STRATEGY FOR REPEAT BIOPSY IN PATIENTS WITH HIGH GRADE PROSTATIC INTRAEPITHELIAL NEOPLASIA

STRATEGY FOR REPEAT BIOPSY IN PATIENTS WITH HIGH GRADE PROSTATIC INTRAEPITHELIAL NEOPLASIA

0022-5347/00/1633-0819/0 THE JOURNAL OF UROLOGY® Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.® Vol. 163, 819 – 823, March 2000 Printed i...

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0022-5347/00/1633-0819/0 THE JOURNAL OF UROLOGY® Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 163, 819 – 823, March 2000 Printed in U.S.A.

STRATEGY FOR REPEAT BIOPSY IN PATIENTS WITH HIGH GRADE PROSTATIC INTRAEPITHELIAL NEOPLASIA KAZUMI KAMOI, PATRICIA TRONCOSO

AND

R. JOSEPH BABAIAN*

From the Departments of Urology and Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas

ABSTRACT

Purpose: The finding of high grade prostatic intraepithelial neoplasia in a biopsy specimen without prostate cancer warrants repeat biopsy because of the risk of concurrent cancer. However, to our knowledge the optimal repeat biopsy technique has not yet been defined. We determined the optimal subsequent biopsy strategy for detecting concurrent cancer in patients diagnosed with high grade prostatic intraepithelial neoplasia. Materials and Methods: Of 63 men with isolated high grade prostatic intraepithelial neoplasia on initial biopsy 45 underwent repeat biopsy within 1 year. Certain biopsy patterns were used for repeat biopsy, including only the neoplasia site in 8 men, sextant in 12, sextant plus bilateral transition zone in 13 and 11 core multisite directed (sextant, bilateral transition zone, bilateral anterior horn of the peripheral zone and midline peripheral zone) in 12. We compared the location of high grade disease on the initial biopsy with the cancer site on repeat biopsy. Results: Repeat biopsy revealed cancer in 10 of the 45 men (22%), and the sites of high grade prostatic intraepithelial neoplasia and cancer correlated in 6. Cancer was detected at the sextant locations in 9 men. Of the 15 cores positive for cancer 8 were at the original high grade neoplasia site, 6 at a random sextant biopsy site and 1 in the transition zone. High grade disease was discovered bilaterally in 1 man, while prostatic intraepithelial neoplasia and cancer were detected on the same side in the remaining 9. Conclusions: The optimal repeat biopsy strategy for patients with high grade prostatic intraepithelial neoplasia has not yet been determined but at a minimum it should include targeting the area of known high grade disease and the ipsilateral sextants. KEY WORDS: prostate, biopsy, prostatic neoplasms, prostatic intraepithelial neoplasia

Prostatic intraepithelial neoplasia was initially described in the 1960s by McNeal1 and more precisely characterized in 1986 by McNeal and Bostwick,2 who first called it intraductal dysplasia. The term high grade prostatic intraepithelial neoplasia refers to what was originally described as grades 2 and 3 prostatic intraepithelial neoplasia, whereas low grade disease was restricted to grade 1.3 Histologically high grade disease is characterized by a distinctive architectural arrangement of cellular proliferations within preexisting ducts and glands that lacks the complete disruption of the basal cell layer and stromal invasion of carcinoma.4 Autopsy and surgical pathology reviews have documented a strong association of high grade prostatic intraepithelial neoplasia with carcinoma within the same gland.2, 4 –9 Several have shown that high grade disease is the most likely precursor of prostate cancer.2, 4, 10 –12 Therefore, the finding of high grade prostatic intraepithelial neoplasia by needle biopsy necessitates repeat biopsy to rule out concurrent cancer as well as close clinical followup if no cancer is detected.13–15 Repeat biopsy in patients with isolated low grade prostatic intraepithelial neoplasia is not warranted since low grade disease is frequently present in benign glands, and the distinction between low grade disease and normal prostatic epithelium is considered to be subjective.15–17 The reported incidence of isolated high grade prostatic

intraepithelial neoplasia ranges from 7.6% to 16.5% in men undergoing transrectal ultrasound guided biopsy.15, 18, 19 The rate of prostate cancer in the repeat biopsy specimen in patients with high grade disease ranges from 35% to 73%.14 –17 Despite general agreement regarding the need for repeat biopsy the optimal method has not been clearly defined.20, 21 Therefore, we sought to define the optimal repeat biopsy strategy for detecting concurrent cancer by comparing the location of high grade prostatic intraepithelial neoplasia on initial biopsy with the cancer site on repeat biopsy. MATERIALS AND METHODS

