Archivio Italiano di Urologia e Andrologia 2018; 90, 4270 ORIGINAL PAPER Lymphocyte-to-monocyte ratio is a valuable marker to predict prostate cancer in patients with prostate specific antigen between 4 and 10 ng/dl Volkan Caglayan, Efe Onen, Sinan Avci, Murat Sambel, Metin Kilic, Sedat Oner, Mustafa Murat Aydos, Halil Emre Yıldız University of Health Sciences, Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey. Objective:To evaluate the diagnostic value of serum inflammation markers derived from complete blood count in diagnosis of prostate cancer (PCa). Methods: We retrospectively analyzed the data of 621 patients who underwent prostate biopsy between March 2013 and April 2018. Age, prostate specific antigen (PSA), free PSA, platelet count, neutrophil count, lymphocyte count, monocyte count, prostate volume (PV) and pathology result of the patients were recorded. Patients were grouped as benign prostatic hyperpla- sia (BPH), prostatitis and PCa. Patients were also grouped according to PSA values, as PSA < 4 , PSA 4-10 and PSA > 10 ng/dl. Results: The mean lymphocyte-to-monocyte ratio (LMR) value of the patients with PCa was significantly lower in the entire cohort (p = 0.047). In the PSA 4-10 ng/dl range, LMR value wassignificantly lower in patients with PCa than those with BPH or prostatitis ( p = 0.012). In this PSA range, free/total PSA ratio and LMR were significant factors to predict PCa. The cut-off values of LMR, free/total PSA were 3.05 and 0.15 respectively. The sensitivities, spesificities, positive predictive values (PPV) and negative predictive values using LMR cut-off, free/total PSA cut-off and their combination were assessed. Specificity and PPV of the combination group were higher (97.2%, 83.3% respectively) compared to free/total PSA cut-off group (91.6%, 76.6%) and LMR cut-off group (67.8%, 43.7%). Conclusions: LMR is a useful tool at detecting PCa especially in patients with PSA value between 4 and 10 ng/dl. The combi- nation of free/total PSA ratio and LMR improves the diagnostic accuracy more than the use of free/total PSA ratio alone. KEY WORDS: Lymphocyte-to-monocyte ratio; Prostate cancer. Aubmitted 19 August 2018; Accepted 19 August 2018 Summary No conflict of interest declared. PCa and reduced the associated mortality. However, the low specificity of PSA can lead to unnecessary biopsies, overdiagnosis and overtreatment (3). PSA is organ but not cancer-specific, therefore it may be elevated in benign conditions such as benign prostate hyperplasia (BPH), prostatitis, urinary tract infections and trauma. After detection of elevated PSA, it is recom- mended to perform prostate biopsy (PBx) which is still the gold standard method for diagnosis of PCa. However PBx is associated with several complications, including pain, hematospermia, haematuria, hema- tochezia, and potentially severe infectious complications, ranging from urinary tract infections (UTIs) and prostati- tis to sepsis (4). Although PSA is a useful tool at detect- ing PCa, concern about performing unnecessary PBx considering overdiagnosis and complications is the cru- cial problem for urologists. Some PSA-related testing parameters (e.g., PSA density, free/total PSA ratio, PSA doubling time, and prostate health index test) have been used to improve the accuracy of PCa prediction (5). Thus, new biomarkers may be needed to improve deci- sion-making regarding initial management, including whether to biopsy. Over the last decade, it has become clear that systemic inflammation plays an important role in the develop- ment and progression of cancer. The markers of the sys- temic inflammatory response are usually based around composite ratios or cumulative scores of different