Brilish Journal of Urolowy (1978). 50, 496-501
Longitudinal Study of Bladder Cancer with Cytology and Biopsy S. LOENING, A. NARAYANA, L. YODER, D . SLYMEN, S. WEINSTEIN, G. PENICK and D. CULP Departments of Urology, Pathology and Preventive Medicine, University of lo wa Hospitals and Clinics, Iowa City, USA
Summary-A study of urinary cytology and selected mucosal biopsies in conjunction with cystoscopy provided additional information of value in the management of 31 8 patients with bladder cancer. These procedures were especially helpful in patients with no visible lesion on follow-up cystoscopies in assessing the bladder epithelium, the behaviour of which may be unpredictable in that no further tumours may occur, or they may arise at irregular intervals.
The study of urinary cytology and selected bladder mucosal biopsies provides additional material of value in classifying patients for further treatment and may have considerable prognostic significance. This report presents results from a prospective clinical investigation in which 3 18 bladder tumour patients were evaluated over a 4year period. Most of these patients had had cystoscopies, cytology and tumour biopsies as part of the initial evaluation or follow-up examinations. During the period of observation, 1265 specimens of bladder washings and urinary cytology and 758 tumour and/or selected mucosal biopsies were obtained. Since the prognosis may depend primarily on the nature and extent of changes in urothelium remaining after the removal of visible lesions, the value of longitudinal studies of urinary cytology and selected mucosal biopsies in detecting field changes in patients with bladder cancer is assessed.
Materials and Methods Between January 1974 and March 1978, 318 patients with bladder tumours were seen and treated at the University of Iowa. The initial evaluation and follow-up of these patients resulted in 1090 cystoscopic examinations. Specimens of 1265 bladder washings and urine cytology were collected. Tumour and/or selected mucosal biopsies were performed in 758 instances. Stage, grade, location and gross appearance of the lesions were recorded. Read at the 34th Annual Meeting of the British Association of Urological Surgeons in Brighton, June 1978.
496
Each time a patient had cystoscopically visible tumour, a deep biopsy of the neoplasm was obtained by electroresection for study of histological characteristics. Mucosal biopsy specimens were also obtained by cold punch technique from pre-selected normal-appearing sites (one lateral to each ureteric orifice, and one on the midposterior bladder wall) and areas adjacent to the tumour. When no tumour was visible but the cytology of the urinary bladder washings or urine was positive, biopsy specimens were obtained from the pre-selected normal-appearing sites and any areas which appeared suspicious. The site of each visible lesion and the site of each mucosal biopsy was recorded on a diagram or “map of the bladder’’ (Fig.). The presence of recurrent tumour, if any, the interval between the initial tumour diagnosis and resection and the site of recurrent tumour were recorded. All specimens were examined grossly and then processed, embedded in paraffin, sectioned and stained with Haematoxylin and Eosin. Bladder urine and saline bladder washings were obtained during cystoscopy from patients with suspected bladder tumour as well as from patients who were under surveillance. Bladder urine was collected through a urethral catheter. The bladder wash consisted of 50 ml of saline alternately injected into and aspirated from the bladder 5 times. The catheterised urine sample and saline bladder washings were collected separately in sterile containers. The volume and appearance were immediately recorded. An equal part of 50% ethyl alcohol was added and the container gently agitated and refrigerated until ready for preparation. All or part of each specimen was
497
LONGITUDINAL STUDY OF BLADDER CANCER WITH CYTOLOGY AND BIOPSY
Bladder Diagram Outline affected areas and indicate as follows F=-
Flat velvety area suspicious of Atypia of Ca in situ
s=
Sessile turnour
P= E=
JLPapillary turnour Bullous oderna
X = Biopsy site = Resection/
Fulguration
Patient’s Left
Patient’s Right Wall
Patient’s Left Wall
fig.
passed through 2 or more 8 micron Millipore filters. They were fixed overnight in 95% ethyl alcohol and stained with a modified Papanicolaou staining technique. One of 6 diagnostic categories was used to describe each cytology slide: (a) negative, (b) atypical cells present compatible with inflammatory origin, (c) radiation changes or drug effects, (d) suspicious for transitional cell cancer, (e) strongly suggestive for transitional cell cancer and (f) tumour cells definitely present. We are currently investigating our cytology specimens for changes typical of cancer in situ. Only the patients in whom tumour cells could definitely be identified were reviewed in this report.
Results Of 318 patients with a documented history of bladder tumour, 299 patients (94%) had cystoscopy as part of their initial evaluation. The morphological descriptions of the tumours found during initial cystoscopy are listed in Table 1 . At the time of our first evaluation, tumour was visible on cystoscopy in 278 patients, with some
patients showing more than one tumour type. No tumour was visible in 18 patients who had undergone treatment before coming to our institution. Two patients had no visible tumour but were evaluated because of recurrent cystitis with bladder biopsy revealing carcinoma in situ. Cystoscopy was positive, but no morphological description of tumour was recorded in 9 patients. Follow-up cystoscopic examinations showed no significant difference in tumour distribution from that found at the initial cystoscopy (Table 2). A total of 661 descriptions of tumour sites was recorded. The locations of these lesions are listed in Table 3. Follow-up cystoscopic examinations were positive in 271 of 791 examinations. Except for fewer tumours in the area of the trigone and lateral bladder walls, no appreciable difference in the distribution of tumours compared to the initial evaluation was found. Cystoscopy was considered positive not only when gross tumour was identified, but also when a suspicious area was seen which was histologically proven to be neoplasm. In 3 14 examinations cystoscopy, cytology and bladder biopsies were performed. A correlation of our cystoscopic findings with cytology and biopsy results is listed in Table 4. When the results of the initial and followup examinations are combined, tumour and/or selected mucosal biopsy confirmed the positive cystoscopic findings in 230 examinations (93%). In 18 (1 ~ V O )suspicious , areas were biopsied during cystoscopy, but the pathology findings were Table 1 Morphology of Tumours Tumour type
No.
Patients with visible tumour (%)
Papillary Flat Sessile No visible tumour Suspicious area No tumour description
179 29 I02 20
64.4 10.4 36.7
1
9
* Some patients had more than one tumour type. Table 2 Type of Tumour at Follow-up Cystoscopies ~
~~~~
~
~
Turnour type
No.
Follow-up exams with visible turnours (%)
Papillary Flat Sessile
153 46 81
56.5 17.0 29.9
498
BKlTlSH JOURNAL OF UKOLOGY
Table 3 Site of primary tumour Tumour site
Trigone Neck Left wall Right wall Right orifice Left orifice Posterior wall Anterior wall Dome Prostatic urethira Prostate Other
Site of tumour on follow-up
No. 87 91 84 96 61 66 52 35 46 26 I2 5
Patients with visible turnour (%)
31.3 32.7 30.2 34.5 21.9 23.7 18.3 12.6 16.5 9.3 4.3 1.8
66 1
No.
51 76 55
65 41 39 56 20 51 21 3 3
Follow-up exams with visible tumours (Yo)
18.8 28.0 20.3 24.0 15.1 14.4 20.7 7.4 18.8 1.7 1.1
1.1
48 I
suspicious area. In contrast, 24 (36%) of those examinations with negative cystoscopy had positive cytology and biopsy. In 52 examinations (21%) the cytology was negative and did not confirm the positive cystoscopic and pathological findings. Positive cytology was found in 6 examinations ( ~ Y O ) , although the selected mucosal biopsy and cystoscopy were both negative. In 11 examinations (4%), a positive cystoscopy and cytology could not be confirmed by bladder biopsy. This contrasts with 8 examinations (1 2 % ) in which the selected mucosal biopsies were positive although cystoscopy and cytology were both negative. A further correlation between the various Table 4 Correlation Between Findings on Cystoscopy, Cytology and Biopsy at Initial and Follow-up Evalua- biopsy findings and cytology reports is provided tions in Table 5 . Of 110 examinations with negative cytology specimens, 5 5 (SOTO) showed either A. Cystoscopy:positive transitional cell cancer or carcinoma in siru in the Cytology biopsy specimens, while 20 (18%) showed atypia and 35 (32%) corresponded with the negative Positive Negative cytology results. In 21 8 cytology specimens, Biopsy Positive 178 52 230 transitional cell cancer was either identified or Negative I1 7 18 suspected, and the biopsy confirmed these find189 59 248 ings in 186 specimens (85%), most of which (53%) showed transitional cell cancer, grade Ill. B. Cystoscopy: negative In 32 patients (IS%), the biopsy readings were either negative or showed only atypia while the Cytology cytologies were suggestive for transitional cell Positive Negative cancer. The initial tumour grade and stage did not Biopsy Positive 24 8 32 Negative 6 28 34 affect the 12-month recurrence rate as shown in 30 36 66 Tables 6 and 7. The 12-month overall recurrence rate was 47.1% (65/138).
negative. In 32 examinations (4870), the selected mucosal biopsies were positive although on gross inspection of the bladder no abnormalities were noted. In 34 examinations (52%) both the cystoscopic findings as well as the selected mucosal biopsies were negative. The cytology and biopsy findings were both positive for tumour in 178 (71%) of the 248 examinations with positive cystoscopy, while in 28 (42%) of the 66 examinations with negative cystoscopy, both these tests were negative. Cytology and biopsy were negative in 7 examinations (3%). although cystoscopy revealed a
499
LONGITUDINAL STUDY OF BLADDER CANCER WITH CYTOLOGY AND BIOPSY
Table 5 Correlation Between Cytology and Biopsy Findings at Initial and Follow-up Evaluations Cytology
Biopsy Atypia
Negative or normal lnflam changes Radldrug effect TCC Suspicious for TCC Strongly suggestive of TCC CIS
Total Negative or normal
20 1 6
15
{:
0
TCC grade I
35 4 5
17
TCC nrade I1
17 0 0
19 0 1
{! $ 12
0
TCC nrade I l l
56
{ii
0
98
(‘I
CIS
15 6 2
0
4 0
[i
20
1
0
110 11 15
218
{i! 10 1 355
Discussion From clinical experience it is known that the urothelium of certain patients has a tendency to develop recurrent bladder tumours. The mapping and histological studies of Koss et al. (1977), Farrow et al. (1976), Melicow (1952) and others and the giant section studies of Friedell (Soto er al., 1977) and of Schade (1972) confirmed that in many cases of bladder cancer there is an associated “field change”. The concept of a multicentric origin of bladder tumours was attributed to Hansemann (1 890). The distribution of bladder tumours was reported in several studies (Eisenberg et al., 1960; Koss et al., 1974; Koss et al., 1977; National Bladder Cancer Collaborative Group A, 1977a). The lateral and posterior walls, as well as the epithelium in the vicinity of bladder tumours, are most frequently involved by pre-cancerous lesions. Others have found that the most common site for vesical tumours, primary or recurrent, is posterolateral to the ureteric orifices (Greene et al., 1973). These findings have led us to biopsy routinely the area next to the tumour as well as to obtain mucosal biopsies lateral to each ureteric orifice and one in the midposterior wall. In our review, this is borne out by the fact that most tumours initially and also on subsequent visits can be found close to the trigone and the lateral bladder walls (Table 3). The first study of exfoliated cells from bladder cancer seems to be that published by Sanders (1865). Extensive cytological studies on urine were first published by Papanicolaou and Marshall (1945). In the study by the National Bladder Cancer Collaborative Group A (1977b), tumour grades were compared with cytology findings. While in patients with grade I or I1 1esions.the cytology confirmed the biopsy results in only 43
(47To), an excellent correlation (93%) was found
in grade I11 lesions. In our study in 355 examinations, cytology and biopsies were available for comparison (Table 5). In 218 patients the cytology showed malignant cells, but the biopsy was negative in 32 cases. This “false-positive” cytology rate of 14.7% can be attributed to the widely distributed microscopic mucosal alterations which appear normal on cystoscopic examination and can therefore be missed by biopsy, but form a basis for the frequently observed tumour recurrences (Kern et al., 1968; Schade, 1972; Cooper et al., 1977; Heney et al., 1977). Of greater concern is the fact that in 136 cases in which the cytology showed no malignant cells, the biopsy was positive in 65, for a false-negative rate of 47.8%. In grade I lesions, cytology confirmed the biopsy in 41 To, in grade I1 Table 6 Incidence of Recurrence Compared to Tumour Grade Initial grade
Recurrence No
Yes
1
8
8
16
I1
26
26
52
111
34
25
59
68
59
127
Table 7 Incidence of
Recurrence Compared to
Tumour Stage Initial stage
Recurrence No
Yes
0 or A
31
35
72
B, C, or D
30
21
51
67
56
123
500
7470, in grade 111 lesions in 81%, and in cancer in situ in 80%. The trend is obvious that cytology correlated best with the higher grades of bladder cancer (Kern et at., 1968; Esposti el al., 1970). Since the tendency to recurrent tumour formation is well recognised, the standard follow-up of patients with bladder turnours is to perform cystoscopy with biopsy of suspicious lesions. In 314 patients, bladder biopsies and cytologies were obtained and cystoscopies were performed (Table 4). In 8 patients (12%) only the bladder biopsy and in 6 patients (9v0) only the cytology was positive when cystoscopy was negative. This demonstrates that in all patients with recurrent bladder turnours, widespread disease of the bladder may exist which cannot be fully estimated by cystoscopic examination alone. The diagnostic accuracy of urinary cytology has been reported to be between 26% and 100% with a false-positive report rate of 1 to 12% (Kern et at., 1968; Harris et a/., 1971). Urinary cytology has not received widespread acceptance by urologists, probably because it is associated with a high incidence of false-positive as well as false-negative results. Nevertheless, it is particularly helpful in the detection of in situ and early invasive non-papillary cancer of the bladder, since cystoscopy in these patients may be normal or indistinguishable from changes of inflammation or other benign conditions. I t is clear that none of the tests, bladder biopsy, cytology, or cystoscopy, are sufficient alone in the work-up of patients with suspicion of bladder cancer. The practising urologist needs information to help him to determine which tumours will recur and how often to follow a patient with cystoscopy. In our study, the overall 12-month recurrence rate was 47.1% (Tables 6 and 7), and no prediction could be based on either tumour grade or stage. Over a one-year period, recurrent bladder carcinoma was noted in 33% of patients with stage 0 or A lesions in the surveillance study by the National Bladder Cancer Collaborative Group A (1977a). Other studies have recorded tumour recurrence in two-thirds with progression in one-third of patients who initially had low stage turnours (Kaplan et at., 195 1; Pyrah et at., 1964; Greene el at., 1973; Varkarakis et at., 1974).
Acknowledgement This investigation was supported by United States Public Health Service Grant C A 15933 from the National Cancer
BRITISH JOUKNAL OF UKOLOGY
Institute through the National Bladder Cancer Project. The authors wish to thank Ms Barbara Ziegler for her help in preparing the typescript.
References Cooper, T. P.. Wheelis, R. F., Correa, R. J., Jr., Gibbons, R. P . , Mason, J. T. and Cummings, K. B. (1977). Random mucosal biopsies in the evaluation of patients with carcinoma of the bladder. Journal of Urology. 117, 46-48. Eisenberg, R. B., Roth, B. R. and Schweinsberg, M. H. (1960). Bladder tumors and associated prolil'erative mucosal lesions. Journal of Urology. 84, 544-550. Esposti. P. L., Moberger, G. and Zajicek. J . (1970). The cytologic diagnosis of transitional cell tumors of the urinary bladder and its histologic basis. Acra Cyrologica. 14, 145-155.
Farrow, G. M., Utz, D. C. and Rife, C. C. (1976). Morphological and clinical observations of patients with early bladder cancer treated with total cystectomy. Cancer Research, 36, 2495-2501. Greene, L. F., Hanash, K. A. and Farrow, G. M. (1973). Benign papilloma or papillary carcinoma of the bladder? Journal of Urology, 110, 205-207. Hansemann, D. (1890). Ueber asymmetrische Zelltheilung in Epithelkrebsen und deren biologische Bedeutung. Virchow Archiv fur Parhologische Anaromie und Physiologie, 119, 299-326.
Harris, M. J.. Schwinn, C. P., Morrow, J . W . , Gray, R. L. and Browell. B. M. (1971). Exfoliative cytology of the urinary bladder irrigation specimen. Acra Cyrologica, IS, 385-399.
Heney, N. M., Szyfelbein. W. M., Daly, J. J.. Prout, G. R. and Bredin, H . C. (1977). Positive urinary cytology in patients without evident tumor. Journal of Urology, 117, 223-224.
Kaplan. J . H., McDonald, J. R. and Thompson, G. J. ( I 95 I ) . Multicentric origin of papillary tumors of the urinary tract. Journal of Urology, 66, 792-804. Kern, W. H., Bales, C. E. and Webster, W . W. (1968). Cytologic evaluation of transitional cell carcinoma of the bladder. Journal of Urology, 100, 616-622. Koss. L. G.. Nakanishi. 1. and Freed, S. %. (1977). Nonpapillary carcinoma in silu and atypical hyperplasia in cancerous bladders. Urology. 9, 442-455. Koss, L. G . , Tiamson, E. M. and Robbins, M. A. (1974). Mapping cancerous and precancerous bladder changes. A study of the urothelium in ten surgically removed bladders. Journal of rhe American Medical Associarion, 227, 28 1-286. Melicow, M. M. (1952). Histological study of vesical urothelium intervening between gross neoplasms in total cystectomy. Journal of Urology, 68, 261-279. National Bladder Cancer Collaborative Group A (1977a). Surveillance, initial assessment, and subsequent progress of patients with superficial bladder cancer in a prospective longitudinal study. Cancer Research, 37, 2907-2910. National Bladder Cancer Collaborative Group A (1977b). Cytology and histopathology of bladder cancer cases in a prospective longitudinal study. Cancer Reseurch, 37, 2911-2915.
Papanicolaou, G. N. and Marshall, V. F. (1945). Urine sedjment smears as a diagnostic procedure in cancers of the urinary tract. Science, 101. 519-520.
LONGITUDINAL STUDY OF BLADDER CANCER WITH CYTOLOGY AND BIOPSY
Pynh, L. N., Raper, F. P. and Thomas, G. M. (1964). Report of a follow-up of papillary tumours of the bladder. British Journal of Urology, 36, 14-25. Sanders, W. R. (1865). Cancer of the bladder. Fragments forming urethral plugs discharged in the urine. Concentric colloid bodies. Edinburgh Medical Journal, 10, 273-274. Schsde, R. 0. K. (1972). Some observations on the pathology and natural history of urothelial neoplasms. Beitrdge zur Pathologischen Anatomie, 145, 325-335. Soto. E. A., Friedell, G . H. and Tiltman, A. J. (1977). Bladder cancer as seen in giant histologic sections. Cancer, 39,44745.
501
A. Narayana, MD, Associate, Department of Urology, University of Iowa Hospitals and Clinics. L. Yoder, PAC, Physician’s Assistant, Department of Urology, University of Iowa Hospitals and Clinics. D. Slymen, MS, Research Assistant, Department of Preventive Medicine, University of Iowa Hospitals and Clinics. S. Weinstein, MD, Resident, Department of Urology, University of Iowa Hospitals and Clinics. G. Penick, MD, Professor and Head, Department of Pathology, University of Iowa Hospitals and Clinics. D. Culp, MD, Professor and Head, Department of Urology, University of Iowa Hospitals and Clinics.
Varkankis. M. J., Gaeta, J., Moore, R. H. and Murphy, G. P. (1974). Superficial bladder tumor: Aspects of clinical progression. Urology, 4, 414-420.
The Authors S . Loening, MD. Assistant Professor, Department of Urology, University of Iowa Hospitals and Clinics.
Requests for reprints to: S. Loening, Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA.
Longitudinal Study of Bladder Cancer with Cytology and Biopsy S. LOENING, A. NARAYANA, L. YODER, D . SLYMEN, S. WEINSTEIN, G. PENICK and D. CULP Departments of Urology, Pathology and Preventive Medicine, University of lo wa Hospitals and Clinics, Iowa City, USA
Summary-A study of urinary cytology and selected mucosal biopsies in conjunction with cystoscopy provided additional information of value in the management of 31 8 patients with bladder cancer. These procedures were especially helpful in patients with no visible lesion on follow-up cystoscopies in assessing the bladder epithelium, the behaviour of which may be unpredictable in that no further tumours may occur, or they may arise at irregular intervals.
The study of urinary cytology and selected bladder mucosal biopsies provides additional material of value in classifying patients for further treatment and may have considerable prognostic significance. This report presents results from a prospective clinical investigation in which 3 18 bladder tumour patients were evaluated over a 4year period. Most of these patients had had cystoscopies, cytology and tumour biopsies as part of the initial evaluation or follow-up examinations. During the period of observation, 1265 specimens of bladder washings and urinary cytology and 758 tumour and/or selected mucosal biopsies were obtained. Since the prognosis may depend primarily on the nature and extent of changes in urothelium remaining after the removal of visible lesions, the value of longitudinal studies of urinary cytology and selected mucosal biopsies in detecting field changes in patients with bladder cancer is assessed.
Materials and Methods Between January 1974 and March 1978, 318 patients with bladder tumours were seen and treated at the University of Iowa. The initial evaluation and follow-up of these patients resulted in 1090 cystoscopic examinations. Specimens of 1265 bladder washings and urine cytology were collected. Tumour and/or selected mucosal biopsies were performed in 758 instances. Stage, grade, location and gross appearance of the lesions were recorded. Read at the 34th Annual Meeting of the British Association of Urological Surgeons in Brighton, June 1978.
496
Each time a patient had cystoscopically visible tumour, a deep biopsy of the neoplasm was obtained by electroresection for study of histological characteristics. Mucosal biopsy specimens were also obtained by cold punch technique from pre-selected normal-appearing sites (one lateral to each ureteric orifice, and one on the midposterior bladder wall) and areas adjacent to the tumour. When no tumour was visible but the cytology of the urinary bladder washings or urine was positive, biopsy specimens were obtained from the pre-selected normal-appearing sites and any areas which appeared suspicious. The site of each visible lesion and the site of each mucosal biopsy was recorded on a diagram or “map of the bladder’’ (Fig.). The presence of recurrent tumour, if any, the interval between the initial tumour diagnosis and resection and the site of recurrent tumour were recorded. All specimens were examined grossly and then processed, embedded in paraffin, sectioned and stained with Haematoxylin and Eosin. Bladder urine and saline bladder washings were obtained during cystoscopy from patients with suspected bladder tumour as well as from patients who were under surveillance. Bladder urine was collected through a urethral catheter. The bladder wash consisted of 50 ml of saline alternately injected into and aspirated from the bladder 5 times. The catheterised urine sample and saline bladder washings were collected separately in sterile containers. The volume and appearance were immediately recorded. An equal part of 50% ethyl alcohol was added and the container gently agitated and refrigerated until ready for preparation. All or part of each specimen was
497
LONGITUDINAL STUDY OF BLADDER CANCER WITH CYTOLOGY AND BIOPSY
Bladder Diagram Outline affected areas and indicate as follows F=-
Flat velvety area suspicious of Atypia of Ca in situ
s=
Sessile turnour
P= E=
JLPapillary turnour Bullous oderna
X = Biopsy site = Resection/
Fulguration
Patient’s Left
Patient’s Right Wall
Patient’s Left Wall
fig.
passed through 2 or more 8 micron Millipore filters. They were fixed overnight in 95% ethyl alcohol and stained with a modified Papanicolaou staining technique. One of 6 diagnostic categories was used to describe each cytology slide: (a) negative, (b) atypical cells present compatible with inflammatory origin, (c) radiation changes or drug effects, (d) suspicious for transitional cell cancer, (e) strongly suggestive for transitional cell cancer and (f) tumour cells definitely present. We are currently investigating our cytology specimens for changes typical of cancer in situ. Only the patients in whom tumour cells could definitely be identified were reviewed in this report.
Results Of 318 patients with a documented history of bladder tumour, 299 patients (94%) had cystoscopy as part of their initial evaluation. The morphological descriptions of the tumours found during initial cystoscopy are listed in Table 1 . At the time of our first evaluation, tumour was visible on cystoscopy in 278 patients, with some
patients showing more than one tumour type. No tumour was visible in 18 patients who had undergone treatment before coming to our institution. Two patients had no visible tumour but were evaluated because of recurrent cystitis with bladder biopsy revealing carcinoma in situ. Cystoscopy was positive, but no morphological description of tumour was recorded in 9 patients. Follow-up cystoscopic examinations showed no significant difference in tumour distribution from that found at the initial cystoscopy (Table 2). A total of 661 descriptions of tumour sites was recorded. The locations of these lesions are listed in Table 3. Follow-up cystoscopic examinations were positive in 271 of 791 examinations. Except for fewer tumours in the area of the trigone and lateral bladder walls, no appreciable difference in the distribution of tumours compared to the initial evaluation was found. Cystoscopy was considered positive not only when gross tumour was identified, but also when a suspicious area was seen which was histologically proven to be neoplasm. In 3 14 examinations cystoscopy, cytology and bladder biopsies were performed. A correlation of our cystoscopic findings with cytology and biopsy results is listed in Table 4. When the results of the initial and followup examinations are combined, tumour and/or selected mucosal biopsy confirmed the positive cystoscopic findings in 230 examinations (93%). In 18 (1 ~ V O )suspicious , areas were biopsied during cystoscopy, but the pathology findings were Table 1 Morphology of Tumours Tumour type
No.
Patients with visible tumour (%)
Papillary Flat Sessile No visible tumour Suspicious area No tumour description
179 29 I02 20
64.4 10.4 36.7
1
9
* Some patients had more than one tumour type. Table 2 Type of Tumour at Follow-up Cystoscopies ~
~~~~
~
~
Turnour type
No.
Follow-up exams with visible turnours (%)
Papillary Flat Sessile
153 46 81
56.5 17.0 29.9
498
BKlTlSH JOURNAL OF UKOLOGY
Table 3 Site of primary tumour Tumour site
Trigone Neck Left wall Right wall Right orifice Left orifice Posterior wall Anterior wall Dome Prostatic urethira Prostate Other
Site of tumour on follow-up
No. 87 91 84 96 61 66 52 35 46 26 I2 5
Patients with visible turnour (%)
31.3 32.7 30.2 34.5 21.9 23.7 18.3 12.6 16.5 9.3 4.3 1.8
66 1
No.
51 76 55
65 41 39 56 20 51 21 3 3
Follow-up exams with visible tumours (Yo)
18.8 28.0 20.3 24.0 15.1 14.4 20.7 7.4 18.8 1.7 1.1
1.1
48 I
suspicious area. In contrast, 24 (36%) of those examinations with negative cystoscopy had positive cytology and biopsy. In 52 examinations (21%) the cytology was negative and did not confirm the positive cystoscopic and pathological findings. Positive cytology was found in 6 examinations ( ~ Y O ) , although the selected mucosal biopsy and cystoscopy were both negative. In 11 examinations (4%), a positive cystoscopy and cytology could not be confirmed by bladder biopsy. This contrasts with 8 examinations (1 2 % ) in which the selected mucosal biopsies were positive although cystoscopy and cytology were both negative. A further correlation between the various Table 4 Correlation Between Findings on Cystoscopy, Cytology and Biopsy at Initial and Follow-up Evalua- biopsy findings and cytology reports is provided tions in Table 5 . Of 110 examinations with negative cytology specimens, 5 5 (SOTO) showed either A. Cystoscopy:positive transitional cell cancer or carcinoma in siru in the Cytology biopsy specimens, while 20 (18%) showed atypia and 35 (32%) corresponded with the negative Positive Negative cytology results. In 21 8 cytology specimens, Biopsy Positive 178 52 230 transitional cell cancer was either identified or Negative I1 7 18 suspected, and the biopsy confirmed these find189 59 248 ings in 186 specimens (85%), most of which (53%) showed transitional cell cancer, grade Ill. B. Cystoscopy: negative In 32 patients (IS%), the biopsy readings were either negative or showed only atypia while the Cytology cytologies were suggestive for transitional cell Positive Negative cancer. The initial tumour grade and stage did not Biopsy Positive 24 8 32 Negative 6 28 34 affect the 12-month recurrence rate as shown in 30 36 66 Tables 6 and 7. The 12-month overall recurrence rate was 47.1% (65/138).
negative. In 32 examinations (4870), the selected mucosal biopsies were positive although on gross inspection of the bladder no abnormalities were noted. In 34 examinations (52%) both the cystoscopic findings as well as the selected mucosal biopsies were negative. The cytology and biopsy findings were both positive for tumour in 178 (71%) of the 248 examinations with positive cystoscopy, while in 28 (42%) of the 66 examinations with negative cystoscopy, both these tests were negative. Cytology and biopsy were negative in 7 examinations (3%). although cystoscopy revealed a
499
LONGITUDINAL STUDY OF BLADDER CANCER WITH CYTOLOGY AND BIOPSY
Table 5 Correlation Between Cytology and Biopsy Findings at Initial and Follow-up Evaluations Cytology
Biopsy Atypia
Negative or normal lnflam changes Radldrug effect TCC Suspicious for TCC Strongly suggestive of TCC CIS
Total Negative or normal
20 1 6
15
{:
0
TCC grade I
35 4 5
17
TCC nrade I1
17 0 0
19 0 1
{! $ 12
0
TCC nrade I l l
56
{ii
0
98
(‘I
CIS
15 6 2
0
4 0
[i
20
1
0
110 11 15
218
{i! 10 1 355
Discussion From clinical experience it is known that the urothelium of certain patients has a tendency to develop recurrent bladder tumours. The mapping and histological studies of Koss et al. (1977), Farrow et al. (1976), Melicow (1952) and others and the giant section studies of Friedell (Soto er al., 1977) and of Schade (1972) confirmed that in many cases of bladder cancer there is an associated “field change”. The concept of a multicentric origin of bladder tumours was attributed to Hansemann (1 890). The distribution of bladder tumours was reported in several studies (Eisenberg et al., 1960; Koss et al., 1974; Koss et al., 1977; National Bladder Cancer Collaborative Group A, 1977a). The lateral and posterior walls, as well as the epithelium in the vicinity of bladder tumours, are most frequently involved by pre-cancerous lesions. Others have found that the most common site for vesical tumours, primary or recurrent, is posterolateral to the ureteric orifices (Greene et al., 1973). These findings have led us to biopsy routinely the area next to the tumour as well as to obtain mucosal biopsies lateral to each ureteric orifice and one in the midposterior wall. In our review, this is borne out by the fact that most tumours initially and also on subsequent visits can be found close to the trigone and the lateral bladder walls (Table 3). The first study of exfoliated cells from bladder cancer seems to be that published by Sanders (1865). Extensive cytological studies on urine were first published by Papanicolaou and Marshall (1945). In the study by the National Bladder Cancer Collaborative Group A (1977b), tumour grades were compared with cytology findings. While in patients with grade I or I1 1esions.the cytology confirmed the biopsy results in only 43
(47To), an excellent correlation (93%) was found
in grade I11 lesions. In our study in 355 examinations, cytology and biopsies were available for comparison (Table 5). In 218 patients the cytology showed malignant cells, but the biopsy was negative in 32 cases. This “false-positive” cytology rate of 14.7% can be attributed to the widely distributed microscopic mucosal alterations which appear normal on cystoscopic examination and can therefore be missed by biopsy, but form a basis for the frequently observed tumour recurrences (Kern et al., 1968; Schade, 1972; Cooper et al., 1977; Heney et al., 1977). Of greater concern is the fact that in 136 cases in which the cytology showed no malignant cells, the biopsy was positive in 65, for a false-negative rate of 47.8%. In grade I lesions, cytology confirmed the biopsy in 41 To, in grade I1 Table 6 Incidence of Recurrence Compared to Tumour Grade Initial grade
Recurrence No
Yes
1
8
8
16
I1
26
26
52
111
34
25
59
68
59
127
Table 7 Incidence of
Recurrence Compared to
Tumour Stage Initial stage
Recurrence No
Yes
0 or A
31
35
72
B, C, or D
30
21
51
67
56
123
500
7470, in grade 111 lesions in 81%, and in cancer in situ in 80%. The trend is obvious that cytology correlated best with the higher grades of bladder cancer (Kern et at., 1968; Esposti el al., 1970). Since the tendency to recurrent tumour formation is well recognised, the standard follow-up of patients with bladder turnours is to perform cystoscopy with biopsy of suspicious lesions. In 314 patients, bladder biopsies and cytologies were obtained and cystoscopies were performed (Table 4). In 8 patients (12%) only the bladder biopsy and in 6 patients (9v0) only the cytology was positive when cystoscopy was negative. This demonstrates that in all patients with recurrent bladder turnours, widespread disease of the bladder may exist which cannot be fully estimated by cystoscopic examination alone. The diagnostic accuracy of urinary cytology has been reported to be between 26% and 100% with a false-positive report rate of 1 to 12% (Kern et at., 1968; Harris et a/., 1971). Urinary cytology has not received widespread acceptance by urologists, probably because it is associated with a high incidence of false-positive as well as false-negative results. Nevertheless, it is particularly helpful in the detection of in situ and early invasive non-papillary cancer of the bladder, since cystoscopy in these patients may be normal or indistinguishable from changes of inflammation or other benign conditions. I t is clear that none of the tests, bladder biopsy, cytology, or cystoscopy, are sufficient alone in the work-up of patients with suspicion of bladder cancer. The practising urologist needs information to help him to determine which tumours will recur and how often to follow a patient with cystoscopy. In our study, the overall 12-month recurrence rate was 47.1% (Tables 6 and 7), and no prediction could be based on either tumour grade or stage. Over a one-year period, recurrent bladder carcinoma was noted in 33% of patients with stage 0 or A lesions in the surveillance study by the National Bladder Cancer Collaborative Group A (1977a). Other studies have recorded tumour recurrence in two-thirds with progression in one-third of patients who initially had low stage turnours (Kaplan et at., 195 1; Pyrah et at., 1964; Greene el at., 1973; Varkarakis et at., 1974).
Acknowledgement This investigation was supported by United States Public Health Service Grant C A 15933 from the National Cancer
BRITISH JOUKNAL OF UKOLOGY
Institute through the National Bladder Cancer Project. The authors wish to thank Ms Barbara Ziegler for her help in preparing the typescript.
References Cooper, T. P.. Wheelis, R. F., Correa, R. J., Jr., Gibbons, R. P . , Mason, J. T. and Cummings, K. B. (1977). Random mucosal biopsies in the evaluation of patients with carcinoma of the bladder. Journal of Urology. 117, 46-48. Eisenberg, R. B., Roth, B. R. and Schweinsberg, M. H. (1960). Bladder tumors and associated prolil'erative mucosal lesions. Journal of Urology. 84, 544-550. Esposti. P. L., Moberger, G. and Zajicek. J . (1970). The cytologic diagnosis of transitional cell tumors of the urinary bladder and its histologic basis. Acra Cyrologica. 14, 145-155.
Farrow, G. M., Utz, D. C. and Rife, C. C. (1976). Morphological and clinical observations of patients with early bladder cancer treated with total cystectomy. Cancer Research, 36, 2495-2501. Greene, L. F., Hanash, K. A. and Farrow, G. M. (1973). Benign papilloma or papillary carcinoma of the bladder? Journal of Urology, 110, 205-207. Hansemann, D. (1890). Ueber asymmetrische Zelltheilung in Epithelkrebsen und deren biologische Bedeutung. Virchow Archiv fur Parhologische Anaromie und Physiologie, 119, 299-326.
Harris, M. J.. Schwinn, C. P., Morrow, J . W . , Gray, R. L. and Browell. B. M. (1971). Exfoliative cytology of the urinary bladder irrigation specimen. Acra Cyrologica, IS, 385-399.
Heney, N. M., Szyfelbein. W. M., Daly, J. J.. Prout, G. R. and Bredin, H . C. (1977). Positive urinary cytology in patients without evident tumor. Journal of Urology, 117, 223-224.
Kaplan. J . H., McDonald, J. R. and Thompson, G. J. ( I 95 I ) . Multicentric origin of papillary tumors of the urinary tract. Journal of Urology, 66, 792-804. Kern, W. H., Bales, C. E. and Webster, W . W. (1968). Cytologic evaluation of transitional cell carcinoma of the bladder. Journal of Urology, 100, 616-622. Koss. L. G.. Nakanishi. 1. and Freed, S. %. (1977). Nonpapillary carcinoma in silu and atypical hyperplasia in cancerous bladders. Urology. 9, 442-455. Koss, L. G . , Tiamson, E. M. and Robbins, M. A. (1974). Mapping cancerous and precancerous bladder changes. A study of the urothelium in ten surgically removed bladders. Journal of rhe American Medical Associarion, 227, 28 1-286. Melicow, M. M. (1952). Histological study of vesical urothelium intervening between gross neoplasms in total cystectomy. Journal of Urology, 68, 261-279. National Bladder Cancer Collaborative Group A (1977a). Surveillance, initial assessment, and subsequent progress of patients with superficial bladder cancer in a prospective longitudinal study. Cancer Research, 37, 2907-2910. National Bladder Cancer Collaborative Group A (1977b). Cytology and histopathology of bladder cancer cases in a prospective longitudinal study. Cancer Reseurch, 37, 2911-2915.
Papanicolaou, G. N. and Marshall, V. F. (1945). Urine sedjment smears as a diagnostic procedure in cancers of the urinary tract. Science, 101. 519-520.
LONGITUDINAL STUDY OF BLADDER CANCER WITH CYTOLOGY AND BIOPSY
Pynh, L. N., Raper, F. P. and Thomas, G. M. (1964). Report of a follow-up of papillary tumours of the bladder. British Journal of Urology, 36, 14-25. Sanders, W. R. (1865). Cancer of the bladder. Fragments forming urethral plugs discharged in the urine. Concentric colloid bodies. Edinburgh Medical Journal, 10, 273-274. Schsde, R. 0. K. (1972). Some observations on the pathology and natural history of urothelial neoplasms. Beitrdge zur Pathologischen Anatomie, 145, 325-335. Soto. E. A., Friedell, G . H. and Tiltman, A. J. (1977). Bladder cancer as seen in giant histologic sections. Cancer, 39,44745.
501
A. Narayana, MD, Associate, Department of Urology, University of Iowa Hospitals and Clinics. L. Yoder, PAC, Physician’s Assistant, Department of Urology, University of Iowa Hospitals and Clinics. D. Slymen, MS, Research Assistant, Department of Preventive Medicine, University of Iowa Hospitals and Clinics. S. Weinstein, MD, Resident, Department of Urology, University of Iowa Hospitals and Clinics. G. Penick, MD, Professor and Head, Department of Pathology, University of Iowa Hospitals and Clinics. D. Culp, MD, Professor and Head, Department of Urology, University of Iowa Hospitals and Clinics.
Varkankis. M. J., Gaeta, J., Moore, R. H. and Murphy, G. P. (1974). Superficial bladder tumor: Aspects of clinical progression. Urology, 4, 414-420.
The Authors S . Loening, MD. Assistant Professor, Department of Urology, University of Iowa Hospitals and Clinics.
Requests for reprints to: S. Loening, Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA.
