0022-5347/89/1426-1510$02.00/0 THE JOURNAL OF UROLOGY Copyright © 1989 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Vol. 142, December Printed in U. S. A.
PROSTATIC BE CONFUSED
MICHAEL K. BRAWER,* MARGARET A. RENNELS, RAYMOND B. NAGLE, MANFRED H. SOlDERER AND FRED LEE From the Departments of Surgery (Urology) and Pathology, University of Arizona and Tucson Veterans Administration Medical Center, Tucson, Arizona, and Departments of Pathology and Radiology, St. Joseph Mercy Medical Center, Ann Arbor, Michigan
Most prostatic adenocarcinomas reveal a hypoechoic peripheral zone lesion on transrectal ultrasonography. Numerous benign processes can have similar transrectal ultrasound findings. We report 8 cases of transrectal ultrasound-guided prostatic biopsies of peripheral zone hypoechoic lesions that demonstrated prostatic intraepithelial neoplasia, a presumed premalignant lesion. Immunohistochemistry using an antibody directed against cytokeratins 5 and 14 was performed to exclude carcinoma. Of the men 2 had invasive carcinoma on repeat biopsy and 1 had carcinoma diagnosed on subsequent transurethral resection. Patients with prostatic intraepithelial neoplasia on biopsy of hypoechoic peripheral zone lesions merit careful monitoring. (J. Ural., 142: 1510-1512, 1989) High resolution transrectal ultrasonography extends our ability to evaluate the internal anatomy of the prostate gland. The majority of adenocarcinomas arise in the peripheral zone of the prostate 1 and are hypoechoic in echogenicity compared to the normal isoechoic peripheral zone. 2-14 Lesions other than adenocarcinoma may give rise . to hypoechoic patterns (false positive), including benign prostatic hyperplasia, prostatitis, glandular atrophy, normal muscular structures and prostatic intraepithelial neoplasia (intraductal dysplasia/ 2 fig. 1). The definitive diagnosis of a hypoechoic lesion is dependent on biopsy. Prostatic intraepithelial neoplasia, also referred to as intraductal dysplasia15 and atypical hyperplasia,16-19 is a lesion in which there is a dysplastic proliferation of the luminal layer of prostatic acini and ductal epithelium (fig. 2). The histological criteria for diagnosis, as well as a grading system have been reported previously.15,20 The highest grade prostatic intraepithelial neoplasms have cytological features indistinguishable from invasive carcinoma. 15 ,20 Prostatic intraepithelial neoplasia has been shown to be associated spatially with invasive carcinoma and foci of invasive carcinoma have been observed to arise directly from prostatic intraepithelial neoplasia. Prostatic intraepithelial neoplasia occurs more commonly in prostates harboring adenocarcinomas than in those without cancer.15 Thus, prostatic intraepithelial neoplasia fulfills many of the criteria for a premalignant lesion. We used immunohistochemistry with a monoclonal antibody directed against cytokeratins to distinguish prostatic intraepithelial neoplasia from invasive carcinoma. This antibody stains the basal cells of normal and hyperplastic prostate tissue,15,21,22 and is nonreactive with prostatic adenocarcinoma (fig. 3) . We describe the transrectal ultrasound appearance of prostatic intraepithelial neoplasia confirmed with immunohistochemistry. MATERIALS AND METHODS
All surgical pathology reports of transrectal ultrasoundguided prostate biopsies obtained between November 1985 and
