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Journal of Pediatric Surgery (2008) 43, 1625–1629

Ureteral extension in Wilms' tumor: a report from theNational Wilms' Tumor Study Group (NWTSG)Michael Ritcheya,⁎, Shane Daleya, Robert C. Shambergerb, Peter Ehrlichc,Thomas Hamiltonb, Gerald Haased, Robert Sawine

aDepartment of Urology, Mayo Clinic Arizona, Scottsdale, AZ 85259, USAbDepartment of Surgery, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USAcDepartment of Surgery, University of Michigan, Ann Arbor, MI 48109, USAdDepartment of Surgery, University of Colorado, Denver, CO 80220, USAeDepartment of Surgery, University of Washington, Seattle, WA 98195-6410, USA

0d

Key words:Wilms' tumor;Ureter;Hematuria

AbstractBackground: Extension of Wilms' tumor into the ureter is a rare event. We reviewed the NationalWilms' Tumor Study Group (NWTSG) database to define the clinical presentation, associatedpathologic features, and clinical outcome of these patients.Methods: Records of children identified to have ureteral extension of Wilms' tumor enrolled in NWTS-3, 4, and 5 were reviewed. Presenting symptoms, diagnostic studies, histopathologic findings, operationperformed, and outcome were recorded. The NWTS-5 surgical data were prospectively collected as partof the quality assurance program.Results: Forty-five children were identified with ureteral extension. For NWTS-5, the incidence ofureteral extension was 2%. Clinical presentations were gross hematuria in 22 patients, 2 had passage oftissue per urethra, and 1 child had a urethral mass. The remainder had nonspecific presentations.Ureteral extension was seen on preoperative imaging in 14 patients, intraoperatively in 22, and onpathologic examination in 9 patients. Hydronephrosis was noted in 12 patients, and there wasnonfunction of the kidney in another 8. Laterality of the tumor was right side in 26 and left in 19.Cystoscopy was performed in 12 children. Findings included tumor seen at the ureteral orifice in6 patients and bleeding from the orifice in one child. All patients had radical nephrectomy includingpartial ureterectomy. The ureteral margin was positive in 3 patients, including 2 of the 7 with separateremoval of the ureteral extension. The number of patients in each clinical stage was as follows: stage I,10; stage II, 18; stage III, 14; and stage IV, 3. The tumor extended into the proximal ureter in 23 patients,distal ureter in 13, 7 had extension into the bladder, and 1 had urethral involvement. The level of ureteralextension was not clearly noted in the 45th child. The median follow-up was 96 months. Overall, 41 of45 patients were alive at last contact. There were 3 deaths because of tumor in patients with unfavorablehistologic tumors, and 1 because of treatment toxicity in a child with favorable histologic findings.Conclusions: Ureteral extension occurs in approximately 2% of patients with Wilms' tumor. Thediagnosis should be suspected in patients with gross hematuria, hydronephrosis, or nonfunctioningkidney. Cystoscopy with retrograde ureterogram may aid in preoperative diagnosis in these patients.

⁎ Corresponding author. Tel.: +1 602 279 1697; fax: +1 602 264 0461.E-mail address: michael.ritchey@gmail.com (M. Ritchey).

022-3468/$ – see front matter © 2008 Elsevier Inc. All rights reserved.oi:10.1016/j.jpedsurg.2008.01.067

1626 M. Ritchey et al.

Preoperative diagnosis is important because complete resection of the involved portion of ureter at thetime of nephrectomy can avoid residual disease and the need for second surgery or radiation therapy.© 2008 Elsevier Inc. All rights reserved.

