Bladder tumours are growths originating in the inner lining of the bladder. Papillomas (small wartlike growths) often recur and eventually become cancerous. Other, more malignant, growths may extend not only into the bladder cavity, but also through the bladder wall to involve nearby organs, such as the colon, rectum, prostate gland, or uterus.
Bladder cancer is more common in smokers and workers in the dye and rubber industries.
Haematuria (blood in the urine) is the main symptom of bladder cancer. A tumour may obstruct the point at which a ureter enters the bladder, causing back pressure and pain in the kidney region, or the urethral exit, causing difficulty in passing, or retaining, urine.
Diagnosis and treatment
Bladder tumours are diagnosed using cystoscopy (passage of a viewing tube up the urethra into the bladder) and biopsy (tissue sampling for microscopic analysis) of the abnormal area. If they are small, the tumours can be treated by heat or removed surgically.
Tumours tend to recur within the bladder, so regular follow-up cystoscopy is usually necessary. Bladder tumours that have spread through the bladder wall may be treated by radiotherapy or by the removal of part or all of the bladder.
Bladder cancer (Urothelial cancer)
Bladder cancer usually arises from the transitional epithelium and typically presents with haematuria, lower urinary tract symptoms, pelvic pain, or (metastatic disease) systemic symptoms. Most cases are sporadic and related to cigarette smoking. They are graded histologically as: 1 (low risk of future progression), 2, or 3 (high risk of progression/metastases), and staged according to the tumour–nodes–metastases (TNM) classification, with the most important issues being whether the tumour is muscle invasive (T2 or above) or localized to urothelium only (Ta), and whether there is metastatic disease.
Management—(1) Low-risk noninvasive cancers (TaG1 and TaG2) are treated by endoscopic resection. (2) High-risk non-invasive cancers (TaG3, T1G3, carcinoma in situ) are treated by endoscopic resection plus intravesical immunotherapy with BCG (bacille Calmette–Guerin). (3) Muscle-invasive cancers with no evidence of metastatic disease are treated with radical surgery (cystoprostatectomy or cystectomy/hysterectomy/oophorectomy, with both requiring urinary diversion) or radiotherapy. Systemic chemotherapy is an option as either neo-adjuvant or adjuvant treatment for muscle invasive disease.
Bladder cancer is the eighth commonest cause of death from malignant disease in England and Wales and the fourth most common cancer in men (data from CRUK 2006). It usually arises from the transitional epithelium that lines the urinary tract from the tips of the renal papillae to the distal urethra, hence transitional cell carcinoma (sometimes known as urothelial cell cancer) may arise in the kidney, ureter, bladder, or urethra. The bladder is the commonest site of origin, where it usually presents with haematuria, lower urinary tract symptoms, pelvic pain, or—when there is metastatic disease—with systemic symptoms.
Other primary epithelial cancers of the bladder include squamous cell carcinoma, which arises in response to chronic inflammation/irritation of the bladder following exposure to schistosomiasis, radiotherapy, chronic infection, or long-term catheterization. Adenocarcinoma can arise from urachal remnants in the dome of the bladder, but more commonly is a consequence of locally invasive or metastatic disease where the bladder is invaded by direct extension from a sigmoid adenocarcinoma.
Risk factors for bladder cancer
The risk factors for urothelial cell cancers are well established (Table 1) and include male sex, increasing age, and smoking. Occupational exposure to aromatic amines, dyes, and anilines increases the risk. The metabolism of aromatic amines involves acetylation through a polymorphic enzyme (N-acetyltransferase 2), with slow acetylator status appearing to be a risk factor. Chronic inflammation associated with schistosomiasis infection predisposes to squamous cell carcinoma and treatment with cyclophosphamide predisposes to bladder cancer. Radiotherapy to the pelvis for the treatment of gynaecological malignancy increases the risk of distal ureteric transitional cell carcinoma fourfold.
|Table 1 Risk factors for transitional carcinoma|
|Risk factors for transitional cell carcinoma of the bladder||Additional risk factors for upper-tract transitional cell carcinoma|
|Increasing age||Papillary necrosis|
|Male gender||Chinese herb nephropathy|
|Chemical/occupational exposure||Balkan nephropathy|
|External beam radiation|
|Genetic risk factors (rare)|
The vast majority of bladder cancer is sporadic and related to cigarette smoking, but one rare genetic syndrome (Lynch’s syndrome—hereditary nonpolyposis colon cancer, OMIM 120435) caused by mutations in DNA mismatch repair genes increases the risk of right-sided colon cancer and transitional cell carcinoma of the upper urinary tract.
