Рак мочевого пузыря: причины, симптомы и лечение

Urinary system cancer that begins in the urinary bladder

Risk factors for bladder cancer include smoking, family history, prior radiation therapy, frequent bladder infections, and exposure to certain chemicals. Staging of the cancer is determined by transurethral resection and medical imaging. Treatment depends on the stage of the cancer. Bladder cancer, as of 2018, affected about 1.6 million people globally with 549,000 new cases and 200,000 deaths. Age of onset is most often between 65 and 84 years of age. Males are more often affected than females. Blood in the urine may also be caused by other conditions, such as bladder or ureteric stones, infection, kidney disease, kidney cancers or vascular malformations, though these conditions (except kidney cancers) would typically be painful. Other possible symptoms include pain during urination, frequent urination, or feeling the need to urinate without being able to do so. These signs and symptoms are not specific to bladder cancer, and may also be caused by non cancerous conditions, including prostate infections, overactive bladder or cystitis. Some rare forms of bladder cancer like urachal adenocarcinoma produce mucin, which is then excreted in the urine causing it to be thick. People with advanced disease may have pelvic or bony pain, lower extremity swelling, or flank pain. Rarely, a palpable mass can be detected on physical examination.

Tobacco smoking is the main known contributor to urinary bladder cancer; in most populations, smoking is associated with over half of bladder cancer cases in men and one third of cases among women, however these proportions have reduced over recent years since there are fewer smokers in Europe and North America. There is an almost linear relationship between smoking duration (in years), pack years and bladder cancer risk. A risk plateau at smoking about 15 cigarettes a day can be observed (meaning that those who smoke 15 cigarettes a day are approximately at the same risk as those smoking 30 cigarettes a day). Smoking in any form (cigar, cigarette, pipe, Egyptian waterpipe and smokeless tobacco) increases the risk for bladder cancer. Quitting smoking reduces the risk. Risk of bladder cancer decreases by 30% within 1–4 years and continues to decrease by 60% at 25 years after smoking cessation. However, former smokers will most likely always be at a higher risk of bladder cancer compared to people who have never smoked. Opium consumption increases the risk of bladder cancer threefold, while concurrent use of opium and tobacco increases the risk of bladder cancer fivefold when compared to the general population.

Thirty percent of bladder tumors probably result from occupational exposure in the workplace to carcinogens. Occupational or circumstantial exposure to the following substances has been implicated as a cause of bladder cancer; benzidine (dyes manufacturing), 4 aminobiphenyl (rubber industry), 2 naphtylamine (azo dyes manufacturing, foundry fumes, rubber industry, cigarette smoke and cancer research), phenacetin (analgesic), arsenic and chlorinated aliphatic hydrocarbons in drinking water, auramine (dye manufacturing), magenta (dye manufacturing), ortho toluidine (dye manufacturing), epoxy and polyurethane resin hardening agents (plastics industry), chlornaphazine, coal tar pitch. Occupations at risk are bus drivers, rubber workers, painters, motor mechanics, leather (including shoe) workers, blacksmiths, machine setters, and mechanics. Hairdressers are thought to be at risk as well because of their frequent exposure to permanent hair dyes.

Infection with Schistosoma haematobium (bilharzia or schistosomiasis) may cause bladder cancer, particularly of the squamous cell type. Schistosoma eggs induces a chronic inflammatory state in the bladder wall resulting in tissue fibrosis. Higher levels of N nitroso compounds has been detected in urine samples of people with schistosomiasis. N Nitroso compounds have been implicated in the pathogenesis of schistosomiasis related bladder cancer. They cause alkylation DNA damage, specially Guanine to Adenine transition mutations in the HRAS and p53 tumor suppressor gene. Mutations of p53 are detected in 73% of the tumors, BCL 2 mutations accounting for 32% and the combination of the two accounting for 13%. Other causes of squamous cell carcinoma of the bladder include chronic catheterizations in people with a spinal cord injury and history of treatment with cyclophosphamide.

The American Institute for Cancer Research have stated that there is strong evidence that drinking water containing arsenic increases the risk of bladder cancer. High consumption of animal fat and dietary cholesterol increases bladder cancer risk in men. Ingestion of aristolochic acid present in many Chinese herbal medications has been shown to cause urothelial carcinoma and kidney failure. Aristolochic acid activates peroxidase in the urothelium and causes transversion mutation in the TP53 tumor suppressor gene.

People who undergo external beam radiotherapy (EBRT) for prostate cancer have a higher risk of developing invasive bladder cancer. In addition to these major risk factors there are also numerous other modifiable factors that are less strongly (i. e. 10–20% risk increase) associated with bladder cancer, for example, obesity. Although these could be considered as minor effects, risk reduction in the general population could still be achieved by reducing the prevalence of a number of smaller risk factor together.

Mutations in FGFR3, TP53, PIK3CA, KDM6A, ARID1A, KMT2D, HRAS, TERT, KRAS, CREBBP, RB1 and TSC1 genes may be associated with some cases of bladder cancer. Deletions of parts or whole of chromosome 9 is common in bladder cancer. Low grade cancer are known to harbor mutations in RAS pathway and the fibroblast growth factor receptor 3 (FGFR3) gene, both of which play a role in the MAPK/ERK pathway. p53 and RB gene mutations are implicated in high grade muscle invasive tumors. Eighty nine percent of muscle invasive cancers have mutations in chromatin remodeling and histone modifying genes. Deletion of both copies of the GSTM1 gene has a modest increase in risk of bladder cancer. GSTM1 gene product glutathione S transferase M1 (GSTM1) participates in the detoxification process of carcinogens such as polycyclic aromatic hydrocarbons found in cigarette smoke. Similarly, mutations in NAT2 (N acetyltransferase) is associated with increased risk for bladder cancer. N acetyltransferase helps in detoxification of carcinogens like aromatic amines (also present in cigarette smoke). Various single nucleotide polymorphisms in PSCA gene present on chromosome 8 have shown to increase the risk for bladder cancer. PSCA gene promoter region has an androgen response region. Loss of reactivity of this region to androgens is hypothesized as a cause of more aggressive tumors in women (unlike in men who have higher amount of androgen). Basal subtype are subdivided into basal and claudin low type group and are aggressive and show metastasis at presentation, however they respond to platinum based chemotherapy. Luminal subtype can be subdivided into p53 like and luminal. p53 like tumors of luminal subtype although not as aggressive as basal type, show resistance to chemotherapy

Currently, the best diagnosis of the state of the bladder is by way of cystoscopy, which is a procedure in which a flexible or rigid tube (called a cystoscope) bearing a camera and various instruments is inserted into the bladder through the urethra. The flexible procedure allows for a visual inspection of the bladder, for minor remedial work to be undertaken and for samples of suspicious lesions to be taken for a biopsy. A rigid cystoscope is used under general anesthesia in the operating room and can support remedial work and biopsies as well as more extensive tumor removal. Unlike papillary lesion, which grow into the bladder cavity and are readily visible, carcinoma in situ lesion are flat and obscure. Detection of carcinoma in situ lesions requires multiple biopsies from different areas of interior bladder wall. Photodynamic detection (blue light cystoscopy) can aid in the detection of carcinoma in situ. In photodynamic detection, a dye is instilled into the bladder with the help of a catheter. Cancer cells take up this dye and are visible under blue light, providing visual clues on areas to be biopsied or resected. However, visual detection in any form listed above, is not sufficient for establishing pathological classification, cell type or the stage of the present tumor. A so called cold cup biopsy during an ordinary cystoscopy (rigid or flexible) will not be sufficient for pathological staging either. Hence, a visual detection needs to be followed by transurethral surgery. The procedure is called transurethral resection of bladder tumor (TURBT). Further, a rectal and vaginal bimanual examination should be carried out before and after the TURBT to assess whether there is a palpable mass or if the tumour is fixed ("tethered") to the pelvic wall. The pathological classification and staging information obtained by the TURBT procedure, is of fundamental importance for making the appropriate choice of ensuing treatment and/or follow up routines. If invasive or high grade (includes carcinoma in situ) cancer is detected on TURBT, an MRI and/or CT scan of the abdomen and pelvis or urogram and CT chest should be conducted for disease staging and to look for cancer spread (metastasis). Increase in alkaline phosphatase levels without evidence of liver disease should be evaluated for bone metastasis by a bone scan. Although 18F fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT has been explored as a viable method for staging, there is no consensus to support its role in routine clinical evaluations. There are newer non invasive urine bound markers available as aids in the diagnosis of bladder cancer, including human complement factor H related protein, high molecular weight carcinoembryonic antigen, and nuclear matrix protein 22 (NMP22). In United States the FDA has approved NMP22, NMP22 BladderChek, and UroVysion tests for detection and surveillance of bladder cancer and ImmunoCyt, BTA TRAK, and BTA STAT tests have been approved for surveillance only. BTA STAT and BladderChek can be performed in the clinic and others are done in the laboratory. Other non invasive urine based tests include the CertNDx Bladder Cancer Assay, which detects FGFR3 mutation and Urine Bladder Cancer test (UBC), which is a sandwich ELISA for Cytokeratin 8/18 fragment. Likewise, NMP22 is a sandwich ELISA and NMP22 BladderChek is a dipstick immunoassay, both of them detect nuclear mitotic apparatus protein (NuMA) tumor marker (a type of nuclear matrix protein). UroVysion is a fluorescence in situ hybridization which detects aneuploidy in chromosomes 3, 7, 17 and loss of the 9p21 locus. ImmunoCyt is an Immunofluorescence test which detects glycosylated CEA and MUCIN like antigens (M344, LDQ10, 19A11).

As of 2019, there is limited high level evidence to suggest that eating vegetable and fruits decreases the risk of bladder cancer. Higher consumption of monounsaturated fat and plant based oils decrease bladder cancer risk in women.

As of 2019 there is insufficient evidence to determine if screening for bladder cancer in people without symptoms is effective or not.

Non muscle invasive bladder cancer (those not entering the muscle layer of the bladder) can be "shaved off" using an electrocautery device attached to a cystoscope, which in that case is called a resectoscope. The procedure is called transurethral resection of bladder tumor (TURBT) and serves primarily for pathological staging. In case of non muscle invasive bladder cancer the TURBT is in itself the treatment, but in case of muscle invasive cancer, the procedure is insufficient for final treatment. It is important to assess the quality of the resection: if there is evidence of incomplete resection, or if there is no muscle in the specimen (without which muscle invasiveness cannot be determined), then a second TURBT is strongly recommended. Moreover, nearly half of the people with high grade noninvasive disease have residual tumor after primary TURBT; in such cases a second TURBT is important for avoiding under staging. At this point classifying people into risk groups is recommended. Treatment and surveillance for different risk groups is indicated in the table below. Another method for reducing recurrence of tumors is medication after TURBT surgery. The two most common medicines used for this purpose are Bacillus Calmette–Guérin (BCG) and mitomycin. For people who have already had a TURBT procedure, BCG may lead to similar risk of death and may reduce the risk of tumor recurrence. Medications which can be used for this purpose are mitomycin C (MMC), epirubicin, pirarubicin and gemcitabine. Instillation of post operative chemotherapy should be conducted within first few hours after TURBT. As time progress residual tumor cells are known to adhere firmly and are covered by extracellular matrix which decrease the efficacy of the instillation. These technologies use different mechanisms to facilitate the absorption and action of a chemotherapy drug instilled directly into the bladder. Another technology – electromotive drug administration (EMDA) – uses an electric current to enhance drug absorption after surgical removal of the tumor. Another technology, thermotherapy, uses radio frequency energy to directly heat the bladder wall, which together with chemotherapy (chemohyperthermia) shows a synergistic effect, enhancing each other's capacity to kill tumor cells.

