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Application of prostate-specific antigen in prostate cancer.

Prostate cancer is the sixth most common cancer in the world and the mosl commonly diagnosed visceral cancer in the United States, representing about 29% of all cancers diagnosed in men each year. In the United States, approximately 218,890 cases are diagnosed annually, and approximately 27,050 men die from prostate cancer. (1) It is the second leading cause of death overall and cancer death in men, next to non-melanoma skin cancer and lung cancer.

For an American male, the lifetime risk of developing prostate cancer is one in six, but the risk of dying from prostate cancer is only one in 33. (1), (2) Many more cases of prostate cancer do not become clinically apparent, as demonstrated in autopsy series, where prostate cancer is identified in one-third of men under the age of 80 and in two-thirds of men older than 80. (3) These data suggest that prostate cancer often progresses so slowly that most men die of other causes before the disease becomes clinically advanced.

Prostate cancer has been detected with increasing frequency, even before the introduction of serum prostate-specific antigen (PSA) testing. The incidence peaked in 1992, declined between 1992 and 1995, and has been rising about 1.1% annually since 1995.' The reasons for the increasing incidence are not known; both genetic and environmental factors have been implicated. Of the several known risk factors, the most important are age, ethnicity, genetic factors, and. possibly, dietary factors. Prostate cancer demonstrates one of the strongest relationships between age and any human malignancy. Prostate cancer rarely occurs before the age of 40, but the incidence rises rapidly thereafter. (1,2) Prostate cancer is more common in black than in white or Hispanic men, perhaps related to a combination of dietary and/or genetic factors. Nevertheless, despite evidence that prostate cancer has a strong genetic component, identifying the genetic and inherited risk factors that underlie the disease has proven more challenging than initially anticipated. Some intriguing work has highlighted certain genes, but results have been inconsistent across studies. A diet high in animal fat could also be a risk factor, while studies have shown that dietary supplement of antioxidants (e.g., lycopene, vitamin E, selenium) may reduce the risk. (1-3) Currently, however, there is no scientific consensus on effective strategies to reduce the risk of prostate cancer.

Prostate-cancer survival is related to many factors, especially the advance of tumor at the time of diagnosis. The 10-year survival among men with cancer confined to the prostate (localized) is 75%, compared with 55% and 15% among those with regional extension and distant metastases, respectively. (4) Bone lesion is the most common metastatic prostate cancer. While men with advanced-stage disease may benefit from palliative treatment, their tumors are generally not curable. As a result, a screening program that could identify asymptomatic men with aggressive localized tumors might be expected to considerably reduce prostate-cancer morbidity, including urinary obstruction and painful metastases, and, hopefully, mortality.

Before PSA was introduced, the diagnosis of prostate cancer was first detected by digital rectal examination (DRE) or because of urinary symptoms (e.g., urinary urgency, nocturia, frequency, and hesitancy). Today, the diagnosis of prostate cancer is most often suspected after finding an elevated serum PSA as a screening test at a routine physical examination. Less commonly, a diagnostic assessment is introduced as a result of abnormal findings on DRE. Prostate biopsy is still considered the gold standard to establish the diagnosis of prostate cancer.

The introduction of PSA testing in the 1980s revolutionized prostate-cancer screening. Although PSA was originally employed as a tumor marker for detecting cancer recurrence or monitoring disease progression following treatment, it became extensively implemented for cancer screening by the early 1990s. Subsequently, professional societies established guidelines supporting prostate-cancer screening with PSA. (5), (6) The application of widespread PSA screening and earlier detection can potentially lead to decrease in prostate-cancer mortality associated with a decline in metastatic disease. PSA-screening testing led to a significant increase in the incidence of prostate cancer, peaking in 1992. (2) The majority of these newly diagnosed cancers were clinically localized, which led to an increase in radical prostatectomy and radiation therapy--aggressive treatments intended to cure these early-stage cancers. (7-10)


