Hematuria is the most common presenting symptom of BC. Patients may describe gross hematuria, or microscopic hematuria may be diagnosed by means of a dipstick test or microscopic examination of urine samples. Occasionally, patients also report frequent micturition, nocturia, and dysuria. Anuria and pain due to urinary obstruction are not characteristic of BC but rather indicate lesions of the upper urinary tract [1] [2].

About 15% of BC cases remain asymptomatic until advanced stages of the disease. Then, constitutional symptoms like anemia, fatigue and weight loss may occur [1].

The diagnosis of BC is based on urine analyses, imaging studies and the histological examination of tissue samples:

• The cytological examination of voided urine or bladder wash specimens has high specificity but low sensitivity for the diagnosis of BC. Thus, if abnormal urothelial, squamous, or glandular cells are observed, the patient is suspicious of BC. On the other hand, the absence of tumor cells doesn't allow for reliable conclusions. Urothelial carcinoma cells often have a very high nuclear-to-cytoplasmic ratio, dark and coarse chromatin, and irregular nuclear borders. Prominent nucleoli may be seen in single large tumor cells [3].
• Cystoscopy is the method of choice to obtain images of the inner surface of the urinary bladder and tissue samples for further analyses. Cystoscopy allows to directly visualize the inner lining of the bladder. It is important to note that it is absolutely necessary to evaluate the entire urothelium because multifocal BC is very common. Biopsy specimens should be collected from conspicuous lesions. Occasionally, cystoscopy may not reveal any anomalies of the urothelium, and it has repeatedly been discussed whether random biopsies should be realized in these cases. No consensus has been reached to this end, but most experts recommend random biopsies only in case of positive urine cytology and for surveillance purposes [4] [5].
• Beyond the visualization of the urinary bladder, the upper urinary tract should be assessed for malignant lesions by means of ureteroscopy, retrograde or intravenous pyelography. The identification of lymph node and distant metastases requires further imaging studies. Computed tomography is most frequently employed in BC patients to display the thoracic, abdominal, and pelvic regions [2].

BC grading and staging systems have been recommended by the World Health Organization [6] [7]. They shall be summarized here for urothelial carcinoma, which affects the vast majority of BC patients. The "WHO Classification of Tumors of the Urinary System and Male Genital Organs" describes invasive and non-invasive types of urothelial carcinoma, whereby the non-invasive variants are papillary urothelial neoplasm of low malignant potential, low or high-grade papillary urothelial carcinoma and flat carcinoma in situ. The former are low-grade neoplasms. The latter are high-grade malignancies that are likely to spread to deeper structures, thereby turning into advanced-stage, invasive urothelial carcinomas. The proposed staging system classifies a neoplasm that is confined to the urothelium as carcinoma in situ (high-grade BC) or Ta tumor (low-grade BC). A urothelial carcinoma that has invaded the lamina propria is classified as a T1 tumor and neoplasms that have reached the muscular layer as T2 lesions. The invasion of perivesical tissues warrants the classification as a T3 tumor, whereas T4 lesions have invaded adjacent organs like the prostate or pelvic wall [6]. Malignancies invading the lamina propia or lower layers of the bladder wall are uniformly considered invasive BC; the term "muscle-invasive BC" refers to T2, T3, and T4 tumors only.

At the time of diagnosis, BC is often confined to the urothelium or lamina propia. This applies to up to 80% of BC patients, and they are generally recommended an endoscopic resection and intravesical therapy with bacillus Calmette-Guérin [8] [9]. Nevertheless, recurrence rates among these patients exceed 50%, and a significant proportion of patients presents with muscle-invasive malignancies within five years after the initial therapy [8]. Radical cystectomy with bilateral pelvic lymphadenectomy should be considered in these cases; radiotherapy with neoadjuvant or adjuvant chemotherapy constitutes an alternative. As opposed to radical cystectomy, radiotherapy is a bladder-preserving approach that may be associated with better quality of life. Studies regarding the survival of BC patients after either therapy yielded contradictory results: Some authors state radical cystectomy to be superior to radiotherapy, but others found that treatment modalities did not affect the outcome [10] [11].

Current research focuses on immunotherapy and molecular targeted therapy as additional and personalized approaches to BC treatment. While bacillus Calmette-Guérin immunotherapy has been carried out for decades, atezolizumab and nivolumab have been approved only recently for the treatment of recurrent BC. They are checkpoint inhibitors that may be administered to patients with neoplasms that express PDL1 to evade immune recognition. Similar agents are currently on trial [12]. Molecular targeted therapy aims at counteracting the pathophysiological mechanisms underlying BC development. For instance, tyrosine kinase inhibitors may be used to antagonize mutated, constitutively active tyrosine kinases like FGFR3 [13].

BC generally follows a chronic course. BC patients require lifelong surveillance because malignancies may recur in the urinary bladder or upper urinary tract many years after the initial diagnosis [8]. Non-invasive papillary urothelial carcinomas are associated with particularly high rates of recurrence, but they are unlikely to progress to muscle-invasive BC, to form lymph node or distant metastases [7]. By contrast, advanced-stage BC is highly likely to metastasize. About half of all patients presenting with muscle-invasive BC die within five years despite aggressive treatment [8]. About 90% of patients diagnosed with non-invasive tumors remain alive after five years. The tumor-specific survival times of these patients range from about a decade in case of high-grade carcinoma to more than three decades in case of papillary urothelial neoplasms of low malignant potential [14].

