Inflammatory lesions associated with BPH impact on post TURP symptoms

Inflammatory lesions associated with BPH impact on post TURP symptoms E. Alexandrescu, D. Georgescu, B. Geavlete, P. Geavlete Depatment of Urology, St John Clinical Emergency Hospital, Bucharest, Romania Clinical studies Abstract Introduction: Association between BPH and prostatic inflammation has been well recognized. The ways that inflammation influences prostatic growth and symptoms progression are still under investigation and generated both interest and controversies. The aim of this study was to assess the impact of prostatic inflammation on early post TURP symptoms. Material and methods: We analyzed 100 consecutive patients who underwent TURP for symptomatic BPH in our clinical department between January and July 2012. The patients with other possible causes of LUTS or with a history of prostatitis within 1 year prior to surgery were excluded. On the basis of the histopathological reports we divided the patients in 4 groups: patients without inflammatory lesions associated to BPH were included in group 1. Group 2, 3 and 4 included patients with mild, moderate and severe inflammation, respectively. All tissue samples were analyzed by the same pathologist. The correlation between the presence and the degree of inflammation and different pre, intra and postoperative parameters were assessed. The patients were evaluated at 6 weeks and 6 months. Results: The comparative evaluation of preoperative parameters of patients from the 4 groups demonstrate higher IPSS, PSA, prostate volume and urinary retention rate values in patients with inflammation on histopathological exam. No significant differences were described concerning the operative time, catheterization and hospital stay period or intra- and postoperative complications. The evaluations at 6 weeks and 6 months demonstrate differences only in symptoms, Qmax and residual volume being relatively similar in the 4 groups. During the follow-up period recatheterisation was necessary in one patient from group 2 and 2 patients from group 4. Conclusions: The presence and the degree of inflammation on histopathological exam correlate with higher IPSS, PSA and prostatic volume values and increased risk of urinary retention. Postoperative, significant differences exist only for symptoms. Key words: BPH, inflammation, TURP, symptoms, postoperative Correspondence: Georgescu Dragoø Adrian Spitalul Clinic de Urgenta Sf. Ioan, Clinica de Urologie Øoseaua Vitan-Bârzesti Nr. 13, Sector 4, 042122 Bucureøti Tel/Fax: 021-334.50.00 E-mail: dgeorgescu2000@yahoo.com nr. 4 / 2013 vol 12 Revista Românæ de Urologie 19

Clinical studies Introduction Frequent association of benign prostatic hyperplasia (BPH) and inflammation has generated much interest in the recent decades. The precise mechanisms that inflammation influences the growth of prostate and the development of symptoms in patients with BPH are still under investigation. The incidence of inflammation (acute but especially chronic) on prostate biopsy specimens or in tissue obtained by transurethral resection of the prostate (TURP) varies between 43 % and 98 % [1, 2]. In the literature has been published many studies and data on various histological and clinical correlations of this association. Most of them were focused on the type of inflammation associated with BPH, predominance of specific inflammatory cells, inflammation influence on PSA and prostate volume, symptom progression and the risk of complications and surgery [3]. The current concern is, however, to evaluate possible drug treatments for inflammation that probably trigger for the histological and clinical progression of BPH. For this reason there are several recent studies in the literature related to the medical treatment of patients with BPH and inflammation, but only limited data regarding the impact of associated inflammation on postoperative evolution in patients undergoing surgery for BPH. For this reason, the aim of this study was to assess the influence of associated inflammation with the development of postoperative patients who underwent TURP. histopathological reports, patients were divided into four groups according to the scale proposed by Irani [4]: patients without associated inflammatory lesions were included in group 1, patients with BPH and mild inflammation in group 2 (fig. 1), those with moderate inflammation in group 3 (fig. 2) and those with severe inflammation associated in group 4 (fig. 3). All tissue samples were analyzed by the same pathologist. Fig. 1 BPH with diffuse interstitial stromal inflammatory infiltrate grade 1 Fig. 2 BPH with inflammatory