S.D. MARKS 662 Complications include: \200 \200 \200 \200 \200 \200 abnormalities, including inguinal herniae, epispadias, hemi- clitoris and anterior anus. Ne onatal bladder closure is required with pelvic bone osteotomies and latter reconstructive s urgery to normalize the urogenital tract and ensure continence. Infants with cloacal extrop hy have the defects of bladder exstrophy with exomphalos, imperforate anus and lum- bosacra l spinal defects. hypertension; VUR; pelviureteric junction obstruction; nephrolithiasis; malignancy; trauma to the isthmus due to its close relationship with the spine. Cloacal anomaly There is a urethra, vagina and colon single channel and opening in girls du e to failure of the urorectal septum to develop. This may result in stenosis and obstructio n of urinary tract, uterine cavity and gastrointestinal tract. Surgical relief of obstructi on and later reconstructive surgery may be required. Obstruction occurs due to compression of the pelviuret- eric junction and proximal ureter b y the aberrant vessels commonly found at the renal hilum or due to distortion of the proxim al ureter as it loops over the renal isthmus. The continuity of both lower poles may be mis sed on USS. Intravenous pyelography is rarely performed in pediatric practice and con \201 rmation of diagnosis by CT or MRI scan- ning is very infrequently required. Urogenital sinus There is a urethra and vaginal single channel and opening in girls due to failure of the urethrovaginal septum to develop. This may result in stenosis and obstructio n of the urinary tract and/or uterine cavity (resulting in hydrocolpos). Urological surgery is required to separate the urethra and vagina. Lower and other urinary tract defects Prune belly syndrome Absent abdominal wall musculatur e, Eagle \200\223Barrett or triad syndrome. It is caused by failure of mesenchymal developm ent predom- inantly in males (otherwise pseudo prune belly syndrome). Clinical features inc lude: \200 Further reading Hiraoka M. Medical management of congenital anomalies of the de \201 ciency or absence of anterior abdominal wall muscu- lature with wrinkled, lax appe arance; bilateral cryptorchidism with empty hypoplastic scrotum; ureter, bladder and urethr al abnormalities (usually mega- cystis, mega-ureter due to dysplasia). kidney and urinary tract. Pediatr Int 2003; 45: 624 \200\223633. Limwongse C, Cassidy SB. Syndromes and malformations of the urinary tract. In: Avner ED, Ha rmon WE, Niaudet P (eds), Pediatric nephrology, 5th edn. Philadelphia: Lippincott Williams & Wilkins; 2004. Miyazaki Y, Ichikawa I. Ontogeny of congenital anomalies of the kidney and urinary tract, CAKUT. Pediatr Int 2003; 45: 598 \200\223604. Nakai H, Asanuma H, Shishido S, Kitahara S, Yasuda K. Changing concepts in urological management of the congenital anoma lies of kidney and urinary tract, CAKUT. Pediatr Int 2003; 45: 634 \200\223641. Nakanishi K , Yoshikawa N. Genetic disorders of human congenital anomalies of the kidney and urinary tr act (CAKUT). Pediatr Int 2003; 45: 610 \200\223616. \200 It is associated with: \200 renal dysplasia; \200 VUR; \200 urinary stasis; \200 na rrowed urethra; \200 obstruction of ureteric, pelviureteric and vesicoureteric junctions; poorly contractile, thick-walled (nontrabeculated) bladder with large diverticulae; uracha l cyst or patent urachus; postmicturition residual volumes; malrotation; gastroschisis; imp erforate anus; constipation; congenital heart disease; talipes equinovarus; developmental d ysplasia of the hips. Schedl A. Renal abnormalities and their developmental origin. Nat Rev Genet 2007; 8: 791 \200\223802. Internet resources Evaluation of congenital anomalies of the kidney and urinary tract (UpTo Date): \200 \200 \200 \200 \200 \200 \200 \200 http://patients.uptodate.com/topic.asp?file= pedineph/17792 Human Renal Tract Malformations : Unraveling The Genes \200\223 summary of lecture by Prof. A. Woolf at the XLIII ERA- EDT A Congress: http://www.ndt-educational.org/ woolfslide2006txt.asp National Congenital Anomaly System: Long-term follow-up is required if there is evidence of CKD. A formal measurement of GFR sh ould be performed at 12 months of age when it is associated with renal dysplasia and/or the re are concerns about renal dysfunction (such as elevated plasma creatinine). http://www.statistics.gov.uk/downloads/theme_ health/National_Congenital_Anomaly_System/ CA _text_v2.pdf NHS