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Keywords:

  • bladder TCC;
  • ureter;
  • frozen section analysis;
  • prognosis

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

OBJECTIVE

To prospectively investigate the value of routine frozen-section analysis (FSA) of the ureteric margin for detecting distal ureteric malignancy in patients undergoing cystectomy for bladder transitional cell carcinoma (TCC).

PATIENTS AND METHODS

In all, 100 consecutive patients had a radical cystectomy for TCC of the bladder; routine FS biopsies were obtained from the lower ureters of all. Definitive pathology with step-sectioning of the lower ureters was reviewed, and the results of paraffin-wax embedded sections and FSA were compared. The true incidence of distal ureteric malignancy was identified and correlated with different clinical and pathological variables.

RESULTS

There were 193 ureteric specimens examined; 16 ureters (8.3%) in 14 patients showed evidence of malignancy by FSA. True distal ureteric malignancy was diagnosed in 29 ureteric specimens (15%) in 24 patients. The sensitivity and specificity of the FSA were 45% and 98%, respectively, while the positive and negative predictive values were 81% and 91%, respectively. There was no significant correlation between distal ureteric malignancy and: patient age, tumour site or morphology, clinical or pathological staging, ipsilateral hydronephrosis, suspicious intraoperative ureter, biopsy or tumour grade, associated carcinoma in situ or nodal involvement. Male gender and positive intraoperative FSA were the only predictors significantly associated with distal ureteric malignancy by univariate analysis (P = 0.01 and <0.01, respectively). Both predictors remained significant on multivariate analysis.

CONCLUSION

A positive ureteric FSA during cystectomy has a high predictive value in the diagnosis of distal ureteric malignancy, and is justified as an independent predictor in male patients with bladder TCC.


Abbreviations
FSA

frozen-section analysis

CIS

carcinoma in situ

PPV

NPV, positive, negative predictive value

ISUP

International Society of Urologic Pathology.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Radical cystectomy has developed as the standard therapy for muscle-invasive bladder cancer and refractory cases of superficial TCC. Concomitant distal ureteric malignancy in bladder specimens was reported to be up to 57%[1], and local recurrence at the site of uretero-ileal anastomosis can induce considerable late morbidity after cystectomy [2]. All previous studies, based on retrospective analyses, did not support the need for routine ureteric frozen-section analysis (FSA) for patients undergoing cystectomy, as FSA has limited capacity to diagnose the pathology, a questionable value for concomitant ureteric margin abnormalities in the development of any future morbidity, and the cost-benefit considerations [3–5]. To our knowledge, the role and accuracy of routine ureteric FSA at the time of cystectomy have not been reported in a prospective study.

Distal ureteric malignancy is usually anticipated in patients at risk, i.e. those with diffuse carcinoma in situ (CIS), prostatic duct involvement or those with multifocal disease [3,4], and hence intraoperative ureteric FSA was suggested only in these selected patients. Nevertheless, there was no evidence-based medicine to support this inclination. The aim of the present study was to prospectively investigate the accuracy of the routine pathological detection of distal ureteric malignancy by FSA during cystectomy, controlled by step-sectioning of the lower end of the ureters, in patients with TCC of the bladder, and to investigate the role of FSA among different clinical and histopathological variables as predictors of distal ureteric malignancy.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

This study comprised 100 consecutive patients (85 men and 15 women, mean age 59.1 years, sd 8.6, range 31–76) with non-metastatic muscle-invasive TCC or superficial TCC and failure of endoscopic control. Patients with other than TCC were excluded from the study. Clinical staging was largely based on a bimanual examination with the patient under anaesthesia, endoscopic assessment and biopsy and CT (or MRI). All patients had a standard radical cystectomy with bilateral iliac lymphadenectomy. The procedure included FSA of the distal ureteric margin before the uretero-enteric anastomosis. Subsequent resection of more proximal portions was indicated in cases with positive margins until a ‘safe’ cut section was obtained. The excised lower ureter in the cystectomy specimen was used for a definitive histopathological examination comprising 3-mm step-sectioning. The results from the paraffin- wax embedded sections and FSA were compared.

The pathological diagnosis followed the WHO/International Society of Urologic Pathology (ISUP) consensus classification of urothelial neoplasms [6]. Positive ureteric malignancy in FSA and definitive specimens was diagnosed among patients with CIS (high-grade intra-urothelial neoplasia), papillary carcinoma (low- or high-grade) and invasive neoplasms (with lamina propria or muscularis propria invasion). Those with hyperplasia, reactive atypia or dysplasia (low-grade intra-urothelial neoplasia) were considered negative for malignancy. The grading also followed the WHO/ISUP consensus [6] where patients were classified as having low- or high-grade urothelial neoplasm. The staging system was stratified according to the 1997 TNM system [7].

