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Keywords:

  • urethral washing;
  • bladder carcinoma;
  • penile urethra;
  • cytopathology

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND

Urethral wash cytopathology (UWC) has been recommended for monitoring patients after cystoprostatectomy with preservation of the penile urethra and urinary diversion. The rationale has been that early detection of urethral neoplasms (recurrences) would allow for urethrectomy to be performed before an invasive tumor developed and thus prevent or delay disease progression. Negative results of UWC would spare the patient a major surgical procedure. The authors analyzed the clinical and pathologic records of patients undergoing cystoprostatectomy with urinary diversion and preservation of the penile urethra to determine the cytohistologic correlations and to document the effect of UWC monitoring on the rate of disease progression.

METHODS

All cases of men undergoing a cystoprostatectomy with urinary diversion and preservation of the penile urethra over a 12-year period at the study institution were included. Records were reviewed to determine the degree of risk associated with the pathologic findings at surgery and to document the presence or absence of disease progression for each individual. The pathologic specimens of all cases monitored with UWC were reviewed separately by both authors to establish cytohistologic correlations. Standard statistical methods were applied.

RESULTS

Of 176 patients, urethral recurrence and disease progression occurred in both high-risk and low-risk groups. Among the 48 individuals monitored with UWC, 13 had a positive diagnosis, and 10 of these 13 had been subsequently treated with urethrectomy. Among 128 patients not monitored with UWC, 16 underwent urethrectomy. Patients in both groups had recurrent urethral neoplasms. Most lesions were focal carcinomas in situ occupying the paraurethral glands. One individual in each group had no further disease progression, even though the urethral tumor was invasive. Urethrectomy was found to have no statistically significant association with the rate of disease progression, regardless of whether the procedure resulted from a positive UWC or was provoked by patient/clinician concern. When groups were compared on the basis of monitoring with UWC, there was no statistical difference in the rate of disease progression between those monitored with UWC and those who were not. Within the monitored group, however, the cytopathologic interpretations of UWC were statistically significant; patients with positive findings were found to have the highest rate of disease progression, and those with negative findings experienced the lowest (P < 0.04).

CONCLUSIONS

Both monitoring with UWC and urethrectomy might benefit selected individuals, but neither method appeared to have a statistically significant effect on disease progression in a nonrandomized group of patients. A positive UWC was associated with a high likelihood of disease progression and could justify more intensive follow-up for progressive disease at other sites. Cancer (Cancer Cytopathol) 2003;99:352–6. © 2003 American Cancer Society.

Preservation of the penile urethra in men undergoing cystoprostatectomy for bladder carcinoma spares this structure and avoids prolonging a major surgery. However, it also leaves an organ that must be monitored to prevent progressive disease at that site. Logically, the detection of urethral recurrences while neoplasms are still in situ would allow for early urethrectomy with prevention of disease progression or at least prolongation of the disease-free interval. Reliance on urethroscopy or urethral bleeding to indicate the presence of a urethral recurrence has been associated with an unfavorable prognosis, but few other modalities are practical.1, 2 Cytopathologic assessment of urethral washings might be beneficial, but to our knowledge the subject has received little attention in the literature.2–4 The current study was intended to review our experience with monitoring using urethral wash cytopathology (UWC). We were especially interested in cytohistologic correlations and in documenting the influence of both UWC monitoring and urethrectomy on the rate of disease progression.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The records of all men treated with cystoprostatectomy and urinary diversion with preservation of the penile urethra from January 1990 through December 2001 were reviewed. Among these patients, the utilization and timing of all cases in which UWC was performed were recorded. Patients undergoing UWC were separated into groups with high and low risks of disease progression on the basis of the pathologic findings in their cystoprostatectomy specimens.1, 5 A high risk for disease progression was defined as the presence of multifocal bladder neoplasms, including carcinoma in situ (CIS), or CIS involving the distal ureters, prostatic urethra, or prostatic ducts. A low risk for disease progression was defined as a single focus of carcinoma without associated CIS in the bladder or adjacent organs. Progression was defined as a recurrent invasive carcinoma in the pelvis, residual urethra, ureters, or renal pelvis, as well as the appearance of metastases or a certification of death from bladder carcinoma. The criteria for interpreting cells as “positive” in the UWC specimens have been published previously.6 Statistical significance was determined using the chi-square test.7

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The results are summarized in Tables 1, 2, 3, 4. Over the period of study, 176 men met the criteria for selection. Patients were ages 38–85 years (mean age, 67 years) at the time of cystoprostatectomy. All patients had urothelial (transitional cell) carcinomas. Muscle-invasive urothelial carcinomas comprised 53% of cases, and 83% of the tumors were classified as high-grade based on the 1998 World Health Organization (WHO)/International Society of Urologic Pathology (ISUP) scheme (Grade 2 and Grade 3 in the 1973 WHO system).8, 9 Of the 176 patients, 127 (72%) were considered to be at high risk and 49 (28%) were considered to be at low risk for disease progression. UWCs were obtained from 48 individuals (27%) during follow-up (32 of 127 high-risk patients and 16 of 49 low-risk patients). Monitoring with UWC was initiated within an average of 10 months of surgery (range, 2–48 months.) and 1–7 specimens per patient (mean, 2 specimens) were obtained.

