The Significance of Plasma C-reactive Protein in Patients With Elevated Serum Prostate-specific Antigen Levels

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1 Urol Sci 2010;21(2):88 92 ORIGINAL ARTICLE The Significance of Plasma C-reactive Protein in Patients With Elevated Serum Prostate-specific Antigen Levels Chang-Chi Chang 1,2,3, Alex T.L. Lin 2,3 *, Kuang-Kuo Chen 2,3, Hsiao-Jen Chung 2,3, Shyh-Chyi Chang 2,3,4 1 Division of Urology, Department of Surgery, Taipei City Hospital, Taipei, Taiwan 2 Division of Urology, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan 3 Department of Urology, National Yang-Ming University, School of Medicine, Taipei, Taiwan 4 Division of Urology, Department of Surgery, Lo-Tung Pohai Hospital, Lo-Tung, Taiwan Objective: Prostatic infection/inflammation may increase serum prostate-specific antigen (PSA) levels. We hypothesized that prostatic infection/inflammation can be identified by elevated plasma C-reactive protein (CRP) levels. Measuring plasma CRP levels may help to differentiate benign conditions from prostate cancer in patients with elevated serum PSA levels. Materials and Methods: A total of 139 patients with serum PSA levels greater than 4.0 ng/ml received transrectal ultrasound guided biopsy. All of the patients had plasma high-sensitivity CRP levels measured. CRP levels higher than 0.5 mg/dl were considered abnormal. CRP and PSA levels, and prostate size were compared between benign and malignant groups. The association of CRP levels with cancer stages was also analyzed. Results: Thirty-four out of 139 (24.5%) patients were found to have prostate cancer. There was no significant difference in CRP levels between the malignant and benign groups. Five out of 34 (14.7%) patients with prostate cancer and 13 of 105 (12.4%) patients with benign lesions had elevated CRP levels. The incidence of abnormal CRP levels was not significantly different between the groups (p = 0.77). Patients with high PSA and CRP levels did not have a higher probability of a benign condition. It is interesting to note that in the malignant group, there was a significant positive correlation between CRP and PSA levels (r = 0.44, p = 0.01). No significant correlation between CRP levels and cancer stages was noted. Conclusion: Measuring plasma CRP levels does not assist in the identification of benign conditions in patients with elevated PSA levels. However, plasma CRP levels are well-correlated with serum PSA levels in prostate cancer patients, suggesting a potential correlation between prostate inflammation and prostate cancer. Received: May 26, 2009 Revised: August 10, 2009 Accepted: October 21, 2009 KEY WORDS: plasma C-reactive protein; prostate cancer; prostate-specific antigen; prostate size *Corresponding author. Division of Urology, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei 11217, Taiwan. lintl@vghtpe.gov.tw 1. Introduction Prostate-specific antigen (PSA) is produced exclusively by epithelial cells of the prostate gland. Disruption of the cell-to-cell architecture of prostate epithelium results in increased serum PSA levels. 1 Apart from prostate cancer, nonmalignant conditions and prostate manipulation such as benign prostatic hyperplasia (BPH), acute/chronic prostatitis, prostate infarction, cystoscopy, biopsy of the prostate gland, prostate massage, and urinary catheterization Taiwan Urological Association. Published by Elsevier Taiwan LLC.

2 Plasma CRP in patients with elevated serum PSA elevate serum PSA levels. 2,3 PSA levels alone are not a reliable discriminator between prostate cancer and benign conditions of the prostate. Subclinical prostate inflammation is one of the most important factors contributing to elevation of serum PSA levels. 4 Currently, other than prostate biopsy, there is no other reliable method to detect prostate inflammation. We speculated that elevated serum C-reactive protein (CRP) levels might serve as an indicator for intraprostatic inflammation. CRP is a surrogate for interleukin 6 (IL-6) action. 5 IL-6 plays an important role in immune and acute-phase inflammatory responses and acts on hepatocytes to increase the synthesis of CRP and other acute phase reactant proteins (e.g., hepatoglobin and fibrinogen). 6 CRP is a non-specific but fairly sensitive marker of acute-phase inflammation. The common conditions associated with major elevations of CRP levels are bacterial infection (e.g., pyelonephritis and endocarditis), inflammatory diseases (e.g., rheumatoid arthritis, Crohn disease and Reiter disease), cancer, tissue necrosis (myocardial infarction and tumor embolization), and trauma. We hypothesized that plasma CRP levels, which are a sensitive marker for inflammation, may reflect prostatic infection/inflammation. The aim of the present study was to determine whether plasma CRP levels can differentiate benign conditions from prostate cancer in patients with elevated serum PSA levels. 2. Materials and Methods The study was granted approval from the Division of Urology, Taipei Veterans General Hospital. One hundred thirty-nine patients who had serum PSA levels > 4.0 ng/ ml and had received transrectal ultrasound-guided six- or eight-core needle biopsy of the prostate were enrolled in the current study after getting informed consents. None of the patients had documented acute prostatitis or urinary tract infection. For each patient, plasma high-sensitivity CRP levels were measured before transrectal ultrasound guided biopsy. A CRP level 0.5 mg/dl was considered abnormal. 