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Clinical Experience with Transitional Cell Carcinoma of the Bladder with Special Reference to Smoking
0022-534 7/89/1413-0527$2,00/0 THE JOURNAL OF UROLOGY
Vol. 141, Iv1arch Printed in. U.S.A.
Copyright© 1989 by The Williams & Wilkins Co.
CLINICAL EXPERIENCE WITH TRANSITIONAL CELL CARCINOMA OF THE BLADDER WITH SPECIAL REFERENCE TO SMOKING A. ALDEN CARPENTER From the South Shore Hospital, South Weymouth, Massachusetts
ABSTRACT
A review was done of 100 consecutive patients with carcinoma of the bladder treated by 1 physician at 1 hospital from June 1982 to December 1986. Special reference was made to the possible effect of cigarette smoking on initial stage, initial grade and recurrences. There was no significant difference in terms of initial tumor stage or grade but smokers had significantly more recurrent tumors. Also, smokers had bladder recurrences after partial cystectomy and urethral recurrences after total cystectomy. The biochemical aspects of smoking as a risk factor in bladder carcinoma are reviewed briefly. (J. Ural., 141: 527-528, 1989) Of the many known risk factors for carcinoma of the bladder it generally is agreed that cigarette smoking is the most important. In 1961 the Scandinavian and French literature reviewed the possible role of tobacco on bladder cancer. In 1971 Cole and associates, in a multiple hospital study of 468 patients, found that the relative risk of bladder cancer in cigarette smokers was approximately twice that of nonsmokers. 1 In a multinational study of approximately 1,400 patients Morrison and associates confirmed the increased incidence among smokers." In a subset of 592 patients they found that smoking 2 or more packs of cigarettes a day increased the risk to about 7 times that for nonsmokers. Although there has been an abundance of information in regard to smoking and the risk of bladder cancer, few studies have addressed the impact of cigarette smoking on stage, grade and number of recurrences. Thompson and associates reviewed a group of 386 patients, primarily military retirees and their dependents, and found a statistically significant influence of smoking on increasing initial stage, initial grade and number of recurrences." This study supports the conclusions of Thompson and associates in regard to initial stage and initial grade, and it confirms the influence of smoking on number of recurrences. PATIENTS AND METHODS
3 of those who smoked but who stopped smoking with the initial diagnosis had downgrading or remission. All 4 patients who underwent partial cystectomy and who were smokers had subsequent recurrences. None of the 3 nonsmokers who underwent partial cystectomy had recurrences. Of the 13 patients who underwent total cystectomy 2 died of urethral metastases. Both patients at cystectomy had no known malignant disease of the bladder neck, trigone or prostatic urethra, and both were smokers. Neither of the 2 nonsmokers who underwent total cystectomy had urethral recurrences. By and large the patients in the failure of followup group had had low grade tumors initially without recurrences. They were undergoing interval cystoscopic examination as outpatients and failure of followup generally occurred after 2 years. Table 2 compared this study to that of Thompson and associates.' The latter group underwent statistical analysis with Fisher's exact test and significant differences between smokers and nonsmokers were present in all categories. The present study did not statistically confirm a difference in initial stage and grade between smokers and nonsmokers. However, this may be due to small sample size, particularly since the data quantitatively parallel the results of Thompson and associates. The data do confirm a statistically significant difference in the number of recurrences between smokers and nonsmokers (Mantel-Haenzel trend test, p <0.01).
The records of 100 patients with carcinoma of the bladder treated by 1 physician at 1 hospital between June 1982 and December 1986 were analyzed statistically. In most of the patients cancer was diagnosed during this interval but 10 were ongoing patients and had had diagnosis or treatment before June 1982. Of these 10 patients 6 smoked and 4 did not smoke. Followup ranged from 6 months to 25 years (average 4.3 years). Patient age ranged from 15 to 92 years (average age 64 years). Of the patients 73 smoked and 27 did not smoke. Smokers did not differ significantly in terms of age (t test greater than 0.5) or gender (Fisher's exact test greater than 0.05) from the nonsmokers. Although there may be other risk factors extant with these patients they were not apparent. The local industry is diverse and there was no clustering of patients geographically. RESULTS
The results of this analysis are outlined in table 1. The unfavorable bias toward smokers is apparent in the first 3 categories. In the multiple recurrences group 15 of the 40 smokers had progression to more advanced disease. None of the 8 patients who did not smoke had progression. In addition, Accepted for publication August 5, 1988.
