Endoscopic Management of Upper Urinary TractTransitional Cell CarcinomaLong-Term Experience

Siamak Daneshmand, M.D.

Marcus L. Quek, M.D.

Jeffry L. Huffman, M.D.

Department of Urology, University of Southern Cal-ifornia, Keck School of Medicine, Los Angeles,California.

Address for reprints: Siamak Daneshmand, M.D.,Department of Urology, USC/Norris ComprehensiveCancer Center, 1441 Eastlake Ave., Suite 7416,Los Angeles, CA 90089; Fax: (323) 865-0120;E-mail: siadaneshmand@yahoo.com

Received January 7, 2003; revision receivedMarch 3, 2003; accepted March 10, 2003.

BACKGROUND. The efficacy and long-term results of endoscopic management of

upper tract transitional cell carcinoma (TCC) were examined. The authors evalu-

ated the accuracy of endoscopic biopsy in determining tumor grade in the subset

of patients who underwent open surgical excision.

METHODS. Between 1987 and 2001, 50 patients (17 with a solitary kidney) under-

went ureteroscopy and biopsy of upper tract TCC. Eleven patients underwent

ureterectomy or nephroureterectomy shortly after endoscopic biopsy. There was

no follow-up for nine patients. Thirty patients underwent endoscopic ablation of

their primary tumor with laser or electrofulguration at the time of the initial biopsy

and were followed with close endoscopic surveillance at 3– 4-month intervals.

RESULTS. For the 30 patients who underwent endoscopic ablation, mean follow-up

was 38 months (range, 4 –106 months). There was an average of 3.4 recurrences,

with an average time to first recurrence of 7 months. Ten of the 30 patients

underwent open resection during follow-up. Six patients exhibited tumor progres-

sion at follow-up. During the follow-up period, one patient died of recurrent

disease, and six died of other causes. Endoscopic biopsy accurately predicted the

tumor grade for 8 of the 9 patients who had open tumor resection within 2 months

of their last biopsy and for 10 of the 11 patients who had open resection shortly

after their initial endoscopic biopsy (overall accuracy, 18 of 20 [90%]).

CONCLUSIONS. Endoscopic treatment of focal low-grade TCC of the upper urinary

tract is feasible and safe, provided that vigilant follow-up and endoscopic surveil-

lance are performed. Endoscopic biopsy provides accurate information regarding

tumor grade. Cancer 2003;98:55– 60. © 2003 American Cancer Society.

KEYWORDS: ureteroscopy, transitional cell carcinoma, kidney neoplasm, endos-copy, upper urinary tract.

Primary transitional cell carcinoma (TCC) of the upper urinary tractoften presents a diagnostic and therapeutic challenge. This ma-

lignancy is relatively uncommon compared with similar tumors in thebladder; it accounts for 5–10% of all renal tumors and less than 5% ofall urothelial tumors.1 The gold standard treatment for upper tractTCC is nephroureterectomy with excision of a cuff of bladder.2 How-ever, in select patients for whom renal sparing surgery is mandatedsecondary to a solitary kidney, renal insufficiency, bilateral disease, orhigh surgical risk, or patients with small, low-grade tumors, endo-scopic management can be a reasonable alternative.1

Because of the development over time of rigid and flexible uret-eroscopes with smaller diameters, along with the development ofimproved optics, the diagnosis and staging of upper urinary tracttumors has improved significantly. Like lower urinary tract endos-copy, ureterorenoscopy can be used for both diagnostic and thera-

55

© 2003 American Cancer Society

DOI 10.1002/cncr.11446

peutic purposes. Accurate biopsy techniques coupledwith effective tumor ablation methods, which can in-volve various energy sources, can be used to treatupper tract tumors. In contrast with staging in thelower urinary tract, however, accurate clinical stagingof the upper tract is limited to the grade of the tumor,because depth of invasion cannot be assessed.

Over the last 15 years, a number of investigatorshave reported results of ureteroscopic and percutane-ous treatment of upper tract tumors.2–15 In the currentstudy, we retrospectively reviewed our experiencewith endoscopic management of upper urinary tractTCC and evaluated the accuracy of endoscopic biopsyin determining tumor grade in the subset of patientswho underwent open surgical excision.

