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The Muscle-Invasive and Metastatic Bladder Cancer (MIBC) Modern Diagnosis and Treatment

Semir A. S. Al Samarrai

1) Epidemiology:

Bladder Cancer (BC) is the most common malignancy of the urinary tract and seventh most common cancer in men and the 17th in woman (1). Incidence varies between regions and countries (2). The world global age standardized mortality rate is 3 for men versus 1 per 100,000 for women (1). The incidence of BC has decreased in some registries possibly reflecting decreased impact of causative agents, mainly smoking and occupational exposure (4).

The mortality of BC has also decreased possibly reflecting increased standard of care (5).

Approximately 75% of patients with BC present with a disease that confined to the mucosa (Stage Ta, CIS) or submucosa (Stage 1). These categories are grouped as non-muscle-invasive bladder cancer (NMIBC). Non-muscle invasive BC has a high prevalence due to low progression rates and long-term survival in many cases. Patients with muscle-invasive bladder cancer (MIBC) are at higher risk of cancer-specific mortality (3). The prevalence of BC is among the highest of all urological malignancies (1).

2) Risk Factors:

Increasing evidence suggests that genetic predisposition has a significant influence on bladder cancer incidence especially via its impact on susceptibility to other risk factors (3, 6). Tobacco smoking is the most important risk factor for BC, accounting for ?50% of cases (3, 7). Tobacco smoke contains aromatic amines and polycyclic aromatic hydrocarbons, which are renally excreted. Occupational exposure to aromatic amines, polycyclic aromatic hydrocarbons and chlorinated hydrocarbons is the second most important risk factor for BC, accounting in the modern era for ?10% of all cases. Such occupational exposure occurs mainly in industrial branches processing paints, dye, metal and petroleum products (3, 8-10).

The relation between the personal hair dye use and BC risk remains uncertain; increased risk has been suggested in users of permanent hair dyes with NAT2 slow acetylation phenotype (12, 13).


A papillary Bladder tumour confined to the interior layer (Mucosa) is classified as stage (Ta) according to the tumor, Node, Metastasis (TNM) classification system. Tumours that have invaded the inner layer (lamina propia) once classified as Stage T1. Ta and T1 tumours can be removed by transurethral resection (TUR), and therefore they are grouped under the heading of Non-Muscle-Invasive Bladder Cancer (NMIBC) for therapeutic purposes. Also included under this heading are flat, high-grade tumours that are confined to the interior layer (mucosa), and classified as CIS (Tis). However, molecular biology techniques and clinical experience have demonstrated the highly malignant potential of CIS and T1 lesions. Therefore, the terms NMIBC and superficial BC are suboptimal descriptions.

The tumour stage and grade should be used for therapeutic purposes.

The histological grading of all bladder urothelial carcinomas was proposed and published by the WHO in 2004 (15, 16), this classification includes the flat lesions as urothelial hyperplasia, reactive urothelial atypia, dysplasia and CIS. Among Non-Invasive papillary urothelial lesions, the 2004 WHO grading differentiates between papillary urothelial neoplasm of low malignant potential (PUNLMP) and low-grade and high-grade urothelial carcinomas.

Papillary urothelial neoplasm of low malignant potential (PUNLMP) are defined as lesions that do not have cytological features of malignancy but show normal urothelial cells in papillary configuration. Although they have a negligible risk for progression, they are not completely benign and still have a tendency to recur. 3) Diagnosis:

A. Patient history should be taken and recorded for all important information with possible connection to Bladder Tumour; including risk factors and history of suspect symptoms.

B. Symptoms: Hematuria is the most common finding in NMIBC. Ta, T1 tumours do not cause bladder pain and rarely present with lower tract symptoms (LUTS). In patients who do complain of these symptoms particularly in these with irritative LUTS refractory to symptomatic treatment, CIS might be suspected.

C. Physical Examination: the physical examination does not reveal NMIBC but only huge urothelial tumour invades the bladderwall and another organs.

D. Imaging:

a) Intravenous Urography (IVU): Large exophytic tumours maybe seen as filling defects in the bladder

b) Computed Tomography (CT): This investigation give more information than IVU does (including status of lymph nodes and neighboring organs)

c) Ultrasonography (US): The US is often used as the initial tool to assess the urinary tract. The transabdominal US permits characterization of renal mass, detection of hydronephrosis, and visualization of intraluminal masses in the bladder. It can be as accurate as IVU for diagnosis of upper urinary tract obstruction (17).

US is therefore a useful tool for detection of obstruction in patients with haematuria, however, it cannot exclude the presence of upper tract tumours.

CIS cannot be diagnosed with imaging methods (IVU, CT urography or US).

d) Urinary Cytology: Examination of voided urine or bladder-washing specimens for exfoliated cells has high sensitivity in low-grade-tumour. As a result of loss of cell cohesion in the epithelial lining of the bladder in CIS, there is a larger number of floating cells in the urine, as well as a high degree of anaplasia. The sensitivity of cytology for CIS detection in 28-100% (18).

