Natural Cures For Prostate Cancer

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How Have the Incidence Rates of Prostate Cancer Changed during the Past Two Decades

During the two decades spanning 1973 to 1992, the age-adjusted prostate cancer incidence rate for all men increased dramatically (Figure 1-1).3 The rate increased linearly between 1973 and 1986 but accelerated between 1987 and 1992. During the 5 years preceding 1992, the age-adjusted incidence rate of prostate cancer increased 84 from 102.9 cases per 100,000 men to 189.4 cases per 100,000 men. The two largest increases were observed in 1990 and 1991. Since 1992, there has been a precipitous drop in the number of new cases so that by 1994, the most current year for which accurate data are available, the incidence rates appear to be returning to the rates present before the introduction of widespread testing for PSA4 (Figure 1-2). The shape of the incidence curves are similar for African Americans and Caucasians although the peak incidence for African Americans was 1 year later. The incidence of prostate cancer in African Americans continues at a rate almost double that among Caucasians.

How Has the Stage of Incident Prostate Cancers Changed Over the Past Decade

Before 1986, the diagnosis of localized prostate cancer accounted for the majority of the increase in incident cases. Only modest increases were detected for regional and distant-stage cases. After 1986, the stage-specific incidence rates began to increase exponentially for all stages except distant-stage disease. From 1986 to 1991, the incidence of localized disease increased 75 while incidences of regional and unstaged disease rose 144 and 161 , respectively.3 The incidence of distant disease remained essentially unchanged. The age-adjusted incident rates for distant disease have fallen dramatically since 1991, and are now approximately half what they were at the beginning of the decade. Decreasing rates of distant disease most likely reflect widespread use of PSA testing. While decreasing rates of distant disease are a significant indicator that early detection may subsequently lead to decreased mortality, this fact alone is not sufficient to demonstrate the efficacy of aggressive...

How Have Prostate Cancer Mortality Rates Changed during the Past Decade

Mortality from prostate cancer has gradually increased among both Caucasians and African Americans during the past two decades. In absolute terms, 33,565 men died of prostate cancer in 1991 and 34,901 men in 1994.5 When viewed in relative terms, however, the data suggest a different trend. Among Caucasian men, the age-adjusted mortality rate rose from 20.3 deaths per 100,000 men in 1973 to 24.7 deaths per 100,000 men in 1991. Rates among African Americans were more than twice as high. Since then the rates have declined. The National Cancer Institute recently reported data showing that the prostate cancer death rate in the United States fell between 1991 and 1995, from 26.5 to 17.3 deaths per 100,000 men in the overall population.7 The percentage decline was greatest for young Caucasion males and smallest for older men and African American men (Figure 1-4). The differences between absolute and relative age-adjusted rates are explained by the increasing number of men dying from prostate...

Screening by Prostate Specific Antigen

Since the late 1980s there has been an unquestionable increase in the detection of prostate cancer and the diagnosis of curable disease.4 Since DRE and TRUS have been shown to be ineffective screening tools, most epidemiologists relate this dramatic rise to PSA-based screening. Regarding PSA's ability to improve detection of curable disease, one may compare stage at time of diagnosis. According to Jacobsen and colleagues, the incidence of clinically organ-confined prostate cancer increased from 61 in the pre-PSA era (i.e., DRE-detected cancers) to more than 90 in the post-PSA era.23 The incidence of pathologically organ-confined disease showed a similar upturn from an average of 33 before the widespread use of PSA testing, to as high as 70 following the introduction of PSA into community medical practice.3,16 In large PSA-based prostate screening trials involving thousands of men, cancer detection rates have ranged from 1.5 to 4 . The positive predictive value of PSA testing in these...

Prostate Specific Antigen

Prostate-specific antigen is the best single test for early diagnosis of prostate cancer and, along with DRE, has recently received FDA approval as an aid in the detection of prostate cancer in men 50 years of age and older.10 Since its introduction as a clinical marker nearly two decades ago, PSA has had a profoundly favorable impact on diagnosis and treatment of prostate cancer. The PSA produced by prostatic epithelial cells is not only secreted into prostatic fluid but enters the systemic circulation.3 In serum, PSA is primarily bound to the protease inhibitor a 1-antichymotrypsin, and only a small fraction exists in an unbound or free form.22 Currently, the most frequently used assays measure total serum PSA, including both PSA bound to a 1-antichymotrypsin and unbound PSA. The findings from six PSA-based prostate cancer screening studies15,20,23-26 are shown in Table 9-1. These results indicate that 8 to 15 of men who are older than Benign prostatic hyperplasia (BPH) is a common...

Prostate Cancer in Jamaicans

The epidemiology of prostate cancer in Jamaicans has only recently been studied.7,8 An extremely high incidence of prostate cancer among Jamaican males has gone unnoticed primarily because of under-reporting. It is now recognized that Jamaican males have the highest incidence of prostate cancer in the world, greater even than African American men. In addition, Jamaican males present with more advanced disease that results in greater morbidity compared to their American counterparts. Familial aggregation of prostate cancer is evident in Jamaican families, with an increased risk for Jamaican men who have relatives affected with the disease, similar to the increase among Caucasian males in the United States who have affected relatives. The very high incidence of prostate cancer among Jamaican blacks compared to other populations is probably due to a combination of both environmental and genetic factors.

Effects of Prostate Specific Antigen Based Early Detection on Prostate Cancer Incidence

While the optimal use of PSA and its derivatives continues to evolve, it is undeniable that screening for cancer with prostate-specific antigen has had a profound impact on incidence patterns for carcinoma of the prostate in the United States. Based on data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, the age-adjusted incidence rate of prostate cancer increased 84 between 1987 and 1992 from 102.9 cases per 100,000 to 189.4 cases per 100,000.50 Pototsky et al. also analyzed data collected by the SEER program and reported that the age-adjusted incidence rate of prostate cancer for men over 65 years of age in four SEER areas rose by 82 from 1986 to 1991, with the most dramatic annual increases occurring in 1990 (20 ) and TABLE 9-2. Probability of Prostate Cancer According to Free Prostate-Specific Antigen Cutoff* TABLE 9-2. Probability of Prostate Cancer According to Free Prostate-Specific Antigen Cutoff*

Prostate Cancer Screening Results of Screening Trials

No randomized clinical trial in prostate cancer screening has been completed and analyzed on an intention-to-treat or intention-to-screen (i.e., as randomized) basis. Recently, Labrie et al.27 have publicly presented interim results of a trial, but it was not analyzed on the basis of intention to treat. When analyzed by randomization allocation, the relative risk of death from prostate cancer in the screened group was 1.16 times greater than in the control group. Only about a third of men randomized to be screened were actually screened, and thus the inclusion of the unscreened men in the analysis of the group randomized to be screened would dilute any potential efficacy of screening. However, their inclusion should not have raised the risk of prostate cancer death above that of the control group if screening is truly efficacious. In the recent past, DRE of the prostate was assumed to be an effective screening technique, and many major health organizations recommended it be done as a...

Screening for Prostate Cancer

Proponents of widespread screening argue that current screening protocols result in detection of medically important prostate cancers while they are still organ-confined and curable.5,7 To date, however, screening has not been proven to reduce morbidity and mortality.8 Critics of widespread screening therefore contend that the financial, emotional, and physical burdens of screening and subsequent diagnostic and therapeutic interventions may outweigh presumed benefits from screening.3 Given these conflicting viewpoints, it is not surprising that screening recommendations issued by various professional organizations have been highly variable and even contradictory. The American Cancer Society and the American Urological Association are in agreement in recommending that annual prostate cancer screening with digital rectal examinations (DRE) and PSA levels should be offered to all men starting at age 50 and for younger men who are at increased risk for prostate cancer.9 This protocol was...

Prostate Specific Antigen Slope

The rate of change in total serum PSA over time (PSA slope or velocity) has been reported to be higher among men with prostate cancer than those with benign prostatic enlargement or no prostatic pathology.41 Several investigators have proposed a PSA slope of 0.75 ng per mL per year as a cutoff to enhance specificity for prostate cancer detection in PSA-based screening programs.41,42 Accurate determination of PSA slope, however, requires measurements over an 18-month time period and is therefore not useful in the short term but may be helpful in determining the need for repeat biopsy.

Prostate Specific Antigen Isoforms

With the discovery of PSA isoforms in the serum, a new era in tumor markers began. Prostate-specific antigen was found to circulate as a free, uncomplexed molecule in the blood or to bind to a number of serum proteins, of which a-antichymotrypsin (ACT) and a2-macroglobulin appeared predominant.58 The complexing process influenced some of the normally available antigenic sites on the free PSA molecule in such a way that various antibodies could no longer detect the PSA molecule. This phenomenon offered the opportunity to measure free and complexed forms, as complexing differed in men with prostate malignancies compared to those without.29 No obvious metabolic explanation for this phenomenon has yet been found. As ACT is abundantly available in the circulation but ACT production is increased within some prostate cancer cells as well as in cells found in hyperplastic nodules,59 research is ongoing to find an intracellular mechanism for complex formation.60 New assays for determining...

Clinical Significance or Insignificance of Prostate Cancer

Length bias has been documented in randomized trials of mammography for breast cancer and chest radiography with sputum cytology for lung cancer. More recently, it has been associated with digital rectal examination (DRE) screening for prostate cancer.7 There are consistently more cases detected in the screened group than in the control group. In the case of lung cancer, virtually all these excess cases of lung cancer were localized surgically operable lesions yet, in the randomized screening trials for lung cancer, virtually identical numbers of lung cancer deaths were observed in the screened arms versus the controlled arms. In two of these studies, there was an increased but not statistically significant number of deaths in the screened group. This illustrates that length biases do exist and do matter in terms of quality of life. not within the remaining natural lifespan of the individual. The latter form of overdiagnosis can be substantial in a disease such as prostate cancer, in...