MATERIALS AND METHODSBetween 1987 and 2001, 50 patients underwent endo-scopic biopsy of a unilateral upper urinary tract tumor(46 ureteroscopic and 4 percutaneous). Patient ageranged from 26 to 93 years, with a mean of 74 years.Seventeen patients had a solitary kidney. All patientshad undergone diagnostic evaluation that included anintravenous pyelogram, cystoscopy, retrograde py-elography, and urine cytology, and each patient wassuspected of having an upper tract tumor based oncytology results or a filling defect that appeared onradiographic studies. For most patients, a biopsy ofthe lesion was obtained, and then resection, laser co-agulation, or electrofulguration was performed in thesame setting.

TechniquesPatients were evaluated and treated in the operatingroom under general or regional anesthesia. For eachpatient, cystoscopy was performed, urine cytology wassent, suspicious bladder lesions were noted and biop-sied, and retrograde pyelograms were obtained usinga cone-tip catheter. The technique of ureteroscopicbiopsy, resection, and fulguration is described in de-tail elsewhere.1 A small-caliber rigid ureteroscope (6.9F or 7.5 F) is used to inspect the intramural and distalureter. A floppy tipped guide wire (0.025 or 0.035 in.) isthen inserted through the instrument and situatedbelow the suspected tumor. If possible a second wireis placed as a “safety” wire to allow removal of theureteroscope with safe reinsertion. The 7.4F flexibleureteroscope is then placed over the wire and theupper ureter and intrarenal collecting system are in-spected. If the ureter does not permit the passage ofthe rigid instrument, a wire is inserted and a balloondilating catheter is used to dilate the intramural por-tion of the ureter.

Once the ureteroscope is advanced to the sus-pected lesion, a biopsy is performed during the initial

pass so the lesion is not traumatized or avulsed inad-vertently during instrument passage. A 3F cup biopsyforceps or alternatively a 1.9F or 2.4F stone basket isused to snare an exophytic tumor. Close visual inspec-tion of each calyx is performed with the aid of fluo-roscopy to delineate the intrarenal collecting system.After specimens are obtained for pathological analysis,the remaining tumor(s) are treated with a 2F bugbeeelectrode or preferably a Holmium:YAG or Neodyni-um:YAG laser. In some instances where the tumorswere large, repeat procedures were performed to com-pletely ablate the tumor.

Four patients were treated percutaneously, thetechnique for which has been previously described.9

Patients were followed by close endoscopic surveil-lance of their upper urinary tract at 3– 4 month inter-vals.

RESULTSFigure 1 shows the distribution of patients who un-derwent endoscopic biopsy and follow-up. Of the 50patients who underwent endoscopic biopsy of uppertract tumors, 9 were referred back to their consultingurologist and could not be reached for follow-up in-formation. Eleven patients underwent ureterectomyor nephroureterectomy shortly following endoscopicbiopsy based on evidence of high-grade disease or atphysician discretion. Endoscopic biopsy accuratelypredicted the grade of the tumor in 10 of 11 patients(91%). One patient who was found to have grade 2TCC of the ureter on endoscopic biopsy was upgradedto grade 3 on the open surgical specimen. Table 1summarizes the pathological correlation between en-doscopic biopsy and the open surgical resection spec-

FIGURE 1. Management of patients with upper urinary tract transitional cell

carcinoma.

56 CANCER July 1, 2003 / Volume 98 / Number 1

imen. The remaining 30 patients underwent endo-scopic ablation of their primary tumor (26ureteroscopic, 4 percutaneous). Median follow-up inthis group was 31 months, respectively (range 4 –106months). Seventeen of these patients had a solitarykidney. On initial biopsy 7 tumors were evaluated asbeing low-grade (grade 1 or 1–2), 6 were intermediategrade (grade 2) and 14 were high grade (grade 2–3, 3,or CIS). Each patient underwent an average of 6.7endoscopic procedures. Average time to first recur-rence was 7 months. Seven of the 30 patients had aprior history of superficial bladder TCC, while 6 pa-tients developed bladder tumors at an average of 29.3months after initial endoscopic treatment of their up-per tract tumors.

