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GENITOURINARY CANCER SYMPOSIUM: ORIGINAL ARTICLE
Year : 2014  |  Volume : 51  |  Issue : 3  |  Page : 335-337
 

Low free to total PSA ratio is not a good discriminator of chronic prostatitis and prostate cancer: An Indian experience


1 Department of Laboratory Medicine, Clinical Biochemistry Lab, New Delhi, India
2 Department of Urology, Batra hospital and Medical Research Center, New Delhi, India

Date of Web Publication10-Dec-2014

Correspondence Address:
V Thakur
Department of Laboratory Medicine, Clinical Biochemistry Lab, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.146790

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 » Abstract 

Aims: To find out the utility of free to total PSA ratio in discriminating chronic prostatitis and prostate cancer. Setting and design: The patients visited urology clinics at Batra Hospital and Medical Research Center, New Delhi. Background: The use of serum free to total PSA as a diagnostic tool for prostate cancer has led to early detection of prostate cancer; however, the effect of inflammation on f/t PSA ratio restricts its use in early detection of cancer. Materials and Methods: The study was conducted in age related 101 patients which include 27 carcinoma patients (group I), 34 BPH patients (group II) and 40 chronic prostatitis patients (group III). Serum total PSA (tPSA) and free PSA (fPSA) were analyzed on Elecsys 2010. These were compared with histological reports of biopsy specimen. Other biochemistry tests were done on Randox Imola. P Value was calculated using one way ANOVA with posthoc Bonferroni analysis. Results: Serum total PSA levels were comparable in group I and III and were higher than group II (P < 0.049). Serum fPSA in group I was not significantly different from group II and III, However, group II has higher levels than group III (P < 0.035). Difference was significant for f/t PSA ratio in group I and II (P < 0.00) and group II and III (P < 0.000).Group I and III were with comparable levels (P < 0.807). Conclusions: f/t PSA ratio is not a good discriminator for malignancy and chronic prostatitis. This limitation of f/t PSA ratio must be taken into consideration while interpreting the results clinically.


Keywords: Prostate cancer, chronic prostatitis, benign hyperplasia, discriminator


How to cite this article:
Thakur V, Talwar M, Singh P P. Low free to total PSA ratio is not a good discriminator of chronic prostatitis and prostate cancer: An Indian experience. Indian J Cancer 2014;51:335-7

How to cite this URL:
Thakur V, Talwar M, Singh P P. Low free to total PSA ratio is not a good discriminator of chronic prostatitis and prostate cancer: An Indian experience. Indian J Cancer [serial online] 2014 [cited 2019 Sep 21];51:335-7. Available from: http://www.indianjcancer.com/text.asp?2014/51/3/335/146790



 » Introduction Top


PSA is a 28.4 kDa glycoprotein that contains 237 amino acids. It is known that increase in serum total PSA is found in malignant as well as benign conditions like benign hyperplasia (BPH) and prostatitis. This rise in serum PSA concentration is found in acute and chronic prostatitis although the elevation is higher in acute prostatitis. [1],[2] This lack of specificity of total PSA and availability of PSA in its molecular forms led to utilization of free to total PSA ratio in differential diagnosis of benign and malignant conditions of prostate gland. The utility of ratio in differential diagnosis of BPH and carcinoma has already been reported by us. [3] We have found 0.16 as the best cutoff ratio for the discrimination of malignant and benign disease. [3] Present study describes the role of f/t PSA ratio in differential diagnosis of chronic prostatitis and prostate carcinoma. The increase in serum PSA in chronic prostatitis patients has earlier been studied. Chronic prostatitis is essentially the chronic inflammation of the prostate gland. It is assumed that PSA is leaked out of acini due to inflammation and responsible for the increase in its serum levels. [4]

There are only few reports available in literature describing utility of f/t PSA ratio in differential diagnosis of carcinoma and chronic prostatitis. Klaus et al. have reported low free to total PSA ratio (0.1) in chronic prostatitis patients, however, the reasons for this change has not been described by them. [5]


 » Materials and Methods Top


The study was conducted on 101 age related male patients (mean age 66.0 ΁ 10.77 years S D) having complaints of lower urinary tract symptoms (LUTS). The patient population was divided into three groups, group I with 27 patients of prostate carcinoma (26.7%, mean age 70.5 ΁ 10.5 years), group II with 34 BPH patients (33.66% mean age 65 ΁ 10.5 years) and 40 chronic prostatitis patients in group III (39.6%, mean age 63.6 ΁ 10.2 years). Digital Rectal Examination (DRE), Transrectal Ultrasound (TRUS) and Uroflowmetry were performed on these patients. Blood samples were collected in plain tubes before any manipulation of prostate for tumor markers. Serum total PSA and free PSA were analyzed on Elecsys 2010 automated analyzer. Free to total PSA ratio was calculated. Routine urine analysis and blood biochemistry like plasma glucose, serum kidney function tests were done in all these patients. Biochemistry was performed on Randox RxL Imola autoanalyser. Urine culture and semen culture were sent for the patients suspected of prostatitis.

Methods

The serum total PSA and free PSA were analyzed on Roche 2010 Electrochemiluminiscence analyser. To avoid any possible errors caused by the release of PSA from the prostate gland following manipulative procedures, all blood samples of these patients were drawn before carrying out any invasive procedure. The drawn samples were processed immediately.

The assay is based on sandwich principle where samples having tPSA or fPSA, a biotinylated monoclonal PSA or fPSA-specific antibody and a monoclonal PSA or fPSA specific antibody labeled with a ruthenium complex react to form a sandwich complex. After addition of streptavidin-coated microparticles, the complex becomes bound to solid phase via interaction of biotin and streptavidin. The concentration of analyte is measured by photomultiplier on induction of chemiluminiscent emission from the reaction mixture, which is aspirated into the measuring cell where the micro particles are magnetically captured onto the surface of the electrode. Application of a voltage to the electrode induces chemiluminiscent emission.

Chronic prostatitis was diagnosed on the basis of Lower Urinary Tract Symptoms (LUTS), prostatic tenderness on DRE, pelvic pain, pyuria and positive semen culture. The patients with positive urine or semen culture were put on the antibiotics for four weeks. Repeat urine or semen culture was sent to the laboratory on completion of the course of antibiotics. Patients with negative urine or semen culture and post treatment high serum PSA were subjected to TRUS guided biopsy. The disease was proved histological on TRUS guided biopsy specimen. Random biopsies from various zones of prostate gland were taken under the guidance of TRUS. TRUS guided biopsy was performed using 3 D Voluson 730 expert ultrasound machine (GE healthcare, USA) having endorectal probe with the prostate biopsy guide (18 gauge diameter and 25 cms length). Twelve cores of biopsy, 6 each from right and left lobe, were taken in all the patients irrespective of hypo, iso or hyperechoic area however special attention was given to any hypoechoic area present.

Final diagnosis in Group I and II patients was done by histological examination of prostate specimens from transurethral prostate resection or prostatectomy. Serum free to total PSA ratio was correlated with DRE, TRUS and histological findings.

Statistical analysis

One way ANOVA with posthoc Bonferroni analysis was used to calculate the P value. P value < 0.05 was considered as statistically significant.


 » Results Top


The mean concentration of tPSA was 15.9 ΁ 10.17 ng/mL, 9.63 ΁ 6.25 ng/mL and 12.86 ΁ 12.09 ng/mL (Mean ΁ SD) in group I, II and III respectively. Group I had significantly higher PSA levels than group II (P < 0.049) but comparable levels with group III (P < 0.652). No significant difference was found in serum total PSA levels in group II and III (P < 0.518). Mean fPSA concentrations were 1.53 ΁ 0.83 ng/mL, 2.18 ΁ 3.0 ng/mL and 1.06 ΁ 0.66 ng/mL in group I, II, III respectively. fPSA concentration in group I was comparable to II and III. It was significantly higher in group II than group III patients (P < 0.035). F/t PSA ratio was significantly different in group I and II (P < 0.00) and group II and III (P < 0.000) however group I and III had the comparable levels (P < 0.807) [Table 1].
Table 1: tPSA, fPSA concentrations and its ratio in group I, II, III patients


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The sensitivity and specificity of ratio was calculated at different cutoff [Table 2]. The sensitivity of the test was increased with increase in ratio cutoff whereas specificity was decreased. In this patient series, the best cutoff was of 0.12, at which sensitivity of the test was 70.37% and specificity was 50.0%.
Table 2: The sensitivity and specificity of ratio calculated at different cutoff


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 » Discussion Top


Prostate specific antigen is a widely accepted serum marker for early detection and monitoring of patients with prostate cancer because elevated levels are found in carcinoma prostate. [6] The serum PSA elevations also occur in benign conditions such as BPH and prostatitis. [2] The manipulation of prostate gland can also give rise to PSA elevations. [7] These benign causes of PSA elevations reduce the sensitivity of the test. To increase the sensitivity of the test, the determination of the molecular forms of the PSA was found to be advantageous. According to Ornstein et al., in serum, immunoreactive PSA exists predominantly in bound form, which is bound to enzyme inhibitor a -1- antichymotrypsin, with a small fraction existing as free PSA. [8],[9] We have documented the utility of free to total PSA ratio in differential diagnosis of carcinoma and BPH in our earlier report, [3] in which we found 85% sensitivity and 67% of specificity for f/t PSA ratio at 0.16 or 16% cutoff. The increase in ratio cutoff thereafter reduced the specificity of the test with no change in sensitivity. It is a known fact that f/t PSA ratio is low in cancer patients however biological reason behind this fact is not known. [10] According to Lilja, prostate cancer produces predominantly complexed PSA resulting in lowering of ratio. [11] The chronic inflammation affects the release of PSA from prostate tissue. There are studies available in literature describing the effect of prostatic inflammation as a significant factor in elevation of total PSA in prostatitis patients. [12] Neal et al. have evaluated the effect of prostatitis on the secretion of PSA in primates. Their data show a rapid rise in PSA between 5-7 days after inoculation of cynomolgus monkeys, induced with bacterial prostatitis. The PSA returned to baseline levels in approximately 8 weeks. [2] After induction of prostatitis, the rapid rise in PSA results in lowering of f/t PSA ratio. Klaus et al. have shown low ratio, calculated as percent free PSA, in chronic prostatitis patients and therefore found this parameter as unspecific means to differentiate carcinoma, BPH and chronic prostatitis. They did not describe the molecular mechanism for this. [5] Our findings are corroborating with these studies. We have found low f/t PSA ratio in chronic prostatitis and carcinoma patients.

It is assumed that inflammation can cause increase in total PSA possibly due to leakage of it from acini. Increased PSA are found when glandular epithelium is disrupted. This increase in total PSA subsequently reduces the ratio. [4] The increase in total PSA in inflammation could also be due to the excess production of a-1-antichymotrypsin, which is required for the production of bound PSA. Bjork et al. have suggested that like, a tumor cell, more a-1-antichymotrypsin is produced in inflammation cells also. Its production is typical to inflammation. [13] In contrast to this, Christensson et al. have suggested that changes in the percentage of free PSA are not related to overproduction of a-1-antichymotrypsin, which is mainly produced in liver and circulates in the blood at 10 4 to 10 5 fold molar excess as compared to PSA. [14] Whatever the reason behind this mechanism might be, this limitation of f/t PSA ratio in cancer detection poses a need of better tumor marker for differential diagnosis of cancer.


 » Conclusions Top


The f/t PSA ratio might be a better parameter for differentiation of carcinoma from BPH, its utility in diagnosis of chronic prostatitis is compromised due to its similar behavior in chronic prostatitis and prostate cancer. This limitation of the test must be taken into consideration while interpreting the results for clinical use.

