Bladder Neoplasm

21
Bladder Neoplasm


Kawa Omar1, Nawal Shamim Khan2, and Muhammad Shamim Khan1,3,4


1 Department of Urology, Guy’s & St. Thomas’ Hospital, NHS Foundation Trust, London, UK


2 Final Year Medical Student, Oradea University, Oradea, Romania


3 MRC Centre for Transplantation, King’s College London, King’s Health Partners, London, UK


4 Guy’s & St. Thomas’ Hospital, NHS Foundation Trust, King’s College, London, UK



Abstract


Bladder cancer is the most common urothelial malignancy. More than 90% arise from the transitional cell lining of the urinary tract. The remainder of the histological variants include squamous cell cancer, adeno carcinoma, and other rare tumours. Urothelial cancer is associated with smoking and exposure to industrial carcinogens. This cancer generally affects people who are older and who have many comorbidities, which makes their management more challenging.


More than two‐thirds of the urothelial cancers are non‐muscle–invasive bladder cancer (NMIBC) confined to the mucosa or submucosal layers of the bladder wall and remainder are muscle‐invasive bladder cancer (MIBC). NMIBC have tendency to recur, and the risk of recurrence varies between 15 and 80% and the majority of the recurrences occur within 6–12 months. Hence, intensive surveillance with cystoscopy and imaging of the urinary tract is required, which in turn incurs a high cost to the healthcare systems. The NMIBC cancers are classified based on their risk of recurrence and progression into low, intermediate, and high risk to tailor subsequent management and surveillance. In addition to the initial transurethral resection, intravesical therapies in the form of chemotherapy, immunotherapy, or a combination are used to reduce recurrence or progression of the disease.


For MIBC or high‐risk NMIBC, radical cystectomy and urinary diversion is the mainstay of treatment. Radical cystectomy is a life‐changing operation and is associated with significant perioperative morbidity and mortality. Therefore, experts in the field are striving to minimise the morbidity of the procedure by using minimal invasive techniques of laparoscopy or robotic surgery in combination with enhanced recovery pathways to expedite recovery.


There remains a risk of recurrence even after radical cystectomy due to micrometastasis. Various chemotherapy regimens have been used to decrease this in the neoadjuvant and adjuvant settings. Neoadjuvant chemotherapy has so far provided 5–8% absolute survival benefit at the expense of significant morbidity. In patients unfit or unwilling to undergo radical cystectomy, bladder preservation is an alternative which includes external beam radiotherapy and chemotherapy after transurethral resection. There is not enough evidence to prove the equivalence of this to radical surgery.


In those with advanced or metastatic disease, patients are put on palliative care pathway because the natural history of the disease is poor with four to six months expected survival. However, some newer immuno‐therapies that inhibit the interaction between programmed death ligand 1 (PD‐L1), present on the surface of tumour or antigen‐presenting cells, and programmed death 1 (PD‐1), present on the surface of activated lymphocytes, are offering new hope to the patients with advanced disease. In some cases of locally advanced cancer, palliative cystectomy can be performed for control of recurrent bleeding.


Keywords: bladder cancer; transitional cell carcinoma; non‐muscle–invasive bladder cancer; muscle‐invasive carcinoma; diagnosis and management of bladder cancer


21.1 Bladder Neoplasm


21.1.1 Incidence


Bladder cancer is the ninth‐most common cancer worldwide. Nearly 429 800 new cases were diagnosed in 2012, accounting for 3% of all the cancers [1]. It is the fifth‐most common cancer in Europe. About 151 000 new cases were diagnosed in 2012, accounting for 4% of all cancers diagnosed that year. The highest incidence of bladder cancer in males is found in Belgium and amongst females in Hungary. In the UK, bladder cancer incidence is the lowest of all males in Europe and 13th lowest in females.


21.1.2 Aetiology


21.1.2.1 Modifiable Risk Factors



  1. Carcinogens: Amongst the numerous causative factors for bladder cancer, the most significant are smoking and occupational exposure to carcinogens. Risk of bladder cancer is 3.8 times higher in current smokers compared with never smokers [2]. Some 37% of bladder cancers in the UK are linked to tobacco smoking [3]. Smokers who develop bladder cancer are incapable of detoxifying the tobacco‐tar carcinogens (4‐aminobiphenyl and 2‐naphthylamine) due to deficiency of N‐acetyl transferase and glutathione S‐transferase M1 (GSTM1) in the liver [4]. The toxic effect of smoking reduces slowly over time with consequences lasting up to nearly 20 years after ceasing smoking. However, the risk is reduced by 40% after four years after smoking cessation.

    Industrial carcinogens have been known to cause bladder cancer since 1895 when Rehn first observed carcinogenesis in aromatic hydrocarbons industry such as the aniline dye workers [5]. Nitrosamines‐linked occupational bladder cancer has led many first‐world countries to stop the use of naphthylamines. It is estimated that about 7% of male and 2% of female bladder cancers can be attributed to occupational exposure [6]. There is a long latency interval of 20–40 years between carcinogen exposure and development of subsequent disease. Therefore, it is often difficult to identify the potentially offending chemicals [7]. Vitamins A and C may play a role in blocking nitrosamine formation from everyday consumables.


    Other occupations that may also be relevant include [8]:



    1. Rat‐catchers (alpha‐naphthylthiourea contaminated with 2‐naphthylamine)
    2. Textile workers (carcinogenic dyes)
    3. Polyurethane plastics industry – car bumpers and soles of shoes (methylenebis(2‐chloroaniline) [MBOCA])
    4. Laboratory workers (benzidine)
    5. Leather work
    6. Printing (used car oil)
    7. Aluminium refining
    8. Machine turning (mineral oil)
    9. Lorry drivers (diesel)
    10. Hairdressers (dyes)
    11. Amateur anglers (maggots stained with chrysoidine)

  2. Social deprivation and ethnicity: Poor socioeconomic conditions are known to be associated with higher risk of bladder cancer [9]. Age‐standardised rates (ASR) for white males are higher (approximately 20 per 100 000) compared to Asian males (6.5–10.1/100 000) and black males (5.6–9.6 per 100 000) [10].
  3. Obesity: Bladder cancer incidence is reported as being 9% higher in patients with body mass index >30. This association is more likely to be limited to males and may be confounded by smoking in this patient population [11, 12].
  4. Chronic irritation: Spinal cord injury predisposes one to bladder cancer due to chronic irritation caused by indwelling urinary catheters, urinary tract infections (UTIs), or bladder calculi [13]. About 1% of patients with spinal cord injuries with indwelling catheters develop bladder cancer [14]. There is well‐known association of schistosomiasis infection with bladder cancer (squamous cell carcinoma [SCC]) and in countries with high prevalence more than 40% of patients with bladder cancer have schistosomiasis [15].
  5. Radiation of the pelvis: approximately 3% of bladder cancers in the UK are attributable to radiation exposure, predominantly diagnostic radiation [3].
  6. Chemotherapy: Bladder cancer risk in women is twice higher due possibly to cyclophosphamide therapy for systemic sclerosis [16]. The tumours can occur years after cyclophosphamide exposure (>10) and is due to the irritation and damage from its metabolite acrolein. Bladder cancer risk is also reported to be threefold greater amongst renal transplant recipients [17].
  7. Human papillomavirus: Bladder cancer risk is up to 2.8 times higher amongst those with human papillomavirus infection. Incidence is three times more common in men who have viral Condylomata acuminata [18, 19].
  8. Diabetes mellitus: Risk of bladder cancer is 20% higher in people with Type 2 diabetes who have been on long‐term therapy with pioglitazone. This increased risk is not associated with other people who do not have diabetes [20]. The risk of bladder cancer in patients with Crohn’s disease has doubled [21]. Excessive analgesic consumption [8] and nitrosamines are considered risk factors for bladder cancer. A high index of suspicion should be held for patients who often have a long history of chronic urinary infection and chronic cystitis [22].

21.1.2.2 Nonmodifiable Risk Factors


Some nonmodifiable risk factors include:


Age: Bladder cancer is more common in the elderly, probably due to the long latency period needed for carcinogenesis with some of the modifiable risk factors.


Sex: Although this was mainly due to exposure of men more than women to the modifiable risk factors, now the incidence is equalising.


Race: People of Afro‐Caribbean descent are less susceptible to bladder cancer than Caucasians; however, people of Afro‐Caribbean descent have a poorer prognosis


Genetic: Genetic abnormalities have been linked to increase bladder cancer; these include deletions of chromosomes 9 (p16 gene), 11, 13 (retinoblastoma [Rb] gene), and 17 (p53 gene) leading to inactivation of tumour suppressor genes such as p53 mutations, Rb gene mutations, and p16 cyclin‐dependent kinase inhibitor gene. In addition, but to a lesser degree, activation of oncogenes such as p21 ras, c‐myc, c‐jun, and erbB‐2, and increased expression of vascular endothelial growth factors (VEGF), leading to increased angiogenesis, also have a role. Deletion of chromosome 9 is associated with low‐grade superficial cancer, while p53 mutations and RB loss with high‐grade disease.


21.1.3 Clinical Features


Visible haematuria (VH) is the presenting symptom in nearly 80–90% of patients. Nonvisible haematuria (NVH) accounts for 5–15% of patients and about 10–15% patients present with lower urinary tract symptoms such as frequency, urgency, dysuria, and suprapubic pain and recurrent UTIs. About 5% have symptoms of advanced or metastatic disease such as anaemia, uraemia obstructive uropathy with renal failure, lower limb oedema due to lymphatic or venous obstruction, bone pain, weight loss, or cachexia. Pneumaturia is highly suggestive of a colovesical fistula. In the early phase of the disease, very few to no signs can be found. While in late cases, induration or mass in the suprapubic region may be felt on rectal examination [23].


21.1.4 Investigations


As the main presenting feature is haematuria, all patients with VH and NVH with symptoms will need full urological investigating to rule out cancer, while patients with NVH with no symptoms will need their investigations tailored.


As general guide, all patients with VH and symptomatic NVH will need urine dipstick with and without urine cultures, upper tract ultrasound, and a flexible cystoscopy, with patients >40 years of age requiring contrast computed tomography (CT) scans. Asymptomatic patients with NVH will need urine dipstick with and without urine cultures, upper tract ultrasound, and a flexible cystoscopy; if those come back clear, there is no need for further investigations.


Patients with persistent NVH do not need repeated investigations; however, if estimated glomerular filtration rate (eGFR) is <60 ml min−1, protein‐to‐creatinine ratio < 50 (or proteinuria), or blood pressure > 180 mm Hg, a nephrology review is warranted. IgA nephropathy is the most common cause of NVH in patients <40 years of age.


