Prostate Cancer

Screening and Diagnosis

Prostate cancer screening with PSA levels and digital rectal examination (DRE) has resulted in not only an increase in prostate cancer detection but also a stage shift. More cancers are now being detected at earlier stages, when they are potentially curable. Prior to screening efforts, most prostate cancers were detected when they produced local symptoms or distant metastases, at which point treatment for cure often was impossible.

Digital Rectal Examination

Prostate biopsy prompted by abnormal findings on DRE, such as nodularity or induration of the prostate, leads to a diagnosis of prostate cancer in only 15% to 25% of cases. This rate compares with a prostate cancer prevalence of < 5% among men of similar age without an abnormal DRE. Although neither accurate nor sensitive for prostate cancer detection, abnormal DRE is associated with a fivefold increased risk of cancer present at the time of screening. Currently, the National Comprehensive Cancer Network (NCCN) and the American Urological Association (AUA) guidelines recommend a DRE as part of the screening process, however, the latest American Cancer Society (ACS) guidelines consider the DRE to be an optional test.

PSA

PSA is a serine protease produced by the prostatic epithelium and secreted in the seminal fluid in large quantities. The level of PSA in serum is increased by inflammation of the prostate, urinary retention, prostatic infection, benign prostatic hyperplasia, prostate cancer, and prostatic manipulation. The optimal threshold to recommend prostatic biopsy has come under increasing scrutiny. The overall sensitivity for PSA levels is approximately 50% to 70% depending on the threshold used, but it is not as specific and does not allow for differentiation between indolent and aggressive disease.

Two large randomized multisite trials examined the role of PSA screening in US and European populations over time. In the PLCO trial (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial), nearly 77,000 US men were randomized to annual PSA and DRE screening or to standard practice (which included PSA screening). After 7 years of follow-up, prostate cancer was more commonly detected in screened men, but fatal disease was not detectably different. In contrast, in the European study, named ERSPC, 182,000 men in various countries were assigned to PSA screening at various intervals or to no screening. Contamination seemed to be less common in the control group in this study, and at 9 years' median follow-up, a 20% reduction in prostate cancer mortality was noted. In this study, nearly twice as many screened men were diagnosed with prostate cancer. The number needed to screen in this study to save 1 prostate cancer death was 1,410, and the number needed to treat with local therapy was 48. Data from the PCPT (Prostate Cancer Prevention Trial) illustrate that there is no "normal" level for PSA. Indeed, there is a continuum of risk that exists, even at low levels of PSA. For example, among men in the placebo arm of the study, 11% of men with a serum PSA level < 1 ng/mL had prostate cancer at the end-of-study biopsy. The proportion of men with prostate cancer rose to 30% among those with PSA levels between 3.1 and 4 ng/mL, which is still within the "normal" range. Furthermore, with a median follow-up of 9 years, the cancer-specific survival rate was improved by 20% in the screening group vs controls. However, they report an overdetection of small, nonlethal cancers.

An additional potentially more worthwhile approach for PSA screening may be to use the rate of rise in PSA (PSA velocity) in combination with the absolute PSA value. This approach has been shown to be useful in the form of age-adjusted PSA velocity, but accepted guidelines are still controversial, and the independent predictive utility of this measure remains to be demonstrated.

Another commonly employed test for patients with a PSA level < 10 ng/mL is the percent free-PSA level. There is an inverse relationship between the free-PSA percentage and the risk of a cancer diagnosis. Most urologists utilize a cutoff of 10% to prompt a recommendation for a repeat biopsy. In men who have never had a prostate biopsy but who have a total PSA level > 4 ng/mL, a free-PSA level less than 25% may suggest a 50% to 60% probability of prostate cancer. In men who have had a prior negative biopsy but who have a persistently elevated PSA level > 4 ng/mL, a free-PSA level < 10% should prompt a repeat biopsy.

Using a baseline PSA value to risk-stratify young men for their future risk of prostate cancer is increasingly recognized as clinically useful by both the NCCN and AUA guidelines. Tang et al, in a study of more than 9,500 men aged 50 or younger, showed that a baseline PSA of 1.5 to 2.4 ng/mL increased the relative risk for prostate cancer by 9.3-fold for white men and sixfold to sevenfold for black men. Overall, an initial PSA > 1.5 was a powerful predictor of subsequent prostate cancer, confirming the Physicians Health Study and other published data.