The study included 611 consecutive patients who underwent prostate needle biopsy to detect prostate cancer at our institution between June 1995 and August 1998. No patient had a previous diagnosis of prostate cancer or had received androgen deprivation therapy, chemotherapy or radiation therapy to the pelvis. Patients underwent transrectal ultrasound and biopsy using a Bruel & Kjaer ultrasound machine and a 7 MHz. ultrasound probe. All biopsies were performed using an automatic spring loaded 18 gauge biopsy gun. Prostatic intraepithelial neoplasia was classified as high grade according to the criteria of McNeal and Bostwick.2 Benign prostatic tissue, cancer and high grade prostatic intraepithelial neoplasia were present in 301 (49%), 247 (40%) and 63 (10%) men, respectively. Atypical foci suspicious for but not diagnostic of cancer were noted in 6 patients, of whom 4 had cancer on repeat biopsy. Low grade prostatic intraepithelial neoplasia was identified in 3 men, of whom none underwent repeat biopsy. Repeat biopsy was performed in 45 of the 63 men (71%) with isolated high grade prostatic intraepithelial neoplasia within 1 year of the initial biopsy (fig. 1). Of the

Accepted for publication September 17, 1999. * Requests for reprints: Department of Urology, Box 110, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030-4095. Editor’s Note: This article is the fourth of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 968 and 969. 819

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STRATEGY FOR REPEAT BIOPSY FOR PROSTATIC INTRAEPITHELIAL NEOPLASIA

FIG. 1. Distributions of high grade prostatic intraepithelial neoplasia at initial biopsy and cancer at repeat biopsy in 45 patients. Number at each biopsy site indicates number of cores positive for high grade prostatic intraepithelial neoplasia or prostate cancer. R, right side. L, left side. AH, anterior horn. TZ, transition zone. ML, midline.

remaining 18 men 8 refused repeat biopsy, 5 received therapy for other concomitant disease and 5 underwent repeat biopsy after a 1-year interval, and cancer was found in 1. Initially prostate biopsy was performed because of increased prostate specific antigen (PSA), abnormal digital rectal examination and/or abnormal transrectal ultrasound. All 494 men with PSA greater than 4 ng./ml. underwent systematic sextant biopsy, as described by Hodge et al,22 including biopsies directed to the sites of abnormal digital rectal examination and transrectal ultrasound findings or a modification, including biopsies of the midline peripheral zone, bilateral transition zone and bilateral anterior horn area (high lateral aspect of peripheral zone). Of the 117 men with a PSA of 4 ng./ml. or less 18 underwent biopsy directed at the abnormal digital rectal examination and transrectal ultrasound sites, while the remaining 99 underwent systematic sextant biopsy. The technique of repeat biopsy in men with isolated high grade prostatic intraepithelial neoplasia was at the discretion of the attending urologist. Certain biopsy patterns were used for repeat biopsy, including the high grade neoplasia site only in 8 men, sextant in 12, sextant plus bilateral transition zone in 13 and 11 core multisite directed (sextant, bilateral transition zone, bilateral anterior horn of the peripheral zone and midline peripheral zone) in 12. Clinical information recorded included patient age, PSA as determined by the Tosoh method, digital rectal examination and transrectal ultrasound findings. Digital rectal examination was performed by staff urologists and results were obtained by chart review. Transrectal ultrasound results for these patients were retrospectively reviewed from video recordings by 1 urologist (K. K.). Clinical information was analyzed using chi-square analysis and the unpaired t test. Logistic regression analysis was done to define the association of a positive result on repeat biopsy with available variables, including patient age, PSA, number of cores in which high grade prostatic intraepithelial neoplasia was detected at initial biopsy, number of cores obtained at repeat biopsy,

strategy of repeat biopsy, digital rectal examination findings and transrectal ultrasound results. The initial high grade prostatic intraepithelial neoplasia site was available for all 10 patients who had prostate cancer on repeat biopsy. We compared that site on the initial biopsy with the cancer site on repeat biopsy. RESULTS

