Urinary Cytology in the Detection of Bladder Carcinoma J. M. O'Donoghue, P. G. Horgan, M. Corcoran*, H. Bredin*, M. McGuire, H. F. Given
Department of Surgery and Urology*, University College Hospital, Galway Abstract We have analysed the accuracy of cytological examination of voided urine in a population of 265 patients presenting with suspected bladder lesions. Bladder carcinoma was confirmed by tissue histopathology in 51 patients. Of these, 42 were identified correctly by urinary cytology examination. Overall 34 patients were labelled as frankly malignant on cytology, of whom 2 were negative on final histology. 13 patients had been designated as suspicious however with 3 benign on final histological diagnosis. These data give a sensitivity for diagnosis of bladder cancer by urinary cytology of 82 %, a specificity of 97%, a positive predictive value of 94%, and a negative predictive value of 96%. TABLE I Criteria for cytological diagnosis.
Introduction The diagnosis of bladder cancer is most commonly made on the basis of cystoscopically aided biopsy. The use of urinary cytology has been mainly confined to that of an adjuvant role in the diagnosis and follow up of such patients. The pioneer.ing work of Papanicoleau in 1947xfirst established exfoliative urinary cytology as a proven diagnostic aid in the detection of renal tract tumours. Since then the method has had widespread use, and has been further refined by procedures to wash the bladder before obtaining a sample, or to obtain urinary catheter sample for cytological assessment. However in recent years newer diagnostic aids have been introduced for diagnosis of urological malignancies such as flow cytometry with great success, and have questioned the value of cytology alone. Nevertheless voided urine cytolgy remains to be useful to monitor patients with superficial bladder tumours, upper renal tract tumours and those with in situ and early invasive changes. The accuracy of exfoliative urine cytology has been assessed in a number of studies but the range of reported sensitivities for the diagnosis of urological malignancy has indeed been wide, with overall sensitivity varying from 41% to 100%. We have therefore reviewed the accuracy of voided urine cytology in our hands in apopulation of patients presenting to this department of urology with suspected lesions of the bladder. We have further looked at the morphological lesions of the bladder tumour, the site of the tumour and the diagnostic yield by voided urinary cytology with regard to the histological grade of the malignancy.
Benign: Suspicious:
Malignant:
Normal transitional cells Mild nuclear changes Variation in cell size Coarse nuclear chromatin Thickened nuclear envelope Multi-nucleoli Dense chromatin granules Irregular/multiple nucleoli Irregular/enlarged nuclear border Unfavourable ratio nucleus: cytoplasm Unfavourable ratio nucleus: nucleoli
Once obtained, urine samples were immediately transferred to the Cytology Unit of the Department of Surgery for assessment. The urine specimens were centrifuged, and a smear prepared from the cellular deposit. This was subsequently stained with Papanicoleau stain and inspected using standard light microcscopy. The slides were evaluated by a single experienc~ cytologist (MMcG), and classified into one of three groups: malignant, suspicious of malignancy or benign (Table I). These results were then compared with the final histological diagnosis obtained by biopsy to determine the overall usefulness of voided cytology. The sensitivity of the technique was the proportion of patients with carcinoma of the bladder who had a positive test result; the specificity was the proportion of patients with benign disease who had a negative test finding. The positive predictive value of a malignant diagnosis measured its correctness, and was the fraction of all malignant cytological diagnoses that was confirmed by histological examination. The false-positive rate was calculated as 100 per cent minus the specificity, and the false-negative rate was 100 per cent minus the sensitivity.
Patients and Methods A single random sample of voided urine was sent for cytological assessment in 265 patients presenting to this surgical unit with suspected bladder lesions. Presenting symptomatology included haematuria, suprapubic pain and recurrent cystitis in all patients. Subsequently all patients had intravenous urographic examination of the renal tract, cystoscopy with biopsy and bimanual examination under general anaesthesia.
Results Of a total of 265 patients investigated with suspected bladder mitotic lesions, 51 patients had a confirmed bladder malignancy on final histological diagnosis. 37 were male and 14 were female with a mean age of 62 years (range 5-92). 42 patients were correctly identified as malignant by voided cytological examination, of whom 32 had been designated frankly malignant by cytology. 13 patients had been labelled as suspicious of malignancy, but of these, 3 proved to be
Correspondence to: Mr. Paul G. Horgan, Surgical Professorial Unit, University College Hospital, Galway. 352
Urinary Cytology in the Detection of Bladder Carcinoma 353
Vol.16o No. 11
TABLE IV Diagnostic yield.