Sidebar: The European Randomized Study of Screening for Prostate Cancer (ERSPC) recently reported updated data on prostate-cancer mortality, with 2 additional years of follow-up. The study involved 182,160 men between the ages of 50 and 74 years at entry, with a predefined core age group of 162,388 men 55 to 69 years of age. The trial was conducted in eight European countries. Men who were randomly assigned to the screening group were offered prostate-specific antigen (PSA)-based screening, whereas those in the control group were not offered such screening. The primary outcome was mortality from prostate cancer. After a median follow-up of 11 years in the core age group, the relative reduction in the risk of death from prostate cancer in the screening group was 21% (rate ratio, 0.79; 95% CI, 0.68–0.91; P = .001), and it was 29% after adjustment for noncompliance. The absolute reduction in mortality in the screening group was 0.1 deaths per 1,000 person-years or 1.07 deaths per 1,000 men who underwent randomization. The rate ratio for death from prostate cancer during follow-up years 10 and 11 was 0.62 (95% CI, 0.45–0.85; P = .003). To prevent 1 death from prostate cancer at 11 years of follow-up, 1,055 men would need to be invited for screening and 37 cancers would need to be detected. Analyses after 2 additional years of follow-up consolidated the ERSPC investigators' previous finding that PSA-based screening significantly reduced mortality from prostate cancer but did not affect all-cause mortality (Schröder FH et al: N Engl J Med 366:981-990, 2012).

Current Screening Recommendations

There remains significant controversy as to the wisdom and effectiveness of PSA screening for the general male population. This is exemplified in recent update by the United States Preventative Services Task Force (USPSTF), which has given PSA screening a "D Rating." This means that this committee believes that risk to population-based PSA screening outweighs the benefits and does not recommend routine testing. This announcement in May 2012 was immediately met with a firestorm of criticism and controversy, and even a US House of Representatives Bill to rebuke the guidelines and adjust the composition of the committee requiring specialists in the field of question. Furthermore, both the AUA and ACS updated their 2010 guidelines. The AUA took a more "proactive" stance by recommending that all men consider having a baseline PSA test at age 40. This guideline is useful to risk-stratify men to future testing frequency. If at age 40 a man's PSA level is less than 1 ng/mL, the man can be reassured that he is at low risk and will be asked to return at age 45 for consideration of additional screening tests.

On the other hand, the ACS took a more cautious stance with its 2010 update. The ACS is now de-emphasizing mass screening programs, while emphasizing a discussion of the pros and cons of testing with PSA levels based on individualized risk. The NCCN has also adapted an individualized risk assessment and informed discussion with patients about the pros and cons of screening, to begin in the 40s for high-risk men, and at 50 for men of average risk. Readers should refer to acs.org or nccn.org for updates of these guidelines.

Using data from the Shared Equal Access Regional Cancer Hospital, the Duke Prostate Center, and Johns Hopkins Hospital, investigators concluded that higher body mass index was significantly associated with higher plasma volume and lower PSA concentrations in men undergoing radical prostatectomy. Hemodilution may therefore be responsible for the lower serum PSA concentrations among obese men with prostate cancer. While obese men may be less likely to be diagnosed with incident prostate cancer, they are, however, more likely to have aggressive disease at presentation, and more likely to suffer relapse and prostate cancer-specific mortality.

Biopsy

When indicated, prostate biopsy is usually performed as an office procedure by transrectal ultrasonographic guidance using an automated 18-gauge biopsy gun. The procedure is performed with, at most, local anesthesia and carries a risk of significant infection in only 1 of 200 cases, although the risk of post-biopsy urosepsis has been increasing recently due primarly to ciprofloxicin-resistant E coli. Additional side effects of hematuria and hematochezia are common for 2 to 3 days following the biopsy. Hematospermia may last for up to 4 to 6 weeks. Since about the year 2000, prostate biopsy includes laterally directed extended core protocols employing 8 to 20 biopsy cores per procedure. Multiple studies have demonstrated that addition of the lateral cores improves the accuracy of biopsy.

