in reduced or absent urinary \202 ow and a high-pressure renal pelvis. \200 May coexist with vesicoureteric re \202 ux ( b p. 712) or VUJ obstruction. Etiology May present antenatally, in childhood, or in adults. \200 Congenital: Intrinsic: \231\202 > \231\200 , proximal ureteric developmental defect. \200 Extrinsic (rare): external compression (e.g. aberrant renal vessel). Acquired: Intrinsic: stricture (infection, trauma), uroepithelial malignancy. \200 Extrinsic: malig nancy, retroperitoneal \201 brosis. Symptoms and signs \200 Increasingly diagnosed with maternal USS screening. It is the mos t common cause of antenatal hydronephrosis ( 7 1 in 1,500 live births). L > R but may be bila teral. Children may present with failure to thrive, \202 ank pain, urinary tract infections, a palpable mass, haematuria, hypertension, or renal impairment (if bilateral). 20% diagnosed as adults (with a large number presumably never diagnosed at all). Classically causes \202 ank pain after alcohol, coffee, or diuretics ( Diettel \200\231 s crisis). Investigation \200 USS (preferred) or CT will show dilatation of the renal pelvis with a normal distal ureter. Diuretic isotope renography demonstrates obstruction with delayed \200\230washout \200\231 . Serial scans are performed to determine optimal management. \200 Micturating cystouretero gram (MCUG) may demonstrate concomitant VUJ obstruction or posterior urethral valves. Management \200 No randomized trials: Generally conservative unless: impaired renal function (often manifesting as a change in split renal function), recurrent UTIs, calculi, persistent pain, increasing hydronephrosis. Prophylactic antibiotics of little bene \201 t. Surgery: Pyeloplasty involves resecting the abnormal ureteric segment and reattaching normal ureter to the renal pelvis. Various techniques are available, including open, laparoscopic, and en doscopic. All are very successful. If the obstruction is due to aberrant vasculature, the PUJ is repositioned above the vessel . PELVI-URETERIC (PUJ) OBSTRUCTION 737 Vesicoureteric junction obstruction \200 VUJ (like PUJ) obstruction can be congenital or acquired. \200 It may present with a similar constellation of symptoms to PUJ obstruction but often later in childhood or as an adult. It is very important to look for associated VUR ( b p. 712) and PUJ obstruction. If surgery is necessary, it involves re-implantation of the ureter. Posterior urethral valves (PUV) \200 A developmental abnormality in males, leaving obstru cting membranous folds in the lumen of the posterior urethra. The most common cause of urinary obstruction in infants ( 7 1 in 8,000). \200 The most co mmon cause of CKD due to obstruction in children ( 7 15% progress to ESRD). PUV cause dilatation of the proximal urethra, with hypertrophy of the bladder wall, bilateral megaureters, and hydronephrosis. \200 Most are identi \201 e d by antenatal USS (bilateral hydronephrosis, dilated bladder, and dilated posterior urethr a: \200\230keyhole sign \200\231 ). Associated with other abnormalities, including urinary tract (VUR, renal dysplasia) and non-urinary tract (e.g. lung hypoplasia). \200 Children present with failure to thrive, abdominal distension, UTIs, incontinence (daytime and nocturnal enuresis), and other urinary symptoms, including frequency, straining, poor stream, and large voids. MCUG is used to con \201 rm diagnosis. \200 Management includes urinary drainage in the newborn, usually by catheterization. Cystoscopic resection of the PUV should be undertaken as early as possible. Fetal intervention is now being undertaken in some specialist centers for severe cases. If PUV ablation is not possible, then a vesicostomy or other form of urinary drainage procedure should be considered. Bladder dysfunction is common and often persistent, requiring ongoing management, such as clean intermittent catheterization. CHAPTER 9 Essential urology 738 Retroperitoneal \201 brosis: overview Overview \200 Retroperitoneal \201 brosis (RPF) describes a group of disorders characterized by the development of \201 broin \202 ammatory tissue that surrounds and e ncases the abdominal aorta and other retroperitoneal structures, including the ureters. Encasement impairs ureteric contractility and causes an obstructive uropathy and then nephropathy. There are idiopathic (70%) and secondary forms. Both are uncommon ( 7 1 per 200,000 \200\223 500,000 population). The idiopathic form usually occurs age 40 \200\223 60, with a 3:1 \231\202 : \231\200 ra tio. Etiology \200 p and s RPF are usually very similar pathologically. \200 A tough, plaque -like material encases the major vessels and ureters. \200 Microscopically, there is a ma crophage- and plasma cell-rich in \202 ammatory in \201 ltrate, with progressive \201 b rotic change. \200 This \201 brous tissue consists