Prostate-Specific Antigen: Any Successor in Sight?
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Diagnostic Review Prostate-Specific Antigen: Any Successor in Sight? Aniebietabasi S. Obort, MSc,1,2 Mary B. Ajadi, MSc,1 Oluyemi Akinloye, PhD, FRSC1,3 1Department of Chemical Pathology, College of Health Sciences, Ladoke Akintola University of Technology, Nigeria; 2Department of Chemical Pathology, University of Uyo Teaching Hospital, Uyo, Nigeria; 3Department of Medical Laboratory Science, College of Medicine, University of Lagos, Lagos, Nigeria Prostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer death in men in the United States and other parts of the world. The lifetime risk of being diagnosed with PCa is approximately 16%. At present, the only widely accepted screening tools for PCa are prostate-specific antigen (PSA) and digital rectal examination. PSA is known to be prostate specific, but not PCa specific, and hence lacks the sensitivity to detect a large number of tumors, especially during the early stages. The PSA level is also known to be affected by many factors, such as medication, inflammation (benign prostatic hyperplasia and prostatitis), and urologic manipulation; hence, the controversy regarding the appropriate level of serum PSA that should trigger a biopsy or have clinical relevance to prostate metastases. Attempts to determine the level of prostate cells in peripheral blood by reverse transcriptase polymerase chain reaction did not significantly improve cancer diagnosis or predict postoperative failure. Therefore, the search continues for a novel biomarker or a panel of markers as well as other possible interventions to improve the use of PSA. This article reviews several possibilities. [ Rev Urol. 2013;15(3):97-107 doi: 10.3909/riu0567] © 2013 MedReviews®, LLC Key words Prostate carcinoma • Prostate-specific antigen • Prostate diagnostic or screening test rostate cancer (PCa), an adenocarcinoma, is the racial and national difference. The highest incidence most common cancer diagnosed in men today. of PCa is seen in North America and Scandinavia, PThe lifetime risk of being diagnosed with PCa especially among black men in the United States is approximately 16%.1 It affects one in nine men (137 per 100,000 per year).4 Each year in the United aged $ 65 years and is a leading cause of cancer- States, approximately 220,000 new PCa cases are related death in men, second only to lung cancer.2,3 diagnosed, and 30,000 men die of the disease.5 The The incidence of the disease presents a remarkable lowest incidence is among Asian men (Japanese, Vol. 15 No. 3 • 2013 • Reviews in Urology • 97 4004170006_RIU0567.indd 97 08/10/13 11:19 AM PSA: Any Successor in Sight? continued 39/100,000; Chinese, 28/100,000) ng/mL became the established level 3.0 ng/mL as the only indication for and men who are vegetarians.6,7 for recommending biopsy, although a biopsy, and excluding the DRE, Emerging data from Africa report it was known that men could have was compared with one in which a an upsurge in the incidence of PCa, cancer with PSA values , 4.0 ng/ PSA of ≥ 4.0 ng/mL, or the presence probably due to the increasing mL and a value . 4.0 ng/mL could of a positive DRE, was the indica- availability of screening facilities in be due to many other factors not tion for a biopsy.17 They identified recent years. PCa has been reported related to prostate metastasis. 430 men with PCa out of the 8612 to be the most common cancer in Thompson and colleagues14 showed men who were screened who had a Nigerian men and constitutes 11% that many cancers are missed with PSA level of $ 4.0 ng/mL or those of all cancers in men.8,9 In South this cutoff, and that earlier medical with positive findings on DRE. Africa, the incidence of invasive intervention may lead to improved The standard PSA reference prostatic malignancy has risen in patient outcome. In men with PCa range of 0.0 to 4.0 ng/mL does not rural black Africans.10 Also, a study whose PSA level was , 4 ng/mL, account for age-related volume from Yaounde, Cameroon, has indi- normal DRE findings were present changes in the prostate that are cated a high age-adjusted incidence in 4% to 9%, whereas DRE findings related to the development of benign rate for PCa.11 PCa is increasingly were positive in 10% to 20%. When prostatic hyperplasia (BPH). In a common and becoming a global the PSA level was . 4 ng/mL, nega- study of 411 black men with PCa, menace. tive DRE results were found in 12% it was reported that 40% of these to 32% of patients, whereas positive cancers would have been missed Prostate-Specific Antigen DRE results were present in 42% using the standard PSA values.18 At present, the only widely accepted to 72%. It was also discovered that Oesterling and associates presented screening tools for PCa are pros- PSA lacks the sensitivity to detect a the concept that age-related refer- tate-specific antigen (PSA) and large number of early-stage tumors, ence ranges would improve cancer digital rectal examination (DRE). because . 15% of men with a nor- detection rates in younger men and Since the PSA test was introduced mal serum PSA level have biopsy- would increase the specificity of into clinical practice in 1986, the proven PCa.14 However, the level PSA testing in older men.19 Using early diagnosis and management of PSA is known to correlate with reference ranges of 0 to 2.5 ng/mL of PCa has been revolutionized and the detection rate of PCa, espe- for men aged 40 to 49 years, 0 to 3.5 much has been learned about the cially in relation to age. Men aged . for men aged 50 to 59 years, 0 to 4.5 strengths and weaknesses of this 50 years have a 20% to 30% possibil- for men aged 60 to 69 years, and 0 assay. In fact, metastases and their ity of having PCa if their PSA level to 6.5 for men aged 70 to 79 years, comorbidities have decreased more is . 4.0 ng/mL. If the PSA level is they reported an overall specific- ity of 95%. These researchers used PSA testing not only helps with early diagnosis, but also assists in a different reference range for assessing the response to therapy, determining tumor progression, black men. With a PSA range of and, in its most controversial role, screening for PCa. 0 to 2 ng/mL for men aged 40 to 49 years, specificity was 93%. A PSA than 75% since the early 1990s, 2.5 to 4.0 ng/mL, a biopsy is likely range of 0 to 4 ng/mL produced a resulting in a higher incidence of to detect cancer in 27% of men. For specificity of 88% for men aged early organ-confined disease.12 PSA levels . 10 ng/mL, the pos- 50 to 59 years, a PSA range of 0 to PSA testing not only helps with sibility of positive biopsy findings 4.5 ng/mL produced a specificity early diagnosis, but also assists in then increases to 42% to 64%.15 of 81% for men aged 60 to 69 years, assessing the response to therapy, To achieve early diagnosis of and a PSA range of 0 to 5.5 ng/mL determining tumor progression, PCa, the upper limit of normal produced a specificity of 78% for and, in its most controversial role, PSA (4.0 ng/mL) has been recom- men aged 70 to 79 years. Using screening for PCa. mended to be lowered. Catalona these reference ranges, Partin and Detection of PCa using a combi- and colleagues observed that 20% colleagues20 detected 74 additional nation of PSA and DRE has been to 30% of tumors will be missed cancers in men aged # 60 years in evaluated by a number of investiga- if the only method of detection a study of 4600 men with clinically tors. The positive predictive value of is serum PSA with a cutoff of localized PCa. Pathology results a PSA . 4.0 ng/mL is only 25% from 4.0 ng/mL.16 A strategy for the early were favorable in men undergoing a pooled meta-analysis of PSA stud- detection of PCa by Schröder and radical prostatectomy (RP); 80% ies.13 Consequently, a value of . 4.0 colleagues using a PSA cutoff of ≥ of these men had organ-confined 98 • Vol. 15 No. 3 • 2013 • Reviews in Urology 4004170006_RIU0567.indd 98 08/10/13 11:19 AM PSA: Any Successor in Sight? disease with a Gleason score of extraprostatic cancer is increased probability of cancer.25,26 Minardi # 7. Using the same ranges for greatly. In the same study, it was and colleagues observed that, men aged . 60 years, , 3% of the noted that 80% of men with PSA although tPSA and fPSA values cancers missed were nonpalpable, levels . 20.0 ng/mL had extra- appeared to be correlated with of which 95% had favorable histol- prostatic disease.20 patient age and prostatic volume, ogy results. The potential detection PSA is prostate specific, but not %fPSA did not show a relation- of PCa increased 18% in younger PCa specific.1 The serum PSA level ship with these parameters. The men and decreased 22% in older can be altered by various medica- specificity, sensitivity, and over- men. Reissigl and Bartsch studied tions, BPH, prostatitis, and uro- all diagnostic accuracy were bet- the effect of biopsy rates and PCa logic manipulations. It can also ter assuming a 16% cutoff value detection using age-specific ranges increase for 24 hours after ejacula- for %fPSA than with other cutoff values.27 A study investigated 113 PSA is prostate specific, but not PCa specific.