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Patients With Prostatic Inflammation Undergoing Transurethral Prostatic Resection Have a Larger Early Improvement of Storage Symptoms
Prostatic Diseases and Male Voiding Dysfunction Patients With Prostatic Inflammation Undergoing Transurethral Prostatic Resection Have a Larger Early Improvement of Storage Symptoms Cosimo De Nunzio, Aldo Brassetti, Mauro Gacci, Enrico Finazzi Agrò, Marco Carini, Fabrizio Presicce, and Andrea Tubaro OBJECTIVE
METHODS
RESULTS
CONCLUSION
To evaluate the association between prostate inflammation, metabolic syndrome (MetS), and postoperative lower urinary tract symptoms in patients treated with transurethral resection of the prostate (TURP). From April 2011, a consecutive series of patients treated with TURP were prospectively included in this observational study. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII) criteria. Patients were evaluated at baseline and 1 month postoperative with the International Prostate Symptom Score (IPSS), including the storage IPSS (sIPSS) and voiding IPSS (vIPSS) subscores, the Overactive Bladder questionnaire (OAB-q), and uroflowmetry. Prostate volume was evaluated at baseline. Complications were classified using the modified Clavien system. TURP specimens were examined to define grade, location, and extent of the inflammatory infiltrate according to the standardized classification system of chronic prostatitis and/or chronic pelvic pain syndrome. One hundred and thirty-one subjects were enrolled, in which 54 patients (41.3%) presented with MetS. No differences were observed in terms of preoperative prostate-specific antigen, OAB score, IPSS, vIPSS, sIPSS, Qmax, post void residual, and prostate volume in subjects with and without MetS. An incidence of postoperative complications of 10.6% was recorded: 79% were classified as Clavien type I or II; 21% Clavien IIIb. Of 131 subjects, 97 (74.1%) presented with an inflammatory infiltrate. Patients with MetS presented a high proportion of inflammatory infiltrates compared to patients without MetS (45 of 54; 83% vs 52 of 77; 67%, P ¼ .01). Patients with prostate inflammation presented a 50% risk reduction of postoperative storage urinary symptoms. We confirmed the association between MetS and prostate inflammation.Patients with inflammatory infiltrates mostly benefit from TURP, particularly regarding storage symptoms. UROLOGY -: -e-, 2015. 2015 Elsevier Inc.
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ower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) are highly prevalent in adult men. Despite the high impact of LUTS and/or BPH on public health, the pathogenesis of this condition is still largely unknown. Several mechanisms seem to be
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Department of Urology, Ospedale Sant’Andrea, University “La Sapienza”, Roma, Italy; the Department of Urology, Careggi Hospital, University of Florence, Firenze, Italy; and the Department of Urology, Policlinico Tor Vergata, “Tor Vergata” University, Roma, Italy Address correspondence to: Cosimo De Nunzio, M.D., Ph.D., Ospedale Sant’Andrea, University “La Sapienza”, Roma, Italy. E-mail: [email protected] Submitted: January 20, 2015, accepted (with revisions): April 9, 2015
ª 2015 Elsevier Inc. All Rights Reserved
involved in its development and progression. In the last few years epidemiological and histopathological studies have clearly indicated the possible role of prostate inflammation in the pathogenesis of LUTS and BPH.1-5 Metabolic syndrome (MetS), a complex disorder that is a worldwide epidemic, describes the combination or clustering of several metabolic abnormalities, including central obesity, dyslipidemia, hypertension, insulin resistance with compensatory hyperinsulinemia, and glucose intolerance. Increasing evidence has revealed a possible positive relationship between MetS and its components and the occurrence and progression of LUTS and BPH.2,6,7 Although the pathophysiological link beyond this association is still to be determined, prostatic http://dx.doi.org/10.1016/j.urology.2015.04.048 0090-4295/15
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inflammation, which is highly prevalent in patients with MetS, has been considered one of the most important factors involved in this association.8 Gacci et al2 recently retrospectively evaluated the association between MetS, defined according to the ATP-III criteria, and LUTS in a group of Italian patients with LUTS and/or BPE treated with open or endoscopic prostatectomy, and they demonstrated an association among MetS features, the presence and grade of prostatic inflammation, and prostate enlargement. Transurethral resection of the prostate (TURP) is still considered the gold standard surgical treatment of benign prostatic obstruction (BPO), as it provides excellent longterm outcomes in terms of maximum flow (Qmax) improvement and a significant reduction of post void residual (PVR) urine and International Prostate Symptom Score (IPSS) and quality of life (QoL) scores.9-12 To this end, it is remarkable that the surgical intervention mainly resolves voiding symptoms and significantly improves QoL, while storage symptoms are reduced to a lesser degree.12 To the best of our knowledge, no studies have evaluated the persistence of urinary symptoms after TURP, particularly in relation to the presence of MetS or the grade and extension of prostatic inflammation. The aim of our study was to evaluate the association between prostate inflammation, MetS, and postoperative LUTS in a group of patients treated with TURP.
METHODS From April 2011, a consecutive series of patients treated in our center with monopolar TURP (mTURP) were prospectively included in this observational study. Indications for surgery were LUTS and/or BPH resistant to medical treatment and chronic urinary retention. Exclusion criteria included history of bladder or prostate cancer, chronic prostatitis, bladder stones, urethral stenosis, and neurological diseases. Patients treated with antimuscarinics or beta-3 adrenergic agonist were also excluded from the series. Age, comorbidities, resting blood pressure, anthropometric parameters, including body mass index (BMI), waist circumference, history of previous medical, and surgical treatments, and details of surgery were recorded from all patients. Obesity was defined as BMI 30 kg/m2. Fasting (8 hours) blood samples were drawn from all patients the day before the TURP and analyzed for blood glucose, high-density lipoprotein (HDL) cholesterol, triglycerides, and total prostate-specific antigen (PSA). Data were used to define a binary variable for the presence or absence of MetS, according to the criteria proposed by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII).13 All men were evaluated at baseline and 1 month postoperative with the IPSS, including the storage IPSS (sIPSS) and voiding IPSS (vIPSS) subscores, and with the 33-item Overactive Bladder questionnaire (OAB-q).14 Uroflowmetry was also recorded at baseline and at follow-up. At baseline, additionally, prostate volume was evaluated by transrectal ultrasound. Antiplatelet and anticoagulant drugs were stopped at least 1 week before the operation. A complete blood count, 2
creatininemia, platelet count, bleeding profile, coagulation profile, and urine culture were collected from all the patients pre- and postoperatively. An enema was routinely administered the afternoon before surgery for bowel preparation. According to the standardized classification system of chronic prostatitis and/or chronic pelvic pain syndrome (CP/CPPS) proposed by Nickel et al in 2001, all TURP specimens were examined to define the grade (no inflammatory cells, mild inflammation with scattered inflammatory cells, moderate inflammation characterized by nonconfluent lymphoid nodules, and severe inflammation defined by large areas of confluent infiltrates), the anatomical location (glandular, periglandular, and/ or stromal), and the extent (focal <10%, multifocal 10%-50%, and diffuse >50%) of the inflammatory infiltrate.15
Surgical Technique Conventional mTURP was performed by a single surgeon (AT) with a Storz 26 Ch continuous irrigation resectoscope and an ERB electrosurgical generator. Mannitol solution was used as irrigation fluid. Subsequently, a 20 F irrigating catheter was inserted and irrigation with physiologic saline solution was initiated in the operating room and continued until the patient was able to drink an adequate amount of fluid for autoirrigation. The catheter was removed about 1 hour after discontinuing bladder irrigation, which was routinely performed for at least 24 hours. The patients were discharged from the hospital at least 8 hours after catheter removal and after passing clear urine, but no patient was routinely discharged from the hospital after 6 PM. Resection time and all complications were recorded and classified according to the modified Clavien classification system (CCS),16 which stratifies perioperative complications into five grades for both groups. The planned follow-up visit was 1 month after treatment, to evaluate all the possible early complications and outcomes after treatment.
Statistical Analysis Statistical analysis was performed using the SPSS, version 12.0, software. Evaluation of data distribution showed a non-normal distribution of the study data set. Differences between groups of patients in medians for quantitative variables and differences in distribution for categorical variables were tested with the Kruskal-Wallis one-way analysis of variance and chi-square test, respectively. We conducted uni- and multivariate logistic regressions to assess the association between prostate inflammation and the overall risk of persistent LUTS after a TURP. As proposed in the Boston Area Community Health Survey, a further categorization in voiding and storage symptoms was done; storage symptoms were considered significant when the sIPSS 4.17 The variables considered for entry into the model included age, presence of inflammation (categorical variable), and baseline storage symptoms. An alpha value of 5% was considered as threshold for significance. Data are presented as median (interquartile range [IQR]), mean standard deviation (SD).
RESULTS Overall 131 subjects were prospectively enrolled. Patients’ characteristics are summarized in Table 1. Fiftyfour patients (41.3%) were diagnosed with MetS UROLOGY
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UROLOGY -
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Overall 70.1 7.5 26.4 3.3 3.6 2.2 67.5 24 103.8 13.5 17 6.1 8.2 4.1 8.8 3.5 4.3 1.3 52.3 18.4 93.8 25.8 124 70.2 44.7 13.3 130.6 10.7 80.9 6.2 8.5 2.9 42 45.6
131 (70; 65/75) (25.6; 24.2/28.3) (4.2; 1.5/5) (62.5; 50/85.2) (101; 95/111) (16; 13/21) (7; 5/11) (8; 6/12) (5; 3/5) (60; 45/80) (87; 78/97) (105; 82/152) (42; 36/52) (130; 120/140) (80; 80/85) (8; 6/10) (30; 0/70)
No Metabolic Syndrome 77/131 69.4 7.4 25.4 2.9 4.2 2.1 66.4 23.5 100 12.7 16.8 5.9 8 3.9 8.8 3.4 4.3 1.2 50.3 17.8 88.5 14.7 99 37 48.6 13.3 128.2 10.6 79 5.4 8.8 3.2 42 48.3
(58.7%) (69; 65/75) (24.8; 23.7/27.2) (4.3; 2.5/5.2) (60; 50/79) (98; 92/105) (15; 13/19) (7; 5.2/10) (8; 7/12) (4; 3/5) (47; 35.5/63.2) (87; 78/96) (94; 69.5/113) (46; 39/58.5) (130; 120/135) (80; 75/80) (9; 6/10) (30; 0/60)
Metabolic Syndrome 54/131 71 7.6 27.7 3.3 3 2.2 68.9 26.1 109.2 12.9 17.3 6.5 8.8 3.8 8.8 3.8 4.3 1.4 54.8 19.1 100.7 34.3 155.8 88.6 39.8 11.7 133.9 10.1 83.7 6.2 7.6 2 42.2 45
(41.3%) (71; 67.5/76) (27.3; 25.2/29.8) (2.1; 0.9/4.5) (65; 50/93) (106.5; 100/117) (16; 12/22) (7; 5/12) (8; 6/11) (5; 3/5) (56.40.2/68.2) (88; 79/105) (145; 98/165) (37; 34/43) (130; 130/140) (85; 80/90) (7; 6/10) (30; 0/82)
P Value .246 .00 .251 .725 .00 .592 .639 .894 .670 .248 .359 .00 .00 .00 .00 .833 968
BMI, body mass index; HDL, high-density lipoprotein; IPSS, International Prostate Symptom Score; OAB, overactive bladder; PSA, prostate-specific antigen; PVR, post void residual; QoL, quality of life; TRUS, trans rectal ultrasound scan. Data are presented as mean DS (median; IQR).
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4 Table 2. Patient’s characteristics according to the presence of prostatic inflammation Covariates Patients Age (years) BMI (kg/m2) PSA (ng/mL) TRUS volume (mL) IPSS IPSS storage IPSS voiding QoL OAB Qmax (mL/s) PVR (mL) Operative time (min) Catheterization time (day) Hospital stay (day) IPSS 1 month IPSS storage 1 month IPSS voiding 1 month OAB 1 month QoL 1 month Qmax 1 month PVR 1 month
No Inflammation 34/131 68.9 7.7 25.8 2.8 3.6 1.1 0.7 28.1 17.7 6.6 8.3 4.5 8.5 3.3 4.2 1.2 53.1 20.6 61 33 15 63.3 28.7 4.5 3.4 7.7 3.9 8.9 6.9 6.3 5.2 4 3.3 37.6 16.7 2.4 1.5 22.8 10.9 10 13
(25.9%) (69; 64/72.2) (25.2; 24/28) (4; 2.4/4.5) (65; 50/89) (17; 13.7/23.2) (8; 4/11.5) (8; 5.7/12) (5; 3/5) (51; 33/68) (6; 4/6) (30; 20/50) (60; 45/78.7) (4; 2/5) (7; 5/10) (6.5; 3.2/15.7) (4.5; 2/11) (3; 1/7.2) (38; 29.5/48) (2.5; 1/3) (18.6; 14.6/32.5) (0; 0/20)
Abbreviations as in Table 1. Data are presented as mean SD (median; IQR).
Inflammation 97/131 70.5 7.4 26.6 3.4 3.6 2.4 65.8 22.5 16.5 6.2 7.2 3.7 9 3.6 4.4 1.3 51.9 17.3 8.7 2.9 43.7 49.4 67.1 29.6 4.6 2 8.1 2.5 4 4.6 2.7 3 3.1 2.5 25.6 24.3 1.7 2.4 22.8 9.8 14.6 20
(74.1%) (71; 66/75.5) (25.6; 24.2/28.3) (4.2; 1.4/5) (59.5; 50/82) (15; 12.5/21) (6; 5/9) (8; 6.2/11.7) (5; 3/5) (50; 41/60) (9; 6/10) (30; 0/88) (60; 45/80) (5; 3/6) (8; 7/9.7) (3; 1.2/6) (0.25/3) (3; 1/4) (10; 10/38) (2; 1/3) (22; 16/28.3) (0; 0/30)
P Value .331 .485 .998 .562 .326 .218 .189 .492 .807 .275 .909 .543 .2 .169 .000 .001 .662 .011 .116 .661 .720
Mild Grade Inflammation 59/97 69.2 7 26.5 3.3 2.9 2 63.6 24.9 16.3 5.4 6.6 3.6 8.8 3.4 4.4 1.3 40.6 13.7 9.4 3 55 56 67.9 33.5 4.2 1.6 8.3 2.6 4.6 4.6 3 3.1 3.1 2.2 30.6 13.7 1.8 1 21.8 7.9 15.5 22
Moderate-to-Severe Grade Inflammation
(60.8%) 38/97 (70; 65/75) 71.9 7.8 (26; 23.8/28.6) 26.8 3.8 (2.1; 1/5) 4.4 2.7 (55; 43/88) 69 18.6 (15; 13/19) 17.4 6.9 (6; 5/8) 8.2 3.6 (7; 6/12) 9.1 4.1 (4.5; 4/5) 4.4 1.3 (30.5; 22/38) 44.2 17 (10; 6/10) 6.5 0.7 (40; 0/100) 29.2 38 (60; 45/80) 65.9 23 (4; 3/6) 5 2.5 (8; 7/10) 7.9 2.5 (3; 2/7) 3.1 4.5 (2; 1/3.2) 2.2 2.7 (3; 1/4) 3.2 3.5 (30; 22/3.85) 44.2 17 (2; 1/3) 1.5 1.9 (2.5; 16/26.8) 24.6 12.5 (0; 0/30) 12.5 19
(39.2%) (71.5; 68/78) (25.5; 24.5/28.1) (4.3; 1.8/6.8) (65; 52/84) (16; 12.5/22.5) (7; 5.5/11) (8; 6.5/10) (3; 3/5) (40; 31/50) (6.5; 6/7) (10; 0/70) (60; 45/87) (5; 3/6) (7; 6/8) (2; 0/3.5) (2; 0/3) (2; 1/4) (40; 31/50) (2; 1/3) (23; 16/30) (0; 0/30)
P Value .153 .770 .370 .247 .519 .034 .829 .46 .640 .333 .408 .735 .298 .324 .06 .330 .666 .437 .375 .249 .798
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Table 3. Exploring the association of prostatic inflammation and postoperative storage urinary symptoms Overall Postoperative Storage Urinary Symptoms (sIPSS 4) OR
Covariates
95% CI
P Value
Age 1.10 0.952-1.071 .740 Baseline storage Symptoms 1.020 0.905-1.151 .744 Prostatic inflammation 0.533 0.079-0.573 .002 CI, confidence interval; OR, odds ratio; sIPSS, storage International Prostate Symptom Score.
according to the ATPIII criteria: they were obese and presented lower serum HDL cholesterol levels and higher blood pressure, glycemia, and triglyceridemia when compared to subjects without MetS. No significant differences were observed in terms of preoperative PSA, OAB score, IPSS, vIPSS, sIPSS, Qmax, PVR, and prostate volume in subjects with and without MetS (Table 1). All patients were treated with mTURP: the mean operative time was 65.7 29 min, and the mean catheterization time was 4.5 2.6 days with a mean hospital stay of 8 3 days. A total of 19 complications were recorded in 14 patients with an incidence of postoperative complications of 10.6%. Most (15 of 19; 79%) were classified as Clavien type I (transient hematuria in 5 patients, urinary retention in 3 patients, and urinary tract infections in 5 patients) or II (hematuria requiring blood transfusion in 2 patients). Higher grade complications were observed: 4 of 19 (21%) Clavien type IIIb (active hematuria requiring endoscopic procedure). No TURPrelated death was recorded during the study period. Overall, 34 of 131 (25.9%) showed no sign of prostate inflammation at the histology report, whereas 97 of 131 subjects (74.1%) presented an inflammatory infiltrate. Inflammation was mild in 59 of 97 (60.8%) and moderate to severe in 38 of 97 (39.2%). Patients with MetS presented a high proportion of inflammatory infiltrates when compared to patients without MetS (45 of 54; 83% vs 52 of 77; 67%, P ¼ .01). In particular, 25 out of 54 patients (46%) with MetS presented moderate-to-severe inflammation, which was present only in 13 of 77 patients (16.8%) without MetS (P ¼ .001). Patients with prostate inflammation presented lower postoperative IPSS, storage IPSS, and OAB scores when compared to those without inflammation (Table 2). No differences were observed between patients with mild and moderate-to-severe inflammation. When compared to baseline, significant improvement was observed 1 month after treatment in terms of Qmax (8.5 2.9 vs 22.8 16; P ¼ .008), PVR (42 45.6 vs 12.5 17; P ¼ .180), IPSS (17 6.1 vs 5.4 5; P ¼ .01), vIPSS (8.8 3.5 vs 3.4 2.8; P ¼ .001), sIPSS (8.2 4.1 vs 3.7 4; P ¼ .001), and OAB score (52.3 18.4 vs 32.3 21; P ¼ .001). Multivariate analysis showed that prostate inflammation was associated with a reduced risk of postoperative UROLOGY
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storage symptoms (odds ratio [OR]: 0.553; confidence interval [CI]: 0.079-0.573; P ¼ .002; Table 3); the risk of having a postoperative IPSS storage subscore 4 is reduced by 55% in patients with that histopathological finding.
COMMENT MetS, historically named by Reaven as “Syndrome X” in 1988,18 is a complex disorder, resulting from physical inactivity and higher intakes of dietary meat, fat, refined carbohydrates, and excess of calories as per Western lifestyle, with a huge socioeconomic cost, affecting >40% of the population in the United States and nearly 30% in Europe.12 A wealth of studies have clearly highlighted the association between MetS and prostate inflammation.2-7,19,20 Gacci et al2 showed that a high-fat diet induces not only the classical features of MetS but also a marked inflammation and stromal derangement of the LUT, including the prostate. In our series, MetS is a highly frequent condition as 54 of 131 patients (41.3%) were diagnosed with this syndrome and it was associated with a more severe prostatic inflammation. In the last few years epidemiological and histopathological studies have clearly indicated that prostate chronic inflammation (PCI) is not only a common finding in BPH2 but also plays a primary role in triggering prostatic cells overgrowth2-4 and a direct relationship exists between the degrees of inflammation and LUTS.20 Hammarsten and H€ogstedt6 suggested that MetS could be itself responsible for LUTS: hyperinsulinemia and hyperglycemia might cause amplified sympathetic nervous system activity contributing to an increase of prostate smooth muscle tone. Recently, Gacci et al2 stated that MetS can be regarded as a new determinant of prostatic inflammation and BPH progression: in their study based on 271 men undergoing prostatectomy, almost one-third of the cohort had MetS and there was a significant positive correlation between prostate volume and the number of MetS components; a correlation between intraprostatic inflammation and BPH symptoms was also found in those patients. In 1979, Kohnen and Drach21 observed in a series of 162 cases of surgically resected hyperplastic prostates that the incidence of inflammation is 98.1%, and 6 different morphologic patterns of inflammation were described. Recently, an examination of baseline prostate biopsies in a subgroup of 1197 patients in the Medical Therapies of Prostatic Symptoms (MTOPS) study found that chronic inflammatory infiltrate was present in 43% of the men in the placebo arm and these subjects were significantly more likely to experience symptom worsening than those without inflammation (5.6% vs 0.0%, P ¼ .003), although there was only a weak correlation at baseline between inflammation and LUTS.22 Moreover, a weak relationship between the degree of chronic inflammation and LUTS was found by Nickel et al20 in 8000 men from the REDUCE population: at baseline 77.6% of the 5
patients had chronic inflammation (mild in 89% of the cases, moderate in 10.7%, and severe in 0.3%), and they reported higher total IPSS and voiding and storage subscores when compared to those without PCI. Our study confirmed that PCI is frequently found in patients with LUTS and/or BPH (97 of 131; 74.1%) but no differences in terms of preoperative total IPSS, sIPSS, vIPSS, and OAB score were observed between patients with and without MetS. The absence of a statistically significant relationship between PCI degree and LUTS severity may be due to our small sample size, exclusively composed of patients resistant to medical treatment and scheduled for surgery with a probably end stage BPH when compared to the previous experiences. TURP is still considered the gold standard in the surgical treatment of BPO as it is efficient, provides excellent outcomes, and represents a safe procedure with a low complications rate and a zero mortality rate.16 In our series TURP was effective in improving LUTS and Qmax with a low morbidity rate. The incidence of postoperative complications was 10.6% and few high-grade complications were observed. These data are in line with those reported in other studies evaluating TURP complications using the CCS.16 We observed a more significant improvement in terms of LUTS and OAB scores in patients with PCI when compared to those without prostatic inflammatory infiltrates. Inflammation was associated with a 55% reduction risk of higher postoperative storage symptoms (sIPSS 4). Although the biological mechanism beyond this association is not clear, our results highlighted that patients with prostatic inflammatory infiltrates mostly benefit from TURP. TURP is considered to be effective because of its result on prostatic obstruction, but several studies have shown positive results even in patients with no obstruction.23-27 Symptoms improvement after TURP may be due to two main factors: surgical relief from bladder outlet obstruction (BOO) and concomitant reduction of detrusor overactivity (DO) and associated OAB.23-26 The latter is reported in about 50% of men undergoing prostatectomy for BPE26; although many theories have been proposed to explain its pathogenesis and its relief after surgery (conversion from unstable to stable detrusor after BPH surgery is reported in 63%-66% of the cases),25,26 these remain unclear. Some have suggested that abnormal sensory stimuli from an anatomically altered prostatic urethra, as per PCI, can induce DO; therefore, its permanent surgical ablation along with the trigonal area and the bladder neck would improve OAB symptoms.24-26 Our study further supports this hypothesis although noncorroborated by an urodynamic diagnosis of DO. Although urodynamic evaluation can add value to the evaluation of patients with LUTS, the most recent European Association of Urology guidelines on LUTS in males, which are the adopted guidelines in our department, summarized that an urodynamic evaluation is not mandatory in patients undergoing invasive treatment 6
while it should be used in selected patients such as those who failed invasive treatment.27 However, in our series the presence of OAB was evaluated using the OAB screener, which probably allows a better description of the storage symptoms and was used in addition to the storage subscore of the IPSS, which is considered the standard to evaluate male LUTS.27 TURP was associated to a significant reduction in terms of OABs score, and particularly a higher reduction was observed in patients with inflammatory infiltrates (50% OAB score reduction) when compared to patients without PCI (30% OAB score reduction). Patients with PCI as those with MetS may mostly benefit from the removal of the prostatic tissue with a more important reduction of the sensory input of the voiding reflex. From a clinical point of view, a strict collaboration with pathologists should be considered in the near future to better report in prostate samples including those from prostate biopsy or TURP to the presence and grade of PCI. In the due time the presence of PCI could be suspected in patients with MetS, which should be advised about the possible effect of MetS on prostate inflammation, and LUTS. We must acknowledge some limitations to our study: it is a single-center study with a small number of patients and a short-term follow-up. Only 1-month data are available considering that the study was designed to evaluate early complications and outcomes according to the CCS. However, in order to overcome these limitations, a further retrospective analysis at 6 and 12 months is ongoing and the results will be soon available. Furthermore, no specific serum or molecular marker of PCI was used. Although inflammatory marker is an interesting topic as they could be used to identify patients with PCI and to evaluate treatment outcome, at this stage nonspecific prostatic inflammatory marker is routinely available in our clinic. In the last few years, preliminary data suggested that the seminal level of interleukin-8 may be considered a valuable marker for detecting BPH inflammation. However, notwithstanding these reports, the question on what the gold standard marker for PCI continues to be debated and answers are eagerly awaited.27 No information was also available on the amount of prostatic tissue resected during the TURP. However, patients with and without prostatic inflammatory infiltrates presented a similar prostate volume and in order to obtain a homogeneous group of patients and to minimize the possible bias related to the surgical technique, a single expert surgeon performed all the operations using the same technique. Notwithstanding all these limitations, it is the first study investigating the influence of inflammatory infiltrates on postoperative urinary symptoms (evaluated with appropriate questionnaires) in patients treated with TURP. Long-term-follow-up data are also ongoing and will be available in the near future. Our results apply to the study cohort only (patients with BPE and LUTS resistant to medical therapy or with chronic urinary retention treated with TURP) and cannot be extended to UROLOGY
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all patients at risk for LUTS.28 The results of the study clearly depend upon the enrolled population, and the prevalence, definition, and type of MetS observed in our series may differ from what is observed in other centers or countries and could influence the observed results regarding the association between LUTS, MetS, and prostatic inflammation. Furthermore, in our study we evaluated exclusively patients scheduled for prostate surgery with a significant IPSS; almost all patients presented an IPSS storage subscore >4 (83%), which is significantly greater when compared to other studies evaluating the association between MetS and LUTS in the general population and could explain the lack of association between MetS and storage symptoms observed in our study.8
CONCLUSION MetS is a prevalent condition in men with LUTS and/or BPE scheduled for TURP, and it is associated to a severe prostatic inflammation. Although it should be confirmed in a large and multicenter trial in our series, the presence of inflammatory infiltrates is associated with a 55% reduced risk of postoperative storage symptoms. References 1. Briganti A, Capitanio U, Suardi N, et al. Benign prostatic hyperplasia and its aetiologies. Eur Urol Suppl. 2009;8:865-871. 2. Gacci M, Vignozzi L, Sebastianelli A, et al. Metabolic syndrome and lower urinary tract symptoms: the role of inflammation. Prostate Cancer Prostatic Dis. 2013;16:101-116. 3. Ribal MJ. The link between benign prostatic hyperplasia and inflammation. Eur Urol Suppl. 2013;12:103-109. 4. Sciarra A, Di Silverio F, Salciccia S, et al. Inflammation and chronic prostatic diseases: evidence for a link? Eur Urol. 2007;52: 964-972. 5. De Nunzio C, Aronson W, Freedland SJ, et al. The correlation between metabolic syndrome and prostatic diseases. Eur Urol. 2012; 61:560-570. 6. Hammarsten J, H€ ogstedt B. Clinical, anthropometric, metabolic and insulin profile of men with fast annual growth rates of benign prostatic hyperplasia. Blood Press. 1999;8:29-36. 7. Rohrmann S, Smit E, Giovannucci E, Platz EA. Association between markers of the metabolic syndrome and lower urinary tract symptoms in the Third National Health and Nutrition Examination Survey (NHANES III). Int J Obes (London). 2005;29:310-316. 8. De Nunzio C, Cindolo L, Gacci M, et al. Metabolic syndrome and lower urinary tract symptoms in patients with benign prostatic enlargement: a possible link to storage symptoms. Urology. 2014;84: 1181-1187. 9. Oelke M, Bachmann A, Descazeaud A, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2013; 64:118-140. 10. Bachmann A, Tubaro A, Barber N, et al. 180-W XPS GreenLight laser vaporisation versus transurethral resection of the prostate for the treatment of benign prostatic obstruction: 6-month safety and efficacy results of a European Multicentre Randomised Trial—the GOLIATH study. Eur Urol. 2014;65:931-942. 11. Ahyai SA, Gilling P, Kaplan SA, et al. Meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement. Eur Urol. 2010;58:384-397.
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12. Gacci M, Bartoletti R, Figlioli S, et al. Urinary symptoms, quality of life and sexual function in patients with benign prostatic hypertrophy before and after prostatectomy: a prospective study. BJU Int. 2003;91:196-200. 13. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421. 14. Lin Y, Chou EC. Assessment of overactive bladder (OAB)— symptom scores. Incontinence Pelvic Floor Dysfunct. 2009;3:318-323. 15. Nickel JC, True LD, Krieger JN, et al. Consensus development of a histopathological classification system for chronic prostatic inflammation. Br J Urol. 2001;87:797-805. 16. De Nunzio C, Lombardo R, Autorino R, et al. Contemporary monopolar and bipolar transurethral resection of the prostate: prospective assessment of complications using the Clavien system. Int Urol Nephrol. 2013;45:951-959. 17. Kupelian V, Wei JT, O’Leary MP, et al. Prevalence of lower urinary tract symptoms and effect on quality of life in a racially and ethnically diverse random sample: the Boston Area Community Health (BACH) survey. Arch Intern Med. 2006;166:2381-2387. 18. Reaven GM. Banting Lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-1607. 19. Moul S, McVary KT. Lower urinary tract symptoms, obesity and the metabolic syndrome. Curr Opin Urol. 2010;20:7-12. 20. Nickel JC, Roehrborn CG, O’Leary MP, et al. The relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the REDUCE trial. Eur Urol. 2008;54:1379-1384. 21. Kohnen PW, Drach GW. Patterns of inflammation in prostatic hyperplasia: a histologic and bacteriologic study. J Urol. 1979;121: 755-760. 22. Roehrborn CG. Definition of at-risk patients: baseline variables. BJU Int. 2006;97:7-11; discussion 21-22. 23. Ameda K, Koyanagi T, Nantani M, et al. The relevance of preoperative cystometrography in patients with benign prostatic hyperplasia: correlating the findings with clinical features and outcome after prostatectomy. J Urol. 1994;152:443-447. 24. Chalfin SA, Bradley WE. The etiology of detrusor hyperreflexia in patients with infravesical obstruction. J Urol. 1982;127:938-942. 25. Abrams PH, Farrar DJ, Turner-Warwick RT, et al. The results of prostatectomy: a symptomatic and urodynamic analysis of 152 patients. J Urol. 1979;121:640-642. 26. De Nunzio C, Franco G, Rocchegiani A, et al. The evolution of detrusor overactivity after watchful waiting, medical therapy and surgery in patients with bladder outlet obstruction. J Urol. 2003;169:535-539. 27. Gratzke C, Bachmann A, Descazeaud A, et al. EAU guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2015;67: 1099-1109. 28. De Nunzio C, Kramer G, Marberger M, et al. The controversial relationship between benign prostatic hyperplasia and prostate cancer: the role of inflammation. Eur Urol. 2011;60:106-117.
EDITORIAL COMMENT This interesting work has the merit of bringing attention to some important aspects of prostatic pathology, which have not yet received the necessary attention.1 In particular, it must be marked: that often the signs and symptoms of benign prostatic disease are intimately connected and exacerbated by situations such as the metabolic syndrome (MetS) and how the MetS can affect the success of a major or minor surgery for benign prostatic hyperplasia (BPH).
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how the prostate inflammation is an important element in pathophysiology of BPH conditioning the expression of storage symptoms. The prostatic inflammation is a significant element in patients with lower urinary tract symptoms. The work of Drach and colleagues,2 rightly cited by the authors, is an interesting starting point to explore the possibility of a close relationship, at least in some patient groups, between storage symptoms of BPH and subacute or chronically recurring prostatic inflammation. In theory, the situation of prostatic adenoma-induced compression accreted in the prostate gland justifies the structural alteration and the difficulty in emptying of the gland itself. These can be considered to be contributing factors in the establishment and the keeping of bacterial and nonbacterial inflammation. In such cases the increase of prostate-specific antigen is related not only to the increase in volume but also to chronic inflammation. The analysis of a subpopulation of the REDUCE study brings interesting clues to understand the role of inflammation in mainly painful symptoms or like chronic prostatitis and the chronic pelvic pain syndromes-type pain in patients labeled as BPH patients. Meanwhile, it was found that “On the basis of data from epidemiological studies suggesting a reasonable percentage of men enrolled in REDUCE would have prostatitis3,4 or prostatitis-like symptoms,5” along with the fact that the use of dutasteride can improve such symptoms.6 Then it appears increasingly evident that in the population of patients with a prevalence of storage symptoms, we need to assess the presence of prostate inflammation. And the latter, a coexisting MetS, can affect the outcome of the unblocking operation, as well as affect the clinical symptoms. Careful assessment of the state of an inflamed prostate is likely to be a decisive step to set the proper medical or surgical therapy, obviously placed in a holistic view of the patient who is no longer “a prostate surgery patient” but a patient with obstructive symptoms or storage symptoms into a total clinical context. This work confirms the correctness of the intuition of Galen that in presence of purulent lesions advised: “Ubi pus, ibi evacua” (“Where there is pus, (there) evacuate it”); an inflamed prostate, often with micro abscesses, conceptually responds to Galen’s policy and must be removed. di Torino, Torino, Italy Roberto M. Scarpa, M.D., Universita di Cagliari, Cagliari, Italy Paolo Usai, M.D., Universita Cecilia M. Cracco, M.D., Ospedale Cottolengo, Torino, Italy di Cagliari, Cagliari, Italy Paolo Usai, M.D., Universita
References 1. De Nunzio C, Brassetti A, Gacci M. Patients with prostatic inflammation undergoing transurethral prostatic resection have a larger early improvement of storage symptoms. Urology. Inpress. 2. Kohnen PW, Drach GW. Patterns of inflammation in prostatic hyperplasia: a histologic and bacteriologic study. J Urol. 1979;121: 755-760. 3. Roberts RO, Lieber MM, Rhodes T, et al. Prevalence of a physicianassigned diagnosis of prostatitis: the Olmsted County Study of urinary symptoms and health status among men. Urology. 1998;51:578. 4. Pontari MA. Chronic prostatitis/chronic pelvic pain syndrome in elderly men: toward better understanding and treatment. Drugs Aging. 2003;20:1111.
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5. Nickel JC, Downey J, Hunter D, et al. Prevalence of prostatitis-like symptoms in a population based study using the National Institutes of Health chronic prostatitis symptom index. J Urol. 2001;165:842. 6. Nickel JC, Roehrborn C, Montorsi F, et al. Dutasteride reduces prostatitis symptoms compared with placebo in men enrolled in the REDUCE study. J Urol. 2011;186:1313-1318.
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REPLY Emerging evidence suggests that prostatic inflammation may play a role in benign prostatic hyperplasia (BPH) development and progression.1 Furthermore, the presence of prostatic inflammatory infiltrates may influence the expression and the severity of lower urinary tract symptoms (LUTS) and/or BPH at different stage. In particular, in naïve and/or untreated patients with BPH, metabolic syndrome (MetS), a well-established cause of systemic inflammation, is associated with an increased risk of storage symptoms2; in pharmacologically treated patients, those with low-grade inflammation presented a 3.5 higher LUTS improvement than high-grade group3; in patients undergoing transurethral resection of the prostate (TURP), we confirmed the association between MetS and prostate inflammation and demonstrated that patients with inflammatory infiltrates mostly benefit from TURP, particularly regarding storage symptoms.4 Unfortunately, despite the growing evidence on the association between inflammation and LUTS and/or BPH, the biological mechanisms beyond this association are still unclear and what we know is only the tip of a very large iceberg. We completely agree about the importance of assessing in a standard method the presence of prostate inflammation in all patients affected by LUTS and/or BPH, but at this time we can accurately diagnose this condition only by the evaluation of prostate samples as in patients treated with TURP or who underwent a prostate biopsy. However, in our study as in previous experiences we confirmed that the presence of different clinical conditions as the presence of MetS,4 the prevalence of storage symptoms,2 the presence of prostatic calcification, or the resistance to a-blockers/5-a-reductase inhibitors (5-ARI) therapy5 can be used as a proxy of prostatic inflammatory infiltrates. The presence of prostatic inflammatory infiltrates can also influence LUTS and/or BPH treatment. In particular, the most commonly used drug for treatments of LUTS and/or BPH as alpha-blockers and 5-ARI are ineffective on the chronic prostatic inflammatory status. Therefore, prostatic inflammation remains an innovative target for the development of new treatment modalities. So far the development of noninvasive diagnostic test to detect and classify the presence of prostate inflammation is needed to better evaluate LUTS and/or BPH patients and to monitor the patient’s response to medical treatment. In our study we confirmed more than 2000 years after Galen that “Ubi pus, ibi evacua.” However, our study open new questions such as the importance of prostatic tissue removal in BPH prostate surgery particularly in patients with severe prostatic inflammation. Considering that several minimally invasive treatment are now available and that they are associated with a different rate of prostatic tissue removal, one can speculate that in patients with severe inflammatory infiltrates the surgical procedure associated with a greater percentage of tissue removal should be preferred. Further studies should address these considerations. In conclusion, we strongly support the hypothesis that prostatic inflammation may play an important role in UROLOGY
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LUTS and/or BPH evaluation with possible implication for LUTS and/or BPH medical and surgical treatment. Further studies are needed to corroborate our hypothesis and to evaluate if we have entered the right path. Cosimo De Nunzio, M.D., Ph.D., Fabrizio Presicce, M.D., and Andrea Tubaro, M.D., Ospedale Sant’Andrea, “Sapienza” University of Rome, Rome, Italy
References 1. De Nunzio C, Kramer G, Marberger M, et al. The controversial relationship between benign prostatic hyperplasia and prostate cancer: The role of inflammation. EurUrol. 2011;60:106-117.
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2. De Nunzio C, Cindolo L, Gacci M, et al. Metabolic syndrome and lower urinary tract symptoms in patients with benign prostatic enlargement: a possible link to storage symptoms. Urology. 2014;84:1181-1187. 3. Kwon YK, Choe MS, Seo KW, et al. The effect of intraprostatic chronic inflammation on benign prostatic hyperplasia treatment. Korean J Urol. 2010;51:266-270. 4. De Nunzio C, Brassetti A, Gacci M, et al. Patients with prostatic inflammation undergoing transurethral prostatic resection have a larger early improvement of storage symptoms. Urology. 2015; in press. 5. Gandaglia G, Briganti A, Gontero P, et al. The role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH). BJU Int. 2013;112:432-441.
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METHODS
RESULTS
CONCLUSION
To evaluate the association between prostate inflammation, metabolic syndrome (MetS), and postoperative lower urinary tract symptoms in patients treated with transurethral resection of the prostate (TURP). From April 2011, a consecutive series of patients treated with TURP were prospectively included in this observational study. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII) criteria. Patients were evaluated at baseline and 1 month postoperative with the International Prostate Symptom Score (IPSS), including the storage IPSS (sIPSS) and voiding IPSS (vIPSS) subscores, the Overactive Bladder questionnaire (OAB-q), and uroflowmetry. Prostate volume was evaluated at baseline. Complications were classified using the modified Clavien system. TURP specimens were examined to define grade, location, and extent of the inflammatory infiltrate according to the standardized classification system of chronic prostatitis and/or chronic pelvic pain syndrome. One hundred and thirty-one subjects were enrolled, in which 54 patients (41.3%) presented with MetS. No differences were observed in terms of preoperative prostate-specific antigen, OAB score, IPSS, vIPSS, sIPSS, Qmax, post void residual, and prostate volume in subjects with and without MetS. An incidence of postoperative complications of 10.6% was recorded: 79% were classified as Clavien type I or II; 21% Clavien IIIb. Of 131 subjects, 97 (74.1%) presented with an inflammatory infiltrate. Patients with MetS presented a high proportion of inflammatory infiltrates compared to patients without MetS (45 of 54; 83% vs 52 of 77; 67%, P ¼ .01). Patients with prostate inflammation presented a 50% risk reduction of postoperative storage urinary symptoms. We confirmed the association between MetS and prostate inflammation.Patients with inflammatory infiltrates mostly benefit from TURP, particularly regarding storage symptoms. UROLOGY -: -e-, 2015. 2015 Elsevier Inc.
L
ower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) are highly prevalent in adult men. Despite the high impact of LUTS and/or BPH on public health, the pathogenesis of this condition is still largely unknown. Several mechanisms seem to be
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Department of Urology, Ospedale Sant’Andrea, University “La Sapienza”, Roma, Italy; the Department of Urology, Careggi Hospital, University of Florence, Firenze, Italy; and the Department of Urology, Policlinico Tor Vergata, “Tor Vergata” University, Roma, Italy Address correspondence to: Cosimo De Nunzio, M.D., Ph.D., Ospedale Sant’Andrea, University “La Sapienza”, Roma, Italy. E-mail: [email protected] Submitted: January 20, 2015, accepted (with revisions): April 9, 2015
ª 2015 Elsevier Inc. All Rights Reserved
involved in its development and progression. In the last few years epidemiological and histopathological studies have clearly indicated the possible role of prostate inflammation in the pathogenesis of LUTS and BPH.1-5 Metabolic syndrome (MetS), a complex disorder that is a worldwide epidemic, describes the combination or clustering of several metabolic abnormalities, including central obesity, dyslipidemia, hypertension, insulin resistance with compensatory hyperinsulinemia, and glucose intolerance. Increasing evidence has revealed a possible positive relationship between MetS and its components and the occurrence and progression of LUTS and BPH.2,6,7 Although the pathophysiological link beyond this association is still to be determined, prostatic http://dx.doi.org/10.1016/j.urology.2015.04.048 0090-4295/15
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inflammation, which is highly prevalent in patients with MetS, has been considered one of the most important factors involved in this association.8 Gacci et al2 recently retrospectively evaluated the association between MetS, defined according to the ATP-III criteria, and LUTS in a group of Italian patients with LUTS and/or BPE treated with open or endoscopic prostatectomy, and they demonstrated an association among MetS features, the presence and grade of prostatic inflammation, and prostate enlargement. Transurethral resection of the prostate (TURP) is still considered the gold standard surgical treatment of benign prostatic obstruction (BPO), as it provides excellent longterm outcomes in terms of maximum flow (Qmax) improvement and a significant reduction of post void residual (PVR) urine and International Prostate Symptom Score (IPSS) and quality of life (QoL) scores.9-12 To this end, it is remarkable that the surgical intervention mainly resolves voiding symptoms and significantly improves QoL, while storage symptoms are reduced to a lesser degree.12 To the best of our knowledge, no studies have evaluated the persistence of urinary symptoms after TURP, particularly in relation to the presence of MetS or the grade and extension of prostatic inflammation. The aim of our study was to evaluate the association between prostate inflammation, MetS, and postoperative LUTS in a group of patients treated with TURP.
METHODS From April 2011, a consecutive series of patients treated in our center with monopolar TURP (mTURP) were prospectively included in this observational study. Indications for surgery were LUTS and/or BPH resistant to medical treatment and chronic urinary retention. Exclusion criteria included history of bladder or prostate cancer, chronic prostatitis, bladder stones, urethral stenosis, and neurological diseases. Patients treated with antimuscarinics or beta-3 adrenergic agonist were also excluded from the series. Age, comorbidities, resting blood pressure, anthropometric parameters, including body mass index (BMI), waist circumference, history of previous medical, and surgical treatments, and details of surgery were recorded from all patients. Obesity was defined as BMI 30 kg/m2. Fasting (8 hours) blood samples were drawn from all patients the day before the TURP and analyzed for blood glucose, high-density lipoprotein (HDL) cholesterol, triglycerides, and total prostate-specific antigen (PSA). Data were used to define a binary variable for the presence or absence of MetS, according to the criteria proposed by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII).13 All men were evaluated at baseline and 1 month postoperative with the IPSS, including the storage IPSS (sIPSS) and voiding IPSS (vIPSS) subscores, and with the 33-item Overactive Bladder questionnaire (OAB-q).14 Uroflowmetry was also recorded at baseline and at follow-up. At baseline, additionally, prostate volume was evaluated by transrectal ultrasound. Antiplatelet and anticoagulant drugs were stopped at least 1 week before the operation. A complete blood count, 2
creatininemia, platelet count, bleeding profile, coagulation profile, and urine culture were collected from all the patients pre- and postoperatively. An enema was routinely administered the afternoon before surgery for bowel preparation. According to the standardized classification system of chronic prostatitis and/or chronic pelvic pain syndrome (CP/CPPS) proposed by Nickel et al in 2001, all TURP specimens were examined to define the grade (no inflammatory cells, mild inflammation with scattered inflammatory cells, moderate inflammation characterized by nonconfluent lymphoid nodules, and severe inflammation defined by large areas of confluent infiltrates), the anatomical location (glandular, periglandular, and/ or stromal), and the extent (focal <10%, multifocal 10%-50%, and diffuse >50%) of the inflammatory infiltrate.15
Surgical Technique Conventional mTURP was performed by a single surgeon (AT) with a Storz 26 Ch continuous irrigation resectoscope and an ERB electrosurgical generator. Mannitol solution was used as irrigation fluid. Subsequently, a 20 F irrigating catheter was inserted and irrigation with physiologic saline solution was initiated in the operating room and continued until the patient was able to drink an adequate amount of fluid for autoirrigation. The catheter was removed about 1 hour after discontinuing bladder irrigation, which was routinely performed for at least 24 hours. The patients were discharged from the hospital at least 8 hours after catheter removal and after passing clear urine, but no patient was routinely discharged from the hospital after 6 PM. Resection time and all complications were recorded and classified according to the modified Clavien classification system (CCS),16 which stratifies perioperative complications into five grades for both groups. The planned follow-up visit was 1 month after treatment, to evaluate all the possible early complications and outcomes after treatment.
Statistical Analysis Statistical analysis was performed using the SPSS, version 12.0, software. Evaluation of data distribution showed a non-normal distribution of the study data set. Differences between groups of patients in medians for quantitative variables and differences in distribution for categorical variables were tested with the Kruskal-Wallis one-way analysis of variance and chi-square test, respectively. We conducted uni- and multivariate logistic regressions to assess the association between prostate inflammation and the overall risk of persistent LUTS after a TURP. As proposed in the Boston Area Community Health Survey, a further categorization in voiding and storage symptoms was done; storage symptoms were considered significant when the sIPSS 4.17 The variables considered for entry into the model included age, presence of inflammation (categorical variable), and baseline storage symptoms. An alpha value of 5% was considered as threshold for significance. Data are presented as median (interquartile range [IQR]), mean standard deviation (SD).
RESULTS Overall 131 subjects were prospectively enrolled. Patients’ characteristics are summarized in Table 1. Fiftyfour patients (41.3%) were diagnosed with MetS UROLOGY
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Overall 70.1 7.5 26.4 3.3 3.6 2.2 67.5 24 103.8 13.5 17 6.1 8.2 4.1 8.8 3.5 4.3 1.3 52.3 18.4 93.8 25.8 124 70.2 44.7 13.3 130.6 10.7 80.9 6.2 8.5 2.9 42 45.6
131 (70; 65/75) (25.6; 24.2/28.3) (4.2; 1.5/5) (62.5; 50/85.2) (101; 95/111) (16; 13/21) (7; 5/11) (8; 6/12) (5; 3/5) (60; 45/80) (87; 78/97) (105; 82/152) (42; 36/52) (130; 120/140) (80; 80/85) (8; 6/10) (30; 0/70)
No Metabolic Syndrome 77/131 69.4 7.4 25.4 2.9 4.2 2.1 66.4 23.5 100 12.7 16.8 5.9 8 3.9 8.8 3.4 4.3 1.2 50.3 17.8 88.5 14.7 99 37 48.6 13.3 128.2 10.6 79 5.4 8.8 3.2 42 48.3
(58.7%) (69; 65/75) (24.8; 23.7/27.2) (4.3; 2.5/5.2) (60; 50/79) (98; 92/105) (15; 13/19) (7; 5.2/10) (8; 7/12) (4; 3/5) (47; 35.5/63.2) (87; 78/96) (94; 69.5/113) (46; 39/58.5) (130; 120/135) (80; 75/80) (9; 6/10) (30; 0/60)
Metabolic Syndrome 54/131 71 7.6 27.7 3.3 3 2.2 68.9 26.1 109.2 12.9 17.3 6.5 8.8 3.8 8.8 3.8 4.3 1.4 54.8 19.1 100.7 34.3 155.8 88.6 39.8 11.7 133.9 10.1 83.7 6.2 7.6 2 42.2 45
(41.3%) (71; 67.5/76) (27.3; 25.2/29.8) (2.1; 0.9/4.5) (65; 50/93) (106.5; 100/117) (16; 12/22) (7; 5/12) (8; 6/11) (5; 3/5) (56.40.2/68.2) (88; 79/105) (145; 98/165) (37; 34/43) (130; 130/140) (85; 80/90) (7; 6/10) (30; 0/82)
P Value .246 .00 .251 .725 .00 .592 .639 .894 .670 .248 .359 .00 .00 .00 .00 .833 968
BMI, body mass index; HDL, high-density lipoprotein; IPSS, International Prostate Symptom Score; OAB, overactive bladder; PSA, prostate-specific antigen; PVR, post void residual; QoL, quality of life; TRUS, trans rectal ultrasound scan. Data are presented as mean DS (median; IQR).
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4 Table 2. Patient’s characteristics according to the presence of prostatic inflammation Covariates Patients Age (years) BMI (kg/m2) PSA (ng/mL) TRUS volume (mL) IPSS IPSS storage IPSS voiding QoL OAB Qmax (mL/s) PVR (mL) Operative time (min) Catheterization time (day) Hospital stay (day) IPSS 1 month IPSS storage 1 month IPSS voiding 1 month OAB 1 month QoL 1 month Qmax 1 month PVR 1 month
No Inflammation 34/131 68.9 7.7 25.8 2.8 3.6 1.1 0.7 28.1 17.7 6.6 8.3 4.5 8.5 3.3 4.2 1.2 53.1 20.6 61 33 15 63.3 28.7 4.5 3.4 7.7 3.9 8.9 6.9 6.3 5.2 4 3.3 37.6 16.7 2.4 1.5 22.8 10.9 10 13
(25.9%) (69; 64/72.2) (25.2; 24/28) (4; 2.4/4.5) (65; 50/89) (17; 13.7/23.2) (8; 4/11.5) (8; 5.7/12) (5; 3/5) (51; 33/68) (6; 4/6) (30; 20/50) (60; 45/78.7) (4; 2/5) (7; 5/10) (6.5; 3.2/15.7) (4.5; 2/11) (3; 1/7.2) (38; 29.5/48) (2.5; 1/3) (18.6; 14.6/32.5) (0; 0/20)
Abbreviations as in Table 1. Data are presented as mean SD (median; IQR).
Inflammation 97/131 70.5 7.4 26.6 3.4 3.6 2.4 65.8 22.5 16.5 6.2 7.2 3.7 9 3.6 4.4 1.3 51.9 17.3 8.7 2.9 43.7 49.4 67.1 29.6 4.6 2 8.1 2.5 4 4.6 2.7 3 3.1 2.5 25.6 24.3 1.7 2.4 22.8 9.8 14.6 20
(74.1%) (71; 66/75.5) (25.6; 24.2/28.3) (4.2; 1.4/5) (59.5; 50/82) (15; 12.5/21) (6; 5/9) (8; 6.2/11.7) (5; 3/5) (50; 41/60) (9; 6/10) (30; 0/88) (60; 45/80) (5; 3/6) (8; 7/9.7) (3; 1.2/6) (0.25/3) (3; 1/4) (10; 10/38) (2; 1/3) (22; 16/28.3) (0; 0/30)
P Value .331 .485 .998 .562 .326 .218 .189 .492 .807 .275 .909 .543 .2 .169 .000 .001 .662 .011 .116 .661 .720
Mild Grade Inflammation 59/97 69.2 7 26.5 3.3 2.9 2 63.6 24.9 16.3 5.4 6.6 3.6 8.8 3.4 4.4 1.3 40.6 13.7 9.4 3 55 56 67.9 33.5 4.2 1.6 8.3 2.6 4.6 4.6 3 3.1 3.1 2.2 30.6 13.7 1.8 1 21.8 7.9 15.5 22
Moderate-to-Severe Grade Inflammation
(60.8%) 38/97 (70; 65/75) 71.9 7.8 (26; 23.8/28.6) 26.8 3.8 (2.1; 1/5) 4.4 2.7 (55; 43/88) 69 18.6 (15; 13/19) 17.4 6.9 (6; 5/8) 8.2 3.6 (7; 6/12) 9.1 4.1 (4.5; 4/5) 4.4 1.3 (30.5; 22/38) 44.2 17 (10; 6/10) 6.5 0.7 (40; 0/100) 29.2 38 (60; 45/80) 65.9 23 (4; 3/6) 5 2.5 (8; 7/10) 7.9 2.5 (3; 2/7) 3.1 4.5 (2; 1/3.2) 2.2 2.7 (3; 1/4) 3.2 3.5 (30; 22/3.85) 44.2 17 (2; 1/3) 1.5 1.9 (2.5; 16/26.8) 24.6 12.5 (0; 0/30) 12.5 19
(39.2%) (71.5; 68/78) (25.5; 24.5/28.1) (4.3; 1.8/6.8) (65; 52/84) (16; 12.5/22.5) (7; 5.5/11) (8; 6.5/10) (3; 3/5) (40; 31/50) (6.5; 6/7) (10; 0/70) (60; 45/87) (5; 3/6) (7; 6/8) (2; 0/3.5) (2; 0/3) (2; 1/4) (40; 31/50) (2; 1/3) (23; 16/30) (0; 0/30)
P Value .153 .770 .370 .247 .519 .034 .829 .46 .640 .333 .408 .735 .298 .324 .06 .330 .666 .437 .375 .249 .798
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Table 3. Exploring the association of prostatic inflammation and postoperative storage urinary symptoms Overall Postoperative Storage Urinary Symptoms (sIPSS 4) OR
Covariates
95% CI
P Value
Age 1.10 0.952-1.071 .740 Baseline storage Symptoms 1.020 0.905-1.151 .744 Prostatic inflammation 0.533 0.079-0.573 .002 CI, confidence interval; OR, odds ratio; sIPSS, storage International Prostate Symptom Score.
according to the ATPIII criteria: they were obese and presented lower serum HDL cholesterol levels and higher blood pressure, glycemia, and triglyceridemia when compared to subjects without MetS. No significant differences were observed in terms of preoperative PSA, OAB score, IPSS, vIPSS, sIPSS, Qmax, PVR, and prostate volume in subjects with and without MetS (Table 1). All patients were treated with mTURP: the mean operative time was 65.7 29 min, and the mean catheterization time was 4.5 2.6 days with a mean hospital stay of 8 3 days. A total of 19 complications were recorded in 14 patients with an incidence of postoperative complications of 10.6%. Most (15 of 19; 79%) were classified as Clavien type I (transient hematuria in 5 patients, urinary retention in 3 patients, and urinary tract infections in 5 patients) or II (hematuria requiring blood transfusion in 2 patients). Higher grade complications were observed: 4 of 19 (21%) Clavien type IIIb (active hematuria requiring endoscopic procedure). No TURPrelated death was recorded during the study period. Overall, 34 of 131 (25.9%) showed no sign of prostate inflammation at the histology report, whereas 97 of 131 subjects (74.1%) presented an inflammatory infiltrate. Inflammation was mild in 59 of 97 (60.8%) and moderate to severe in 38 of 97 (39.2%). Patients with MetS presented a high proportion of inflammatory infiltrates when compared to patients without MetS (45 of 54; 83% vs 52 of 77; 67%, P ¼ .01). In particular, 25 out of 54 patients (46%) with MetS presented moderate-to-severe inflammation, which was present only in 13 of 77 patients (16.8%) without MetS (P ¼ .001). Patients with prostate inflammation presented lower postoperative IPSS, storage IPSS, and OAB scores when compared to those without inflammation (Table 2). No differences were observed between patients with mild and moderate-to-severe inflammation. When compared to baseline, significant improvement was observed 1 month after treatment in terms of Qmax (8.5 2.9 vs 22.8 16; P ¼ .008), PVR (42 45.6 vs 12.5 17; P ¼ .180), IPSS (17 6.1 vs 5.4 5; P ¼ .01), vIPSS (8.8 3.5 vs 3.4 2.8; P ¼ .001), sIPSS (8.2 4.1 vs 3.7 4; P ¼ .001), and OAB score (52.3 18.4 vs 32.3 21; P ¼ .001). Multivariate analysis showed that prostate inflammation was associated with a reduced risk of postoperative UROLOGY
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storage symptoms (odds ratio [OR]: 0.553; confidence interval [CI]: 0.079-0.573; P ¼ .002; Table 3); the risk of having a postoperative IPSS storage subscore 4 is reduced by 55% in patients with that histopathological finding.
COMMENT MetS, historically named by Reaven as “Syndrome X” in 1988,18 is a complex disorder, resulting from physical inactivity and higher intakes of dietary meat, fat, refined carbohydrates, and excess of calories as per Western lifestyle, with a huge socioeconomic cost, affecting >40% of the population in the United States and nearly 30% in Europe.12 A wealth of studies have clearly highlighted the association between MetS and prostate inflammation.2-7,19,20 Gacci et al2 showed that a high-fat diet induces not only the classical features of MetS but also a marked inflammation and stromal derangement of the LUT, including the prostate. In our series, MetS is a highly frequent condition as 54 of 131 patients (41.3%) were diagnosed with this syndrome and it was associated with a more severe prostatic inflammation. In the last few years epidemiological and histopathological studies have clearly indicated that prostate chronic inflammation (PCI) is not only a common finding in BPH2 but also plays a primary role in triggering prostatic cells overgrowth2-4 and a direct relationship exists between the degrees of inflammation and LUTS.20 Hammarsten and H€ogstedt6 suggested that MetS could be itself responsible for LUTS: hyperinsulinemia and hyperglycemia might cause amplified sympathetic nervous system activity contributing to an increase of prostate smooth muscle tone. Recently, Gacci et al2 stated that MetS can be regarded as a new determinant of prostatic inflammation and BPH progression: in their study based on 271 men undergoing prostatectomy, almost one-third of the cohort had MetS and there was a significant positive correlation between prostate volume and the number of MetS components; a correlation between intraprostatic inflammation and BPH symptoms was also found in those patients. In 1979, Kohnen and Drach21 observed in a series of 162 cases of surgically resected hyperplastic prostates that the incidence of inflammation is 98.1%, and 6 different morphologic patterns of inflammation were described. Recently, an examination of baseline prostate biopsies in a subgroup of 1197 patients in the Medical Therapies of Prostatic Symptoms (MTOPS) study found that chronic inflammatory infiltrate was present in 43% of the men in the placebo arm and these subjects were significantly more likely to experience symptom worsening than those without inflammation (5.6% vs 0.0%, P ¼ .003), although there was only a weak correlation at baseline between inflammation and LUTS.22 Moreover, a weak relationship between the degree of chronic inflammation and LUTS was found by Nickel et al20 in 8000 men from the REDUCE population: at baseline 77.6% of the 5
patients had chronic inflammation (mild in 89% of the cases, moderate in 10.7%, and severe in 0.3%), and they reported higher total IPSS and voiding and storage subscores when compared to those without PCI. Our study confirmed that PCI is frequently found in patients with LUTS and/or BPH (97 of 131; 74.1%) but no differences in terms of preoperative total IPSS, sIPSS, vIPSS, and OAB score were observed between patients with and without MetS. The absence of a statistically significant relationship between PCI degree and LUTS severity may be due to our small sample size, exclusively composed of patients resistant to medical treatment and scheduled for surgery with a probably end stage BPH when compared to the previous experiences. TURP is still considered the gold standard in the surgical treatment of BPO as it is efficient, provides excellent outcomes, and represents a safe procedure with a low complications rate and a zero mortality rate.16 In our series TURP was effective in improving LUTS and Qmax with a low morbidity rate. The incidence of postoperative complications was 10.6% and few high-grade complications were observed. These data are in line with those reported in other studies evaluating TURP complications using the CCS.16 We observed a more significant improvement in terms of LUTS and OAB scores in patients with PCI when compared to those without prostatic inflammatory infiltrates. Inflammation was associated with a 55% reduction risk of higher postoperative storage symptoms (sIPSS 4). Although the biological mechanism beyond this association is not clear, our results highlighted that patients with prostatic inflammatory infiltrates mostly benefit from TURP. TURP is considered to be effective because of its result on prostatic obstruction, but several studies have shown positive results even in patients with no obstruction.23-27 Symptoms improvement after TURP may be due to two main factors: surgical relief from bladder outlet obstruction (BOO) and concomitant reduction of detrusor overactivity (DO) and associated OAB.23-26 The latter is reported in about 50% of men undergoing prostatectomy for BPE26; although many theories have been proposed to explain its pathogenesis and its relief after surgery (conversion from unstable to stable detrusor after BPH surgery is reported in 63%-66% of the cases),25,26 these remain unclear. Some have suggested that abnormal sensory stimuli from an anatomically altered prostatic urethra, as per PCI, can induce DO; therefore, its permanent surgical ablation along with the trigonal area and the bladder neck would improve OAB symptoms.24-26 Our study further supports this hypothesis although noncorroborated by an urodynamic diagnosis of DO. Although urodynamic evaluation can add value to the evaluation of patients with LUTS, the most recent European Association of Urology guidelines on LUTS in males, which are the adopted guidelines in our department, summarized that an urodynamic evaluation is not mandatory in patients undergoing invasive treatment 6
while it should be used in selected patients such as those who failed invasive treatment.27 However, in our series the presence of OAB was evaluated using the OAB screener, which probably allows a better description of the storage symptoms and was used in addition to the storage subscore of the IPSS, which is considered the standard to evaluate male LUTS.27 TURP was associated to a significant reduction in terms of OABs score, and particularly a higher reduction was observed in patients with inflammatory infiltrates (50% OAB score reduction) when compared to patients without PCI (30% OAB score reduction). Patients with PCI as those with MetS may mostly benefit from the removal of the prostatic tissue with a more important reduction of the sensory input of the voiding reflex. From a clinical point of view, a strict collaboration with pathologists should be considered in the near future to better report in prostate samples including those from prostate biopsy or TURP to the presence and grade of PCI. In the due time the presence of PCI could be suspected in patients with MetS, which should be advised about the possible effect of MetS on prostate inflammation, and LUTS. We must acknowledge some limitations to our study: it is a single-center study with a small number of patients and a short-term follow-up. Only 1-month data are available considering that the study was designed to evaluate early complications and outcomes according to the CCS. However, in order to overcome these limitations, a further retrospective analysis at 6 and 12 months is ongoing and the results will be soon available. Furthermore, no specific serum or molecular marker of PCI was used. Although inflammatory marker is an interesting topic as they could be used to identify patients with PCI and to evaluate treatment outcome, at this stage nonspecific prostatic inflammatory marker is routinely available in our clinic. In the last few years, preliminary data suggested that the seminal level of interleukin-8 may be considered a valuable marker for detecting BPH inflammation. However, notwithstanding these reports, the question on what the gold standard marker for PCI continues to be debated and answers are eagerly awaited.27 No information was also available on the amount of prostatic tissue resected during the TURP. However, patients with and without prostatic inflammatory infiltrates presented a similar prostate volume and in order to obtain a homogeneous group of patients and to minimize the possible bias related to the surgical technique, a single expert surgeon performed all the operations using the same technique. Notwithstanding all these limitations, it is the first study investigating the influence of inflammatory infiltrates on postoperative urinary symptoms (evaluated with appropriate questionnaires) in patients treated with TURP. Long-term-follow-up data are also ongoing and will be available in the near future. Our results apply to the study cohort only (patients with BPE and LUTS resistant to medical therapy or with chronic urinary retention treated with TURP) and cannot be extended to UROLOGY
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all patients at risk for LUTS.28 The results of the study clearly depend upon the enrolled population, and the prevalence, definition, and type of MetS observed in our series may differ from what is observed in other centers or countries and could influence the observed results regarding the association between LUTS, MetS, and prostatic inflammation. Furthermore, in our study we evaluated exclusively patients scheduled for prostate surgery with a significant IPSS; almost all patients presented an IPSS storage subscore >4 (83%), which is significantly greater when compared to other studies evaluating the association between MetS and LUTS in the general population and could explain the lack of association between MetS and storage symptoms observed in our study.8
CONCLUSION MetS is a prevalent condition in men with LUTS and/or BPE scheduled for TURP, and it is associated to a severe prostatic inflammation. Although it should be confirmed in a large and multicenter trial in our series, the presence of inflammatory infiltrates is associated with a 55% reduced risk of postoperative storage symptoms. References 1. Briganti A, Capitanio U, Suardi N, et al. Benign prostatic hyperplasia and its aetiologies. Eur Urol Suppl. 2009;8:865-871. 2. Gacci M, Vignozzi L, Sebastianelli A, et al. Metabolic syndrome and lower urinary tract symptoms: the role of inflammation. Prostate Cancer Prostatic Dis. 2013;16:101-116. 3. Ribal MJ. The link between benign prostatic hyperplasia and inflammation. Eur Urol Suppl. 2013;12:103-109. 4. Sciarra A, Di Silverio F, Salciccia S, et al. Inflammation and chronic prostatic diseases: evidence for a link? Eur Urol. 2007;52: 964-972. 5. De Nunzio C, Aronson W, Freedland SJ, et al. The correlation between metabolic syndrome and prostatic diseases. Eur Urol. 2012; 61:560-570. 6. Hammarsten J, H€ ogstedt B. Clinical, anthropometric, metabolic and insulin profile of men with fast annual growth rates of benign prostatic hyperplasia. Blood Press. 1999;8:29-36. 7. Rohrmann S, Smit E, Giovannucci E, Platz EA. Association between markers of the metabolic syndrome and lower urinary tract symptoms in the Third National Health and Nutrition Examination Survey (NHANES III). Int J Obes (London). 2005;29:310-316. 8. De Nunzio C, Cindolo L, Gacci M, et al. Metabolic syndrome and lower urinary tract symptoms in patients with benign prostatic enlargement: a possible link to storage symptoms. Urology. 2014;84: 1181-1187. 9. Oelke M, Bachmann A, Descazeaud A, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2013; 64:118-140. 10. Bachmann A, Tubaro A, Barber N, et al. 180-W XPS GreenLight laser vaporisation versus transurethral resection of the prostate for the treatment of benign prostatic obstruction: 6-month safety and efficacy results of a European Multicentre Randomised Trial—the GOLIATH study. Eur Urol. 2014;65:931-942. 11. Ahyai SA, Gilling P, Kaplan SA, et al. Meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement. Eur Urol. 2010;58:384-397.
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12. Gacci M, Bartoletti R, Figlioli S, et al. Urinary symptoms, quality of life and sexual function in patients with benign prostatic hypertrophy before and after prostatectomy: a prospective study. BJU Int. 2003;91:196-200. 13. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421. 14. Lin Y, Chou EC. Assessment of overactive bladder (OAB)— symptom scores. Incontinence Pelvic Floor Dysfunct. 2009;3:318-323. 15. Nickel JC, True LD, Krieger JN, et al. Consensus development of a histopathological classification system for chronic prostatic inflammation. Br J Urol. 2001;87:797-805. 16. De Nunzio C, Lombardo R, Autorino R, et al. Contemporary monopolar and bipolar transurethral resection of the prostate: prospective assessment of complications using the Clavien system. Int Urol Nephrol. 2013;45:951-959. 17. Kupelian V, Wei JT, O’Leary MP, et al. Prevalence of lower urinary tract symptoms and effect on quality of life in a racially and ethnically diverse random sample: the Boston Area Community Health (BACH) survey. Arch Intern Med. 2006;166:2381-2387. 18. Reaven GM. Banting Lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-1607. 19. Moul S, McVary KT. Lower urinary tract symptoms, obesity and the metabolic syndrome. Curr Opin Urol. 2010;20:7-12. 20. Nickel JC, Roehrborn CG, O’Leary MP, et al. The relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the REDUCE trial. Eur Urol. 2008;54:1379-1384. 21. Kohnen PW, Drach GW. Patterns of inflammation in prostatic hyperplasia: a histologic and bacteriologic study. J Urol. 1979;121: 755-760. 22. Roehrborn CG. Definition of at-risk patients: baseline variables. BJU Int. 2006;97:7-11; discussion 21-22. 23. Ameda K, Koyanagi T, Nantani M, et al. The relevance of preoperative cystometrography in patients with benign prostatic hyperplasia: correlating the findings with clinical features and outcome after prostatectomy. J Urol. 1994;152:443-447. 24. Chalfin SA, Bradley WE. The etiology of detrusor hyperreflexia in patients with infravesical obstruction. J Urol. 1982;127:938-942. 25. Abrams PH, Farrar DJ, Turner-Warwick RT, et al. The results of prostatectomy: a symptomatic and urodynamic analysis of 152 patients. J Urol. 1979;121:640-642. 26. De Nunzio C, Franco G, Rocchegiani A, et al. The evolution of detrusor overactivity after watchful waiting, medical therapy and surgery in patients with bladder outlet obstruction. J Urol. 2003;169:535-539. 27. Gratzke C, Bachmann A, Descazeaud A, et al. EAU guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2015;67: 1099-1109. 28. De Nunzio C, Kramer G, Marberger M, et al. The controversial relationship between benign prostatic hyperplasia and prostate cancer: the role of inflammation. Eur Urol. 2011;60:106-117.
EDITORIAL COMMENT This interesting work has the merit of bringing attention to some important aspects of prostatic pathology, which have not yet received the necessary attention.1 In particular, it must be marked: that often the signs and symptoms of benign prostatic disease are intimately connected and exacerbated by situations such as the metabolic syndrome (MetS) and how the MetS can affect the success of a major or minor surgery for benign prostatic hyperplasia (BPH).
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how the prostate inflammation is an important element in pathophysiology of BPH conditioning the expression of storage symptoms. The prostatic inflammation is a significant element in patients with lower urinary tract symptoms. The work of Drach and colleagues,2 rightly cited by the authors, is an interesting starting point to explore the possibility of a close relationship, at least in some patient groups, between storage symptoms of BPH and subacute or chronically recurring prostatic inflammation. In theory, the situation of prostatic adenoma-induced compression accreted in the prostate gland justifies the structural alteration and the difficulty in emptying of the gland itself. These can be considered to be contributing factors in the establishment and the keeping of bacterial and nonbacterial inflammation. In such cases the increase of prostate-specific antigen is related not only to the increase in volume but also to chronic inflammation. The analysis of a subpopulation of the REDUCE study brings interesting clues to understand the role of inflammation in mainly painful symptoms or like chronic prostatitis and the chronic pelvic pain syndromes-type pain in patients labeled as BPH patients. Meanwhile, it was found that “On the basis of data from epidemiological studies suggesting a reasonable percentage of men enrolled in REDUCE would have prostatitis3,4 or prostatitis-like symptoms,5” along with the fact that the use of dutasteride can improve such symptoms.6 Then it appears increasingly evident that in the population of patients with a prevalence of storage symptoms, we need to assess the presence of prostate inflammation. And the latter, a coexisting MetS, can affect the outcome of the unblocking operation, as well as affect the clinical symptoms. Careful assessment of the state of an inflamed prostate is likely to be a decisive step to set the proper medical or surgical therapy, obviously placed in a holistic view of the patient who is no longer “a prostate surgery patient” but a patient with obstructive symptoms or storage symptoms into a total clinical context. This work confirms the correctness of the intuition of Galen that in presence of purulent lesions advised: “Ubi pus, ibi evacua” (“Where there is pus, (there) evacuate it”); an inflamed prostate, often with micro abscesses, conceptually responds to Galen’s policy and must be removed. di Torino, Torino, Italy Roberto M. Scarpa, M.D., Universita di Cagliari, Cagliari, Italy Paolo Usai, M.D., Universita Cecilia M. Cracco, M.D., Ospedale Cottolengo, Torino, Italy di Cagliari, Cagliari, Italy Paolo Usai, M.D., Universita
References 1. De Nunzio C, Brassetti A, Gacci M. Patients with prostatic inflammation undergoing transurethral prostatic resection have a larger early improvement of storage symptoms. Urology. Inpress. 2. Kohnen PW, Drach GW. Patterns of inflammation in prostatic hyperplasia: a histologic and bacteriologic study. J Urol. 1979;121: 755-760. 3. Roberts RO, Lieber MM, Rhodes T, et al. Prevalence of a physicianassigned diagnosis of prostatitis: the Olmsted County Study of urinary symptoms and health status among men. Urology. 1998;51:578. 4. Pontari MA. Chronic prostatitis/chronic pelvic pain syndrome in elderly men: toward better understanding and treatment. Drugs Aging. 2003;20:1111.
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5. Nickel JC, Downey J, Hunter D, et al. Prevalence of prostatitis-like symptoms in a population based study using the National Institutes of Health chronic prostatitis symptom index. J Urol. 2001;165:842. 6. Nickel JC, Roehrborn C, Montorsi F, et al. Dutasteride reduces prostatitis symptoms compared with placebo in men enrolled in the REDUCE study. J Urol. 2011;186:1313-1318.
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REPLY Emerging evidence suggests that prostatic inflammation may play a role in benign prostatic hyperplasia (BPH) development and progression.1 Furthermore, the presence of prostatic inflammatory infiltrates may influence the expression and the severity of lower urinary tract symptoms (LUTS) and/or BPH at different stage. In particular, in naïve and/or untreated patients with BPH, metabolic syndrome (MetS), a well-established cause of systemic inflammation, is associated with an increased risk of storage symptoms2; in pharmacologically treated patients, those with low-grade inflammation presented a 3.5 higher LUTS improvement than high-grade group3; in patients undergoing transurethral resection of the prostate (TURP), we confirmed the association between MetS and prostate inflammation and demonstrated that patients with inflammatory infiltrates mostly benefit from TURP, particularly regarding storage symptoms.4 Unfortunately, despite the growing evidence on the association between inflammation and LUTS and/or BPH, the biological mechanisms beyond this association are still unclear and what we know is only the tip of a very large iceberg. We completely agree about the importance of assessing in a standard method the presence of prostate inflammation in all patients affected by LUTS and/or BPH, but at this time we can accurately diagnose this condition only by the evaluation of prostate samples as in patients treated with TURP or who underwent a prostate biopsy. However, in our study as in previous experiences we confirmed that the presence of different clinical conditions as the presence of MetS,4 the prevalence of storage symptoms,2 the presence of prostatic calcification, or the resistance to a-blockers/5-a-reductase inhibitors (5-ARI) therapy5 can be used as a proxy of prostatic inflammatory infiltrates. The presence of prostatic inflammatory infiltrates can also influence LUTS and/or BPH treatment. In particular, the most commonly used drug for treatments of LUTS and/or BPH as alpha-blockers and 5-ARI are ineffective on the chronic prostatic inflammatory status. Therefore, prostatic inflammation remains an innovative target for the development of new treatment modalities. So far the development of noninvasive diagnostic test to detect and classify the presence of prostate inflammation is needed to better evaluate LUTS and/or BPH patients and to monitor the patient’s response to medical treatment. In our study we confirmed more than 2000 years after Galen that “Ubi pus, ibi evacua.” However, our study open new questions such as the importance of prostatic tissue removal in BPH prostate surgery particularly in patients with severe prostatic inflammation. Considering that several minimally invasive treatment are now available and that they are associated with a different rate of prostatic tissue removal, one can speculate that in patients with severe inflammatory infiltrates the surgical procedure associated with a greater percentage of tissue removal should be preferred. Further studies should address these considerations. In conclusion, we strongly support the hypothesis that prostatic inflammation may play an important role in UROLOGY
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LUTS and/or BPH evaluation with possible implication for LUTS and/or BPH medical and surgical treatment. Further studies are needed to corroborate our hypothesis and to evaluate if we have entered the right path. Cosimo De Nunzio, M.D., Ph.D., Fabrizio Presicce, M.D., and Andrea Tubaro, M.D., Ospedale Sant’Andrea, “Sapienza” University of Rome, Rome, Italy
References 1. De Nunzio C, Kramer G, Marberger M, et al. The controversial relationship between benign prostatic hyperplasia and prostate cancer: The role of inflammation. EurUrol. 2011;60:106-117.
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2. De Nunzio C, Cindolo L, Gacci M, et al. Metabolic syndrome and lower urinary tract symptoms in patients with benign prostatic enlargement: a possible link to storage symptoms. Urology. 2014;84:1181-1187. 3. Kwon YK, Choe MS, Seo KW, et al. The effect of intraprostatic chronic inflammation on benign prostatic hyperplasia treatment. Korean J Urol. 2010;51:266-270. 4. De Nunzio C, Brassetti A, Gacci M, et al. Patients with prostatic inflammation undergoing transurethral prostatic resection have a larger early improvement of storage symptoms. Urology. 2015; in press. 5. Gandaglia G, Briganti A, Gontero P, et al. The role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH). BJU Int. 2013;112:432-441.
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