May 1987 at our medical center were reviewed. Those that described prostatic intraepithelial neoplasia or its synonyms were included in the investigation. Two men were evaluated in a prostate cancer early detection program, while the remainder were referred because of a palpable prostatic abnormality. All lesions initially were suspicious for carcinoma on transrectal ultrasound. Patients underwent ultrasound-guided biopsy by either the transperineal or transrectal routes. Images were obtained with a Bruel and Kjaer 1846 scanner with 7.0 MHz. transducers capable of axial and sagittal scans, an Aloka Model 256 scanner with a 5.0 MHz. transducer for sagittal scanning and a General Electric RT3600 scanner with a 6.2 MHz. biplanar transducer. The ultrasonic criterion for cancer was a hypoechoic lesion arising mainly in the peripheral zone of the prostate. Transperineal biopsies were performed under ultrasound needle guidance with either the 14 gauge Tru-Cutt or the 19 gauge Sure-Cutt needle. Transrectal biopsies were done with the Bard automatic Biopty gun system with an 18 gauge "trucut" type needle. § Needle placement within the lesion was confirmed ultrasonographically. Only peripheral zone hypoechoic lesions were sampled. All images were recorded on multiformat film and 3/i-inch videotape. The tissue was fixed in 10% neutral buffered formalin and embedded in paraffin. Sections (5 J.L.) were cut and stained with hematoxylin and eosin. Immunohistochemistry was performed at room temperature using 2 anticytokeratin antibodies: KAI (developed in our laboratory) and 903.11 Step-sections (5 J.L.) were made from the paraffin embedded biopsy material. These sections were deparaffinized with xylene and rehydrated in decreasing concentrations of alcohol. Then, 0.3 % hydrogen peroxide in methanol was used to block endogenous peroxidase activity. Keratin immunoreactivity was unmasked with 0.1 % pronase as we have reported previously.2o,21 The primary anticytokeratin antibodies were applied overnight in a 1 to 2,000 dilution. Bridging rabbit antimouse IgG was applied for 20 minutes. The incubation then was done with peroxidase-antiperoxidase complex. 3-3' -Diaminobenzidine was used as a substrate for the peroxidase enzyme and was incubated with hydrogen peroxide for 5 minutes. Sections were counterstained
Accepted for publication June 7, 1989. Supported in part by a Veterans Administration Research Advisory Group Award. * Requests for reprints: Department of Urology (RL-10), University of Washington, Seattle, Washington 98195. 1510
t Travenol Laboratories, Inc., Deerfield, Illinois. :j: Meadox Surgimed Company, Inc., Oakland, New Jersey.
§ Bard Urological Division, Covington, Georgia. II Enzobiochemicals, New York, New York.
FIG. 1. Transrectal prostatic ultrasound, transverse image of mid gland. Left peripheral zone hypoechoic lesion biopsy demonstrated grade 2 prostatic intraepithelial neoplasia (Bruel & Kjaer 1846 scanner, 7.0 MHz. axial transducer).
lesion ~lnn'~1"'''~ntis ties can result in similar ul1~rasonogr~lpJhlC Prostatic intraepithelial ne()plaSl.a lesion. We have nr..r>n."""f">'¥"IrY' 1"t'"\r>,,'aOC:<1""HYI"'t7
was demonstrates stratification increased 2 there is increased stratification and occasional lesions are similar to 2 large nuirregular chromatin condensation and cleoli. The cytological features of grade 3 are indistinguishable from invasive carcinoma. Biopsies fulfilling these architectural and cytological characteristics were scrutinized closely using the basal cell specific anticytokeratin immunohistochemistry to exclude early invasive adenocarcinoma. RESULTS
There were 14 biopsies initially interpreted as revealing prostatic intraepithelial neoplasia or its synonym at our department of pathology. Patient age ranged from 53 to 80 years
3. Grade 2 prC)stcltlC labeling of basal nohistochemistry,
Pt.-Age Diameter of Hypoechoic Lesion (cm.)
1-71 2-75 3-73
4-61 5-66 6-70 7-70 8-65
0.7 0.9 0.9 0.9 0.4 1.0 1.1 1.2
ne()plasl,a. Note antibody immu-
Grade of Prostatic . . . Intraepithelial CarcInoma DI~gnosIs Neoplasm 20 (mos. after bIOPSY)
1 1 1 1 2 2
* Carcinoma diagnosed on repeat ultrasound-guided biopsy. t Carcinoma diagnosed at transurethral prostatectomy.
No No No No No Yes (2)* Yes (6)t Yes
BRAWER AND ASSOCIATES
monoclonal antibodies to distinguish this entity from invasive carcinoma. 2o-22 Antibodies 903 and KA1 stain only the basal cell layer of benign prostatic tissue. No invasive carcinoma has been shown to be labeled with this antibody.20-22 Antibody KA1 has been shown by dot blot analysis to react with cytokeratins 5 and 14. 22 Prostatic intraepithelial neoplasia maintains a basal cell layer (although there may be disruption)20 and this stains with these antibodies, allowing ready distinction from carcinoma. In our investigation prostatic intraepithelial neoplasia was found in the ultrasound-guided biopsies of 8 hypoechoic peripheral zone lesions. No obvious differentiation between the ultrasonographic appearance of these lesions and invasive adenocarcinoma was apparent. The subsequent detection of carcinoma in 3 of these cases is particularly noteworthy. In the patient who underwent repeat biopsy 1 month after the initial procedure the cancer clearly was missed initially. We reported previously the spatial relationship between prostatic intraepithelial neoplasia and carcinoma, and, thus, this clinical situation is explained easily.20 However, it is intriguing to speculate whether the patient whose cancer was diagnosed 2 years after the initial biopsy revealed prostatic intraepithelial neoplasia had a carcinoma that was missed or whether there was progression of the neoplasm. The patient whose carcinoma was diagnosed after transurethral resection is of interest. Since he did not undergo radical prostatectomy we cannot determine the location of the neoplasm. Perhaps the tumor was limited to the transitional zone artd the peripheral zone hypoechoic lesion biopsied represented only prostatic intraepithelial neoplasia. However, missing the carcinoma again on biopsy is a possibility. Irrespective of the pathogenic relationship, our 3 patients with prostatic adenocarcinoma after prior biopsy revealed prostatic intraepithelial neoplasia clearly illustrate the need for close monitoring of men with hypoechoic peripheral zone lesions whose biopsies demonstrate prostatic intraepithelial neoplasia. Currently, we are recommending repeat transrectal ultrasoundguided biopsy in such patients 6 months after the initial procedure. REFERENCES 1. McNeal, J. E.: Origin and development of carcinoma in the prostate. Cancer, 23: 24, 1969. 2. Rifkin, M. D., Kurtz, A. B., Choi, H. Y. and Goldberg, B. B.: Endoscopic ultrasonic evaluation of the prostate using a transrectal probe: prospective evaluation and acoustic characterization. Radiology, 149: 265, 1983. 3. Peeling, W. B. and Griffiths, G. J.: Imaging of the prostate by ultrasound. J. Urol., 132: 217, 1984. 4. Spirnak, J. P. and Resnick, M. I.: Transrectal ultrasonography. Urology, 23: 461, 1984. 5. Resnick, M. I., Willard, J. W. and Boyce, W. H.: Ultrasonic evaluation of the prostatic nodule. J. Urol., 120: 86, 1978. 6. Fritzsche, P. J., Axford, P. D., Ching, V. C., Rosenquist, R. W. and Moore, R. J.: Correlation of transrectal sonographic findings in patients with suspected and unsuspected prostatic disease. J. Urol., 130: 272, 1983. 7. Okafor, P. I. S., Wild, S. R., Beynon, L. L. and Chisholm, G. D.: Progress in transrectal ultrasonography for prostatic disease. Brit. J. Urol., 55: 721,1983. 8. Peeling, W. B., Griffiths, G. J., Evans, K. T. and Roberts, E. E.: Diagnosis and staging of prostatic cancer by transrectal ultrasonography. A preliminary study. Brit. J. Urol., 51: 565, 1979. 9. Pontes, J. E., Ohe, H., Watanabe, H. and Murphy, G. P.: Transrectal ultrasonography of the prostate. Cancer, 53: 1369, 1984. 10. Watanabe, H., Igari, D., Tanahashi, Y., Harada, K. and Saitoh, M.: Transrectal ultrasonotomography of the prostate. J. Urol., 114: 734, 1975. 11. Lee, F., Gray, J. M., McLeary, R. D., Meadows, T. R., Kumasaka, G. H., Borlaza, G. S., Straub, W. H., Lee, F., Jr., Solomon, M.
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H., McHugh, T. A. and Wolf, R. M.: Transrectal ultrasound in the diagnosis of prostate cancer: location, echogenicity, histopathology, and staging. Prostate, 7: 117, 1985. Lee, F., Littrup, P. J., McLeary, R. D., Kumusaka, G. H., Borlaza, G. S., McHugh, T. A., Soiderer, M. H. and Roi, L. D.: Needle aspiration and core biopsy of prostate cancer: comparative evaluation with biplanar transrectal US guidance. Radiology, 163: 515,1987. Egender, G., Furtschegger, A., Schachtner, W., Pirker, E. and Bartsch, G.: Transrectal ultrasonography in diagnosis and staging of prostatic cancer. World J. Urol., 4: 163,1986. Cooner, W. H., Mosley, B. R., Rutherford, C. L., Jr., Beard, J. H., Pond, H. S., Bass, R. B., Jr. and Terry, W. J.: Clinical application of transrectal ultrasonography and prostate specific antigen in the search for prostate cancer. J. Urol., 139: 758, 1988. McNeal, J. E. and Bostwick, D. G.: Intraductal dysplasia: a premalignant lesion of the prostate. Human Path., 17: 64, 1986. Helpap, B.: The biological significance of atypical hyperplasia of the prostate. Virch. Arch. Path. Anat., 387: 307, 1980. Kastendieck, H.: Correlations between atypical primary hyperplasia and carcinoma of the prostate. A histological study of 180 total prostatectomies. Path. Res. Pract., 169: 366, 1980. Oyasu, R., Bahnson, R. R., Nowels, K. and Garnett, J. E.: Cytological atypia in the prostate gland: frequency, distribution and possible relevance to carcinoma. J. Urol., 135: 959, 1986. Kovi, J., Mostofi, F. K., Heshmat, M. Y. and Enterline, J. P.: Large acinar atypical hyperplasia and carcinoma of the prostate. Cancer' 61: 555, 1988. Bostwick, D. G. and Brawer, M. K.: Prostatic intra-epithelial neoplasia and early invasion in prostate cancer. Cancer, 59: 788, 1987. Brawer, M. K., Peehl, D. M., Stamey, T. A. and Bostwick, D. G.: Keratin immunoreactivity in the benign and neoplastic human prostate. Cancer Res., 455: 3663, 1985. Nagle, R. B., Ahmann, F. R., McDaniel, K. M., Paquin, M. L., Clark, V. A. and Celniker, A.: Cytokeratin characterization of human prostatic carcinoma and its derived cell lines. Cancer Res., 47: 281, 1987. EDITORIAL COMMENT
The participants in the recent consensus conference held on March 6, 1989 in Bethesda, Maryland agreed on prostatic intraepithelial neoplasia as the most appropriate terminology to describe noncancerous, atypical lesions of prostatic epithelium. This is the first study to appear in the Journal using this terminology since the consensus conference. The key feature that distinguishes the prostatic intraepithelial neoplasm from prostatic carcinoma is the preservation of the basal cell layer located at the periphery of the prostatic acinus resting on intact basement membrane. The prostatic intraepithelial neoplasia terminology emphasizes the luminal location of the atypical cells being found either in the duct or acinus portion of the gland. The term neoplasia is used in the broadest sense indicating proliferating cells without distinguishing the benign or malignant character. From a semantics perspective, the terminology works well as long as the precise definition of neoplasia is observed. In this context and in contradistinction to common use neoplasia does not equal carcinoma. The authors note that prostatic intraepithelial neoplasia may be found in biopsies from hypoechoic prostate lesions seen on transrectal ultrasound. Whether the ultrasound aided in detecting these lesions or whether the prostatic intraepithelial neoplasia tissue actually accounts for the hypoechoic appearance is not clear from this study. The data suggest that patients with higher grade prostatic intraepithelial neoplasia are at higher risk than those with lower grade for prostatic carcinoma, which is consistent with our findings in a series of 296 prostatic biopsies. They rightfully note the need for close monitoring of patients with high grade lesions and imply, which needs emphasis, that these patients should not be treated for prostatic carcinoma without a clearcut diagnosis of carcinoma. John Garnett Department of Urology Northwestern University Medical School Chicago, Illinois