We evaluated the diagnostic performance of PSA testing using a community-based analysis of men who underwent prostate biopsy within 12 months of PSA testing. Data were analyzed for 930 prostate cancer cases and 1690 controls ages 40 years and older. The area under the ROC curve was 0.67, indicating fair discriminating power for detecting prostate cancer. PSA testing performed equally well in detecting localized cancers and in detecting cancers across all age ranges and in non-Hispanic white and Hispanic men. The standard cutpoint of 4 ng/ml had a sensitivity of 86% and a specificity of 33% and was most sensitive – but least specific – for older men. The 4 ng/ml cutpoint was associated with a likelihood ratio for a positive test of 1.28 and 0.42 for a negative test, representing only moderate probability revisions [18
]. PSA values < 2 ng/ml or greater than 20 ng/ml were associated with large probability revisions. Likelihood ratios did not change substantially when we used age-specific reference ranges, though test sensitivity decreased with increasing age while specificity increased. Lowering the PSA cutpoint to 2 ng/ml raised the sensitivity to 97% but led to an 80% false positive rate.
Most previous reports from the urologic literature provided similar estimates for the discriminating power of the PSA test. Areas under the ROC curve have been reported to range from 0.65 to 0.77 in case series comprised of patients enrolled in screening trials [4
] or followed in urologic practice [22
]. Among urologic studies, we found only Labrie and colleagues reporting a substantially higher area under the ROC curve: 0.88 (SE 0.03) [23
]. However, biopsies were performed only when digital rectal or transrectal ultrasound examinations were abnormal, which would inflate the apparent sensitivity of an elevated PSA level. Gann and colleagues reported an area under the ROC curve of 0.83 in a nested case-control study of Physicians Health Study participants with 10 years of follow-up [24
]. Stored serum from cases clinically diagnosed with prostate cancer and age-matched controls were assayed for PSA. However, the specificity of PSA was probably overestimated because asymptomatic men were unlikely to be biopsied.
We identified only three population-based studies evaluating PSA testing performance [23
]. The two urologic studies [23
] randomly selected men from either electoral rolls or census records and invited them to have prostate examinations. However, neither study used PSA levels as a criterion for biopsy thus confounding the reported predictive values with results from digital rectal examinations and transrectal ultrasonography. Jacobsen and colleagues conducted a retrospective, case-control study analyzing 177 prostate cancer cases diagnosed in Olmsted County, Minnesota in the early 1990s [26
]. PSA was highly discriminating with an area under the ROC curve of 0.94 (SE, 0.01) for all patients. Age-stratified analyses showed that the discriminating power remained high across all age groups, even for men in their 70s. Test sensitivity was approximately 85% for all age groups, though specificity decreased from 98% among men in their 50s to 81% among men in their 70s.
Methodologic differences in study design may explain the disparities in the results between the New Mexico and Minnesota cohorts. Controls in Olmsted County were drawn from a longitudinal Mayo Clinic study on the natural history of lower urinary tract symptoms. Men with initial PSA elevations > 4 ng/ml or an abnormal DRE were biopsied and cancer cases were excluded. However, men with normal PSA and DRE results did not undergo biopsy, thus potentially inflating estimates for specificity. Sensitivity may have been higher if urologists at the Mayo Clinic had a lower false negative biopsy rate than did New Mexico urologists.
Our estimates for the sensitivity (86%), specificity (33%), and positive predictive value (41%) for PSA levels ≥ 4 ng/ml were similar to previously reported values. In the urologic literature, sensitivities ranged from 67% to 90%, specificities ranged from 28% to 59%, and positive predictive values ranged from 30% to 43% [9
]. However, almost all of the published studies, including our own, are flawed by potential work-up bias because men with elevated PSA levels were significantly more likely to be biopsied. In our cohort, men with a PSA level ≥ 4 ng/ml had a 15-fold increased rate of biopsy compared to men with normal values.
Accurately estimating the true and false negative rates for PSA requires that men with normal PSA values undergo biopsy, but we found only one small urologic series where all PSA-tested subjects were subsequently biopsied. Vallencian and colleagues biopsied 100 consecutive men with normal or non-suspicious digital rectal examinations and detected only 14 cancers, none with PSA levels below 10 ng/ml [29
]. The Gann study provided the least biased estimate of sensitivity and specificity, but even these results were limited because asymptomatic cancers would not have been detected [24
]. Additionally, serum was stored for about 10 years and PSA is not completely stable [30
Modifications of the PSA level have been proposed to improve the discriminating power of the test. Oesterling and colleagues developed age-specific PSA reference ranges that lowered the cutpoint in younger men, to increase sensitivity, and raised the cutpoint in older men in order to increase specificity [16
]. We found that using age-specific reference ranges did not substantially change likelihood ratios for prostate cancer, though we confirmed that sensitivity would increase in younger men and specificity would increase in older men.
The age-specific reference ranges have been further modified for racial differences in PSA and cancer risk [32
]. Because African-Americans have an increased incidence of prostate cancer and higher PSA levels at diagnosis, the age-specific reference ranges have been adjusted to maintain a high sensitivity [32
]. Our study cohort had too few African-Americans for a subgroup analysis, but we were able to compare non-Hispanic white with Hispanic men. We found that PSA testing discriminated equally well for Hispanics and non-Hispanic whites and that PSA cutpoints do not need to be adjusted for Hispanics. We are unaware of any other studies comparing the performance of PSA testing between non-Hispanic white and Hispanic men, though Abdalla and colleagues have reported similar PSA levels in non-Hispanic white and Hispanic men with and without prostate cancer [35
Some investigators are now recommending that lower PSA cutpoints should be used as an indication for prostate biopsy [37
]. Catalona and colleagues detected cancer in 22% of men biopsied with PSA levels between 2.6 to 4 ng/ml [37
] and Lodding and colleagues detected cancers in 13% of men with PSA values between 3 to 4 ng/ml [39
]. We found that lowering the cutpoint to 2 ng/ml, while greatly increasing sensitivity, led to an 80% false positive rate.
Aside from work-up bias, there were some other important limitations in our study. We do not know the indications for testing or results from digital rectal examinations. The positive predictive value of 41% that we found for a PSA cutpoint of 4 ng/ml was at the high end of values reported in screening studies and cancer was detected in 24% of men in our cohort with normal PSA levels. These findings suggest that our estimates for sensitivity and specificity may be less applicable to a true screening population. However, we believe that our results more accurately reflect community testing practices than the data reported by urologic series of volunteer subjects. Finally, our study cohort was largely comprised of non-Hispanic white and Hispanic men. Data suggest that the PSA assay may perform differently in African-Americans and our results may not be generalizable to other populations [32