Urological Neoplasia
Basic pathology and molecular biology
Neoplasia (the formation and growth of a tumour) may be a benign or malignant process. Malignant neoplasms, characterized by local invasion of normal tissue or distant spread (metastasis) via lymphatic or vascular channels, may be primary or secondary. Neoplasms are considered to arise by clonal expansion of a single abnormal cell through uncontrolled aberrant divisions. This cell may be a stem cell rather than a terminally differentiated cell. Tumour formation results from the loss of balance between cell division and withdrawal from the cell cycle by differentiation or programmed cell death (apoptosis). Signals regulating cell proliferation and interactions come from proteins encoded by messenger RNA that is in turn transcribed from genomic DNA. An identifiable precursor lesion may exist.
Urological neoplasms most commonly arise from the lining epithelium of the genitourinary tract. Benign epithelial neoplasms from glandular or transitional epithelium are, respectively, termed adenoma or transitional cell papilloma. Malignant epithelial neoplasms are carcinomas; they may be further characterized histologically by prefixing either adeno if the neoplasm is glandular or squamous cell or transitional cell, according to the epithelium from which it has arisen. Carcinomas arise from noninvasive epithelial lesions, some of which are identifiable histologically: in the bladder, it is flat carcinoma in situ (CIS) while in the prostate, it is prostatic intraepithelial neoplasia (PIN). Connective tissue neoplasms are described according to their components, adding benign (-oma) or malignant (-sarcoma) suffixes. For example, a benign neoplasm composed of blood vessels, fat, and smooth muscle is an angiomyolipoma; a malignant neoplasm composed of smooth muscle is a leiomyosarcoma. Genitourinary sarcomas are rare, constituting 1% of all neoplasms.
There are exceptions. In the testis, the most common primary neoplasms arise from seminiferous tubules and are termed germ cell tumours. Rarely, primary malignant lymphoma can arise in the testis. In the kidney, the childhood Wilms’ tumour arises from the embryonic mesenchyme of the metanephric blastema while the benign oncocytoma is thought to arise from cells of the collecting ducts.
Secondary malignant neoplasms within urological tissues are uncommon; they may arise by direct invasion from adjacent tissues (for example, adenocarcinoma of the sigmoid colon may invade the bladder) or hae-matogenous metastasis from a distant site such as the lung.
Neoplasia is a genetic disease: it may be hereditary or sporadic, depending on whether the genetic abnormalities are constitutional (germ-line) or somatic (acquired). Hereditary tumours tend to appear at a younger age than their sporadic counterparts and are often multifocal due to an underlying constitutional genetic abnormality.
Genetic and epigenetic abnormalities may promote tumour development or growth in a number of ways.
Activation (overexpression) of oncogenes encoding transcription factors, e.g. c-myc.
Inactivation (reduced expression) of tumour suppressor genes; their diverse protein products stabilize the cell, ensuring differentiation
and a finite lifespan in which it performs its function. Inactivation of such genes by deletion or mutation may result in loss of this negative growth control. For example, PTEN (chromosome 10q) is a prostate tumour suppressor gene, encoding a phosphatase that is active against protein and lipid substrates. It is present in normal epithelium, but is commonly reduced in prostate cancer due to allele loss of chromosome 10q. It inhibits one of the intracellular signalling pathways, PI3 kinase-Akt, that is essential for cell cycle progression and cell survival. Inactivation of PTEN, therefore, promotes cell immortalization and proliferation.
Overexpression of peptide growth factors, e.g. insulin-like growth factor type 1 in prostate cancer or the highly angiogenic vascular endothelial growth factor in renal cancer.
Promoter methylation or acetylation inactivating genes encoding detoxification enzymes, e.g GSTP1.
Gene fusions: a translocation occurs during mitosis to bring a promoter gene adjacent to a transcription factor gene on a particular chromosome, resulting in overexpression of this factor and abnormal positive growth control, e.g. TMPRSS2-ERG fusions are found in 50% of prostate cancers.
Interest in the molecular pathology of urological neoplasia has begun to result in the development of screening tests for hereditary diseases, diagnostic or prognostic gene profiling, and new strategies for treatment. Examples include the PCA3 test for prostate cancer and the development of targeted therapies for advanced renal cancer.
Wilms’ tumour and neuroblastoma
Wilms’ tumour (nephroblastoma)
First described by the German surgeon, Max Wilms (1867-1918), this is a rare childhood tumour, affecting 1 in 10 000 children. It is, however, the commonest intra-abdominal tumour of childhood (20% of all childhood malignancies) and it represents 80% of all genitourinary tumours affecting children under 15y. Male and female are equally affected, 20% are familial, and 5% are bilateral. Seventy-five percent present under the age of 5y. Children of African descent are at greatest risk.
Pathology and staging
Wilms’ tumour is a soft pale grey tumour (it looks like brain). It contains metanephric blastema, primitive renal tubular epithelium, and connective tissue components. Two distinct histological subtypes are described: favourable (well differentiated) and anaplastic (poorly differentiated).
In at least 20% of cases, mutation or deletion of both copies (alleles) of the chromosome 11p13 WT1 tumour suppressor gene results in tumouri-genesis. The familial disease exhibits autosomal dominant inheritance, but is recessive at the cellular level. Affected family members harbour a germ-line WT1 mutation, conferring susceptibility. One further ‘hit’ is required while two ‘hits’ are required to cause the sporadic disease. This explains why hereditary Wilm’s tumours tend to develop multifocally and at a slightly younger age than its sporadic counterpart. Mutations of three further genes, WT2 (11p15.5), WTX (on the X chromosome), and CTNNB1 account for a further 30% of cases. Loss of chromosome 1p and 16q alleles defines a subgroup with worse prognosis.
Stage I Wilms’ tumour (43% of patients)—at least one of the following criteria must be met.
Tumour is limited to the kidney and is completely excised.
The surface of the renal capsule is intact.
The tumour is not ruptured or biopsied (open or needle) prior to removal.
No involvement of extrarenal or renal sinus lymph-vascular spaces.
No residual tumour apparent beyond the margins of excision.
Metastasis of tumour to lymph nodes not identified.
Stage II Wilms’ tumour (23% of patients)—at least one of the following criteria must be met.
Tumour extends beyond the kidney, but is completely excised.
No residual tumour apparent at or beyond the margins of excision.
Any of the following conditions may also exist.
Tumour involvement of the blood vessels of the renal sinus and/or outside the renal parenchyma.
The tumour has been biopsied prior to removal or there is local spillage of tumor during surgery, confined to the flank.
Extensive tumour involvement of renal sinus soft tissue.
Stage III Wilms’ tumour (23% of patients)—at least one of the following criteria must be met.
Unresectable primary tumour.
Lymph node metastasis.
Tumour is present at surgical margins.
Tumour spillage involving peritoneal surfaces, either before or during surgery, or transected tumour thrombus.
Stage IV Wilms’ tumour (10% of patients) is defined as the presence of haematogenous metastases (lung, liver, bone, or brain) or lymph node metastases outside the abdominopelvic region.
Stage V Wilms’ tumour (5% of patients) is defined as bilateral renal involvement at the time of initial diagnosis.
Presentation
Ninety percent have a mass, 33% complain of abdominal or loin pain, 30-50% develop haematuria, 50% are hypertensive. Fifteen percent of patients exhibit other anomalies such as hemihypertrophy/macroglos-sia (Beckwith-Wiedemann syndrome), gonadal dysgenesis/nephropathy (Denys-Drash syndrome) aniridia/retardation (WAGR), and fetal overgrowth (Perlman’s syndrome).
Investigations
The first-line investigation for a child with an abdominal mass or haematuria is ultrasound which will reveal a renal tumour. Further to diagnostic imaging, staging is obtained by CT, including the chest. Needle biopsy is avoided.
Treatment and prognosis
Children with renal tumours should be managed by a specialist paediatric oncology centre. Staging nephrectomy, with or without preoperative or post-operative chemotherapy, remains the mainstay of treatment. The chemotherapy most frequently used is vincristine and doxorubicin. Flank irradiation may be used in higher stage tumours. Survival is generally good at 92% overall, ranging from 55% to 97%, according to stage at presentation and histology.
Neuroblastoma
The most common extracranial solid tumour of childhood. Eighty percent are diagnosed <4y old. The tumour is of neural crest origin; 50% occur in the adrenal gland and most of the remainder arise along the sympathetic trunks.
Presentation
Systemic symptoms and signs are common: fever, abdominal pain/distension, mass, weight loss, anaemia, and bone pain. Retro-orbital metastases may cause proptosis.
Imaging and staging
Ultrasound initially; CT of chest and abdomen. Calcification in tumour helps distinguish neuroblastoma from Wilms’ tumour. MIBG scans are very sensitive for detection of neuroblastomas (Table 7.1).
Table 7.1 Imaging and staging | ||||||||||
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Treatment and prognosis
Surgical excision; radiotherapy; combination chemotherapy, possibly with autologous bone marrow transplantation. Stage 4S tumours may resolve with little or no treatment. Prognosis is poor, except for stages 1 and 4S disease.
Radiological assessment of renal masses
Abdominal USS is the first-line investigation for a patient with loin pain or a suspected renal mass. The size resolution for renal masses is 1.5cm, exhibiting variable echo patterns. Ultrasound may also detect renal cysts, most of which are simple: smooth-walled, round or oval, without internal echoes, and complete transmission with a strong acoustic shadow posteriorly. If the cyst has a solid intracystic element, septations, an irregular or calcified wall, further imaging with CT is indicated. Ten to twenty-five percent of RCC contain cysts. Yale radiologist, Morton Bosniak, developed the following radiological classification of renal cysts in Table 7.2.1
Table 7.2 Radiological classification of renal cysts | ||||||||
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If a renal mass is detected by USS, a thin slice or helical CT scan before and after IV contrast is the most important investigation for characterization and staging. Around 90% of solid-enhancing renal masses will be RCC. Ten percent of RCC will contain calcifications or fat. Even relatively avascular renal carcinomas enhance by 10-25* Hounsfield units. Occasionally, an isodense, but enhancing, area of kidney is demonstrated: this is termed ‘pseudotumour’ and may correspond to a harmless hypertrophied cortical column (of Bertin) or dysmorphic segment. CT may mislead with respect to liver invasion (rare) due to ‘partial volume effect’; real-time ultrasound is more accurate. Lymphadenopathy >2cm is invariably indicative of metastasis.
MRI with gadolinium contrast may be used for imaging the IVC, locally advanced disease, renal insufficiency, or for patients allergic to iodinated contrast. Doppler USS may also evaluate IVC tumour thrombus. Renal arteriography is seldom used in the diagnostic setting, but may be helpful to delineate the number and position of renal arteries in preparation for nephron-sparing surgery or surgery for horseshoe kidneys.
Ultrasound or CT-guided fine needle aspiration (FNA) or needle biopsy
This is increasingly indicated due to the trend in managing small masses with surveillance or minimally invasive ablative therapies. Also, a histological diagnosis is usually required prior to treating inoperable patients with systemic therapies. Needle biopsy is highly specific, but less sensitive for detecting malignancy: 80% of biopsy cores are diagnostic, of which 75% are RCC. Repeat biopsy is diagnostic in 80%. There are also risks of haemorrhage (5%) and tumour spillage (rare). FNA is useful for aspiration of renal abscess or infected cyst or to diagnose suspected lymphoma or metastatic lesions. Table 7.3 shows a practical radiological classification of renal masses.
