Prostate-specific antigen and transition zone index powerful predictors for acute urinary retention in men with benign prostatic hyperplasia

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1 1071 Prostate-specific antigen and transition zone index powerful predictors for acute urinary retention in men with benign prostatic hyperplasia Clinic of Urology, Kaunas University of Medicine Hospital, Lithuania Key words: prostate-specific antigen, transition zone index, benign prostatic hyperplasia, acute urinary retention. Summary. Objectives. To examine the efficacy of prostate-specific antigen and various parameters obtained by transrectal ultrasonography as predictors of acute urinary retention in patients with benign prostatic hyperplasia. Methods. Eighty-nine men with symptoms of benign prostatic hyperplasia were enrolled in this study from February 2002 to June Among them, 21 patients presented with acute urinary retention. Transrectal ultrasonography was used to calculate the total prostate volume, transition zone volume and transition zone index. Sample of prostatespecific antigen was taken in outpatient clinic or in clinic before first insertion of the catheter into the bladder, because of urinary retention. If the patient presented with inserted catheter, we used latest prostate-specific antigen date from the medical notes of outpatient clinic. To compare the usefulness of the various indexes, the area under the receiver-operator characteristic curve was calculated for each index. Results. There were significant differences between patients with and without acute urinary retention in the total prostate volume (58.16 cm 3 and cm 3, p=0.0028), transition zone volume (36.62 cm 3 and cm 3, p=0.0001), transition zone index (0.62 and 0.51, p= ), prostate-specific antigen (4.96 ng/ml and 2.97 ng/ml, p= ), age and quality of life score, but no significant difference in International Prostate Symptom Score. In patients with acute urinary retention, the area under the receiver-operator characteristic curve was for transition zone index, for prostate-specific antigen, for transition zone volume, for total prostate zone volume and for International Prostate Symptom Score. Conclusions. The transition zone index and prostate-specific antigen are accurate predictors of acute urinary retention in patients with benign prostatic hyperplasia and may be useful for deciding between surgical intervention and medical treatment. Introduction In elderly men, benign prostatic hyperplasia (BPH) is a common disease and reduces substantially their quality of life (1 ). In particular, acute urinary retention (AUR) is one of the most undesirable events associated with the disease. The incidence of AUR has been reportedly different among subjects examined, ranging from 6.8 per 1000 person-years in community based population (2) to 17 per 1000 and 25 per 1000 person-years in patients with BPH who were candidates for medical therapy (3) and prostate surgery (4). It has been reported that AUR is the indication for surgery in 30% of patients undergoing transurethral resection of the prostate (5). Although the conventional treatment of AUR is catheterization with alpha blocators, 50% of patients develop further retention within 1 week and 70% require definitive outflow revision within 1 year (6). It is very important to find clinical parameters which can lead to predict AUR. In recent studies, several of its have been suggested to be possible predictors for AUR. These include age, lower tract symptoms, urinary flow rates, prostate volume and its indices, prostate-specific antigen (PSA) and ultrasound Correspondence to D. Milonas, Clinic of Urology, Kaunas University of Medicine Hospital, Eivenių 2, 3007 Kaunas, Lithuania. dmilonas@takas.lt