PSA is a 27-kD glycoprotein that is produced by prostate epithelial cells and with chymotrypsin-like serine protease activity. Its major function in vivo is to activate the major in-gel proteins, seminogelin I, IT, and fibronectin, in freshly ejaculated semen, which then liquefies semen through proteolytic fragmentation and releases progressively motile sperm. Extensive study in this field over the years has revealed that PSA in serum is present in several molecular forms and that the understanding of the proportions of these PSA forms can aid in the diagnosis of the status for cancer from benign disease. Under normal conditions. PSA is produced as a precursor form (pPSA) by the secretory cells that line the prostate glands (acini) and secreted into the lumen, where the 7-amino acid propeptide is then cleaved by the enzyme--human kallikrein 2-to generate active PSA. This molecule, in turn, undergoes a proteolytic process and become inactive PSA, which then enters the bloodstream and circulates in an unbound state (free PSA). A small amount of active PSA diffuses into the circulation and is covalently bound by protease inhibitors, including alpha-1-antichymotrypsin (ACT) (complexed PSA) and, to a lesser extent, with a0lpha-2-macroglobulin. (11), (12) A higher percentage of free PSA in the serum is correlated with a lower risk of prostate cancer. The ratio of free to total PSA in serum has been demonstrated to significantly improve the differential of prostate cancer from benign prostatic hyperplasia (BPH). (13)

Free (uncomplexed) PSA in serum is now identified as being composed of at least three distinct forms of inactive PSA. One form has been identified as the precursor form of PSA, or pPSA, and is associated with cancer. (12) A second form of PSA, called benign PSA (BPSA), is an internally cleaved or degraded form of the active PSA that is more highly associated with BPH. (12) The third PSA form is known to be an intact, denatured PSA that is similar to native, active PSA, except for changes in structure or conformation that render the molecule enzymatically inactive. The association of this form with prostate cancer is still largely unknown.

pPSA. Studies have revealed that there are a number of minor variants for pPSA. In addition to the intact pPSA, there are also significant levels of truncated pPSA, which refer to pPS A in which any length of the first seven amino acids in the proleader peptide have been removed. The truncated pPSA forms containing proleader peptides of four and two amino acids, [-4]pPSA and [-2JpPSA, respectively, are of particular interest. Truncated pPSA forms are more resistant to activation to mature PSA than the intact pPSA with the 7-aa proleader peptide. (13) The truncated pPSAforms are, therefore, more stable since they cannot be converted to active PSA. The sum or all pPSA forms represents about a third of the free PSA typically present in cancer scrum. (13)

BPSA. Studies have also demonstrated that there is another isoform of PSA in BPH tissues and seminal plasma, which has been demonstrated to have higher degree of internal peptide bond cleavages and is more enzymatically inactive. (13) The distinct degraded form of PS A, BPSA, has been identified in BPH tissue. BPSA concentrations were relatively lower in cancer tissue from the same prostate. (13) BPSA is highly associated with the presence of BPH nodules in the prostate, the primary pathological feature of BPH. (13) BPSA contains two internal peptide bond cleavages at Lys 145 and Lys 182, while native PSA and pPSA contain no internal cleavages. BPSA has no known natural function in the prostate and is considered to result from post-translational cleavage by proteases in the hyperplastic BPH tissue. BPSA-specific immunoassays have been developed, and BPSA has been shown to be significantly elevated in the serum of biopsy-negative men with elevated PSA. (13) BPSA is detected in seminal plasmal3 and can range from 0% to 50% in individual seminal-plasma specimens, which suggests that BPSA formation changes as a function of biochemical processes in the transition zone of the prostate gland.

Although producing less PSA per cell than normal tissue, prostate cancer causes the disruption of the basement membrane, basal cells, and normal lumen architecture. This mechanism has caused the secreted pPSA and several truncated forms to have direct access to the circulation; and as a result, a larger fraction of the PSA generated by malignant cells escapes the proteolytic processing (i.e., activation of pPSA to active PSA and degradation of active PSA to inactive PSA).