Ten of the 30 patients (33%) underwent open sur-gical resection of the tumor bearing kidney and/orureter during the follow-up period (6 ureterectomies,3 nephroureterectomies, and 1 partial nephrectomy).In 9 of these patients, the open surgical resection wasperformed within 2 months of the last endoscopicbiopsy. One patient underwent a distal ureterectomy 1year after the last endoscopic treatment secondary toa stricture which proved to be invasive TCC. The bi-opsy grade of the tumor correlated with the opensurgical specimen in 8 of the 9 cases (89%) (Table 2).

Six patients had progression of their tumor duringfollow-up (1 with grade 1, 5 with grade 2 or higher,including CIS). One of these patients (1/6) whose ini-tial tumor was grade 2, developed a metastatic neckmass which was resected and found to be TCC. Sheunderwent 4 cycles of MVAC (methotrexate, vinblas-tine, adriamycin and cisplatin) and had no evidence ofdisease anywhere on last follow-up 6 months later.Three (3/6) underwent open surgical resection and arecurrently alive without progression. The other 2 (2/6)are not surgical candidates secondary to advanced ageand are currently alive undergoing continued endo-scopic surveillance and treatment. During the follow-up period, one patient with initial Gr 2–3, T2 diseasedied from recurrent disease after 48 months and 6others died from other causes. Table 2 summarizes thepatient characteristics and outcomes. Eleven patientsreceived adjuvant topical treatment in the form ofBCG, thiotepa, or mitomycin at various times in thecourse of their follow-up, the technique for which hasbeen previously described.16 The small number of pa-tients treated and the inconsistent use of adjuvanttherapy prevents statistical analysis or determinationof its added benefit.

Complications were limited to the development ofureteral strictures. Overall 5 patients developed ure-

TABLE 1Pathologic Correlation of Endoscopic Biopsy Results with Open Resection Results

Patientno. Date Procedures Endoscopic findings Pathology Correlation?

1 9/24/99 Ureteroscopy, laser fulguration of tumor Multiple bladder tumors, � 1/2 incollecting system

Gr 3/4 TCC bladder,kidney

Yes

11/19/99 Nephroureterectomy Gr 3/4 TCC N02 5/17/99 Ureteroscopy, laser fulguration of tumor TCC at mouth of midcalyceal infundibulum Gr 3/4 TCC Yes

6/6/99 Nephroureterectomy Gr 3/4 TCC renal pelvis N03 4/11/91 Ureteroscopy, biopsy Gr 2–3 T1 TCC renal pelvis Yes

4/15/91 Nephroureterectomy Gr 2–3 T1 TCC renal pelvis4 10/11/90 Ureteroscopy, biopsy 3-cm tumor in lower ureter Gr 2–3 TCC Yes

10/23/90 Ureteral resection, psoas reimplant Gr 3 TCC T2N05 1/18/90 Ureteroscopy, biopsy 2–3-cm TCC in renal pelvis Gr 3/4 TCC T1 Yes

2/1/90 Nephroureterectomy Gr 3/4 TCC T3N06 6/16/00 Ureteroscopy, laser resection of tumor 5–6-cm midureteral tumor, Gr 2/4 Gr 2/4 TCC No (upgraded)

7/17/00 Ureterectomy, ileal ureter Gr 3/4 TCC N07 2/2/89 Ureteroscopy, biopsy Gr 1 TCC Yes

3/9/89 Nephroureterectomy Gr 1 TCC TaN08 9/4/90 Ureteroscopy, biopsy Solid tumor in renal pelvis Gr 3/4 TCC Yes

9/21/90 Nephroureterectomy Gr 3/4 TCC T1N0 TCCpelvis

9 2/5/92 Ureteroscopy, biopsy of renal pelvic tumor Extensive tumor in renal pelvis Gr 3/4 TCC Yes2/10/92 Nephroureterectomy Gr 3/4 TCC T3N1

10 10/26/88 Ureteroscopy, biopsy of renal pelvic tumor Gr 3/4 TCC Yes11/9/88 Nephroureterectomy Gr 3/4 TCC T3

11 11/1/93 Ureteroscopy with biopsy mass Lower pole infundibular mass High-grade TCC Yes12/17/93 Nephroureterectomy Invasive high-grade TCC

N1

Gr: Grade; TCC: transitional cell carcinoma.