infiltrate and no tissue destructions ( grade 2) Material and methods The study was conducted on a group of 100 patients operated in the Urology Clinic of Emergency Hospital St. John between January 2012 and July 2012. Patients with other causes of lower urinary tract symptoms (urethral strictures, neurological disorders, bladder stones, etc.) and those with a history of prostatitis in the last 12 months prior to surgery were excluded from the study. All patients had sterile urine cultures and normal number of leukocytes in preoperative urinalysis. We considered that a high number of leukocytes in urinalysis may signify the presence of inflammation induced by infection in adjacent tissues, including the prostate. Assessment protocol included preoperative patient history to calculate IPSS score, digital rectal exam, abdominal ultrasound to determine prostate volume and residual volume, PSA and Qmax. Based on Fig. 3 HBP with diffuse interstitial inflammatory infiltrate grade 3 and massive tissue destructions Based on these data, we evaluated the correlations between the presence and degree of inflammation and different pre-operative parameters: prostate volume, IPSS score, residual urine volume, presence of urine retention (AUR). We also studied the immediate postoperative aspects such as intra- and postoperative complications rate, duration of catheterization, length of hospital stay and re-catheterization rate for all groups. The patients were re-evaluated at 6 weeks after surgery and then at every 6 months. Control at 6 weeks included clinical and rectal examination, abdominal 20 Revista Românæ de Urologie nr. 4 / 2013 vol 12

ultrasound to determine the residual urine volume and Qmax. Assessment at 6 months included the determination of PSA. Results After histopathological evaluation of resected tissue, patients were included in 4 groups as follows (Table 1): Group 1 (without associated inflammation) - 34 patients Group 2 (with mild inflammation) - 28 patients Group 3 (with moderate inflammation) - 24 patients Group 4 (with severe inflammation) - 14 patients. The average preoperative IPSS score was 23.1. In the group of patients without inflammation was 22.5 compared to 23.4 in those with inflammatory issues highlighted histopathological. The differences were significant, especially in patients with severe inflammation (26.2). PSA has values which ranged from 1.7 ng/ml in group 1 to 3.7 ng/ml in patients in group 4. And in terms of the average prostate volume, there were differences depending on the presence of inflammation, this being 48.5 cc in patients with non-inflammatory aspects and 54.2 cc in those with inflammation. Similar, the differences in the case of PSA were more importants in patients with severe inflammation (62.3 cc). In all seven patients who presented preoperative urinary retention, inflammatory factors were detected on histopathological examination. Clinical studies Table 1. Preoperative characteristics of the patients in the study group Number IPSS PSA Prostatic Qmax Urinary Residual of cases volume retention volume Group 1 34 22,5 1,7 n ml/s 48,5 cc 7,3 ml/s - 68 cc Group 2 28 21,4 1,9 ng/ml 45,8 cc 7,2 ml/s 1 65 cc Group 3 24 24,2 2,5 ng/ml 59,2 cc 6,5 ml/s 3 82 cc Group 4 14 26,2 3,7 ng/ml 62,3 cc 5,8 ml/s 3 104 cc There were no significant differences in the duration of surgery, the rate of intra or immediate postoperative complications (Table 2). Table 2. Perioperative issues in the 4 groups Duration Catheterisation Hospital Intraoperative Early of surgery period stay complications postoperative complications Group 1 38 min 72,5 hours 4,3 days 5,9% 2,9% Group 2 40 min 74,6 hours 4,5 days 7,1% 7,1% Group 3 46 min 73,3 hours 4,3 days 4,1% 8,3% Group 4 43 min 75,4 hours 4,8 days 7,1% 7,1% The patients evaluation at 6 weeks (Table 3) showed difference regarding symptomatology, this being significantly improved in patients without inflammation, while the residual urine volume and Qmax and were very similar in the four groups. Table 3. Results at 6 weeks IPSS Qmax Residual volume Group 1 5,1 23,4 ml/s 25 ml Group 2 6,2 24,5 ml/s 31 ml Group 3 8,2 22,8 ml/s 28 ml Group 4 8,5 23,2 ml/s 32 ml In addition, assessment at 6 months (Table 4) showed no difference in the Qmax, residual urine volume or PSA values, but the differences being main- nr. 4 / 2013 vol 12 Revista Românæ de Urologie 21

Clinical studies tained regarding to symptoms. During follow-up, recatheterization was necessary for a patient in group 2 and for 2 patients in group 4. Table 4. Results at 6 months IPSS Qmax Residual volume PSA Group 1 5,2 22,4 ml/s 22 ml 0,82 ng/ml Group 2 5,4 23,5 ml/s 34 ml 0,76 ng/ml Group 3 7,2 22,5 ml/s 25 ml 0,92 ng/ml Group 4 7,6 23,2 ml/s 37 ml 1,2 ng/ml Discussions Benign prostatic hyperplasia (BPH), the most common urological disease of elderly men, is defined histologically by epithelial and stromal cells hyperplasia of the transition zone and periurethral area of the prostate. It is a progressive disease, histological incidence of BPH is over 70% in men 61 to 70 years and over 90% of those over 70 years of age [5]. Enlargement of the prostate leads to bladder neck obstruction and clinically to the development of lower urinary tract symptoms, the risk of acute urinary retention and the need for surgery [3, 6]. The literature data has shown that there is not a close correlation between histological BPH and symptoms, meaning that the presence of histologic BPH does not necessarily imply the occurrence of clinical symptoms. Although highly studied, BPH pathogenesis remains unclear. It was clearly demonstrated that androgens play a key role in pathogenesis, but at the same time, there are multiple theories regarding other factors involved in the development and progression of this disease. More recent data suggest that inflammation is an important factor that affects the growth of the prostate and progression of the symptoms. Both acute inflammation, but especially the chronic inflammation was frequently detected in fragments of tissue obtained by prostate biopsy or after TURP with an incidence ranging between 43% and 98% [1]. In our study, inflammation was detected in 66% of cases. The association of histological BPH - inflammation aroused much interest and, therefore, there are numerous published data in the literature on the frequency of this association. These include MTOPS (Medical Therapies of Prostatic Symptoms) and REDUCE (Reduction by Dutasteride of prostate Cancer Events), regarded as two of the largest randomized clinical trials conducted, both in terms of number of patients enrolled and the duration of the deployment period. Thus, based on the data provided by REDUCE study, Nickel et al reported the identification of association of chronic inflammation in 77.6% of patients enrolled, while acute inflammation was present in only 16.5% of cases [7]. In another study, the same author prospectively examined the tissue specimens obtained after TURP in 80 patients with BPH and no history or symptoms of prostatitis and incidence of inflammation was 100% [8]. Analysis of prostatic biopsy specimens collected at the enrollment in MTOPS study identified the presence of acute prostatic inflammation in 2.6% of patients while chronic inflammation had an incidence of 43% [9]. An increased incidence of association HBP - chronic inflammation, ranging between 43% and 98% is confirmed by Kohnen and Drach after the analysis of post TURP tissue samples from patients with no symptoms of prostatitis [10]. Once demonstrated the frequent association of inflammation in patients with BPH there were also studied and its implications on prostate volume, lower urinary tract symptoms progression and risk of acute urinary retention. Thus, the 2.6% of patients enrolled in the MTOPS study on which it was identified the presence of acute inflammation, the prostate volume were significantly higher compared with patients without associated inflammation, respectively 41.1 ml vs. 36.8 ml [9]. Di Silverio et al found, after analysis of tissue specimens obtained by TURP, that the incidence of chronic inflammation founded parallel increases with prostate volume from 8.9% in prostates volume of 30-39 ml at 61.4% in prostates of 80-89 ml [11]. In our study group there were also significant differences, prostate volume being 48.5 cc in those without inflammatory aspects comparing with 54.2 cc in those with inflammation. Several authors have suggested that the presence of histologic inflammation is a predictor of clinical progression of BPH. The impact of BPH associated inflammation on LUTS and risk of urinary retention was probably the most intensively studied by Roehrborn who has published several articles on this subject, the most important being that result from the analysis of data generated by MTOPS study. Follow-up of the patients enrolled in this study demonstrated that regardless of the treatment arm they were included, the progression of symptoms and the risk of urinary retention or surgery was higher in patients with associated inflamma- 22 Revista Românæ de Urologie nr. 4 / 2013 vol 12

tion. The progression of symptoms was described in 13.2% of patients without inflammation, need for surgery in 3.9%, and no patients in this category did not developed acute urinary retention. Comparison, in patients with chronic inflammation, the progression of symptoms occurred in 21% of them, need for surgery in 7.3% and urinary retention in 5.6% [12]. In our study, all patients who had urinary retention have had inflammatory elements detected on histopathological examination. Several studies suggest a strong correlation between the presence of prostatic inflammation and the risk of urinary retention. Roehrborn in the same MTOPS data analysis shows that patients with acute inflammation associated have a higher risk of urinary retention (2.4%) than in patients without inflammation (0.6%) [12]. Kefi et al concluded that chronic prostatic inflammation is a predictive factor for acute urinary retention more important than age, prostate volume or PSA value [13]. With the demonstration of frequent association inflammation - BPH and its close correlations with clinical progression and complications such as urinary retention appeared natural assumption that the treatment of associated inflammation may represent a new target for the treatment of BPH. A proponent of this theory is Nickel that stresses the importance of additional treatment (anti-inflammatory) in patients with BPH and inflammation [3]. Some of the usual treatments of BPH (alpha blockers, 5-alpha reductase inhibitors) besides the main mechanism of action presents and anti-inflammatory effects by inducing or increasing prostate apoptosis [14, 15]. However, most published studies relate to effects of using NSAIDs in combination with usual medication to treat inflammation associated with BPH. A study by Di Silverio however shows that there are no significant differences in IPSS score improvement between patients treated with finasteride and rofecoxib (COX-2) and those treated with finasteride only [16]. More recent data published by Minnery and Getzenberg however shows that it can achieve significant improvement in IPSS score using anti-inflammatory - alpha blocker association comparing to alpha blocker monotherapy [17]. In the past decade, herbal medicine treatment has been widely increasingly used for BPH, and one of the main effects attributed to these products is antiinflammatory. A study published by Navarrete show a reduction of inflammatory infiltrates in prostatic resection tissue in patients who have received treatment with extract of Serenoa repens [18]. Other authors have found that use of NSAIDs decreases twice the risk of prostate volume growth, reducing lower urinary tract symptoms and the risk of urinary retention [19]. Using different types of medication to treat inflammation associated with BPH is still under investigation, and obtaining data to reduce inflammation and clinical response is hampered by the low rate of confirmation of inflammation before treatment [6]. In literature there are few data on the influence of inflammation on the results of surgical treatment of prostate adenoma. A study published in 2011 by Yalcinkaya [20] assessed the impact of asymptomatic prostatitis (NIH IV) association in patients with BPH. Studying the data of 247 patients, the authors observed a significantly higher rate of re-catheterisation in patients with associated inflammation. Also, symptoms assessed at 90 days after surgery by IPSS and QoL was significantly improved in the group with BPH without histological evidence of prostatitis. From the point of view of Qmax, no differences were found between the two groups. Another recently published study on 144 cases [21] points out that the severity of lower urinary tract symptoms is increased both preoperatively and after TURP in the presence of inflammatory lesions, which are correlated with the degree of inflammation. Data from our study showed a correlation between the symptomatic postoperative score and the presence of inflammation in resection specimens, without Qmax and residual volume to be influenced. Also, recatheterisation was necessary only in patients with associated inflammation. Conclusions The presence and degree of histopathological evidenced inflammation is associated with significantly higher values of IPSS score, prostate volume, PSA and incidence of urinary retention. Intraoperative and immediate postoperative issues are not influenced by the presence of these lesions. After the surgery, there are significant only in respect of the symptoms and the rate of recatheterisation. Further studies are needed to confirm these data and to determine any additional remedial measures to improve the results of surgical treatment in these patients. Clinical studies nr. 4 / 2013 vol 12 Revista Românæ de Urologie 23

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