Of the 45 men who had high grade prostatic intraepithelial neoplasia on the initial biopsy 10 (22%) had prostate cancer, 13 (29%) again had high grade neoplasia without cancer and 22 (49%) had benign histology on repeat biopsy. Chi-square analysis showed no significant difference in abnormal digital rectal examination or transrectal ultrasound findings among these 3 groups. There was no significant difference in mean patient age, PSA, number of cores with high grade prostatic intraepithelial neoplasia on initial biopsy, number of cores obtained on repeat biopsy or the interval to repeat biopsy (table 1). Logistic regression analysis indicated no significant effect on the prostate cancer detection rate at repeat biopsy from abnormal digital rectal examination or transrectal ultrasound, age, PSA, number of cores with high grade neoplasia on initial biopsy, number of cores obtained at repeat biopsy or strategy of repeat biopsy. Cancer was detected at only the high grade prostatic intraepithelial neoplasia site by repeat biopsy in 2 of 8 cases (25%), sextant biopsy in 2 of 12 (17%), sextant plus transition zone biopsy in 5 of 13 (38%) and 11 core multisite biopsy in 1 of 12 (8%). Chi-square analysis revealed no significant difference in cancer on repeat biopsy, or abnormal digital rectal examination or transrectal ultrasound findings among these 4 groups. There were no significant differences among these 4 groups in mean age, PSA or number of cores showing high grade prostatic intraepithelial neoplasia on the initial biopsy (table 2). Prostate cancer was diagnosed at 15 sites in the 10 patients with cancer. Cancer was detected in 8 of 74 biopsy cores (11%) obtained at repeat biopsy of the sextant area

TABLE 1. Correlation of repeat biopsy result with patient characteristics Mean ⫾ SD Final Diagnosis

No. Pts.

Ca Prostatic intraepithelial neoplasia Benign tissue Overall

10 13 22 45

No. Pts. (%)

Age (yrs.)

PSA (ng./ml.)

Repeat Biopsy Cores

Initial Biopsy Cores Prostatic Intraepithelial Neoplasia Pos.

Mos. Between Biopsies

Palpable Abnormality

Abnormal Ultrasound

64.0 ⫾ 6.2 63.9 ⫾ 6.6 61.8 ⫾ 9.2 62.9 ⫾ 7.8

6.28 ⫾ 2.45 5.88 ⫾ 2.44 8.52 ⫾ 5.57 7.26 ⫾ 4.39

7.80 ⫾ 2.62 8.31 ⫾ 2.66 8.41 ⫾ 2.94 8.24 ⫾ 2.74

1.60 ⫾ 1.07 1.77 ⫾ 0.93 1.59 ⫾ 0.96 1.64 ⫾ 0.96

3.57 ⫾ 2.63 2.63 ⫾ 2.73 3.90 ⫾ 3.32 3.45 ⫾ 3.01

2 (20) 4 (31) 3 (14) 9 (20)

7 (70) 6 (46) 13 (59) 26 (58)

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STRATEGY FOR REPEAT BIOPSY FOR PROSTATIC INTRAEPITHELIAL NEOPLASIA TABLE 2. Correlation of repeat biopsy method with patient characteristics Mean ⫾ SD No. Pts.

Biopsy Method

Prostatic intraepithelial neoplasia site only Sextant Sextant ⫹ transition zone Sextant, transition zone, midline ⫹ anterior horn

Age (yrs.)

PSA (ng./ml.)

Initial Biopsy Cores Prostatic Intraepithelial Neoplasia Pos.

