Natural History of Prostate Cancer Epidemiologic Considerations

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1 Epidemiologic Reviews Copyright 2001 by the Johns Hopkins University Bloomberg School of Public Health All rights reserved Vol. 23, No. 1 Printed in U.S.A. Natural History of Prostate Cancer Epidemiologic Considerations Gary J. Miller 1 and Kathleen C. Torkko 2 INTRODUCTION Adenocarcinoma of the prostate is most correctly characterized as a heterogeneous disease both in terms of its morphology and its clinical behavior. Because of this, analysis of its natural history from both the pathologic and epidemiologic viewpoints attains greater importance as chemoprevention and treatment options broaden. The intention of this brief review is to present some of the most pertinent facts regarding the pathobiology of the prostate and its malignancies, and thereby facilitate the future work of epidemiologists studying this important disease. PROSTATE BASICS The prostate is a tubuloalveolar gland that surrounds the urethra and is located between the bladder neck and the pelvic diaphragm (1). It encases the ejaculatory ducts and is adjacent to the seminal vesicles. The gland is composed of a smooth muscle stroma and acini lined by a bilayered epithelium composed of basal cells and mature columnar secretory cells. The latter contribute a number of components to the seminal plasma including prostatic acid phosphatase and prostate-specific antigen (PSA). In humans, the gland is divided into zones (peripheral, transition, and central) that attain their greatest distinction in disease states such as benign prostatic hyperplasia. While the prostate is one anatomic structure in primates, it consists of multiple anatomically distinct lobes (i.e., ventral, dorsal, lateral, and coagulating gland) in rodents (2). The functional relation of these lobes to the human zones is still somewhat unclear. The prostate develops from the urogenital sinus epithelium through the process of branching morphogenesis as do the breast and salivary glands. PSA production begins at approximately 32 weeks of gestational age (3). At parturition, the gland is a simplified form of the adult structure. Received for publication September 14, 2000, and accepted for publication February 7, Abbreviation: PSA, prostate-specific antigen; TNM, tumor/node/metastasis. 1 Deceased. Former member of both the Department of Pathology and Division of Urology, University of Colorado Health Sciences Center, Denver, Co. 2 Department of Pathology, University of Colorado Health Sciences Center, Denver, CO. Reprint requests to Kathleen Torkko, MS, MsPH, Department of Pathology, Box B-216, University of Colorado Health Sciences Center, 4200 E. 9th Avenue, Denver, CO ( kathleen. torkko@uchsc.edu). The weight of the prostate remains relatively constant (approximately 1-2 g) until puberty at which point it increases to approximately g (4). Its weight plateaus at about age 20 years when the prostate is a highly epithelial organ. Increases in gland weight after 30 years of age are largely due to stromal and epithelial hyperplasia, which is nearly ubiquitous among western populations. BENIGN ABNORMALITIES Numerous benign conditions affect the prostate, the most clinically significant of which is benign prostatic hyperplasia. While its name is derived from the term hyperplasia, benign prostatic hyperplasia may also include elements of smooth muscle hypertrophy or benign neoplasia. It is a nodular disease of varying composition. The nodules can be composed of stromal cells (leiomyomatous or fibromatous nodules) or admixtures of these with epithelial components (fibromyoadenomatous nodules). Benign prostatic hyperplasia most often occurs in the transition zone lateral to the urethra (5). Local consequences include infarct, atrophy, and inflammation. It has long been debated whether or not benign prostatic hyperplasia has a precursor relation to carcinoma. Most contemporary analyses have concluded that the majority of carcinomas arise in the peripheral zone of the prostate, away from the benign prostatic hyperplasia-prone transition zone. Recently, it has been suggested that a subset of carcinomas arising in the transition zone is indirectly derived from benign prostatic hyperplasia (6). It is likely, however, that the overall temporal association of these two diseases is a coincidence based on their common association with the aging process rather than the result of any mechanistic interrelations. Acute and chronic inflammation of the prostate is also extremely common in North American adults. Focal aggregates of lymphocytes are found in most radical prostatectomy specimens. In most cases, the inciting etiologic agents remain unknown. Small atrophic acini can occasionally be confused with carcinoma in diagnostic specimens. Several other benign conditions are known to mimic the histology of prostate cancer (7). These include sclerosing adenosis and reparative changes, such as reserve cell hyperplasia, that are associated with previous injury or inflammation. Because it is accepted that carcinomas do not contain a basal cell layer, the presence of cells containing basal cell-specific cytokeratins by immunohistochemistry is generally taken as evidence that a given suspicious lesion is benign (8). 14

