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URETEROSCOPIC MANAGEMENT OF PATIENTS WITH UPPER TRACT TRANSITIONAL CELL CARCINOMA
MINIMALLY INVASIVE SURGERY OF T H E KIDNEY A l'I
0094-0143/00 $15.00
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URETEROSCOPIC MANAGEMENT OF PATIENTS WITH UPPER TRACT TRANSITIONAL CELL CARCINOMA Dean G. Assimos, MD, M. Craig Hall, MD, and Jeffrey H. Martin, MD
Advances in technology and surgical skills have fostered the development of endoscopic treatment for select patients with transitional cell carcinoma (TCC) of the upper urinary tract. Percutaneous and ureteroscopic tumor resection has become a viable treatment option for a disease in which nephroureterectomy and removal of a bladder cuff surrounding the ipsilateral ureteral orifice is considered standard therapy. An overview of this approach is presented herein. EPIDEMIOLOGY
Transitional cell carcinoma of the upper urinary tract accounts for 5% of urothelial malignancies and 10% of renal tum0rs.4~Upper tract disease develops in 2%to 4% of patients with TCC of the bladder."3 TCC may arise anywhere in the renal collecting system, including the calices, infundibula, and renal pelvis. Tumors in the renal collecting system are more prevalent than tumors in the ureter? Seventy percent of TCC occurring in the ureter is found in the distal end in comparison with 20% in the middle ureter and 10% in the proximal ureter.8 Risk factors for this disease include cigarette smoking; occupational exposure (e.g., aromatic amines, coal,
tar, coke, and asphalt); TCC of the lower urinary tract, especially in the presence of multifocal disease with tumor location in the vicinity of the ureteral orifice or in the prostate; concomitant vesicoureteral reflux and bladder tumors; Balkan nephropathy; ureteral diverticula; analgesic nephropathy; exposure to thorium dioxide (thorotrast); nephrolithiasis; and Lynch syndrome II.43In approximately 50% of individuals with upper tract TCC, recurrent disease develops in another area of the urinary tract, most commonly in the bladder, which indicates that this disorder is a panurothelial di~ease.4~ The risk for contralateral disease is low, approximately 1%to 3%, with most tumors being asynchronous.8 RENAL-SPARING OPEN SURGERY
Experience with open surgical parenchymal-conserving approaches in individuals with upper tract TCC who have anatomically or functionally solitary kidneys, bilateral tumors, or renal insufficiency indicates that nephroureterectomy may not be necessary for all patients with this disorder. Renal-sparing surgery was first proposed by Vest6' for ureteral tumors in 1945 and by Ferris and DentI7 for renal pelvic malignancies in 1948. The re-
From the Department of Urology, Wake Forest University School of Medicine, Winston-Salem, North Carolina ~~
UROLOGIC CLINICS OF NORTH AMERICA
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VOLUME 27 * NUMBER 4 NOVEMBER 2000
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sults obtained with open surgical resection of ureterectomy, probably owing to micrometadistal ureteral tumors and ureteral reimplanstatic disease. Other potential predictive factation support this concept. M a ~ e m a nre~ ~ tors have been assessed, including patient ported on a large series of patients with upper age, DNA ploidy, and small vessel invasion; 36, 39 however, their utility remains tract TCC treated with various open surgical operations. Excellent results were achieved in the group with lower ureteral tumors treated with distal ureterectomy including a bladder RATIONALE FOR ENDOSCOPIC cuff and reimplantation. Johnson and BaTHERAPY baian3' achieved similar results in six patients having noninvasive, low-grade distal ureteral The rationale for considering endoscopic therapy in patients having superficial bladder tumors treated in this manner. Five of the six patients remained disease free at a mean tumors or upper tract TCC is similar in that the whole tumor is potentially removable follow-up of 3.7 years. In one patient, a proximal ureteral tumor developed on the ipsilatwith this approach. Nevertheless, there are era1 side 26 months postoperatively, and the important differences. The wall thickness of patient underwent nephroureterectomy, rethe ureter and renal collecting system are maining disease free after this inter~ention.~] much thinner than in the lower urinary tract, The results with segmental ureteral resection increasing the risk for perforation and limfor proximal ureteral tumors have not been as iting local pathologic staging. Access to the good. M a ~ e m a nreported ~~ on 50 individuals lower urinary tract is typically straightfortreated in this fashion. Recurrence developed ward, whereas endoscopy of the upper tract in the ipsilateral ureter or bladder in 50%. is more challenging, creating a potential Acceptable results have been achieved with drawback for therapy and follow-up. The latopen surgical removal of tumors in the renal ter factor is especially important because collecting system. Ziegelbaum and colthese patients are at significant risk for recurleagues@treated 13 patients in this manner; 1 rence in the ipsilateral upper urinary tract.29 individual died in the postoperative period, and 9 of the remaining 12 patients remained DIAGNOSIS OF UPPER TRACT disease free 4 to 72 months after tumor resecTRANSITIONAL CELL CARCINOMA t i ~ nOther . ~ ~ investigators have noted higher recurrence rates with local surgical resection Radiography is still the primary diagnostic of renal pelvic tumors, ranging from 45% to 650/o.42. 6i avenue for TCC of the upper urinary tract. Filling defects are present on intravenous pyelography in 50% to 75% of cases (Fig. 1). PROGNOSTIC FACTORS Retrograde pyelography is indicated when better definition of the collecting system or Data concerning the natural history and ureteral anatomy is needed, when patients prognosis of upper tract TCC following surgicannot receive intravenous contrast owing to cal therapy are limited. Most reports have allergic problems or renal dysfunction, or been retrospective reviews of small singlewhen there is nonvisualization of the collectcenter experiences. Furthermore, few series ing system on intravenous pyelography. CT is mainly used for evaluating patients with have systematically analyzed patterns of refilling defects in the renal collecting system lapse and the influence of prognostic factors demonstrated on the aforementioned studies. on recurrence and survival. Grade and stage This modality is accurate in distinguishing have been identified to predict recurrence and radiolucent stones [80-250 Hounsfield units survival when data are analyzed with univar(HU)] from soft-tissue masses such as TCC iate analysis23*27; however, only stage was found to be a significant prognostic factor (10-70 HU).43 when multivariate analysis was employed in Cytologic testing can be performed to help three recently reported studies.2,12, 23 This confirm the diagnosis. Voided urine cytology finding is expected because the majority of is not very sensitive when there is a lownoninvasive tumors are low grade, whereas grade tumor. The sensitivity for low-grade invasive lesions are usually high grade. Patumors ranges from 10% to 40%, whereas the sensitivity for high-grade lesions is approxitients with invasive tumors (T2-T4) are at risk for distant failure even after radical nephromately 80%.'o Treatment based on a positive
URETEROSCOPIC MANAGEMENT OF UPPER TRACT TRANSITIONAL CELL CARCINOMA
753
Figure 1. A, Intravenous pyelogram with filling defect in renal pelvis. This is due to transitional cell carcinoma. 6, Postoperative intravenous pyelogram after ureteroscopic tumor removal.