Ca

8

64.4 ⫾ 8.2

7.08 ⫾ 3.15

1.75 ⫾ 1.05

2 (25)

3 (38)

3 (38)

2 (25)

3 (38)

12 13 12

64.9 ⫾ 6.0 63.0 ⫾ 6.3 59.8 ⫾ 10.3

5.64 ⫾ 2.92 8.59 ⫾ 4.76 7.56 ⫾ 5.57

1.75 ⫾ 1.06 1.62 ⫾ 1.12 1.50 ⫾ 0.67

2 (17) 5 (38) 1 (8)

4 (33) 3 (23) 3 (25)

6 (50) 5 (38) 8 (67)

2 (17) 3 (23) 2 (17)

6 (50) 10 (77) 7 (58)

where prostatic intraepithelial neoplasia was originally discovered. When patients with prostatic intraepithelial neoplasia underwent sextant biopsy at repeat biopsy the cancer detection rate was 4% (6 cores positive of 155 overall). When repeat biopsy included the transition zone or other alternate sites, cancer was detected in 1 of 48 transition zone biopsy cores (2%) and none of 36 at the other sites (anterior horn and midline) (table 3). The site of high grade prostatic intraepithelial neoplasia on the original biopsy specimen and cancer diagnosed at repeat biopsy matched in 6 of 10 patients (60%). Two patients had 2 positive cores from matching locations. These 6 patients who had matching prostatic intraepithelial neoplasia and cancer sites were among the 9 in whom cancer was identified at a sextant location (fig. 2). Therefore, in 9 of the 10 patients (90%) cancer was diagnosed at a sextant location. In the remaining patient high grade prostatic intraepithelial neoplasia was observed in the left apical sextant site on initial biopsy and cancer was diagnosed in the left transition zone site on repeat biopsy. High grade neoplasia was bilateral in 1 man. In the remaining 9 patients the side of high grade neoplasia was the same as the side on which cancer was detected. DISCUSSION

High grade prostatic intraepithelial neoplasia is clinically important because it has a high predictive value as a marker for adenocarcinoma. Its identification in biopsy specimens warrants further search for concurrent invasive carcinoma. Davidson et al noted that prostatic intraepithelial neoplasia detected by needle biopsy indicated a greater relative risk of prostate cancer than serum PSA or patient age.17 Of the men with prostatic intraepithelial neoplasia 35% had adenocarcinoma on repeat biopsy compared with 13% of the control biopsies. Keetch et al compared the cancer detection rate in 37 men with and 427 without high grade neoplasia, and noted that the yield of cancer on repeat biopsy was significantly greater in those with high grade disease (51% versus 19%).16 They reported that high grade intraepithelial neoplasia significantly predicts a repeat biopsy positive for prostate cancer. In our study there was no significant difference among diagnostic categories at repeat biopsy for patient age, PSA, number of cores with high grade prostatic intraepithelial

TABLE 3. Detection rates of prostate cancer, high grade prostatic intraepithelial neoplasia and benign tissue at each biopsy site on repeat biopsy Biopsy Site Prostatic intraepithelial neoplasia Sextant Transition zone Midline or anterior horn

No. Pts. (%)

No. Biopsy Cores

No. Ca Cores (%)

No. Prostatic Intraepithelial Neoplasia Cores (%)

No. Benign Tissue Cores (%)

74

8 (11)

10 (14)

56 (75)

155 48 36

6 (4) 1 (2) 0

7 (5) 0 3 (8)

142 (91) 47 (98) 33 (92)