Perinatal Institute: Bladder extrophy There is exposure of the posterior wall of the bladder. It occurs due to a breakdown of the cloacal membrane caused by the infra-umbilical mesenchyme failing to sepa - rate the cloaca component that develops into the bladder from the overlying ectoderm. It is commoner in boys with lower abdominal wall defects, symphisis pubis diastasis, pelvic, b ladder, urethral and genital http://www.perinatal.nhs.uk/car/anomaly/renal/ renal.htm See also Renal dysplasia, p. 646 Vesicoureteric re \202 ux and re \202 ux nephropathy, p. 648 Rare syndromes with renal involvement, p. 640 This page intentionally left blank S.D. MARKS 664 Medullary sponge kidney Introduction Medullary sponge kidney (MSK) is also called renal tubular ectasia or Cacchi \200\223Ricci disease. It is a congenital renal developmental abnormality and part of a gro up of renal cystic disorders but rarely encountered even in pediatric nephrological practic e. Its name is derived from the sponge appearance of the renal medulla which can occur foca lly in one or both kidneys (usually both kidneys) due to collect- ing duct ectasia and cyst formation in one or more renal pyramids. MSK is believed to arise from hyperplasia or obst ruction of fetal collecting tubules and hypercalciuria with increased urinary pH causing th e associated nephrolithiaisis and structural changes. Renal duplication or malrotation. Caroli \200\231s disease. Congenital heart disease. Pylor ic stenosis. Parathyroid adenoma. Hemihypertrophy. Beckwith \200\223Wiedemann syndrome (wit h associated increased malignancy rates). Marfan and Ehlers \200\223Danlos syndrome. Differential diagnosis Polycystic kidney disease, especially ADPKD. Renal papillary necrosi s or tuberculosis. Calyceal diverticulum. Nephrolithiasis. Epidemiology MSK is commoner in males than females (although more females are affected with hypercalciuria). It affects children (from 2 years of age) and adults, although commoner i n adolescents and young adults with progres- sive degeneration of the collecting tubules oc curring later in life. The prevalence is 1 in 5000 \200\22320 000 individuals but this is a n underestimate as many patients are asymptomatic. MSK is detected in 0.5 \200\2231% of pat ients undergoing intrave- nous pyelography. Investigations Abdominal X-ray Linear/rounded clusters of medullary nephrocalcinosis. Nephr olithiasis within renal pelvis, ureter or bladder. Renal ultrasound Normal-sized kidneys or renal hypertrophy (especially if associated with A DPKD) with echogenic medullary pyramids with calci \201 cation. Genetics Most cases are sporadic. Familial clustering (including autosomal dominant inherit - ance) has been described. Intravenous pyelography Findings include: Discrete linear papillary striations due to dilat ed collecting tubules of renal medulla (Fig. 16.5.1). Nephrolithiasis arranged in groups ar ound a calyx (bunch of grapes pattern). Hypertrophy of renal pyramids. Distorted calyces, w hich are broad and shallow (Fig. 16.5.2). Clinical features Presentation Incidental \201 nding in asymptomatic patient. Failure to thrive (with growth failure due to distal renal tubular acidosis). Loin pain Microscopic (> 90% of patients) and macroscopic (<20% of patients) hematuria. Urinary tract infection (30% of symptomatic patients) with possible recurrent acute and chronic pyelonephritis due to u rinary stasis and nephrolithiasis. CT Medullary nephrocalcinosis and tubular ectasia. Contrast-enhanced scans may demonstrate papillary archi- tecture (Fig. 16.5.3). Interstitial nephritis and renal abscess formation. MRI This is not sensitive for calci \201 cation (CT preferred). It has a limited role, esp ecially in patients with known aller- gies to contrast media. Associated renal features Distal renal tubular acidosis. Proximal renal tubular dysfunction . Mild urinary concentration impairment and acidi \201 cation defects. Nephrocalcinosis an d nephrolithiaisis (calcium oxalate and apatite calculi or struvite calculi from bacteria). DMSA renogram Photopenic areas of renal parenchymal scarring may be found and differential renal function can be assessed. Pathology MSK is a developmental defect with ectasia and cyst forma- tion (of 1 \200\2238 m m size representing dilated terminal collect- ing tubules) with hyperplasia affecting the i ntrapyramidal or intrapapillary segments of renal medullary collecting tubules. Noncommunic