CHAPTER 7 Urological neoplasia 256 Renal cell carcinoma: surgical treatment II and non-surgical alternatives for localized dis ease Localized RCC \200\224lymphadenectomy Lymph node involvement in RCC is a poor prognost ic factor. Incidence ranges from 6% in T1 \200\2232 tumors, 46% in T3A, and 62 \200\22366% in higher stage disease. Lymphadectomy at time of nephrectomy may add prognostic in- format ion, especially if there is obvious lymphadenopathy, but therapeu- tic bene \201 t 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 surv ival 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 treatme nt 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 nephrecto my. Localized RCC: alternatives to surgery - Renal artery embolization haematuria who are un \201 t for curative surgery. Active survei llance followed with repeat scans in elderly or un \201 t individuals. Metastasis is rare in masses <3cm. For every 1cm size increase, the estimated prevalence of metastasis increas es 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, 70. 15cm per year. Over a minimum 2y period, 25 (12%) progressed locally (i.e. grew to (cid:116 )4cm or volume doubled in (cid:100)12 months) and only 2 (1.1%) developed bone/lung metasta ses.1 Cryosurgery intraoperative ultrasound by open, percutaneous, or laparoscopic routes, is gaining popularity as a nephron-sparing treatment option. HIFU under evaluation as a nep hron-sparing treatment option. Image-guided percutaneous extracorporeal or laparoscopic rou tes, remains under evaluation as a nephron-sparing treatment option. : indicated for patients with gross : small (T1a; <4cm) solid renal masses may be : this minimally invasive treatment (MIT) performed using : this MIT delivered percutaneously or extracorporeally, is RFA: this MIT, delivered by Cryosurgery, HIFU, and Image-guided percutaneous RFA have the advantage of being outpatient -based, low morbidity, and repeatable; they are currently RENAL CELL CARCINOMA: SURGICAL TREATMENT II 257 recommended only for those patients un \201 t or unwilling to undergo surgery (since curre nt data show recurrence rates are higher), ideally within clinical trials. Locally advanced RCC Disease involving the IVC, right atrium, liver, bowel, or posterior ab dom- inal wall demand special surgical skills. In appropriate patients, an aggres- sive sur gical approach involving a multidisciplinary surgical team to achieve negative margins appe ars to provide survival bene \201 t. Adjuvant treatment: To date no adjuvant therapy has demonstrated any survival bene \201 t, even in those who are predicted to have a higher risk of recurrence. With the advent of th e newer tyrosine kinase inhibitors that have demonstrated a bene \201 t in metastatic dise ase, multiple randomized trials are ongoing and results are awaited. Metastatic RCC Nephrectomy has long been indicated for symptom palliation (pain, haema- tur ia) in patients with metastatic RCC (if inoperable, arterial embolization can be helpful) a nd is also performed prior to systemic therapy, if appro- priate. A median survival bene \201 t of 10 months for patients with good performance status treated with cytoreductive ne phrectomy prior to immunotherapy (interferon-A) has been reported. Studies are ongoing to i nvestigate whether there is a similar bene \201 t to cytoreductive nephrec- tomy with the tyrosine kinase inhibitors. Currently, the standard prac- tice is to recommend it, extrapol ating from the cytokine era. Patients should be recruited to the studies that are investiga ting 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 sion patterns of early stage kidney cancer. Eur Urol 60:39 \200\22344. Jewett MA, Mattar K, Basiuk J, et al. (2011) Active surveillance of small renal masses: pro gres- CHAPTER 7 Urological neoplasia 258 Renal cell carcinoma: management of metastatic disease Approximately 25% of patients with R CC have metastatic disease at presentation; a further 30% progress subsequently to this sta ge following nephrectomy. Prognostic risk strati \201 cation: The MSKCC (Motzer) criteria may be used, based on Karn ofsky performance status <80%; absence of pri- or nephrectomy; hemoglobin subnormal; LDH >1 .5 times upper limit; corrected calcium > normal. No factors confers favorable risk, median time to death \200\22420 months; one to two factors carry intermediate risk (10 months med ian survival); >3 factors carry poor