Prostate cancer: a current perspective.

American Journal of Epidemiology Copyright 1991 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved

Vol. 13, No. 1991 Printed in U.S.A.

Prostate Cancer: A Current Perspective

Abraham M. Y. Nomura1 2 and Laurence N. Kolonel2

INTRODUCTION

world, followed by whites in Norway, Switzerland, and Sweden (4). Asian men in Singapore, Japan, and Hong Kong have the lowest mortality rates. This review addresses the major topics in the epidemiology of prostate cancer. Unresolved issues, such as the role of dietary and hormonal factors in the etiology of the disease, are emphasized, and areas in need of additional research are noted. Because the high prevalence of latent disease is a unique feature of prostate cancer, affecting the determination of disease incidence as well as the identification of etiologic factors, this topic is discussed first.

The age-adjusted incidence of prostate cancer now surpasses that of all other cancers among men in the United States (1). It was estimated for 1991 that 122,000 new prostate cancer cases would be diagnosed in the United States, representing 22 percent of all new cancer cases among men. In addition, 32,000 prostate cancer deaths were projected for 1991. This makes prostate cancer the second leading cause of all male cancer deaths in the country, following cancer of the lung (2). Prostate cancer is especially common in elderly men. In the age group 85 years or older, the average US mortality rate is 629 per 100,000 men per year (1). Lung cancer, which is the second most common cancer among men in this age group, has a much lower annual mortality rate of 435 per 100,000 men. A distinctive feature of prostate cancer is that latent carcinoma, which is a clinically unsuspected, incidental lesion, is frequently found in elderly subjects, especially at the time of autopsy. Its prevalence has been reported at over 40 percent in men aged 70 years or more (3). Blacks in the United States have the highest mortality rates for prostate cancer in the

GENERAL CONSIDERATIONS Latent prostate cancer

Histologically, the prostate is a rounded mass of smooth muscle and connective tissue filled with tubuloalveolar glands. It is often divided into a central zone and a peripheral zone (5). The central zone is shaped like an inverted pyramid and is characterized by larger and more irregular secretory acini than the acini in the peripheral zone. The peripheral zone occupies three fourths of the prostate proper. About 96 percent of malignant neoplasms of the prostate are adenocarcinomas (6). They arise, in most instances, in the peripheral zone of the prostate gland (7). Although these lesions are glandular, the term "carcinoma" is generally preferred. Latent carcinoma of the prostate is usually ascertained microscopically and is difficult to detect macroscopically. It is defined here as an unsuspected, usually localized, welldifferentiated neoplastic lesion found inci-

Received for publication January 9, 1991, and in final form April 22, 1991. 1 Japan-Hawaii Cancer Study, Kuakini Medical Center, Honolulu, Hawaii. 2 Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii. Reprint requests to Dr. Abraham M. Y. Nomura, JapanHawaii Cancer Study, Kuakini Medical Center, 347 N. Kuakini Street, Honolulu, HI 96718. This work was supported in part by grants RO1 CA 33644 and PO1 CA 33619 from the National Cancer Institute.

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dentally at the time of autopsy or after surgical removal of prostate tissue, commonly for benign prostatic hypertrophy. This definition does not distinguish between tumors that are truly latent (i.e., that would not progress to clinical disease) and those that have simply been detected very early in the course of their progression. At present, there are no means available with which to separate these two important subgroups of latent prostate tumors. Although latent lesions are less extensive than clinically overt cancers, they are not morphologically or histologically distinct. Autopsy studies in the United States have reported latent carcinoma prevalence rates of 29-31 percent (3). Since the lifetime risk of death due to prostate cancer is about 2-3 percent among men in the United States (8), latent lesions occur much more frequently than does the fatal disease. In earlier autopsy studies conducted independently in different countries, prevalence rates of latent carcinoma ranged from 8.8 percent in the United States (9) to 10.9 percent in Japan (10) and 37.6 percent in England (11). As Yatani et al. (12) pointed out, these rates cannot be compared because of intercountry differences in the criteria for diagnosing prostate carcinoma, differences in the numbers of blocks of tissue examined, and variations in study techniques. As a result, several studies have used a standardized pathology protocol to report the prevalence of latent cancer among various countries, although this does not take into account intercountry differences in selection factors which determine who receives an autopsy. Akazaki and Stemmermann (13) found that the prevalence of total latent prostate cancer did not differ between Japanese men in Japan and Japanese men in Hawaii. However, the Hawaiian Japanese men, who have a higher incidence of prostate cancer, did have a significantly higher prevalence of the proliferative or invasive type of latent carcinoma than did their counterparts in Japan (19.1 percent vs. 8.7 percent). The authors suggested that causative factors operated equally between the two groups but that exposure to promoting factors was greater in Hawaii than in Japan.