ating, and more commonly communicating, cysts (proximally with collecting tubules and dista lly with papillary ducts or calyx) are occasionally associated with calculus formation. Risk of chronic kidney disease Few cases progress with renal dysfunction. Proteinuria and h ypertension are rare, although pregnancy- induced hypertension has been reported. Clinical associations Autosomal dominant polycystic kidney disease (ADPKD). Horseshoe kidne y. CHAPTER 16.5 Medullary sponge kidney 665 Treatment and prognosis Urinary tract infection, nephrocalcinosis and nephrolithiasis requi re standard treatment including antibiotics, increased \202 uid intake and thiazide diure tics. A few cases are associated with CKD. There is no associated increased mortality rate. Further reading Forster JA, Taylor J, Browning AJ, Biyani CS. A review of the natural progr ession of medullary sponge kidney and a novel grading system based on intravenous urography \201 ndings. Urol Int 2007; 78: 264 \200\223269. Gambaro G, Feltrin GP, Lupo A, Bonfante L, D \200\231Angelo A, Antonello A. Medullary spong e kidney (Lenarduzzi \200\223Cacchi \200\223Ricci disease): a Padua Medical School discover y in the 1930s. Kidney Int 2006; 69: 663 \200\223670. Kasap B, Soylu A, Oren O, T rkmen M, Kavuk u S. Medullary sponge kidney associated with d istal renal tubular acidosis in a 5-year-old girl. Eur J Pediatr 2006; 165: 648 \200\223651 . Fig. 16.5.2 Intravenous pyelography: 15 min image of patient who presented with hematuria a nd had renal calculi on control \201 lm with irregularity of calyces (dilated without cup ping). Maw AM, Megibow AJ, Grasso M, Goldfarb DS. Diagnosis of medullary sponge kidney by computed tomographic urography. Am J Kidney Dis 2007; 50: 146 \200\223150. Internet resources National Organization for Rare Disorders: http://www.rarediseases.org/ Medullary Sponge Kidney Support Group: http://groups.msn.com/medullaryspongekidney National Kidney Federation patient information: http://www.kidney.org.uk/Medical-Info/kidney- disease/cysts.html See also Lower and upper urinary tract infection in the adult, p. 244 Nephrocalcinosis, p. 278 Medical management of stone disease, p. 270 Surgical management of stone disease, p. 27 4 Congenital abnormalities of the urinary tract, p. 658 Fig. 16.5.3 CT scan performed for congenital hepatic \201 brosis in a child with contrast nephrogram demonstrating medullary cysts. Fig. 16.5.1 Renal tubular ectasia without nephrolithiasis on intravenous pyelography. This page intentionally left blank 667 Chapter 17 Malignancy of the kidney and urinary tract Chapter contents Tumors of the kidney 668 Wilms \200\231 tumor 672 Tumors of the renal pelv is and ureter 676 Tumors of the bladder 680 Tumors of the prostate 684 L. GRIFFITHS AND N. MAYER 668 Tumors of the kidney Introduction Renal cell carcinoma (RCC) is the most frequently occur- ring solid lesion wit hin the kidney. It comprises different tumor subtypes with speci \201 c genetic characteri stics. The study of the hereditary types of kidney cancer syndromes has helped to elucidate the genetic basis of sporadic renal tumor formation, and provided the background for devel - oping molecular-targeted agents in the treatment of RCC. Levels of evidence are indicated as used by the US Department of Health and Human Services. The classic triad of \202 ank pain, abdominal mass and gross hematuria (6 \200\22310%). P resentation may alternatively be with symptoms associated with, but not directly caused by, metastatic disease (30%). Paraneoplastic syndromes can occur in 30% of patients with symp tomatic RCC: \200 \200 \200 \200 hypertension; hypercalcemia; erythrocytosis; Stauffer \200\231s syndrome (paraneoplastic ch olestatic jaundice). De \201 nition By far the most common renal tumor is renal cell carci- noma, followed by W ilms \200\231 tumor, which is found in chil- dren, and \201 nally urothelial tumors of th e calyces and renal pelvis. Because of their gross yellow color and resemblance of the tumo r cells to clear cells of the adrenal cortex, it was once thought that they arose from adre nal tissue, accounting for the term hypernephroma. It is now clear that these tumors arise from tubular epithelium and are therefore renal adenocarcinomas. Physical examination \200 Abdominal mass. \200 Cervical lymphadenopathy. \200 Nonredu cing varicocele. \200 Bilateral lower limb edema. All of these signs should initiate imaging. Renal cell tumors and syndromes A number of rar e syndromes can be associated with the development of RCC (Table 17.1.1). Epidemiology Kidney tumors account for 2 \200\2233% of all cancers. Male predominance over female (1.5:1). Within the European Union: \200 \200 von Hippel \200\223Lindau (VHL) disease The commonest syndrome associated with RCC Autosomal dominant. 