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Role of voided urine cytology in diagnosing primary urethral carcinoma
ADULT UROLOGY
ROLE OF VOIDED URINE CYTOLOGY IN DIAGNOSING PRIMARY URETHRAL CARCINOMA A. KARIM TOUIJER
AND
GUIDO DALBAGNI
ABSTRACT Objectives. To evaluate the role of voided urine cytology in diagnosing primary carcinoma of the urethra in male and female patients. Methods. We reviewed the medical records of all patients with urethral carcinoma seen at Memorial Sloan-Kettering Cancer Center between 1958 and 1996. The patients who had undergone voided urine cytology before any treatment were the subject of this report. Results. This report included 41 female and 29 male patients. In the cohort of female patients, the most common histologic type was adenocarcinoma (n ⫽ 16), followed by squamous cell carcinoma (SCC; n ⫽ 9) and transitional cell carcinoma (TCC; n ⫽ 6). Urine cytology was positive in 24 patients (59%). The sensitivity was greatest in patients with SCC (77%) and lowest in patients with TCC (50%). In the cohort of male patients, the most common histologic type was SCC (n ⫽ 14) followed by TCC (n ⫽ 10). Urine cytology was positive in 16 patients (55%). The sensitivity was greatest for patients with TCC (80%) and lowest for patients with SCC (50%). Conclusions. Voided urine cytology is not a very reliable method of diagnosing primary carcinoma of the urethra in either male or female patients. A cystoscopic evaluation with possible biopsy is warranted if suspicion of carcinoma of the urethra is high. UROLOGY 63: 33–35, 2004. © 2004 Elsevier Inc.
P
rimary urethral carcinoma is an uncommon disease, characterized by an advanced stage at diagnosis and, hence, a poor outcome.1 Unlike bladder cancer, urethral carcinoma shows clinical and histologic dissimilarities between male and female patients.2 In addition, unlike bladder cancer, the role of urine cytology as a diagnostic tool in primary urethral carcinoma is unknown. We evaluated the Memorial Sloan-Kettering Cancer Center series to define the role of voided urine cytology in diagnosing primary carcinoma of the urethra in male and female patients. MATERIAL AND METHODS
We reviewed the medical records of all patients with primary urethral carcinoma seen at Memorial Sloan-Kettering Cancer Center between 1958 and 1996. Excluded from the analysis were patients with urethral metastases, patients with secondary urethral tumors arising from surrounding organs, From the Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York Reprint requests: Guido Dalbagni, M.D., Department of Urology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 Submitted: May 15, 2003, accepted (with revisions): August 1, 2003 © 2004 ELSEVIER INC. ALL RIGHTS RESERVED
patients with concomitant or prior bladder cancer, and patients in whom pretreatment voided urine cytology was not available. The tumors were staged according to the TNM system of the International Union against Cancer.3 In the male and female patients, four variables were evaluated: pretreatment voided urine cytology, histologic type, stage, and site of disease, all of which were abstracted from the medical charts and pathology reports.
RESULTS This report included 41 female and 29 male patients with primary urethral carcinoma. In the cohort of female patients, the mean age was 58.4 years (range 34 to 88). The most common histologic type was adenocarcinoma (n ⫽ 16) followed by squamous cell carcinoma (SCC; n ⫽ 9) and transitional cell carcinoma (TCC; n ⫽ 6). The cancer involved the entire urethra in 18 patients (44%), proximal urethra in 10 (24%), and distal urethra in 6 (14%) and was located in a urethral diverticulum in 1 patient. Two thirds of the patients had T3 or T4 disease, 10 patients (24.3%) had positive nodes, and 1 had M1 disease (Table I). The urine cytology was positive in 24 patients (59%). The sensitivity was greatest in patients with SCC (77%) and lowest in patients with TCC 0090-4295/04/$30.00 doi:10.1016/j.urology.2003.08.007 33
TABLE I. Female patient characteristics Age (yr) Mean Range Tumor stage (n) Tx T0 Ta Tis T1 T2 T3 T4 N0 N⫹ Nx M0 M1 Histologic type (n) SCC TCC Epidermoid Adenocarcinoma Melanoma Small cell Anaplastic Lymphoma Site (n) Whole urethra Proximal Distal Not available Diverticulum
58.4 34–88 5 (12) 3 (7.3) 0 1 (2.4) 1 (2.4) 5 (12) 14 (34) 12 (29.2) 9 (21.9) 10 (24.3) 22 (53.6) 40 (97.5) 1 (2.4) 9 6 5 16 1 1 2 1
(21.9) (14.6) (12) (39) (2.4) (2.4) (4.8) (2.4)
18 10 6 6 1
(44) (24) (14) (14.6) (2.4)
KEY: SCC ⫽ squamous cell carcinoma; TCC ⫽ transitional cell carcinoma. Data in parentheses are percentages.
