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THE CHRONIC PROSTATITIS-CHRONIC PELVIC PAIN SYNDROME CAN BE CHARACTERIZED BY PROSTATIC TISSUE PRESSURE MEASUREMENTS
0022-5347/02/1671-0137/0 THE JOURNAL OF UROLOGY® Copyright © 2002 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
Vol. 167, 137–140, January 2002 Printed in U.S.A.
THE CHRONIC PROSTATITIS-CHRONIC PELVIC PAIN SYNDROME CAN BE CHARACTERIZED BY PROSTATIC TISSUE PRESSURE MEASUREMENTS ¨ M, J. CURTIS NICKEL,* ANSA KILPONEN, MARKKU LESKINEN, AARE MEHIK, PEKKA HELLSTRO ARI SARPOLA AND OLAVI LUKKARINEN From the Division of Urology, Departments of Surgery and Public Health Science and General Practice, Oulu University Hospital, Oulu and Division of Urology, Department of Surgery, Seina¨joki Central Hospital, Seina¨joki, Finland, and Department of Urology, Queen’s University, Kingston, Ontario, Canada
ABSTRACT
Purpose: We performed a prospective study to confirm early results implying that intraprostatic tissue pressure is elevated in men with the chronic prostatitis-chronic pelvic pain syndrome. We planned to determine further whether this technique would detect a significant difference in inflammatory and noninflammatory categories IIIA and IIIB. Materials and Methods: A total of 48 patients with the chronic prostatitis-chronic pelvic pain syndrome, including 18 with inflammatory category IIIA and 30 with noninflammatory category IIIB disease, and 12 asymptomatic controls completed a Finnish version of the National Institutes of Health-Chronic Prostatitis Symptom Index. In addition, culture and microscopy of lower urinary tract segmented specimens, serum prostate specific antigen determination, transrectal ultrasound, uroflowmetry and ultrasound post-void residual urine measurement were done. All patients and controls also underwent independent intraprostatic right and left lobe tissue pressure measurement using a standard intracompartmental tissue pressure monitor system. Pressure was measured via an intraprostatic needle placed percutaneously in the perineum at baseline, and 10, 60 and 120 seconds after standard saline injection. Results: All patients with the chronic prostatitis-chronic pelvic pain syndrome had significantly higher pressure at all measurement points compared with controls (p ⬍0.001). Mean intraprostatic tissue pressure was significantly higher (p ⬍0.01) in category IIIA with greater than 10 leukocytes per high power field in prostate specific specimens compared with category IIIB with less than 10. Conclusions: Our study supports the suggestion that patients with the chronic prostatitischronic pelvic pain syndrome have significantly higher prostate tissue pressure than controls. Findings also validated the previous clinical assumption that there is a rationale for differentiating chronic prostatitis-chronic pelvic pain syndrome cases into inflammatory and noninflammatory categories. KEY WORDS: prostate; prostatitis; pelvic pain; diagnosis, differential
The etiology of the chronic prostatitis-chronic pelvic pain syndrome is unknown but possibilities include cryptic unculturable infection, trauma, voiding disturbances, anatomical abnormalities, intraprostatic ductal reflux, and immunological and/or neurogenic causes.1 This syndrome likely arises from a spectrum of pathogenic entities initiated and propagated by any number of these factors.2 Although it is commonly diagnosed by physicians,3, 4 there are no real objective parameters for specifically diagnosing the chronic prostatitis-chronic pelvic pain syndrome.2, 5 The only parameters are a constellation of symptoms and absent uropathogenic bacteria in prostate specific specimens, which only enables differentiation from rare cases of category II chronic bacterial prostatitis. Differentiation of the syndrome into inflammatory category IIIA and noninflammatory category IIIB based on an undetermined cutoff number of white blood cells detected by microscopic evaluation of expressed prostatic secretions, sediment of postprostatic massage urine or semen has not been conclusively validated.6, 7 These 2 categories have a similar
presentation and symptom complex, and there is no solid proof that they respond any differently to specific treatment.1 However, Nadler8 and Alexander9 et al suggested that the inflammatory category IIIA can be differentiated from noninflammatory category IIIB by measuring specific cytokines in expressed prostatic secretions and semen, respectively. It was recently shown that patients diagnosed with the chronic prostatitis-chronic pelvic pain syndrome may have elevated intraprostatic tissue pressure compared with those not diagnosed with the clinical condition.10, 11 This finding may have important ramifications for determining pathogenic mechanisms and directing therapeutic approaches, and it may enable the differentiation of the 2 disease categories. We performed a prospective study to determine whether these initial results would be replicated and further determine whether this technique would detect a significant difference in the inflammatory and noninflammatory categories based on inflammation detected in expressed prostatic secretions or post-prostatic massage urine sediment, thus, validating the differentiation of chronic prostatitis-chronic pelvic pain syndrome categories IIIA and IIIB.