Economics of Prostate Cancer Screening

Since prostate cancer is the most common visceral neoplasm in American men, the costs associated with its diagnosis and treatment represent a not insignificant component of United States health care expenditures. In a 1990 analysis by Optenberg and Thompson, it was estimated that the annual cost for clinical management of prostate cancer for men between 50 and 70 years of age prior to the widespread implementation of PSA-based screening programs was 255 million.69 However, as screening with PSA has become widely accepted in the past decade, estimates of health care expenditures related to prostate cancer have increased dramatically. Numerous studies have attempted to predict the actual costs associated with a single year of screening for prostate cancer in men between the ages of 50 and 70 years. In an updated analysis, Lubke, Optenberg, and Thompson estimated that the first-year cost of screening with PSA and DRE would be 25.7 billion in a scenario where organ-confined disease was...

Characteristics of Prostate Cancers Currently Detected

It is well known that prostate cancer is a ubiquitous disease among older men if autopsy data are used for analysis. Data from these autopsy series suggest that prostate cancer can be found in 34 of men in the fifth decade of life and in as many as 54 of men in their eighth decade.23,24 From these data, some have suggested that prostate cancer screening will detect many of these indolent, autopsy tumors. Evidence suggests otherwise. In the American Cancer Society-National Prostate Cancer Detection Project, 2999 men aged 55 to 70 years underwent DRE, transrectal ultrasonography, and prostate-specific antigen (PSA) determi nations on an annual basis for up to 5 years.25 In these men, a total of 164 tumors were detected, with 83 found during the first year (the so-called harvest effect). During the subsequent years, 2 to 5 prostate cancers were found in 38, 16, 21, and 6 patients. Similar findings were published by Catalona in a series of 10,251 men who underwent prostate cancer...

Algorithms for Prostate Cancer Detection

All clinicians use algorithms when they evaluate men for the possibility of prostate cancer. Most of these algorithms consist of the clinician's thought processes when assessing a patient. For example, the clinician will consider digital rectal examination (DRE) findings, the man's age, his PSA value, and perhaps his race to decide if further intervention is needed. Basic algorithms were developed even in the earliest studies of PSA.1 For example, a basic algorithm was that if the PSA was between 4.1 to 10.0 ng per mL, there was an approximate 30 risk of prostate cancer, and if the PSA was greater than 10 ng per mL, the risk increased to approximately 60 to 67 . The work on PSA density was also an algorithm of sorts in that the clinician had another factor to consider.2 The first widely used accepted algorithm was the age-specific reference ranges (ASRR) for PSA developed by Mayo Clinic investigators.3 This was followed by age- and race- Table 7-1 shows the age- and race-specific...

Example 3 Prostate Cancer Clinical Trial

This example concerns a VACURG (Veterans Administration Cooperative Urological Research Group) prostate treatment study. This study was the first of a series of multicenter randomized clinical trials to study treatments for newly diagnosed prostate cancer (see Byar and Corle, 1988 and references therein). Here, we reanalyze a subset of study I of those trials, where 299 patients were randomized to either radical prostatectomy and placebo, or radical prostatectomy and 5.0 mg diethylstilbestrol (DES) daily. The primary endpoint was death from any cause. Patients entered study I from 1960 until 1967, and here we have followup for patients until February 1995. We compare patients in the initial treatment groups, under an intent-to-treat analysis, noting that clinicians were free to change treatments at their discretion. In these data, all patients had either stage I or stage II prostate cancer, defined prior to randomization. In these two stages the cancer is confined to the prostate, and...

Stem cells and cancer the origins of prostate carcinomas

Widely accepted as the cellular mechanism for development of carcinomas. This is particularly true for prostate cancer, for which it has long been postulated that these cancers arise from transformed secretory cells (16,111,112) or progenitors with an intermediate phenotype (8,32,87). Dedifferentiation has been generally accepted as the model of choice because the majority of malignant prostate cells have a luminal phenotype (PSA+ CK18+), and the minority of cells coexpress basal and luminal markers (32). Moreover, basal cells are absent in high-grade PIN (113). Many pathways that regulate stem cell maintenance are associated with carcinogenesis. For example, bcl-2 and telomerase (normally restricted to the basal cells in normal prostate) are overexpressed in prostate cancer (52,58). Many other pathways, such as Notch, Sonic hedgehog, and Wnt pathways that regulate stem cell self-renewal, are also associated with oncogenesis (reviewed in ref. 114). The demonstration that genes...

Prostate Specific Antigen Density

Prostate-specific antigen density is calculated by dividing the serum PSA level (in ng per mL) by the transrectal ultrasonography (TRUS)-determined prostate volume (in cubic centimeters). The PSA density has been promoted by some authors as a method of improving the specificity and PPV of PSA testing.38 Most studies that have evaluated PSA density report higher values in men with prostate cancer than in those without.38 Recommendations for PSA density cutoffs in men with total PSA levels between 4.0 and 10.0 ng per mL have ranged from 0.09 to 0.15 with

Characteristics of Prostate Specific Antigen Detected Cancers

The preceding data demonstrates rather robustly that screening with PSA improves our ability to detect early, pathologically organ-confined carcinoma of the prostate. However, some have questioned whether this downward stage migration will improve mortality from prostate cancer and have suggested that many of the cancers detected through PSA screening are indolent and clinically unimportant. The controversy surrounding this question arises from the fact that, historically (in the pre-PSA era), there has been a discrepancy between the incidence of clinical prostate cancer and the high prevalence of the disease found at autopsy. Specifically, it has been reported that 30 of men over 50 years of age with no clinical evidence of disease are found to have adenocarcinoma of the prostate at the time of autopsy.59 To appropriately address this question, a number of studies have examined whether screening with PSA successfully detects cancer at an earlier stage without identifying an increased...

Animal Models of Human Prostate Cancer

Human Prostate Cancer After lung cancer, cancer of the prostate (CaP) is the second most common cause of cancer death in American males. A latent disease, many men have prostate cancer cells long before overt signs of the disease are apparent. The annual incidence of CaP is over 100,000 in the United States, of which over 40,000 will die of the disease. Nearly a third of patients present with locally advanced or metastatic disease, and androgen deprivation therapy forms the basis of conventional therapy for the majority of these patients. However, currently available approaches for advanced CaP are not curative 137 , primarily because the cells lose their dependence on androgenic stimulation. The mechanisms of progression of CaP cells to hormone independence under androgen ablation therapy remain unclear. To investigate the factors and mechanisms that underlie the development of androgen resistance and metastasis, reliable in vivo models that mimic human CaP progression are...

Effects of Prostate Specific Antigen Based Early Detection on Prostate Cancer Stage

Prostate-specific antigen-based screening has also resulted in a dramatic stage migration among newly diagnosed prostate cancers and has increased the number of tumors that are organ-confined at the time of diagnosis twofold compared to the pre-PSA era. Historically, only 33 of cancers were pathologically organ-confined at the time of diagnosis.26,57 In contrast, cancers detected through PSA-based screening programs are much more likely to be organ-confined. In a study of 24,346 men by Smith and Catalona, 69 of tumors detected by initial PSA screening and 74 of those detected through serial screening were shown to be pathologically organ-confined when surgical staging was available.58 Similar findings were described by Catalona and associates who reported that pathologically organ-confined cancers were found in 63 and 71 of men undergoing initial or serial PSA-based screening, respectively.26 Mettlin et al. reported on a cohort of 2999 asymptomatic men between 55 and 70 years of age...

Results of Surveillance for Localized Prostate Cancer

Perhaps the best method to evaluate the natural history of carcinoma of the prostate is to review series of patients without treatment who were followed up. These results then become the floor for any treatment of the disease. For example, if 10-year data from a surveillance series finds that the risk of development of metastatic disease is 20 , the treatment series must improve upon that figure, and any cost and morbidity arising from treatment must be compared directly with gains in such outcomes. Unfortunately, such comparisons suffer greatly from patient selection biases. Two of these are extremely important. First is the bias that surveillance series have generally enrolled patients with low-risk (well-differentiated, low-volume, low-stage) tumors as well as older patients who have other competing causes of death. These two factors tend to exaggerate the efficacy of surveillance. The other bias is that historically detected tumors may not be similar to tumors detected...

Free Prostate Specific Antigen

Free PSA represents the small fraction of PSA that is unbound in serum. Several recent studies have shown that the percent serum free PSA (free PSA total PSA x 100) is lower in patients with malignant prostatic disease than in those with benign prostates.45-47 These studies have demonstrated that free PSA measurements improve the specificity of prostate cancer detection in PSA-based screening trials without dramatically reducing sensitivity, and that the utility of free PSA may be greatest for patients whose total PSA falls in the diagnostic gray zone of 2.5 to 10.0 ng per mL. Results from a recently completed prospective, multicenter clinical trial by Catalona et al. suggest that a free PSA cutoff of 25 or less is optimal for patients with total PSA values between 4.0 and 10.0 ng per mL and a benign DRE, irrespective of their age or prostate size. Using this cutoff, improvement in specificity over total PSA alone was evident in that 20 of unnecessary biopsies were avoided. Moreover,...

Maintenance of prostatic stem cells and regulation of homeostasis in prostate epithelium

In a multicellular organism is programmed to die unless it receives external survival signals (45). In the prostate epithelium, the highest rate of cell death is observed in the luminal cell layer, whereas the basal cell compartment undergoes a much lower rate of apoptosis (46). Several molecular mechanisms appear to protect stem cells from apoptosis, differentiation, and senescence, thereby maintaining the genomic integrity of these cells. Expression of Bcl-2, an antiapoptotic protein (47) is restricted to the basal cell compartment in normal prostate (48,49). In typical self-renewing epithelial (gastrointestinal tract, skin) cells, the expression of Bcl-2 is restricted to stem cells and proliferative zones (50). Downregulation of Bcl-2 in secretory luminal cells, in the prostate, correlates with differentiation, reduced prolif-erative capacity, and reduction in remaining lifespan. This suggests that, after terminal differentiation, secretory luminal cells undergo programmed cell...

