Low serum neutrophil count predicts a positive prostate biopsy

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1 Prostate Cancer and Prostatic Diseases (2012) 15, All rights reserved /12 ORIGINAL ARTICLE Low serum neutrophil count predicts a positive prostate biopsy K Fujita, R Imamura, G Tanigawa, M Nakagawa, T Hayashi, N Kishimoto, M Hosomi and S Yamaguchi BACKGROUND: Asymptomatic prostatic inflammation may cause increased PSA in some men, leading to unnecessary prostate biopsy. We investigated whether the differential white cell count could predict the result of prostate biopsy. METHODS: Prostate needle biopsy was carried out in 323 Japanese men with elevated PSA levels or abnormal digital rectal findings. White blood cell count (WBC), differential white cell count (neutrophils, lymphocytes, basophils, eosinophils, and monocytes), and serum C-reactive protein level were assessed for associations with biopsy findings. RESULTS: In all, 203 (62.1%) were positive for prostate cancer. WBC, neutrophil count, age, PSA, prostate volume, and PSA density (PSAD) were associated with the results of biopsy (Po0.05). Multivariate analysis showed that neutrophil count, age, PSA, prostate volume and PSAD were independent predictors. When the cut-off neutrophil count was set at 2900 ml 1,78of 104 men (75.0%) with a count below this value had a positive biopsy, while 125 of 219 (57.0%) men with a count above this value were positive. The area under the receiver-operator characteristics curve (AUC) for the predicted probability of a positive biopsy for prostate cancer according to the optimum logistic model was 0.83 (95% confidence interval (CI) ), while the AUC for PSA was 0.70 (95% CI ) and that for PSAD was 0.79 (95% CI ). CONCLUSIONS: An elevated neutrophil count may be a good indicator of a benign prostate biopsy. Men with a low neutrophil count and an increase of serum PSA should strongly be considered for biopsy. Prostate Cancer and Prostatic Diseases (2012) 15, ; doi: /pcan ; published online 10 July 2012 Keywords: biopsy; prostate; inflammation; neutrophil INTRODUCTION PSA is secreted from prostate luminal cells, and serum PSA level is used for detection of prostate cancer. If elevation of serum PSA is found, prostate biopsy is performed next. Biopsy is currently the only way to confirm the diagnosis of prostate cancer in a patient with an abnormal PSA level and/or abnormal findings on digital rectal examination, but biopsy is associated with significant morbidity. It is also well recognized that PSA lacks sufficient sensitivity and specificity for detecting prostate cancer, leading to numerous unnecessary biopsies. In addition to cancer, prostatic inflammation and benign prostatic hypertrophy can cause an increase of the serum PSA level. Many models have been proposed to predict the results of biopsy that use the age, the findings on digital rectal examination, and the PSA, PSA density (PSAD), PSA velocity, and prostate cancer antigen 3. 1,2 Prostatic inflammation is detected in most biopsy specimens and subclinical prostatitis is known to increase the serum PSA level. 3,4 Acute and chronic inflammation in biopsy specimens is a significant predictor of the serum PSA level. Histological inflammation in needle biopsy specimens and infiltration of polymorphonuclear leukocytes are correlated with an increase of serum PSA and with the results of repeat biopsy. 5,6 However, information of histological inflammation is not utilized before initial biopsy. Chronic inflammation may also have an important role in prostate cancer carcinogenesis. 7 Only a few markers related with inflammation have been reported to be possible serum markers of prostate cancer. Serum interleukin-7 levels, a cytokine important for B- and T-cell development, is increased in patient with localized prostate cancer as compared with patients with BPH, 8 and C-reactive protein (CRP) is associated with poor survival in men with metastatic prostate cancer. 