Immunotherapy by Bacillus Calmette–Guérin (BCG) delivery into the bladder is also used to treat and prevent the recurrence of NMIBC. BCG is a vaccine against tuberculosis that is prepared from attenuated (weakened) live bovine tuberculosis bacillus, Mycobacterium bovis, that has lost its virulence in humans. BCG immunotherapy is effective in up to 2/3 of the cases at this stage, and in randomized trials has been shown to be superior to standard chemotherapy. The exact mechanism by which BCG prevents recurrence is unknown. However, it has been shown that the bacteria are taken up by the cancer cells. The infection of these cells in the bladder may trigger a localized immune reaction which clears residual cancer cells. BCG is delivered as induction and a maintenance course. The induction course consists of 6 week course of intravesical and percutaneous BCG. This is followed by a maintenance course. There is no consensus regarding the maintenance schedule, however the most commonly followed is the Southwestern Oncology Group (SWOG) schedule. The SWOG maintenance schedule consists of intravesical and percutaneous BCG every week for 3 weeks given at 3, 6, 12, 18, 24, 30 and 36 months. Side effects of BCG therapy include cystitis, prostatitis, epididymo orchitis, balanitis, ureteral obstruction, bladder contraction, mycobacterial osteomyelitis, reactive arthritis, mycobacterial pneumonia, granulomatous hepatitis, granulomatous nephritis, interstitial nephritis, infectious vasculitis and disseminated infection. Local infection (i. e. prostatitis, epididymo orchitis, balanitis) because of BCG should be treated with triple tubercular therapy, with one of the drug being fluoroquinolone for 3 to 6 months. In people with systemic infections, BCG therapy should be stopped and anti tubercular multidrug treatment for at least 6 months should be started. Medications that can be used for this treatment are INH, rifampicin, ethambutol, fluoroquinolones, clarithromycin, aminoglycosides, and doxycycline. BCG strains are not sensitive to pyrazinamide therefore, it should not be a part of anti tubercular treatment. Nogapendekin alfa inbakicept (Anktiva), used in combination with Bacillus Calmette Guérin was approved for medical use in the United States in April 2024.

People with non muscle invasive tumors have a favorable outcome (5 year survival is 95% vs. 69% of muscle invasive bladder cancer). However, 70% of them will have a recurrence after initial treatment with 30% of them presenting with muscle invasive disease. Recurrence and progression to a higher disease stage have a less favorable outcome. Survival after radical cystectomy and pelvic lymph node dissection is dependent on the pathological stage. If the disease has not spread to the lymph node and is limited to the bladder (T1 or T2, N0) the 5 year survival is 78%. If it has spread locally around the region of the bladder with no lymph node involved (T3, N0) then the 5 year survival drops to 47%. In disease with lymph node spread (N+, irrespective of T stage) the 5 year survival is 31%. Locally advanced and metastatic disease drastically decreases survival, with a median survival of 3–6 months without chemotherapy. Cisplatin based chemotherapy has increased the median survival to 15 months. However, the 5 year survival is still 15%. There are several prognostic factors which determine cancer specific survival after radical cystectomy. Factor with detrimental effect of cancer specific survival are old age, higher tumor grade and pathological stage, lymph node metastasis, presence of lymphovascular invasion and positive soft tissue margin. Lymph node density (positive lymph nodes/total lymph nodes observed in the specimen from surgery) is a predictor of survival in lymph node positive disease. Higher the density lower is the survival.

After radical cystectomy, urinary and sexual function remain inferior to the general population. People who have a neobladder have better emotional function and body image compared with ones with cutaneous diversion (who need to wear a bag to collect urine over their abdomen). Social factors such as family, relationships, health and finances contribute significantly for determining good quality of life in people who have been diagnosed with bladder cancer. A high percentage of people with bladder cancer have anxiety and depression. People who are young, single and have advanced clinical disease have a high risk for getting diagnosed with a psychiatric illness post treatment. People with psychiatric illness post treatment seem to have worse cancer specific and overall survival.

In 2015, 131,000 news cases were diagnosed in the European Union with 40,000 deaths. It is the 5th most common cancer and 9th most common cause of cancer deaths The 5 year relative survival for bladder cancers diagnosed between 2000 and 2007 is 69%. Geographic variation is seen in survival rates with 5 year survival rates of 75% in Northern to 65% in Eastern Europe.

Bladder cancer is the ninth most common cancer in the UK accounting for 2.7% of all the new cancers cases. In 2018, there was 12,200 new cases and 6100 people died from it.

In the United States in 2019 80,470 cases and 17,670 deaths are expected making it the sixth most common type of cancer in the region. Around 62,000 men and 19,000 women are diagnosed with bladder cancer in 2019. Between 2012 and 2016 annual rate of new bladder cancer cases decreased by one percent per year.