risk (4 months median survival). Surgery: despite the rare possibility of spontaneous metastatic regres- sion (<5%) followin g nephrectomy, it was rarely undertaken except to relieve local symptoms of pain or haematu ria. The role of nephrectomy in metastatic RCC is discussed on b p. 257. Metastasectomy may be of bene \201 t to the 1.5 \200\2233% of patients who develop a solit ary metastasis (particularly in lung, adrenal, or brain) fol- lowing nephrectomy. Angiogenesis (signal transduction) inhibitors As discussed earlier (see b p. 250), most RCC s are highly angiogenic so fortunately become good therapeutic targets for angiogenesis inh ibitors. Via its cell surface receptor (VEGFR), VEGF is a pro-angiogenic peptide growth fac tor that activates the PI3kinase/AKT signal transduction path- way, which is one of three m ajor receptor tyrosine kinase (RTK) signaling pathways. VEGF is overexpressed in most spora dic RCC as a result of HIF-1 overexpression caused by inactivation of the VHL tumor sup- pr essor gene. In randomized trials, two well-tolerated oral multi-RTK inhibitors, sunitinib a nd pazopanib, have demonstrated signi \201 cant bene- \201 t in the \201 rst-line meta static setting, prolonging progression-free survival (PFS) in metastatic RCC patients by 3 \200\2238 months compared with interfer- on alpha (IFNA) or placebo. The UK NICE approved b oth in 2009 and 2011, respectively. Complete responses are rare, partial responses modest ( 30 \200\22340%), they also stabilize the disease in approximately 30% of patients.1 Pazopan ib is effective as second-line treatment (prior cytokine therapy). A further randomized trial demonstrated >3-month survival advantage of temsirolimus, an inh ibitor of cytoplasmic mTOR kinase (a downstream component of the same pathway) in metastati c RCC patients compared with IFNA.2 This is currently recommended for \201 rst-line treat ment of poor risk disease. For second-line, everolimus is an orally available mTOR inhib- i tor: it confers a 2-month PFS over placebo when used for patients failing the treatments. H owever, 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 + IFNA compared w ith IFNA alone, with a 4.8-month PDS RENAL CELL CARCINOMA: MANAGEMENT OF METASTATIC DISEASE 259 advantage for low and intermediate risk patients. This combination is an option for \201 rst-line treatment. These agents represent a major advance in the \201 rst- and second-line treatment of meta static RCC. There are multiple newer thymidine kinase inhibitors (TKI) that are also curren tly being investigated. Immunotherapy The immunogenicity of RCC is discussed on b p. 246. The \201 rst cytokines to be used therapeutically to activate anti-tumor immune response were interferons and subs equently IL-2. Randomized studies in the 1990 \200\231s dem- onstrated modest response rate s (10 \200\22320%) after systemic immunotherapy using these cytokines alone and in combinat ion; 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 IFNA vs med roxyprogesterone demonstrated a 2.5-month survival advan- tage in the immunotherapy group. The use of immunotherapy has been overshadowed recently by the development of RTK inhibitor s, although there may still be a role for IL-2 in a very select group of patients and is st ill being used for appropriate patients (excellent performance status, small volume lung on ly metastases, and no prior treatment). Chemotherapy: little role in RCC; ineffective due to high multidrug resistance P glycoprote in expression. Radiotherapy: useful for palliation of metastatic lesions in bone and brain and in combinat ion with surgery for spinal cord compression. Palliative care Steroids (e.g. dexamethazone 4mg qds) improve appetite and mental state, bu t are unlikely to impact on tumor growth. The involvement of multidisciplinary uro-oncology , palliative, and primary care teams is essen- tial to support these patients and their rel atives. 1 Motzer RJ, Hutson TE, Tomczak P, et al. (2007) Sunitimib versus interferon alfa in metast atic renal-cell carcinoma. N Engl J Med 356:115 \200\22324. 2 Sternberg CN, Davis ID, Mardiak J, et al. (2010) Pazopanib in locally advanced or metasta tic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28:1061 \200\2238. 