Learn more about Bladder Cancer

Overview and epidemiology

Bladder cancer is a common urologic cancer characterized by the highest recurrence rate of all cancers.

Nine out of every ten patients diagnosed with bladder cancer are 55 years old (mean age at diagnosis: 70 years).

The overall lifetime risk for presenting with bladder cancer is 2.4%. Both in Europe and the USA the annual number

of deaths attributed to bladder cancer is 4.4 per 100,000 persons. Bladder cancer develops in both men and women.

In men bladder cancer is the fourth most common cancer. Older men ( above 65 years old) are 3 to 4 times more likely to develop

bladder cancer than their female counterparts.


At diagnosis, approximately 70% of the bladder cancer patients have tumors which are either non-muscle-invasive

or carcinomas in situ. The rest (approximately 30%) of incident bladder cancer cases have tumors, which are muscle-invasive.

This includes patients with tumors which have invaded nearby organs and structures of the pelvis, and also patients diagnosed with

distant metastases (approximately 4%), primarily to the lungs, liver, and bone.


Histological types of bladder cancer

Five known histological types of bladder cancer exist, arising as tumorous growths in the inner tissue lining of the urinary bladder

wall. The most frequent type of bladder cancer, found in excess of 90% of all newly diagnosed patients, is Transitional Cell Carcinoma

(TCC). TCC arises from abnormal growths of the innermost bladder lining, known as the urothelium, or transitional epithelium.

TCC is identified as either non-muscle-invasive bladder cancer if tumorous growth is confined to the transitional epithelium, or as

muscle-invasive bladder cancer if the tumor has infiltrated the bladder's muscle or deeper tissue layers, such as the fatty connective

tissue. Due to perpetration into the deeper tissue layers, invasive bladder cancer is more likely to penetrate nearby structures and

organs, as well as to metastasize to distant organs, such as liver, lungs, and bone. As a result, muscle-invasive bladder cancer is more

difficult to treat. TCC presents as either papillary or flat carcinomas. Papillary carcinomas are well-differentiated nodular projections

of the transitional epithelium into the hollow cavity of the urinary bladder. In contrast, flat carcinomas develop within the bladder

lining. When confined to the transitional epithelium, flat carcinomas are identified as carcinoma in situ (CIS). If timely treatment

is neglected, though, both papillary and flat carcinomas (particularly CIS) can develop into muscle-invasive bladder cancer.

Squamous Cell Carcinoma (SCC) accounts for 5% of bladder cancer cases. The majority of SCCs are invasive cancers. SCCs are most

often found in patients with chronic parasitic bladder infections, such as Schistosomiasis. Other types of bladder cancer are even

more rare. Adenocarcinomas account for 1% of cases, and Small Cell Carcinomas, arising from neuroendocrine cells, account for 0.5%

of cases. Sarcomas of the bladder have been reported but are extremely rare. Finally, other rare bladder cancer types include

secondary malignancies, mesenchymal tumors, lymphomas, and lymphoepithelial variants.


Etiology and prevention

The exact etiology of bladder cancer is multifactorial and still under investigation. However, several risk factors for bladder cancer

have been identified. Four fifths of bladder cancer cases are attributed to environmental exposures, including exposures to cigarette

smoking, industrial chemicals, dietary supplements, and contaminated drinking water. Avoidance and or modification of these risk

factors may prevent onset and/or progression of bladder cancer. The remaining one fifth of cases is attributed to patient clinical and

genetic factors.

The most prominent environmental risk factor for bladder cancer is cigarette smoking. Smoking history is documented in

approximately 50% of bladder cancer patients. Disease risk is correlated with both duration and intensity of smoking history, with no

differential risk between genders. A second environmental risk for bladder cancer is occupational and/or other exposures to industrial

chemicals (ie aromatic amines and aniline dies) used in the paint, textiles, rubber, and leather industries. Additional suspected

occupational hazards which have been associated with increased disease risk are occupational exposures to hair dyes (ie hair-

dressers) and diesel fumes (ie occupational drivers). Consumption of dietary supplements containing aristolochic acid have also

been associated with an increased risk of bladder cancer. Finally, consumption of arsenic in drinking water, such as from

contaminated well water sources, is also associated with increased cancer risk.