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These observations were supported in subsequent autopsy studies which also used uniform methods in examining prostate glands from different countries. Breslow et al. (14) reported that the frequency of small latent carcinoma did not vary with age and was about 12 percent in all seven countries they studied. In contrast, the large latent carcinomas increased with age and showed a variation by country (5-27 percent) similar to the differences in prostate cancer mortality rates. ("Small" lesions contained tumor in 1-2 out of 40-48 octants, based on 5-6 sections of the gland; "large" lesions contained tumor in nine or more octants.) In a separate study, Yatani et al. (12) observed that there was no consistent trend in age or race in the prevalence of latent noninfiltrative prostate carcinoma (a frequency range of 12-16 percent in five different population groups), but the prevalence of latent infiltrative tumors showed a racial variation (9-24 percent) similar to the incidence of prostate cancer. Even though these autopsy studies do not explain the high prevalence of latent prostate cancer, they do support the view that initiating factors for this cancer are relatively common in many different population groups, whereas exposure to promoting factors associated with infiltrative tumors may differ significantly. In past epidemiologic studies of prostate cancer, all incident cases were usually combined. Investigators should design future studies to permit the separation of patients with latent prostate cancer from patients with clinically apparent disease. If latent cancers could be identified by type (infiltrative vs. noninfiltrative) as a subset in a casecontrol or cohort study, then their risk factors could be studied separately. Although this would necessitate the inclusion of larger numbers of study subjects than in the past, it should be feasible. In a recent study, 25 percent of the prostate cancer cases were identified as latent cancers (15), while 33 percent of 402 incident cases were discovered incidentally in a population-based survey (16). Another consideration in the design of future studies that merits careful thought is the choice of the most suitable comparison

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group for cases with latent cancer. Because these cancer cases, in nonautopsy studies, are mainly diagnosed among a select group of patients who receive a transurethral resection for clinically benign prostatic hypertrophy, a comparison group of transurethral resection patients without latent cancer might be more appropriate than a neighborhood or other population-based control group. However, if benign prostatic hypertrophy and latent cancer have etiologic factors in common, use of such controls would underestimate or even fail to identify risk factors for the cancer. The role of benign prostatic hypertrophy in the etiology of prostate cancer is discussed below. Clinical prostate cancer

Latent prostate cancer is not distinguished from clinically overt disease in the International Classification of Diseases for Oncology (17). Because latent carcinomas are typically localized and asymptomatic, their identification is often dependent on prevailing medical care practices, such as the frequency of autopsy, transurethral resection, or prostatectomy, and the thoroughness with which tissue obtained by these procedures is examined. For example, the autopsy rate is exceptionally high in Malmo, Sweden. About 8 percent of all Swedish prostate cancer cases were reported as incidental cases at the time of autopsy, but 35 percent of the Malmo cases were reported as incidental (18). Consequently, reported incidence rates are higher in Malmo than in other regions of Sweden. Although it has been suggested (19) that latent prostate cancer be separated from clinically overt disease in the International Classification of Diseases for Oncology in order to distinguish between these two entities, this has not occurred in the latest revision (17). Currently, there are several classification systems for prostate cancer. They include the TNM (Tumor-Node-Metastasis) classification of malignant tumors (20), the American Urological Association staging of prostate cancer (21), and the staging of cancer by the American Joint Committee on Cancer (21). Under the TNM classification, prostate carcinomas that are considered an


incidental histologic finding are coded as T1. These tumors could be categorized as latent carcinoma for tumor registry coding purposes. Any unsuspected incidental tumor detected at the time of autopsy would also be considered a latent carcinoma. This would enable registries to more reliably compute the incidence rates of clinical prostate cancer, although it should be noted that intercountry differences in access to medical care and in the frequency of diagnostic imaging, needle biopsies, or other diagnostic procedures would still influence these rates. Furthermore, a small percentage of patients with incidental or clinically unsuspected cancers that were detected in tissue removed for apparently benign disorders subsequently develop clinical problems that can lead to fatal prostate cancer. In one case series, this occurred in 4 percent of the 72 incidental cases in which the cancer occupied less than 25 percent of the total surgical specimen (22). The phenomenon of tumor latency and progression from an undetected microscopic carcinoma to metastatic disease is not well understood. McNeal et al. (23) observed that prostate tumors which grow larger than 1 ml and have poorly differentiated areas are the ones that are more likely to progress and metastasize. They suggested that carcinoma identified at necropsy, clinically detected carcinoma, and metastatic carcinoma may be different phases in the biologic continuum of a single type of cancer. In their view, the unpredictable behavior of prostate cancer does not indicate that there is a separate cancer type that is inherently innocuous. Nevertheless, because of the high prevalence of latent prostate carcinomas that do not become clinically significant during a person's lifetime, it may still be useful to distinguish between them. Furthermore, as has been suggested previously, different factors may initiate the latent carcinoma and promote the development of clinical disease (12-14). Geographic and migrant variations in incidence and mortality

