Bladder cancer

Bladder cancer is any of several types of cancer arising from the tissues of the urinary bladder. It is a disease in which cells grow abnormally and have the potential to spread to other parts of the body. Symptoms include blood in the urine, pain with urination, and low back pain.

Risk factors for bladder cancer include smoking, family history, prior radiation therapy, frequent bladder infections, and exposure to certain chemicals. The most common type is transitional cell carcinoma. Other types include squamous cell carcinoma and adenocarcinoma. Diagnosis is typically by cystoscopy with tissue biopsies. Staging of the cancer is typically determined by medical imaging such as CT scan and bone scan.

Treatment depends on the stage of the cancer. It may include some combination of surgery, radiation therapy, chemotherapy, or immunotherapy.Surgical options may include transurethral resection, partial or complete removal of the bladder, or urinary diversion. Typical five-year survival rates in the United States are 77%.

Bladder cancer, as of 2015, affects about 3.4 million people globally with 430,000 new cases a year. In 2015 it resulted in 188,000 deaths. Age of onset is most often between 65 and 85 years of age. Males are more often affected than females. In the United States in 2018 81,000 cases and 17,000 deaths are expected making it the 6th most common type of cancer in the region.

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Signs and symptoms

Location of bladder cancer

Bladder cancer characteristically causes blood in the urine (hematuria), which may be visible (gross/macroscopic hematuria) or detectable only by microscope (microscopic hematuria). Blood in the urine is the most common symptom in bladder cancer, and is painless. Visible blood in the urine may be of only short duration, and a urine test may be required to confirm non visible blood. Between 80-90% of people with bladder cancer initially presented with visible blood. 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 (dysuria), 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.

Patients with advanced disease refer pelvic or bony pain, lower-extremity swelling, or flank pain. Rarely, a palpable mass can be detected on physical examination.

Causes

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). Quitting smoking reduces the risk, however former smokers will most likely always be at a higher risk of bladder cancer compared to people who have never smoked. Passive smoking does not appear to be a risk.

Thirty percent of bladder tumors probably result from occupational exposure in the workplace to carcinogens such as benzidine. 2-Naphthylamine, which is found in cigarette smoke, has also been shown to increase bladder cancer risk. 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.

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.

It has been suggested that mutations at HRAS, KRAS2, RB1, and FGFR3 may be associated in some cases.

Diagnosis

Bladder wall thickening due to cancer

Bladder tumor in FDG PET due to the high physiological FDG-concentration in the bladder, furosemide was supplied together with 200 MBq FDG. The uptake cranial to the lesion is a physiological uptake in the colon.

Currently, the best diagnosis of the state of the bladder is by way of cystoscopy, which is a procedure in which a flexible tube bearing a camera and various instruments is introduced into the bladder through the urethra. The 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.

Urine cytology can be obtained in voided urine or at the time of the cystoscopy (“bladder washing”). Cytology is not very sensitive (a negative result cannot reliably exclude bladder cancer). 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). NMP22 is also available as a prescription home test. Other non-invasive urine based tests include the CertNDx Bladder Cancer Assay, which combines FGFR3 mutation detection with protein and DNA methylation markers to detect cancers across stage and grade, UroVysion, and Cxbladder.

The diagnosis of bladder cancer can also be done with a Hexvix/Cysview guided fluorescence cystoscopy (blue light cystoscopy, Photodynamic diagnosis), as an adjunct to conventional white-light cystoscopy. This procedure improves the detection of bladder cancer and reduces the rate of early tumor recurrence, compared with white light cystoscopy alone. Cysview cystoscopy detects more cancer and reduces recurrence. Cysview is marketed in Europe under the brand name Hexvix.

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, 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 obtained by the TURBT-procedure, is of fundamental importance for making the appropriate choice of ensuing treatment and/or follow-up routines.

Pathological classification

Histopathology of urothelial carcinoma of the urinary bladder. Transurethral biopsy. H&E stain.

95% of bladder cancers are transitional cell carcinoma. The other 5% are squamous cell carcinoma, adenocarcinoma, sarcoma, small cell carcinoma, and secondary deposits from cancers elsewhere in the body.

Carcinoma in situ (CIS) invariably consists of cytologically high-grade tumour cells.

Staging

Diagram showing the T stages of bladder cancer

Bladder cancer is staged (classified by the extent of spread of the cancer) and graded (how abnormal and aggressive the cells appear under the microscope) to determine treatments and estimate outcomes.

In the TNM staging system for bladder cancer, the following apply:

T (Primary tumour)

  • TX Primary tumour cannot be assessed
  • T0 No evidence of primary tumour
  • Ta Non-invasive papillary carcinoma
  • Tis Carcinoma in situ (‘flat tumour’)
  • T1 Tumour invades subepithelial connective tissue
  • T2a Tumour invades superficial muscle (inner half)
  • T2b Tumour invades deep muscle (outer half)
  • T3 Tumour invades perivesical tissue:
    • T3a Microscopically
    • T3b Macroscopically (extravesical mass)
  • T4a Tumour invades prostate, uterus or vagina
  • T4b Tumour invades pelvic wall or abdominal wall

N (Lymph nodes)

  • NX Regional lymph nodes cannot be assessed
  • N0 No regional lymph node metastasis
  • N1 Metastasis in a single lymph node 2 cm or less in greatest dimension
  • N2 Metastasis in a single lymph node more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, none more than 5 cm in greatest dimension
  • N3 Metastasis in a lymph node more than 5 cm in greatest dimension

M (Distant metastasis)

  • MX Distant metastasis cannot be assessed
  • M0 No distant metastasis
  • M1 Distant metastasis.
5-year survival in the U.S.
Stage %
0 98%
I 88%
II 63%
III 46%
IV 15%

Numerical
The stages above can be integrated into a numerical staging (with Roman numerals) as follows:

  • Stage 0a: Ta, N0, M0
  • Stage 0is: Tis, N0, M0
  • Stage I: T1, N0, M0
  • Stage II: T2a or T2b, N0, M0
  • Stage III: T3a, T3b, or T4a, N0, M0
  • Stage IV; any of the following:
  • T4b, N0, M0
  • any T, N1 to N3, M0
  • any T, any N, M1

Grading

By the WHO classification of 1973, bladder cancers are histologically graded into:

  • G1 – Well differentiated,
  • G2 – Moderately differentiated
  • G3 – Poorly differentiated

Micrometastatic disease

In order to address the problem of micrometastatic disease, which in itself has implications on longtime survival, new treatment options are needed. Micrometastatic dissemination is often not treatable with only major surgery and the concept of neoadjuvant chemotherapy has evolved. In this patients first receive chemotherapy in 3 or 4 cycles, and after that proceed to major surgery. In a number of meta-analyses of randomised prospective trials worldwide, the results have shown survival benefits between 5–8% with this therapy, in a follow up time of 5 years.

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