information gained about the anatomy of the tumor and surrounding organs is of less importa nce in patients who receive preoperative chemotherapy. Other investigations \200 FBC to detect anemia resulting from hemorrhage into the tumor PT and aPTT as some patients may have an acquired form of von Willebrand disease. Urea, creatinine and urinalysis to det ect any gross abnor- malities of renal function. It is important to know that the contralat eral kidney is functioning adequately before surgery. IVU, DMSA scan or excretion of contra st at the end of CT scan of chest/ abdomen are all useful for this. Treatment There is overwhelming evidence that Wilms \200\231 tumor ought to be treated in r ecognized pediatric oncology centers and that there is no place for the casual therapist. S urgeons, radiotherapists, pediatricians, or nephrologists not working in a center with pedi atric oncological expertise who \201 nd they are unexpectedly dealing with a child with W ilms \200\231 tumor should make an urgent referral to an appropriate unit. It has been show n that patients not treated in a recog- nized trial or at a recognized pediatric oncology c enter are overtreated compared to current recommendations and are more likely to receive ra diotherapy. Pathology Two broad groups of tumors may be recognized by their histological appearances. Favorable histology \200\223 by far the larger group Classical triphasic histology: epithe lial, blastemal, and stro- mal elements are all present. An additional feature that may be seen in triphasic tumors is rhabdomyoblastic differentiation, such that the cells resemble fetal rhabdomyoblasts. This should not be con- fused with the malignant rhabdoid tumor of t he kidney, which has a poor prognosis. Monomorphic epithelial variant. This variant consist s of entirely primitive tubules and is usually found in children aged <1 year. It has a fav orable prognosis and patients are often treated by nephrectomy alone. Surgery Surgical extirpation is, and almost certainly will remain, fundamental treatment fo r Wilms \200\231 tumor. There is debate about the timing of surgical intervention, the plac e of per- cutaneous needle biopsy, and the use of preoperative chemotherapy. North American practice remains steadfastly in favor of immediate surgery followed by adjuvant therapy di ctated by the surgical stage. In contrast, the SIOP group in Europe has conducted a series of trials based on the use of preoperative therapy. By downstaging the tumor fewer patients would be subjected the morbidities of abdominal radiation and anthra- cycline therapy. Bet ween 1991 and 2001 the UKCCSG con- ducted a prospective randomized trial comparing immediat e surgery with 6 weeks of chemotherapy and delayed surgery. The trial showed there was a si gni \201 cant improvement in stage distribution for patients with Wilms \200\231 histologi es receiv- ing preoperative chemotherapy compared to those having immediate nephrectomy, wh ile maintaining excellent event- free and overall survival in children with nonmetastatic W ilms \200\231 tumor. Current SIOP trials aim to reduce the use of anthracyclines in stage I I and III disease further. The debate as to the role of preoperative chemotherapy versus im medi- ate nephrectomy continues but it is notable that the overall survival rates between N orth American and European groups are very similar. Surgery for Wilms \200\231 tumor should start with a transverse abdominal incision that allows a thorough examination of the abdom inal cavity and contralateral kidney. It will also ease tumor removal, which should be done en bloc with any associated tissue. Para-aortic lymph nodes are then biopsied, especially if they are enlarged. Contraindications to surgery are bilateral disease, a large \201 xe d tumor, hepatic invasion and extension of the tumor into the inferior vena cava. Unfavorable histology Anaplasia: an unfavorable feature occasionally observed in triphasic tumors. It is often patchy. Histological characteris- tics include large hyperchromatic nuc lei, an increased nuclear:cytoplasmic ratio, and abnormal mitoses. The other major unfavora ble histological types are distinct tumors, rather than true variants of Wilms \200\231 tum or: Bone-metastasizing renal tumor of childhood (clear cell sarcoma) This tumor has a propensit y for skeletal metastasis and an aggressive clinical course. In NWTS3 (US National Wilms \200\231 Tumor Study Group) the tumor represented nearly 6% of cases making it the most fre quent form of \200\230unfavorable \200\231 histology. In the second UKCCSG (United Kingdom Children \200\231s Cancer Study Group) Wilms \200\231 tumor study 5% of cases were bone-me tastasizing renal tumor of childhood and patients had a 4 year overall survival of 82%, com para- ble with that of patients with favorable histology. Malignant rhabdoid tumor It is the least common of the unfavorable