Although men are more frequently diagnosed with BC than women, females tend to present with advanced-stage disease and have worse survival rates [15]. It has been speculated that this may partially be because hematuria in women is generally attributed to urinary tract infections, which may considerably delay the diagnosis of BC [1]. Furthermore, gender differences regarding the exposure to carcinogens, as well as genetic, anatomical, and hormonal factors may contribute to this situation [8].

Cigarette smoking, occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons, water arsenic, schistosomiasis, radiation, the administration of phenacetin-containing analgesics, cyclophosphamide, and chlornaphazine, and genetic susceptibility have been confirmed as risk factors for BC. However, it has not yet been possible to associate unique combinations of conditions to low and high-grade tumors, non-invasive and invasive forms of BC. What's more, a myriad of lifestyle, dietary, occupational, and medical factors is still discussed regarding their possible role in urinary bladder carcinogenesis. Suggestive evidence has been presented for tobacco inhalation, low fluid intake, low consumption of fresh fruits and vegetables, exposure to disinfection byproducts, diabetes, urinary tract infections, spinal injury and indwelling catheters, the administration of non-steroidal anti-inflammatory drugs or pioglitazone as triggers of BC development [15]. Accordingly, BC has been described as a "malignant disease with relatively well-defined carcinogenic agents and factors", a condition that provides excellent opportunities for disease prevention [16].

BC is usually diagnosed in the elderly, the patients' mean age at the time of diagnosis being 67 years. It rarely affects individuals aged <40 years. Males are affected about three times as often as females. Indeed, BC is the fourth most common type of cancer in men but only the tenth most common one in women [15]. The incidence of BC is highest in industrialized nations and areas where Schistosoma haematobium is endemic [17].

Urothelial carcinoma accounts for >90% of BC cases, and about 5% of BC patients are diagnosed with squamous cell carcinoma [9]. The latter is typically associated with schistosomiasis [17]. Adenocarcinoma accounts for about 2% of BC cases [9].

Urothelial carcinoma originates from the urothelium, the transitional epithelium lining the bladder. It is usually assumed that this type of BC develops from areas of premalignant urothelial cells that give rise to high-grade papillary urothelial carcinomas or flat carcinomas in situ. Both types of non-invasive urothelial carcinoma are high-grade lesions, but they differ largely with regard to their progressively altering molecular landscape. Therefore, it has been hypothesized that they are intermediate stages in two major, but mutually exclusive pathophysiological pathways [17].

Although a broad spectrum of mutations in tumor suppressor genes and oncogenes has been identified in urothelial carcinoma cells, evidence regarding their relevance for cancerogenesis is lacking for most of them. The most common mutations affect genes FGFR3, which encodes for receptor tyrosine kinase fibroblast growth factor receptor 3, and TP53, which encodes the well-known tumor suppressor P53. It thus seems likely that pathological alterations of the FGFR3-Ras-Raf and p53-RB1 pathways play essential roles in the pathogenesis of urothelial cancer [7].

According to the risk factors mentioned above, people may be advised to make lifestyle decisions in agreement with cancer prevention: It has been estimated that about two-thirds of European BC cases in males are related to smoking, and about one-third of cases in females. Cessation of smoking is likely to reduce the acquired risk of cancer development. Furthermore, occupational safety measures may be taken to reduce the exposure of workers to cancerogenic compounds [16]. Additional preventive measures can be deduced directly from the information given in the Etiology section.

BC is a general term that may refer to numerous types of neoplasms that vary with regards to morphology, differentiation and tumor grade, and genomic landscape. The "WHO Classification of Tumors of the Urinary System and Male Genital Organs" describes more than a dozen variants of urothelial carcinoma, which is the most common type of BC. This same classification also mentions squamous cell carcinoma and adenocarcinoma, as well as rare entities like neuroendocrine carcinoma and sarcoma of the urinary bladder [7].

Malignant neoplasm of the urinary bladder is another term for bladder cancer (BC). BC is one of the most common forms of cancer, especially in men. It is typically diagnosed in the elderly and the incidence of BC is particularly high among smokers. Indeed, it has been estimated that about two-thirds of BC cases in males are related to smoking, and about one-third of cases in females. Besides smoking, occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons has been identified as a trigger of BC. In African countries, BC is often related to infections with the parasite Schistosoma haematobium. In sum, knowledge about the causes of BC provides excellent opportunities to prevent this disease, which usually follows a chronic course, lowers life quality and may lead to death.

The most common presenting symptom is hematuria. Affected individuals may actually see blood in their urine, but dipstick tests or microscopic examinations may be required in other cases. If hematuria can't be explained by other conditions, like urinary tract infections, patients are referred for cystoscopy. During cystoscopy, the inner lining of the urinary bladder is visualized and tissue samples may be obtained for further analyses. The diagnosis of BC is made if tumor cells are identified in biopsy specimens. The histological examination of such samples also allows for an assessment of tumor grade and stage, i.e., of its aggressiveness and spread within the urinary bladder or beyond. Treatment modalities comprise bladder-conserving endoscopic tumor resection, radiotherapy, and removal of the entire urinary bladder. Unless radical radiotherapy or cystectomy is performed, recurrence is likely. To avoid the burden imposed by relapses, medication, and surgery, everyone is highly recommended to make lifestyle decisions in agreement with cancer prevention. The decision not to smoke - and to a lesser extent, the decision to cease smoking - is the easiest and most effective way to reduce the individual risk of BC.

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