THE JOURNAL OF UROLOGY Copyright 0 1998 by AMERICAN UROUXICAL ASSOCIATION, INC

0022-5347/98/1606-2418$03.00/0

Vol. 160, 2418-2424, December 1998 Printed in U S A .

ANATOMIC RADICAL PROSTATECTOMY: EVOLUTION OF THE SURGICAL TECHNIQUE

PATRICK CRAIG WALSH
From the James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland

ABSTRACT

Purpose: Although radical prostatectomy provided excellent cancer control, it never gained widespread popularity because of the major side effects of incontinence, impotence and excessive blood loss. The reason for this morbidity was a deficit in the understanding of the periprostatic anatomy. The evolution of the surgical technique for anatomic radical prostatectomy is described. Materials and Methods: Beginning in 1974 anatomic observations in the operating room were used to clarify the anatomy of the dorsal vein complex, pelvic plexus, striated urethral sphincter and lateral pelvic fascia. These intraoperative observations were amplified using dissections in stillborns a nd step section whole mount adult cadaveric studies. Results: Armed with improved information about the periprostatic anatomy, a n anatomical approach to radical prostatectomy was developed. This surgical technique has improved surgical exposure, lowered blood loss, reduced urinary incontinence, made it possible to preserve potency and provided excellent cancer control. Conclusions: With the reduction in morbidity, radical prostatectomy today is a n ideal treatment for the cure of prostate cancer in a patient who is curable and who is going to live long enough to need to be cured. Also the widespread application of radical prostatectomy has provided tissue and valuable pathological information that has galvanized research in the field.
KEY WORDS: prostatectomy, anatomy, morbidity

During the last 100 years there have been 3 chairmen of urology at Hopkins. The first, Dr. Hugh Hampton Young, is considered by many to be the founder of modern urology. Doctor Young, who served in this capacity for almost 50 years, created a n institute that provided major discoveries in clinical urology and trained many of its leaders. In 1946 William Wallace Scott, armed with a n M.D. and Ph.D. from the University of Chicago and trained in urology by the legendary Dr. Charles Huggins, succeeded Doctor Young. Doctor Scott brought basic research and scientific investigation to the institute, and trained numerous graduates who went on to spread this philosophy to great institutions throughout the world. This had a tremendous impact on our field and for this contribution Doctor Scott should be recognized as a founder of scientific urology. This tribute to Doctor Scott is heartfelt. I had the privilege of training under Dr. Willard Goodwin, a former resident of Doctor Scotts, who started the program a t UCLA. During my year in the laboratory I was smitten by research, and recognized the opportunities and needs for discovery in urology. I t changed my life. Parenthetically, Doctor Goodwin also trained briefly under Doctor Young before World War 11. Doctor Goodwin always believed that he was the link between the 3 generations of chairmen at Hopkins since he trained under Doctors Young and Scott, and he trained me. In 1974 I had the privilege to succeed Doctor Scott and become the third Director of the Brady Urological Institute. Recognizing the heritage of excellence that I was following, I was inspired to identify and solve a major problem. This article describes the use of a n anatomical approach to improve the outcome of radical prostatectomy.

radical prostatectomy provided excellent cancer control, it never gained widespread popularity because of major side effects. Virtually all men who underwent radical prostatectomy were impotent, many had significant urinary incontinence and, when performed via the retropubic approach, excessive bleeding was common. With the introduction of external beam radiotherapy for the treatment of prostate cancer, it was possible to avoid many side effects. Thus, by 1970 radical prostatectomy was rarely performed. I embarked on a series of anatomical studies in a n attempt to understand the source of morbidity from radical prostatectomy with the hope that it might be avoided. Soon it became clear that impotence was universal because the location of the autonomic innervation to the pelvic organs and the corpora cavernosa was not known, incontinence was common because the anatomical understanding of the sphincteric complex was incorrect, and excessive bleeding occurred because the anatomy of the dorsal venous complex and Santorinis plexus was not charted. This deficit in the understanding of the periprostatic anatomy can be traced to the use of adult cadavers, which were not ideal for these investigations. The agents used for tissue fixation dissolve adipose tissue, thus obscuring normal tissue planes, and the pelvic viscera compress the pelvic organs into a thick pancake of tissue making anatomical dissection difficult. As outlined in this article, these problems were overcome by intraoperative anatomical dissections and the use of infant cadavers for anatomical studies. This experience is described with the hope that others may be inspired to improve other surgical procedures through anatomical discovery. I t is humbling to realize that even today basic anatomy may not be known or underRadical perineal prostatectomy was first developed at The stood. Johns Hopkins Hospital in 1904 by Young, and in 1947 the retropubic approach was introduced by Millin.2 Although
ANATOMY OF THE DORSAL VENOUS COMPLEX

Supported by The Fund for Research and Progress in Urology, Johns Hopkins University.