of \201 broblasts (including activ ated myo \201 broblasts) and type I collagen. The causes of this process remain poorly understood. Suggestions: \200 They are an in \202 ammatory reaction to aortic atherosclerosis. Evidence: leakage of proin \202 ammatory lipid-derived material, such as ceroid (an oxidiz ed LDL) across the wall of atheromatous aortas. \200 It is an autoimmune phenomenon. Evid ence: coexisting autoimmune conditions, autoantibodies (60% ANA +ve in one series), HLA associations (HLA-B27 or HLA-DR B1 03). Causes \200 Idiopathic. \200 In \202 ammatory periaortitis (severe atherosclerosis), e .g. aortic aneurysm. \200 Drug-induced: classically methysergide, but also bromocriptine, methyldopa, and possibly beta-blockers. Chronic retroperitoneal infection (particularly TB). \200 Other in \202 ammatory conditi ons (e.g. sarcoidosis). \200 After retroperitoneal trauma. \200 Erdheim \200\223 Chest er disease: a rare histiocyte disorder, characterized by osteosclerotic bone lesions. Extra skeletal effects may include retroperitoneal in \201 ltration. Malignant: Lymphoma, lymphoproliferative disorders, carcinoid. \200 Metastatic or locally invasive m alignancies (e.g. colon). \200 Post-radiotherapy. Clinical features \200 Symptoms may be insidious and present >6 months prior to diagnosis (which is often considered only when i SCr becomes apparent). \200 Usually non-speci \201 c, e.g. malaise, anorexia, fever, and weight loss. \200 Flank and low back pain are relatively common. RETROPERITONEAL FIBROSIS: OVERVIEW 739 Vascular encasement may produce oedema or claudication. \200 Associations: in \202 ammat ory bowel disease, sclerosing cholangitis, ankylosing spondylitis, SLE, scleroderma, vascul itides, Raynaud \200\231 s. An association is also emerging with the relatively new clinicopathological entity of IgG4-related sclerosing disease. This has been described in v arious tissues, particularly pancreatic ( \200\230 autoimmune pancreatitis \200\231 ), an d is characterized by i circulating IgG4 as well as IgG4 plasma cell-rich in \202 ammatory in \201 ltrates. Investigations \200 FBC (normocytic normochromic anemia). \200 U&E, SCr, eGFR (impaired renal function). \200 ESR (a consistent marker of in \202 ammation, useful for monitori ng). \200 CRP. \200 ANA and other autoantibodies (variably +ve). \200 Immunoglobulins (polyclonal hypergammaglobulinaemia). \200 High serum IgG4 concentration. \200 Urinaly sis is typically bland. Imaging \200 USS will demonstrate uni- or bilateral hydronephrosis. \200 CT shows \201 brotic plaque enveloping the aorta and IVC and extending laterally to encompass the ur eters (see Fig. 9.2, b p. 741). May also show associated atherosclerosis and aneurysmal cha nge. Metastatic deposits, hemorrhage, and other disorders can have similar appearances. Look for other signs of malignancy: local bone destruction, lymphadeno pathy, and anterior aortic displacement. \200 Variable degree of enhancement with contras t, particularly in early in \202 ammatory phase. MRI is an alternative, showing high signal density in early stages and lower density with \201 brosis or treatment. PET scanning shows high levels of uptake in active areas. Biopsy \200 A tissue biopsy is desirable to exclude alternative diagnoses. A CT-guided TruCut needle biopsy can be performed but can miss active areas (PET may help to identify these). Open or laparoscopic may be preferred. CHAPTER 9 Essential urology 740 Retroperitoneal \201 brosis: management Management The aims of management of RPF include: \200 Preservation of renal function; obstruction requires urgent treatment, as per b p. 734. Resolution of in \202 ammatory processes (and 6 both local and systemic symptoms). Prevention of progressive \201 brosis. \200 Exclusion of secondary causes, particularly malignancy. Patients are best managed with an integrated medical and surgical approach, although there are no controlled trials to guide therapy. Medical management \200 May be appropriate without surgery if no renal impairment. \200 Stop any possible contributory drugs. \200 Corticosteroids d in \202 ammatory tissue en casing the ureter(s) and may restore ureteric contractility and patency. Response is unpred ictable. \200 Start prednisolone 0.5 \200\223 1mg/kg/day for 7 4 \200\223 8 weeks. \200 Slowly taper to 10mg, according to in \202 ammatory markers (ESR, CRP) and serial imaging. Reconsider diagnosis if unresponsive. \200 Aim to discontinue after 12 \200\223 24 month s. \200 Relapse in not uncommon, so long-term surveillance is mandatory. Combined corticosteroids and MMF show promise as initial therapy. \200 Azathioprine and m ethotrexate have both been used successfully, both when steroid therapy has failed and as steroid-sparing agents. Tamoxifen ( (cid:2) SE: thromboembolism) is a potential alternative