Age-specific reference levels of serum prostate-specific antigen and prostate volume in healthy Arab men

Transcription

1 Original Article KEHINDE et al. Age-specific reference levels of serum prostate-specific antigen and prostate volume in healthy Arab men ELIJAH O. KEHINDE, OLUSEGUN A. MOJIMINIYI*, MEHRAJ SHEIKH, KALEEL A. AL-AWADI, ABDALLAH S. DAAR, ADEL AL-HUNAYAN, JEHORAM T. ANIM* and AISHA A. AL-SUMAIT* Departments of Surgery (Division of Urology), *Pathology and Radiology, Faculty of Medicine, Kuwait University, Kuwait, and College of Medicine, Sultan Qaboos University, Muscat, Oman Accepted for publication 18 February 25 OBJECTIVE To determine age-specific reference ranges for serum prostate-specific antigen (PSA) concentration and prostate volumes in a population of healthy Arab men. SUBJECTS AND METHODS Blood samples were taken from 396 healthy Arab men (from Kuwait and Oman) aged years and from across the social spectrum. Men aged >4 years had a digital rectal examination and transrectal ultrasonography of the prostate to determine prostate volume. The serum PSA level was measured using commercial kits, and agespecific ranges for PSA levels and prostate volume determined. RESULTS The serum PSA ranges (ng/ml) for each age range in Arab men were: 4 49 years,.9; 6 69, 2.7; 7 79, 5.5 ng/ml; the respective prostate volumes were 8 22, 9 3 and 1 33 ml. The serum PSA level and prostate volume correlated with age (P <.1). Arab men had lower serum PSA levels and prostate volumes than those reported for Caucasians, but similar to those reported for Asians (Japanese and Chinese). CONCLUSION These results indicate that Arab men have lower PSA levels and prostate volumes than Caucasians. The levels are slightly lower than those reported in the Japanese and, as in the Japanese, low PSA levels and small prostate volumes might be related to the low incidence of clinical prostate cancer in Arab men. KEYWORDS prostate-specific antigen, prostate volume, Arab, Caucasian, Asian INTRODUCTION Factors responsible for differences in the incidence of prostate cancer in different parts of the world remain unclear. The incidence is low in Asia (3 8 per men per year), intermediate in Africa and Eastern Europe, and high in Western Europe and North America (Fig. 1) [1 4]. PSA remains the most useful clinical tumour marker in the diagnosis of prostate cancer and strategies to enhance its performance include age- and racespecific ranges, measurement of free to total PSA ratio (f/tpsa), PSA density and PSA velocity [5 7]. The aim of the present study was to determine age-specific reference ranges for serum PSA levels and prostate volumes in apparently healthy Arab men aged years. SUBJECTS AND METHODS Venous blood samples were taken from 396 healthy indigenous Arab men from Kuwait and Oman, aged years. Most were selected from healthy men attending the Central Blood Banks in Kuwait and Oman to donate blood. We selected volunteers from all governorates or districts in both countries and representative samples from across different social classes. To be included in the study, men aged >4 years did not have LUTS and had normal urinary flow rates (maximum urinary flow rate >15 ml/s with a voided volume of >15 ml). Men aged >4 years had a DRE and TRUS to determine prostate volume using the formula for a prolate ellipsoid (width length height.52). All TRUS examinations were by one radiologist (M.S.) using a Logic 5 Scanner (GE Medical Systems, Milwaukee, WI, USA) with a 7.5 MHz endocavity transducer (model E721), scanning the gland in sagittal and axial planes. The DRE was performed by three experienced urologists (E.O.K., K.A.A. and A.A.). None of the volunteers had any known serious systemic disease or were on any medications known to affect normal hormone production or serum PSA levels, in accordance with previously established standards [8]. Other demographic data collected from each volunteer included social habits, particularly smoking, marital status and whether they had problems with fertility. Each patient's weight and height were also recorded. Serum total and free PSA levels were measured using third-generation kits (Immulite, Diagnostic Products Corp. Inc. Webster, TX, USA). Serum samples were aliquoted in 2.5-mL batches and stored at -8 C until analysis within 6 months of sample collection. The study was approved by the Local Ethics Committee and informed consent was obtained from all volunteers. The volunteers were further informed that, should a disease be diagnosed as a result of these tests, they would be informed and additional tests conducted before recommending further treatment. Volunteers found to have an abnormal DRE irrespective of PSA value, or a PSA level of >1 ng/ml, had a sextant prostate biopsy with TRUS guidance. Similarly, volunteers with an abnormal echo pattern at TRUS had a prostate biopsy. The biopsies were taken from the apex, middle and base of the right and left lobes in the parasagittal plane. If a hypoechoic lesion was detected in the peripheral or BJU INTERNATIONAL 96, doi:1.1111/j x x