21.1.4.1 Urine Cytology


Urine for cytology must be fixed in formalin; otherwise, cytolysis makes interpretation difficult. The cytological features of malignancy include increased nuclear‐to‐cytoplasm ratio or clumps of multinucleate cells. False‐positive findings occur with urothelial injury (e.g. by a stone). Nuclear enlargement is better assessed by flow cytometry [24]. Improved sensitivity of cytology is achieved if three separate specimens on three consecutive days are analysed. The sensitivity is reported to be 9% in grade 1 (G1) tumours, 32% in grade 2 (G2) and in high‐grade lesions sensitivity is up to 90% and specificity 98–100% [25, 26]. However, false‐positives occur due to infection, inflammation, stones, instrumentation and catheterization, intravesicular instillations, and in patients who had previous radiotherapy.


21.1.4.2 Urinary Biomarkers


Specific bladder cancer urinary markers have recently been shown to increase the detection rates of bladder cancer using noninvasive methods. Enzyme‐linked immunosorbent assay (ELISA) tests for bladder tumour antigen or nuclear matric protein 22 increase the sensitivity for detecting transitional cell cancer (TCC). ImmunoCyt has a high sensitivity for low‐grade cancers, fluorescence in situ hybridization (FISH) (urovysion) detects chromosome nine mutations, leading to increased detections. Despite the progress made in urinary biomarkers, they still remain costly and do not replace cystoscopy. Therefore, direct visualisation of the bladder tumour remains the gold standard.


21.1.4.3 Imaging


21.1.4.3.1 Ultrasound

Ultrasound assessment of the kidneys and bladder has largely been replaced with CT urography. As sensitivity of ultrasound for detection of ureteric and pelvic tumours is low, most patients require a CT urogram [27].


21.1.4.3.2 Intravenous Urogram

Traditional intravenous urograms (IVUs) have almost entirely been replaced with CT urography. Standard IVU may show filling defects in the upper urinary tract and bladder as well as ureteric obstruction which usually signifies invasion of the muscle [27].


21.1.4.3.3 CT

A CT, besides assessing the local stage, may show enlarged pelvic lymph nodes and other metastases [28].


21.1.4.3.4 Magnetic Resonance Imaging

The main advantage of magnetic resonance imaging (MRI) in staging bladder tumours over CT is its ability to distinguish between oedema and infiltrating cancer [29].


21.1.4.3.5 Bone Scan

Bone scan is not routinely performed in bladder cancer. If a patient is symptomatic or liver function tests are abnormal, specifically the alkaline phosphatase, a bone scan can be performed to rule out metastasis.


21.1.4.4 Cystoscopy


Unless a tumour is clearly demonstrated on ultrasound or CT urogram, the next investigation for haematuria or suspected bladder cancer is a cystoscopy.


21.1.4.4.1 Flexible Cystoscopy

Flexible cystoscopy has revolutionised outpatient assessment of the lower urinary tract under local anaesthesia. Flexible cystoscopes can be classified as fibrescopes because they contain fibre‐optic bundles within a flexible shaft that illuminate the viewing area and transmit images to the eye piece. In these cystoscopes tip deflection is up to 210º.


Digital flexible cystoscopes use a video chip instead of fibres. Focusing is not necessary as video chip delivers a uniform‐focused picture with a high optical resolution. The tip of these is only 9.8 F and hence easier to insert.


21.1.4.4.2 Rigid Diagnostic Cystoscopy

Technological advances in optical diagnosis of bladder cancer have exploited the physical properties of light and biochemical principles to enhance diagnostic yield of the procedure.


Narrow band imaging (NBI) involves filtration of white light into two distinct bands: blue (415 nm) and green (540 nm) with different penetration depths. The blue band enhances the superficial capillary network, whereas the green component enhances the visibility of deeper vessels. As tumours are vascular, the contrast between the tumours and the normal bladder is enhanced by NBI [30, 31].


NBI‐assisted resection of the bladder tumours improves complete surgical removal of the bladder tumours compared to resection with white light cystoscopy (WLC) [32].


Photodynamic diagnostic cystoscopy (PDD) involves administration of 5‐aminolevulinic acid (5‐ALA), which bypasses the rate limiting step in the biosynthesis of heme. It induces high levels of proto‐porphyrin IX (PpIX) in mitochondria of neoplastic or highly proliferating cells. PpIX is an effective photo‐sensitizer. Lipophilic derivative of 5‐ALA, hex aminolevulinic acid (HAL) has better penetration of cell membranes and interstitial spaces producing twice as good fluorescence in half long dwell time compared at a concentration that is 45 times lower [33].


Fluorescence is caused by interaction of light (photons) with the outer electrons of fluoro‐chromes. Fluorochromes absorb light with higher energy per photon and re‐emit light with lower energy per (secondary photon). This produces a shift in colour between excitation and fluorescent light. A special endoscope system which has a xenon lamp and is equipped with blue filter illuminates the bladder cavity. A gel cable is used for light transmission as light intensity is higher. Scope and camera head are fitted with additional filters to increase contrast and sharpness of the images. Pp IX + blue light (high energy 400 nm) = red fluorescence (low energy 640n.).


PDD is more sensitive in detecting additional tumours (by 20%) than WLC (Figure 21.1). This is particularly the case in patients with carcinoma in situ (by 23%). PDD‐assisted tumour resection achieves better clearance of the tumours, and hence, reduced the risk of residual tumours (WLC = 1 : 2 vs PDD = 1 : 7). This translates into longer recurrence‐free survival [34]. However, the higher diagnostic sensitivity with PDD does not translate into improved recurrence‐free survivals [35].

Image described by caption.

Figure 21.1 Showing difference between white light cystoscopy (WLC) and blue light cystoscopy (BLC).


21.1.5 Transurethral Resection


Transurethral resection of bladder tumour (TURBT) is the most common oncological operation in urological surgery, usually performed under general anaesthesia (GA) with full muscle relaxation. In patients unfit for GA, the procedure can be carried out under spinal anaesthesia. Bimanual examination should be performed before and after resection routinely, to assess palpable masses that can give an indication of the stage (no palpable mass post‐TURBT: T2 disease; palpable mass: T3l fixed mass: T4).


This procedure has three clear objectives [36]:



  1. Removal of all the visible tumours
  2. Establishing type of the tumour and grade
  3. Accurate pathological staging

There is a tendency in many units to delegate the procedure to junior team members without any supervision, resulting in need for repeat resections due to the higher rate of residual tumours left and variable rates of recurrence at three months (single tumours 0–36% and multiple tumours 7–75%) [37]. Recurrences detected at the first follow‐up cystoscopy may represent residual tumour rather than recurrence. Hence, recurrence at the first check cystoscopy is regarded as one of the surrogate markers of quality of resection. This is also an important prognostic marker for subsequent recurrences and progression in higher grade and T1 disease [38, 39].


Small tumours may be removed with a single stroke of the resectoscope loop (Figure 21.2). In resecting a larger bladder tumour, one should keep to a regular plan [40].

3 Illustrations depicting a small papillary tumour removed with a divot of underlying muscle with a single stroke of the retoscope (a and b), with the base coagulated (c).

Figure 21.2 (a and b) A small papillary tumour can be removed with a divot of underlying muscle with a single stroke of the resectoscope. (c) The base is coagulated.


The first step is to find the edge of the stalk by trimming away the overhanging papillary bush at one side (Figure 21.3). Once the edge has been found, the base of the stalk is coagulated with the roly‐ball electrode to seal the vessels in the stalk; the rest of the resection then becomes relatively bloodless.

2 Illustrations depicting the overhanging bush of a tumour resected (left) and its stalk coagulated (right)

Figure 21.3 To reach the stalk of a larger tumour the overhanging bush must be resected (a), then the stalk can be coagulated (b).


The resection is continued by following the edge of the stalk all round carrying the strokes of the resectoscope from the periphery towards the centre, to keep the margin of the stalk cleanly cut and prevent the bush from overhanging. Eventually, the entire bush will have been removed. The chips are now evacuated and sent to the laboratory in formalin labelled ‘bladder tumour’.


A second deliberate resection is then performed of the base of the stalk to sample the deeper layers of muscle. This tissue is sent separately labelled as ‘deep tumour base’ to help the pathologist stage the tumour (Figure 21.4). The base is thoroughly coagulated with the roly‐ball to seal off blood vessels and destroy any malignant cells that may have been left behind. Haemostasis must be complete.

Illustration depicting the stalk resected and sent separately to assist in staging the tumour.

Figure 21.4 After removing the bush, the stalk is resected and sent separately to assist in staging the tumour.


If the tumours are situated on the lateral wall of the bladder near the base, there is a risk of obturator nerve stimulation, which in turn can cause perforation or bleeding due to the sudden jerking movement as the thigh muscles are stimulated (obturator supplies the adductors of the thigh). Risk can be reduced by anticipating potential obturator stimulation, low intensity short bursts of the current, avoiding overfilling the bladder and even leaving it slightly underfilled, and using muscle relaxation to paralyse the patient. After removal of a small tumour, a catheter is not always necessary, but for larger tumours it is wise to leave an irrigating catheter in place for 24 hours.


21.1.5.1 Complications


Complications of TURBT include:



  1. Infection and bleeding
  2. Small perforations of the detrusor are of little consequence; in fact, as a complete resection needs to include detrusor muscle, small perforations can be deemed as part of the procedure with an intent to cure. A minor extravasation of the irrigant will soon be reabsorbed, so long as the catheter is draining freely.
  3. Large perforations will need repair, especially if into peritoneal cavity; laparotomy will be required for closure of the hole in the bladder and to detect and repair any potential diathermy injury to the adjacent bowel (Figure 21.5). If the perforation is extraperitoneal, a leaving urinary catheter in situ for 10–21 days will be sufficient.
  4. Transurethral syndrome: fluid overload can occur with large tumours
  5. Urethral strictures if the resectoscope was forcibly entered causing urethral trauma.
Image described by caption.

Figure 21.5 (a and b) A moderate sized bladder tumour on computed tomography (CT); (c–e) CT cystogram showing preformation post‐transurethral resection of bladder tumour (TURBT) with contrast leaking outside the bladder.


Source: Photographs courtesy of Dr Neil Collins Southmead Hospital.


21.1.5.1.1 Very Large Papillary Tumours

Papillary tumours may fill the whole bladder. In these unusual situations, it is best to plan a staged resection (Figures 21.6 and 21.7). If the tumour proves to be of lower grade and noninvasive then one should proceed to clear the residual tumour. On the contrary, if the tumour is of higher grade or invasive radical cystectomy would be the treatment of choice [41, 42].

