and the risk of aggressive BC tumours has been described [28].

3.2.5. Metabolic disorders

In a large prospective study pooling six cohorts from Norway, Sweden, and Austria (The Metabolic syndrome and Cancer project, Me-Can 2.0), metabolic aberrations, especially elevated blood pressure and triglycerides, were associated with increased risks of BC among men, whereas high body mass index (BMI) was associated with decreased BC risk. The associations between BMI, blood pressure and BC risk significantly differed between men and women [29].

The association of diabetes mellitus (DM) with the risk of BC has been evaluated in numerous meta-analyses with inconsistent results. When analysing specific subpopulations, DM was associated with BC or CSM risk especially in men [30]. Thiazolidinediones (pioglitazone and rosiglitazone) are oral hypoglycaemic drugs used for the management of type 2 DM. Their use and the association with BC is still a matter of debate. In a recent meta-analysis of observational studies the summary results indicated that pioglitazone use was significantly associated with an increased risk of BC which appears to be linked to higher dose and longer duration of treatment [31]. The U.S. Food and Drug Administration (FDA) recommend that healthcare professionals should not prescribe pioglitazone in patients with active BC [32]. Several countries in Europe have removed this agent from the market or included warnings for prescription. Moreover, the benefits of glycaemic control vs. unknown risks for cancer recurrence with pioglitazone should be considered in patients with a prior history of BC.

3.2.6. Bladder schistosomiasis and chronic urinary tract infection

Bladder schistosomiasis (bilharzia) is the second most common parasitic infection after malaria, with about 600 million people exposed to infection in Africa, Asia, South America, and the Caribbean [33]. There is a well- established relationship between schistosomiasis and urothelial carcinoma (UC) of the bladder, which can progress to squamous cell carcinoma (SCC), however, better control of the disease is decreasing the incidence of SCC of the bladder in endemic zones such as Egypt [34,35].

Similarly, invasive SCC has been linked to the presence of chronic urinary tract infection (UTI) distinct from schistosomiasis. A direct association between BC and UTIs has been observed in several case- control studies, which have reported a two-fold increased risk of BC in patients with recurrent UTIs in some series [36]. However, a recent meta-analysis found no statistical association when pooling data from the most recent and highest quality studies which highlights the need for better quality data to be able to draw conclusions [37].

Similarly, urinary calculi and chronic irritation or inflammation of the urothelium have been described as possible risk factors for BC. A meta-analysis of case-control and cohort studies suggests a positive association between history of urinary calculi and BC [38].

3.2.7. Gender

Although men are more likely to develop BC than women, women present with more advanced disease and have worse survival rates. A meta-analysis including nearly 28,000 patients shows that female gender was associated with a worse survival outcome (hazard ratio [HR]: 1.20, 95% CI: 1.09–1.32) compared to male gender after radical cystectomy (RC) [39]. This finding had already been presented in a descriptive nationwide analysis based on 27,773 Austrian patients. After their analysis the authors found that cancer-specific survival (CSS) was identical for pT1-tumours in both sexes, while women had a worse CSS in both age cohorts (< 70 years and ≥ 70 years) with higher tumour stages [40]. However, treatment patterns are unlikely to explain the differences in overall survival (OS) [41]. In a population-based study from the Ontario Cancer Registry analysing all patients with BC treated with cystectomy or radical RT between 1994 and 2008, no differences in OS, mortality and outcomes were found between males and females following radical therapy [42]. The gender-specific difference in survival for patients with BC was also analysed in the Norwegian population. Survival was inferior for female patients but only within the first two years after diagnosis. This discrepancy was partly attributed to a more severe T-stage in female patients at initial diagnoses [43].

A population-based study from the MarketScan Databases suggests that a possible reason for worse survival in the female population may be that women experienced longer delays in diagnosis than men, as the differential diagnosis in women includes diseases that are more prevalent than BC [44]. Furthermore, differences in the gender prevalence of BC may be due to other factors besides tobacco and chemical exposure. In a large prospective cohort study, post-menopausal status was associated with an increase in BC risk, even after adjustment for smoking status. This finding suggests that the differences in oestrogen and androgen levels between men and women may be responsible for some of the difference in the gender prevalence of BC [45-47]. Moreover, a recent population study assessing impact of hormones on BC suggests that younger age at menopause (≤ 45 years) is associated with an increased risk of BC [48].

3.2.8. Genetic factors

There is growing evidence that genetic susceptibility factors and family association may influence the incidence of BC. A recent population-based study of cancer risk in relatives and spouses of UC patients showed an increased risk for first- and second-degree relatives, and suggests genetic or environmental roots independent of smoking-related behaviour [49]. Shared environmental exposure was recognised as a potentially confounding factor [50]. Recent studies detected genetic susceptibility with independent loci, which are associated with BC risk [51].

Genome-wide association studies (GWAS) of BC identified several susceptibility loci associated with BC risk

3.2.9. Summary of evidence and guidelines for epidemiology and risk factors

Summary of evidence


Worldwide, bladder cancer is the 10th most commonly diagnosed cancer.


Several risk factors associated with BC diagnosis have been identified.


Active and passive tobacco smoking continues to be the main risk factor, while exposure-related incidence is decreasing.


The increased risk of developing BC in patients undergoing EBRT, brachytherapy, or a combination of EBRT and brachytherapy, must be considered during patient follow-up. As BC requires time to develop, patients treated with radiation at a young age are at the greatest risk and should be followed-up closely.