9 The purpose of this study was to assess whether the white blood cell count (WBC) or the differential white cell count (neutrophils, lymphocytes, basophils, eosinophils, and monocytes) was correlated with the results of prostate biopsy and/or with various prostatic parameters. MATERIALS AND METHODS Subjects We retrospectively analyzed the medical records of 323 Japanese men who underwent transrectal ultrasound-guided 12-core prostate needle biopsy between 2010 and 2011 at our institution. Biopsy was performed if men without symptomatic prostatic inflammation had elevation of PSA or abnormal findings on digital rectal examination. All cases were used for the analysis. Laboratory data, including the serum PSA, WBC, differential white cell count (neutrophils, lymphocytes, basophils, eosinophils, and monocytes), and CRP were obtained by screening tests before biopsy. The absolute leukocyte counts were calculated as the WBC multiplied by the percentage of each differential leukocyte count. Prostate volume was measured by transrectal ultrasound. This study was approved by the Osaka General Medical Center institutional review board. Statistical analysis Results are shown as the median (range). Univariate analysis was performed with the Mann--Whitney U test and the w 2 test. Correlations between PSA, prostate volume, WBC, and leukocyte counts were assessed by Spearman s correlation analysis. Stepwise multiple regression analyses were performed to assess the relative contributions of factors (age, PSA, prostate volume, WBC, the neutrophil count, the lymphocyte count, and CRP) to PSA and the prostate volume. Independent predictors of a positive Department of Urology, Osaka General Medical Center, Osaka, Japan. Correspondence: Dr K Fujita, Department of Urology, Osaka General Medical Center, , Bandai-Higashi, Sumiyoshi, Osaka, , Japan. kazufujita2@gmail.com Received 22 March 2012; revised 1 June 2012; accepted 4 June 2012; published online 10 July 2012

2 biopsy were identified by logistic regression analysis. The optimum cutoff value for the neutrophil count was determined from the receiver-operator characteristics curve by using the Youden index, and then the patients were stratified into low or high neutrophil count groups at this cutoff value (assigned a score of 0 or 1, respectively). Variables entered into the model were the age, PSA, PSAD, WBC, CRP, and neutrophil count group or neutrophil count. As the variable PSAD is made up of PSA and prostate volume, prostate volume was removed from the models. The predicted probability of a positive biopsy result was estimated as P ¼ 1/(1 þ exp[ S]). Logistic regression yields a score (S), where S is b 0 þ b 1 w 1 þ b 2 w 2 þ b 3 w 3 y, which is a linear combination of the predictors (w 1, w 2, w 3 y) in the model. The model coefficients (b 0, b 1, b 2 y) were chosen to optimize the ability to predict a positive biopsy result. A nomogram predicting the probability of prostate cancer was constructed based on this formula. All probability (P) values were two-sided, with statistical significance being accepted at Po0.05. RESULTS Of the 323 men, 203 (62.8%) had a positive biopsy for prostate cancer and 120 (37.2%) had a negative biopsy. The characteristics of the patients are summarized in Table 1. Of the 323 men, 2 (0.6%) had corticosteroids, of which 2 men had a positive biopsy. Five (1.5%) had the infectious diseases within 3 months before biopsy, of which 3 had a positive biopsy and 2 had a negative biopsy. Forty (12.3%) had been hospitalized for surgery or medical diseases within 3 months before biopsy, of which 27 had a positive biopsy and 13 had a negative biopsy. The WBC was significantly higher in the negative biopsy group (6.1 ( ) 10 3 ml 1 ) compared with the positive biopsy group (5.7 ( ) 10 3 ml 1 ; P ¼ 0.040). The median (range) CRP value of the negative biopsy group was 0.08 ( ) mg l 1, while that of the positive biopsy group was 0.07 ( ) mg l 1 (P ¼ 0.83). The neutrophil count was significantly higher in the negative biopsy group (3.58 (1.80 to 9.07) 10 3 ml 1 ) compared with the positive biopsy group (3.32 (1.32 to 8.43) 10 3 ml 1 ; P ¼ 0.017), while the other leukocyte subsets