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Cirrhosis and Carcinoma of the Prostate Gland
THE JOURNAL OF UROLOGY
Vol. 91, No. 3 March 1964 Copyright © 1964 by The Williams & Wilkins Co. Printed in U.S.A.
CIRRHOSIS AND CARCINOMA OF THE PROSTATE GLAND GEORGE M. GLANTZ From the Squier Urological Service, Presbyterian Hospital, Columbia-Presbyterian Medical Center, New York, New York
A large amount of literature has accmnulated concerning the place of estrogens in the treatment of carcinoma of the prostate. The use of the hormone as an important means of palliative therapy has become routine. Little consideration has been given, however, to the possible role of estrogens m the development of prostatic carcinoma. One would expect patients with hyperestrogenism during their lifetimes to have a lower incidence of malignant disease of the prostate. This has not, however, been the feeling of some who have studied this particular point. Several authors have expressed the opinion that chronic estrogen exposure might be a factor in the development of carcinoma of the prostate. Franks, in 1954, suggested that sclerotic atrophy of the prostate which may occur in the aged might be a precursor of carcinoma. These same lesions were produced in rats which were given estrogen. 1 • 2 In addition, Sommers, in 1957, felt that excess estrogen had a definite role in the pathogenesis of the disease. 3 On the other hand, it is the consensus that hyperestrogenism should produce a lower incidence of carcinoma of the prostate. It occurred to the author that this controversy could be resolved by a study of a group of patients who had been exposed to elevated estrogen levels for a significant length of time. A natural group of this type is found in patients with cirrhosis of the liver. The fact that patients with advanced hepatic cirrhosis have hyperestrogenism has been well recognized for many years. Testicular atrophy, change in pubic hair distribution, loss of libido, loss of hair, and gynecomastia have been described in cases of hepatic cirrhosis by Lloyd Accepted for publication July 3, 1963. The paper was read at the residents' prize essay contest, New York Section, American Urological Association, Inc., April 17, 1963. 1 Franks, L. JVI.: Latent carcinoma of the prostate. J. Path. & Bact., 68: 603-616, 1954. 2 Franks, L. M.: Atrophy and hyperplasia in the prostate proper. J. Path. & Bact., 68: 617-622, 1954.
Sommers, S. C.: Endocrine changes with prostatic carcinoma. Cancer, 10: 345, 1957. 3
and \Villiams in 1948.' It has been felt by many that these changes are caused by excessive estrogen blood levels due to a damaged liver which is unable to metabolize the horn10ne. 5 In 1957, Barr and Sommers, in reviewing 100 autopsied cases of hepatic cirrhosis, found changes in many organs including the prostate and testicles which microscopically indicated estrogen effect. 6 They found that 91 per cent of the 70 male patients demonstrated evidence of estrogen effect as compared to a control group in which only 50 per cent revealed these changes. This finding is in accord with the generally accepted theory that hyperestrogenism plays a role in the cirrhotic syndrome. A group of patients with cirrhosis is an ideal one in which to study the incidence of carcinoma of the prostate to determine whether there is any estrogen effect. Stumpf and Wilens studied the incidence of benign prostatic hypertrophy in 333 cases of cirrhosis of the liver. 7 They felt that there was a lower incidence of benign hyperplasia in the autopsy series, and they believed this to be due to hyperestrogenism. It is the purpose of this paper to study the incidence of carcinoma of the prostate in a group of patients with cirrhosis of the liveL MATERIAL AND METHODS
The study was conducted on a group of autopsied caseB of patients with cirrhosis of the liver at the Columbia-Presbyterian Hospital 4 Lloyd, C. W. and Williams, R. H.: Endocrine changes associated with Laennec's cirrhosis of the liver. Amer. J. Med., 4: 315-330, 1948. 5 Paschles, K. E. and Rakoff, A. E.: Some aspects of the physiology of estrogenic hormones. In Recent Progress on Hormone Research. Proc. of the Laurentian Hormonal Conference, vol. .5, edited by G. Pincus. New York· Academic Press, Inc., 1950, p. 115. 6 Barr, R. VV. and Sommers, S. C.: Endocrine abnormalities accompanying hepatic cirrhosis and hepatoma. J. CJin. Endocr. & Meta., 17: 1017-1029,
