Non-muscle bladder cancer

Bladder cancer is the most common malignancy of the urinary tract and 7th most common cancer in men and the 17th in women.¹ In total, it is the 9th most common cancer worldwide (consisting of 7% of all cancers), yet it is only the 13th most common cause of cancer death responsible for only 3% of all cancer deaths. This suggests the majority of patients have curable or controllable disease. Its incidence and prevalence increases with age peaking in the eighth decade of life. Bladder cancer is rare before the fifth decade of life. Even though the incidence of bladder cancer is increasing, the mortality is decreasing. Men are 2.5 times more likely to develop the disease than women.¹ The exact reasons for this are unclear but it may be associated with greater urine residuals within the bladder. Black people appear to have a lower incidence of bladder cancer than white people although inexplicably they appear to carry a worse prognosis. Approximately 75% of patients present with disease that is confined to the mucosa or submucosa. These categories are grouped together as non-muscle-invasive bladder tumours. Non-muscle invasive bladder cancer (NMIBC) has a high prevalence due to low progression rates and long-term survival in many cases.

Risk factors The main risk factors in the development of bladder cancer are:

1. Cigarette smoking: This accounts for 50% of cases.^2,3 After cessation of smoking the time taken for the risk of development of bladder cancer to fall to that of the background population is 15€“20 years 
2. Occupational exposure to carcinogens for example in the rubber and paint industries (aniline dyes and beta naphthylamine), phenacetin, cyclophosphamide (used in chemotherapy management of many haematological malignancies) and previous radiotherapy are also known risk factors for development of bladder cancer.

Bladder cancer presentationThe most common presentation of non-muscle invasive bladder cancer is haematuria. NMIBCs do not cause bladder pain and rarely present with lower urinary tract symptoms. In patients with these symptoms, particularly irritative symptoms, which are refractory to symptomatic treatment, a diagnosis of carcinoma-in-situ (CIS) should be considered.

Initial investigationsThe diagnosis of bladder cancer depends on cystoscopic examination of the bladder and histological assessment of resected tissue. An initial diagnostic flexible cystoscopy can be performed as a day case under a local anaesthetic. A thorough inspection of the bladder should be performed to avoid missing a tumour.Urine cytology (examination of voided urine for exfoliated cancer cells) has high sensitivity in high-grade tumours but low sensitivity in low-grade tumours. As a result of loss of cell cohesion in the epithelial lining of the bladder in CIS, there are a larger number of floating cells in the urine, as well as a high degree of anaplasia. The sensitivity of cytology for CIS detection is 28€“100%.⁴ Cytology is thus useful when a high-grade malignancy or CIS is present. However, urinary cytology often is negative in the presence of low-grade cancer. Positive voided urinary cytology can indicate a urothelial tumour anywhere in the urinary tract. Negative cytology, however, does not exclude the presence of a tumour in the urinary tract.Ultrasound scanning is often used as the initial tool to assess the urinary tract. It is a non-invasive test, which allows characterisation of renal masses, detection of hydronephrosis, and visualisation of bladder masses. It is a useful test for the detection of obstruction in patients with haematuria, however it cannot exclude the presence of upper tract tumours.CT urography is used to detect filling defects in the calyces, renal pelvis and ureters, and hydronephrosis, which can indicate the presence of a ureteric tumour. Large exophytic tumours may be seen as filling defects within the bladder. The incidence of upper urinary tract tumours is low (1.8%), but increases to 7.5% with tumours located in the trigone.⁵ The risk of tumour recurrence in the upper urinary tract during follow-up increases in multiple and high-risk tumours.⁶

Definitive diagnosis: transurethral resectionWhen a bladder cancer is detected at flexible cystoscopy the location, number and nature (ie. papillary, solid or mixed solid-papillary) of the tumours are recorded. Trans-urethral resection of the bladder tumour is performed either under a general or a spinal anaesthetic.  Bimanual examination of the bladder is performed to assess for palpable tumour indicating muscle-invasive disease. Loop resection is performed to remove all visible tumours and provide specimens for histological examination to determine stage and grade. After all visible tumour is resected an additional pass of the resecting loop or a cold cup biopsy of the tumour base is taken to ensure that detrusor is sampled to assess for muscle involvement. It is believed that tumour cell implantation immediately after resection is responsible for many early recurrences. This has been used to explain the observation that initial tumours are most commonly found on the floor and lower sidewalls of the bladder, whereas recurrences are often located near the dome.⁷Photodynamic diagnosisPhotodynamic diagnosis, fluorescence cystoscopy or blue light cystoscopy is performed using blue light (wavelength 375€“440nm after instillation of 5-aminolaevuulinic acid (ALA) or hexaminolaevulinic acid (HAL). The ALA or HAL is instilled into the bladder at least one hour prior to cystoscopy; it is taken up by the urothelium and converted to protoporphyrin this is preferentially taken up by malignant cells. When cystoscopy is performed in blue light there is higher intensity fluorescence from abnormal mucosa compared to the surrounding normal mucosa. This means that when illuminated with blue light malignant tissue appears red. It has been shown that fluorescence guided biopsies and resection are more sensitive than standard white light resection in the detection of malignant tumours, particularly for CIS.^8,9 Interestingly, PDD has a lower specificity than white light cystoscopy. False positives can be induced by inflammation, recent TUR and during the first three months after BCG instillation.

HistologyAlmost 95% of patients with bladder cancer have a transitional cell carcinoma (TCC). The important remaining types include:

1. Squamous cell carcinoma: often associated with chronic inflammation and irritation in the bladder due to long term catheterisation, stone disease or schistosomiasis
2. Adenocarcinoma of the bladder: it is even more rare, it can either be primary or secondary with an association with cystitis glandularis; there is also an increased incidence of adenocarcinoma in bladder exstrophy patients and bladder augmentation or substitution patients who have bowel incorporated into the urinary tract.

GradingHistological grading has traditionally been divided into: well, moderately and poorly-differentiated abbreviated to G1, G2 and G3 respectively (1973 WHO classification). The World Health Organization proposed a new classification system in 2004. However, the majority of clinical trials published thus far on Ta and T1 bladder cancers use the 1973 classification.Carcinoma in situ or CIS is a histological diagnosis, it is a flat non-invasive (ie. it does not cross the basement membrane) high risk malignancy of the bladder.Staging of NMIBCBladder cancer is staged using the TNM system. Stage Ta tumours are confined to the urothelium ie. they do not penetrate from the urothelium to the lamina propria or underlying detrusor muscle.Stage T1 tumours originate from the urothelium but penetrate the basement membrane, which separates the urothelium from the deeper layers invading the lamina propria, but not the detrusor muscle.

Risks for recurrence and progression of NMIBCThe risks for recurrence and progression are individual entities. Some tumours may have a high risk for recurrence while having a low risk for progression while some may have high risk for both. For predicting these risks, the European Organisation for Research and Treatment of Cancer (EORTC) Genito-Urinary Cancer Group (GUCG) has developed a scoring system and risk tables.¹⁰ There are six most significant factors:€¢ number of tumours€¢ tumour size€¢ prior recurrence rate€¢ t stage€¢ presence of concomitant CIS€¢ tumour grade (WHO, 1973).There are electronic calculators available for iPhone, iPad and Android phones and tablets (http://www.eortc.be/tools/bladdercalculator/), which make it easier to explain these risks to patients in outpatient clinics. The risks are individually calculated for both recurrence and progression at one and five years.Further prognostic factors are also described in certain cases eg. female sex and presence of CIS in G3T1 cases treated with induction course of intravesical BCG.Without any treatment, approximately 54% of patients with CIS will progress to muscle invasive disease.¹¹ There are no reliable prognostic factors for CIS with studies reporting worse prognosis with concomitant CIS and T1 disease compared to primary CIS^12,13, in widespread CIS¹⁴ and in CIS in prostatic urethra.¹⁵Response to intravesical treatment with BCG/chemotherapy is an important prognostic factor for subsequent progression and death. About 10€“20% of patients with complete response eventually progress to muscle-invasive disease cf 66% of non-responders.¹⁶Based on the EORTC risk tables, EAU guidelines recommend stratification of patients into three risk groups to facilitate treatment options:1. Low-risk tumours: Primary, solitary Ta, G1(low grade), <3cm, no CIS2. Intermediate-risk tumours: All tumours not defined in the low- and high-risk categories3. High-risk tumours: Any of the following:€¢ T1 tumour€¢ G3(high grade) tumour€¢ CIS€¢ Multiple and recurrent and large (>3cm) Ta G1G2 tumours

How to reduce risk of recurrence and progression

Mitomycin CMitomycin C (MMC) is an anti-tumour antibiotic. Its mechanism of action involves the cross-linking of DNA strands and alkylation of single DNA strands within bladder tumour cells. It is given at a dose of 40mg in 40mL of normal saline via a urinary catheter. The catheter is then clamped allowing the MMC to come in to contact with the walls of the bladder over a one-hour period. The catheter is subsequently removed or unclamped. Administration of MMC is contra-indicated after transurethral resection of bladder tumour (TURBT) if bladder perforation is suspected or if there is significant haematuria after TURBT or there is a large post-resection defect. Patients should be made aware of the risks of MMC installation, which include irritative voiding symptoms and a chemical dermatitis of the palms of the hands and genitalia.Post-TURBT mitomycin CAlthough a state-of-the-art TURBT can by itself eradicate a Ta, T1 tumour completely, these tumours can recur and progress to muscle invasive disease. The high variability in the three-month recurrence rate indicates either an incomplete resection or cause of recurrences in a high percentage of patients being reimplantation.¹⁷ It is therefore necessary to consider adjuvant intravesical chemotherapy. Early single installation of chemotherapeutic agents is thought to function by destruction of circulating tumour cells after TUR and a chemoresection mechanism on residual tumour cells and small overlooked tumours.^18,19 In a meta-analysis of seven randomised controlled trials involving 1,476 patients with superficial bladder cancer, one immediate installation of a chemotherapeutic agent after TURBT resulted in an absolute risk reduction of recurrence by 11.7% compared to TUR alone (number needed to treat 8.5) with a relative risk reduction of 39%.²⁰ Instillation of MMC is ideally given within six hours of TUR but no longer than 24 hours after TUR. If instillation was not given the same day as TUR, there was a two-fold increase in the relative risk of recurrence.²¹Adjuvant chemotherapyThe need for further adjuvant intravesical chemotherapy depends on the patient prognosis. In low risk patients, a single post-op treatment reduces the risk of recurrence and is suggested as the standard of care. For other patients, however, a single immediate instillation of chemotherapy remains an incomplete treatment due to the significant risk of recurrence and/or progression. The choice between further chemotherapy and immunotherapy is largely based on the risk that needs to be reduced: recurrence or progression. A combined analysis of the EORTC-GU Group and Medical Research Council data, comparing intravesical chemotherapy with TUR alone, demonstrated that chemotherapy prevents recurrence but not progression.²² The most commonly used installation schedule in the UK in an adjuvant setting is once weekly mitomycin C 40mg for six weeks.BCGBCG was first used by Morales in 1976 for non-invasive bladder cancer.²³ It is live attenuated Mycobacterium bovis. There are three different strains available across the world though no difference in the efficacy between them has been reported.The mechanism of action is still poorly understood. We do know that it acts by means of an immunological reaction strongly associated with cell apoptosis. Several studies have suggested that the immune response cascade in local areas of the bladder is involved in the anti-tumour action of BCG.^24,25 BCG specifically binds to the urothelium fibronectin in the basement membrane, which is necessary for development of the immune response. Mycobacterial antigen presentation by phagocytes to T helper cells is the pivotal interaction with animal studies suggesting that an intact immune system is required for the anti-tumour activity of BCG.²⁶BCG is administered into the bladder using a catheter and the patient is then asked to hold it in for up to two hours following which it is voided with instructions given to the patients to void sitting down to avoid splashing for six hours after treatment. They are also advised to clean the toilet with bleach and to wash their hands after voiding.The instillation has to be at least two weeks after TURBT and urine testing to rule out infection prior to instillation is mandatory. The induction regime consists of once weekly instillation for six weeks, then a six week break and then once a week for another three weeks. The maintenance regime consists of once a week instillations for three weeks every six months up to a maximum of three years ie. 27 instillations.²⁷ Studies have shown an absolute risk reduction (ARR) of 4% and relative risk reduction (RRR) of 27% in progression of bladder cancer with intravesical BCG as compared to TURBT alone or other adjuvant treatments.²⁸ In patients with CIS of bladder, the ARR for recurrence was 20.5% and RRR was 59% as compared to intravesical chemotherapy.²⁹Contraindications to BCG treatment include known systemic hypersensitivity reactions to any component, active TB, current symptoms or previous history of systemic BCG reaction, concurrent febrile illness, UTI or gross haematuria and congenital or acquired immune deficiencies/immunosuppressive therapy. Immunosuppression or radiotherapy interferes with the immune response and increases the risk of disseminated BCG infection. Antimicrobial therapy, especially quinolones, may interfere with the effectiveness of intravesical BCG.

Follow upEven though these cancers are considered €˜superficial€™, they should be followed up due to the risk of recurrence and progression. The follow-up , however, is based on the degree of risk for each patient. This is where the risk-stratification becomes useful. EAU guidelines for follow up of NMIBC reflect this very well.The aim of follow-up is prompt detection of high-grade non-muscle invasive or muscle-invasive recurrence as delay in such diagnosis and further treatment can be life threatening. Tumour recurrence in the low-risk group is nearly always low stage and low grade. Also, the risk of recurrence in low-risk group patients after five years recurrence-free period is low.³⁰ The follow-up for TaT1 tumours is based on regular cystoscopy as less-invasive methods such as urine cytology and novel urinary markers have not demonstrated the same level of sensitivity and specificity for detection of tumours/recurrences.The first check cystoscopy after TURBT should be at three months as it has been shown to be a very important prognostic indicator for tumour recurrence and progression.^10,31 In intermediate or high-risk groups, recurrences after 10-years-tumour-free interval are not unusual hence life-long cystoscopic follow-up is recommended.³² EAU guidelines for follow-up of patients after TURBT in NMIBC:€¢ Patients with low-risk Ta tumours: Check cystoscopy at three months€”if negative, then next cystoscopy at nine months, then yearly for five years.€¢ Patients with intermediate-risk TaT1 tumours: individualised follow-up between low-risk and high-risk based on personal and subjective factors.€¢ Patients with high-risk tumours: cystoscopy and urine cytology at three months€”if negative, then cystoscopy and cytology every three months for two years, then every six months until five years, then yearly.€¢ Upper tract imaging: yearly CTU/IVU for high-risk tumours.€¢ Check flexible cystoscopy shows suspicious findings  or urine cytology positive: rigid cystoscopy under anaesthesia and bladder biopsies.€¢ No visible tumour in bladder on check flexible cystoscopy but positive cytology. Random bladder biopsies or PDD and investigation of extravesical locations ie. CTU, prostatic urethral biopsies.

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