voided urine cytology should only be undertaken if TCC is proved to be absent from the lower urinary tract. Obtaining urine from the collecting system via ureteral catheterization improves the diagnostic yield, but reported sensitivities with this approach are only 65% to 78%. Saline washings seem to amplify the diagnostic yield with this technique.43 Brush biopsy of upper tract lesions directed through a ureteral catheter can also be used to establish a diagnosis. This technique was introduced by Gill and The sensitivity and specificity of this sampling method have been reported to be 72% to 91% and 88% to 94%' re~pectively.'~, 53 Retrograde ureterorenoscopy permits visual inspection of the lesion and tissue sampling. Streem and reported that the accuracy of this approach for determining the etiology of upper tract filling defects was 83%. Blute and colleagues9were able to confirm the diagnosis of upper tract TCC endoscopically in 88% of their patients. Bagley and Rivas4 were able to establish the correct diagnosis in 62 of 62 patients with upper urinary tract filling defects evaluated with retrograde flexible ureteroscopy, including 25 patients with TCC. Endoscopic examination of the ureter can be performed with a smallcaliber semirigid ureteroscope or a flexible ureteroscope. The latter instrument is prefera-
ble for inspection of the renal collecting system. Retrograde flexible ureterorenoscopy can also be attempted in patients with cutaneous urinary diversions. This procedure is accomplished by initially examining the conduit with a flexible cystoscope and cannulating the targeted ureteral orifice with a guidewire with subsequent manipulation of the wire into the renal collecting system under fluoroscopic guidance. The flexible instrument is then passed over the guidewire, and visual inspection of the ureter and collecting system is conducted. Fluoroscopy is used to facilitate diagnostic ureteroscopy. Contrast can be injected through the ureteroscope to opacify the collecting system and to ensure that it has been entirely inspected. Normal saline is used as an irrigant for diagnostic ureteroscopy. It is instilled by gravity and not by a pressurized system because the latter could lead to pyelovenous and pyelolymphatic backflow and tumor dissemination. The collecting system should also be decompressed intermittently by aspiration to limit intrapelvic pressure. There are several methods for tissue sampling once the lesion is visualized. A piece of the tumor can be entrapped and removed with a stone basket or using a small-caliber flexible biopsy device. Brush biopsy and saline irrigation of the lesion for cytologic analysis can also be performed under direct vi-
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sion. Bian and associates7reported on the use of these various tissue sampling techniques in 62 patients. Cytologic analysis demonstrated findings consistent with malignancy in 23 patients, suspicious for malignancy in 9, atypical in 19, and negative in 8. The cytologic sample was unsatisfactory in three patients. Histologic confirmation of malignancy was achieved in 28 of 32 patients with malignant or suspicious findings, in 2 of 19 with atypical findings, in none of 8 with normal findings, and in none of 3 with unsatisfactory cytologies7 Tumor grade can usually be assessed with these techniques. Keeley and demonstrated tumor grade in 82.4% of cases. They have found good correlation between tumor grade determined from ureteroscopically harvested cytologic and tissue specimens and tumor grade derived from histologic analysis of open surgical material. Twenty-seven of 30 patients with low- or intermediate-grade specimens and 11 of 12 with high-grade ureteroscopic specimens had this diagnosis confirmed with histologic analysis of the open surgical tissue.34 Tumor dissemination can occur during diagnostic ureteroscopy. Lim and colleagues40 reported on a patient with grade 2 TCC of the renal pelvis confined to the mucosa who underwent diagnostic ureteroscopy before nephroureterectomy and in whom tumor cells were found in the submucosal vessels and lymphatics as well as the surrounding renal parenchyma. They theorized that these pathologic findings may have been the result of migration of tumor cells to these areas occurring during the ureteroscopic procedure. Long-term follow-up was not provided in this report.40Hendin and associateszsperformed a retrospective study in an attempt to determine whether diagnostic retrograde ureteroscopy had an adverse effect on patients with upper TCC treated with distal ureterectomy or nephroureterectomy. One group of patients underwent diagnostic ureteroscopy and the other did not. Tumor grade and stage were similar in both groups. Disease-free and overall survival were similar in both Kulp and B a g l e ~reported ~~ on 13 patients who underwent one to four endoscopic treatments for upper tract TCC and who were ultimately subjected to nephroureterectomy because of recurrent or persistent disease. Pathologic analysis of the nephroureterectomy specimens demonstrated no clumps of tumor cells in the submucosal vascular and lymphatic spaces or in the adjacent renal pa-
renchyma. Only one patient had disease progression at a mean follow-up of 33.5 months, and this progression was anticipated because the patient had a high-grade T3 The results of these two studies indicate that diagnostic and therapeutic ureteroscopy do not have an adverse effect in patients with upper tract TCC who are eventually subjected to standard open surgical procedures. Antegrade ureterorenoscopy is reserved for patients in whom the diagnosis cannot be established with conventional techniques. This group includes individuals in whom the ureter or collecting system is not accessible via a retrograde approach. There is a risk of tumor seeding of the nephrostomy tract with this procedure; therefore, it should only be employed in these highly selected cases. TUMOR STAGING
Computed tomography can be helpful in determining the local extent of tumor, especially if there is high-volume disease involving the renal parenchyma, regional lymph nodes, periureteral soft tissue, renal vein, and adjacent structures. Hepatic metastases can also be identified. CT does not readily distinguish between low-volume TA, T2, and T3 tumors, nor does it predictably identify multifocal lesions.43Computed tomographic virtual endoscopy of the renal collecting system may prove to be a more sensitive and accurate staging method. A group of investigators recently reported encouraging results using this radiographic method for evaluating patients with collecting system tumors.59 Other clinicians have reported that endoluminal ultrasonography is a promising technique for staging ureteral tumor^.^ Chest radiography should be performed to assess for pulmonary metastases. Bone scans should be obtained selectively in patients who have skeletal symptoms or elevated serum alkaline phosphatase. INDICATIONS FOR ENDOSCOPIC THERAPY
The standard indications for endoscopic therapy include a solitary kidney, significant contralateral renal dysfunction, chronic renal insufficiency, bilateral upper tract tumors, and medical comorbidity precluding an open surgical approach. Endoscopic therapy may
URETEROSCOPIC MANAGEMENT OF UPPER TRACT TRANSITIONAL CELL CARCINOMA
be considered for palliation in select patients with metastatic disease. Lee and associates3s recently proposed that percutaneous removal of low- to intermediate-grade collecting system tumors is a viable option for the standard patient providing that the individual is willing to abide by a strict long-term, follow-up protocol. This recommendation was based on their retrospective analysis of patients with collecting system tumors who were treated with percutaneous resection or nephroureterectomy. Disease-specific survival rates for patients with low- or intermediate-grade tumors were similar for patients undergoing endoscopic and open A randomized prospective study needs to be conducted to demonstrate the merits of such an approach before it is universally embraced. TECHNIQUES
Retrograde ureteroscopic tumor removal can be accomplished using rigid, semirigid, or flexible instrumentation. Ureteroscope selection is based on tumor size and location and anatomic considerations. A flexible ureteroscope is usually employed for the treatment of collecting system tumors, although some renal pelvic tumors can be accessed with rigid instrumentation. Gravity irrigation with normal saline is used unless electrofulguration is contemplated; glycine is the preferred solution in such cases. A guidewire should be manipulated up the ureter and into the renal collecting systems at the beginning of the procedure. A hydrophilic guidewire should be used if electroresection is contemplated because, unlike standard guidewires, it will not conduct electrical current. Tumors can initially be removed with a biopsy forceps, grasping device, or stone basket. The base of the tumor can then be fulgurated with an electrode or with laser energy. Rigid ureteroresectoscopes are available for tumor removal. These large instruments (12to 13-F) should be mainly used for resection of larger distal ureteral tumors. Great care must be taken not to perforate the ureter during the resection. A variety of lasers have been used for tumor ablation, including the neodymium:YAG laser. Schmeller and Hofstetter50 and others have reported successful results when this laser is used for upper tract tumors. The laser energy is directed at the tumor tangentially in a noncontact fashion until the tumor blanches