(50%). The sensitivity was greatest in patients with tumors involving the proximal or entire urethra (60% and 61%, respectively) and lowest in tumors involving the distal urethra (20%). In the cohort of male patients, the median age was 58.9 years (range 36 to 92). The most common histologic type was SCC (n ⫽ 14), followed by TCC (n ⫽ 10). The cancer involved the bulbomembranous urethra in 17 patients (59%) and pendulous urethra in 11 (38%). In 1 patient, both the anterior and bulbomembranous urethra were involved. The tumors were of an advanced stage in 22 patients (75.8%). Six patients had node-positive disease and one had distant metastases (Table II). The urine cytology was positive in 16 patients (55%). The sensitivity was greatest in patients with TCC (80%) and lowest in patients with SCC (50%). When evaluated in relation to tumor site, the sensitivity was greatest in patients with tumors involving the pendulous urethra (73%) and lowest in tumors involving the bulbomembranous urethra (40%). 34
TABLE II. Male patient characteristics Age (yr) Mean Range Tumor stage (n) Tx T0 Ta Tis T1 T2 T3 T4 N0 N⫹ Nx M0 M1 Histologic type (n) SCC TCC Epidermoid Anaplastic Site (n) Anterior and posterior Bulbomembranous Pendulous
58.9 36–92 1 (3.4) 0 1 (3.4) 1 (3.4) 4 (13.7) 12 (41) 8 (27.5) 2 (6.8) 8 (27.5) 6 (20.6) 15 (51.7) 28 (96.5) 1 (3.4) 14 10 4 1
(48) (34) (13.7) (3.4)
1 (3.4) 17 (59) 11 (38)
Abbreviations as in Table I. Data in parentheses are percentages.
COMMENT The treatment of primary urethral carcinoma in both male and female patients has lagged behind that of other cancers because of the scarcity of cases and the lack of uniformity in the management of this disease. The prognosis remains poor, because most of these patients’ tumors are high stage at diagnosis. In a previously published series from our institution, the 5-year survival rate was 36% for male patients with high-stage tumors and 83% for male patients with low-stage tumors. The 5-year survival rate was 22% for female patients with highstage and 78% for female patients with low-stage tumors.1,4 The strong association between survival rate and disease stage at diagnosis warrants efforts to detect primary urethral carcinoma at earlier stages. In the bladder, urine cytology is an important tool for screening and surveillance of TCC. However, it is characterized by a variable sensitivity. In low-grade lesions, the shed cells are well differentiated and closely resemble normal urothelial cells, thus making a distinction difficult. In a literature review of urine cytology in low-grade urothelial carcinoma, Renshaw et al.5 reported sensitivities ranging from 0% to 100% and specificities ranging from 6% to 100%. Efforts to enhance the reliability UROLOGY 63 (1), 2004
of urine cytology in low-grade urothelial carcinoma using distinctive nucleocytoplasmic features failed to reproduce prospectively the results obtained retrospectively.6 Sensitivity is also augmented when the voided cytology specimens are obtained on three separate days or by catheterization, rather than simple voiding. However, in high-grade bladder urothelial carcinoma and carcinoma in situ, urine cytology has an excellent track record, with a sensitivity of 90% and a specificity of 98% to 100%. In previously published Memorial Sloan-Kettering series, 98 patients with low-stage bladder cancer underwent 325 examinations during a 2-year interval. Cytology agreed with cystoscopy in 75% of the cases.7 In another series from the same institution, of 228 patients with histologically proven superficial bladder cancer, 110 had carcinoma in situ, 54 had Stage Ta, and 61 had Stage T1. The combined sensitivity for all tumors was 78% with four cytology examinations per patient. The cytologic sensitivities varied according to the category; it was greater in high-grade carcinoma in situ and Stage