2 1072 estimated bladder weight (UEBW) (7-11). The aim of the present study was to evaluate the usefulness of various indices obtained by transrectal ultrasonography (TRUS) and PSA as risk factors for acute urinary retention in patients with BPH. Material and methods From January 2002 to June 2003, 89 patients with BPH were enrolled in this study. (The study was approved by the regional ethical committee and all men gave written informed consent). Among them 21 patients presented to our clinic with AUR. BPH was diagnosed on the basis of history, symptoms, physical findings, flow rate (Qmax), postvoid residual volume (PVR) and TRUS. Symptoms were assessed using the International Prostate Symptom Score (IPSS) with quality of life score (QoL). All patients had moderate to severe symptoms. The patients with AUR were asked to record their symptoms for 1 month before the onset of retention. All patients had no disorders suggesting the presence of neurogenic bladder dysfunction and had specified inclusion criteria of the International Scientific Committee on BPH (12). All TRUS examinations were performed by two authors (D. M, P. J) using MHz transrectal probe (SIEMENS Sonoline SI-250). Images were obtained with the patient in the left decubitus position. The transverse and sagittal sections were recorded after marking the transition zone (TZ). The transverse and anteroposterior diameters of the total prostate and the TZ at the largest cross-sectional area were used for various calculations. The superoinferior diameter of the prostate was measured on midline sagital images and that of the TZ was measured at the point of its largest diameter on the sagittal image. Total prostate and TZ volumes were calculated using the formula of volume estimation of an ellipsoid: volume 0.52 transverse diameter anteroposterior diameter superoinferior diameter (13). TRUS was done for each patient. Uroflowmetry was performed using the Urodyn Urinary flow data were only used for analysis if at least 100 ml of urine was excreted (14). The postvoid residual volume was measured by suprapubic ultrasonography using diameters in sagittal and transverse sections (15). Samples of PSA were taken in out patient clinic or in clinic before first insertion of the catheter into the bladder. If the patient presented to our clinic with inserted catheter, we used latest PSA data from the medical notes of outpatient clinic. In suspicion of prostate cancer sextant transrectal biopsies were performed. Patients with histologically approved prostate cancer were excluded from the study. No patient had significant hydronephrosis or renal failure. The necessary data were obtained in the remaining 89 patients. All values in the text were expressed as the minimal, maximal and mean plus or minus standard deviation (SD). Statistical comparison of the AUR and non-retention groups was performed using unpaired Student s t test. Relationships among two parameters were analyzed using Pearson s correlation coefficients. Analysis was done using Statistica 5.0 statistical software. The positive predictive value, sensitivity, and specificity for detecting AUR were calculated for the IPSS, total prostate volume, TZ volume, TZ index and PSA. Receiver-operator characteristic (ROC) curves were plotted with the sensitivity on the Y axis versus 1 minus the specificity on the X axis. To compare the usefulness of the IPSS, total prostate volume, TZ volume, TZ index and PSA, the area under the corresponding ROC curve was calculated (8). These statistical analyses were performed using statistical software SPSS 9.0. For all statistical tests, a p value less than 0.05 was considered significant. Results Age in all patients was significantly correlated with TZ index (r=0.232, p=0.028), total prostate volume (r=0.258, p=0.015). Age has strongest correlation with TZ volume (r=0.258, p=0.006). PSA in all patients was significantly correlated with the TZ index (r=0.481, p=0.0002), total prostate volume (r=0.585, p=0.0001) and TZ volume (r=0.607, p=0.0001). In the patients without AUR (n=68) (Table 1) there were no significant correlation between total IPSS, Qmax, PVR, QoL and all indices obtained by TRUS. Significant, but not very strong, correlation was detected between obstructive symptoms of IPSS and total prostate volume and TZ volume. In this group PSA was found significant correlation with TZ index, TZ volume and total prostate volume. Table 2 shows a comparison of nine clinical variables in patients with and without AUR. There were significant differences in age, irritative symptoms, QoL score, TZ volume, total prostate volume, PSA and TZ index, but no significant difference was found for total IPSS and obstructive symptoms. ROC curves for the prediction of AUR are shown in Figure 1. The area under the ROC curve was for the TZ index, for the PSA, for the TZ volume, for the total prostate volume

