Epdemiology

In 2010, it was estimated that 217,730 American men would be diagnosed with prostate cancer, accounting for 25% of all newly diagnosed cancers in men.¹ It appears that one in six American men will develop a clinically recognized invasive prostate cancer during his lifetime. Ninety-one percent of cases were expected to be diagnosed of local or regional stage disease for which the 5-year relative survival rate approaches 100%. The age-adjusted annual incidence rate increased 6.4% per year between 1983 and 1989,² with a 66% overall increase between the periods of 1975 to 1979 and 1987 to 1991.³ This change largely reflected the increased detection of localized, rather than regionally advanced or metastatic, prostate cancer cases.^2,4 From 2001 to 2005 the incidence of newly diagnosed cases dropped 4.4% per year.^5,6 This decrease in the incidence of prostate cancer may reflect stabilization related to PSA screening. Prostate cancer remains the second leading cause of cancer death in men, with 32,050 deaths being estimated in 2010. As with the incidence of newly diagnosed cancers there has been a significant drop in prostate cancer death rates from 1990 to 2005. The death rate from prostate cancer was 38.56/100,000 men in 1990 compared with 24.65/100,000 men in 2005 (p <.05), representing a 36% decline.¹

The incidence of incidental (or latent) prostate cancer observed at autopsy examination and the incidence and prevalence of clinically manifest prostate cancer increase substantially with age.^6–9 Information from the Surveillance, Epidemiology, and End Results (SEER) program indicates that approximately 1.8% of American men between ages 40 and 59 years had a clinical diagnosis of prostate cancer whereas 15% of men 60 to 79 years old would have prostate cancer by the time they attained this age. Although the prevalence of incidental carcinoma does not exhibit marked geographic variation, the regional disparity in the antemortem clinical expression of the disease and the cancer mortality rate of prostatic carcinoma is noteworthy.^7,10 Men in North America, Australia/New Zealand, Western and Northern Europe, and the Caribbean have a much higher incidence of this disease than men in Asia and China.¹⁰

Etiology

Cohort and case-control studies are the two principal methods used to ascertain the etiology of cancer.¹¹ Several reports describe various host-related and environmental factors that appear associated with prostate cancer (Table 51-1), but it is not yet understood which factors directly initiate or promote prostate carcinogenesis. As discussed by several authors,^12,13 long-term androgen exposure, which is required for normal prostatic development and for cancer growth and maintenance, advanced age,¹ race/ethnicity,^14–16 and familial history of prostate cancer^17,18 are presently viewed as the most likely risk factors. Other associations such as diet, body mass index, energy balance, and physical activity are becoming more suspect.^19–23

TABLE 51-1 Potential Risk Factors for Prostate Cancer

Prevention

Prostate cancer is an androgen-dependent tumor with a prolonged latency between initial malignant transformation and clinical expression, which are features well-suited to disease prevention efforts.⁷ Progression from tumor inception to invasive carcinoma often takes decades, allowing sufficient time for intervention.⁹ Chemoprevention strategies that use high-risk target populations, particularly those with premalignant lesions (e.g., high-grade PIN), have the greatest potential to identify promising agents in a time-efficient manner.⁹⁸ The results of focused studies such as these can then be confirmed in large-scale trials applied to the general population. The ability to alter the hormonal environment of the host provides an excellent opportunity to interrupt the multistep process that results in clinical expression of the disease.⁷ Advances in our understanding of the process of carcinogenesis and the availability of promising new chemopreventive agents, including those producing reversible androgen deprivation, have the potential to favorably affect the morbidity and mortality of prostate cancer in the foreseeable future.

Luteinizing hormone-releasing hormone analogues (e.g., goserelin, leuprolide) reduce luteinizing hormone and (secondarily) testosterone levels. The long-term use of these agents may cause anemia, atrophy of reproductive organs, diminished muscle mass, loss of libido, and vasomotor instability, which limits the utility of these agents for chemoprevention in the general population. Nonsteroidal antiandrogens (e.g., flutamide, bicalutamide) competitively bind to androgen receptors in target tissues. These agents are well tolerated in most patients, although adverse effects may include gastrointestinal disturbance, gynecomastia, and vasomotor instability.

Intracellular 5α-reductase converts testosterone to dihydrotestosterone (DHT), the hormone responsible for prostate epithelial proliferation. DHT has greater affinity for the androgen receptor and is the primary agonist leading to prostate maintenance and growth. Three isoforms of 5α-reductase have been identified with various levels in different tissues. Type 1 is expressed in benign prostate hyperplasia, and its expression is greatly increased in prostate cancer, especially high-grade tumors.⁹⁹ Type 2 5α-reductase expression is decreased in PIN and some early cancers but is increased in metastatic and recurrent prostate cancer.⁹⁹ The role of type 3 5α-reductase is less defined. Competitive inhibitors of 5α-reductase (e.g., finasteride and dutasteride) suppress intraprostatic dihydrotestosterone to castrate levels. The Prostate Cancer Prevention (PCP) trial was initiated to test the efficacy of finasteride as a chemoprevention agent in men at low risk of having prostate cancer.¹⁰⁰ This placebo-controlled phase III trial randomized 18,882 eligible men (age ≥55 years, normal digital rectal examination [DRE] and PSA levels <3 ng/mL) to finasteride (5 mg daily) or placebo for 7 years. There was a 25% reduction in the prevalence of prostate cancer over this 7-year period from 30.6% in the placebo group to 18.6% in the finasteride group.¹⁰⁰ Of note, however, is that more aggressive tumors, with Gleason score 7 to 10, were more common in patients who took finasteride: 37% of all tumors and 6.4% of all men on the finasteride arm versus 22% of all tumors and 5.1% of all men on the placebo arm. The increased incidence of high-grade cancers seen in the PCP trial has been a topic of great debate. The investigators have argued that the increase in high-grade cancers is due to a detection bias related to the reduced volume of prostate tissue and therefore a greater ratio of cancer to benign tissue. Furthermore, there was no dose effect from the finasteride with no significant increase in worse cancers with higher cumulative doses of the drug.¹⁰¹ The PCP trial was not designed or powered to detect differences in cancer-specific survival (CSS) or overall survival (OS). Finasteride did reduce urinary symptoms compared with placebo, but there were also significantly more adverse sexual side effects.¹⁰⁰ A reduced volume of ejaculate, erectile dysfunction, loss of libido, and gynecomastia were more common in the finasteride group (p <.001), but urinary urgency, frequency, retention, urinary tract infection, and prostatitis were less common with finasteride (p <.001).¹⁰⁰

The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, a phase III study testing inhibition of 5α-reductase with dutasteride, has completed its accrual of patients.¹⁰² Unlike finasteride, which blocks 5α-reductase type 2, dutasteride blocks both types 1 and 2, suggesting it may be more effective at preventing the development of prostate cancer.^99,103 Phase III trials evaluating dutasteride for the treatment of benign prostatic hyperplasia coincidentally showed a significant reduction in the incidence of prostate cancer.^102,104 The REDUCE trial is a randomized trial of placebo versus dutasteride, 0.5 mg, administered daily to evaluate it as a chemopreventive agent for prostate cancer. This trial completed its accrual of 8000 subjects in 2004. Unlike the PCP trial, which enrolled men with a low risk of prostate cancer, the REDUCE trial sought patients with a higher risk of developing or being diagnosed with prostate cancer (e.g., PSA >2.5).¹⁰²

The association of dietary consumption or serum levels of selenium and α-tocopherol and a low rate of prostate cancer have suggested that dietary supplements of these nutrients may protect men from the development of this disease.⁶¹ Despite this association, two prospective phase III clinical trials did not show a reduction in the incidence of prostate cancer with vitamin E or selenium supplementation. In the Selenium and Vitamin E Cancer Prevention Trial (SELECT) there was no significant reduction in prostate cancer incidence related to either selenium or vitamin E supplementation.¹⁰⁵ SELECT enrolled 32,400 participants to a phase III randomized, double-blind, placebo-controlled trial with a 2 × 2 factorial design. The study was designed to determine the efficacy of selenium, vitamin E, or a combination of the two to prevent prostate cancer. Unfortunately, neither supplement alone nor in combination lowered the risk of prostate cancer in healthy men.¹⁰⁵ The Physicians’ Health Study II enrolled 14,641 male physicians and randomized them to receive vitamin E and C supplements daily. Neither vitamin E nor vitamin C supplementation reduced the risk of prostate or other cancers.¹⁰⁶

Early Detection

Considerable controversy surrounds the use of early detection programs for prostate cancer. Some argue that early detection efforts are too costly and will lead to the recognition of an increased number of clinically insignificant tumors, because autopsy studies demonstrate a high prevalence of incidental tumors in older men.^9,10 Likewise, a study of prostate cancer discovered in organ donors found incidental prostate cancer in one third of men aged 60 to 69 and 46% in men older than age 70.¹⁰⁷

Contributing further to the arguments against prostate cancer screening are the limited sensitivity and specificity of serum PSA level, DRE, and ultrasonography in diagnosing cancer. Although DRE has high specificity for prostate cancer, it has a low sensitivity profile and is not considered an effective detection tool on its own.¹⁰⁸ In contemporary series,¹⁰⁹ PSA testing with a threshold of 4.0 ng/mL has a sensitivity of only about 20%. Although the sensitivity of PSA testing could be improved by lowering the threshold value for all men, this would compromise the specificity and increase the detection of clinically insignificant cancers. Early detection strategies have also been criticized for exaggerated improvements in cancer-specific survival related to an early detection bias. In an early report the use of PSA resulted in a diagnostic lead time of approximately 5 years^110,111 and longer in the detection of earlier-stage and lower-grade tumors.¹¹² Data from the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the SEER registry suggest the lead-time bias could range from 5.9 to 7.9 years.¹¹³ Included in the debate over prostate cancer screening are the risks of overdetection and overtreatment. Overdetection occurs when men are found to have disease that would never have remained silent and contributed no morbidity in their lifetime. Overtreatment occurs when an intervention plays no role in extending a patient’s life or preventing morbidity from the illness. The real challenge for clinicians involved in the management of prostate cancer is the identification of clinically significant disease.

Arguments in support of prostate cancer screening include the 36% reduction in prostate cancer deaths seen between 1990 and 2005.¹ This trend began shortly after the introduction of PSA testing, and statistical models suggest that PSA testing contributed to this decline.^114,115 Furthermore, PSA testing is responsible for the migration of prostate cancer diagnoses to earlier and more curable stages.^1,116 These findings, as well as data from studies suggesting a survival benefit to treatment for early cancers, support a role for early detection and treatment. The Swedish randomized trial of surgery versus watchful waiting demonstrated an improvement in disease-specific and overall mortality in men undergoing radical prostatectomy (RP) for early-stage disease.¹¹⁷ In the United States, an observational cohort of 44,630 men from the SEER registry suggests a survival advantage with active treatment for low- and intermediate-risk prostate cancer in men aged 65 to 80 years.¹¹⁸

Early data from two large prospective randomized trials seeking to measure the benefit from prostate cancer screening contribute to this screening controversy.^119,120 The U.S. Prostate, Lung, Colon and Ovary (PLCO) screening trial registered 76,693 men at 10 study centers to determine the impact of annual PSA determination and DRE on the cause-specific mortality for cancers in each of these organ sites.¹²⁰ The primary exclusion criteria were a history of a PCLO cancer, current cancer therapy, and more than one PSA blood test in the 3 years prior to study enrollment. Subjects in the screening group were offered annual DRE for 4 years and annual PSA testing for 6 years. A PSA of more than 4.0 ng/mL or a DRE indicating nodularity or induration were considered suggestive of prostate cancer, and patients with these findings were advised to seek diagnostic evaluation. With a median follow-up of 11.5 years, although there were significantly more cancers diagnosed in the screened group there was no reduction in prostate cancer mortality.¹²⁰ The ERSPC recruited 182,000 men between the ages of 50 and 74 years from seven European countries. The men were randomized to receive PSA screening once every 4 years or to a control group that did not get PSA screening. There was country to country variability in enrollment criteria and screening regimens, age of eligibility, case selection criteria, thresholds for PSA levels, and the inclusion of DRE in the screening assessments. PSA values as low as 3.0 ng/mL were considered abnormal and would prompt referral for further testing that differed between participating countries. Of 162,387 eligible men enrolled, 5,990 prostate cancers were diagnosed in the study group compared with 4307 (20% fewer) in the control group. With a median follow-up of 8.8 and 9.0 years in the screening and control groups, respectively, the adjusted rate ratio of prostate cancer death in the screened arm was 0.80 (95% confidence interval [CI], 0.65 to 0.98, p = .04).¹¹⁹ In the ERSPC trial the number of men who would need to be screened to prevent one prostate cancer death is 1,410. More importantly, 48 men would need to be treated to prevent each prostate cancer death.¹¹⁹

There are important differences in these two screening trials that help explain the apparent differences in conclusions. The U.S. trial enrolled a group of men who in as many as 42% of cases underwent previous screening, effectively reducing the prevalence of cancer relative to that of a completely unscreened population. In addition, over the period of the trial 52% of nonscreened men had PSA testing, contaminating the control group. The follow-up of 11 years for prostate cancer mortality is relatively short for a group of men with screened cancers. The heterogeneity of eligibility and screening criteria in the ERSPC trial make it challenging to determine the exact population that would benefit from screening. Finally, the quality of life outcomes and cost-effectiveness analyses for both these trials have yet to be reported and these results will undoubtedly contribute significantly to our understanding of the merits of population-wide screening for prostate cancer.

One criticism of published trials of PSA screening is the use of singular thresholds to prompt further diagnostic evaluation. Because serum PSA levels directly correlate with age in men without prostate cancer, several investigators sought to improve the diagnostic accuracy of PSA by defining the normal test range as a function of age and race^121–127 (Table 51-2). In particular, DeAntoni and colleagues¹²⁷ found that the mean PSA level was significantly different for successive decades of age and there was increased variability in PSA values with advancing age. It was this age-related variability that largely accounted for the phenomenon of age-specific reference ranges. El-Galley and associates¹²⁶ studied the clinical impact of age-specific reference ranges in 2657 men who underwent prostatic biopsy. Analysis of the sensitivity, specificity, and positive predictive value profiles supported use of age-specific reference ranges because of increased detection sensitivity in younger men and increased specificity in older men.

Measuring PSA velocity (PSAV), defined as the change in serum PSA over time, is another method to account for prostatic changes that occur during the aging process. In men who develop prostate cancer, an exponential increase in PSA values begins approximately 5 years before the diagnosis is established,¹²⁸ and detecting a PSAV of 0.75 ng/mL/yr or more appears to be a sensitive means to distinguish these men from those without prostatic disease or those with benign prostatic hyperplasia.^128–130 However, owing to interassay variability, only a PSA change exceeding +7.5% may be considered significant according to Kadmon and colleagues.¹³¹

Additional attempts to improve the screening accuracy of PSA measurements are based on the observation that serum PSA level depends on cancer volume, tumor differentiation, and the amount of benign prostatic tissue.¹³² To account for coexistent benign prostatic hyperplasia, the concept of PSA density (PSAD) was introduced by Benson and colleagues.¹³³ PSAD is the total serum PSA value divided by the volume of the prostate gland, as determined by TRUS using the prolate ellipsoid formula (volume × length × width × height × 0.52). PSAD appears most useful for patients with a total serum PSA level in the range of 4 to 10 ng/mL, particularly when palpable prostatic abnormalities are absent. In this setting it is believed a PSAD of 0.15 ng/mL/cm³ or more best identifies men in whom prostatic biopsy should be considered.^134,135 In other investigations, however, diagnostic accuracy was not enhanced by the PSAD compared with using the upper normal PSA concentration, defined as 4.0 ng/mL, as a cutoff point for early detection.^136–138 Another PSA derivative, transition zone volume-adjusted PSA (PSAT) was introduced as an evolution in the PSAD concept for men with a serum PSA value in the indeterminate range (i.e., 4 to 10 ng/mL).¹³⁹ PSAT is calculated by dividing the serum PSA value by the TRUS-determined transition zone volume and is based on the rationale that benign prostatic hyperplasia results exclusively from transition zone hyperplasia.

Because the proportion of PSA complexed to α₁-antichymotrypsin is greater in patients with prostate cancer than in men with benign prostatic disease, the ratio of free-to-total (i.e., percent free) PSA will be lower in men with prostate cancer and may help discriminate between benign and malignant prostate conditions.^140–144 Although the free-to-total PSA ratio can be applied to any serum PSA level, performing a free PSA determination improves the specificity for prostate cancer detection when the total serum PSA range is 3 to 10 ng/mL.^142,145 To determine the optimal cutoff point that may warrant prostatic biopsy, various free-to-total PSA ratios were examined for their association with prostate cancer.^144,145 A multicenter clinical performance study demonstrated that a free-to-total PSA ratio of less than 7% was highly suggestive of cancer whereas a free-to-total PSA ratio of above 25% was rarely associated with malignancy. In association with other study results, a diagnostic algorithm for the detection of early-stage prostate cancer based on the percent free PSA has been suggested.¹⁴⁵ However, larger population-based trials must be conducted and the utility of prostate cancer screening must be ascertained before widespread application can be recommended.¹⁴⁶

Screening Recommendations

The controversy in prostate cancer screening is evident when the current recommendations from various professional societies are reviewed. The American Cancer Society (ACS) previously recommended annual DRE and PSA testing in men older than 50 years of age with a life expectancy of at least 10 years.¹⁴⁷ In 2009, after the publication of the interim results of the PLCO and ERSPC trials, the ACS no longer supports routine testing for prostate cancer. The ACS does support health care professionals discussing the potential benefits and limitations of early detection with an offer to test with annual PSA screening and DRE beginning at age 50 in men who are at average risk of prostate cancer with a life expectancy of more than 10 years.¹⁴⁸ The American Urological Association (AUA)¹⁴⁹ recommends PSA screening for well-informed men who wish to pursue early diagnosis beginning at age 50 and sooner for those men with a higher life-time risk (positive family history in a first-degree relative or African-American race). A baseline PSA value at age 40 above the median value (0.6 to 0.7 ng/mL) may identify a group of men with a significant risk of prostate cancer in the future.^150,151 Based on the findings of the PLCO and ERSPC studies, the U.S. Preventative Services Task Force (USPSTF) concluded that for men younger than age 75 years the benefits of screening for prostate cancer are uncertain and the balance of benefits and harms cannot be determined. For men 75 years or older there is moderate certainty that the harms of screening for prostate cancer outweigh the benefits.¹⁵²

Anatomy

Prostatic anatomy is readily understood by using the urethra as a reference point. The verumontanum is a major anatomic landmark and protrudes from the posterior prostatic wall at the midpoint of the urethra. Most prostatic ducts and the ejaculatory ducts empty into the urethra in this region, whereas the periurethral glands empty throughout the length of the urethra. Immediately proximal to the verumontanum is the müllerian remnant, the utricle, an approximate 0.5-cm length of epithelium-lined cul-de-sac. A circumferential sleeve of muscle surrounds the entire urethra and is composed of the proximal preprostatic smooth muscle sphincter, which prevents retrograde ejaculation, and a distal sphincter of striated and smooth muscle at the apex that is essential for urinary control.

The prostate is composed of three zones: peripheral, central, and transition. The peripheral zone includes approximately 70% of the prostatic volume and is the most common site of PIN and carcinoma. DRE often includes a description of the prostatic lobes based on palpation of the median furrow, which divides the peripheral zone into the right and left halves. The central zone is a cone-shaped area that includes the base of the prostate and encompasses the ejaculatory ducts; it represents approximately 25% of the volume of the prostate. The transition zone is the smallest component of the normal prostate, accounting for approximately 5% of the gland, but it usually enlarges as men age owing to benign prostatic hyperplasia and may grow to dwarf the remainder of the prostate.

The prostatic capsule consists of an inner smooth muscle layer and an outer covering of collagen, with marked variability in the relative amount of each in different areas. At the apex, acinar elements are sparse and the capsule is ill defined. As a result, the prostatic capsule cannot be regarded as a well-defined anatomic structure with constant features.

The nerve supply of the prostate is furnished by paired neurovascular bundles along the posterolateral edge of the prostate. Autonomic ganglia are clustered near the neurovascular bundles, and small nerve trunks arising at this site penetrate the capsule to form an extensive network within the gland.

The primary blood supply of the prostate is furnished by the internal iliac artery, and the venous drainage is directly into the prostatic plexus, which eventually empties into the internal iliac vein. This route may account for hematogenous metastases, most often in osseous sites.

The lymphatics of the prostate and the seminal vesicles were detailed through anatomic dissections described by Rouvière.¹⁵³ Lymphatic drainage of the prostate originates in an extensive intraprostatic network that coalesces to form a subcapsular system and henceforth coalesces into a periprostatic lymphatic network and the four pedicles of the collecting trunks: the external iliac, hypogastric (or internal iliac), and posterior and inferior pedicles that terminate in the external iliac (including the obturator), presacral, and hypogastric lymph nodes, respectively. The lymphatics of the seminal vesicle originate in the mucous and muscular networks and give rise to the superficial plexus, which culminates in the lymph nodes of the external iliac system. Modern surgical series of extended pelvic lymph node dissections report involved lymph nodes commonly in the obturator fossa and external and internal iliac regions.^154,155 These sites account for nearly 85% of lymph node metastases in prostate cancer.¹⁵⁵ Another 15% of involved nodes can be identified in the presacral, paravesicular, and pararectal sites.¹⁵⁵

Histology

The prostatic epithelium consists of three main histologic types: secretory, basal, and neuroendocrine cells. Despite having the lowest proliferative activity of the epithelial elements, secretory cells produce PSA, prostatic acid phosphatase (PAP), acid mucin, and other secretory products. The basal cells form a flattened layer of cells surmounting the basement membrane at the periphery of the glands. These cells possess the highest proliferative activity of the prostatic epithelium and are thought to act as stem or “reserve” cells that repopulate the secretory cell layer.¹⁵⁶ Basal cells, selectively labeled with antibodies to high-molecular-weight keratin (e.g., 34βE12), are used to differentiate benign acinar processes from adenocarcinoma, which lacks a basal cell layer. Neuroendocrine cells are the least common epithelial cell type and are often not identified in routinely stained sections.

The seminal vesicles have a variable anatomic distribution, portions of which may occasionally be found within the prostatic capsule where they may be mistaken for prostatic nodularity or induration on examination. The cells of the epithelial component have large, irregular hyperchromatic nuclei with coarse chromatin and prominent nucleoli that often show nuclear abnormalities. When encountered in needle biopsies, such “pseudomalignant” cytologic atypia may lead to a mistaken diagnosis of prostatic adenocarcinoma. Cowper’s glands consist of lobules of closely packed uniform acini and are noteworthy in that they may also be mistaken for prostatic carcinoma in biopsy specimens.

Pathology of Prostate Cancer