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Keywords:

  • biopsy;
  • bladder neoplasms;
  • cystoscopy;
  • cytology;
  • neoplasm staging

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References

Objectives:  To investigate whether random bladder, and prostatic urethral biopsies and individual upper tract cytologies (restaging) provide useful clinical information in addition to cystoscopy and bladder cytology in assessing initial intravesical therapy response for high-grade non-muscle invasive bladder cancer.

Methods:  We retrospectively reviewed records of all patients who underwent restaging at our institution after treatment for high-grade non-muscle invasive bladder cancer (Ta, T1 and Tis) between January 2000 and October 2009. A total of 78 patients undergoing 116 consecutive restagings were included. The presence of intravesical cancer at restaging was assessed by cystoscopy, bladder wash cytology and random bladder biopsies, whereas ureteral and prostatic urethral disease was determined using upper tract barbotage cytology and prostatic urethral biopsies.

Results:  Indication for intravesical treatment was carcinoma in situ in 86, high-grade T1 in 16 and high-grade Ta in 14 cases. A total of 48 patients had primary disease and 68 had recurrence. Overall, 59 of 116 (50.9%) restagings showed positive bladder or prostatic biopsy and/or a positive cytology localized to the upper tract. Of the total number of recurrences, 12.9% (15 of 116) showed a negative cystoscopy and negative bladder cytology, and would have been missed on routine surveillance. A total of 23 of 116 (19.8%) restagings showed evidence of prostatic urethral and or ureteral disease.

Conclusion:  Roughly 25% of high-grade non-muscle invasive bladder cancer early recurrences after induction intravesical therapy would go unnoticed without the addition of random and directed prostate biopsies, and isolated upper tract cytologies to standard cystoscopy and bladder cytology.


Abbreviations & Acronyms
BCG =

bacillus Calmette–Guérin

CIS =

carcinoma in situ

NMIBC =

non-muscle invasive bladder cancer

TURBT =

transurethral resection of bladder tumor

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References

All patients with NMIBC (Ta, T1 or CIS) are at high-risk for recurrence and progression. Both the American Urological Association and the European Association of Urology recommend initial intravesical treatment with BCG for patients with high-grade papillary disease (Ta, T1) or CIS after TURBT.1,2

To adequately assess the response of intravesical BCG therapy in the treatment of NMIBC, the Southwest Oncology Group began evaluating all patients after intravesical therapy with transurethral bladder biopsies at the time of 3-month cystoscopy.3 Many urologists continue this practice of routine bladder biopsy at 3–6 months; however, several authors suggest instead that biopsies only be carried out in select patients based on initial pathology or 3-month cystoscopy and cytology.4–8

It has been our practice to carry out restaging, including cystoscopy, bladder wash cytology, upper tract barbotage cytology, and transurethral bladder and prostate biopsy on all patients 6–8 weeks after completion of intravesical treatment of high-grade NMIBC. We investigated whether random bladder and prostatic urethral biopsies, and individual upper tract cytologies (restaging) provide additional useful clinical detail to cystoscopy and bladder cytology in assessing intravesical therapy response for high-grade NMIBC.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References

On Institutional Review Board approval, we retrospectively reviewed records of all patients undergoing treatment of NMIBC from January 2000 and October 2009. We identified all patients who underwent restaging (cystoscopy, bladder cytology, bladder and prostatic urethra biopsies, and isolated upper tract cytologies) under anesthesia, after treatment for high-grade NMIBC (Ta, T1 and Tis). High-grade was determined by either grade III findings based on the definitions of the 1973 World Health Organization grading system or high-grade findings after changes to the grading system in 2004. Our pathologists reviewed all pathology for specimens retrieved at outside institutions. All patients that did not undergo their initial TURBT at the University of Iowa underwent cystoscopy, and those with residual tumor underwent repeat TURBT before intravesical treatment. All patients in the present study received at least six treatments of immunotherapy (n = 88) or chemotherapy (n = 28).

All patients underwent restaging approximately 6 weeks after the last treatment. Cystoscopy was classified as normal or suspicious (defined as visible tumor, erythematous lesions or both). Cytology for the bladder and isolated upper tracts were considered positive when definitively high-grade or suspicious for high-grade.

All patients received five random geographic bladder biopsies of the midline dome, midline posterior, midline trigone, and right and left lateral biopsies. Patients with suspicious bladder lesions also underwent directed biopsies of each lesion. Male patients with prostates received right and left prostatic urethral biopsies in the peri-verumontanum area.

