Berman JJ, Moore GW, Alonsozana ELC, Mamo GF.
Elevated prostate specific antigen level and the negative prostate biopsy.
Southern Medical Journal, 87(2):290-291, 1994.
Prostate specific antigen (PSA) is a sensitive and specific screening test for prostate cancer, but some patients have a high PSA and a negative first prostate biopsy. Results of 1,009 consecutive prostate biopsies examined over a 30-month period at the Baltimore VA Medical Center were reviewed. Among 215 patients with a PSA level drawn before the first biopsy by less than 4 months, there were 25 negative first biopsies (38%) in the 66 cases where the PSA exceeded 10, including four negative cases (16%) with a positive diagnosis on subsequent biopsy. In addition, positive biopsies occurred in 6 cases where the PSA level was normal or only mildly elevated (6.2% of 97 patients). Results show that serum PSA levels have limited value in predicting the outcome of a single biopsy, and that negative biopsies occur at virtually any PSA level.
Serum PSA levels have been suggested as a screening test for prostate cancer, in conjunction with digital rectal examination and/or transrectal ultrasonography. The rationale for prostate cancer screening programs is that detection and treatment of cancer at an early stage can improve patient survival. PSA has proved to be a valuable tool in prostate cancer screening programs, but there is no evidence at present to indicate that early prostate cancer detection improves patient survival. [1-3] The National Cancer Institute has recently sponsored a 16-year, $97 million study to determine the value of prostate cancer screening (and early cancer detection) on overall patient survival.  Despite uncertainties in the value of prostate cancer screening, it is generally accepted that elevated serum PSA (exceeding 4 ng/ml), with or without an abnormal digital rectal examination, may be an indication for performing a needle biopsy of the prostate [4-8].
The urologist and the pathologist are faced with a dilemma when a negative biopsy is obtained in a patient with a high serum PSA. For instance, suppose the PSA is 100 ng/ml and the patient's prostate biopsy is negative. Is this a remarkable event, or can a laboratory expect this combination of findings to occur with some regularity? Babaian and Camps  have reported a prostate cancer incidence of 87.5% when the PSA exceeds 20 ng/ml, but neither their study or any other study has determined the predictive value of PSA's that fall in specific ranges exceeding 20 ng/ml. Since most of the data collected to date has been used to define the role of PSA measurement as a screening tool (not as a diagnostic tool), little attention has been paid to "outlier" data. But such data are valuable to the urologist who must respond to situations that occur uncommonly. To address this problem, we collected biopsy results on patients with all ranges of PSA levels, stratifying results for ranges of PSA that are high-abnormal. The study included specimens submitted by at least 14 urologists, representing the range of biopsy results that many urologists are likely to experience in their practice. Results were compiled specifically to address the incidence of negative prostate biopsies in ranges of PSA that are associated with a very high risk of prostate cancer.
MATERIALS AND METHODS
The original database consisted of every prostate biopsy accessioned in the 30-month period between October 1, 1989 and March 31, 1992, at the Baltimore VA Medical Center. There were 1,009 cases SNOMED-coded under "prostate." Of those cases, there were 316 which had PSA levels drawn within a four month interval prior to the surgical procedure and which had no previous prostate biopsies filed in our institution; 91 of these cases were transurethral resections or radical prostatectomies; 6 cases were biopsies of a tumor other than prostatic carcinoma; 4 cases were metastatic prostate carcinoma from a site other than prostate; and 2 cases were consultation slides from an outside hospital, leaving 215 cases for analysis. Biopsies were performed by at least 14 different urologists from the section of Urologic Surgery. Each biopsy result was reviewed by at least one other pathologist. There were no cases of discordance between pathologists, and there were no cases in the period under study where the diagnosis rendered on a prostatectomy specimen disagreed with the diagnosis rendered on biopsy (i.e., no proven false positive diagnoses). In those cases where multiple PSA levels were drawn prior to biopsy, the PSA level drawn closest to the date preceding the biopsy was used. PSA levels in hospital laboratories were assayed by the Tandem-R-PSA assay (registered, Hybritech, Inc., San Diego). A normal PSA level for the Baltimore VA Medical Center is 4 ng/ml or lower. There is as yet no international standard (no SI unit) for PSA level.
All patients included in this study were initially evaluated and biopsied by a urologist. The decision to perform the prostate biopsy was based upon one of four criteria: (1) A suspicious digital rectal examination; (2) a suspicious transrectal ultrasound as determined by finding a hypoechoic region within the prostate; (3) an elevated PSA level greater than 4.0 ng/ml; or (4) patients with adenocarcinoma of unknown primary origin who needed to have a prostate cancer ruled out.