3 CT Cystograms depicting a very large bladder tumour occupying the majority of the bladder.

Figure 21.6 Very large bladder tumour occupying the majority of the bladder.


Source: Photographs courtesy of Dr Neil Collins Southmead Hospital.

Cystogram displaying a large leiomyoma presenting with obstructive uropathy.

Figure 21.7 A large leiomyoma presenting with obstructive uropathy.


21.1.5.1.2 Large Solid Tumours

There is little point in attempting to resect a large solid tumour completely because some permutation of radiation, chemotherapy, or cystectomy is going to be needed. A few deep bites should be taken from the rolled edge of the tumour for the purpose of staging and grading (Figures 21.6 and 21.7).


21.1.5.1.3 Tumours in the Diverticula

On performing a cystoscopy for haematuria in a bladder with diverticula, it is important to get a good look inside each of them. Cancer inside a diverticulum may cause erythema and also oedema of the edge of the opening causing complete closure. Imaging (MRI/CT) is advisable in suspected tumours within diverticula with a narrow neck [43].


21.1.5.1.4 Re‐resection in High‐Risk NMIBC

Repeat transurethral resection two to six weeks after initial resection can increase recurrence‐free and progression‐free survival by completely clearing any residual tumours or reducing the risk of under staging particularly in cases of T1 tumours whereby up to 25% are understaged T2 tumours. The principal indications for re‐resection TURBT include:



  1. Incomplete initial resection – extensive tumour or complication requiring early termination of the procedure.
  2. High‐grade tumours (G3 or T1)
  3. Absence of adequate muscle (muscularis propria) in the specimen

21.2 Field Biopsies


These are not recommended as a routine, but should be obtained in the following situations;



  1. Positive urine cytology in the absence of a visible tumour.
  2. Nonpapillary exophytic tumour.
  3. Abnormal appearance of urothelium.

Prostatic urethral biopsies are indicated if



  1. Positive cytology but no visible tumour in the bladder.
  2. Multifocal tumours in the bladder or bladder neck.
  3. Carcinoma in situ (CIS) at the bladder neck or trigone.
  4. Visible abnormalities in the urethra.
  5. Patient who is a potential candidate for orthotopic bladder substitution.

These biopsies should be sent in separate containers for pathologic assessment. The biopsy sites should be coagulated to stop bleeding.


21.3 Pathology


21.3.1 Benign Lesions of the Bladder


Many benign lesions of the bladder pose diagnostic challenge on endoscopic examination. The definitive diagnosis relies on histology (Table 21.1).


Table 21.1 Benign lesions of the bladder.



















































Postoperative spindle cell nodule

  1. Reactive spindle cell proliferation at the site of a previous surgical procedure, evident about 4 months after the procedure.
  2. Friable nodule on cystoscopy
  3. Microscopically – interlacing bundles of unremarkable spindle cells with background of inflammation, haemorrhage, oedema, neo‐vacularisation, and myxoid change [44].
Inflammatory pseudo‐tumour

  1. Appears as a broad‐based polyp.
  2. Histologically similar to spindle cell nodule but may involve full thickness of the bladder.
  3. No history of previous surgery in these patients
  4. Differential diagnosis includes leiomyosarcoma and or sarcomatoid carcinoma [45].
Urothelial hyperplasia

  1. Flat or papillary.
  2. Papillary hyperplasia – mucosa is thrown into folds but without secondary branching of papillary structures. These are lined by benign papillary epithelium with increased thickness of more than seven layers [46].
Nephrogenic metaplasia

  1. Reactive mucosal lesion associated with trauma, stones, infection, or a recent surgical procedure.
  2. Single or multiple sessile or papillary lesions ranging 1–4 cm
  3. Differential diagnosis – mucin producing adenocarcinoma or papillary urothelial carcinoma.
  4. Histologically it may be cystic, papillary or polypoid. The cells lining the tubules and cysts are however uniform and benign showing no mitotic activity [47].
Ectopic Prostate

  1. Cystoscopy – papillary or polypoid lesion either on trigone or bladder neck.
  2. Histologically similar to the prostate gland covered by normal urothelium [48].
Fibro‐epithelial polyp Commonly a solitary polyp composed of a fibromuscular core with scanty inflammatory infiltrate covered by normal urothelium.
Amyloidosis

  1. Primarily from the bladder without evidence of systemic amyloidosis.
  2. Primary bladder amyloidosis – sessile or nodular lesion on cystoscopy.
  3. Microscopically there is deposition of amyloid within the submucosal and muscle layers of the bladder.
  4. Systemic disease – amyloid deposition is mainly in the blood vessels and lamina propria [49].
Endometriosis

  1. Found in 1% of patients with pelvic disease.
  2. Most patients are asymptomatic.
  3. Symptomatic patients – increased urinary frequency, dysuria, and haematuria. Almost 50% of patients have a lower abdominal mass on examination.
  4. Cystoscopy – blue, red, black, or brown cysts.
  5. Microscopically lesion consists of glandular spaces lined by endometrial epithelium surrounded by a variable amount of endometrial stroma [50].
Endocervicosis

  1. Müllerian lesion involving the bladder after a Caesarean section.
  2. Storage symptoms, lower abdominal pain, or haematuria.
  3. Cystoscopy – mucosal nodules
  4. Microscopically consist of mucin containing glandular structure involving the detrusor muscle lined by a single layer of cuboidal or columnar epithelium [51].
Villous adenoma

  1. Exophytic papillary tumour which usually has a mucinous surface.
  2. Microscopically it is composed of papillary structures lined by atypical columnar epithelium mixed with goblet cells.
  3. Once removed, they do not tend to recur [52].
Papilloma As per WHO Criteria, for a lesion to be qualified as papilloma, it should have the following five features:

  1. Size <2 cm in greatest dimension
  2. Number: Usually solitary with one or more fine fibromuscular cores
  3. Lining: architecturally and cytologically normal urothelium
  4. Intact umbrella cell layer and no mitotic figures
  5. Patients younger than 50 years

Bladder papilloma accounts for less than 3% of the papillary lesions It has a single layer of cells, with no malignant cytological features, and an intact basement membrane [53].
Inverted papilloma

  1. Rare tumour (accounts for <1% of the bladder neoplasms)
  2. May vary in size from small sessile or pedunculated lesion to as large as 8 cm mostly on the trigone.

On histology, it consists of urothelial cells growing downward into the lamina propria forming nests, sheets or cords which may contain occasional luminal spaces containing mucin secretions. There is minimal cytological atypia or mitosis. Although the risk of recurrence is <1% it should be followed up carefully [54].
Haemangioma

  1. Occur in all sizes and may cause profuse haemorrhage.
  2. Commonly in males younger than 30 years. May be associated with cutaneous haemangiomas.
  3. Cystoscopy – collection of veins, often confined to one side of the bladder or as purple nodules which may mimic endometriosis or melanoma varying in size from 2 to 10 cm. Respond very well to coagulation with diathermy or the neodymium‐yttrium aluminium garnet (YAG) laser [55].
Leiomyoma

  1. Benign lesion arising from the bladder muscle.
  2. Commonly affects females and children but can occur in men.
  3. Can present with voiding difficulties or rarely with upper tract obstruction. Grossly it can be sessile or polypoid and vary in dimensions from less than 4 cm to much larger size.
  4. Composed of spindle cells with cigar shaped nuclei and pink cytoplasm [56].
Neurofibroma

  1. Usually associated with generalised neurofibromatosis (von Recklinghausens disease).
  2. Predominantly affects males
  3. These can be sessile or pedunculated and solitary or multiple. Composed of elongated spindle cells with thin nuclei and fibrillar matrix [57].
Granular cell tumour

  1. Believed to be of Schwann cell origin as the cytoplasm demonstrates positive immunostatining with S‐100 protein.
  2. Grossly appears as yellow white submucosal nodule and microscopically consists of polygonal cells with pink cytoplasm [58].

21.4 Malignant Tumours of the Bladder


Malignant tumours can be classified into primary and secondary. The primary can be further divided into urothelial and nonurothelial tumours. The majority of primary bladder cancer (>95%) arises from the epithelium.


21.4.1 Primary Tumours


21.4.1.1 Urothelial Neoplasm


For classification of the urothelial tumours and its variants (Table 21.2) [59].


Table 21.2 Classification of urothelial (transitional cell) neoplasms including variants of urothelial carcinoma.

































































































I.
Urothelial (transitional cell) neoplasia

A. Benign


i. Transitional papilloma (WHO [2002]/ISUP; WHO, 1973, grade 0)


ii. Inverted papilloma

B. Papillary urothelial neoplasm of low malignant potential (WHO [2002]/ISUP; WHO, 1973, grade I)

C. Malignant


i. Papillary


 a. Typical (low grade or high grade, WHO [2002]/ISUP; WHO 1973, grade I, II and III)


  1. Variant


   (a) With squamous or glandular differentiation


 b. Micropapillary


ii. Nonpapillary


 a. Carcinoma in situ


 b. Microinvasive carcinoma


 c. Frankly invasive carcinoma


  1. Variants containing or exhibiting


   (a) Squamous differentiation


   (b) Glandular differentiation


   (c) Deceptively benign features








      • Nested pattern








      • Small tubular or glandular pattern








      • Microcystic pattern








      • Inverted pattern


   (d) Micropapillary histology


   (e) Sarcomatoid foci (‘sarcomatoid carcinoma’)


   (f) Urothelial carcinoma with unusual cytoplasmic features








      • Clear cell (Glycogen rich)








      • Plasmacytoid








      • Rhabdoid








      • Lipoid rich


   (g) Urothelial carcinoma with trophoblastic differentiation


   (h) Unusual stromal reactions








      • Pseudosarcomatous stroma








      • Stromal osseous or cartilaginous metaplasia








      • Osteoclast‐type giant cells








      • With prominent lymphoid infiltrate


(i) Urothelial carcinoma with multiple patterns of divergent differentiation
II.
Undifferentiated Carcinoma


i. Small‐cell carcinoma


ii. Large‐cell neuroendocrine carcinoma


iii. Lymphoepithelioma‐like carcinoma


iv. Osteoclast‐rich carcinoma


v. Giant cell carcinoma


vi. Not otherwise specified

21.4.1.2 Urothelial Dysplasia


Urothelial dysplasia may represent an early phase in the sequence of evolution to malignant change in the bladder. It is characterised by cell crowding and loss of cell polarity. The changes within cell structure include enlargement and variation in the shape of the nuclei, whereas the nucleoli remain small. Additional features include coarsening of the chromatin and hyperchromasia and absence of mitosis.