There is a 50-fold difference between populations with the highest rates of prostate

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cancer (blacks in Detroit, Michigan: 91.1 per 100,000 population) and populations with the lowest incidence (Shanghai, China: 1.8 per 100,000 population), as figure 1 shows (24). Besides blacks in the United States, high rates are found among whites in the United States and whites in Sweden and Canada. Within the Nordic countries, there is considerable variation, the rate in Sweden being much higher than the rate in Denmark. Intermediate rates are found in Western Europe, and somewhat lower rates are seen in Eastern and Southern Europe. The lowest incidence rates are reported in Asian

countries such as Japan, Hong Kong, India, and the People's Republic of China. Incidence data are more difficult to obtain than mortality data but are usually more informative, since mortality data exclude the patients who survive their disease. However, as was discussed above, because of the high prevalence of latent carcinoma, incidence rates for prostate cancer may be misleading. In figure 1, the countries which excluded unsuspected cancers found at necropsy from the incidence rates are marked with an asterisk. In contrast to incidence data, mortality

20 —l—

Detroit, Michigan, US (blacks) Detroit, Michigan, US (whites) Sweden Canada Norway Geneva, Switzerland Queensland, Australia Finland New Zealand (non-Maori) Eindhoven, Netherlands Denmark •Hamburg, Germany Costa Rica *Doubs, France Scotland Los Angeles, California, US (Japanese) England and Wales Navarra, Spain Southern Ireland Israel Ragusa, Italy Slovenia, Yugoslavia Vas, Hungary Los Angeles, California, US (Chinese) Warsaw, Poland County Cluj, Romania •Singapore (Chinese) *Miyagi, Japan #Hong Kong *Poona, India Shanghai, China

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40

60

80

100

—I—

91.1 51.2 45.9 43.7 42.0 39.6 38.8 34.2 33.3 28.3 27.7 26.5 26.1 24.9 23.3 22.8 20.9 20.5 20.3 18.8 18.8 18.7 16.9 16.9 11.5 9.8 6.6 6.3 6.2 4.8 1.8

FIGURE 1. International average annual age-adjusted prostate cancer incidence rates per 100,000 men, 19781982. The rates for some countries cover less than a 5-year period. The asterisk designates countries which do not include cancers found at autopsy in computing incidence rates. Data from Muir et al. (24).


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data do not include latent prostate cancers, but they also have limitations. Mortality data can be affected by various factors such as changes in rules for assigning causes of death and improved treatment that reduces mortality. Prostate cancer mortality rates are presented in figure 2 by country for 1980-1981 (4). The pattern is similar to that of the incidence rates, with a few exceptions. The mortality rate for Hungary ranks in the upper half of the listed countries, while its incidence rate is in the lower half (figure 1). The mortality rates for Canadians and US whites lie in the middle of the listed countries, but the incidence rates for these groups are among the top four listed in figure 1. There is about a 10-fold difference in mortality rates between US nonwhite men and

men in Hong Kong and Japan. Although both genetic and environmental factors may contribute to this geographic variation in rates, migrant studies suggest that environmental exposures play a dominant role. Immigrants to the United States from Poland have experienced a marked increase in prostate cancer mortality compared with their peers in Poland (25). Similarly, Japanese immigrants to the United States have had at least a fourfold increase in prostate cancer mortality (26) and a greater increase in incidence (27). More recent incidence rates (figure 1) for Japanese men in Los Angeles, California, and Miyagi, Japan, and for Chinese men in Los Angeles, Singapore, Hong Kong, and Shanghai, China, also suggest that prostate cancer rates increase substantially in populations that migrate from

10 Non-Whites, US Norway Switzerland Sweden Denmark New Zealand Netherlands Germany Finland France Hungary Australia Canada Whites, US Ireland Spain England and Wales Scotland Costa Rica Italy Yugoslavia Poland Israel Romania Singapore Japan Hong Kong

20

30

26.8 20.7 20.2 19.1 16.9 16.4 16.3 15.6 15.5 15.4 15.1 14.9 14.5 13.9 13.6 12.6 12.3 12.2 12.1 10.5 10.4 8.5 7.8 7.6 3.2 2.8 2.0

FIGURE 2. International average annual age-adjusted prostate cancer mortality rates per 100,000 men, 19801981. Data from Kurihara et al. (4).


