9 7 4 PROSTATE CANCER DETECTION

to date. The numbers are large, the division between positive and negative digital rectal examinations required the agreement of 2 independent urologists, serum prostate specific antigen was ob- tained in an ambulatory setting, any potential elevation of antigen levels from prostatic manipulation was avoided, and more than 99% of the sonographic examinations and biopsies were done by a single urologist (W. H. C.) highly expert in transrectal ultrasound and digital rectal examination, a combination that is ideal for the early detection of prostatic cancer.

The authors have established that impalpable peripheral and cen- tral zone hypoechoic tumors are half the size of palpable lesions and contain half as many tumors with a Gleason score of 7 or greater, leaving no doubt that these impalpable tumors are earlier in the biological development and raising the serious question of whether they would ultimately become palpable on digital rectal examination before they become incurable.

Because 2 urologists had to concur that 1,242 of these patients had a prostate that was nonsuspicious for prostate cancer on digital rectal examination, these results in patients who had negative dig- ital findings have substantial implications for screening or early detection programs. Cancer was found in 4.8% of the patients over- all but only 2% if prostate specific antigen was 4 ngJml, or less, 7% at 4.1 to 10 ngJml. (probably statistically not different than the 4.8% rate obtained without knowledge of antigen levels) and 28% with antigen levels of greater than 10 ngJml. (18 ngJml, by the Yang assay). This 28% number argues strongly that a prostate specific antigen of this magnitude, when combined with a normal digital rectal examination (which includes palpably normal prostates en- larged by benign hyperplasia), might be cost-effective in detecting prostate cancer. To achieve the 4.8% over-all cancer detection rate, however, 30% of the patients had to undergo biopsy; of the 89 patients with a prostate specific antigen level of greater than 10 ngJml. 91% were biopsied to obtain a 28% positive biopsy rate. Thus, i t is clear that hypoechogenicity is nonspecific. Without question, 6 systematic biopsies would produce a higher detection rate in the presence of a hypoechoic lesion but the exact percentage is un- known. I

Few would argue that transrectal ultrasound biopsy rates of 76% for palpable nodules and 56% for abnormally firm or asymmetrical prostates are cost-effective in the early detection of prostate cancer (reference 32 in article). It is possible that when the serum prostate specific antigen level is greater than 10 ngJml, by the Hybritech assay (18 ngJml, by the Yang assay) in the presence of a normal digital rectal examination a 28% positive biopsy rate also may prove to be cost-effective, even if 91% of the patients must undergo biopsy. However, it is questionable whether patients with smaller elevations in serum prostate specific antigen should undergo transrectal ultra- sound if the digital rectal examination is normal and if extenuating circumstances, such as a strong family history, are absent. A pros- tate specific antigen level of 18 ngJml, by the Yang assay is compat- ible with 60 gm. benign prostatic hyperplasia (0.3 ngJmIJgm, benign hyperplasia, reference 12 in article). Not many men with benign prostatic hyperplasia less than 70 years old have benign hyperplasia of this magnitude, which~nay be why screening men with prostate specific antigen levels of greater than 10 ngJml, by the Hybritech assay appears to be intriguing.

It also is interesting that in the total population of 1,807 patients an abnormal prostate specific antigen level (35%) was as predictable for the presence of cancer as was a suspicious digital rectal exami- nation (36%); when both were abnormal the cancer detection rate increased to 60%.

The authors correctly emphasize that all of these data relate to cancer detection in the peripheral and central zones of the prostate, and not to the transition zone where approximately 24% of all can- cers arise. 2,3 Since most of these transition zone (benign prostatic hyperplasia) cancers are less than 0.1 cc in volume, 4 it is just as well that they remain undetected until the patient requires transurethral resection of the prostate for obstructive symptoms, at which time better tumor volume estimates can be made from analysis of the resected tissue.

Lastly, it must be emphasized that these data show that the positive predictive values of biopsied, hypoechoic lesions in patients with a normal digital rectal examination are dismally low (16% over-all, 31% when serum prostate specific antigen was greater than 10 ngJml, by the Hybritech assay). We must be reminded that if the positive predictive value for inverted T-waves in a treadmill electro- cardiogram was this low for evidence of ischemic hear t disease it would have been discarded long ago. These low positive predictive

values serve to emphasize that in men with a normal digital rectal examination the presence of hypoechoic lesions, even in the periph. eral and central zones, constitutes nonspecific and sometimes sub- jective observations.

Thomas A. Stamey Division of Urology Stanford University ltledical Center Stanford, California

1. Hodge, K. K., McNeal, J. E., Terris, M. K. and Stamey, T. A.: Random systematic versus directed ultrasound guided trans- rectal core biopsies of the prostate. J. Urol., 142: 71, 1989.

2. McNeal, J. E., Price, H. M., Redwine, E. A., Freiha, F. S. and Stamey, T. A.: Stage A versus stage B adenocarcinoma of the prostate: morphological comparison and biological signifi- cance. J. Urol., 139: 61, 1988.

3. McNeal, J. E., Redwine, E. A., Freiha, F. S. and Stamey, T. A.: Zonal distribution of prostatic adenocarcinoma: correlation with histologic pat tern and direction of spread. Amer. J. Clin. Path., 89: 897, 1988.

4. Kabalin, J . N., McNeal, J . E., Price, H. M., Freiha, F. S. and Stamey, T. A.: Unsuspected adenocarcinoma of the prostate in patients undergoing cystoprostatectomy for other causes: inci- dence, histology and morphometric observations. J. Urol., 141: 1091, 1989.

REPLY BY AUTHORS

It is entirely possible that random, digitally guided prostatic bi- opsy might achieve a detection rate comparable to that obtained in this study. Indeed, it is likely that such a procedure would achieve an even higher detection rate, in view of the prostate cancer prevalence rate of 30% in men older than 50 years. However, the important point that is missed is that such a procedure would identify many small, even microscopic cancers, the clinical significance of which is not known. If sonographic criteria are used to drive biopsy, identifi- cation of these small lesions is avoided, since cancers that are less than 5 mm. in diameter cannot be seen reliably. It has been shown that sonographie measurement underestimates true tumor volume by about 4 mm. 1 Thus, a 5 mm. sonographic lesion may well have a true diameter of about 9 mm., which, if a sphere, would represent a true tumor volume of 0.4 cc. At a sonographic diameter of 15 mm. (true diameter 19 ram.) actual tumor volume would be 3.7 cc. In view of the correlation between tumor volume and disease stage (refer- ence 17 in article), sonography may provide a window of opportunity for improving detection of cancer while it is apt to be organ confined but it will avoid the detection of "incidental" cancers.

The comment that hypoechoicism is a nonspecific finding on sonog- raphy is correct. Conversely, i t must be pointed out that early pros- tate cancer is almost always hypoechoic. Until we have a less subjective means of interpreting sonographic images, biopsy will remain the sole method of establishing the significance of visually suspicious areas, just as it is for determining the significance of tactilely suspicious areas.

We have stated clearly in the article that no evidence exists which proves that improvement in morbidity and survival will result from early detection of confined cancers, although common sense would indicate such a relationship. Appropriate investigations, such as the 16-year screening trial probably to be started during 1990 by the National Cancer Institute, should provide definitive information. In the meantime, the Chief of the Early Detection Branch of the Insti- tute, Dr. Charles R. Smart, provides food for thought for the physi- cian who is working in today's clinical arena. In the draft of an article yet to be published, for which permission for quotation has been granted, Smart says, "While striving for perfection let us not ignore the indirect evidences that patterns of earlier stage disease nearly always correlate with a better outcome. The dictum 'At all costs do no harm' has a corollary ~ro him that knoweth to do good and doeth it not to him it is sin'. The obligation we have to our patients is to do the best we can for them within the limits of our imperfect knowledge. "2

1. Shinohara, K., Scardino, P. T., Carter, S. St. C. and Wheeler, T. M.: Pathologic basis of the sonographic appearance of the normal and malignant prostate. Urol. Clin. N. Amer., 16: 675, 1989.

2. Smart, C. R. and Chu, K. C.: Stage as a measure of evaluating changing patterns in early cancer detection: a clinical perspec- tive. Unpublished Draft, Early Detection Branch, Division ot Cancer Prevention and Control, National Cancer Institute, Bethesda, Maryland 20892-4200.