when steroids are contr aindicated. Protocols vary, and mechanisms are unclear (may increase \201 broblastic rele ase of anti \201 brotic TGF- B ). \200 Potential therapies include anti-CD20 therapy and TNF- A inhibitors. Surgical management \200 Preoperative medical therapy may have reduce d in \202 ammation. \200 Open exploration with ureterolysis is the \201 rst step. The ureters (usually with JJ stents in situ ) are identi \201 ed, freed, and moved laterally. The ureters are then manipulated to prevent re-obstruction. Wrapping with a protective layer of omental fat is the commonest approach. Ureteric intraperitoneal transplantation is an alternative. RETROPERITONEAL FIBROSIS: MANAGEMENT 741 Fig. 9.2 Retroperitoneal \201 brosis \200\224 CT appearances. Note the peri-aortic mass and aortic calci \201 cation. Reproduced with permission from Warrell D, Cox T, Firth, and Benz EJ (eds) (2004) Oxford Textbook of Medicine , 4th edn, p.454. Oxford University Press , Oxford. CHAPTER 9 Essential urology 742 Investigation of a renal mass 2 The primary goal of investigation of a renal mass is to exc lude malignancy. Renal masses may be single or multiple, cystic or solid (see Table 9.7). Table 9.7 Types of renal masses Solid Cystic Single Renal cell carcinoma Angiomyolipoma Oncocytoma Xanthogranulomatous pyelonephritis Metanephr ic adenoma AV malformation Simple cyst Complex cyst Cystic RCC Multiple Inherited, e.g. von Hippel \200\223 Lindau disease, tuberous sclerosis Autosomal dominant (or recessive) polycystic kidney disease Acquired cystic disease They are often asymptomatic: 7 50% of new cases of renal cancer are incidental \201 ndings on imaging. Simple renal cysts are commonly observed in normal kidneys. Their incidence increases with age. USS will not detect lesions <5mm. \200 The differential diagnosis and investigation of re nal cystic disease are discussed elsewhere ( b p. 598). See Table 9.8 for classi \201 cation. Simple cysts \200 USS criteria: \200 Round. \200 Smooth-walled. \200 Anechoic. \200 Good ultrasound transmission through the cyst. If all these features are present, a cyst is very likely to be benign. \200 2 If uncertai nty persists, proceed to contrast-enhanced CT. \200 CT criteria: Smooth and thin-walled. \200 Similar density to water. \200 No contrast enhancement. The Bosniak classi \201 cation is the standard for radiological assessment of renal cysts (see Table 9.8). Equivocal cases should be followed, with repeat scans every 6 \200\223 12 months. The solid renal mass \200 The concern is malignancy (carcinoma), but solid lesions can al so be benign (e.g. angiomyolipoma). INVESTIGATION OF A RENAL MASS 743 CT, and particularly MRI, may detect small quantities of fat, highly suggestive of an angiomyolipoma. (cid:2) However, imaging cannot exclude malignancy with absolute certainty. Lesions <1.5cm cannot be accurately characterized by imaging. Active surveillance of these is generally advocated. 2 Features of concern: Contrast enhancement. \200 Thickened or irregular wall. \200 Necrotic areas (implying r apid growth). \200 Diameter >3cm (more likely to metastasize). \200 In these circumstan ces, removal is usually necessary. \200 For smaller lesions in patients at high surgical risk, alternatives beyond surveillance are percutaneous radiofrequency ablation or cryother apy. Biopsy \200 High false \200\223 ve rate is the principal problem with CT-guided biopsy. \200 (cid:2) If you \201 nd yourself discussing a biopsy \200\224 ask yourself, \200 \230Should I be considering removal? \200\231. Hemorrhage is an important complication. \200 X The risk of tumor seeding along the needl e track has probably been exaggerated in the past. \200 Useful if mass in a single kidney . Table 9.8 Bosniak classi \201 cation of renal cysts Bosniak class Features Malignant potential 0% I Simple cyst Simple cyst, hairline thin wall, no septa, no calci \201 cations, no solid components. No contrast enhancement. II Cystic lesion A few hairline thin septations. Fine calci \201 cation in the wall or septa. Uniformly hyp erdense lesions <3cm that are well marginated. No contrast enhancement. IIF Complex cyst Increased number of septa, which may be minimally thickened. Nodular calci \201 cation. No contrast enhancement. Hyperdense intrarenal lesions \211 3cm also included here. Cystic masses, with thick or multiple septation and irregular calci \201 cation. Contrast enhancement of wall or septa. III Indeterminate cyst IV Presumed malignant cyst All of the above, with additional enhancing soft tissue components, independent of the wall or septum. >85% Reproduced from Bosniak MA Radiology 262 (3) 781 \200\223 5 (2012), with permission. CHAPTER 9 Essential urology 744 Renal cell carcinoma: general Overview \200 RCCs are adenocarcinomas arising from tubular epithelium. \200 