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ORIGINAL ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 2  |  Page : 279-283

Diagnostic efficacy of free prostate-specific antigen/total prostate-specific antigen ratio for the diagnosis of prostate cancer in low concentration (≤4 ng/ml) and intermediate levels of total prostate-specific antigen (4.01–10.0 ng/ml)


Department of Urology, Hitit University Çorum Training and Research Hospital, Çorum, Turkey

Date of Web Publication23-Jun-2017

Correspondence Address:
Selahattin Caliskan
Bahçelievler Mah. Çamlık Cad. No: 2, Çorum
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.183177

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 > Abstract 

Aim of Study: Serum prostate-specific antigen (PSA) is a useful tumor biomarker for prostate cancer (PCa) diagnosis. In this study, I aimed to compare the free/total PSA (fPSA%) with PSA alone for their usefulness in diagnosis for PCa.
Methods: The patients who underwent prostate biopsy between January 2010 and January 2015 were evaluated retrospectively. Data were expressed as a mean + standard error and P < 0.05 as considered with statistical significance (Med Calc 14.12–2014). The receiver operating characteristic curves were calculated to study the sensitivity and specificity of fPSA and PSA and compared to each other in different PSA levels.
Results: There were 1055 patients in the study. The mean age of the patients was 64.2 + 7.5 and 66.3 + 6.4 years in Groups 1 and 2. The mean PSA and free/total PSA of the patients was 2.79 + 1 ng/ml, 0.2 + 0.08 and 6.49 + 1.59 ng/ml and 0.19 + 0.09 in Groups 1 and 2, respectively. I found the optimal cutoff for fPSA% was ≤18 and ≤14 in Groups 1 and 2 with a sensitivity of 62–45% and specificity of 58–79%. There was a statistical significant difference for fPSA when comparing the area under curve in the PSA level of 4.01–10 ng/ml (P = 0.0009).
Conclusion: In this study, serum fPSA% has advantages for diagnosis of PCa when comparing PSA alone in different levels of PSA. These advantages are significant in PSA level of 4.01–10 ng/ml.

Keywords: Diagnosis, free/total prostate-specific antigen, prostate cancer, sensitivity, specificity


How to cite this article:
Caliskan S. Diagnostic efficacy of free prostate-specific antigen/total prostate-specific antigen ratio for the diagnosis of prostate cancer in low concentration (≤4 ng/ml) and intermediate levels of total prostate-specific antigen (4.01–10.0 ng/ml). J Can Res Ther 2017;13:279-83

How to cite this URL:
Caliskan S. Diagnostic efficacy of free prostate-specific antigen/total prostate-specific antigen ratio for the diagnosis of prostate cancer in low concentration (≤4 ng/ml) and intermediate levels of total prostate-specific antigen (4.01–10.0 ng/ml). J Can Res Ther [serial online] 2017 [cited 2019 Nov 15];13:279-83. Available from: http://www.cancerjournal.net/text.asp?2017/13/2/279/183177


 > Introduction Top


Prostate cancer (PCa) is one of the most common cancers and one of the leading causes of death in industrialized countries.[1] Serum prostate-specific antigen (PSA) is a useful biomarker for PCa screening and monitoring for disease progression of the patients.[2] PSA was firstly detected in 1980 and is responsible for semen liquefaction and secreted into the seminal plasma.[3] In serum, PSA occurs with different isoforms complexed by plasma proteins; 70–90% of PSA is complexed with a1 antichymotrypsin, <5% is bound inter-a-trypsin inhibitor and protein C inhibitor.[4] Some undetectable PSA is complexed a2 macroglobulin and the remaining level of PSA (10–30%) is not bound to serum proteins and is called free PSA (fPSA).

Although PSA testing has become widespread and has shown to be the most useful marker for early detection of PCa, but PSA is not specific for PCa.[4] Despite its adequate sensitivity and limited specificity; which resulted in unnecessary biopsies, use of free/total PSA% ratio has been shown to improve specificity in the detection of PCa.[2]

The aim of this study is to evaluate the sensitivity and specificity of free/total PSA ratio in different PSA levels (≤4 ng/ml and 4.01–10 ng/ml).


 > Methods Top


The patients who underwent transrectal ultrasound-guided prostate biopsy between January 2010 and January 2015 were evaluated retrospectively. The patients' age, levels of free PSA and total PSA, pathological results were recorded. The patients who had insufficient records, total PSA more than 10 ng/ml, older than 80 years, younger than 45 years, dutasteride therapy, radiotherapy, and prostate surgery previously were excluded from the study. All patients had at least eight core prostate biopsy with transrectal ultrasound-guided under left lateral decubitus position. The patients were divided into two groups according to the PSA level. The PSA levels of the patients were ≤4 ng/ml and 4.01–10 ng/ml in Group 1 and Group 2.