In men with a normal prostate, the majority of free PSA in the serum reflects the mature protein that has been inactivated by internal proteolytic cleavage. In contrast, this cleaved fraction is comparatively decreased in prostate cancer. Therefore, the percentage of free or unbound PSA is lower in the serum of men with prostate cancer (and, conversely, the amount of complexed PSA is higher) compared with those who have a normal prostate or BPH. (14-17) This finding has been exploited in the use of the ratio of free to total PSA and complexed PSA as a means of distinguishing between prostate cancer and BPH as a cause of an elevated total PSA.


Although serum total PSA is a prostate-specific marker, elevations can be caused by both cancer and benign conditions such as BPH. Malignant prostate tissue generates more PSA than normal or hyperplastic tissue, probably because of the increased cellularity associated with cancer. Moreover, malignant prostate tissue may disrupt the prostate-blood barrier, causing more PSA to leak into the circulation and further increasing the serum concentration of total PSA.

The traditional cutoff for an abnormal total PSA level in the major screening studies has been 4.0 ng/mL. (18-21) At this level, the sensitivity of PSA has been estimated to be about 70% to 80%, while the specificity is anticipated to be about 60% to 70%. (22) PSA has poorer discriminating ability in men with prostate cancer and symptomatic BPH, of which both would have elevated total PSA. (23)

The test performance statistic that has been best characterized by screening studies is the positive predictive value: the proportion of men with an elevated PSA who have prostate cancer. Overall, the positive predictive value for a PSA level >4.0 ng/mL is approximately 30%, meaning that slightly less than one in three men with an elevated PSA will have prostate cancer detected on biopsy--the gold standard of diagnosis. (24"26) The positive predictive value is 42% to 64% for PSA levels >10 ng/mL. (25) Prostate biopsy is regularly recommended in men whose serum PSA is > 10.0 ng/mL, since the chance of finding prostate cancer is over 50%. It is also true, however, that more than 50% of these men will have malignancy that is no longer organ-confined, and therefore, not amenable to cure.(24) For PSA levels between 4.0 ng/mL to 10.0 ng/mL, the positive predictive value is about 25%(25); however, nearly 75% of cancers detected within the "gray zone," PSA values between 4.0 ng/mL to 10.0 ng/mL, are organ confined and potentially curable. (24) Thus, detecting the curable cancers in men with PSA levels less than 10.0 ng/mL presents a diagnostic challenge because the high false-positive rate, identified by biopsy result, leads to many unnecessary biopsies and generates anxieties.

PS A is not an ideal biomarker for prostate cancer, so numerous strategies have been proposed to improve the diagnostic performance of PSA when levels are less than 10.0 ng/mL, including lowering PSA cutoffs, serial measurements, and alternatively processing PSA data (e.g., PSA velocity [change in PSA over time], PSA density [PSA per unit volume of prostate]). None of them, however, can resolve the controversy of PSA as a screening test and fulfill the significant current clinical diagnostic needs due to its low specificity for prostate cancer. Therefore, the scientific community is still searching for the ideal and novel biomarkers for early detection in prostate cancer.


The use of multiple-marker panels has been proposed for many years in the search for improved clinical utility of tumor markers. With the rapid development of mass spectrometry, it is possible that proteomic technologies may also help to lead to a new frontier of multiple-analyte testing or multiplexed assays, to achieve significant new insights into prostate-disease management.


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By Shu-Ling Liang, PhD, DABCC

Shu-Ling Liang, PhD, DABCC, is an instructor in pathology at Harvard Medical School, and the assistant director of clinical chemistry in the department of pathology at Beth Israel Deaconess Medical Center in Boston, MA. See related product information beginning on page 62.
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Title Annotation:SPECIAL FEATURE
Author:Liang, Shu-Ling
Publication:Medical Laboratory Observer
Geographic Code:1USA
Date:Oct 1, 2008
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