Endoscopic Management of Upper Tract TCC/Daneshmand et al. 57

TABL

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Prog

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Initi

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kidn

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No.o

fpr

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Firs

tre

curr

ence

(mos

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Tim

eto

blad

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deve

lopm

ent

(mos

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1U

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opy

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——

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deN

182

44

192

Ure

tero

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——

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1N

533

624

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tero

scop

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Ure

ter

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yr,s

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——

Gr1

T1to

Gr2

T3Gr

1N

275

74

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303

103

95

Ure

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——

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220

20

—6

Ure

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COPD

—Gr

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45

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59—

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320

30

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612

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43—

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45

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82U

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(Gr2

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106

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972

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23

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520

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Gr3/

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586

64

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85—

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80—

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teral strictures over the course of their follow-up.Three patients underwent distal ureterectomy and apsoas hitch ureteral reimplant, 2 of whom proved tohave invasive disease on final surgical pathologicalexamination. One of these patients is alive with noevidence of upper tract recurrence and the other re-mained tumor free for the subsequent 72 months andthen was lost to follow-up. One of the 5 patients wastreated endoscopically and one other treated percuta-neously died of coronary artery disease 3 months afterdiagnosis of high grade disease.

DISCUSSIONThe gold standard treatment for upper tract TCC hasbeen nephroureterectomy with excision of a cuff ofbladder. However, advances in percutaneous and en-doscopic techniques have allowed more conservativenephron sparing procedures for patients who havesolitary kidneys or are otherwise not ideal candidatesfor open surgical resection. In the early 1980’s uret-eroscopic and percutaneous techniques became morerefined allowing access to the upper urinary tract andcalyceal system. With the development of uretero-scopic biopsy instruments as well as small diameter,flexible laser fibers (holmium:YAG and neodynium:YAG), accurate diagnosis and treatment of small tu-mors has become feasible and safe.17 Since the earlyreports of endoscopic management of these tumors,3

numerous investigators have reported on the long-term outcome of ureteroscopic and percutaneoustreatment of upper tract urothelial tumors.4 –15 Morerecently, there has been an interest in the endoscopictreatment of select patients with normal contralateralkidneys.11

It is imperative that patients are properly selectedfor endoscopic treatment. In contrast to cystoscopictechniques where biopsy yields accurate staging of thetumor, ureteroscopic biopsy of upper tract tumorsusually does not yield deep or full-thickness sample toallow microscopic determination of invasion. Stagingis therefore limited to the grade of the tumor. There isa well established correlation between tumor gradeand stage. Murphy et al. reported that 47 of 49 patients(96%) with grade 1 upper tract transitional carcinomaalso had stage 1 disease.18 In 1997, Keeley reported onthe accuracy of ureteroscopic biopsies compared toopen surgical specimens of upper tract transitionalcarcinoma.19 Of 30 low or moderate grade uretero-scopic specimens 26 (86.6%) had a low stage (Ta or T1)tumor. In contrast, 8 of 12 high grade ureteroscopicspecimens (66.7%) had invasive tumor (stage T2 or T3)in the surgical specimens. Low grade upper urinarytract TCC carries an excellent 5 year survival rate ap-proaching 100%.20 In our series, endoscopic biopsyaccurately predicted the grade of the tumor in 8 of 9

patients who had open resection of their tumor within2 months of the last biopsy and 10 of 11 patients whohad open resection following initial endoscopic biopsy(overall 18/20, 95%).

