Abstract
Mean platelet volume (MPV) has been reported to be related to inflammation. Prostate-specific antigen (PSA) is a protein produced by the prostate, and this protein may be elevated for several reasons, including prostatitis, benign prostatic hyperplasia, and/or cancer. The aim of the current study was to investigate the predictive effect of MPV values on nonsymptomatic prostatitis diagnosis and the relation between MPV and PSA. A total of 275 patients, 89 affected by benign prostate hyperplasia, 94 by prostate adenocancer, and 92 by prostatitis were included in the current study. PSA, total blood count parameters, and urine analysis were investigated. Findings were compared with the groups. The correlation between MPV and the other parameters were analyzed. Univariate and multivariate logistic regression analysis was performed to determine independent predictors of nonsymptomatic prostatitis diagnosis. MPV was significantly higher in patients with nonsymptomatic prostatitis than the other groups. There were negative correlations between MPV and age, total PSA or free PSA (r = −.123; p = .042, r = −.235; p < .001, r = −.184; p = .006, respectively). According to multivariate regression model, only MPV was identified as the predictive factor for nonsymptomatic prostatitis (odds ratio: 1.451, 95% confidence interval [1.116, 1.887], p = .005). MPV, in the absence of other reasons that increased the MPV level, was significantly increased in cases with nonsymptomatic prostatitis; this increase is significantly higher than elevated PSA level in nonsymptomatic prostatitis patients. MPV could have a predictive value for the diagnosis of nonsymptomatic prostatitis.
Introduction
Prostate-specific antigen (PSA) is a protein produced by the prostate. This protein may be elevated for several reasons including prostatitis, benign prostatic hyperplasia (BPH), and/or cancer. PSA is not cancer-specific, cannot be used as a cancer marker, and it has been demonstrated that there is no level of PSA that is definitive for prostate cancer. The value of the PSA test varies when used for screening, diagnosis, prognosis, or as a signal of disease recurrence (Haythorn & Ablin, 2011).
Mean platelet volume (MPV) is a simple indicator of platelet size and has been known to be a marker of platelet activity. Some platelet markers, such as MPV, have been reported to be related to inflammation. MPV is correlated with inflammation in inflammatory bowel diseases, rheumatoid arthritis, and ankylosing spondylitis, as reported in previous studies (Balbaloglu, Korkmaz, Yolcu, Karaaslan, & Beceren, 2014). The relationship between MPV values and prostatitis remain unclear. The aim of current study is to investigate the predictive effect of MPV values on nonsymptomatic prostatitis diagnosis and the relation between MPV and PSA levels.
Material and Method
At Mustafa Kemal University Medical Faculty, between 2009 and 2013, prostate pathology reports were retrospectively reviewed. Exclusion criteria were atherosclerotic heart disease, any medication use that can influence platelet function (e.g., aspirin), asthma, diabetes mellitus, chronic obstructive pulmonary disease, hematological disorders, portal hypertension, peripheral and cerebral vascular disease, cirrhosis, malignancies other than prostate adenocarcinoma (PCa), and symptomatic prostatitis. Laboratory data were obtained from the computerized patient database. Patients with missing data, the results of prostate pathologies other than BPH, PCa, and prostatitis, and patients with two diseases, such as PCa and BPH or BPH and prostatitis, were also excluded. A total of 275 patients, 89 affected by BPH, 94 by PCa, and 92 by prostatitis were included in the current study. Of 275 patients, total PSA (tPSA), free PSA (fPSA) levels, total blood count including hemoglobin, white blood cell, platelet, MPV parameters, and urine analysis were obtained from the computerized patient database. All patients had sterile urine cultures. Informed consent was taken from each patient prior to taking the prostate specimens.
Pathologic Evaluation
Major and minor criteria were used to establish the PCa diagnosis, based on the microscopic appearance of slides stained using haematoxylin and eosin. Major criteria included an infiltrative glandular growth pattern, an absence of basal cells, and nuclear atypia in the form of nucleomegaly and nucleolomegaly. Minor criteria included intraluminal wispy blue mucin, pink amorphous secretions, mitotic figures, intraluminal crystalloids, adjacent high-grade prostatic intraepithelial neoplasia, amphophilic cytoplasm, and nuclear hyperchromasia. Another useful diagnostic marker detectable by immunohistochemistry was used, a-methylacyl coenzyme A racemase, an enzyme selectively expressed in neoplastic glandular epithelium (Humphrey, 2007).
Prostatitis was diagnosed as grade ≥2 extention and grade ≥1 aggressivity of inflammation using the grading system designed by Irani et al. (1997). The values under these grades did not evaluate as prostatitis. BPH is correctly defined as enlargement of the prostate gland from the progressive hyperplasia of stromal and glandular prostatic cells (Berry, Coffey, Walsh, & Ewing, 1984).
Biochemical Assessment
Blood values were taken into consideration when patients were admitted to the hospital before obtaining the prostate pathological material. MPV was measured in a blood sample collected in tripotassium EDTA (7.2 mg) tubes. These blood samples were analyzed within 2 hours of venipuncture by automatic blood counter (A Cell-Dyn 3500, Abbot, IL, USA). MPV was measured by the method of laser-based flow cytometric impedance in patients (Rifaioglu, Sen, & Ekiz, 2013). The expected values for MPV in the laboratory ranged from 6.5 to 12.0 fL (Tavil et al., 2010).
Statistical Analyses
SPSS 16 for Windows (SPSS, Inc., Chicago, IL, USA) computer package was used for statistical analysis. The tPSA, fPSA levels, routine laboratory tests of the red, white, and platelet blood cell systems (red cell count, hemoglobin, white blood cell count, platelet count), and urine analysis were investigated using Kolmogorov–Simirnov test to determine normal or not normal distribution. The parameters were not normally distributed, the Kruskal–Wallis tests were conducted to compare these parameters among the pathological groups (BPH/PCa/prostatitis). The Mann–Whitney U test was performed to test the significance of pairwise differences using Bonferroni correction to adjust for multiple comparisons. The capacity of MPV in predicting presence of prostatitis was analyzed using receiver operating characteristic curve analysis. When a significant cutoff value was observed, the sensitivity, specificity, positive, and negative predictive values were presented. The correlation between MPV and the other parameters were calculated using the Spearman correlation test. In the univariate analyses, Mann–Whitney U test for continuous data was performed to compare the prostatitis and nonprostatitis groups. For multivariate analysis, the possible factors indentified with univariate analyses were further entered into binary logistic regression analysis to determine independent predictors of prostatitis. Hosmer–Lemeshow statistics were used to assess model fit. A 5% Type I error level was used to infer statistical significance.
Results
Of 275 patients, 189 (68.7%) pathologies (43 [15.6%] BPH, 89 [32.4%] PCa, 57 [20.7%] prostatitis) were obtained from transrectal ultrasound guided biopsy materials. The remaining 86 (31.3%) pathologies (46 [16.7%] BPH, 5 [1.8%] PCa, 35 [12.7%] prostatitis were obtained from the material of transurethral resection of prostate. The comparison of the patients’ age, tPSA, fPSA levels, routine laboratory tests of the red, white, and platelet blood cell systems, and urine analysis are summarized in Table 1. Age, tPSA, fPSA, and MPV had significant differences between groups (p < .05, Table 1). In the PCa group, age was identified higher than the prostatitis group (p = .010, Mann–Whitney U test with Bonferroni correction), and tPSA and fPSA values were identified higher than the other two groups (p < .001, Mann–Whitney U test with Bonferroni correction). In the nonsymptomatic prostatitis group, MPV was identified with significantly higher values than the other two groups (p < .001, Mann–Whitney U test with Bonferroni correction, Table 1 and Figure 1). There were negative correlations between MPV and age, tPSA, or fPSA results (r = −.123; p = .042, r = −.235; p < .001, r = −.184; p = .006, respectively). The correlation between MPV and PSA is reported in Figure 2, and the correlation between MPV and the other parameters is summarized in Table 2. In univariate analyses, age, tPSA, fPSA, and MPV were identified as significant factors for nonsymptomatic prostatitis presence in comparison with prostatitis and nonprostatitis groups (p < .05, Table 3). According to multivariate binary logistic regression model, MPV was the only predictive factor for nonsymptomatic prostatitis (odds ratio: 1.451, 95% confidence interval [1.116, 1.887], p = .005, Table 4). The Hosmer–Lemeshow goodness-of-fit test was performed and obtained a p value of .352, which indicated a good fit of the data. The optimal MPV value cutoff point on the receiver operating characteristic curve for diagnosing prostatitis was 8.425 fL, with a sensitivity of 50%, specificity of 78.7%, positive predictive value of 54.1%, and negative predictive value of 78.6% (area under the curve 0.664, p < .001, Figure 3).