Table 7.3 Classification of renal masses by radiographic appearance | |||||||||||||||||||||||||||||||||||||||||
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It has been suggested that abdominal USS could be used as a screening test for early detection and treatment of RCC; this has been piloted in Germany and Japan. While there is currently no plan for population screening in the UK, it would be appropriate to offer USS to high-risk individuals such as relatives of VHL syndrome patients.
* Hounsfield units are a measure of X-ray attenuation applied to CT scanning: -1000 units equates with air, 0 units equates with water, and +1000 equates with bone.
1 Bosniak MA (1986) The current radiological approach to renal cysts. Radiology 158: 1-10.
Benign renal masses
The most common (70%) are simple cysts, present in >50% of those aged >50y. Rarely symptomatic, treatment by aspiration or laparoscopic deroofing is seldom considered.
Most benign renal tumours are rare; the two most clinically important are oncocytoma and angiomyolipoma.
Oncocytoma
This is uncommon, accounting for 3-7% of renal tumours. Males are twice as commonly affected as females. They occur simultaneously with RCC in 7-32% of cases.
Pathology
Oncocytomas are spherical, capsulated, brown/tan colour, mean size 4-6cm. Half contain a central scar. They may be multifocal and bilateral (4-13%) and 10-20% extend into perinephric fat. Histologically, they comprise aggregates of eosinophillic cells thought to arise from intercalated cells of the collecting duct. Cells are packed with mitochondria, mitoses are rare, large nucleoli are present; they are considered benign, not known to metastasize. There is often loss of the Y chromosome.
Presentation
Oncocytomas often (83%) present as an incidental finding or with loin pain or haematuria.
Investigations
Oncocytoma cannot often be distinguished radiologically from RCC; they may coexist with RCC. Rarely, they exhibit a ‘spoke-wheel’ pattern on CT scanning, caused by stellate central scar. Percutaneous biopsy is not usually recommended since there is often continuing uncertainty about the diagnosis. The main differential diagnosis of renal oncocytoma is chromophobe RCC oncocytic variant which, like the renal oncocytoma, has eosinophilic cytoplasm, but has perinuclear clearing and typically, some degree of nuclear atypia.
Angiomyolipoma (AML)
Eighty percent of these benign clonal neoplasms (PEComa, formerly considered as a hamartoma) occur sporadically, mostly in middle-aged females. Twenty percent are in association with tuberous sclerosis (TS), an autosomal dominant syndrome characterized by mental retardation, epilepsy, adenoma sebaceum, and other hamartomas. Up to 80% of TS patients develop AMLs, mean age 30y, 66% female, frequently multifocal, and bilateral.
Pathology
AML is composed of perivascular epithelioid cells (PEC) containing blood vessels, immature smooth muscle, and fat. They are always considered benign although extrarenal AMLs have been reported in venous system, hilar lymph nodes, and liver. Macroscopically, it looks like a well circumscribed lump of fat. Solitary AMLs are more frequently found in the right kidney.
Presentation
Investigations
Ultrasound reflects from fat, hence a characteristic bright echo pattern. This does not cast an ‘acoustic shadow’ beyond, helping to distinguish an AML from a calculus. CT shows fatty tumour as low density (Hounsfield units <10) in 86% of AMLs. If the proportion of fat is low, a definite diagnosis cannot be made as other renal tumours may contain fat. Measurement of the diameter is relevant to treatment.
Treatment
In studies, 52-82% of patients with AML >4cm are symptomatic compared with only 23% with smaller tumours. Therefore, asymptomatic AMLs can be followed with serial USS if <4cm while those bleeding or >4cm should be treated surgically. Emergency nephrectomy or selective renal artery embolization may be life-saving. Patients with kidney loss should be monitored for hypertension (and treated for it if discovered) and avoid nephrotoxic drugs such as certain pain relievers and IV contrast agents. In patients with TS, in whom multiple bilateral lesions are present, annual renal USS and conservative treatment should be attempted. HIFU could be considered for asymptomatic tumours.
Renal cell carcinoma: pathology, staging, and prognosis
RCC is adenocarcinoma of the renal cortex, believed to arise from the proximal convoluted tubule (although the majority of VHL gene deletions occur in the distal tubule). Usually tan-coloured, lobulated, and solid, 7% are multifocal, 1-2% bilateral, 10-20% contain calcification, and 10-25% contain cysts or are predominantly cystic. There may be zones of haemorrhage, necrosis, and scarring. Rarely grossly infiltrative, they are usually circumscribed by a pseudocapsule of compressed tissue.
Spread is by: direct extension to adrenal gland (7.5% in tumours >5cm), through the renal capsule (25%), into renal vein (up to 44%), IVC (5%), right atrium; by lymphatics to hilar and para-aortic lymph nodes; haematogenously to lung (75%), bone (20%), liver (18%), and brain (8%).
Histological classification of RCC
Conventional (80%): arise from the proximal tubule; highly vascular; clear cells (glycogen, cholesterol) or granular (eosinophillic cytoplasm, mitochondria); involves loss of VHL, PBRM1, and others genes on chromosome 3.
Papillary (10-15%): papillary, tubular, and solid variants; 40% multifocal; small incidental tumours could equate with Bell’s legendary ‘benign adenoma’; trisomy 7, 16, 17.
Chromophobe (5%): arises from the cortical portion of the collecting duct; possesses a perinuclear halo of microvesicles; hypodiploid with loss of chromosomes 1, 2, 6, 10, 13, 17, 21.
Collecting duct (Bellini): rare, young patients, poor prognosis.
Medullary cell: rare, arises from calyceal epithelium; young sickle cell sufferers; poor prognosis.
‘Sarcomatoid” describes an infiltrative poorly differentiated variant of any type in 5-25%. Coagulative necrosis is seen in 30%. Array-based karyotyping performs well on paraffin-embedded tumours and can be used to identify characteristic chromosomal aberrations in renal tumours with challenging morphology.
Genetic changes associated with RCC are described on 
p. 250. RCC is an unusually immunogenic tumour, expressing numerous antigens (e.g. RAGE-1, MN-9). Reports of spontaneous regression, prolonged stabilization, and complete responses to immunotherapy support this. Tumour-infiltrating lymphocytes are readily obtained from RCCs, including T-helper, dendritic, natural killer, and cytotoxic T cells. RCC is also unusually vascular, overexpressing angiogenic factors, principally VEGF, but also bFGF and TGF-β.
p. 250. RCC is an unusually immunogenic tumour, expressing numerous antigens (e.g. RAGE-1, MN-9). Reports of spontaneous regression, prolonged stabilization, and complete responses to immunotherapy support this. Tumour-infiltrating lymphocytes are readily obtained from RCCs, including T-helper, dendritic, natural killer, and cytotoxic T cells. RCC is also unusually vascular, overexpressing angiogenic factors, principally VEGF, but also bFGF and TGF-β.Grading is by the Fuhrman system (1 = well differentiated; 2 = moderately differentiated; 3 and 4 = poorly differentiated), based on nuclear size, outline, and nucleoli. It is an independent prognostic factor.
Staging
Staging is by the TNM classification following histological confirmation of the diagnosis (see Table 7.4 and Fig. 7.1). All rely upon physical examination and imaging; the pathological classification (prefixed ‘p’) corresponds to the TNM categories. Staging is the most important prognostic indicator for RCC.
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Prognosis (Table 7.5)
Factors for RCC survival include:
TNM stage.
Fuhrman grade, necrosis, or sarcomatoid features.
Performance status and systemic symptoms.
 Fig. 7.1 Renal cell carcinoma staging. (a) Primary tumour limited to kidney (T1/T2). (b) Primary tumour invading perinephric fascia or adrenal gland (T3a). (c) Primary tumour extends into renal veins or IVC below diaphragm (T3b); above diaphragm/into right atrium (T3c); outside perinephric fascia (e.g. into liver, bowel, or posterior abdominal wall) (T4). (d) N and M staging: multiple para-aortic/paracaval nodes; pulmonary, bone, or brain metastases (T1-4N2M1). |
Table 7.5 RCC: 5y survival | ||||||||
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A prognostic nomogram has been developed to predict 5y probability of treatment failure for patients with newly diagnosed RCC. It is available for download at: 
http://www.mskcc.org/mskcc/html/6156.cfm.
http://www.mskcc.org/mskcc/html/6156.cfm.Renal cell carcinoma: epidemiology and aetiology
Renal cell carcinoma (RCC) (also known as hypernephroma since it was erroneously believed to originate in the adrenal gland, clear cell carcinoma, and Grawitz tumour) is the commonest of renal tumours, constituting 2-3% of all cancers. It is an adenocarcinoma, accounting for 85% of renal malignancies; the remainder are TCC (10%), sarcomas, Wilms’, and other rarities (5%). It occurs in sporadic (common) and hereditary (rare) forms.
Incidence, mortality, and survival
In the UK, both incidence and mortality are rising, with 8228 patients diagnosed (compared with 3676 patients in 1999) and 3848 deaths in 2008. RCC is the most lethal of all urological tumours, approximately 50% of patients dying of the condition; it is the tenth most common cause of cancer death. Relative 5y survival, heavily dependent on stage at diagnosis, is 50% while 10y survival fell to 43% for UK patients. Survival has increased since the 1970’s. As with most cancers, there is a steady fall in survival with advancing age at diagnosis: rates for patients under 50y are twice that for patients over 80.
Aetiology
Males are affected 1.5 times as commonly as females; peak incidence of sporadic RCC is between 60-70y of age.
Environmental
Studies have shown associations with cigarette pipe or cigar smoking (1.4-2.3-fold risk), renal failure and dialysis (30-fold risk), obesity, hypertension (1.4-2-fold risk), urban dwelling, low socio-economic status, tobacco chewing, occupational asbestos and cadmium exposure, the analgesic phenacitin, thorium dioxide, and sickle cell trait (medullary carcinoma only). Nutrition is considered important: Asian migrants to western countries are at increased risk of RCC; vitamins A, C and E, and fruit/vegetable consumption are protective. Anatomical risk factors include polycystic and horseshoe kidneys.
Genetic
VHL syndrome: 50% of individuals with this autosomal dominant syndrome, characterized by phaeochromocytoma, renal and pancreatic cysts, and cerebellar haemangioblastoma, develop RCC, often bilateral and multifocal. Patients typically present in 3rd, 4th, or 5th decades. VHL syndrome occurs due to loss of both copies of a tumour suppressor gene at chromosome 3p25-26; this and other 3p genes (RASSF1A; PBRM1) are implicated in causing >80% of sporadic RCCs. Inactivation of the VHL gene leads to effects on gene transcription, including dysregulation of hypoxia inducible factors 1 and 2, intracellular proteins that play an important role in the cellular response to hypoxia and starvation. This results in an upregulation of VEGF, the most prominent angiogenic factor in RCC, explaining why some RCCs are highly vascular and enabling targeted treatment approaches (see 
p. 258).
p. 258).A papillary variant of RCC also has an autosomal dominant familial component, characterized by trisomy 7 and 17, with activation of the c-MET proto-oncogene. c-MET is the receptor tyrosone kinase for hepatocyte growth factor which regulates epithelial proliferation and differentiation in a wide variety of organs, including the normal kidney.