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and penetrates to a depth of 5 to 6 mm. The coagulated surface of tumors 5 mm or larger can be removed with a biopsy forceps or grasping device to expose the deeper portions of the lesion for more treatment. Animal experimentation and clinical experience indicate that a power setting of 20 W administered at an interval of no longer than 3 seconds should be used in the upper urinary tract.56 Johnson30has described use an argon laser for the treatment of ureteral tumors. This laser is used in a contact mode with a power setting of 5 W. It is best suited for smaller tumors because tissue penetration is only 1 mm. The Ho1mium:YAG laser can be used for tumor ablation with a recommended energy setting of 1 J delivered at 10 HzZ1It can also be used in combination with the neodymium:YAG laser for larger vascular tumors when the latter device is first employed, after which the resultant devascularized tumor is resected down to a smooth surface. Circumferential treatment of the ureter should be avoided when using laser ablation or electrocautery resection because it would promote stricture formation. An internalized stent is inserted at the termination of the procedure and left in place for at least 2 to 3 weeks or longer if further endoscopic ablation or adjuvant therapy is contemplated. This duration of stenting is recommended because there is normally transient ureteral obstruction after such treatments. ADJUNCTIVE THERAPY
Patients who have undergone ureteroscopic tumor ablation can receive bacillus CalmetteGuerin therapy by placement of an internalized ureteral stent and bladder instillation in the Trendelenburg position. Pate1 and F u c ~ s ~ ~ describe the use of a transvesical single J stent for delivery of bacillus Calmette-Guerin. One must ensure that there is no extravasation before embarking on retrograde delivery of adjuvant therapy. Other agents that have been used for adjuvant therapy include mitomycin C, thiotepa, and interferon-alpha 2.41Eastham and Huffman14reported on the percutaneous instillation of dilute mitomycin C (40 mg in 1000 mL saline) at 50 mL/hour for 24 hours. Intrapelvic pressure was monitored to prevent it from exceeding 15 cm of water. Eastham and Huffman have also described a retrograde instillation technique in which 5 mg of this drug is
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delivered to patients on the first and second postoperative days.I4 Keeley and B a g l e ~re-~ ~ ported the retrograde instillation of a higher dose of mitomycin C (40 mg) in the early postoperative period. The efficacy of adjuvant therapy has not yet been established. Jarrett and reported that adjuvant bacillus Calmette-Guerin therapy did not improve survival in patients subjected to percutaneous tumor ablation. Martinez-Pineiro and colleague^^^ found that recurrence rates were lower in patients subjected to either ureteroscopic or percutaneous tumor removal who received adjuvant bacillus Calmette-Guerin or mitomycin C therapy, 12.5% and 14.2%, respectively, when compared with patients treated with thiotepa (60%); however, they also found that the local recurrence rates were similar in patients who received and did not receive adjuvant therapy.41Both of these investigations were retrospective studies. Prospective randomized trials are needed to establish the merits of adjuvant therapy. RESULTS
The results of ureteroscopic treatment of patients with upper tract TCC are summarized in Table 1. Bladder tumors developed in 41% of the patients in these series after ureteroscopic resection. Local recurrences developed in 35% of the patients with collecting system tumors and in 32% of subjects with ureteral tumors treated with this approach. Nephroureterectomy was performed on 7.4% of these individuals for management of suspected local recurrence or disease progression. COMPLICATIONS
Patients undergoing ureteroscopic tumor removal are at increased risk for complications when compared with subjects undergoing ureteroscopy for stone removal or diagnostic reasons. Perforation can occur, especially when deeper tumor resection is undertaken. This complication usually can be managed with placement of an internalized ureteral stent. The reported stricture rate has 33, 41 This risk is ranged from 5% to 13'%0.'~, probably greater in patients having larger tumors, especially when circumferentially located. The risk of stricture may also be greater
when tumor ablation is undertaken with electrocautery or a neodymium:YAG laser. The use of a Holmium laser for tumor resection may decrease the risk of stricture because this device has a more limited tissue penetration. Keeley and reported that no strictures developed in 22 patients undergoing ureteroscopic tumor resection with this laser. One must rule out recurrent disease at the stricture site or other areas of the ureter or collecting system before embarking on endourologic or open surgical correction of the stricture. Andrews and Segura' reported a unique complication, intrarenal explosion and resultant extravasation, during ureteroscopic tumor fulguration. It was thought that this complication might have been caused by the combustion of hydrogen and oxygen; therefore, it is important to prevent air from entering the collecting system when electrofulguration is contemplated.' SURVEILLANCE
Patients with upper tract TCC who are subjected to endoscopic therapy are at significant risk for recurrent disease in the ipsilateral collecting system, ureter, and bladder; therefore, close follow-up is mandatory. Cystoscopy, urine cytologic testing, and an upper tract evaluation should be performed every 3 months until the patient is tumor free for 1 year. After this period, the patient should be followed up using similar techniques every 6 months. Flexible ureterorenoscopy is the preferred method of upper urinary tract evaluation in these cases because the sensitivity of retrograde pyelography and intravenous pyelography for diagnosing recurrences is poor. Keeley and reported that the sensitivity of retrograde pyelography for detecting recurrent upper tract tumors was only 25%. CARCINOMA IN SlTU OF THE UPPER URINARY TRACT
Carcinoma in situ of the upper urinary tract has usually been diagnosed by cytologic examination of saline washings obtained from this area. There should be no endoscopic or radiographic evidence of tumor in the ureter or collecting system. One must rule out contamination by a lower urinary tract source as the cause of the positive cytology. Biopsy of
Grasso et al, 19992’
Keeley et al, 199733
Martinez-Pineiro et al, 199641
Elliott et al. 199615
Bales et al, 19955 Engelmyer and Belis, 199616
Kaufman et al, 199332 Gaboardi et al, 1994ly
Tasca et al. 1992M
Papadopoulos et al, 1990d5 Johnson, 199230 Grossman et al, 1992”
Schmeller and Hofstetter, 1989”
Blute. 1989’
Huffman et al, 19852H
Series
14 (15 renal units)
1 6 5 13 8 8 1 3 1 7 1 5 9 3 15 3 4 6 16 21 7 21 23 18
Number of Patients
u (8)
cs U cs U cs U cs U cs (7)
U U
cs
U U
cs U cs
U U U U U
cs U cs
Location
Nd:YAC and Holmium, electroresection
Electroresection and Nd:YAG Fulguration and Nd:YAG Fulguration and Nd:YAG Fulguration and Nd:YAG Fulguration a n d / o r Nd:YAG Nd:YAG or fulguration Nd:YAG or electroresection Fulguration, Nd:YAG or Holmium
Nd:YAG Nd:YAG
Nd:YAG Nd:YAG and fulguration Electroresection and Nd:YAG Argon laser Nd:YAG Nd:YAG Forceps
Electroresection Electroresection Nd:YAG and fulguration
Technique
Table 1. URETEROSCOPIC TREATMENT OF PATIENTS WITH UPPER URINARY TRACT TUMORS
4
1 1 1 2 2 1 0 1 0 5 0 1 1 3 5 1 2 5 8 9 2 6 3 5 4
Recurrent UTT
2
2
15
NS
19
NS NS NS NS NS NS NS NS
4
0
3
NS
NS
4
NS NS 0
Recurrent BT
N
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ASSIMOS et a1
the collecting system is a more definitive method of establishing this diagnosis. The natural history of this disorder has not been characterized, and appropriate treatment has not been established. Nevertheless, attempts at treatment have been undertaken. Bacillus Calmette-Guerin has been administered to patients using retrograde and antegrade delivery techniques. Sharpe and associa t e P treated 11 patients (12 renal units) with upper tract carcinoma in situ by weekly retrograde instillation of this agent for 6 weeks. Eight renal units had normalization of urinary cytology at a median of 36 months’ follow-up. Studer and colleagues58treated eight patients (ten renal units) with at least six courses of bacillus Calmette-Guerin administered percutaneously. Cytologies became negative and remained so in seven renal units during an 18- to 28-month follow-up period. Yokogi and associate^^^ administered bacillus Calmette-Guerin either by a retrograde or antegrade route to five patients (eight renal units). Cytologies became negative in five renal units and remained negative for 10 to 46 months following treatment. Systemic immunotherapy has also been used to treat patients with this disorder. Sarosdy and c011eagues~~ treated 24 patients with presumed upper tract carcinoma in situ with bropirimine. Ten of 21 evaluable subjects (48%) had negative upper tract cytologies at short-term follow-up.