Prostatic Benign Palpable Intraepithelial Tissue Abnormality Neoplasia

Abnormal Ultrasound

neoplasia on initial biopsy, abnormal digital rectal examination or abnormal transrectal ultrasound. Logistic regression analysis showed no significant effect on prostate cancer detection rate at repeat biopsy from abnormal digital rectal examination, abnormal transrectal ultrasound, age, PSA, number of cores with high grade prostatic intraepithelial neoplasia on initial biopsy or the number of cores obtained at repeat biopsy. These findings indicate that there is no reliable index for predicting who will have a positive repeat biopsy when isolated high grade neoplasia is detected. Our results demonstrate a lower yield of cancer at repeat biopsy (22%) than previously reported.14 –17 This difference is not likely to be associated with the number of cores obtained on repeat biopsy. An average of 8.2 cores were obtained on repeat biopsy and 37 of 45 men (82%) underwent at least sextant biopsy. The difference seems to correlate with patient characteristics and the initial cancer detection rate in men with biopsy proved prostatic intraepithelial neoplasia. The rate of palpable abnormality was 25% and mean PSA plus or minus standard deviation was relatively low (7.3 ⫾ 4.4 ng./ml.). In most men at least 6 sites were biopsied in a systematic manner at the initial biopsy. In our series 78 of 141 patients (55%) with high grade prostatic intraepithelial neoplasia were simultaneously diagnosed with cancer at the initial biopsy. Potentially the low cancer detection rate may have been due to the absence of a uniform repeat biopsy strategy in our series. Brawer et al reported on 21 patients who underwent repeat biopsy after initial biopsy of a palpable abnormality revealed prostatic intraepithelial neoplasia.14 Cancer was detected in 8 of 12 men (67%) who underwent random repeat biopsy. Repeat biopsy limited to the initial prostatic intraepithelial neoplasia site was positive for carcinoma in 4 of 9 cases (44%). Cancer was detected in all 10 patients with high grade neoplasia. Brawer et al concluded that patients with an abnormal digital rectal examination and a diagnosis of high grade prostatic intraepithelial neoplasia should undergo repeat biopsy of the neoplasia site only. Weinstein and Epstein reported that the sites of high grade intraepithelial neoplasia and carcinoma were more often ipsilateral in patients undergoing repeat biopsy but often contralateral in those with neoplasia and simultaneously diagnosed cancer.15 They concluded that the focus of prostate cancer may not be associated with the prostatic intraepithelial neoplasia site in the prostate needle biopsy specimen and high grade neoplasia simply results in a greater chance of prostate carcinoma detection at subsequent biopsies. Langer et al noted a limited association of the location of neoplasia detected by the initial prostate needle biopsy with the subsequent location of prostate cancer on repeat biopsy.20 They concluded that the strategy for repeat biopsy should include random biopsy, sites of transrectal ultrasound abnormalities and previous sites of prostatic intraepithelial neoplasia. Shepherd et al concluded that the optimal repeat biopsy technique should include contralateral systematic biopsy of the prostate based on the result that repeat biopsy only on the side with high grade prostatic

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STRATEGY FOR REPEAT BIOPSY FOR PROSTATIC INTRAEPITHELIAL NEOPLASIA

FIG. 2. Distributions of high grade prostatic intraepithelial neoplasia at initial biopsy and cancer at repeat biopsy in all 10 patients who had cancer on repeat biopsy. Patients 1 and 9 underwent repeat biopsy exclusively at neoplasia sites. Gray areas represent biopsy positive for high grade prostatic intraepithelial neoplasia or prostate cancer. R, right side. L, left side. AH, anterior horn. TZ, transition zone. ML, midline.

intraepithelial neoplasia would miss cancer in 35% of cases21 (table 4).14, 15, 20, 21 Our results are consistent with the fact that high grade prostatic intraepithelial neoplasia and prostate cancer frequently develop at different locations. Repeat biopsy only of the neoplasia site would have missed cancer in 4 of our 10 patients (40%). Based on the result that cancer was detected exclusively on the side with high grade prostatic intraepithelial neoplasia, we advocate that at a minimum repeat biopsy should include the ipsilateral sextant sites. In our study we did not detect concurrent cancer at the alternative sites except in 1 positive biopsy specimen from the transition zone. Since the number of patients who underwent the 11 core strategy at repeat biopsy was too small, we did not determine the significance of biopsy at the alternative sites. CONCLUSIONS

We noted a limited predictability of PSA, palpable abnormality and abnormal transrectal ultrasound for detecting prostate cancer at repeat biopsy in patients with isolated high grade prostatic intraepithelial neoplasia. To maximize the detection of prostate cancer in men in whom previous biopsy revealed neoplasia we recommend that repeat biopsy should not only include the sextant area where neoplasia was originally identified, but also the ipsilateral and contralateral sextant sites. To our knowledge the number of cores obtained at each site as well as the significance of repeat

TABLE 4. Comparison of reported data of prostatic intraepithelial neoplasia sites on initial biopsy and subsequent cancer on repeat biopsy No. Pts./Total No. (%) References Brawer et al14 Weinstein and Epstein15 Langer et al20 Shepherd et al21 Present study Totals

Ipsilat. Side

Contralat. Side Only

Same Site

21/21 (100) 9/10 (90) 9/15 (60) 20/31 (65) 10/10 (100) 69/87 (79)

0/21 (0) 1/10 (10) 6/15 (40) 11/31 (35) 0/10 (0) 18/87 (21)

4/21 (19) — 6/15 (40) 6/31 (19) 6/10 (60) 22/87 (25)

biopsy at the transition zone or other alternative sites remains to be determined.