were not significantly different between the negative and positive biopsy groups. Univariate analysis showed that the age, PSA, prostate volume, and PSAD were associated with the outcome of biopsy (Po0.05). When the cutoff neutrophil count was set at 2900 ml 1 based on the best receiver-operator characteristics, 78 (75.0%) of 104 men with a count below this value had a positive biopsy versus 125 (57.1%) of 219 men with a count above this value (P ¼ 0.002). Logistic regression analysis revealed that the age, PSAD, and neutrophil score were independent predictors of the outcome of biopsy (Po0.05), whereas PSA, WBC, and CRP were not (Table 2). Without 47 patients with corticosteroids, infectious diseases, or hospitalization, neutrophil score was still independently associated with biopsy outcome. Logistic regression analysis with the continuous form of neutrophil count in overall cohort also showed that neutrophil count was an independent predictor (P ¼ 0.034, odds ratio (OR) ¼ 0.999, 95% confidence interval (CI) ). Prostate volume was correlated with PSA (r ¼ 0.167, P ¼ 004), WBC (r ¼ 0.179, P ¼ 0.002), the lymphocyte count (r ¼ 0.173, P ¼ 0.002), and the neutrophil count (r ¼ 0.164, P ¼ 0.004). PSA was correlated with CRP (r ¼ 0.150, P ¼ 0.007) and with prostate volume. Among the 120 men with a negative biopsy, prostate volume was correlated with PSA (r ¼ 0.438, Po0.001), WBC (r ¼ 0.311, P ¼ 0.001), the lymphocyte count (r ¼ 0.257, P ¼ 0.006), and the neutrophil count (r ¼ 0.252, P ¼ 0.007). In addition, PSA was correlated with the monocyte count (r ¼ 0.202, P ¼ 0.027), CRP (r ¼ 0.190, P ¼ 0.039), and prostate volume. Among the men with a positive biopsy, prostate volume was only correlated with PSA (r ¼ 0.273, Po0.001), and not with the WBC or the neutrophil count. Six of these variables, (age, PSA, prostate volume, WBC, the neutrophil count, the lymphocyte count, and CRP) were then utilized as predictors in stepwise multiple regression analyses using PSA and prostate volume each as dependent variables in overall cohort. Stepwise multiple regression analyses revealed that only WBC was independently associated with the prostate volume (Po0.001) and only age was independently associated with PSA (P ¼ 0.002) in overall cohort. Regression coefficients for the optimum model were estimated and the following model predicting the probability of detecting cancer by biopsy was obtained: P ¼ [1 þ exp ( age to PSAD þ neutrophil score)] 1. The area under the receiver-operator characteristics curve (AUC) for the probability of detecting cancer in all patients, as predicted by the optimum logistic model, was 0.83 (95% CI ), while the AUC for PSA was 0.70 (95% CI ) and that for PSAD was 0.79 (95% CI ) (Figure 1a). The sensitivity and specificity of the model at the best cutoff value was 74.7 and 80.3%, respectively. We then repeated this analysis in the subgroup of men with PSA levels o10 ng ml 1. Among these 159 men, 77 (48.1%) had a positive biopsy for prostate cancer and 82 (51.9%) had a negative biopsy. Table 3 lists their characteristics. The WBC was significantly higher in men with a negative biopsy (6.1 (3.3 to 11.3) 10 3 ml 1 ) than in men with a positive biopsy (5.5 ( ) 10 3 ml 1 ; P ¼ 0.035). The median (range) CRP of biopsy negative men was 0.07 ( ) mg ml 1 and that of biopsy positive men was 0.07 ( ) mg ml 1 (P ¼ 0.93). Although the neutrophil count was significantly higher in men with a negative biopsy (3.54 (1.87 to 387 Table 1. Cohort demographics of all cases Patient characteristics Negative biopsy Positive biopsy P-value No. of pts Age 68 (48--82) 73 (36--89) o PSA (ng ml 1 ) 7.84 ( ) 12.4 ( ) o Prostate volume (ml) 44.7 ( ) 29.2 ( ) o PSA density (ng ml 1 per ml) ( ) ( ) o Serum WBC ( 10 3 ml 1 ) 6.1 ( ) 5.7 ( ) CRP (mg l 1 ) 0.08 ( ) 0.07 ( ) Neutrophil ( 10 3 ml 1 ) 3.58 ( ) 3.32 ( ) Lymphocyte ( 10 3 ml 1 ) 1.74 ( ) 1.60 ( ) Eosinophil (ml 1 ) 139 ( ) 142 ( ) Basophil (ml 1 ) 34 (0--174) 33 (0--279) Monocyte (ml 1 ) 450 ( ) 442 ( ) Abbreviations: CRP, C-reactive protein; WBC, white blood cell count. Median (range).