Upper tract cytologies were taken by inserting a fresh 5-Fr open-ended catheter attached to a 10 cc syringe of normal saline into the respective ureter while maintaining positive pressure injection during insertion to minimize bladder contamination. Washings were obtained twice in the renal pelvis and at 5-cm intervals down the ureter and pooled. Upper tract cytologies were carried out before biopsies.

Restagings were considered positive whenever histology or cytology were definitive for malignancy.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References

In total, 78 consecutive patients underwent 116 consecutive restagings after treatment of high-grade NMIBC (patients were eligible for repeat restaging if intravesical treatment failed and they underwent repeat therapy). During this time period, a total of 241 patients were treated for NMIBC. Patient characteristics are described in detail in Table 1. The most common indication for intravesical treatment was CIS alone (70/116 cases). A total of 86 of 116 (74%) restagings had CIS involvement, either alone or concomitant with papillary NMIBC, before therapy. A total of 30 cases were high-grade Ta or T1 disease with no concomitant CIS.

Table 1. Patient characteristics
 All patientsPositive restageNegative restage
  • Two additional patients had high-grade cytology of the bladder with negative biopsies and upper tract studies.

Patient characteristics   
 Total # of cases (male : female)86:3046:1940:11
 Age   
  Median6669.564
  Range30–9130–9130–81
 Primary/recurrent48/6822/4326/25
 No. prior treatments (median/mean)2.0/2.32.0/2.61.0/1.9
Prebiopsy   
 Type of treatment   
  Chemotherapy based281612
  Immunotherapy based884343
 Cancer stage and grade of biopsy   
  CIS724327
  CIS + TaG3743
  CIS + T1G3734
  TaG31459
  T1G316412
  Total1165955
 Concomitant upper tract involvement17143
Postbiopsy   
 Cancer stage and grade of biopsy   
  CIS32320
  TaG1330
  TaG3440
  T1G1110
  T1G3110
  T4G3110
  Benign741755
  Total1165955
 Concomitant upper tract involvement21210
 Upper tract involvement only17170
 High-grade bladder cytology only220

All patients

Overall, 59 of 116 (50.9%) restagings showed positive bladder/prostatic biopsy and/or a positive cytology localized to the upper tract (Table 2). Two additional patients had high-grade cytology of the bladder with negative biopsies and negative upper tract cytologies, and subsequently underwent intravesical treatment. Of the 59 restagings with evidence of disease, 36 (61%) had a minimum of a positive bladder biopsy, six (10.2%) had positive prostatic urethral biopsies in the presence of negative bladder biopsies and 17 (28.8%) had positive cytology localized to the upper tract in the presence of negative bladder biopsies. Of these 59 positive restagings, 15 (25.4%) showed disease with a negative cystoscopy and negative bladder cytology. If all patients received only cystoscopy and cytology, 15 of 116 (12.9%) restagings would have been falsely negative. Similar results were seen for patients with CIS, Ta or T1 disease after treatment with BCG-based immunotherapy only, and for those who were undergoing treatment for the first time (Table 3).

Table 2. Cystoscopy, cytology and bladder biopsy outcomes on all patients
Cystoscopy findingsPositive cytologyNegative cytologyTotal
Positive biopsyNegative biopsyPositive biopsyNegative biopsy
  1. †Two patients had positive upper tract cytology and one had positive bladder cytology only. ‡Four patients had positive upper tract cytology and five had positive bladder cytology only. §Four patients had CIS, 1 TaG3, 1 TaG1 and 1 T1G1.

Tumor30227
Erythema8361835
Both20103
Negative1298§4271
Total25121762116
Table 3. Results for each subcategory reviewed
 Positive restagePositive biopsyPositive upper tract cytologyPositive cancer with negative cystoscopy and cytologyFalsely negative cystoscopy and cytology for all patients
All patients59/116 (50.9%)42/59 (71.2%)17/59 (28.8%)15/59 (25.4%)15/116 (12.9%)
CIS involvement50/86 (58.1%)34/50 (68%)16/50 (32%)12/50 (24%)12/86 (14%)
Ta or T1 involvement9/30 (30%)8/9 (88.9%)1/9 (11.1%)3/9 (33%)3/30 (10%)
After BCG-based immunotherapy treatment only42/86 (48.8%)29/42 (69%)13/42 (31%)13/42 (31%)13/86 (15.1%)
First treatment18/48 (37.5%)15/18 (83.3%)3/18 (16.7%)6/18 (33%)6/48 (12.5%)

CIS

Overall, 50 of 86 (58.1%) restagings involving patients with CIS returned positive for cancer. Of the 50 restagings, 34 (68%) had a minimum of a positive bladder biopsy and 16 of 50 (32%) had evidence of a positive isolated upper tract cytology in the presence of a negative bladder biopsy. Of the 50 restagings with evidence of cancer, 12 (24%) showed negative cystoscopy and negative bladder cytology. If all patients with CIS received only cystoscopy and cytology, 12 of 86 (14%) restagings would have been falsely negative.