histological types and r epresented only 2% of cases entered in the American national studies. Malignant rhabdoid tu mor is associated with various primary tumors arising in the midline of the posterior intra cranial fossa. Genetic analysis of malignant rhabdoid tumors shows that they contain mutati ons of the hSNF5/INI1 gene that controls the shape of the DNA \200\223 histone complex. Hyp ercalcemia has been reported in a number of cases. Staging Most staging systems currently in use rely heavily on the system devised for the Th ird National Wilms \200\231 Tumor Study, which itself was a derivation of the systems used in NWTS Biopsy In Europe the majority of patients with suspected Wilms \200\231 tumor will have pre operative chemotherapy for 6 weeks C. MITCHELL AND J. MUSSAI 674 with deferred surgery. Current UK practice is to biopsy the tumor using a Trucut needle. In the UKW3 trial, an analysis of biopsy results demonstrated that 10% of patients either had unfavorable histology or other diagnoses. However, many pediatric oncologists and surgeons feel that biopsy is unnecessary and there is a risk of providing an unrepre- sentative sam ple or causing local tumor spillage along the biopsy track. Boosts were given for areas of residual disease or if lymph nodes were positive. As with ch emotherapy, differences occur between patients treated in the American trials and the SIOP trials. Follow-up Pulmonary relapse is more common than local relapse. PA and lateral CXR should be obtained regularly during and after treatment. Typically patients should have a CXR every 9 weeks during treatment, every 2 months for the \201 rst year and every 3 months for the 2nd and 3rd years after completing treatment. Stage IV patients should continue to have CX R for a further year. It is suf \201 cient to screen for local relapse with an abdominal U SS at the end of treatment and then 6-monthly for the next 2 years. Evaluation of renal fun ction in the remaining kidney shows some evidence of dysfunction in a third of cases with o nly about a half of patients undergoing signi \201 cant compensa- tory renal hypertrophy. Blood pressure measurement and assessment of proteinuria must be carried out at intervals. Chemotherapy The use of chemotherapy as an adjuvant to surgery is now an essential part of Wilms \200\231 tumor treatment. The major advances in treatment have come as a result of th e multi- center co-operative trials run by the NWTS, the SIOP and the UKCCSG. Consecutive s tudies have con \201 rmed the role of vincristine, actinomycin D and doxorubicin as adjuva nt agents in the treatment of Wilms \200\231 tumor. An integral part of all therapy protoco ls is the \200\230stage \200\231 of the tumor and progress has been made in optimizing tre at- ments according to the stage and therefore the risk of relapse. The second UKCCSG Wilms \200\231 tumor study dem- onstrated that stage 1 favorable histology tumors treated with m inimal therapy (nephrectomy and only 10 weekly doses of vincristine) had an excellent 4 yea r overall sur- vival of 94%. This is a signi \201 cant reduction in treatment compared to the NWTS3 study in which stage I favorable histology patients received a nephrectomy and 6 months of vincristine and actinomycin D with a similar 4 year over- all survival of 97.4%. The neurotoxic effects of vincristine as well as the myelosuppressive and hepatotoxic effec ts of actinomycin D are therefore signi \201 cantly decreased. By contrast the treatment f or stage IV Wilms \200\231 tumors is more intensive with delayed surgery, triple chemothera py (vincristine, actinomycin, and doxorubicin), and abdominal radiotherapy. Pulmonary radio therapy may also be required if pulmonary metastases are present. Trials continue with the aim of reducing the amount of treatment, and hence the morbidity, for all stages of Wilms \200\231 tumor. It may be possible, even in those with stage IV tumors, to reduce the need for pulmonary radiotherapy and doxorubicin while maintaining overall survival rates. The ma in outcome \201 ndings of the European trial SIOP study (SIOP 9) are summarized in Table 17.2.2. All patients were randomized to receive either 4 or 8 weeks preopera- tive actinomy cin D and vincristine, followed by the postop- erative chemotherapy listed. Prognosis The great majority of patients with Wilms \200\231 tumor will be cured as indicat ed in Table 17.2.2 (SIOP 9 results). Long-term evaluation of cardiac function in those pati ents treated with anthracyclines must be carried out. Patients who received radiotherapy wi ll have a disturbance of growth, often asymmetrical. Future prospects To further re \201 ne therapy in patients with a good prognosis in order to minimize treatment-related morbidity. To improve therapy for those few patients with an identi \201 - able poor prognosis or who relapse. To understand further the genetic basis for Wilms \200\231 tumor