circu- lating white blood cells representing the systemic responses of lymphoid/myeloid tissue. The main approach is to take the ratio of different white blood cells and then apply a prognostic threshold to the ratio such that outcome is effectively stratified. The most repeatedly validated examples of this approach are the neutrophil-lymphocyte ratio (NLR) based on the ratio of circulating neutrophil and lymphocyte counts, the platelet-lymphocyte ratio (PLR) based on the ratio of cir- culating platelet and lymphocyte counts and the lympho- cyte-monocyte ratio (LMR) based on the ratio of circulat- ing lymphocyte and monocyte counts. In this study, we aimed to investigate the role of the sys- temic inflammatory response markers prior to PBx at predicting histologic≠al outcomes. DOI: 10.4081/aiua.2018.4.270 INTRODUCTION Prostate cancer (PCa) is the second most frequently diag- nosed cancer and the fifth most common cause of can- cer-associated death in men worldwide (1). Despite the recent advances in diagnostic and therapeutic approach- es, it is still a major health concern especially in devel- oped countries and especially in elderly men (2). Serum prostate-specific antigen (PSA) is widely used as a biomarker for this cancer, and its widespread introduc- tion has undoubtedly enhanced the early detection of Caglayan_Stesura Seveso 10/01/19 16:08 Pagina 270 271Archivio Italiano di Urologia e Andrologia 2018; 90, 4 Lymphocyte-to-monocyte ratio is a valuable marker to predict prostate cancer in patients with prostate specific antigen between 4 and 10 ng/dl. METHODS We retrospectively analyzed the data of 621 patients who underwent 12-core PBx between March 2013 and April 2018. PBx was performed within 4 weeks after blood tests. Age, total PSA level, free PSA level, hemoglobin level, platelet count, neutrophil count, lymphocyte count, monocyte count, prostate volume and pathology result of the patients were recorded. Patients with symptomatic prostatitis or urinary tract infection or systemic inflammatory disease or any histo- ry of anti-inflammatory drug use with- in 2 weeks before PBx were excluded. Also patients with high grade intraep- ithelial neoplasia (H-PIN) and atypical small acinar proliferation (ASAP) were excluded due to the low number of cases. Finally the patients whose PSA was less than 100 ng/ml and those had no evidence of metastasis in imaging reports were included. The patients were laid down in left lat- eral decubitus position and in the flex- ion of knees and hips. General Electric LOGIQ 100 PRO Series ultrasound device was used with 6.5 MHz rectal probe, the widest diameter of which was 23 mm. Biopsy samples were taken as 12 cores with the use of 30 cm 18 Gauge full automatic biopsy needle. Data analysis Biopsy results, Gleason scores, PSA, free/total PSA ratio, prostate volume, age, NLR results, PLR results, LMR results were assessed using the Chi- square test or Mann-Whitney U-test to determine statistically significant dif- ferences. After adjusting for confound- ing factors, univariate and multivariate logistic regression analyses were per- formed to determine the factors effect- ing PCa diagnosis. The predictive accuracy of the multivariate model was assessed using receiver operating characteristic (ROC)-derived area under the curve (AUC) analysis. The IBM SPSS software package ver- sion 21.0 (Statistical Package for Social Sciences™, Chicago, IL, USA) weas used for statistical analysis. A two-tailed P < 0.05 was considered as significant for all analyses. RESULTS A total of 800 patients who underwent transrectal ultrasound guided PBx were recorded. Of these, 179 did not meet inclusion criterias and were excluded (lack of data regarding