Urology - Bladder cancer

Question 1

What is the most common bladder cancer?

Answer 1

Over 90% of bladder tumours are urothelial carcinoma (previously called TCCs). Non muscle invasive tumours are the most common.

NB - the term carcinoma is used in an imprecise way when applied to bladder cancers. Many bladder tumours that are called carcinomas show no evidence of basement membrane invasion and should perhaps be called papillomas. But historically they have been called carcinomas.

Question 2

What are the macroscopic differences between high and low grade tumours?

Answer 2

Tumours can either be high grade or low grade. Low grade tumours are often easy to identify and often papillary. High grade tumours are often flat and difficult to visualise.

Question 3

What is the most important factor when determining treatment for bladder cancer?

Answer 3

Muscle invasion is important. If this occurs, transurethral resection (TURBT) is insufficient and a radical cystoprostatectomy is advised.

Question 4

Where is bladder cancer more common?

Answer 4

The incidence of bladder cancer varies significantly worldwide. Egypt, Western Europe, and North America have the highest rates. Asian countries have the lowest rates.

Question 5

In what group of patients is bladder cancer more common?

Answer 5

Bladder cancer is more common in men cf. women (3:1) Although the disease can occur in young people, >90% of new cases occur in the >55 group.

Question 6

Which groups of patients experience a higher mortality from bladder cancer?

Answer 6

Women, the elderly and black people all experience higher mortality from bladder cancer. There are many factors that may explain this increase.

Question 7

Name some important predisposing/ risk factors for bladder cancer?

Answer 7

1) Chemical substances - e.g. aromatic amines used in rubber and dye industries, arsenic exposure in drinking water, high risk occupations such as painters, hairdressers and medical personnel (due to chemical exposure), pelvic radiation, chemotherapeutic agents (cyclophosphamide)

2) Smoking - most important causative factor
3) Type 2 diabetes - pyoglitazone may increase risk of bladder cancer in T2DM patients
4) Chronic inflammation
5) Schistosomiasis
6) Indwelling catheters
7) Leukoplakia
8) Bladder diverticula
9) Ectopic vesicae

Question 8

What sites are most common for bladder tumours?

Answer 8

Most tumours are at the base on the trigone and around the ureteric orficies.

Question 9

What is the pathophysiology of bladder cancer?

Answer 9

Carcinogens are concentrated and excreted in the urine, thereby exposing the cells lining the urinary tract. This exposure is concentrated however in the bladder (where 95% of urothelial carcinomas arise) but malignant transormation can occur anywhere along the urinary tract.

Question 10

What is the “field effect”?

Answer 10

About 70% of tumours in newly diagnosed patients are multiple, and in >50% of patients there is accompanying areas of dysplasia up to carcinoma in situ, either next to or in remote areas away from the primary tumour. These findings have led to the concept of the “field effect” in which exposure of the urothelium to carcinogens at roughly the same concentration gives rise to an epithelium, from which occassional cells become initiated and give rise to independent clones of transformed cells.

Question 11

Are there any problems with the “field effect” theory of bladder cancer?

Answer 11

X chromosome inactivation studies suggest a single cell origin for most tumours, rather than the multifocal nature of cancer explained by the field effect. But both concepts are clinically useful: a point mutation may initiate the process, confering a growth advantage to cells that later develop the malignant phenotype.

Question 12

What genes play a role in the development of bladder cancer? Are any genes associated with a better or worse prognosis?

Answer 12

Genes involved in chemical detoxification such as glutathione S transferase play a role in the development of bladder cancer. The first demonstration of ras as an oncogene was in bladder cancer cell line, but ras and other dominant cancer genes are infrequently involved.

Non muscle invasive tumours that show loss of heterozygocity in the long arm of chromosome 9 has a favourable prognosis.

Loss of tumour suppressor genes pRB and p53 is associated with invasive tumours and has a poor prognosis.

Question 13

What measures are used in the primary prevention of bladder cancer?

Answer 13

Avoidance of tobacco smoke and occupational exposure to carcinogens such as nitrosamines, avoidance of water polluted with chemicals such as arsenic, and, where possible, limiting exposure to pelvic radiation.