If the biopsy result is negative, these men are typically followed conservatively with serial PSA levels and DRE repeated annually. Repeat biopsy is performed only when PSA levels rise at abnormal rates (> 0.8 ng/mL/year) or if DRE findings show new nodularity or induration. Men in whom high-grade prostatic intraepithelial neoplasia (PIN) or atypical small acinar proliferation (ASAP) found on biopsy usually should undergo repeat biopsy, since one-third to one-half will be found to have prostate cancer. Recently, the recommendation of repeat biopsy for PIN alone has been relaxed, such that repeat biopsy may not be recommended and a more personalized approach to follow-up is taken. Age and overall health status must also be considered, and rebiopsy decisions should be individualized.

A recently approved urine test called PCA-3 has become more widely available. This test, performed on voided urine after an "attentive" DRE, is based on reverse transcriptase-polymerase chain reaction assay for a prostate-specific gene (DD3). It is becoming useful not as a primary screening test, but to dictate the need for repeat prostate biopsy in men with persistently elevated PSA levels.

Additional studies are investigating the role of a novel fusion protein (TMPRSS2-ETS) commonly found in prostate tumors, both as a diagnostic and prognostic marker. This fusion gene is androgen-regulated, directs oncogenic signals, and has been found in over 50% of localized prostate cancers. Other markers will need to be employed to detect the 50% of tumors that lack this fusion protein before this test is likely to be useful as a screening tool.

Pathology

Adenocarcinomas

Adenocarcinomas make up the vast majority of prostate carcinomas. A total of 70% of prostate adenocarcinomas occur in the peripheral zone, 20% in the transitional zone, and approximately 10% in the central zone.

Other Tumor Types

Other tumor types are relatively rare and include ductal adenocarcinoma, which occurs in the major ducts and often projects into the urethra; and mucinous adenocarcinoma, which secretes abundant mucin and does not arise from the major ducts. Transitional carcinoma of the prostate occurs within the ducts and, to a lesser extent, in the prostatic acini. Typically, primary transitional carcinomas are aggressive cancers that have a poor prognosis. Similarly, neuroendocrine (small-cell) tumors are rare and aggressive, have a poor prognosis, and typically require aggressive management. Other rare types include foamy carcinoma, mucinous adenocarcinoma, large-cell neuroendocrine tumors, and signet ring tumors.

Histologic Grade

The grading system developed by Gleason from data accumulated by the Veterans Administration Cooperative Urologic Research Group appears to provide the best prognostic information in addition to clinical stage and is the predominant grading system in widespread use. The Gleason system was developed using radical prostatectomy surgical specimans and not modern era needle biopsies. While the original system graded cases from a sum of 2 (best/lowest grade) to 10 (worst/highest grade), the international pathology community held a consensus panel in the last few years and adjusted the reading criteria, given that modern small-core needle biopsy samples are not able to reflect traditional Gleason 2-4 scores. As a result, the vast majority of contemporary Gleason grading is 6 (low/good); Gleason 3 + 4 = 7 (intermediate/low); Gleason 4 + 3 = 7 (intermediate/high); and Gleason 8–10 (high/bad). From a clinical standpoint, this renders the older literature on Gleason grading less useful for current-era patients.

Metastatic Spread

Adenocarcinoma of the prostate may spread locally through direct extension into periprostatic fat or via the ejaculatory ducts into seminal vesicles; lymphatically to regional lymph nodes, including the hypogastric and obturator lymph nodes; and hematogenously to bone. The most common sites of bony metastases are the lumbosacral spine (probably related to venous drainage of the prostate through Batson's plexus) and the axial skeleton, but any bone, including the skull and ribs, can be involved. Rare sites of metastatic spread include the liver and lungs. This physiology forms the basis for staging studies to traditionally include nuclear medicine Tc-99 whole-body bone scans and CT scans of the abdomen and pelvis primarily looking for adenopathy. Most recently, sodium fluoride(Drug information on sodium fluoride) positron emission tomography (PET) bone scanning is starting to replace traditional bone scans at major centers. Also, some, but not all experts favor pelvic and prostate MRI over CT. In particular, prostate MRI with an endorectal coil and/or a 3 Tesla magnet machine is becoming popular for intra-gland and peri-gland imaging but is not universally accepted nor reimbursed. Some experts are using prostate MRI to better select candidates for active surveillance, although this is not yet confirmed by level 1 evidence.