CBC in 77 patients, presence of HPIN or ASAP in 30 patients, presence of metastasis in the imaging reports in 47 patients and presence of PSA higher than 100 ng/dl in 25 patients). Finally the data of 621 patients were inves- tigated. The mean age was 64.97 ± 6.36 years. The mean prostate volume was 71.64 ± 39.9 cc. The mean PSA and free/total PSA value were 9.86±7.43 ng/dl and 0.23 ± 0.10, respectively. The mean NLR, PLR and LMR values were 2.50 ± 1.17, 124.94 ± 51.81 and 3.84 ± 1.44, respectively. Additionally, patients were grouped with regard to histology of the biopsy. Among all Table 1. Comparison of the study parameters of 3 histology groups in entire cohort. BPH (n = 357) Prostatitis (n = 24) PCa (n = 240) p value Age, years (mean ± SD) 64,45 ± 6,08 64 ± 5,87 65,85 ± 6,74 0,004 Total PSA, ng/dl (mean ± SD) 8,82 ± 6,61 6,27 ± 2,46 11,79 ± 8,68 0,001 Free/total PSA (mean ± SD) 0,25 ± 0,10 0,29 ± 0,06 0,18 ± 0,10 0.000 Prostate volume, cc (mean ± SD) 82,82 ± 43,49 72,75 ± 51,14 54,90 ± 24,30 0.000 Comparison of the study parameters of 3 histology groups in PSA 4-10 range BPH (n = 252) Prostatitis (n = 18) PCa (n = 150) Age, years (mean ± SD) 64.58 ± 5.89 63.17 ± 6.5 66.64 ± 6.04 0.000 Total PSA, ng/dl (mean ± SD) 6.6 ± 1.63 6.13 ± 1.72 6.86 ± 1.72 0.106 Free/total PSA (mean ± SD) 0.25 ± 0.09 0.30 ± 0.06 0.19 ± 0.11 0.000 Prostate volume, cc (mean ± SD) 80.3 ± 39.6 80.17 ± 54.75 50.78 ± 19.08 0.000 PCa: Prostate cancer; BPH: Benign prostate hyperplasia; SD: Standart deviation; PSA: Prostate spesific antigen. Table 2. Mean ± SD values of the inflammation markers and p values for comparison of the histological groups in the entire cohort. BPH (n = 357) Prostatitis (n = 24) PCa (n = 240) NLR value BPH = 2,50 ± 1,22 1 0,529 0,543 (mean ± SD) Prostatitis = 2,34 ± 0,96 0,529 1 0,207 PCa = 2,51 ± 1,10 0,543 0,207 1 PLR value BPH = 124,02 ± 49,25 1 0,480 0,669 (mean ± SD) Prostatitis = 108,93 ± 39,05 0,480 1 0,512 PCa = 127,89 ± 56,30 0,669 0,512 1 LMR value BPH = 3,92 ± 1,45 1 0,485 0,047 (mean ± SD) Prostatitis = 4,11 ± 1,19 0,485 1 0,098 PCa = 3,67 ± 1,44 0,047 0,098 1 PCa: Prostate cancer; BPH: Benign prostate hyperplasia; SD: Standart deviation; PSA: Prostate spesific antigen; NLR: Neutrophile to lymphocyte ratio; PLR: Platelet to lymphocyte ratio; LMR: Lymphocyte to monocyte ratio. BPH (n = 252) Prostatitis (n = 18) PCa (n = 150) NLR value BPH = 2.52 ± 1.31 1 0.439 0.295 (mean ± SD) Prostatitis = 2.64 ± 0.94 0.439 1 0.982 PCa = 2.55 ± 1.10 0.295 0.982 1 PLR value BPH = 123.64 ± 49.58 1 0.910 0.743 (mean ± SD) Prostatitis = 114.06 ± 28.13 0.910 1 0.782 PCa = 124.13 ± 48.79 0.743 0.782 1 LMR value BPH = 3.95 ± 1.54 1 0.536 0.012 (mean ± SD) Prostatitis = 3.80 ± 1.19 0.536 1 0.533 PCa = 3.56 ± 1.33 0.012 0.533 1 PCa: Prostate cancer; BPH: Benign prostate hyperplasia; SD: Standart deviation; PSA: Prostate spesific antigen; NLR: Neutrophile to lymphocyte ratio; PLR: Platelet to lymphocyte ratio; LMR: Lymphocyte to monocyte ratio. Table 3. Mean ± SD values of the inflammation markers and p values for comparison of the histological groups in the cohort PSA 4-10 ng/dl range. Caglayan_Stesura Seveso 10/01/19 16:08 Pagina 271 Archivio Italiano di Urologia e Andrologia 2018; 90, 4 V. Caglayan, E. Onen, S. Avci, M. Sambel, M. Kilic, S. Oner, M. Murat Aydos, H. Emre Yıldız 272 the individuals, BPH was detected in 357 patients, pro- statitis was detected in 24 and PCa was detected in 240. The mean age and the mean PSA value of the PCa group were significantly higher when compared to the other groups. Also the mean prostate volume and free/total PSA ratio were significantly lower (Table 1). NLR, PLR and LMR values of the histological groups were compared. Any statistically