SUMMARY
Endoscopic therapy for the management of upper urinary tract TCC is mainly indicated for patients with an anatomically or functionally solitary kidney, renal insufficiency, bilateral tumors, or severe medical comorbidity. It may be a reasonable alternative to distal ureterectomy with bladder-cuff resection in individuals with low-grade superficial distal ureteral tumors. Although use of this approach has been suggested for treating standard patients with low-grade, low-stage collecting system tumors, this recommendation should not be embraced until more supporting evidence is generated.38 The efficacy of adjuvant therapy for the prevention of recurrent or progressive disease needs to be defined. If current adjuvant strategies prove ineffective, alternative ones will need to be developed. It is anticipated that advancements in endoscopic technology will facilitate
the performance of this type of surgery in the future.
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URETEROSCOPIC MANAGEMENT OF UPPER TRACT TRANSITIONAL CELL CARCINOMA treatment of upper urinary tract tumors with Nd:YA<; laser. J Endourol 8:3741, 1994 20. Gill WB, Lu CT, Thomsen S: Retrograde brushing: A new technique for obtaining histologic and cytologic material from ureteral, renal pelvic and renal caliceal lesions. J Urol 109573-578, 1973 21. Grasso M, Fraiman M, Levine M: Ureteroscopic diagnosis and treatment of upper urinary tract urothelial malignancies. Urology 54:240-246, 1999 22. Grossman HB, Schwartz SL, Konnak JW: Ureteroscopic treatment of urothelial carcinoma of the ureter and renal pelvis. J Urol 148:275-277, 1992 23. Hall MC, Womack S, Sagalowsky AI, et al: Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: A 30-year experience in 252 patients. Urology 52:594401, 1998 24. Hasui Y, Nishi S, Kitada S, et al: The prognostic significance of vascular invasion in upper urinary tract transitional cell carcinoma, J Urol 148:17831785, 1992 25. Hendin BN, Streem SB, Levin HS, et al: Impact of diagnostic ureteroscopy on long-term survival in patients with upper tract transitional cell carcinoma. J Urol 161:783-785, 1999 26. Huang A, Low RK, White RD: Nephrostomy tract tumor seeding following percutaneous manipulation of a ureteral carcinoma, J Urol 153:1041-1042, 1995 27. Huben RP, Mounzer AM, Murphy GP: Tumor grade and stage as prognostic variables in upper tract urothelial tumors. Cancer 62:20162020, 1988 28. Huffman JL, Bagley DH, Lyon ES, et al: Endoscopic diagnosis and treatment of upper tract urothelial tumors: A preliminary report. Cancer 55:1422-1428, 1985 29. Jarrett TW, Sweetser PM, Weiss GH, et al: Percutaneous management of transitional cell carcinoma of the renal collecting system: 9-Year experience. J Urol 154:1629-1635, 1995 30. Johnson DE: Treatment of distal ureteral tumors using endoscopic argon photoirradiation. Lasers Surg Med 12:490493, 1992 31. Johnson DE, Babaian RJ: Conservative surgical management for noninvasive distal ureteral carcinoma. Urology 13:365-367, 1979 32. Kaufman RP Jr, Carson CC 111, Carson CC: Ureteroscopic management of transitional cell carcinoma of the ureter using the neodymium:YAG laser. Lasers Surg Med 13:625428, 1993 33. Keeley FX, Bibbo M, Bagley DH: Ureteroscopic treatment and surveillance of upper tract transitional cell carcinoma. J Urol 157:1560-1565, 1997 34. Keeley FX, Kulp DA, Bibbo M, et al: Diagnostic accuracy of ureteroscopic biopsy in upper tract transitional cell carcinoma. J Urol 157:33-37, 1997 35. Keeley FX Jr, Bagley DH: Adjuvant mitomycin C following endoscopic treatment of upper tract transitional cell carcinoma. J Urol 158:2074-2077, 1997 36. Krogh J, Kvist E, Rye B: Transitional cell carcinoma of the upper urinary tract: Prognostic variables and post-operative recurrences. Br J Urol 67:32-36, 1991 37. Kulp DA, Bagley DH: Does flexible ureteropyeloscopy promote local recurrence of transitional cell carcinoma? J Endourol 8:111, 1994 38. Lee BR, Jabbour ME, Marshall FF, et al: 13-Year survival comparison of percutaneous and open nephroureterectomy approaches for management of transitional cell carcinoma of renal collecting system: Equivalent outcomes. J Endourol 13:289, 1999 39. Lee SH, Lin JSN, Chow NH, et al: Prognostic factors
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of primary transitional cell carcinoma of the upper urinary tract. Eur Urol 29:266-271, 1996 40. Lim DJ, Shattuck MC, Cook WA: Pyelovenous lymphatic migration of transitional cell carcinoma following flexible ureterorenoscopy. J Urol 149:109-111, 1993 41. Martinez-Pineiro JA, Garcia MJ, Matres JG, et al: Endourological treatment of upper tract urothelial carcinomas: Analysis of a series of 59 tumors. J Urol 1.561377-385, 1996 42. Mazeman E: Tuniours of the upper urinary tract calyces, renal pelvis and ureter. Eur Urol 2:120-128, 1976 43. Messing EM, Catalona W: Urothelial tumors of the urinary tract. It7 Walsh I’C, Retik AB, Vaughan ED Jr, et al (eds): Campbell’s Urology, ed 7, vol 3. Philadelphia, WB Saunders, 1998, pp 2383-2393 44. Nakada SY, Clayman R V Percutaneous electrovaporization of upper tract transitional cell carcinoma in patients with functionally solitary kidneys. Urology 461751-755, 1995 45. Papadopoulos I, Wirth B, Berterman H, et al: Diagnosis and treatment of urothelial tumors by ureteropyeloscopy. J Endourol 45-60, 1990 46. Patel A, Fuchs GJ: New techniques for the administration of topical adjuvant therapy after endoscopic ablation of upper urinary tract transitional cell carcinoma. J Urol 159:71-75, 1998 47. Patel A, Soonawalla P, Shepherd SF, et al: Long-term outcome after percutaneous treatment of transitional cell carcinoma of the renal pelvis. J Urol 155:868874, 1996 48. Plancke HRF, Stribjos WEM, Delaere KPJ: Percutaneous endoscopic treatment of urothelial tumours of the renal pelvis. Br J Urn1 75736739, 1995 49. Sarosdy MF, Pisters LL, Carroll PR, et al: Bropirimine immunotherapy of upper urinary tract carcinoma in situ. Urology 482-32, 1996 50. Schmeller NT, Hofstetter AG: Laser treatment of ureteral tumors. J Urol 141:840-843, 1989 51. Sharma NK, Nicol A, Powell C S Track infiltration following percutaneous resection of renal pelvic transitional cell carcinoma. Br J Urol 73597-598, 1994 52. Sharpe JR, Duffy G, Chin JL: Intrarenal bacillus Calmette-Guerin therapy for upper urinary tract carcinoma in situ. J Urol 149:457460, 1993 53. Sheline M, Amendola MA, Pollack HM, et al: Fluoroscopically guided retrograde brush biopsy in the diagnosis of transitional cell carcinoma of the upper urinary tract: Results in 45 patients. AJR Am J Roentgenol 153:313, 1989 54. Shepherd SF, Patel A, Bidmead AM, et al: Nephrostomy tract brachytherapy following percutaneous resection of transitional cell carcinoma of the renal pelvis. Clin Oncol 7385-387, 1995 55. Smith AD, Orihuela E, Crowley AR: Percutaneous management of renal pelvic tumors: A treatment option in selected cases. J Urol 137852-856, 1987 56. Smith JA Jr: Neodymium: YAG laser photoradiation of canine ureters: An analysis of penetration depth and subsequent healing. American College of Surgeons Surgical Forum 34596698, 1983 57. Streem SB, Pontes JE, Novick AC, et al: Ureteropyeloscopy in the evaluation of upper tract filling defects. J Urol 136:388, 1986 58. Studer UE, Casanove G, Kraft R, et al: Percutaneous bacillus Calmette-Guerin perfusion of the upper urinary tract for carcinoma in situ. J Urol 142:975-977, 1989 59. Takebayashi S, Hosaka M, Takase K, et al: Computerized tomography nephroscopic images of renal pelvic carcinoma. J Urol 162:315-318, 1999