Accepted for publication August 17, 2001. * Financial interest and/or other relationship with Merck, Bayer Canada, Janssen-Ortho Canada, Alza, Situs, Abbott Canada and Glaxo-Wellcome. 137
138
CHRONIC PROSTATITIS-CHRONIC PELVIC PAIN SYNDROME MATERIALS AND METHODS
Patients with the chronic pelvic pain syndrome. Patients with a clinical diagnosis of symptomatic chronic prostatitis at least 6 months in duration were eligible for study enrollment if they met accepted criteria for the diagnosis of the chronic prostatitis/chronic pelvic pain syndrome, as outlined by the National Institutes of Health (NIH) Steering Committee.5 They were ineligible if they had participated in a previous prostate tissue measurement study or had any exclusion criteria according to NIH Chronic Prostatitis Collaborative Research Network criteria for clinical studies in chronic prostatitis.12 Further study exclusion criteria included a history of or concurrent clinical urethritis, history of recurrent urinary tract infection, concurrent bacterial cystitis or bacteriuria in any urine or prostate specimen, NIH-Chronic Prostatitis Symptom Index (CPSI) score less than 15 or maximum urinary flow less than 10 cc per second; post-void residual urine greater than 50 cc; transrectal ultrasound measurement of prostate volume greater than 40 cc to minimize the possible influence of benign prostatic hyperplasia on tissue pressure measurement; serum or prostate specific antigen (PSA) greater than 3 ng./dl. or a free-to-total PSA ratio of less than 15% unless appropriate sextant biopsies were performed. When biopsy was positive for prostate cancer, the patient was subsequently excluded from analysis. Participants completed a Finnish version of the NIH-CPSI. The verification process for the Finnish translation of the NIH-CPSI included English to Finnish translation and then independent translation back again to English to ensure question stability. The Finnish version was then completed by 163 men with prostatitis, including 100 re-test completions at a second visit, 15 normal healthy controls and 24 patients in whom hemorrhoidectomy was planned. Except for the quality of life/impact domain in hemorrhoidectomy cases the Finnish version of the NIH-CPSI discriminated prostatitis and no prostatitis, as in the study validating the original English version.13 This validation process is planned to be the subject of a future report to the Finnish urological community. Patients underwent physical examination, lower urinary tract evaluation (culture and microscopy of pre-prostatic massage urine, expressed prostatic secretions and postprostatic massage urine), serum PSA determination, uroflowmetry, post-void residual urine estimation by transabdominal ultrasound and transrectal ultrasound. They were stratified into 2 categories based on leukocytosis in prostate specific specimens, namely expressed prostatic secretion or post-prostatic massage urine specimens. Cases were considered category IIIA or the inflammatory chronic pelvic pain syndrome when there were 10 or more leukocytes per high power field in expressed prostatic secretions or in the sediment of post-prostatic massage urine. Cases were considered category IIIB or the noninflammatory chronic pelvic pain syndrome when there were fewer than 10 leukocytes per high
power field in similar specimens. Leukocyte evaluation was standardized by having a single laboratory technician perform all cases, using a standard 0.1 ml. aliquot of fluid and examining samples under 400⫻ magnification in a bright line chamber. Microscopy of semen specimens was not performed in this study to differentiate further categories IIIA and IIIB. Controls. Control candidates for study inclusion included patients hospitalized for hemorrhoid surgery without a history of or concurrent chronic prostatitis-chronic pelvic pain syndrome, as defined. Patients were excluded from study due to a significant history of lower urinary tract problems that had required medical or surgical intervention in the past. They underwent similar evaluation, including the NIHCPSI, lower urinary tract localization studies, uroflowmetry, post-void residual urine determination, transrectal ultrasound and serum PSA measurement. Study exclusion criteria in regard to the flow rate, post-void residual urine, prostate volume and PSA were identical to that in the chronic pelvic pain syndrome group. Prostate tissue pressure measurement. Prostate tissue pressure measurement was done with all patients and controls under spinal anesthesia, as previously described.10, 11 In our study an 18 gauge 2.5-inch needle was introduced through the perineal skin and advanced into the prostatic apex under finger guidance. Intraoperative transrectal ultrasound was performed to ensure appropriate needle positioning in the prostate gland as necessary. Sterile