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Biopsy of Apparently Normal Urothelium in Patients with Bladder Carcinoma
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0022-5347/78/1205-0559$02. 00/0 Vol. 120, November
THE JOURNAL OF UROLOGY
Copyright © 1978 by The Williams & Wilkins Co.
Printed in U _S_A_
BIOPSY OF APPARENTLY NORMAL UROTHELIUM IN PATIENTS WITH BLADDER CARCINOMA N. M. HENEY,* J. DALY, G. R. PROUT, JR., P. T. NIEH, J. A. HEANEY
AND
N. E. TREBECK
From the Urological Service and Department of Pathology, Massachusetts General Hospital and Department of Surgery, Harvard Medical School, Boston, Massachusetts
ABSTRACT
We obtained 246 cold cup biopsies from pre-selected sites of apparently non-tumor-bearing bladder urothelium from 82 patients who presented with bladder cancer for the first time. Of 75 patients with transitional cell carcinoma 32 (43 per cent) suffered coincidental urothelial abnormalities, the most common being atypia. Significant abnormalities occurred more commonly (77 per cent) in association with high grade tumors than with low grade tumors (15 per cent). Detailed histological examination of cystectomy specimens has revealed a high incidence of atypia and carcinoma in situ in areas cystoscopically unsuspected of harboring malignancy. 1 • 2 To investigate the hypothesis that bladder cancer is a gross manifestation of a diffuse neoplastic diathesis of the urothelium a protocol was prepared by members of the National Bladder Cancer Collaborative Group A to study the cytopathological characteristics of normal appearing urothelium distant from and adjacent to bladder tumors, as well as the bladder tumors themselves. Preliminary results of the group's experience have been report."· ' We describe the findings in 82 patients presenting with their first bladder tumor(s) at our hospital.
significant proportion (5 per cent) occurred in patients less than 30 years old (see figure). Of the 246 biopsies 61 (26 per cent) revealed significant urothelial abnormalities (tables 2 and 3). Biopsies of mucosa adjacent to a visible tumor were abnormal most frequently (36 per cent), while those taken lateral to the right and left ureteral orifices and from the midline posteriorly revealed a slightly lower rate of abnormal findings, 22, 26 and 21 per
TABLE
1. D istribution of tumors within bladder %
Trigone Rt. orifice Lt. orifice Rt. wall Lt. wall Anterior wall Posterior wall Dome Neck Other
MATERIALS AND METHODS
Between November 1973 and October 1976, 322 bladder cancer patients were seen at our hospital. Of these patients 82 presented with the disease for the first time. From the latter group a total of 246 cold cup biopsies were taken from nontumorous urothelium lateral to the ureteral orifices, in the midline posteriorly, adjacent to the tumor and from the tumor itself. Pathological terms used in the biopsy reports included: 1) atypia - urothelial cells showing cytological and histological abnormalities tending towards anaplasia, 2) papilloma-exophytic papillary excrescence composed of a fibrovascular core covered by a normal thickness (3 to 7 layers) of normal urothelial cells and 3) hyperplasia-cytologically and histologically normal urothelium but with more than the norma l 3 to 7 layers of thickness. Urothelium described as showing cystitis is considered normal for the purpose of this report, recognizing that there may be an important but as yet undefined relationship between certain types of cystitis and bladder cancer.
11 13 11 17 17 2 14 6 9
DISTRIBUTION BY AGE OF 82 PATIENTS PRESENTING WITH THEIR FIRST BLADDER TUMOR 30
25
"RESULTS
~ osterior and lateral_y_esical walls (48 per ~ r e the most common tumor sites (table 1). The trigone and ne[griborhood of the urefeiaLorifi.ces--also__wei:e_irw-0-Lv-ed- freuentl (35 er cent). Tumors w und unc -onlµn.t he d~ome an antEll'.ior (8 p~ e v e r al patients presented with more than 1 visible tumor. The initial presentation of bladder carcinoma was most common in patients in the sixth decade (30 per cent) but a Accepted for publication March 10, 1978. Read at annual meeting of American Urological Association, Chicago, Illinois, April 24-28, 1977_ Supported in part by a grant from the United States Public Health Service, National Cancer Institute, National Bladder Cancer Project - CA15944 and by a grant from the Skerryvore Foundation, New York, New York. * Requests for reprints: Department of Urology, Massachusetts General Hospital, Boston, Massachusetts 02114. 559
0
20-29 30-39 40-49 50-59 60-69 70-79 80-89
AGE
560
HENEY AND ASSOCIATES
TABLE
can.c_er_harbor-GQincidenmLlat.enLaty.pical.Jll: malignant uroitis undert elium elsewhere in the bladder. In this con~ standa e w y the future course of low stage bladder cancer has been so difficult to prognosticate, since urologists traditionally have tended to concentrate on the presenting tumor and have tended to ignore the cystoscopically normal or inflamed urothelium elsewhere. Koss and associates recently drew attention to the finding of flat invasive carcinoma in cystectomy patients, which was unsuspected preoperatively.2
2. Number of abnormal selected mucosal biopsies relative to
s ite of origin No. Cases Adjacent to tumor Lateral to rt. orifice Lateral to It. orifice Midline posterior Other Totals
Abnormal No.(%) 12 15 18 15 1 61
33 68 68 70 7 246
TABLE
Adjacent to tumor Rt. orifice Lt. orifice Midline posterior Other Totals
TABLE
Ca
33 68 68 70 7
4
246
3. Results of biopsies in relation to biopsy site Cystitis Atypia GlanduMetaplasia Ca in Situ laris
5 1
7 12 11 11
10
41
1 2 2 1
1 1 1
1 1
6
3
2
Hyperplasia
Chronic Cystitis
Normal
1 1
10 23 19 22 4
11 29 30 32 2 104
2
78
4. Analysis of the most unfavorable biopsy in each patient and relationship to grade and cell type of tumor
Papilloma Ca in situ Grade I Grade II Grade III Adenoca. Squamous
TABLE
No.
(36) (22) (26) (21) (14) (26)
No. Pts.
Ca
Atypia
4 1 33 29 13 1 1
2 5 2
2 10 7
Metaplasia
Ca in Situ
HyperplaSia
Cystitis Glandularis
Chronic Cystitis 3
1
1
6 5 3
22 6
Normal Limits
1 1 1
1
5. Relationship of dysplastic biopsies to tumor grade in 75 patients with transitional cell carcinoma Tumor Grade
Abnormal Urothelial No.(%)
I II III
5/33 (15) 17/29 (59) 10/13 (77)
cent, respectively. Atypia was the most common urothelial abnormality and was present in 41 samples obtained from the 82 patients (17 per cent). The differentiation and the degree of differentiation of the bladder tumors were related to the biopsy findings (table 4). None of 4 patients with papilloma harbored abnormal urothelium apart from the tumor, while 5 of33 patients (15 per cent) with grade I carcinoma, 17 of 29 patients (59 per cent) with grade II carcinoma and 10 of 13 patients (77 per cent) with grade III carcinoma showed significant urothelial abnormalities (table 5). Thus, 32 of75 patients (43 per cent) with bladder cancer suffered coincidental urothelial abnormalities at sites other than the actual tumor. Transitional cell carcinoma was found in 9 patients (12 per cent), atypia in 19 (25 per cent) and carcinoma in situ in 2 (3 per cent) .
Our findings suggest that urothelial biopsy of selected sites in the bladder might be performed routinely in the patient undergoing (bladder) tumor biopsy so as to acquire more complete information regarding the urothelium. The possibility of tumor cell implantation at the biopsy sites exists and careful followup of patients whose bladders have been biopsied at sites distant to the tumor itself being conducted, particularly relating the sites of any future recurrence to previous biopsy sites. REFERENCES
1. Melicow, M. M. : Histological study of vesical urothelium inter-
2.
3.
4. 5.
DISCUSSION
These findings support the concept that bladder cancer is a 6. gross manifestation of a field change disease affecting urothelium_5- 7 The prognostic significance of abnormal urothelium 7. adjacent to or distant from the tumor can only be surmised at the moment and must await further followup. Althausen and a~ oci:~.tes h ID7e rep.or.tea-th e presence of atypia or carci- _., noma m sit u adjacent to the main tumor m 1cates a greater 8. likel'inood that m cl.e.i.r.1.¥ a s ~ll occur subsequently. 8 0 1::S results show that 43 per cent of patients with gross bladder /
vening between gross neoplasms in total cystectomy . J. Urol., 68: 261, 1952. Koss, L. G., Nakanishi, I. and Freed, S. Z.: Nonpapillary carcinoma in situ and atypical hyperplasia in cancerous bladder. Further studies of surgically removed bladder by mapping. Urology, 9: 442, 1977. National Bladder Cancer Collaborative Group A: Surveillance, initial assessment and subsequent progress in patients with superficial bladder cancer in a prospective longitudinal study. Cancer Res., 37: 2907, 1977. National Bladder Cancer Collaborative Group A: Cytology and histopathology of bladder cancer cases in a prospective longitudina l study. Cancer Res ., 37: 2911, 1977. Cooper, T . P., Wheelis, R. F ., Correa, R. J ., Jr., Gibbons, R. P ., Mason, J. T. and Cummings, K . B.: Random mucosa! biopsies in the evaluation of patients with carcinoma of the bladder. J. Urol., 117: 46, 1977. Schade, R. 0. and Swinney, J.: Pre-cancerous changes in bladder epithelium. Lancet, 2: 943, 1968. Gibbons, R. P., Mandler, J. I. and Hartmann, W. H.: The significance of epithelial atypia seen in non-invasive transitional cell papillary tumors of the bladder. J . Urol. , 102: 195, 1969. Althausen, A. F., Prout, G. R., Jr. and Daly, J. J. : Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ. J . Urol., 116: 575, 1976.
0022-5347/78/1205-0559$02. 00/0 Vol. 120, November
THE JOURNAL OF UROLOGY
Copyright © 1978 by The Williams & Wilkins Co.
Printed in U _S_A_
BIOPSY OF APPARENTLY NORMAL UROTHELIUM IN PATIENTS WITH BLADDER CARCINOMA N. M. HENEY,* J. DALY, G. R. PROUT, JR., P. T. NIEH, J. A. HEANEY
AND
N. E. TREBECK
From the Urological Service and Department of Pathology, Massachusetts General Hospital and Department of Surgery, Harvard Medical School, Boston, Massachusetts
ABSTRACT
We obtained 246 cold cup biopsies from pre-selected sites of apparently non-tumor-bearing bladder urothelium from 82 patients who presented with bladder cancer for the first time. Of 75 patients with transitional cell carcinoma 32 (43 per cent) suffered coincidental urothelial abnormalities, the most common being atypia. Significant abnormalities occurred more commonly (77 per cent) in association with high grade tumors than with low grade tumors (15 per cent). Detailed histological examination of cystectomy specimens has revealed a high incidence of atypia and carcinoma in situ in areas cystoscopically unsuspected of harboring malignancy. 1 • 2 To investigate the hypothesis that bladder cancer is a gross manifestation of a diffuse neoplastic diathesis of the urothelium a protocol was prepared by members of the National Bladder Cancer Collaborative Group A to study the cytopathological characteristics of normal appearing urothelium distant from and adjacent to bladder tumors, as well as the bladder tumors themselves. Preliminary results of the group's experience have been report."· ' We describe the findings in 82 patients presenting with their first bladder tumor(s) at our hospital.
significant proportion (5 per cent) occurred in patients less than 30 years old (see figure). Of the 246 biopsies 61 (26 per cent) revealed significant urothelial abnormalities (tables 2 and 3). Biopsies of mucosa adjacent to a visible tumor were abnormal most frequently (36 per cent), while those taken lateral to the right and left ureteral orifices and from the midline posteriorly revealed a slightly lower rate of abnormal findings, 22, 26 and 21 per
TABLE
1. D istribution of tumors within bladder %
Trigone Rt. orifice Lt. orifice Rt. wall Lt. wall Anterior wall Posterior wall Dome Neck Other
MATERIALS AND METHODS
Between November 1973 and October 1976, 322 bladder cancer patients were seen at our hospital. Of these patients 82 presented with the disease for the first time. From the latter group a total of 246 cold cup biopsies were taken from nontumorous urothelium lateral to the ureteral orifices, in the midline posteriorly, adjacent to the tumor and from the tumor itself. Pathological terms used in the biopsy reports included: 1) atypia - urothelial cells showing cytological and histological abnormalities tending towards anaplasia, 2) papilloma-exophytic papillary excrescence composed of a fibrovascular core covered by a normal thickness (3 to 7 layers) of normal urothelial cells and 3) hyperplasia-cytologically and histologically normal urothelium but with more than the norma l 3 to 7 layers of thickness. Urothelium described as showing cystitis is considered normal for the purpose of this report, recognizing that there may be an important but as yet undefined relationship between certain types of cystitis and bladder cancer.
11 13 11 17 17 2 14 6 9
DISTRIBUTION BY AGE OF 82 PATIENTS PRESENTING WITH THEIR FIRST BLADDER TUMOR 30
25
"RESULTS
~ osterior and lateral_y_esical walls (48 per ~ r e the most common tumor sites (table 1). The trigone and ne[griborhood of the urefeiaLorifi.ces--also__wei:e_irw-0-Lv-ed- freuentl (35 er cent). Tumors w und unc -onlµn.t he d~ome an antEll'.ior (8 p~ e v e r al patients presented with more than 1 visible tumor. The initial presentation of bladder carcinoma was most common in patients in the sixth decade (30 per cent) but a Accepted for publication March 10, 1978. Read at annual meeting of American Urological Association, Chicago, Illinois, April 24-28, 1977_ Supported in part by a grant from the United States Public Health Service, National Cancer Institute, National Bladder Cancer Project - CA15944 and by a grant from the Skerryvore Foundation, New York, New York. * Requests for reprints: Department of Urology, Massachusetts General Hospital, Boston, Massachusetts 02114. 559
0
20-29 30-39 40-49 50-59 60-69 70-79 80-89
AGE
560
HENEY AND ASSOCIATES
TABLE
can.c_er_harbor-GQincidenmLlat.enLaty.pical.Jll: malignant uroitis undert elium elsewhere in the bladder. In this con~ standa e w y the future course of low stage bladder cancer has been so difficult to prognosticate, since urologists traditionally have tended to concentrate on the presenting tumor and have tended to ignore the cystoscopically normal or inflamed urothelium elsewhere. Koss and associates recently drew attention to the finding of flat invasive carcinoma in cystectomy patients, which was unsuspected preoperatively.2
2. Number of abnormal selected mucosal biopsies relative to
s ite of origin No. Cases Adjacent to tumor Lateral to rt. orifice Lateral to It. orifice Midline posterior Other Totals
Abnormal No.(%) 12 15 18 15 1 61
33 68 68 70 7 246
TABLE
Adjacent to tumor Rt. orifice Lt. orifice Midline posterior Other Totals
TABLE
Ca
33 68 68 70 7
4
246
3. Results of biopsies in relation to biopsy site Cystitis Atypia GlanduMetaplasia Ca in Situ laris
5 1
7 12 11 11
10
41
1 2 2 1
1 1 1
1 1
6
3
2
Hyperplasia
Chronic Cystitis
Normal
1 1
10 23 19 22 4
11 29 30 32 2 104
2
78
4. Analysis of the most unfavorable biopsy in each patient and relationship to grade and cell type of tumor
Papilloma Ca in situ Grade I Grade II Grade III Adenoca. Squamous
TABLE
No.
(36) (22) (26) (21) (14) (26)
No. Pts.
Ca
Atypia
4 1 33 29 13 1 1
2 5 2
2 10 7
Metaplasia
Ca in Situ
HyperplaSia
Cystitis Glandularis
Chronic Cystitis 3
1
1
6 5 3
22 6
Normal Limits
1 1 1
1
5. Relationship of dysplastic biopsies to tumor grade in 75 patients with transitional cell carcinoma Tumor Grade
Abnormal Urothelial No.(%)
I II III
5/33 (15) 17/29 (59) 10/13 (77)
cent, respectively. Atypia was the most common urothelial abnormality and was present in 41 samples obtained from the 82 patients (17 per cent). The differentiation and the degree of differentiation of the bladder tumors were related to the biopsy findings (table 4). None of 4 patients with papilloma harbored abnormal urothelium apart from the tumor, while 5 of33 patients (15 per cent) with grade I carcinoma, 17 of 29 patients (59 per cent) with grade II carcinoma and 10 of 13 patients (77 per cent) with grade III carcinoma showed significant urothelial abnormalities (table 5). Thus, 32 of75 patients (43 per cent) with bladder cancer suffered coincidental urothelial abnormalities at sites other than the actual tumor. Transitional cell carcinoma was found in 9 patients (12 per cent), atypia in 19 (25 per cent) and carcinoma in situ in 2 (3 per cent) .
Our findings suggest that urothelial biopsy of selected sites in the bladder might be performed routinely in the patient undergoing (bladder) tumor biopsy so as to acquire more complete information regarding the urothelium. The possibility of tumor cell implantation at the biopsy sites exists and careful followup of patients whose bladders have been biopsied at sites distant to the tumor itself being conducted, particularly relating the sites of any future recurrence to previous biopsy sites. REFERENCES
1. Melicow, M. M. : Histological study of vesical urothelium inter-
2.
3.
4. 5.
DISCUSSION
These findings support the concept that bladder cancer is a 6. gross manifestation of a field change disease affecting urothelium_5- 7 The prognostic significance of abnormal urothelium 7. adjacent to or distant from the tumor can only be surmised at the moment and must await further followup. Althausen and a~ oci:~.tes h ID7e rep.or.tea-th e presence of atypia or carci- _., noma m sit u adjacent to the main tumor m 1cates a greater 8. likel'inood that m cl.e.i.r.1.¥ a s ~ll occur subsequently. 8 0 1::S results show that 43 per cent of patients with gross bladder /
vening between gross neoplasms in total cystectomy . J. Urol., 68: 261, 1952. Koss, L. G., Nakanishi, I. and Freed, S. Z.: Nonpapillary carcinoma in situ and atypical hyperplasia in cancerous bladder. Further studies of surgically removed bladder by mapping. Urology, 9: 442, 1977. National Bladder Cancer Collaborative Group A: Surveillance, initial assessment and subsequent progress in patients with superficial bladder cancer in a prospective longitudinal study. Cancer Res., 37: 2907, 1977. National Bladder Cancer Collaborative Group A: Cytology and histopathology of bladder cancer cases in a prospective longitudina l study. Cancer Res ., 37: 2911, 1977. Cooper, T . P., Wheelis, R. F ., Correa, R. J ., Jr., Gibbons, R. P ., Mason, J. T. and Cummings, K . B.: Random mucosa! biopsies in the evaluation of patients with carcinoma of the bladder. J. Urol., 117: 46, 1977. Schade, R. 0. and Swinney, J.: Pre-cancerous changes in bladder epithelium. Lancet, 2: 943, 1968. Gibbons, R. P., Mandler, J. I. and Hartmann, W. H.: The significance of epithelial atypia seen in non-invasive transitional cell papillary tumors of the bladder. J . Urol. , 102: 195, 1969. Althausen, A. F., Prout, G. R., Jr. and Daly, J. J. : Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ. J . Urol., 116: 575, 1976.