The PSA is a 240-amino acid serine protease that belongs to the larger family of glandular kallikreins. It was isolated by both Wang and Graves separately in 1979 [6, 7]. It was initially investigated as a marker for detecting semen in cases of rape. In 1987, in an attempt to see if a link existed between elevated PSA levels and adenocarcinoma of the prostate, PSA levels were measured in 2200 samples taken from 699 patients and were found to be elevated in 122 out of 127 patients with newly diagnosed prostate cancer. PSA levels fell following treatment with radical prostatectomy, and rising PSA levels after surgery were associated with recurrence of the disease [8].

Within a few years, the feasibility of using PSA as a screening test for prostate cancer was investigated in 1653 healthy men aged 50 years or greater. Using a cutoff value of greater than or equal to 4.0 micrograms/liter (mcg/l), men with an elevated PSA underwent digital rectal examination (DRE) and transrectal ultrasound (TRUS) of the prostate with biopsies done in men with abnormal DRE or TRUS. In the 107 men with a PSA of 4.0–9.9 mcg/l, 85 required biopsy (85/107, or 79 %) and 19 of those were diagnosed with prostate cancer (19/85, or 22 %). In the 30 men with a PSA above 10, 27 required biopsy (27/30, or 90 %) and 18 had prostate cancer (18/27, or 67 %) (Fig. 14.2). The authors noted that “Our results provide no information about the value of serum PSA measurement with respect to morbidity and mortality” and concluded that the results “suggest that measurement of serum PSA and rectal examination combined, with the addition of ultrasonography in patients with abnormal findings, will provide a better method of detecting prostate cancer than rectal examination alone.” [9] Despite this, about 95 % of male urologists and 78 % of male primary care physicians older than 50 years report that they have had a PSA test themselves [10].

In 2012, results of the US-based Prostate, Lung, Colorectal, and Ovarian screening trial (PLCO) were published. Over 76,000 men aged 55–74 years, including 4 % African Americans and 7 % with a family medical history of prostate cancer, were randomized to no screening or screening with annual PSA for 6 years and annual DRE for 4 years and followed for 13 years. Of note, the degree of contamination, defined as the percentage of men in the control group who received screening, reached 50 % by year 6. The incidence of prostate cancer was nonsignificantly higher in the screened group (11 % versus 9.9 %), and mortality was nonsignificantly lower in the screened group (0.38 % versus 0.41 %). The authors concluded that there was no mortality benefit seen from combined screening [24].

In the same year, the results of the European Randomized Study of Screening for Prostate Cancer (ERSPC) were also published. This study, conducted in 7 countries in Europe, included over 180,000 men aged 55–69 years. Men were randomized to either PSA every 4 years or no screening and patients were followed for 11 years. The degree of PSA screening contamination was lower than in PLCO at 20 %. The incidence of prostate cancer was significantly higher in the screened group (9.6 % versus 6 %) and mortality was significantly lower in the screened group (0.41 % versus 0.52 %). This corresponds to a 20 % relative risk reduction and an absolute risk reduction of seven prostate cancer deaths for 10,000 men screened [25]. It is important to note that both the PLCO and the ERSPC trials included a predominance of white men, which may negatively bias the impact and predictive value of screening African American men, who have the highest statistical risk of developing and dying from prostate cancer.

In 2013, a Cochrane review including five randomized controlled trials and over 340,000 men addressed whether prostate cancer screening reduced prostate-specific mortality or all-cause mortality and whether it had an impact on quality of life or adverse events. The authors concluded that prostate cancer screening did not significantly reduce prostate cancer-specific or overall mortality. Furthermore, harms associated with screening and diagnosis were frequent and moderate in severity and there were also harms associated with treatment. Only screening with PSA was assessed in the review; no evidence of the utility and limitations of DRE or other tests were studied [18].

Taken together, these two large trials and Cochrane review suggest that screening for prostate cancer with serial PSA testing has only a modest reduction in prostate cancer mortality during the first 10 years of initiating such screening. However, both the costs and the risks associated with overdiagnosis of prostate cancer are substantial.

Characteristics of ideal screening programs include [26]:

In general, prostate cancer screening programs with PSA testing meets the first and third criteria of an ideal screening program. No studies to date have evaluated the effect of PSA screening on the development of subsequent metastatic disease, so the primary outcome that has been evaluated is reduction in prostate cancer-specific mortality. Based upon the results of the PLCO and ERPSPC trials, there is adequate evidence that the benefits of PSA screening and subsequent early treatment are a reduction of 0–1 deaths for every 1000 men screened and an estimated diagnosis of 1 case of prostate cancer in every 1470 men screened [3].