and its variants and to analyze the role these genetic mark- ers m ay have in stratifying the therapy required. Further reading Barr RD, Chalmers D, De Pauw S, et al. Health-related quality of life in su rvivors of Wilms \200\231 tumor and advanced neuroblastoma: a cross-sectional study. J Clin Oncol 2000; 18: 3280 \200\2233287. Radiotherapy Dome JS, Cotton CA, Perlman EJ, et al. Treatment of anaplastic histology Wilms \200\231 tum or: results from the \201 fth National Wilms \200\231 Tumor Study. J Clin Oncol 2006; 24: 2352 \200\2232358. The use of radiotherapy has decreased due to the long- term morbidity it imposes on growing tissues. Radiotherapy doses have been decreased as a consequence of the results of several trials. More effective and rational use of chemo- therapy may allow it to supplant radioth erapy in some instances. The NWTS3 trial showed that survival was not signi \201 cantly di fferent in stage II patients who received 2000 cGy of radiotherapy compared with those who had chemotherapy alone. Furthermore in stage III patients 2000 cGy of irradiation did not i mprove overall survival or the risk of relapse compared to 1000 cGy. The result is that few er patients will be exposed to the deleterious effect of poor muscle growth caused by radio therapy. In SIOP 9 radiotherapy was reserved for those patients with stage II N1 and III fa vorable histology tumors and all unfavorable histology tumors greater than stage I. This wa s a total of 21% of patients. The total dose delivered to the midplane was 15 Gy, increased to 30 Gy in unfavorable histology. Huang CC, Cutcliffe C, Cof \201 n C, et al. Renal Tumor Committee of the Children \200\231 s Oncology Group. Classi \201 cation of malignant pedi- atric renal tumors by gene express ion. Pediatr Blood Cancer 2006; 46: 728 \200\223738. Mitchell C, Pritchard-Jones K, Shannon R, et al. For the United Kingdom Cancer Study Group. Immediate nephrectomy versus preoperative chemotherapy in the management of non-meta- stat ic Wilms \200\231 tumor: results of a randomized trial (UKW3) by the UK Children \200\231s Cancer Study Group. Eur J Cancer 2006; 42: 2554 \200\2232562. Reinhard H, Semler O, B rger D, et al. Results of the SIOP 93-01/ GPOH trial and study for the treatment of patients with unilateral nonmetastatic Wilms tumor. Klin Padiatr 2004; 21 6: 132 \200\223140. Weirich A, Ludwig R, Graf N, et al. Survival in nephroblastoma treated according to the tri al and study SIOP-9/GPOH with respect to relapse and morbidity. Ann Oncol 2004; 15: 808 \200\223820. CHAPTER 17.2 Wilms \200\231 tumor 675 Table 17.2.1 Wilms \200\231 tumor staging based on the Third National Wilms \200\231 Tumor Study Table 17.2.2 Percentage outcomes for patients in SIOP 9 Stage and histology 2 year event- free survival 5 year overall survival Postoperative treatment Tumor completely within renal capsule, completely resected. Stage I Extension of tumor outside renal capsule, but still completely resected. Includes vessel in \201 ltration, tumor biopsy, or tumor spillage con \201 ned to the \202 ank Stage II 100 100 None Stage I Favorable histology Residual nonhematogenous tumor, con \201 ned to the abdomen. Extension outside the renal c apsule, with incomplete excision. Lymph node involved. Diffuse peritoneal contamination fol lowing tumor spillage either microscopically or macroscopically. Stage III 88 93 Acintomycin D and vincristine \227 3 courses Stage I Anaplasia/ standard histology 84 88 Actinomycin D and vincristine and anthracycline \227 5 courses RT Stage II N0 Standard histology Hematogenous metastases to lung, liver, or brain. Stage IV Bilateral renal tumors. Stage V 71 85 Actinomycin D and vincristine and anthracycline \227 5 courses Stage II N1/III Standard histology Internet resources International Society of Pediatric Oncology: http://www.siop.nl/ US National Wilms \200\231 Tumor Study Group: 71 71 Actinomycin D, vincristine, anthracycline and ifosphamide \227 5 courses RT Stage II/III Anaplasia http://www.nwtsg.org/ Children \200\231s Cancer and Leukemia Group (formerly UKCCSG): SIOP, International Society of Pediatric Oncology RT, radiotherapy. http://www.ukccsg.org/ Cancerbackup: http://www.cancerbackup.org.uk/home See also Tumors of the kidney, p. 668 Rare syndromes with renal involvement, p. 640 J.K. MELLON AND AJ COLQUHOUN 676 Tumors of the renal pelvis and ureter De \201 nition Benign or malignant lesions arising from the lining of the upper renal trac t anywhere between the renal calyces and the vesicoureteric junction. Rigid/ \202 exible ureteroscopy with or without biopsy (Fig. 17.3.2) There is good concord ance between biopsy and surgical specimen grade, but not stage. It allows accurate assessme nt of tumor grade, permitting subsequent endoscopic/percutaneous management if appropriate. The time delay performing ureteroscopy and biopsy does not negatively impact on survival, if radical surgery is required. Selective upper tract saline washings for cytology Only of value for high grade lesions. Epidemiology Upper tract transitional cell carcinoma (UTTCC) is rare, with ureteric tumors being less common than renal pelvic tumors. 