3 Hudes G, Carducci M, Tomczak P, et al. (2007) Temsirolimus, interferon alfa, or both for ad- vanced renal-cell carcinoma. N Engl J Med 356:2271 \200\22381. CHAPTER 7 Urological neoplasia 260 Upper urinary tract transitional cell carcinoma (UUT-TCC) UUT-TCC accounts for 90% of upper urinary tract tumors, the remain- der being benign inverted papilloma, \201 broepithelia l polyp, squamous cell carcinoma (associated with longstanding staghorn calculus disease), ad- enocarcimona (rare), and various rare non-urothelial tumors, including sarcoma. TCC of the renal pelvis is uncommon, accounting for 10% of renal tumors and 5% of all TCC. Ureteric TCC is rare, accounting for only 1% of all newly presenting TCC. Half are multifoc al; 75% located distally while only 3% are located in the proximal ureter. Risk factors are similar to those of bladder TCC (see b p. 264). Males Incidence increases with Smoking causes. Phenacetin ingestion. There is a high incidence of in Balkan countries ( \200\230Balkan nephropathy \200\231) that remains unexplained. Lynch syndrome (hereditar y non-polyposis colon cancer) is an autosomal dominant condition caused by a DNA mismatch r epair defect; it is associated with various cancers, including UUT-TCC, most in middle-aged females. - are affected three times as commonly as females. age. confers a 2-fold risk and there are various occupational UUT-TCC in families from some villages Pathology and grading The tumor usually has a papillary structure, but occasionally solid. It is bi- lateral in 2 \200\2234%. It arises within the renal pelvis, less frequently in on e 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; ly mphatic spread to para-aortic, para-caval, and pelvic nodes; bloodborne spread, most common ly to liver, lung, and bone. Presentation - - Painless total haematuria (80%). Loin pain (30%), often caused by clots passing down the ur eter ( \200\230clot colic \200\231). Asymptomatic when detected, associated with synchronou s bladder TCC (4%). At follow-up, approximately 50% of patients will develop a metachronous bladder TCC and 2% will develop contralateral upper tract TCC. Investigations Ultrasound is excellent for detecting the more common renal parenchy- mal tu mors, but not sensitive in detecting tumors of the renal pelvis or ureter. Diagnosis is usually made on urine cytology and CTU, respectively, reveal- ing malignant ce lls and a \201 lling defect in the renal pelvis or ureter. If doubt exists, selective ure teric urine cytology, retrograde ureteropyelgraphy, or UPPER URINARY TRACT TRANSITIONAL CELL CARCINOMA 261 \202 exible ureterorenoscopy with biopsy are indicated. Some surgeons prefer to have hist ological proof of malignancy prior to treatment. Additional staging is obtained by chest CT and occasionally, isotope bone scan. Staging uses the TNM (2009) classi \201 cation (Table 7.7) following his- tological con \201 rmation of the diagnosis. All rely on physical examination and imaging, the pathologic al classi \201 cation corresponding to the TNM categories. Table 7.7 TNM 2009 staging of carcinomas of the renal pelvis and ureter Tx Primary tumor cannot be assessed T0 No evidence of primary tumor Ta Non-invasive papillary carcinoma Tis Carcinoma in situ T1 Tumor invades subepithelial connective tissue T2 Tumor invades muscularis propria T3 Tumor invades beyond muscularis propria into perinephric or perureteric fat or renal parenc hyma T4 Tumor invades adjacent organs or through kidney into perinephric fat Nx Regional (para-aortic) lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node (cid:100)2cm N2 Metastasis in a single lymph node >2 \200\2235cm or multiple nodes up to 5cm N3 Metastasis in a single lymph or multiple nodes >5cm Mx Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis present Treatment If staging indicates non-metastatic disease in the presence of a normal contralat eral kidney, the gold standard treatment with curative intent is nephroureterectomy with ex cision 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 extraperitoneal ly; 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, bene \201 ts inc lude reduced CHAPTER 7 Urological neoplasia 262 post-operative pain and faster recovery. Tumor spillage and port site metastases are theore tical hazards. Long-term results are equivalent with the open approach. Percutaneous, segmental, or ureterorenoscopic resection/laser ablation of the tumor are the minimally invasive options for patients with a single functioning kidney, bilateral diseas e, unilateral low-grade tumors <1cm, or those who are un \201 t. Topical