isotonic saline solution (1 ml.) was injected and tissue pressure was measured by an intracompartmental pressure monitor system.10 Prostate tissue pressure was measured in the left and then the right prostate lobe. Baseline pressure was measured before injection, and then 10, 60 and 120 seconds after saline injection. All patients received prophylactic antibiotics 1 hour before the procedure, namely 500 mg. ciprofloxacin. Analysis. The study was conceived and the protocol was developed using a collaborative approach. The study was performed in Finland and the results were independently analyzed and interpreted in Canada. Statistical analysis involved Student’s t test with Bonferroni’s corrections and calculations were performed using commercially available software. This study was approved by the appropriate hospital ethics committees as well as the University of Oulu Ethics Committee. Written informed consent was obtained from all subjects. RESULTS
We evaluated 48 patients with the chronic prostatitischronic pelvic pain syndrome, including 18 with category IIIA and 30 with category IIIB disease. There was a less than 5-year, 5 to 9-year and greater than 10-year history of symptoms in 8 (25%), 8 (17%) and 28 (58%) cases, respectively. Enrolled in the study were 12 controls. The table lists demo-
Baseline demographics in the various groups Category III
IIIA
IIIB
Controls
No. pts. Mean age (range) Mean NIH-CPSI score ⫾ SD: Pain (range 0–21) Voiding (range 0–10) Quality of life (range 0–12)
48 53 (21–79)
18 54 (21–79)
30 52 (27–75)
12 44 (35–65)
10.5 ⫾ 4.4 3.3 ⫾ 3.2 7.0 ⫾ 2.9
9.2 ⫾ 4.6 2.7 ⫾ 2.9 6.6 ⫾ 3.0
11.3 ⫾ 4.2 3.7 ⫾ 3.3 7.2 ⫾ 2.8
0.08 ⫾ 0.3 0.3 ⫾ 0.6 5.5 ⫾ 4.3
Totals (range 0–43) Mean PSA ⫾ SD (ng./ml.) Mean prostate vol. ⫾ SD (cc) Mean flow rate ⫾ SD (cc/sec.) Mean voided urine ⫾ SD (cc) Mean post-void residual urine ⫾ SD (cc)
20.8 ⫾ 4.5 2.1 ⫾ 2.8 22 ⫾ 7 16 ⫾ 7 316 ⫾ 144 29 ⫾ 26
18.4 ⫾ 8.1 3.2 ⫾ 3.8 24 ⫾ 8 16 ⫾ 8 268 ⫾ 118 24 ⫾ 17
22.2 ⫾ 8.5 1.5 ⫾ 1.8 21 ⫾ 6 15 ⫾ 6 345 ⫾ 151 33 ⫾ 29
5.8 ⫾ 4.5 1.5 ⫾ 1.4 21 ⫾ 6 16 ⫾ 4 367 ⫾ 157 24 ⫾ 21
CHRONIC PROSTATITIS-CHRONIC PELVIC PAIN SYNDROME
graphics, baseline characteristics and average NIH-CPSI scores. All patients tolerated prostate pressure measurement without any problem. There were no cases of urinary tract infection, urosepsis or any other significant complications but the incidence of asymptomatic hematospermia was not assessed. Figure 1 shows the comparison of left and right prostate tissue pressure measurements in controls and patients. Intraprostatic tissue pressure was significantly higher at all measurement points in patients versus controls (p ⬍0.01). Pressure in the right lobe at 10 seconds was slightly higher in patients and in controls. This difference was only significant at a prostate volume of less than 20 cc (p ⬍0.05) and it was not observed in 20 to 40 cc organs (data not shown). At all other time points there was no significant difference in pressure measurement in the right and left prostate lobes. Figure 2 graphically shows mean right and left lobe pressure measurements averaged per patient per period in categories IIIA and IIIB, and controls. After baseline measurement there was a significant difference in the 2 category III groups and controls (p ⬍0.001) as well as in categories IIIA and IIIB (p ⬍0.01) at 10, 60 and 120 seconds. DISCUSSION
In 1978 Drach et al proposed a classification system to categorize the majority of patients presenting with the diagnosis of chronic prostatitis as chronic nonbacterial prostatitis or prostatodynia.14 This categorization was based on the assumption that inflammatory cells detected in prostate specific specimens by the lower urinary tract localization tests originally described by Meares and Stamey 10 years previously6 were reflective of an inflammatory process in the prostate gland, while the lack of leukocytosis in the specimens implied no prostatic inflammation. To our knowledge until recently there has been no evidence that this differentiation of the chronic prostatitis syndromes into an inflammatory and noninflammatory category was valid and/or clinically important. Earlier findings in the Finnish studies implied that tissue pressure would be elevated in patients with the chronic prostatitis/chronic pelvic pain syndrome compared with control patients.10, 11 That initial finding was confirmed in our prospective study. Our series has some limitations. Semen analysis was not performed, there was a difference in age and prostate size in patients and controls, men in whom hemor-
FIG. 1. Comparison of mean left (L) and right (R) side prostate tissue pressure measurements (PTPM) in patients (Case) and controls showed no significant difference for right versus left lobes but significant difference (p ⬍0.01) in patients and controls at all times in right and left measurements.
139
FIG. 2. Mean prostate tissue pressure (PTPM) values of right and left lobe measurements averaged per patient per period for categories IIIA, IIIB and controls showed significant difference in all patients versus controls (p ⬍0.001) and in categories IIIA and IIIB (p ⬍0.01) after baseline measurement.
rhoidectomy is planned may not be ideal controls since they are not really an asymptomatic population, ejaculation was not controlled for and the investigators were not blinded. Despite these limitations patients with the chronic prostatitis-chronic pelvic pain syndrome appear to have an average prostate tissue pressure that is higher than in control patients when measured by the technique described. Perhaps the most interesting and important finding of this study was that significantly higher tissue pressure was measured at all time points in cases diagnosed by expressed prostatic secretion leukocyte differentiation as chronic prostatitis-chronic pelvic pain syndrome category IIIA compared with those diagnosed as category IIIB. This finding would indicate an association of elevated prostate tissue pressure with documented inflammation in prostate specific specimens. The prostate gland is situated inside a compartment system surrounded by Denonvillier’s fascia, the endopelvic fascia and the anterior surface of the surgical prostate capsule with the puboprostatic ligaments.15, 16 It may be hypothesized that inflammation within the prostate gland causes tissue edema, disturbed microcirculation and hypoxia, consequently resulting in the most common symptom of the chronic prostatitis-chronic pelvic pain syndrome, namely pain. After injecting 1 ml. isotonic saline solution into the prostate enclosed in this closed compartmental system the elevation of tissue pressure and the time needed to achieve equilibrium are based on balancing Starling forces, which depend on tissue density/stiffness and possible scarring processes in the prostate tissue as well as on microcirculation patency.17, 18 The fact that we replicated the same findings in the right and left lobes of the prostate gland added further validation to our technique and our subsequent findings. Thus, this study would indicate that the prostate gland may be involved in the pathogenesis of chronic prostatitis-chronic pelvic pain syndrome category IIIA. Nadler8 and Alexander9 et al also suggested that there may be objective parameters differentiating categories IIIA and IIIB. They noted increased cytokine in expressed prostatic secretions and semen, respectively, in patients in whom leukocytosis was detected in prostate specific specimens (category IIIA) compared with those in whom no significant leukocytosis was detected (category IIIB). The association of the objective parameters of inflammation, the cytokine level and prostatic tissue pressure may be further extrapolated to include a correlation with etiological mechanisms and per-
140
CHRONIC PROSTATITIS-CHRONIC PELVIC PAIN SYNDROME
haps even the symptom complex in patients with category IIIA disease. The fact that patients diagnosed with the clinical chronic prostatitis-chronic pelvic pain syndrome category IIIA may have objectively measurable prostate pathology may indicate further avenues of research into the etiology of this disease as well as the differentiation of therapeutic strategies in patients with the chronic prostatitis-chronic pelvic pain syndrome. The results of this study do not imply that clinicians should consider prostate tissue pressure measurement as part of the standard differential diagnostic evaluation in patients who present with the chronic prostatitis-chronic pelvic pain syndrome. Rather, this study supports the suggestion that patients with that syndrome have significantly higher prostate tissue pressure than control patients without the syndrome. The findings also provide further evidence to support the rationale for the differentiation of chronic prostatitis-chronic pelvic pain syndrome cases into an inflammatory and a noninflammatory category. In conclusion, we hope that the interpretation of this study may promote further research into the differential etiology of the 2 categories of the chronic prostatitis-chronic pelvic pain syndrome, ultimately resulting in specific differential therapy based on the categorization of this disease into inflammatory and noninflammatory categories. REFERENCES
1. Nickel, J. C.: Prostatitis: evolving management strategies. Urol Clin North Am, 26: 737, 1999 2. Nickel, J. C.: Prostatitis: myths and realities. Urology, 51: 362, 1998 3. McNaughton-Collins, M., Stafford, R. S., O’Leary, M. P. et al: How common is prostatitis? A national survey of physician visits. J Urol, 159: 1224, 1998 4. Roberts, R. O., Lieber, M. M., Rhodes, T. et al: Prevalence of physician-assigned diagnosis of prostatitis: the Olmsted county study of urinary symptoms and health status among men. Urology, 51: 578, 1998 5. Krieger, J. N., Nyberg, L. and Nickel, J. C.: NIH consensus definition and classification of prostatitis. JAMA, 282: 236, 1999
6. Meares, E. M. and Stamey, T. A.: Bacteriologic localization patterns in bacterial prostatitis and urethritis. Invest Urol, 5: 492, 1968 7. Krieger, J. N., Jacobs, R. R. and Ross, S. O.: Does the chronic prostatitis/pelvic pain syndrome differ from nonbacterial prostatitis and prostatodynia? J Urol, 164: 1554, 2000 8. Nadler, R. B., Koch, A. E., Calhoun, E. A. et al: IL-1b and TNF-a in prostatic secretions are indicators in the evaluation of men with chronic prostatitis. J Urol, 164: 214, 2000 9. Alexander, R. B., Ponniah, S., Hasday, J. et al: Elevated levels of proinflammatory cytokines in the semen of patients with chronic prostatitis/chronic pelvic pain syndrome. Urology, 52: 744, 1998 10. Mehik, A., Hellstro¨ m, P., Lukkarinen, O. et al: Increased intraprostatic pressure in patients with chronic prostatitis. Urol Res, 27: 277, 1999 11. Mehik, A., Hellstro¨ m, P., Lukkarinen, O. et al: Prostatic tissue pressure measurement as a possible diagnostic procedure in patients with chronic nonbacterial prostatitis/chronic pelvic pain syndrome. Urol Res, 28: 316, 2000 12. Nickel, J. C., Nyberg, L. M. and Hennenfent, M.: Research guidelines for chronic prostatitis: consensus report from the first National Institutes of Health International Prostatitis Collaborative Network. International Prostatitis Collaborative Network. Urology, 54: 229, 1999 13. Litwin, M. S., McNaughton-Collins, M., Fowler, F. J., Jr. et al: The Chronic Prostatitis Collaborative Research Network: the National Institutes of Health Chronic Prostatitis Symptom Index: development and validation of a new outcome measure. J Urol, 162: 369, 1999 14. Drach, G. W., Meares, E. M., Fair, W. R. et al: Classification of benign diseases associated with prostatic pain: prostatitis or prostatodynia? J Urol, 120: 266, 1978 15. Blacklock, N. J.: The anatomy of the prostate: relationship with prostatic infection. Infection, suppl., 19: 111, 1991 16. Brooks, J. D.: Anatomy of the lower urinary tract and male genitalia. In: Campbell’s Urology, 7th ed. Edited by P. C. Walsh et al. Philadelphia: W. B. Saunders, p. 104, 1998 17. Cho, I. R., Keener, T. S., Nghiem, H. V. et al: Prostate blood flow characteristics in the chronic prostatitis/pelvic pain syndrome. J Urol, 163: 1130, 2000 18. Ashton, H.: The effect of increased tissue pressure on blood flow. Clin Orthoped Rel Res, 113: 15, 1975
Vol. 167, 137–140, January 2002 Printed in U.S.A.
THE CHRONIC PROSTATITIS-CHRONIC PELVIC PAIN SYNDROME CAN BE CHARACTERIZED BY PROSTATIC TISSUE PRESSURE MEASUREMENTS ¨ M, J. CURTIS NICKEL,* ANSA KILPONEN, MARKKU LESKINEN, AARE MEHIK, PEKKA HELLSTRO ARI SARPOLA AND OLAVI LUKKARINEN From the Division of Urology, Departments of Surgery and Public Health Science and General Practice, Oulu University Hospital, Oulu and Division of Urology, Department of Surgery, Seina¨joki Central Hospital, Seina¨joki, Finland, and Department of Urology, Queen’s University, Kingston, Ontario, Canada
ABSTRACT
Purpose: We performed a prospective study to confirm early results implying that intraprostatic tissue pressure is elevated in men with the chronic prostatitis-chronic pelvic pain syndrome. We planned to determine further whether this technique would detect a significant difference in inflammatory and noninflammatory categories IIIA and IIIB. Materials and Methods: A total of 48 patients with the chronic prostatitis-chronic pelvic pain syndrome, including 18 with inflammatory category IIIA and 30 with noninflammatory category IIIB disease, and 12 asymptomatic controls completed a Finnish version of the National Institutes of Health-Chronic Prostatitis Symptom Index. In addition, culture and microscopy of lower urinary tract segmented specimens, serum prostate specific antigen determination, transrectal ultrasound, uroflowmetry and ultrasound post-void residual urine measurement were done. All patients and controls also underwent independent intraprostatic right and left lobe tissue pressure measurement using a standard intracompartmental tissue pressure monitor system. Pressure was measured via an intraprostatic needle placed percutaneously in the perineum at baseline, and 10, 60 and 120 seconds after standard saline injection. Results: All patients with the chronic prostatitis-chronic pelvic pain syndrome had significantly higher pressure at all measurement points compared with controls (p ⬍0.001). Mean intraprostatic tissue pressure was significantly higher (p ⬍0.01) in category IIIA with greater than 10 leukocytes per high power field in prostate specific specimens compared with category IIIB with less than 10. Conclusions: Our study supports the suggestion that patients with the chronic prostatitischronic pelvic pain syndrome have significantly higher prostate tissue pressure than controls. Findings also validated the previous clinical assumption that there is a rationale for differentiating chronic prostatitis-chronic pelvic pain syndrome cases into inflammatory and noninflammatory categories. KEY WORDS: prostate; prostatitis; pelvic pain; diagnosis, differential
The etiology of the chronic prostatitis-chronic pelvic pain syndrome is unknown but possibilities include cryptic unculturable infection, trauma, voiding disturbances, anatomical abnormalities, intraprostatic ductal reflux, and immunological and/or neurogenic causes.1 This syndrome likely arises from a spectrum of pathogenic entities initiated and propagated by any number of these factors.2 Although it is commonly diagnosed by physicians,3, 4 there are no real objective parameters for specifically diagnosing the chronic prostatitis-chronic pelvic pain syndrome.2, 5 The only parameters are a constellation of symptoms and absent uropathogenic bacteria in prostate specific specimens, which only enables differentiation from rare cases of category II chronic bacterial prostatitis. Differentiation of the syndrome into inflammatory category IIIA and noninflammatory category IIIB based on an undetermined cutoff number of white blood cells detected by microscopic evaluation of expressed prostatic secretions, sediment of postprostatic massage urine or semen has not been conclusively validated.6, 7 These 2 categories have a similar
presentation and symptom complex, and there is no solid proof that they respond any differently to specific treatment.1 However, Nadler8 and Alexander9 et al suggested that the inflammatory category IIIA can be differentiated from noninflammatory category IIIB by measuring specific cytokines in expressed prostatic secretions and semen, respectively. It was recently shown that patients diagnosed with the chronic prostatitis-chronic pelvic pain syndrome may have elevated intraprostatic tissue pressure compared with those not diagnosed with the clinical condition.10, 11 This finding may have important ramifications for determining pathogenic mechanisms and directing therapeutic approaches, and it may enable the differentiation of the 2 disease categories. We performed a prospective study to determine whether these initial results would be replicated and further determine whether this technique would detect a significant difference in the inflammatory and noninflammatory categories based on inflammation detected in expressed prostatic secretions or post-prostatic massage urine sediment, thus, validating the differentiation of chronic prostatitis-chronic pelvic pain syndrome categories IIIA and IIIB.
Accepted for publication August 17, 2001. * Financial interest and/or other relationship with Merck, Bayer Canada, Janssen-Ortho Canada, Alza, Situs, Abbott Canada and Glaxo-Wellcome. 137
138
CHRONIC PROSTATITIS-CHRONIC PELVIC PAIN SYNDROME MATERIALS AND METHODS
Patients with the chronic pelvic pain syndrome. Patients with a clinical diagnosis of symptomatic chronic prostatitis at least 6 months in duration were eligible for study enrollment if they met accepted criteria for the diagnosis of the chronic prostatitis/chronic pelvic pain syndrome, as outlined by the National Institutes of Health (NIH) Steering Committee.5 They were ineligible if they had participated in a previous prostate tissue measurement study or had any exclusion criteria according to NIH Chronic Prostatitis Collaborative Research Network criteria for clinical studies in chronic prostatitis.12 Further study exclusion criteria included a history of or concurrent clinical urethritis, history of recurrent urinary tract infection, concurrent bacterial cystitis or bacteriuria in any urine or prostate specimen, NIH-Chronic Prostatitis Symptom Index (CPSI) score less than 15 or maximum urinary flow less than 10 cc per second; post-void residual urine greater than 50 cc; transrectal ultrasound measurement of prostate volume greater than 40 cc to minimize the possible influence of benign prostatic hyperplasia on tissue pressure measurement; serum or prostate specific antigen (PSA) greater than 3 ng./dl. or a free-to-total PSA ratio of less than 15% unless appropriate sextant biopsies were performed. When biopsy was positive for prostate cancer, the patient was subsequently excluded from analysis. Participants completed a Finnish version of the NIH-CPSI. The verification process for the Finnish translation of the NIH-CPSI included English to Finnish translation and then independent translation back again to English to ensure question stability. The Finnish version was then completed by 163 men with prostatitis, including 100 re-test completions at a second visit, 15 normal healthy controls and 24 patients in whom hemorrhoidectomy was planned. Except for the quality of life/impact domain in hemorrhoidectomy cases the Finnish version of the NIH-CPSI discriminated prostatitis and no prostatitis, as in the study validating the original English version.13 This validation process is planned to be the subject of a future report to the Finnish urological community. Patients underwent physical examination, lower urinary tract evaluation (culture and microscopy of pre-prostatic massage urine, expressed prostatic secretions and postprostatic massage urine), serum PSA determination, uroflowmetry, post-void residual urine estimation by transabdominal ultrasound and transrectal ultrasound. They were stratified into 2 categories based on leukocytosis in prostate specific specimens, namely expressed prostatic secretion or post-prostatic massage urine specimens. Cases were considered category IIIA or the inflammatory chronic pelvic pain syndrome when there were 10 or more leukocytes per high power field in expressed prostatic secretions or in the sediment of post-prostatic massage urine. Cases were considered category IIIB or the noninflammatory chronic pelvic pain syndrome when there were fewer than 10 leukocytes per high
power field in similar specimens. Leukocyte evaluation was standardized by having a single laboratory technician perform all cases, using a standard 0.1 ml. aliquot of fluid and examining samples under 400⫻ magnification in a bright line chamber. Microscopy of semen specimens was not performed in this study to differentiate further categories IIIA and IIIB. Controls. Control candidates for study inclusion included patients hospitalized for hemorrhoid surgery without a history of or concurrent chronic prostatitis-chronic pelvic pain syndrome, as defined. Patients were excluded from study due to a significant history of lower urinary tract problems that had required medical or surgical intervention in the past. They underwent similar evaluation, including the NIHCPSI, lower urinary tract localization studies, uroflowmetry, post-void residual urine determination, transrectal ultrasound and serum PSA measurement. Study exclusion criteria in regard to the flow rate, post-void residual urine, prostate volume and PSA were identical to that in the chronic pelvic pain syndrome group. Prostate tissue pressure measurement. Prostate tissue pressure measurement was done with all patients and controls under spinal anesthesia, as previously described.10, 11 In our study an 18 gauge 2.5-inch needle was introduced through the perineal skin and advanced into the prostatic apex under finger guidance. Intraoperative transrectal ultrasound was performed to ensure appropriate needle positioning in the prostate gland as necessary. Sterile isotonic saline solution (1 ml.) was injected and tissue pressure was measured by an intracompartmental pressure monitor system.10 Prostate tissue pressure was measured in the left and then the right prostate lobe. Baseline pressure was measured before injection, and then 10, 60 and 120 seconds after saline injection. All patients received prophylactic antibiotics 1 hour before the procedure, namely 500 mg. ciprofloxacin. Analysis. The study was conceived and the protocol was developed using a collaborative approach. The study was performed in Finland and the results were independently analyzed and interpreted in Canada. Statistical analysis involved Student’s t test with Bonferroni’s corrections and calculations were performed using commercially available software. This study was approved by the appropriate hospital ethics committees as well as the University of Oulu Ethics Committee. Written informed consent was obtained from all subjects. RESULTS
We evaluated 48 patients with the chronic prostatitischronic pelvic pain syndrome, including 18 with category IIIA and 30 with category IIIB disease. There was a less than 5-year, 5 to 9-year and greater than 10-year history of symptoms in 8 (25%), 8 (17%) and 28 (58%) cases, respectively. Enrolled in the study were 12 controls. The table lists demo-
Baseline demographics in the various groups Category III
IIIA
IIIB
Controls
No. pts. Mean age (range) Mean NIH-CPSI score ⫾ SD: Pain (range 0–21) Voiding (range 0–10) Quality of life (range 0–12)
48 53 (21–79)
18 54 (21–79)
30 52 (27–75)
12 44 (35–65)
10.5 ⫾ 4.4 3.3 ⫾ 3.2 7.0 ⫾ 2.9
9.2 ⫾ 4.6 2.7 ⫾ 2.9 6.6 ⫾ 3.0
11.3 ⫾ 4.2 3.7 ⫾ 3.3 7.2 ⫾ 2.8
0.08 ⫾ 0.3 0.3 ⫾ 0.6 5.5 ⫾ 4.3
Totals (range 0–43) Mean PSA ⫾ SD (ng./ml.) Mean prostate vol. ⫾ SD (cc) Mean flow rate ⫾ SD (cc/sec.) Mean voided urine ⫾ SD (cc) Mean post-void residual urine ⫾ SD (cc)
20.8 ⫾ 4.5 2.1 ⫾ 2.8 22 ⫾ 7 16 ⫾ 7 316 ⫾ 144 29 ⫾ 26
18.4 ⫾ 8.1 3.2 ⫾ 3.8 24 ⫾ 8 16 ⫾ 8 268 ⫾ 118 24 ⫾ 17
22.2 ⫾ 8.5 1.5 ⫾ 1.8 21 ⫾ 6 15 ⫾ 6 345 ⫾ 151 33 ⫾ 29
5.8 ⫾ 4.5 1.5 ⫾ 1.4 21 ⫾ 6 16 ⫾ 4 367 ⫾ 157 24 ⫾ 21
CHRONIC PROSTATITIS-CHRONIC PELVIC PAIN SYNDROME
graphics, baseline characteristics and average NIH-CPSI scores. All patients tolerated prostate pressure measurement without any problem. There were no cases of urinary tract infection, urosepsis or any other significant complications but the incidence of asymptomatic hematospermia was not assessed. Figure 1 shows the comparison of left and right prostate tissue pressure measurements in controls and patients. Intraprostatic tissue pressure was significantly higher at all measurement points in patients versus controls (p ⬍0.01). Pressure in the right lobe at 10 seconds was slightly higher in patients and in controls. This difference was only significant at a prostate volume of less than 20 cc (p ⬍0.05) and it was not observed in 20 to 40 cc organs (data not shown). At all other time points there was no significant difference in pressure measurement in the right and left prostate lobes. Figure 2 graphically shows mean right and left lobe pressure measurements averaged per patient per period in categories IIIA and IIIB, and controls. After baseline measurement there was a significant difference in the 2 category III groups and controls (p ⬍0.001) as well as in categories IIIA and IIIB (p ⬍0.01) at 10, 60 and 120 seconds. DISCUSSION
In 1978 Drach et al proposed a classification system to categorize the majority of patients presenting with the diagnosis of chronic prostatitis as chronic nonbacterial prostatitis or prostatodynia.14 This categorization was based on the assumption that inflammatory cells detected in prostate specific specimens by the lower urinary tract localization tests originally described by Meares and Stamey 10 years previously6 were reflective of an inflammatory process in the prostate gland, while the lack of leukocytosis in the specimens implied no prostatic inflammation. To our knowledge until recently there has been no evidence that this differentiation of the chronic prostatitis syndromes into an inflammatory and noninflammatory category was valid and/or clinically important. Earlier findings in the Finnish studies implied that tissue pressure would be elevated in patients with the chronic prostatitis/chronic pelvic pain syndrome compared with control patients.10, 11 That initial finding was confirmed in our prospective study. Our series has some limitations. Semen analysis was not performed, there was a difference in age and prostate size in patients and controls, men in whom hemor-
FIG. 1. Comparison of mean left (L) and right (R) side prostate tissue pressure measurements (PTPM) in patients (Case) and controls showed no significant difference for right versus left lobes but significant difference (p ⬍0.01) in patients and controls at all times in right and left measurements.