3 Prostate-specific antigen and transition zone index 1073 Table 1. Correlations of the total IPSS, irritative and ostructive symptoms, QoL, PVR volume, PSA with various TRUS parameters Parameter Irritative Obstructive PVR n=68 IPSS symptoms symptoms QoL Qmax index PSA Total prostate r=0.122 r=0.079 r=0.238 r= r=0.044 r= r=0.618 volume p=0.252 p=0.460 p=0.024 p=0.714 p=0.678 p=0.558 p< TZ r=0.098 r=0.103 r=0.228 r= r=0.019 r= r=0.629 volume p=0.360 p=0.336 p=0.030 p=0.900 p=0.859 p=0.628 p< TZ r=0.055 r=0.133 r=0.197 r=0.014 r= r= r=0.557 index p=0.610 p=0.210 p=0.062 p=0.898 p=0.887 p=0.586 p< Table 2. Values of nine parameters in all patients stratified by the presence or absence of AUR No AUR AUR Parameter (n=68) (n=21) p value mean S. D. mean S. D. Age ± ±5.74 p=0.023 IPSS ± ±7.65 p=0.10 Irritative symptoms 8.44 ± ±3.31 p=0.015 Obstructive symptoms 12.5 ± ±5.15 p=0.529 QoL 4.5 ± ±1.02 p=0.049 PSA (ng/ml) 2.97 ± ±2.57 p= Total prostate volume (cm 3 ) ± ±20.57 p= TZ volume (cm 3 ) ± ±15.34 p= TZ index 0.51 ± ±0.07 p= and for the IPSS. The TZ index was superior to the all other parameters, but difference between TZ index and IPSS was no significant. The performance of different cutoff values for the TZ index in predicting AUR is shown in Table 3. As the cutoff value increased, the specificity increased and the sensitivity decreased. As the cutoff value decreased, the sensitivity increased and the specificity decreased (8). The cutoff value that provided almost equivalent sensitivity and specificity and had the highest efficiency (sensitivity specificity / 100) was 0.6. Using this cutoff value the TZ index detected AUR in 13 of the 21 patients (62%) and had a positive predictive value of 52%. The same calculation was performed for the PSA (data shown in table 4). Cutoff value for the PSA was 3 ng/ml and using this value PSA detected AUR in 16 of the 21 patients (76%), whereas the positive predictive value was only 39%. The importance of the PSA increased if we analyzed patients with TZ index more than 0.6. In this group 11 of the 13 patients (85% sensitivity) had AUR and positive predictive value increased until 61% (data not shown). Discussion BPH is characterized by the obstruction of urine outflow from the bladder caused by an enlarged prostate. This then leads to clinical manifestations of irritative and obstructive lower urinary tract symptoms, reduction in urinary flow rates and QoL. Data from clinical trials shown that BPH is a progressive disease associated with an increase in prostate volume and risk of serious complications such as AUR (2). BPH progression is different between individuals (7).

4 1074 Sensitivity Sensitivity 1.0 1, , , , , , , , ,2 TZ index TZ index 0.1 0,1 total prostate prostate volume 0.0 0,0 0, , , , , , , , , , ,0 1-specificity PSA PSA TZ volume TZ volume IPSS IPSS Fig. Receiver-operating curve analysis comparing the TZ index, TZ volume, PSA, total prostate volume, IPSS in patients with or without AUR Table 3. Sensitivity, specificity, and positive predictive value (PPV) for AUR of various TZ index values TZ No. of With Without Sensitivity Specificity PPV index patients AUR AUR % % % > /21(100) 0/68(0) 21/89(24) > /21(100) 0/68(0) 21/89(24) > /21(100) 7/68(10) 21/82(26) > /21(100) 10/68(15) 21/79(27) > /21(95) 31/68(46) 20/57(35) > /21(81) 43/68(63) 17/42(40) > /21(62) 56/68(82) 13/25(52) > /21(43) 60/68(88) 9/17(53) > /21(10) 64/68(94) 2/6(33) Although the etiology of AUR is not fully understood (16), it is conceivable that bladder outlet obstruction plays a key role in its occurrence. Recent advances in ultrasonic evaluation of the zonal anatomy of the prostate developing BPH have promoted the understanding of its pathophysiology. McNeal noted that mechanical obstruction in BPH patients is closely related to the TZ volume and especially compression of the peripheral and central zone (17). TZ is responsible for urethral compression and evaluation

5 Prostate-specific antigen and transition zone index 1075 Table 4. Sensitivity, specificity, and positive predictive value (PPV) for AUR of various PSA values PSA No. of With Without Sensitivity Specificity PPV (ng/ml) patients AUR AUR % % % > /21(100) 0/68(0) 21/89(24) > /21(100) 13/68(19) 21/76(28) > /21(95) 24/68(35) 20/64(31) > /21(90) 33/68(49) 19/54(35) > /21(76) 41/68(68) 16/41(39) > /21(57) 46/68(68) 12/34(35) > /21(52) 50/68(74) 11/29(38) > /21(48) 56/68(82) 10/22(45) > /21(38) 58/68(85) 8/18(44) > /21(33) 60/68(88) 7/15(47) > /21(33) 62/68(91) 7/13(54) > /21(24) 64/68(94) 5/9(56) of bladder outlet obstruction. Greene et al. noted that patients with clinical BPH had a TZ volume of ml in contrast to a volume of ml in those without clinical BPH (18). Kaplan et al. first demonstrated a significant correlation of the TZ index with obstruction, approved urodinamically, symptom score and peak flow rate (19). On the other hand, Lepor et al. reported that the total prostate and TZ volume and TZ index were not directly related to the symptom score and were only weakly related to the peak flow rate (20). Discrepancy between the two reports possible explain by different inclusion criteria. Kaplan et al. included men with clinical BPH, whereas Lepor et al. did not use the BPH specific selection criteria. Our results did not show significant correlation between total prostate volume, TZ volume, TZ index and IPSS, Qmax, PVR volume. We detected significant but negative correlation between obstructive symptoms and total prostate and TZ volume. All of our patients without AUR had IPSS more than 13 and Qmax less than 15 ml/s. Kurita et al. showed that TZ index was more potent predictor of AUR than total prostate volume and its indices, using an ROC curve analysis (8). These results seem to be related to the significant correlation of TZ index with bladder outlet obstruction, as reported by Kaplan et al. In our series of patients also, prostate volume and its indices were all significantly greater in patients with AUR than in those without it and TZ index has a highest risk of developing AUR particularly with TZ index more than 0.6. Based on the data obtained from the present study we found some controversial results. There were no correlations between prostate volume and its indices and BPH severity, and on the other hand TZ index, TZ volume and total prostate volume had powerful prediction of the AUR using ROC curve analysis. Our results support that BPH severity parameters as Qmax, IPSS, PVR volume and total prostate volume has no or only weakly correlations with bladder outlet obstruction (21,22). There are still not clear how we could measure BPH severity because of controversial estimation of various parameters. Interesting data reported Miyashita et al. Bladder outlet obstruction is well-known to be followed by hypertrophic changes of the bladder detrusor (11). UEBW was developed originally to evaluate the degree of this hypertrophic change (23). Data of that study showed that UEBW was better predictor of AUR than TZ index, TZ volume and total prostate volume. In recent years PSA become a powerful predictors of the risk of AUR. Sometimes there is a difficulty to separate the causes of the PSA increasing between BPH and prostate cancer, but authors showed a strong PSA correlation with prostate growth related AUR (24). Than patient has PSA level from 1.4 to 3.2 ng/ml, prostate growth during 4 years was 16%, but if the PSA was between 3.3 and 12 ng/ml, prostate volume changed 22%. In Olmsted county study subjects with PSA levels greater than 1.4 ng/ml were three times as likely to