70% of ureteric tumors occur in the distal uret er, 25% within the mid-ureter and 5% in the upper ureter. Bilateral tumors are very rare (1 .5% of UTTCC). UTTCC represents 5% of all diagnosed transitional cell carcinomas (TCC). Tum or incidence increases with age and UTTCC is twice as common in men. Other investigations Contrast CT of abdomen/chest and pelvis required for staging. Bone sca n is reserved for symptomatic patients. Concern regarding contralateral renal function mand ates that a DMSA renogram is performed to accurately assess differential function. Predisposing factors Smoking (dose-dependent effect, RR = 2.6 \200\2237.2). Occupational ex posure (aniline dyes, -naphthylamine, benzidine, RR = 4.0 \200\2235.5). Drug exposure: \200 \200 analgesic (phenacetin) abuse (RR = 3.3 \200\2233.6); cyclophosphamide exposure. Pathology Benign lesions are very rare and include: \200 \200 \200 Chronic urinary infection/presence of urinary stones (typically cause squamous cell carcino ma, SCC). Balkan nephropathy (degenerative interstitial nephro- pathy occurring in patients from Balkan countries) is typically associated with low grade, bilateral tumors (RR = 57.0 \200\22361.0). Coffee consumption (RR = 1.3). Hereditary syndromes, e.g. Lynch II syndrome (hereditary nonpolyposis colonic cancer, endometrial, ovarian and pan- creatic adenocarcin oma and UTTCC). \201 broepithelial polyps; neuro \201 bromas; inverted papillomas. Malignant lesions predominate: \200 \200 98% TCC; 2% SCC, adeno-, sarcomatoid or small cell carcinomas. Staging Staging is described by the TNM system (Table 17.3.1). 40% of UTTCC are invasive at presentation (cf. 20% bladder TCC), which is thought to relate to the relative paucity of ureteric musculature. Tumor spread is epithelial (down- stream seeding or \201 eld change ), lymphatic (para-aortic, para-caval, ipsilateral common iliac and pelvic lymph nodes) or hematogenous (liver, lung and bone). Genetics The chromosomal abnormalities underlying UTTCC mirror those of bladder TCC (deleti ons of chromosomes 9, 13 and 17). 5% of patients with bladder TCC will develop UTTCC, where as 30 \200\22340% of patients with UTTCC will subsequently develop bladder TCC. Presence of synchronous/meta- chronous lesions correlates strongly with tumor stage. Metachronous tumo rs occurring after high grade UTTCC frequently share common speci \201 c genetic mutations sup- porting the theory of downstream tumor seeding. Treatment Endoscopic/percutaneous strategies Indications: \200 \200 \200 \200 solitary kidney; bilateral disease; impaired renal function; signi \201 cant comorbidity p recluding major surgical inter- vention; low grade/stage disease with normal contralateral kidney. Clinical features Frank hematuria (60 \200\223100%). Flank pain (30%). Clot colic. Symptoms of metastatic disease in 20% (abdominal mass, anorexia, loss of weight, and bone pain). 15 % of patients are asymptomatic. Choice of procedure Ureteroscopy and laser ablation: \200 \200 rigid ureteroscope for distal/mid-ureteric tumors; \202 exible ureteroscope for more prox imal/small renal pelvic tumors. Investigations IVU/CT urogram/retrograde studies Percutaneous antegrade resection: \200 \200 suitable for larger renal pelvic lesions; minute risk of percutaneous tumor seeding. These studies will demonstrate a \201 lling defect (Fig. 17.3.1). They allow assessment o f the contralateral kidney. Cystoscopy This is mandatory to assess for synchronous bladder TCC Both procedures can be combined with retrograde and antegrade instillation of topical chemo - or immunotherapy. CHAPTER 17.3 Tumors of the renal pelvis and ureter 677 Table 17.3.1 TNM classi \201 cation of upper tract transitional cell carcinoma (UTTCC) Table 17.3.2 Five year UTTCC survival rates Stage 5 year survival (%) Stage Description Ta/1/is 60 \200\22390 TX Primary tumor cannot be assessed T2 43 \200\22375 T0 No evidence of primary tumor T3 16 \200\22333 Ta Papillary noninvasive carcinoma T4 0 \200\2235 Tis Carcinoma in situ T1 Tumor invades subepithelial connective tissue Ureterectomy This can be achieved by: \200 \200 T2 Tumor invades muscularis open distal ureterectomy endoscopic or laparoscopic transvesical ureteric detach- ment; dis tal ureteric stapling; ureteric intussusception ( \200\230stripping \200\231). T3 Tumor invades periureteric/peripelvic fat or into renal parenchyma T4 Tumor invades adjacent organs or through kidney into perinephric fat \200 NX Regional lymph nodes cannot be assessed No evidence exists con \201 rming the superiority of any of the above techniques. N0 No regional lymph node metastasis N1 Single lymph node metastasis <2 cm Lymphadenectomy This