Morphometric analysis of prostate zonal anatomy using magnetic resonance imaging: impact on age-related changes in patients in Japan and the USA

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1 Morphometric analysis of prostate zonal anatomy using magnetic resonance imaging: impact on age-related changes in patients in Japan and the USA Toru Matsugasumi*, Atsuko Fujihara, So Ushijima, Motohiro Kanazawa, Yasuhiro Yamada, Takumi Shiraishi, Fumiya Hongo, Kazumi Kamoi, Koji Okihara, Andre Luis de Castro Abreu*, Masakatsu Oishi*, Toshitaka Shin*, Suzanne Palmer, Inderbir S. Gill* and Osamu Ukimura* *Institute of Urology, University of Southern California, Los Angeles, CA, USA, Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan, and Department of Radiology, University of Southern California, Los Angeles, CA, USA Objectives To evaluate the impact of morphometric magnetic resonance imaging (MRI) analysis of the prostate zonal anatomy on aging, prostatic hypertrophy and lower urinary tract symptoms in patients from Japan and the USA. Subjects and Methods A retrospective analysis of 37 men, including 6 men from Japan and 1 from the USA, who consecutively underwent 3-Tesla MRI and International Prostate Symptom Score (IPSS) assessment because of elevated PSA levels. Using Synapse-Vincent (Fujifilm), the prostatic zones were segmented in each axial step-section of the T2-weighted MRI to reconstruct a three-dimensional model of the prostate, which was used to calculate: zonal volumes (whole-gland prostate, transition zone and peripheral zone volumes); the presumed circle area ratio (PCAR); and PZ thickness. Bivariate associations were quantified using Spearman s rank correlation coefficients. Results The USA subgroup had a greater prostate volume (49 vs 42 ml; P =.3) and TZ volume (26 vs ml; P <.1) than the Japan subgroup, with no difference in PZ volume (19 vs ml; P =.2). There was no age-related increase in PZ volume in either of the subgroups or in the entire cohort (P =.9, P =.2, P =.3, respectively). PZ thickness had a significant negative correlation with PCAR (P <.1) and TZ volume (P <.1). The greater the increase in the TZ volume with the increase in PCAR, which probably correlates with obstructive pressure, the thinner the PZ became. PCAR had a significant positive correlation with IPSS (P =.3) and obstructive symptoms (P =.7), while PZ thickness had a significant negative correlation (P =.18). Conclusions No age-related increases and no differences between the Japanese and the US subgroups were found with regard to PZ volume. The more TZ volume increased, the higher the obstructive pressure and the thinner the PZ became; these changes were associated with increased obstructive symptoms. MRI analysis of prostate zonal anatomy enhanced our understanding of age-related changes in morphology and urinary symptoms. Keywords prostate, MRI, anatomy, aging, morphology, benign prostatic hyperplasia Introduction The use of MRI provides excellent resolution for examining prostate tissue, allowing prostate zonal anatomy to be visualized to obtain precise volume measurements [1 3]. Based on prostate volume measurements conducted with at least two serial MRI scans in 278 men from a community in the USA, Loeb et al. [3] found that 172 (61.9%) of the men had prostate growth, four men (1.4%) had a stable prostate size, and 2 men (36.7%) had a decrease in prostate size during a median follow-up of 4.3 years. In a longitudinal study assessing changes in prostate volume in 67 Japanese men with at least two serial TRUS measurements, prostate volume was found to have increased in 46 men (7%), to have remained stable in men (%) and to have decreased in 11 men (%). BJU International 17 BJU International doi:.1111/bju BJU Int 17; 1: Published by John Wiley & Sons Ltd. wileyonlinelibrary.com