When a man is told that his PSA test is abnormal, it is often associated with negative psychological effects such as excessive worry about prostate cancer itself, the effects of treatment, and the impact on his life and his family [27], although the magnitude of these effects has not been measured [28]. Transrectal ultrasound (TRUS)-guided biopsy of the prostate, the diagnostic test of choice, is also associated with a number of side effects, such as pain, fever, urethral and rectal bleeding, infection, transient urinary tract symptoms, and, in 1 % of patients, hospitalization due to pain and/or sepsis [29, 30]. The risk of a false-positive PSA test is substantial. In the PLCO trial, there was a 12.9 % cumulative risk of at least one false-positive PSA test after four screening tests [24]. In the Finnish center of the ERPSC trial, 12.5 % of men had at least one false-positive result after three rounds of PSA testing [25]. Conversely, false-negative results also occur, and there is no absolute PSA level below which prostate cancer cannot occur.

In the United States, approximately 9 out of every 10 men diagnosed with localized prostate cancer opted for treatment [31], typically radical prostatectomy and radiation, and these treatments are associated with a number of side effects. In the 2012 United States Preventive Services Task Force (USPSTF) final recommendation statement, it was estimated that there is a 20 % increase in absolute risk of urinary incontinence and a 30 % increase in absolute risk for erectile dysfunction among men who were treated with a radical prostatectomy. The absolute risk of urinary incontinence was estimated to increase by 17 % among men treated with radiation [3]. Thus, the USPSTF recommendation was changed to a D category recommendation, citing that PSA-based prostate cancer screening causes harm. The USPSTF summarized the population-based risks and benefits of prostate cancer screening in the same recommendation statement. They assumed PSA testing every 1–4 years in men at average risk for developing prostate cancer who were aged 55–69 years old and who were followed for 10 years (Table 14.1).

A number of national organizations have published recommendations for prostate cancer screening. This section will discuss recommendations from the United States Preventive Services Task Force (USPSTF) , the American Urological Association (AUA) , the American Cancer Society (ACS) , and the American College of Physicians (ACP) .

The 2012 USPSTF recommends against PSA-based screening for prostate cancer (grade D). The authors noted that “all men deserve to know what the science tells us about PSA screening: there is a very small potential benefit and significant potential harms.” If patients specifically request PSA screening, the USPSTF recommends that men should be given sufficient information about the relative benefits and harms in order to make an informed choice [3]. The American Academy of Family Physicians (AAFP) endorses the USPSTF statement [32].

The AUA clinical practice guideline for early detection of prostate cancer was updated in 2013. The expert panel recommends against screening any men under the age of 40 years, noting that in this population the incidence of prostate cancer is very low, there is no compelling evidence of the benefit of screening, and the harms of screening are likely high. Similarly, low-risk men (e.g., non-African American and no family history of prostate cancer) between the ages of 41 and 54 years should not be screened, but high-risk men should have individualized discussions about screening. Using the same projected morbidity and mortality data as the USPSTF, the expert panel recommends that men aged 55–69 have a screening strategy that involves “shared decision making” with their physician and incorporates a man’s “values and preferences.” Finally, the AUA does not recommend prostate cancer screening for men aged 70 years or older or men with a life expectancy of less than 10–15 years. The recommended screening test, if used, is PSA with a 2-year testing interval preferred over an annual test [19].

The ACS clinical practice guideline for prostate cancer screening was last updated in 2010. The ACS recommends that discussions about screening should occur at age 50 years for average-risk men, 45 years for moderate-risk men (African American and/or one first-degree relative diagnosed with prostate cancer prior to age 65 years), and 40 years for high-risk men (two or more first-degree relatives diagnosed with prostate cancer prior to age 65 years). Men with a life expectancy of less than 10 years and men older than 70 years of age and older should not be screened, regardless of risk category. As with the AUA guideline, the ACS recommends that men must be made aware of the risks and benefits of prostate cancer screening and be allowed to make an informed decision. Screening, if performed, should be done with a PSA test. DRE may be considered in conjunction with PSA, but the value is likely low. If the PSA is less than 2.5 ng/mL, it can be repeated in 2 years; if the PSA is 2.5–3.9 ng/mL, it should be repeated in 1 year; and if the PSA is 4 ng/mL or higher, the man should be referred to a urologist for consideration of prostate biopsy [33].