21.4.1.3 Carcinoma in Situ


CIS is a flat lesion featuring severe cellular atypia, which is a form of noninvasive urothelial carcinoma. The hallmark of CIS is loose cells, which easily slough off, thus making urine cytology a reliable test. CIS is primary when occurs in isolation, concurrent when it is associated with exophytic tumours, or secondary when occurring in patients with a history of previous tumour. At cystoscopy, CIS may appear entirely normal or at worse, slightly injected, resembling ordinary bacterial cystitis, and looks like velvety patch on cystoscopy [60].


21.4.1.4 Papillary and Solid Urothelial Carcinoma


Other tumours arising from urothelium are either papillary or solid. Some urothelial cancers are however non‐papillary and classified as (i) a papillary growth, (ii) a solid nodule, or (iii) an ulcer. In general, the less differentiated the tumour, the more solid and ulcerated it becomes. Bladder tumours may be single (60%) or multiple (40%) and sometimes are associated with urothelial tumours of the kidney pelvis and ureter. The rare variants of the urothelial tumours include:



  • Nested
  • Microcystic
  • Inverted growth pattern
  • Giant Cell
  • Lymphoepithelioma‐like
  • Lymphoma like
  • Sarcomatoid

21.4.1.5 Nonurothelial Tumours


Most of the tumours arising from urothelium are TCCs. Neoplastic transformation in metaplastic transitional epithelium leads to squamous cell and adenocarcinoma. Primary nonurothelial tumours account for less than 5% of all bladder malignancies in the Western world.


These tumours include:



  1. Squamous cell carcinoma: This arises in areas of urothelium that have undergone metaplasia due to chronic irritation such as is usual in bilharziasis, long‐term catheters, bladder stones, or recurrent UTIs. It is preceded by keratinising squamous metaplasia (leucoplakia), also called ‘squamous pearls’ [61]. This needs to be distinguished from the ‘squamous metaplasia’ of the trigone, which is a normal finding in many women and is not pre‐malignant [62]. Mutations in the p53 and retinoblastoma (RB) genes have also been implicated.
  2. Adenocarcinoma: Primary adenocarcinoma of the bladder may originate in the bladder or urachus. Nonurachal adenocarcinoma accounts for the majority of tumours (80%). The urachus is the foetal allantois, a continuation of the hindgut. It is usually lined by columnar epithelium and almost invariably gives rise to adenocarcinoma arising from the dome or outside the bladder invading into the dome (Figure 21.8). Elsewhere, adenocarcinoma arises in areas of urothelium that have undergone metaplasia through the intermediate stage of cystitis cystica and cystitis glandularis [63]. Adenocarcinoma is classified according to its cellular features into enteric, mucinous or colloid, signet ring, clear cell, mixed, and nonspecific subtypes. Presentation is either of haematuria, bloody discharge from the umbilicus, or as a subumbilical mass. Treatment is by a partial cystectomy with excision of the median umbilical ligaments and umbilicus.
  3. Lymphoma: Primary lymphomas of the bladder account for 0.2% of extranodal disease. The majority of the patients are women in sixth or seventh decades of life presenting with haematuria or storage symptoms. Bladder involvement may be diffuse or appear as polypoid lesion. Immunohistochemistry helps in clinching the diagnosis and classification of the type of lymphoma. The variants include mucosa‐associated lymphoid tissue (MALT), diffuse large cell, small cell, and rarely, Hodgkin lymphoma [64]. Involvement of the bladder can be secondary to the systemic disease.
  4. Plasmacytoma: This may be part of the multiple myeloma or primarily a bladder lesion called ‘plasmacytoma’. It appears as sessile or pedunculated mural nodule with intact overlying mucosa. On histology, it appears as sheets of atypical cells. Solitary plasmacytoma is radiosensitive lesion with low risk of recurrence. Almost 25% patients with terminal leukaemia have bladder involvement [65].
  5. Melanoma of the bladder can be primary or secondary, usually presenting with haematuria. Lesions vary in size and appear as polypoid fungating lesions usually with dark pigmentation. They are composed of polygonal or spindle‐shaped cells with some pigment, and diagnosis is supported if immunostaining for s‐100 protein and HMB45 is positive [66, 67]
  6. Paraganglioma (Pheochromocytoma): This lesion usually affects adolescents or young adults. There is no sex predilection. About 50% patients may experience symptoms caused by catecholamine release on bladder filling or voiding (i.e. paroxysmal hypertension during micturition). The manifestations include tachycardia, headache, and dizziness or fainting. On cystoscopy, the lesion is intramural and varies in size. If suspected, TURBT should be avoided because the procedure can lead to a hypertensive crisis. Paragangliomas are usually lobulated, well circumscribed, yellow‐brown or pink, and composed of nests of cells (zellballen) with nuclei, which may be round or oval but bland. The cells contain abundant cytoplasm. Up to 15% of these paragangliomas are malignant [68, 69]. Treatment is by a partial cystectomy.
  7. Rhabdomyosarcoma: This presents with painful frequency in children and until recently was almost uniformly fatal. It is important to be aware of its existence and make sure the child is referred to a specialist paediatric urological centre, where today a survival rate of 55% may be obtained by a combination of systemic chemotherapy and radiation; the bladder can be preserved in more than half of these cases.
Image described by caption.

Figure 21.8 Urachal adenocarcinoma arising from the dome of the bladder along the rout of the foetal allantois to the anterio‐abdominal wall.


Source: Photographs courtesy of Dr Neil Collins Southmead Hospital.


21.4.2 Secondary Bladder Tumours


Secondary bladder involvement from neoplasms of the other organs either by direct spread or metastases accounts for 13% of the bladder lesions. Of these almost 75% are direct extension from surrounding organs such as colon, rectum, prostate, ovary, or uterine cervix. Nearly 17% are metastases from distant sites or infiltration by haematological malignancies (11%). Metastases accounts for slightly more than 2% tumours, and the most common sites include stomach, breast, kidney, and lung. These lesions are generally asymptomatic but rarely may be the first manifestation of a systemic disease.


21.5 Grading of Transitional Cell Carcinoma


Bladder cancers are classified into three grades G1, G2, and G3 [70]. Flow cytometry gives a more objective measure of ploidy [71, 72]. The following Table 21.3 compares the histological characteristics of the different grades.


Table 21.3 Characteristics of different grades of urothelial cancer.

















































Features G1 G2 G3
Orderliness Intact Slight variation Complete loss
Architecture Minimal change Variable change Loss of normal architecture
Nuclei Uniform, normal spacing Moderate nuclear crowding, variation of polarity Pleomorphic
Chromatin Finely granular Hyperchromasia Variable
Urothelium Normal maturation, polarity and cohesiveness Variable Loss of polarity and cohesiveness
Nucleolus No enlargement Mild enlargement Abundant enlargement
Cellular Polarity Normal Mild loss of polarity Loss of polarity
Mitosis Rare Present Abundant

21.5.1 Grading ISUP/WHO2004


Grading of tumours is according to the WHO/ISUP 2004 classification:



  1. Urothelial papilloma
  2. Papillary urothelial neoplasm of low malignant potential (PUNLMP)
  3. Low‐grade papillary urothelial carcinoma
  4. High‐grade papillary urothelial carcinoma

21.6 Staging of Bladder Tumours


TCC is staged using tumour, node, and metastasis (TNM) classification, the details are provided in Table 21.4 and (Figure 21.9).


Table 21.4 TNM staging of bladder cancer.


























































T (Primary Tumour)
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ: ‘flat tumour’
Ta Noninvasive papillary carcinoma
T1 Tumour invades subepithelial connective tissue
T2

  • T2a
  • T2b
Tumour invades muscle (muscularis propira)
Tumour invades superficial muscle (inner half)
Tumour invades deep muscle (outer half)
T3

  • T3a
  • T3b
Tumour invades beyond muscluaris propira into perivesical fat
Microscopic invasion
Macroscopic invasion
T4

  • T4a
  • T4b
Tumour invades other adjacent structures
Tumour invades any of: prostate, uterus, vagina, bowel
Tumour invades pelvic wall or abdominal wall
N (Regional lymph nodes)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single lymph node in the true pelvis (below the common iliac bifurcation) (hypogastric, obturator, external iliac, or presacral)
N2 Metastasis in multiple lymph nodes in the true pelvis (below the common iliac bifurcation) (hypogastric, obturator, external iliac, or presacral)
N3 Metastasis in common iliac lymph node(s)
M (Distant metastasis)
M0 No distant metastasis
M1 Distant metastasis

TNM, tumor, node metastasis.

Illustration of the staging of bladder cancer depicting carcinoma in situ, non-invasive papillary carcinoma, tumour invades superficial muscle, etc. over the layers of bladder lumen, lamina propria, etc.

Figure 21.9 Staging of bladder cancer.


21.7 Risk Stratification after Transurethral Resection of Bladder Tumour


The risk of recurrence and progression of non‐invasive–muscle bladder cancer (NMIBC) is dependent on many variables; therefore, risk stratification is helpful in rationalising management. A multivariate analysis of the European Organisation for Research and Treatment of Cancer (EORTC) trials led to the development of a scoring system to calculate the short‐ and long‐term risks of recurrence and progression based on available clinical and pathological data (Tables 21.5 and 21.6) [73]. Main prognostic factors are the size and number of the tumours, recurrence history, histological type, and grade, stage, and presence of flat lesions (CIS). Recurrent tumours, high‐grade T1 tumours, and recurrence at the three‐month cystoscopy are significant independent predictors of muscle‐invasive disease [74].


Table 21.5 Variables and assigned scores in European Organisation for the Research and Treatment of Cancer (EORTC) nomogram.


























































































Factor Recurrence score Progression score
Number of tumours
Single 0 0
2–7 3 3
≥8 6 3
Tumour size
<3 cm 0 0
≥3 cm 3 3
Prior recurrence rate
Primary 0 0
≤1 per year 2 2
>1 per year 4 2
T classification
Ta 0 0
T1 1 4
Carcinoma in situ
No 0 0
Yes 1 6
Grade (1973 WHO)
G1 0 0
G2 1 0
G3 2 5
Total score 0–17 0–23

Table 21.6 Risks of recurrence and progression.

















































Probabilities (95% CI)
Total score At 1 year (%) At 5 years (%)
Recurrence
0 15 (10–19) 0
1–4 24 (21–26) 1–4
5–9 38 (35–41) 5–9
10–17 61 (55–67) 10–17
Progression
0 0.2 (0–0.7) 0
2–6 1.0 (0.4–1.6) 2–6
7–13 5 (4–7) 7–13
14–23 17 (10–24) 14–23

The pitfalls of this nomogram include:



  1. This table was based on a combined analysis of individual patient data with superficial bladder cancer included in seven EORTC trials.
  2. Most of their patients were treated with chemotherapy, and in the 171 treated with bacillus Calmette‐Guérin (BCG) therapy, no maintenance was administered.
  3. The tables overestimate the risk of recurrence and progression in patients treated with BCG (for the reason cited previously).
  4. Very few cases of were CIS included; hence not accurate in assessing risk of recurrence and progression in CIS

21.8 Treatment of Transitional Cell Carcinoma


21.8.1 Non‐Muscle–Invasive Bladder Cancer


This group constitutes more than 75% of the bladder tumours. Of these 60% are Ta, 30% are T1m, and 10% are CIS. Following even an adequate TURBT of NMIBC, risk of recurrence is in the range of 15–80% (Table 21.7). Most of the recurrences occur within 6–12 months after initial resection. Recurrences are generally of the same stage, but 10–15% of these tumours can progress to a higher grade or stage and even metastasise [75]. Thus transurethral resection of the tumour as monotherapy is an inadequate treatment. To reduce the risk of recurrence and progression, adjuvant therapies are required in the form of intravesical chemotherapy or immunotherapy. Checking cystoscopy in three months’ time is essential because it can demonstrate either incomplete resection or recurrence. If clear, then future recurrence is <30%.


Table 21.7 Risk stratification of bladder cancer and recommended treatment options.




























Risk Group Components Risk of recurrence Risk of progression Recommended treatment options
Low Risk G1pTa
G2pTa
Low‐grade tumours
PUNLMP
<3 cm in size
Solitary tumours		 15–30% 0–15% TURBT
Single MMC instillation within 24 hours (better within 1 hour of TURBT)
Intermediate Risk Recurrent tumours within 12 months
High‐grade tumours
>3 cm in size
Multiple tumours		 >70% 10–15% TURBT
Course of MMC installations (six doses, once weekly)
High Risk G3
T1
CIS
Nest or micorpapillary subtypes (highly aggressive)		 >80% >40% TURBT
Re‐Resection TURBT
Course of BCG (total 27 doses) or Cystectomy

BCG, Bacillus Calmette‐Guerin; MMC, Mitomycin C; TURBT, transurethral resection of bladder tumour.


21.8.2 Intravesical Chemotherapy (Mitomycin)


Instillation of a single dose of Mitomycin immediately following TURBT in patients thought to have NMIBC eliminates residual tumour cells and prevents reimplantation of tumour cells in other areas of urothelium [76]. Mitomycin C (MMC) is an antibiotic agent that inhibits DNA synthesis. It is produced by Streptomyces caespitosus or lavendula bacterium. The standard dose is 40 mg in 50 ml of saline instilled for about an hour after TURBT. This has to be administered in the 24 hours after the initial resection.


A single instillation reduced the overall recurrence by 35% and reduced 5‐year recurrence rate from 58.8 to 44.8%. This benefit was not observed in patients with >1 recurrence in a year or EORTC recurrence score ≥ 5. The single instillation does not prolong either time to progression or death from bladder cancer. Hence, it is not advisable to administer intravesical agents to patients at high risk of recurrence because of its lack of efficacy in this subgroup [76].


Although a single instillation is considered sufficient in low‐risk disease, it is inadequate for patients with higher‐risk NMIBC [77]. MMC is beneficial in reducing the risk of recurrence but does not decrease risk of progression [78–80]. A six‐week course of MMC can be offered to patients with newly diagnosed intermediate risk.


The efficacy of chemotherapeutic agent can be enhanced by reducing the urine output with preinstillation restriction of fluid intake and dissolving the drug in a buffered solution at optimal pH [81].


21.8.2.1 Contraindications: Bleeding or Bladder Perforation


Bladder irritation as a side effect is seen in nearly 15% of patients, presenting with suprapubic or back pain, dysuria, frequency, urgency (similar symptoms to cystitis, which it normally gets confused with and is treated with antibiotics; however, symptoms settle with time, ergo presuming an infection was treated). With rashes and itching where the chemicals came in contact with skin. Flulike symptoms can occur. Systemic toxicity is rare but leads to significant consequences of bone marrow suppression: neutropenia, thrombocytopenia, and anaemia.


21.8.2.2 Adjuvant Therapy with Bacillus Calmette‐Guérin


Calmette and Guérin developed BCG as a live attenuated vaccine for tuberculosis originally. In 1929, Pearl noted fewer numbers of malignancies at autopsy studies in patients dying of tuberculosis. The landmark publication by Morales in 1976 on intravesical BCG in the treatment of bladder cancer changed the landscape of managing high‐risk NMIBC including CIS [82]. Although there are still gaps in understanding of the anti‐cancer mechanism of BCG, it is attributed to interplay of direct cytotoxic effects of BCG on the host immune response, leading to stimulation, activation, and upregulating of the immunity. A summary of key steps is presented in Table 21.8 [83].


Table 21.8 Summary of mode of action of intravesical Bacillus Calmette‐Guerin (BCG).
















Steps in BCG activity Mediated by


  1. Infection of urothelial or bladder cancer cells
Fibronectin


  1. Induction of immune reaction
Cell types: granulocytes, T‐helper cells, dendritic cells and macrophages.
Immune molecules: MHC class I, CD4+, various cytokines including IL‐1, IL‐2, IL‐6, IL‐8, IL‐10, IL‐12, IL17, TNF‐á, and IFN‐ã.


  1. Induction of anti‐tumour effects
ThI cells (acquired immunity) via CD4+ cells and CD8+ cytotoxic T lymphocytes (driven by IL‐2, TNF, IL‐12 and IFN‐ã)
Th2‐cell (innate immunity) through NK cells (driven by IL‐4, IL‐5, IL‐6 and IL‐10)
Neutrophil recruitment (via IL‐17 release) and macrophages

IL; interleukin, MHC; major histocompatibility complex, NK; natural killer, TNFα; tumour necrosis factor‐alpha, IFNϒ; Interferon gamma.


BCG is more efficacious in reducing risk of recurrence compared to intravesical chemotherapy. BCG may delay or prevent progression in high risk tumours by 27% and reduces recurrence by 31%. This risk reduction is observed in a spectrum of high‐risk G3, T1, and CIS. BCG therapy involves a period of induction, generally once weekly for six weeks followed by maintenance therapy. BCG (80 mg in 50 ml saline) is instilled into the bladder for one hour, at least two weeks after TURBT. There is no consensus on the optimal maintenance schedule. At least one year of maintenance BCG is required to demonstrate its superiority over Mitomycin in preventing recurrence as well as progression [84]. The reduction in stage progression is only seen in patients who receive induction and maintenance BCG (for at least 27 treatments over three years) (Tables 21.9 and 21.10) [85].


Table 21.9 Induction intravesical Bacillus Calmette‐Guerin (BCG).



































Induction Course
Week 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Therapy BCG BCG BCG BCG BCG BCG




GA Cystoscopy and biopsy BCG BCG BCG

Table 21.10 Maintenance schedule of intravesical Bacillus Calmette‐Guerin (BCG).





















Maintenance
Month 6th 12th 18th 24th 30th 36th
BCG instillations 3 weekly 3 weekly 3 weekly 3 weekly 3 weekly 3 weekly

Nearly 60–70% of patients will have a complete response to BCG treatment, with two‐thirds of non‐responders and about 20% of initial responders maybe progressing to MIBC and requiring a radical cystectomy; however, they have a cure rate of >90%.


21.8.2.2.1 BCG Side Effects

About half of patients are able to complete the induction course of BCG with only one in six completing the full three years (27 doses) course [85].


BCG can cause either local irritation with cystitis symptoms in nearly all patients (95%). It can also be associated with a fever lasting a couple of days. Systemic side effects occur in nearly 25% of patients with flulike symptoms and myalgia. Treatment is with paracetamol and anticholinergics. Rarely, hospitalisation is required.


BCGosis, or BCG sepsis is rare (<5%), but it has devastating side effects. Patients develop a high‐grade fever, rigours, and progress to shock. In severe cases multiorgan failure may occur leading to death. Treatment is with anti‐tuberculous drugs for six months (i.e. isoniazid, rifampicin, ethambutol, and pyridoxine).


The risk of systemic toxicity is due to systemic absorption if BCG is administered within two weeks of transurethral resection of tumour, if patient is having active bleeding, or if BCG is administered after traumatic catheterisation. During six weeks of BCG instillations, immune stimulation peaks at six weeks, and during maintenance, at three weeks. The dose response is bell‐shaped and suggests that excess BCG may actually reduce the anti‐tumour activity [86, 87].


21.8.2.2.2 Other

Allergic reactions with arthralgia and conjunctivitis requiring antihistamine and stopping BCG if persists over seven days.


Granulomatous prostatitis or epididymitis, requires anti‐tuberculous treatment.


BCG is contraindicated in patients who are immunosuppressed or immunocompromised, pregnant, or breastfeeding, who have had a traumatic catheterisation, or a haematological malignancy.


The combination of intravesical BCG and intravesical electromotive drug administration (EMDA) MMC intravesical therapy has shown superior results to BCG alone; however, it is still being studied [88].


21.8.2.2.3 BCG Failure


  • BCG‐refractory: Recurrence or persistence of cancer after BCG induction treatment or presence of MIBC at first check cystoscopy.
  • BCG‐resistance: persistence of cancer at first check cystoscopy.
  • BCG‐relapse: recurrence after clearance after BCG induction treatment.

These patients will either need a radical nephrectomy or second‐line chemotherapy.


21.8.2.2.4 BCG‐Resistant CIS

The options for patients with CIS who will have recurrence subsequent to BCG therapy are:



  1. Radical cystectomy
  2. Thermo‐chemotherapy, 50–80%
  3. Intravesical gemcitabine, 50%
  4. Photodynamic therapy (Photofrin 1.5 mg/Kg) + Red Laser (630 nm) 15 J cm−2 ‐RR 75% (CIS)

Thermo‐chemotherapy involves uniform heating of the bladder by radiofrequency (microwave) radiation (Figure 21.10). The temperature will be monitored by thermocouples. Cooled Mitomycin is circulated into and out of the bladder.

Diagram of circuit of bladder thermos‐chemotherapy with parts labeled applicator, thermocouples, catheter, radiation, bladder, computer, monitor, peristaltic pump, thermocouples probe’s connection, etc.

Figure 21.10 A diagram of circuit of bladder thermos‐chemotherapy.


Adverse effects of thermo‐chemotherapy include local pain, haematuria, dysuria, and bladder contracture.


21.8.3 Photodynamic Therapy


It relies on photosensitization of cancerous cells with subsequent administration of light of a specific wavelength in the presence of oxygen. These interactions lead to generation of free radicals causing cell death through apoptosis. Additionally, acute inflammatory response enhances cytotoxicity of this therapy similar to BCG therapy [89].


21.8.4 Adjuvant Intravesical Chemotherapy


The anatomical design of bladder renders it most suitable for treatment with intravesical administration of anti‐tumour agents and subsequent monitoring of the response with follow‐up cystoscopies. This is essentially a topical therapy which minimises the systemic toxicity of these agents due to limited absorption. Table 21.11 shows the list of drugs used.


Table 21.11 Follow‐up of non‐invasive–muscle bladder cancer (NMIBC).
















Recurrence or progression risk Recommendation
Low risk

  • Check cystoscopy at 3 months
  • If negative, the following cystoscopy at 9 months
  • Consideration for either yearly check cystoscopies thereafter or discharge
Intermediate risk

  • Patients should have an intermediate follow‐up scheme (low & high risk) adapted according to individual factors
  • Check cystoscopy at 3 months
  • If negative, the following cystoscopies at 9 and 18 months
  • If negative, yearly cystoscopy checks for 5 years
  • Consideration for either yearly check cystoscopies thereafter or discharge
High risk

  • Cystoscopy at 3 months.
  • If negative, flexibly cystoscopy 3 monthly for 2 yrs.
  • 6 monthly for 2 yrs.
  • Yearly thereafter
  • A yearly assessment of the upper tract is recommended

21.8.4.1 Failure of Intravesical Therapy


If BCG and chemotherapy have failed to suppress multiple recurrences, cystectomy is the best option for those few patients with well‐differentiated tumours which are too numerous or extensive to resect. Radiation is futile, so that the patient can be offered a continent urinary diversion.


21.8.5 Follow‐up of NMIBC


Because majority of the bladder tumours are NMIBC (Ta or T1), they can be managed by endoscopic treatment, but in view of the tendency to recur, they need careful follow‐up. A graphic record of the tumour site, grade, and T stage of each recurrence and number of recurrences should be maintained for continuity of care. Follow‐up regimes are based on the risk stratification of each patient (Table 21.12) [90]:


Table 21.12 Intravesical chemotherapies and their characteristics.














































Drug Type of agent Molecular Mass Dose Side effects Advantage/Disadvantage
Thiotepa Alkylating 189.23 g mol−1 30 mg Myelosuppression Inexpensive
Mitomycin C DNA crosslinker 334.33 g mol−1 40 mg Skin rashes
Bladder calcification		 May work when other drugs have failed
Expensive
Doxorubicin Anthracycline anti‐tumor antibiotic 543.52 g mol−1 50 mg Chemical cystitis
Haematuria
Fever
Epirubicin Anthracycline 543.519 g mol−1 80 mg Chemical cystitis
Haematuria		 Lower risk of myelosuppression
Gemcitabine Nucleoside analogue 263.198 g mol−1 2000 mg/twice a week Cystitis
Myelosuppression		 May salvage some patients who failed with BCG

BCG, Bacillus Calmette‐Guerin.


Any recurrent tumours are biopsied and resected or coagulated with laser or diathermy. Very‐low‐risk tumours in high‐risk patients may be managed with laser coagulation under local anaesthesia or even surveillance. When tumours recur often, and in large numbers one should have high index of suspicion of seeding from the upper tract. This should be assessed with appropriate imaging (CT urography). Blue light cystoscopy (BLC) is helpful in achieving complete clearance. Once all visible tumours have been removed, adjuvant intravesical therapy may help in reducing the recurrences. The high rate of tumour recurrence in patients with NMIBC mandates lifetime surveillance and leads to high healthcare‐related costs despite the use of adjuvant intravesical therapy.


21.9 Muscle‐Invasive Bladder Cancer


Almost a third of patients have MIBC at presentation. Patients with NMIBC may also progress to MIBC. Prognosis of patients varies with the stage of the disease and status of the pelvic nodes. MIBC confined to the bladder muscle (T2) without evidence of the lymph node metastases and absence of lymphovascular invasion has an almost 90% disease‐free survival at five years. On the contrary, this is reduced to 40–50% in patients with locally advanced disease (PT3‐T4) and 15–35% in those with lymph node metastases [91].


Despite advancement of surgical technique, little progress has been made in improving the outcome of MIBC. The majority of patients succumb to systemic disease (22%) despite excellent local control with surgery (7% recurrence) [92]. This suggests that a significant number of patients have micrometastatic disease at diagnosis. Hence, research is focusing on methods of eradicating occult micrometastasis with perioperative chemotherapy in MIBC.


21.9.1 Spread of Bladder Tumours


21.9.1.1 Direct Spread


Bladder cancer spreads directly through the perivesical fat into adjacent bowel, uterus, and bone. It also spreads across the wall of the bladder probably by direct implantation – ‘kiss cancer’ [93].


21.9.1.2 Urine‐Borne Spread


Tumours may be carried down the urethra and implanted onto abrasions caused by the passage of urethral instruments and are often implanted near the air‐bubble presumably because particles of tumour are carried there at the time of transurethral resection [93].


21.9.1.3 Lymphatic Permeation


Spread by lymphatic permeation, embolism carries the tumour to the regional nodes along the branches of the internal iliac artery, and from there, along the para‐aortic nodes.


21.9.1.4 Haematogenous Spread


Blood‐borne spread by veins is a late event in bladder cancer, but occasionally it is seen even in well‐differentiated and apparently superficial tumours which unexpectedly give rise to pulmonary or other distant metastases.


21.9.1.5 Prostatic Route


Once a bladder cancer has invaded the prostate, it can spread by lymphatics and veins directly into the bone marrow of the pelvis, femora, and lumbar vertebrae.


21.9.2 Investigations in MIBC


After the initial investigations for investigation of bladder cancer, in patients established to have MIBC, a CT of the chest, abdomen, and pelvis or MRI is required to stage the disease. Bone scan is not routinely performed, but it can be useful in patients with suspected bone metastasis. These scans should be performed during the preceding six weeks prior to considering cystectomy because rate of disease progression can be fluid.


21.9.3 Management of Localised Muscle‐Invasive Bladder Cancer (MIBC) (T2 disease + − T3a)


Radical cystectomy with appropriate urinary diversion remains the mainstay of surgical treatment for MIBC. In those who are unfit or unwilling for surgery, external beam radiotherapy (EBRT) may be of use. Radical cystectomy has traditionally been performed through the open approach, but in recent years, minimally invasive surgical (MIS) approaches for cystectomy (laparoscopic or robotic) has been increasingly adopted worldwide in an attempt to reduce the morbidity of the procedure and improve postoperative recovery.


Parra et al. reported the first cystectomy performed laparoscopically in 1992 [94]. Since then, the operation has been widely adopted in many urological centres. Improved dexterity has aided pelvic lymph node dissection and suturing in laparoscopy. With the advent of da Vinci (Intuitive) robotic systems, which utilises a master–slave concept and three‐dimensional visual planes, Menon et al. [95] carried out the first robot‐assisted radical cystectomy (RARC) in 2002.


The technique of robotic‐assisted cystectomy is to mimic movements of the surgeon through the arms of the ‘slave’ robot in the abdomen and pelvis. In this technique, the bladder is dissected and pelvic lymph node dissection is performed. The urinary diversion was initially performed extracorporeally, but the improvement in surgical skills has also enabled intracorporeal urinary diversions. However, robotic systems are expensive and are often inaccessible for many centres.


Lymphadenectomy is the integral component of radical cystectomy. Interestingly, there are considerable variations in outcomes with well‐defined templates of lymphadenectomy. This is due to lack of standardisation of pathologic assessment of the tissue removed, variation in the number of regional lymph nodes in individual patients, and the quality of dissection amongst surgeons despite defined templates [96].


There is a therapeutic benefit of extended lymphadenectomy in patients with locally advanced disease (pT3), with 30% improvement of five‐year disease‐free survival regardless of the nodal status [97].


The surgical technique of a radical cystectomy begins with a long midline incision, then adhesions are separated. The peritoneum is divided to mobilise the caecum and mesentery (Figure 21.11). The bowel is packed away from the pelvis. The incision in the peritoneum is continued anteriorly to separate the bladder from the symphysis and allow the bladder to be retracted medially. If not already done, a bilateral node dissection is performed, taking the lymph nodes medial to the common and external iliac artery (Figure 21.12). The internal iliac artery is cleaned on one side and all its medial branches are ligated and divided one after the other (Figures 21.13 and 21.14). The ureters are divided and marked with stay sutures. The same procedure is repeated on the other side.

2 Illustrations depicting the peritoneum mobilized on the right side (left) and the left side (right) to reveal bifurcation of the aorta and iliac vessels with their lymph nodes.

Figure 21.11 (a and b) The peritoneum is mobilised on either side to reveal the bifurcation of the aorta and the iliac vessels with their lymph nodes.

Illustration depicting the lymph nodes dissected from the iliac vessels.

Figure 21.12 The lymph nodes are dissected from the iliac vessels.

Illustration depicting the common and internal iliac vessels cleaned, with parts labeled rectum, ureter, external iliac artery and vein, and vas deferens.

Figure 21.13 The common and internal iliac vessels are cleaned.

Illustration depicting the sleeve around the obturator nerve slit open to dissect off the lymph nodes.

Figure 21.14 The sleeve around the obturator nerve must be slit open to dissect off the lymph nodes.


Retracting the bladder upwards, the fat is carefully cleaned from the puboprostatic ligaments to define the retropubic veins which are meticulously taken up by suture ligature and divided (Figure 21.15). If one plans to retain the urethra, the neurovascular bundles may be pushed down and laterally, without compromising the dissection and may preserve penile erection in men (Figure 21.16). Lifting the bladder upwards and depressing the rectum, the plane of cleavage between the layers of Denonvilliers fascia is opened, and the dissection carried down behind the prostate and seminal vesicles, keeping clear of the rectum (Figure 21.17).

Illustration depicting the prevesical veins and symphysis defined and divided.

Figure 21.15 The dorsal veins are defined and divided.

4 Illustrations depicting the fascia incised on either side of the dorsal veins (a), the veins ligated (b), the neurovascular bundles displaced literally (c) and posteriorly revealing the urethra (d).

Figure 21.16 To spare the neurovascular bundle to the penis, (a) the fascia is incised on either side of the dorsal veins. (b) The veins are ligated. (c) The neurovascular bundles are displaced laterally and posteriorly to reveal the urethra (d).

Illustration depicting the bladder pulled up and the plane between the layers of fascia of Denonvilliers opened between the bladder and rectum.

Figure 21.17 The bladder is pulled up, and the plane between the layers of fascia of Denonvilliers is opened between the bladder and rectum.