T1 disease than in low-grade Stage Ta disease.8 The role of urine cytology in primary carcinoma of the urethra is unknown. To our knowledge this is the first study to address this issue. In our experience of 41 female and 29 male patients with primary urethral carcinoma, the voided urine cytology sensitivity was relatively low, 59% and 55%, respectively. In the female cohort, the sensitivity was greatest for SCC, with adenocarcinoma as the most predominant histologic type. In the male cohort, the sensitivity was highest for TCC. Different results were also found between male and female patients regarding tumor site and urine
UROLOGY 63 (1), 2004
cytology sensitivity, with greater sensitivity for tumors involving the proximal or entire urethra in the female patients and greater sensitivity for distal tumors in the male patients. CONCLUSIONS Voided urine cytology is not a very reliable method of diagnosing primary carcinoma of the urethra in either male or female patients. A cystoscopic evaluation with biopsy is warranted if the index of suspicion for carcinoma of the urethra is high. REFERENCES 1. Dalbagni G, Zuo-feng Z, Lacombe L, et al: Male urethral carcinoma: analysis of treatment outcome. Urology 53: 1126 – 1132, 1999. 2. Amin M, and Young R: Primary carcinomas of the urethra. Semin Diagn Pathol 14: 147–160, 1997. 3. Beahrs O, Henson D, Hutter R, et al: Manual for Staging of Cancer, 4th ed. Philadelphia, Lippincott-Raven, 1992, pp 209 –213. 4. Dalbagni G, Zuo-feng Z, Lacombe L, et al: Female urethral carcinoma: analysis of treatment outcome and a plea for a standardized management strategy. Br J Urol 82: 835–841, 1998. 5. Renshaw A, Nappi D, and Weinberg D: Cytology of grade 1 papillary transitional cell carcinoma: a comparison of cytologic, architectural and morphometric criteria in cystoscopically obtained urine. Acta Cytol 40: 676 –682, 1996. 6. Raab S, Lenel J, and Cohen M: Low grade transitional carcinoma of the bladder: cytologic diagnosis by key features as identified by logistic regression analysis. Cancer 74: 1621– 1626, 1994. 7. Klein FA, Whitmore WF Jr, Herr HW, et al: Flow cytometry follow-up in patients with low stage bladder tumor. J Urol 128: 88 –92, 1982. 8. Badalament RA, Kimmel M, Gay H, et al: The sensitivity of flow cytometry compared with conventional cytology in the detection of superficial bladder carcinoma. Cancer 59: 2078 – 2085, 1987.
35
ROLE OF VOIDED URINE CYTOLOGY IN DIAGNOSING PRIMARY URETHRAL CARCINOMA A. KARIM TOUIJER
AND
GUIDO DALBAGNI
ABSTRACT Objectives. To evaluate the role of voided urine cytology in diagnosing primary carcinoma of the urethra in male and female patients. Methods. We reviewed the medical records of all patients with urethral carcinoma seen at Memorial Sloan-Kettering Cancer Center between 1958 and 1996. The patients who had undergone voided urine cytology before any treatment were the subject of this report. Results. This report included 41 female and 29 male patients. In the cohort of female patients, the most common histologic type was adenocarcinoma (n ⫽ 16), followed by squamous cell carcinoma (SCC; n ⫽ 9) and transitional cell carcinoma (TCC; n ⫽ 6). Urine cytology was positive in 24 patients (59%). The sensitivity was greatest in patients with SCC (77%) and lowest in patients with TCC (50%). In the cohort of male patients, the most common histologic type was SCC (n ⫽ 14) followed by TCC (n ⫽ 10). Urine cytology was positive in 16 patients (55%). The sensitivity was greatest for patients with TCC (80%) and lowest for patients with SCC (50%). Conclusions. Voided urine cytology is not a very reliable method of diagnosing primary carcinoma of the urethra in either male or female patients. A cystoscopic evaluation with possible biopsy is warranted if suspicion of carcinoma of the urethra is high. UROLOGY 63: 33–35, 2004. © 2004 Elsevier Inc.