2 Matsugasumi et al. Age-related increases in prostate volume are considered to be attributable to age-related development of BPH, which causes obstructive urinary symptoms. Based on autopsy studies, the incidence of histological evidence of BPH increases from 8% of men aged 3 39 years to >7% of men aged >7 years [4]. As described by McNeal [] and Freiha et al. [6], BPH is pathologically characterized by hyperplasia of the transition zone (TZ). As a morphometric predictor of the severity of BPH, the presumed circle area ratio (PCAR; the ratio of the area of the maximum horizontal section of the prostate to the area of a presumed circle whose circumference is equal to the circumference of the maximum horizontal section) has been shown to be correlated with LUTS (especially obstructive symptoms) and with markers of urodynamic obstruction, representing intraprostatic pressure [7 9]. PCAR can be used to evaluate how closely the shape of the horizontal prostate section approaches a circle. The greater the intraprostatic pressure resulting from an enlarged TZ, the rounder the shape of the prostate becomes. Similarly, the TZ index (the ratio between the TZ volume and prostate volume) is another morphometric variable that is significantly correlated with the severity of BPH, predicting LUTS and urodynamic parameters []. By contrast, the natural history of the peripheral zone (PZ) has been more frequently discussed in terms of the development of cancer, as more aggressive prostate cancers are likely to originate from the PZ [11]; however, possible age-related changes in PZ morphology and volume with special reference to age-related enlargement of the TZ have not been elucidated thus far. In the present study, we sought to evaluate whether MRI can facilitate the morphometric analysis of prostate zonal anatomy, with special reference to the morphology of the PZ in relation to age-related prostatic enlargement in patients from the USA and Japan. Materials and Methods Between January 11 and December 12, after obtaining institutional review board approval, we retrospectively analysed a total of 37 consecutive men who underwent MRI and IPSS assessment prior to prostate biopsy because of elevated PSA levels. These men included Japanese outpatients of the Department of Urology, Kyoto Prefectural University of Medicine (n = 6) and outpatients of the Institute of Urology, University of Southern California, USA (n = 1). The MRI was evaluated using a 3-Tesla magnet body coil (without endorectal coil) with a slice thickness of 3 mm, with sequences of T2-weighted, diffusion-weighted and contrastenhanced images at both institutions. Of the 37 consecutive men who underwent MRI assessment prior to prostate biopsy because of elevated PSA levels, 46% of the US cohort (7/1 men) and 39% of the Japanese cohort (6/6 men) had significant cancer. Morphometry Using Synapse Vincent version 2 (Fujifilm, Tokyo, Japan), the boundary of the prostate zonal anatomy was segmented in each axial 3-mm step section of a T2-weighted image obtained through MRI to reconstruct a three-dimensional model of the prostate zonal anatomy to calculate the following variables: (1) the volume of the whole prostate gland (prostate volume); (2) the volume of the transition zone (TZ); (3) the volume of the peripheral zone (PZ), which includes both the PZ and the central zone of McNeal s zonal anatomy []; (4) the PCAR, which is defined as the ratio of the area of the maximum axial section of the prostate to the area of a presumed circle with a circumference equal to that of the section (PCAR evaluates how closely the shape of the section approaches a circle and might suggest the increase in intraprostatic pressure because the obstructive pressure by the enlarged TZ is likely to extend over the circumference of the TZ equally, and the shape of the whole prostate probably becomes round, in accordance with Pascal s principle; Fig. 1) [7,8]; and () PZ thickness (mm), which is defined as PZ volume divided by the maximum coronal section area of the prostate, determined through computerized calculation based on the reconstructed three-dimensional prostate volume. The maximum coronal section area of the prostate was determined as the coronal section along the body axial plane which had the maximum section area, selected amongst the all coronal sections along the body axial plane (although the presence or absence of median lobe did not matter at the time of determining the maximum