Prognosis and Natural History

TABLE 12010 TNM staging system of prostate cancer

TABLE 22010 TNM staging system of prostate cancer (anatomic stage/ prognostic group)

TABLE 3D'Amico et al risk stratification for clinically localized prostate cancer

TABLE 4Risk of dying of clinically localized prostate cancer without definitive locoregional therapy

Staging Systems

The most widely used and universally accepted staging system for prostate cancer is the TNM system (Table 1). In the TNM system, T1 and T2 tumors are confined to the gland, whereas T3 and T4 tumors have local extension.

In 2010, the AJCC updated prostate cancer staging recommendations in its 7th edition of the AJCC Cancer Staging Manual. These guidelines incorporate a more risk-based approach that utilizes the Gleason grading system and current PSA value in the staging system, which brings this system more in line with the risk-adapted approaches described in this chapter. Additionally, microscopic bladder neck invasion as a form of extracapsular extension was incorporated into T3 disease rather than as T4, given the more favorable outcomes of this subgroup of men. This scoring system is shown in Table 2. Use of either this staging system or the NCCN/D'Amico approach, or a nomogram-based risk assessment will provide a more accurate prognostic classification system for prostate cancer at initial diagnosis.

Risk-Adapted Staging

The development of the "Partin Tables" in 1993 ushered in a new era of combining clinical stage, Gleason score, and PSA level to predict pathologic stage after radical prostatectomy. More recently, this has led to the D'Amico et al risk groupings for newly diagnosed men with clinically localized disease (Table 3). Patients are divided into three risk groups (low, intermediate, or high) of occult micrometastases and relapse after initial local therapy. Although not perfect, this system is currently in widespread use and allows a framework for multimodal and multidisciplinary treatment strategies based on risk grouping. Kattan et al have developed preoperative and postoperative nomograms as clinical tools to predict the risk of recurrence after radical prostatectomy. Although these nomograms are imperfect, they may be useful for estimating risk and planning therapy as well as for stratifying and selecting patients for clinical trials. In addition, Stephenson et al have developed a fairly robust postsurgical nomogram of over 12,000 men that is able to predict with > 80% accuracy 15-year prostate cancer-specific mortality. In this model, Gleason sum, PSA level, and clinical stage were the most important factors in predicting long-term outcome, whereas body mass index and PSA velocity were not able to add to the predictive accuracy of the model. According to the 2010 Guidelines, the NCCN defines as a "very low" risk group men with prostate cancer who have low volume using the Epstein criteria (T1c stage, Gleason < 7, PSA level < 10 ng/mL, fewer than three positive biopsy cores, < 50% cancer in each core, and PSA density < 0.15 ng/mL/g). These patients have a very low risk of prostate cancer death within 10 to 20 years and could be considered good candidates for active surveillance. These criteria are imperfect, and current efforts to improve upon them using nomograms may better help to select men who can safely defer initial aggressive therapy.

Prognosis

The optimal management of patients with prostate cancer varies widely and is highly dependent upon a patient's age, overall health, and tumor risk assessment. The natural history of the disease process can be heterogeneous, ranging from an incidental finding unlikely to result in cancer-specific mortality, to very aggressive disease, resulting in early widespread metastatic disease and death. Therefore, treating physicians should carefully consider the value of curative therapy with potential toxicity in the context of a patient's comorbidities and life expectancy.

Among patients with clinically localized prostate cancer treated conservatively (observation or hormonal therapy alone), those with a low Gleason score (2-4) have a small risk of dying of their cancer within 15 years (4% to 7%). However, those with poorly differentiated tumors (Gleason score 8 to 10) have a greater risk of dying of prostate cancer than of any other cause, even when the cancer is diagnosed in the eighth decade of life. Indeed, a man diagnosed before the age of 60 with a clinically localized, Gleason score 8 to 10 prostate cancer has an 87% risk of dying of the disease within 15 years if untreated (Table 4).

D'Amico et al combined a number of national datasets to report 10-year cancer-specific mortality rates for men undergoing radical prostatectomy or external-beam radiotherapy (EBRT) by this risk grouping and age at diagnosis. These 10-year mortality graphs are useful to counsel contemporary-era men contemplating surgery or radiation therapy. Given recent advances in the treatment of metastatic disease, identifying men at high risk for metastatic disease following local therapy is important, as these agents are incorporated earlier in the disease course.