Serum Prostate Specific Antigen and Prostate Specific Antigen Density in Patients Receiving Radical Prostatectomy

Objective: To study the significance of prostate specific antigen (PSA) and prostate specific antigen density (PSAD) for predicting the risk of occult metastatic disease and extra-prostatic invasion of prostate cancer in patients receiving radical prostatectomy.
Patients and methods: The cases of 41 consecutive patients who underwent radical prostatectomy were reviewed. Relations of PSA and PSAD using Market M PA^1M assay for grade, preopvrative clinical stage, postoperative pathological stage, capsular penetration, seminal vesicle invasion, resection margins and lymphnode metastasis are discussed.
Results: Although serum PSA was correlated with PSAD and PSA was correlated with preoperative prostate volume, PSAO was not influenced by prostate volume. PSA correlated only with the grade, while PSAD was correlated with grade, preoperative clinical Stage, postoperative pathological stage, capsular penetration, seminal vesicle invasion, resection margins and lymphnode metastasis. In addition, sixty-two percent (8/13) of margin positive patients showed a PSAD value of more than 0.4, while 93% (26/28) of margin negative patients showed less than 0.4. Sixty-seven percent (6/9) of lymphnode positive patients showed a PSAD of more than 0.4, while 91% (29/32) of lymphnode negative patients showed less than 0.4.
Conclusion: We concluded that PSAD was useful for predicting extraprostatic involvement of prostatic cancer.     

Free-to-Total Prostate Specific Antigen Ratio as a Single Test for Detection of Significant Stage T1c Prostate Cancer

Purpose

We investigated whether impalpable, invisible (stage T1c) but significant prostate cancer can be detected better by determining the free-to-total prostate specific antigen (PSA) ratio of equivocal PSA serum levels.

Materials and Methods

The specificity of free-to-total PSA ratio using research monoclonal enzyme immunoassays was compared to that of PSA greater than 4.0 ng./ml. in 117 consecutive patients with PSA 3 to 15 ng./ml. (Hybritech Tandem-R assay) due to untreated benign prostatic hypertrophy or prostate cancer. Of the patients 77 percent underwent adenectomy or radical prostatectomy with thorough pathological evaluation of surgical specimens.

Results

Benign prostatic hypertrophy had a greater median free-to-total PSA ratio than stages T1c and T2 or greater prostate cancer (0.16 versus 0.09 and 0.11 ng./ml., p = 0.0001 and p = 0.0268, respectively). In stage T1c prostate cancer, areas under receiver operating characteristic curves were 0.58 and 0.84 for PSA and free-to-total PSA ratio, and free-to-total PSA ratio correlated with prostate volume (r = 0.49, p = 0.005) and Gleason score (r = -0.37, p = 0.036). Pathologically, 84 percent of stage T1c cancers were significant and comparable to stage T2 or greater cancers.

Conclusions

Free-to-total PSA ratio enhances the efficacy of PSA measurement by improving specificity for detecting impalpable, invisible but significant stage T1c prostate cancer.     

Prospective Evaluation of Prostate Specific Antigen and Prostate Specific Antigen Density in the Detection of Nonpalpable and Stage T1C Carcinoma of the Prostate

Purpose

We evaluated prospectively prostate specific antigen (PSA) and prostate specific antigen density in the detection of prostate cancer in patients with normal findings on digital rectal examination with and without normal transrectal ultrasound.

Materials and Methods

Consecutive patients (184) with an elevated serum PSA and normal digital rectal examination underwent transrectal ultrasound with lesion directed and systematic biopsies (6 if prostatic volume was 50 cc or less and 12 if volume was more than 50 cc). Receiver operating characteristic curves, predictive values and likelihood ratios were calculated for PSA and PSA density.

Results

Of the 184 patients 50 (27 percent) with a normal digital rectal examination had cancer compared to 30 of 112 (27 percent) with a normal digital rectal examination and transrectal ultrasound. Median PSA or PSA density did not differ between the positive and negative biopsy groups among patients with a normal digital rectal examination (8.4 versus 7.1 and 0.22 versus 0.14 ng./ml., respectively) or a normal digital rectal examination and transrectal ultrasound (8.2 versus 7.5 and 0.21 versus 0.14 ng./ml., respectively). PSA density was superior to PSA by receiver operating characteristic analysis for cancer detection when all PSA values or those between 4 and 20 ng./ml. were considered. However, the significance was lost for a PSA of 4 to 10 ng./ml. Likelihood ratios demonstrated insignificant changes in the post-test probability if PSA density was used to determine the need for biopsy and many cancers would have been missed.