6 1076 experience AUR compared with subjects having PSA levels of 1.4 ng/ml or less (25). Another study reported a 4-fold AUR risk in men with PSA level more than 1.4 (26). Results of our study showed a significant PSA correlation with total prostate volume and especially TZ volume (r=0.607), also we detected that PSA is a strong predictor of AUR. If cutoff value of PSA was 3 ng/ml the positive predictive value to detect AUR is 39%, with sensitivity 76% and specificity 60%. Then we use cutoff value for the TZ index 0.6 and for the PSA 3 ng/ml, PSA positive prognostic value increased until 61%. Such data suggested that then we use these factors together we can predict patents in a greatest risk of developing of AUR. For patients with PSA more than 3 ng/ml and TZ index more than 0.6 surgical intervention is indicated. If PSA and TZ index are less than cutoff value, medical or surgical treatment is object of discussion. Although the sample size in the present study was not large enough to allow definite conclusions, the TZ index and PSA were found to be best predictors of AUR. We think that further studies in a larger population are needed to confirm our findings. Conclusions Patients with TZ index more than 0.6 and PSA value more than 3 ng/ml have a greatest risk for AUR. For this group of patients indicated more aggressive surgical treatment. Prostatos specifinis antigenas ir tranzitorinės zonos indeksas reikšmingi šlapimo ūminio susilaikymo faktoriai ligoniams, sergantiems gerybine prostatos hiperplazija Kauno medicinos universiteto Urologijos klinika Raktažodžiai: gerybinė prostatos hiperplazija, tranzitorinė zona, šlapimo ūminis susilaikymas, prostatos specifinis antigenas. Santrauka. Tyrimo tikslas. Įvertinti transrektine echoskopija nustatytų prostatos parametrų bei prostatos specifinio antigeno reikšmę nuspėjant šlapimo ūminį susilaikymą vyrams, sergantiems gerybine prostatos hiperplazija. Tyrimo metodai metų sausio 2003 metų birželio mėnesiais į tyrimą įtraukti 89 pacientai, sergantys simptomine gerybine prostatos hiperplazija. Pagrindinis simptomas 21 pacientui buvo šlapimo ūminis susilaikymas. Visiems tiriamiesiems atlikta transrektinė prostatos echoskopija, išmatuotas bendras prostatos, tranzitorinės zonos tūris bei apskaičiuotas tranzitorinės zonos indeksas. Prostatos specifinio antigeno tyrimas atliktas ambulatoriškai, iki tiriamajam atvykstant į kliniką, arba stacionare iki pirmojo šlapimo pūslės kateterizavimo esant šlapimo ūminiam susilaikymui. Jei pacientas į kliniką atvykdavo jau esant kateteriui šlapimo pūslėje, jo prostatos specifinio antigeno duomenys buvo sužinomi iš ankstesnių įrašų ambulatorinėje kortelėje. Echoskopiškai nustatytų parametrų bei prostatos specifinio antigeno reikšmingumas, nuspėjant šlapimo ūminį susilaikymą, įvertintas naudojant gautų duomenų efektyvumą charakterizuojančias (angl. receiver operator characteristic ROC) kreives bei apskaičiuojant po jomis esantį plotą. Rezultatai. Rastas statistiškai patikimas skirtumas lyginant tiriamųjų grupes su (be) šlapimo ūminiu susilaikymu pagal vidutinius bendrąjį prostatos tūrį (58,16 cm 3 ir 44,28 cm 3, p=0,0028), tranzitorinės zonos tūrį (36,62 cm 3 ir 23,70 cm 3, p=0,0001), tranzitorinės zonos indeksą (0,62 ir 0,51, p=0,00022), prostatos specifinį antigeną (4,96 ng/ml ir 2,97 ng/ml, p=0,00069) bei ligonio amžių ir gyvenimo kokybės indeksą. Analizuojant apatinių šlapimo takų simptomus, tarp tiriamųjų grupių statistiškai patikimo skirtumo nerasta. Pacientams, kuriems buvo šlapimo susilaikymas, plotas po ROC kreive buvo toks: 0,775 tranzitorinės zonos indeksui, 0,742 prostatos specifiniam antigenui, 0,737 tranzitorinės zonos tūriui, 0,696 bendram prostatos tūriui ir 0,633 tarptautinei prostatos simptomų skalei. Išvados. Didžiausią prognostinę vertę, nuspėjant šlapimo ūminį susilaikymą, turi tranzitorinės zonos indeksas ir prostatos specifinis antigenas. Jie gali būti naudojami kaip reikšmingi rodikliai pasirenkant chirurginį ar medikamentinį gerybinės prostatos hiperplazijos gydymo būdą. Correspondence to D. Milonas, Clinic of Urology, Kaunas University of Medicine Hospital, Eivenių 2, 3007 Kaunas, Lithuania. dmilonas@takas.lt

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