BCG or chemothera py (for example, mitomycin C) may subsequently be instilled through the nephrostomy or uret eric catheters, though bene \201 t has not been proven. This nephron- sparing approach is less likely to be curative than de \201 nitive surgery. Follow-up should continue at least 5y: T1-2 detect metachronous TCC development. T3-4 and m inimally invasive management should be at 3 months, then 6-monthly for the \201 rst 2y, t ogether with urine cytology. : cystoscopy at 3 months, then annually, plus annual CTU to : cystoscopy and CTU Metastatic disease - Systemic combination chemotherapy (platinum-based) unresectable or metastatic disease is as sociated with a 30% total or partial response at the expense of moderate toxicity. Palliati ve surgery or arterial embolization troublesome haematuria. Radiotherapy is generally ineff ective. : for : may be necessary for Prognostic factors (Table 7.8) Muscle-invasive UUT-TCC, constituting 60% of new presentatio ns, have a poor prognosis. The following are recognized prognostic factors, in de- scending order of importance: - Tumor grade and stage. - Associated Tis. - Age. - Lymphovascular in vasion. - Tumor architecture. - Extensive tumor necrosis. - Tumor location. - Molecular mar kers, e.g. epithelial cadherin, TK MET. HIF-1A, telomerase RNA, Table 7.8 5y survival Organ-con \201 ned (T1, 2) 60 \200\223100% Locally-advanced (T3, 4) 10 \200\22350% Node-positive (N+) 10% Pulmonary, bone metastases (M+) 10% This page intentionally left blank CHAPTER 7 Urological neoplasia 264 Bladder cancer: epidemiology and etiology 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 fa ct, 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 suc h trends. These data indicate about half of patients diagnosed have curable or controllable disease; hence, 10y survival is 750% 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 ar e unclear, but may be associated with greater urine residuals in the bladder Age and rare b elow age 50y. Smoking : is the major cause of bladder cancer in the developed world. Smoker s have a 2 \200\2235-fold risk of developing bladder cancer, subsequent recurrences, and hi gher mortality compared to non-smokers. Estimates suggest that 30 \200\22350% of bladder ca ncer is caused by smoking. Cigarette smoke contains the carcinogens 4-aminobiphenyl (4-ABP) and 2-naphthylamine (Fig. 7.2). Slow hepatic acetylation (detoxi \201 cation) of 4-ABP by N-acetyltransferase and glutathione S-transferase M1 (GSTM1) or induction of the cytochrom e P450 1A2 demethylating enzyme appear to increase urothelial carcinogenic exposure. There is a slow (20y) risk reduction following cessation of smoking. Occupational exposure hydroc arbons like aniline, is a recognized cause of bladder cancer. Examples of \200\230at risk \200\231 occupations are shown in Box 7.1. A latent period of 25 \200\22345y exists between exposure and carcinogenesis. Environmental carcinogens bladder cancer. Chronic in \202 am mation of bladder mucosa term catheters, and notoriously the ova of Schistosoma haematobium (bilharziasis) are implicated in the development of SCC of the bladder. Drugs Race inexpli cably they appear to carry a poorer prognosis. Pelvic radiotherapy brachytherapy) or a gyne cological malignancy, a relative risk of 1.4 \200\2234 exists for the later development of a second primary malignancy in the bladder. : increases risk, most commonly diagnosed in the eighth decade : to carcinogens, in particular aromatic : found in urine are the major cause of : bladder stones, long- : phenacitin and cyclophosphamide. : Black people have a lower incidence than white people, but : either for prostate cancer (external beam or BLADDER CANCER: EPIDEMIOLOGY AND etiology 265 NH2 NH2 enilina enimalyhthpan-2 NH2 4-aminobiphenyl Fig. 7.2 Carcinogens known to increase risk of bladder cancer. Box 7.1 Occupations associated with TCC - Rubber manufacture, e.g. tires or electric cable . - Paint and dye manufacture. - Fine chemical manufacture, e.g. auramine. - Gas and tar ma nufacture. - Iron and aluminum processing. - Hairdressers. - Leather workers. - Plumbers. - Painters. - Drivers exposed to diesel exhaust. No evidence for a hereditary genetic etiology exists, though many somatic genetic abnormali ties have been identi \201 ed. The most common cytogenetic abnormality is loss of chromoso mes 9p, 9q, 11p 13q, and 17q. Activation/ampli \201 cation of oncogenes (p21 ras, c-myc, c -jun, erbB-2), inac- tivation of tumor suppressor genes (p53 mutations appear to worsen sur vival after treatment, retinoblastoma, p16 cyclin-dependent kinase inhibitor), and increase d expression of angiogenic factors (for example, VEGF) are reported in TCCs. CHAPTER 7 Urological neoplasia 266 Bladder cancer: pathology, grading, and staging Benign tumors of the bladder, including inv erted urothelial papilloma and nephrogenic adenoma, are uncommon. The vast majority of primary bladder cancers are malignant and epithe- lial in origin. - >90% are - 1 \200\2237% are endemic. 