confers no survival bene \201 t although it does permit more accurate tumor staging. N2 Single lymph node metastasis 2 \200\2235 cm or multiple lymph nodes <5 cm N3 Lymph node metastasis >5 cm Adjuvant therapy As high grade/stage disease is associated with poor out- come, effective a djuvant therapy should be beneficial. There is no evidence to support use of adjuvant radio - therapy. There are also no RCTs determining the ef \201 cacy of chemotherapy in this set ting. Current regimens are based on (neo-)adjuvant bladder TCC regimens, i.e. meth- otrexat e, vinblastine, adriamycin and cisplatin or gemcitab- ine and cisplatin. MX Distant metastasis cannot be assessed M0 No evidence of distant metastasis M1 Distant metastasis present Such treatments are technically feasible but no outcome data exists regarding ef \201 cacy . Outcome Endoscopic/percutaneous treatment regimens are associ- ated with a 30 \200\22340% tumor rec urrence rate (directly related to tumor grade). Several series report the ef \201 cacy of these strategies in low grade/stage tumors although it is com- mon to require repeat treatm ents. Results for multifocal and/or high grade/stage tumors are less favorable. Such treatm ent strategies require intense patient and surgeon commitment to 3 \200\2236-monthly ureter oscopic surveillance. Follow-up This should aim to detect: \200 \200 \200 local recurrence; metastatic spread; metachronous upper and/or lower tract TCC. Follow-up depends on original tumor histology and the type of surgical intervention underta ken. Typically the following are required: Regular clinical, cystoscopic and, if ureter ret ained, ureter- oscopic evaluation (initially 3-monthly, then 6-monthly and annually thereaf ter) Regular evaluation of the contralateral upper tract using IVU/retrograde studies (3-ye arly for low grade/stage dis- ease and annually for all others). Regular evaluation for met astatic disease using blood parameters and CT scanning. Nephron-sparing techniques \200 \200 Segmental renal pelvis resection (rarely used). Segmental ureteric resection uretero-ure terostomy/ ureteric reimplantation (suitable for large mid/distal ureteric tumors). Any retained ureter requires careful inspection for concomitant lesions. Nephroureterectomy This is the gold standard procedure for management of UTTCC and can be p erformed: \200 \200 \200 Prognosis Several factors have independent prognostic signi \201 cance with respect to sur vival in UTTCC: \200 \200 \200 \200 \200 open; laparoscopically; combined open/laparoscopically. stage (most important, Table 17.3.2); grade (low vs high grade); age; location (renal pelvi s better prognosis); carcinoma in situ. Open procedures carry a higher morbidity (dual loin and lower abdominal incisions). Laparos copic procedures per- mit more rapid recovery and recent series con \201 rm the oncologica l safety of this approach. Successful nephroureterectomy requires removal of the entire ure ter in continuity, preventing spillage of tumor cells (Figs 17.3.3 and 17.3.4). Tumor recur rence occurs in 30% of retained ureteric stumps. An extensive literature exists regarding numerous poten- tial molecular makers associated w ith impaired survival (p53 status, lymphovascular invasion, microsatellite insta- bility, t umor ploidy and p27). None reproducibly aid sur- vival prognostication using multivariate a nalysis. J.K. MELLON AND A.J. COLQUHOUN 678 Fig. 17.3.3 En bloc kidney and ureter following nephroureterectomy. Fig. 17.3.1 Filling defect in the left mid-ureter seen on retrograde ureterogram. Fig. 17.3.4 Opened ureter demonstrating a distal papillary ureteric tumor. Reddened ureteri c mucosa represents areas of carcinoma in situ. Further reading Flanigan RC. Urothelial tumors of the upper urinary tract. In: Wein AJ (ed. ), Campbell \200\223Walsh Urology, 9th edn. Philadelphia: WB Saunders; 2007. Vol. 2, pp. 16 30 \200\2231652. Sagalowsky AI, Jarrett TW. Management of urothelial tumors of the renal pelvis and ureter. In: Wein AJ (ed.), Campbell \200\223Walsh Urology, 9th edn. Philadelphia: WB Saunders; 2007 . Vol. 2, pp. 1653 \200\2231685. Internet resources European Association of Urology: http://www.uroweb.org/ Cancerbackup: http://www.cancerbackup.org.uk/home Fig. 17.3.2 Endoscopic view of same ureteric tumor as shown in Fig. 17.3.1. See also Tumors of the kidney, p. 668 Tumors of the bladder, p. 680 Future prospects The identi \201 cation of reliable urine biomarkers may aid future follow -up of the bladder and contralateral upper tract in UTTCC. More clinical trials are needed to con \201 rm that our current understanding of the behavior of bladder cancer can be ext rapolated to UTTCC. This page intentionally left blank J.K. MELLON, R.F.J. STANFORD AND J.F. THORPE 680 Tumors of the bladder Introduction Bladder cancer is the second commonest cancer of the genitourinary tract, with transitional cell carcinoma due to