2 Natural History of Prostate Cancer 15 PREMALIGNANCY The search for a precursor to human prostate cancer has led to the identification of two plausible candidate lesions. The first, prostatic intraepithelial neoplasia, is characterized by the presence of nuclear crowding, loss of nuclear polarity, and the presence of prominent nucleoli in glands of otherwise normal architecture (9). The second, atypical adenomatous hyperplasia, is a lesion in which small glandular proliferations occur adjacent to benign normal or hyperplastic glands, predominately in the transition zone (10). Prostatic intraepithelial neoplasia has been selected as a putative precursor due to its physical and temporal association with carcinoma (9). Lowand high-grade variants have been described; however, only high-grade prostatic intraepithelial neoplasia is reproducibly diagnosed and associated with concurrent malignancy (11). Atypical adenomatous hyperplasia has largely been implicated due to its morphologic similarity to well-differentiated carcinomas. Clinically, both of these lesions are considered to be red flags that prompt rebiopsy and/or increased clinical surveillance (12, 13). In selected cases, small, invasive acini are present that morphologically arise from prostatic intraepithelial neoplasia. These lesions are termed microcarcinomas (14) and probably do represent the origins of invasive malignancy. However, the concept that prostatic intraepithelial neoplasia is "the" precursor to cancer remains controversial. Recent molecular data bring this relation into question. Using analysis of loss of heterozygosity, it has been found that prostatic intraepithelial neoplasia lesions can contain molecular alterations that are not detected in adjacent carcinomas (15-17). Furthermore, in all but the smallest volume tumors, it is difficult to be certain that the prostatic intraepithelial neoplasia found in temporal association with a given carcinoma is actually related to that carcinoma (18). By the time most carcinomas have reached 1 cc of volume, they probably would surround and efface the morphology of their precursor lesion(s) that might originally have been composed of only a few progenitor cells. Consequently, it is unlikely that the precise origins of most carcinomas would be morphologically apparent at the time of their clinical detection. ADENOCARCINOMA OF THE PROSTATE Diagnosis The vast majority of prostatic carcinomas are adenocarcinomas. Historically, the diagnosis of prostate cancer was driven by the detection of palpable abnormalities upon digital rectal examination. Over the past 10 years, however, digital rectal examination has been gradually augmented by determination of the serum PSA level (19). PSA is a serine protease that is prostate-specific, but not prostate cancerspecific. Gland size and the presence of benign diseases such as benign prostatic hyperplasia and prostatitis also influence the serum levels of PSA. Men with PSA values above the currently accepted cut-off point (4.0 ng/ml) will have cancer only one-third of the time, or less, based on biopsy results (20). Continuing efforts have been made to increase the sensitivity and specificity of PSA assays for cancer detection. PSA is typically present in the plasma bound to enzyme inhibitors. The most recent approach to improve diagnostic specificity has been to determine the percentage of free PSA. Levels of free PSA less than 20 percent suggest the presence of malignancy (21, 22). In spite of improvements in body imaging and chemical pathology, however, the diagnosis of carcinoma must be confirmed by needle biopsy prior to definitive therapy. Unfortunately, with the currently used sextant sampling techniques, the false negative rate is about 20 percent in men with an abnormal digital rectal examination and/or a PSA of 4.0 ng/ml or greater (23). Studies have shown that increasing the number of biopsy cores taken may improve cancer detection (23, 24). However, in spite of their shortcomings, the combined current modalities apparently detect clinically meaningful cancers earlier in their natural histories (25). Complicating the situation is the fact that prostate cancer is a multifocal disease (26). Numerous studies using whole-mount sections have demonstrated that multiple carcinomas are present in at least 50 percent of radical prostatectomy specimens. These multicentric lesions typically have different grades, may arise in all three anatomic zones, and are genetically distinct. This of course, leads to problems with sampling error. Specifically, until a prostate has been removed and thoroughly examined, it is impossible to be sure that the characteristics of a carcinoma found on biopsy are representative of the status of the gland as a whole. Clinical staging The tumor/node/metastasis (TNM) system has become the most widely adopted method for prostate cancer staging in the United States (27). Perceptions of the presence, size, location, and degree of local invasion of any given carcinoma are still most often derived from the digital rectal examination. This is an observer-dependent technique, the accuracy of which is highly dependent on the experience of the clinician performing the examination. Consequently, it has been found that approximately percent of carcinomas believed to be clinically localized are pathologically non-localized (28, 29). Prior to prostatectomy, combinations of clinical stage, serum PSA, and histologic grade are the most predictive of pathologic stage (30). Following radical prostatectomy, pathologic staging is carried out. This technique currently takes into account whether a given carcinoma is unilateral or bilateral, confined within the prostatic capsule, locally invasive, or involves regional lymph nodes. Again, issues of sampling error arise. While the whole-mount technique is perhaps the most reliable method to determine pathologic stage, it is also the most costly and technically demanding. Consequently, it is not widely performed. Submission of sections from the entire specimen is an acceptable alternative if it is done in a systematic fashion. Patients who undergo only external beam radiotherapy or brachytherapy cannot be pathologically staged.