2% are adenocarcinoma. Small cell an d spindle cell carcinomas (rare). Other rare primary tumors include phaeochromocytoma, mela noma, lymphoma, and sarcoma arising within the bladder muscle. Secondary bladder cancers ar e mostly directly spread by adenocarcinomas from the gut, prostate, kidney or ovary, or squ amous carcinoma of the urerine cervix. TCC, usually high-grade. SCC; 75% are SCC in areas where schistosomiasis is - Tumor spread is: - : tumor growth to involve the detrusor, the ureteric ori \201 ces, Direct prostate, urethr a, uterus, vagina, perivesical fat, bowel, or pelvic side walls. Implantation Lymphatic Hae matogenous gland (21%), and bone (27%). Any other organ may be involved. - : into wounds/percutaneous catheter tracts. : in \201 ltration of the iliac and para-aorti c nodes. : most commonly to liver (38%), lung (36%), adrenal Histological grading has traditionally (1973 WHO Classi \201 cation) been di- vided into: benign urothelial papilloma; well, moderately, and poorly dif- ferentiated (G1, G2, and G3, respectively) carcinoma. Most retrospective studies, clinical trials, and guidelines are b ased on this classi \201 cation. The 2004 WHO grading uses cytological/architectural crite ria to distinguish \202 at 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 reproduci ble, 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 tumors being called eithe r low-grade or high-grade. Staging is by the TNM (2009) classi \201 cation (Table 7.9 and Fig. 7.3). All rely upon ph ysical examination and imaging, the pathological classi \201 cation (pre \201 xed \200 \230p \200\231) corresponding to the TNM categories. TCC: may be single or multifocal. Because 5% of patients will have a syn- chronous upper tr act TCC and metachronous recurrences may develop after several years, the urothelial \200 \230 \201 eld change \200\231 theory of polyclonality has been favored over the theory of tumor monoclonality with transcoe- lomic implantation (seeding). Primary TCC is either non-muscle invasive (formerly known as \200\230super \201 - cial \200\231) or muscle-invasive. BLADDER CANCER: PATHOLOGY, GRADING, AND STAGING 267 70% of tumors are papillary, usually G1 or G2, exhibiting at least seven transitional cell layers covering a \201 brovascular core (normal transitional epithelium has approximately \201 ve cell layers). Papillary TCC is usually super \201 cial, con \201 ned to the bl adder mucosa (Ta) or submucosa (T1); 10% of patients subsequently develop muscle-invasive o r metastatic disease. However, G3T1 tumors are more aggressive, with 40% subsequently upsta ging. 10% of are solid. These are usually G3, half of which are muscle-invasive at presenta tion. 10% of TCC is \202 at CIS. This is poorly differentiated carcinoma, but con \201 n ed to the epithelium and associated with an intact basement membrane; 50% of CIS lesions oc cur in isolation; the remainder occurs in association with muscle-invasive TCC. CIS usually appears as a \202 at red velvety patch on the bladder mucosa; 15 \200\22340% of such les ions are CIS, the remainder being focal cystitis of varying etiology. The cells are poorly cohesive, up to 100% of patients with CIS exhibiting positive urine cytology in contrast to much lower yields (17 \200\22372%) with G1/2 papillary TCC; 40 \200\22383% of untreated CI S lesions will progress to muscle-invasive TCC, making CIS the most aggressive form of supe r \201 cial TCC. 5% of patients with (including CIS) have vascular or lymphatic spread. Me tastatic lymph node disease is found in: 0% Tis, 6% Ta, 10% T1, 18% T2 and T3a, 25 \200\223 33% T3b and T4 TCC. TCC have mixed papillary and solid morphology and 10% G1/2 TCC and at least 20% with G3 TCC SCC: is usually solid or ulcerative and muscle-invasive at presentation. SCC accounts for o nly 1% of