Mutations of the FLCN gene on chromosome 17p results in the autosomal dominant Birt-Hogg-Dubé syndrome. This rare disease is characterized by benign tumours of hair follicles (mainly facial), pulmonary cysts, pneumothoraces, and renal tumours, including oncocytomas and RCC.
Renal cell carcinoma: presentation and investigation
At least half of all RCCs are detected incidentally on abdominal imaging carried out to investigate vague or unrelated symptoms. Thus, there has been a downward stage migration at diagnosis since ultrasound and CT scanning came into routine use in the 1980’s.
Presentation
History: of the symptomatic RCCs diagnosed, 50% of patients present with haematuria, 40% with loin pain, 25% of patients notice a mass, and 30% have symptoms or signs of metastatic disease, including bone pain, night sweats, fatigue, weight loss, and haemoptysis. Less than 10% of patients exhibit the classic triad of haematuria, pain, and abdominal mass. Less common presenting features include pyrexia of unknown origin (9%), acute varicocoele due to obstruction of the testicular vein by tumour within the left renal vein (2-5%), and lower limb oedema due to venous obstruction. Paraneoplastic syndromes due to ectopic hormone secretion by the tumour occur in 30% of patients; these may be associated with any disease stage (Table 7.6).
Table 7.6 Paraneoplastic syndromes | ||||||||||||||||||
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Clinical examination: may reveal abdominal mass, cervical lymphadenopathy, non-reducing varicocele, or lower limb oedema (both suggestive of venous involvement).
Investigations
Radiological evaluation: of haematuria, loin pain, and renal mass is described on
pp. 242 and 270, together with discussion of the role of needle biopsy.
Urine cytology and culture: should be normal.
FBC: may reveal polycythaemia or anaemia.
Serum creatinine and electrolytes, calcium, and liver function tests: are essential.
When RCC is diagnosed radiologically, staging chest CT will follow and bone scan, if clinically indicated. Any suggestion of renal vein or IVC involvement on CT may be further investigated with Doppler USS or MRI. Angiography may be helpful in planning partial nephrectomy or surgery for horseshoe kidneys. Contralateral kidney function is assessed by the uptake and excretion of CT contrast and the serum creatinine. If doubt persists, isotope renography is used.
Renal cell carcinoma (localized): surgical treatment I
Surgery is the mainstay of treatment for RCC. Increasing diagnosis of smaller, early stage RCC and the concept of cytoreductive surgery for advanced RCC has impacted on investigation and surgical treatment strategies while reduction in mortality remains elusive.
Localized disease—partial nephrectomy (PN) is now the gold standard
Nephron-sparing surgery without adrenalectomy is indicated as follows.
Absolute: tumour in single anatomical/functioning kidney; bilateral tumours.
Relative: multifocal RCC, particularly if the patient has VHL syndrome, aiming to avoid renal replacement therapy; contralateral kidney threatened by another condition.
Elective: T1 (up to 7cm) tumours with a normal contralateral kidney unless the tumour is close to the pelvicalyceal system.
Three-dimensional CT reconstructions provide the surgeon with preoperative identification of the arterial anatomy. Open transperitoneal or loin approaches are used. The renal artery is clamped and the kidney packed with crushed ice to avoid warm ischaemia. If the surgical margin is clear of tumour, the depth of the margin (>1mm) does not influence risk of local recurrence (which is up to 10%). PN for T2 RCC carries increased risk of local recurrence. Specific complications include urinary leak from the collecting system and hyperfiltration renal injury which may eventually require renal replacement therapy; proteinuria is a prognostic sign. Oncological outcomes are comparable with radical surgery.
Robot-assisted or laparoscopic PN is becoming the standard approach in centres with expertise for small peripheral RCC. Oncological outcomes are comparable with open PN. Disadvantages include a longer (up to 30min) warm ischaemia time (this is less with the Da Vinci®) and increased peroperative complications. Functional recovery is within hours after 20min of warm ischaemia and days after 30min; it may take several weeks after 60min of clamping. Attempts at achieving cold ischaemia using renal artery or retrograde ureteric infusions or crushed ice in endo-bags have proved difficult and laborious. Some enthusiasts are performing ‘zero ischaemia’ laparoscopic PN and accepting significant blood loss.
Radical nephrectomy
This remains the gold standard treatment of T2-4 RCC and in T1 RCC in patients unsuitable for PN. There is no difference in outcome favouring a specific surgical approach so the default is now laparoscopic for localized RCC. In the case of upper pole or T2 tumours, adrenalectomy is also necessary.
Laparoscopic approach: has become a widely available option in centres treating RCC. Approaches are either transperitoneal or retroperitoneal. The specimen is removed whole or morselated in a bag through an iliac incision. Advantages over open surgery include
less pain, reduced hospital stay, and quicker return to normal activity. Morbidity is reported in 8-38% of cases, including PE and poorly understood effects on renal function. Long-term (10y) results are equivalent to those obtained by open surgery; cancer-specific survival (CSS) was 92% in a mixed US series.
Open approach: this should be carried out only for large or locally advanced RCCs. The aim is to remove all tumour with adequate surgical margins by excising the kidney with Gerota’s fascia, vein tumour thrombus, adrenal gland (if invasion indicated by imaging), and limited regional nodes for staging. Surgical approach is transperitoneal (good access to hilar vessels) or thoracoabdominal (for very large or T3c tumours). Following renal mobilization (avoiding tumour manipulation), the ureter is divided; ligation and division of the renal artery or arteries should ideally take place prior to ligation and division of the renal vein to prevent vascular swelling of the kidney. Complications include mortality up to 2% from bleeding or embolism of tumour thrombus; bowel, pancreatic, splenic, or pleural injury.
Post-operative follow-up aims to detect local or distant recurrence to permit additional treatment, if indicated; incidence is 7% for T1N0M0 RCC, 20% for T2N0M0, and 40% for T3N0M0. After partial nephrectomy, concern will also focus on recurrence in the remnant kidney. There is no consensus regarding the optimal regime, typically stage-dependent 6-monthly clinical assessment and annual CT imaging of chest and abdomen for 5-10y.
Post-operative prognosis
The Leibovich scoring system groups patients into low, intermediate, or high risk for development of metastasis at 1, 3, 5, 7, and 10y according to tumour stage, size, nuclear grade, presence of necrosis, and regional nodal status. This is particularly useful when selecting patients for trials of adjuvant therapy.1
A nomogram combining prognostic factors for prediction of 5y recurrence risk following surgery can be downloaded at: 
http://www.mskcc. org/mskcc/html/6156.cfm
http://www.mskcc. org/mskcc/html/6156.cfm1 Leibovich BC, Blute ML, Cheville JC, et al. (2003) Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer 97: 1663-71.
Renal cell carcinoma: surgical treatment II and non-surgical alternatives for localized disease
Localized RCC—lymphadenectomy
Lymph node involvement in RCC is a poor prognostic factor. Incidence ranges from 6% in T1-2 tumours, 46% in T3A, and 62-66% in higher stage disease. Lymphadectomy at time of nephrectomy may add prognostic information, especially if there is obvious lymphadenopathy, but therapeutic benefit remains unclear. Extended lymphadenectomy adds time and increases blood loss while nodes are clear in about 95% of cases so is not recommended.
Localized RCC: adjuvant therapy
To date, no adjuvant therapy has been shown to improve survival after nephrectomy.
Localized RCC: treatment of local recurrence
Though uncommon, if there is local recurrence in the renal bed after radical nephrectomy, surgical excision remains the preferred treatment choice, provided there are no signs of distant disease. Local recurrence is more common after partial nephrectomy where it can be treated by a further partial or radical nephrectomy.
Localized RCC: alternatives to surgery
Renal artery embolization: indicated for patients with gross haematuria who are unfit for curative surgery.
Active surveillance: small (T1a; <4cm) solid renal masses may be followed with repeat scans in elderly or unfit individuals. Metastasis is rare in masses <3cm. For every 1cm size increase, the estimated prevalence of metastasis increases by 3.5%. Of 178 patients, 101 had renal biopsy, of which 55% were malignant, 12% benign, and 33% non-diagnostic. Average growth rate was similar for these histological groups, ˜0.15cm per year. Over a minimum 2y period, 25 (12%) progressed locally (i.e. grew to ≥4cm or volume doubled in ≤ 12 months) and only 2 (1.1%) developed bone/lung metastases.1
Cryosurgery: this minimally invasive treatment (MIT) performed using intraoperative ultrasound by open, percutaneous, or laparoscopic routes, is gaining popularity as a nephron-sparing treatment option.
HIFU: this MIT delivered percutaneously or extracorporeally, is under evaluation as a nephron-sparing treatment option.
Cryosurgery, HIFU, and Image-guided percutaneous RFA have the advantage of being outpatient-based, low morbidity, and repeatable; they are currently
recommended only for those patients unfit or unwilling to undergo surgery (since current data show recurrence rates are higher), ideally within clinical trials.
recommended only for those patients unfit or unwilling to undergo surgery (since current data show recurrence rates are higher), ideally within clinical trials.
Locally advanced RCC
Disease involving the IVC, right atrium, liver, bowel, or posterior abdominal wall demand special surgical skills. In appropriate patients, an aggressive surgical approach involving a multidisciplinary surgical team to achieve negative margins appears to provide survival benefit.
Adjuvant treatment: To date no adjuvant therapy has demonstrated any survival benefit, even in those who are predicted to have a higher risk of recurrence. With the advent of the newer tyrosine kinase inhibitors that have demonstrated a benefit in metastatic disease, multiple randomized trials are ongoing and results are awaited.
Metastatic RCC
Nephrectomy has long been indicated for symptom palliation (pain, haematuria) in patients with metastatic RCC (if inoperable, arterial embolization can be helpful) and is also performed prior to systemic therapy, if appropriate. A median survival benefit of 10 months for patients with good performance status treated with cytoreductive nephrectomy prior to immunotherapy (interferon-α) has been reported. Studies are ongoing to investigate whether there is a similar benefit to cytoreductive nephrectomy with the tyrosine kinase inhibitors. Currently, the standard practice is to recommend it, extrapolating from the cytokine era. Patients should be recruited to the studies that are investigating cytoreductive nephrectomy.
Resection of a solitary metastasis is an appropriate option for a small number of patients, usually a few months after nephrectomy, to ensure the lesion has remained solitary.
1 Jewett MA, Mattar K, Basiuk J, et al. (2011) Active surveillance of small renal masses: progression patterns of early stage kidney cancer. Eur Urol 60: 39-44.
Renal cell carcinoma: management of metastatic disease
Approximately 25% of patients with RCC have metastatic disease at presentation; a further 30% progress subsequently to this stage following nephrectomy.