If the urethra is to be removed, a second midline incision is made in the perineum (Figure 21.18). The corpus spongiosum is separated from the corpora cavernosa piecemeal, until the entire corpus spongiosum has been removed by turning the penis inside out (Figure 21.19).

Illustration depicting urethrectomy, with a midline incision made in the perineum.

Figure 21.18 Urethrectomy. A midline incision is made in the perineum.

3 Illustrations depicting the urethra progressively dissected off the corpora carnevosa (a and b) until penis turns inside out (c).

Figure 21.19 (a) The urethra is progressively dissected off the corpora cavernosa (b), until the penis is turned inside out (c).


The dissection of the membranous urethra is easiest from the perineum. In front, the bulbar arteries can be seen and ligated before being divided (Figure 21.20), as are the two dorsal arteries of the penis on either side of its dorsal vein. Once this has been done, each side of the membranous urethra is freed by dividing the tough fascial bands on each side. Finally, the urethra is pulled upwards, while one finger either side of the midline depresses the rectum, and throws into prominence the rectoprostatic ligament which is divided close to the prostate (Figure 21.21). The membranous urethra is now free and is drawn up into the pelvis, allowing the prostate to be separated from the rectum under vision.

2 Illustrations depicting the dorsal arteries and vein (left), and bulbar arteries (right) divided.

Figure 21.20 The dorsal arteries and vein (a), and the bulbar arteries (b) are divided.

Illustration depicting the rectum pushed down with 2 fingers to display the rectoprostatic ligament divided.

Figure 21.21 The rectum is pushed down with two fingers to display the rectoprostatic ligament which is divided.


The specimen is now free. The rest of the operation is determined by the choice of urinary diversion to be employed in the particular case.


21.9.4 Perioperative Chemotherapy


21.9.4.1 Neoadjuvant Chemotherapy


Patients with MIBC who have a good performance status and glomerular filtration rate (GFR) > 60 ml min−1 can receive neoadjuvant chemotherapy to downgrade the cancer as part of perioperative chemotherapy. The regimens used have only been of modest survival benefit in the range of 5–7%. A 10‐year follow‐up of MRC/EORTC trial of neoadjuvant CMV Phase 3 trial has demonstrated improved 10‐year survival from 30 to 36%. The combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy regimen has shown an improved survival of 77 months versus 46 months with surgery alone [98].


MVAC neoadjuvant chemotherapy is associated with significant toxicity such as leucopoenia, mucositis, and drug‐related mortality of 3–4% [99], but adding granulocyte colony‐stimulating factor has significantly improved safety profile [100]. Alternative combination of gemcitabine and cisplatin (GC) therapy has gained popularity as safer alternative after a study showing equivalent efficacy (GC = 49% and MVAC = 46%) but better safety profile [101]. However, there is no prospective study to date on comparative efficacy of this alternative regimen in the neoadjuvant setting. In an attempt to shorten the duration of therapy and improve the efficacy a dose‐dense (DD) regimen of MVAC, involving administration every two weeks instead of four weeks with growth factor support have been tried in the treatment of metastatic bladder cancer. Similar protocols have been used in neoadjuvant setting and reported to be well tolerated [102].


Currently three different drug regimens are used in the context of neoadjuvant setting for treatment of MIBC including: (MVAC), accelerated DD MVAC, or GC have similar efficacy with response rates of 40–60%. Patients with good performance status and no visceral disease, who account for 20% of patients with MIBC, are reported to achieve more durable remission rates [101, 103, 104].


Although evidence is in support of effectiveness of neoadjuvant chemotherapy in improving survival in patients with operable bladder cancer and negative lymph node based on radiological assessment (T2‐T4aN0M0) [105, 106], multi‐institutional studies revealed underutilization of neoadjuvant chemotherapy; with only around 15% of patients receiving ir [107].


Patients are not suitable candidates for neoadjuvant chemotherapy if they have impaired renal function, have bilateral obstruction of the upper urinary tract, or have intractable haematuria, severe lower urinary tract symptoms, or a poor performance status. Finally, patients may refuse to receive neoadjuvant chemotherapy and patient choice should always be considered.


21.9.4.2 Adjuvant Chemotherapy


Approximately half of patients undergoing curative cystectomy develop metastasis within two years [108]. Underutilization of neoadjuvant chemotherapy has prompted encouragement of adjuvant chemotherapy in patients who have not received neoadjuvant chemotherapy to improve outcomes. A meta‐analysis of cisplatin, has shown reduction of mortality by 23% with adjuvant chemotherapy. Similarly, Tjokrowidjaja et al. showed 25% risk reduction in mortality with adjuvant chemotherapy [106, 109]. The greatest effect of adjuvant chemotherapy is in extravesical extension (pT3a‐T4a) or patients with positive lymph node diagnosis [110]. One trial of MVAC has suggested a similar long‐term outcome between neoadjuvant and adjuvant chemotherapy [111].


Studies for patients with pT3a or pT4a with or without lymph node positivity randomised 327 patients to cisplatin and methotrexate (CM) against M‐VAC. The five‐year overall survival and tumour progression were not significantly different, although patient on the M‐AC arm had a higher rate of leucopoenia [112]. A phase III trial by the Association of Urogenital Oncology of adjuvant gemcitabine compared to usage after disease progression failed to show significant difference in three‐year overall survival [113].


Currently, no evidence is available to support usefulness of non‐cisplatin–based chemotherapy regimens in adjuvant setting. There is also lack of evidence to support the effectiveness of disease progression triggered adjuvant chemotherapy [114]. The International Consultation on Bladder Cancer in 2012, based on the available data, recommends that patients with pT3/4 or lymph node‐positive post‐cystectomy who have not received neoadjuvant chemotherapy could be considered for cisplatin‐based adjuvant chemotherapy if they are medically fit [105].


21.9.4.2.1 Bladder Preservation

Not all patients are fit for radical surgery or prefer such a life‐changing operation. The alternative to radical surgery is EBRT. The five‐year overall survival rates of concomitant radiation and chemotherapy in addition to TURBT demonstrates a median overall survival of 57% as compared to 52% in patients having a radical cystectomy [115].


21.9.4.2.2 Urethrectomy

The risk of urethral recurrence is <10%. In men, urethrectomy is considered if there is prostatic urethral involvement or positive distal urethral surgical margin of the specimen. Alternatively, a frozen section of the distal urethral margin can be done, proceeding to a urethrectomy if positive. In women, urethrectomy is considered standard practice.


21.9.4.2.3 Radiotherapy

There is no role for radiation as a monotherapy or in the neoadjuvant setting. Radiotherapy is currently used as component of multimodal treatment of MIBC in blade‐sparing strategy or for palliation of bladder cancer symptoms. The dose is 60–66 Gy to the bladder with 1.5–2 cm margin and also limited pelvic lymph nodes. EBRT is given once or twice daily in a course limited to six to seven weeks. A further booster dose to the bladder can also be given [116, 117].


Complications occur in the majority of patients (>70%); however it is self‐limiting in 95% of cases. These are radiation cystitis, radiation proctitis, urethral stricture, and haematuria. Rarely, haematuria due to radiation cystitis will require intravesical treatments with transurethral resection diathermy; however, it is invariably futile. Other measure includes intravesical alum, hyperbaric oxygen, segmental artery, or even iliac embolisation, or ongoing palliative cystectomy.


Radiotherapy is not recommended in the following situations:



  • Squamous cell bladder cancer.
  • CIS involving large areas of the bladder.
  • No response to initial chemotherapy.
  • Obstructed ureters.
  • Significant storage symptoms.
  • Upper tract obstruction [118].

Palliative radiotherapy at a lower dose of 30–50 Gy is effective for metastatic disease‐related symptoms such as bone pain and bleeding and with management of spinal cord compression.


21.9.4.2.4 Partial Cystectomy

Partial cystectomy (PC) has been categorised as a bladder‐sparing modality for MIBC. It is usually reserved for tumours in the dome or in anterior bladder wall and is particularly suited for patients with relatively small urachal tumours (Figure 21.8). PC includes full‐thickness excision of the tumour with pelvic lymph node dissection. It has been reported to have 39–67%, five‐year recurrence‐free survival [119]. However, these patients remain at risk of intravesical recurrence and therefore need close surveillance [120].


21.9.4.2.5 Brachytherapy

Brachytherapy has been used in selected group of patients with tumours less than 5 cm and distant from the bladder neck. A 5‐year and 10‐year overall survival of patient with T1–3 disease is around 62% and 45%, respectively [121]. Cancer‐specific survival 5 and 10 years after brachytherapy is 71 and 57%, respectively, compared to cystectomy with 76 and 64%, respectively [122]. However, these findings are limited due to the retrospective nature of the studies and variable patient population which drew up these figures. Therefore, it is difficult to draw any firm conclusions. However, in the future, brachytherapy may have potential for incorporation into a mainstay for bladder preservation.


21.9.4.2.6 Enhanced Recovery after Surgery for Cystectomy

Enhanced recovery after surgery (ERASC) is a multimodal approach to reduce postoperative complications and expedite recovery from surgery. There are four principles of enhanced recovery: preoperative planning and preparation, reducing stress of surgery, postoperative care, and early mobilisation [123].


21.9.4.2.7 Palliative Cystectomy

Management of locally advanced bladder cancer is a huge challenge. Locally advanced bladder cancer can be associated with debilitating symptoms such as bleeding, pain, severe voiding symptoms, and ureteric obstruction. The majority of patients are not eligible for radical surgery because operative management carries substantial morbidity [124].


Some studies have suggested that radical cystectomy can be offered in selected patients with reasonable general health [125–127]. Primary cystectomy in T4 bladder cancer is technically possible [128]; palliative cystectomy should only be offered when it is the only option available [129]. The alternatives are repeated transurethral resection or palliative radiotherapy or chemotherapy; palliation and nephrostomy insertion can also be offered to relieve urinary obstruction [130].


21.10 Recurrence and Follow‐up of MIBC


After cystectomy, patients remain at risk of cancer recurrence and are also prone to complications from urinary diversion. Therefore, they need adequate follow‐up after cystectomy. Knowledge of the patterns of recurrence is paramount to having an efficient monitoring strategy from a cost perspective and also to maximise detection of recurrences. A recurrence rate of 48.6% has been reported after radical cystectomy over an extended 20‐year follow‐up [131].


Most recurrences occur in the first two years after cystectomy. Recurrence can occur either locally in the pelvis, upper part of the urinary tract, urethra, or at distant anatomical locations [132]. The most common sites of distant metastases are lung, liver, and bone [133]. As expected, recurrence is dependent on the pathological stage of the disease [132], with risk being higher in locally advanced tumours and in case with a positive lymph node involvement [134].