cigarette smoking being the predominant type. Accurate histopathological staging is crucial to ensure appropriate management which ranges from end oscopic surveillance only to radical combination therapy. It is hoped that uri- nary biomar kers will in due course reduce the need for repeat cystoscopies in patients who are being f ollowed for bladder cancer. Radical surgery for bladder cancer has begun to be performed la paroscopically/robotically in increasing numbers of centers. Loin pain may indicate ureteric obstruction due to bladder carcinoma. Pelvic mass, weight l oss and hepatomegaly are late signs. Investigations Urine cytology The sensitivity of urinary cytology varies widely between cen ters. The sensitivity is higher for high grade disease including CIS. Urine proteomics Many tests for urinary molecules correlated with transi- tional cell carci noma (TCC) have been proposed to reduce the need for cystoscopy, but they have not been wid ely adopted. Those urinary molecules with US Food and Drug Administration approval include: \200 Epidemiology Bladder cancer is the \201 fth commonest cancer in the UK but its incidence has been falling. Incidence rises sharply after 55 years of age with the median age at diag nosis being 70 years. It is 2.5-fold more common in men than women. It is more common in th e Caucasian compared with Afro- Caribbean population. Survival by stage is more favorable i n Caucasians. human complement factor H-related protein (BTA TRAK/BTA Stat); nuclear matrix protein 22 (N MP22 BladderChek); mucin glycoprotein and carcinoembryonic antigen com- bination (ImmunoCyt /uCyt+); aneuploidy of chromosomes 3, 7 and 17 with deletion of chromosome 9p21 (UroVysion) . \200 Bimanual examination under anesthetic To assess presence and mobility of a mass. Predisposing factors Cigarette smoking is associated with a four-fold increased incidence. Known urothelial carcinogens in cigarette smoke include -naphthylamine and 4-aminobipheny l. Occupational exposure to aromatic amines and polyaro- matic hydrocarbons. Exposure of th e bladder to ionizing radiation such as fol- lowing treatment for cervical or prostate canc er. Cyclophosphamide and phenacetin. Prolonged immunosuppression, e.g. in organ transplant recipients. Chronic cystitis, bladder calculi, indwelling catheters and Schistosoma hematob ium cystitis (bilharzia) predispose to squamous cell carcinomas. Cystoscopy To assess size, number, position, morphology of tumors. The sensitivity of cysto scopy can be increased by use of photodynamic diagnosis. The bladder is instilled with a so lution containing aminolevulinic acid 2 h before cystos- copy. This accumulates in carcinom a tissue and \202 uoresces red under blue light. Tumor resection/biopsy Transuretheral resection should include muscularis propria in the sp ecimen to enable accurate histological staging. Bladder biopsies should be taken from any a rea showing abnormal urothelium or hyperemia. However, random biopsies to detect CIS should be reserved for cases with positive cytology. Repeat transurethral resection should be per formed after all high grade, Ta or T1 diagnoses to avoid understaging. Genetics p73 (chromosome 1p36) and cyclin D1 (chromosome 11) are frequently ampli \201 ed. Losses from chromosome 9, especially 9q, are found fre- quently, even in early bladder can cer, but it is not known through which genes this alteration has its effect. Altered expres sion of tumor suppression genes Rb (chro- mosome 13q14) and p53 (chromosome 17p13) are both commonly found in muscle invasive bladder cancer. IVU/CT scan with contrast All con \201 rmed cases of bladder carcinoma should have assessm ent of the upper tracts by either IVU (Fig. 17.4.1) or contrast CT scan. Other investigations FBC, U&Es, alkaline phosphatase (ALP), urinalysis and urine culture. E valuation of muscle invasive disease also includes a CXR; a radionuclide bone scan in the c ase of bone pain or raised ALP; and MRI (Fig. 17.4.2) to assess the extent of extravesi- ca l extension and nodal involvement. Clinical features Hematuria is the cardinal feature, either frank or micro- scopic. Any pat ient aged >40 years with persistent or intermittent microscopic hematuria (two or more dips ticks 1+ or more in the absence of signs of urinary tract infection or known glomerular dis ease) needs a full urological evaluation. Irritative symptoms may occur such as frequency, urgency, nocturia and dysuria. Irritative symptoms predominate with carcinoma in situ (CIS) . Pathology More than 90% of bladder cancers are TCCs that arise from the urothelium. TCCs of the bladder are often multifocal; 30 \200\22340% of cases have synchronous tumors at initi al presentation. CHAPTER 17.4 Tumors of the bladder 681 Other possible bladder malignancies include: \200 \200 \200 \200 understaging and reduces recurrence; recurrence within three months is itself an important prognostic