Prognostic risk stratification: The MSKCC (Motzer) criteria may be used, based on Karnofsky performance status <80%; absence of prior nephrectomy; haemoglobin subnormal; LDH >1.5 times upper limit; corrected calcium ” class=LK href=”javascript:void(0)” target=right xpath=”/CT{06b9ee1beed594192fe83c602fef4af9a59e63f847d6df62927a64e26327cf0cf06e8cf028309944a61bd528dbfb4c9b}/ID(AB2-M1)”>> normal. No factors confers favourable risk, median time to death—20 months; one to two factors carry intermediate risk (10 months median survival); >3 factors carry poor risk (4 months median survival).
Surgery: despite the rare possibility of spontaneous metastatic regression (<5%) following nephrectomy, it was rarely undertaken except to relieve local symptoms of pain or haematuria. The role of nephrectomy in metastatic RCC is discussed on 
p. 257.
p. 257.Metastasectomy may be of benefit to the 1.5-3% of patients who develop a solitary metastasis (particularly in lung, adrenal, or brain) following nephrectomy.
Angiogenesis (signal transduction) inhibitors
As discussed earlier (see 
p. 250), most RCCs are highly angiogenic so fortunately become good therapeutic targets for angiogenesis inhibitors. Via its cell surface receptor (VEGFR), VEGF is a pro-angiogenic peptide growth factor that activates the PI3kinase/AKT signal transduction pathway, which is one of three major receptor tyrosine kinase (RTK) signalling pathways. VEGF is overexpressed in most sporadic RCC as a result of HIF-1 overexpression caused by inactivation of the VHL tumour suppressor gene. In randomized trials, two well-tolerated oral multi-RTK inhibitors, sunitinib and pazopanib, have demonstrated significant benefit in the first-line metastatic setting, prolonging progression-free survival (PFS) in metastatic RCC patients by 3-8 months compared with interferon alpha (IFNα) or placebo. The UK NICE approved both in 2009 and 2011, respectively. Complete responses are rare, partial responses modest (30-40%), they also stabilize the disease in approximately 30% of patients.1 Pazopanib is effective as second-line treatment (prior cytokine therapy).
p. 250), most RCCs are highly angiogenic so fortunately become good therapeutic targets for angiogenesis inhibitors. Via its cell surface receptor (VEGFR), VEGF is a pro-angiogenic peptide growth factor that activates the PI3kinase/AKT signal transduction pathway, which is one of three major receptor tyrosine kinase (RTK) signalling pathways. VEGF is overexpressed in most sporadic RCC as a result of HIF-1 overexpression caused by inactivation of the VHL tumour suppressor gene. In randomized trials, two well-tolerated oral multi-RTK inhibitors, sunitinib and pazopanib, have demonstrated significant benefit in the first-line metastatic setting, prolonging progression-free survival (PFS) in metastatic RCC patients by 3-8 months compared with interferon alpha (IFNα) or placebo. The UK NICE approved both in 2009 and 2011, respectively. Complete responses are rare, partial responses modest (30-40%), they also stabilize the disease in approximately 30% of patients.1 Pazopanib is effective as second-line treatment (prior cytokine therapy).A further randomized trial demonstrated >3-month survival advantage of temsirolimus, an inhibitor of cytoplasmic mTOR kinase (a downstream component of the same pathway) in metastatic RCC patients compared with IFNα.2 This is currently recommended for first-line treatment of poor risk disease. For second-line, everolimus is an orally available mTOR inhibitor: it confers a 2-month PFS over placebo when used for patients failing the treatments. However, NICE has not approved its use (2011).
VEGF antibodies
Bevacizumab is a humanized monoclonal antibody that binds to VEGFR. A phase III randomized trial demonstrated a median 31% response with bevacizumab + IFNα compared with IFNα alone, with a 4.8-month PDS
advantage for low and intermediate risk patients. This combination is an option for first-line treatment.
advantage for low and intermediate risk patients. This combination is an option for first-line treatment.
These agents represent a major advance in the first- and second-line treatment of metastatic RCC. There are multiple newer thymidine kinase inhibitors (TKI) that are also currently being investigated.
Immunotherapy
The immunogenicity of RCC is discussed on 
p. 246. The first cytokines to be used therapeutically to activate anti-tumour immune response were interferons and subsequently IL-2. Randomized studies in the 1990’s demonstrated modest response rates (10-20%) after systemic immunotherapy using these cytokines alone and in combination; toxicity could be severe. Responses were more likely in patients with good performance status, prior nephrectomy, and small-volume metastatic burden. An MRC trial of IFNα vs medroxyprogesterone demonstrated a 2.5-month survival advantage in the immunotherapy group. The use of immunotherapy has been overshadowed recently by the development of RTK inhibitors, although there may still be a role for IL-2 in a very select group of patients and is still being used for appropriate patients (excellent performance status, small volume lung only metastases, and no prior treatment).
p. 246. The first cytokines to be used therapeutically to activate anti-tumour immune response were interferons and subsequently IL-2. Randomized studies in the 1990’s demonstrated modest response rates (10-20%) after systemic immunotherapy using these cytokines alone and in combination; toxicity could be severe. Responses were more likely in patients with good performance status, prior nephrectomy, and small-volume metastatic burden. An MRC trial of IFNα vs medroxyprogesterone demonstrated a 2.5-month survival advantage in the immunotherapy group. The use of immunotherapy has been overshadowed recently by the development of RTK inhibitors, although there may still be a role for IL-2 in a very select group of patients and is still being used for appropriate patients (excellent performance status, small volume lung only metastases, and no prior treatment).Chemotherapy: little role in RCC; ineffective due to high multidrug resistance P glycoprotein expression.
Radiotherapy: useful for palliation of metastatic lesions in bone and brain and in combination with surgery for spinal cord compression.
Palliative care
1 Motzer RJ, Hutson TE, Tomczak P, et al. (2007) Sunitimib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356: 115-24.
2 Sternberg CN, Davis ID, Mardiak J, et al. (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28: 1061-8.
3 Hudes G, Carducci M, Tomczak P, et al. (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356: 2271-81.
Upper urinary tract transitional cell carcinoma (UUT-TCC)
UUT-TCC accounts for 90% of upper urinary tract tumours, the remainder being benign inverted papilloma, fibroepithelial polyp, squamous cell carcinoma (associated with longstanding staghorn calculus disease), adenocarcimona (rare), and various rare non-urothelial tumours, including sarcoma.
TCC of the renal pelvis is uncommon, accounting for 10% of renal tumours and 5% of all TCC. Ureteric TCC is rare, accounting for only 1% of all newly presenting TCC. Half are multifocal; 75% located distally while only 3% are located in the proximal ureter.
Males are affected three times as commonly as females.
Incidence increases with age.
Smoking confers a 2-fold risk and there are various occupational causes.
Phenacetin ingestion.
There is a high incidence of UUT-TCC in families from some villages in Balkan countries (‘Balkan nephropathy’) that remains unexplained.
Pathology and grading
The tumour usually has a papillary structure, but occasionally solid. It is bilateral in 2-4%. It arises within the renal pelvis, less frequently in one of the calyces or ureter. Histologically, features of TCC are present; grading is as for bladder TCC. Spread is by direct extension, including into the renal vein and vena cava; lymphatic spread to para-aortic, para-caval, and pelvic nodes; bloodborne spread, most commonly to liver, lung, and bone.
Presentation
Painless total haematuria (80%).
Loin pain (30%), often caused by clots passing down the ureter (‘clot colic’).
Asymptomatic when detected, associated with synchronous bladder TCC (4%).
Investigations
Ultrasound is excellent for detecting the more common renal parenchymal tumours, but not sensitive in detecting tumours of the renal pelvis or ureter.
Diagnosis is usually made on urine cytology and CTU, respectively, revealing malignant cells and a filling defect in the renal pelvis or ureter. If doubt exists, selective ureteric urine cytology, retrograde ureteropyelgraphy, or
flexible ureterorenoscopy with biopsy are indicated. Some surgeons prefer to have histological proof of malignancy prior to treatment. Additional staging is obtained by chest CT and occasionally, isotope bone scan.
flexible ureterorenoscopy with biopsy are indicated. Some surgeons prefer to have histological proof of malignancy prior to treatment. Additional staging is obtained by chest CT and occasionally, isotope bone scan.
Staging uses the TNM (2009) classification (Table 7.7) following histological confirmation of the diagnosis. All rely on physical examination and imaging, the pathological classification corresponding to the TNM categories.
Table 7.7 TNM 2009 staging of carcinomas of the renal pelvis and ureter | ||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Treatment
If staging indicates non-metastatic disease in the presence of a normal contralateral kidney, the gold standard treatment with curative intent is nephroureterectomy with excision of the bladder cuff and node sampling (if possible).
The open approach uses either a long transperitoneal midline incision or separate loin and iliac fossa incisions. The entire ureter is taken with a cuff of bladder because of the 50% incidence of subsequent ureteric stump recurrence.
The laparoscopic approach focuses on mobilizing the kidney and upper ureter extraperitoneally; the lower ureter with bladder cuff is dissected via a Gibson-type open incision through which the entire specimen is retrieved. As for laparoscopic nephrectomy, benefits include reduced
post-operative pain and faster recovery. Tumour spillage and port site metastases are theoretical hazards. Long-term results are equivalent with the open approach.
post-operative pain and faster recovery. Tumour spillage and port site metastases are theoretical hazards. Long-term results are equivalent with the open approach.
Percutaneous, segmental, or ureterorenoscopic resection/laser ablation of the tumour are the minimally invasive options for patients with a single functioning kidney, bilateral disease, unilateral low-grade tumours <1cm, or those who are unfit. Topical BCG or chemotherapy (for example, mitomycin C) may subsequently be instilled through the nephrostomy or ureteric catheters, though benefit has not been proven. This nephron-sparing approach is less likely to be curative than definitive surgery.
Follow-up should continue at least 5y:
Metastatic disease
Systemic combination chemotherapy (platinum-based): for unresectable or metastatic disease is associated with a 30% total or partial response at the expense of moderate toxicity.
Palliative surgery or arterial embolization: may be necessary for troublesome haematuria. Radiotherapy is generally ineffective.
Prognostic factors (Table 7.8)
Muscle-invasive UUT-TCC, constituting 60% of new presentations, have a poor prognosis. The following are recognized prognostic factors, in descending order of importance:
Tumour grade and stage.
Associated Tis.
Age.
Lymphovascular invasion.
Tumour architecture.
Extensive tumour necrosis.
Tumour location.
Table 7.8 5y survival | ||||||||
|---|---|---|---|---|---|---|---|---|
|
Bladder cancer: epidemiology and aetiology
Incidence, mortality, and survival
Bladder cancer is the second most common urological malignancy and the fourth most common cancer in men. UK incidence has fallen since the mid-1990s in all age groups; 10 091 patients diagnosed in 2008. Mortality has fallen since the early 1990s, more pronounced in men than women (in fact, mortality of elderly women is still increasing), accounting for 5002 UK deaths in 2007. This represents 3% of all cancer deaths. Perhaps the reduction in smoking accounts for such trends. These data indicate about half of patients diagnosed have curable or controllable disease; hence, 10y survival is ˜50% for women and approaching 60% in men.
Risk factors
Men: are 2.5 times more likely to develop the disease than women, the reasons for which are unclear, but may be associated with greater urine residuals in the bladder
Age: increases risk, most commonly diagnosed in the eighth decade and rare below age 50y.
