The penis, testes, epididymis, vas deferens, seminal vesicles, and the prostate comprise the male genital tract. Circulating markers have been identified for prostate cancer and testicular cancer. For that reason, a discussion of these tumors and their serum markers is presented in this chapter (Table 19–1). Also, laboratory tests are often used in evaluating men with gonadal dysfunction and men who may be subfertile, infertile, or sterile. A summary of these tests and their usage is also provided. The male genital tract is the site of many infectious diseases, a significant proportion of which are sexually transmitted. These are discussed in Chapter 5.

Description

Prostate cancer is a common malignancy of men that increases in incidence with age. It is second only to nonmelanoma skin cancer as the most commonly diagnosed cancer in men (over 150 cases/100,000 men), and second only to lung cancer as the most common cause of cancer death in males. However, most cases are slowly progressive and do not cause major morbidity or lead to death. A major unresolved challenge is differentiating the rapidly progressive and fatal form of prostate cancer from the indolent forms that do not cause death. Mortality associated with the disease has been decreasing. This has been attributed by some to early detection, although a systematic review of published studies has shown no consistent difference in prostate cancer mortality between those who have and those who have not been screened for the disease. The use of laboratory assays to measure the serum prostate-specific antigen (PSA) concentration, however, has had the greatest impact on increased detection of this cancer.

Prostate-specific Antigen

PSA is a serine protease enzyme (also called human kallikrein 3) synthesized almost exclusively by the prostate and secreted into the seminal fluid. A small amount is also found in the blood. In the blood, PSA is largely bound to enzyme inhibitor proteins such as alpha₁-antichymotrypsin and alpha₂-macroglobulin. A small fraction of circulating PSA is free (unbound).

PSA levels in blood generally correlate with the size of the prostate. The larger the gland, the higher the PSA value. PSA may also increase transiently after a vigorous rectal examination, and after prostate biopsy or surgery. Inflammation and infarction of the prostate can also cause increased PSA, which returns to normal gradually. It is therefore recommended that elevated PSA levels should be confirmed by repeat measurement (at least 2-3 months apart) before any other action is taken, to exclude 1 of these insignificant causes of high PSA.

Prostate disease is common in men after the age of 50 years, and by age 70 years the majority of men have prostate disease. The 2 major diseases of the aging prostate are prostate carcinoma and benign prostatic hyperplasia (BPH). A number of factors have been evaluated to try to distinguish between these causes of increased prostate size and/or increased PSA levels. Both prostate cancer and BPH contribute to elevations in serum PSA.

In most laboratories, the PSA threshold considered positive for cancer screening is >4 ng/mL; above that threshold concentration, the positive predictive value for prostate cancer (the likelihood that cancer will be found in a biopsied prostate gland) is about 30%. In general, PSA is increased to a greater extent in prostate cancer than in BPH; PSA is rarely >20 ng/mL in BPH, and in only about 10% of cases is it >10 ng/mL, so higher values suggest cancer. A high PSA in a man with a small prostate gland on rectal examination is more worrisome for cancer than a similar PSA value in a person with a very large gland. The ratio of free PSA/total PSA may be a better diagnostic marker for prostate cancer than total PSA; in general, a lower proportion of free PSA is found in patients with prostate cancer, but there is a wide overlap in values.

PSA has been used for several purposes related to prostate cancer: screening (testing in persons without symptoms or signs of disease), prediction of the course of disease, prediction of the stage of disease, and follow-up after treatment. The most controversial use of PSA measurements is in screening. Two large randomized trials have been published with long-term outcomes of prostate cancer screening. The US Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial showed no effect on cancer-specific or all-cause mortality after 10 years. The European Randomized Study of Screening for Prostate Cancer found that screening was associated with reduced cancer-specific mortality in men aged 55 to 69 years after 9 years of follow-up; to prevent 1 cancer death, 1400 men would need to be screened and 48 treated.

Because of the side effects of diagnostic biopsy and complications of treatment of prostate cancer and the minimal, if any, survival benefit from prostate cancer screening, in 2012, the US Preventive Services Task Force recommended that men not be screened for prostate cancer. Guidelines for prostate cancer screening from other professional groups, including the American Urological Association (AUA) and the American College of Physicians (ACP), recommend individual decision making with information provided to the patient about both potential risks and benefits, and that screening might be reasonably offered to men between ages 50 (for the ACP) or 55 (for the AUA) and 69.

It should be noted that PSA is not highly sensitive for detecting cancer. It is estimated that only about 50% to 60% of those with localized and potentially curable cancer have increased PSA, and recent studies have found that many patients with less well-differentiated prostate cancers actually have PSA values as low as 1 ng/mL.

Limited evidence suggests that the rate of rise in PSA can predict more aggressive cancers. A review of published studies found that men with more rapid rises in PSA (a rise >0.35 ng/mL per year, 10 years before a definitive diagnosis, or a rise >2 ng/mL in the year before a definitive diagnosis) were far more likely to have recurrence after surgery and to die from cancer than those with more slowly rising PSA. In men who have decided to not have surgery, the rate of rise of PSA was also found to be predictive; if the PSA doubling time was less than 3 years, the likelihood of locally progressive disease was high, while it was very low for those whose PSA increased less than 2-fold over 10 years. More studies will be needed to confirm these findings and to determine whether this information can be useful in determining treatment.

PSA measurement is of some use in the initial staging of a patient with prostate cancer. In general, the higher the PSA, the less likely that cancer is localized to the prostate and the more likely that it has spread. Distant metastases are rare in persons with PSA <20 ng/mL, so performance of imaging studies of bone (the most common site of metastasis) for preoperative staging of cancer has little benefit in those with lower PSA values.

The most widely accepted use of PSA is to monitor patients after treatment. Since about 99% of prostate cancers produce PSA, and since PSA is made almost solely in the prostate, successful surgical removal of the gland (and cancer) should result in a serum PSA less than 0.1 ng/mL by 3 months after surgery. Failure of PSA to become undetectable indicates residual cancer that was not removed by surgery. With recurrence of cancer, PSA levels increase up to a year and a half before clinical evidence of recurrent cancer, allowing treatment of persons with rising PSA before their clinical condition deteriorates. With radiation therapy, PSA typically will fall to normal (usually to <1 ng/mL by 1 year after completion of radiation) with successful treatment, but will usually not be undetectable. Because prostate cancer responds to androgens, removal of the testes and the use of drugs that block androgen production are widely used to treat metastatic prostate cancer. The production of PSA is androgen dependent. Rarely, PSA levels will fall dramatically with androgen deprivation even though there is little or no change in the amount of tumor. In most cases, though, PSA is a reliable marker of tumor response to androgen deprivation as a treatment for prostate cancer.

Description