Cytology is thus useful when a high-grade malignancy or CIS is present. Positive voided urinary cytology can indicate a urothelial tumour anywhere in the urinary tract, from the calyx to the ureters, bladder, and proximal urethra.

Negative cytology, however, does not exclude the presence of a tumour in the urinary tract.

e) Urinary molecular marker test: Driven by the low sensitivity of urine cytology, extensive laboratory research has developed numerous urinary tests for BC detection (19-25).

Considering the frequency of cystoscopy for follow-up, markers for recurrent urothelial cancer would be especially useful.

Microsatellite analysis is the most promising of the methods listed in the Table below (26-28).

f) Cystoscopy: The diagnosis of papillary Bladder Tumour ultimately depends on cystoscopic examination of the bladder and histological evaluation of the resected tissue.

CIS is diagnosed by a combination of cystoscopy, urine cytology, and histological evaluation of multiple bladder biopsies (29). Cystoscopy is initially performed in the clinic. A flexible instrument with topical intraurethral anaesthetic lubricant instillation results in better compliance, especially in men (30). Careful inspection of the whole urolthelial lining in the bladder should be performed to prevent missing the tumour.

If a bladder tumour has been visualized in earlier imaging studies, diagnostic cystoscopy can be omitted because the patient will undergo TUR (31).

g) Transurethral resection of Ta, T1 bladder tumours: The goal of the TURB in Ta, T1 BC is to make the correct diagnosis and remove all visible lesions.

It is crucial procedure in the diagnosis and treatment of BC.

The strategy of resection depends on the size of the lesion. Small tumours (<1cm) can be resected en bloc, which includes the entire tumour and part of the underlying bladder wall. Larger tumours should be resected separately in fractions, including the exophytic part of the tumour, the underlying bladder wall with the Bladderwall (detrusor) muscle, and the edges of the resection area. This approach provides good information about the vertical and horizontal extent of the tumour and helps to improve resection completeness (32).

Deep resection is not necessary in small, apparently low-grade lesions with previous history of low-grade Ta (GI) tumour.

The specimens from different biopsies and resection fractions must be referred to the pathologist in separate containers and labeled separately, to enable him/her to make a correct diagnosis. Complete and correct TURB is essential to achieve a good prognosis (33). It has been confirmed that absence of detrusor muscle in the specimen is associated with a significantly higher risk of residual disease and early recurrence (34).

h) New TURB techniques: Compared to monopolar resection, the bipolar electrocautery system may reduce the risk of complications (e.g., bladder perforation � due to obturator nerve stimulation) (35).

i) New methods of tumour visualization: As a standard procedure, cystoscopy and TUR are performed using white light. However, the use of white light can lead to missing lesions that are present but not visible, which is why new techniques are being developed.

Photodynamic diagnosis (fluorescence cystoscopy)

Photodynamic diagnosis (PDD) is performed using violet light after intravesical instillation of 5-amino-laevulinic acid (ALA) or hexaminolaevulinic acid (HAL). It has been confirmed that fluorescence-guided biopsy and resection are more sensitive than conventional procedures for detection of malignant tumour, particularly for CIS (36, 37).

In summary, PDD improves tumour detection rate, particularly in CIS. HAL but not ALA fluorescence-guided TURB was shown to have a beneficial effect on disease recurrence rate.

j) Second resection: The significant risk of residual tumour after initial TURB of Ta, T1 lesions has been demonstrated (33, 38). Persist disease after resection of T1 tumours has been observed in 33-53% of patients (38-43). Moreover, the tumour is often understaged by initial resection. The likelihood that a T1 tumour has been understaged and muscle-invasive disease detected by second resection ranges from 4 to 25%.

There is no consensus about the strategy and timing of second TURB. Most authors recommend resection at 2-6 weeks after initial TURB. The procedure should include resection of the primary tumour sites.

Adjuvant Treatment

Although state-of-the-art TUR by itself can eradicate a Ta, T1 tumour (NMIBC) completely, these tumours commonly recur and can progress to Muscle-Invasive Bladder Tumour (MIBC). The high variability in the 3-month recurrence rate indicate that TUR is incomplete on provokes recurrences in a high percentage of patients (33). It is therefore necessary to consider adjuvant therapy in all patients.

The Intravesical Bacillus Calmette-Guerin (BCG) immunotherapy

Five meta-analysis has confirmed that BCG after TUR is superior to TUR alone or TUR and chemotherapy for prevention of recurrence of non-muscle-invasive tumours (46, 47-50).

Induction BCG instillations are classically given according the empirical 6-weekly schedule that was introduced by Morales in 1976 (51). For optimal efficacy, BCG must be given in a maintenance schedule (44-46, 50). Many different maintenance schedules have been used, ranging from total of 10 instillations given in 18-weeks, to 27 over 3 years.


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Professor Doctor of Medicine-Urosurgery, Andrology, and Male Infertility
Dubai Healthcare City, Dubai, United Arab Emirates.
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