UK bladder cancers. SCC in the bladder is associated with chronic in \202 ammati on and urothelial squamous metaplasia rather than CIS. In Egypt, 80% of SCC is induced by t he ova of Schistosoma haematobium. Five percent of paraplegics with long-term catheters dev el- op SCC. Smoking is also a risk factor for SCC. The prognosis is better for bilharzial S CC than for non-bilharzial disease, probably because it tends to be lower-grade and metasta ses are less common in these patients. Adenocarcinoma: is rare, usually solid/ulcerative, G 3, and carry a poor prognosis. One-third originate in the urachus, the remnant of the allan - tois, located deep to the bladder mucosa in the dome of the bladder. Adenocarcinoma is a long-term (10 \200\22320+ year) complication of bladder exstrophy and bowel implantation in to the urinary tract, particularly blad- der substitutions and ileal conduits after cystect omy. There is association with cystitis glandularis rather than CIS. Secondary adenocarcino ma of the bladder may arise. CHAPTER 7 Urological neoplasia 268 Table 7.9 The 2009 UICC TNM staging of bladder carcinoma Tx Primary tumor cannot be assessed T0 No evidence of primary tumor Ta Non-invasive papillary carcinoma Tis Carcinoma in situ ( \202 at disease) T1 Tumor invades subepithelial connective tissue T2 Tumor invades muscularis propria (detrusor): T2a = inner half T2b = outer half T3 Tumor invades beyond muscularis propria into perivesical fat: T3a = microscopic T3b = macro scopic T4a Tumor invades any of: prostate, uterus, vagina, bowel T4b Tumor invades pelvic or abdominal wall Nx Regional (iliac and para-aortic) lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node below the common iliac bifurcation N2 Metastasis in a group of lymph nodes below the common iliac bifurcation N3 Metastasis in a common iliac node Mx Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis present Pelvic side wall T3b T3a T2 BLADDER T1 T4b Ta Submucosa CIS (red patch) Mucosa (urothelium) Bladder detrusor muscle T4a Prostate URETHRA Fig. 7.3 The T staging of bladder cancer. This page intentionally left blank CHAPTER 7 Urological neoplasia 270 Bladder cancer: clinical presentation Symptoms - The commonest presenting symptom (85% of cases) is haematuria. Haematuria may be initial or terminal if the lesion is at the bladder neck or in the prostatic urethra. Thirty-four per cent of patients >50y and 10% <50y with macroscopic haematuria have bladder cancer. A histo ry of smoking or occupational exposure is relevant. Asymptomatic non-visible haematuria tes ting accounts for an important minority of presentations. Up to 16% of females and 4% of ma les have stick-test haematuria: <5% of those <50y and 7 \200\22313% of those >50y will have a malignancy. Filling-type almost always microscopic or macroscopic haematuria. This so-ca lled \200\230malignant cystitis \200\231 is typical in patients with CIS. Recurrent though less common than benign causes (diverticular and Crohn \200\231s disease). Urachal adenoca rcinomas may present with a blood or mucus umbilical discharge or a deep subumbilical mass. More advanced cases may present with to lymphatic/venous obstruction, bone pain, weight lo ss, anorexia, confusion, and anuria (renal failure due to bilateral ureteric obstruction). Pain obstruction and renal deterioration arise gradually. painless visible found on routine urine stick- LUTS such as urgency or suprapubic pain. There is UTIs and pneumaturia due to malignant colovesical \201 stula, lower limb swelling due is unusual, even if the patient has obstructed upper tracts since Signs General examination may reveal pallor, indicating anemia due to blood loss or chronic renal impairment. Abdominal examination may reveal a suprapubic mass in the case of locall y 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 b p. 272). This page intentionally left blank CHAPTER 7 Urological neoplasia 272 Bladder cancer: haematuria, diagnosis, and transurethral resection of bladder tumor (TURBT) Investigation of haematuria After a UTI has been excluded or treated and menstruation rule d 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 \200\230macroscopic haematuria \200\231 o r \200\230gross haematuria \200\231) requires consideration of other (rare) causes of disc olored urine (myoglobinuria, haemoglobi- nuria, beeturia, drug discoloration \200\224rifamp icin, doxorubicin). Twenty-two percent of patients with VH will harbor a urological maligna ncy. Non- visible haematuria (NVH, otherwise referred to as \200\230microscopic haematu- r ia \200\231 or \200\230dipstick-positive haematuria \200\231) is further subdivided as fol lows: - Symptomatic hesitancy, frequency, urgency, dysuria. Asymptomatic LUTS or upper urinary trac t symptoms. Five percent of patients with more frequently in patients >40y. NVH (s-NVH): symptoms such as voiding LUTS, NVH (a-NVH): incidental detection in the absence of NVH will harbor urological malignancy, Dipstick vs microscopy Urine dipstick of a fresh voided urine sample, containing no preserv ative, is considered a sensitive means of detecting the presence of haematuria. Community-b ased urine samples sent for microscopy have a signi \201 cant false negative rate; the pro cedure is more labor intensive and adds little to establishing the diagnosis of haematuria. Routine microscopy for con- \201 rmation of dipstick haematuria is not necessary. Whilst the sensitivity of urine dipsticks may vary from one manufacturer to another, signi \201 cant haematuria is considered to be 1+ or greater. Trace haematuria should be considered ne gative. There is no distinction in signi \201 cance between non- haemolysed and haemolysed dipstick-positive haematuria. A 1+ positive for either should be considered of equal signi \201 cance.1 Urological investigations are tailored according to patient age and symptoms: - Over 40y old with macroscopic haematuria cystoscopy, and cytology. Under 40y with macroscop ic haematuria followed by CT-KUB, cystoscopy, and cytology. Over 40y with cystoscopy 9 urin e cytology. Under 40y with cystoscopy for s-NVH. : urgent CTU, : urgent USS renal tract NVH: CT-KUB followed by USS renal tract, NVH: USS renal tract alone for a-NVH and with CTU is faster and more sensitive than ultrasound or IVU in the detection of renal (parenchy mal and urothelial) and ureteric tumors. However, it carries a higher radiation dose and is more expensive. CTU also detects BLADDER CANCER: HAEMATURIA, DIAGNOSIS, AND TURBT 273 some bladder tumors, but may overcall bladder wall hypertrophy as tu- mour and will miss \202 at CIS and urethral pathology so it cannot replace cystoscopy. CT-KUB requires less ra diation dose and is preferred in pa- tients who are more likely to have stone than malignan cy. If all investigations are normal, consideration should be given to neph- rological disorder s 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 micro- scopic haematuria 9 proteinuria and hypertension or eGFR <60mL/min. Refe rral back for further urological investigation is required if haema- turia becomes visible (CTU indicated) or NVH persists, but becomes symptomatic. Patients with predominantly \201 lling-type LUTS, suprapubic pain, or recurrent UTI/pneumaturia should also have urine cytology and cystoscopy. 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 haem atobium infection. Less common - - - - - Radiation cystitis. Urethral strictures. TB Medullary sponge kidney. Cyclophosphamide-induc ed cystitis. . Rare - - - - - Arteriovenous malformation. Renal artery thrombosis. Polycystic kidney disease. Papillary n ecrosis of any cause. Loin pain haematuria syndrome. Nephrological causes Common - - IgA nephropathy (Berger \200\231s disease). Thin basement membrane disease. Less common/rare - Acute glomerular disease. \200 \200 \200 \200 \200 Post-infectious glomerulonephritis. Rapidly progressive glomerulonephritis. Systemic lupus nephritis. Vasculitis. Goodpasture \200\231s disease. CHAPTER 7 Urological neoplasia 274 Henoch \200\223Sch nlein purpura syndrome. \200 Haemolytic uraemic syndrome. Chronic pri mary glomerulonephritis. \200 \200 \200 \200 Familial causes. \200 Polycystic kid ney disease (autosomal dominant or recessive). Focal segmental glomerulonephritis. Mesangiocapillary glomerulonephritis Membranous nephrop athy. Mesangial proliferative glomerulonephritis. Hereditary nephritis (Alport \200\231s syndrome). Urine cytology Examination of voided urine for exfoliated cells is most sensitive (90 \200 \223100%) in patients with high-grade TCC and CIS, anywhere in the urinary tract. It is cos tly and <1% of cancers are detected by cytology alone when other investigations are normal. False-negative cytology is frequent (40 \200\22370%) in patients with papillary TCC while false-positive cytology can arise due to infection, in \202 