Account for >80% of primary malignant renal tumors and 7 3% of cancers overall. Risk factors: Smoking (1/3 of cases; often present with more advanced disease). \200 Long-standing hype rtension (mechanism unknown). \200 Obesity. \200 Acquired cystic disease (including lon g standing ESRD patients and ADPKD). Occupational exposures (cadmium, asbestos, and others). \200 Analgesic nephropathy. Sever al important subtypes with speci \201 c pathological and molecu- lar characteristics (see RCC: pathological and molecular subtypes, b p. 745). Epidemiology \200 Peak incidence age 60 \200\223 70. \200 1.5:1 \231\202 : \231\200 ratio. \200 More common in developed world. \200 Incidence is increasing (partly becaus e of small incidental tumors presenting earlier on imaging) and survival rates improving. Genetics \200 There is evidence for a strong genetic predisposition, including: Risk of a second RCC is high in those with \201 rst at a young age. \200 Several heredi tary syndromes are associated with RCC, including: von Hippel \200\223 Lindau (VHL) (most common), hereditary papillary renal carc inoma, familial oncocytoma, and Birt \200\223 Hogg \200\223 Dube syndrome. Factors suggesting a genetic in \202 uence in those without a de \201 ned hereditary syndrome include: onset age <40, multifocal disease, and close relatives with RC C. Several genetic mutations in both sporadic and hereditary RCC have been identi \201 ed, pa rticularly on the short arm of chromosome 3 (3p). Inactivating mutations of the VHL gene (chromosome 3p25) are particularly common. VHL protein functions as a tumor suppressor, targeting the products of hypoxia-inducible genes for proteasomal degradation. These include: \200 VEGF ( l angi ogenesis). \200 TGF- A ( l cell growth). d VHL protein l protein overexpression l epithelial proliferation + angiogenesis l neoplastic transformation. Genetic heterogeneity is suggested by the involvement of other genes. \200 Inactivating m utations of two genes ( SETD2 and JARID1C ) involved in the histone integrity have recently been described. Overexpression of p53 protein is present in 7 50% tumors (and associated with a worse prognosis). RENAL CELL CARCINOMA: GENERAL 745 RCC: pathological and molecular subtypes Clear cell ( 7 75%) Originate from proximal tubule. Cells have clear cytoplasm. Deletion of chromosome 3p typical. Papillary ( 7 15%) Originate from proximal tubule but pathologicall y and genetically dis- tinct. Frequently multifocal. Classi \201 ed into two subtypes, wit h different genetic and prognostic inferences. Chromophilic. Chromophobic ( 7 5%) Originate from intercalated cells. Lack the lipid content of clear cell tumors and appear darker mac roscopically. Chromosome 3p intact. Oncocytic (<5%) Originate from cells of the collecting duct. Oncocytes are recognized as well-differentiated cells with eosinophilic, mitochondria -rich cytoplasm. Generally behave in a benign manner. Collecting duct (<1%) Younger age gro ups. Aggressive tumor, with some similarities to urothelial cancer. Often presents with hae maturia. Medullary carcinoma (<1%) Variant of collecting duct carcinoma. Associated with si ckle cell trait. Translocation carcinomas (<1%) Younger age groups, especially those receiv ing chemotherapy for other childhood cancers. Heterogeneous genetic abnormalities, often in volv- ing transcription factors. Incidence increasing. von Hippel \200\223Lindau (VHL) disease \200 Autosomal dominant multisystem disorder, cha racterized by benign and malignant tumors in many organ systems. \200 7 1 in 35,000 live births. 7 90% penetra nce by age 65. \200 VHL gene inactivation l overproduction of vascular growth factors. \200 Manifestations: Renal involvement in 60%: cysts (70%), RCC (always clear cell, usually multiple) (50%), ESRD from the required surgical removal of renal tissue (25%). Retinal and CNS haemangioblastomas. \200 Phaeochromocytoma. \200 Pancreatic neuroendocr ine tumors and pancreatic cysts. \200 Epididymal cystadenoma. \200 Endolymphatic sac tu mors (arise in the temporal bone, causing hearing loss, tinnitus, vertigo, and facial nerve dysfunction). Families often subcategorized, according to their phaeochromocytoma and RCC pedigree. Mean onset of clinically manifest disease is age mid-20s. A multidisciplinary approach, with surveillance from childhood, is mandatory. CHAPTER 9 Essential urology 746 Renal cell carcinoma: diagnosis Clinical features \200 <10% exhibit the classic triad of pain, haematuria, and a palpable mass. \200 Up to 50% are asymptomatic (incidental radiol ogical \201 nding). This is increasing with the widespread use of abdominal imaging. Haematuria ( l invasion of the collecting system; occurs in 7 40% of those presenting \200\230non-radiologically \200\231 ). Flank or back pain ( l capsular stretch), radiating to the