1 in 35 000 individuals. The re is a spectrum of germline mutations of VHL in 99% of VHL families. The three major manif estations are: \200 \200 \200 30 000 patients were diagnosed with RCC in 1998; 15 000 patients died of RCC in 1998. The highest incidence is in developed countries. The peak incidence is between 60 and 70 ye ars of age. Worldwide annual increase in incidence is 2%. clear cell RCC; CNS hemangioblastoma; pheochromocytoma. Predisposing factors Cigarette smoking (evidence: 2a). Obesity (evidence: 2a). Prolonged in take of antihypertensives (evidence: 2a). Affected families may not have all three conditions. The kidneys of affected patients often contain multiple, bilateral solid tumors and cysts. Nephron-sparing surgery is recommended when solid renal lesions reach 3 cm. Genetics A number of genetic mutations have been found in association with sporadic and her editary renal cell tumors (Table 17.1.1). Of sporadic clear cell RCC, 75% show loss of von Hippel \200\223 Lindau (VHL) activity and 13% of sporadic papillary type 1 tumors have act ivating mutations in the MET proto- oncogene. VHL protein functions as a tumor suppressor a nd inhibits hypoxia-inducible genes. These genes encode several proteins involved in: \200 \200 \200 \200 Investigations Abdominal ultrasound The detection of a solid renal mass with ultrasound alw ays requires further investigation. CT scan of the abdomen and chest with contrast To determine the extent of any spread within the abdomen and to detect pulmonary metastases. MRI of abdomen and chest This is reserved for those with renal insuf \201 ciency or an all ergy to intravenous contrast. angiogenesis: vascular endothelial growth factor (VEGF); cell growth: transforming growth f actor- ; glucose uptake: the GLUT-1 glucose transporter; acid \200\223base balance: carbon ic anhydrase IX. Percutaneous biopsy This is usually only considered in selected cases (e.g. when there is s uspicion that the renal mass is a secondary), although there is now a move towards biopsy o f small lesions. When VHL protein is lost, these proteins are overexpressed, creating conditions favoring ep ithelial proliferation. Other investigations \200 \200 \200 Clinical features Symptoms Asymptomatic: incidental detection of RCC using noninva- sive im aging (> 50%). Estimate of renal fuction (serum creatinine and eGFR); Full blood count. Bone pro \201 le and liver function tests if the disease is metastatic. CHAPTER 17.1 Tumors of the kidney 669 Table 17.1.1 Sporadic and hereditary renal cell tumors and genetic alterations Sporadic renal cell tumors Renal cell tumors in an inherited syndrome Histological appearance Incidence Gene alteration and freqency VHL, 60% Syndrome Gene alteration Chromosome affected 3p 3p 1q VHL Clear cell 75% VHL disease FCRC Hereditary paraganglioma SDHB MET Papillary type 1 5% MET, 13% HPRC 7q FH Papillary type 2 10% TFE3, <1% HLRCC 1q BHD Chromophobe 5% Birt \200\223Hogg \200\223Dub 17p BHD Oncocytoma 5% Birt \200\223Hogg \200\223Dub 17p \200\223 \200\223 \200\223 \200\223 Collecting duct Rare (<1%) \200\223 \200\223 \200\223 \200\223 Medullary carcinoma Rare VHL, von Hippel \200\223Lindau; FCRC, familial clear cell cancer; HPRC, hereditary papillar y renal carcinoma; HLRCC, hereditary leiomyomatosis and renal cell cancer; SDHB, succinate dehydrogenase B; FH, fumarate hydratase. DMSA renogram if there is concern about the relative function of the contralateral kidney. Papillary type 1 tumors are indolent compared with the more aggressive type 2 tumors. Renal oncocytomas are almost invariably benign, but rare hybrid tumors with chromophobe RCC exis t. Pathology Histological grading Fuhrman nuclear grade (1 \200\2234) is the most widely accep ted histological grading system in RCC. Pathology and natural history of small enhancing renal tumors (<4 cm) on CT Approximately t wo-thirds are malignant. The mean growth rate of these tumors managed by sur- veillance is slow (<3 mm per year) and the metastasis rate is 1%. If RCC is proven, the growth rate is 4 mm per year and the metastasis