7 Based on the pathologic results, we divided all patients into two groups: the malignant group (prostate cancer, n = 34) and the benign group (n = 105). Both groups were stratified into two subgroups by plasma CRP levels as follows: normal CRP (< 0.5 mg/dl) and abnormal CRP ( 0.5 mg/dl). The following parameters were compared between the benign and malignant groups: mean age, plasma CRP levels, serum PSA levels, and prostate size (volume = prostate length [cm] width [cm] depth [cm] 0.52) based on a previous report. 8 Correlations of plasma CRP levels with serum PSA levels and prostate size were evaluated. Additionally, in the malignant group, the association between plasma CRP levels and cancer stage (T1, T2, T3, metastasis) was evaluated. The stage was determined based on the TNM staging system (American Joint Committee on Cancer, 2002). 9 The t test, Fisher exact test, Pearson correlation test, and one-way analysis of variance were used to determine statistical significance, which was set at p < Results Thirty-four out of 139 patients (24.5%) were found to have prostate cancer. The baseline characteristics in both groups of patients are shown in Table 1. The mean serum PSA level was higher in the malignant group than that in the benign group (53.0 ± vs. 8.8 ± 5.4 ng/ml; p = 0.02). However, prostate size was significantly larger in the benign group than that in the malignant group (55.5 ± 30.0 cm 3 vs ± 21.0 cm 3 ; p = 0.01). There was no significant difference in CRP levels between the malignant and benign groups. Five out of 34 patients with prostate cancer (14.7%) and 13 out of 105 patients with benign lesions (12.4%) had elevated CRP levels. The incidence of abnormal CRP levels was not significantly different between the groups (p = 0.77). Can cer detection rates did not differ between the abnormal CRP and normal CRP subgroups (27.8% [5 of 18] vs. 24.0% [29 of 121]; p = 0.77). Plasma CRP levels were positively correlated with serum PSA levels only in those patients with prostate cancer (r = 0.44, p = 0.01; Table 2). Although there was no significant correlation between CRP levels and cancer stages (T1, T2, T3, metastasis) (one-way ANOVA, p = 0.16), CRP levels tended to be higher in patients with metastatic prostate cancer than in those with non-metastatic prostate cancer. Table 1 Baseline characteristics of the malignant and benign groups* Characteristic Malignant group (n = 34) Benign group (n = 105) p Age (yr) 73.4 ± 9.1 (45 89) 71.1 ± 9.3 (35 90) 0.21 CRP (mg/dl) 0.3 ± 0.3 ( ) 0.4 ± 1.1 ( ) 0.47 PSA (ng/ml) 53.0 ± ( ) 8.8 ± 5.4 ( ) 0.02 Prostate size (cm 3 ) 41.0 ± 21.0 ( ) 55.5 ± 30.0 ( ) 0.01 *Data presented as mean ± standard deviation, with ranges in parentheses; t test; volume = length (cm) width (cm) depth (cm) CRP = C-reactive protein; PSA = prostate-specific antigen. Vol. 21, 88 92, June

3 C.C. Chang, et al Table 2 Correlation of C-reactive protein (CRP) with prostatespecific antigen (PSA) levels and prostate size in malignant and benign conditions We also found that patients who had high serum PSA levels combined with elevated CRP levels did not have a higher probability of benign conditions (Table 3). 4. Discussion Malignant group Benign group (n = 34) (n = 105) r p* r p* CRP PSA* CRP prostate size* *Pearson correlation test. r = Pearson product-moment correlation coefficient. Table 3 The probability of a benign condition when prostatespecific antigen (PSA) and C-reactive protein (CRP) levels are high PSA level CRP level Benign condition, (ng/ml) (mg/dl) n (%) > /18 (72.2)* > 4 < /121 (76.0)* *Fisher exact test; p = Increased serum PSA levels are an important indicator for prostate cancer. However, PSA levels are prostate-specific but not cancer-specific. 10 Adenocarcinoma of the prostate, as well as BPH and prostatic infection/inflammation (acute/chronic, symptomatic/asymptomatic), can cause elevation of serum PSA levels. 1,2,11,12 It is well known that both malignancy and inflammation of benign prostates can elevate serum PSA levels. Pansadoro et al. 3 reported that the incidence of increased PSA levels is high in acute bacterial prostatitis. Brawer et al. 13 observed that elevated PSA levels are found in 69% and 4% of patients with acute and chronic inflammation in prostatic tissue, respectively. Acute inflammation is thought to be the more important contributor to PSA elevation according to previous reports Conversely, in a study of PSA-based prostate cancer screening, many of the prostate biopsy specimens that did not show cancer showed inflammation, although there were no symptoms to suggest prostatitis. 4 A total of 98.1% of patients who undergo prostatectomy or transurethral resection of the prostate have histologic inflammation. 16 In the current study, symptoms and signs of acute prostatitis were exclusion criteria. Therefore, it is doubtful whether subclinical (asymptomatic) prostatic inflammation increases serum PSA levels as well. Nickel et al. 17 demonstrated that histologic (subclinical) prostatitis is an extremely common finding in prostate biopsies taken in men without clinical inflammation. Irani et al. 18 concluded that inflammation seen on prostate biopsies is not significantly related to serum PSA levels unless associated with glandular epithelial disruption (aggressiveness). Several reports have shown that histologic inflammation is significantly correlated with serum PSA levels. 4,19 Plasma CRP levels have been proposed to reflect inflammation in the prostate and might be related to the severity of lower urinary tract symptoms (LUTS) in BPH patients. Drachenberg et al. 20 found higher serum IL-6 levels in men with BPH, and serum IL-6 levels were often associated with prostatic inflammation. Theoretically, plasma CRP levels, which are a marker of inflammation, might be higher in men with BPH, because production of CRP is induced by IL-6. In a series of 2377 men with LUTS, there was a non-statistically significant but positive association between serum CRP levels and LUTS, which was suggestive of BPH. 21 The investigators suggested that serum CRP levels might be an indicator of intraprostatic inflammation in symptomatic BPH. 21 Based on these reported observations, we speculated that patients with LUTS and a higher CRP level may have prostatic inflammation and associated abnormal PSA levels. In other words, patients with abnormal PSA levels and elevated CRP levels might have a higher probability of benign lesions than those with abnormal PSA levels and normal CRP levels. However, we found that mean plasma CRP levels and the incidence of abnormal plasma CRP levels were not significantly different between the malignant and benign groups. Patients with high PSA and CRP levels did not have a higher probability of benign conditions. It appears that prostate inflammation may not universally induce an elevation in CRP levels. It is also possible that prostate inflammation is involved both in BPH and prostate cancer, indicating that plasma CRP levels are an unreliable marker for differential diagnosis. Chronic inflammation has been advocated to play a role in the pathogenesis of prostate cancer. Inflammatory infiltrates are observed in and around foci of proliferative inflammatory atrophy, which have a high proliferative index as well as frequent association with inflammation. 22 Proliferative inflammatory atrophy, which occurs diffusely in the anatomic peripheral zone of the prostate where prostate cancer predominantly develops, has been suggested to be the precursor of prostate cancer or indicator of prostatic environment favorable to carcinogenesis. 23 Studies have revealed that regular use of non-steroidal anti-inflammatory drugs may reduce the risk of prostate cancer. 24 In this study, we observed a significant positive correlation between CRP and PSA levels in the malignant group, further suggesting a correlation between prostatic inflammation and prostate cancer. Lehrer et al. 25 also found a positive correlation between CRP and PSA 90 Vol. 21, 88 92, June 2010

4 Plasma CRP in patients with elevated serum PSA levels in their prostate cancer patients. Furthermore, CRP levels in men with metastatic prostate cancer are higher than in those with non-metastatic disease. 26 In the current study, although we failed to demonstrate a statistically significant difference in CRP levels between patients with metastatic disease and localized prostate cancer, CRP levels tended to be higher in patients with metastatic prostate cancer. Trautner et al. 27 found that elevated CRP levels are associated with a higher probability of tumor recurrence and poor prognosis. Elevated CRP levels appear to be an indicator of tumor progression, recurrence, and less favorable prognosis. In the present study, a positive correlation between plasma CRP levels and serum PSA levels was observed only in the malignant group but not in the benign group. Possible explanations for this finding may be as follows. First, the abnormal plasma CRP values were 0.509, 0.557, 0.607, 0.685, 0.819, 0.834, 0.91, 1.35, 3.3, 3.5, 4.79, 5.7, 8.23 mg/dl in the benign group and 0.594, 0.609, 0.873, 1.14, 1.46 mg/dl in the malignant group. According to our abnormal CRP data, five individuals with benign prostatic diseases had particularly high plasma CRP levels (> 3 mg/dl). We speculate that these surprisingly high plasma CRP levels in the benign group might have been produced by unknown factors other than the prostate gland, such as cardiovascular disease, injury or even other cancers, thus resulting in no association between plasma CRP levels and serum PSA levels in patients with benign prostatic diseases. In prostate cancer patients, the synthesis of CRP is also stimulated by IL-6, and therefore, elevated levels of IL-6 might cause elevated CRP levels. 28 Moreover, Shariat et al. 29 showed that direct local production of IL-6 by malignant cells significantly contributes to increased circulating levels of IL-6 in patients with prostate cancer. They also found a correlation between circulating IL-6 and PSA levels. These findings are consistent with our finding of a positive correlation between plasma CRP levels and serum PSA levels in the malignant group. In summary, our results indicate that plasma CRP levels do not help distinguish between benign and malignant prostatic conditions in men with elevated PSA levels. However, plasma CRP levels are well-correlated with serum PSA levels in prostate cancer patients, suggesting a potential correlation between prostate inflammation and prostate cancer. Acknowledgments Hui-Chen Lee assisted with the statistical analysis. References 1. 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