Table 1. Results of Urethrectomy According to Risk Conferred by the Bladder Carcinoma
 High risk (n = 127)Low risk (n = 49)
UWCNo UWCUWCNo UWC
  1. UWC: urethral wash cytopathology.

Frequency of UWC32951633
Frequency of urethrectomy81224
Histopathology    
 Invasive carcinoma1201
 Carcinoma in situ4221
 Denuded papillary neoplasm1000
 Dysplasia1400
 No neoplasm1402
Table 2. Outcomes of Patients with Cystoprostatectomy and Urinary Diversion with Preservation of the Penile Urethra
 High risk (%)Low risk (%)
Number127 (72)49 (28)
Alive, no disease71 (56)37 (76)
Alive, disease progression40 (31)8 (16)
Dead of disease1 (4)0 (0)
Lost to follow-up15 (12)4 (8)
Table 3. Effect of UWC on Disease Progressiona
 UWC (%)No UWC (%)
  • UWC: urethral wash cytopathology.

  • a

    Determinate cases only.

Number48109
Alive, no disease36 (75)72 (66)
Alive, disease progression12 (25)36 (33)
Dead of disease0 (0)1 (1)
Table 4. Progression Rates of Patients According to UWC and Ux*a
 Disease Progression (%)
  • UWC: urethral wash cytopathology; Ux: urethectomy.

  • a

    Determinate cases only.

UWC positive, plus Ux only6/10 (60)
UWC positive, all cases7/13 (54)
UWC negative, no Ux5/35 (14)
No UWC, plus Ux only6/16 (38)
No UWC, all cases37/109 (34)
No UWC, no Ux31/93 (33)

Among the 48 patients monitored with UWC, positive results were confirmed in 13 (Fig. 1). Two of these 13 patients had urethral bleeding. Urethrectomy was performed between 4–20 months (mean, 12.3 months) after cystoprostatectomy in 10 individuals (8 high-risk patients and 2 low-risk patients); the other 3 patients (all high risk) refused surgery (Table 1). One urethrectomy specimen contained an invasive urothelial carcinoma, and six others had at least one focus of CIS. The areas of carcinoma were small, focal, and usually confined to paraurethral glands (Fig. 2). The surface urothelium of the penile urethra was extensively denuded in every case, and multiple sections often were required for histopathologic correlation. No patient with negative UWCs underwent a urethrectomy.

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Figure 1. Cytopathology result from a patient during follow-up after cystoprostatectomy. The specimen contained high-grade malignant cells (arrows) (× 400).

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Figure 2. Urethrectomy from the patient in FIGURE 1. Recurrent carcinoma, shown in the top panel (× 150), is often present only in the paraurethral glands. A denuded urothelium, shown in the bottom panel (× 100), is characteristic of urethrectomy specimens from such patients.

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Urethrectomy was performed between 2–20 months (mean, 8.9 months) after cystoprostatectomy in 16 of the 128 patients who were not monitored with UWC (Table 1). Urethrectomy was apparently undertaken based on patient or clinician concern. Of the 16 patients, 12 were in the high-risk group. Three individuals were found to have urethral bleeding during follow-up. Among these 16 patients, 3 had invasive carcinoma, 3 had CIS, and 4 had dysplasia; no lesions were identified in the remaining 6 patients.

There was no apparent statistical difference in the rate of disease progression between patients undergoing a urethrectomy because of a positive UWC and patients undergoing urethrectomy as a result of patient/clinician concern (P < 0.51). Nor was there a statistically significant difference in the rate of disease progression between those undergoing urethrectomy and those spared the surgery, regardless of the reason for the procedure (P < 0.19). However, it should be noted that one individual with invasive urethral carcinoma in the monitored group and one of three patients with invasive carcinoma in the unmonitored group developed no further disease progression during follow-up after urethrectomy.

Patients were followed for up to 142 months after cystoprostatectomy, (mean, 37 months) [Tables 2, 3]. Among the 48 individuals who were monitored with UWC, 75% were alive at last follow-up with no evidence of disease, and 25% had developed disease progression. No patient had died of bladder carcinoma. No patient was lost to follow-up. In contrast, 19 of the 128 patients who were not monitored with UWC were lost to follow-up. Among the 109 determinate cases, 66% were alive without disease at the time of last follow-up, and 34% had developed disease progression. One patient had died of bladder carcinoma.