significant difference was not observed for NLR and PLR val- ues. Mean LMR value of the patients with PCa was significantly lower than patients with BPH and prostatitis (p = 0.047) (Table 2). The patients were divided into 3 groups as; with PSA lower than 4 ng/dl, with PSA between 4 and 10 ng/dl and with PSA higher than 10 ng/dl. In the patients with PSA between 4 and 10 ng/dl, LMR value was significantly lower in patients with PCa than those with BPH or prostatitis (p = 0.012) (Table 3). Any statistically significant difference between the groups was not observed in NLR and PLR in the PSA 4- 10 ng/dl range. In the group of the patients with PSA higher than 10 ng/dl, there was not any statistically signifi- cant variation for NLR, PLR and LMR (Table 4). In this group, the presence of prostatitis could not be compared due to the low number of patients. The patients with PCa were seperated into 2 groups as patients with Gleason score 6 and patients with Gleason score 7 and above. There was no statistically significant difference between the groups in NLR, PLR and LMR value (Table 5). In the patients with PSA between 4 and 10 ng/dl, age, free/total PSA ratio and LMR were significant factors to predict PCa. Based on the AUROC curve, the cut-off points of LMR, free/total PSA and age were 3.05, 0.15 and 65.5 respectively (Figure 1). Multivariate analysis showed that LMR (HR = 1.65), age (HR = 2.77) and free/total PSA ratio (HR = 12.3) were independent risk fac- tors to predict PCa (Table 6). The sen- sitivities, spesificities, positive predic- tive values and negative predictive val- ues using LMR cut-off, free/total PSA cut-off and their combination were showed in Table 7. Specificity and positive predictive value of the combination group were higher (97.2%, 83.3% respectively) compared to the free/total PSA cut-off group (91.6%, 76.6% respectively) and LMR cut-off group (67.8%, 43.7% respectively) (Table 7). Table 4. Mean ± SD values of the inflammation markers and p values for comparsion of the histological groups in the patients with PSA higher than 10 ng/dl. BPH (n = 78) PCa (n = 72) NLR (mean ± SD) BPH = 2.63 ± 1.0 1 0.839 PCa = 2.66 ± 1.1 0.839 1 PLR (mean ± SD) BPH = 133.3 ± 51.1 1 0.965 PCa = 143±71 0.965 1 LMR (mean ± SD) BPH = 3.76 ± 1.1 1 0.892 PCa = 3.69 ± 1.3 0.892 1 PCa: Prostate cancer; BPH: Benign prostate hyperplasia; SD: Standart deviation; PSA: Prostate spesific antigen; NLR: Neutrophile to lymphocyte ratio; PLR: Platelet to lymphocyte ratio; LMR: Lymphocyte to monocyte ratio. Table 5. Mean ± SD values of the inflammation markers and p values for comparsion of the Gleason score groups in the entire cohort. Gleason 6 (n = 173) Gleason > 7 (n = 67) NLR (mean ± SD) GS 6 = 2.5 ± 1.05 1 0.454 GS > 7 = 2.57 ± 1.23 0,454 1 PLR (mean ± SD) GS 6 = 122.1 ± 46.8 1 0.082 GS > 7 = 142.8 ± 73.8 0,082 1 LMR (mean ± SD) GS 6 = 3.7 ± 1.15 1 0.177 GS > 7 = 3.6 ± 2.02 0,177 1 SD: Standart deviation; NLR: Neutrophile to lymphocyte ratio; PLR: Platelet to lymphocyte ratio; LMR: Lymphocyte to monocyte ratio; GS: Gleason score. Table 6. Univariate and multivariate analyses for predicting prostate cancer. n Univariate analysis Multivariate analysis HR 95% CI p HR %95 CI p Age (year) < 65.5 186 1 1.14-1.86 0.01 1 1.68-4.56 < 0.001 > 65.5 216 1.45 2.77 LMR value > 3.05 258 1 0.99-1.37 0.04 1 1.02-2.6 0.037 < 3.05 144 1.17 1.65 Free/total PSA value > 0.15 1 1.45-1.97 < 0.001 1 6.80-22.22 < 0.001 < 0.15 1.69 12.3 PSA: Prostate spesific antigen; LMR: Lymphocyte to monocyte ratio; HR: Hazard ratio; CI: confidence interval. Sensitivity Specificity PPV NPV Free/total PSA < 0.15 46% (69 of 150) %91.6 (231of 252) %76.6 (69 of 90) %71.7 (231 of 322) LMR < 3.050 %42 (63 of 150) %67.8 (171 of 252) %43.7 (63 of 144) %73 (171 of 234) Free/total PSA < 0.15 & LMR < 3.050 %16.6 (25 of 150) %97.2 (247 of 252) %83.3 (25 of 30) %66.4 (247 of 372) PPV: Positive predictive value; NPV: Negative predictive value; PSA: Prostate spesific antigen; LMR: Lymphocyte to monocyte ratio. Table 7. Mean ± SD values of the inflammation markers and p values for comparison of the histological groups in the cohort PSA 4-10 ng/dl range. Caglayan_Stesura Seveso 10/01/19 16:08 Pagina 272 273Archivio Italiano di Urologia e Andrologia 2018; 90, 4 Lymphocyte-to-monocyte ratio is a valuable marker to predict prostate cancer in patients with prostate specific antigen between 4 and 10 ng/dl. DISCUSSION The immune system plays an important role in cancer pathogenesis. Serum biomarkers which can be easily derived from complete blood count (CBC) are useful tools to estimate the prognosis and survival in many solid can- cers. The presence of low LMR, high PLR and high NLR values were associated with poor overall survival (OS) in the published systemic reviews (6-8). In the study per- formed by Gu et al., elevated NLR was closely associated with poor OS in PCa (9). Also a similar study in Japan, revealed that elevated NLR was correlated with both poor cancer-spesific survival (p = 0.018) and OS (p = 0.008) in patients with metastatic PCa.10 Besides, nonsteroidal anti-inflammatory drug medications have been suggested to reduce the development risk of PCa (11, 12). Additionally to the prognostic value of serum inflamma- tion markers, there are also many studies assessing the diagnostic value of those prior to the PBx with contro- versial results in the literature. In the study performed by Kamali et al., 500 patients who underwent PBx were evaluated but statistically sig- nificant difference was obtained between the NLR of the patients with positive biopsy and those with negative biopsy p = 0.112): NLR was not described as a predictive factor for positive PCa biopsy (13). In another study, 3913 men who underwent PBx were analyzed retrospectively. The NLR value was higher in the biopsy-positive group than in the biopsy-negative group (p < 0.001). Also the NLR value was significantly higher in high-grade Gleason PCa group than the biop- sy-negative group and low-grade PCa group (p < 0.001). On multivariate analyses, a higher NLR was associated with PCa detection (OR = 1.37, 95% CI: 1.017-1.850, p = 0.038) (14). Kawahara et al. investigated the data of 810 men with PSA value between 4 and 10 ng/ml who underwent PBx. NLR value was significantly higher in men with positive biopsy than in those with negative biopsy (p < 0.001). Using NLR cut-off point of 2.40 determined by the AUROC curve, positive/negative predictive values of NLR alone and NLR combined with free/total PSA ratio (cut-off: 0.15) were 56.6%/60.8% and 80.7%/60.1%, respectively (15). Huang et al. analyzed a total of 662 patients who under- went transperineal template guided PBx. In the entire cohort, any significant difference was not found in NLR when patients were grouped with regard to histology of the biopsy (cancer and no cancer) (p = 0.424). However, they observed additional significant difference in NLR Figure 1. AUROC for variables to predict prostate cancer. Caglayan_Stesura Seveso 10/01/19 16:08 Pagina 273 Archivio Italiano di Urologia e Andrologia 2018; 90, 4 V. Caglayan, E. Onen, S. Avci, M. Sambel, M. Kilic, S. Oner, M. Murat Aydos, H. Emre Yıldız 274 value (p = 0.002) when analyses were restricted to patients with PSA ranged from 4 to 10 ng/ml (cut-off value was set at 2.44). Accordingly the patients were classified into high-NLR and low-NLR group. The high- NLR showed significantly high PCa detection