Bladder cancer

Bladder cancer is the most common cancer of the urinary system. The most common histological type is urothelial carcinoma, previously called transitional cell carcinoma (90% of cases), and 90% of urothelial carcinoma cases are in the bladder. The other histological types of bladder cancer are squamous cell carcinoma and adenocarcinoma.

Urothelial carcinoma can occur anywhere there is urothelium, although it occurs most commonly in the bladder and renal pelvis and more rarely in the ureters and urethra. It's usually asymptomatic in early stages, and the most common presenting symptom is painless gross haematuria, which is present in 80% of bladder cancer patients.

Bladder cancer is mostly a disease of older men. In the majority of cases, the disease is not muscle-invading and therefore has high chances of cure and good prognosis.

Risk factors

Urothelial carcinoma is the second most frequent cancer in smokers, after lung cancer of course. This is because the urothelium is exposed to the toxins in the cigarette smoke after it has been excreted by the kidney. It’s also associated with occupational toxins like aromatic hydrocarbons and arsenic. Other risk factors include:

• Lynch syndrome
• Family history of urothelial cancer
• Previous radiation to the pelvis

Squamous cell bladder cancer is related to urinary schistosomiasis (a parasite specially in endemic countries like Egypt), chronic bladder irritation and infection.

Pathology

90% of bladder cancer cases are urothelial carcinoma, previously called transitional cell carcinoma.

Classification

The new WHO classification of urothelial carcinoma distinguishes between flat and papillary urothelial lesions:

• Flat lesions
  • Urothelial dysplasia
  • Urothelial carcinoma in situ – flat carcinoma
• Papillary lesions
  • Urothelial papilloma – exophytic growth with normal-looking urothelium
  • Urothelial neoplasm of low malignant potential – similar to papilloma but thicker urothelium
  • Low grade papillary urothelial carcinoma – minimal atypia. retained polarity of cells.
  • High grade papillary urothelial carcinoma – high atypia. loss of polarity.

Less than 10% of low-grade cancers invade, but as many as 80% of high-grade cancers do. Invasion majorly affects the prognosis; 5-year survival is 90% in non-invasive cancer but only 10% in invasive cancer. The degree of which the urothelial tumor has invaded the bladder wall is important in the prognosis. Invasive tumors may extend not only into the bladder wall but to adjacent structures like the prostate, seminal vesicles, ureters and retroperitoneum. Haematogenous dissemination usually involves the liver, lungs and bone marrow.

Polychronotropy

Urothelial carcinoma shows polychronotropy, which means that when one urothelial carcinoma is found it is very likely that other urothelial tumors are present or currently developing at other places of the mucous membrane. Because of this, urothelial carcinoma has a high risk of recurrence.

Pathogenesis

Carcinogenesis involves deletions of tumor-suppressor genes on chromosome 9p or 9q. The p16 or p53 genes are commonly involved.

Other histological types

Adenocarcinoma is rare and histologically identical to gastrointestinal adenocarcinomas.

Squamous cell carcinoma is rare and related to chronic inflammation of the bladder, especially schistosomiasis.

Clinical features

The most common symptom is painless gross haematuria. There may also be symptoms of bladder irritation, like dysuria, pollakisuria, and urgency.

Some may present as incidentally discovered microscopic haematuria (defined as 2+ or more on a urinanalysis on 3 separate urine tests with 1 month between the tests).

Bimanual examination (one hand per rectum and the other in the vagina (women) or lower abdominal wall (men) can be used to palpate for evidence of local extension of bladder cancer, which is usually evident of muscle-invasive disease.

Diagnosis and evaluation

Haematuria on urine analysis is seen in most cases of bladder cancer. Urine cytology may show cancer cells.

Patients suspected of having bladder cancer should be referred to cystoscopy. Cystoscopy allows for taking biopsy sample, cytology sample, or even resecting the tumour in its entirety in some cases.

CT with contrast is the first choice imaging modality if bladder cancer is suspected based on cystoscopy. It allows for visualisation of the local spreading of the malignancy and to look for other tumours as urothelial carcinoma is often multifocal. Because contrast is filtered by the kidneys, it enters the urinary tract, and a tumour may therefore produce a filling defect. If the tumour has invaded the bladder wall, it will appear thickened on the CT. CT urography also allows for examination of the entire urinary tract, as bladder cancer is often multifocal. CT abdomen and pelvis to look for metastasis is also indicated for staging. In Norway, CT of the abdomen is performed before cystoscopy (because positive findings may allow the patient to skip cystoscopy and proceed directly to TUR-B).

Stages

Non-muscle invasive bladder cancer (NMIBC), also called stage I, refers to when the disease has not invaded the muscle of the urinary bladder. Muscle-invasive disease (MIBC) may be stage II or III, depending on how far it has spread locally. Metastatic disease is stage IV, where metastasis is present.

Non-muscle invasive and muscle-invasive disease can only be distinguished by transurethral resection of the bladder or by MRi. CT cannot distinguish them.

Management

Management for non-metastatic disease (stages I - III) involves either cystoscopic surgical removal of the tumour (TUR-B), complete surgical removal of the bladder (radical cystectomy), or radiotherapy + chemotherapy. For metastatic disease, only chemotherapy and/or immunotherapy is indicated.

Transurethral resection of the bladder

Transurethral resection of the bladder (TUR-B) is a cystoscopic procedure where the tumour and surrounding bladder tissue are removed with a transurethral resectoscope. After the resection, chemotherapeutical drugs or BCG are instilled into the bladder to reduce any residual cancer cells.

TUR-B is both diagnostic and therapeutic and is indicated for all stages of bladder cancer. If the histological examination following TUR-B shows no muscle invasion and shows complete removal, the patient should receive regular installation of chemotherapy or BCG in the bladder for months/years. If there is evidence of muscle invasion, radical cystectomy or bladder preservation therapy is indicated.

Radical cystectomy

Radical cystectomy is indicated for muscle-invasive disease. It involves removal of the bladder, prostate, seminal vesicles, uterus, and adnexae. Lymph node dissection should also be performed. Without a bladder, a bladder substitute should be made. There are multiple options:

• An ileal conduit urinary diversion, also called a Bricker conduit. A new bladder is made from part of the ileum, with the ureters connected to one end, and the other end opens through the abdominal wall like an enterostoma. Urine is collected in a bag connected to the stoma. This is the most common option
• Continent cutaneous urinary diversion. A reservoar for urine is made from a portion of the bowel remade to be like a "sack", which is opened to the abdominal wall. To empty the reservoar of urine, the opening must be catheterised with aseptic technique.
• Continent orthotopic diversion or neobladder. It is similar to an ileal conduit except that the urethra is connected to the new bladder, which allows urination through the urethra as normal.

Bladder preservation therapy

Bladder preservation therapy, also called trimodal treatment, refers to extensive TUR-B followed by radiochemotherapy. This option preserves the bladder.

BCG

BCG (Bacille Calmette-Guérin) is a live vaccine used to prevent tuberculosis. Somehow someone discovered that administering it into the bladder acts like an immunotherapy, where it stimulates the immune system to kill the cancer cells. It may be administered into the bladder following TUR-B for non-muscle-invasive disease.

Chemotherapy

Chemotherapy is usually a combination of gemcitabine and cisplatin. It is indicated as part of bladder preservation therapy or for palliation in metastastic disease.

Immunotherapy

Immunotherapy, usually with immune checkpoint inhibitors like anti-PD-L1 or anti-PD-1 antibodies, is indicated for palliation in metastatic disease.

Radiotherapy

Radiotherapy may be part of bladder preservation therapy or be used palliatively for metastatic disease.