TABLE II Cytological diagnosis and histology. Cytology
Final Diagnosis Benign Malignant
Grade of Tumour Carcinoma in situ (IS) Well differentiated (I) Moderately diff. (1I) Poorly diff. (HI) Anaplastic (Ill)
Malignant Suspicious Bemgn
34 13 218
2 3 209
32 10 9
TOTAL
265
219
51
TOTAL benign on final histopathological diagnosis. 218 patients were deemed benign after cytological assessment, and 209 patients were indeed benign when results were correlated with histology, but 9 patients in this group were malignant on final diagnosis (Table II). When we looked at the morphology of these bladder tumours, we found that 41 were papillary in nature, and 83% of these were correctly identified by cytology. 8 tumours were of the solid type, and the diagnostic yield by cytology was 6 correctly detected. Both of the 2 tumours with mixed morphology were detected by cytology (Table III). 12 tumours were in the base of the bladder, 19 were situated in the bladder trigone, and 20 were adjacent to the ureteric orifices. In each case the diagnostic yield by cytological assessment was close to 80% with no differences in detection rates depending on tumour site. Finally we looked at the grade of the tumour. 16 cancers were designated in situ on histology, and all 16 were correctly diagnosed as malignant on cytology. 14 tumours were well differentiated grade 1 malignancies, but only 8 (57%) were detected by voided cytological assessment. 13 cancers were grade 2 disease, with 10 tumours detected correctly (77%). 7 tumours were poorly differentiated (grade 3), and here all 7 were correctly identified as malignant on cytology (Table IV). When we compile these results, we find that the sensitivity for cytological diagnosis of bladder cancer in our hands was 82%, and the specificity was 97%. The positive predictive value was 94% and the negative predictive value was 96%. Discussion Carcinoma of the bladder, especially transitional cell carcinoma, tends to remain within the bladder until late in the course of illness. The development of extramural and metastatic disease may well influence treatment, and thus it is important to know whether an investigation such as voided urine cytological analysis can give consistently positive resuits. It is generally accepted that voided urine cytology is a useful test in high grade tumours, but that it is difficult to
TABLE III Diagnostic yield. Morphology
Number
Number 16 14 13 7 1
True Positive (malignant/suspicious) 100% 57% 77% 100% 100%
51
distinguish well-differentiated, low grade tumours from normal exfoliated epithelium. Curling et al in 19862, reported on the result of cytological testing on the urine of 260 new cases of histologically proven urothelial cancer, and found that cytology was positive or suspicious in 63% and negative in 37%. They found that cytolgy was most often accurate when urothelial tumours were large, papillary, and solid, moderately or poorly differentiated, and invasive (T2-4). Esposti etal, in 19703, reported similar results amongst a group of 170 untreated bladder cancers. Once again the main determinant of a positive cytological disagnosis was the degree of differentiation of the cancer, with only 40% of well-differentiated tumours giving a positive diagnosis. It appears from the literature therefore, that voided mine cytology cannot replace the well tested methods of investigation of the urinary tract such as intravenous urography and -cystoscopy with biopsy, in the diagnosis of bladder cancer. Nevertheless a number of investigators believe the test to have a useful supplementary role 2,4. We have, in this paper, also described similar results with regard to higher pick-up rates with decreasing tumour differentiadon, but report a higher sensitivity and specificity for diagnosis of bladder cancer by voided urine cytology. No correlation was found between morphology or site of tumour within the bladder, and a positive cytological diagnosis. It was striking, however, to note the 100% pick-up rate for voided urine" cytology with in-situ carcinoma of the bladder. This finding alone gives a clear indication for the continued use of the investigation in the diagnosis and particularly in the follow-up of the patient with carcinoma of the bladder. In summary therefore, voided urine cytology was a rapid, easy inexpensive and painless method of diagnosing bladder carcinoma. We would be concemed, however to recommend that definitive therapy be planned based solely on.the results of urinary cytology. The test is unreliable in the presence of well differentiated grade 1 and 2 disease. References
True positive
Papillary Solid Mixed
41 8 2
34 (83%) 6 (75%) 2 (100%)
TOTAL
51
42
1. Papanicoleau, G.N. Cytology of the urine sediment in neoplasms of the renal tract. J. Urol. 1947: 57, 375-9. 2. Curling,M., Broome, G., Hendry, W. F. How accurate is urine cytology? J. Roy. Soc. Med. 1986: 79, 336-339. 3. Esposti, P. L., Moberger, G., Zajicek, J. The cytological diagnosis of transitional cell turnouts of the urinary bladder and its histological basis. Acta Cytol. (Baltimore) 1970: 14, 145-155. 4. Murphy, W. M., Soloway, M. S., Jukkola, A. F., Crabtree, W. N., Ford, K.S. Urinary cytolgy and bladder cancer: the cellular features of transitional cell neoplasms. Cancer 1984: 53, 1555-65.
Department of Surgery and Urology*, University College Hospital, Galway Abstract We have analysed the accuracy of cytological examination of voided urine in a population of 265 patients presenting with suspected bladder lesions. Bladder carcinoma was confirmed by tissue histopathology in 51 patients. Of these, 42 were identified correctly by urinary cytology examination. Overall 34 patients were labelled as frankly malignant on cytology, of whom 2 were negative on final histology. 13 patients had been designated as suspicious however with 3 benign on final histological diagnosis. These data give a sensitivity for diagnosis of bladder cancer by urinary cytology of 82 %, a specificity of 97%, a positive predictive value of 94%, and a negative predictive value of 96%. TABLE I Criteria for cytological diagnosis.
Introduction The diagnosis of bladder cancer is most commonly made on the basis of cystoscopically aided biopsy. The use of urinary cytology has been mainly confined to that of an adjuvant role in the diagnosis and follow up of such patients. The pioneer.ing work of Papanicoleau in 1947xfirst established exfoliative urinary cytology as a proven diagnostic aid in the detection of renal tract tumours. Since then the method has had widespread use, and has been further refined by procedures to wash the bladder before obtaining a sample, or to obtain urinary catheter sample for cytological assessment. However in recent years newer diagnostic aids have been introduced for diagnosis of urological malignancies such as flow cytometry with great success, and have questioned the value of cytology alone. Nevertheless voided urine cytolgy remains to be useful to monitor patients with superficial bladder tumours, upper renal tract tumours and those with in situ and early invasive changes. The accuracy of exfoliative urine cytology has been assessed in a number of studies but the range of reported sensitivities for the diagnosis of urological malignancy has indeed been wide, with overall sensitivity varying from 41% to 100%. We have therefore reviewed the accuracy of voided urine cytology in our hands in apopulation of patients presenting to this department of urology with suspected lesions of the bladder. We have further looked at the morphological lesions of the bladder tumour, the site of the tumour and the diagnostic yield by voided urinary cytology with regard to the histological grade of the malignancy.
Benign: Suspicious:
Malignant:
Normal transitional cells Mild nuclear changes Variation in cell size Coarse nuclear chromatin Thickened nuclear envelope Multi-nucleoli Dense chromatin granules Irregular/multiple nucleoli Irregular/enlarged nuclear border Unfavourable ratio nucleus: cytoplasm Unfavourable ratio nucleus: nucleoli
Once obtained, urine samples were immediately transferred to the Cytology Unit of the Department of Surgery for assessment. The urine specimens were centrifuged, and a smear prepared from the cellular deposit. This was subsequently stained with Papanicoleau stain and inspected using standard light microcscopy. The slides were evaluated by a single experienc~ cytologist (MMcG), and classified into one of three groups: malignant, suspicious of malignancy or benign (Table I). These results were then compared with the final histological diagnosis obtained by biopsy to determine the overall usefulness of voided cytology. The sensitivity of the technique was the proportion of patients with carcinoma of the bladder who had a positive test result; the specificity was the proportion of patients with benign disease who had a negative test finding. The positive predictive value of a malignant diagnosis measured its correctness, and was the fraction of all malignant cytological diagnoses that was confirmed by histological examination. The false-positive rate was calculated as 100 per cent minus the specificity, and the false-negative rate was 100 per cent minus the sensitivity.
Patients and Methods A single random sample of voided urine was sent for cytological assessment in 265 patients presenting to this surgical unit with suspected bladder lesions. Presenting symptomatology included haematuria, suprapubic pain and recurrent cystitis in all patients. Subsequently all patients had intravenous urographic examination of the renal tract, cystoscopy with biopsy and bimanual examination under general anaesthesia.
Results Of a total of 265 patients investigated with suspected bladder mitotic lesions, 51 patients had a confirmed bladder malignancy on final histological diagnosis. 37 were male and 14 were female with a mean age of 62 years (range 5-92). 42 patients were correctly identified as malignant by voided cytological examination, of whom 32 had been designated frankly malignant by cytology. 13 patients had been labelled as suspicious of malignancy, but of these, 3 proved to be
Correspondence to: Mr. Paul G. Horgan, Surgical Professorial Unit, University College Hospital, Galway. 352
Urinary Cytology in the Detection of Bladder Carcinoma 353
Vol.16o No. 11
TABLE IV Diagnostic yield.
TABLE II Cytological diagnosis and histology. Cytology
Final Diagnosis Benign Malignant
Grade of Tumour Carcinoma in situ (IS) Well differentiated (I) Moderately diff. (1I) Poorly diff. (HI) Anaplastic (Ill)
Malignant Suspicious Bemgn
34 13 218
2 3 209
32 10 9
TOTAL
265
219
51
TOTAL benign on final histopathological diagnosis. 218 patients were deemed benign after cytological assessment, and 209 patients were indeed benign when results were correlated with histology, but 9 patients in this group were malignant on final diagnosis (Table II). When we looked at the morphology of these bladder tumours, we found that 41 were papillary in nature, and 83% of these were correctly identified by cytology. 8 tumours were of the solid type, and the diagnostic yield by cytology was 6 correctly detected. Both of the 2 tumours with mixed morphology were detected by cytology (Table III). 12 tumours were in the base of the bladder, 19 were situated in the bladder trigone, and 20 were adjacent to the ureteric orifices. In each case the diagnostic yield by cytological assessment was close to 80% with no differences in detection rates depending on tumour site. Finally we looked at the grade of the tumour. 16 cancers were designated in situ on histology, and all 16 were correctly diagnosed as malignant on cytology. 14 tumours were well differentiated grade 1 malignancies, but only 8 (57%) were detected by voided cytological assessment. 13 cancers were grade 2 disease, with 10 tumours detected correctly (77%). 7 tumours were poorly differentiated (grade 3), and here all 7 were correctly identified as malignant on cytology (Table IV). When we compile these results, we find that the sensitivity for cytological diagnosis of bladder cancer in our hands was 82%, and the specificity was 97%. The positive predictive value was 94% and the negative predictive value was 96%. Discussion Carcinoma of the bladder, especially transitional cell carcinoma, tends to remain within the bladder until late in the course of illness. The development of extramural and metastatic disease may well influence treatment, and thus it is important to know whether an investigation such as voided urine cytological analysis can give consistently positive resuits. It is generally accepted that voided urine cytology is a useful test in high grade tumours, but that it is difficult to
TABLE III Diagnostic yield. Morphology
Number
Number 16 14 13 7 1
True Positive (malignant/suspicious) 100% 57% 77% 100% 100%
51
distinguish well-differentiated, low grade tumours from normal exfoliated epithelium. Curling et al in 19862, reported on the result of cytological testing on the urine of 260 new cases of histologically proven urothelial cancer, and found that cytology was positive or suspicious in 63% and negative in 37%. They found that cytolgy was most often accurate when urothelial tumours were large, papillary, and solid, moderately or poorly differentiated, and invasive (T2-4). Esposti etal, in 19703, reported similar results amongst a group of 170 untreated bladder cancers. Once again the main determinant of a positive cytological disagnosis was the degree of differentiation of the cancer, with only 40% of well-differentiated tumours giving a positive diagnosis. It appears from the literature therefore, that voided mine cytology cannot replace the well tested methods of investigation of the urinary tract such as intravenous urography and -cystoscopy with biopsy, in the diagnosis of bladder cancer. Nevertheless a number of investigators believe the test to have a useful supplementary role 2,4. We have, in this paper, also described similar results with regard to higher pick-up rates with decreasing tumour differentiadon, but report a higher sensitivity and specificity for diagnosis of bladder cancer by voided urine cytology. No correlation was found between morphology or site of tumour within the bladder, and a positive cytological diagnosis. It was striking, however, to note the 100% pick-up rate for voided urine" cytology with in-situ carcinoma of the bladder. This finding alone gives a clear indication for the continued use of the investigation in the diagnosis and particularly in the follow-up of the patient with carcinoma of the bladder. In summary therefore, voided urine cytology was a rapid, easy inexpensive and painless method of diagnosing bladder carcinoma. We would be concemed, however to recommend that definitive therapy be planned based solely on.the results of urinary cytology. The test is unreliable in the presence of well differentiated grade 1 and 2 disease. References
True positive
Papillary Solid Mixed
41 8 2
34 (83%) 6 (75%) 2 (100%)
TOTAL
51
42
1. Papanicoleau, G.N. Cytology of the urine sediment in neoplasms of the renal tract. J. Urol. 1947: 57, 375-9. 2. Curling,M., Broome, G., Hendry, W. F. How accurate is urine cytology? J. Roy. Soc. Med. 1986: 79, 336-339. 3. Esposti, P. L., Moberger, G., Zajicek, J. The cytological diagnosis of transitional cell turnouts of the urinary bladder and its histological basis. Acta Cytol. (Baltimore) 1970: 14, 145-155. 4. Murphy, W. M., Soloway, M. S., Jukkola, A. F., Crabtree, W. N., Ford, K.S. Urinary cytolgy and bladder cancer: the cellular features of transitional cell neoplasms. Cancer 1984: 53, 1555-65.