527
DISCUSSION
The fact that 2 patients in this small series of cystectomy patients died of urethral metastasis is discouraging. In 1976 Schellhammer and Whitmore described 2 patients who had urethral recurrences: 1 clinically apparent at 1 year and 1 at 3 years after cystectomy.4 Ahlering and associates found that in patients followed after cystectomy with urethral washings, positive washings were found within 6 months of cystectomy." In those followed for clinical evidence of urethral involvement, either urethral bleeding or a mass, the average duration was 42 months after cystectomy. In a review of 18 patients with urethral tumor after cystectomy Ji-Lun and associates found the interval between initial cystectomy and the appearance of the urethral tumor to average 2.5 years. 0 None of these studies stratified patients into smokers and nonsmokers. These observations led to the larger question of how long the urothelium remains susceptible to malignant change after discontinuing smoking or after cystectomy without urethrectomy. Sato and associates stated that the urine of most cigarette smokers is strongly mutogenic and the mutogenicity is lost after 48 hours of nonsmoking. 7 The study of Ahlering and associates would suggest that the urothelium of the urethra
528
CARPENTER TABLE
1. Comparative categories in 100 consecutive patients Smokers No.(%)
Total No. No recurrences ~2 recurrences Multiple recurrences Partial cystectomy Total cystectomy Death of tumor Unrelated deaths Failure of followup
Nonsmokers No.(%)
73 14 12 40 4 11 11
27 12 4 8 3 2 2 2 3
(18) (16) (55) (6) (15) (15) 6 (8) 7 (9)
P Value
(44) (15) (29) (11) (7) (9) (9) (11)
0.02* 1.0 0.03* 0.38 0.50 0.50 1.0 0.72
* Significant by Fisher's exact test.
TABLE 2.
Results from our study compared to those of Thompson and associates (in parentheses) 3 % Smokers
Initial tumor stage: 0 and A
B C D Initial tumor grade: I
II III IV Tumor recurrences: None 1 or 2 Multiple No followup
78 11 8 3
(70) (18) (6) (6)
% Nonsmokers 81 15 4 0
(86) (6) (6)
(2)
28 (32) 45 (40) 15 (26) 11
41 (47) 33 (42) 18 (13) 7
18 16 55 9
44 15 29 11
(53) (31) (16) -
(70) (24) (6)
-
develops malignant change fairly quickly after cessation of exposure to urine. These uncontrolled observations suggest that the urothelium is at risk for at least 3 years after either cystectomy without urethrectomy or cessation of smoking. Bladder cancer and smoking pose an enormous problem. In 1986, 40,500 cases of bladder cancer were diagnosed in the United States, of which approximately 15,000 were related to tobacco. 8 The Surgeon General's report of 1982 reviewed the research and conclusion in regard to smoking. 9 The burning cone of the cigarette reaches a temperature of 950C and more than 3,600 smoke components are formed by this combustion. Main stream smoke (voluntary) and side stream smoke (involuntary) share these products, which include more than 50 toxic or carcinogenic agents. The volatile nitrosamines are of particular concern but many other chemicals, including polonium210, have come under scrutiny. To date there has been almost no inclusion of cigarette smoking as a risk factor in review of the clinical course of bladder carcinoma patients. Prout and associates reviewed 160 patients with low grade transitional cell carcinoma of the
bladder and found that high risk factors included positive cytological studies after therapy and 3 or more recurrences. 10 It might be assumed that these high risk factors were associated with smoking but this was not addressed in the study. CONCLUSIONS
From the epidemiological viewpoint it cannot be overemphasized that patients with bladder cancer must stop smoking. The data from this study would suggest that if the patient is a smoker partial cystectomy is not indicated. Furthermore, if the patient smokes urethrectomy should be considered if radical cystectomy is planned. The duration of the urothelial risk for malignant change after cessation of smoking or after cystectomy without urethrectomy is not known but these observations suggest a period of at least 3 years. An additional finding from the study is that the patient with low grade nonrecurring transitional cell carcinoma may be lost to followup after 2 years. The importance of followup should be emphasized again to the patient at that time. Dr. E. John Orav of the Harvard University School of Public Health provided statistical analysis. REFERENCES
1. Cole, P., Monson, R. R., Haning, H. and Friedell, G. H.: Smoking and cancer of the lower urinary tract. New Engl. J. Med., 284: 129, 1971. 2. Morrison, A. S., Buring, J.E., Verhoek, W. G., Aoki, K., Leck, I., Ohno, Y. and Obata, K.: An international study of smoking and bladder cancer. J. Ural., 131: 650, 1984. 3. Thompson, I. M., Peek, M. and Rodriguez, F. R.: The impact of cigarette smoking on stage, grade and number of recurrences of transitional cell carcinoma of the bladder. J. Ural., 137: 401, 1987. 4. Schellhammer, P. F. and Whitmore, W. F., Jr.: Transitional cell carcinoma of the urethra in men having cystectomy for bladder cancer. J. Ural., 115: 56, 1976. 5. Ahlering, T. E., Lieskovsky, G. and Skinner, D. G.: Indications for urethrectomy in men undergoing single stage radical cystectomy for bladder cancer. J. Ural., 131: 657, 1984. 6. Ji-Lun, Z., Fang-Liu, G., Wen-Xiang, M. and Yi-Ming, L.: Transitional cell carcinoma of urethra after treatment of urinary bladder cancer. Chinese Med. J., 99: 407, 1986. 7. Sato, S., Seino, Y. and Ohka, T.: Mutagenicity of smoke condensates from cigarettes, cigars and pipe tobacco. Cancer Lett., 3: 1, 1977. 8. Lewis, A.: Research report: bladder cancer. National Cancer Institute, p. 4, March 1987. 9. A Report of the Surgeon General: The Health Consequences of Smoking. Washington, D. C.: U. S. Department of Health and Human Services, 1982. 10. Prout, G. R., Jr., Bassil, B. and Griffin, P.: The treated histories of patients with Ta grade 1 transitional-cell carcinoma of the bladder. Arch. Surg., 121: 1460, 1986.
Vol. 141, Iv1arch Printed in. U.S.A.
Copyright© 1989 by The Williams & Wilkins Co.
CLINICAL EXPERIENCE WITH TRANSITIONAL CELL CARCINOMA OF THE BLADDER WITH SPECIAL REFERENCE TO SMOKING A. ALDEN CARPENTER From the South Shore Hospital, South Weymouth, Massachusetts
ABSTRACT
A review was done of 100 consecutive patients with carcinoma of the bladder treated by 1 physician at 1 hospital from June 1982 to December 1986. Special reference was made to the possible effect of cigarette smoking on initial stage, initial grade and recurrences. There was no significant difference in terms of initial tumor stage or grade but smokers had significantly more recurrent tumors. Also, smokers had bladder recurrences after partial cystectomy and urethral recurrences after total cystectomy. The biochemical aspects of smoking as a risk factor in bladder carcinoma are reviewed briefly. (J. Ural., 141: 527-528, 1989) Of the many known risk factors for carcinoma of the bladder it generally is agreed that cigarette smoking is the most important. In 1961 the Scandinavian and French literature reviewed the possible role of tobacco on bladder cancer. In 1971 Cole and associates, in a multiple hospital study of 468 patients, found that the relative risk of bladder cancer in cigarette smokers was approximately twice that of nonsmokers. 1 In a multinational study of approximately 1,400 patients Morrison and associates confirmed the increased incidence among smokers." In a subset of 592 patients they found that smoking 2 or more packs of cigarettes a day increased the risk to about 7 times that for nonsmokers. Although there has been an abundance of information in regard to smoking and the risk of bladder cancer, few studies have addressed the impact of cigarette smoking on stage, grade and number of recurrences. Thompson and associates reviewed a group of 386 patients, primarily military retirees and their dependents, and found a statistically significant influence of smoking on increasing initial stage, initial grade and number of recurrences." This study supports the conclusions of Thompson and associates in regard to initial stage and initial grade, and it confirms the influence of smoking on number of recurrences. PATIENTS AND METHODS
3 of those who smoked but who stopped smoking with the initial diagnosis had downgrading or remission. All 4 patients who underwent partial cystectomy and who were smokers had subsequent recurrences. None of the 3 nonsmokers who underwent partial cystectomy had recurrences. Of the 13 patients who underwent total cystectomy 2 died of urethral metastases. Both patients at cystectomy had no known malignant disease of the bladder neck, trigone or prostatic urethra, and both were smokers. Neither of the 2 nonsmokers who underwent total cystectomy had urethral recurrences. By and large the patients in the failure of followup group had had low grade tumors initially without recurrences. They were undergoing interval cystoscopic examination as outpatients and failure of followup generally occurred after 2 years. Table 2 compared this study to that of Thompson and associates.' The latter group underwent statistical analysis with Fisher's exact test and significant differences between smokers and nonsmokers were present in all categories. The present study did not statistically confirm a difference in initial stage and grade between smokers and nonsmokers. However, this may be due to small sample size, particularly since the data quantitatively parallel the results of Thompson and associates. The data do confirm a statistically significant difference in the number of recurrences between smokers and nonsmokers (Mantel-Haenzel trend test, p <0.01).