3 388 Table 2. Stepwise logistic regression analysis of variables associated with positive biopsy in overall cohort Variable included Univariate Multivariate Odds ratio 95% CI P-value Odds ratio 95% CI P-value Age o o0.001 PSA PSAD o0.001 Neutrophil score o WBC CRP Abbreviations: CI, confidence interval; CRP, C-reactive protein; PSAD, PSA density; WBC, white blood cell count. Figure 1. Receiver-operator characteristics (ROC) curve of the predicted probability of cancer detection by the optimum logistic model (solid curves), serum PSA (dotted curves) and PSA density (dashed curves) for the prediction of prostate cancer on biopsy. (a) ROC curve for 323 cases. (b) ROC curve for 159 cases with PSA p10 ng ml ) 10 3 ml 1 ) compared with men with a positive biopsy (2.97 (1.32 to 7.03) 10 3 ml 1 ; P ¼ 0.003), other leukocyte subsets were not significantly different between the negative and positive biopsy subgroups. Univariate analysis showed that age, prostate volume, and PSAD were associated with the result of biopsy (Po0.05), but not PSA (P ¼ 0.07). When the same cutoff neutrophil count of ml 1 was used, 32 of 47 men (68.0%) with a count below this value had a positive biopsy, whereas 45 of 112 men (40.1%) with a count above this value were positive (P ¼ 0.001). Logistic regression analysis revealed that the age, PSAD, and neutrophil score were independent predictors of the biopsy result (Po0.05), whereas PSA, WBC, and CRP were not (Table 4). Without 20 patients with corticosteroids, infectious diseases, or hospitalization, neutrophil score was still independently associated with biopsy outcome. Logistic regression analysis with the continuous form of neutrophil count also showed that neutrophil count was an independent predictor in 159 men with PSA levels o10 ng ml 1 (P ¼ 0.038, odds ratio ¼ 0.999, 95% CI ). Prostate volume was correlated with WBC (r ¼ 0.257, P ¼ 0.002) and with the neutrophil count (r ¼ 0.264, P ¼ 0.001), whereas PSA was not significantly correlated with any factor. Among 82 men with a PSA o10 ng ml 1 and a negative biopsy, prostate volume was correlated with PSA (r ¼ 0.270, Po0.018), WBC (r ¼ 0.295, P ¼ 0.010), and the neutrophil count (r ¼ 0.244, P ¼ 0.034), while PSA was correlated with the monocyte count (r ¼ 0.229, P ¼ 0.038) and the prostate volume. Among men with a positive biopsy, none of the leukocyte parameters were correlated with either the PSA or the prostate volume. Four of these variables, (age, PSA, prostate volume, WBC, and the neutrophil count) were then utilized as predictors in stepwise multiple regression analyses using PSA and prostate volume each as dependent variables in cohort with PSA p10 ng ml 1. Stepwise multiple regression analyses revealed that only WBC was independently associated with the prostate volume (P ¼ 0.003) and no variable was independently associated with PSA in cohort with PSA p10 ng ml 1. When the regression coefficients of the optimum model were estimated, the following model for predicting the probability of detecting cancer by biopsy was obtained: P ¼ [1 þ exp (6.501 to age PSAD þ neutrophil score)] 1. The AUC for the probability of predicting a positive biopsy by this model in the men with low PSA levels was 0.81 (95% CI ), while the AUC for PSA was 0.58 (95% CI ) and that for PSAD was 0.74 (95% CI ) (Figure 1b). The sensitivity and specificity of the model at the best cutoff value was 77.3 and 81.5%, respectively. DISCUSSION The association between histological detection of inflammation and the result of biopsy is well known, with inflammation of the prostate being an indicator of a negative biopsy. It was reported that histological inflammation in needle biopsy specimens is inversely associated with a positive biopsy, 10 while decreased infiltration of macrophage scavenger receptor-positive cells in negative initial biopsy specimens is correlated with a positive repeat biopsy. 