Epidemiologic Reviews Copyright © 2001 by the Johns Hopkins University School of Hygiene and Public Health All rights reserved Vol. 23, No. 1 Printed in U.S.A. Medical History and Etiology of Prostate Cancer Edward Giovannucci 12 INTRODUCTION Clinical conditions and medical procedures may provide insight as to the etiologies of some cancers. The clinical course of prostate cancer is clearly influenced by hormonal therapies; hormones may be involved in its etiology, and various clinical conditions such as cirrhosis and diabetes mellitus may be related to hormonal imbalances. A number of studies have examined vasectomy in relation to risk of prostate cancer, though no clear underlying mechanism has emerged. Chronic inflammatory diseases cause cancer at a variety of sites, but chronic prostatitis has not been studied as a contributor to the risk of prostate cancer. Studies examining these conditions and procedures in relation to prostate cancer risk will be briefly summarized here. Prostate cancers tend to be slow-growing and exhibit a wide range of biologic potential with regards to aggressive behavior. Thus, screening and diagnostic practices largely influence the apparent incidence of prostate cancer. Because medical conditions and procedures could impact on screening and diagnostic tendencies, studies relating these factors to prostate cancer risk should be interpreted with a great deal of caution. CLINICAL CONDITIONS AND PROCEDURES Cirrhosis Cirrhosis may affect levels of a variety of hormones that are produced or metabolized in the liver, including estrogens, testosterone, and insulin-like growth factors. Cirrhosis induces changes in estrogen metabolism, and it is known clinically that male cirrhotics may have hyperestrogenism severe enough to lead to testicular atrophy and gynecomastia. Through such influences, cirrhosis may be related to risk of prostate cancer. In 1964, Glantz (1) stud- Received for publication August 31, 2000, and accepted for publication February 2, 2001. Abbreviations: Cl, confidence interval; PSA, prostate-specific antigen; RR, relative risk. 1 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. 2 Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA. Correspondence to Dr. Edward Giovannucci, Channing Laboratory, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115 (e-mail: Edward.Giovannucci@channing. harvard.edu). 159 Downloaded from http://epirev.oxfordjournals.org/ by guest on June 15, 2014 ied 350 autopsy cases with cirrhosis and 650 cases without cirrhosis and found prostate cancer simultaneously present in 3.3 percent of the former and 9.0 percent of the latter. Glantz hypothesized that hyperestrogenism in cirrhosis may have accounted for the lower prevalence of prostate cancer in cirrhotics. In another autopsy study by Robson (2), the prevalence of prostate cancer was somewhat decreased in 205 cirrhotics compared with 2,227 noncirrhotics (8.3 percent versus 11.7 percent). No case of prostate cancer was found in 49 instances of "severe" cirrhosis compared with 10 percent in the nonsevere group consisting of 100 men (p < 0.01). However, there did not appear to be an association between clinical signs of hyperestrogenism and prevalence of prostate cancer, though the numbers were small and blood levels of estrogen were not measured. Another autopsy study conducted in Japan (3) also found that the prevalence of cirrhosis at autopsy was significantly lower in prostate cancer cases than in all male autopsy cases registered in Japan from 1958 to 1975. In 1,210 prostate cancer cases there were 37 cases of cirrhosis (3.1 percent), but there were 12,594 cases of cirrhosis out of 192,412 autopsy cases overall (6.5 percent). Whereas the autopsy studies found an inverse relation between cirrhosis and prostate cancer prevalence, this association was not supported in a follow-up study of 11,605 one-year survivors of cirrhosis identified from the Danish National Registry of Patients from 1977 to 1989 (4). Occurrence of any cancer through 1993 was determined by linkage to the Danish Cancer Registry. For comparison, the expected number of cancer cases was estimated from national age-, sex-, and site-specific incidence cancer rates. The standardized incidence ratio for prostate cancer was 1.0 (95 percent confidence interval (CI): 0.7, 1.3); there were 40 cases observed and 41.6 cases expected. There are obvious limitations to autopsy studies; these are based on prevalence measures of the two conditions at the time of death. The relative timing of the occurrence of cirrhosis or prostate cancer cannot be known, making it impossible to infer causality. Also, the relation of autopsy-detected to clinically-detected prostate cancer is complex and unclear. Differences in the results among the studies may also be related to the severity, duration, and cause of cirrhosis, which may all influence the endocrinologic disturbances. Future studies should account for these characteristics of cirrhosis and better document hormonal changes related to cirrhosis not only of testosterone and estrogen, but also of the insulin-like growth factors. 160 Giovannucci Diabetes mellitus Vasectomy Vasectomy is used in many parts of the world as an effective method of contraception. This procedure is generally regarded as safe and has had few documented acute or longterm adverse effects (13-15). However, in the recent past, some studies have found that men who have had a vasectomy to be at moderately increased risk of prostate cancer (16-25). For the most part, the elevations in risk among men Another possibility for the frequent positive associations is confounding by uncontrolled factors (34, 35). It is plausible that men with higher testosterone levels or who may have a more "fertile" endocrine profile (36), who may be inherently at higher risk of prostate cancer, may be more likely to have a vasectomy. However, it is speculative that significant enough, if any, differences in testosterone concentrations between men with and without vasectomy exist. The biologic basis underlying the relation between vasectomy and prostate cancer remains speculative. Elevations in anti-spermatozoa antibodies, decreased seminal hormone concentrations, and decreased prostatic secretion have been reported in men who have undergone vasectomy and in animal models (21). Whether these changes influence prostate carcinogenesis remains unknown. A better understanding of the effects of vasectomy on the prostate would help clarify the biologic plausibility of the association. Future studies should examine whether more consistent associations are observed in specific subgroups of men who have had a vasectomy. For example, some data suggest an increased risk of prostate cancer limited to men who had their vasectomy at a relatively young age (20, 22, 25-27), or only after several decades after the vasectomy was performed (21, 22, 26, 27). Consistent patterns in subgroups, though, have not emerged thus far. Future studies should also take into account screening patterns to examine the potential role of detection bias. Epidemiol Rev Vol. 23, No. 1, 2000 Downloaded from http://epirev.oxfordjournals.org/ by guest on June 15, 2014 Several prospective studies have examined the relation between type II diabetes mellitus with risk of prostate cancer and have found about a 30—70 percent reduction in prostate cancer risk among diabetic men (5—7). The risk appears to decrease over time since diagnosis of diabetes; in male health professionals (7), a suggestive decrease in risk occurred after 6 years postdiagnosis of diabetes, and a statistically significant decrease occurred only after 10 years (relative risk (RR) = 0.5; 95 percent CI: 0.4, 0.8). Detection bias did not appear to account for this association because diabetics, despite their reduced risk, appeared to receive even more screening for prostate cancer (7). However, no clear evidence of an inverse association could be detected in another prospective study (8) and in case-control studies (9, 10). Recently, an analysis of the Cancer Prevention Study of the American Cancer Society (11) reported little association between self-reported diabetes mellitus (types I and II) at baseline and even a moderately elevated risk among men who had had diabetes for 5 or more years. The relation between diabetes and risk of prostate cancer is likely to be quite complex. As a marker of hyperinsulinemia, diabetes should be associated with higher levels of circulating insulin and possibly higher free insulin-like growth factor-1 because high insulin decreases one of the insulinlike growth factor-1 binding proteins. These factors would presumably be growth-enhancing and may increase risk. On the other hand, men with severe type II diabetes have substantially lower androgen levels, probably resulting from toxic effects of hyperglycemia on the testosterone-producing Leydig cells of the testis (12). Of note, hyperglycemia tends to worsen and insulin levels tend to decrease over time, and the risk of prostate cancer appears to decrease with increasing time since diagnosis of diabetes (7). The complex timing of relations between type II diabetes mellitus and specific hormonal changes may help explain the discrepancies between the study of health professionals (7) and the Cancer Prevention Study (11). The study of health professionals found the inverse association primarily among men who had had a diagnosis of diabetes mellitus for at least 10-15 years. Also, that study was conducted in 1986-1994, a time period of considerably earlier detection of prostate cancer due mostly to prostate specific antigen (PSA) screening, compared with the Cancer Prevention Study which took place from 1959 to 1972. It is important for future studies to examine whether the longer time lag between the diagnosis of diabetes and prostate cancer, and the detection of prostate cancer at earlier stages, may account for the apparent discrepancies. who have had a vasectomy have been in the range of 1.5-2.0. This relation remains controversial because almost an equal number of studies have found no association (26-35). Overall, the epidemiologic literature is consistent with either a weak positive association, or no appreciable association. Given the weak nature of the association, bias and confounding need to be seriously considered. The possibility of detection bias has not been adequately addressed. Most studies were conducted prior to the widespread use of PSA screening. Thus, differences in PSA screening between men with and without vasectomy were unlikely to bias the results. Nonetheless, the possibility remains that men who had seen a urologist because of the vasectomy may have been exposed to more digital rectal examinations subsequently, or were more likely to undergo invasive procedures required to diagnose prostate cancer. In a prospective study conducted prior to PSA screening, enhanced detection by more frequent digital rectal examinations did not appear to account for a positive association (21). In some studies, vasectomy has been associated with advanced stage of disease (18, 21, 22, 25) or symptomatic cancers (16) arguing against detection bias, which would typically produce stronger associations with less advanced disease. However, two recent studies conducted largely in the "PSA era" have reported suggestive associations only with earlier-stage, lower-grade prostate cancer (26, 27). Positive associations have also been reported for non-Western populations (18, 25), for which screening should not have been an issue. Unfortunately, no study has reported on risk of prostate cancer mortality, which would be less prone to detection bias. Medical History and Prostate Cancer Etiology Chronic inflammation of the prostate Epidemiol Rev Vol. 23, No. 1, 2000 epidemiologic studies. Until a valid practical definition can be used for population-based studies, this hypothesis will be difficult to study from an epidemiologic perspective. An inflammatory etiology of prostate cancer is important to establish because this could enhance preventive efforts, particularly if a specific agent is identified. Although a cause of inflammation is not yet apparent, it is critical to note that anti-inflammatory and antioxidant mechanisms are likely to play an important anticarcinogenic role if chronic inflammation is important. An inflammatory process could possibly account for the suggestive evidence that antioxidants (e.g., lycopene, vitamin E, selenium) and that nonsteroidal anti-inflammatory drugs such as aspirin may be protective (40). CONCLUSIONS Prostate cancer is a hormonally-related cancer; thus, it is quite plausible that clinical syndromes that influence hormonal levels also affect risk of prostate cancer. There has been a modest degree of study related to diabetes mellitus and cirrhosis, and while the data are suggestive of a protective association for each, the studies are inconsistent. The complex natural history of such diseases and their varying impact on hormones complicates the interpretation of results from such studies. Investigators who have access to existing databases which have substantially large numbers to examine these associations are encouraged to evaluate these hypotheses. However, prospective studies with archived blood samples which can directly examine hormonal hypotheses are preferable. A relation between vasectomy and prostate cancer cannot be ruled out at this time, but any association is likely to be relatively modest. Nonetheless, as vasectomy remains an important contraceptive option, further study of this relation, particularly in potentially susceptible subgroups, is warranted. There are almost no epidemiologic data on chronic prostatitis and risk of prostate cancer. As it is quite plausible that prostatitis is carcinogenic, as evidenced by carcinogenic effects of chronic inflammation in other organs, study of prostatitis in relation to prostate cancer should be undertaken. REFERENCES 1. Glantz GM. Cirrhosis and carcinoma of the prostate gland. J Urol 1964,91:291-3. 2. Robson MC. Cirrhosis and prostatic neoplasms. Geriatrics 1966;21:150-4. 3. Araki H, Mishina T, Miyakoda K, et al. An epidemiological survey of prostatic cancer from the Annual of the Pathological Autopsy Cases in Japan. Tohoku J Exp Med 1980; 130:159-64. 4. S0rensen HT, Friis S, Osen JH, et al. Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark. Hepatology 1998;28:921-5. 5. Thompson MM, Garland C, Barrett-Connor E, et al. Heart disease risk factors, diabetes, and prostatic cancer in an adult community. Am J Epidemiol 1989; 129:511-17. 6. Adami HO, McLaughlin J, Ekbom A, et al. Cancer risk in patients with diabetes mellitus. Cancer Causes Control Downloaded from http://epirev.oxfordjournals.org/ by guest on June 15, 2014 Long-standing chronic inflammation by diverse agents is a cause of carcinoma of the liver, large bowel, urinary bladder, esophagus, and stomach. Chronic inflammatory states are characterized by activated phagocytic macrophages, which produce bactericidal reactive oxygen and nitrogen species. Inflammatory states cause substantial potential for mutational and promoting effects through exposure to highly reactive compounds and growth factors, and increased cell turnover. Given the strong link between inflammatory states and carcinogenesis, prostatitis is an obvious candidate to consider with regards to carcinogenic potential, although there has been essentially no epidemiologic study of this relation. Prostatitis is an inflammation or infection of the prostate typically characterized by pain and discomfort in the rectal or perineal region. This condition, common in adult men, is categorized as acute bacterial, chronic bacterial, and nonbacterial. One community-based population (37) estimated a prevalence of physician-diagnosed prostatitis of 11 percent based on medical record documentation, which may be incomplete. The actual prevalence of prostatitis, including undiagnosed cases, is likely to be much higher. In acute and chronic bacterial prostatitis, the causative agents are generally gram-negative bacteria, usually Escherichia coli, that gain access to the prostate by means of urinary reflux during a urinary tract infection. In nonbacterial prostatitis, inflammatory cells are present but a causative bacterial agent cannot be cultured in prostatic secretions or urine. Nonbacterial prostatitis, often called idiopathic prostatitis, is by far the most common form of prostatitis, especially in older men. Novel infectious agents may be involved, as detected by the isolation and sequencing of prokaryotic ribosomal DNA in idiopathic prostatitis (38). Recent pathologic evidence summarized by De Marzo et al. (39) suggests that chronic inflammation may contribute to prostate carcinogenesis. Focal prostatic glandular atrophy, which has been suggested as a potential precursor to prostatic adenocarcinoma, is closely associated with chronic inflammation. 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