The records of 100 patients with carcinoma of the bladder treated by 1 physician at 1 hospital between June 1982 and December 1986 were analyzed statistically. In most of the patients cancer was diagnosed during this interval but 10 were ongoing patients and had had diagnosis or treatment before June 1982. Of these 10 patients 6 smoked and 4 did not smoke. Followup ranged from 6 months to 25 years (average 4.3 years). Patient age ranged from 15 to 92 years (average age 64 years). Of the patients 73 smoked and 27 did not smoke. Smokers did not differ significantly in terms of age (t test greater than 0.5) or gender (Fisher's exact test greater than 0.05) from the nonsmokers. Although there may be other risk factors extant with these patients they were not apparent. The local industry is diverse and there was no clustering of patients geographically. RESULTS
The results of this analysis are outlined in table 1. The unfavorable bias toward smokers is apparent in the first 3 categories. In the multiple recurrences group 15 of the 40 smokers had progression to more advanced disease. None of the 8 patients who did not smoke had progression. In addition, Accepted for publication August 5, 1988.
527
DISCUSSION
The fact that 2 patients in this small series of cystectomy patients died of urethral metastasis is discouraging. In 1976 Schellhammer and Whitmore described 2 patients who had urethral recurrences: 1 clinically apparent at 1 year and 1 at 3 years after cystectomy.4 Ahlering and associates found that in patients followed after cystectomy with urethral washings, positive washings were found within 6 months of cystectomy." In those followed for clinical evidence of urethral involvement, either urethral bleeding or a mass, the average duration was 42 months after cystectomy. In a review of 18 patients with urethral tumor after cystectomy Ji-Lun and associates found the interval between initial cystectomy and the appearance of the urethral tumor to average 2.5 years. 0 None of these studies stratified patients into smokers and nonsmokers. These observations led to the larger question of how long the urothelium remains susceptible to malignant change after discontinuing smoking or after cystectomy without urethrectomy. Sato and associates stated that the urine of most cigarette smokers is strongly mutogenic and the mutogenicity is lost after 48 hours of nonsmoking. 7 The study of Ahlering and associates would suggest that the urothelium of the urethra
528
CARPENTER TABLE
1. Comparative categories in 100 consecutive patients Smokers No.(%)
Total No. No recurrences ~2 recurrences Multiple recurrences Partial cystectomy Total cystectomy Death of tumor Unrelated deaths Failure of followup
Nonsmokers No.(%)
73 14 12 40 4 11 11
27 12 4 8 3 2 2 2 3
(18) (16) (55) (6) (15) (15) 6 (8) 7 (9)
P Value
(44) (15) (29) (11) (7) (9) (9) (11)
0.02* 1.0 0.03* 0.38 0.50 0.50 1.0 0.72
* Significant by Fisher's exact test.
TABLE 2.
