The association between histological prostatitis and benign prostatic hyperplasia: a single-center retrospective study

Abstract Objective To investigate the relationship between histological prostatitis (HP) and clinical parameters related to benign prostatic hyperplasia (BPH) in male. Method The clinical data of 196 BPH patients who underwent transurethral resection of the prostate were collected. According to the results of hematoxylin-eosin (H&E) staining of prostate tissue, patients were divided into two groups: BPH with HP group and BPH without HP group. Differences in acute urinary retention (AUR), prostate volume (PV), serum sex hormones, lower urinary tract symptoms (LUTS) related parameters, and systemic inflammation indicators were compared between the two groups. SPSS software v.25 was used for statistical analysis. Results Compared with the BPH without HP group, the BPH with HP group had greater AUR rate, PV, total IPSS, and IPSS-storage in BPH with HP group (p < 0.05). However, there were no significant differences in IPSS-voiding, post-void residual volume, maximum urinary flow rate, serum sex hormones, and systemic inflammation indicators between the two groups (p > 0.05). Conclusions This study suggests that patients with HP have larger PV, more severe LUTS, and a higher risk of AUR. HP is closely related to BPH and may be a key factor in the occurrence and clinical progress of BPH.


Introduction
Benign prostatic hyperplasia (BPH) is a common benign disease in older men, and its incidence increases with age [1]. Analysis of pertinent data demonstrated that more than 70% of men between the ages of 60 and 69 are suffering from BPH disease, and more than 90% of men aged 70 years had pathological BPH [2]. The appearance of lower urinary tract symptoms (LUTS) secondary to BPH brings great distress to the patient [3]. Moreover, bladder outlet obstruction associated with BPH can cause hydronephrosis, which in turn negatively affects graft function [4]. Thus, delayed treatment of clinical BPH is considered as an independent risk factor for transplant failure in kidney transplant recipients [5]. The goal of BPH therapy is to improve LUTS and prevent or reduce complications, and understanding the etiology of BPH may have important implications for the treatment of this disease. Abundant evidence suggests that agingrelated metabolic disturbances, changes in sex hormones, multiple cytokines, and chronic inflammation are the risk factors for BPH [6-9]; however, the specific pathogenic mechanisms remain unclear.
In recent years, the etiology hypothesis has shown that inflammation is involved in the occurrence and development of BPH, and the specific role of inflammation in the development of BPH is mainly manifested in the strong correlation between histological prostatitis (HP), clinical symptoms, and prostate volume (PV) [10][11][12]. HP is frequently detected in the prostate tissue of BPH patients [13]. According to the published studies, continuous inflammatory infiltrate leads to tissue damage and to a chronic process of wound healing that might subsequently determinate prostatic enlargement. Therefore, this study aims to explore the relationship between HP and BPH-related parameters to better understand the etiology of BPH.

Patients and selection criteria
This study retrospectively analyzed the clinical data of 196 BPH patients who underwent transurethral resection of the prostate (TURP) at Nanchong Central Hospital (Sichuan, China) from December 2019 to January 2021. The procedure was performed by an experienced surgeon. Patients were excluded if they had one of the following conditions: (1) had complaints of the perineum, suprapubic pain, or urination pain, (2) indwelling catheter before surgery, (3) combined urinary tract tumors or prostatitis, (4) preoperative urinary bacteria culture-positive, (5) urethral stricture before surgery, a1 adrenergic antagonists, cholinergic drugs, 5-a reductase inhibitors or phosphodiesterase type 5 inhibitors within one month before surgery, (6) had a history of prostate surgery, (7) had other major diseases that are not suitable for surgery. This study was approved by the Institutional Review Boards of Nanchong Central Hospital, and all the participants entering the study provided written informed consent.