Benign Prostatic Hyperplasia

There are virtually no published data available regarding fundamental differences that might exist between the his-tologically normal prostates of Chinese compared to North American Caucasians or African Americans. However, a limited amount of information has been published on the differences in benign prostatic hyperplasia (BPH) between Asians and others. TABLE 4-2. Age-Adjusted Mortality Rates of Prostate TABLE 4-2. Age-Adjusted Mortality Rates of Prostate

Other putative stemprogenitor cell markers of the prostate

Over the last decade, several putative stem cell markers have been identified in the prostate, including prostate stem cell antigen (PSCA), p63, and pp32. Although their cellular location and function are still relatively unclear, their involvement in tissue development and cancer suggests a role in prostate stem cell biology. 7.1. Prostate Stem Cell Antigen PSCA is a prostate-specific cell surface antigen with homology to stem cell antigen 2 (Sca-2), a marker for early hematopoietic development (85). PSCA was originally identified by its high expression in the LAPC-4 prostatic cancer xenograft model (86). RNA in situ hybridization localized PSCA to a subset of basal cells in normal prostate sections (86). However, further work has demonstrated that it marks cells coexpressing basal and secretory cytokeratins (87). The p53 homolog p63 encodes for different isotypes able either to transactivate p53 reporter genes or TO act as p53-dominant negatives (88). Homolog p63 is expressed in the...

The architecture of the prostate epithelium and its patterning during development

The prostate is a complex tubulo-alveolar gland composed of an epithelial parenchyma embedded in a connective tissue matrix. The epithelial cells are arranged in glands composed of ducts that branch out from the urethra and terminate into acini. From the 20th wk of gestation until puberty, the immature prostatic acini and ducts are lined with multiple layers of immature cells with round nuclei and scant cytoplasm. In the immature epithelium, cytokeratins of simple and stratified epithelium are expressed (primary cytokeratins numbers 8, 18, and 19 and the large molecular weight forms, numbers 4 to 7, 10, 11, 14, 15) (15). During puberty, this immature, multi-layered epithelium differentiates into a two-layer epithelium consisting of peripheral flattened-to-cuboidal basal cells and inner secretory cylindrical epithelium. This androgen-induced differentiation process is associated with an alteration in the expression of several cytokeratins. Thus, the high molecular weight cytokeratins...

ARCAs for Prostate Cancer CV706 and CV787

We hypothesized that tropism of a virus could be redirected if expression of an essential viral gene could be controlled. Viruses generated from this approach would have the same capsid as its parental virus and they should be able to penetrate all cell types that express the CAR receptor. Presumably, in all cells containing the CAR receptor, these viruses would follow the normal cell entry process they would penetrate the endosome, fuse with the endosome membrane, reach the cytoplasm, find transport to the nucleus, and uncoat the viral DNA. In a normal adenovirus replication cycle the E1A gene is the only gene expressed during the first 2.5 h of infection 52-55 . In turn, the E1A proteins as transcription factors upregulate expression of the impending cascade of viral genes. However, we have genetically engineered prostate tissue-specific promoters and enhancers so as to drive the E1A genes. Viral replication should preferentially take place in cells that express the necessary...

The Classic Three Prostate Specific Antigen Digital Rectal Examination Transrectal Ultrasonography

Various diagnostic modalities are discussed below, starting with the classic three PSA, DRE, and TRUS. Most early detection efforts focused on these modalities, and each of them was at some time thought to be useful as an independent screening tool. In these studies, younger age was excluded from analysis, based on the clinical presentation of prostate cancer. Age, however turned out to be a valuable tool, especially in relation to PSA, and will be discussed in the section on prostate volume and age-related PSA adjustments. Prostate-specific antigen isoforms are discussed as well as tools for repeat screening.

Evidence for stem cells in prostate epithelia 51 Androgen Cycling Studies

The existence of stem cells in the prostate is probably best illustrated by animal studies investigating the effect of androgen on the prostate. The majority of prostatic epithelial cells in the adult gland are androgen dependent for their survival (20). Thus, castration of male rats leads to rapid involution of the gland, with loss of up to 90 of the total epithelial cells (20). The remaining epithelial cells do not require androgen for survival, yet some of these androgen-independent cells are sensitive to androgen because subsequent administration of exogenous androgen results in induction of proliferation and regeneration of the prostate to its original size and function (24,25). By cyclically inducing prostate involution and regeneration, it is Fig. 1. Stem cell model for the organization of the prostate epithelium. Stem cells in the basal cell layer give rise to a population of transit-amplifying cells, which in turn differentiate into the functional, secretory luminal cells....

Prostate Diseases

The prostate gland weighs about 20 g by age 20, remains at that weight until age 45 or so, and then begins to grow slowly again. By age 70, over 90 of men show some degree of benign prostatic hyperplasia-noncancerous enlargement of the gland. The major complication of this is that it compresses the urethra, obstructs the flow of urine, and may promote bladder and kidney infections. Prostate cancer is the second most common cancer in men (after lung cancer), affecting about 9 of men over the age of 50. Prostate tumors tend to form near the periphery of the gland, where they do not obstruct urine flow therefore, they often go unnoticed until they cause pain. Prostate cancer often metastasizes to nearby lymph nodes and then to the lungs and other organs. It is more common among American blacks than whites and very uncommon among Japanese. It is diagnosed by digital rectal examination and by detecting prostate specific antigen (PSA) and acid phosphatase (a prostatic enzyme) in the blood....

The prostate Fig 262

In health the prostate is approximately the size of a walnut. It surrounds the prostatic urethra and lies between the bladder neck and the urogenital diaphragm. The apex of the prostate rests on the external urethral sphincter of the bladder. It is related anteriorly to the pubic symphysis but separated from it by extraperitoneal fat in the retropubic space (cave of Retzius). Posteriorly, the prostate is separated from the rectum by the fascia of Denonvilliers. Structure the prostate comprises anterior, posterior, middle and lateral lobes. On rectal examination a posterior median groove can be palpated between the lateral lobes. The prostatic lobes contain numerous glands producing an alkaline secretion which is added to the seminal fluid at ejaculation. The prostatic glands open into the prostatic sinus. The ejaculatory ducts, which drain both the seminal vesicles and the vas, enter the upper part of the prostate and then the prostatic urethra at the verumontanum.

Peter C Albertsen MD MS

Adenocarcinoma of the prostate is the most common non-skin cancer among American men. The American Cancer Society estimates that 184,500 new cases of prostate cancer will be diagnosed in the United States in 1998 and that 39,200 men will die from the disease.1 The rate of new prostate cancer diagnoses has increased exponentially over the past three decades.2 During the 5 years preceding 1992, there has been an even more dramatic surge in prostate cancer incidence following the introduction of widespread testing for serum prostate-specific antigen (PSA).3 Since 1992, however, the annual incidence rate has declined by 11 and continues to decline.4 The mortality rate from prostate cancer has also changed during the past two decades. After increasing steadily from 1973 to 1990, the mortality rate from prostate cancer fell by 6.3 from 1991 to 1995.5 The rate for men under 75 years fell by 7.4 while the rate for men aged 75 years and older, a group accounting for two-thirds of all prostate...

How Is Information Reported

Cancer incidence rates are often reported either as actual counts at a given point in time or are expressed as age-adjusted rates. Simply reporting the raw number of new cases annually provides some information concerning the magnitude of the disease incidence within a population. Unfortunately, this approach does not take into account the number of patients at risk for developing cancer. The age distribution of populations changes over time. Western countries, for example, generally have a greater number of elderly people compared to most developing nations. As more people live longer, the risk of developing prostate cancer increases. This will be especially true when the large baby boom generation enters its seventh and eighth decades. As a consequence, the absolute number of new cancer cases may increase but the relative incidence rate may increase, decrease, or remain constant. Epidemiologists often express incidence rates as an age-adjusted rate when they need to determine...

How Do Incidence Rates Vary by Patient Age at Diagnosis

Prostate cancer incidence by stage for all ages. Data are from four Surveillance, Epidemiology, and End Results areas. From Potosky AL, Miller BA, Albertsen PC, Kramer BS. The role of increasing detection in the rising incidence of prostate cancer. JAMA 1995 273 548-52. FIGURE 1-1. Prostate cancer incidence by stage for all ages. Data are from four Surveillance, Epidemiology, and End Results areas. From Potosky AL, Miller BA, Albertsen PC, Kramer BS. The role of increasing detection in the rising incidence of prostate cancer. JAMA 1995 273 548-52. suggest that prostate cancer is a disease of older men. For the two decades leading up to 1993, the age-adjusted incidence rates were highest for men aged 75 years and older, followed by that for men aged 65 to 74 years.5 Since 1993, the age-adjusted rate has decreased sharply among men aged 75 years and older, so that the highest age-adjusted rate of prostate cancer now occurs among men aged 65 to 74 years. Prostate cancer is...

Multistep Process of Carcinogenesis

Development of a histologic or clinical prostate cancer requires multiple malignant events.1 Progression of prostate cancer from a histologic form to clinically manifest disease requires additional malignant events that have not been clearly elucidated. One explanation for the differences in prostate cancer incidence among racial groups may be inheritance of susceptibility alleles that vary among populations and confer a modest increase in risk of disease development. These polymorphic (variable) alleles may confer increased risk for the development of histologic prostate cancer and increased risk of progression of histologic disease to clinically manifest disease. For example, there are multiple androgen receptor (AR) alleles in the general population that vary in activity and may affect the role of androgens in prostatic car-cinogenesis.2 The frequency distribution of AR alleles varies in different racial groups that have significantly different incidence rates of prostate cancer.3...

George A Alexander MD Otis W Brawley MD

The geographic distribution of prostate cancer has intrigued scientists and physicians for decades. While it is a common disease in the United States and Western Europe, it has been believed that prostate cancer is rare in Africa.1,2 Africa is a very large continent with an extremely diverse population. There are significant phe-notypic differences even among the black African populations. Within its mixture of countries with varying socioeconomic developmental status and differing cultures and ethnicities are a number of distinct populations. Prostate cancer screening is not common in Africa. The age-standardized incidence of the disease has been reported to range from 9.1 to 19.7 per 100,000 in black Africans.3 However, the incidence of prostate cancer in Africa and its mortality rate are not easily discernible from published data. While the problems associated with inadequate or sketchy epidemiologic data on prostate cancer in Africa are well recognized, it is possible to glean...