Conclusions

PSA density should not be used to determine the need for biopsy in patients with a normal digital rectal examination and/or transrectal ultrasound.     

Pitfalls in Interpreting Prostate Specific Antigen Velocity

Purpose

The concept of prostate specific antigen (PSA) velocity as an improved marker for prostate cancer detection is intriguing. However, before this concept is applied to individual patients several confounding parameters must be addressed. We determined the variability of serum PSA levels in men without prostate cancer.

Materials and Methods

We reviewed data from a prostate cancer screening program, and determined inter-assay and individual variability of the serum PSA values for a 2-year followup period in 265 men clinically free of prostate cancer.

Results

Our average inter-assay coefficient of variation was 7.5 percent. Therefore, we considered only PSA changes exceeding plus/minus 15 percent as significant. Fluctuations in serum PSA occurred in 78 percent of the men during the observation period, and 12.5 percent had at least a single PSA increase exceeding 0.75 ng./ml. per year. Fluctuations were noted throughout the entire range of serum PSA levels but became progressively larger with an increasing mean PSA.

Conclusions

The inter-assay variability must be considered when interpreting PSA velocity. Individual fluctuations in serum PSA dictate an observation period of at least 2 years before PSA velocity is considered abnormal.     

Value of the Free to Total Prostate Specific Antigen Ratio and Prostate Specific Antigen Density for Detecting Prostate Cancer in Japanese Patients

Background : This study evaluated the free to total serum prostate specific antigen (f/t PSA) ratio and prostate specific antigen density (PSAD) in detecting prostate cancer in Japanese males with a PSA level between 2.5 and 20.0 ng/mL in a community-based urology practice.
Methods : Twenty-six patients with clinically localized prostate cancer and 44 patients with histologically-proven benign prostatic hyperplasia (BPH) were studied. The serum levels of free PSA (fPSA) and total (t) PSA were determined using a chemiluminescent enzyme immunoassay. The f/t PSA ratio was calculated by dividing the fPSA value by the total PSA value and was compared with the PSA and PSAD via the receiver operating characteristic (ROC) curves.
Results: Patients with prostate cancer had a significantly lower f/t PSA ratio than patients with BPH. The PSAD was a superior diagnostic tool over PSA (P < 0.01) when analyzed by ROC curves. The f/t PSA ratio was also superior to PSA, but lacked significance (P=0.12), and similarly, the PSAD was superior, but not significant, to the f/t PSA ratio. Using a cut-off value of 0.1 9, the PSAD had a sensitivity of 81% and a specificity of 82%. With a cut-off value of 14.0%, the f/t PSA ratio had a sensitivity of 81% and a specificity of 66%.
Conclusion: This study showed that PSAD alone improved cancer detection significantly better than PSA. However, it is still unclear whether the f/t PSA ratio is superior to PSA or PSAD in the discrimination between BPH and prostate cancer in Japanese male patients.     

Prostate Specific Antigen Density is not an Independent Predictor of Response for Prostate Cancer Treated by Conformal Radiotherapy

Although prostate specific antigen (PSA) density appears to be an important discriminator between benign and malignant prostatic disease, conflicting data exist concerning its prognostic value. The present study was undertaken to confirm whether PSA density represents a new prognostic indicator of disease-free survival for prostate cancer treated with conformal radiotherapy. Between April 1989 and December 1992, 186 patients with organ confined prostate cancer were treated with definitive irradiation according to previously published conformal guidelines. The PSA density was defined as the ratio of the pretreatment serum PSA (ng./ml.) to the prostate volume (ml.) as determined from treatment planning computerized tomography. The median PSA density was 0.15 with a range of 0.02 to 2.12. A statistically significant advantage in actuarial freedom from biochemical relapse was noted for patients with pretreatment PSA levels less than 15 ng./ml. when compared to those with higher pretreatment PSA levels (3-year freedom from biochemical relapse 85 percent versus 28 percent, p less than 0.001). Also, patients with PSA density of 0.15 or less had statistically superior freedom from biochemical relapse compared to their counterparts with higher PSA density (3-year freedom from biochemical relapse 88 percent versus 28 percent, p less than 0.001). In a multivariate analysis only the baseline PSA (p less than 0.002) and the Gleason score (p less than 0.002) emerged as significant predictors of prolonged freedom from biochemical relapse. The PSA density had no impact on freedom from biochemical relapse whether it was entered into this multivariate model as a continuous or a dichotomous variable. In our data base baseline PSA levels remain the most powerful independent discriminant of response to conformal irradiation. PSA density is only a surrogate for baseline PSA levels and does not refine the ability to predict prolongation of freedom from biochemical relapse following conformal radiotherapy.     