rate in the entire cohort and in the cohort with PSA ranged from 4 to 10 ng/ml (175/338, 142/324, p = 0.041 and 36/77, 14/87, p < 0.001 respectively) (16). Gokce et al. investigated the data of 1836 patients. Patients were divided as follows: the group with BPH, the group with prostatitis and the group with PCa. Pre-biopsy mean NLR value of the prostatitis group was significantly higher compared to the PCa and BPH groups (p = 0.0001). The mean NLR of PCa group was significantly higher com- pared to the BPH group (p = 0.002). Also, the PCa patients with high Gleason score (GS) (GS 8 and above) had a sig- nificantly higher mean NLR compared to the PCa patients with GS 5-6 and GS 7 (p = 0.0001) (17). In the present study; when evaluating the NLR, any sta- tistically significant difference was not observed based on the biopsy results. Also, cohort were seperated into 3 groups as men with PSA value of < 4, PSA between 4 and 10 and PSA of > 10 ng/dl. No statistically significant NLR difference was observed based on the biopsy results in any PSA range. We divided the PCa patients into 2 groups as the group with GS 6 and GS 7 and above. There was not a statistically significant difference between the GS groups. Additionally, controversial to the study performed by Gokce et al., we did not observe a significant highness in the prostatitis group compared to the PCa and BPH group. Our data showed that chronic prostatitis does not effect the inflammation markers derived from CBC con- siderably. Kaynar et al. retrospectively reviewed the data of 201 patients. Pathological sample results were categorized as chronic prostatitis, BPH and PCa. PSA levels were also categorized as 0-4 ng/ml, 4-10 ng/ml, and 10 ng/ml and above.Any statistically significant difference was not observed between benign or malign groups in terms of age, NLR and mean prostate volume. Statistically signifi- cant differences were present only in the PSA 10 ng/ml and above group related to mean PLR values (p: 0.044) (18). In another study, PLR value was statistically higher in PCa group than in BPH group while NLR value was not (19). In our study, pre-biopsy PLR value was not associated with higher PCa detection rate in any PSA range or in any Gleason score range. To our knowledge, there is not any study assessing the predictive value of LMR for PCa risk. In the present study, LMR was the only inflammation marker associated with PCa diagnosis (p = 0.047 ). Interestingly, in the 4-10 ng/dl PSA range LMR value was extremely lower in patients with positive biopsy than those with negative biopsy (p = 0,012). In this group free/total PSA ratio lower 0.15 and age higher than 65.5 were also risk factors to predict PCa. Additionally our data showed that, when LMR and free/total PSA cut-off values were combined, the specifici- ty and positive predictive value were higher compared to the use of LMR or free/total PSA ratio alone. There are many limitations in our study. Firstly, our data derived from retrospective cohort. 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Ploussard G, Nicolaiew N, Marchand C, et al. Risk of repeat biopsy and prostate cancer detection after an initial extended nega- tive biopsy: longitudinal follow-up from a prospective trial. BJU Int. 2013; 111:988-996. Correspondence Volkan Caglayan volkantuysuz@hotmail.com Efe Onen efe17@yahoo.com Sinan Avci sinavci@yahoo.com Murat Sambel muratsambel@hotmail.com Metin Kilic kilicmetin@yahoo.com Sedat Oner sedatoner@yahoo.com Mustafa Murat Aydos mudos16@hotmail.com Halil Emre Yıldız halilemreyldz@gmail.com University of Health Sciences, Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey Caglayan_Stesura Seveso 10/01/19 16:08 Pagina 275