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60. Tasc'i A, Zattoni F, Garbeglio A, et al: Endourologic
trcatmcnt of transitional cell carcinoma of the upper urinary tract. J Endourol 6253-256, 1992 61. Vest SA: Conservative surgery in certain benign tumors of the ureter. J Urol 53:97-120, 1945 Percutane62. Woodhouse CRJ, Kellett MJ, Bloom HJG: ous renal surgery and local radiotherapy in the management of renal pelvic transitional cell carcinoma. Br J Urol 58:245-249, 1986
63. Yokogi H,Wada Y, Mizutani M, et al: Bacillus Calmette-Guerin perfusion therapy for carcinoma in situ of the upper urinary tract. Br J Urol 7767&679, 1996 64. Ziegelbaum M, Novick AC, Streem SB, et al: Conservative surgery for transitional cell carcinoma of the renal pelvis. J Urol 138:1146-1149, 1987 65. Zincke H,Neves RJ: Feasibility of conservative surgery for transitional cell carcinoma of the upper urinary tract. Urol Clin North Am 11:717, 1984
Address reprint requesfs to Dean G . Assimos, MD Department of Urology Wake Forest University School of Medicine Medical Center Blvd Winston-Salem, NC 27157-1094 e-mail: [email protected]
0094-0143/00 $15.00
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.OO
URETEROSCOPIC MANAGEMENT OF PATIENTS WITH UPPER TRACT TRANSITIONAL CELL CARCINOMA Dean G. Assimos, MD, M. Craig Hall, MD, and Jeffrey H. Martin, MD
Advances in technology and surgical skills have fostered the development of endoscopic treatment for select patients with transitional cell carcinoma (TCC) of the upper urinary tract. Percutaneous and ureteroscopic tumor resection has become a viable treatment option for a disease in which nephroureterectomy and removal of a bladder cuff surrounding the ipsilateral ureteral orifice is considered standard therapy. An overview of this approach is presented herein. EPIDEMIOLOGY
Transitional cell carcinoma of the upper urinary tract accounts for 5% of urothelial malignancies and 10% of renal tum0rs.4~Upper tract disease develops in 2%to 4% of patients with TCC of the bladder."3 TCC may arise anywhere in the renal collecting system, including the calices, infundibula, and renal pelvis. Tumors in the renal collecting system are more prevalent than tumors in the ureter? Seventy percent of TCC occurring in the ureter is found in the distal end in comparison with 20% in the middle ureter and 10% in the proximal ureter.8 Risk factors for this disease include cigarette smoking; occupational exposure (e.g., aromatic amines, coal,
tar, coke, and asphalt); TCC of the lower urinary tract, especially in the presence of multifocal disease with tumor location in the vicinity of the ureteral orifice or in the prostate; concomitant vesicoureteral reflux and bladder tumors; Balkan nephropathy; ureteral diverticula; analgesic nephropathy; exposure to thorium dioxide (thorotrast); nephrolithiasis; and Lynch syndrome II.43In approximately 50% of individuals with upper tract TCC, recurrent disease develops in another area of the urinary tract, most commonly in the bladder, which indicates that this disorder is a panurothelial di~ease.4~ The risk for contralateral disease is low, approximately 1%to 3%, with most tumors being asynchronous.8 RENAL-SPARING OPEN SURGERY
Experience with open surgical parenchymal-conserving approaches in individuals with upper tract TCC who have anatomically or functionally solitary kidneys, bilateral tumors, or renal insufficiency indicates that nephroureterectomy may not be necessary for all patients with this disorder. Renal-sparing surgery was first proposed by Vest6' for ureteral tumors in 1945 and by Ferris and DentI7 for renal pelvic malignancies in 1948. The re-
From the Department of Urology, Wake Forest University School of Medicine, Winston-Salem, North Carolina ~~
UROLOGIC CLINICS OF NORTH AMERICA
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VOLUME 27 * NUMBER 4 NOVEMBER 2000
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sults obtained with open surgical resection of ureterectomy, probably owing to micrometadistal ureteral tumors and ureteral reimplanstatic disease. Other potential predictive factation support this concept. M a ~ e m a nre~ ~ tors have been assessed, including patient ported on a large series of patients with upper age, DNA ploidy, and small vessel invasion; 36, 39 however, their utility remains tract TCC treated with various open surgical operations. Excellent results were achieved in the group with lower ureteral tumors treated with distal ureterectomy including a bladder RATIONALE FOR ENDOSCOPIC cuff and reimplantation. Johnson and BaTHERAPY baian3' achieved similar results in six patients having noninvasive, low-grade distal ureteral The rationale for considering endoscopic therapy in patients having superficial bladder tumors treated in this manner. Five of the six patients remained disease free at a mean tumors or upper tract TCC is similar in that the whole tumor is potentially removable follow-up of 3.7 years. In one patient, a proximal ureteral tumor developed on the ipsilatwith this approach. Nevertheless, there are era1 side 26 months postoperatively, and the important differences. The wall thickness of patient underwent nephroureterectomy, rethe ureter and renal collecting system are maining disease free after this inter~ention.~] much thinner than in the lower urinary tract, The results with segmental ureteral resection increasing the risk for perforation and limfor proximal ureteral tumors have not been as iting local pathologic staging. Access to the good. M a ~ e m a nreported ~~ on 50 individuals lower urinary tract is typically straightfortreated in this fashion. Recurrence developed ward, whereas endoscopy of the upper tract in the ipsilateral ureter or bladder in 50%. is more challenging, creating a potential Acceptable results have been achieved with drawback for therapy and follow-up. The latopen surgical removal of tumors in the renal ter factor is especially important because collecting system. Ziegelbaum and colthese patients are at significant risk for recurleagues@treated 13 patients in this manner; 1 rence in the ipsilateral upper urinary tract.29 individual died in the postoperative period, and 9 of the remaining 12 patients remained DIAGNOSIS OF UPPER TRACT disease free 4 to 72 months after tumor resecTRANSITIONAL CELL CARCINOMA t i ~ nOther . ~ ~ investigators have noted higher recurrence rates with local surgical resection Radiography is still the primary diagnostic of renal pelvic tumors, ranging from 45% to 650/o.42. 