groin, can occur with larger tumors. Palpable mass. \200 Scrotal varicocele (left > right) due to testicular vein obstruction ( \201 nding one should always provoke suspicion. Arrange an USS). Lower limb oedema s to IVC invasion. \200 7 25% present with metastases (nodes, skeletal, liver, lung, cerebral). Paraneoplastic syndromes with RCC \200 Paraneoplastic phenomena are relatively common wit h RCC. \200 RCC has 6 been called \200\230the internist \200\231 s tumor \200\231 beca use it can present with non-speci \201 c symptoms to a general physician. These tend to occur late and suggest a poorer prognosis. \200 Caused by tumor cytokine (e .g. IL-6) or hormone (e.g. EPO) production. Include: Fever and night sweats. \200 Weight loss and cachexia. \200 Malaise. \200 Erythrocyto sis (RCC produces EPO). \200 Disproportionate anemia. \200 Hypercalcaemia (skeletal met astases or production of PTHrP). \200 Hepatic dysfunction without liver metastases (Stauf fer syndrome). \200 s AA amyloid deposition. \200 Polymyalgia. \200 Dermatomyositis. \200 Neuropathy. \200 Hypertension ( i renin). \200 Ectopic hormonal production (e.g. ACTH-like substance). \200 Elevated ESR. Work-up \200 Imaging ( b p. 742): USS: usually \201 rst-line. \200 CT: for diagnosis and initial staging. Chest CT for me tastases. \200 MRI: more sensitive for collecting system and IVC involvement. \200 Bone scan: if skeletal pain, i Ca 2+ , or i alkaline phosphatase. \200 PET: not used for rout ine staging. May detect occult metastases. \200 DMSA: to determine split renal function, i.e. what would the consequence of a nephrectomy be? RENAL CELL CARCINOMA: DIAGNOSIS 747 Biopsy: CT-guided. Increasingly used to guide treatment. Risks: hemorrhage (tumor seeding has been overstated in the past). Prognosis Staging, histological grading, and tumor subtype are relevant, and models to inte grate all three have been developed in some centers. Staging \200 The TNM (2010) classi \201 cation is used (see Table 9.9). T1N0: 5-year survival >90%; T4N2M1: 5-year survival <10%. Table 9.9 The TNM stage classi \201 cation for renal cell cancer T Primary tumor T1a Tumor <4cm; renal limited Tumor >4cm, but \211 7cm; renal-limited Tumor \211 7cm, but \211 10cm; renal-limited Tumor \211 10cm; renal-limited Invades renal vein or branches, or perirenal fat, but not beyond Gerota \200\231 s fascia Extends into vena cava below the diaphragm Extends into ve na cava wall or vena cava above the diaphragm Invades beyond Gerota \200\231 s fascia, inc luding extension into adrenal gland T1b T2a T2b T3a T3b T3c T4 N Regional nodes N0 N1 N2 No regional node involvement Single regional node More than one regional node M Distant metastases M0 M1 No distant metastases Distant metastases Fuhrman s nuclear grade \200 Grading, according to histological criteria, also predicts s urvival. Fuhrman \200\231 s grading (1 \200\223 4) is the most widely used. Tumor subtype \200 Tumor subtype may also in \202 uence the prognosis of localized disea se, e.g. chromophobe survival > papillary > clear cell. Other \200 Poor patient performance status and paraneoplastic symptoms are adverse prognostic indicators. Molecular and cytogenetic markers are likely to play a progressively more important role in the future. CHAPTER 9 Essential urology 748 Renal carcinoma: management and follow-up Management Management is directed by the possibil ity of cure \200\224 based principally on tumor staging. For localized disease, surgical r esection alone may be curative. Unfortunately, tumors are often already locally advanced or metastatic at presentation. Recurrence after resection is not uncommon. Surgery \200 Radical nephrectomy is the conventional approach and preferred when evidence of local invasion (e.g. renal vein, perinephric fat, or adrenal). Partial nephrectomy (open or laparoscopic) may be favored for smaller, non-invasive tumors. Outcomes are good and local recurrence rates low. Such \200\230nephron-sparing \200\231 surgery is particularly useful in several situations: \200 Single functioning kidney. \200 Contralateral kidney has signi \201 cant functiona l impairment. \200 Bilateral tumors or hereditary multicentric disease. Surgery to remove isolated metastases (e.g. lung) is recommended in carefully selected cases. A debulking nephrectomy prior to systemic therapy has shown a survival bene \201 t. Remova l of RCCs rarely induces spontaneous remission of metastases through immunological mechanis ms. X The role of adjuvant systemic therapy, in addition to surgery, for localized disease is unproven. Trials are ongoing. Energy ablation therapy \200 Cryotherapy or radiofrequency ablation can be used to oblite rate tumor tissue in situ . Option for smaller (<4cm) tumors in patients unsuitable for surgery. \200 Follow-up data now emerging. Local recurrence not uncommon. \200\230Conventional \200\231 chemotherapy \200 Limited role, as RCC, particularly clear cell tumors, often exhibit P - glycoprotein-mediated multidrug resistance. Cytokines \200 Systemic treatment of RCC is one of the most rapidly evolving areas in med ical oncology. Enrolment into approved clinical trials should be encouraged. Cytokine therapy (IFN- A 9 IL-2) was the standard \201 rst-line systemic therapy until relatively recently. Mechanism of action is unknown but probably involves induction of anti-tumor immunity. However, response rates were low and relatively short-lived. Remission in 7 10%. High-dose IL-2 causes signi \201 cant toxicity ( l proin \202 ammatory cytokine cascades). 