Serum tPSA was measured by immunometric assay (Immulite 2000, DPC, Los Angeles, USA). Free PSA levels were analyzed using a solid phase, two-site sequential chemiluminescent assay (Immulite 2000, DPC, Los Angeles, USA). The %fPSA was calculated the ratio of fPSA to tPSA ×100.

The receiver operating characteristic curves were analyzed to assess the diagnostic utility of free/total PSA in different PSA levels (0–4 and 4.01–10 ng/ml). Data were expressed as a mean + standard error and P< 0.05 as considered with statistical significance and Mann–Whitney test was used for comparison of the results (Med Calc 14.12–2014).


 > Results Top


One thousand and fifty-five patients included in the study. Of these patients, 177 and 878 patients' PSA level was 0–4 ng/ml and 4.01–10 ng/ml. The mean age of the patients was 64.2 + 7.5 and 66.3 + 6.4 years in Groups 1 and 2. The mean PSA and free/total PSA of the patients was 2.79 + 1 ng/ml, 0.2 + 0.08 and 6.49 + 1.59 ng/ml and 0.19 + 0.09 in Groups 1 and 2, respectively [Table 1]. Among the 1055 patients, 224 patients were diagnosed with PCa with an incidence of 21.23%. Of these 224 patients, 29 patients (16.38%) and 195 patients (22.20%) were in Groups 1 and 2. Positive predictive values (PPVs) of free/total PSA in groups are seen in [Table 2].
Table 1: Comparison of the groups prostate-specific antigen

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Table 2: Positive predictive values of free/total prostate-specific antigen (free prostate-specific antigen percentage) in groups

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Specificity and sensitivity were 93.92–6.9 when the cutoff for fPSA% ≤10, this parameters were 24.32–82.76 for fPSA% ≤25 in Group 1 [Table 3]. The sensitivity and specificity of PSA are shown in [Table 3]. Although there was no significant differences (P = 0.53) between fPSA% and PSA of area under curve [Table 4], but also area under the curve is bigger in fPSA% than PSA alone.
Table 3: Sensitivity and specificity of free prostate-specific antigen percentage in Groups 1 and 2

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Table 4: Comparision of the free positive predictive values percentage and positive predictive values in Groups 1 and 2

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In Group 2, specificity and sensitivity were 92.40–16.92 when the cutoff for fPSA% ≤10, these parameters were 23.39–87.18 for fPSA% ≤25 [Table 3]. [Table 4] shows the area under curve for fPSA%, PSA and comparison of each parameter. There was a significant difference between fPSA% and PSA for the area under curve analysis (P = 0.0009) [Figure 1].
Figure 1: Receiver operating characteristic analysis of groups

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 > Discussion Top


PCa is the most frequently diagnosed malignancy in men older than 60 years and the second most common cause of cancer deaths after lung cancer in worldwide.[5] The PSA testing is widely used as a screening for the early detection of PCa.[6] However, benign prostate diseases such as benign prostate hyperplasia or prostatitis as well as manipulations of the prostate (catheterization, digital rectal examination, and bicycling) may also cause elevated PSA levels.[3] Despite its adequate sensitivity, the use of PSA testing is limited and free/total PSA ratio has been shown to improve specificity of PCa detection.[2]

The authors have reported that in men with an elevated PSA level, the proportion of free/total PSA (fPSA%) is lower among individuals with PCa than benign prostate diseases.[7] The investigators demonstrated that at the PSA level of 4–10 ng/ml, the proportion of fPSA% significantly improves discrimination between PCa and benign diseases and help identify the need for prostate biopsy and avoid unnecessary biopsies.[2] Partin et al.[8] reported that using the fPSA% ≤15 can detect advanced, nonorgan confined, large volume tumors, and avoides 80% of biopsies in men with insignificant disease in the total PSA of 4.1–10 ng/ml. In a study from Nigerian that included small number of cases (105 patients), the fPSA% ≤15 had a specificity of 100%.[6] Erol et al.[2] reported that fPSA% ≤15 had a specificity of 53, 58.5 and 73.8% in the age of 50–59 years, 60–69 years, and ≥70 years, respectively, in Turkish people with a PSA level of 4–10 ng/ml. Sensitivity of fPSA% ≤15 was 75, 50 and 50 in the age of 50–59 years, 60–69 years, and ≥70 years, respectively.[2] The authors found that optimal cutoff for fPSA% (≤14.78) had a sensitivity of 89.29% and specificity of 54.29% in the patient of PSA >3 ng/ml.[4] Matsuda and Saika [9] demonstrated that the detection rate of PCa in Asian men with a PSA in the gray zone is much lower than men in Western countries. In this study, the optimal cutoff for fPSA% is ≤14 with a sensitivity and specificity of 45.64 and 79.09%. In addition, sensitivity and specificity of fPSA% ≤25 is 87.18 and 23.39 in the present study. Our results are similar with the study of Erol et al.[2] and difference with others.[4],[6] I think that the main reason of difference is the nationality of people and study design. The authors reported that the patients with ≥3 ng/dl of PSA level were included. The upper limit of PSA was not mentioned and mean PSA level was 9.79 ng/dl.[4]

Although there are many studies about the fPSA% for PCa with aPSA level of 4–10 ng/ml, less number of studies investigated the clinical application of fPSA% for PCa diagnosis in men with PSA level <4 ng/ml. For low PSA concentrations <3 ng/ml, the authors demonstrated the risk of PCa detection was 33% when the total PSA level was 2–3 ng/ml and fPSA% is below 10 and men with an fPSA% in the lowest quartile (<14.2) had an almost 7-fold higher PCa risk compared with the highest quartile (>23.7).[10] In another study, the authors reported that the cutoff of fPSA% was ≤24 to detect 90% of cancers and to avoid 18% of benign results in patients with a PSA level of 2.6–4.0 ng/ml.[11] Chang et al.[12] reported that fPSA% was an effective predictor for PCa in patients with PSA level of 4 ng/ml or less.[12] In addition, the authors demonstrated that the sensitivity and specificity were 80 and 81.3% at the cutoff the fPSA% ≤15, specificity increased to 100%, sensitivity decreased to 40% at the level of fPSA% ≤10 in the analysis of 21 patients from Taiwan. The sensitivity was 100% at the cutoff fPSA% ≤20. On the contrary, Stephan et al.[13] revealed that no advantage for the use of fPSA% at the PSA level of 2–4 ng/ml. The 90% sensitivity and specificity cutoff level of fPSA% were 25.3 and 8, respectively, in men with a PSA level of 2–4 ng/ml. The authors from Turkey investigated the sensitivity and specificity of fPSA% ≤10 and ≤25; found the sensitivity of 33.3–41% and 85.7–89.5% specificity of 93.1–95.7% and 46.8–52.4%, respectively.[2] Data from the current study showed that sensitivity and specificity of fPSA% ≤10 were 7 and 94% in Turkish men with a PSA level of 4 ng/ml or less. The fPSA% ≤25 has a sensitivity and specificity of 83 and 24%, respectively. Study results are similar with Erol et al.[2] and I think that this difference from the other studies is a result of study design and number of patients. The study from Taiwan includes 21 patients and other study evaluated the patients with aPSA level of 2–4 ng/ml. We know that percentage of PCa diagnosis is associated with the PSA level. Gilbert et al.[14] reported that the PCa detection rate was 18.67%, 26.52%, and 33.67% in the PSA level of <2, 2–4, and ≤4 ng/ml.

The authors reported that PPV of the fPSA% ≤25 and ≤10 was 84.6% and 100% in patients with a PSA level of 4–10 ng/ml.[6] Yilmaz et al.[15] reported the PPV of fPSA% ≤25 and ≤10 in Turkish men with PSA 2.5–10 ng/ml was 29.1% and 48%, respectively. The current study showed the PPV of the fPSA% ≤25 and ≤10 was 17.26% and 20% and 26.30% and 40% in patients with a PSA level of 0–4 ng/ml and 4.01–10 ng/ml.

The limitations of this study are retrospective design, single institution data, lack of patients' weight of prostate, and rectal examination findings. To my knowledge, this is the first study from Turkey to report the value of fPSA% for the diagnosis of PCa in the low concentration of PSA level (≤4 ng/ml).


 > Conclusion Top


This study showed that fPSA% is superior than PSA alone for the diagnosis of PCa in the level of PSA of 4–10 ng/ml and PSA ≤4 ng/ml. The diagnostic efficacy of fPSA% is more clear in the level of PSA of 4–10 ng/ml than PSA ≤4 ng/ml. Further studies are needed to define the diagnostic efficacy of fPSA% for PCa.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

1.
Nazim SM, Abbas F, Faruqui N, Islam M, Ahmad Z. Validation of updated partin's table in Pakistani patients undergoing radical prostatectomy for prostate cancer. J Cancer Sci Ther 2011;183:1-5.  Back to cited text no. 1
    
2.
Erol B, Gulpinar MT, Bozdogan G, Ozkanli S, Onem K, Mungan G, et al. The cutoff level of free/total prostate specific antigen (f/t PSA) ratios in the diagnosis of prostate cancer: A validation study on a Turkish patient population in different age categories. Kaohsiung J Med Sci 2014;30:545-50.  Back to cited text no. 2
    
3.
Stephan C, Ralla B, Jung K. Prostate-specific antigen and other serum and urine markers in prostate cancer. Biochim Biophys Acta 2014;1846:99-112.  Back to cited text no. 3
    
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Pérez-Lanzac-Lorca A, Barco-Sánchez A, Romero E, Martinez-Peinado A, López-Elorza F, Sanchez-Sanchez E, et al. Correlation between the complex PSA/total PSA ratio and the free PSA/total PSA ratio, sensitivity and specificity of both markers for the diagnosis of prostate cancer. Actas Urol Esp 2013;37:498-503.  Back to cited text no. 4
    
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Memis A, Ugurlu O, Ozden C, Oztekin CV, Aktas BK, Akdemir AO. The correlation among the percentage of positive biopsy cores from the dominant side of prostate, adverse pathology, and biochemical failure after radical prostatectomy. Kaohsiung J Med Sci 2011;27:307-13.  Back to cited text no. 5
    
6.
Ezenwa EV, Tijani KH, Jeje EA, Soriyan OO, Ogunjimi MA, Ojewola RW, et al. The value of percentage free prostate specific antigen (PSA) in the detection of prostate cancer among patients with intermediate levels of total PSA (4.0-10.0 ng/mL) in Nigeria. Arab J Urol 2012;10:394-400.  Back to cited text no. 6
    
7.
Stenman UH, Hakama M, Knekt P, Aromaa A, Teppo L, Leinonen J. Serum concentrations of prostate specific antigen and its complex with alpha 1-antichymotrypsin before diagnosis of prostate cancer. Lancet 1994;344:1594-8.  Back to cited text no. 7
    
8.
Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JI, Pearson JD. Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millennium. Urology 2001;58:843-8.  Back to cited text no. 8
    
9.
Matsuda T, Saika K. Comparison of time trends in prostate cancer incidence (1973-2002) in Asia, from cancer incidence in five continents, Vols IV-IX. Jpn J Clin Oncol 2009;39:468-9.  Back to cited text no. 9
    
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Finne P, Auvinen A, Määttänen L, Tammela TL, Ruutu M, Juusela H, et al. Diagnostic value of free prostate-specific antigen among men with a prostate-specific antigen level of <3.0 microg per liter. Eur Urol 2008;54:362-70.  Back to cited text no. 10
    
11.
Catalona WJ, Smith DS, Wolfert RL, Wang TJ, Rittenhouse HG, Ratliff TL, et al. Evaluation of percentage of free serum prostate-specific antigen to improve specificity of prostate cancer screening. JAMA 1995;274:1214-20.  Back to cited text no. 11
    
12.
Chang CC, Lee YC, Tsai HW, Yii SC, Yen TH, Chu FY. Diagnostic role of serum free-to-total prostate specific antigen (PSA) ratio in prostate cancer with serum total concentration of PSA below 4 ng/mL. Asian Pac J Cancer Prev 2015;16:5261-4.  Back to cited text no. 12
    
13.
Stephan C, Stroebel G, Heinau M, Lenz A, Roemer A, Lein M, et al. The ratio of prostate-specific antigen (PSA) to prostate volume (PSA density) as a parameter to improve the detection of prostate carcinoma in PSA values in the range of <4 ng/mL. Cancer 2005;104:993-1003.  Back to cited text no. 13
    
14.
Gilbert SM, Cavallo CB, Kahane H, Lowe FC. Evidence suggesting PSA cutpoint of 2.5 ng/mL for prompting prostate biopsy: Review of 36,316 biopsies. Urology 2005;65:549-53.  Back to cited text no. 14
    
15.
Yilmaz H, Ciftci S, Yavuz U, Ustuner M, Saribacak A, Dillioglugil O. Percentage of free prostate-specific antigen (PSA) is a useful method in deciding to perform prostate biopsy with higher core numbers in patients with low PSA cut-off values. Kaohsiung J Med Sci 2015;31:315-9.  Back to cited text no. 15
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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