Age and gender are the most prominent patient factors associated with bladder cancer risk. Bladder cancer risk increases with

advancing age, as nine out of 10 patients are >55 years at diagnosis (mean age: 70 years). In particular, males aged above 65 years

are 3 to 4 times more likely to develop bladder cancer than their female counterparts. In addition, chronic urinary tract infections -

e.g. from parasitic infections such as schistosomiasis, or long-term indwelling urethral catheters - increase bladder cancer risk. Other

patient clinical risk factors include a personal history of bladder birth defects,prior urothelial cancer, and/or prior radiation therapy or

chemotherapy (ie cyclophosphamide use). A family history of bladder cancer also increases individual's risk of developing the disease.

While investigations of genetic variants causing tumor progression are underway, accumulating evidence has indicated that mutations

in both tumor suppressor genes (ie RB1 and TP53) and oncogenes (ie FGFR and RAS) are implicated in bladder cancer development.



Staging of disease

Staging of disease is used for clinical decision-making of optimal treatment. Staging is also used to predict patient's prognosis for

disease progression. The Tumor Node Metastasis (TNM) classification is applied for disease staging. The TNM system is based on

tumor size and infiltration into deeper bladder tissue layers (Tumor), dissemination to lymph nodes (Nodes), and metastasis to distant

organs (Metastasis). TNM Stages range from T0 through T4. TNM stages Ta through T1 are non-muscle-invasive tumors, while stages

T2 through T4 refer to muscle-invasive tumors.

According to the TNM system, Ta stage refers to non-muscle-invasive papillary carcinomas, while Tis growths are non-muscle-

invasive flat superficial carcinomas (carcinoma in situ, CIS). T1 tumors are non-muscle-invasive subepithelial tumors which have

penetrated the underlying lamina propria, but not the muscle layer. In particular, superficial or non-muscle-invasive bladder cancers

are those which have penetrated, albeit not completely, the lamina propria, but not the bladder muscularis propria. T2 tumors are

invasive tumors which have infiltrated the muscularis propria. More advanced disease stages include T3 tumors, which entail

perivesical invasion, and T4 tumors involving invasion into neighboring pelvic structures and organs, or metastasis to distant

organs, primarily including lungs, liver, and bone.


Disease prognosis

Disease prognosis depends primarily on bladder cancer type and stage, tumor grade, and other concomitant patient health conditions.

The 5-year survival rate diminishes markedly with advancing stage of disease. In particular, while T1 tumors are associated with a

relative 5-year survival rate of 88%, this rate is limited to 46% and 15% in T3 and T4 tumors, respectively.


Treatment strategies

Optimal treatment for bladder cancer depends upon tumor type, stage, grade, number of foci, and infiltration into deeper bladder

tissue layers, as well as presence of distant metastasis and other concomitant health conditions.


For early stage non-invasive bladder cancer, TURBT is the treatment strategy of choice. TURBT entails the removal of non-invasive

lesions with a resectoscope during cystoscopy. Despite treatment, risk factors for recurrence in other parts of the bladder and/or

urothelium of the urogenital tract include tumor size, type, and grade, as well as number of tumor foci and presence of CIS.

For invasive and/or disseminated bladder cancer, radical cystectomy with extended lymph node dissection is the treatment of choice,

depending on tumor invasion to nearby structures and organs. Radical cystectomy entails the surgical formation of diversions for

urinary voidance through either ileal or colonic conduits, catheterizable pouches or neobladders.

Adjuvant intravesical therapies include immunotherapy and chemotherapy. In early stage bladder cancer, intravesical

immunotherapy with Bacille Calmette Guerin is often administered as adjuvant treatment following TURBT. Adjuvant intravesical

chemotherapy, primarily with mitomycin C, epirubicin or doxorubicin, may also be used in early stage disease. Advanced bladder

cancer requires systematic (intravenous) administration of chemotherapeutic agents.

Treatment options for recurrent bladder cancer include surgery (with or without chemotherapy and biologic therapy) or combination

chemotherapy. Palliative treatment options include radiation therapy.


Recurrence and surveillance

Bladder cancer has the highest recurrence rate of any malignancy. The European Organization for Research and Treatment of

Cancer (EORTC)scoring system is used to predict the short-term (1-year) and long-term (5-year) risks of disease recurrence and

progression in non-muscle invasive bladder cancer patients. The EORTC scoring system is based on 6 clinical and pathological factors,

including tumor size, number of tumor foci, tumor stage and grade, prior tumor recurrence, and presence of CIS.




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BioMedBC is a Marie Sklodowska Curie Actions (MSCA) Individual Fellowship programme (H2020-MSCA-IF-2016)
funded by the European Union under the Horizon2020 Framework Programme (Grant Agreement:752755) and
coordinated by Mosaiques diagnostics