rate is 2.8%. Sporadic renal cell tumor subtypes The current World Health Organization (2004) classi \201 ca- tion is based on the Heidelberg classification system (Table 17.1.1). The trend fo r better prognosis in pT1 \200\223T2 RCC is: \200 chromophobe > papillary > clear cell RC C. Staging The 2002 UICC TNM stage classification system is recommended (Table 17.1.2). The pT 1 substrati \201 cation, introduced in 2002, has been validated by a number of studies. Collecting-duct carcinoma is frequently metastatic at diagnosis. Renal medullary carcinoma has some morpho- logical overlap, occurs in younger patients and is associated with sickle cell disease. Table 17.1.2 TNM stage classi \201 cation system for renal cell cancer T Primary tumor T1a Tumor \211 4 cm in greatest dimension, limited to the kidney T1b Tumor >4 cm but \211 7 cm in greatest dimension T2 Tumor >7 cm in greatest dimension, limited to the kidney T3a Tumor directly invades adrenal gland or perinephric tissues but not beyond T3b Tumor grossly extends into renal vein(s) or its segmental branches, or the vena cava below the diaphragm T3c Tumor grossly extends into vena cava or its wall above diaphragm T4 Tumor directly invades beyond Gerota \200\231s fascia N Regional nodes N0 No regional lymph node metastasis N1 Metastasis in a single regional lymph node N2 Metastasis in more than one regional lymph node M Distant metastasis M0 No distant metastasis M1 Distant metastasis aUICC (International Union Against Cancer, 2002). L. GRIFFITHS AND N. MAYER 670 (a) (b) (c) (d) Fig. 17.1.1. Renal cell carcinoma (RCC). (a) Gross appearance of a large upper pole clear c ell RCC. The adrenal gland is also included on the superior aspect of the specimen. (b) Typ ical morphology of clear cell RCC, solid pattern. (c) Papillary RCC (Type I), papillae line d by a single layer of small cuboidal cells. Also note prominent foamy macrophages. (d) Chr omophobe RCC; characterized by large polygonal cells with prominent cell membranes and peri nuclear halos. Treatment Treatment of localized RCC Radical nephrectomy Radical nephrectomy is the gold st andard curative therapy for patients with localized RCC. The adrenal gland can be spared in the majority of patients. Laparoscopic nephrectomy is a standard of care for patients with T1 \200\2232 RCCs. Radical nephrectomy and thrombectomy can be per- formed for T3b and T3c tumors. Lymph node dissection is not routinely performed. Treatment of metastatic RCC (mRCC) Cytokines Tumor nephrectomy in combination with interfer on- (INF- ) improves the survival of patients with mRCC and good performance status (evi dence: 1b). Those with a clear cell subtype derive clinical bene \201 t from INF- or int erleukin-2 (IL-2) (evidence: 1b). Angiogenesis inhibitor drugs Sorafenib (an oral multikina se inhibitor of Raf-1, B-Raf, VEGFR-2, PDGFR, FLT-3, KIT) delays progression in cytokine-re fractory patients (evidence: 1b). Sunitinib (an oral multikinase inhibitor of PDGFR, VEGFR, KIT, FLT-3) improves progression-free survival compared with interferon in cytokine-naive, good and intermediate prognosis tumors (evidence: 1b). Temsirolimus (an intravenous inhibi tor of the kinase mTOR (mammalian target of rapamycin)) monotherapy in poor prognosis patie nts is more effective than INF- or tem- sirolimus plus INF- (evidence: 1b). Nephron-sparing surgery Indications \200 Absolute: anatomical or functional solitary kidney or bilateral RCC. Relative: a functionin g opposite kidney that is affected by a condition that might impair renal function, and her edi- tary forms of RCC. Open partial nephrectomy (OPN) \200 Follow-up There is no evidence-based standard for the follow-up of patients with nonmetasta tic RCC. Consequently, the European Association of Urology Guidelines (2006) makes no recom mendations. A number of scoring systems have divided patients with clear cell RCC into low, intermediate and high risk for developing metastases. This allows the urologist to be sele ctive in the use of imaging and outpatient follow-up. An internationally validated algorith m which is increasingly used was created by Leibovich et al. from the Mayo Clinic. (see Fur ther Reading) OPN currently remains the standard of care for neph- ron-sparing surgery. It is used for T1 a tumors in the presence of a normal contralateral kidney. It has gained popularity because OPN for patients with T1a tumors has long-term survival rates