Association between the neutrophil‐to‐lymphocyte ratio and intravesical prostatic protrusion in men with benign prostatic hyperplasia

Abstract Objective To analyze the association between neutrophil‐to‐lymphocyte ratio (NLR) and intravesical prostatic protrusion (IPP) in men with benign prostatic hyperplasia. Methods Two hundred and fifty men aged >50 years who presented with lower urinary tract symptoms at our institution between 2014 and 2018 were analyzed. Pearson's method was used for analysis of the correlation between NLR and IPP. Multivariate logistic regression analysis was used to identify predictors of IPP. Further analysis according to total prostate volume (TPV) was performed. Results The NLR correlated positively with IPP (Pearson's r = 0.459, P < 0.001) and was an independent predictor of IPP ≥10 mm (odds ratio, 2.95; 95% confidence interval, 1.59–5.47; P = 0.0006). Among the 142 men with prostates <40 cm3, mean NLR was 2.50 ± 0.71 in those with IPP ≥10 mm and 1.71 ± 0.57 in those with IPP < 10 mm (P < 0.001). The NLR differed significantly between those with a prostate <40 cm3 and IPP ≥10 mm and those with a larger prostate and IPP < 10 mm (2.50 ± 0.71 vs 2.07 ± 0.77, respectively; P = 0.020). Conclusions NLR can be used as a surrogate marker for presence of IPP. Its clinical value would be especially important in men with a small prostate gland but high IPP. The NLR seemed to be more strongly correlated with IPP than with TPV.


| INTRODUCTION
Male lower urinary tract symptoms (LUTS) have conventionally been considered as merely the result of age-related prostatic enlargement.
However, such a simple explanation is not accepted due to the heterogenous characteristics of LUTS and their relationships with systemic diseases. 1 Numerous studies have demonstrated that benign prostatic hyperplasia (BPH) may be caused by a chronic inflammatory process or immune cell infiltration. [2][3][4][5][6] In response to prostatic inflammation, immune cells generate cytokines that affect other cells to produce growth factors. This enhances the proliferation of stromal and epithelial cells, and this is sustained by an autoimmune mechanism, leading to an increase in prostate volume. 5 Chronic inflammation can cause tissue damage, potentially resulting in a repetitive process of wound healing which is associated with BPH. [3][4][5][6] systemic inflammatory response, metabolic syndrome, outcomes in oncologic fields, cardiovascular disorders, and other medical disorders. [7][8][9][10][11][12][13] There have also been reports of its significance in urology.
For example, associations have been reported with biochemical failure in prostate cancer, 14 the cancer-specific survival of patients with metastatic renal cell carcinoma, 15 and the spontaneous passage of ureteral stones. 16 Ozer et al. 3 showed an association of NLR with severe LUTS and the progression of BPH. Similarly, Tanik et al. 2 suggested NLR was a predictor of BPH progression. However, there are only limited data on an association between NLR and intravesical prostatic protrusion (IPP), an anatomical feature caused by the growth of prostatic lateral and median lobes. Considering the role of IPP as a marker of bladder outlet obstruction (BOO), [17][18][19][20] we need well-designed studies to establish how prostatic morphological features (especially the degree of IPP, as well as the total prostate volume [TPV] and the transitional zone volume [TZV]) vary according to the NLR. We aimed to analyze the association between NLR and the degree of IPP. To our knowledge, this is the first study on this topic.

| Ethics statement
This study was approved by the Institutional Ethics Committee of Catholic Kwandong University College of Medicine after reviewing the study protocol and procedures (IS18RISI0076). The requirement for written consent was waived because of the retrospective nature of the study. The data were anonymized before the analysis.

| Study population
Medical records from 250 men aged >50 years who presenting with LUTS at our outpatient clinic between January 2014 and December 2018 were retrospectively analyzed. We collected data on patient demographics and clinical characteristics, including age, body mass index, prostate-specific antigen values, TPV and TZV on transrectal ultrasound (TRUS), degree of IPP, and neutrophil/lymphocyte counts from peripheral blood samples. The peripheral blood sampling for NLR assessment was done just before performing TRUS. The exclusion criteria included the following: suspected bacterial or viral infection by laboratory results; malignancy; autoimmune or systemic inflammatory diseases that may influence NLR values; the use of anti-inflammatory drugs or 5-alpha reductase inhibitors; immunotherapy; urinary tract stone; and history of prostatic surgery. Patients with incomplete data were excluded from the statistical analysis.

| Measurement of the prostate
TPV, TZV, and IPP were measured using TRUS. TPV was automatically calculated by multiplying together the largest antero-posterior, transverse, and cephalocaudal diameters, and multiplying this by 0.52.
Measuring TZ was done in a similar manner, as previously presented. 21 Determination of IPP was done after checking the vertical length between two points; end of the protrusion and base of bladder. 18 All the measurements were made by a single urologist (MSC).