The disease progression rates among the various categories of patients on the basis of UWC and urethrectomy are listed in Table 4. Patients with positive UWC with or without subsequent urethrectomy suffered the highest rate of disease progression, whereas those with negative UWC experienced the lowest rate of disease progression (60% and 54% vs. 14%, respectively; P < 0.034 and P < 0.04, respectively). Overall, patients monitored with UWC had a disease progression rate of 25% (12 of 48 patients), whereas those not monitored with UWC experienced a disease progression rate of 34% (37 of 109 determinate cases; P < 0.42).

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

To our knowledge, UWC is currently the only practical means of monitoring the residual urethra for noninvasive recurrences after cystoprostatectomy with urinary diversion. Nevertheless, this approach is used sparingly in our practice, and to our knowledge the literature contains very few reports detailing the experiences of others.1–5 Considering the implications of a positive diagnosis and the inability in most cases to confirm the UWC findings histologically prior to performing urethrectomy, a conservative approach to cytopathologic assessment appears prudent. Conversely, a positive diagnosis must be accepted as definitive for at least the presence of a noninvasive urethral recurrence, and monitoring with UWC may not detect every neoplasm while it is still in situ. Urethrectomy specimens should be thoroughly examined and adequately sampled for histologic evaluation, but serial sectioning solely to correlate the histology with the cytopathology seems unwarranted, especially because the recurrent neoplasm can be expected to be very focal and confined to the paraurethral glands.

In the current study, monitoring patients using UWC did not appear to result in a statistically significant decrease in the rate of disease progression compared with the rate among individuals not monitored. Disease progression was recorded among high-risk and low-risk patients in both groups. Even when a positive UWC resulted in urethrectomy, the rate of disease progression was not statistically better compared with the rate in unmonitored individuals undergoing urethrectomy for other reasons.4 Urethrectomy was performed relatively early in the follow-up of both groups, and any effect of cytopathologic monitoring might not be appreciated, but the overall disease progression rate among those treated with urethrectomy was actually higher than the rate for those spared the surgery (46% vs. 27%; P < 0.19). Statistics notwithstanding, two of five patients with invasive urethral carcinoma experienced no further disease progression after urethrectomy and could be considered to have benefited from the surgery.

When only monitored individuals were considered, UWC appeared to stratify patients into groups with favorable and unfavorable disease progression rates, and this finding was statistically significant (P < 0.04). Among all patients, those with a positive UWC diagnosis had the highest rates, and individuals with a negative UWC had the lowest. The disease progression rate of 60% among patients with a positive UWC and urethrectomy was nearly double the rate of 32% for all individuals considered to be at high risk at the time of cystoprostatectomy. In contrast, patients with negative findings in their UWC specimens experienced a rate of disease progression that was slightly lower than that for patients with low risk factors at cystoprostatectomy. Even in this group, however, the statistical significance of a positive result was marginal. Had invasive carcinoma in the urethra not been considered disease progression, for example, the P value would have changed from P < 0.04 to P < 0.08.

The belief that early detection of urethral disease recurrence and subsequent urethrectomy might prevent disease progression and thus benefit patients after cystoprostatectomy with urinary diversion has not been substantiated by recent evidence.4 Individuals might benefit from urethrectomy, but the overall results are not statistically valid. Still, the limited published experience has described small series of nonrandomized patients, and the results cannot be considered conclusive. Monitoring the residual urethra with UWC can spare patients a urethrectomy and help to prevent the development of invasive carcinomas in this organ. It also may identify those patients who are most likely versus those who are least prone to develop disease progression and could justify a more intensive approach to the evaluation of nonurethral sites in the high-likelihood group.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The authors thank Professor James K. Massey, M.E., for performing the statistical analyses.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  • 1
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    Hickey DP, Soloway MS, Murphy WM. Selective urethrectomy following cystoprostatectomy for bladder cancer. J Urol. 1986; 136: 828830.
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  • 5
    Nixon RG, Chang SS, Lafleur BJ, Smith JA Jr., Cookson MS. Carcinoma in situ and tumor multifocality predict the risk of prostatic urethral involvement at radical cystectomy in men with transitional cell carcinoma of the bladder. J Urol. 2002; 167: 502505.
  • 6
    Murphy WM. Urinary cytopathology. Chicago: ASCP Press, 2000: 1345.
  • 7
    Mendenhall W, Ott L, Larson RF. Statistics: a tool for the social sciences. 2nd edition. Belmont, CA: Duxbery Press,, 1974: 242248.
  • 8
    Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol. 1998; 22: 14351448.
  • 9
    Mostofi FK, Sobin LH, Torloni H. Histological typing of urinary bladder tumors. International classification of tumors, no. 19. Geneva: World Health Organization, 1973.