Prostatic urethral and ureteral involvement

A total of 38 (32.8%) of the 116 restagings showed positive isolated upper tract disease in at least one ureter (Table 4). Of the 38 positive isolated upper tract cytologies, 21 (55.3%) were concomitant with positive bladder biopsies and 17 (44.7%) were not. The 21 patients with positive bladder biopsies were excluded from evaluation secondary to possible introduction of abnormal cells from the known bladder cancer. Interestingly, of the 17 evaluable patients with upper tract disease, eight (47.1%) had a negative cystoscopy and negative cytology. Furthermore, just six of 17 (35.3%) restagings of isolated positive upper tract cytology in the presence of negative transurethral biopsies were associated with a positive bladder cytology. A total of 16 of 17 (94.1%) restagings of isolated positive upper tract cytology in the absence of positive bladder biopsies had undergone treatment for CIS of the bladder before the restaging. Interestingly, of the 17 restaging procedures with positive upper tract cytologies and negative bladder biopsies, five of 17 (29%) went on to nephroureterectomy. In total, eight of 38 (21%) restaging procedures with positive upper tract cytologies went on to require nephroureterectomy, whereas eight of 78 (10%) of restaging procedures with negative upper tract cytologies went on to require nephroureterectomies.

Table 4. Extravesical involvement
 ProstateUpper tractBoth Prostate and upper tract
Positive biopsyPositive biopsy, benign bladderPositive cytologyPositive cytology, benign bladderPositive upper tract cytology, prostate biopsyPositive biopsy, benign bladder
+Cystology and +cytology5212220
+Cystology and −cytology227422
−Cystology and +cytology1111400
−Cystology and −cytology118700
Total96381742

Before restaging, 11 of 38 (28.9%) positive upper tract cases had undergone treatment for upper tract disease, as described previously.9 Similar results were seen for cases of isolated positive upper tract cytology and negative bladder biopsies with four of 17 (23.5%) patients undergoing upper tract treatment before restaging.

Of 116 restagings, nine (7.8%) had prostatic urethral involvement. Interestingly, six (66%) had benign bladder biopsies, and one (11.1%) with prostatic urethral involvement had a negative cystoscopy and cytology. In total, 86 of 116 (74%) of restagings were carried out on men. One of the nine men (11%) went on to require cystectomy. In contrast, two of 77 (3%) of restagings carried out on men with negative prostatic urethral biopsies went on to require cystectomy.

Complications

After biopsy, four patients developed hematuria. All cases resolved spontaneously and did not require intervention, hospitalization or transfusion. One patient had an extraperitoneal bladder rupture identified at the time of the procedure and was managed conservatively with prolonged catheterization. One final patient suffered a myocardial infarction after anesthesia and remained hospitalized for several days, but was eventually discharged without further sequelae.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References

Recent literature suggests that routine biopsy after treatment of NMIBC with intravesical BCG is unnecessary. Multiple authors have suggested that in the presence of a negative cystoscopy and negative cytology, biopsies are not warranted.5,6,8 Dalbagni et al. were the first to suggest that routine biopsies were not warranted in patients with a normal office cystoscopy or a cystoscopy with evidence of erythema in the presence of a normal bladder cytology.7 Limitations of that study included a lack of description of the biopsies and the fact that isolated upper tract cytologies were not evaluated. We reviewed the restaging results in our patients with a normal office cystoscopy or a cystoscopy with evidence of erythema in the presence of normal bladder cytology. When using this criteria to determine appropriate patients to biopsy, 41 of 59 cancers (69.5%; 26 bladder/prostate and 15 upper tract) in our data set would have been missed. Skemp et al. reported similar findings to ours when using this criteria for biopsy selection.5

Three other studies that did not recommend biopsy in the presence of a negative cystoscopy and cytology contained limitations.5,6,8 These studies did not include isolated upper tract cytologies or prostatic urethral biopsies. Furthermore, the study by Skemp et al. was limited by a variable number of biopsies (3–7), and location sites.5 Although Guy et al. carried out thorough and systematic biopsies, the authors did not carry out biopsies on all patients undergoing treatment with a history of CIS or Ta disease, thereby limiting their results.6 The study by Murakami et al. was limited by small biopsy numbers.8