The biopsies were performed using a Bard Biopty (R) gun with an 18 gauge biopty needle. The needle was introduced transrectally under digital guidance and fired directly into the prostate to obtain the specimen. If a suspicious area was felt digitally or seen on transrectal ultrasound, then this area was biopsied directly. A second random biopsy was also taken from the same lobe and two other random biopsies were taken from the opposite lobe. If there were no suspicious areas on digital or transrectal ultrasound examination, then two random biopsies were taken from each prostate lobe, usually one near the apex and one near the base. At least 14 different urologists submitted specimens included in the database. Statistical significance was determined by the unpaired Student t-test.
In the 30-month period under review, there were 215 patients having a first needle biopsy of prostate, preceded within four months by a serum PSA level determination. Patients were males ranging in age from 45 to 85 years (average: 69 years). Biopsies in 65 (30%) of patients showed adenocarcinoma of prostate, with Gleason scores ranging from 4 to 10 (average: 6.8). PSA levels ranged from 0.1 to 11,000 ng/ml, and there was a highly significant, positive correlation between PSA level and positive biopsy (p<0.001).
The relationship between PSA level and positive biopsy is shown in Fig 1, in which the clear-bar represents patients with a negative biopsy and the solid-bar represents patients with a positive biopsy. Although a positive correlation between PSA level and positive biopsy is apparent, there were negative prostate biopsies at all PSA levels examined. These included 4 cases where the PSA exceeded 40 ng/ml (PSA 47.8 ng/ml, 60.9 ng/ml 84.0 ng/ml and 1877 ng/ml). There were 25 negative biopsies (38%) among the 66 cases in which the PSA exceeded 10. Four of these negative cases (16%) had a positive diagnosis rendered on a repeat biopsy. Positive biopsies occurred in instances where the PSA level was normal or only mildly elevated, including 6 positive biopsies (6.2%) in the 97 cases with PSA levels of 4 ng/ml or less. When the PSA level showed intermediate elevation (>4 and < 10 ng/ml), there were 18 positive biopsies (35%) in 52 cases.
The positive predictive value for a PSA level was calculated as the number of cases with PSA exceeding that level that had cancer on their biopsy, divided by the total number of cases with PSA's exceeding that level. Results are shown in Table 1.
The urologist is often faced with the dilemma created by a single negative biopsy in the face of clinical evidence that predicts cancer. The positive predictive values in our patient population (Table 1) are similar to those reported elsewhere. Oesterling reported a positive predictive value of 49% when the PSA exceeded 4.0 and 75% when the PSA exceeded 10.  Babaian and Camps reported a positive predictive value of 69% when the PSA exceeded 4.0 and 83% when the PSA exceeded 10.  These earlier studies address the problem of negative biopsies occurring with abnormal PSA levels, but they do not determine the likelihood of encountering a negative biopsy coincident with stratified high ranges of PSA.
Our study demonstrates that no level of PSA was associated with a 100% positive predictive value. No doubt, some negative biopsies occurring in patients with high PSA levels represent sampling errors. In fact, in this study, 16% of the cases of negative biopsies occurring in patients with PSA exceeding 10 ng/ml were found to be positive on rebiopsy. In the current sampling, there was an instance of a negative biopsy with a PSA level of 1877 ng/ml.
These results indicate that although serum PSA is an excellent screening test, PSA values have limited value in predicting the outcome of a single needle biopsy. Negative needle biopsies commonly occur when PSA levels exceed 20 ng/ml and positive needle biopsies commonly occur with PSA levels under 4 ng/ml (neither situation indicates than an error has been committed by pathologist or urologist). When the clinical findings and PSA levels predict cancer, and the subsequent prostate biopsy is negative, clinical surveillance and rebiopsy, preferably under ultrasound guidance, are suggested.
TABLE 1. POSITIVE PREDICTIVE VALUES FOR INCREASING PSA LEVELS.
PSA LEVEL (NG/ML) POSITIVE PREDICTIVE VALUE
*This predictive value represents the overall positive rate, regardless of measured PSA level.
Fig 1. Serum prostate specific antigen (PSA) value in ng/ml vs. number of patients biopsied for 215 consecutive patients. Negative biopsies (clear bars); positive biopsies (solid bars). PSA level and positive biopsy were highly correlated (p<0.001).
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