6i avenue for TCC of the upper urinary tract. Filling defects are present on intravenous pyelography in 50% to 75% of cases (Fig. 1). PROGNOSTIC FACTORS Retrograde pyelography is indicated when better definition of the collecting system or Data concerning the natural history and ureteral anatomy is needed, when patients prognosis of upper tract TCC following surgicannot receive intravenous contrast owing to cal therapy are limited. Most reports have allergic problems or renal dysfunction, or been retrospective reviews of small singlewhen there is nonvisualization of the collectcenter experiences. Furthermore, few series ing system on intravenous pyelography. CT is mainly used for evaluating patients with have systematically analyzed patterns of refilling defects in the renal collecting system lapse and the influence of prognostic factors demonstrated on the aforementioned studies. on recurrence and survival. Grade and stage This modality is accurate in distinguishing have been identified to predict recurrence and radiolucent stones [80-250 Hounsfield units survival when data are analyzed with univar(HU)] from soft-tissue masses such as TCC iate analysis23*27; however, only stage was found to be a significant prognostic factor (10-70 HU).43 when multivariate analysis was employed in Cytologic testing can be performed to help three recently reported studies.2,12, 23 This confirm the diagnosis. Voided urine cytology finding is expected because the majority of is not very sensitive when there is a lownoninvasive tumors are low grade, whereas grade tumor. The sensitivity for low-grade invasive lesions are usually high grade. Patumors ranges from 10% to 40%, whereas the sensitivity for high-grade lesions is approxitients with invasive tumors (T2-T4) are at risk for distant failure even after radical nephromately 80%.'o Treatment based on a positive
URETEROSCOPIC MANAGEMENT OF UPPER TRACT TRANSITIONAL CELL CARCINOMA
753
Figure 1. A, Intravenous pyelogram with filling defect in renal pelvis. This is due to transitional cell carcinoma. 6, Postoperative intravenous pyelogram after ureteroscopic tumor removal.
voided urine cytology should only be undertaken if TCC is proved to be absent from the lower urinary tract. Obtaining urine from the collecting system via ureteral catheterization improves the diagnostic yield, but reported sensitivities with this approach are only 65% to 78%. Saline washings seem to amplify the diagnostic yield with this technique.43 Brush biopsy of upper tract lesions directed through a ureteral catheter can also be used to establish a diagnosis. This technique was introduced by Gill and The sensitivity and specificity of this sampling method have been reported to be 72% to 91% and 88% to 94%' re~pectively.'~, 53 Retrograde ureterorenoscopy permits visual inspection of the lesion and tissue sampling. Streem and reported that the accuracy of this approach for determining the etiology of upper tract filling defects was 83%. Blute and colleagues9were able to confirm the diagnosis of upper tract TCC endoscopically in 88% of their patients. Bagley and Rivas4 were able to establish the correct diagnosis in 62 of 62 patients with upper urinary tract filling defects evaluated with retrograde flexible ureteroscopy, including 25 patients with TCC. Endoscopic examination of the ureter can be performed with a smallcaliber semirigid ureteroscope or a flexible ureteroscope. The latter instrument is prefera-
ble for inspection of the renal collecting system. Retrograde flexible ureterorenoscopy can also be attempted in patients with cutaneous urinary diversions. This procedure is accomplished by initially examining the conduit with a flexible cystoscope and cannulating the targeted ureteral orifice with a guidewire with subsequent manipulation of the wire into the renal collecting system under fluoroscopic guidance. The flexible instrument is then passed over the guidewire, and visual inspection of the ureter and collecting system is conducted. Fluoroscopy is used to facilitate diagnostic ureteroscopy. Contrast can be injected through the ureteroscope to opacify the collecting system and to ensure that it has been entirely inspected. Normal saline is used as an irrigant for diagnostic ureteroscopy. It is instilled by gravity and not by a pressurized system because the latter could lead to pyelovenous and pyelolymphatic backflow and tumor dissemination. The collecting system should also be decompressed intermittently by aspiration to limit intrapelvic pressure. There are several methods for tissue sampling once the lesion is visualized. A piece of the tumor can be entrapped and removed with a stone basket or using a small-caliber flexible biopsy device. Brush biopsy and saline irrigation of the lesion for cytologic analysis can also be performed under direct vi-
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sion. Bian and associates7reported on the use of these various tissue sampling techniques in 62 patients. Cytologic analysis demonstrated findings consistent with malignancy in 23 patients, suspicious for malignancy in 9, atypical in 19, and negative in 8. The cytologic sample was unsatisfactory in three patients. Histologic confirmation of malignancy was achieved in 28 of 32 patients with malignant or suspicious findings, in 2 of 19 with atypical findings, in none of 8 with normal findings, and in none of 3 with unsatisfactory cytologies7 Tumor grade can usually be assessed with these techniques. Keeley and demonstrated tumor grade in 82.4% of cases. They have found good correlation between tumor grade determined from ureteroscopically harvested cytologic and tissue specimens and tumor grade derived from histologic analysis of open surgical material. Twenty-seven of 30 patients with low- or intermediate-grade specimens and 11 of 12 with high-grade ureteroscopic specimens had this diagnosis confirmed with histologic analysis of the open surgical tissue.34 Tumor dissemination can occur during diagnostic ureteroscopy. Lim and colleagues40 reported on a patient with grade 2 TCC of the renal pelvis confined to the mucosa who underwent diagnostic ureteroscopy before nephroureterectomy and in whom tumor cells were found in the submucosal vessels and lymphatics as well as the surrounding renal parenchyma. They theorized that these pathologic findings may have been the result of migration of tumor cells to these areas occurring during the ureteroscopic procedure. Long-term follow-up was not provided in this report.40Hendin and associateszsperformed a retrospective study in an attempt to determine whether diagnostic retrograde ureteroscopy had an adverse effect on patients with upper TCC treated with distal ureterectomy or nephroureterectomy. One group of patients underwent diagnostic ureteroscopy and the other did not. Tumor grade and stage were similar in both groups. Disease-free and overall survival were similar in both Kulp and B a g l e ~reported ~~ on 13 patients who underwent one to four endoscopic treatments for upper tract TCC and who were ultimately subjected to nephroureterectomy because of recurrent or persistent disease. Pathologic analysis of the nephroureterectomy specimens demonstrated no clumps of tumor cells in the submucosal vascular and lymphatic spaces or in the adjacent renal pa-
renchyma. Only one patient had disease progression at a mean follow-up of 33.5 months, and this progression was anticipated because the patient had a high-grade T3 The results of these two studies indicate that diagnostic and therapeutic ureteroscopy do not have an adverse effect in patients with upper tract TCC who are eventually subjected to standard open surgical procedures. Antegrade ureterorenoscopy is reserved for patients in whom the diagnosis cannot be established with conventional techniques. This group includes individuals in whom the ureter or collecting system is not accessible via a retrograde approach. There is a risk of tumor seeding of the nephrostomy tract with this procedure; therefore, it should only be employed in these highly selected cases. TUMOR STAGING
Computed tomography can be helpful in determining the local extent of tumor, especially if there is high-volume disease involving the renal parenchyma, regional lymph nodes, periureteral soft tissue, renal vein, and adjacent structures. Hepatic metastases can also be identified. CT does not readily distinguish between low-volume TA, T2, and T3 tumors, nor does it predictably identify multifocal lesions.43Computed tomographic virtual endoscopy of the renal collecting system may prove to be a more sensitive and accurate staging method. A group of investigators recently reported encouraging results using this radiographic method for evaluating patients with collecting system tumors.59 Other clinicians have reported that endoluminal ultrasonography is a promising technique for staging ureteral tumor^.^ Chest radiography should be performed to assess for pulmonary metastases. Bone scans should be obtained selectively in patients who have skeletal symptoms or elevated serum alkaline phosphatase. INDICATIONS FOR ENDOSCOPIC THERAPY
The standard indications for endoscopic therapy include a solitary kidney, significant contralateral renal dysfunction, chronic renal insufficiency, bilateral upper tract tumors, and medical comorbidity precluding an open surgical approach. Endoscopic therapy may
URETEROSCOPIC MANAGEMENT OF UPPER TRACT TRANSITIONAL CELL CARCINOMA
be considered for palliation in select patients with metastatic disease. Lee and associates3s recently proposed that percutaneous removal of low- to intermediate-grade collecting system tumors is a viable option for the standard patient providing that the individual is willing to abide by a strict long-term, follow-up protocol. This recommendation was based on their retrospective analysis of patients with collecting system tumors who were treated with percutaneous resection or nephroureterectomy. Disease-specific survival rates for patients with low- or intermediate-grade tumors were similar for patients undergoing endoscopic and open A randomized prospective study needs to be conducted to demonstrate the merits of such an approach before it is universally embraced. TECHNIQUES
Retrograde ureteroscopic tumor removal can be accomplished using rigid, semirigid, or flexible instrumentation. Ureteroscope selection is based on tumor size and location and anatomic considerations. A flexible ureteroscope is usually employed for the treatment of collecting system tumors, although some renal pelvic tumors can be accessed with rigid instrumentation. Gravity irrigation with normal saline is used unless electrofulguration is contemplated; glycine is the preferred solution in such cases. A guidewire should be manipulated up the ureter and into the renal collecting systems at the beginning of the procedure. A hydrophilic guidewire should be used if electroresection is contemplated because, unlike standard guidewires, it will not conduct electrical current. Tumors can initially be removed with a biopsy forceps, grasping device, or stone basket. The base of the tumor can then be fulgurated with an electrode or with laser energy. Rigid ureteroresectoscopes are available for tumor removal. These large instruments (12to 13-F) should be mainly used for resection of larger distal ureteral tumors. Great care must be taken not to perforate the ureter during the resection. A variety of lasers have been used for tumor ablation, including the neodymium:YAG laser. Schmeller and Hofstetter50 and others have reported successful results when this laser is used for upper tract tumors. The laser energy is directed at the tumor tangentially in a noncontact fashion until the tumor blanches
755
and penetrates to a depth of 5 to 6 mm. The coagulated surface of tumors 5 mm or larger can be removed with a biopsy forceps or grasping device to expose the deeper portions of the lesion for more treatment. Animal experimentation and clinical experience indicate that a power setting of 20 W administered at an interval of no longer than 3 seconds should be used in the upper urinary tract.56 Johnson30has described use an argon laser for the treatment of ureteral tumors. This laser is used in a contact mode with a power setting of 5 W. It is best suited for smaller tumors because tissue penetration is only 1 mm. The Ho1mium:YAG laser can be used for tumor ablation with a recommended energy setting of 1 J delivered at 10 HzZ1It can also be used in combination with the neodymium:YAG laser for larger vascular tumors when the latter device is first employed, after which the resultant devascularized tumor is resected down to a smooth surface. Circumferential treatment of the ureter should be avoided when using laser ablation or electrocautery resection because it would promote stricture formation. An internalized stent is inserted at the termination of the procedure and left in place for at least 2 to 3 weeks or longer if further endoscopic ablation or adjuvant therapy is contemplated. This duration of stenting is recommended because there is normally transient ureteral obstruction after such treatments. ADJUNCTIVE THERAPY
Patients who have undergone ureteroscopic tumor ablation can receive bacillus CalmetteGuerin therapy by placement of an internalized ureteral stent and bladder instillation in the Trendelenburg position. Pate1 and F u c ~ s ~ ~ describe the use of a transvesical single J stent for delivery of bacillus Calmette-Guerin. One must ensure that there is no extravasation before embarking on retrograde delivery of adjuvant therapy. Other agents that have been used for adjuvant therapy include mitomycin C, thiotepa, and interferon-alpha 2.41Eastham and Huffman14reported on the percutaneous instillation of dilute mitomycin C (40 mg in 1000 mL saline) at 50 mL/hour for 24 hours. Intrapelvic pressure was monitored to prevent it from exceeding 15 cm of water. Eastham and Huffman have also described a retrograde instillation technique in which 5 mg of this drug is
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ASSIMOS et al
delivered to patients on the first and second postoperative days.I4 Keeley and B a g l e ~re-~ ~ ported the retrograde instillation of a higher dose of mitomycin C (40 mg) in the early postoperative period. The efficacy of adjuvant therapy has not yet been established. Jarrett and reported that adjuvant bacillus Calmette-Guerin therapy did not improve survival in patients subjected to percutaneous tumor ablation. Martinez-Pineiro and colleague^^^ found that recurrence rates were lower in patients subjected to either ureteroscopic or percutaneous tumor removal who received adjuvant bacillus Calmette-Guerin or mitomycin C therapy, 12.5% and 14.2%, respectively, when compared with patients treated with thiotepa (60%); however, they also found that the local recurrence rates were similar in patients who received and did not receive adjuvant therapy.41Both of these investigations were retrospective studies. Prospective randomized trials are needed to establish the merits of adjuvant therapy. RESULTS