11 We have also previously reported that polymorphonuclear leukocytes in the initial biopsy specimen are an indicator of the result of repeat biopsy. 5 The association of serum PSA with histological inflammation has also been reported. 3 Thus, histological inflammation in the initial biopsy specimens can be useful to predict the result of repeat biopsy, but this strategy cannot be used to predict the initial biopsy findings. Models for predicting the result of initial biopsy have used many parameters, such as abnormal digital rectal examination, age, PSA, percent-free PSA, prostate volume, and prostate cancer antigen 3. 1,2,12 Addition of information on inflammation to such models could improve prediction of the probability of prostate cancer. In this study, we sought a new indicator of inflammation in the prostate. The association of serum CRP with biopsy outcome has already been studied, but no significant correlation was found. 13 The leukocyte count is a routine test and easily performed. We found that men with a high neutrophil count were less likely to have a positive biopsy compared with men with a low neutrophil count. This result was consistent with our previous finding that polymorphonuclear leukocyte infiltration of the initial biopsy specimen is a good indicator of a negative repeat biopsy in men with a persistent increase of PSA after a negative initial biopsy. 5 There are many evidences to suggest that chronic inflammation have a potential role in carcinogenesis and tumor progression. 14 Recent prospective study showed that chronic inflammation and infectious agents related to prostatitis and sexual transmitted diseases may be involved in prostate cancer susceptibility. Longer duration of prostatitis symptom was associated with an increased

4 Table 3. Cohort demographics with PSA p10 ng ml Patient characteristics Negative biopsy Positive biopsy P-value No. of pts Age 67 (48--82) 71 (36--85) PSA (ng ml 1 ) 6.18 ( ) 6.84 ( ) 0.07 Prostate volume (ml) 38.2 ( ) 27.0 ( ) o PSA density (ng ml 1 per ml) ( ) ( ) o Serum WBC ( 10 3 ml 1 ) 6.1 ( ) 5.5 ( ) CRP (mg l 1 ) 0.07 ( ) 0.07 ( ) Neutrophil ( 10 3 ml 1 ) 3.54 ( ) 2.97 ( ) Lymphocyte ( 10 3 ml 1 ) 1.69 ( ) 1.56 ( ) Eosinophil (ml 1 ) 134 ( ) 160 (8--707) Basophil (ml 1 ) 34 (0--174) 37 (0--160) Monocyte (ml 1 ) 433 ( ) 420 ( ) Abbreviations: CRP, C-reactive protein; WBC, white blood cell count. Median (range). Table 4. Stepwise logistic regression analysis of variables associated with positive biopsy in PSA p10 ng ml 1 cohort Variable included Univariate Multivariate Odds ratio 95% CI P-value Odds ratio 95% CI P-value Age PSA PSAD o Neutrophil score o WBC CRP Abbreviations: CI, confidence interval; CRP, C-reactive protein; PSAD, PSA density; WBC, white blood cell count. risk of prostate cancer. 15 In this study, neutrophil count was measured before the biopsy that would represent the systemic inflammation before the biopsy, not the chronic inflammation for the long duration. The correlation between neutrophil and cancer has been recently reported. Neutropenia (neutrophil count o1500 ml 1 ) carries a risk of having poorly differentiated prostate caner among African-American men, whereas neutrophilia has been associated with a poor prognosis in metastatic melanoma and renal cell carcinoma. 