Comparison of the Pathologic Groups With Kruskal–Wallis Test.
Note. BPH = benign prostatic hyperplasia; tPSA = total prostate-specific antigen; fPSA = free prostate-specific antigen; WBC = white blood cell; MPV = mean platelet volume.
p = .010 compared with prostatitis group (Mann–Whitney U test with Bonferroni correction). bp < .001 compared with BPH and prostatitis groups (Mann–Whitney U test with Bonferroni correction). cp = .008 compared with adenocancer group (Mann–Whitney U test with Bonferroni correction). dp < .001 compared with BPH and adenocancer groups (Mann–Whitney U test with Bonferroni correction). Bolded values are p < .05.
Mean platelet volume (MPV) results of the pathologic groups.
Correlation between mean platelet volume (MPV) and prostate-specific antigen (PSA).
Correlation of Mean Platelet Volume With the Other Parameters.
Note. tPSA = total prostate-specific antigen; fPSA = free prostate-specific antigen; WBC = white blood cell. Bolded values are p < .05.
Univariate Comparison of the Prostatitis and Nonprostatitis Pathologic Groups.
Note. tPSA = total prostate-specific antigen; fPSA = free prostate-specific antigen; MPV = mean platelet volume. Bolded values are p < .05.
Predictive Factors for Chronic Prostatitis: Outcome of Multivariate Binary Logistic Regression Analysis.
Note. tPSA = total prostate-specific antigen; fPSA = free prostate-specific antigen; MPV = mean platelet volume.
Odds ratio: The 95% confidence intervals (CI) for the relative risk.
Bolded value is p < .05
Receiver operating characteristic (ROC) curve analysis result of mean platelet volume.
Discussion
A complete blood test is an easy, routine, and inexpensive examination which provides more information on many diseases. MPV is a widely used laboratory indicator associated with platelet function based on inflammatory conditions (Balbaloglu et al., 2014). MPV also represents platelet function, which is central to processes that are involved in coronary heart disease pathophysiology and endothelial dysfunction. Platelet parameters might be influenced by coronary risk factors including age, obesity, smoking, diabetes mellitus, hypertension, hyperlipidemia, metabolic syndrome, stroke, peripheral artery disease, and deep vein thrombosis (Gasparyan, Ayvazyan, Mikhailidis, & Kitas, 2011; Tavil et al., 2010). MPV can also be affected by thyroid diseases, bullous pemphigoid, malignancy, and medications such as anticoagulant therapy and statins (Rifaioglu et al., 2013; Thomopoulos et al., 2006). Karaman, Karakukcu, and Kocer (2013) initially reported that MPV values significantly decreased after treatment in all grades of prostatitis. In the present study, it was identified that MPV levels increased in nonsymptomatic prostatitis patients compared with other groups (p < .001, Figure 1). It might be possible that the elevation of MPV in nonsymptomatic prostatitis patients results from the effect of inflammation on thrombopoiesis.
Bancroft, Abel, McLaren, and Belch (2000) reported that MPV decreased with age but there was no difference between genders. In parallel with the literature, in current study, it was identified that there was a negative correlation between age and MPV (Table 2). Karaman et al. (2013) reported that there was no correlation between the histopathological grades of prostatitis and the MPV, PSA of patients. In contrast to study of Karaman et al. (2013), in current study, a negative correlation was identified between MPV and PSA. This negative correlation might be because Karaman et al. (2013) compared the groups within prostatitis groups, but in the present study, nonprostatitis (BPH, PCa) and nonsymptomatic prostatitis group were compared, and symptomatic prostatitis patients were excluded from the study (Table 1). The PSA level was much increased and MPV level was much decreased in nonprostatitis (BPH + PCa) compared with prostatitis group. The other reason might be that the elevation of the PSA was as not much as the elevation of the MPV in nonsymptomatic prostatitis group. The PSA level was more elevated than MPV in nonprostatitis group. Although the current study was retrospective, the accuracy of the current results will be shown better by future prospective studies.
Prostate inflammation can lead to an elevation in the serum PSA concentration and confound the use of PSA kinetics. This can have considerable clinical consequences, since these measurements form the basis for important clinical decisions. There has been investigation into ways to decrease the confounding from inflammation, including repeat PSA measurements after a period of observation or a course of empiric antibiotics (Loeb, Gashti, & Catalona, 2009). Karaman et al. (2013) concluded that MPV values might be used as an inflammation marker in patients with prostatitis. The current study’s result revealed that the best cutoff point for MPV in predicting the diagnosis of prostatitis was 8.425 fL. Patients with increased MPV were 1.451 times more likely to be diagnosed as nonsymptomatic prostatitis (Table 4 and Figure 3). Although the cutoff point did not have a high positive predictive value (54.1%), it had a high negative predictive value (78.6%). The present study revealed that the specificity of this value was 78.7%. The cutoff point may be revised by future prospective randomized studies. In patients with elevated PSA, unless there is another infection or disease, MPV levels could be used as a simple and third method for distinction in PCa and nonsymptomatic prostatitis patients. At low values of MPV in a patient with an elevated PSA level, the histopathological result will not be 78.7% likely prostatitis. In addition, it might also reduce unnecessary transrectal ultrasound guided biopsy counts. This issue will be better understood by future prospective and randomized studies.
Inflammation is associated with the pathogenesis, symptoms, and progression of BPH; therefore, a biomarker would be invaluable. Merendino et al. (2003) suggested that measurement of serum malondialdehyde, an index of inflammation and oxidative stress, may be a useful marker in BPH. Serum malondialdehyde levels were analyzed in 22 BPH patients and 22 healthy donors and an increase was reported in levels in the BPH patients and a positive correlation with PSA. To current knowledge this association has not been replicated. The association of serum C-reactive protein (CRP) concentration, a nonspecific marker of inflammation, and lower urinary tract symptoms suggestive of BPH was examined in 2,337 men who participated in the Third National Health and Nutrition Examination Survey between 1988 and 1994 (Rohrmann, De Marzo, Smit, Giovannucci, & Platz, 2005). The survey results reported that men with a CRP concentration above the limit of detection (>3.00 mg/L) were 1.47 times more likely to have three or more symptoms than men with a CRP concentration below the detection limit, but it was not statistically significant. Cytokines and chemokines, inflammatory mediators, are believed to be important in the pathogenesis of prostate inflammation. Increased expression of IL-8 is noted in BPH tissue culture, which by direct and indirect mechanisms could promote proliferation of nonsenescent epithelial and stromal cells thus contributing to the increased tissue growth seen in BPH. Such processes may lead to the discovery of potential biomarkers for prostate inflammation in BPH (Castro, Xia, Gomez, Lamb, & Ittmann, 2004). Although a number of potential markers (CRP, IL-8, and markers of oxidative stress) have been evaluated, these markers are generally nonspecific for prostatitis (Nickel, 2008). Milicević et al. (2014) performed research to clarify whether serum levels of proinflammatory cytokine interleukin-6 (IL-6) could be a useful marker in prostate diseases. Serum IL-6 levels were compared with tPSA, fPSA, and f/tPSA serum levels. Statistically significant differences were not found in serum IL-6 levels among the PCa, BPH, high-grade prostatic intraepithelial neoplasia, and chronic prostatitis groups (Milicević et al., 2014). A complete blood test, which includes MPV, is an easy, routine, and inexpensive examination. The present study revealed that MPV values had a relation with nonsymptomatic prostatitis, and could be an effective way to distinguish prostatitis from BPH and PCa. In the future, using MPV with PSA will facilitate the differentiation of these three prostate pathologies.
The present study has some limitations. The first limitation is the retrospective character of the current study. The second limitation is the small subject count. In spite of these two limitations, the relationship between prostatitis and MPV is actual and has not been discussed in literature yet. Moreover, the caseload was sufficient for statistical analyses. Another limitations is that MPV level could be increasing for other reasons except prostatitis. Clinicians should check MPV with PSA levels in patients with suspected prostatitis. An elevated MPV level may be a good indicator for a prostatitis biopsy. Men with a low MPV level and an increase of serum PSA should strongly be considered for biopsy. Future research should investigate the relationship between MPV and prostatitis in more detail if this is to become standard of pathological differentiation.
Conclusion
Different from patients with PCa and BPH, MPV was significantly increased in patients with nonsymptomatic prostatitis; this increase was significantly higher than the elevated level of PSA. Regardless of the level of PSA, higher MPV values, in the absence of other reasons that increased the MPV level, could be a predictive factor for the diagnosis of nonsymptomatic prostatitis. The present study demonstrated the relationship between MPV, PSA, and prostatitis. Further studies are needed to confirm the current findings.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.