similar to those of radical nephrectomy (evidence: 2b). Local recurrence rates after OPN for presumed RCC with 3 \200\2236 years of follow-up are l ow (0 \200\2234%). Laparoscopic partial nephrectomy (LPN) \200 This is feasible if time-sensitive intracorporeal suturing can be performed. LPN is associa ted with more complications than OPN. Prognosis The following contribute important prognostic informa- tion (evidence: 2): \200 TNM stage. \200 Fuhrman nuclear grade. \200 RCC subtype. Energy ablative techniques These are used to destroy tissue in situ. They are developmental (evidence: 2b). Most published series have used cryotherapy or radiofre- quency probes pla ced either laparoscopically or percuta- neously depending on tumor position. The 5 year loc al recurrence rate following renal cryoabla- tion (RCA) is 6 \200\22310%; 5 year data for r adiofrequency abla- tion are not available. Histological features carrying a poor prognosis: \200 \200 coagulative necrosis in clear cell RCC. microvascular invasion may be important. Future prospects A serum biomarker for RCC. CHAPTER 17.1 Tumors of the kidney 671 Percutaneous biopsy of small renal masses is likely to become more routine when fears conce rning safety and diagnostic accuracy are allayed. Ablative therapies for small nonmetastati c renal tumors may develop from being minimally invasive to noninvasive. Molecular biologic al advances are likely to lead to the development of further targeted therapies. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon- alpha in metastatic re nal-cell carcinoma. N Engl J Med 2007; 356: 115 \200\223114. Stein RJ, Kaouk JH. Renal cryotherapy: a detailed review including a 5-year follow-up. BJU Int 2007; 99: 1265 \200\2231270. Internet resources European Association of Urology Guidelines: http://www.uroweb.org Cancerbackup: Further reading Chawla SN, Crispen PL, Hanlon AL, Greenberg RE, Chen DY, Uzzo RG. The natur al history of observed enhancing renal masses: meta-analysis and review of the world litera ture. J Urol 2006; 175: 425 \200\223431. http://www.cancerbackup.org.uk/home See also Wilms \200\231 tumor , p. 672 Tumors of the renal pelvis and ureter, p. 676 Tubero us sclerosis and von Hippel \200\223Lindau disease, p. 578 Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med 2005; 353: 2477 \200\2232490. Escudier B, Eisen T, Stadler WM, et al. TARGET Study group. Sorafenib in advanced clear-cel l renal-cell carcinoma. N Engl J Med 2007; 356: 15 \200\22334. Lane BR, Novick AC. Nephron-sparing surgery. BJU Int 2007; 99: 1245 \200\2231250 Leibovich BC, Blute ML, Cheville JC, et al. Prediction of progression after radical nephrec tomy for patients with clear cell renal cell carcinoma: a strati \201 cation tool for pros pective clinical trials. Cancer 2003; 97: 1663 \200\2231671. McDougal WS. Radiofrequency ablation of renal cell carcinoma. BJU Int 2007; 99: 1271 \200\2231272. C. MITCHELL AND J. MUSSAI 672 Wilms \200\231 tumor Introduction Wilms \200\231 tumor is the most common renal malignancy in childhood. It was \201 rst described in 1899 by Max Wilms, when he noted what is now recognized as classic, triphasic histology. Multinational trials over the last 20 years have led to a signi \201 cant improvement in outcome for patients with Wilms \200\231 tumor so that the majority ar e cured, usually with little or no long-term morbidity. WT1 gene was the \201 rst Wilms \200\231 tumor gene to be identi \201 ed at the 11p locu s. The precise role of the protein product of the WT1 is unclear although it is known to be a transcrip- tion factor. In WAGR there is a deletion of one copy each of the WT1 gene and the associated PAX6 gene on chromosome 11p13. Germline mutations in the WT1 gene are also found in Denys \200\223Drash syndrome. A second gene, WT2, has been identi \201 ed on the basis of loss of heterozygosity at the 11p15 locus. Genetic abnormalities have been consist ently found in chromosomes 16q, 1p and 7p. p53 mutations, -catenin mutations, and deletio ns in the X chromosome have also been reported. De \201 nition Wilms \200\231 tumor is an embryonal neoplasm arising in the kid- ney. Clas sical, \200\230triphasic \200\231 Wilms \200\231 tumor consists of stromal, blastemal and epithelial elements. Other renal tumors occurring in children are often included under the Wilms \200\231 tumor heading, but only anaplasia is a true variant. The bone-metastasizing renal tumor (clear cell sarcoma) and malignant rhabdoid tumor are pathologically and geneti - cally distinct entities, and have distinct clinical courses. Renal cell carcinoma and per ipheral neuroectodermal tumors may also occur. Clinical features 74% of patients present with an abdominal mass arising in the loin often detected by a parent. The mass may be rounded or lobulated, usually ballotable and does not move with respiration. 