The results of ureteroscopic treatment of patients with upper tract TCC are summarized in Table 1. Bladder tumors developed in 41% of the patients in these series after ureteroscopic resection. Local recurrences developed in 35% of the patients with collecting system tumors and in 32% of subjects with ureteral tumors treated with this approach. Nephroureterectomy was performed on 7.4% of these individuals for management of suspected local recurrence or disease progression. COMPLICATIONS
Patients undergoing ureteroscopic tumor removal are at increased risk for complications when compared with subjects undergoing ureteroscopy for stone removal or diagnostic reasons. Perforation can occur, especially when deeper tumor resection is undertaken. This complication usually can be managed with placement of an internalized ureteral stent. The reported stricture rate has 33, 41 This risk is ranged from 5% to 13'%0.'~, probably greater in patients having larger tumors, especially when circumferentially located. The risk of stricture may also be greater
when tumor ablation is undertaken with electrocautery or a neodymium:YAG laser. The use of a Holmium laser for tumor resection may decrease the risk of stricture because this device has a more limited tissue penetration. Keeley and reported that no strictures developed in 22 patients undergoing ureteroscopic tumor resection with this laser. One must rule out recurrent disease at the stricture site or other areas of the ureter or collecting system before embarking on endourologic or open surgical correction of the stricture. Andrews and Segura' reported a unique complication, intrarenal explosion and resultant extravasation, during ureteroscopic tumor fulguration. It was thought that this complication might have been caused by the combustion of hydrogen and oxygen; therefore, it is important to prevent air from entering the collecting system when electrofulguration is contemplated.' SURVEILLANCE
Patients with upper tract TCC who are subjected to endoscopic therapy are at significant risk for recurrent disease in the ipsilateral collecting system, ureter, and bladder; therefore, close follow-up is mandatory. Cystoscopy, urine cytologic testing, and an upper tract evaluation should be performed every 3 months until the patient is tumor free for 1 year. After this period, the patient should be followed up using similar techniques every 6 months. Flexible ureterorenoscopy is the preferred method of upper urinary tract evaluation in these cases because the sensitivity of retrograde pyelography and intravenous pyelography for diagnosing recurrences is poor. Keeley and reported that the sensitivity of retrograde pyelography for detecting recurrent upper tract tumors was only 25%. CARCINOMA IN SlTU OF THE UPPER URINARY TRACT
Carcinoma in situ of the upper urinary tract has usually been diagnosed by cytologic examination of saline washings obtained from this area. There should be no endoscopic or radiographic evidence of tumor in the ureter or collecting system. One must rule out contamination by a lower urinary tract source as the cause of the positive cytology. Biopsy of
Grasso et al, 19992’
Keeley et al, 199733
Martinez-Pineiro et al, 199641
Elliott et al. 199615
Bales et al, 19955 Engelmyer and Belis, 199616
Kaufman et al, 199332 Gaboardi et al, 1994ly
Tasca et al. 1992M
Papadopoulos et al, 1990d5 Johnson, 199230 Grossman et al, 1992”
Schmeller and Hofstetter, 1989”
Blute. 1989’
Huffman et al, 19852H
Series
14 (15 renal units)
1 6 5 13 8 8 1 3 1 7 1 5 9 3 15 3 4 6 16 21 7 21 23 18
Number of Patients
u (8)
cs U cs U cs U cs U cs (7)
U U
cs
U U
cs U cs
U U U U U
cs U cs
Location
Nd:YAC and Holmium, electroresection
Electroresection and Nd:YAG Fulguration and Nd:YAG Fulguration and Nd:YAG Fulguration and Nd:YAG Fulguration a n d / o r Nd:YAG Nd:YAG or fulguration Nd:YAG or electroresection Fulguration, Nd:YAG or Holmium
Nd:YAG Nd:YAG
Nd:YAG Nd:YAG and fulguration Electroresection and Nd:YAG Argon laser Nd:YAG Nd:YAG Forceps
Electroresection Electroresection Nd:YAG and fulguration
Technique
Table 1. URETEROSCOPIC TREATMENT OF PATIENTS WITH UPPER URINARY TRACT TUMORS
4
1 1 1 2 2 1 0 1 0 5 0 1 1 3 5 1 2 5 8 9 2 6 3 5 4
Recurrent UTT
2
2
15
NS
19
NS NS NS NS NS NS NS NS
4
0
3
NS
NS
4
NS NS 0
Recurrent BT
N
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ASSIMOS et a1
the collecting system is a more definitive method of establishing this diagnosis. The natural history of this disorder has not been characterized, and appropriate treatment has not been established. Nevertheless, attempts at treatment have been undertaken. Bacillus Calmette-Guerin has been administered to patients using retrograde and antegrade delivery techniques. Sharpe and associa t e P treated 11 patients (12 renal units) with upper tract carcinoma in situ by weekly retrograde instillation of this agent for 6 weeks. Eight renal units had normalization of urinary cytology at a median of 36 months’ follow-up. Studer and colleagues58treated eight patients (ten renal units) with at least six courses of bacillus Calmette-Guerin administered percutaneously. Cytologies became negative and remained so in seven renal units during an 18- to 28-month follow-up period. Yokogi and associate^^^ administered bacillus Calmette-Guerin either by a retrograde or antegrade route to five patients (eight renal units). Cytologies became negative in five renal units and remained negative for 10 to 46 months following treatment. Systemic immunotherapy has also been used to treat patients with this disorder. Sarosdy and c011eagues~~ treated 24 patients with presumed upper tract carcinoma in situ with bropirimine. Ten of 21 evaluable subjects (48%) had negative upper tract cytologies at short-term follow-up.
SUMMARY
Endoscopic therapy for the management of upper urinary tract TCC is mainly indicated for patients with an anatomically or functionally solitary kidney, renal insufficiency, bilateral tumors, or severe medical comorbidity. It may be a reasonable alternative to distal ureterectomy with bladder-cuff resection in individuals with low-grade superficial distal ureteral tumors. Although use of this approach has been suggested for treating standard patients with low-grade, low-stage collecting system tumors, this recommendation should not be embraced until more supporting evidence is generated.38 The efficacy of adjuvant therapy for the prevention of recurrent or progressive disease needs to be defined. If current adjuvant strategies prove ineffective, alternative ones will need to be developed. It is anticipated that advancements in endoscopic technology will facilitate
the performance of this type of surgery in the future.
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Address reprint requesfs to Dean G . Assimos, MD Department of Urology Wake Forest University School of Medicine Medical Center Blvd Winston-Salem, NC 27157-1094 e-mail: [email protected]