Strength rating

Counsel patients to stop active and avoid passive smoking.


Inform workers in potentially hazardous workplaces of the potential carcinogenic effects of a number of recognised substances, including duration of exposure and latency periods. Protective measures are recommended.


Do not prescribe pioglitazone to patients with active bladder cancer or a history of bladder cancer.


3.3. Pathology

3.3.1. Handling of transurethral resection and cystectomy specimens

During transurethral resection (TUR), a specimen from the tumour and normal looking bladder wall should be taken, if possible. Specimens should be taken from the superficial and deep areas of the tumour and sent to the pathology laboratory separately, in case the outcome will impact on treatment decisions. If random biopsies of the flat mucosa are taken, each biopsy specimen of the flat mucosa should be submitted separately [54]. The sampling sites must be recorded by the urologist; the pathologist report should include location of tumour tissue in the cystectomy specimen. Anatomical tumour location is relevant for staging and prognosis [55,56].

In RC, bladder fixation must be carried out as soon as possible. The pathologist must open the specimen from the urethra to the bladder dome and fix the specimen. In a female cystectomy specimen, the length of the urethral segment removed en bloc with the specimen should be checked, preferably by the urological surgeon [57].

Specimen handling should follow the general rules as published by a collaborative group of pathologists and urologists [58,59]. It must be stressed that it may be very difficult to confirm the presence of a neoplastic lesion using gross examination of the cystectomy specimen after TUR or chemotherapy, so the entire retracted or ulcerated area should be inked and included before fixation.

It is compulsory to study the urethra, the ureters, the prostate in men and the radial margins [60]. In urethra-sparing cystectomy; the level of urethral dissection, completeness of the prostate, specifically at the apex (in men), and the inclusion of the entire bladder neck and amount of adjacent urethra, uterus and vaginal vault (in women) have to be documented by the pathologist.

All lymph node (LN) specimens should be provided in their totality, in clearly labelled containers to allow for pTNM staging. In case of doubt or adipose differentiation of the LNs, the entire specimen is to be included. Lymph nodes should be counted and measured on slides; capsular extension and percentage of LN invasion should be reported as well as vascular embols [61,62]. In case of metastatic spread in the perivesical fat without real LN structures (capsule, subcapsular sinus), this localisation should nevertheless be considered as N+. Potentially positive soft tissue margins should be inked by the pathologist for evaluation [63]. In rare cases, fresh frozen sections may be helpful to determine treatment strategy [64].

3.3.2. Pathology of muscle-invasive bladder cancer

All MIBC cases are high-grade UCs. For this reason, no prognostic information can be provided by grading MIBC [65]. Identification of morphological subtypes is important for prognostic reasons and treatment decisions [66-68].

The data presented in these guidelines are based on the 2004/2016 World Health Organization (WHO) classifications [69,70]. An update was presented in 2022 [71].

Currently the following subtypes of UC are used [71,72]:

  1. urothelial carcinoma (more than 90% of cases);
  2. urothelial carcinomas with partial squamous and/or glandular or divergent differentiation;
  3. micropapillary UC;
  4. nested/microcystic;
  5. large nested;
  6. microtubular UC;
  7. plasmacytoid, signet ring;
  8. lymphoepithelioma-like;
  9. giant cell, diffuse, undifferentiated;
  10. sarcomatoid UC;
  11. some UCs with other rare differentiations;
  12. urothelial carcinomas with partial NE (neuroendocrine differentiation, % to be given);
  13. pure neuroendocrine carcinoma (including small and large cell neuroendocrine carcinomas [Chapter NE carcinomas in the genitourinary tract]).

In the new WHO 2022 all subtypes are considered HG [71]. The percentage of subtype in the specimen must be reported since it has been shown to be of prognostic value [73]. The majority of subtypes are MIBC, with no more than 15–30% being non-muscle invasive [73-80] (LE: 3).

3.3.3. Guidelines for the assessment of tumour specimens


Strength rating

Record the depth of invasion for the entire specimen (categories pT2a and pT2b, pT3a and pT3b or pT4a and pT4b).


Record margins with special attention paid to the radial margin, prostate, ureter, urethra, peritoneal fat, uterus and vaginal vault.

Record the total number of lymph nodes (LNs), the number of positive LNs and extranodal spread.

Record lymphovascular invasion.

Record the presence of carcinoma in situ.

Record the sampling sites as well as information on tumour size when providing specimens to the pathologist.

3.3.4. EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer [81,82]*

Consensus statement

Bladder UC with small cell neuroendocrine variant should be treated with neoadjuvant chemotherapy followed by consolidating local therapy.

Muscle-invasive pure SCC of the bladder should be treated with primary radical cystectomy and lymphadenectomy.

Muscle-invasive pure adenocarcinoma of the bladder should be treated with primary radical cystectomy and lymphadenectomy.

Muscle-invasive small cell neuroendocrine variant of bladder UC should not receive preventive brain irradiation to avoid brain recurrence.

Differentiating between urachal and non-urachal subtypes of adenocarcinoma is essential when making treatment decisions.

T1 high-grade bladder urothelial cancer with micropapillary histology (established after complete TURBT and/or re-TURBT) should be treated with immediate radical cystectomy and lymphadenectomy.

*Only statements which met the a priori consensus threshold across all three stakeholder groups are listed(defined as ≥ 70% agreement and ≤ 15% disagreement, or vice versa).