marker. squamous carcinomas (5%); adenocarcinomas (2%); sarcomas (2%); secondar y metastatic deposi ts and small cell carcinomas. Low risk tumors G1pTa. Require continued surveillance (see \200\230Follow-up \200\231). Intermediate risk tumors Single G2pT1, multifocal G2pTa or G1pT1. May be offered subsequent intravesical treatment to reduce recurrence (occurring in 50% of these patients) and/or p rogression ( 2%). Intravesical therapy in these patients takes the form of either chemother apy (mitomycin-C, epirubicin or doxoru- bicin) which reduces recurrence and is relatively w ell-tol- erated, or immunotherapy (bacillus Calmette \200\223Gu rin, BCG) which reduces bo th recurrence and progression but is less well-tolerated and has greater risk of systemic c om- plications (fever, arthralgia, hepatitis and pneumonitis). TCC is morphologically classi \201 ed as: \200 \200 \200 papillary; sessile; carcinoma in situ. Grading of nonmuscle-invasive TCC is of more prognostic importance than in cases of muscle- invasive TCC. The 1973 WHO grading system of TCC (papilloma, G1, G2 or G3) is still widely used but there are concerns about high rates of interobserver variability. In 2004, the WHO grading system was updated (papillary neoplasm of low malignant potential (PNLMP), low and high grade papillary carcinoma). Accurate identi \201 cation of PNLMP allows the identi \201 cation of patients requiring less intensive follow-up. CIS, by de \201 nition, is com posed of cytologically high grade tumor cells con \201 ned to the urothelium. High risk tumors Any CIS, any G3 tumor(s) or multiple G2pT1 tumors. These have an 15% risk of progressing to muscle invasion. Clear evidence suggests that a maintenance course of in travesical BCG reduces the risk of progression by 25%. A response to intravesical BCG shou ld occur within 6 months, therefore in patients who show treatment failure (development of higher stage or grade tumor, or CIS (new or refractory) during treatment, or recurrence of even the same stage/grade tumor at 3 and 6 months), radical treat- ment should be offered ( as for muscle-invasive disease). Staging Bladder TCC is staged using the 2002 TNM system (Table 17.4.1). About 70% of bladde r carcinomas present as nonmuscle- invasive disease (Ta/T1), 25% as muscle-invasive disease (T2+) and 5% as CIS. Muscle-invasive TCC Patients found to have muscle-invasive disease (T2 \200\223T4a, N0 \200 \223Nx, M0) or those with high risk nonmuscle-invasive disease in whom conservative treatme nt fails may be can- didates for radical treatment in the form of either radical cystectomy or radical external beam radiotherapy. Treatment Accurate staging is a prerequisite to the correct manage- ment of bladder TCC, as the management of nonmuscle- invasive versus muscle-invasive tumors differs signi \201 ca ntly. Management of all but the lowest risk bladder transitional cell carcinomas should be discussed within multidiscipli- nary teams. Radical cystectomy with urinary diversion This is currently regarded as the gold standard t reatment. It also includes bilateral lymph node dissection, the limits of which are current ly debated with recent evidence sug- gesting that a more radical lymph node dissection lead s to a better outcome. Three main options exist for the urinary diversion: \200 Nonmuscle-invasive TCC Initial management is by transurethral resection (TURBT). Small tumo rs can often be resected in one chip which includes detrusor muscle; larger tumors may requ ire more extensive resection followed by a separate deep muscle biopsy. For large tumors, t he tumor edge should be resected separately to allow thorough pathological exami- nation fo r CIS. Bladder biopsies should also be taken of any abnormal areas within the bladder, or r andom biopsies taken from throughout an otherwise normal bladder if cytology is positive. I f tumor is found at the bladder neck, or CIS is suspected, the prostatic urethra should als o be biopsied in males. Within 24 h of the initial TURBT, a single dose of an intra- vesica l chemotherapy agent (commonly mitomycin-C, but epirubicin and doxorubicin are also used) s hould be given to reduce the risk of recurrence. Subsequent management depends on a variety of factors related to the initial tumor and is based on the likelihood of the tumor either recurring or progressing. Re-resection should be performed, usually within 6 weeks, if res idual tumor is known to have been left, if no detrusor muscle is present in the TURBT speci men, or if high grade disease is reported. Re-resection decreases the risk of ileal conduit using a segment of exteriorized ileum to form a stoma; orthotopic neobladder using a pouch formed from detu- bularized bowel segments anastomosed to the urethra; contin ent cutaneous pouches, similar to neobladders, but which are connected to the skin via the appendix or a bowel segment to allow catheterization for