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FIG. 2. Mean prostate tissue pressure (PTPM) values of right and left lobe measurements averaged per patient per period for categories IIIA, IIIB and controls showed significant difference in all patients versus controls (p ⬍0.001) and in categories IIIA and IIIB (p ⬍0.01) after baseline measurement.
rhoidectomy is planned may not be ideal controls since they are not really an asymptomatic population, ejaculation was not controlled for and the investigators were not blinded. Despite these limitations patients with the chronic prostatitis-chronic pelvic pain syndrome appear to have an average prostate tissue pressure that is higher than in control patients when measured by the technique described. Perhaps the most interesting and important finding of this study was that significantly higher tissue pressure was measured at all time points in cases diagnosed by expressed prostatic secretion leukocyte differentiation as chronic prostatitis-chronic pelvic pain syndrome category IIIA compared with those diagnosed as category IIIB. This finding would indicate an association of elevated prostate tissue pressure with documented inflammation in prostate specific specimens. The prostate gland is situated inside a compartment system surrounded by Denonvillier’s fascia, the endopelvic fascia and the anterior surface of the surgical prostate capsule with the puboprostatic ligaments.15, 16 It may be hypothesized that inflammation within the prostate gland causes tissue edema, disturbed microcirculation and hypoxia, consequently resulting in the most common symptom of the chronic prostatitis-chronic pelvic pain syndrome, namely pain. After injecting 1 ml. isotonic saline solution into the prostate enclosed in this closed compartmental system the elevation of tissue pressure and the time needed to achieve equilibrium are based on balancing Starling forces, which depend on tissue density/stiffness and possible scarring processes in the prostate tissue as well as on microcirculation patency.17, 18 The fact that we replicated the same findings in the right and left lobes of the prostate gland added further validation to our technique and our subsequent findings. Thus, this study would indicate that the prostate gland may be involved in the pathogenesis of chronic prostatitis-chronic pelvic pain syndrome category IIIA. Nadler8 and Alexander9 et al also suggested that there may be objective parameters differentiating categories IIIA and IIIB. They noted increased cytokine in expressed prostatic secretions and semen, respectively, in patients in whom leukocytosis was detected in prostate specific specimens (category IIIA) compared with those in whom no significant leukocytosis was detected (category IIIB). The association of the objective parameters of inflammation, the cytokine level and prostatic tissue pressure may be further extrapolated to include a correlation with etiological mechanisms and per-
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haps even the symptom complex in patients with category IIIA disease. The fact that patients diagnosed with the clinical chronic prostatitis-chronic pelvic pain syndrome category IIIA may have objectively measurable prostate pathology may indicate further avenues of research into the etiology of this disease as well as the differentiation of therapeutic strategies in patients with the chronic prostatitis-chronic pelvic pain syndrome. The results of this study do not imply that clinicians should consider prostate tissue pressure measurement as part of the standard differential diagnostic evaluation in patients who present with the chronic prostatitis-chronic pelvic pain syndrome. Rather, this study supports the suggestion that patients with that syndrome have significantly higher prostate tissue pressure than control patients without the syndrome. The findings also provide further evidence to support the rationale for the differentiation of chronic prostatitis-chronic pelvic pain syndrome cases into an inflammatory and a noninflammatory category. In conclusion, we hope that the interpretation of this study may promote further research into the differential etiology of the 2 categories of the chronic prostatitis-chronic pelvic pain syndrome, ultimately resulting in specific differential therapy based on the categorization of this disease into inflammatory and noninflammatory categories. REFERENCES
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