Serum Pro Prostate Specific Antigen Improves Cancer Detection Compared to Free and Complexed Prostate Specific Antigen in Men With Prostate Specific Antigen 2 to 4 Ng/Ml

PurposePro prostate specific antigen (pPSA) is a precursor form of PSA enriched in tumor compared to benign prostate tissues that may be a more specific serum marker for prostate cancer. Serum pPSA was measured in the clinically relevant early detection PSA range of 2 to 10 ng/ml.Materials and MethodsResearch use immunoassays were used to measure native and truncated forms of pPSA. The subject cohort contained 1,091 serum specimens from men enrolled in prostate cancer screening studies at 2 sites who had undergone prostate biopsy and were divided into PSA ranges of 2 to 4 ng/ml (benign 320, cancer 235) and 4 to 10 ng/ml (benign 315, cancer 221).ResultsIn PSA ranges 2 to 4, 2 to 6, 4 to 10 and 2 to 10 ng/ml, pPSA in a ratio with free PSA (%pPSA) gave the highest cancer specificity. At 2 to 4 ng/ml and 90% sensitivity, %pPSA spared 19% of unnecessary biopsies compared to 10% for free PSA and 11% for complexed PSA(p <0.001). Similar results were obtained at PSA 2 to 6 ng/ml. At 90% sensitivity in the PSA 4 to 10 ng/ml range, %pPSA spared 31% of unnecessary biopsies compared to 20% for % free PSA and 19% for complexed PSA (p <0.0001). In the combined 2 to 10 ng/ml range, %pPSA spared 21% of unnecessary biopsies compared to 13% for % free PSA and 9% for complexed PSA (p <0.0001).ConclusionsThe %pPSA significantly improved specificity for cancer detection and decreased the number of unnecessary biopsies in the PSA 2 to 4 ng/ml range. This relative improvement of %pPSA compared to % free PSA and complexed PSA was maintained throughout the PSA range of 2 to 10 ng/ml.     

Pathological Characteristics and Prognosis of Nonpalpable and Palpable Prostate Cancers with a Hybritech Prostate Specific Antigen of 4 to 10 ng./ml

Purpose

We compared the surgical pathological findings and postoperative course of patients with palpable and nonpalpable prostate cancers.

Materials and Methods

All patients with untreated prostate specific antigen (PSA) 4 to 10 ng./ml. who underwent radical prostatectomy between December 1984 and December 1993 were reviewed to select 61 with clinical stage T1c (nonpalpable) and 209 with stages T2a to c (palpable) disease.

Results

Nonpalpable cancers were smaller (2.99 versus 4.42 cc for palpable tumors), had smaller volumes of Gleason grade 4 or 5 cancer (0.66 versus 1.32 cc, respectively) and were less likely to have positive surgical margins (13 versus 22 percent, respectively) or significant (1 cm. or more) capsular penetration (10 versus 26 percent, respectively). Nonpalpable and palpable cancers had similar rates of seminal vesicle invasion (3.3 versus 4.3 percent, respectively) and positive lymph nodes (1.6 versus 0 percent, respectively). More than 90 percent of patients with nonpalpable cancer were biochemically cancer-free postoperatively, and the remainder were alive with disease after a mean followup of 25.1 months, compared to 69 percent disease-free, 28 percent alive with disease and 2.5 percent dead of prostate cancer after a mean followup of 43.8 months among those with palpable disease.

Conclusions

We conclude that nonpalpable prostate cancers are pathologically more favorable than palpable prostate cancers with PSA 4 to 10 ng./ml. Our preliminary results also indicate that nonpalpable cancers are less likely to recur postoperatively than palpable cancers with a similar PSA range.     

Prostate Specific Antigen Density Versus Prostate Specific Antigen Slope as Predictors of Prostate Cancer in Men with Initially Negative Prostatic Biopsies

Purpose

We determined if prostate specific antigen (PSA) density and PSA slope alone or in combination could be used to predict which men with persistently elevated serum PSA and prior negative prostate biopsies will have prostate cancer on repeat evaluation.

Materials and Methods

In our PSA-1 data base we identified 327 men 50 years old or older with an initially negative prostate biopsy who had persistent PSA elevation, and compared those who did and did not have prostate cancer on subsequent serial prostatic biopsy.

Results

Of 70 men with a PSA density of 0.15 or more and PSA slope of 0.75 ng./ml. or more annually compared to 83 with a PSA density of less than 0.15 and PSA slope of less than 0.75 ng./ml. annually 32 (46 percent) and only 11 (13 percent), respectively, had prostate cancer on subsequent prostate biopsies (p less than 0.0001). In a hierarchical logistic regression analysis PSA density and PSA slope were predictive of prostate cancer on subsequent biopsy (p = 0.001 and 0.03, respectively). PSA density of 0.15 or more alone or PSA slope of 0.75 ng./ml. or more annually alone as the indicator for repeat biopsy would have missed 35 and 40 percent of cancers, respectively.

Conclusions

In men with persistently elevated serum PSA after an initially negative prostate biopsy, PSA density and PSA slope alone or in combination provide useful predictive information about the results of repeat prostate biopsies. However, these parameters are not sufficiently sensitive to identify all patients with detectable prostate cancer.     

An Algorithm for Predicting Nonorgan Confined Prostate Cancer Using the Results Obtained from Sextant Core Biopsies with Prostate Specific Antigen Level

Purpose

We determined the enhanced ability to predict nonorgan confined prostate cancer using several histopathological and quantitative nuclear imaging parameters combined with serum prostate specific antigen (PSA).

Materials and Methods

Several independent pathological and quantitative image analysis variables obtained from sextant biopsy specimens, as well as preoperative PSA were used. The study population included 210 patients with pathologically staged disease (192 with PSA). All variables were examined by univariate and multivariate logistic regression analyses to assess ability to predict disease organ confinement status.

Results

Univariate logistic regression analysis demonstrated that, in decreasing order, quantitative nuclear grade, preoperative PSA, total percent tumor involvement, number of positive sextant cores, preoperative Gleason score and involvement of more than 5 percent of a base and/or apex biopsy were significant (p less than or equal 0.006) for prediction of disease organ confinement status. Backward stepwise logistic regression was applied to these univariately significant variables, including deoxyribonucleic acid ploidy, to calculate a multivariate model for prediction of disease organ confinement status. This algorithm had a sensitivity of 85.7 percent, specificity 71.3 percent, positive predictive value 72.9 percent, negative predictive value 84.7 percent and area under the receiver operating characteristic curve 85.9 percent.

Conclusions

Information from pathological study of sextant prostate biopsies, preoperative PSA blood test and a new image analysis variable termed quantitative nuclear grade can be combined to create a multivariate algorithm that can predict more accurately nonorgan confined prostate cancer compared to previously reported methods.     

Cancer Diagnosis with Prostate Specific Antigen Greater than 10 ng./ml. and Negative Peripheral Zone Prostate Biopsy

Purpose

We assessed the results of additional diagnostic procedures in men with prostate specific antigen (PSA) more than 10 ng./ml. and a peripheral zone prostate biopsy negative for cancer.

Materials and Methods

A total of 68 men with PSA more than 10 ng./ml. and a peripheral zone biopsy negative for cancer was investigated with 1 or more peripheral zone biopsies (17), prostatectomy (18), or 1 or more peripheral zone biopsies and needle biopsy of the transition zone or prostatectomy (33).

Results

Cancer was detected in 20 of 68 patients (29 percent) with 1 or more additional diagnostic procedures. Of 51 patients whose transition zone was biopsied or who underwent prostatectomy 16 had cancer, and in 8 the malignancy appeared to be isolated to the transition zone. Mean PSA density and proportion of patients with PSA density more 0.15 were significantly greater and mean prostate volume was significantly less in the 20 patients with compared to 31 without identifiable cancer.

Conclusions

At least 30 percent of men with PSA more than 10 ng./ml. and a negative peripheral zone biopsy have prostate cancer. In approximately 50 percent of cases the cancer appears to reside in the transition zone, and transition zone biopsy or prostatectomy is required for diagnosis.