Signs and symptoms
Diagnosis
Those suspected of having bladder cancer undergo several tests to assess the presence and extent of any tumors. TheClassification
Bladder tumors are classified by their appearance under the microscope, and by their cell type of origin. Over 90% of bladder tumors arise from the cells that form the bladder's inner lining, called urothelial cells or transitional cells; the tumor is then classified as urothelial cancer or transitional cell cancer. Around 5% of cases are squamous cell cancer (from a rarer cell in the bladder lining), which are less rare in countries where schistosomiasis occurs. Up to 2% of cases are adenocarcinoma (from mucus-producing gland cells). The remaining cases are sarcomas (from the bladder muscle) or small-cell cancer (from neuroendocrine cells), both of which are relatively rare. The pathologist also grades the tumor sample based on how distinct the cancerous cells look from healthy cells. Bladder cancer is divided into either low-grade (more similar to healthy cells) or high-grade (less similar).Staging
Treatment
Non-muscle-invasive bladder cancer
NMIBC is primarily treated by surgically removing all tumors by TURBT in the same procedure used to collect biopsy tissue for diagnosis. For those with a relatively low risk of tumors recurring, a single bladder injection of chemotherapy ( mitomycin C, epirubicin, or gemcitabine) reduces the risk of tumors regrowing by about 40%. Those with higher risk are instead treated with bladder injections of the BCG vaccine (a live bacterial vaccine, traditionally used for tuberculosis), administered weekly for six weeks. This nearly halves the rate of tumor recurrence. Recurrence risk is further reduced by a series of "maintenance" BCG injections, given regularly for at least a year. Tumors that do not respond to BCG may be treated with the alternative immune stimulants nadofaragene firadenovec (sold as "Adstiladrin", a gene therapy that makes bladder cells produce an immunostimulant protein), nogapendekin alfa inbakicept ("Anktiva", a combination of immunostimulant proteins), or pembrolizumab ("Keytruda", an immune checkpoint inhibitor).Metastatic disease
Stage IV bladder cancer that has reached the pelvic or abdominal wall (T4b), spread to distant lymph nodes (M1a) or other parts of the body (M1b) is difficult to completely remove surgically, the initial treatment usually being chemotherapy. The 2022 standard of care for metastatic bladder cancer is combination treatment with the chemotherapy drugs cisplatin and gemcitabine. The average person on this combination survives around a year, though 15% experience remission, with survival over five years. Around half of those with metastatic bladder cancer are in too poor health to receive cisplatin. They instead receive the related drug carboplatin along with gemcitabine; the average person on this regimen survives around 9 months. Those whose disease responds to chemotherapy benefit from switching to immune checkpoint inhibitors pembrolizumab or atezolizumab ("Tecentriq") for long-term maintenance therapy. Immune checkpoint inhibitors are also commonly given to those whose tumors do not respond to chemotherapy, as well as those in too poor health to receive chemotherapy. Alternate treatment options might include: * the immunotherapy drug pembrolizumab (Keytruda) combined with the antibody-drug conjugate (ADC) enfortumab vedotin (Padcev). This combination has also been recommended as a first-line therapy in place of chemotherapy. * the immunotherapy drug nivolumab (Opdivo) in conjunction with chemotherapy * chemotherapy, followed by the immunotherapy drug avelumab (Bavencio) Those whose tumors continue to grow after platinum chemotherapy and immune checkpoint inhibitors can receive the ADC enfortumab vedotin ("Padcev", targets tumor cells with the protein nectin-4). Those with genetic alterations that activate the proteins FGFR2 or FGFR3 (around 20% of those with metastatic bladder cancer) can also benefit from the FGFR inhibitor erdafitinib ("Balversa"). Bladder cancer that continues growing can be treated with second-line chemotherapies. Vinflunine is used in Europe, while paclitaxel, docetaxel, and pemetrexed are used in the United States; only a minority of those treated improve on these therapies. If medicines are no longer controlling the cancer, other treatments may still be helpful, e.g., palliative care that focuses on preventing or relieving problems the cancer may cause. Because metastatic bladder cancers are rarely cured by current treatment methods, many experts suggest considering clinical trials evaluating alternative treatments.Treatment adverse effects
Radical cystectomy has both immediate and lifelong side effects. It is common for those recovering from surgery to experience gastrointestinal problems (29% of those who underwent radical cystectomy), infections (25%), and other issues with the surgical wound (15%). Around 25% of those who undergo the surgery end up readmitted to the hospital within 30 days; up to 2% die within 30 days of the surgery. Rerouting the ureters, urinary diversions, can cause permanent metabolic issues. The piece of ileum used to reroute urine flow can absorb more ions from the urine than the original bladder would, resulting in metabolic acidosis (blood becoming too acidic), which can be treated with sodium bicarbonate. Shortening the small intestine can result in reduced vitamin B12 absorption, which can be treated with oral vitamin B12 supplementation. Issues with the new urine system can cause urinary retention, which can damage the ureters and kidneys and increase one's risk of urinary tract infection. Chemotherapy common side effects include; hair loss, mouth sores, loss of appetite, diarrhea, nausea and vomiting, premature menopause, infertility, and damage to the blood-forming cells within bone marrow. Most acute side effects are temporary, dissipating when treatment ceases, but some can be long-lasting or permanent. Long-term chemotherapy side effects include changes in the menstrual cycle, neuropathy, and nephrotoxicity. Checkpoint inhibitor (immunotherapy) side effects commonly include injection site pain, soreness, itchiness or rash. Additional flu-like symptoms may occur like fever, weakness, dizziness, nausea or vomiting, headache, fatigue, or blood pressure changes. More serious side effects might include heart palpitations, diarrhea, infection and organ inflammation. Some people might have allergic reactions with wheezing or breathing problems. Autoimmune reactions are possible because checkpoint inhibitors function by altering or removing immune system safeguards which can cause serious or even life-threatening problems. Antibody-drug conjugate side effects frequently include diarrhea and liver problems. Other side effects might include issues with blood clotting and wound healing, high blood pressure, fatigue, mouth sores, nail changes, loss of hair color, skin rash, or dry skin. Very rarely, a hole might form through the wall of the esophagus, stomach, small intestine, large bowel, rectum, or gallbladder. Radiotherapy acute side effects involve the gastrointestinal system, e.g., diarrhea and constipation; the urinary tract; and may cause cervicitis. Common late effects include: premature ovarian failure; telangiectasias, and subsequent hemorrhage; and progressive myelopathy. Pelvic radiotherapy late effects (with occurrence rates) include osteonecrosis (8-20%), vaginal stenosis (>2.5%) and chronic pelvic radiation disease (1-10%), e.g., lumbosacral plexopathy. Radiation also induces secondary malignancies such as leukemia, lymphoma, bone and soft-tissue sarcoma with occurrence rates between 0.2-1.0% per year for each. See also: Radiation therapy#Side effects.Causes
Bladder cancer is caused by changes to the DNA of bladder cells that result in those cells growing uncontrollably. These changes can be random, or can be induced by exposure to toxic substances such as those from consuming tobacco. Genetic damage accumulates over many years, eventually disrupting the normal functioning of bladder cells and causing them to grow uncontrollably into a lump of cells called a tumor. Cancer cells accumulate further DNA changes as they multiply, which can allow the tumor to evade the immune system, resist regular cell death pathways, and eventually spread to distant body sites. The new tumors that form in various organs damage those organs, eventually causing the death of the affected person.Smoking
Tobacco smoking is the main contributor to bladder cancer risk; around half of bladder cancer cases are estimated to be caused by smoking. Tobacco smoke contains carcinogenic molecules that enter the blood and are filtered by the kidneys into the urine. There they can cause damage to the DNA of bladder cells, eventually leading to cancer. Bladder cancer risk rises both with number of cigarettes smoked per day, and with duration of smoking habit. Those who smoke also tend to have an increased risk of treatment failure, metastasis, and death. The risk of developing bladder cancer decreases in those who quit smoking, falling by 30% after five years of smoking abstention. However, the risk will remain higher than those who have never smoked before. Because development of bladder cancer takes many years, it is not yet known if use of electronic cigarettes carries the same risk as smoking tobacco; however, those who use electronic cigarettes have higher levels of some urinary carcinogens than those who do not.Occupational exposure
Up to 10% of bladder cancer cases are caused by workplace exposure to toxic chemicals. Exposure to certain aromatic amines, namely benzidine, beta-naphthylamine, and ortho-toluidine used in the metalworking and dye industries, can increase the risk of bladder cancer in metalworkers, dye producers, painters, printers, hairdressers, and textiles workers. The International Agency for Research on Cancer further classifies rubber processing, aluminum production, and firefighting as occupations that increase one's risk of developing bladder cancer. Exposure to arsenic – either through workplace exposure or through drinking water in places where arsenic naturally contaminates groundwater – is also commonly linked to bladder cancer risk.Medical conditions
Chronic bladder infections can increase one's risk of developing bladder cancer. Most prominent is schistosomiasis, in which the eggs of the flatworm '' Schistosoma haematobium'' can become lodged in the bladder wall, causing chronic bladder inflammation and repeated bladder infections. In places withGenetics
Bladder cancer does not typically run in families. Only 4% of those diagnosed with bladder cancer have a parent or sibling with the disease, potentially inheriting a gene syndrome associated with bladder cancer, for example: * Mutations of the RB1 gene, while associated with 95% of Retinoblastoma cases, are also linked with bladder cancer. * Cowden disease is caused by mutations in the PTEN gene; see Cowden syndrome#Genetics. People with this syndrome have increased risk of developing several cancers, including bladder cancer. * Lynch syndrome is caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2; see main article Hereditary nonpolyposis colorectal cancer (HNPCC). People with this syndrome have increased risk of developing several cancers, including bladder and urinary tract cancers. Large population studies have identified additional gene variants that each slightly increase bladder cancer risk. Most of these are variants in genes involved in metabolism of carcinogens ( NAT2, GSTM1, and UGT1A6), controlling cell growth ( TP63, CCNE1, MYC, and FGFR3), or repairing DNA damage ( NBN, XRCC1 and 3, and ERCC2, 4, and 5).Diet and lifestyle
Several studies have examined the impact of lifestyle factors on the risk of developing bladder cancer. A 2018 summary of evidence from the World Cancer Research Fund and American Institute for Cancer Research concluded that there is "limited, suggestive evidence" that consumption of tea, and a diet high in fruits and vegetables reduce a person's risk of developing bladder cancer. They also considered available data on exercise, body fat, and consumption of dairy, red meat, fish, grains, legumes, eggs, fats, soft drinks, alcohol, juices, caffeine, sweeteners, and various vitamins and minerals; for each they found insufficient data to link the lifestyle factor to bladder cancer risk. Other studies have indicated a slight increased risk of developing bladder cancer in those who are overweight or obese, as well as a slight decrease in risk for those who undertake high levels of physical activity.Pathophysiology
Bladder tumors typically arise from the urothelium, the cell layer that lines the urine-storing part of the bladder. Parts of the urothelium can accumulate DNA mutations over years, making these areas more likely to give rise to tumors. This effect, called field cancerization, can allow several tumors to arise in the same area, or tumors to re-emerge from a given area after a first tumor was removed. Additionally, a cell that becomes cancerous can grow to give rise to several tumors – nearby and recurrent tumors are often monoclonal (descended from the same cancerous cell). Despite arising from the same tissue, NMIBC and MIBC develop along distinct pathways and bear distinct genetic mutations. Most NMIBC tumors start as low-grade papillary (finger-like, projecting into the bladder) tumors. Mutations in cell growth pathways are common. Most common are mutations that activate FGFR3 (present in up to 80% of NMIBC tumors). Mutations activating the growth pathway PI3K/AKT/mTOR pathway are also common, including mutations in PIK3CA (in around 30% of tumors) and ERBB2/Prognosis
Bladder cancer prognosis varies based on how widespread the cancer is at the time of diagnosis. For those with tumors confined to the innermost layer of the bladder (stage 0 disease), 96% are still alive five years from diagnosis. Those whose tumors have spread to nearby lymph nodes (stage 3 disease) have worse prognoses; 36% survive at least five years from diagnosis. Those with metastatic bladder cancer (stage 4 disease) have the most severe prognosis, with 5% alive five years from diagnosis.Epidemiology
Veterinary medicine
Bladder cancer is relatively rare in domestic dogs and cats. In dogs, around 1% of diagnosed cancers are bladder cancer. Shetland sheepdogs, beagles, and various terriers are at increased risk relative to other breeds. Signs of a bladder tumor – blood in the urine, frequent urination, or trouble urinating – are common to other canine urinary conditions, and so diagnosis is often delayed. Urine tests can aid in diagnosis; they test for the protein bladder tumor antigen (high in bladder tumors) or mutations in the BRAF gene (present in around 80% of dogs with bladder or prostate cancer). Dogs with confirmed cancer are treated with COX-2 inhibitor drugs, such as piroxicam, deracoxib, and meloxicam. These drugs halt disease progression in around 50% of dogs, shrink tumors in around 12%, and eliminate tumors in around 6%. COX-2 inhibitors are often combined with chemotherapy drugs, most commonly mitoxantrone, vinblastine, or chlorambucil. Bladder cancer is much less common in cats than in dogs; treatment is similar to that of canine bladder cancer, with chemotherapy and COX-2 inhibitors commonly used.Charities and funding
Several charities provide support for individuals affected by bladder cancer and fund research into improved treatments. Organisations such as Cancer Research UK (United Kingdom), Fight Bladder Cancer (United Kingdom), Bladder Cancer Advocacy Network (United States), and The World Bladder Cancer Patient Coalition (international), offer patient support, educational resources, and advocacy initiatives. These organisations contribute to research funding, early diagnosis campaigns, and patient support services, aiming to improve outcomes for those diagnosed with bladder cancer. Independent studies and health reports have recognised their role in advancing bladder cancer awareness and care.References
Works cited
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{{DEFAULTSORT:Bladder Cancer Health effects of tobacco Types of cancer