The FSA results were considered as the test while the results from ureteric step-sectioning were considered as the reference standard. The sensitivity was defined as the number of true positive test results divided by the overall positive cases in the reference standard, and specificity as the number of true negative test results divided by the overall negative cases from the reference standard. The accuracy was defined as true positive and true negative test results divided by the total number of specimens examined. The positive predictive value (PPV) was defined as the number of true positive test results divided by the overall test positive results, and the negative PV (NPV) as the number of true negative test results divided by the overall test negative results.

The patients’ characteristics and incidence of ureteric malignancy were recorded in an electronic database. The incidence of true distal ureteric malignancy (by step-sectioning of lower ureters) was correlated with different clinical and pathological variables. The Pearson chi-square test was used, with P < 0.05 considered to indicate significance, for univariate analysis, while forward logistic regression was used for the multivariate analysis [8].

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Of the 100 patients who had a radical cystectomy and urinary diversion, 58 had orthotopic ileal neobladders, 38 an ileal loop conduit and four a continent cutaneous diversion. There were 193 ureteric specimens examined, as seven patients had a unilateral nephroureterectomy before or at the time of cystectomy because of associated upper urothelial malignancy. Sixteen ureters (8%) in 14 patients had evidence of malignancy by FSA (14 ureters with CIS and two with invasive disease infiltrating the lamina propria). Five ureters required a single resection to reach a negative margin, while 10 required two extra cuts. The remaining ureter needed seven consecutive cuts to reach a negative margin. None of the ureters were shortened enough to affect the previously planned mode of urinary diversion.

On definitive histopathology compared with FSA, there were four specimens with false-negative results while three gave false-positive results. However, step-sectioning showed an extra 12 malignant foci. Therefore, the true incidence of lower ureteric malignancy included 29 ureters (15%) in 24 patients. Table 1 shows the true- and false-positive and -negative results of FSA compared with step-sectioning (reference standard). The specificity of the FSA for detecting ureteric malignancy was 98% and the sensitivity 45%, with an overall accuracy of 90%. The PPV was 81% and the NPV 91%.

Table 1. True- and false-positive and -negative results of the FSA as controlled by step-sectioning of the lower end of the ureters (reference standard)
FSA resultStep sectioning resultTotal
Disease presentDisease absent
Positive13 (true positive)  3 (false positive) 16
Negative16 (false negative) 161 (true negative)177
Total29164193

Table 2 shows that no significant association was identified between true distal ureter malignancy and: patient age, tumour site or morphology, clinical or pathological staging, biopsy or tumour grade, ipsilateral hydronephrosis, suspicious intraoperative ureter, associated CIS or nodal involvement. Male gender and a positive FSA were the only predictors significantly associated with true distal ureteric malignancy by univariate analysis (P = 0.01 and <0.01, respectively). By multivariate analysis, both variables remained significant as independent predictors (Table 3).

Table 2. The univariate analysis of possible risk factors for true distal ureteric malignancy among patients with TCC treated by cystectomy
VariableNumber of reno-ureteric unitsN (%) with ureteric malignancyP
  • *

    Clinical staging as determined by CT and examination under anaesthesia.

Clinical
Age, years
 ≤6010412 (11.5) 
 >60 8917 (19.1)0.14
Gender
 Male16329 (17.8) 
 Female 30 00.01
Tumour morphology
 Fungating13621 (15.4) 
 Papillary 41 6 (14.6) 
 Ulcerative 16 2 (12.5)0.95
Tumour site
 Lateral wall 7813 (16.7) 
 Posterior wall 62 8 (12.9) 
 Anterior wall 16 2 (12.5) 
 Dome 14 2 
 Multi-centric 23 4 (17.4)0.97
Ipsilateral hydronephrosis
 Normal16423 (14) 
 Hydronephrotic 29 6 (20.7)0.35
FSA
 Positive 1613 (81.3) 
 Negative17716 (9)<0.01
Intraoperative ureter
 Normal18526 (14.1) 
 Suspicious  8 30.07
Clinical stage*
 No mass 20 4 (20) 
 T2  4 1 
 T314222 (15.5) 
 T4 27 2 (7.4)0.58
Pathological
Biopsy grade
 Low 60 8 (13.3) 
 High13321 (15.8)0.66
Tumour cell grade
 Low 46 5 (10.9) 
 High14724 (16.3)0.59
Pathological stage
 Organ-confined (pT1, pT2) 8610 (11.6) 
 Extravesical (pT3, pT4)10719 (17.8)0.24
Lymph node involvement
 Negative16323 (14.1) 
 Positive 30 6 (20)0.41
Associated CIS
 Negative16321 (12.9) 
 Positive 30 8 (26.7)0.06
Table 3. Multivariate analysis of possible risk factors for true distal ureteric malignancy among patients with TCC treated by cystectomy
VariableRegression estimate, B (sem)Exp (B)P
Gender
 Male  1.0 
 Female−9.980 (1.071)  0.0010.71
FSA
 Positive  1.0 
 Negative4.683 (0.265)108.10.001