REFERENCES

1. McNeal, J. E.: Morphogenesis of prostatic carcinoma. Cancer, 18: 1659, 1965 2. McNeal, J. E. and Bostwick, D. G.: Intraductal dysplasia: a premalignant lesion of the prostate. Hum Pathol, 17: 64, 1986 3. Drago, J. R., Mostofi, F. K. and Lee, F.: Introductory remarks and workshop summary. Urology, suppl., 34: 2, 1989 4. Bostwick, D. G. and Brawer, M. K.: Prostatic intra-epithelial neoplasia and early invasion in prostate cancer. Cancer, 59: 788, 1987 5. Troncoso, P., Babaian, R. J., Ro, J. Y. et al: Prostatic intraepithelial neoplasia and invasive prostatic adenocarcinoma in cystoprostatectomy specimens. Urology, suppl., 34: 52, 1989 6. Kovi, J., Mostofi, F. K., Heshmat, M. Y. et al: Large acinar atypical hyperplasia and carcinoma of the prostate. Cancer, 61: 555, 1988 7. Greene, D. R., Wheeler, T. M., Egawa, S. et al: A comparison of the morphological features of cancer arising in the transition zone and in the peripheral zone of the prostate. J Urol, 146: 1069, 1991 8. Oyasu, R., Bahnson, R. R., Nowels, K. et al: Cytological atypia in the prostate gland: frequency, distribution and possible relevance to carcinoma. J Urol, 135: 959, 1986 9. Sakr, W. A., Haas, G. P., Cassin, B. F. et al: The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol, 150: 379, 1993 10. Bostwick, D. G.: Prostatic intraepithelial neoplasia (PIN). Urology, suppl., 34: 16, 1989 11. Brawer, M. K.: Prostatic intraepithelial neoplasia: a premalignant lesion. Hum Pathol, 23: 242, 1992 12. McNeal, J. E., Villers, A., Redwine, E. A. et al: Microcarcinoma in the prostate: its association with duct-acinar dysplasia. Hum Pathol, 22: 644, 1991 13. Bostwick, D. G.: Prostatic intraepithelial neoplasia (PIN): current concepts. J Cell Biochem, suppl., 16H: 10, 1992 14. Brawer, M. K., Bigler, S. A., Sohlberg, O. E. et al: Significance of prostatic intraepithelial neoplasia on prostate needle biopsy. Urology, 38: 103, 1991 15. Weinstein, M. H. and Epstein, J. I.: Significance of high-grade prostatic intraepithelial neoplasia on needle biopsy. Hum Pathol, 24: 624, 1993

STRATEGY FOR REPEAT BIOPSY FOR PROSTATIC INTRAEPITHELIAL NEOPLASIA 16. Keetch, D. W., Humphrey, P., Stahl, D. et al: Morphometric analysis and clinical followup of isolated prostatic intraepithelial neoplasia in needle biopsy of the prostate. J Urol, 154: 347, 1995 17. Davidson, D., Bostwick, D. G., Qian, J. et al: Prostatic intraepithelial neoplasia is a risk factor for adenocarcinoma: predictive accuracy in needle biopsies. J Urol, 154: 1295, 1995 18. Wills, M. L., Hamper, U. M., Partin, A. W. et al: Incidence of high-grade prostatic intraepithelial neoplasia in sextant needle biopsy specimens. Urology, 49: 367, 1997 19. Bostwick, D. G., Qian, J. and Frankel, K.: The incidence of

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high-grade prostatic intraepithelial neoplasia in needle biopsies. J Urol, 154: 1791, 1995 20. Langer, J. E., Rovner, E. S., Coleman, B. G. et al: Strategy for repeat biopsy of patients with prostatic intraepithelial neoplasia detected by prostate needle biopsy. J Urol, 155: 228, 1996 21. Shepherd, D., Keetch, D. W., Humphrey, P. A. et al: Repeat biopsy strategy in men with isolated prostatic intraepithelial neoplasia on prostatic needle biopsy. J Urol, part 1, 156: 460, 1996 22. Hodge, K. K., McNeal, J. E., Terris, M. K. et al: Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol, 142: 71, 1989