2 Side effects common and often severe ( d BP, arrhythmias, dyspnoea, f ever, nausea, i SCr, CNS toxicity, skin rashes). IFN- A SE: \202 u-like symptoms (fever, malaise, myalgia, etc.). RENAL CARCINOMA: MANAGEMENT AND FOLLOW-UP 749 Molecularly targeted therapy \200 Improved understanding of the molecular pathogenesis of RCC has identi \201 ed VEGF and mTOR as targets for therapeutic intervention. Systemic therapy targeting VEGF is now the standard of care for \201 rst-line treatment of metastatic RCC. There are two approaches to VEGF inhibition: Blockade of intracellular VEGF signaling through tyrosine kinase inhibition, e.g. sunitinib, sorafenib, and pazopanib. Sunitinib and pazopanib are NICE-appr oved and have become \201 rst-line treatment. SE: i BP, renal and hepatic toxicity, throm boembolism, cardiac toxicity, thyroid dysfunction, GI toxicity, skin rashes. Monoclonal Abs to circulating VEGF (e.g. bevacizumab). Rare in the UK. Temsirolimus and everolimus inhibit mTOR and provide an option if disease progresses despit e VEGF inhibition (SE: nausea, anorexia, anemia, pneumonitis). Follow-up Surveillance for local and contralateral recurrence as well as metastatic disease is mandatory. The frequency of follow-up appointments and repeat imaging is based on risk strati \201 cation for each given clinical sce- nario. Several algorithms have been develo ped to assist this process. Wilms \200\231 tumor (nephroblastoma) \200 Embryonal neoplasm arising in the kidney. It i s the commonest renal malignancy in children and represents 7 8% of all childhood cancer. Peak age 3 \200\223 4 years (rare age >10). \231\202 = \231\200 . \200 More common in a number of congenital syndromes, but these still represent only a small proportion of the total. WT1 was the initial Wilms \200\231 associated gene identi \201 ed. However, the situation is much more complex, with several others now known. Clinical features: 7 3/4 present with an abdominal mass (often noticed by a parent). \200 7 1/2 report abdom inal pain. \200 i BP ( l tumor renin production), haematuria, fever. \200 Staging delin eates local spread and presence of metastases (particularly pulmonary). X Diagnostic biopsy not always undertaken (although desirable if preoperative chemotherapy is under consideration). Classic \200\230triphasic \200\231 histology: epithelial, stromal, and blastemal elements all coexist. Anaplastic features carry a worse prognosis. Treatment: The majority of patients will be cured. \200 Surgery, followed by adjuvant chemotherapy ( e.g. vincristine 9 dactinomycin), as determined by staging. Preoperative chemotherapy is fa vored in many centers. The use of radiotherapy is diminishing ( l subsequent growth restric tion). Follow-up: pulmonary relapse is more common than renal. In addition, prospective assessment of the long-term side effects of anthracycline-based chemo therapy (e.g. cardiac function) is mandatory. CHAPTER 9 Essential urology 750 Tumors of the bladder: overview \200 Bladder cancer is the second commonest malignancy of the urinary tract and one of the top \201 ve cancers in the UK and USA. Median age: 70; 2.5 \231\202 :1 \231\200 . \200 Caucasians > black people (although pro gnosis worse in the latter). \200 90% are transitional cell cancers (TCCs), derived from urothelium. \200 Although the bladder is the most common site, TCCs can arise anywhere fr om the renal pelvis to the urethra ( b p. 756). Squamous cell cancers (SCCs), often s to chronic schistosomal infection, are much more comm on in developing countries ( 7 75% cases). SCCs can also be secondary to stone disease and other causes of chronic in \202 ammation. Prognosis is varied, depending on histology and staging. Low-grade, \200\230super \201 ci al \200\231 tumors have a very different outcome from high-grade \200\230invasive \200 \231 ones. TCCs have one of the highest recurrence rates of any malignancy. Risk factors Transitional cell (TCC) \200 2 7 80% of TCCs are associated with an environm ental exposure. \200 Cigarette smoking is the most important (by far) and associated with a 4-fold risk (relevant carcinogens include B -naphthylamine and 4-aminobiphenyl). Aromatic amines, aniline dyes, and hydrocarbons. Occupations at i risk include: petroleum i ndustry and lorry drivers (diesel fumes), plumbers, metal workers, dry cleaners, painters, hairdressers, rubber, textile and leather industry workers. Urban > rural areas. \200 Previous haemorrhagic cystitis from cyclophosphamide therapy ( l acrolein; a carcinogenic urinary metabolite. Mesna inactivates urinary acrolein and may b e used as chemoprophylaxis). Previous pelvic radiotherapy. \200 Prolonged immunosuppression (e.g. transplant recipient ). \200 Late risk after bladder augmentation procedure (e.g. ileocystoplasty). \200 Phe nacetin (an analgesic), prior to its withdrawal. \200 X High \202 uid intake may dilute carcinogens, reducing urothelial exposure and 6 risk. Squamous cell (SCC) \200 Squamous metaplasia l i risk of SCC. \200 Causes: chronic cyst itis, bladder stones, long-term urinary catheters. \200 Schistosoma haematobium infection is responsible for the majority worldwide, particularly the Middle East. Genetics \200 Several genetic mutations have been identi \201 ed. Altered tumor suppressor expression, e.g. p53 (chromosome 17). \200 Deletion of 9p21 (sit e of tumor suppressor p16). \200 Aneuploidy of chromosomes 3, 7, and 17. \200 Altered c -myc and c-jun oncogene expression. tumors OF THE BLADDER: OVERVIEW 751 Clinical features \200 Haematuria: Painless visible haematuria in 7 80% patients. \200 7 15% patients presenting with macros copic haematuria will have bladder cancer. <5% patients presenting with microscopic haematuria will have bladder cancer. Irritative symptoms ( b p.78), e.g. frequency, urgency, nocturia, dysuria. \200 More adva nced disease: pain, pelvic mass, systemic symptoms (weight loss, fatigue, anorexia, etc.). Investigations \200 Urine cytology: 100mL freshly voided urine. Avoid \201 rst morning sample. \200 Sensitivity is quite lo w and center-dependent. \200 Sensitivity increases for higher-grade tumors ( l pleomorphi sm and increased nuclear:cytoplasmic ratio). Urinary biomarkers: Novel protein and genetic markers are gradually expanding their diagnostic utility. They include tumor cell-associated antigens (via immunohistochemistry) and genetic abnormalities (via \202 uorescence in situ hybridization \200\224 FISH). Many identi \201 ed but few routinely available. Further proof of clinical utility is required. Commercially available tests include: (i) a FISH assay with probes for chromosomes 3, 7, 17 , and 9p21 and (ii) a quantitative immunoassay for nuclear matrix protein (NMP-22), a house keeping protein active during cell division. Cystoscopy: Size, number, position, morphology of tumors. Rigid cystoscopy allows biopsy. Photodynamic cystoscopy: a photoactive substance that accumulates in neoplastic cells (e.g. 5-aminolevulinic acid) is instilled and \202 uoresc es under light of the appropriate wavelength. Aids the identi \201 cation of carcinoma in situ (CIS). Biopsy/cystoscopic resection: Biopsy areas displaying abnormal urothelium. \200 Random biopsies may be necessary to det ect CIS, including of prostatic urethra. Inclusion of muscularis propria necessary to ensure accurate staging. Imaging: USS to exclude hydronephrosis (even if SCr normal \200\223as unilateral obstruction may occur). Not useful for staging. CT: for staging. In addition, upper tracts must be assessed for synchronous tumors by contrast-enhanced CT. MRI as good as CT for staging and may better delineate extravesical invasion. Bone scan if skeletal pain, i ALP, or i Ca 2+ . \200 CXR for lung metastases if muscle-in vasive (and if CT chest not undertaken during staging). PET: limited role in local disease, as 18F-FDG undergoes urinary excretion. May have a role in detection/monitoring of metastases. CHAPTER 9 Essential urology 752 Tumors of the bladder: pathology and management Pathology \200 TCC (90%) > SCC (5%) > ade nocarcinoma (2%) > sarcomas (rare) > small cell (rare). TCC has a range of phenotypic expressions: papillary ( 7 70%), sessile ( 7 10 \200\223 20%), nodular ( 7 10%), or carcinoma in situ (CIS). The usual growth pattern is papillary, projecting out into the bladder lumen. This may gradually invade deeper, breaching basement membrane, lamina propria, and, eventually, muscle, prior to distant spread. Often multifocal. 7 30% tumors are synchronous at presentation ( s to the \200\230 \201 eld change \200\231 effect of environmental exposures). WHO classi \201 es tumors pathologically as low-grade (formerly grades 1 \200\223 2) or h igh-grade (grade 3). Low-grade tumors rarely progress to more aggressive, muscle-invasive f orms (see Table 9.10). The term \200\230super \201 cial \200\231 tumor is misleading and best avoided. Low- and high-grade tumors follow different biological pathways, have different outcomes, and requi re different treatments, regardless of \200\230super \201 ciality \200\231 . 