1957. 7 Stumpf, H. H. and Wilens, F. C.: Inhibitory effects of portal cirrhosis of the liver on prostatic enlargement. A.M.A. Arch. Int. Med., 91: 304-309,
1953. 291
292
GLANTZ
and some additional cases from an affiliated hospital between the years 1920 and 1962. All cases below the age of 45 years were excluded. The autopsies were routine in nature and included both gross and microscopic examination of the livers and prostate glands. In this manner, a figure for the incidence of carcinoma for the entire group was determined. Incidence figures were also established for each 10-year group. Included in the study were cases of Laennec's or portal cirrhosis, post-hepatitic cirrhosis, biliary cirrhosis, and cardiac cirrhosis. In a similar manner, a control group of autopsy cases in patients without cirrhosis was collected for comparison. These were unselected cases, and the group was gathered from random routine autopsies performed during the same years as the study group. RESULTS
Five hundred fifty autopsied cases of cirrhosis of the liver were examined (table 1). The ages at time of death ranged from 45 to 87 years. The number of cases with carcinoma of the prostate discovered was 18; the incidence of carcinoma was 3.3 per cent. 1. Incidence of prostatic carcinoma in autopsied cases of cirrhosis and a control group
TABLE
Total No. of Cases
No. of Cases of Percentage with Carcinoma of Carcinoma of Prostate Prostate
59 18
Control, 650 Cirrhotics, 550
9.0% 3. 3%
2. Incidence of prostatic carcinoma according to age category in autopsied cases of cirrhosis and a control group
TABLE
Age
45-54 Cirrhotics Control 55-64 Cirrhotics Control 65-74 Cirrhotics Control 75-90 Cirrhotics Control
Total No. of Cases
Ko. of Cases with Carcinoma of Prostate
Percentage with Carcinoma of Prostate
142 143
3 0
2.% 0
222 233
5 20
2.3% 8.6%
163 184
9
23
5.5% 12.5%
23 90
1 16
4.3% 17.7%
20 /
15
/
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,,,., CONTROL
I
CIRRHOSIS
I 45-54
55-64 AGE
65-74
75-90
GROUPS
Fm. 1. Incidence of prostatic carcinoma according to age groups in autopsied cases of cirrhosis and control group. Similarly, the ages in the control group at time of death ranged from 45 to 90 years. There were 650 cases collected and prostatic carcinoma was discovered in 59 cases, an incidence of 9 per cent. In the study there were 358 with Laennec's or portal cirrhosis, 43 with post-hepatic cirrhosis, 105 with biliary cirrhosis, and 34 with cardiac cirrhosis. According to age group distribution (table 2 and fig. 1) there was an incidence of carcinoma of 2.1 per cent in the 45 to 54-year age group in cirrhotics, while in the same control age group, the percentage was 0. In the 55 to 64-year age group, the cirrhotics had an incidence of 2.3 per cent, and the control 8.6 per cent. Similarly, in the 65 to 74-year age group, the cirrhotic incidence for carcinoma was 5.5 per cent, with a control group percentage of 12.5 per cent. In the 75 to 90-year age group, the carcinoma percentage in cirrhotics was 4.3 per cent, while the control group had an incidence of 17 .7 per cent, All of these figures were analyzed statistically and a significant difference was discovered between the cirrhotic and control groups. These results would seem to indicate that there is a lower incidence of carcinoma of the prostate in patients with cirrhosis of the liver as compared to a control group. DISCUSSION
In general, these statistics are lower than those reported by some for the incidence of carcinoma of the prostate according to age grouping. The
CIRRHOSIS AND CARCINOMA OF PROSTATE GLAND
cases, of course, were routine autopsies and there was no specific search directed toward discovering carcinoma of the prostate. Examination of the prostate, however, was performed both grossly and microscopically with an average of two sections taken from the gland for microscopic study. It was hoped that bias would be minimized by the fact that the control group was gathered from the same institutions and during the same years from which the cirrhotics were collected. In the over-all study there was a lower incidence of prostatic carcinoma in patients with cirrhosis as compared with the control group. In the control group there was a gradual increase in incidence of carcinoma for each advancing IO-year age group. In the cirrhotics this gradually increasing incidence with age did not appear in the study. In fact, the oldest age group of cirrhotics (over 75 years) had a lower incidence (4.3 per cent) than the next lowest age group (5.5 per cent). There may be some question about this point, since there were only 20 cirrhotic patients over age 75 years in the study, because unfortunately few of these patients with advanced cirrhosis lived to an old age. The possibility, however, that cirrhotics do not have the usual increasing incidence of carcinoma with advancing age might seem to indicate that prolonged exposure to high estrogen levels could prevent or at least delay the development of carcinoma of the prostate. SUMMARY