Smoking: is the major cause of bladder cancer in the developed world. Smokers have a 2-5-fold risk of developing bladder cancer, subsequent recurrences, and higher mortality compared to non-smokers. Estimates suggest that 30-50% of bladder cancer is caused by smoking. Cigarette smoke contains the carcinogens 4-aminobiphenyl (4-ABP) and 2-naphthylamine (Fig. 7.2). Slow hepatic acetylation (detoxification) of 4-ABP by N-acetyltransferase and glutathione S-transferase M1 (GSTM1) or induction of the cytochrome P450 1A2 demethylating enzyme appear to increase urothelial carcinogenic exposure. There is a slow (20y) risk reduction following cessation of smoking.
Occupational exposure: to carcinogens, in particular aromatic hydrocarbons like aniline, is a recognized cause of bladder cancer. Examples of ‘at risk’ occupations are shown in Box 7.1. A latent period of 25-45y exists between exposure and carcinogenesis.
Environmental carcinogens: found in urine are the major cause of bladder cancer.
Chronic inflammation of bladder mucosa: bladder stones, long-term catheters, and notoriously the ova of Schistosoma haematobium (bilharziasis) are implicated in the development of SCC of the bladder.
Drugs: phenacitin and cyclophosphamide.
Race: Black people have a lower incidence than white people, but inexplicably they appear to carry a poorer prognosis.
Pelvic radiotherapy: either for prostate cancer (external beam or brachytherapy) or a gynaecological malignancy, a relative risk of 1.4-4 exists for the later development of a second primary malignancy in the bladder.
 Fig. 7.2 Carcinogens known to increase risk of bladder cancer. |
Box 7.1 Occupations associated with TCC
No evidence for a hereditary genetic aetiology exists, though many somatic genetic abnormalities have been identified. The most common cytogenetic abnormality is loss of chromosomes 9p, 9q, 11p 13q, and 17q. Activation/amplification of oncogenes (p21 ras, c-myc, c-jun, erbB-2), inactivation of tumour suppressor genes (p53 mutations appear to worsen survival after treatment, retinoblastoma, p16 cyclin-dependent kinase inhibitor), and increased expression of angiogenic factors (for example, VEGF) are reported in TCCs.
Bladder cancer: pathology, grading, and staging
Benign tumours of the bladder, including inverted urothelial papilloma and nephrogenic adenoma, are uncommon.
The vast majority of primary bladder cancers are malignant and epithelial in origin.
” class=LK href=”javascript:void(0)” target=right xpath=”/CT{06b9ee1beed594192fe83c602fef4af9a59e63f847d6df62927a64e26327cf0cf06e8cf028309944a61bd528dbfb4c9b}/ID(AB2-M1)”>> 90% are TCC, usually high-grade.
2% are adenocarcinoma.
Small cell and spindle cell carcinomas (rare).
Other rare primary tumours include phaeochromocytoma, melanoma, lymphoma, and sarcoma arising within the bladder muscle.
Secondary bladder cancers are mostly directly spread by adenocarcinomas from the gut, prostate, kidney or ovary, or squamous carcinoma of the urerine cervix.
Tumour spread is:
Direct: tumour growth to involve the detrusor, the ureteric orifices, prostate, urethra, uterus, vagina, perivesical fat, bowel, or pelvic side walls.
Implantation: into wounds/percutaneous catheter tracts.
Lymphatic: infiltration of the iliac and para-aortic nodes.
Haematogenous: most commonly to liver (38%), lung (36%), adrenal gland (21%), and bone (27%). Any other organ may be involved.
Histological grading has traditionally (1973 WHO Classification) been divided into: benign urothelial papilloma; well, moderately, and poorly differentiated (G1, G2, and G3, respectively) carcinoma. Most retrospective studies, clinical trials, and guidelines are based on this classification. The 2004 WHO grading uses cytological/architectural criteria to distinguish flat lesions (hyperplasia, dysplasia, carcinoma in situ) and raised lesions (urothelial papilloma, papillary urothelial neoplasms of low malignant potential (PUNLMP), low-grade and high-grade urothelial carcinomas). The 2004 system is more reproducible, but is as yet not proven to be of better prognostic value than the 1973 system. Hence, both systems are used in contemporary clinical practice, with G2 tumours being called either low-grade or high-grade.
Staging is by the TNM (2009) classification (Table 7.9 and Fig. 7.3). All rely upon physical examination and imaging, the pathological classification (prefixed ‘p’) corresponding to the TNM categories.
TCC: may be single or multifocal. Because 5% of patients will have a synchronous upper tract TCC and metachronous recurrences may develop after several years, the urothelial ‘field change’ theory of polyclonality has been favoured over the theory of tumour monoclonality with transcoelomic implantation (seeding).
70% of tumours are papillary, usually G1 or G2, exhibiting at least seven transitional cell layers covering a fibrovascular core (normal transitional epithelium has approximately five cell layers). Papillary TCC is usually superficial, confined to the bladder mucosa (Ta) or submucosa (T1); 10% of patients subsequently develop muscle-invasive or metastatic disease. However, G3T1 tumours are more aggressive, with 40% subsequently upstaging.
10% of TCC have mixed papillary and solid morphology and 10% are solid. These are usually G3, half of which are muscle-invasive at presentation.
10% of TCC is flat CIS. This is poorly differentiated carcinoma, but confined to the epithelium and associated with an intact basement membrane; 50% of CIS lesions occur in isolation; the remainder occurs in association with muscle-invasive TCC. CIS usually appears as a flat red velvety patch on the bladder mucosa; 15-40% of such lesions are CIS, the remainder being focal cystitis of varying aetiology. The cells are poorly cohesive, up to 100% of patients with CIS exhibiting positive urine cytology in contrast to much lower yields (17-72%) with G1/2 papillary TCC; 40-83% of untreated CIS lesions will progress to muscle-invasive TCC, making CIS the most aggressive form of superficial TCC.
SCC: is usually solid or ulcerative and muscle-invasive at presentation. SCC accounts for only 1% of UK bladder cancers. SCC in the bladder is associated with chronic inflammation and urothelial squamous metaplasia rather than CIS. In Egypt, 80% of SCC is induced by the ova of Schistosoma haematobium. Five percent of paraplegics with long-term catheters develop SCC. Smoking is also a risk factor for SCC. The prognosis is better for bilharzial SCC than for non-bilharzial disease, probably because it tends to be lower-grade and metastases are less common in these patients.
Adenocarcinoma: is rare, usually solid/ulcerative, G3, and carry a poor prognosis. One-third originate in the urachus, the remnant of the allantois, located deep to the bladder mucosa in the dome of the bladder. Adenocarcinoma is a long-term (10-20+ year) complication of bladder exstrophy and bowel implantation into the urinary tract, particularly bladder substitutions and ileal conduits after cystectomy. There is association with cystitis glandularis rather than CIS. Secondary adenocarcinoma of the bladder may arise.
Table 7.9 The 2009 UICC TNM staging of bladder carcinoma | ||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
 Fig. 7.3 The T staging of bladder cancer. |
Bladder cancer: clinical presentation
Symptoms
The commonest presenting symptom (85% of cases) is painless visible haematuria. Haematuria may be initial or terminal if the lesion is at the bladder neck or in the prostatic urethra. Thirty-four percent of patients >50y and 10% <50y with macroscopic haematuria have bladder cancer. A history of smoking or occupational exposure is relevant.
Asymptomatic non-visible haematuria found on routine urine sticktesting accounts for an important minority of presentations. Up to 16% of females and 4% of males have stick-test haematuria: <5% of those <50y and 7-13% of those >50y will have a malignancy.
Filling-type LUTS such as urgency or suprapubic pain. There is almost always microscopic or macroscopic haematuria. This so-called ‘malignant cystitis’ is typical in patients with CIS.
Recurrent UTIs and pneumaturia due to malignant colovesical fistula, though less common than benign causes (diverticular and Crohn’s disease).
Urachal adenocarcinomas may present with a blood or mucus umbilical discharge or a deep subumbilical mass.
More advanced cases may present with lower limb swelling due to lymphatic/venous obstruction, bone pain, weight loss, anorexia, confusion, and anuria (renal failure due to bilateral ureteric obstruction).
Pain is unusual, even if the patient has obstructed upper tracts since obstruction and renal deterioration arise gradually.
Signs
General examination may reveal pallor, indicating anaemia due to blood loss or chronic renal impairment. Abdominal examination may reveal a suprapubic mass in the case of locally advanced disease; DRE may reveal a pelvic mass above or involving the prostate.
Although the likelihood of diagnosing bladder cancer in patients <50y is low, all patients with these presenting features should be investigated (see 
p. 272).
p. 272).Bladder cancer: haematuria, diagnosis, and transurethral resection of bladder tumour (TURBT)
Investigation of haematuria
After a UTI has been excluded or treated and menstruation ruled out as the cause, all patients with persistent microscopic (2 out of 3 dipstick tests) or macroscopic haematuria require investigation of their upper tracts, bladder, and urethra. Visible haematuria (VH, otherwise referred to as ‘macroscopic haematuria’ or ‘gross haematuria’) requires consideration of other (rare) causes of discoloured urine (myoglobinuria, haemoglobinuria, beeturia, drug discoloration—rifampicin, doxorubicin). Twenty-two percent of patients with VH will harbour a urological malignancy. Nonvisible haematuria (NVH, otherwise referred to as ‘microscopic haematuria’ or ‘dipstick-positive haematuria’) is further subdivided as follows:
Asymptomatic NVH (a-NVH): incidental detection in the absence of LUTS or upper urinary tract symptoms.
Five percent of patients with NVH will harbour urological malignancy, more frequently in patients >40y.
Dipstick vs microscopy
Urine dipstick of a fresh voided urine sample, containing no preservative, is considered a sensitive means of detecting the presence of haematuria. Community-based urine samples sent for microscopy have a significant false negative rate; the procedure is more labour intensive and adds little to establishing the diagnosis of haematuria. Routine microscopy for confirmation of dipstick haematuria is not necessary. Whilst the sensitivity of urine dipsticks may vary from one manufacturer to another, significant haematuria is considered to be 1+ or greater. Trace haematuria should be considered negative. There is no distinction in significance between non-haemolysed and haemolysed dipstick-positive haematuria. A 1+ positive for either should be considered of equal significance.1
Urological investigations are tailored according to patient age and symptoms:
Over 40y old with macroscopic haematuria: urgent CTU, cystoscopy, and cytology.
Under 40y with macroscopic haematuria: urgent USS renal tract followed by CT-KUB, cystoscopy, and cytology.
CTU is faster and more sensitive than ultrasound or IVU in the detection of renal (parenchymal and urothelial) and ureteric tumours. However, it carries a higher radiation dose and is more expensive. CTU also detects
some bladder tumours, but may overcall bladder wall hypertrophy as tumour and will miss flat CIS and urethral pathology so it cannot replace cystoscopy. CT-KUB requires less radiation dose and is preferred in patients who are more likely to have stone than malignancy.
some bladder tumours, but may overcall bladder wall hypertrophy as tumour and will miss flat CIS and urethral pathology so it cannot replace cystoscopy. CT-KUB requires less radiation dose and is preferred in patients who are more likely to have stone than malignancy.