Results from our study compared to those of Thompson and associates (in parentheses) 3 % Smokers
Initial tumor stage: 0 and A
B C D Initial tumor grade: I
II III IV Tumor recurrences: None 1 or 2 Multiple No followup
78 11 8 3
(70) (18) (6) (6)
% Nonsmokers 81 15 4 0
(86) (6) (6)
(2)
28 (32) 45 (40) 15 (26) 11
41 (47) 33 (42) 18 (13) 7
18 16 55 9
44 15 29 11
(53) (31) (16) -
(70) (24) (6)
-
develops malignant change fairly quickly after cessation of exposure to urine. These uncontrolled observations suggest that the urothelium is at risk for at least 3 years after either cystectomy without urethrectomy or cessation of smoking. Bladder cancer and smoking pose an enormous problem. In 1986, 40,500 cases of bladder cancer were diagnosed in the United States, of which approximately 15,000 were related to tobacco. 8 The Surgeon General's report of 1982 reviewed the research and conclusion in regard to smoking. 9 The burning cone of the cigarette reaches a temperature of 950C and more than 3,600 smoke components are formed by this combustion. Main stream smoke (voluntary) and side stream smoke (involuntary) share these products, which include more than 50 toxic or carcinogenic agents. The volatile nitrosamines are of particular concern but many other chemicals, including polonium210, have come under scrutiny. To date there has been almost no inclusion of cigarette smoking as a risk factor in review of the clinical course of bladder carcinoma patients. Prout and associates reviewed 160 patients with low grade transitional cell carcinoma of the
bladder and found that high risk factors included positive cytological studies after therapy and 3 or more recurrences. 10 It might be assumed that these high risk factors were associated with smoking but this was not addressed in the study. CONCLUSIONS
From the epidemiological viewpoint it cannot be overemphasized that patients with bladder cancer must stop smoking. The data from this study would suggest that if the patient is a smoker partial cystectomy is not indicated. Furthermore, if the patient smokes urethrectomy should be considered if radical cystectomy is planned. The duration of the urothelial risk for malignant change after cessation of smoking or after cystectomy without urethrectomy is not known but these observations suggest a period of at least 3 years. An additional finding from the study is that the patient with low grade nonrecurring transitional cell carcinoma may be lost to followup after 2 years. The importance of followup should be emphasized again to the patient at that time. Dr. E. John Orav of the Harvard University School of Public Health provided statistical analysis. REFERENCES
1. Cole, P., Monson, R. R., Haning, H. and Friedell, G. H.: Smoking and cancer of the lower urinary tract. New Engl. J. Med., 284: 129, 1971. 2. Morrison, A. S., Buring, J.E., Verhoek, W. G., Aoki, K., Leck, I., Ohno, Y. and Obata, K.: An international study of smoking and bladder cancer. J. Ural., 131: 650, 1984. 3. Thompson, I. M., Peek, M. and Rodriguez, F. R.: The impact of cigarette smoking on stage, grade and number of recurrences of transitional cell carcinoma of the bladder. J. Ural., 137: 401, 1987. 4. Schellhammer, P. F. and Whitmore, W. F., Jr.: Transitional cell carcinoma of the urethra in men having cystectomy for bladder cancer. J. Ural., 115: 56, 1976. 5. Ahlering, T. E., Lieskovsky, G. and Skinner, D. G.: Indications for urethrectomy in men undergoing single stage radical cystectomy for bladder cancer. J. Ural., 131: 657, 1984. 6. Ji-Lun, Z., Fang-Liu, G., Wen-Xiang, M. and Yi-Ming, L.: Transitional cell carcinoma of urethra after treatment of urinary bladder cancer. Chinese Med. J., 99: 407, 1986. 7. Sato, S., Seino, Y. and Ohka, T.: Mutagenicity of smoke condensates from cigarettes, cigars and pipe tobacco. Cancer Lett., 3: 1, 1977. 8. Lewis, A.: Research report: bladder cancer. National Cancer Institute, p. 4, March 1987. 9. A Report of the Surgeon General: The Health Consequences of Smoking. Washington, D. C.: U. S. Department of Health and Human Services, 1982. 10. Prout, G. R., Jr., Bassil, B. and Griffin, P.: The treated histories of patients with Ta grade 1 transitional-cell carcinoma of the bladder. Arch. Surg., 121: 1460, 1986.