16 Prostate cancer secretes interleukin-8 and epithelial neutrophil-activating peptide-78, which enhance the proliferation and migration of prostate cancer. Interleukin-8 and epithelial neutrophil-activating peptide-78 are proinflammatory chemokines and recruit neutrophils. These chemokines might affect the neutrophil count in men with prostate cancer. Similar to M1 and M2 macrophages, tumor-associated neutrophils have been proposed to polarize to N1 and N2 phenotype. When neutrophils traffic to tumor, transforming growth factor-beta promotes the polarization of tumor-associated neutrophils to a pro-tumoral N2 phenotype, whereas a shift towards an N1 type with antitumoral properties occurs following transforming growth factor-beta inhibition. 17 The association between decreased serum neutrophil count in men with prostate cancer and tumorassociated neutrophil remains to be studied. Interestingly, both the WBC and the neutrophil count were correlated with the prostate volume. Multiple regression analyses showed that WBC was independently associated with prostate volume. These finding should be confirmed in a larger study. The reason for this correlation between WBC and prostate volume remains to be elucidated. There have been reports that inflammation is a cause of prostatic enlargement, 18 so a possible explanation is that asymptomatic inflammation of the prostate may increase the WBC and the neutrophil count. Serum WBC was reportedly associated with serum monocyte chemotactic protein-1 levels. 19 Monocyte chemotactic protein-1 is secreted from prostatic stromal cells and stimulates the proliferation of prostatic epithelial cells in vitro. 20 Monocyte chemotactic protein-1might be another possible explanation of the correlation between WBC and prostate volume. Our study had several limitations. Men included in our study are all Japanese, and the results may not be extended to other races. The proportion of men with prostate cancer was relatively high (63.7%). In Japan, PSA testing is still done on a very low percentage of men (approximately 10%) compared with with its use in the USA or Europe. 21 Some men with very high PSA levels were included in our cohort, resulting in a relatively high positive biopsy rate. Men with advanced prostate cancer were also included in this cohort that might have biased the results. To exclude the possibility that severe inflammation or advanced prostate cancer that increase PSA might have skewed the results, we repeated our analysis in men with PSA levels of o10 ng ml 1. The results of this subgroup analysis were consistent with those for the entire cohort, and suggested that the neutrophil count may be an indicator of a benign biopsy. Prostate needle biopsy suffers from inherent inadequacies in tissue sampling, resulting in a sensitivity deficit. Some men with negative biopsy results still have a possibility of prostate cancer. Men with prostate cancer might be in the negative group in this study that might have affected the results. Our prediction model may be useful to indicate to patients the probability of prostate cancer being detected by biopsy. However, overdiagnosis of indolent and nonaggressive forms of prostate cancer is a problem, and new markers for aggressive high-grade prostate cancer should be developed.