Some Chinese medicines containing aristocholic acid are a cause of Chinese herb nephropathy, and this agent is likely to be the cause of Balkan nephropathy, both of which are strongly associated with upper urinary tract urothelial cell carcinoma (see: Chronic tubulointerstitial nephritis).
Oncogenes and tumour suppressor genes are involved in the pathogenesis of bladder cancer, and there are mutually exclusive genetic alterations that lead to the development of either papillary noninvasive transitional cell carcinoma (stage pTa) or high-grade invasive carcinomas. The most common sporadic genetic mutations in low-grade transitional cell carcinoma are loss of heterozygosity of chromosome 9 and alterations in fibroblast growth factor (FGF) 3. By contrast, high-grade invasive cancers most frequently show loss of tumour suppressor genes which affect the cell cycle such as TP53, RB, and E2F3. Loss of chromosome 8p and alterations in methylation of cytosine residues of particular genes in DNA are also associated with tumour progression in this high-grade invasive group. In the future such alterations may lead to new biomarkers of bladder cancer.
Staging and grading
Histological grade is usually ascribed as grade (G) 1, 2 or 3, with grade 1 tumours being at low risk of future progression and—regardless of tumour stage—grade 3 disease being at high risk for progression and development of metastatic disease.
Clinical bladder cancer staging follows the TNM classification (Table 2; Fig. 1).
Figure 1: Staging of bladder cancer
The most important issues are whether the local tumour is muscle invasive (T2 or above) or localized to the urothelium only (Ta), or invading lamina propria (pT1)and whether there is any evidence of metastatic disease to pelvic lymph nodes, bone or lung. Traditionally, bladder cancers were described as either superficial (located in the urothelium or lamina propria—pTa or pT1) or muscle invasive. This division arose on the basis that superficial disease may be resected completely endoscopically via the urethra using electrocautery, but unfortunately this distinction does not truly reflect the risk to patients from a T1G3 bladder cancer or carcinoma in situ, up to one-third of whom will die of bladder cancer.
|Table 2 TNM classification of transitional cell carcinoma of the bladder|
|Bladder cancer stage||Stage descriptor|
|Primary tumour (T stage)|
|Ta||Noninvasive papillary tumour|
|Tis/Cis||Carcinoma in situ|
|T1||Tumour invades lamina propria|
|T2a||Superficial muscularis propria invaded|
|T2b||Deep muscularis propria invaded|
|T3a||Microscopic perivesical fat invasion|
|T3b||Macroscopic perivesical fat invasion|
|N0||No lymph node metastases|
|N1||Single nodal metastasis, <2 cm in size|
|N2||Node 2–5 cm or multiple nodes|
|N3||Nodes >5 cm|
|M0||No distant metastases|
Low-risk noninvasive bladder cancer—TaG1, TaG2
These tumours comprise most of all new bladder cancers (60%), usually present with painless macroscopic haematuria, and are easily diagnosed using flexible cystoscopy under local anaesthetic. Treatment is by endoscopic resection under either spinal or general anaesthesia: a cystoscope is inserted into the bladder through the urethra and electrocautery is used to remove the lesion.
The tumours are usually papillary and are often found on a stalk are fronded, but may be multifocal and will recur locally in the bladder in about 75% of patients in the long term. The risk of progression to muscle-invasive disease with TaG1 disease is extremely low. The risk of recurrent superficial disease can be reduced by the instillation of chemotherapeutic agents (mitomycin C) into the bladder immediately following endoscopic resection. These chemotherapeutic drugs have a high molecular weight, which means that they are usually not absorbed through the bladder mucosa or associated with neutropenia or other systemic side effects.
Patients with noninvasive bladder cancer require long-term endoscopic surveillance of the bladder until they have been free of recurrence disease for 5 years.
High-risk superficial bladder cancer—TaG3, T1G3, carcinoma in situ
Poorly differentiated high-grade bladder tumours have a different genetic profile from low-risk tumours, more akin to muscle-invasive tumours. It is uncommon for a low-risk cancer (pTa, G1, or G2) to progress to a high-risk one, but progression of pT1 or pTa G3 disease to muscle invasion occurs commonly. Isolated TaG3 disease progresses to muscle-invasive disease in up to 40% of patients after 5 years in the absence of aggressive local therapy following endoscopic resection. Adjuvant treatment in the form of intravesical immunotherapy with BCG (bacille Calmette–Guérin) is offered to such patients. This is instilled in to the bladder once per week for 6 weeks, its mechanism of action being via stimulation of T cells that coordinate an immune response to destroy residual disease and reduce the risk of future recurrence. A diagnosis of T1G3 disease should prompt an early second endoscopic resection as some patients will have muscle-invasive disease. If no evidence of muscle invasion is found on repeat resection, a 6-week course of BCG with maintenance dosing every 3 months is advised.