ammation, stones, instrumentat ion, and intravesical instilla- tions such as chemotherapy. Guidelines do not specify if an d when to use it so practices vary. Urine molecular markers ELISA tests for detecting tumor-speci \201 c urinary markers such as bladder tumor antigen (BTA) or nuclear matrix protein 22 (NMP22) tend to have greater se nsitivity, but reduced speci \201 city for detecting TCC, compared with urine cytology. Im munoCyt has the highest sensitivity for detection of low-grade tumors and is less affected by other urological diseases. However, with a 60% detection rate for low-grade tumors, the test remains largely inadequate to replace cystoscopy. The absence of clinical trials and t he 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 de \201 nitive hi stological diagnosis, grade, and clini- cal and pathological stage and is the \201 rst (s ometimes sole) treatment. This is undertaken under general or spinal anesthesia; bimanual e xamination is mandatory before and after bladder tumor resection to assess size, position, and mobility. If possible, the surgeon should resect the tumor(s) completely. The pathologi st should report on the tumor type, grade, and stage; in particular, the presence or absenc e 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 bl adder reconstruction is under consideration. Particular care is taken when resecting tumors at the dome since intraperitoneal bladder per- foration may occur, especially in women wit h thin-walled bladders. Care is also taken when resecting posterolateral tumors due to the proximity of the obturator nerve; stimulation may result in a \200\230kick \200\231 unless the patient is under full paralysis, which may lead to bladder perforation and/or trou- bl esome bleeding. BLADDER CANCER: HAEMATURIA, DIAGNOSIS, AND TURBT 275 Narrow-band imaging (NBI) and photodynamic detection (PDD) - : is an optical image enhancement technology in which the narrow NBI bandwidth of light is strongly absorbed by hemoglobin and penetrates only the surface of tissue, increasing the v isibility 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 standar d white light cystoscopy for the detection of new and recurrent tumors. PDD a porphyrin-bas ed photosensitizer, hexaminolevulinic acid (HAL; Hexvix ). Several randomized studies have revealed CIS lesions and developing papillary tumors which cannot be seen using standard w hite light for tumor 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 \200\22327% This technique is gaining popularity, but is expensi ve; however, it has been suggested that improved tumor detection leads to better patient ma nagement 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, tho ugh it has gained a place in routine management of selected patients, particularly in those with positive urine cytology, but normal-looking bladder mucosa. ( \202 uorescence cystocopy): uses blue light in combination with Staging investigations are usually reserved for patients with biopsy-proven muscle-invasive bladder cancer unless clinically indicated since non-mus- cle-invasive TCC and CIS are rar ely associated with metastases. 1 Kelly JD, Fawcett DP, Goldberg LC (2009) Assessment and management of non-visible haema- turia in primary care. BMJ 338:a3021. 2 Fradet Y, Grossman HB, Gomella L, et al. (2007) A comparison of hexaminolevulinate \202 uores- cence 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 \200\22373. CHAPTER 7 Urological neoplasia 276 Bladder cancer (non-muscle invasive TCC): surgery and recurrence TURBT The diagnostic role of TURBT has been discussed on b p. 274. As a primary treatment, a visually complete tumor resection is adequate for 70% of newly presenting patients with Ta/T1 super \201 cial dise ase. The re- maining 30% of patients experience early recurrence, 15% with upstaging. Becau se of this, it is standard care that all new patients receive adjuvant treatment with a sin gle dose of post-operative intravesical chemotherapy (usually mitomycin; see b p. 280). Com plications of TURBT are uncom- mon, including bleeding, sepsis, bladder perforation, incomp lete resection, and urethral stricture. Alternatives to TURBT Transurethral cystodiathermy or laser are accepted, quicker and less mor- bid procedure for ablating small super \201 cial recurrences when obtaining tissue fo r histology is not considered necessary. Fluorescence and NBI cystocopy are discussed on b p. 275.