Data collection and measurements
All patients completed the International Prostate Symptoms Score (IPSS) and quality of life (QoL) score questionnaire translated in Chinese and underwent a baseline survey that focused on anthropometric and socio-demographic characteristics, as well as the baseline BPH components measurements. The incidence of acute urinary retention (AUR) of all patients was collected. Weight (kg) and height (cm) were measured by a trained nurse using a standardized protocol. Body mass index (BMI) was as weight divided by the square of the height (kg/m 2 ). PV was measured by transrectal ultrasound and is calculated using the following formula for an elliptic volume (height � width � length � p/6), and post-void residual urine volume (PVR) was also measured by ultrasound. The maximum urinary flow rate (Qmax) was evaluated by uroflowmetry, and the voided volumes had to be > 150 ml to avoid bias. Blood samples were drawn from participants after a 12-h fast, and serum prostate-specific antigen (PSA), testosterone (T), estradiol (E 2 ), and E 2to-T ratio (E 2 /T) were recorded. In addition, neutrophilto-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) were obtained based on the patient's complete blood count to assess systemic inflammation. NLR and PLR were calculated as absolute neutrophil count/absolute lymphocyte count and absolute platelet count/absolute lymphocyte count, respectively. SII was calculated as platelet count � neutrophil/lymphocyte count.
Prostate tissues from all patients are sent for pathological examination. The specimens were fixed in formalin, dehydrated, embedded in paraffin, and sliced at 5 mm each, and finally hematoxylin-eosin (H&E) stained. Two senior pathologists evaluated the stained sections, and according to the histopathological classification recommended by the Chronic Prostatitis Collaborative Research Network and (CPCRN) the International Prostatitis Collaborative Network (IPCN) in 2001 [14], the pathological sections of the patients were classified for inflammation. The grade of HP ranges from 0 to 3, and its specific classification criteria are given in Supplementary Table 1.

Statistical analysis
Comparing the differences in clinical characteristics between patients with and without HP. Continuous variables are presented as mean ± standard deviation, and the Kolmogorov-Smirnov test was used to determine the normal distribution of variables. Student's independent t-test or Mann-Whitney U-test compared the differences between the two groups. Categorical variables are presented as a percentile, and differences between the two groups were tested using Chi-square tests. All statistical analyses were performed using SPSS v.25 (IBM Corp., Armonk, NY, USA). A two-sided p value < 0.05 was considered statistically significant.

Patients' characteristic
In this study, 196 patients with BPH were analyzed. Among them, 154 cases (78.6%) in the BPH with HP group, and 42 cases (21.4%) in the BPH without HP group. The clinical characteristics of the study subjects are shown in Table 1. In terms of the HP group, there were 64 cases (41.6%) with mild inflammation, 51 cases (33.1%) with moderate inflammation, and 39 cases (25.3%) with severe inflammation (Figure 1).
The results of this study indicated that compared with the BPH without HP group, the incidence of AUR, PV, resected volume, total IPSS, IPSS-storage, and QoL was higher in the BPH with HP group (p < 0.05), whereas there were no significant differences in age, BMI, the rate of hypertension and diabetes mellitus, PSA, IPSS-Voiding, Qmax, PVR, T, E 2, E 2 /T, NLR, PLR, and SII between the two groups (p > 0.05).