| Statistical analysis
To compare continuous and categorical variables, Student's t test (or Kruskal-Wallis test) and the χ 2 test were performed. Pearson's method was used for the correlation analysis. Multivariate logistic regression models that included all the collected variables were constructed to identify the factors that were predictive of IPP. The cutoff values were determined using the area under the receiver operating characteristic (ROC) curve. The statistical analyses were performed with R statistics version 3.5.1. Results were considered significant at P < 0.05. Table 1   the patients had IPP ≥10 mm. In the overall cohort, there was a significant difference in NLR according to IPP (P < 0.001, Table 2). Pearson correlation analysis revealed a positive correlation between NLR and IPP (P < 0.001, r = 0.459; Figure 1). The predictors for IPP ≥10 mm are presented in Figure 2. In the multivariate logistic regression analysis, NLR was found to be an independent predictor of IPP  Figure 3).

| RESULTS
For further analyses, we used two cut-off values: 40 cm 3 for TPV and 10 mm for IPP ( We also compared NLR between the patients with TPV <40 cm 3 and IPP ≥10 mm (n = 22, group 2) and those with TPV ≥40 cm 3 and IPP <10 mm (n = 69, group 3), which again revealed a significant difference (2.50 ± 0.71 vs 2.07 ± 0.77; P = 0.020; Table 3). Table 4 shows the result when we compared NLR between the patients with small (<40 cm 3 ) prostates or prostates with IPP < 10 mm (n = 211) and those with larger prostates and IPP ≥10 mm (n = 39).    IPP results from the growth of prostatic lateral and median lobe.
Several authors have reported that IPP might cause an obstruction of 'ball valve' type and malfunction of the funneling action by the bladder neck. 18,28 This protrusion has been reported to be significantly correlated with greater obstructive IPSS, decreased Q max , and increased postvoid residual urine volume. 17,18,20 Thereafter, numerous studies have examined IPP and it has been reported to be a valuable anatomical marker for determining BOO which should be confirmed by urodynamic study. 17 Lim et al. 20 reported that IPP was a better predictor for BOO than was prostate volume, emphasizing that the existence of BOO is important to the urologists who can offer a more proactive treatment strategy such as surgery.
For these reasons, we focused in this study on the association between NLR and IPP. Although several studies 2,3 have reported associations between NLR and TPV (or TZV) or BPH progression, there was no report showing an association between NLR and IPP.
The IPP threshold for defining BOO is recognized to be 10 mm, as was highlighted in a systematic review; this reported that IPP > 10 mm had a similar diagnostic accuracy as uroflowmetry alone. 29 We therefore used the cut-off value of 10 mm for IPP in the present study.
NLR showed a significant correlation with IPP ( Figure 1). In multivariate logistic regression analysis (Figure 2), NLR was found to be an independent predictor of IPP ≥10 mm. The cut-off value for NLR predicting IPP ≥10 mm in our cohort was 2.2. A possible explanation of the correlation between NLR and IPP may be that chronic inflammation and the repetitive wound healing process results in a specific morphological change, intravesical protrusion of the prostatic median lobe.
Our analysis of patients with relatively small TPV (<40 cm 3 ) showed that high NLR was associated with a high likelihood of having IPP ≥10 mm (group 1 vs group 2, Table 3). This unique group of patients having a small prostate gland with high IPP (and who would therefore be expected to be unobstructed according to TPV size criteria) is important because they experience obstruction during voiding due to the 'ball valve' effect caused by the IPP. 20 As seen in Table 3, the difference in the NLR according to IPP was greater in the smaller prostate group than in the larger prostate group (1.71 vs 2.50 in group 1 vs 2 and 2.07 vs 2.50 in group 3 vs 4), although both had statistically significant differences.
We also compared NLR between the patients with small TPV (<40 cm 3 ) and IPP ≥10 mm (group 2) and those with TPV ≥40 cm 3 but with IPP < 10 mm (group 3). Interestingly, those with a small prostate and high IPP showed much higher NLR values than those with a larger prostate but without IPP (2.50 ± 0.71 vs 2.07 ± 0.77; P = 0.020, Table 3). This finding suggests that NLR is more closely related to the IPP of the median lobe than to TPV; however, a future study with a larger number of cases is needed to confirm this.
When we compared NLR between the patients with small (<40 cm 3 ) prostates or prostates with IPP <10 mm and those with larger prostates and IPP ≥10 mm, those with a larger prostate and high IPP showed much higher NLR values than those with a smaller prostate or a prostate with IPP <10 mm (Table 4). This finding is in line with a previous report 3 which demonstrated that more patients study revealed a positive correlation between NLR and IPP. We think these findings provide additional data for future study to elucidate whether NLR can be used to determine who may benefit most from the anti-inflammatory medication.
Although our study revealed a novel finding, the retrospective nature and relatively small number of patients of this investigation is the main limitation. Second, we were unable to clearly investigate the pathogenesis of the formation of IPP in patients with high NLR.
Clearly, inflammation is not the only factor to cause IPP, and it is likely that various factors are associated with this morphological change. In particular, in men with normal NLR but high IPP, the IPP may have other causes than inflammation. On this issue, further studies of men with IPP at initial presentation are needed to determine whether the progression of IPP over time differs according to NLR. Nevertheless, we believe the present study provides adequate preliminary data with respect to the association between NLR and IPP. Finally, generalization of this study's results should be drawn with prudence, because all patients we studied were selected from a single institution in Korea.
In conclusion, our analysis demonstrated that NLR can be used as a surrogate marker for presence of a specific morphological change, IPP. The clinical value of NLR would be especially important in men with a small prostate gland but high IPP. The NLR was more strongly correlated with IPP than with TPV. Further studies are needed to confirm our findings.