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Asia to the United States. The effect of migration upon prostate cancer rates among black men is discussed below.

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slope of its age-specific mortality curve is a characteristic of prostate cancer. It is unclear why the US prostate cancer mortality rate in the age group 85 years or older far surpasses that of other cancers in men (1). Because the incidence of prostate cancer is strongly associated with age, it is clear that longevity influences the likelihood of a man's being diagnosed with this disease. In one prospective study, participants had a greater risk of being diagnosed with prostate cancer than did nonparticipants (28). In contrast, study participants had lower total mortality rates than nonparticipants. Members of the Church of Jesus Christ of Latterday Saints (Mormons) in Utah also have a

Age, race, and time trends

Age. Although prostate cancer can occur in men under age 50, it is primarily a disease of older men, especially among black men in the United States. Figure 3 shows that US blacks have about 2-3 times the prostate cancer mortality rates of US whites at all ages, and the rates in both ethnic groups increase significantly with age (1). The steep

1,000 Black Males White Males

100

-

10

-

o o o o" o

45-49

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85+

Age (years)

FIGURE 3. Average annual age-specific prostate cancer mortality rates for US blacks and whites, 1983-1987. Data from Rieset al. (1).


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greater risk of prostate cancer than nonMormons but lower total mortality than non-Mormons (29, 30). This suggests that health-conscious subjects who live longer increase their risk for prostate cancer. However, Seventh-day Adventists, another religious group that promotes a healthy lifestyle, have lower prostate cancer rates than the general population (31). Race. There are no obvious reasons why incidence and mortality rates for prostate cancer are much higher among blacks than among whites in the United States. Although there is considerable variation in the incidence of prostate cancer among different African populations (32), the reported rates among Africans are much lower than the rates among African-Americans (33). In the Caribbean, prostate cancer incidence (16.8 per 100,000 men) ranks first among various cancers for black males, but the rate among these men is still much lower than that among African-American men (34). These data suggest that migration and the accompanying change in environmental exposures has affected prostate cancer risk in US blacks. Although epidemiologic studies have been carried out to identify risk factors for prostate cancer among blacks (35-39), they have not been able to provide an explanation for the exceptionally high rates in this population in the United States. Further investigations into genetic-environmental interactions related to diet and other factors capable of influencing hormone levels in men (see below) may yield clues to the whiteblack differences in prostate cancer incidence in the United States. Time trends. Because of the difficulties in determining the true incidence rates of clinical prostate cancer and the limitations of mortality data, the extent to which the occurrence of clinical prostate cancer has increased over time is unclear. Time trend analyses of prostate cancer mortality rates have shown varying patterns. The rates for US whites were virtually unchanged from 1950 to 1975, while the rates among US nonwhites increased (18). During the same time period, slight annual increases of about 1 percent were observed in Canada, Co-


lombia, and Austria; increases of about 2 percent were observed in Denmark, Finland, and Norway; and increases of about 3-4 percent were seen in Hungary, Italy, and Greece (18). Most of these increases occurred in men over the age of 65. In a recent study conducted to identify reasons for the dramatic increase in prostate cancer incidence in the United States from 1973 to 1986, Potosky et al. (40) explored the relation between changing rates of transurethral prostatectomy and prostate cancer incidence. They found a strong positive correlation between the incidence of prostate cancer and use of transurethral resections. The authors suggested that the increased detection of existing tumors by transurethral resection was the primary reason for the observed recent increase in incidence rates of prostate cancer in the United States. However, they also noted that analysis of mortality trends, especially in nonwhites, suggested that part of the increase may reflect real changes in the risk of prostate cancer. If this is so, then increasing exposure to causal factors in nonwhites is likely to have occurred. ASSOCIATION WITH OTHER CONDITIONS

Certain medical conditions, including benign prostatic hypertrophy, cirrhosis, and vasectomy, have been studied for their effects on the incidence of prostate cancer. A change in prostate cancer risk associated with these conditions would support the possibility of a role for hormonal or other endogenous factors in the etiology of this disease and might identify certain high-risk groups of men who should be followed closely for prostate cancer. Benign prostatic hypertrophy

Benign prostatic hypertrophy is found commonly in elderly men. It is estimated that as much as 75 percent of men aged 8090 years have benign prostatic hyperplasia (41). Benign prostatic hypertrophy usually arises in the inner periurethral group of