A study was undertaken to determine the effect of cirrhosis with hyperestrogenism on the
293
incidence of carcinoma of the prostate. The material was collected from a group of autopsied cases of cirrhosis of the liver and a control autopsy group. A comparison of the two groups indicated a lower incidence of carcinoma of the prostate of 3.3 per cent in the cases of cirrhosis which had been chronically exposed to hyperestrogen levels. The contra! group incidence was 9.0 per cent. The entire study was also evaluated according to IO-year age grouping. The age groups were: 45 to 54, 55 to 64, 65 to 74 and 75 to 90 years. In the cirrhotics, the incidence for carcinoma of the prostate was found to be 2.1 per cent, 2.3 per cent, 5.5 per cent and 4.3 per cent for each respective age group. In comparison, the control percentages were O per cent, 8.6 per cent, 12.5 per cent and 17.7 per cent. All of these figures were found to be statistically significant. The control study had an increasing incidence of carcinoma with advancing age, but this was not found to be the case in cirrhosis. The possibility that hyperestrogenism in cirrhosis might play a protective role in preventing the development of carcinoma of the prostate has been discussed. The author wishes to express his appreciation to Dr. John K. Lattimer for advice in the preparation of this paper.
REFERENCES E.
Incidence of occult adenocarcinoma of the prostate after 50 years of age. Arch. Path., 32: 787-793, 1941. MooRE, R. A.: The morphology of small prostatic carcinoma. J. Urol., 33: 224-234, 1935. RrcH, A. R.: On the frequency of occurrence of occult carcinoma of the prostate. J. Urol., 33: BARON,
AND ANGRIST, A.:
215-223, 1935.
Vol. 91, No. 3 March 1964 Copyright © 1964 by The Williams & Wilkins Co. Printed in U.S.A.
CIRRHOSIS AND CARCINOMA OF THE PROSTATE GLAND GEORGE M. GLANTZ From the Squier Urological Service, Presbyterian Hospital, Columbia-Presbyterian Medical Center, New York, New York
A large amount of literature has accmnulated concerning the place of estrogens in the treatment of carcinoma of the prostate. The use of the hormone as an important means of palliative therapy has become routine. Little consideration has been given, however, to the possible role of estrogens m the development of prostatic carcinoma. One would expect patients with hyperestrogenism during their lifetimes to have a lower incidence of malignant disease of the prostate. This has not, however, been the feeling of some who have studied this particular point. Several authors have expressed the opinion that chronic estrogen exposure might be a factor in the development of carcinoma of the prostate. Franks, in 1954, suggested that sclerotic atrophy of the prostate which may occur in the aged might be a precursor of carcinoma. These same lesions were produced in rats which were given estrogen. 1 • 2 In addition, Sommers, in 1957, felt that excess estrogen had a definite role in the pathogenesis of the disease. 3 On the other hand, it is the consensus that hyperestrogenism should produce a lower incidence of carcinoma of the prostate. It occurred to the author that this controversy could be resolved by a study of a group of patients who had been exposed to elevated estrogen levels for a significant length of time. A natural group of this type is found in patients with cirrhosis of the liver. The fact that patients with advanced hepatic cirrhosis have hyperestrogenism has been well recognized for many years. Testicular atrophy, change in pubic hair distribution, loss of libido, loss of hair, and gynecomastia have been described in cases of hepatic cirrhosis by Lloyd Accepted for publication July 3, 1963. The paper was read at the residents' prize essay contest, New York Section, American Urological Association, Inc., April 17, 1963. 1 Franks, L. JVI.: Latent carcinoma of the prostate. J. Path. & Bact., 68: 603-616, 1954. 2 Franks, L. M.: Atrophy and hyperplasia in the prostate proper. J. Path. & Bact., 68: 617-622, 1954.
Sommers, S. C.: Endocrine changes with prostatic carcinoma. Cancer, 10: 345, 1957. 3
and \Villiams in 1948.' It has been felt by many that these changes are caused by excessive estrogen blood levels due to a damaged liver which is unable to metabolize the horn10ne. 5 In 1957, Barr and Sommers, in reviewing 100 autopsied cases of hepatic cirrhosis, found changes in many organs including the prostate and testicles which microscopically indicated estrogen effect. 6 They found that 91 per cent of the 70 male patients demonstrated evidence of estrogen effect as compared to a control group in which only 50 per cent revealed these changes. This finding is in accord with the generally accepted theory that hyperestrogenism plays a role in the cirrhotic syndrome. A group of patients with cirrhosis is an ideal one in which to study the incidence of carcinoma of the prostate to determine whether there is any estrogen effect. Stumpf and Wilens studied the incidence of benign prostatic hypertrophy in 333 cases of cirrhosis of the liver. 7 They felt that there was a lower incidence of benign hyperplasia in the autopsy series, and they believed this to be due to hyperestrogenism. It is the purpose of this paper to study the incidence of carcinoma of the prostate in a group of patients with cirrhosis of the liveL MATERIAL AND METHODS
The study was conducted on a group of autopsied caseB of patients with cirrhosis of the liver at the Columbia-Presbyterian Hospital 4 Lloyd, C. W. and Williams, R. H.: Endocrine changes associated with Laennec's cirrhosis of the liver. Amer. J. Med., 4: 315-330, 1948. 5 Paschles, K. E. and Rakoff, A. E.: Some aspects of the physiology of estrogenic hormones. In Recent Progress on Hormone Research. Proc. of the Laurentian Hormonal Conference, vol. .5, edited by G. Pincus. New York· Academic Press, Inc., 1950, p. 115. 6 Barr, R. VV. and Sommers, S. C.: Endocrine abnormalities accompanying hepatic cirrhosis and hepatoma. J. CJin. Endocr. & Meta., 17: 1017-1029,
1957. 7 Stumpf, H. H. and Wilens, F. C.: Inhibitory effects of portal cirrhosis of the liver on prostatic enlargement. A.M.A. Arch. Int. Med., 91: 304-309,
1953. 291
292
GLANTZ
and some additional cases from an affiliated hospital between the years 1920 and 1962. All cases below the age of 45 years were excluded. The autopsies were routine in nature and included both gross and microscopic examination of the livers and prostate glands. In this manner, a figure for the incidence of carcinoma for the entire group was determined. Incidence figures were also established for each 10-year group. Included in the study were cases of Laennec's or portal cirrhosis, post-hepatitic cirrhosis, biliary cirrhosis, and cardiac cirrhosis. In a similar manner, a control group of autopsy cases in patients without cirrhosis was collected for comparison. These were unselected cases, and the group was gathered from random routine autopsies performed during the same years as the study group. RESULTS
Five hundred fifty autopsied cases of cirrhosis of the liver were examined (table 1). The ages at time of death ranged from 45 to 87 years. The number of cases with carcinoma of the prostate discovered was 18; the incidence of carcinoma was 3.3 per cent. 1. Incidence of prostatic carcinoma in autopsied cases of cirrhosis and a control group
TABLE
Total No. of Cases
No. of Cases of Percentage with Carcinoma of Carcinoma of Prostate Prostate
59 18
Control, 650 Cirrhotics, 550
9.0% 3. 3%
2. Incidence of prostatic carcinoma according to age category in autopsied cases of cirrhosis and a control group
TABLE
Age
45-54 Cirrhotics Control 55-64 Cirrhotics Control 65-74 Cirrhotics Control 75-90 Cirrhotics Control
Total No. of Cases
Ko. of Cases with Carcinoma of Prostate
Percentage with Carcinoma of Prostate
142 143
3 0
2.% 0
222 233
5 20
2.3% 8.6%
163 184
9
23
5.5% 12.5%
23 90
1 16
4.3% 17.7%
20 /
15
/
LL.I
I:> <(
1-
z
LL.I 0
10
y
a:
LL.I Cl.
5
I
I
I
I
.,, ,,, ,,,
/
,.
/
,,,., CONTROL
I
CIRRHOSIS
I 45-54
55-64 AGE
65-74
75-90
GROUPS
Fm. 1. Incidence of prostatic carcinoma according to age groups in autopsied cases of cirrhosis and control group. Similarly, the ages in the control group at time of death ranged from 45 to 90 years. There were 650 cases collected and prostatic carcinoma was discovered in 59 cases, an incidence of 9 per cent. In the study there were 358 with Laennec's or portal cirrhosis, 43 with post-hepatic cirrhosis, 105 with biliary cirrhosis, and 34 with cardiac cirrhosis. According to age group distribution (table 2 and fig. 1) there was an incidence of carcinoma of 2.1 per cent in the 45 to 54-year age group in cirrhotics, while in the same control age group, the percentage was 0. In the 55 to 64-year age group, the cirrhotics had an incidence of 2.3 per cent, and the control 8.6 per cent. Similarly, in the 65 to 74-year age group, the cirrhotic incidence for carcinoma was 5.5 per cent, with a control group percentage of 12.5 per cent. In the 75 to 90-year age group, the carcinoma percentage in cirrhotics was 4.3 per cent, while the control group had an incidence of 17 .7 per cent, All of these figures were analyzed statistically and a significant difference was discovered between the cirrhotic and control groups. These results would seem to indicate that there is a lower incidence of carcinoma of the prostate in patients with cirrhosis of the liver as compared to a control group. DISCUSSION
In general, these statistics are lower than those reported by some for the incidence of carcinoma of the prostate according to age grouping. The
CIRRHOSIS AND CARCINOMA OF PROSTATE GLAND
cases, of course, were routine autopsies and there was no specific search directed toward discovering carcinoma of the prostate. Examination of the prostate, however, was performed both grossly and microscopically with an average of two sections taken from the gland for microscopic study. It was hoped that bias would be minimized by the fact that the control group was gathered from the same institutions and during the same years from which the cirrhotics were collected. In the over-all study there was a lower incidence of prostatic carcinoma in patients with cirrhosis as compared with the control group. In the control group there was a gradual increase in incidence of carcinoma for each advancing IO-year age group. In the cirrhotics this gradually increasing incidence with age did not appear in the study. In fact, the oldest age group of cirrhotics (over 75 years) had a lower incidence (4.3 per cent) than the next lowest age group (5.5 per cent). There may be some question about this point, since there were only 20 cirrhotic patients over age 75 years in the study, because unfortunately few of these patients with advanced cirrhosis lived to an old age. The possibility, however, that cirrhotics do not have the usual increasing incidence of carcinoma with advancing age might seem to indicate that prolonged exposure to high estrogen levels could prevent or at least delay the development of carcinoma of the prostate. SUMMARY
A study was undertaken to determine the effect of cirrhosis with hyperestrogenism on the
293
incidence of carcinoma of the prostate. The material was collected from a group of autopsied cases of cirrhosis of the liver and a control autopsy group. A comparison of the two groups indicated a lower incidence of carcinoma of the prostate of 3.3 per cent in the cases of cirrhosis which had been chronically exposed to hyperestrogen levels. The contra! group incidence was 9.0 per cent. The entire study was also evaluated according to IO-year age grouping. The age groups were: 45 to 54, 55 to 64, 65 to 74 and 75 to 90 years. In the cirrhotics, the incidence for carcinoma of the prostate was found to be 2.1 per cent, 2.3 per cent, 5.5 per cent and 4.3 per cent for each respective age group. In comparison, the control percentages were O per cent, 8.6 per cent, 12.5 per cent and 17.7 per cent. All of these figures were found to be statistically significant. The control study had an increasing incidence of carcinoma with advancing age, but this was not found to be the case in cirrhosis. The possibility that hyperestrogenism in cirrhosis might play a protective role in preventing the development of carcinoma of the prostate has been discussed. The author wishes to express his appreciation to Dr. John K. Lattimer for advice in the preparation of this paper.
REFERENCES E.
Incidence of occult adenocarcinoma of the prostate after 50 years of age. Arch. Path., 32: 787-793, 1941. MooRE, R. A.: The morphology of small prostatic carcinoma. J. Urol., 33: 224-234, 1935. RrcH, A. R.: On the frequency of occurrence of occult carcinoma of the prostate. J. Urol., 33: BARON,
AND ANGRIST, A.:
215-223, 1935.