Prompt treatment of UTI, removal of calculi and avoiding prolonged indwelling devices (such as catheters) can reduce inflammatory causes of bladder cancer. Limiting use of cyclophosphamide and minimising exposure to radiation can reduce iatrogenic causes.

Metformin, which potentiates the anti-cancer effect of chemotherapy and radiotherapy, is reported to significantly reduce the incidence of bladder cancer.

Question 14

Is there currently a screening programme for bladder cancer?

Answer 14

Bladder cancer is not currently screened for. However, one study looking at long term screening for bladder cancer using haematuria dipstick showed the mortality was 0% in the screened vs 20% in the registry groups when comparing stage at presentation.

Question 15

Are there any secondary preventative measures useful in bladder cancer?

Answer 15

High dose vitamins A, B6, and C are reported to reduce recurrence.

Question 16

What are the key diagnostic factors in bladder cancer?

Answer 16

The first key diagnostic factor is to consider the presence of risk factors for bladder cancer (i.e. male sex, family hx, tobacco smoking, chemical exposure, pelvic radiation, systemic chemotherapy, age >55).

Gross or macroscopic haematuria is the most common presenting complaint in bladder cancer in >80% of patients. Gross painless haematuria occuring throughout the urinary stream is most common. But episodes are typically intermittent and therefore resolution should not be attributed to treatment, with e.g. antibiotics.

Dysuria is also a common feature but is usually associated with aggressive bladder cancer such as high grade urothelial carcinoma or CIS. In the absence of infection to account for the dysuria, cytology is key and is positive in up to 90% of patients.

Question 17

What is the most important first line investigation in suspected bladder cancer? What is second line?

Answer 17

Urinalysis is the first line investigation. Gross (macroscopic) haematuria is the presenting complaint in 80% of cases. It is also important to assess for dysuria (burning pain on urination) and urinary frequency (rarely the sole symptom in bladder cancer).

Cystoscopy is second line for bladder cancer. Remember low grade tumours are papillary and easy to visualise, but high grade tumours are often flat or in situ and difficult to visualise. If a patient undergoes cystoscopy and a lesion is suspicious of a urothelial tumour then they should be rescheduled for a TURBT which allows the diagnosis to be confirmed pathologically and the extent of the disease assessed.

Question 18

What features are suggestive of a non muscle invasive tumour on cytoscopy?

Answer 18

Include papillary tumours with a fine stalk (Ta) or thick stalk (T1). Rough erythematous patches can be indicative of Tis (carcinoma in situ), although urothelium often appears normal. Staining biopsies with 0.2% methylene blue is required to confirm Tis.

Question 19

What are features suggestive of a muscle invasive tumour on cystoscopy?

Answer 19

Multifocal tumours that are sessile. Vascularity around the tumour is increased. Tumours are often large. Bimanual examination may reveal tumours that have progressed beyond the lumen of the bladder.

Question 20

What should happen if the visual appearance of the lesion suggests it is non invasive disease?

Answer 20

The patient should undergo imaging of the upper tract if they have not already done so. This can be by intravenous pyelogram, CT urography or renal ultrasound with retrograde pyelography. This should be followed by a TURBT.

Question 21

What should happen next if the visual appearance of the lesion suggests it is muscle invasive?

Answer 21

Patients should have FBC, U&E, chemistry profile (including alk phosphastase), CXR, imaging of the upper tract collecting system, and abdominal/pelvic CT or MRI before TURBT. A pelvic CT is best performed before TURBT if a high grade lesion is suspected because surgical changes can be confused with extravesical extension. If the alk phos is raised then the patient should have a bone scan.

Question 22

What is important when performing a TURBT?

Answer 22

Biopsy fragments must be of adequate size and depth to allow for proper assessment of detrusor muscle involvement. Muscle invasive tumours cannot be reliably resected transurethrally and are generally best treated by radical cystoscopy.

Question 23

What does carcinoma in situ increase the risk of?

Answer 23

Bladder Tis increases the risk of upper tract and urethral carcinoma. Carcinoma of the prostatic urethra, if untreated, can progress to active invasive disease. Early invasion of the prostate may be managed by TURP if the resection margins are free of disease, but deeper invasion carries a poor prognosis.

Question 24

Are there any urinary markers for bladder cancer?

Answer 24

Cytology is the accepted urinary marker for bladder cancer, but it can have false negatives. Additional markers are available (e.g. dipstick for haematuria) that have increased sensitivity but this comes at the expense of reduced specificity. These new marks also include bladder tumour antigen (BTA), nuclear matrix protein 22 and others.

Question 25

How does bladder cancer spread?

Answer 25

Bladder cancer can spread by:
1) Direct invasion - the TNM classification system is used widely to stage bladder cancer. The p stands for pathology, T for tumour and the letter or number for the degree of spread

2) Lymphatic - common in fatal cases to iliac and para-aortic lymph nodes
3) Haematogenous - a late phenomenon with metastases to liver and lungs most frequently
4) Implantation - may occur at cystectomy with implantation in the prostatic bed, urethra and scars in bladder or abdominal wall

Question 26

How are bladder tumours classified?

Answer 26

Bladder tumours are classified based on their macroscopic appearance, microscopic appearance (grade) and the degree of spread or staging (TNM).

Question 27

What are the macroscopic features of bladder tumours?

Answer 27

Bladder tumours come in a number of shapes that are visible on cystoscopy (i.e. with the naked eye):
1) Papillary - fronded masses growing into the lumen with little or no invasion of the wall (commonly low grade)

2) Solid - tumour growing directly into the bladder wall with little or no projection into the lumen. These are often ulcerated or encrusted.
3) Papillary and solid - mixture of 1 and 2.
4) Flat in situ carcinoma - a distinct form of surface malignancy causing reddening of the bladder mucosa due to underlying telangiectatic blood vessels

Most solid tumours are invasive from the outset and only a small percentage of papillary tumours evolve into invasive carcinoma. A significant portion of in situ carcinomas become invasive and patients with this condition need careful follow up, such as cystectomy, if required to prevent spread.

Question 28

What system is used to grade bladder tumours?

Answer 28

Grading refers to the microscopic appearance of the tumour. The most common grading system is the WHO 1973 grading system which grades tumours from I to III according to the degree of differentiation:

1) Papilloma - papillary growth with no significant stroma, the urothelium of which is indistinguishable from normal
2) Well differentiated (grade I) TCC - vast majority are papillary growths with no evidence of invasion. Fronds of the tumour have more cell layers than normal urothelium and cells have slightly larger nuclei than normal
3) Moderately well differentiated (grade II) TCC - usually papillary in which a significant number are invasive at presentation or become so. The cells of the fronds are atypical with an increase in mitotic figures
4) Poorly differentiated (grade III) - least likely to be papillary, almost all are solid extensively invasive tumours. The cells are pleomorphic with numerous mitoses and may be difficult to recognise as being urothelial in origin.

Question 29

What is the TNM classification system? What tumours under this system are considered non muscle invasive?

Answer 29

This is the staging system for bladder cancer (cancers are both graded AND staged).
T = tumour
N = nodes (biopsy)
M = metastases (imaging/ examination)

pTa = no invasion
pTis = carcinoma in situ
pT1 = invasion confined to the lamina propria
pT2 (a + b) = extension into muscle
pT3 (a + b) = extension into perivesical tissue
pT4 = extension beyond muscle (e.g. into prostate, uterus, vagina, pelvic wall)

Under this system the following tumours are considered non muscle invasive:

• papillary tumours confined to the epithelial mucosa (pTa)
• tumours invading subepithelial tissue (lamina propria) (pT1)
• Tis (carcinoma in situa)

Question 30

What are the effects of bladder tumours?

Answer 30

• haematuria
• infection: cystitis and pyelonephritis
• ureteric obstruction: hydronephrosis and pyonephrosis
• urethral obstruction: retention of urine
• extension into other organs: fistula formation, vesico-colic fistula with pneumaturia and vesico-vaginal fistula giving incontinence

Question 31

How is non muscle invasive bladder cancer managed?

Answer 31

Management of non muscle invasive cancer depends on whether the cancer is classed as low, medium or high risk (defined by the American Urological Association, AUA). Luckily this is essentially the same for all of the non muscle invasive bladder cancers!

• low risk = low grade, stage pTa (pTa = non invasive papillary carcinoma)
• intermediate risk = low grade, stage pTa but with a high risk of recurrance but low risk of progression
• high risk = high grade pTa, pTis, or pT1

Management is:

• 1st line TURBT +
• immediate post op chemo (usually mitomycin) +
• concurrant TURP if patient has coexisting BPH (reduces risk of recurrance) +/-
• delayed BCG if intermediate risk +/-
• radical cystectomy if high risk with risk factors - e.g. recurrance, mutliple high grade pT1s high grade pT1 + CIS +/-

Question 32

How is muscle invasive bladder cancer managed?

Answer 32

Unlike non muscle invasive cancers, management of muscle invasive cancer is determined by TNM staging alone and is roughly the same for each stage.

• organ contained = pT2 (a+b)
• non-organ contained = pT3 (a+b)
• non-organ contained = pT4 (a+b)

Rx:

• 1st line radical or partial cystectomy with pelvic lymph node dissection +
• preoperative chemotherapy (usually 3 cycles of the MVAC preparation: methotrexate, vinblastine, doxorubicin, cisplatin) +
• post operative chemotherapy if none given pre operatively and considered based on pathological risk (e.g. positive nodes or higher stage tumours) +/-
• post operative chemotherapy or chemo-radiotherapy if non organ contained pT3 (a+b)

The order is changed in non organ contained pT4 disease:

• 1st line chemotherapy, MVAC if tumour not resectable
• radiotherapy if no contraindications (e.g. previous pelvic radiation, irritative bladder symptoms)
• radical cystoprostatectomy when the tumour responds to chemotherapy and a fixed mass is no longer palpable

Question 33

What options are available for metastatic disease?

Answer 33

Patients who present with metastatic disease or who subsequently develop metastatic disease are generally treated with systemic chemotherapy. Specific regime can vary depending on local factors and comorbidities.

Generally speaking, cisplatin, the taxanes, and gemcitabine are the 3 drugs generally used for this purpose. Contrary to previous belief, the addition of paclitaxel does not does appear to improve results with gemcitabine plus cisplatin.

Question 34

Would surgery be offered to a patient with metastatic disease?

Answer 34

Surgery or radiotherapy, often in combination with chemotherapy, may be considered in patients who show a major response to chemotherapy in an unresectable primary tumour. If the disease is completely resected then 2 additional cycles of chemotherapy are required.

Question 35

What monitoring is required for patients with bladder cancer?

Answer 35

Lifelong risk of tumour recurrance requires lifelong monitoring, primarily by cystoscopy. High risk patients have cystoscopy every 3 months for 2 years, then every 6 months for 2-3 years. Low risk patients have cystoscopy at 3 months. Patients should stop smoking and increase vitamin consumption.

Question 36

What are the complications of bladder cancer?

Answer 36

1) Prostatic urethra TCC - risk of urothelial carcinoma of the prostatic urethra is low in low risk risk disease, but up to 25% of high risk patients will develop prostatic urethra TCC by 15 years when BCG maintenance is not given
2) Upper tract TCC - can occur in low or high grade disease
3) Hydronephrosis
4) Urinary retention - tumours of the bladder neck can cause outlet obstruction. Bleeding from the tumour or following tumour resection can cause clot retention

Question 37

What is associated with squamous cell carcinoma of the bladder?

Answer 37

Squamous cell carcinoma is characterised by bulky, widely invasive tumour of keratinizing squamous cell type arising from metaplastic epithelium - luekoplakia. It commonly complicates bilharzia (schistosomiasis).

Question 38

Where does adenocarcinoma affect the bladder?

Answer 38

Usually arises from the urachus at the dome of the bladder or at the base where a proportion are a complication of intestinal metaplasia of the urothelium.