The Status of Screening

There are reports that support the notion that since the introduction of PSA in the late 1980s, PSA-based prostate cancer screening has led to dramatic changes in the epidemiology of the disease, which are suggestive of effective screening.4,23 Data supplied by the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 1994 have shown a substantial increase in the number of newly diagnosed cases of prostate cancer. This trend accelerated when PSA use became widespread in the late 1980s. New prostate cancer Screening for Prostate Cancer the Case for Screening 77 TABLE 11-2. Percent of Free to Total PSA Ratio and

John J Bauer MD Judd W Moul MD

There are a number of factors coming together in the field of prostate cancer as the millennium approaches causing risk assessment using algorithms to proliferate. First, prostate cancer is generally receiving more attention and research funding. Second, widespread use and acceptance of prostate-specific antigen (PSA) has given the field an objective measurement to better categorize patients, driving further algorithm work in risk assessment. Third, more research groups are developing institutional prostate cancer databases that allow this type of research. Fourth, prostate cancer researchers are becoming more involved with statistics and statistical collaboration which make this type of investigation possible. Finally, and most important, the rapid advancement of computer software and hardware has allowed this area to flourish. With these factors in mind, we will review the emerging field of algorithms for prostate cancer detection and for staging and prognostic risk assessment for...

Robert J Nejat MD Christopher W Johnson MD Mitchell C Benson MD

The American Cancer Society (ACS) estimates that there will be 179,300 new cases of prostate cancer diagnosed in 1999, making it the most commonly diagnosed malignancy among men in the United States. In addition, a projected 37,000 men will die this year secondary to prostate cancer. As a result, the ACS and the American Urological Association (AUA) have put forth guidelines recommending that annual serum prostate-specific antigen (PSA) testing and digital rectal examination (DRE) be offered to men aged 50 and older who have at least a 10-year life expectancy. The PSA and DRE should also be offered to younger men at high risk for developing prostate cancer, such as African American men or men with a strong family predisposition to the disease (two or more affected first-degree relatives, e.g., father, brother). Information should be provided to patients regarding the risks and benefits of intervention.1 In order for prostate cancer screening to be deemed a successful and worthwhile...

Frank E Glover Jr MD Patrick C Walsh MD H Ballentine Carter MD

Prostate cancer incidence and mortality vary markedly across geographic regions and populations. Exploration of the reasons for this variability could lead to avenues for disease prevention in the future. The general prevalence of histologic prostate cancer is similar among ethnic groups while the incidence of clinically manifest disease markedly differs.1 These data suggest that the key difference may be the rate of progression of histologic cancers to clinically manifest cancers between populations, a process that involves multiple steps that have not yet been clearly defined.

Androgen Receptor CAG Repeats

Surprisingly, consistent mutations in genes associated with the androgen signaling pathway have yet to be described as a risk factor for prostate cancer. However, Several studies indicate that prostate cancer risk may be linked to germline androgen receptor gene CAG repeat length. In a preliminary study, Ingles and colleagues7 noted approximately a twofold increased risk of prostate cancer in men having a CAG repeat length of less than 20. Giovan-nucci et al.8 reported that the risk for developing prostate cancer was inversely proportional to CAG repeat length. In this report, 587 prostate cancer patients and 588 controls from the Physician's Health Study were examined using a nested case-control design. Men with a repeat length of less than 19 had a 1.5-fold relative risk of prostate cancer compared to men with a repeat length of greater than 25. In addition to being at higher risk for prostate cancer, men TABLE 8-2. Selected Polymorphisms Potentially Linked to Prostate Cancer Risk...

Molecular Epidemiology

The biology of prostate cancer is being examined in several studies, one of which includes racial or ethnic comparisons. Chromosome 8p studies demonstrate frequent alterations at several sites in prostate cancer, and it has been suggested that these changes may be early rather than late promotional events during prostate tumorigen-esis. More specifically, there is thought to be a prostate suppressor gene on chromosome 8p. In 135 prostate cancers, Macoska et al. examined the correlation of 8p allelic loss with patients' ethnic origins. The tumors examined were from radical prostatectomy specimens that were matched for stage and grade. No significant differences between African American men and Caucasian men were observed in terms of fractional allelic loss frequencies among the three deletion domains, or total 8p loss. With regard to loss differences between individual 8p loci, the reported trends are unclear.44 One recent study was conducted to determine whether primary prostate...

Barriers to Health Care Affecting Diagnosis and Outcome

Barriers to health care, both financial and nonfinancial, have been proposed as factors responsible for the delayed diagnosis of prostate cancer among African Americans and their more advanced stage of diagnosis compared to Caucasians. Lack of health insurance resulting in lack of access to care has been suggested as being responsible for poorer survival rates among African Americans.38,39 Several investigations conducted in Veteran Administration Medical Centers, in which financial consideration may be minimized, have demonstrated a more advanced prostate cancer stage presentation and worse overall survival among African Americans than Caucasians.21 However, data on survival outcome have been conflicting. Recently reported results from the Kaiser Permanente medical care program, a health maintenance organization (HMO), show poorer prostate cancer survival rates among African Americans compared to Caucasians in an equal-access medical care setting.40 Nonfinancial barriers have a...

Histologic Features and Tumor Volume

Although only a few investigators have examined characteristics of radical prostatectomy specimens relative to race, the data in these early studies are consistent. African Americans present with a significantly greater percentage of locally advanced prostate cancer compared to Cau-casians.25,32 These findings are consistent with evidence demonstrating a higher PSA among African American men versus Caucasians who undergo radical prostatectomy. However, studies by Moul et al. and Powell et al. demonstrate similar rates of lymph node metastases among the two races.30,32 In fact, in the study by Moul et al. no African Americans presented with lymph node metas-tases.32,33 The explanation for this finding is unclear. Recently investigators have examined the difference of location of prostate cancer between African Americans and Caucasians in radical prostatectomy specimens. In this series of studies between 1991 and 1997, 831 patients were evaluated for the location of tumor as mainly ante...

Insulin Like Growth FactorI

Insulin-like growth factor-I has recently been linked to prostate cancer risk in a series of studies. The initial observation was a relatively small case-control study noting increased IGF-I in men with prostate cancer but not benign prostate hyperplasia.30 A much larger nested case-control study using data derived from the Physicians' Health Study cohort has confirmed and extended this initial report.31 In the Chan et al.31 report, increasing plasma levels of IGF-I were directly linked to increasing prostate cancer risk. Importantly, this increased risk was detected in men with both normal and elevated PSA measurements, suggesting that these risk factors were independent of one another. When examining men with the highest quartile of IGF-I, the prospective risk of prostate cancer was increased 2.4-fold, relative to those with an IGF-I in the lowest quartile. In a multivariate analysis adjusting for PSA and the major circulating IGF-I binding protein (IGFBP-3), men with a PSA < 4 ng...

Barnett S Kramer Md Mph Otis W Brawley MD

The American medical community, more so than the medical communities of other developed countries and countries with organized health care systems, has recently embraced prostate cancer screening without rigorous evaluation. Indeed, prostate cancer screening may be done without the patient's knowledge or consent and even more frequently is done without advising the patient of the uncertain efficacy of prostate cancer screening and treatment.5 In a real sense, the country has embarked upon a large uncontrolled clinical experiment.6 Though as yet unproven, screening for and aggressive treatment of localized prostate cancer may well be beneficial in that it may decrease prostate cancer mortality and save lives. However, it does have a definite cost of human suffering. At this point, we must weigh proven risks against unproven benefits. Ten years into the prostate-specific antigen (PSA) screening era, evidence shows that PSA screening still needs definitive evaluation. Many have concluded...

John P Foley MD Ian M Thompson MD

An intimate knowledge of the natural history of adenocarcinoma of the prostate is essential for any physician who treats patients with this disease. As prostate cancer can be a relatively slow-growing tumor associated with a long asymptomatic and latent period and usually occurs in men who are at risk of dying from other causes (effectively eliminating the opportunity of the tumor to manifest itself clinically), decision making by both clinicians and patients is often based on the disease's natural history. In this chapter, we will examine the experience of published series of patients in whom no treatment was provided for localized disease to develop an understanding of what appears to be the natural history. We will further examine how the behavior of the disease has changed over time (as methods of detection, diagnosis, and staging have changed) as well as a number of tumor and host features that can modulate tumor behavior. Specifically excluded from this review are those studies...

Metaanalysis of Outcomes Data

In 1994, Chodak published the results of a by-patient meta-analysis of six surveillance series comprising 828 patients.22 The principal conclusion of the authors was the impact of tumor grade on outcome. At 10 years, disease-specific survival for well-differentiated and moderately differentiated tumors was 87 and was 34 for poorly differentiated tumors. Of note, the authors also conducted an analysis of metastatic disease-specific survival, finding 10-year results of 81 for well-differentiated tumors, 58 for moderately differentiated tumors, and 26 for poorly differentiated tumors. This second analysis is extremely important as it must be recalled that (1) the median age for most surveillance series is approximately 72 years, and (2) the evidence is compelling that the median survival for patients with metastatic prostate cancer is 2 years. Thus, if surveillance is offered to younger men, the likelihood of death from prostate cancer is extremely high within 10 to 12 years of follow-up.

Polymorphisms in the 5 Alpha Reductase Gene

The 5 a-reduction of testosterone to the potent androgen dihydrotestosterone (DHT) is catalyzed by the 5 a-reduc-tase enzymes. Two forms of the 5 a-reductase enzyme have been described current nomenclature designates these as type I and type II enzymes. A TA repeat is present in the 31 untranslated region of the type II gene. After examination of appropriate data sets, Kantoff et al.17 concluded that there was no relationship between type II 5 a-reductase TA repeat length and prostate cancer risk.