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

The incidental finding of malignant ureteric changes in the cystectomy specimens varies significantly in different series due to different diagnostic criteria and the extent of the pathological study of the ureter. With routine specimen processing, most studies showed an incidence of 6–8%[5,9–11]. Three decades ago, two different studies showed a significant increase in the incidence, up to 23% and 57%, respectively, based on a systematic 3-mm step-sectioning pathological technique [1,12]. In the present study the incidence was 15% using a more assiduous approach. To our knowledge, this is the only study investigating the true incidence of lower ureteric malignancy after using a universally accepted consensus for classifying urothelial neoplasia to overcome the problem of pathological overlap [6]. Notably, we excluded patients with other than TCC to achieve an accurate incidence for the target population.

Despite this relatively high incidence of distal ureteric malignancy, the clinical value of routine FSA of the ureteric margins before constructing the uretero-intestinal anastomosis was often unsupported in previous studies. This conclusion was based on three main assumptions: (i) the limited ability of FSA to accurately identify ureteric pathology; (ii) the questionable effect of a malignant ureteric margin anastomosis in the development of future oncological failure; and (iii) the cost implications [3–5].

On the first point, we showed that the sensitivity of FSA is low (45%) when compared with step-sectioning, but this low sensitivity is insufficient to negate the ability of FSA to diagnose distal ureteric malignancy in patients with bladder cancer. Any diagnostic method is judged by its PPV, which in the present study was 81% for FSA; moreover, the logistic regression confirmed the value of a positive ureteric FSA as an independent predictor of true distal ureteric malignancy.

On the second point, although a uretero-enteric anastomosis using a malignant margin was previously reported to be a permissible procedure [3,5], we consider that such an anastomosis might contribute to the future development of serious sequelae in many patients. So et al.[2] reported a late uretero-enteric anastomotic leak within an ileal conduit that occurred as the result of recurrent urothelial carcinoma of the ureter at the site of the anastomosis. Interestingly, this point has been used to deny the value of FSA; Johnson et al.[3] reported a case of anastomotic recurrence among seven in whom the uretero-enteric anastomosis included epithelial abnormalities at the cut margin. Silver et al.[5] reported a similar case of among 21 with positive ureteric margins (5%). We consider that this incidence of anastomotic site recurrence represents a significant and easily avoidable morbidity if an accurate predictor is available. Currently, we are closely following the four patients in whom the uretero-ileal anastomosis included a positive margin, to answer the question of whether there is potential harm to the patient if malignant or premalignant tissue at the ureteric margin is not resected.

Although the prevalence of associated ureteric neoplasia among male patients with bladder cancer was reported previously [5,11], none suggested male gender as a possible risk factor. Interestingly, in the present study male gender was one of two independent predictors of lower-end ureteric malignancy. A decade ago FSA of the ureters was estimated to cost ≈ US$800 for evaluating two ureteric margins [4]. Defining male gender as an independent risk factor for distal ureteric malignancy would limit FSA to this group, with a subsequent decrease in cost.

Sharma et al.[9] reported that ureteric marginal CIS was common in patients with multifocal tumours and those with high-stage and high-grade disease. Similarly, Cooper et al.[13] noted the prevalence of epithelial abnormalities at the ureteric margin among patients with high grade and stage of the disease. Thus it was suggested intraoperative examinations of the lower ureters be limited to these high-risk groups, including patients with CIS, multifocal disease or those with intraoperative findings suspicious for malignancy (ureteric obstruction and peri-ureteric fibrosis) [3,4]. These recommendations were based on the investigators’ experience rather than analysis of the pathological criteria of the target group. The present analysis found none of these risk factors to be statistically significant predictors of distal ureteric malignancy.

The incidence of a positive FSA from the distal end of the ureters during cystectomy varies in different series. Although Johnson et al.[3] reported a low incidence of 2%, Schoenberg et al.[3] showed a higher incidence of up to 8%, similar to that in the present study. This relatively high incidence could be attributed to a high tumour stage among the present patients, as more than half had pathological stage T3 or T4. The present study provides practising urologists with evidence based on logistic regression that positive intraoperative ureteric FSA has an independent high predictive value in diagnosing distal ureteric malignancy, justifying its need as a routine procedure.

In conclusion, by modern pathological consensus, concomitant distal ureteric malignancy could be diagnosed in 15% of bladder cancer specimens. As a positive ureteric FSA and male gender were the only independent predictors of distal ureteric malignancy, FSA should be routine for all male patients undergoing cystectomy for TCC of the bladder.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES