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Benign Papilloma or Papillary Carcinoma of the Bladder?
THE JDUFJ\l).:.
U:?,OLC-GY
Copyright © 1973 by 'The 1JlJilEan1s
Vlilkins
BENIGN PAPILLOMA OR PAPILLARY CARCINOMA OF THE BLADDER? LAURENCE F. GREENE, KAMAL A. HANASH
AND
GEORGE M. FARROW
From the Mayo Clinic and Mayo Foundation, Rochester, Minnesota
The proper histopathologic classification and biologic potential of transitional cell papilloma or epithelioma of the bladder remain uncertain and controversiaL The gross appearance and the histologic and cytologic features of this tumor convey the impression of benignancy, with limited potential for aggressive growth. However, experience has revealed that recurrent tumors and invasive carcinoma may occur and aggressive malignancy may develop. Herein we have attempted to define this tumor, shed some light on its history as affected by treatment and discuss its place among the benign and malignant neoplasms of the bladder. Transitional cell papilloma, well differentiated transitional cell epithelioma and grade 1 transitional cell carcinoma are used interchangeably to designate a tumor composed of transitional epithelial cells arranged in a papillary, frond-like growth on a basement membrane with delicate intervening stroma of reticulin fibers and vascular channels. The typical iayering of the transitional cells is maintained, the cells do not differ significantly in their cytologic features from normal transitional cells and the rate of mitotic activity is not appreciably greater than that in normal transitional epithelium (see figure). MATERIALS AND METHODS
We reviewed clinical records, operative findings, pathologic specimens and, when available, autopsy protocols of 100 consecutive patients with vesical tumors first seen at the Mayo Clinic between 1949 and 1951. The diagnosis in each case was grade l transitional cell carcinoma.' None of the patients had been previously treated for vesical neoplasm. All tumors were removed by the transurethral approach, with electrocoagulation of the base. Each patient was advised to return periodically for cystoscopic examination and such other studies as seemed indicated. ~uos,eq1.1e11t forms of treatment consisted of thio-tepa '-'"'"""'·" administration of ascorbic acid or 5-fluorouracil, irradiation, resection or total cystectomy. was for 15 years or more in all cases. A of the initial and subsequent examinations was recorded. Histologic sections of ail biopsy IY"''""'·""''·'" were reviewed and graded according to the method of Brode:rs. 1 Major and contributing causes of death were ascertained from autopsy protocols or medical reports by the family physician. Accepted for publication December 29, 197?, . 1 Broders, A. C.: Epithelioma of the gemto-unnary organs. Ann. Surg., 75: 574, 1922. 205
RESULTS
The majority of patients were in the sixth or seventh decade of life; the youngest was 33 and the oldest was 79 years old. Men predominated in a ratio of approximately 3 to 1 (72 men to 28 women). The duration of urinary symptoms before diagnosis varied from 1 day to more than 20 years; 44 patients delayed seeking medical assistance for more than a year after onset of symptoms. The most common complaint (73 per cent) was intermittent, painless, gross hematuria (table 1). The hematuria was considered terminal by 10 patients "'nd initial by 2, whereas the other patients described it as total, spotty or continuous. Urinalysis revealed various degrees of microhematuria in 85 per cent of the patients and pyuria in 61 per cent. Thirty-three patients had microhematuria of grade 1 (3 to 8 cells per high power field). Findings on excretory urography (IVP) were normal in 56 patients and revealed a filling defect in the bladder suggestive of vesical neoplasm in 35 patients. Hydronephrosis was present unilaterally in 6 patients and bilaterally in 1. Two patients had a non-functioning kidney. The cystoscopic appearance of the tumors did not vary significantly and most of the lesions were described as villous, pedunculated, frond-like structures attached to the bladder by a narrow pedicle. The most common location ( 45 per cent) of the initial single and multiple tumors was over the base adjacent to the ureteral orifice (table 2). Initial lesions were solitary in 74 patients and in 26 (table 3). Seventy-three per cent of the patients had recurrent tumors and the number of recurrences varied from 1 to 20 per patient with a mean of 6. The incidence of recurrent tumors was significantly higher (88 per cent) in patients who presented with multiple tumors than in those whose original tumor was single (68 per cent, table 3). the the the greater was the ""·"u.uu,vu of recurrent tumors (table 4). The interval between initial diagnosis and first recurrence varied from less than 3 months to more than 10 years (table 5). Tumors were detected in the urethra in 14 patients, in the renal pelvis in 5 and in the ureter in 4. In 50 of the 73 patients who had recurrent tumors, the cystoscopic appearance of the recurrent lesions indicated the need for biopsy. Twentytwo of the specimens demonstrated a more undifferentiated neoplasm and invasion of the wall of the bladder was detected in 10 patients (table 6).
206
GREENE, HANASH AND FARROW
The interval between the initial diagnosis and the appearance of histologic invasion of the bladder wall varied from 3 months to 13 years, with a mean of 8 years. All 10 patients with recurrent infiltrative vesical neoplasms subsequently had extravesical extension of the neoplasm with diffuse metas-
4. Recurrences and size of original lesion (single)
TABLE
No. Pts.
Size of Lesion (cm.)
Total Recurrences
0 to 1 2 to3 4to5 >5
7 (50) 28 (62)
14 45 10
5
No.(%)
10(1()())
5 (100)
5. Time between initial diagnosis and first recurrence in 73 patients with vesical tumors
TABLE
No. Pts. 14 8
6 8 9
6 4
Interval
No.Pts.
Interval
0 to 3 mos. 4 to 6 mos. 7 to 9 mos. 1 yr. 2yrs. 3 yrs. 4 yrs.
3 2 2 2 1 8
5 yrs. 6 yrs. 7yrs. 8yrs. 9yrs. > lOyrs.
6. Results of biopsy in 50 cases of recurrent vesical tumors, according to grade and infiltration
TABLE
Well differentiated transitional cell epithelioma. Orderly arrangement of cells in delicate fronds. Cells do not differ significantly from normal transitional cells. Mitotic activity is not significantly increased. H & E, reduced from x350. 1. Presenting symptoms according to sex of 100
TABLE
patients with vesical tumors Women
Totals
54 14
19
5
73 19
4 0
2 5 1
2 1 1
* Frequency, urgency, dysuria.
TABLE
2. Site of primary epitheliomas No. Cases
Posterolateral to ureteral orifice Lateral walls Base Dome, anterior wall Vesical neck Posterior wall Trigone Total
TABLE
55 26 14 11 7 5 3
121
3. Recurrences, original lesion and sex of patient
in 100 cases of vesical tumors Women
Men Original Lesion
Single Multiple Totals
No. Pts. 55 17 72
No. With Recurrences 38 15 53
No. Pts. 19 9
28
No. With Recurrences 12 8 20
Non-Infiltrating
1 2
7
3
28 10 2
Totals
40
10
Infiltrating 0
3
* Broders' classification.
Men Painless, gross hematuria Bladder irritability* and gross hematuria Prostatism Bladder irritability* Microhematuria
Grade*
Percentage of Recurrences
68 88 73
tases and died of vesical cancer. The 5, 10 and 15-year survival rates for the entire series were 80, 65 and 50 per cent, respectively. DISCUSSION
The clinical impressions of most experienced urologists in respect to these tumors are supported in our study. Thus, we have evidence for the concept that the uroepithelium of certain patients has a proclivity to develop neoplasms and that when such patients initially have multiple tumors, recurrent tumors may be expected. Likewise, our statistical data indicate that the incidence of recurrent tumors varies proportionally with the size of the original tumor and that the most common site for such vesical tumors, primary or recurrent, is posterolateral to the ureteral orifices. Although our study provides some clues as to which patients are likely to have recurrences, we found no indication of which tumors will become less differentiated, be invasive, produce metastasis or result in death. We have found that such development cannot be predicted by currently available histopathologic techniques. Other avenues of research have been explored in an effort to measure the benignancy or malignancy of vesical neoplasms. Veenema and associates studied deoxyribonucleic (DNA) and ribonucleic acid syntheses in vesical neoplasms and concluded that high DNA synthesis appeared to indicate a
Th.ese cor1cJ.usions Levi and associates v1ho Err1ited their observations to tra.!'.i.Sitional cell carcin01T1Hs of the huxnan bladder and ureter,~ On the basis of their studies DNA stated it is not
car-cmomas of the bladder and noted a triad of marker chromosomes and concluded that these genetic invasive carcinoma of the .
<1..
1n Lne
The n1ost are that 1) ?3 per cent of had recurrent tumors, 2) 22 per cent had recurrent that were less differentiated and more lethal than the lesion and 3) 10 per cent had invasive carcinoma with diffuse metastasis that caused. death. Somewhat similar ·····-·'"·"- were and associates, who noted :recu:rrent tumors in 70 per cent of a11d frank carcinoma in 13 cent. 5 Such son1ber data that the
tuY..no:ts cannot be considbut must be conside:rtd carci:-ciomas and treated as suc:i1. In the management of these it is necessary to n.v,aHu,c their J. K.: bladUroL, 3 Levi, P. E., K. and VVilliains, R. E,: '""·'""''"" and cell urolifera:tion of transitional cell carcinoma 1n ma.no Can~ce:r, 23: 1074) 1£.69. ,;, Falor\ 1-L: Ch:romosoraes in noninvasive ca~cino1nc. of the bladder. 791) L. N., of a UmL,
the foHov·,;ed exan1inations. r2spect, our data indicate that 15 per c2nt of had a first recurrence 5 years or n1ore after rer.aoval the ~···o"""-· , these recurrences vvould not have been discovered in a routine manner if an decision had been made to discontinue re-examinations after 5 years. a decision to discontinue examinations after 10 yearn without recurrences would have resulted in failure to detect 1,,,,..,m.,,1, recurrences in routine manner in 8 cent of patients. patients be re-examined at 2-year intervals for the rnst of their lives, even though recurrences seem to have m.,nnnF,fi The treatment of rences will involve mustard" or other measures. the "'"'""''rn must be alert to the development of less differentiated recurrent epitheliomas and the need for their treat-ment. SUMMARY
in 73 pe:r
well differentiated vesical · omas who were followed for 15 yeacrs Recurrences the lesions vvere 1nultiper cent of recurrent were less differentiated and invasive carcinoma developed in 10 it is advisable to consider with such tumors should exarnin.ations for the rest 6 Drew, J.E. and !Vfarshall, V. F'.: The effects thictepa en the recurrence rate of su:cerficial . !l!l: 1968. .
U:?,OLC-GY
Copyright © 1973 by 'The 1JlJilEan1s
Vlilkins
BENIGN PAPILLOMA OR PAPILLARY CARCINOMA OF THE BLADDER? LAURENCE F. GREENE, KAMAL A. HANASH
AND
GEORGE M. FARROW
From the Mayo Clinic and Mayo Foundation, Rochester, Minnesota
The proper histopathologic classification and biologic potential of transitional cell papilloma or epithelioma of the bladder remain uncertain and controversiaL The gross appearance and the histologic and cytologic features of this tumor convey the impression of benignancy, with limited potential for aggressive growth. However, experience has revealed that recurrent tumors and invasive carcinoma may occur and aggressive malignancy may develop. Herein we have attempted to define this tumor, shed some light on its history as affected by treatment and discuss its place among the benign and malignant neoplasms of the bladder. Transitional cell papilloma, well differentiated transitional cell epithelioma and grade 1 transitional cell carcinoma are used interchangeably to designate a tumor composed of transitional epithelial cells arranged in a papillary, frond-like growth on a basement membrane with delicate intervening stroma of reticulin fibers and vascular channels. The typical iayering of the transitional cells is maintained, the cells do not differ significantly in their cytologic features from normal transitional cells and the rate of mitotic activity is not appreciably greater than that in normal transitional epithelium (see figure). MATERIALS AND METHODS
We reviewed clinical records, operative findings, pathologic specimens and, when available, autopsy protocols of 100 consecutive patients with vesical tumors first seen at the Mayo Clinic between 1949 and 1951. The diagnosis in each case was grade l transitional cell carcinoma.' None of the patients had been previously treated for vesical neoplasm. All tumors were removed by the transurethral approach, with electrocoagulation of the base. Each patient was advised to return periodically for cystoscopic examination and such other studies as seemed indicated. ~uos,eq1.1e11t forms of treatment consisted of thio-tepa '-'"'"""'·" administration of ascorbic acid or 5-fluorouracil, irradiation, resection or total cystectomy. was for 15 years or more in all cases. A of the initial and subsequent examinations was recorded. Histologic sections of ail biopsy IY"''""'·""''·'" were reviewed and graded according to the method of Brode:rs. 1 Major and contributing causes of death were ascertained from autopsy protocols or medical reports by the family physician. Accepted for publication December 29, 197?, . 1 Broders, A. C.: Epithelioma of the gemto-unnary organs. Ann. Surg., 75: 574, 1922. 205
RESULTS
The majority of patients were in the sixth or seventh decade of life; the youngest was 33 and the oldest was 79 years old. Men predominated in a ratio of approximately 3 to 1 (72 men to 28 women). The duration of urinary symptoms before diagnosis varied from 1 day to more than 20 years; 44 patients delayed seeking medical assistance for more than a year after onset of symptoms. The most common complaint (73 per cent) was intermittent, painless, gross hematuria (table 1). The hematuria was considered terminal by 10 patients "'nd initial by 2, whereas the other patients described it as total, spotty or continuous. Urinalysis revealed various degrees of microhematuria in 85 per cent of the patients and pyuria in 61 per cent. Thirty-three patients had microhematuria of grade 1 (3 to 8 cells per high power field). Findings on excretory urography (IVP) were normal in 56 patients and revealed a filling defect in the bladder suggestive of vesical neoplasm in 35 patients. Hydronephrosis was present unilaterally in 6 patients and bilaterally in 1. Two patients had a non-functioning kidney. The cystoscopic appearance of the tumors did not vary significantly and most of the lesions were described as villous, pedunculated, frond-like structures attached to the bladder by a narrow pedicle. The most common location ( 45 per cent) of the initial single and multiple tumors was over the base adjacent to the ureteral orifice (table 2). Initial lesions were solitary in 74 patients and in 26 (table 3). Seventy-three per cent of the patients had recurrent tumors and the number of recurrences varied from 1 to 20 per patient with a mean of 6. The incidence of recurrent tumors was significantly higher (88 per cent) in patients who presented with multiple tumors than in those whose original tumor was single (68 per cent, table 3). the the the greater was the ""·"u.uu,vu of recurrent tumors (table 4). The interval between initial diagnosis and first recurrence varied from less than 3 months to more than 10 years (table 5). Tumors were detected in the urethra in 14 patients, in the renal pelvis in 5 and in the ureter in 4. In 50 of the 73 patients who had recurrent tumors, the cystoscopic appearance of the recurrent lesions indicated the need for biopsy. Twentytwo of the specimens demonstrated a more undifferentiated neoplasm and invasion of the wall of the bladder was detected in 10 patients (table 6).
206
GREENE, HANASH AND FARROW
The interval between the initial diagnosis and the appearance of histologic invasion of the bladder wall varied from 3 months to 13 years, with a mean of 8 years. All 10 patients with recurrent infiltrative vesical neoplasms subsequently had extravesical extension of the neoplasm with diffuse metas-
4. Recurrences and size of original lesion (single)
TABLE
No. Pts.
Size of Lesion (cm.)
Total Recurrences
0 to 1 2 to3 4to5 >5
7 (50) 28 (62)
14 45 10
5
No.(%)
10(1()())
5 (100)
5. Time between initial diagnosis and first recurrence in 73 patients with vesical tumors
TABLE
No. Pts. 14 8
6 8 9
6 4
Interval
No.Pts.
Interval
0 to 3 mos. 4 to 6 mos. 7 to 9 mos. 1 yr. 2yrs. 3 yrs. 4 yrs.
3 2 2 2 1 8
5 yrs. 6 yrs. 7yrs. 8yrs. 9yrs. > lOyrs.
6. Results of biopsy in 50 cases of recurrent vesical tumors, according to grade and infiltration
TABLE
Well differentiated transitional cell epithelioma. Orderly arrangement of cells in delicate fronds. Cells do not differ significantly from normal transitional cells. Mitotic activity is not significantly increased. H & E, reduced from x350. 1. Presenting symptoms according to sex of 100
TABLE
patients with vesical tumors Women
Totals
54 14
19
5
73 19
4 0
2 5 1
2 1 1
* Frequency, urgency, dysuria.
TABLE
2. Site of primary epitheliomas No. Cases
Posterolateral to ureteral orifice Lateral walls Base Dome, anterior wall Vesical neck Posterior wall Trigone Total
TABLE
55 26 14 11 7 5 3
121
3. Recurrences, original lesion and sex of patient
in 100 cases of vesical tumors Women
Men Original Lesion
Single Multiple Totals
No. Pts. 55 17 72
No. With Recurrences 38 15 53
No. Pts. 19 9
28
No. With Recurrences 12 8 20
Non-Infiltrating
1 2
7
3
28 10 2
Totals
40
10
Infiltrating 0
3
* Broders' classification.
Men Painless, gross hematuria Bladder irritability* and gross hematuria Prostatism Bladder irritability* Microhematuria
Grade*
Percentage of Recurrences
68 88 73
tases and died of vesical cancer. The 5, 10 and 15-year survival rates for the entire series were 80, 65 and 50 per cent, respectively. DISCUSSION
The clinical impressions of most experienced urologists in respect to these tumors are supported in our study. Thus, we have evidence for the concept that the uroepithelium of certain patients has a proclivity to develop neoplasms and that when such patients initially have multiple tumors, recurrent tumors may be expected. Likewise, our statistical data indicate that the incidence of recurrent tumors varies proportionally with the size of the original tumor and that the most common site for such vesical tumors, primary or recurrent, is posterolateral to the ureteral orifices. Although our study provides some clues as to which patients are likely to have recurrences, we found no indication of which tumors will become less differentiated, be invasive, produce metastasis or result in death. We have found that such development cannot be predicted by currently available histopathologic techniques. Other avenues of research have been explored in an effort to measure the benignancy or malignancy of vesical neoplasms. Veenema and associates studied deoxyribonucleic (DNA) and ribonucleic acid syntheses in vesical neoplasms and concluded that high DNA synthesis appeared to indicate a
Th.ese cor1cJ.usions Levi and associates v1ho Err1ited their observations to tra.!'.i.Sitional cell carcin01T1Hs of the huxnan bladder and ureter,~ On the basis of their studies DNA stated it is not
car-cmomas of the bladder and noted a triad of marker chromosomes and concluded that these genetic invasive carcinoma of the .
<1..
1n Lne
The n1ost are that 1) ?3 per cent of had recurrent tumors, 2) 22 per cent had recurrent that were less differentiated and more lethal than the lesion and 3) 10 per cent had invasive carcinoma with diffuse metastasis that caused. death. Somewhat similar ·····-·'"·"- were and associates, who noted :recu:rrent tumors in 70 per cent of a11d frank carcinoma in 13 cent. 5 Such son1ber data that the
tuY..no:ts cannot be considbut must be conside:rtd carci:-ciomas and treated as suc:i1. In the management of these it is necessary to n.v,aHu,c their J. K.: bladUroL, 3 Levi, P. E., K. and VVilliains, R. E,: '""·'""''"" and cell urolifera:tion of transitional cell carcinoma 1n ma.no Can~ce:r, 23: 1074) 1£.69. ,;, Falor\ 1-L: Ch:romosoraes in noninvasive ca~cino1nc. of the bladder. 791) L. N., of a UmL,
the foHov·,;ed exan1inations. r2spect, our data indicate that 15 per c2nt of had a first recurrence 5 years or n1ore after rer.aoval the ~···o"""-· , these recurrences vvould not have been discovered in a routine manner if an decision had been made to discontinue re-examinations after 5 years. a decision to discontinue examinations after 10 yearn without recurrences would have resulted in failure to detect 1,,,,..,m.,,1, recurrences in routine manner in 8 cent of patients. patients be re-examined at 2-year intervals for the rnst of their lives, even though recurrences seem to have m.,nnnF,fi The treatment of rences will involve mustard" or other measures. the "'"'""''rn must be alert to the development of less differentiated recurrent epitheliomas and the need for their treat-ment. SUMMARY
in 73 pe:r
well differentiated vesical · omas who were followed for 15 yeacrs Recurrences the lesions vvere 1nultiper cent of recurrent were less differentiated and invasive carcinoma developed in 10 it is advisable to consider with such tumors should exarnin.ations for the rest 6 Drew, J.E. and !Vfarshall, V. F'.: The effects thictepa en the recurrence rate of su:cerficial . !l!l: 1968. .