If all investigations are normal, consideration should be given to nephrological disorders that may cause haematuria such as glomerulonephritis. Annual monitoring of BP, urinalysis, and eGFR is recommended. Cross-referral to a renal physician is advised in patients with persisting microscopic haematuria ± proteinuria and hypertension or eGFR <60mL/min.
Causes of persistent NVH
Urological causes
Common
Benign prostatic hyperplasia.
Cancer (bladder, kidney, prostate, ureter).
Calculus disease or nephrolithiasis.
Cystitis or pyelonephritis.
Prostatitis or urethritis.
Schistosoma haematobium infection.
Less common
Radiation cystitis.
Urethral strictures.
TB.
Medullary sponge kidney.
Cyclophosphamide-induced cystitis.
Rare
Arteriovenous malformation.
Renal artery thrombosis.
Polycystic kidney disease.
Papillary necrosis of any cause.
Loin pain haematuria syndrome.
Nephrological causes
Common
IgA nephropathy (Berger’s disease).
Thin basement membrane disease.
Less common/rare
Acute glomerular disease.
Post-infectious glomerulonephritis.
Rapidly progressive glomerulonephritis.
Systemic lupus nephritis.
Vasculitis.
Goodpasture’s disease.
Henoch-Schönlein purpura syndrome.
Haemolytic uraemic syndrome.
Chronic primary glomerulonephritis.
Focal segmental glomerulonephritis.
Mesangiocapillary glomerulonephritis
Membranous nephropathy.
Mesangial proliferative glomerulonephritis.
Familial causes.
Hereditary nephritis (Alport’s syndrome).
Polycystic kidney disease (autosomal dominant or recessive).
Urine cytology
Examination of voided urine for exfoliated cells is most sensitive (90-100%) in patients with high-grade TCC and CIS, anywhere in the urinary tract. It is costly and <1% of cancers are detected by cytology alone when other investigations are normal. False-negative cytology is frequent (40-70%) in patients with papillary TCC while false-positive cytology can arise due to infection, inflammation, stones, instrumentation, and intravesical instillations such as chemotherapy. Guidelines do not specify if and when to use it so practices vary.
Urine molecular markers
ELISA tests for detecting tumour-specific urinary markers such as bladder tumour antigen (BTA) or nuclear matrix protein 22 (NMP22) tend to have greater sensitivity, but reduced specificity for detecting TCC, compared with urine cytology. ImmunoCyt has the highest sensitivity for detection of low-grade tumours and is less affected by other urological diseases. However, with a 60% detection rate for low-grade tumours, the test remains largely inadequate to replace cystoscopy. The absence of clinical trials and the costs involved mean that it is unclear whether these tests, alone or in combination, may replace any of the standard investigations for haematuria.
Diagnosis and initial treatment of bladder cancer
TURBT usually provides definitive histological diagnosis, grade, and clinical and pathological stage and is the first (sometimes sole) treatment. This is undertaken under general or spinal anaesthesia; bimanual examination is mandatory before and after bladder tumour resection to assess size, position, and mobility. If possible, the surgeon should resect the tumour(s) completely. The pathologist should report on the tumour type, grade, and stage; in particular, the presence or absence of muscularis propria should be noted since its absence will preclude reliable T staging. Red areas are biopsied separately; the prostatic urethra is biopsied if cystectomy with bladder reconstruction is under consideration. Particular care is taken when resecting tumours at the dome since intraperitoneal bladder perforation may occur, especially in women with thin-walled bladders. Care is also taken when resecting posterolateral tumours due to the proximity of the obturator nerve; stimulation may result in a ‘kick’ unless the patient is under full paralysis, which may lead to bladder perforation and/or troublesome bleeding.
Narrow-band imaging (NBI) and photodynamic detection (PDD)
NBI: is an optical image enhancement technology in which the narrow bandwidth of light is strongly absorbed by haemoglobin and penetrates only the surface of tissue, increasing the visibility of capillaries and other delicate tissue surface structures by enhancing contrast between the two. A number of small studies have demonstrated NBI to be superior to standard white light cystoscopy for the detection of new and recurrent tumours.
PDD (fluorescence cystocopy): uses blue light in combination with a porphyrin-based photosensitizer, hexaminolevulinic acid (HAL; Hexvix®). Several randomized studies have revealed CIS lesions and developing papillary tumours which cannot be seen using standard white light for tumour detection and resection. For example, a total of 113 CIS lesions in 58 patients 104 (92%) were detected by PDD, 77 (68%) were detected by white light cystoscopy, while 5 were detected only by biopsy of visually normal mucosa.2 The 1y risk of papillary recurrence is reduced by 9-27% This technique is gaining popularity, but is expensive; however, it has been suggested that improved tumour detection leads to better patient management and reduced long-term recurrence rates and costs. The value of PDD for improvement of the outcome in relation to progression rate or survival remains to be demonstrated, though it has gained a place in routine management of selected patients, particularly in those with positive urine cytology, but normal-looking bladder mucosa.
1 Kelly JD, Fawcett DP, Goldberg LC (2009) Assessment and management of non-visible haematuria in primary care. BMJ 338: a3021.
2 Fradet Y, Grossman HB, Gomella L, et al. (2007) A comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of carcinoma in situ in patients with bladder cancer: a phase III, multicenter study. J Urol 178: 68-73.
Bladder cancer (non-muscle invasive TCC): surgery and recurrence
TURBT
The diagnostic role of TURBT has been discussed on 
p. 274. As a primary treatment, a visually complete tumour resection is adequate for 70% of newly presenting patients with Ta/T1 superficial disease. The remaining 30% of patients experience early recurrence, 15% with upstaging. Because of this, it is standard care that all new patients receive adjuvant treatment with a single dose of post-operative intravesical chemotherapy (usually mitomycin; see 
p. 280). Complications of TURBT are uncommon, including bleeding, sepsis, bladder perforation, incomplete resection, and urethral stricture.
p. 274. As a primary treatment, a visually complete tumour resection is adequate for 70% of newly presenting patients with Ta/T1 superficial disease. The remaining 30% of patients experience early recurrence, 15% with upstaging. Because of this, it is standard care that all new patients receive adjuvant treatment with a single dose of post-operative intravesical chemotherapy (usually mitomycin; see p. 280). Complications of TURBT are uncommon, including bleeding, sepsis, bladder perforation, incomplete resection, and urethral stricture.Alternatives to TURBT
Transurethral cystodiathermy or laser are accepted, quicker and less morbid procedure for ablating small superficial recurrences when obtaining tissue for histology is not considered necessary.
Follow-up after TURBT
Second resection: an early repeat TUR (within 2-6 weeks) should be undertaken: (a) if the first resection was incomplete, (b) when the pathologist reports that the resected specimen contains no muscularis propria, or (c) if a high-grade, but apparently non-invasive, T1 tumour has been reported since perhaps 10% (3-25%) of these G3pT1 tumours are understaged T2 tumours. This strategy improves recurrence-free survival and prognosis while complications include bladder perforation.
In the absence of these indications for a second resection, review cystoscopy is performed at 3 months. If this demonstrates recurrence, 70% will recur further. If not, only 20% will recur further. If the bladder is clear at follow-up, subsequent cystoscopies are performed under local anaesthetic at 9 months and thereafter annually for 5y (patients with low-risk TCC) or until the patient is no longer fit to undergo treatment (patients with high-risk disease).
Patients with G3T1 TCC, and CIS are at significantly higher risk of recurrence and 40% subsequently upstage. Some patients experience persistent symptomatic multifocal G1/2, Ta/1 recurrent TCC, demanding frequent follow-up procedures. In these circumstances, adjuvant treatment is indicated (see 
p. 280).
p. 280).Predicting recurrence and progression in Ta/T1 TCC
Number of tumours (e.g. 1 = 0 points; 2-7 = 3 points; ≥8 = 6 points).
Tumour diameter (<3cm vs >3cm).
Prior recurrence <1 vs >1 per year).
T stage (Ta vs T1).
Presence of concomitant CIS.
This system divides superficial tumours into those at low risk (50%), intermediate risk (35%), or high risk (15%) of recurrence and progression at 1y or 5y. The scoring tables and risk calculators are available at: 
http://www.eortc.be/tools/bladdercalculator/.
http://www.eortc.be/tools/bladdercalculator/.See Table 7.10 for a summary of the management of bladder cancer by grade and stage.
Table 7.10 A summary of the management of bladder cancer | |||||||||||||||||||||||||||||||||||
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1 European Association of Urology Guidelines on Non-Muscle-Invasive Urothelial Carcinoma of the Bladder, the 2011 update. Eur Urol 59: 997-1008.
2 Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. (2006) Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 49: 466-77.
Bladder cancer (non-muscle invasive TCC): adjuvant treatment
Intravesical chemotherapy (e.g. mitomycin C (MMC) 40mg in 50mL saline) is used for G1-2, Ta or T1 tumours, and recurrent multifocal TCC. MMC is an antibiotic chemotherapeutic agent that inhibits DNA synthesis. In experimental studies, it may cause regression of small papillary TCC so it should be cytotoxic for microscopic residual disease post-TURBT. A meta-analysis of seven randomized trials1 demonstrated that a single dose given within 24h of first TURBT significantly (24%) reduces the likelihood of tumour recurrence compared to TURBT alone, from 48% to 37%. This is now standard treatment for all new papillary bladder tumours post-TURBT.
For many patients at low risk of recurrence, the risk reduction seen with single-dose chemotherapy is equivalent to that seen using weekly instillations for 6 weeks, commencing up to 2 weeks post-TURBT. Such longer courses are still recommended for patients at higher risk of recurrence or who have multifocal recurrences, excluding those with high-grade Ta/1 TCC or CIS.
Intravesical chemotherapy has never been shown to prevent progression to muscle invasion and has no impact upon survival. It is administered via a urethral catheter, is held in the bladder for 1h, and should not be used if there is ongoing haematuria or if bladder perforation is suspected. Toxicity of MMC: 15% patients report transient filling-type LUTS; occasionally a rash develops on the genitals or palms of the hands so treatment must be stopped. Systemic toxicity is rare with MMC.
Other effective intravesical chemotherapy agents include doxorubicin and epirubicin, but not gemcitabine.
Intravesical BCG: is an attenuated strain of Mycobacterium bovis. Commercially available strains include Pasteur, Connaught, and Tice. It acts as an immune stimulant, upregulating cytokines such as IL-6 and IL-8 in the bladder wall, activating immune effector cells.
BCG produces complete responses in 60-70% of patients. It is as effective as chemotherapy for adjuvant treatment of low- and intermediate-risk G1/2, Ta/1 TCC, therefore, is not often used (except as second-line) because of the additional toxicity. In high-risk patients, with multiple G2T1, high-grade G2 or G3Ta/T1, or CIS, the benefit of BCG over chemotherapy in reducing risk of recurrence is clear and it is standard care. BCG is given as a 6-week induction course, starting at least 2 weeks post-TURBT. It is administered via a urethral catheter, 80mg in 50mL saline and retained in the bladder for 1h.