Race and Age Specific PSA

The database that led to the development of age-specific ranges for PSA was composed almost entirely of Caucasian men. It has been known for a long time that Asian men generally have smaller prostates and a lower incidence of prostate cancer than Caucasian or African American men. African American men have the highest incidence of prostate cancer in the world.37 These facts led investigators to evaluate the effect of race on age-specific ranges. Oester-ling and colleagues performed a study similar to the one outlined above in an attempt to clarify age-specific reference ranges in Japanese men.38 The resulting age-specific ranges for Japanese men are posted in Table 11-1. cohort would have been missed. The age-specific reference ranges for African Americans are also listed in Table 11-1. The differences appear minor, but they have tremendous clinical significance because it is in African Americans that prostate cancer is more prevalent it occurs at an earlier age, and it has the...

Screening by Digital Rectal Examination

Before the widespread clinical use of PSA, DRE was the most common initial test for the diagnosis of prostate cancer. While several earlier reports have concluded that annual screening using DRE leads to improved early detection of disease and prolonged survival,14,15 other studies contradicted these findings.16,17 The limitation of DRE as a screening test appears to be its poor sensitivity in detecting curable (i.e., pathologically organ-confined) disease. In fact, approximately 40 to 60 of men with clinically localized prostate cancer detected by annual DRE have local or systemic spread of disease when pathologic staging is available.14,16,18 In addition, a study by Gerber and colleagues that evaluated disease-specific survival following routine screening by DRE in over 4000 men suggests that this approach will not decrease the mortality rate from prostate cancer.17 The investigators compared cancers diagnosed during the initial screen (prevalence group) with those identified during...

Algorithms for Staging

After prostate biopsy has been performed and a diagnosis of adenocarcinoma of the prostate is confirmed pathologically, prognostic algorithms, nomograms, and statistical equations can be employed preoperatively to help determine pathologic stage. These models may help guide the clinician and patient toward the most suitable therapy. The most helpful determination is whether the prostate cancer is contained within the capsule of the gland, that is, organ confined. Physicians or patients, for example, might decide that if the probability of extra-capsular extension is too high, a radical prostatectomy may not be desirable. Studies early in the PSA era evaluating various prognostic markers consistently showed that pretreatment PSA, pathologic or histologic grade, and clinical stage were useful independent predictors of organ-confined prostate cancer. Other prognostic variables such as deoxyribonucleic acid (DNA) ploidy, transrectal ultrasound, magnetic resonance imaging, and various...

Digital Rectal Examination

Historically, the DRE was considered the first-line approach to screening for carcinoma of the prostate. Digital rectal examination has long been a component of routine health screening examinations for middle-aged and older men and is not associated with any additional risks or extra financial cost.11 Abnormalities on DRE associated with cancer and thereby indicating the need for prostate biopsy include induration, asymmetry, or nodules.14,15 While the true sensitivity and specificity of DRE remain undetermined, the positive predictive value of DRE for detecting prostate cancer has been estimated by various studies to be between 15 and 30 .11 Using the presence of nodules as criteria for biopsy, Thompson et al.16 reported a positive predictive value (PPV) of 26 while Chodak and associates detected 36 malignancies in 144 biopsies (PPV of 25 ) that were performed based on detection of induration, asymmetry, or nodules on exam-ination.14 In addition, DRE appears to have a low negative...

Targeting the Hispanic Population

Attitudes and perceptions among Hispanics toward prostate or any other cancer may lead to scant participation in cancer screening programs as well as clinical trials. Perez-Stable et al. found that a larger proportion of Hispanic patients have a more fatalistic attitude toward cancer than do Anglo-Saxon patients.21 Under-representation of Ramirez et al. have proposed several strategies to target the Hispanic population.24 These include focused epi-demiologic and clinical research, recruitment of minorities into health professions, and improved access to health care for minorities. Zimmerman found several important factors influencing Hispanic male participation in prostate cancer screening programs, including availability of examinations at little or no cost.25 Various institutions have demonstrated the value of formal and informal support groups for Hispanic oncology patients.26,27 Tejeda et al. recently reviewed the representation of non-Hispanic Caucasians, African Americans, and...

Effects of Early Detection on Cancer Mortality

Reduction in mortality based on the ability of currently available therapy, particularly radical prostatectomy, to cure organ-confined disease.6,63 It is argued, therefore, that continued detection of early-stage disease through PSA-based screening protocols is the most effective strategy for ultimately achieving decreased mortality.6 In addition, there is significant indirect epidemiologic evidence suggesting that screening may indeed have a profoundly beneficial effect on survival and mortality. For instance, data from the SEER program indicates that the 5-year relative survival rates from prostate carcinoma have improved from 66.7 between 1974 and 1976 to 79.6 in the interval from 1983 to 1990.64 In a separate analysis of SEER data, a 20 increase in relative survival from carcinoma of the prostate from 1985 to 1993 compared to the period 1973 to 1980 was revealed.65 In addition, a decision model developed by the American College of Physicians suggests that, with appropriate...

Histologic Definitions

To ensure that data regarding differences in incidence or prevalence of prostate cancer between various populations are accurate, similar definitions must be used by pathologists in the cognate countries. This question is of considerable concern since there were no Chinese language textbooks on modern histopathology until 1951.19 Reports in the Chinese medical literature still treat prostate cancer as a medical curiosity.20 In view of this, cross-validation studies are of particular importance. Only one report exists in the published literature that directly attempted to address this issue.21 A limited analysis of diagnostic nomenclature usage was performed. A group of Chiefs of Surgical Pathology from selected Chinese military medical schools in Szechwan Province were shown a test set of slides. The set of slides included examples of well-differentiated adenocarcinoma, atypical adenomatous hyperplasia, prostatic intraepithelial neoplasia (PIN), reserve cell hyperplasia, and atrophic...

Chris H Bangma MD PhD Fritz H Schrder MD PhD

Screening for prostate cancer (PCa) is feasible due to the availability of diagnostic tools to detect prostate malignancy at an early and asymptomatic stage. None of the current diagnostic modalities, however, will detect cancer at an initial stage in which only molecular changes have occurred, or a stage in which only a few cells show histo-logic features of malignancy. Histologic studies of whole mount sections of prostate glands at autopsy have shown that the true incidence of prostate cancer at death is far more common than any early detection study with current diagnostic tools has ever indicated.1 The incidence of his-tologic cancer increases with age, as shown in population-based early detection studies. This illustrates the lack of sensitivity of current screening modalities. What defines an optimal diagnostic tool In terms of detection, this could be the tool (or combination of tools) that maximizes the number of detected cancers. The biologic behavior of prostate cancer...

General Principles of a Screening Test

Screening tests are used to identify asymptomatic individuals with early stage, potentially curable disease. The ultimate goal of screening is to alter the prognosis of a given condition by identifying patients early and instituting effective therapy. For a screening program to be worthwhile, the disease of interest must fulfill a number of criteria including, but not limited to, the following the disease must be common it must be accompanied by significant morbidity and mortality if not treated therapy must alter its natural history and there must be some benefit in terms of outcome or associated morbidity when the disease is treated in the presymptomatic versus the symptomatic stage.3 Based on these criteria, prostate cancer screening is unquestionably appropriate,3 but the question of whether or not current screening programs have been successful in altering the natural history of this disease or improving outcomes for patients remains controversial.4,5

Screening by Transrectal Ultrasound

Following the introduction of transrectal ultrasonogra-phy of the prostate, there was a great deal of enthusiasm regarding its use in the early detection of prostate cancer. It was felt that TRUS would be able to detect many non- palpable small tumors that were missed by DRE alone.20 However, studies have shown that TRUS has several limitations with regard to its use as a screening test for prostate cancer. Most importantly, TRUS has low positive and negative predictive values, which were reported to be 36 and 89 , respectively, in one study.21 Cooner and colleagues reported the positive predictive value of TRUS to be only 16 in men with a palpably benign prostate.22 This number drops to 9.8 when both DRE and PSA are normal. Additional limitations of TRUS as a screening tool include the procedure's invasiveness, cost, and limited detection rate when the less invasive DRE and PSA are normal. It is the authors' belief that the major value of TRUS is its ability to allow for anatomic...

Algorithms for Prognosis

The prediction of preoperative pathologic stage is important in counseling a patient before proceeding with radical prostatectomy. Despite these predictions, many patients, even those without organ-confined disease, are long-term disease-free survivors and surgical therapy is appropriate. Once surgical intervention is completed, a new set of predictive algorithms and statistical equations predicting recurrence and progression are now available to adequately inform the patient of future expectations. Approximately 65 of prostate cancers are clinically localized at the time of diagnosis and despite improved preoperative pathologic stage prediction, between 40 to 60 of men are found to have extracapsular disease after radical prostatectomy.35-37 Of these patients, the reported 5-year progression-free survival rate is 93 for PSA between 4.1 to 9.9 ng per mL and 71 for patients with a PSA greater than 10.0 ng per mL.38 Overall, approximately 25 to 40 of patients will have evidence of...

Paracrine and Autocrine Growth Factors

In addition to hormonal regulation, the prostate is clearly under paracrine and autocrine regulation, as has been demonstrated by epithelial mesenchymal recombination studies in vivo14,16,240,241 and coculture conditioned media studies in vitro.242-244 Some growth factors such as nerve-growth factor (NGF) trfc and NGF-P receptors245,246 as well as hepatocyte growth factor met recep-tors247-249 operate as classic paracrine mediators, with ligand produced by the prostatic stroma and the receptors present on the basal and or luminal epithelial cells. In contrast, TGF-P250,251 and IGF-II134 have the necessary components to utilize both paracrine and autocrine (epithelial to epithelial or stromal to stromal) pathways. The role played by these growth factor pathways in pro-static physiology and disease as well as their integration into the other prostatic regulatory pathways are currently being actively researched. This review focuses on three of the better characterized systems in the...

Regulation of Prostatic Function and Growth

Although androgens play a key role in the regulation of prostatic growth, function, and disease, it is now clear that they act in concert with, or as a backdrop for, a host of other regulatory pathways. Prostatic growth and the development of differentiated function take place under the influence of increased expression of testosterone during puberty,1,2 although castration prior to puberty does not entirely prevent subsequent prostatic growth.155,156 Once its mature size is reached, however, the prostate and other accessory sex glands cease growing, even though testosterone levels remain elevated. Supraphysiologic doses of exogenous testosterone do not stimulate additional growth.157,158 Withdrawal of testosterone results in massive involution of the gland, characterized by apoptosis of the secretory epithelium.105,159 At maturity, therefore, testosterone becomes responsible for survival of the prostate and maintenance of its differentiated functions. The mechanism for this switch...

Androgen Receptor GGC Repeats

Hakimi and colleagues9 report that men with prostate cancer are 4.6-fold more likely to have GGC repeats of < 15. Stanford and colleagues,10 in a study of 281 cases and 266 controls, reported that men with < 17 repeats have a 1.6-fold relative risk of prostate cancer compared to men with 17 or more repeats. Platz et al.,16 in the largest reported study of 582 cases and 794 controls, presented data suggesting that both increases and decreases above the mean were associated with slight elevations of risk. Taken together, these studies suggest modest increases in risk for men with a less-than-average number of GGC repeats.

Racial Ethnic Epidemiologic Statistics

The clinical incidence of prostate cancer reported by the American Cancer Society in 1997 was 66 higher among African American men than among Caucasian men.9 In the past, the clinical incidence of prostate cancer has ranged from 30 to 50 higher among African Americans than among Caucasians. Also, there have been variations among the two groups in the lifetime risk of being diag nosed with prostate cancer. In 1993, 1 of 11 African Americans was diagnosed with prostate cancer compared to 1 of 9 Caucasians. In 1996, the lifetime risk of prostate cancer diagnosis changed to 1 of 5 for both populations.10 The cause of this variation is unclear. One variable possibly accounting for the differences noted may be differing attitudes toward screening and early detection. Taylor and colleagues demonstrated that from 1972 to 1991 prostate cancer diagnosis increased by 100 in Caucasian men but by only 40 in African American men. They reasoned that Caucasian men are more likely to take part in...

Free to Total PSA Ratio

(A2M).43'44 The PSA bound to A2M (PSA-A2M) is anti-genically shielded and not measurable by any PSA assay. The PSA-ACT complex, however, is immunoreactively unique and can be measured in the serum as a separate moiety. As a result, it is possible to compare the amount of free PSA to the total amount of PSA (free + PSA-ACT). Lilja and colleagues documented that the majority of PSA in the serum is complexed to ACT, accounting for approximately 85 of the total serum PSA.44 They later compared the ratio of free total (FT) PSA in men with BPH to the FT PSA of men with prostate cancer. They found that the FT ratio was significantly lower in men with prostate cancer than men with BPH (18 versus 28 , respectively, p < .0001).45 Importantly, this difference was present for PSA values above and below 10 ng per mL. They concluded that the use of FT PSA ratio would allow for a differentiation of elevated PSA levels secondary to BPH and prostate cancer without decreasing the sensitivity of PSA....

Diagnosis by Biopsy the Gold Standard

Biopsy represents the gold standard of prostate cancer diagnosis. There is no better proof of the presence of a cancer than the histologic evidence. It is clear that the incidence of PCa is influenced by the method of prostate sampling. The real incidence of prostate cancer is unknown, as is the natural history concerning size and location within the prostate. In a small series of radical cystoprostatectomy specimens, removed for urothelial carcinoma, small volume prostate cancers were found in the absence of clinical symptoms.5 Prostate biopsies on autopsy specimens could provide data on the accuracy of prostate biopsies, permitting some extrapolation to a younger screening group. The biopsy procedure is a sampling procedure, and therefore PCa cannot be excluded with complete certainty. To assess the qualities of the sampling procedures, several attempts have been made to relate the technical aspects of taking biopsies (such as number, location, and direction) with histologic outcome...

Screening at the Population Level Trends in Incidence and Mortality

Prostate cancer screening, especially screening with serum PSA in the late 1980s and early 1990s, has profoundly increased the age-adjusted incidence of diagnosed prostate cancer in the United States. Steady rises in the 1970s and early l980s can be attributed to an increase in the number of transurethral resections of the prostate (TURPs) for benign prostatic hyperplasia.2 The subsequent acceleration of incidence can be attributed to increasing use of PSA.3 It should be noted that the use of TURP actually decreased during the late 1980s. A more recent decline in the incidence of prostate cancer may be due to a clearing of the prevalent cases. It may also be due to the fact that several organizations began recommending against prostate cancer screening in the early 1990s. By 1993, a number of American organizations that publish screening recommendations recommended against screening for prostate cancer or took the Prostate cancer mortality rates have increased over the past 20 years...

David C Miller BS David K Ornstein MD Gerald L Andriole MD

Prostate cancer is the most commonly diagnosed noncuta-neous malignancy in American men and is exceeded only by lung cancer as a cause of cancer death among United States males.1 Estimates for 1998 indicated that over 180,000 men would be diagnosed with carcinoma of the prostate in the United States and more than 39,000 would die from this disease.1 In addition, a substantial fraction of United States health care dollars are allocated to diagnosis and treatment of this disease.2 The identification of serum prostate-specific antigen (PSA) measurements as a valuable tool for early diagnosis of prostate cancer has resulted in widespread implementation of early detection as a means to reduce the morbidity and mortality of this cancer. The importance of improving diagnosis and treatment for men with prostate cancer is unchallenged however, the most efficient way of accomplishing this has been debated.

Clinical Features

Serum prostate-specific antigen (PSA) is a powerful prognostic indicator of prostate cancer outcome. African American men have been reported to have a significantly higher mean pretreatment PSA than Caucasian men.25 The cause of this difference is unclear. It has also been reported that PSA has a greater predictive value for detecting prostate cancer among African Americans (42 to 45 ) than among Caucasians (30 to 35 ).26-28 These findings may indicate that PSA-driven prostate cancer detection is more cost effective among African Americans than among Caucasians. To date, racial data on PSA have come from single institutions. Investigators examining age-specific PSA reference ranges have recommended a higher PSA cut-point for biopsy in African American men over the age of 50 years than in Caucasians.29 However, this recommendation seems inconsistent with clinical outcome. Subsequent examination by other investigators has demonstrated a worse outcome when applying these cut-points to...

Epidemiology

Glover et al. have studied the epidemiology of prostate cancer in Jamaican blacks.7 They evaluated 1121 cases of prostate cancer diagnosed from 1989 to 1994 in Kingston. Table 5-1 shows the age-adjusted incidence of prostate cancer among Jamaican blacks, African Americans, and TABLE 5-1. Age-Adjusted Incidence of Prostate Cancer (1988-1992) TABLE 5-3. Presenting Symptoms at Prostate Cancer Diagnosis* TABLE 5-3. Presenting Symptoms at Prostate Cancer Diagnosis*

Conclusion

Perhaps the most striking feature of the epidemiology of prostate cancer in Africa concerns the differences in prostate cancer incidence in various regions of Africa. These differences can be explained in part by the differences in the socioeconomic status of the countries even though the data is age adjusted, differences in life expectancy may be a contributing factor.32 It can be argued that in the developing countries, where the life expectancy is lower, an insufficient number of men will live long enough to develop the disease and therefore the incidence of prostate cancer will most likely be low. Prostate cancer rates are lower in Africa than in the United States, but the idea that prostate cancer is uncommon in Africans is inaccurate. Note the relatively high incidences in Zimbabwe11 and Nigeria.33 Large portions of the African population are adopting Western habits and diet. In the future, the trend of prostate cancer in the black African population will likely increase....

Hormone Levels

The androgen sensitivity of prostate cancer has been well described over the past five decades. Androgen withdrawal is clearly recognized as one of the cornerstones of management in patients with advanced prostate cancer disease. In addition, androgens are necessary for normal prostatic growth and development during puberty. Interestingly, however, data suggesting that variations in serum testosterone or DHT are a risk factor for prostate cancer in normal men are minimal or contradictory. A variety of studies measuring these potent androgens in both typical case-control and prospective studies indicate no significant elevation in risk associated with alterations in circulating testosterone levels.18-21 Low DHT levels have been associated with elevations in prostate cancer risk in some19 but not all20,21 studies. Low DHT testos-terone ratios have also been implicated as a prostate cancer risk factor in some18 but not all studies. Taken together, studies of hormones and prostate cancer...

Incidence

Although significant differences in the incidence, presentation, and mortality rates of prostate cancer have been noted between different ethnic groups,5 data concerning Hispanics are scarce. According to Surveillance, Epidemiology, and End Results (SEER) data, the percentage of Hispanics among all patients diagnosed with various types of malignancies ranges from 2.5 to 3.4 , depending on the site of the cancer.6 In 1990, approximately 2.5 of men diagnosed with prostate cancer in the United States were Hispanics.7 Gilliland et al. noted a sharp increase from 1969 to 1991 in the age-adjusted incidence rate of prostate cancer among New Mexico's Hispanics.8 During this period, the age-adjusted incidence of prostate cancer among Hispanics grew by 75 , from 54.0 to 94.7 cases per 100,000. This rise in the incidence of prostate cancer among Hispanics compared to an increase in the incidence of prostate cancer among non-Hispanic Caucasians of 87 and was felt to result from increased...

Frequency of Cancer

Published reports of the relative frequency of prostate cancer in Africa over a 45-year period are shown in Table 3-1.4-13 These data cover the time period from 1950 to 1995. They originate from reports from hospital-based or pathology-based registries and more recently from population-based cancer registries. The relative frequency of prostate cancer ranges from a low of 1.9 of all histologically confirmed cancers in black Kenyan men to a high of 11 of all cancers in black Liberian men. Although the actual prevalence of prostate cancer in Africa is not known, it is the most common cancer in males over 60 years of age. in black Africans the percentage frequency ranges from 1.9 to 11.3 whereas for black and white Americans, it is 29.9 and 28.3 , respectively.14 In the mid-1980s it is estimated that prostate cancer constituted 15 of all cancers diagnosed in Americans.15 In 1995, prostate cancer constituted 36 of all tumors diagnosed in American men and 19.5 of all cancers diagnosed in...

Cancer Incidence

Prostate cancer incidence rates in black Africans are summarized in Table 3-28-11,13,14,19-28 by country or region. The incidence rates cover the time period from 1958 to 1995. Incidence rates from all 16 reports are age adjusted and are standardized to either the African Standard Population20,24 or the World Standard Population.25,27,28 The age-standardized incidence rate of prostate cancer in Africa ranges from a low of 3.1 per 100,000 in Swaziland blacks to a high of 29.2 per 100,000 in Zimbabwe blacks. Without considering the low crude incidence rate of 1.2 per 100,000 from Gambia, the former findings suggest that there are notable geographic differences in prostate cancer incidence in Africa. In addition, estimates of age-standardized incidence rates (new cases per 100,000 population in 1985) of prostate cancer also suggest that regional differences exist in prostate cancer incidence. The age-standardized incidence rates for prostate cancer are 22 per 100,000 for Eastern Africa,...

Oliver Sartor MD

Adenocarcinoma of the prostate is by far the most common visceral malignancy in men. In the past, prediction of adenocarcinoma of the prostate was linked to well-established clinical risk factors such as age, race, and family history. Over the past several years, a series of studies have begun to address the molecular markers that might add additional insights into the understanding of prostate cancer risk. In the future, there is hope that clinicians can use these (as yet undiscovered) molecular measurements to more accurately predict prostate cancer risk in individual men. In this chapter, recent progress toward that goal will be reviewed. Any molecular risk factors for prostate cancer will be evaluated in concert with well-established clinical risk factors thus, a brief discussion of clinical risk factors is warranted as part of the background discussion for this chapter (Table 8-1). Age is the most dramatic and least understood of the conventional factors implicated in prostate...

Gary J Miller MD PhD

Prostatic cancer remains the leading cancer of adult males in the United States. It is expected that 137,000 new cases and 37,000 deaths will be recorded in 1999.1 While this disease remains a significant health hazard in the United States, Canada, and Europe, other regions of the world enjoy markedly lower incidence rates. Epidemiologic studies have consistently shown that there is both a decreased incidence and a lower mortality rate for prostate cancer among Asians compared to North American Caucasians or African Americans. The peoples of Southeast Asia, i.e., China, Indonesia, Japan, Korea, and Singapore, have a four- to 10-fold lower incidence of, and death from, prostate cancer.2 As early as 1936 the published literature indicated that prostatic cancer was uncommon in Singapore,3 and that it was rare among the Chinese.4 It is also clear that incidence rates in Asian countries have begun to rise over the past few years.5 In spite of this increase, the differences between Western...

Age at Diagnosis

Prostate cancer occurs primarily in older men, regardless of race. Cancer of the prostate is rare under age 5010 and increases steadily with age from about 40. In Soweto, Johannesburg, South Africa, the median age of a series of 101 patients studied was 68 years 7.0 and 2.0 , respectively, were aged under 50 and 40 years.31 In Lagos, Nigeria, the median age of 125 patients diagnosed with prostate cancer was 68.3 years.30 In the United States, the median age at diagnosis prior to the PSA screening era was 72 for whites and 70 for blacks.

Cancer Mortality

In the developing countries of Africa, mortality statistics are unavailable in many areas and are seriously inaccurate.28 Some data on the causes of death for South Africans have been available since 1968.31 South Africa has a diverse population that includes black Africans, Asian Indians, whites, and mixed-race peoples. There are wide differences in cancer mortality rates in South Africa among the races. In 1970 to 1974, South African urban blacks had prostate cancer standardized mortality rates of 5.2 to 8.4 per 100,000. This pattern for blacks comprised the fourth lowest quintile of prostate cancer mortality in South Africa. White and colored males were in the highest quintile (16.8 to 19.0 per 100,000 and 13.0 to 17.0 per 100,000, respectively). Asian males were in the lowest quintile (2.0 to 8.5 per 100,000). Earlier or additional reports of prostate cancer mortality rates in Africa are not available.

Isaac J Powell MD

The definition of blacks or African Americans as a race in the United States is unclear. There is no genetic definition of any race at this time. Phenotypic heterogeneity is characteristic of the United States population of African Americans. However, there are cultural factors that may define African Americans as an ethnic group or race in relation to health. Recent data demonstrate a strong association between prostate cancer progression and a high-fat diet.1 Whittemore recently reported that among groups of men who consume high amounts of saturated fats, African Americans consumed the most, compared to Caucasians, Chinese Americans, and Japanese Americans.2 Evidence indicating a greater percentage of bioactive lipids in the biologic system of African Americans suggests a diet high in fat content, or greater expression of enzymes converting free fatty acids to bioactive lipids.3 Thus, diet as an epige-netic factor in prostate cancer (PCa) may distinguish African Americans from other...

Summary

This chapter clearly demonstrates that African American men have a worse outcome from prostate cancer than do Caucasian men. The multiple factors described in the chapter probably account for this difference. The initial event distinguishing African Americans from Caucasians is high-grade PIN, which may account for an earlier malignant transformation to clinically significant PCa. If hormonal levels and activity are influenced by a high-fat diet as suggested by Ross and Henderson,54 then the pathway of high-fat content-high level of hormonal activity-high-grade PIN may be significantly responsible for the increased clinically significant PCa among African Americans compared to Caucasians at a younger age. High-fat diet or bioactive lipids may also have an independent role in increasing invasiveness and metastases, as is suggested by Gao et al.3 It may be assumed that men who consume a high-fat diet may take in less fiber containing lycopene which may be protective against prostate...

Decision Analyses

While not specifically designed to determine the natural history of localized prostate cancer, several decision analyses have been published over the past 5 to 6 years that have addressed a similar question the impact and utility of prostate cancer screening or treatment for localized disease. Many of the conclusions reached from these decision analyses are based on estimates of the natural history of the disease and therefore will be discussed in this chapter. The first such analysis was performed by Fleming et al.30 The authors developed a series of outcomes for men 60 to 75 years of age, using estimates of the disutility of complications of treatment and of the disease and concluded that only with the most optimistic assumptions regarding treatment efficacy would treatment for prostate cancer affect patient outcomes. Unfortunately, for reasons that are inexplicable, of the five natural history studies of prostate cancer that the authors used to estimate what would happen to...

Pathologic Outcome

In a retrospective review of 336 men (24 Hispanics, 33 African Americans, 279 non-Hispanic Caucasians) who did not receive neoadjuvant hormonal therapy and were treated at the authors' institution with radical prostatectomy for clinically localized prostate cancer, the incidence of extraprostatic extension of the disease was confirmed in the Other studies have also suggested a less favorable pathologic outcome in Hispanic patients with prostate cancer compared to non-Hispanic Caucasians. Villar demonstrated that Hispanics with prostate, stomach, colon, rectum, lung, breast, and cervical cancer presented at a more advanced stage of disease compared to non-Hispanic Caucasians, particularly those of moderate- to high-income.12 In this study, 39.9 of Hispanic men with prostate cancer presented with advanced disease versus 35.6 and 33.8 of low-income and moderate- to high-income non-Hispanic Caucasians, respectively. The 1994 National Cancer Data Base report on prostate cancer found...

PSA Velocity

Another derivative used to improve PSA screening is known as PSA velocity (PSAV). Utilizing data and frozen serum from the Baltimore Longitudinal Study of Aging, Carter and colleagues were able to plot the PSA values of 73 men, aged 60 or older, over a 7-year period.40 They observed that men without prostate symptoms or prostate cancer had little change in their PSA value over time. Patients with BPH had a linear slope of PSA velocity, while patients with prostate cancer had an initial linear component that became exponential. Investigators calculated PSAV with an equation utilizing at least three separate points and suggested that a PSAV greater than 0.75 ng per mL per year was suspicious for prostate cancer.

Androgen Metabolism

CYP3A activity is expressed in both normal and malignant prostatic tissue, however interindividual variation is high 25 only 61 of prostate cancers express the protein.26 This variability in expression has been hypothesized to result from a polymorphism within the 5' regulatory promoter.27 Approximately 14 of white men are heterozy-gotic and 3 homozygotic for an allele containing an A to G transition (CYP3A4-V) approximately 290 base pairs upstream from the CYP3A4 transcriptional start site in a region known to bind nuclear proteins and known to regulate CYP3A4 transcription rates.28 When examining a cohort of prostate cancer patients, men carrying a CYP3A4-V allele were more likely to present with advanced-stage disease as compared to men carrying the wild type (CYP3A4-W) allele.27 The authors of this study hypothesize that individuals expressing CYP3A4-V may have more bioavailable testosterone as a consequence of expressing less CYP3A4 enzyme. Whether or not men with or without this...

Dietary Factors

The definition of dietary factors is far ranging, and any attempts to characterize individual diets are fraught with confounding factors. On the other hand, it is becoming well accepted that diet can make considerable contributions to the multifactorial nature of diseases such as prostate cancer. To this end, a number of dietary components have been examined. It appears that there are two main possibilities that could explain the differences in prostate cancer risk observed between North Americans and Asians. The first possibility is that something in the Western diet predisposes Westerners to a higher risk for prostate cancer. Data continue to support the idea that total fat intake (especially animal fat derived from red meat) contributes to prostate cancer risk. The Chinese diet is well recognized to be low in meat consumption and enriched for the consumption of vegetables, especially as a source of protein. The second possibility is that something in the Asian diet protects Asians...

Age Specific PSA

An age-specific reference range for serum PSA is a variation of total PSA which was designed to increase sensitivity in younger men and to increase specificity in older men. The concept of age-specific PSA follows that as most men get older they develop BPH, with a resultant increase in their prostate size and an increase in their serum PSA. In a community-based study, Oesterling and colleagues enrolled 537 men aged 40 to 79 into a screening protocol that included serum PSA, DRE, and TRUS.34 Of the 537 men, 471 had all three tests performed without any evidence of prostate cancer. Utilizing this subset of patients, they correlated serum PSA with age and prostate volume. The results indicated that PSA increased by 0.04 ng per mL (3.2 ) per year. From these data, using 95th percentile confidence limits, age-specific reference ranges for serum PSA were developed (Table 11-1). ing PSA and DRE screening followed by TRUS, with prostate biopsy for those with abnormal results.35 They reported...