44% of patients present with abdominal pain. Epidemiology Wilms \200\231 tumors account for 8% of all childhood neoplasia. It ranks \201 fth in incidence among the solid tumors of child- hood. The annual incidence is 8 per million children <15 years. Racial and regional variation in incidence exist. The peak age s for diagnosis are the 3rd and 4th years of life. The frequency in males and females is eq ual. It is very rare in the neonatal period and after the age of 10 years. Careful review o f cases of \200\230Wilms \200\231 tumor \200\231 seen in adults will usually determine tha t the histology is in fact that of a peripheral neuroectodermal tumor or a renal cell carci noma. Additional features may include: \200 \200 \200 \200 hematuria; fever; hypertension; pulmonary metastases. Hypertension may arise from vascular compression of the tumor, excessive renin production o r pre-existing renal dis- ease. Blood pressure should be measured. Angiotensin- converting enzyme inhibitors, -blockers, and calcium channel antagonists have been used to control B P in these patients. Pulmonary metastases present at diagnosis are only rarely detected by clinical examination. Physical examination should include a search for the signs of the var ious predisposing conditions such as Beckwith \200\223 Wiedemann syndrome, aniridia and hem ihypertrophy. Predisposing factors There are a number of conditions known to predispose to the developmen t of Wilms \200\231 tumor, but this group of patients represents only a small proportion of the total number seen. \200 Essential investigations The major differential diagnosis of abdominal neuroblast- oma must be excluded, not only to make a correct diagno- sis, but because immediate surgery may the n not be appropriate and catecholamine-secreting tumors pose anesthetic problems. The minim um set of investigations must include: Genitourinary abnormalities with or without aniridia (the WAGR syndrome). Aniridia. Hemihyp ertrophy. Beckwith \200\223Wiedemann syndrome. Denys \200\223Drash syndrome. Perlmann syndr ome. Simpson \200\223Golabi \200\223Behmel syndrome. \200 \200 \200 \200 \200 Abdominal ultrasound \200 \200 \200 Con \201 rm organ of origin. Determine extent of any spread within the abdomen. Con \201 rm patency of the inferior vena cava. Chest X-ray (PA and lateral) \200 There is no clear evidence that screening examinations and investigations leads to signi \201 cant improvement in stage distribution or outcome. However, in patients with aniridia, Beckwith \200\223Wiedemann syndrome and hemihypertrophy screening is recommended. The inci dence of familial Wilms \200\231 tumor is extremely low. Detect pulmonary metastases. Urinary catecholamines \200 \200 Exclude intrarenal neuroblastoma. Aid interpretation of imaging investigations which can oc casionally be erroneous. Genetics Wilms \200\231 tumor was initially thought to represent a simple model for studyin g the genetics of the etiology of cancer. This belief is now known to be incorrect. CT scan of the abdomen and chest \200 Common practice, although role in detection of pulmo- nary metastases is not yet establishe d and additional CHAPTER 17.2 Wilms \200\231 tumor 673 1 and 2 (Table 17.2.1). This staging system is based on tumor location at the time of surge ry, before any adjuvant therapy has been given. By contrast the European staging system use d by the SIOP (International Society of Pediatric Oncology) group is based on radiological, biopsy, and sur- gical \201 ndings after preoperative chemotherapy. The differ- ences me an that trial data from the two groups cannot be easily compared. In the European model pre operative chemotherapy downstages the tumor and reduces the risks at the time of nephrectom y. However, it is argued by the North American group that by giving preoperative chemothera py the virgin stage and histology of the tumor will be unknown and there is a risk of givin g unneeded chemotherapy to benign tumors. 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