2 CIS does not imply early disease or a good outcome \200\224 it is often characterized by high-grade dysplasia and a poor prognosis. Many patients with CIS have coexisting papillar y tumors ( \200\230 pure \200\231 CIS in <10%). Staging and prognosis \200 The most signi \201 cant prognostic factors are: (i) depth of invasion (stage); (ii) histological grade; (iii) presence of CIS; (iv) previous recurrence s. Progression risk relates to grade. Low-grade <10% progression (rarely invade muscle). High-grade >30% progression. The majority of tumors (>70%) are non-muscle-invasive at diagnosis. \200 Non-muscle-invas ive tumors have a relatively good prognosis, with 5-year survival rates of >80%. Tumors are much more likely to recur than progress. 5-year s urvival deteriorates to <25% by stage T4. \200 Prognosis therefore depends on both stage and grade. As a rough guide, for super \201 cial tumors: \200 Ta low grade: prognosis very good. \200 Ta hig h grade: prognosis less good. \200 T1 low grade: prognosis good. \200 T1 high grade: pr ognosis poor. Diffuse CIS l higher recurrence rates and poorer prognosis. \200 7 50% with muscle-invasi ve disease have occult metastases at diagnosis. \200 Prognosis for those with distant dis ease is poor (<10% alive at 2 years). tumors OF THE BLADDER: PATHOLOGY AND MANAGEMENT 753 Table 9.10 TNM staging of bladder cancer T Primary tumor CIS Carcinoma in situ , high-grade dysplasia, con \201 ned to the urothelium Ta Papillary tumor con \201 ned to the urothelium T1 Invasion into the lamina propria T2 Invasion into the muscularis propria T3 Invasion into the perivesical fat T4 Involvement of adjacent organs (e.g. prostate, rectum) N Regional nodes N+ Lymph node involvement M Distant metastases M+ Distant metastases Management \200 The depth of bladder wall invasion determines treatment (non-muscle-invasive: Ta, T1, and CIS. Muscle-invasive: T2 \200\223 T4). Non-muscle-invasive \200 Transurethral resection (TURBT): Smaller TCCs may be resected as one piece with underlying muscle. Larger tumors require mor e extensive resection. Should be followed with a single dose of intravesical chemotherapy (e.g. mitomycin) to d re currence risk (administered within 6h of resection). Repeat TURBT at 7 6 weeks if: (i) residual tumor; (ii) no muscle in initial specimen ( l ri sk of understaging); (iii) high-grade disease. Subsequent treatment depends on the risk of recurrence and progression. Broadly: \200 Low-risk (Ta staging, <3 lesions, <3cm, low-grade dysplasia, papillary): follow with active surveillance. High-risk (T1 staging or above, CIS, >3 lesions, >3cm, high-grade dysplasia, non-papillary) : further intravesical treatment. Usually immunotherapy with bacille Calmette \200\223 Gu rin (BCG). Usually induction treatment weekly for 6 weeks (+/ \200\223 intermittent main tenance therapy for 1 \200\2233 years). Reduces progression risk by 7 25% (SE: cystitis, ha ematuria, fever, arthralgia, hepatitis, and pneumonitis). CHAPTER 9 Essential urology 754 Muscle-invasive disease (or failure of conservative treatment) Radical cystectomy with urin ary diversion \200 Bladder removed with local lymph node dissection. The prostate and sem inal vesicles are also removed in \231\202 (SE: impotence), and cervix, uterus, ovaries, a nd anterior vagina in \231\200 . Commonly performed as open surgery, but laparoscopic and robotic techniques are becoming well established. Operative mortality of 2 \200\2235%, but overall perioperative morbidity (cardiovascular, atelectasis, sepsis, bowel and urine leaks, bleeding, wound infections) hi ghly signi \201 cant ( 7 30 \200\223 60%). There is evidence that neoadjuvant chemotherapy has a role prior to surgery, and it should be considered in all suitable patients. Urinary diversion: Ileal conduit: a segment of ileum is used to create a stoma. \200 Orthotopic neobladder: pouch formed from bowel and connected to the urethra (prostatic urethral disease precludes this option). Continent cutaneous pouch: similar to neobladder, but externalization using bowel (often appendix) allows drainage via a catheter. Metastatic disease is treated with cisplatin-based chemotherapy. \200 In patients who are not considered to be candidates for cystectomy, bladder preservation with a radical TURBT +/ \200\223 chemotherapy may be an option. Radical external beam radiotherapy \200 Generally reserved for those un \201 t for surge ry, in a poor prognostic group, or needing palliation of local symptoms (e.g. haematuria). Follow-up See b p. 757. Bladder adenocarcinoma \200 Uncommon; 2% malignant bladder tumors. \200 Varied histolo gic patterns, but most often a glandular (enteric) morphology. Need to be differentiated from metastatic adenocarcinoma; e.g. prostate, colon.