Sequential Screening

Prostate-specific antigen velocity might be such a tool. In small retrospective studies, an exponential increase in the PSA level was observed during the 5-year period previous to cancer diagnosis. This PSA change correlated roughly with the cancer stage at the time of diagnosis. Increase in PSA, often expressed for reasons of simplicity in ng per mL per yr (PSA velocity), has been analyzed in several screening settings.57,70,71 The cutoff value of 0.75 ng per mL per year, proposed by Carter and based on observations in a selected group of patients with PCa, did not have any discriminatory value over a study period of 1 year.71 In Mettlin's study57 extending over 5 years, men with PCa appeared to have, in almost 50 of cases, a PSA increase of more than 0.5 ng per mL per year compared to 12 of men with benign prostates. It is not clear from this study how many observations were involved or the mean observation period until the diagnosis of cancer. It is obvious, however, that an...

Statistical Aspects

It is important to discuss some of the statistical terms and methods used in evaluating diagnostic tools before examining specific modalities. Comparing different methods as diagnostic tools requires reproducibility of each method and agreement between different methods on the same item of diagnosis. Reproducibility of a tool, or test, can be expressed in intraobserver or assay variability (by the same observer), or interobserver (by two or more observers) variability. When measuring prostate-specific antigen (PSA), for example, it is possible to relate the numeric values of various determinations of the same serum sample at different closely related time points, and calculate the coefficient of variation by the ratio of the mean and its standard variation. This variation is theoretically dependent on the batch of chemicals and stan To improve the methods of diagnosis, intense research has been carried out to compare different diagnostic tools or tests, or their combinations, and seek...

Development

The prostate originates from five pairs of buds arising on the posterior side of the urogenital sinus on either side of the verumontanum, which then invade the mesenchyme of the urogenital sinus.1,2 The topmost buds arise from the inner mesoderm and eventually develop into the transition zone of the human prostate, while the lower buds arising from the endoderm ultimately form the peripheral zones of the prostate.1,2 Cannulation of ductules begins almost immediately.1 The period of development of the fetal prostate (10 to 12 weeks) roughly coincides with that of maximal testosterone production by the fetal testis (12 to 18 weeks). At about 17 weeks, pro-static acid phosphatase (PAP) can be detected within the fetal prostate. Androgen receptor protein can be detected in both the epithelium and stroma of the fetal prostate, while expression of 5 a-reductase protein is limited to the stroma.3 In humans, a distinct anterior lobe is present only until 16 weeks, after which it regresses...

Proteins

Prostatic-Binding Protein Prostatic-binding protein is secreted by both the rodent and human prostate and has been referred to variously as prostatein and estramustine-binding protein.110 It is a member of the uteroglobulin superfamily of proteins and is a serine protease.111 In the rat, PBP is the major secretory protein of the prostate, with its expression limited to the ventral lobe.16,112 In humans, PBP is a minor prostatic secretory product113 and is expressed in a variety of organs, including the liver and colon.114 Prostatic-binding estramustine-binding protein has been detected in the normal and diseased human prostate.115,116 It is a tetramer with one subunit composed of C1-C3 submits and the other of C1-C2 submits.117 serve to traffic secretory products out of the cell, as 3-hydro-estramustine injected into rats is localized first in the prostate, then in the acinar lumens.120 The expression of PBP has been studied extensively, however, in gaining a better understanding of...

Endocrine Regulation

The prostate is dependent on testicular-derived testosterone despite the presence of the 3p-hydroxysteroid dehydrogenase-a5-a4 isomerase complex,160 the prostate has not been reported to synthesize testosterone de novo. It can reversibly metabolize testosterone to androstenedione (17P-hydroxysteroid dehydrogenase161) and, possibly irreversibly, to estrogens (see below). The prostate's primary metabolite of testosterone is dihydrotestosterone (DHT), an irreversible reaction catalyzed by 5 a-reductase.162 This is a more potent ligand for the androgen receptor than is testosterone, as it binds the receptor with greater affinity, enhances translocation from the cytoplasm to the nucleus, and is more effective in activating many androgen-response elements.163,164 Following 5 a-reduction, DHT and androstanedione are further metabolized by 3a p -hydroxysteroid dehydrogenase to 5 a-androstane-3a p-17P-diol and androsterone.165,166 The reader is referred to the work of Amann and colleagues167...

Ionic Composition

The composition of human prostatic fluid and that of other mammalian species has been detailed in Aumuller2 and in Setchell et al.55 Little is known about the biochemical composition of rat prostatic fluid. In humans, the prostate contributes about 0.5 to 1 mL to the total ejaculate (2 to 6 mL total ejaculate, 40 to 240 million sperm per mL).56,57 Due to the high concentration of citric acid (approximately 91 mM, range 45 to 176 mM), the pH is slightly acidic at 6.5. Compared to plasma and interstitial fluid, human prostate secretions contain extremely high levels of divalent cations, including Ca++, Zn++, and Mg++, roughly equivalent amounts of Na+, and relatively low amounts of Cl- and HCO3-. Protein averages about 24 mg per mL. The primary sugar present is inositol (8.2 mM), with low levels of glucose (0.9 mM) and virtually no fructose.

Citrate

In many species, the concentration of citrate in the semen (5 to 50 mM) greatly exceeds that of the blood (0.07 to 0.12 mM).21 In humans, the peripheral zone of the prostate is the primary source of seminal citrate, while in the rat, citrate is secreted by the lateral and ventral lobes of the prostate as well as by the seminal vesicles.21,55 Because of its key role in the tricarboxylic acid cycle (TCA) and in fatty-acid synthesis, citrate is conserved rather than secreted by most tissues. In contrast, the human prostate is able to concentrate citrate in the pro-static fluid to levels of 24 to 130 mM (making it the predominant anion), compared to plasma extracellular concentrations of 0.1 mM.21 Mitochondrial aconitate hydratase activity (citrate catalyzed to isocitrate) is inhibited by chelation with Zn++ 21,58 the excess citrate then replaces Cl- as the primary anion utilized by the luminal sodium transporter (Figure 14-3).21,59 Replenishment of four carbon submits for the TCA cycle...

Susan R Marengo PhD

This chapter focuses on the normal physiology of the human prostate and its regulation. Because of the pronounced interspecies variation in the types of accessory sex glands present and the constitution of their secretions, this review cannot be considered a review of general prostatic physiology that can be extrapolated to other species. Since the rodent model (rats and mice) has been utilized extensively as a model for investigation of prostatic physiology and pathology, these species will be included where pertinent.

Gross Anatomy

The gross and microscopic anatomy of the human4,20-22 and rodent23-28 prostates have been described in detail and will be covered only briefly here. The gross anatomy of the human prostate is best described as a zonal arrangement consisting of the peripheral zone (70 to o), central zone (20 to 25 ), transitional zone (5 to ), and the periurethral zones (approximately 1 ) (Figure 14-2).20,24,27 For a comparison of the original lobular nomenclature of prostatic anatomy with that of the currently used zonal nomenclature, the reader is referred to the 1980 work of McNeal.4 The human prostate has two unique features that contribute to the development of the obstructive symptoms of prostatic disease. First, the gland completely surrounds and envelops the urethra, which makes a 3 5-degree bend at the verumontanum. Second, a large fibrous capsule accounting for approximately one-third of the total prostatic mass covers the entire anterior and anterolateral surface of the gland.20 The capsule...

PSA Density

PSA density (PSAD) is one such variation and is defined mathematically as total PSA (ng mL) divided by the volume of the prostate gland (cc). The concept of PSAD is based on the assumption that the PSAD calculation would standardize the amount of PSA produced per cubic centimeter of prostate tissue. A volume occupied by cancer will result in a higher serum PSA than a volume occupied by benign tissue. It was postulated that PSAD would be able to identify which patients had an elevated PSA secondary to benign enlargement, BPH, versus those with elevations secondary to prostate carcinoma.29 TABLE 11-1. Age- and Race-Specific Reference Ranges for Prostate-Specific Antigen TABLE 11-1. Age- and Race-Specific Reference Ranges for Prostate-Specific Antigen

Latent Carcinoma

Perhaps one of the most commonly accepted paradigms of the prostatic cancer literature relates to the worldwide incidence of latent prostatic cancer. Specifically, it is commonly believed that the incidence of latent and small prostate cancers in Asian countries is the same as that for men living in Western countries, despite the large differences in clinical incidence and mortality rates that have been observed. Latent prostate cancer is defined as those carcinomas that are clinically unsuspected and are found by other means. While such carcinomas are often detected during transurethral prostatectomy for BPH, the term is more widely used to describe those carcinomas detected at autopsy. First, it is obvious that autopsy studies in the Detroit Metropolitan area indicate that as many as one-third of the men between 40 and 49 years of age harbor focal carcinomas in their prostate.25 By comparison, such rates are not reached in Southeast Asians until they are approximately two to three...

Tumor Specific Antigens

This category of tumor antigens, which represents non-mutated gene products that are not processed and presented on normal adult tissues, is predominantly comprised of members of the cancer testis (C T) family of genes (Table 2). The expression of C T gene products is limited in adult tissues to the normal testis, which lacks expression of HLA class I and class II molecules. The prototype for this family, MAGE-1, represents the first antigen to be identified as a target of human tumor reactive T cells, and was cloned by transfecting an autologous tumor cell line that appeared to have lost antigen expression with a cosmid library containing genomic DNA from antigen positive tumor cells (1). The cancer testis genes have been clustered into 10 families, 6 of which have been mapped to the X chromosome (3 8), and subsequent studies have lead to the identification of T cell epitopes expressed on multiple products derived from these gene families. The MAGE gene family includes 17 members,...