During radical retropubic prostatectomy excessive bleeding was common because the large venous complex that

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travels over the anterior surface of the urethra and prostate must be divided. In the early 1970s the anatomy of this complex was unknown because this venous complex is covered with a thick sheath of dense fascia which obscured the anatomical location of the venous tributaries. For this reason excessive bleeding was assumed to be a necessary complication of this radical operation. Anatomical studies revealed that the deep dorsal vein leaves the penis under Bucks fascia between the corpora cavernosa and penetrates the urogenital diaphragm, dividing into the superficial branch, and the right and left lateral venous plexuses.3 The superficial branch lies outside the pelvic fascia but the common trunk and lateral venous plexuses are covered and concealed by this fascia (fig. 1). The lateral venous plexuses travel posterolateral and communicate freely with the pudendal, obturator and vesicle plexuses. These anatomical observations made it possible to devise 3 major alterations in the surgical technique that avoided excessive bleeding: 1) the endopelvic fascia was opened adjacent t o the pelvic sidewall to avoid injury to the lateral venous plexus; 2) the puboprostatic ligaments were divided with care not to injure the superficial branch of the dorsal vein or enter the anterior prostatic fascia covering Santorinis plexus and the dorsal venous complex, and 3) the common trunk of the dorsal vein over the urethra was isolated with a right angle clamp, transected and ligated, thus avoiding most of the major bleeding associated with this procedure. The development of this technique made the operation safer and provided a relatively bloodless field that made it possible t o view the periprostatic anatomy in a way not possible previously. Shortly after this technique was developed, a patient reported that he was fully potent following surgery. It has been 20 years since the operation and this patient is still potent. Based on that experience I questioned why any man was impotent following radical prostatectomy. At that time it was believed that impotence following radical prostatectomy was neurogenic in origin and caused by injury to the cavernous nerves that traveled through the prostate. For this reason it was assumed that impotence was a necessary complication of radical prostatectomy. From this 1 experience, however, I knew that was not true.

cavernosa and sensory supply to the skin. Because the pudendal nerve is not close to the operative field and because sensation is intact in impotent men following surgery, injury to the pudendal nerve could not be implicated. Rather, it was assumed that injury to the pelvic plexus or its branches must be responsible. The pelvic plexus provides autonomic innervation to all of the pelvic organs but until the time of this work the exact location of the pelvic plexus and the branches to the corpora cavemosa in man was not known. In 1981 while visiting The Netherlands, I had the opportunity to perform fetal dissections with Dr. Pieter Donker, Emeritus Professor of Urology at Leiden University. Doctor Donker was using the fetus for these studies because the fibrofatty tissue was less abundant, the pelvic structures were not disturbed by the pressure of the abdominal viscera and the nerves were correspondingly larger in relation to adjacent structures. At the time I met Doctor Donker he was performing dissections of the pelvic plexus to characterize the autonomic innervation to the bladder. After informing him that the exact location of the branches of the pelvic plexus to the corpora cavernosa was also not known, we traced these pathways in male stillborns. The pelvic plexus, which provides autonomic innervation to the pelvic organs, rests on the lateral surface of the rectum. The branches that innervate the corpora cavernosa were seen clearly outside the capsule of the prostate and its surrounding tissue as they travel between the prostate and rectum before penetrating the urogenital diaphragm and innervating the corpora cavernosa (fig. 2).4 This study, which demonstrated clearly that the prostate could be removed completely with preservation of these nerves, provided the schematic anatomy of the pelvic plexus and cavernous nerves. Next, landmarks in the adult needed to be developed. In the operating room it became clear that the capsular arteries and veins of the prostate were in the same region as the cavernous branches. This finding suggested that these vessels may serve as the scaffolding for these microscopic nerves and that the neurovascular bundle could be used as a visual landmark for their identification. To confirm this impression an adult cadaver was perfused completely with Bouins solution shortly after death. Lepor and I removed the pelvic organs en bloc, 10,000 whole mount step sections were AUTONOMIC INNERVATION OF T H E CORPORA CAVERNOSA prepared and a 3-dimensional reconstruction was perThe autonomic innervation t o the corpora cavernosa is formed.5 This 3-dimensional reconstruction demonstrated derived from the pudendal nerve and the pelvic plexus. The clearly that the cavernous nerves did travel in association pudendal nerve provides autonomic supply to the corpora with the capsular arteries and veins of the prostate outside the capsule and fascia of the prostate. Armed with these findings, Schlegel characterized the full neuroanatomy of the male pelvis using dissections performed in fresh cadavers.6 This study demonstrated that the pelvic plexus is located 5 to 11 cm. from the anal verge on the lateral surface of the rectum with its mid point at the tip of the seminal vesicle. After providing branches to the bladder, lower ureter and prostate, the branches from the pelvic plexus travel in association with the capsular arteries and veins of the prostate dorsolateral to the prostate where the nerves exit to innervate the corpora cavernosa.
PELVIC FASCIA

FIG. 1. Santorinis venous plexus. A, view of trifurcation of dorsal vein of penis with patient su ine Relationship of venous branches to Puboprostatic ligaments is fepicted. B , lateral view shows anatomical relationship at trifurcation. In this schematic illustration lateral pelvic fascia has been removed. In reality these structures are never msualized in this skeletonized manner because they are encased by pelvic fascia. Reprinted with permi~sion.~

The prostate is covered with Denonvilliers fascia, which covers the posterior surface of the prostate, and the lateral pelvic fascia, which covers the pelvic musculature. Both of these fascia1 layers are distinct and separate, and they are intimately associated with the dorsal vein complex, the neurovascular bundle and the striated sphincter (fig. 3). These intimate relationships must be well understood for the surgeon to remove localized prostate cancer completely. However, at the time of these discoveries the periprostatic configuration of the lateral pelvic fascia was not understood.

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RADICAL PROSTATECTOMY

FIG. 3. Cross section through adult prostate demonstrates anatomical relationships of lateral pelvic fascia, Denonvilliers' fascia and neurovascular bundle. Note how neurovascular bundle is located between 2 layers of lateral pelvic fascia, levator fascia and prostatic fascia.

bundle is located between the layers of the levator fascia and prostatic fascia. When performing nerve sparing prostatectomy the plane between these 2 layers of fascia must be developed leaving all layers of the prostatic fascia on the prostate.
ANATOMY OF THE STRIATED SPHINCTER CONTINENCE MECHANISM

FIG.2. A, dissection of left pelvic plexus in male newborn. Bladder has been retracted to right side. Peritoneum, pelvic vessels, pelvic fascia and pubic symphysis have been removed. B , branches from pelvic plexus to corpora cavernosa (Br. to corp. cavernous) travel dorsolateral to prostate before exiting pelvis to innervate corpora cavernosa (corpus cavern). Reprinted with permi~sion.~

Anteriorly and anterolaterally the prostate is covered with the prostatic fascia. The major tributaries of Santorini's plexus travel within this fascia. Laterally the prostatic fascia fuses with the levator fascia, which covers the pelvic musculature, to form the lateral pelvic f a ~ c i aIn a n effort to avoid .~ injury to the dorsal vein of the penis and Santorini's plexus during radical perineal prostatectomy, the lateral and anterior pelvic fasciae are reflected off of the prostate, which accounts for the reduced blood loss associated with radical perineal prostatectomy. When performing radical retropubic prostatectomy the prostate is approached from outside these fascia1 investments and must be divided. The neurovascular

For years it was widely believed that the urinary continence mechanism in man was composed of a group of horizontally oriented pelvic floor muscles contained in the levator ani complex. However, in 1980 Oelrich demonstrated that the sphincteric complex responsible for passive urinary control was a vertically oriented tubular sheath." In utero this sphincter extends without interruption from the bladder to the perineal membrane. As the prostate develops from the urethra it invades the sphincter muscle, thinning the overlying parts and causing a reduction or atrophy of some of the muscle. In the adult at the apex of the prostate the fibers are circular and form a tubular striated sphincter surrounding the membranous urethra (fig. 4). Thus, as Myers et a1 have shown, the prostate does not rest atop a flat transverse urogenital diaphragm like an apple on a shelf with no striated muscle proximal to the apex.3 Rather, the external striated sphincter is more tubular and has broad attachments over the fascia of the prostate near the apex. This anatomy had important implications in transection of the dorsal vein complex, which is intimately associated with the striated sphincter, in the apical dissection and in reconstruction of the urethra.1 Also it can now be appreciated why incontinence rates were so high in the past. Before the anatomical approach was developed, the surgeon cut the dorsal vein complex next to the pelvic floor. The dorsal vein retracted out of sight and could not be controlled, and the anterior portion of the striated sphincter was excised. With improved approaches to the control of hemostasis, more of the anterior striated sphincter was preserved.
SURGICAL TECHNIQUE

Armed with this information, a n anatomical approach to radical prostatectomy has been developed. With improved

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FIG. 4. A, cross section of urethra just distal to apex of prostate demonstratesinner circular layer of smooth muscle, outer striated urethral sphincter and perineal body. B , anatomical relationship of prostate to pelvic fascia (window of fascia removed to illustrate prostatic capsule), pelvic plexus and neurovascular bundle (NVB).Note attachment of striated urethral sphincter to apex of prostate.

understanding of the periprostatic anatomy it is now possible to remove the prostate completely with less blood loss and better intraoperative visualization. Discovery of the location of the cavernous branches of the pelvic plexus and their relationship to the neurovascular bundle made it possible to preserve potency when possible and to excise lesions widely when necessary. Enhanced understanding of the sphincteric complex improved urinary continence.10 Recently, the surgical technique has been published in detail.7 However, there is 1 recent refinement that I would like to share. As stated previously, because the dorsal vein complex and striated sphincter are intimately associated, care in control of bleeding from the dorsal vein can improve urinary continence. Toward this end, I have limited the manipulation of this complex by dividing the puboprostatic ligaments down to their junction with the dorsal vein complex (and not extending the dissection into the pubourethral component) and have stopped passing a clamp around the venous complex (fig. 5, A). The goal is to divide the complex with minimal blood loss while avoiding excision or damage to the striated sphincter. I do not like bunching sutures because I have found that they pull too much of the striated sphincter into the specimen that is removed. Instead, after placing the superficial %zero monocryl suture in the dorsal vein complex, recently I have reversed the needle in the needle holder and placed the suture through the perichondrium of the pubic symphysis (fig. 5, B). If the complex is wide 2 sutures can be used in the right and left halves of the complex. Once this horizontal mattress suture is tied, it accomplishes 3 important goals: 1)control of much of the venous bleeding without a bunching effect, 2) recapitulation of the puboprostatic ligaments to provide anterior support of the striated sphincter and 3) fixation of the distal dorsal vein complex. Using downward pressure on the anterior surface of the prostate with a sponge stick, initially the fascia a t the junction of the apex of the prostate and dorsal vein complex is divided with a No. 15 blade on a long handle (fig. 5, B ) . Next, using the Metzenbaum scissors, the complex is divided down to the urethra. Because the distal complex is fmed in position, by using downward pressure on the sponge stick the exact plane on the anterior surface of the prostate can be visualized,

avoiding inadvertent entry into the anterior prostate and ensuring minimal excision of the striated sphincter musculature. There is 1 important caveat when performing this maneuver. When the striated sphincter is divided closer to the apex of the prostate, there is a risk that the neurovascular bundle may be damaged. To avoid this possibility, the sphincter should only be divided down to the lateral edge of the urethra and not any further posteriorly. The rest of the procedure is performed as described previously.7
CANCER CONTROL

Recognizing that radical prostatectomy had been performed for 80 years before the development of this technique and that virtually all men were impotent following surgery, it was reasonable to question whether preservation of sexual function would compromise cancer control. However, from the inception of this technique the surgical pathologists at The Johns Hopkins have scrutinized the surgical technique and helped formulate the sound anatomicaVpathologica1 principles upon which it is based. The neurovascular bundle lies outside the capsule and fascia of the prostate and, thus, there is no compromise to cancer control if the tumor is organ confined. Previously, the neurovascular bundle was never widely excised because of its firm attachment to the rectum and poor visualization from bleeding. However, now it was possible through direct intraoperative assessment to preserve the neurovascular bundle when possible or excise it when necessary to obtain wider margins of resection than were possible in the past. This is the reason why I do not call this operation nerve sparing radical prostatectomy. Nerve sparing is only 1 technique. Wide excision is the other technique that was introduced with this approach. From 1982 through 1995, 1,623 men with clinically localized (T1 to T2) adenocarcinoma of the prostate underwent anatomic radical prostatectomy at The Johns Hopkins Hospital. These patients have been followed for a mean of 5 ? 3 years (range 1to 13) and 128 have been followed for 10 years or longer. The major end point for cancer control is the presence of an undetectable prostate specific antigen (PSA) (less than 0.2 ng./ml.). These results were recently summa-

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RADICAL PROSTATECTOMY

FIG. 5. A, puboprostatic ligaments are divided superficially without disturbing pubourethral component. B and C, 3-zero monocryl suture on 5/8 circle taper needle is placed superficially through dorsal vein complex. D and E,needle is turned around in needle holder and passed through perichondrium of pubic symphysis. F, suture is tied. If complex is wide 2 sutures are used. G , using number 15 blade, fascia is incised superficially. Metzenbaum scissors is used to deepen incision down to smooth muscle of urethra.
rized.13 The overall actuarial progression-free rate at 10 years w a s 68%. Of the men 18%h a d an isolated elevation of PSA, 8%' h a d local recurrence a n d 9% h a d distant metastases. The actuarial likelihood of postoperative recurrence increased with pathological stage b u t not with preservation of potency (fig. 6).When t h e results were analyzed based on t h e s t a t u s of postoperative sexual function, m e n who were potent had t h e same outcome as m e n who were impotent. These findings provide strong evidence that preservation of sexual function did not compromise cancer control. T h e overall actuarial cause specific survival at 5 a n d 10 years was 99 a n d 93%, respectively.

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1.o .75 .50 .25

-

t Potent Impotent

oc

CP+, +SM

.25

CP+, -SM

+SV

Impotent

Years following surgery

FIG. 6. Actuarial probability of undetectable level of PSA in serum of men who were potent or impotent following radical prostatectomy based on final pathological stage of radical prostatectomy specimen. OC, organ confined. CP+ - SM, capsular penetration, negative surgical margins. CP+ + S M , capsular penetration, positive surgical margins. +SV, positive seminal vesicles.

IMPACT ON RESEARCH

The impact of radical prostatectomy on research in prostate cancer cannot be overestimated. In the fields of breast and colon cancer tissue has always been available for clinical pathological correlations and for biochemical and molecular studies. However, before the popularity of radical prostatectomy these studies were not possible because most men underwent radiation therapy and only small tissue samples obtained by needle biopsy were available for study. Today tissue harvested from surgical specimens has galvanized research. From a clinical standpoint, in the past it took many years to identify prognostic factors because of the protracted natural history of the disease. Today with the availability of information from pathological evaluation of surgical specimens, these findings provide a surrogate for long-term followup and make it possible to evaluate prognostic factors more rapidly. As a result, the staging and predictability of curability today are more accurate.14 In addition, molecular genetic analysis of this tissue has provided insight into factors responsible for the initiation and progression of disease, such as the identification of the glutathione-s transferase mutation, androgen receptor mutations,16 loss of hetero~ygosity~ the search for the heand reditary prostate cancer gene.18 In the years to come, when it is possible to prevent prostate cancer or cure it reliably without surgery, this may be the most important legacy of this surgical technique. An anatomical approach to radical prostatectomy has improved surgical exposure, lowered blood loss, reduced urinary incontinence, made i t possible to preServe potency, provided excellent cancer control and galvanized research in prostate cancer. I wish to thank my co-investigators: Dr. Pieter Donker, whose valuable studies of the neuroanatomy of the pelvis using t h e fetus, spearheaded this work; Drs. Herb Lepor and Peter Schlegel, former residents, who helped perform the anatomical studies: Dr. Jonathan Epstein. Professor of Surgical Pathology, for his careful monitoring of cancer control

and scholarly contributions; Drs. Alan Partin, Charles Pound, Ronald Morton, Mitchell Steiner, David Quinlan, Franklin Lowe and Joseph Oesterling, who as residents, provided thoughtful and timely analysis of outcome; Mr. Leon Schlossberg, medical illustrator, who brought this anatomy to life in surgical drawings, thereby training urologists around the world in this surgical technique, and most of all, to my patients who have been my partners in the process of discovery.
REFERENCES

1. Young, H. H.: The early diagnosis and radical cure of carcinoma of the prostate: being a study of 40 cases and presentations of a radical operation which was carried out in 4 cases. Johns Hopkins Hosp. Bull., 1 6 315, 1905. 2. Millin, T.: Retropubic Urinary Surgery. London: Livingstone, 1947. 3. Reiner, W. B. and Walsh, P. C.: An anatomical approach to the surgical management of the dorsal vein and Santorinis plexus during radical retropubic surgery. J. Urol., 121: 198, 1979. 4. Walsh, P. C. and Donker, P. J.: Impotence following radical prostatectomy: insight into etiology and prevention. J. Urol., 128 492, 1982. 5. Leoor. H . , Greaerman. M., Crosbv, R., Mostofi, F. K. and Walsh. P.C.: Precise localization of che autonomic nerves from the pelvic plexus to the corpora cavernosa: a detailed anatomical study of the adult male pelvis. J. Urol., 133 207, 1985. 6. Schlegel, P. N. and Walsh, P. C.: Neuroanatomical approach to radical cystoprostatectomy with preservation of sexual function. J. Urol., 138 1402, 1987. 7. Walsh, P. C.: Anatomic radical retropubic prostatectomy. In: Campbells Urology, 7th ed., P. C. Walsh, A. B. Retik, E. D. Vaughan, Jr. and A. J. Wein. Philadelphia: W.B. Saunders, Co., vol. 3, chapt. 86, pp. 2565-2588, 1998. 8. Oelrich. T. M.: The urethral suhincter muscle in the male. h e r . J. Anat., 158: 229, 1980. 9. Mvers. R. P.. Goellner, J . R. and Cahill, D. R.: Prostate shape, kxternal striated urethral sphincter and radical prostateitomy: the apical dissection. J. Urol., 138 543, 1987. 10. Walsh. P. C.. 0uinlan. D. M.. Morton. R. A. and Steiner. M. S.: Radical retropubic prostatectomy-improved anastomosis and

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RADICAL PROSTATECTOMY human prostatic carcinogenesis. Iroc. Natl. Acad. Sci. USA,
91: 11733,1994. 16. Newmark, J. R., Hardy, D. O., Tonb, D. C., Carter, B. S., Epstein,

urinary continence. Urol. Clin. N. Amer., 17: 679,1990. 11. Walsh, P. C., Lepor, H. and Eggleston, J. C.: Radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. Prostate, 4 473, 1983. 12. Walsh, P. C.: Radical prostatectomy, preservation of sexual function, cancer control. The controversy. Urol. Clin. N. Amer., 1 4 663, 1987. 13. Pound, C. R.,Partin, A. W., Epstein, J. I. and Walsh, P. C.: Prostate-specific antigen after anatomic radical retropubic prostatectomy. Urol. Clin. N. Amer., 2 4 395, 1997. 14. Partin, A.W., Yoo, J., Carter, H. B., Pearson, J. D., Chan, D. W., Epstein, J. I. and Walsh, P. C . : The use of prostate specific antigen, clinical stage and Gleason score to predict Datholoaical stage in men with localized prostate cancer. J. Urol., 156: 110,1993. 15. Lee, W.-H., Morton, R. A., Epstein, J. I., Brooks, J. D., Campbell, P. A., Bova. G. S., Hsier, W.-S., Isaacs, W. B., Isaacs, W. B. and Nelson, W. G.: Cytidine methylation of regulatory sequences near the rr-class glutathione S-transferase gene accompanies

J. I., Isaacs, W. B., Brown, T. R. and Barrack, E. R.: Androgen receptor gene mutations in human prostate cancer. Proc. Natl. Acad. Sci. USA, 89 6319,1992. 17. Carter, B. S., Ewing, C. M., Ward, W. S., Treiger, B. F., Aalders, T. W., Schalken, J. A., Epstein, J. I. and Isaacs, W. B.: Allelic loss of chromosomes 1 q and 1Oq in human prostate cancer. 6 Proc. Natl. Acad. Sci. USA, 87:8751,1990. 18. Smith, J. R., Freije, D., Carpten, J. D., Gronberg, H., Xu, J., Isaacs, S. D., Brownstein, M. J., Bova, G. S., Guo, H., Bujnovszky, P., Nusskern, D. R., Damber, J.-E., Bergh, A,, Emanuelsson, M., Kallioniemi, 0. P., Walker-Daniels, J., Bailey-Wilson, J. E., Beaty, T. H., Meyers, D. A,, Walsh, P. C., Collins, F. S., Trent, J. M. and Isaacs, W. B.: Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science, 2 7 4 1371,1996.