2 FIG. 1. Incidence (age standardized rate) of prostate cancer by world region (using data from [1]). USA Blacks USA Whites Australia Germany England Wales Zimbabwe (White) Zimbabwe (Black) Kuwait China (Shanghai) 5 15 central zone on TRUS, 3 6 biopsies of those areas were also taken. Before biopsies, patients received oral ciprofloxacin 5 mg, 1 h before the procedure and 5 mg twice Number of cases per men/year TABLE 1 Mean (SD) serum levels of total PSA, free PSA, and f/tpsa, and prostate volumes in normal Arab men* Age group, years N patients Total PSA, ng/ml Free PSA, ng/ml f/tpsa, % Prostate volume, ml Range, ml (.25).7 (.5) 25 (6.12) (.32).12 (.11) 21.1 (3.11) (.33).11 (.8) 21.2 (4.22) (.68).13 (.25) 23.2 (5.22) 14.4 (2.3) (2.9).18 (.17) 14.2 (2.67) 17.8 (3.3) (4.26).43 (.43) 14.8 (3.11) 22.4 (6.1) (3.49).68 (.58) 14.2 (2.31) 22.9 (4.1) 1 33 *Arab men (Kuwaitis and Omanis), none had symptoms of prostatism, all had normal urinary flow rates. FIG. 2. Frequency distribution of total PSA profile in normal Arab men. Median.47, 396 men, reference range Frequency Total PSA, ng/ml daily for 3 days. Men found to have prostate cancer were excluded from the analysis. All assays were carried out while unaware of sample origin. Quality control samples were included within assay runs, as specified by the kit's manufacturers. The number of serum samples analysed for PSA or free PSA was determined when a statistically significant trend was established with age from regression plots. The interassay coefficients of variation for PSA and free PSA were 2.1% and 5.1% respectively, and the intra-assay coefficients of variation were 3.1% and 3.2%, respectively. Descriptive statistical methods were applied for the entire study cohort. For normally distributed variables the reference range was the mean ± 2 SD, while for those with nonnormal distribution the reference range was the median ( percentile). Pearson product-correlation coefficients were calculated to measure the association between serum PSA levels and age, prostate volume and age, and PSA levels and prostate volume. For all analyses, P <.5 was considered to indicate significance. Nomograms showing the distribution of serum PSA levels and prostate volumes as a function of age were generated from leastsquares regression models. A nomogram of the distribution of serum PSA levels as a function of prostatic volume was also constructed similarly. RESULTS Table 1 shows the mean (SD) total PSA, free PSA and f/tpsa levels in normal healthy Arab men aged years, and the number of men sampled in each age group, which ranged from 52 in those years old to 12 in those aged 7 79 years. The few men in the latter group reflects the scarcity of this age group in Kuwait and Oman, where the population distribution is skewed, with more than half the population aged <25 years, and thus finding volunteers aged >6 years who were suitable for inclusion in this study proved difficult. The mean (SD) PSA level was.56 (.7) ng/ml for men aged 4 49 years and 4.79 (3.65) ng/ml for men aged 7 79 years. Figure 2 shows the frequency distribution of total PSA in these Arab men; it is not a normal distribution, hence the median PSA of.47 ng/ml and reference range of (2.5 and 97.5 percentiles) is more appropriate than using the mean. Figure 3 shows the good correlation (r =.52) between total PSA level and age in Arab men, with the total PSA value for age derivable as.76 (age) ng/ml (P <.1). Free PSA values closely mirrored those of total PSA (Figs 4 and 5); like total PSA, free PSA increased with age (P <.1), but f/tpsa declined with age (Table 1). Table 1 also shows that the mean prostate volume and range increased with age in Arab men; the mean (SD) volume was 14.4 (2.3) ml for men aged 4 49 and 22.9 (4.1) ml for men aged 7 79 years. The relationships between serum levels of PSA and fpsa and age were similar to the trends previously reported for Caucasians. The 25 BJU INTERNATIONAL 39