Wilms' tumor (nephroblastoma) is the most commonrenal tumor of childhood. Although invasion of the renalcollecting system is common [1], extension down into theureter is not [2-17]. The staging system used by the NationalWilms' Tumor Study Group (NWTSG) defines disease thatextends beyond the kidney as stage II. Patients with tumorsof favorable histologic finding and stage II disease areusually effectively treated by complete nephrectomy andpartial ureterectomy, followed by adjuvant chemotherapyusing vincristine and dactinomycin. Such treatment results inexcellent long-term disease-free survival. Some reports in theliterature have suggested that tumors with ureteral extensionare more resistant to therapy [9,10,16]. Others havesuggested the need for cystoscopic surveillance postopera-tively to detect tumor recurrence [16]. This review of a largeseries of children with ureteral extension enrolled in theNWTS studies was performed to determine the clinicalpresentation, imaging findings, surgical management, andoutcome of these patients.

1. Methods

Ureteral extensions of Wilms' tumor were identified in45 children enrolled in NWTS-3, 4, and 5 from 1979 to 2003.Of the patients with ureteral extension in NWTS-3, 4 wereidentified during several surgical reviews of patients fromthese studies. We did not review the charts of all patientsenrolled in these 2 studies to determine the incidence ofureteral extension. There were 26 NWTS-5 patientsidentified prospectively during the quality assurance reviewconducted by the surgical committee. The incidence ofureteral extension for NWTS-5 was 2%. The records of eachpatient maintained at the NWTSG data and statistical centerin Seattle, Wash, were reviewed. This included operative andpathologic reports, imaging reports, and flow sheets detailingthe patients' treatment and outcome. Data collected includedpresenting signs and symptoms, age at diagnosis, sex,laterality of tumor, method of diagnosis, level of ureteralextension, cystoscopic findings, diagnostic imaging find-ings, size of the primary tumor, operative proceduresperformed, histopathologic findings, and the developmentof recurrent or metastatic disease.

2. Results

The median age at diagnosis was 33 months. The meanweight of the kidney and tumor was 417 grams. There were

20 females and 25 males. The stage that was assigned to thepatients for treatment on study was as follows: 10 patientshad stage I disease; 18 stage II; 14 stage III; and 3 stage IV.The laterality of the tumor was right-sided in 26 cases andleft-sided in 19.

Clinical presentation was gross hematuria in 22 patients.One patient presented with flank pain, 1 had a urethral mass,and 2 passed tissue per urethra. Cystoscopy was performedin 12 patients. Six children were noted to have tumorprotruding from the ureteral orifice, and bleeding from theureteral orifice was seen in 1 child. Four children hadretrograde ureterograms performed at the time of cystoscopy,and this was diagnostic in all patients. Two of the latterpatients had a presumptive diagnosis of ureteral extensionfrom the preoperative imaging.

Preoperative imaging confirmed ureteral extension in14 cases. Ureteral extension was diagnosed intraoperativelyin 22 patients and on pathologic examination in 9 patients.There was no difference by NWTS study. Only 8 of the26 children with ureteral extension noted in NWTS-5 weredetected on preoperative imaging. There were 10 patients inwhom the preoperative CT scan demonstrated a mass in theureter or bladder. Six of these patients also had anultrasound performed that either showed a mass in thebladder or a mass in the collecting system. There was onlyone patient in whom only the ultrasound demonstrated theureteral mass when the CT did not. Four patients hadretrograde ureterograms performed during cystoscopy withfilling defects noted. In 2 of these children, the otherpreoperative imaging failed to identify the ureteral exten-sion. One child had a nephrostomy tube placed forhydronephrosis, and the antegrade nephrostogram demon-strated the tumor extending into the collecting system. Eightchildren in whom the diagnosis was not made beforesurgery had the nonspecific finding of nonfunction of theinvolved kidney on either CT or intravenous pyelogram.Hydronephrosis was also a common finding on preoperativeimaging seen in 7 children in whom the ureteral extensionwas not diagnosed preoperatively.

Nephrectomy and partial or complete resection of theureter was performed in all 45 children. Tumor extended intothe proximal ureter in 23 patients, distal ureter in 13, into thebladder in 7, and exited the urethra in 1 child. The level ofureteral extension was not clearly noted in one child. Enbloc removal of the kidney and ureter was performed in38 patients, and 7 patients had separate removal of the ureteralextensions. Six patients had removal of a bladder cuff tofacilitate removal of the distal ureteral extension. Three ofthese patients had undergone cystoscopy before surgery, anda mass was seen at the ureteral orifice. Favorable histologic

Table 1 Outcome of patients with tumor relapse

Site of relapse Stage Histologic finding Positive ureteralmargin

Irradiation ofrenal bed

Outcome after treatment of relapse

Renal bed 2 FH No No No evidence of recurrenceAbdomen 3 RTK Yes Yes Patient died of progressive tumorAbdomen 4 DA No Yes Patient died of progressive tumorAbdomen, pelvis, lung 3 RTK Yes Yes Patient died of progressive tumorLung 3 FH No No No evidence of recurrenceLung 3 FH No Yes No evidence of recurrence

FH, favorable histology; RTK, rhabdord tumor of the kidney; DA, diffuse anaplasia.

1627Ureteral extension in Wilms' tumor

finding of Wilms' tumor was identified in 38 patients. Therewere 4 patients with anaplasia, 2 had rhabdoid tumor of thekidney, and 1 had clear cell sarcoma of the kidney. Intralobarnephrogenic rests (ILNR) were identified in 20 patients and3 patients were found likely to have ILNR. The location of theprimary tumor was described as centrilobar in 31 patients and3 children had midlobar tumors.

The histologic condition of the tumor extension in theureter was examined. The distal portion of the tumorextension showed necrosis in 7 patients. Differentiatedskeletal muscle was observed in 5 patients, epithelialpapillary differentiation in 1, and stromal differentiation in4. There was no histologic evidence of tumor invasionthrough the wall of the ureter in any of the specimens.

There were 4 children reported by the surgeon to havetumor spill during the removal of the ureteral extension. Allpatients who had separate removal of the renal tumor andureteral extension would theoretically have had tumor spillfrom cutting across the ureter with tumor in the lumen. Theresected ureteral margin was positive in 3 patients. Allreceived postoperative irradiation of the renal bed. Two ofthese patients with positive ureteral margins had abdominalrecurrences, and both had rhabdoid tumor of the kidney.There was one other patient with unfavorable histologicfinding who developed an abdominal recurrence. The thirdchild had a tumor with diffuse anaplasia and stage IV diseasewho received postoperative irradiation of the renal bed. All 3of these patients with unfavorable histologic finding andabdominal recurrence died of progressive disease. There wasone recurrence in the renal bed in a patient with a favorablehistologic stage II tumor and clear ureteral margin. Of note,this patient had undergone preoperative needle biopsy of theprimary tumor (Table 1).

Median follow-up time was 96 months. Of 45 patients, 41were alive at the time of last contact. Three deaths occurredin patients with unfavorable histologic finding; 2 hadrhabdoid tumor of the kidney, and 1 had diffuse anaplasia.One child with a favorable histologic tumor died because ofacute respiratory distress syndrome (ARDS) as a result oftreatment toxicity. Eighteen patients underwent irradiationof the renal bed after surgery. All children were treated with achemotherapy regimen appropriate for the assigned stage andhistologic finding for the enrolled NWTSG study.

3. Discussion

Ureteral extension of Wilms' tumor is uncommon withonly 16 cases reported in the literature [2-16]. Of thesereports, 11 were synchronous lesions seen at the time ofpresentation of Wilms' tumor, and 5 were metachronous,occurring 3 months to 2 years after the primary renal tumorwas removed [2,4-7]. It is unclear if the subsequent ureteraltumors were lesions missed at initial exploration orrepresent recurrent disease because of seeding of theurothelium from tumor cells in the urine. In contrast, allof the cases in our review were synchronous. Although anuncommon finding, preoperative detection of ureteralextension may prevent the surgeon from cutting acrosstumor in the ureter producing local tumor spill and leavingresidual tumor in the distal ureter.

Gross hematuria was a common finding in this series(49%). This symptom may be a significant clue of the tumorinvolvement of the collecting system. Although 25% to30% of all patients with Wilms' tumor present with micro-scopic hematuria, gross hematuria is uncommon. Only 8 ofthe 22 children who presented with gross hematuria had acystoscopy performed, but most of the cystoscopic examina-tions were abnormal and identified either tumor or bloodemanating from the ureteral orifice.

Preoperative imaging studies were able to detect theureteral extension in 14 patients. The CT scans wereespecially helpful, with 10 patients diagnosed by CT imagingalone. The ureteral extension was seen less often withultrasound. We can only speculate as to why the ureteralextension was not documented more often on imaging. Mostlikely it is because of the lack of a soft tissue mass expandingthe ureter. The imaging findings are usually nonspecific. Thefinding of hydronephrosis or nonfunction of the kidneyshould alert the surgeon to the possibility of ureteralextension. These nonspecific findings were common in thiscohort. Other causes of nonfunction could be extrinsiccompression of the ureter by the tumor or intravascularextension of tumor [18].

If there is suspicion of ureteral extension because of grosshematuria or hydronephrosis or nonfunction on preoperativeimaging, cystoscopy with retrograde ureterogram canestablish the diagnosis. It is important to ascertain the extent

1628 M. Ritchey et al.

of the tumor before transecting the ureter. It is recommendedthat the tumor and ureteral extension be removed en bloc toavoid cutting across tumor and causing tumor spill. Thecurrent Children's Oncology Group Studies classify alltumor spills as stage III disease increasing the intensity ofpostoperative therapy. If the ureteral extension is entirelyremoved intact, the patient would be considered stage II.Correct identification of ureteral extension is also importantto avoid residual disease. One could speculate that priorpublished reports of asynchronous ureteral tumor were frommissed ureteral extension at the initial surgical procedure.

Of the 16 previously reported patients with ureteralextension, there were 3 tumor-related death [1,4,9]. Two ofthese children were treated in the era before multimodaltherapy was standard treatment of Wilms' tumor. The otherdeath was in a child with metastatic disease. Several reportshave suggested that these tumors are resistant to therapy[9,10,16]. In our review, there were 3 deaths from tumor inchildren with unfavorable histologic finding, and this likelycontributed more to the poor prognosis than the ureteralextension. One child with a favorable histologic tumor died ofARDS as a result of treatment toxicity. Two patients withrelapse were alive at last follow-up; one had relapse to thelung, and the other to the renal bed. Because of the smallnumbers of patients in this review, we cannot speculate on theimpact of tumor spill from the ureter or positive ureteralmargins on survival. In any event, increased awareness ofureteral extension and preoperative detection is important.This would allow for complete resection of the ureteralextension and minimize the risk of local recurrence.

One report suggested the need for cystoscopic surveil-lance postoperatively to detect tumor recurrence [16]. Ourdata do not support such a recommendation. No distal orbladder recurrences have been noted. It would appear thatcomplete resection of the ureteral extension is the mostimportant factor in preventing local recurrence.

Intralobar nephrogenic rests were noted in nearly 50% ofthese children with ureteral extension. This finding maysignify a relationship between ILNR and the developmentof Wilms' tumor involving the collecting system and ureter.Nephrogenic rests are precursor lesions found in the kidneysthat usually undergo involution during development [19].Rests are separated into 2 categories, perilobar and intralobar(PLNR and ILNR). Perilobar nephrogenic rests are onlyfound at the periphery, whereas ILNR are foundanywhere within the lobe as well as the renal sinus andeven within the wall of the pelvicaliceal regions. Tumors thatarise from ILNR are more likely to have a central locationseen in most of our patients. Tumors that arise from ILNRoften appear more differentiated with heterologous tissues,for example, skeletal muscle, commonly present. Fetalmuscle histologic finding has been reported in several ofthe previous reports of ureteral tumor extension [5,11,14].Approximately one quarter of those separately analyzedureteral tumors had these histologic features in the presentseries. The number of patients is too small to permit

conclusions about the prognostic significance, but none ofthe tumors with this fetal muscular appearance developedrecurrence or metastatic disease.

4. Conclusion

Tumor extension into the ureter is an unusual finding innephroblastoma, but its recognition is important. Clues tothe presence of ureteral involvement include presentationwith gross hematuria and the finding of hydronephrosis ornonfunction of the kidney on preoperative imaging studies.Cystoscopy should be considered in patients with theseclinical presentations. Once identified, complete resectionof the ureteral disease is important. This may include a cuffof bladder if necessary to obtain a negative microscopicmargin for tumor extending out the ureteral orifice. Theprognosis for these children with complete resectionremains excellent and does not necessitate adjuvantradiation therapy or 3-drug chemotherapy. Our data donot support a recommendation for cystoscopic surveillanceto monitor for intravesical recurrence.

References

[1] Breslow N, Churchill G, Beckwith JB, Fernbach DJ, et al. Prognosisfor Wilms' tumor patients with nonmetastatic disease at diagnosis—results of the second National Wilms' Tumor Study. J Clin Oncol1985;3:521-31.

[2] Taykurt A. Wilms tumor at the lower end of the ureter extending to thebladder: case report. J Urol 1972;107:142-3.

[3] Mertz HO, Howell RD, Hendricks JW. The limitations of irradiation ofsolid renal tumors in children. J Urol 1941;46:1103-28.

[4] Ferris DO, Beare JS. Wilms' tumor: report of a case with unusualpostoperative metastasis. Mayo Clin Proc 1947;22:94-8.

[5] Watkins JP. Wilms' tumor with ureteral metastasis extending into thebladder. J Urol 1957;77:593-6.

[6] Woodhead DM, Gigax JH, Wahle WH, et al. Urothelial implantation ofWilms tumors. Ann Surg 1968;167:127-31.

[7] Taykurt A. Wilms tumor at lower end of the ureter extending to thebladder: case report. J Urol 1972;107:142-3.

[8] Pagano F, Penelli N. Ureteral and vesical metastasis in nephroblas-toma. Br J Urol 1974;46:409-13.

[9] Stevens PS, Eckstein HB. Ureteral metastasis from Wilms tumor.J Urol 1976;115:467-8.

[10] Chiba T, Ohashi E. Wilms tumor extending into the dilated renal pelvisas a mold. J Urol 1980;124:130-1.

[11] Stanley K, Khoudary KP, Nasrallah PF. Urothelial extension of Wilmstumor presenting as a prolapsing urethral mass. J Urol 1995;153:1981-3.

[12] Mitchell CS, Yeo TA. Noninvasive botryoid extension of Wilms tumorinto the bladder. Pediatr Radiol 1997;27:818-20.

[13] Honda A, Shima M, Onoe S. Botryoid Wilms tumor: case report andreview of literature. Pediatr Nephrol 2000;14:59-61.

[14] Fernandes ET, Parham DM, Ribeiro C, et al. Teratoid Wilms' tumor:the St Jude experience. J Pediatr Surg 1988;23:1131-4.

[15] Groeneveld D, Robben SGF, Meradji M, et al. Intrapelvic Wilmstumor simulating xanthogranulomatous pyelonephritis. Pediatr Radiol1995;25:S 68-9.

1629Ureteral extension in Wilms' tumor

[16] Johnson F, Luttenton C, Limbert D. Extrarenal and urothelial Wilmstumor. Urology 1980;15:370-3.

[17] Johnson KM, Horvath LJ, Gaisie G, et al. Wilms tumor occurr-ing as a botryoid renal pelvicalyceal mass. Radiology 1987;163:385-6.

[18] Shamberger RC, Ritchey ML, Haase GM, et al. Intravascularextension of Wilms tumor. Ann Surg 2001;234:116-21.

[19] Beckwith JB, Kiviat NB, Bonadio JF. Nephrogenic rests, nephro-blastomatosis, and the pathogenesis of Wilms tumor. Pediatr Pathol1990;10:1-36.