P
rimary urethral carcinoma is an uncommon disease, characterized by an advanced stage at diagnosis and, hence, a poor outcome.1 Unlike bladder cancer, urethral carcinoma shows clinical and histologic dissimilarities between male and female patients.2 In addition, unlike bladder cancer, the role of urine cytology as a diagnostic tool in primary urethral carcinoma is unknown. We evaluated the Memorial Sloan-Kettering Cancer Center series to define the role of voided urine cytology in diagnosing primary carcinoma of the urethra in male and female patients. MATERIAL AND METHODS
We reviewed the medical records of all patients with primary urethral carcinoma seen at Memorial Sloan-Kettering Cancer Center between 1958 and 1996. Excluded from the analysis were patients with urethral metastases, patients with secondary urethral tumors arising from surrounding organs, From the Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York Reprint requests: Guido Dalbagni, M.D., Department of Urology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 Submitted: May 15, 2003, accepted (with revisions): August 1, 2003 © 2004 ELSEVIER INC. ALL RIGHTS RESERVED
patients with concomitant or prior bladder cancer, and patients in whom pretreatment voided urine cytology was not available. The tumors were staged according to the TNM system of the International Union against Cancer.3 In the male and female patients, four variables were evaluated: pretreatment voided urine cytology, histologic type, stage, and site of disease, all of which were abstracted from the medical charts and pathology reports.
RESULTS This report included 41 female and 29 male patients with primary urethral carcinoma. In the cohort of female patients, the mean age was 58.4 years (range 34 to 88). The most common histologic type was adenocarcinoma (n ⫽ 16) followed by squamous cell carcinoma (SCC; n ⫽ 9) and transitional cell carcinoma (TCC; n ⫽ 6). The cancer involved the entire urethra in 18 patients (44%), proximal urethra in 10 (24%), and distal urethra in 6 (14%) and was located in a urethral diverticulum in 1 patient. Two thirds of the patients had T3 or T4 disease, 10 patients (24.3%) had positive nodes, and 1 had M1 disease (Table I). The urine cytology was positive in 24 patients (59%). The sensitivity was greatest in patients with SCC (77%) and lowest in patients with TCC 0090-4295/04/$30.00 doi:10.1016/j.urology.2003.08.007 33
TABLE I. Female patient characteristics Age (yr) Mean Range Tumor stage (n) Tx T0 Ta Tis T1 T2 T3 T4 N0 N⫹ Nx M0 M1 Histologic type (n) SCC TCC Epidermoid Adenocarcinoma Melanoma Small cell Anaplastic Lymphoma Site (n) Whole urethra Proximal Distal Not available Diverticulum
58.4 34–88 5 (12) 3 (7.3) 0 1 (2.4) 1 (2.4) 5 (12) 14 (34) 12 (29.2) 9 (21.9) 10 (24.3) 22 (53.6) 40 (97.5) 1 (2.4) 9 6 5 16 1 1 2 1
(21.9) (14.6) (12) (39) (2.4) (2.4) (4.8) (2.4)
18 10 6 6 1
(44) (24) (14) (14.6) (2.4)
KEY: SCC ⫽ squamous cell carcinoma; TCC ⫽ transitional cell carcinoma. Data in parentheses are percentages.
(50%). The sensitivity was greatest in patients with tumors involving the proximal or entire urethra (60% and 61%, respectively) and lowest in tumors involving the distal urethra (20%). In the cohort of male patients, the median age was 58.9 years (range 36 to 92). The most common histologic type was SCC (n ⫽ 14), followed by TCC (n ⫽ 10). The cancer involved the bulbomembranous urethra in 17 patients (59%) and pendulous urethra in 11 (38%). In 1 patient, both the anterior and bulbomembranous urethra were involved. The tumors were of an advanced stage in 22 patients (75.8%). Six patients had node-positive disease and one had distant metastases (Table II). The urine cytology was positive in 16 patients (55%). The sensitivity was greatest in patients with TCC (80%) and lowest in patients with SCC (50%). When evaluated in relation to tumor site, the sensitivity was greatest in patients with tumors involving the pendulous urethra (73%) and lowest in tumors involving the bulbomembranous urethra (40%). 34
TABLE II. Male patient characteristics Age (yr) Mean Range Tumor stage (n) Tx T0 Ta Tis T1 T2 T3 T4 N0 N⫹ Nx M0 M1 Histologic type (n) SCC TCC Epidermoid Anaplastic Site (n) Anterior and posterior Bulbomembranous Pendulous
58.9 36–92 1 (3.4) 0 1 (3.4) 1 (3.4) 4 (13.7) 12 (41) 8 (27.5) 2 (6.8) 8 (27.5) 6 (20.6) 15 (51.7) 28 (96.5) 1 (3.4) 14 10 4 1
(48) (34) (13.7) (3.4)
1 (3.4) 17 (59) 11 (38)
Abbreviations as in Table I. Data in parentheses are percentages.