coronal section). Correlation with LUTS Assessed via the IPSS Associated LUTS were assessed using the IPSS questionnaire. The relationship between the MRI morphometric variables and LUTS was evaluated based on the total IPSS, the sum of Fig. 1 Presumed circle area ratio (PCAR): the ratio of the area of the maximum axial prostate section to the area of a presumed circle with a circumference equal to that of the section, thus representing intraprostatic pressure and correlating with the severity of prostate obstruction. S, area of the maximum axial MRI prostate section; L, circumference of the maximum axial MRI prostate section; S, area of a presumed circle with the circumference equal to the circumference of S. A S B S =π(l/2π) 2 PCAR=S/S S 498 BJU International 17 BJU International

3 MRI analysis of age-related changes in prostate zonal anatomy obstructive scores (incomplete emptying, intermittency, slow stream and hesitancy) and the sum of irritative scores (frequency, urgency and nocturia). Statistics Statistical analyses were performed using SPSS Statistics Version 21. (IBM Corp., Armonk, NY, USA) software. Bivariate associations were quantified using Spearman s rank correlation coefficient. For comparison of the variables between the Japanese and US subgroups, the Mann Whitney test was used. All tests were two-tailed, and the results were considered statistically significant at P <.. Results In the comparisons between the US and Japanese subgroups, the median (range) age (6. [4 87] years vs 69.3 [43 92] years; P <.1) was significantly higher in the Japanese subgroup, and prostate volume (48.8 [21 193] ml vs 41.7 [19 99] ml; P =.3) was significantly greater in the US subgroup. PSA level, however, was not significantly different between the two groups (6.38 [ ] ng/ml vs 6.12 [1.6.7] ng/ml; P =.2 [Table 1]). The US subgroup had a greater TZ volume (26.1 vs 19.6 ml; P <.1), while there was no significant difference in PZ volume between the subgroups (19.2 vs. ml; P =.2), nor was there an agerelated increase in PZ volume in either of the subgroups or in the entire cohort (P =.9, P =.2, P =.2, respectively [Table 1 and Fig. 4A]). There was a significant positive correlation between PCAR and TZ volume (r =.347, P <.1; Fig. 2). PZ thickness had a significant negative correlation with PCAR (r =.37, P <.1) as well as with TZ volume (r =.41, P <.1; Fig. 3). Correlations between age and PZ thickness, TZ volume and PCAR, PCAR and PZ thickness, and TZ volume and PZ thickness are shown in Figs 4B E. Among the MRI morphometric variables, PCAR and prostate volume were found to have significant associations with LUTS, followed by PZ thickness and TZ volume. PCAR had a Fig. 2 MRI scans showing the magnitude of the presumed circle area ratio (PCAR). The progression of prostatic hypertrophy correlates with a greater PCAR, indicating that the shape of the prostate is approaching a circle (i.e. PCAR = 1.). PCAR in a normal prostate without an enlarged TZ is ~.67, in a moderately enlarged TZ is ~.8, and in a severely enlarged TZ is >.8. PCAR is used to evaluate how closely the shape of horizontal prostate section approaches a circle. The greater the intraprostatic pressure, the rounder the prostate shape becomes. PCAR,.67 (TZ volume., 7mL) PCAR,.72 (TZ volume., 9mL) PCAR,.77 (TZ volume., 18mL) PCAR,.82 (TZ volume., 29mL) PCAR,.86 (TZ volume., 39mL) PCAR,.9 (TZ volume., 73mL) BJU International 17 BJU International 499

4 Matsugasumi et al. Fig. 3 MRI scans showing the compression of peripheral zone (PZ) thickness attributable to an enlarged transitional zone (TZ). The greater the increase in TZ volume, the thinner the PZ becomes; however, there were no age-related changes in PZ volume, with the median volume being 19.2 ml in the US and. ml in the Japanese subgroups. PZ thickness, 14.3mm PCAR,.77 PZ thickness,.4mm PCAR,.8 PZ thickness, 8.2mm PCAR,.88 PZ thickness, 4.7mm PCAR,.91 Table 1 Characteristic comparison between the American and Japanese subgroups. Total cohort, N = 37 Median (IQR) Japanese subgroup, n = 6 Median (IQR) USA subgroup, n = 1 Median (IQR) P* Age 68 [4 92] 69.3 [43 92] 6. [4 87] P <.1 PSA 6.24 [ ] 6.12 [1.6.7] 6.38 [ ] P =.2 Pr-Volume (ml) 44.1 [ ] 41.7 [ ] 48.8 [.9 193] P =.3 TZ-Volume (ml) 22.8 [ ] 19.6 [.6 84] 26.1 [ ] P <.1 TZ-index (TZ-vol/Pr-vol).3 [..96].47 [.26.92].7 [..96] P <.1 PCAR.86 [.67.91].8 [.67.91].86 [.73.91] P =.1 PZ-Volume (ml) 19.8 [7.2 4]. [7.2 4] 19.2 [7.2 38] P =.2 PZ-Thickness (mm) 12.8 [ ] 13. [ ] 11.9 [ ] P <.1 PCAR, presumed circle area ratio; PZ, peripheral zone; TZ, transition zone. *Mann Whitney test. significant positive correlation with all three symptom scores: IPSS (r =.287, P =.3); obstructive symptoms (r =.266, P =.7); and irritative symptoms (r =.26, P =.8). Similarly, PZ thickness was found to have a significant negative correlation with IPSS (r =.234, P =.18) and with both obstructive (r =.3, P =.41) and irritative symptoms (r =.3, P =.41; Table 2). TZ volume also showed a significant positive correlation with all three symptom scores: IPSS (r =.3, P =.1); obstructive symptoms (r =., P =.11); and irritative symptoms (r =., P =.38). The multiparametric analysis carried out to predict total IPSS value showed that the best predictor was PCAR (P =., B-value.28), followed by PZ thickness (P =.1), PSA (P =.21) and TZ volume (P =.3). Discussion It is well known that prostate and TZ volumes increase with age, and that these have a significant association with the severity of LUTS [7,12,13], but only a few reports have identified the relationship between the morphology of the PZ and age. The present study showed that there was no agerelated increase in PZ volume in the men from either Japan or the USA. This suggests that PZ volume is stable during aging and no differences were found between the US and the Japanese subgroups in this regard; however, PZ thickness, a novel concept introduced in the present study, was found to have a significant negative correlation with PCAR as well as with IPSS and obstructive symptoms. Because PCAR, which might represent obstructive pressure or intraprostatic pressure, significantly increased with TZ volume, we interpreted these results as indicating that the greater the increase in TZ volume, the higher the intraprostatic pressure might be and the thinner the PZ becomes, with a stable PZ volume of ~ ml. IPSS and obstructive symptoms were found to have the closest relationship with PCAR attributable to an enlarged TZ, which was associated with a thinner PZ. MRI analysis of the prostate zonal anatomy enhanced our BJU International 17 BJU International

5 MRI analysis of age-related changes in prostate zonal anatomy Fig. 4 Bivariate associations with Spearman s rank correlation coefficients. (A) Correlation with age and PZ volume. (B) Correlation with age and peripheral zone (PZ) thickness. (C) Correlation with transition zone (TZ) volume and presumed circle area ratio (PCAR). (D) Correlation with PCAR and PZ thickness. (E) Correlation with TZ volume and PZ thickness. A PZ volume.(ml) 4 3 r=.78 P=.2 Entire cohort (n=37) JPN (n=6) USA (n=1) 4 3 r=.12 P=.9 r=.9 P= Age(years) Age(years) Age(years) 4 3 B Entire cohort (n=37) JPN (n=6) USA (n=1) PZ thickness(mm) r=-.118 P=.39 r=-. P=.62 r=-.7 P= Age(years) Age(years) Age(years) C PCAR Entire cohort (n=37) JPN (n=6) USA (n=1) r=.347 P< r=.34 P< r=.313 P<.1 D Entire cohort (n=37) JPN (n=6) USA (n=1) PZ thickness(mm) r=-.37 P<.1 r=-.293 P<.1 r=-.4 P<.1 E PZ thickness(mm) PCAR PCAR PCAR Entire cohort (n=37) r=-.41 P<.1 JPN (n=6) r=-.336 P<.1 USA (n=1) r=-.33 P<.1 Figure : The correlation between TZ-vol. and PZ-thickness. The higher TZ-vol. becomes, the thinner PZ-thickness becomes. BJU International 17 BJU International 1

6 Matsugasumi et al. Table 2 Relationship between urinary symptoms and morphometric parameters. Q7 Nocturia Q6 Straining Q4 Urgency Q Weak stream Q3 Intermittency Q2 Frequency Ql Incomplete emptying Sum of irritative score Total IPSS Sum of obstructive score PCAR r =.287 r =.266 r =.26 r =.36 r =.278 r =.4 r =.1 r =.183 r =.78 r =.1 P =.3 P =.7 P =.8 P <.1 P =. P =.39 P =.43 P =.66 P =.4 P =.3 PZ-thickness r =.234 r =.3 r =.3 r =.7 r =.92 r =.123 r =.19 r =.227 r =.2 r =.2 P =.18 P =.41 P =.41 P =.37 P =.37 P =.2 P =. P =.22 P =.6 P =.23 TZ-vol. r =.3 r =. r =. r =.199 r =. r =.37 r =.193 r =.164 r =.3 r =.233 P =. P =.11 P =.38 P =.4 P =.3 P =.2 P =.2 P =. P =.9 P =.18 PCAR, presumed circle area ratio; PZ, peripheral zone; r, Spearman s coefficient; TZ, transition zone. Obstructive score: Q1 (incomplete emptying), Q3 (intermittency), Q (weak stream) and Q6 (straining); irritative score: Q2 (frequency), Q4 (urgency) and Q7 (nocturia). Statistically significant relationship (P <.) were demonstrated with bold values. understanding of age-related changes in morphology, not only for the TZ but also for the PZ in association with LUTS. The PCAR has been recognized as one of the most important predictors of the severity of prostatic obstruction and LUTS, while the correlation between overall prostatic volume and the development of LUTS is modest [7 9]. The rationale of the PCAR theory suggests that, as the TZ grows, it exerts pressure on the surrounding surgical capsule, including the PZ, as well as the prostate capsule. When the surgical capsule reaches a point at which it cannot be stretched further, the prostatic shape approximates a circle. The present findings suggest that as the TZ grows, the PZ becomes thinner as a part of the stretched surgical capsule. Morphometric analyses of prostate volume have been performed with volume measurements conducted using TRUS or MRI; however, the available longitudinal serial monitoring data on the natural history of the morphological zonal anatomy are very limited, and such data are also limited to short follow-up periods, such as median periods of 2.7 years [13], 2.3 years [2] or 4.3 years [3]. Two later studies conducted as part of the Baltimore Longitudinal Study of Aging [2,3] used two or more T2-weighted serial MRI scans to evaluate prostate volume in 278 men. These serial longitudinal monitoring studies of the entire prostate volume showed that, although BPH commonly results in an increased prostate volume as a result of aging, a considerable proportion of aging men have a stable or decreased prostate volume [2,3,13]. Although Loeb et al. [3] did not evaluate the longitudinal changes according to the zonal volume of the prostate, Williams et al. [2] reported the longitudinal changes in PZ volume, TZ volume and prostate volume in a limited cohort of 64 men in the Baltimore longitudinal study. Interestingly, in that study with its small sample size and median follow-up period of 2.3 years, regression analysis showed a weak relationship between age and each individual s zonal volume, where the square of the correlation coefficient was. (P <.1) for the whole gland,. (P <.1) for the TZ and.3 (P <.4) for the PZ. Even though a significant increase in the PZ was found in this small cohort, the change in PZ volume was only. ml when considering the difference in the maximum PZ volume between men aged <4 years (PZ volume,.9 2. ml, n = 9) and men aged 6 6 years (PZ volume, ml, n = ). Further studies will be necessary to monitor the longitudinal changes in the zonal volume over a longer study period to reach a conclusion regarding the natural history of an individual s zonal prostatic volume. Age-related changes in prostate and TZ volumes were evaluated based on TRUS measurements in 3 Japanese men with LUTS in a study by Gupta et al. [14]. Calculations based on the obtained data on the prostate volume and TZ volume showed little age-related change in PZ volume, with values of 2 BJU International 17 BJU International

7 MRI analysis of age-related changes in prostate zonal anatomy 16.1 ml being found for men aged 9 years (n = 89), 18.3 ml for men aged 6 69 years (n = 89), 18.9 ml for men aged 7 79 years (n = 18), and 16.2 ml for men aged 8 89 years (n = 27). In contrast, there were obvious agerelated changes in the whole prostate volume (range ml) and TZ volume (range ml) in the same population aged 89 years [14]. In a recent study, Turkbey et al. [] reported the age-related changes in prostate zonal volumes measured in 3 patients in one-time assessments using MRI, before any treatment for prostate cancer []. They also found no correlation between age and PZ volume (P =.173), and changes in the whole prostate volume and TZ volume were inversely correlated with IPSS. These findings were duplicated in the present study, not only in the US subgroup, but also in the Japanese cohort, as PZ was found to be similar in volume to that originally observed at a younger age, with a volume of ml. The thickness of the PZ is introduced in the present study as a new metric intended to represent additional morphological characteristics or changes in the PZ attributable to aging or prostate hypertrophy. PZ thickness was found to have a significant negative correlation with PCAR (r =.37, P<.1) as well as TZ volume (r =.41, P <.1). These findings suggest that the greater the increase in intraprostatic pressure (represented by the higher PCAR) attributable to greater growth of TZ volume, the thinner the PZ becomes. When evaluating axial MRI scans, we often recognize a very thin PZ accompanied by an enlarged TZ. We therefore wondered whether a decrease in PZ volume could accompany increased prostate hypertrophy, and we hypothesized that PZ thickness may only be compressed, resulting in its becoming thinner without a change in PZ volume. The present findings support this hypothesis. The PZ was compressed, showing a significant decrease in thickness as a result of the age-related increase in TZ volume, causing possible increased intraprostatic pressure, which was probably indicated by an increased PCAR. No age-related change, however, was found in PZ volume and there was no difference between the US and Japanese cohorts, with both having a PZ volume of ~ ml. This is a key finding and implies that there is no age-related change in the PZ volume in contrast to the age-related increase in TZ volume. The present study suggests that the important age-related change in prostate volume is attributable only to enlargement of TZ volume (not PZ volume). Interestingly, with such age-related enlargement of the TZ, the morphological change in the prostate can be characterized by the compressed PZ, which becomes thinner but extends wider, maintaining a stable PZ volume of ~ ml. Morphometric analyses of prostate volume have been discussed in relation to LUTS, as shown in the present study; however, it is important to recognize that the lack of age-related increase in PZ volume (with a stable PZ volume of ~ ml) may have an impact on prostate biopsy strategy. Because PZ volume is stable, the total core numbers for the sum of the series of repeat biopsies from the PZ could be saturated by limited numbers, such as a total of two or three sets of 12 cores of PZ biopsies, which would correspond to 24 or 36 cores in total. Recent advances in the technology of TRUS-guided biopsy to document the location for future reference has an impact on this [16,17]. If we document the biopsy trajectories of the initial set of 12-core biopsies for future reference at the time of repeat biopsy [18], it will allow intentional saturated sampling from the initially non-sampled parts of the PZ to cover the entire PZ (theoretically, cores sampled from a PZ with a volume of ml corresponds to 1 core per <1 ml of the PZ). The present study has some limitations. First, we did not monitor the longitudinal changes in the zonal volume in our study cohort, although our findings implied that the PZ showed no age-related increase in the distribution analysis between PZ volume vs age. As such, the individual natural history of the PZ remains unknown. Second, the patients in our cohort represented a highly selected population, consisting of men with clinical indications for prostate biopsy; therefore, the study cohort may not represent the general population. Third, there were differences in age, prostate volumes and TZ volumes in the two subgroups of the study cohort (US and Japanese); however, interestingly, there were no differences in PZ volume found in the comparison between the US and Japanese subgroups, even with the significant differences in age, prostate volume and TZ volume. Although direct physical measurements of zonal anatomy from prostatectomy specimens would represent one of the most accurate techniques, the examination of agerelated, longitudinally monitored