3 16 Miller and Torkko Histologic grading Histologic grading of prostate cancer has been a topic of debate and interest since the 1970s. While many systems have been proposed, the Gleason system (31) has become the de facto standard in the United States. The method is based on recognition of numerous histologic patterns that are stratified into five separate groups, each of which is designated by a pattern score. Because Gleason recognized the characteristic heterogeneity of morphologies in prostate cancer, he incorporated the approach of identifying the two most predominant pattern scores and adding them together to produce a score sum. If only one pattern is observed, the same score is used twice. Thus, Gleason sums range from 2 through 10. To date, the Gleason system has been found to correlate with nearly every relevant endpoint that has been examined including pathologic stage and cancer related death (32, 33). One of the most important misconceptions about Gleason grades is that they are somehow arranged in an order of morphologic or biologic progression. In fact, Gleason stratified the many patterns he observed into five categories retrospectively using outcome data from the Veterans Administration diethylstilbestrol clinical trials. There was no intention to imply that pattern 1 gives rise to pattern 2 and so forth. As discussed previously, prostate cancer is known to be multicentric and one cannot rule out the overgrowth of a lesion with one histologic pattern by another lesion of a higher pattern score. It remains controversial, therefore, as to whether or not Gleason patterns "progress" in a given patient over time. It is recognized, however, that those lesions arising in the transition zone tend to have low Gleason scores compared with their peripheral zone counterparts, and consequently have a better prognosis (34). Basic aspects of histopathologic interpretation by surgical pathologists are relatively consistent, and it is likely that the vast majority of prostate cancer diagnoses made in routine practice are correct. More subtle aspects such as histologic grading, however, are another matter. Gleason himself has said that the ability to apply his grading system rests with the experience of the individual (35). It is prudent, therefore, to enlist the aid of an accomplished uropathologist in clinical trials (36). In addition, the issue of sampling error causes apparent inconsistencies. Generally, grades assigned to needle biopsies are similar to those found at prostatectomy. However, approximately 40 percent of cases will receive a different grade, and approximately one-third of these will increase and two-thirds will decrease (37, 38). Training and repetition are the keys to eliminating problems of observer inconsistency, but cannot eliminate sampling error. Disease progression Prostate cancer remains as a significant clinical problem among aging men in Europe and North America. Substantial differences in incidence and mortality have been observed around the world with African-American men having rates that are times higher than Chinese men in Shanghai (39). World incidence and prevalence rates are, however, likely to be influenced by detection bias. For example, while previously considered low, recent data suggest that rates in Africa are also high and are comparable to those found in African-Americans (40, 41). While modest differences in grade exist, overall the disease appears to be similar in its morphology between various ethnic groups. Comparison between African-Americans and Caucasians in Detroit, Michigan, has revealed that African-Americans develop higher-grade carcinomas earlier in life than their Caucasian counterparts (42, 43). In addition, molecular analyses have detected ras gene mutations in carcinomas from Japan that are rare in the United States (44). One of the topics that continue to be a point of confusion regarding prevalence is the concept of "latent" carcinoma. Since there is a large gap between the number of carcinomas known to be present at autopsy and those that present clinically, it is widely assumed that many carcinomas are "dormant" or "quiescent" and pose no threat to patients. Those carcinomas of the prostate that are clinically unsuspected and are found only by chance at transurethral resection or autopsy are known as latent carcinomas. It has been assumed that these latent carcinomas are the "dormant" ones and that they are, therefore, clinically insignificant. However, while their method of detection is different, it is not clear that these carcinomas are fundamentally different from those that are detected clinically. It is important to remember that the terms "latent" and "clinically significant" are conventions of nomenclature that may or may not have any foundation in biologic difference. It is more likely that these latent carcinomas have simply occurred in patients in whom clinical surveillance has failed to detect them. Certainly, it would follow that as clinical detection rates increase, the numbers of clinically undetected "latent" carcinomas found at autopsy would have to decrease. While early studies suggested that the prevalence of latent cancer was the same around the world (45), more recent information has brought this conclusion into question. For example, it is now clear that the rates of latent cancers in Asians aged >60 years are less than those among men in Detroit aged >30 years (46). Earlier studies had restricted the types of tumors they had detected in autopsy specimens to those they believed should be latent tumors, thereby biasing the data (45). While continued analysis is necessary, it appears that in populations where clinical prostate cancer is a rarity, latent prostate carcinomas are also relatively scarce. It is most likely, therefore, that latent carcinomas represent a phase in the natural history of the disease as a whole and not a separate subset. One of the most important residual issues surrounding prostate cancer biology is related to the effect of time on progression and tumor doubling. While numerous studies have attempted to use proliferation index as a measure of proliferative potential, these are static measurements that tell us little about rate. Based on the concept that carcinomas secrete constant amounts of PSA into the serum in direct proportion to their volume, tumor-doubling times have been calculated in a series of patients who did not receive confounding forms of therapy (47). Doubling times ranged from less than 2 months to greater than 48 months, and the majority of cases had doubling times in excess of 48 months.

4 Natural History of Prostate Cancer 17 Independent confirmations of these estimates are still lacking but are of crucial importance in understanding the early natural history of this disease. However, based on doubling times of 2-6 years, it can be calculated that those carcinomas that attain clinical significance need only have doubling times from 2 to 3 years, depending on the age at which the malignant process begins (48). Better estimates of doubling time could help to determine the age above which "screening" for prostate cancer becomes less justifiable. Regarding molecular mechanisms of progression, there have been numerous genes and gene products that have been implicated in the process of prostate cancer metastasis. These include type IV collagenases, E-cadherin, (J4-integrin subunit, and CD44 (49). What coordinates the activities of such diverse genes remains unknown. Surprisingly, unlike carcinomas of the urinary bladder, mutations of classic tumor suppressor genes are uncommon in prostate cancer (50). CLINICAL MATERIALS AND ANCILLARY STUDIES As molecular epidemiology becomes more entrenched, there is an increasing need for specimens of human carcinomas to analyze for polymorphisms and mutations. High throughput molecular analysis has removed the prior "bottleneck" in this process and emphasized the need for large numbers of specimens for comparison. The accuracy of the results obtained by such analyses is largely dependent on the amounts and quality of the specimens that are analyzed. Retrospective analyses can be adversely impacted by routine clinical practices. While it has little effect on routine diagnosis, the quality of routine fixation can make a major impact on subsequent immunohistochemical or molecular investigations. Due to their small size, needle biopsies are invariably better fixed than large blocks of tissue from prostatectomy specimens. Over fixation can occur and can decrease the ability to recognize tissue antigens as well as diminish the ability to extract DNA from tissue specimens. One possible solution to such problems is the use of microwave fixation (51); however, this is only possible in prospective analyses where follow-up information is lacking. Tissue specimens are removed from the prostate in five basic manners. While more common in Europe than in the United States, fine needle aspiration removes clumps of cells through a gauge needle. In the United States, springloaded biopsy "guns" have become widely used. These produce cylinders of tissue that are approximately 1 mm x 1.5 cm in greatest dimension. While once the second-most common surgical procedure in the United States, transurethral resection is less frequently performed since the advent of medical management of benign prostatic hyperplasia. The process of electrocautery may also damage the tissue derived from this procedure. In cases of benign prostatic hyperplasia where the prostate is estimated to be greater than g, suprapubic prostatectomy is often performed. This provides good sampling of the transition zone but does not usually provide significant portions of peripheral or central zone tissue. Perhaps the most reliable source of tissue is the radical prostatectomy specimen. Since these procedures are nonemergent, they are scheduled and can be coordinated with procurement efforts. However, issues arise regarding informed consent for research, the necessity of not violating the specimen in such a way that pathologic inspection is hindered, and rapid freezing for preservation of RNA. Ethanol fixation may preserve DNA and RNA better than standard formalin fixation (52). However, studies using pathologic specimens are only as good as the clinical and outcome data collected by clinical researchers. Hence, wellperformed prostate cancer studies must include both surgical pathologists and urologists. SUMMARY Multicentricity, heterogeneity, and sampling error complicate the study of the natural history of prostate cancer. Carcinomas previously termed "latent" are probably similar to those detected clinically. The diagnosis of carcinoma is only made following biopsy and histologic confirmation. Estimates of grade and stage made at the time of detection are prone to sampling error and are likely to change following examination of radical prostatectomy specimens. In regions with lower life expectancies, the problem of prostate cancer becomes a lower priority due to its association with aging. Access to care, numbers of medical facilities, and differing public health priorities make international rates difficult to compare. However, in view of the high worldwide prevalence of the disease, further epidemiologic studies of prostate cancer are warranted. ACKNOWLEDGMENTS This work was supported in part by US Public Health Service grants CA and CA to the senior author (G. J. M). REFERENCES 1. McNeal JE. Prostate. In: Steinberg SS, ed. Histology for pathologists. New York, NY: Raven Press, 1992: Jesik CJ, Holland JM, Lee C. An anatomic and histologic study of the rat prostate. Prostate 1982;3: Popek EJ, Tyson RW, Miller GJ, et al. Prostate development in prune belly syndrome (PBS) and posterior urethral valves (PUV): etiology of PBS lower urinary tract obstruction or primary mesenchymal defect? Pediatr Pathol 1991; 11: Tanner JM. The development of the reproductive system. In: Tanner JM, ed. Growth at adolescence. 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