A meta-analysis of 24 trials has demonstrated that BCG reduces risk of stage progression (to muscle invasion) by 27%, based on a median follow-up of 2.5y.2 This effect was only seen in patients who received maintenance BCG (e.g. 30 treatments over 3y after the initial 6-week induction), which is now the standard recommendation for high-grade Ta/T1 or CIS initial responders, though the optimal dose and schedule remain unclear. For recurrent high-grade Ta/T1 or CIS, a second course of BCG may
be offered if maintenance was not given, as 50% will respond. A total of 66% of BCG non-responders and 10-20% of initial responders will eventually progress to muscle-invasive TCC. Hence, if no response is seen or relapse diagnosed despite BCG maintenance or a second course, proceed without delay to radical cystectomy; the cure rate is 90%.
be offered if maintenance was not given, as 50% will respond. A total of 66% of BCG non-responders and 10-20% of initial responders will eventually progress to muscle-invasive TCC. Hence, if no response is seen or relapse diagnosed despite BCG maintenance or a second course, proceed without delay to radical cystectomy; the cure rate is 90%.
Though less expensive and more effective, BCG is more toxic than intravesical chemotherapy, causing cystitis symptoms in >90% patients and low-grade fever with myalgia in 25%. Up to 6% of patients develop a high persistent fever, requiring antituberculous therapy for 6 months with isoniazid and pyridoxine or standard triple therapy (rifampicin, isoniazid, and ethambutol) in critically ill patients. Death due to BCG sepsis, granulomatous prostatitis, and epididymo-orchitis are rare complications.
Contraindications to intravesical BCG include:
Immunosuppressed patients.
Pregnant or lactating women.
Patients with haematological malignancy.
Following traumatic catheterization.
The appearances at cystoscopy performed too soon after BCG can appear alarming due to a generalized inflammatory response. Cystoscopy and biopsy 3 months after BCG may still reveal chronic granulomatous inflammation.
1 Sylvester RJ, Oosterlinck W, van der Meijden AP (2004) A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage TaT1 bladder cancer: a meta-analysis. J Urol 171: 2186-90.
2 Sylvester RJ, van der Meijden AP, Lamm DL (2002) Intravesical BCG reduces the risk of progression in patients with superficial baldder cancer: a combined analysis of results of published clinical trials. J Urol 168: 1964-70.
Bladder cancer (muscle-invasive): staging and surgical management of localized (pT2/3a) disease
This is a dangerous disease; the untreated 5y survival is just 3%. Management of patients with invasive bladder cancer requires a multidisciplinary team approach, involving case-by-case discussion between the urological surgeon, radiotherapist, and medical oncologist, with support from the pathologist, radiologist, and cancer specialist nurse.
Staging investigations
Pelvic CT or MRI: may demonstrate extravesical tumour extension, upper tract obstruction, or iliac lymphadenopathy reported if >8mm in maximal diameter. T stage correlation with pathological findings at cystectomy is 65-80%. Both modalities will miss microscopic nodal disease in 70% of cases.
Chest CT or plain X-ray.
Isotope bone scan (positive in 5-15% of patients with muscle-invasive TCC): is obtained in cases being considered for radical treatment.
Ultrasound scanning: is used for detection of liver metastases if the serum liver function is abnormal; albumin indicates the nutritional status of the patients; alkaline phosphatase is not a reliable marker for bone disease in bladder cancer patients.
In the absence of prospective randomized trials comparing the surgical and non-surgical treatments, the options for a patient with newly diagnosed confined muscle-invasive bladder cancer are:
Bladder preserving.
Radical TURBT plus systemic chemotherapy: little data, not mainstream.
Partial cystectomy ± neoadjuvant systemic chemotherapy.
Radical cystectomy with:
Ileal conduit urinary diversion.
Ureterosigmoidostomy urinary diversion.
Continent urinary diversion.
± Neoadjuvant chemotherapy: some evidence of benefit (see
p. 286).
Partial cystectomy is a good option for well selected patients with small solitary disease located near the dome and for urachal carcinoma. Morbidity is less than with radical cystectomy and diversion is not required. The surgical specimen should be covered with perivesical fat, with a 1.5cm margin of macroscopically normal bladder around the tumour. There should be no biopsy evidence of CIS elsewhere in the bladder.
The bladder must be closed without tension and catheterized for 7-10 days to allow healing. Subsequent review cystoscopies are mandatory to ensure no tumour recurrence.
The bladder must be closed without tension and catheterized for 7-10 days to allow healing. Subsequent review cystoscopies are mandatory to ensure no tumour recurrence.
Radical cystectomy with urinary diversion
This is the most effective primary treatment for muscle-invasive TCC, SCC, and adenocarcinoma and can be performed as salvage treatment if RT has failed. It is also a treatment for G3T1 TCC and CIS, refractory to BCG. Any ureteric obstruction caused by the primary tumour will be relieved by the concomitant urinary diversion. However, this is a major undertaking for the patient and surgeon, requiring support from the cancer specialist nurse, stomatherapist, or continence advisor. Preoperative bowel preparation is discouraged by ‘enhanced recovery’ specialists since it is considered to cause unnecessary dehydration without any evidence of benefit.
The procedure: through a midline transperitoneal or extraperitoneal approach, a bilateral pelvic lymphadenectomy is undertaken. The extent of lymphadenectomy ranges from limiting dissection to the obturator fossa to extending the dissection up to the aortic bifurcation. Studies have suggested a survival advantage to the extended approach, provided the primary cancer is stage T2 or less. The findings of frozen section histology may influence the decision to proceed in some cases. The entire bladder is then excised along with perivesical fat, vascular pedicles, and urachus, plus the prostate/seminal vesicles or anterior vaginal wall. The anterior urethra is not excised unless there is prior biopsy evidence of tumour at the female bladder neck or prostatic urethra (when recurrence occurs in 37%). The ureters are divided close to the bladder, ensuring their disease-free status by frozen section histology, if necessary, and anastomosed into the chosen urinary diversion (see 
p. 290).
p. 290).Some centres are pioneering laparoscopic and robot-assisted cystectomy. Advantages include less blood loss, less post-operative analgesia requirement, and reduced hospital stay. However, long operating times, high cost, and technical considerations may limit widespread adoption of this approach. Oncological outcomes are still under evaluation.
Major complications affect 25% of cystectomy patients. These include perioperative death (1.2%), reoperation (10%), bleeding, thromboembolism, sepsis, wound infection/dehiscence (10%), intestinal obstruction or prolonged ileus (10%), cardiopulmonary morbidity, and rectal injury (4%). Erectile dysfunction is likely after cystectomy due to cavernosal nerve injury.
The complications of urinary diversion are discussed on 
p. 290.
p. 290.Post-operative care
Many patients will spend the first 24h in the high dependency unit or ITU.
Daily clinical evaluations, including inspection of the wound (and stoma, if present), fluid balance, urine and drain outputs, blood count, creatinine/electrolytes, and albumin.
Broad-spectrum antimicrobial prophylaxis.
Venous thromboembolism prophylaxis with TED stockings, pneumatic calf compression, and subcutaneous LMWH (unfractionated heparin for patients with renal impairment); NICE (2010) recommends continuing heparin for 28 post-operative days.
Early mobilization within 24h, if possible.
Chest physiotherapy and adequate analgesia is especially important in smokers and patients with chest comorbidity.
Oral intake is commenced early, an integral part of the Enhanced Recovery concept; however, patients may require parenteral nutrition in the presence of GI complications or prolonged ileus.
Drains are usually sited in the pelvis and near the ureterodiversion anastamosis; ureteric catheters pass from the renal pelves through the diversion and exit percutaneously; a catheter drains the diversion (except in the case of ileal conduit), exiting urethrally or suprapubically.
Most patients stay in hospital for 10-14 days.
Salvage radical cystectomy is technically a more difficult and slightly more morbid procedure. Relatively few patients who have failed primary RT are suitable for this second chance of a cure; these are fit patients with mobile clinically localized disease.
Efficacy of radical cystectomy
Failure to cure may result from inadequate excision of the primary tumour or presence of metastases (Table 7.11). Treatment delay should be avoided if possible; cystectomy performed within 3 months of diagnosis (T2 TCC) results in significantly improved survival compared with >3 months.1 Pathological upstaging of the primary can occur in up to 40% of cases. Lymph node metastases occur in 10% of T1 and up to 33% of T3-4 cancers. The use of neoadjuvant chemotherapy in muscle-invasive disease is discussed on 
p. 288.
p. 288.Table 7.11 5y survival rates for cystectomy alone | ||||||||||||||||
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1 Lee CT, Madii R, Daignault S, et al. (2006) Cystectomy delay more than 3 months from initial bladder cancer diagnosis results in decreased disease specific and overall survival. J Urol 175: 1262-7.
Bladder cancer (muscle-invasive): radical radiotherapy and palliative treatment
Management of patients with invasive bladder cancer requires a multidisciplinary team approach, involving case-by-case discussion between the urological surgeon, radiotherapist, and medical oncologist, supported by the pathologist, radiologist, and cancer nurse specialist.
Radical external beam RT is a good option for pT2-4 TCC in patients who are unfit or unwilling to undergo cystectomy, but who still wish to have the chance of cure. Typically, a total dose of 66 Gray is administered in 30 fractions over 6 weeks. The target field comprises the bladder only, with a 1.5cm safety margin to allow for movement.
The 5y survival rates at 40-60%, are inferior to those of cystectomy, but the bladder is preserved and the complications are less significant (Table 7.12). Higher-grade tumours tend to do less well, perhaps because of the undetected presence of disease outside the field of irradiation. Beyond this, prediction of RT response remains difficult, relying on follow-up cystoscopy, and biopsy. Local recurrence occurs in approximately 30% of patients. There may be a small benefit in the use of neoadjuvant or adjuvant cisplatin-based combination chemotherapy with RT in locally advanced (pT3b/4) disease (see 
p. 288).
p. 288).Interstitial brachytherapy using caesium or iridium sources can be used to treat small T2 TCC in combination with RT and bladder-preserving surgery. Use of this technique is not widespread.
CIS, SCC, and adenocarcinoma are poorly sensitive to RT. There is no advantage in giving precystectomy RT for invasive TCC.
Complications occur in 70% of patients, self-limiting in 95% of cases. These include radiation cystitis (filling LUTS and dysuria) and proctitis (diarrhoea and rectal bleeding), usually lasting only a few months. Refractory radiation cystitis and haematuria may rarely require desperate measures such as intravesical alum, formalin, hyperbaric oxygen, iliac artery embolization, or even palliative cystectomy.
Table 7.12 Efficacy of RT: 5y survival | ||||||||||
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If disease persists or recurs, salvage cystectomy may still be successful in appropriately selected patients, 5y survival rates 30-50% (see 
p. 284). Otherwise, cytotoxic chemotherapy (see 
p. 289) and palliative measures may be considered.
p. 284). Otherwise, cytotoxic chemotherapy (see p. 289) and palliative measures may be considered.Palliative treatment
RT (30 Gray) is effective for metastatic bone pain or to palliate symptomatic (bleeding) local tumour (40-50 Gray).
Intractable haematuria may be controlled by intravesical formalin or aAlum, hyperbaric oxygen, bilateral internal iliac artery embolization or ligation, or palliative cystectomy/diversion.
Ureteric obstruction may be relieved by percutaneous nephrostomy and antegrade stenting (see 
pp. 363 and 546).
pp. 363 and 546).Involvement of the palliative care team can be very helpful to the patient and family.