5 390 CONCLUSIONS The neutrophil count, which is a routine test and easily performed, may be a good indicator of the result of prostate biopsy, although this remains to be confirmed in a larger study. Men with a low neutrophil count and increased serum PSA level should be strongly considered for prostate biopsy. CONFLICT OF INTEREST The authors declare no conflict of interest. REFERENCES 1 Deras IL, Aubin SM, Blase A, Day JR, Koo S, Partin AW et al. PCA3: a molecular urine assay for predicting prostate biopsy outcome. J Urol 2008; 179 (4): Thompson IM, Ankerst DP, Chi C, Goodman PJ, Tangen CM, Lucia MS et al. Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst 2006; 98 (8): Schatteman PH, Hoekx L, Wyndaele JJ, Jeuris W, Van Marck E. Inflammation in prostate biopsies of men without prostatic malignancy or clinical prostatitis: correlation with total serum PSA and PSA density. Eur Urol 2000; 37 (4): Kandirali E, Boran C, Serin E, Semercioz A, Metin A. Association of extent and aggressiveness of inflammation with serum PSA levels and PSA density in asymptomatic patients. Urology 2007; 70 (4): Fujita K, Hosomi M, Tanigawa G, Okumi M, Fushimi H, Yamaguchi S. Prostatic inflammation detected in initial biopsy specimens and urinary pyuria are predictors of negative repeat prostate biopsy. J Urol 2011; 185 (5): Okada K, Kojima M, Naya Y, Kamoi K, Yokoyama K, Takamatsu T et al. Correlation of histological inflammation in needle biopsy specimens with serum prostatespecific antigen levels in men with negative biopsy for prostate cancer. Urology 2000; 55 (6): De Marzo AM, Platz EA, Sutcliffe S, Xu J, Gronberg H, Drake CG et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer 2007; 7 (4): Mengus C, Le Magnen C, Trella E, Yousef K, Bubendorf L, Provenzano M et al. Elevated levels of circulating IL-7 and IL-15 in patients with early stage prostate cancer. J Transl Med 2011; 9: Beer TM, Lalani AS, Lee S, Mori M, Eilers KM, Curd JG et al. C-reactive protein as a prognostic marker for men with androgen-independent prostate cancer: results from the ASCENT trial. Cancer 2008; 112 (11): Terakawa T, Miyake H, Kanomata N, Kumano M, Takenaka A, Fujisawao M. Inverse association between histologic inflammation in needle biopsy specimens and prostate cancer in men with serum PSA of ng/ml. Urology 2008; 72 (6): Nonomura N, Takayama H, Kawashima A, Mukai M, Nagahara A, Nakai Y et al. Decreased infiltration of macrophage scavenger receptor-positive cells in initial negative biopsy specimens is correlated with positive repeat biopsies of the prostate. Cancer Sci 2010; 101 (6): Karakiewicz PI, Benayoun S, Kattan MW, Perrotte P, Valiquette L, Scardino PT et al. Development and validation of a nomogram predicting the outcome of prostate biopsy based on patient age, digital rectal examination and serum prostate specific antigen. J Urol 2005; 173 (6): Kato T, Suzuki H, Komiya A, Imamoto T, Naya Y, Tobe T et al. Clinical significance of urinary white blood cell count and serum C-reactive protein level for detection of non-palpable prostate cancer. Int J Urol 2006; 13 (7): Sfanos KS, De Marzo AM. Prostate cancer and inflammation: the evidence. Histopathology 2012; 60: Cheng I, Witte JS, Jacobsen SJ, Haque R, Quinn VP, Quesenberry CP et al. Prostatitis, sexually transmitted diseases, and prostate cancer: the California Men s Health Study. PLoS One 2010; 5 (1): e Fridlender ZG, Albelda SM. Tumor-associated neutrophils: friend or foe? Carcinogenesis 2012; 33 (5): Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L et al. Polarization of tumorassociated neutrophil phenotype by TGF-beta: N1 versus N2 TAN. Cancer Cell 2009; 16 (3): Kramer G, Marberger M. Could inflammation be a key component in the progression of benign prostatic hyperplasia? Curr Opin Urol 2006; 16 (1): Fukami A, Yamagishi S, Adachi H, Matsui T, Yoshikawa K, Ogata K et al. High white blood cell count and low estimated glomerular filtration rate are independently associated with serum level of monocyte chemoattractant protein-1 in a general population. Clin Cardiol 2011; 34 (3): Fujita K, Ewing CM, Getzenberg RH, Parsons JK, Isaacs WB, Pavlovich CP. Monocyte chemotactic protein-1 (MCP-1/CCL2) is associated with prostatic growth dysregulation and benign prostatic hyperplasia. Prostate 2010; 70 (5): The Committee for Establishment of the Guidelines on Screening for Prostate Cancer, Association JU. Updated Japanese Urological Association Guidelines on prostate-specific antigen-based screening for prostate cancer in Int J Urol 2010; 17: