Serum prostate-specific antigen as a predictor of prostate volume in Korean men with lower urinary tract symptoms

Abstract

The aim of the study was to assess the utility of prostate-specific antigen (PSA) as a predictor of prostate volume indexes (total prostate volume (TPV), transition zone volume and transition zone index) in Korean men with lower urinary tract symptoms (LUTS). From September 2003 to April 2006, 3431 patients with LUTS were included in the study; they had a median age of 63.8 years, a median prostate volume of 22.6 ml and a median serum PSA of 1.04 ng/ml. Men with a baseline PSA of >10 ng/ml were excluded, to reduce the likelihood of including occult prostate cancer. Prostate volume indexes and serum PSA levels had an age-dependent log-linear relationship. Receiver operating characteristic curve analysis showed that PSA had good predictive value for various prostate volume indexes thresholds. The approximate age-specific criteria for detecting men with a TPV of >40 ml are PSA levels of 1.20, 1.44 and 1.72 ng/ml for men with LUTS in their sixth, seventh and eighth decades, respectively. The results show that serum PSA identifies Korean men with large prostates reasonably well. Korean men may produce and/or release more PSA per unit prostate volume than white men. The cutoffs for PSA and prostate volume to response to LUTS therapy should be determined in this population.

Introduction

Preventing the progression and alleviating symptoms are important aims of benign prostatic hyperplasia (BPH) therapy. Although numerous medical and surgical therapeutic options are now available for BPH, α-receptor blockers and 5α-reductase inhibitors are currently the mainstay of medical therapy for BPH. The prostate volume is a significant predictive factor for progression of BPH and the response to 5α-reductase inhibitors. The prostate volume is closely related to the aggravation of symptoms, development of acute urinary retention and increasing incidence of BPH-related surgery.1, 2, 3, 4 In addition, the larger the prostate volume, the greater the risk that pharmacotherapy will fail.5 Therefore, to optimize clinical management of BPH patients there is a need for estimating prostate volume.

Owing to the high prevalence of BPH and lower urinary tract symptoms (LUTS) in the aging male population, recent focus has been directed at the role of prostate-specific antigen (PSA) in the assessment of patients with BPH. PSA offers a less invasive, less time consuming and less expensive alternative to the more conventional radiographic assessment of prostate size. Roehrborn et al.6 have introduced the concept of PSA as a surrogate measurement for prostate volume in patients with clinical BPH and LUTS. However, it is not known whether the PSA-prostate volume relationship is the same across different races. The objective of this study is to analyze the relationship between prostate volume indexes and serum PSA levels and age. Moreover, we tried to determine whether prostate volume indexes could be predicted appropriately for individual patients.

Methods

From September 2003 to April 2006, 3566 patients who first visited our hospital with complaints of LUTS were included in the study. To be included in the present analysis, patients should have a serum PSA10 ng/ml. Patients with an abnormal digital rectal examination (DRE) and/or serum PSA level greater than 4.0 ng/ml underwent a biopsy. Patients were excluded from the analysis if they were younger than 50 years old or older than 80 years old, had received a diagnosis of prostate cancer, had undergone prostate surgery or radiation treatment, had received 5α-reductase inhibitors, had acute urinary retention or an indwelling catheter or had evidence of acute urinary infection (pyuria and bacteriuria) on urinalysis. A total of 3431 men met these criteria and constituted the study cohort.

All men underwent detailed clinical examinations, including determination of serum levels of total PSA quantified by immunoradiometric assay (Izotop, Budapest, Hungary), DRE and transrectal ultrasonography (TRUS). Blood samples were obtained before patients were examined by a physician. All blood was stored at −70°C for less than 1 week and assayed for serum PSA concentration. Transaxial and sagittal scanning of the prostate was performed by a radiologist experienced in this procedure using a 7.0-MHz transducer (Ultramake 9, ATL Inc., Washington, DC, USA). Total prostate volume (TPV) and transition zone volume (TZV) were measured and transition zone index (TZI) was calculated as the ratio of TZV to TPV.

Baseline measurements of prostate volume and PSA were extracted for analysis and summary statistics were computed by age category. Pearson's correlation and linear regression analyses were performed. The relationship between age and log PSA and log prostate volume indexes was also explored using a simple linear model. Receiver operating characteristic (ROC) curves were constructed and various summary statistics characterizing the performance of serum PSA as a predictor of prostate volumes were computed. The statistical software package SPSS 11.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses.

Results

In patients examined, the median age was 63.8 years. The median prostate volume of the patients was 22.6 ml (range 5.2–136.1) and serum PSA ranged from 0.003 to 9.89 ng/ml (median 1.04). These characteristics and qualitative distribution are summarized in Table 1. Table 2 provides serum PSA and prostate volume summary statistics by decade of age. The relationships among age, serum PSA and prostate volume indexes are shown in Table 3. Most parameters correlated with each other. Correlation analysis between serum PSA and different prostate volumes showed a more positive correlation for TZV than for TPV.

Table 1 Descriptive statistics
Table 2 Patient characteristics
Table 3 Correlation among serum prostate-specific values, prostate volumes and age

Figure 1 graphically summarizes the relationships between age and log PSA (Figure 1a), log prostate volume indexes (Figure 1b), and log PSAD (PSA density) and log PSA-TZ (PSA adjusted to TZV) (Figure 1c). Log serum PSA, log prostate volume indexes and log PSAD were nearly linearly related to age but log PSA-TZ was not. The slope (b±s.e.) of the relationship between age and log serum PSA was 0.0097±0.001, corresponding to a 9.7% increase in serum PSA with each decade of life. The slope (b±s.e.) of the relationship between age and log prostate volume indexes was 0.0049±0.0001 for TPV, 0.0099±0.001 for TZV and 0.0051±0.0001 for TZI. The slope (b±s.e.) of the relationship between age and log PSAD was 0.0110±0.002. Figure 2 displays observed values and predicted values of prostate volume indexes given by serum PSA levels. The observed values fall near the prediction line.

Figure 1
figure1

(a) Log serum PSA by decade of age. (b) Log prostate volume indexes by decade of age. (c) Log PSA density (PSAD) and log PSA adjusted to TZV (PSA-TZ) by decade of age.

Figure 2
figure2

(a) Observed values and predicted values of (TPV given by serum PSA. (b) Observed values and predicted values of TZV given by serum PSA. (c) Observed values and predicted values of TZI given by serum PSA.

The diagnostic utility of serum PSA for identifying patients with prostate volume indexes was evaluated using ROC curve analysis. Table 4 provides the area under the curve and the appropriate critical value based on the data. The results show that serum PSA identifies men with large prostates reasonably well. For example, to achieve both a specificity and sensitivity of 70% the approximate age-specific criteria for detecting men with TPVs of >40 ml are a PSA level of 1.20, 1.44 and 1.72 ng/ml for men with LUTS in their sixth, seventh and eighth decades, respectively.

Table 4 ROC AUC values and optimal serum prostate-specific antigen valuesa for prediction of TPV, TZV and TZI

Discussion

Information on individual patients' prostate volume has became increasingly important owing to evidence indicating that it strongly predicts BPH outcomes such as acute urinary retention and the need for BPH-related surgery.1, 2, 3 Two meta-analyses on randomized controlled trials for BPH patients treated with either finasteride or placebo concluded the importance of an ‘enlarged prostate' (40 ml) at baseline as an important prognostic factor for successful treatment outcome.1, 7 Thus, 5α-reductase inhibitors are preferentially used in men with large prostate volume.

However, routine measurement of prostate volume in all patients is not feasible because of the lack of availability, inconvenience and the high cost of TRUS at the primary care level. In addition, DRE tends to underestimate prostate size considerably.8 Moreover, as BPH occurs in the transition zone (TZ) of the prostate, DRE is an inaccurate measure of TZV. Thus, other tests are needed that may predict the progression of LUTS and BPH or predict these prostate volume indexes with reasonable certainty, and yet be freely available for use at the community level. Of several variables, prostate volume was most significantly related to the PSA level.9 PSA is an ideal proxy to serve this role because it is a routine part of the assessment of patients with LUTS and BPH, relatively inexpensive and widely available. If the prostate volume can be estimated from PSA levels, patients at greater risk of medical treatment failure owing to a large prostate volume could be detected more easily, especially by physicians who do not have easy access to TRUS. Recent data also indicate that a similar correlation of risk exists with serum PSA level.4 PSA has been demonstrated to be a powerful predictor of both acute urinary retention and the need for surgery in clinical BPH and as a surrogate for prostate volume, and it has been shown to predict the outcome of medical therapy.1, 6

There have been numerous reports that the prostate volume can be predicted from the PSA level.6, 10, 11 Roehrborn et al.6 first assessed the PSA threshold as a predictor of prostate volume by characterizing the relationship between prostate volume and serum PSA level in men with symptomatic BPH. To achieve a specificity of 70% while maintaining a sensitivity between 65 and 70%, approximate age-specific criteria detecting men with prostate glands >40 ml are PSA levels >1.6, 2.0 and 2.3 ng/ml for men with BPH in their 50s, 60s and 70s, respectively. Mochtar et al.10 also reported that prostate volume correlated with PSA level and that the PSA threshold predicting prostate volumes of >30 and >40 ml were 2.0 and 2.5 ng/ml, respectively. Morote et al.12 found that both total and free PSA would be able to predict the TRUS prostate volume within the interval of 20% in more than 90% of the individuals. They could assume that patients with a PSA of 10 ng/ml have 80% probability to have a prostate volume >40 cm3 whereas it would be around 20% with a PSA of 1 ng/ml. On the contrary, Hedelin et al.13 questioned the usefulness of serum PSA for making treatment decisions in men with LUTS as interindividual variation in serum PSA was so large. However, in their study, only 119 men were evaluated. Thus, this variation might be easily influenced by a small sample size.

Although nomograms to predict prostate volume using PSA are available for white men, such nomograms are not available for other ethnic groups. The PSA–TPV relationship in Asian men is different from that in white men. Japanese men with LUTS and clinical BPH might produce and/or release more PSA per unit prostate volume than white men.14 Aoki et al.15 studied racial differences in the cellular composition of BPH and found that Japanese men have a higher glandular component and a lower stromal component than white or black Americans. The relatively higher glandular component in Japanese men might be an explanation for the higher PSA per unit prostate volume in Japanese men compared to white men. Although the prostate volume in men with BPH level and an age-dependent increase, the PSA and prostate volume were smaller in Asian men than in white men in a similar age group. In addition, Korean men are more likely to have a smaller prostate when older than are white men of the same age.16

Generally, in BPH, both total PSA and free PSA are predomintantly expressed within the TZ.17 Although the peripheral zone contains a significantly greater area density and absolute volume of epithelium than the TZ, the serum PSA level is most strongly correlated only with the volume of epithelium in the TZ.18 In the study of Hammerer et al.,19 the correlation coefficients among serum PSA and TZ, peripheral zone and central zone volumes were 0.934, 0.546 and 0.368, respectively, strongly suggesting that most PSA leakage from the prostate into the serum comes from the TZ. Korean men demonstrated a higher ratio of TZ enlargement relative to total prostate in comparison to Caucasian, Hispanic and African-American men.20 Our findings showed that TZV contributed to the prostate growth increasingly with age in Korean men (i.e., as age increases, TZI increases).

In this study, we aim to evaluate the ability of serum PSA to estimate prostate volume in patients with LUTS without evidence of prostate cancer because the difference in prostate volume between Korean and Caucasian men might result in a different relationship between prostate volume and serum PSA level in Korean men. In work carried out by Roehrborn et al.,6 the ROC area under the curves ranged from 0.76 to 0.78 in the overall age group for various prostate volume cutoffs (30, 40 and 50 ml), whereas in the study of Mochtar et al.10 this value was around 0.82. This study suggests that serum PSA can also estimate ‘prostate enlargement’ sufficiently accurately to be useful for therapeutic, especially medical, management in Korean men. In the present study, the approximate age-specific criteria for detecting men with a TPV of >40 ml are PSA levels of 1.20, 1.44 and 1.72 ng/ml for men with LUTS in their sixth, seventh and eighth decades, respectively. However, the approximate age-PSA thresholds for detecting Korean men with larger prostates at a specificity and sensitivity of 70% were lower than in Caucasian men.6, 11 Asian men generally have smaller prostate gland size than their Western counterparts. The therapeutic effect of 5α-reductase inhibitors is mediated through its effect on the epithelial cells and that of blockers through the smooth muscle component of the prostate. Because Asian men are likely to have a different histological component of the prostate than white men, it is likely that the optimal cutoffs for predicting the response to therapy and development of complications is different in this population. In Korean men, according to the ROC curve based on the failure for medical therapy, the best cutoff value of prostate volume was 32 ml.21 Therefore, further research is needed on the appropriate criteria for a large prostate volume to predict the treatment response to 5α-reductase inhibitors in Asian patients with LUTS.

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Correspondence to J H Ku.

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Shim, H., Lee, J., Jung, T. et al. Serum prostate-specific antigen as a predictor of prostate volume in Korean men with lower urinary tract symptoms. Prostate Cancer Prostatic Dis 10, 143–148 (2007). https://doi.org/10.1038/sj.pcan.4500937

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Keywords

  • prostate-specific antigen
  • prostate volume
  • prostatic hyperplasia

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