In the global context, bladder cancer ranks as the 10th most prevalent cancer, witnessing 573,278 new cases and 213,000 reported deaths in 2020. Across different regions worldwide, there are notable disparities in the incidence rates of bladder cancer. Southern and Western Europe, as well as North America, stand out for their notably high rates of bladder cancer. Greece holds the distinction of having the highest incidence of bladder cancer among males globally, while Hungary leads in terms of incidence among females. Specifically, Southern Europe reports the most substantial bladder cancer incidence rates globally, with approximately 26.6 cases per 100,000 males and 5.8 cases per 100,000 females diagnosed each year. In contrast, regions such as Middle Africa, South Central Asia, and Western Africa, primarily consisting of countries with lower-than-average Human Development Index scores, tend to exhibit the lowest prevalence of bladder cancer [1]. Developed countries exhibit a higher incidence rate of bladder cancer, primarily affecting men, with incidence rates four times higher than in women.

By 2023, it is estimated that the United States will experience around 62,420 new cases of bladder cancer in men (76%), ranking it as the fourth most prevalent cause of cancer among males. Over the last few decades, bladder cancer incidence has increased to the mid-2000s, followed by a decline of 1.8% per year from 2015 to 2019. However, this trend might vary among ethnicities or races [2]. In contrast to white men, both white women (hazard ratio [HR]: 1.20, 95% confidence interval [CI]: 1.17–1.23) and Black women (HR: 1.57, 95% CI: 1.49–1.66) exhibited an increased likelihood of bladder-cancer-related mortality, regardless of the stage, as indicated by the results [3].

Bladder cancer predominantly affects older individuals, with around 90% of diagnosed cases occurring in people over 55 years old. The average age for this cancer diagnosis is approximately 72 years for men and 75 years for women ^[4][5][4,5]. It also manifests considerable variations across different races. While the frequency of tumor incidence is twice as high among individuals of Caucasian descent compared to African Americans, the latter subgroup tends to experience a less favorable prognosis and a greater prevalence of advanced tumor stages upon presentation ^[6][7][6,7]. Pronounced disparities in mortality rates are observed among African Americans, older individuals, and female patients ^[8][9][10][8,9,10].

Despite a gradual decrease in incidence and prevalence, the medical costs associated with managing bladder cancer, including follow-up and complications, have significantly increased. In 2015, bladder cancer incurred direct and indirect medical costs of USD 7.93 billion in the U.S. This figure is anticipated to rise by 45% to reach USD 11.6 billion by 2030 [11]. Since follow-up and treatment for recurrences constitute 60% of the total medical costs, early detection of bladder cancer could potentially alleviate this economic burden [12].

While cystoscopy remains the established standard for bladder cancer detection, the approximate total cost per procedure, around USD 216.18 [13], coupled with its invasiveness and the potential for complications, significantly add to the overall cost burden. Voided urine cytology has long been used as a highly specific and non-invasive supplementary test compared to cystoscopy. However, it has two significant limitations: low sensitivity to detect low-grade tumors (ranging from only 4 to 31%) and dependence on the expertise of cytopathologists, leading to challenges in achieving consistent and high-quality readings [14].

These observations emphasize the urgency of incorporating new diagnostic tests in managing bladder cancer patients. The ideal characteristics of these new tests include being easy, better, faster, and cost-efficient for detecting bladder cancer, with a specific emphasis on monitoring low-grade papillary tumors. In addition, such non-invasive methods should rely on highly sensitive and specific bladder cancer markers to reduce the frequency of cystoscopies and improve the patient’s quality of life. Furthermore, enhancing the markers’ sensitivity in cases of high-grade disease is vital for the early identification of tumor recurrence and, consequently, for enhancing patient survival rates [15].

Bladder cancer is commonly identified as localized in the absence of metastatic disease. Then, it can be classified as non-muscle invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC). Approximately 70% of new bladder cancer cases are NMIBC, and this category is further categorized into low, intermediate, and high-risk groups after a transurethral resection or cystoscopy biopsy, according to the American Urologic Association’s risk classification ^[16][18].

The recurrence rate is high, with almost 60–80% of cases of NMIBC eventually recurring despite treatment ^[17][19]. Individuals diagnosed with low-risk and intermediate-risk NMIBC achieve 5-year recurrence-free survival rates of 43% and 33%, respectively. In contrast, among those with high-risk disease, as many as 21% will eventually progress to MIBC ^[18][19][20,21]. Based on histopathology and clinical presentations, two different types of NMIBC have been classified: the frequently recurring papillary tumor (Ta) and the more aggressive carcinoma in situ (CIS). While both types can progress into invasive tumors (T1–T4), the probability that low-grade Ta tumors progress to invasive disease is much less likely than high-grade Ta tumors and CIS ^[20][21][22,23]. In terms of histology, urothelial carcinoma makes up 75% of bladder cancer cases, while the remaining 25% is attributed to variant histology ^[22][24].

Numerous environmental factors have been linked to bladder cancer. Among these, cigarette smoking stands out as the most established factor, contributing to approximately 55% of cases in the United States ^[23][25]. Tobacco consumption significantly raises the risk of developing bladder cancer by a factor of two to three ^[24][26].