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glands, in contrast to cancerous lesions, which most often are located in the outer zone of the peripheral glands (42). Nonetheless, it is conceivable that benign prostatic hypertrophy predisposes to cancer or that both benign and malignant disease of the prostate share a common factor. Two studies have examined the relation between benign prostatic hypertrophy and prostate cancer (43, 44). The first study consisted of two parts, one using a retrospective cohort design, the other a case-control design (43). In the cohort portion of the study, 296 patients with a primary diagnosis of benign prostatic hypertrophy were identified either clinically (48 percent), by biopsy (27 percent), or by operation (26 percent). They were followed for an average of 8 years, along with 299 randomly selected control patients who were discharged with nonneoplastic diagnoses. In the case-control part of the study, there were 290 prostate cancer cases and 290 matched controls who were other hospital patients without cancer. The two parts of the study gave similar results, with relative risks of 3.7 and 5.1, respectively. However, concern has been expressed regarding the identification of benign prostatic hypertrophy patients without histologic confirmation of the diagnosis and regarding the process of selecting hospital controls (45, 46). The second study, in contrast, found no association between benign prostatic hypertrophy and prostate cancer in an analysis based on follow-up of both a cohort of 838 patients who had subtotal prostatectomies for benign prostatic hypertrophy and a comparison group of 808 surgical controls (44). A potential bias in this study was the elimination of latent cancer cases in the prostatectomized group but not from the control group (47). The issue of whether subjects with benign prostatic hypertrophy do have an increased risk of prostate cancer will be difficult to resolve, because of the very high prevalence of benign prostatic hypertrophy in older men, the selection factors that determine which subjects undergo a transurethral resection (which usually leads to a diagnosis


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of benign prostatic hypertrophy), and the tendency for benign prostatic hypertrophy patients to be examined more often than other men. A well-designed cohort study in an elderly population with a benign prostatic hypertrophy prevalence of less than 50 percent, preferably screened using the best available methods with which to identify subjects with and without benign prostatic hypertrophy, would yield informative results. Cirrhosis

Patients with cirrhosis have hyperestrogenism due to increased estrone production and increased conversion of androgen to estrogen (48). They also have decreased plasma levels of testosterone and dihydrotestosterone, as well as decreased testosterone production (49, 50). Since estrogen has a beneficial effect in the treatment of prostate cancer, it has been hypothesized that men with cirrhosis may have a reduced risk of prostate cancer. Little has been done to confirm this hypothesis. Two autopsy studies found that subjects with cirrhosis had a lower prevalence of prostate cancer than control subjects (51, 52). Glantz (51) reported that 18 of 550 subjects with cirrhosis (3.3 percent) had prostate cancer compared with 59 of 650 noncirrhosis subjects (9.0 percent), based on routine autopsy examination. In the other study, Robson (52) found that 8.3 percent of 205 autopsied cirrhotics had prostate carcinoma compared with 11.7 percent of 2,227 autopsied subjects without cirrhosis, based on gross morphology and the histologic finding in a single section of the prostate gland. Deaths due to prostate cancer should be excluded from these autopsy studies to reduce the chance of a biased estimate of the prevalence of this cancer among noncirrhotic subjects. Although it is unclear whether this was done, the magnitude of the differences would suggest that cirrhotic subjects may have a lower prevalence of prostate cancer. However, in one case-control study, there was no difference in past history of hepatitis, jaundice, or liver cirrhosis between

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prostate cancer cases (7.0 percent) and controls (5.5 percent) (53). Because cirrhotic patients have a shortened life span, it would be difficult to conduct a long-term followup study for prostate cancer incidence in such a group of patients. Vasectomy

A protective effect of vasectomy on the risk of prostate cancer is suggested by studies showing decreased prostatic activity following vasectomies in both human males (54) and laboratory animals (55). On the other hand, other studies have reported that vasectomy increases levels of serum testosterone (56), which is suspected of being a contributing factor in prostate cancer risk (57). In one case-control study, there was a nonsignificant reduced relative risk of 0.5 associated with a history of vasectomy (58). In contrast, three other case-control studies found that subjects with a history of vasectomy had an increased risk of prostate cancer (59-61). We note that several noncausal explanations have been suggested for the positive findings in these studies (62). A major problem in studying the association between vasectomy and prostate cancer has been the relative infrequency of this procedure. However, Sidney (63) identified 5,332 vasectomized men and 15,996 nonvasectomized men among Kaiser Permanente Health Plan members. After an average follow-up period of 4.6 years, 17 incident cases of prostate cancer were identified in the vasectomy group and 51 were identified in the nonvasectomy group, which resulted in a relative risk of 1.0. Age at vasectomy did not have an effect on the risk. Thus, the evidence for an association between vasectomy and prostate cancer is inconsistent at present. Additional studies will be needed to resolve this issue. FAMILIAL AND GENETIC FACTORS

The question of a familial or genetic component in prostate cancer risk has received little study. A few case-control studies that focused on other risk factors reported a higher rate of prostate cancer in family members of cases than in family members


of controls (64-66). Steinberg et al. (67) designed a case-control study specifically to address this question. They found a twofold increase in risk of prostate cancer among first-degree relatives of cases compared with first-degree relatives of controls and an increasing trend in risk with the number of relatives affected. Several other reports on this subject have come from studies in the population of Utah. Woolf (68) reported that the fathers and brothers of men who died of prostate cancer also had a higher rate of death from prostate cancer (but not from other cancers) than did age-matched controls, whereas there was no difference in overall cancer deaths for mothers and sisters of the cases compared with controls. In Utah, Meikle and Stanish (69) showed that the risk of developing prostate cancer was greater in the brothers of prostate cancer probands than in their brothers-in-law or men in the general population of the state. They also showed that there was a high correlation of serum testosterone and apparent free testosterone concentration among probands and brothers and among probands and sons. Cannon et al. (70) conducted a genetic-epidemiologic study using the genealogic records of the Church of Jesus Christ of Latter-day Saints. They found that prostate cancer ranked fourth among cancer sites in the mean coefficient of kinship. They also found significantly increased relative odds of prostate cancer in brothers of prostate cancer cases compared with controls (except for men aged 80 years or more). Although these data suggest that there may be familial aggregation of prostate cancer, they cannot answer the question of a genetic factor. Family members share a common environment, and several exogenous risk factors, such as diet, have been implicated in this cancer. Furthermore, the data showing a substantial increase in incidence among Japanese immigrants to Hawaii (71) indicate that environmental factors play a major role in the occurrence of this cancer. However, the concordance of serum testosterone levels among brothers and fathers and sons (69) suggests that a genetic factor should be further examined.

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The ras oncogene has been related to prostate cancer (72). It has also been reported that a mutated ras oncogene protein (p21) is expressed in prostatic carcinoma tissue (but not in normal or hyperplasic tissue) and is highly correlated with the grade of the prostate cancer (73). These studies suggest that future genetic research may contribute to an understanding of how and why certain latent cancers progress to clinical and fatal outcomes. ENVIRONMENTAL RISK FACTORS Viruses and sexual activity

Certain epidemiologic observations suggest that viruses could have an important role in the etiology of this cancer. A number of investigators compared cases and controls with regard to sexual factors (35, 59, 64, 65, 74, 75). They found that prostate cancer patients had become sexually active at an earlier age (59, 74), had had more sexual partners before marriage (64, 65, 74), had higher fertility (75), and more often had a history of venereal disease (35, 59, 64, 65, 74) than controls. These findings support the hypothesis that a venereally transmitted virus could be a causal agent of the disease. However, not all of the observations related to this subject are supportive. For example, Ross et al. (76) found that mortality from prostate cancer among Catholic priests, who take a vow of celibacy, was somewhat higher than expected based on rates for US white males. Furthermore, since sexual behavior could also be a consequence of higher androgen levels, these observations are also consistent with a hormonal etiologic hypothesis. Reports that prostate cancer is less common among Jews in the United States than among other groups (53, 64, 77), that it constitutes a higher proportion of deaths among non-Jews than among Jews in Sweden (where almost all non-Jewish men are uncircumcised) (78), and that it has a higher incidence in Sweden than in Israel (78) also support a viral hypothesis, since transmission of venereal disease factors should be lower in circumcised men than in uncircumcised men. Determination of circumcision


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status in individuals through self-reports is not totally reliable (79), and comparisons of cases and controls on this basis have produced both positive (35, 80) and negative (53) findings. Finally, several investigators have looked for direct evidence of viral involvement in prostate cancer (81). Reports on serum titers for herpes simplex virus type 2 in cases compared with benign prostatic hypertrophy controls have been both positive (82) and negative (83). A positive relation to prostate cancer has also been reported for cytomegalovirus (84). However, an attempt to isolate herpes simplex virus type 2 and cytomegalovirus viral RNA from prostate cancer tissue was not successful (85). The lack of direct evidence for a viral etiology of prostate cancer and the inconsistency of the epidemiologic data related to sexual activity do not argue strongly for this causal mechanism. Unless further refinements of this hypothesis or newer approaches are developed, it appears that additional research in this area is unlikely to be productive. Anthropometry

A number of studies carried out to determine whether obese men have an increased risk of prostate cancer have produced conflicting results. A case-control study conducted by Talamini et al. (86) found that cases had an increased body mass index (weight (kg)/height (m)2) compared with controls, but four other case-control studies using either relative weight or body mass index as a measure of obesity reported no differences (35, 53, 66, 87). In two prospective studies, relative weight or percentage of desirable weight was positively related to prostate cancer risk (88, 89), but this finding was not confirmed in other prospective studies (90, 91). The body mass index estimates both the weight of lean tissue and the weight of fat tissue (92). Detailed evaluation of a series of anthropometric measurements in a cohort study by Severson et al. (93) showed that the positive association with prostate cancer was stronger when upper arm girth was mea-

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sured instead of body mass index. Further analysis revealed that the muscle area of the upper arm was significantly related to prostate cancer risk and the fat area of the upper arm was not. Because androgens affect muscle mass, it is possible that the increased muscle mass reflects higher levels of androgens in subjects susceptible to prostate cancer. A positive correlation between arm muscle area and the testosterone:dihydrotestosterone ratio in the serum has been reported (94). Additional studies are needed to identify more specifically which anthropometric measurements may be related to prostate cancer. Methods are being developed to improve the measurement of human body composition, especially with regard to percentage of body fat and body fat distribution (95). Improved methods of measuring total body muscle mass are also needed. Hormones

It seems likely that sex hormones have some role in the development of prostate cancer (57). Androgens are required for the growth, maintenance, and functional activity of the prostate gland. Eunuchs, whose testes have been removed or never developed, have not been observed clinically with prostate cancer or even benign prostatic hypertrophy (58, 96). Furthermore, castration or estrogen therapy can have a palliative effect on prostate cancer (97). However, some researchers believe it is unlikely that sex hormones are involved in the initiation of prostate cancer (98). Testosterone, secreted mainly by the Leydig cells of the testis, is the principal androgenic hormone in men. Only 2 percent of total serum testosterone is free (not bound to protein) and available for metabolism by the liver and intestines. Dihydrotestosterone is a metabolite of testosterone, and its plasma concentration is about 10 percent of that of testosterone (99). The female sex hormones estrone and estradiol can be synthesized from testosterone or androstenedione. Androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate


are weak androgens that are secreted primarily by the adrenal gland. Urinary levels of testosterone and 17ketosteroids do not accurately reflect testosterone production and consequently may be of limited value in studying prostate cancer risk. Although testosterone is metabolized mainly to 17-ketosteroids, nonandrogenic steroids and other steroids from the adrenal glands can also be metabolized to 17-ketosteroids in the urine. Furthermore, less than 2 percent of the testosterone produced daily enters the urine without being metabolized (99). Thus, past hormonal studies of prostate cancer have focused primarily on measuring hormone levels in serum or plasma. The results of case-control investigations of serum or plasma levels of male sex hormones have been inconsistent. Serum testosterone levels in prostate cancer cases have been found to be elevated (36, 100), depressed (36, 37, 101, 102), and similar to those of controls (103). Dihydrotestosterone was also measured in some studies and was found to be similar in cases and controls (36, 101) or lower in cases than in controls (102). Some researchers have also examined the testosterone:dihydrotestosterone ratio in the serum. A high ratio was associated with an increased prostate cancer risk in one study (100) but not in others (36, 101). Equivocal results were also observed with regard to levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate (37, 102). Analyses of female hormones have also yielded inconsistent findings. Researchers have found serum estrone levels to be both similar in prostate cancer cases and controls (101) and higher in prostate cancer cases than in controls (36, 37, 102). Plasma estradiol was higher in cases than in controls in one study (37), but no significant differences were noted in three other investigations (36, 101, 103). To date, two studies have measured hormone levels in serum obtained before the prostate cancer cases were diagnosed (104, 105). Data from the first study suggested that an elevated testosterone:dihydrotestosterone ratio increased the risk of pros-

Prostate Cancer

tate cancer (104), while the second study found a positive association with serum levels of androstenedione (105). Both studies found no effect of testosterone, estrone, estradiol, or sex hormone binding globulin on prostate cancer risk. Hormone levels in prostatic fluid were measured in a preliminary study (106). Fluid levels of estradiol and prolactin, but not levels of estrone or testosterone, were elevated in 15 prostate cancer cases compared with controls. Several factors may account for such a high degree of inconsistency in the results of case-control studies of serum testosterone and other hormones. Testosterone levels in the blood have a circadian rhythm, with peak levels usually occurring in the early morning and declining progressively until the lowest levels are reached in the early evening (107). Thus, all serum should be collected at the same time of day in cases and controls because of the limitations of a single specimen as an indicator of a man's serum testosterone profile. Furthermore, if the metabolic clearance rate of testosterone is greater in prostate cancer cases than in controls, as was suggested in one study (101), then serum testosterone levels might not be elevated in cases, even if testosterone production is greater. Another consideration is that anxiety or stress can affect serum testosterone levels (108, 109). This could influence serum measurements in cases, just before or after surgery. Consequently, it would be difficult to clearly show by serum studies that testosterone was associated with prostate cancer. The tissue concentration of dihydrotestosterone in the prostate gland (5 ng per g of tissue wet weight) is five times higher than that of testosterone, even though the concentration of testosterone in the plasma is 10 times greater than that of dihydrotestosterone (99). Dihydrotestosterone appears to be 1.5-2.5 times more potent than testosterone in most bioassay systems, and dihydrotestosterone binds to androgen receptors in the nuclei of prostate cells. As a result, dihydrotestosterone is the major intracellular androgenic hormone regulating the growth and