changes in the morphometric zonal prostate anatomy using high-resolution MRI would also be promising. In conclusion, MRI can be used in the morphometric analysis of prostate zonal anatomy. The PZ was found to have no agerelated increase in volume in either US or Japanese men aged 4 8 years, but is substantially compressed as a result of an enlarged TZ. The greater the increase in TZ volume, the higher the obstructive pressure or possible intraprostatic pressure and the thinner the PZ becomes. LUTS, including obstructive and irritative symptoms, were significantly associated with an increased PCAR as well as with a thinner PZ in the analysis of the morphometric variables of prostate zonal anatomy. A stable PZ volume of ~ ml independently of age and race may have an impact on the longitudinal sampling strategy for prostate biopsy. Conflict of Interest None declared. BJU International 17 BJU International 3

8 Matsugasumi et al. References 1 Hricak H, Dooms GC, McNeal JE et al. MR imaging of the prostate gland: normal anatomy. AJR Am J Roentgenol 1987; 148: Williams AM, Simon I, Landis PK et al. Prostatic growth rate determined from MRI data: age-related longitudinal changes. J Androl 1999; : Loeb S, Kettermann A, Carter HB et al. Prostate volume changes over time: results from the Baltimore Longitudinal Study of Aging. J Urol 9; 182: Berry SJ, Coffey DS, Walsh PC. The development of human benign prostatic hyperplasia with age. J Urol 1984; 132: McNeal JE. The zonal anatomy of the prostate. Prostate 1981; 2: Freiha FS, McNeal JE, Stamey TA. Selection criteria for radical prostatectomy based on morphometric studies in prostate carcinoma. NCI Monogr 1988; 7: Kojima M, Ochiai A, Naya Y et al. Correlation of presumed circle area ratio with infravesical obstruction in men with lower urinary tract symptoms. Urology 1997; : 48 8 Watanabe H. New concept of BPH: PCAR theory. Prostate 1998; 37: St Sauver JL, Jacobson DJ, McGree ME et al. Presumed circle area ratio of the prostate in a community-based group of men. BJU Int 9; 4: 8 62 Kaplan SA, Te AE, Pressler LB et al. Transition zone index as a method of assessing benign prostatic hyperplasia: correlation with symptoms, urine flow and detrusor pressure. J Urol 199; 4: McNeal JE, Redwine EA, Freiha FS et al. Zonal distribution of prostatic adenocarcinoma. Correlation with histologic pattern and direction of spread. Am J Surg Pathol 1988; 12: Tsukamoto T, Masumori N, Rahman M et al. Change in International Prostate Symptom Score, prostrate-specific antigen and prostate volume in patients with benign prostatic hyperplasia followed longitudinally. Int J Urol 7; 14: Tsukamoto T, Masumori N, Nakagawa H et al. Changes in prostate volume in Japanese patients with benign prostatic hyperplasia: association with other urological measures and risk of surgical intervention. Int J Urol 9; 16: Gupta A, Aragaki C, Gotoh M et al. Relationship between prostate specific antigen and indexes of prostate volume in Japanese men. J Urol ; 173: 3 6 Turkbey B, Huang R, Vourganti S et al. Age-related changes in prostate zonal volumes as measured by high-resolution magnetic resonance imaging (MRI): a cross-sectional study in over patients. BJU Int 12; 1: Ukimura O, Desai MM, Palmer S et al. 3-Dimensional elastic registration system of prostate biopsy location by real-time 3-dimensional transrectal ultrasound guidance with magnetic resonance/transrectal ultrasound image fusion. J Urol 12; 187: Ukimura O, Coleman J, de la Taille A et al. Contemporary role of systematic prostate biopsies: indications, technique, implications on patient care. Eur Urol 13; 63: Ukimura O, Gross M, Abreu A et al. A novel technique using threedimensionally documented biopsy mapping allows precise re-visiting of prostate cancer foci with serial surveillance of cell cycle progression gene panel. Prostate ; 7: Correspondence: Osamu Ukimura, Department of Urology, Kyoto Prefectural University of Medicine, 46 Kawaramachi- Hirokoji, Kamikyo-ku, Kyoto , Japan. ukimura@koto.kpu-m.ac.jp Abbreviations: TZ, transition zone; PZ, peripheral zone; PCAR, presumed circle area ratio. 4 BJU International 17 BJU International