Discussion
At present, the relationship between chronic inflammation and BPH has gradually attracted the attention of researchers. Studies have found that inflammatory cells gather significantly around the prostate gland, which indicates that the prostate immune response may start from this area [15]. Epithelial injury exposes periglandular tissues to prostatic secretions, which are highly proteolytic activity. These secretions can destroy connective tissue cells and dissolve major matrix regions, and allow autoantigen molecules to widely enter the prostatic immune system [16]. In addition, some irritants, such as infectious factors, urinary reflux, metabolic syndrome, changes in sex hormones, the aging process, and autoimmune response, participate in inflammation infiltration through different molecular pathways and cause prostate immune disorders [17]. Thus, BPH may be an immune inflammatory disease, and the development and progression of BPH may be associated with chronic inflammation [18,19]. HP infiltration is a common pathological phenomenon in the prostate tissue of patients with BPH. A multicenter REDUCE study showed that 77.6% of 8224 patients were affected by HP [20]. Cao et al. [21] also reported that the prevalence of HP associated with BPH was 91.7%. This study indicated that the incidence of HP in BPH patients is 78.6%, which is roughly the same as the results reported in the previous literature. Moreover, the HP in BPH also shows a certain correlation with the clinical characteristics of patients. Nickel et al. evaluated the relationship between inflammation of prostate tissue, PV and LUTS, and they found that the degree of HP was positively correlated with the size of PV. Patients with chronic inflammation on biopsy had higher PV than those without inflammation (46.5 vs. 43.4 ml, p < 0.001), and these patients had higher total IPSS [20]. Robert et al. [13] demonstrated that compared with patients without inflammation, patients with HP had larger PV, higher total IPSS, and greater risk of AUR. The MTOPS study also confirmed that stronger inflammation in the prostate transition zone is related to the progression of LUTS and the occurrence of AUR [22]. In our study, although the IPSS-Voiding, Qmax, PVR, and PSA were not significantly different between the two groups, PV, IPSS total score, IPSS-Storage, QoL, and the incidence of AUR in the BPH with HP group were all higher than those in the BPH without HP group. These data reveal a statistically and clinically significant association between HP and the severity of LUTS in patients, which supports the hypothesis that HP at least contributes to the clinical progression of BPH.
As the target organ of sex hormones, the development and growth of the prostate are jointly regulated by T and E 2 . According to reports, the T level of 20year-old men is the highest, and thereafter it has steadily decreased by 1-2% every year [23]. The E 2 level remains constant or slightly decreases, which leads to an increase in the E 2 /T in the circulation and prostate [24]. Studies have also shown that sex hormone changes related to aging may be related to the occurrence and progression of BPH [9]. Liao et al. [25] found that serum T and E 2 levels are not correlated with PV. A cross-sectional study of 2308 patients who underwent a health check showed that there was no significant correlation between the T level of men and the severity of LUTS [26]. However, Wu et al. [27] reported that serum T was inversely proportional to total IPSS score, IPSS voiding period score, and nocturia symptoms. They also found E 2 /T was proportional to IPSS, but the E 2 level had nothing to do with IPSS. This indicated that the severity of LUTS in patients with BPH is related to the T and E 2 /T, and patients with lower T levels have increased nocturia. Recently, Zheng et al. [28] also evaluated the correlation between serum hormone levels and clinical symptoms in patients with BPH. They found patients with higher T levels had greater PV, and those with greater E 2 /T had lower Qmax, whereas in E 2 there was no significant correlation with clinical symptoms. Although these studies presented different results, they reflect the correlation between T and E 2 levels and the clinical symptoms of BPH patients to some extent.
There is growing evidence that too high, low T, and E 2 levels, may contribute to chronic inflammation of the prostate tissue, suggesting that T and HP can influence each other, resulting in pathological changes in patients with BPH prostate stromal and epithelial tissue, thus affecting the occurrence and development of BPH [23,29]. This study revealed that compared with the pure BPH group, the average T, E 2 level, and E 2 /T of the BPH with histological inflammation group tended to increase, but the difference between the two groups was not statistically significant. Considering the complex pathogenesis of BPH, further studies are needed to better explain the internal relationship among hormones, HP, and BPH.
Currently, systemic inflammation markers based on complete blood counts have been proposed as surrogate markers for various diseases because they are inexpensive and readily available. Moreover, risk factors related to BPH, such as diabetes mellitus, obesity, and metabolic syndrome have also been confirmed to be correlated with systemic inflammation [30][31][32]. Tanik et al. [33] found that NLR was positively associated with IPSS and negatively correlated with Qmax. Ozer et al. [34] reported that NLR was associated with severe symptoms and progression of BPH. In a recent study, Kang et al. [35] found that higher NLR was significantly correlated with the presence of BPH. These results indicate that NLR may play an important role in the occurrence and development of BPH. It should be noted that Zhang et al. [36] reported that NLR was significantly associated with prostate tissue inflammation. However, our analysis indicated that NLR was similar between the patients with and without HP groups. In addition, no significant differences in PLR and SII were also observed between the two groups. Although inflammation markers in the blood, such as NLR, may be the potential candidate markers for BPH, it is difficult to assess the state of HP by measuring clinical inflammation markers [36]. Prospective studies are needed to confirm the relationship between NLR and HP.
Compared with previous studies, the advantage of this study lies in the preliminary discussion of the relationship between sex hormone levels, blood inflammation markers, and HP. We believe that our data add additional evidence for the influence of local and systemic inflammation on the occurrence and clinical progression of BPH. Of course, as a retrospective study, this study has inevitable flaws. First, the sample size of the study was relatively small (only 196 patients were included), which may have influenced the study's final results. Second, the study was conducted in a single medical center, which may be affected by selection bias and may not accurately represent the overall population. Third, serum sex hormone levels were measured only once, similar to most previous studies. A single measurement provides an imperfect estimate of the patient's usual hormonal status and may be affected by individual and analytical errors. Another limitation was the older average age of patients in the study, which could lead to other complications of aging that affect BPH, such as diabetes mellitus or metabolic syndrome.

Conclusions
This study suggests that BPH patients with HP have greater PV, more severe LUTS, and a higher risk of AUR. HP is closely related to BPH and may be a key factor in the occurrence and clinical progress of BPH.