In the endoscopically treated group, the mean andmedian follow up was 38 and 31 months. During thisperiod 27 of the 30 patients (90%) had tumor recur-rence in the upper tract. There were an average of 3.3recurrences with an average of 6.7 procedures per-formed per patient (Table 3). Time to 1st recurrencewas 9.3 months for the low grade (grade 1–2) tumorsand 6 months for the high grade tumors (grade 3– 4).In their series of long term follow up of endoscopicallytreated upper tract TCC, Elliott et al. found that sev-enteen of 44 patients (38.6%) had local tumor recur-rence with mean time to recurrence of 12.8 months.8

Chen and Bagley observed that 15 of 23 patients (65%)treated ureteroscopically had multiple recurrencesover an average follow-up of 35 months.11 Most recur-rences in our series were very small, most of whichmeasured less than 5mm. There were no recurrencesseen in the intramural ureter in the subset of patientswho required balloon dilation for access.

It is important to note that 14 patients in thisseries started with high grade disease on initial biopsy.These patients had either severe co-morbid disease oradvanced age obviating a more conservative ap-proach. One of the patients managed endoscopicallywho was found to have a high grade tumor on biopsydied from recurrent disease after 48 months. This pa-tient had invasive disease on biopsy and the prohibi-tive anesthesia risk prevented optimal managementwith nephroureterectomy. Overall, six patients hadprogression of disease during follow-up. One of thesepatients who was found to have no evidence of diseaseendoscopically presented with a neck mass thatproved to be metastatic TCC one month later. Afterreceiving a 4 cycles of chemotherapy this patient iscurrently alive and has no evidence of disease at 6month follow-up. Despite progression 2 patients con-tinue to be followed endoscopically secondary to ad-vanced age (85 and 91 years of age). The remaining 3patients have had open resection of their tumor andare currently alive.

A major concern with any conservative surgicaltreatment is increasing the risk of recurrence. Zinckeand Neves demonstrated an overall 5 year survival rateof 64% in open surgical treatment of upper tractTCC.21 In the endoscopically treated group, the 5 yearsurvival was 57%. Elliott et al. also reported a 5 yeardisease free rate of 57%.8 The recurrence rate in ourseries for small tumors is low enough to warrant thesafety of this modality of treatment. It should be notedhowever that 2 of the 5 patients who developed ure-teral strictures were found to have invasive disease on

Endoscopic Management of Upper Tract TCC/Daneshmand et al. 59

open surgical specimens. Perhaps the finding of astricture should warrant a more aggressive approachto management.

There does not appear to be a higher risk of de-veloping bladder tumors in those treated endoscopi-cally who did not have a prior history of bladder TCC.Keely et al. reported a 33% rate of bladder tumors inthose without a history of bladder cancer.9 In ourseries, 6 patients (26%) developed de novo bladdertumors at a mean of 29.3 months after initial endo-scopic treatment of upper tract tumors. Seven otherpatients had a prior history of bladder tumors. A the-oretical risk of endoscopic treatment of upper tractTCC is local or systemic spread of tumor from py-elovenous or pyelolymphatic backflow. The finding ofa distant nodal metastasis in one of our patients whohad an intermediate grade tumor and was otherwisefree of disease in the urinary tract may possibly beexplained by this iatrogenic phenomenon. Certainlyall efforts are made to limit high-pressure flow duringthe procedure.

Eleven patients received adjuvant topical treat-ment after resection of their tumor at various timesduring the course of management. Significant urothe-lial dwell time remains a challenge in topical therapyof the upper tract. Although the techniques and safetyhave been well established, its value remains theoret-ical and anecdotal at this time.22,23 Data from prospec-tive randomized trials are necessary to determine itstrue efficacy.

Endoscopic biopsy of upper tract urothelial tu-mors can provide accurate information regarding tu-mor grade and guide in subsequent treatment deci-sion. Endoscopic treatment of focal, low-gradesuperficial TCC of the upper urinary tract is feasibleand safe provided vigilant follow-up and surveillanceis performed. It is essential that patients understandthat there are frequent recurrences and that lifetimefollow-up is necessary. Low grade tumors are bestsuited for endoscopic treatment however in high riskpatients or those with solitary kidneys, it offers a prac-tical alternative that has reasonable results.

REFERENCES1. Huffman, JL. Management of upper tract transitional cell

carcinomas. In: Vogelzang NJ, Scardino PT, Shipley WU,Coffey DS, editors. Genitourinary oncology, 2nd edition.Philadelphia: Lippincott Williams & Wilkins, 2000:367–383.

2. Mazeman, E. Tumours of the upper urinary calyces, renalpelvis and ureter. Eur Urol. 1976;2:120 –126.

3. Huffman JL, Bagley DH, Lyon ES, Morse MJ, Herr HW,Whitmore WF Jr. Endoscopic diagnosis and treatment ofupper-tract urothelial tumors. A preliminary report. Cancer.1985;55:1422–1428.

4. Huffman JL. Ureteroscopic management of transitional cell

carcinoma of the upper urinary tract. Urol Clin N Am. 1988;15:419 – 424.

5. Grossman HB, Schwartz SL, Konnac JW. Ureteroscopictreatment of urothelial carcinoma of the ureter and renalpelvis. J Urol. 1992;148:275–277.

6. Engelmyer EL, Belis, JA. Long-term ureteroscopic manage-ment of low-grade transitional cell carcinoma of the upperurinary tract. Tech Urol. 1996;2:113–116.

7. Martınez-Pineiro JA, Matres JG, Martınez-Pineiro L. En-dourological treatment of upper tract urothelial carcinomas:analysis of a series of 59 tumors. J Urol. 1996;156:377–385.

8. Elliott DS, Blute ML, Patterson DE, Bergstralh EJ, Segura JW.Long-term follow-up of endoscopically treated upper uri-nary tract transitional cell carcinoma. Urology. 1996;47:819 –825.

9. Keely FX, Bibbo M, Bagley DH. Ureteroscopic treatment andsurveillance of upper urinary tract transitional cell carci-noma. J Urol. 1997;157:1560 –1565.

10. Clark PE, Streem SB, Geisinger MA. 13-year experience withpercutaneous management of upper tract transitional cellcarcinoma. J Urol. 1999;161:772–776.

11. Chen GL, Bagley DH. Ureteroscopic management of uppertract transitional cell carcinoma in patients with normalcontralateral kidneys. J Urol. 2000;164:1173–1176.

12. Lee D, Trabulsi E, McGinnis D, Strup S, Gomella LG, BagleyD. Totally endoscopic management of upper tract transi-tional-cell carcinoma. J Endourol. 2002;16:37– 41.

13. Elliott DS, Segura JW, Lightner D, Patterson DE, Blute ML. Isnephroureterectomy necessary in all cases of upper tracttransitional cell carcinoma? Long-term results of conserva-tive endourologic management of upper tract transitionalcell carcinoma in individuals with a normal contralateralkidney. Urology. 2001;58:174 –178.

14. Stoller ML, Gentle DL, McDonald MW, et al. Endoscopicmanagement of upper tract urothelial tumors. Tech Urol.1997;3:152–157.

15. Jarrett TW. Endoscopic management of upper urinary tractTCC. Contemp Urol. 1998;10:61–72.

16. Eastham JA, Huffman JL. Technique of mitomycin C instil-lation in the treatment of upper urinary tract urothelialtumors. J Urol. 1993;150:324 –325.

17. Grasso M, Bagley D. Small diameter, actively deflectable,flexible ureteropyeloscopy. J Urol. 1998;160:1648 –1653.

18. Keeley FX, Kulp DA, Bibbo M. Diagnostic accuracy of uret-eroscopic biopsy in upper tract transitional cell carcinoma.J Urol. 1997;157:33–37.

19. Murphy DM, Zincke H, Furlow WL. Primary grade 1 transi-tional cell carcinoma of the renal pelvis and ureter. J Urol.1980;123:629 – 631.

20. Reitelman C, Sawczuk IS, Olsson CA. Prognostic variables inpatients with transitional cell carcinoma of the renal pelvisand proximal ureter. J Urol. 1987;138:1144 –1145.

21. Zincke H, Neves RJ. Feasability of conservative surgery fortransitional cell cancer of the upper urinary tract. Urol ClinNorth Am. 1984;11:717–724.

22. Keely FX, Bagley DH. Adjuvant mitomycin C following en-doscopic treatment of upper tract transitional cell carci-noma. J Urol. 1997;158:2074 –2077.

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60 CANCER July 1, 2003 / Volume 98 / Number 1