 
 » References Top

1.
Stamey TA, Yang N, Hay AR, Mc Neal JE, Freiha FS, Redwine E. Prostate specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987;317:909-16.  Back to cited text no. 1
    
2.
Neal DE Jr, Clejan S, Sarma D, Moon TD. Prostate specific antigen and prostatitis. I. Effect of prostatitis on serum PSA in the human and nonhuman primate. Prostate 1992;20:105-11.  Back to cited text no. 2
    
3.
Thakur V, Singh PP, Talwar M, Mukherjee U. Utility of free/total prostate specific antigen (f/t PSA) ratio in diagnosis of prostate carcinoma. Dis Markers 2004;9:287-92.  Back to cited text no. 3
    
4.
Irani J, Levillain P, Goujon JM, Bon D, Dore B, Aubert J. Inflammation in benign prostatic hyperplasia: Correlation with prostate specific antigen value. J Urol 1997;157:1301-3.  Back to cited text no. 4
    
5.
Jung K, Meyer A, Lein M, Rudolph B, Schnorr D, Loenings A. Ratio of free to total Prostate Specific Antigen in serum cannot distinguish patients with prostate cancer from those with chronic inflammation of the prostate. J Urol 1998;159:1595-8.  Back to cited text no. 5
    
6.
Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ, et al. Measurement of prostate specific antigen in serum as a screening test for prostate cancer. N Engl J Med 1991;324:1156-61.  Back to cited text no. 6
    
7.
Yuan JJ, Coplen DE, Petros JA, Figenshau RS, Ratliff T, Smith DSL, et al. Effects of rectal examination, prostatic massage, ultrasonography and needle biopsy on serum prostate specific antigen levels. J Urol 1992;147:810-4.  Back to cited text no. 7
    
8.
Ornstein DK, Smith DS, Humphrey PA, Catalona WJ. The effect of prostate volume, age, total prostate specific antigen level and acute inflammation on the percentage of free serum prostate specific antigen levels in men without clinically detectable prostate cancer. J Urol 1998;159:1234-7.  Back to cited text no. 8
    
9.
Lilja H, Christensson A, Dahlen U, Matikainen MT, Nilsson O, Petterson K, et al. Prostate specific antigen in serum occurs predominantly in complex with a-1-antichymotrypsin. Clin Chem 1991;37:1618-25.  Back to cited text no. 9
    
10.
Ornstein DK, Rao GS, Smith DS, Ratliff TL, Basler JW, Catalona WJ. Effect of digital rectal examination and needle biopsy on serum total and percentage of free prostate specific antigen levels. J Urol 1997;157:195-8.  Back to cited text no. 10
    
11.
Lilja H. Significance of different molecular forms of serum PSA, the free noncomplexed form of PSA versus that complexed to alpha-1 antichymotrypsin. Urol Clin North Am 1993;20, 681-6.  Back to cited text no. 11
    
12.
Nadler RB, Humphrey PA, Smith DS, Catalona WJ, Ratliff TL. Effect of inflammation and benign prostatic hyperplasia on elevated serum prostate specific antigen levels. J Urol 1995;154:407-13.  Back to cited text no. 12
    
13.
Bjork T, Bjartell A, Abrahamsson PA, Hulkko S, di Sant'Agnese A, Lilja H. a-1-antichymotrypsin production in PSA producing cells is common in prostate cancer but rare in benign prostatic hyperplasia. Urology 1994;43:427-34.  Back to cited text no. 13
    
14.
Christensson A, Bjork T, Nilsson O, Dahlen U, Matikainen MT, Cockett AT, et al. Serum prostate specific antigen complexed to a-1-antichymotrypsin as an indicator of prostate cancer. J Urol 1993;150:100-105.  Back to cited text no. 14
    



 
 
    Tables

  [Table 1], [Table 2]

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