drainage. Urethrectomy should be p erformed when tumor has been identi \201 ed in the prostatic urethra in males or the bladd er neck in females. This then precludes the creation of an orthotopic neobladder. Radical c ystectomy has an operative mortality rate of 3%. Perioperative morbidity is between 20% an d 56% and long- term morbidity is between 28% and 94%, mainly being due to the method of ur inary diversion. Five year survival rates are 40 \200\22360%. Radical external beam radiotherapy Radiotherapy traditionally has been reserved for patient s who are less \201 t or have poorer outlooks. A dose of 60 \200\22366 J.K. MELLON, R.F.J. STANFORD AND J.F. THORPE 682 Prognosis 60 \200\22370% of nonmuscle-invasive bladder cancers recur, 10 \200\22320% progre ss in stage or grade. Risk factors that correlate with recurrence and progres- sion of supe r \201 cial disease are: \200 lamina propria invasion (T1); \200 grade; \200 presenc e of CIS; \200 >3 tumors; \200 tumor >3 cm; \200 previous recurrence. Gy with a subsequent boost can be given within a 6 \200\2237 week course, to give a 5 year survival rate of 40 \200\22360%. Patients who relapse or fail to respond to radiotherapy ca n be considered for salvage cystectomy. Neoadjuvant chemotherapy Chemotherapy has a role in managing muscle-invasive tumors. Good q uality evidence supports the use of neoad- juvant rather than adjuvant chemotherapy, using regimes such as MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) or newer ones s uch as GC (gemcitabine and cis- platin), along with radical cystectomy and radiotherapy to improve survival. Approximately half of patients with muscle-invasive blad- der carcinoma have occult metasta ses at presentation, which become overt within 5 years. Metastatic disease MVAC and GC chemotherapy regimes can prolong life, although outcome with metastatic disease is invariably poor. External beam radiotherapy can also be used in the pallia- tive setting to manage symptoms such as recurrent hema- turia, urinary urgency and pain. Future prospects For nonmuscle-invasive disease, urinary biomarkers have the potential to r educe the need for follow-up cystoscopy and newer methods of administering intravesical age nts (e.g. hyperthermia, electromotive drug administration) and photodynamic therapy are gai ning in popularity. For inva- sive tumors, laparoscopic and robotic cystectomy are being pe rformed increasingly and new chemotherapeutic agents are being tested in clinical trials fo r this type of aggressive cancer. Squamous cell carcinoma Both pure squamous cell carcinoma and bilharzial squa- mous cell ca rcinoma have poor long-term outcomes. The treatment of choice is radical cystectomy, althou gh there is limited evidence for neoadjuvant chemotherapy and radio- therapy in bilharzial squamous cell carcinoma. Further reading Jakse G, Algaba F, Fossa S, Stenzl A, Sternberg C. Guidelines on Bladder Ca ncer (Muscle-invasive and Metastatic). European Association of Urology Guidelines; 2006. Adenocarcinoma The treatment of choice for primary adenocarcinoma is radical cystectomy. Pa tients with urachal adenocarcinoma should be treated with en bloc resection of the urachus and umbilicus combined with partial cystectomy, or radical cys- tectomy for larger tumors. Oosterlinck W, van der Meijden A, Sylvester R, et al. Guidelines on TaT1 (Non-muscle-invasi ve) Bladder Cancer. European Association of Urology Guidelines; 2006. Parekh DJ, Bochner BH, Dalbagni G. Super \201 cial and muscle-invasive bladder cancer: pri nciples of management for outcomes assess- ments. J Clin Oncol 2006; 24: 5519 \200\2235527. Follow-up Nonmuscle-invasive TCC \200\223 low risk tumors Patients with low risk tumors (G 1pTa) should have check \202 exible cystoscopies at 3, 12, 24, 36, 48 and 60 months, or u ntil they develop a recurrence. Recurrences may be dealed with by repeat TURBT or cystodiat hermy (electrocautery or laser) depending on size and equipment availability. Table 17.4.1 TNM classi \201 cation of transitional cell carcinoma Stage Description Non muscle-invasive TCC \200\223 intermediate risk tumors The follow-up cystoscopy protoco l for these patients is often intermediate to that of low and high risk patients and allows for patient factors and local availability. Ta Papillary tumor con \201 ned to the urothelium T1 Invasion into the lamina propria T2a Invasion into the inner half of the muscularis propria Non muscle-invasive TCC \200\223 high risk tumors Cystoscopic follow-up for these patients is 3-monthly for two years, then 4-monthly for 1 year, 6-monthly until 5 years and then ye arly after, or until recurrence or pro- gression intervenes. T2b Invasion into the deeper half of the muscularis propria T3a Microscopic invasion into the perivesical fat T3b Macroscopic invasion into the perivesical fat T4a Invasion into prostate, uterus or vagina T4b Invasion into pelvic or abdominal wall