3 KEHINDE ET AL. numbers of serum samples analysed for PSA and free PSA were determined when a statistical significant trend (P <.1) with age was established, as shown in Figs 3 and 5. Thus total and free PSA levels showed progressive increases with age (Figs 3 and 5). DISCUSSION Log 1 total PSA, ng/ml FIG. 3. Serum PSA level as a function of age in healthy Arab men; r =.52, P <.1, total PSA =.76 (age) The present study shows that, as in other communities, the reference range for total PSA levels and prostate volume must be established for each community, as there are substantial differences in normal reference values. For clarity, the values determined in the present study are tabulated with values reported previously for White men from the USA, Japanese, and Chinese (Table 2). In all four populations, PSA levels and prostate volumes increased with age. For Arab men, the normal median total PSA level of.45 ng/ ml is lower than the.8 ng/ml reported for Japanese men [5]. Similarly Arab men aged >59 years have smaller prostates than Japanese men (P <.6) and White men (P <.1). As shown by studies in other populations, the present study also confirmed that there is a significant (P <.5) correlation between patient age, total PSA level (r =.387) and prostate volume (r =.29) [5,9 11]. Frequency Age, years Free PSA, ng/ml FIG. 4. Frequency distribution of free PSA profile in normal Arab men; median.9, 152 men, reference range In 1993, Oesterling et al. [9] and Dalkins et al. [1] developed age-specific reference ranges for serum PSA levels for White men from the USA; the reference ranges are higher than for Japanese men, which in turn are higher than for Arab men (Table 2). Chinese men appear to have the lowest age-specific reference ranges for PSA levels, as reported by He et al. [12] (Table 2). For each age group, from 4 79 years, the upper limit of normal for serum PSA levels for Arab men is lower than in Japanese or in White men. The clinical implication of this finding is that the serum PSA value for an Arab man has a different clinical meaning than the same value for a similarly aged Japanese or a White man. Hence, whereas a PSA level of 2 ng/ml will be considered normal for a White man or a Japanese man aged 4 49 years, for an Arab man of the same age and PSA value, the possibility of prostate cancer needs to be excluded. The Japanese PSA values were measured with the IMx PSA assay (Abbott Laboratories, Abbott Park, IL, USA) and those of the White men reported by Oesterling et al. Log 1 free PSA, ng/ml Age, years [9] by the Tandem-R PSA assay (Hybritech Inc. San Diego, CA, USA), whereas we used thirdgeneration Immulite kits. However, it is unlikely that the lower values in Arab men can be attributed solely to the diagnostic kits used [5,9,13,14]; as Jacobsen et al. [13] showed, FIG. 5. Serum free PSA level as a function of age in healthy Arab men; r =.563, P <.1, free PSA =.6219 (age) PSA is fairly stable, especially if the serum has been separated early after blood sample collection and stored appropriately. This implies that the assay technique should not substantially affect the values of PSA measured, and this was confirmed by Junker BJU INTERNATIONAL

4 TABLE 2 Comparison of serum PSA levels and prostate volumes as a function of age in healthy White men from the USA [9], Japanese [5], Chinese [12] and Arab men Age range, Serum PSA range, ng/ml Prostate volume range, ml years USA White* Japanese* Arab Chinese USA White* Japanese* Arab , * Data from [5,9]; Data from [12]; 1 P <.1 (Arab vs USA White); 2 P <.6 (Arab vs Japanese); P calculated using Student's t-test. et al. [14], who compared four different total and free PSA assays and found no significant difference in the mean values obtained, especially when the total PSA level was < 25 ng/ml. Furthermore, as prostate glands in Arab men are smaller than in White or Japanese men, and as it is known that the larger the prostate the higher the PSA level, the smaller prostate in Arab men is the most likely explanation for the low PSA levels [15]. Prostate volume was measured with the formula used by Oesterling et al. [9] for White men and by Oesterling et al. [5] for Japanese men, so the differences in PSA values and prostate volumes are probably real. After adjusting for prostatic size and patient's