A comprehensive meta-analysis encompassing 89 observational studies revealed that current smokers experience a threefold increase in bladder cancer risk in comparison to individuals who have never smoked (summary odds ratio [SOR] 3.14, 95% confidence interval [CI] 2.53–3.75) and twofold increased risk compared to former smokers (SOR 1.83, 95% CI 1.52–2.14). Even after 20 years post-smoking cessation, former smokers still show a 50% higher risk compared to those who have never smoked ^[25][27].

In addition, when examining 15 case–control studies, it becomes evident that a higher risk of urinary bladder cancer is associated more strongly with prolonged smoking over an extended period with a lower daily cigarette intake, rather than smoking a greater number of cigarettes per day for a shorter duration when considering equal pack years ^[26][28].

In a meta-analysis comprising 17 studies, it was determined that active smokers exhibited a higher risk of mortality after radical cystectomy with a hazard ratio [HR] of 1.21 and a 95% confidence interval [CI] of 1.08–1.36, p = 0.001, a greater likelihood of cancer-specific mortality (HR 1.24, 95% CI 1.13–1.36, p < 0.001), and an elevated risk of bladder cancer recurrence (HR 1.24, 95% CI 1.12–1.38, p < 0.001) ^[27][29]. Luckily, in 2014, the Centers for Disease Control and Prevention (CDC) showed a report of the significant fall in smoking trends in the U.S. among adults from 42.4% in 1965 to 16.8% ^[28][30].

When considering occupation, the greatest risks of bladder cancer were associated with jobs involving exposure to aromatic amines (such as tobacco, dye, rubber industry workers, hairdressers, printers, and leather workers) and polycyclic aromatic hydrocarbons (including chimney sweeps, nurses, waitstaff, aluminum workers, seamen, and oil/petroleum industry workers) ^[29][31].

Occupational exposures to these diverse carcinogens including aromatic amines, toluene, perchloroethylene, polycyclic aromatic hydrocarbons (PAHs), and metalworking fluids are responsible for around 20% of cases ^[30][31][32][32,33,34]. A systematic review and meta-analysis involving 263 studies showed that individuals exposed to aromatic amines exhibited the highest incidence of bladder cancer. Conversely, occupations characterized by exposures to PAHs and heavy metals are associated with the highest risks of bladder-cancer-related mortality ^[33][35]. Noteworthy occupational sectors with the most significant bladder cancer susceptibility include those within the paint, dye, rubber, metal, and petroleum industries. Furthermore, emerging data indicate an elevated bladder cancer incidence among firefighters ^[29][31], attributed to their exposure to combustion byproducts such as PAHs and benzene ^[34][35][36,37]. Moreover, individuals with substantial occupational exposure to diesel exhaust fumes, such as bus and truck drivers, railroad workers, and heavy equipment engine mechanics, also demonstrate an increased risk of bladder cancer ^[36][38].

In a population-based study conducted by Rushton et al., it was determined that 7.1% of bladder cancer cases in men could be attributed to occupational factors, while no such attribution was observed in women ^[33][35]. Furthermore, a case–control study revealed statistically significant elevated risk in men employed as machine operators in the printing industry, while male farmers exhibited a reduced risk. Among women, after accounting for smoking duration, no notable associations between occupation and bladder cancer risk were identified (HR: 5.4; 96% CI, 1.6–17.7) ^[30][32].

A retrospective analysis, conducted across multiple institutions, involved a substantial population of over 2000 patients who underwent trans-urethral resection of the bladder. Among the participants, more than 81% received a confirmed diagnosis of bladder cancer through pathological evaluation. The study highlighted that cardiovascular disease acted as an independent protective factor against bladder cancer, but this effect was not observed in cases of high-risk tumors ^[37][39]. It is widely recognized that low-risk and high-risk cancers follow distinct pathways. In low-risk cases, altered cells typically progress through hyperplasia toward the development of low-grade tumors. In contrast, in high-risk cases, these cells become dysplastic, often involving the tp53 mutation, and follow the CIS pathway, which can eventually lead to invasive carcinoma ^[38][40]. This mechanism should also be considered to gain a deeper insight into why cardiovascular disease fails to exert its protective effect on high-risk tumor development ^[37][39].

Currently, no widely recognized genetic or hereditary basis has been established for bladder cancer. Nevertheless, emerging research suggests that genomic instability and mutations or alterations in genetic pathways may contribute to the development of bladder cancer. Some studies indicate that specific gene variations in GSTM-1 and NAT-2, which are involved in detoxifying carcinogens, could potentially increase the susceptibility of certain individuals to bladder cancer ^[39][41].

Factors like slow acetylation may not inherently result in bladder cancer but could increase susceptibility to carcinogens, such as those found in tobacco products. N-acetyl transferase enzymes (NAT1, NAT2) play a role in both activating and detoxifying these carcinogens. Notably, individuals with a slow NAT2 acetylator genotype were identified as a significant risk group for bladder cancer, particularly among smokers (HR: 1.31; 95% CI, 1.01–1.70) ^[40][42].

Genetically speaking, single-nucleotide polymorphisms (SNPs), within specific genes situated on chromosome 8q24, with a focus on the PSCA gene, have been associated with a notably higher risk of bladder cancer (OR 1.33). The PSCA gene features an androgen response element (ARE) in its promoter region, leading to the suggestion that this region may lose its responsiveness to androgen receptors (ARs). Consequently, it could develop an independent mechanism not reliant on androgens, which increases the potential for metastasis. To illustrate this, a reduction in the affinity of AR binding to the ARE within the PSCA gene due to such an SNP might initiate pathways independent of androgens, such as IGFBP2, which, in turn, would foster tumor growth and metastatic spread. It could be postulated that alterations in androgen levels in females might accelerate the activation of this mechanism, potentially contributing to the more aggressive tumor behavior noted in women with bladder cancer ^[41][43].

In an innovative approach, one study stands out as being one of the first investigations of its kind. It conducted a comprehensive prospective cohort spanning over two decades, involving more than 2000 newly diagnosed bladder cancer cases. It showed a connection between prolonged periods of sitting and the incidence of invasive bladder cancer. Specifically, individuals who engaged in 6 or more hours of daily sitting exhibited a 22% higher risk of developing invasive bladder cancer compared to those who spent less than 3 h seated each day. Notably, this correlation retained its statistical significance even after adjustments for critical risk factors such as smoking status, moderate-to-vigorous physical activity (MVPA), and body mass index (BMI) ^[42][44].

Numerous epidemiological investigations have explored the relationship between the consumption of red or processed meats and the incidence of bladder cancer. These studies have revealed a direct link between bladder cancer risk and the consumption of processed meats, which undergo processes such as salting, fermentation, smoking, or other treatments ^[43][44][45,46]. Specifically, a 20% increase in bladder cancer risk is associated with a daily intake of 50 g of processed meat (RR = 1.20, 95% CI: 1.06–1.37) ^[45][47]. A prospective study also identified a positive correlation between the consumption of processed red meat and bladder cancer risk, even after adjusting for potential confounding factors (HR = 1.47, 95% CI: 1.12–1.93) ^[46][48].

In terms of physiology, the normal urothelium in the bladder expresses both androgen receptors and estrogen receptors alpha and beta (ERa and ERb) ^[47][48][49,50]. Interestingly, while testosterone appears to promote the onset of bladder cancer, exposure to estrogen may initially offer protection against bladder cancer development, potentially contributing to the fact that women are nearly three times less likely to be diagnosed with bladder cancer than men. However, once bladder cancer is established, estrogens may play a role in promoting its progression ^[49][50][51,52].

Although the association between the expression of androgen receptors and the stage and grade of bladder cancer is a topic of debate, most studies indicate a decreased detection of androgen receptors in cases of high-grade and high-stage disease ^[51][53]. For instance, Miyamoto et al. ^[52][54] demonstrated a notably lower presence of androgen receptors in high-grade and muscle-invasive bladder cancer compared to low-grade bladder cancer (p = 0.023) and NMIBC (p = 0.018), respectively. In line with these findings, another research group reported that the expression of androgen receptors is lower in T2 tumors (21%) when compared to Ta (60%) and T1 (60%) tumors ^[53][55]. Additionally, a study examining the mRNA expression of androgen receptors in bladder cancer cell lines disclosed an inverse relationship between the transcript expression of androgen receptors and the severity, stage, and spread of bladder cancer ^[54][55][56,57].

As mentioned, the incidence of bladder cancer is clearly higher in men than in women. However, when evaluating the ratio of cancer-specific mortality (CSM) to the incidence of bladder cancer, it becomes evident that women face a greater risk of CSM in bladder cancer [1]. Furthermore, women tend to receive diagnoses of locally advanced disease more frequently and have a higher proportion of nonurothelial cell types at the time of diagnosis compared to men ^[56][58].

In cases where patients presented with hematuria and were later diagnosed with bladder cancer, women experienced a significantly longer period from their initial hematuria report to the bladder cancer diagnosis compared to men (85.4 vs. 73.6 days; p < 0.001). Additionally, women presenting with hematuria were more likely than men to be diagnosed with a urinary tract infection (OR 2.32) and less likely to undergo abdominal or pelvic imaging (OR 0.80) ^[57][59].

A research study ^[58][60] noted that there was no significant gender-based differences in clinical symptoms at the time of initial presentation, including hematuria and irritative lower urinary tract symptoms, among patients newly diagnosed with bladder cancer. However, a substantial gender discrepancy arose in healthcare-seeking behaviors: 78% of men, as opposed to 55% of women, consulted with a urologist (p < 0.05). Moreover, prior to their bladder cancer diagnosis, symptomatic treatment without further diagnostic evaluation was administered to 19% of men, whereas this proportion significantly increased to 47% for women (p < 0.05). Alarmingly, 16% of women received three or more courses of treatment for presumed urinary tract infections. Importantly, it was consequently found that patients presenting with hematuria and given a delayed diagnosis for bladder cancer faced a considerably elevated risk of cancer-specific mortality ^[59][61].