Recurrence can be detected either on routine follow‐up tests or by symptoms such as flank pain and visible haematuria. There is a slight survival benefit for recurrences detected on routine follow‐up compared to recurrences identified as a result of symptoms. This justifies the need for routine cross‐sectional imaging [135]. Table 21.13 details the follow‐up schedule [136].


Table 21.13 Recommended follow‐up for bladder cancer after radical treatment (cystectomy or radiotherapy).










































Cancer stage Year 1 Year 2 Year 3 Year 4 Year 5
T1 History, physical examination, laboratory testing, upper tract ultrasound History, physical examination, laboratory testing, upper tract ultrasound History, physical examination, laboratory testing, upper tract ultrasound History, physical examination, laboratory testing, upper tract ultrasound History, physical examination, laboratory testing, upper tract ultrasound
T2 6 monthly: history and physical examination
Laboratory testing
Chest/abdo/pelvic CT scan
bone scan if symptomatic		 6 monthly: history and physical examination
Laboratory testing
Chest/abdo/pelvic CT scan
bone scan if symptomatic		 6 monthly: history and physical examination
Laboratory testing
Chest/abdo/pelvic CT scan
bone scan if symptomatic		 Annual:
history and physical examination
Laboratory testing
Chest/abdo/pelvic CT scan
bone scan if symptomatic		 Annual:
history and physical examination
Laboratory testing
Chest/abdo/pelvic CT scan
bone scan if symptomatic
T3 History and physical examination, laboratory study at 3 months, repeat 6 monthly.
CT at 6 and 12 months, upper tract imaging at 12 months		 6 monthly: history and physical examination
laboratory study
CT at 24 months
bone scan if symptomatic		 6 monthly: history and physical examination laboratory study
Chest/abdo/pelvic CT scan loopogram
bone scan if symptomatic		 Annual:
history and physical examination laboratory study
Chest/abdo/pelvic CT scan loopogram
bone scan if symptomatic		 Annual:
history and physical examination laboratory study
Chest/abdo/pelvic CT scan loopogram
bone scan if symptomatic
Radiotherapy Similar Follow up as for high‐risk NMIBC
History and physical examination, laboratory study
Chest/abdo/pelvic CT scan at 6 and 12 months		 Similar Follow up as for high‐risk NMIBC
History and physical examination, laboratory study
Chest/abdo/pelvic CT scan		 Similar Follow up as for high‐risk NMIBC
History and physical examination, laboratory study
Chest/abdo/pelvic CT scan		 Similar Follow up as for high‐risk NMIBC
History and physical examination, laboratory study
Chest/abdo/pelvic CT scan		 Similar Follow up as for high‐risk NMIBC
History and physical examination, laboratory study
Chest/abdo/pelvic CT scan
T4, metastatic
SCC, adenocarcinoma		 Symptomatic control

Laboratory study: renal function, FBC, liver function test, vitamin B12.


CT: CT to include chest, abdomen, and pelvis.


Bone scan is not a routine follow‐up study, it can only be performed in patients suspected of having bone metastasis.


FDG‐PET whole body is indicated for suspected or nodal metastasis.


CT, computed tomography; FDG‐PET, fluorodeoxyglucose‐positron emission tomography; NMIBC, non‐invasive–muscle bladder cancer; SCC, squamous cell carcinoma.


Upper urinary tract recurrence is in the range of 2–9% at median 24–41 months after cystectomy [137–141]. The risk factors for recurrence of urothelial cancer in the upper urinary tract are history of CIS, history of recurrent bladder tumours before cystectomy, and involvement of distal ureter in cystectomy histopathology. Fifteen‐year recurrence rate was 0.8% in the upper tract in patients without any risk factors, whilst rate of recurrence was found to be 8.4 and 13.5% for one to two risk factors and three to four risk factors, respectively. This risk was non‐existent for non‐TCCs of the bladder [142]. Therefore, the routine follow‐up should be based on risk factor stratification.


Suspicious findings on cross‐sectional imaging can be further investigated by ureterorenoscopy to obtain a histologic diagnosis. However, it has limitations in acquiring adequate amount of tissue to determine accurate extent of the tumour. In cases of invasive upper tract recurrence, radical nephroureterectomy may provide prolonged survival in patients [139].


Local recurrence rate is 5–16.5% over five years [143, 144]. About 50% of tumours metastasise without local recurrence. However, 70% of local recurrences are associated with distant metastasis. The prognosis from local recurrence is very poor; survival from diagnosis is four to eight months. Approximately 80% of patients die of disease within one year, and only 3.5% experience five‐year survival [145].


Recurrence rate in urethra at median 14–24‐months is 3.7–8.1%. Patients at high risk of urethral recurrences are those with positive urethral margins at cystectomy [146], bladder neck tumours, and tumours involving the vagina in females [147]. Routine follow‐up has not been shown to increase chance of earlier diagnosis in urethral recurrences. Urethral bleeding, mass, or pain should prompt thorough assessment by urethral washing and ureteroscopy. When recurrence occurs, the treatment option can be either fulguration for CIS and noninvasive tumours; or urethrectomy for invasive tumours [148, 149].


21.11 Management of Locally Advanced MIBC (T3b/T4) and Metastatic Disease (N1 or M1)


The natural history of metastatic bladder cancer has a median survival of four to six months. Survival is better in metastasis to lymph nodes, lung, and soft tissue compared to bone and liver [99, 150].


Poor prognostic indicators include Karnofsky performance status (<80), weight loss, elevated serum alkaline phosphatase or lactate dehydrogenase (LDH) levels, and non‐transitional cell histology [108, 150, 151]. Unfavourable outcomes are also associated with visceral metastasis [152] and multiple metastatic sites [103]. However, age alone has a negligible impact on response or toxicity to chemotherapy [153–159]. This led to introduction of combination regimens (MVAC) which achieved 36% complete response [160]. In a randomised trial, MVAC was compared with cisplatin alone and a superior response rate of 39 vs 12%, respectively, was achieved [99]. Combination of gemcitabine with cisplatin (GC), has however been shown to have improved response by 25–40% and are better tolerated than MVAC. GC combination is quickly becoming the standard chemotherapy regimen, with <1% toxic death rate as opposed to 3% with MVAC, mainly from neutropenic sepsis. Carboplatin can be used if cisplatin is contraindication such as those with poor performance status or eGFR <60 ml min−1. Taxanes, such as paclitaxel and docetaxel, are microtubule disassembly inhibitors and are used as second‐line agents, with responses ranging between 25 and 80% when used with cisplatin.


21.12 Bladder Cancer Variants


21.12.1 Squamous Cell Carcinoma


Squamous cell cancer is almost never diagnosed before it has invaded deeply into the wall of the bladder. The squamous cell cancer that occurs as a sequela of chronic bilharziasis is said to be unresponsive to radiation treatment. Treatment by radical total cystectomy has excellent results. Bilharzias is endemic in countries where the standard of living is poor, and few patients can afford urostomy appliances even if they would stick on in conditions of heat and moisture. This should be taken into consideration for the type of urinary diversion to be fashioned. Where squamous cancer is not associated with bilharziasis, it is also somewhat radioresistant, and total cystectomy is advised for cases with muscle invasion. The diagnosis of squamous cell cancer is usually obvious at cystoscopy; there is a thick dead white crust of keratin, and the urine has a characteristic and unforgettable stink.


21.12.2 Carcinoma of the Urachus


This rare carcinoma presents with haematuria (Figure 21.8). On cystoscopy, a cherry‐red swelling is seen in the vault near the air‐bubble. Bimanual palpation always shows a much larger mass outside the bladder than the lump seen on cystoscopy (Figure 21.22).

Illustration depicting a hand touching the large mass larger than the little cherry outside of the bladder formed by a carcinoma of the urachus.

Figure 21.22 A carcinoma of the urachus forms a mass outside the bladder much larger than the little cherry which is seen through the cystoscope.


Through a midline incision, the skin and anterior rectus sheath are separated (Figure 21.23), and then a wedge‐shaped en bloc excision is performed of all the tissues from the umbilicus downwards and outwards to the obliterated hypogastric arteries (Figure 21.24). This broad wedge of tissue is taken down to the trigone, leaving only a rim, perhaps 1‐cm wide, well clear of the dome of the bladder (Figure 21.25). This is closed over a catheter. It was shown more than 90 years ago that the bladder will regenerate to a normal capacity from this rim of trigone within a few weeks. There is no need to perform a total cysto‐prostatectomy or to enlarge the bladder with ileum or colon.

Illustration of a human body with a vertical midline incision separating the skin and anterior rectus sheath.

Figure 21.23 The incision for carcinoma of the urachus includes the umbilicus.

Illustration depicting a wedge‐shaped en bloc excision performed of all the tissues from the umbilicus downwards and outwards to the obliterated hypogastric arteries.

Figure 21.24 Most of the bladder, urachus, and the wedge of tissue extending to the obliterated hypogastric arteries on either side, is removed en bloc. The bladder is opened well away from the tumour.

Illustration depicting a narrow rim of bladder left around the trigone, with ureters marked with catheters.

Figure 21.25 Only a narrow rim of bladder is left around the trigone. The ureters are marked with catheters.


21.12.3 Cancer in a Diverticulum


The wall of a diverticulum is so thin that a tumour has only to penetrate the lamina propria, and it has gone through its wall (Figure 21.26). For this reason, tumours in diverticula have a sinister reputation, and even a small and apparently superficial one calls for wide partial cystectomy.

Illustration depicting a carcinoma in a very thin wall of diverticulum.

Figure 21.26 Carcinoma in a diverticulum. The wall is always so thin that invasion has usually occurred.


Through an adequate midline incision, the superior vesical artery on the side of the diverticulum is divided between ligatures to allow the lateral wall of the bladder to be rolled forwards. The bladder is opened and ureteric catheters are placed in both ureters to protect them. A wide cuff of bladder is removed including the orifice of the diverticulum (Figure 21.27). The diverticulum itself is removed together with all its surrounding fat and the internal iliac and obturator lymph nodes. The bladder is closed with drainage.

3 Illustrations depicting the bladder opened well clear of the diverticulum (a), the ureter marked with catheter, and a wide ellipse of bladder taken en bloc (b), and the bladder closed (c).

Figure 21.27 Carcinoma in a diverticulum. (a) The bladder is opened well clear of the diverticulum. (b) The ureter is marked with a catheter, and a wide ellipse of bladder taken en bloc with the diverticulum, the extravesical fat, and the lymph nodes along the internal iliac vessels. (c) The bladder is closed.

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Aug 6, 2020 | Posted by in UROLOGY | Comments Off on Bladder Neoplasm

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