Carcinoma in situ is an aggressive intraepithelial neoplasia with a high risk of progression to solid muscle-invasive tumours. It is also treated with intravesical BCG, to which up to 65% of people will respond. Recurrent disease should be treated by cystectomy, if the patient is fit.
Muscle invasive bladder cancer
One in four new bladder tumours are found to be muscle invasive on resection, and up to 50% of these have overt or covert metastases at presentation. Patients with muscle-invasive bladder tumour require staging with a bimanual rectal or vaginal examination at the time of resection to designate a clinical T stage. Staging is completed with a CT scan of the abdomen, pelvis, and chest (Fig. 2). Routine biochemistry should be checked and if the alkaline phosphatase is elevated a bone scan should be performed.
Figure 2: CT scan of the pelvis showing a transitional cell carcinoma of the bladder (arrowhead) demonstrating muscle invasion (arrows).
A patient with muscle-invasive bladder cancer and no evidence of metastatic disease requires aggressive local treatment. Treatment options for the local tumour include either surgery or radiotherapy. There are no recent randomized trials comparing the two treatments, but it is generally accepted that surgery provides better local control at the expense of higher risk. Some patients (e.g. those with small pT2 lesions away from the trigone of the bladder) will respond well to resection and radiation, or chemoradiation. Radical surgery involves cystoprostatectomy in men and cystectomy, hysterectomy, and oophorectomy in women (anterior exenteration). An extended pelvic lymph node dissection is also performed: this provides prognostic information and is therapeutic for patients with low-volume micrometastatic disease. Urinary diversion is then established by means of an ileal conduit (incontinent cutaneous diversion), or bladder substitution (folding 55 cm of small bowel into a sphere and anastomosing it to the urethra—continent urethral diversion), or a continent cutaneous reservoir (less common, as it frequently requires reoperation).
Alternative local therapy can be provided by means of radiotherapy to the bladder. The major benefit of this approach is that it allows bladder preservation, thereby avoiding the many long-term side effects of urinary diversion. However, it does place the patient at risk of developing a second muscle-invasive bladder cancer. Overall up to 50% of patients have persistent or subsequent recurrent disease in the bladder, and up to 30% will require a subsequent cystectomy.
Bladder cancer is moderately chemosensitive, hence systemic chemotherapy is an option as either neo-adjuvant or adjuvant treatment for patients with muscle-invasive bladder cancer. Neo-adjuvant treatment in the form of MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) provides a 5 to 7.5% overall survival benefit for patients who subsequently undergo radical cystectomy or radiation treatment. Chemotherapy is also used in patients with node-positive disease or lymphovascular space invasion at the time of cystectomy, although many are too debilitated following surgery to receive chemotherapy.
Metastatic transitional cell carcinoma
Patients with regional metastatic disease to lymph nodes in the pelvis can be given chemotherapy if they are fit enough. This may result in complete radiological resolution, after which cystectomy can be performed. If residual active cancer is identified in the pelvic lymph nodes or there is invasion of the lymphovascular space, then the patient has a very poor prognosis.
Patients with nonregional metastatic disease to bones, liver, lungs, or abdominal lymph nodes have a very low 5-year survival. Chemotherapy can be offered if the patient has good performance status. Palliative radiotherapy to the bladder helps in local control and reduces haematuria, or ureteric obstruction which can lead to renal failure.
Transitional cell carcinoma of the kidney or ureter
Patients with high-grade bladder cancer are at risk of developing upper-tract transitional cell carcinoma (c.5%), but there are several other specific risk factors for its development, including phenacetin abuse, papillary necrosis, Balkan nephropathy, and Chinese herb nephropathy, as well as hereditary nonpolyposis colon cancer (HNPCC). Accurate staging, grading, and surveillance of the upper tracts is difficult and recurrence rates are high, hence these patients are generally best treated with nephroureterectomy if the contralateral kidney is normal. Annual cystoscopy is recommended thereafter because over 50% of patients with new upper-tract transitional cell carcinoma will go on to develop transitional cell carcinoma of the bladder.