Bladder cancer: management of locally advanced and metastatic disease
Management of patients with invasive bladder cancer requires a multidisciplinary team approach, involving case-by-case discussion between the urological surgeon, radiotherapist and medical oncologist, with support from the pathologist, radiologist, and cancer specialist nurse.
Locally advanced bladder cancer (pT3b/4)
Many patients treated with primary cystectomy or RT with curative intent succumb to metastatic disease due to incomplete tumour excision or micrometastases. Up to 50% of patients develop metastases, mostly at distant sites. At this stage, the 5y survival is only 25%. There is interest in augmenting primary treatment in an effort to improve outcomes.
Neoadjuvant and adjuvant RT
Randomized studies have suggested improvements in local control (pathological downstaging) using RT (45-50 Gray in 25 fractions) 4-6 weeks prior to cystectomy, but no survival benefit has been demonstrated. The rationale for post-cystectomy RT is that patients with proven residual or nodal disease may benefit from locoregional treatment. However, it leads to unacceptably high morbidity and has no demonstrable advantages. Post-treatment bowel obstruction occurs 4.5 times more commonly in RT patients.
Adjuvant cystectomy
Two studies have demonstrated an improvement in local control and a survival advantage when treating locally advanced disease with cystectomy after RT compared to RT alone. However, this treatment strategy does not happen in current UK practice, probably due to the increased morbidity of surgery in this setting.
Neoadjuvant chemotherapy with cystectomy
Preoperative chemotherapy is increasingly given to operable patients with non-metastatic T2-T4a disease. It may downstage the disease and treat micrometastases before the patient is debilitated by surgery. A metaanalysis of 10 trials1 has suggested a 5-7% 5y survival advantage with the use of cisplatin-based combination chemotherapy prior to cystectomy compared with cystectomy alone. The absolute gain was the same regardless of stage; from 55 to 60% for T2, 40-45% for T3, and 25-30% for T4 patients. The relative gain was, therefore, greater for higher stage patients. One randomized trial demonstrated a median survival of advantage of 31 months in the group treated with neoadjuvant combination chemotherapy compared to the group receiving cystectomy alone.2 Eligible patients must have a good performance status (<2—ambulatory and able to carry out light work) and renal function (GFR >60mL/min). This treatment should be discussed with suitable patients suspected of having locally advanced or micrometastatic disease prior to cystectomy.
Adjuvant chemotherapy
The rationale for post-cystectomy chemotherapy is that patients with proven residual or nodal disease may benefit from systemic treatment. Trials have been hampered by protocol problems, small numbers,
surgical complications interfering with treatment, and difficulty in assessing response in the absence of measurable disease. However, two of four studies have shown a survival benefit of almost 2y in the treated groups, using cisplatin-based regimes.
surgical complications interfering with treatment, and difficulty in assessing response in the absence of measurable disease. However, two of four studies have shown a survival benefit of almost 2y in the treated groups, using cisplatin-based regimes.
Neoadjuvant or adjuvant chemotherapy with RT
While controversial, neoadjuvant cisplatin-based combination chemotherapy with bladder preservation has been demonstrated to produce 5y survival rates of 42-72% when RT was used as definitive treatment. This may be offered to patients suspected of having locally advanced disease after clinical examination and staging imaging.
Metastatic bladder cancer
Five percent of patients have metastatic disease at the time of diagnosis.
Systemic chemotherapy
TCC is a chemosensitive cancer; it is recommended for patients with unresectable, diffusely metastatic measurable disease. Combination is more effective than single-agent treatment. A complete response is seen in 15% of patients given methotrexate, vinblastine, adriamycin, and cisplatin (MVAC), though 20% of patients develop neutropenia and 3% die of sepsis. Median survival is 14 months. Most UK centres are using gemcitobine, an antimetabolite agent, alone or in combination with cisplatin. Complete responses are reported in 25-40% of patients and it is better tolerated than MVAC, with 1% toxic death rate. Carboplatin may be used if cisplatin is contraindicated (i.e. performance status ≥2 of GFR <60mL/min). Taxanes (paclitaxel and docetaxel) are microtubule disassembly inhibitors; responses range from 25 to 80%, using these agents alone or in combination.
Prognostic factors predicting response to chemotherapy include alkaline phosphatase, age >60y, performance status, and visceral metastases. Depending on the number of factors, median survival varies from 9 to 30 months.3 In future, molecular markers such as tumour p53 status may be shown to predict chemosensitivity. Unfortunately, no biomarker is currently available to predict outcome, drive treatment decisions, or monitor response to treatment.
Radiotherapy
Roles for RT include palliation of metastatic pain, haematuria, and spinal cord compression.
Surgery
There is no surgical role in treatment of extravesical metastatic disease. Palliative cystectomy or urinary diversion is justified for severe local symptoms.
1 Advanced bladder cancer meta-analysis collaboration (2003) Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 361: 1927-34.
2 Grossman HB, Natale RB, Tangen CM, et al. (2003) Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349: 859-66.
3 Bajorin DF, Dodd PM, Mazumbar M, et al. (1999) Long-term survival in metastatic transitional cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 17: 3173-81.
Bladder cancer: urinary diversion after cystectomy
The choice of urinary diversion requires consideration of both clinical and quality of life (QoL) issues. Patients planned for cystectomy should be informed of the possible options. Contraindications to the continent reconstructive procedures include debilitating neurological and psychiatric illness, short life expectancy, and impaired renal or liver function. These patients must be motivated and able to perform ISC. Contraindications to orthotopic neobladder include tumour in the prostatic urethra, widespread CIS, and urethral stricture disease.
The majority of patients report good overall QoL following urinary diversion. The reconstructive procedures were expected to be better for social functioning compared to the ileal conduit; most QoL studies have not shown significant differences, although patients with continent diversions generally score more favourably in terms of body image, social activity, and physical function.
Ureterosigmoidostomy
Dating back to 1821, the oldest form of urinary diversion, whereby the ureters drain into the sigmoid colon, either in its native form or following detubularization and reconstruction into a pouch (Mainz II). This diversion requires no appliance (stoma bag, catheter) so remains popular in developing countries. In recreating a ‘cloaca’, the patient may be prone to upper UTI with the risk of long-term renal deterioration, metabolic hyperchloraemic acidosis, and loose frequent stools. The low-pressure and capacious Mainz II pouch reduces, but does not abolish, these complications.
Ileal conduit
This was developed during the 1940’s by Eugene Bricker of St. Louis; it remains the most popular form of urinary diversion in the UK. Fifteen cm of subterminal ileum is isolated on its mesentery and the ureters are anastomosed to the proximal end. The distal end is brought out in the right iliac fossa as a stoma. The native ileum is anastomosed to gain enteral continuity.
Complications of ileal conduit are:
Prolonged ileus.
Urinary leak.
Enteral leak.
Pyelonephriris.
Uretero-ileal stricture.
Stoma problems (20%—skin irritation, stenosis, and parastomal hernia).
Upper tract dilatation (30%).
Patients require stomatherapy support and some find difficulty in adjusting their lifestyle to cope with a stoma bag. Metabolic complications are uncommon.
In post-RT salvage patients, a jejunal or colonic conduit is used because of concerns about the healing of radiation-damaged ileum. The conduit
may be brought out in the upper abdomen and patients require careful electrolyte monitoring due to sodium loss and hyperkalaemia.
may be brought out in the upper abdomen and patients require careful electrolyte monitoring due to sodium loss and hyperkalaemia.
Continent diversion
The advantage is the absence of an external collection device. There are two types of continent diversion.
A continent pouch is fashioned from 60cm of detubularized ileum or right hemicolon. The ureters drain into this low-pressure balloon-shaped reservoir, usually through an antireflux submucosal tunnel. This is drained by the patient via a continent catheterizable stoma, such as the appendix or uterine tube (the Mitrofanoff principle) brought out in the right iliac fossa.
A similarly constructed pouch may be anastomosed to the patient’s urethra to act as an orthotopic neobladder so that natural voiding can be established and no stoma is necessary. Patients void by relaxing their external sphincter and performing a Valsalva. This neobladder should require no catheter, unless the pouch is too large and fails to empty adequately. In this case, the patient must be prepared to perform ISC.
Popular ileal pouches include those of Studer (see Fig. 7.4), Camey II, and Kock. Ileocaecal pouches include the Indiana and Mainz I. Which one is chosen often comes down to the surgeon’s preference; they carry similar complication risks. Previously irradiated bowel can safely be used to form pouches though complications are more likely.
Complications relating to pouches and neobladders are divided into early (12%) and late (37%). They include:
Urinary leakage and peritonitis.
Pelvic abscess.
Stone formation.
Catheterizing difficulties and stomal stenosis.
Urinary incontinence and nocturnal enuresis (particularly with neobladders).
Pouch ureteric reflux and UTI.
Ureteropouch anastomotic stricture.
Late neobladder rupture.
Metabolic abnormalities include early fluid and electrolyte imbalances; later, urinary electrolyte absorption may cause hyperchloraemic acidosis and loss of small bowel may result in vitamin B12 deficiency. Metabolic acidosis is less likely in patients with normal renal function; treatment is with sodium bicarbonate and potassium citrate. Annual B12 monitoring should be undertaken with supplementation if necessary.
Adenocarcinoma may develop (5%) in intestinal conduit, neobladder, or sigmoid colon mucosa in the long term due to the carcinogenic bacterial metabolism of urinary nitrosamines. This tends to occur near to the inflow of urine. It is, therefore, advisable to perform annual visual surveillance of urinary diversions after 10y. If the urethra is in situ, annual urethroscopy and cytology is important.
 Fig. 7.4 (a) The distal 40-44 cm of resected ileum opened along the antimesenteric border with scissors. Spatulated ureters are anastomosed end to side with 4-0 running suture on either side of proximal end of afferent tubular ileal limb. Ureters are stented. (b) The two medial borders of the U-shaped, opened distal ileal segment are oversewn with a single layer seromuscular continous suture. The bottom of the U is folded between the two ends of the U. (c) Before complete closure of the reservoir, a 8-10 mm hole is cut into the most caudal part of the reservoir (left). Six sutures are placed between the seromuscular layer of the anastomotic area of the reservoir and the membraneous urethra (right). An 18F urethral catheter is inserted. (d) Before complete closure of the pouch, a cystostomy tube is inserted and brought out suprapubically adjacent to the wound. (Reproduced with permission from Studer et al. 1996).1 |
1 Studer UE, Danuser H, Hochreiter W, et al. (1996) Summary of 10 years experience with an ileal low-pressure substitute combined with an afferent tubular isoperistaltic segment. World J Urol 14: 29-39.
Prostate cancer: epidemiology and aetiology
Hormonal and growth factors and diet
Growth of prostate cancer (PC), like benign prostatic epithelium, is largely under the promotional influence of testosterone and its potent metabolite, DHT. Androgen ablation by orchidectomy results in programmed epithelial cell death (apoptosis) and involution of the prostate. PC is not seen in eunuchs or people with congenital deficiency of 5α-reductase. Response to castration therapy in the treatment of patients with PC may be suboptimal if the serum testosterone is not fully suppressed (<50nmol/L).
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