COMMENT The treatment of primary urethral carcinoma in both male and female patients has lagged behind that of other cancers because of the scarcity of cases and the lack of uniformity in the management of this disease. The prognosis remains poor, because most of these patients’ tumors are high stage at diagnosis. In a previously published series from our institution, the 5-year survival rate was 36% for male patients with high-stage tumors and 83% for male patients with low-stage tumors. The 5-year survival rate was 22% for female patients with highstage and 78% for female patients with low-stage tumors.1,4 The strong association between survival rate and disease stage at diagnosis warrants efforts to detect primary urethral carcinoma at earlier stages. In the bladder, urine cytology is an important tool for screening and surveillance of TCC. However, it is characterized by a variable sensitivity. In low-grade lesions, the shed cells are well differentiated and closely resemble normal urothelial cells, thus making a distinction difficult. In a literature review of urine cytology in low-grade urothelial carcinoma, Renshaw et al.5 reported sensitivities ranging from 0% to 100% and specificities ranging from 6% to 100%. Efforts to enhance the reliability UROLOGY 63 (1), 2004
of urine cytology in low-grade urothelial carcinoma using distinctive nucleocytoplasmic features failed to reproduce prospectively the results obtained retrospectively.6 Sensitivity is also augmented when the voided cytology specimens are obtained on three separate days or by catheterization, rather than simple voiding. However, in high-grade bladder urothelial carcinoma and carcinoma in situ, urine cytology has an excellent track record, with a sensitivity of 90% and a specificity of 98% to 100%. In previously published Memorial Sloan-Kettering series, 98 patients with low-stage bladder cancer underwent 325 examinations during a 2-year interval. Cytology agreed with cystoscopy in 75% of the cases.7 In another series from the same institution, of 228 patients with histologically proven superficial bladder cancer, 110 had carcinoma in situ, 54 had Stage Ta, and 61 had Stage T1. The combined sensitivity for all tumors was 78% with four cytology examinations per patient. The cytologic sensitivities varied according to the category; it was greater in high-grade carcinoma in situ and Stage T1 disease than in low-grade Stage Ta disease.8 The role of urine cytology in primary carcinoma of the urethra is unknown. To our knowledge this is the first study to address this issue. In our experience of 41 female and 29 male patients with primary urethral carcinoma, the voided urine cytology sensitivity was relatively low, 59% and 55%, respectively. In the female cohort, the sensitivity was greatest for SCC, with adenocarcinoma as the most predominant histologic type. In the male cohort, the sensitivity was highest for TCC. Different results were also found between male and female patients regarding tumor site and urine
UROLOGY 63 (1), 2004
cytology sensitivity, with greater sensitivity for tumors involving the proximal or entire urethra in the female patients and greater sensitivity for distal tumors in the male patients. CONCLUSIONS Voided urine cytology is not a very reliable method of diagnosing primary carcinoma of the urethra in either male or female patients. A cystoscopic evaluation with biopsy is warranted if the index of suspicion for carcinoma of the urethra is high. REFERENCES 1. Dalbagni G, Zuo-feng Z, Lacombe L, et al: Male urethral carcinoma: analysis of treatment outcome. Urology 53: 1126 – 1132, 1999. 2. Amin M, and Young R: Primary carcinomas of the urethra. Semin Diagn Pathol 14: 147–160, 1997. 3. Beahrs O, Henson D, Hutter R, et al: Manual for Staging of Cancer, 4th ed. Philadelphia, Lippincott-Raven, 1992, pp 209 –213. 4. Dalbagni G, Zuo-feng Z, Lacombe L, et al: Female urethral carcinoma: analysis of treatment outcome and a plea for a standardized management strategy. Br J Urol 82: 835–841, 1998. 5. Renshaw A, Nappi D, and Weinberg D: Cytology of grade 1 papillary transitional cell carcinoma: a comparison of cytologic, architectural and morphometric criteria in cystoscopically obtained urine. Acta Cytol 40: 676 –682, 1996. 6. Raab S, Lenel J, and Cohen M: Low grade transitional carcinoma of the bladder: cytologic diagnosis by key features as identified by logistic regression analysis. Cancer 74: 1621– 1626, 1994. 7. Klein FA, Whitmore WF Jr, Herr HW, et al: Flow cytometry follow-up in patients with low stage bladder tumor. J Urol 128: 88 –92, 1982. 8. Badalament RA, Kimmel M, Gay H, et al: The sensitivity of flow cytometry compared with conventional cytology in the detection of superficial bladder carcinoma. Cancer 59: 2078 – 2085, 1987.
35