211

function of the prostate. This suggests that measurement of prostate tissue levels of dihydrotestosterone and other androgens in prostate cancer cases and noncases would be desirable. However, because it is difficult to obtain prostate tissue from normal subjects, such studies would be difficult to carry out. (Past studies have used benign prostatic hypertrophy patients as controls (110).) It would be beneficial to determine the correlation between prostate tissue levels of androgenic hormones and serum levels in the same individual. If serum and tissue levels of specific androgens such as dihydrotestosterone were highly correlated, this would broaden the usefulness of serum measurements. The relation of serum or tissue androgen levels to anthropometric measurements should also be studied. If arm muscle or body muscle mass adequately reflected androgenic load, this would increase the importance of studying the association of anthropometric measurements with prostate cancer risk. Diet

The plausibility of diet's having a major role in the etiology of prostate cancer is supported by certain observations based on the descriptive epidemiology of the disease: 1) The incidence of prostate cancer has been rising in Japan, where dramatic dietary changes have occurred in the past three decades (111); 2) the incidence of the disease increases greatly in Japanese immigrants to Hawaii (71); and 3) the incidence of prostate cancer is positively correlated with that of other cancers that have been related to diet (breast, endometrium, ovary, colon) in international comparisons (112). Fat. The main dietary component which has been associated with prostate cancer risk is fat (table 1). Ecologic correlations of per capita fat consumption with prostate cancer incidence and mortality both within and among different countries have shown strong positive associations (113, 114). Furthermore, in a correlational analysis based on quantitative diet history data collected by personal interview in Hawaii, prostate

212

Nomura and Kolonel

TABLE 1. Summary of results from epidemiologic studies of dietary fat and prostate cancer Year

Investigators) (reference)

Location

No. of subjects

Major findings*

Ecologic studies 1974

Howell(113)

International

Correlations among 41 countries

Positive association of mortality with per capita intake of meat, milk, and fats (r = 0.7).

1978

Blair and Fraumeni (114)

United States

Correlations among four regions

Positive association of mortality with average household consumption of high-fat foods.

1981

Kolonel et al. (115)

Hawaii

Correlations among five ethnic groups

Positive association of incidence with age-specific intakes of animal fat and saturated fat (r = 0.9).

Case-control studies 1982

Schuman et al. (116)

MinneapolisSt. Paul, MN

223 cases 223 neighborhood controls

No association with meat; suggested positive association with ice cream and eggs.

1983

Graham et al. (87)

Buffalo, NY

262 cases 259 hospital controls

Positive association with total fat (RRt = 1.9, linear trend NS|) and animal fat (RR = 3.2, linear trend p < 0.05) in men aged >70 years.

1985

Heshmat et al. (38)

Washington, DC


Positive association with total fat and saturated fat (especially consumption at ages 30-49 years: p70 years.

1989

Mettlin et al. (117)

Buffalo, NY


Positive association with animal fat (RR = 1.5, NS) and whole milk (RR = 3.1, p < 0.05), especially in men aged 70 years (RR = 2.0, linear trend p < 0.05).

1985

Heshmat et al. (38)

Washington, DC


Positive association with vitamin A (especially consumption at ages 30-49 years: p70 years. Inverse association with betacarotene intake from green/ yellow vegetables (RR = 2.2, p < 0.05). Positive association with betacarotene intake from fruits (RR = 2.0, p < 0.05).

1987

Kolonel et al. (128)

Oahu, HI

452 cases 899 population controls

Positive association with total vitamin A (RR = 2.0, p < 0.05), beta-carotene (RR = 1.5, NS), and other carotenes (RR = 1.6, p = 0.05) in men aged >70 years.

1988

Hayes etal. (132)

Rotterdam, The Netherlands


Inverse association with serum retinol (RR = 2.4, p = 0.04) and beta-carotene (RR = 1.3, NS).

1989

Mettlin et al. (117)

Buffalo, NY


Inverse association with betacarotene index (RR = 3.3, p < 0.05) in men aged

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A perspective on the current management of advanced colorectal cancer.

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Current challenges in prostate cancer: an interview with Prostate Cancer UK.

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