We reviewed the restaging results in our patients with a negative cystoscopy and negative bladder cytology. When using this criteria to determine appropriate patients to biopsy, 15 of 59 (25.4%) cancers would not have been identified. This trend of negative cystoscopy and negative cytology, accounting for roughly one-quarter to one-third of all cases of cancer, was appreciated regardless of stage, intravesical treatment, or whether the patient was naïve to treatment. Similar results to ours were recently seen by Hara et al., who reviewed 127 restagings after BCG treatment.10 Restagings in that study involved a minimum of eight biopsies, including the prostatic urethra, and isolated upper tract cytologies were also reviewed. In that study, 10 of 27 cases (37%) with recurrence had a negative cystoscopy and cytology.

The present study highlights the limitation of cystoscopy and cytology alone in the evaluation of bladder cancer persistence or recurrence after intravesical therapy for high-grade disease. Overall, 15 of 116 (12.9%) restagings showed evidence of recurrence that would not have been detected with routine cystoscopy and cytology. As in all retrospective analyses there are limitations. Based on the results of the present study, as well as that of Hara et al., patients with thorough and consistent biopsies of the bladder and prostate are more likely to have bladder cancer recognized, even in the presence of a negative cystoscopy and negative cytology. The identification of bladder cancer in patients with a history of bladder cancer and normal appearing urothelium is a well-established phenomenon. May et al. prospectively carried out six random bladder biopsies on normal appearing urothelium in 1033 patients with known bladder cancer.11 In total, 128 (12.4%) demonstrated cancer in areas of normal appearing urothelium. Similar results were shown by van der Meijden et al.12

In regard to prostatic urethral and ureteral disease, only one previous study assessing the need for restaging after treatment of high-grade NMIBC with BCG examined the upper tracts with isolated cytologies.10 In one study of 138 patients with CIS, 786 with Ta or T1 disease and 179 with muscle invasive disease: 34 (24.6%), 18 (7.3%) and seven (3.9%) had CIS upper tract involvement, respectively.13 The results of the present study were consistent with these findings, in that 38 of 116 (32.8%) restagings showed a positive cytology isolated to at least one upper tract. One could argue that upper tract cytology might be falsely positive in the presence of high-grade bladder disease secondary to reflux or introduction of cells during ureteral catheterization. However, 17 of 38 restagings with isolated positive upper tract cytology were found in the presence of negative bladder biopsies, indicating that isolated upper tract cytology did not stem from within the bladder. Therefore a minimum of 17 of 116 (14.7%) patients had upper tract disease. A total of 11 of these 17 restagings were associated with a negative bladder cytology. Finally, 16 of these 17 restagings were associated with CIS before treatment.

Similarly to upper tract involvement after the diagnosis of high-grade NMIBC, the prostatic urethra can be a sanctuary site for urothelial carcinoma. One study examining prostatic urethral involvement showed a sevenfold increase in patients with CIS when compared with other bladder tumors.14 In the present study, we identified nine of 116 cases (7.8%) with prostatic urethral involvement. Eight of nine (88.9%) had CIS before treatment.

With regard to prostatic urethral and ureteral involvement, we recommend considering thorough and consistent transurethral bladder biopsies, as well as upper tract cytologies for those patients with a prior history of CIS. Patients with either high-grade Ta or T1 NMIBC might also be considered for isolated upper tract cytologies and prostatic urethral biopsies.

The present study was limited by the fact that it was retrospective in nature. It was further limited by the total number of patients with CIS of the bladder. It is estimated that of all patients with NMIBC, just 5–10% present with primary or concomitant CIS. Conservatively speaking, patients with CIS should therefore account for an estimated 15–20% of all patients presenting with high-grade NMIBC. In the present study, approximately 75% of patients had CIS involvement, which is most likely a result of patient mix bias. As a tertiary/quaternary care center for NMIBC, patients with CIS are commonly referred to our facility. However, the high percentage of patients with CIS has reinforced the importance in evaluating prostatic urethral biopsies and upper tract cytologies despite non-suspicious cystoscopy and cytology. One other key point is the relatively low complete response rate seen in patients with CIS. In this patient population, we saw 36 of 86 (42%) patients have a complete response to therapy. With the understanding that the median number of prior intravesical treatments for these patients was two, these results are not that surprising. After one BCG failure, up to 50% of patients treated with a second course of BCG will develop a complete response to therapy.1,2 Further courses of BCG are associated with a reduced chance of success (<20%).15 In the present study, 42% of our patients saw a complete response to therapy; this appears to be similar to what other studies have shown.

The present findings suggest that in high-risk populations, approximately 13% of all patients undergoing restaging after the treatment of high-grade NMIBC will have cancer in the presence of a negative cystoscopy and cytology regardless of stage, treatment type and number of prior treatments. Both cystoscopy and cytology, and even pathology to lesser extent, remain somewhat subjective.16 Until more objective tests prevail, it remains our recommendation that restaging should be considered after treatment of patients with high-risk NMIBC. In the future, a prospective trial would be beneficial to confirm the present results, as well as to determine the overall benefit in recognizing recurrence early in the disease process.

Approximately 25% of patients with a positive restaging had a negative cystoscopy and cytology. If all patients received only cystoscopy and cytology, 15 of 116 (12.9%) restagings would have been falsely negative. Patients with a prior history of CIS should also be considered for isolated upper tract cytologies and prostatic urethral biopsies.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References
  • 1
    Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Bohle A, Palou-Redorta J. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur. Urol. 2008; 54: 30314.
  • 2
    Hall MC, Chang SS, Dalbagni G et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J. Urol. 2007; 178: 231430.
  • 3
    Lamm DL, Blumenstein BA, Crissman JD et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J. Urol. 2000; 163: 11249.
  • 4
    Highshaw RA, Tanaka ST, Evans CP, deVere White RW. Is bladder biopsy necessary at three or six months post BCG therapy? Urol. Oncol. 2003; 21: 2079.
  • 5
    Skemp NM, Fernandes ET. Routine bladder biopsy after bacille Calmette-Guerin treatment: is it necessary? Urology 2002; 59: 2246.
  • 6
    Guy L, Savareux L, Molinie V, Botto H, Boiteux JP, Lebret T. Should bladder biopsies be performed routinely after bacillus Calmette-Guerin treatment for high-risk superficial transitional cell cancer of the bladder? Eur. Urol. 2006; 50: 51620; discussion 520.
  • 7
    Dalbagni G, Rechtschaffen T, Herr HW. Is transurethral biopsy of the bladder necessary after 3 months to evaluate response to bacillus Calmette-Guerin therapy? J. Urol. 1999; 162: 7089.
  • 8
    Murakami T, Ebara S, Saika T et al. Routine transurethral biopsy of the bladder is not necessary to evaluate the response to bacillus calmette-guerin therapy. Acta Med. Okayama 2007; 61: 3414.
  • 9
    Nepple KG, Joudi FN, O'Donnell MA. Review of topical treatment of upper tract urothelial carcinoma. Adv. Urol. 2009; 2009: Article ID 472831.
  • 10
    Hara T, Takahashi M, Gondo T et al. Discrepancies between cytology, cystoscopy and biopsy in bladder cancer detection after Bacille Calmette-Guerin intravesical therapy. Int. J. Urol. 2009; 16: 1925.
  • 11
    May F, Treiber U, Hartung R, Schwaibold H. Significance of random bladder biopsies in superficial bladder cancer. Eur. Urol. 2003; 44: 4750.
  • 12
    van der Meijden A, Oosterlinck W, Brausi M, Kurth KH, Sylvester R, de Balincourt C. Significance of bladder biopsies in Ta,T1 bladder tumors: a report from the EORTC Genito-Urinary Tract Cancer Cooperative Group. EORTC-GU Group Superficial Bladder Committee. Eur. Urol. 1999; 35: 26771.
  • 13
    Solsona E, Iborra I, Ricos JV, Dumont R, Casanova JL, Calabuig C. Upper urinary tract involvement in patients with bladder carcinoma in situ (Tis): its impact on management. Urology 1997; 49: 34752.
  • 14
    Witjes JA. Bladder carcinoma in situ in 2003: state of the art. Eur. Urol. 2004; 45: 1426.
  • 15
    O'Donnell MA, Boehle A. Treatment options for BCG failures. World J. Urol. 2006; 24: 4817.
  • 16
    Witjes JA, Kiemeney LA, Schaafsma HE, Debruyn FM. The influence of review pathology on study outcome of a randomized multicentre superficial bladder cancer trial. Members of the Dutch South East Cooperative Urological Group. Br. J. Urol. 1994; 73: 1726.