age, there is still a significant difference in PSA values between White and Arab men (P <.1). The higher levels of serum PSA beyond that which can be accounted for by prostate size alone might also reflect differences in the cellular composition of the prostate glands in the three communities. This has clinical implications for prostate pathology; e.g. while the autopsy prevalence of latent prostate cancer shows little racial or geographical variation, the autopsy prevalence of proliferative (more extensive and less well differentiated) latent prostate cancer shows racial and geographical variations similar to those seen for clinically diagnosed prostate cancer [16,17]. Similarly, from local experience of TURP for BPH in Arab men over a 1-year period, the prostate causing symptoms of BOO is smaller than in Caucasians, and histology tends to show that the prostate has more stromal elements and fewer glandular elements than found in Caucasians [18]. Finally, a recent prospective report indicated that, in men with no prostate cancer at initial screening, the risk of developing prostate cancer in any given 4-year period is greater for Dutch men aged years than for their Japanese counterparts, because the former have higher normal PSA levels [19]. The f/tpsa in the Arab men studied also declined with age, from 25% in those years old to 14.2% in those aged 7 79 years. There is considerable disagreement about the effect of age on f/tpsa in healthy men; some have reported an increase with age [2,21], some a decrease [22], and others claim that f/tpsa is independent of age [23]. Reasons given for these differences include that in some of the studies [23] prostate cancer was not excluded in men whose sera were used for the analysis. The present study included only men who did not have clinically detectable prostate cancer, so the present finding that age independently influences f/tpsa is likely to be more accurate, and is consistent with the findings of Lein et al. [22]. However, it would appear that the only reason to determine the f/tpsa is as a guide as to whether to take a prostate biopsy, to exclude prostate cancer for men with PSA levels in the grey zone of ng/ml. Thus, it is used to enhance the specificity of total PSA values in the grey zone [24,25]. The value of estimating f/tpsa in normal men is at present unclear. However, Carter et al. [26] argued that men with no prostate cancer but with very low f/tpsa levels are at greater risk of developing prostate cancer. They further stated that the lower the value, the more aggressive the prostate cancer that the patient develops [26]. The threshold for suspicion of prostate cancer is a f/tpsa of <14.5% [22]. In the present study, the mean f/tpsa in normal men in the prostate cancer years (>6 years) was 14.2%, about the same as the threshold for the diagnosis of suspicion of prostate cancer. This high mean f/tpsa in Arab men might be another reason for their low incidence of prostate cancer. Alternatively, it might reflect an underlying biological difference between Arab and Caucasian prostates. In conclusion, the present study confirms earlier reports that serum PSA levels and prostate volume are age- and racedependent, so it is appropriate to have agespecific reference ranges for these variables in various communities around the world. This will enhance the positive predictive value of PSA estimation in the diagnosis of prostate cancer in each community. The present results indicate that Arab men have lower PSA levels and prostate volumes than reported previously for White men. The levels are only slightly lower than those found in Japanese men. As in Japanese and Chinese men, low PSA levels and small prostate volumes might partly explain the low incidence of prostate cancer in Arab men. CONFLICT OF INTEREST None declared. Source of funding: Kuwait University Research Grant MS 1/99. ACKNOWLEDGEMENTS This work was supported by Kuwait University Research Grant MS 1/99. We thank Mrs Ramani Varghese, Mr Mathew Abraham and Dr Anjum Menon, Faculty of Medicine, Kuwait University for assistance with specimen processing, data processing and advice regarding statistical methods, respectively. REFERENCES 1 Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J, eds. Cancer Incidence in Five Continents, Vol. VII, no Lyons, France: IARC Scientific Publications, 1997: Memon A, Al Muhanna AN. 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