Advanced Therapy of Prostate Disease

Advanced Therapy of Prostate Disease

Advanced Therapy of Prostate Disease Martin I. Resnick, MD Lester Persky Professor and Chair Department of Urology Case Western Reserve University University Hospitals of Cleveland Cleveland, Ohio

Ian M. Thompson, MD Chief, Department of Surgery University of Texas Health Sciences Center Uniformed Services University of Health Sciences Director of Urologic Oncology Brooke Army Medical Center San Antonio, Texas

2000

B.C. Decker Inc. Hamilton • London

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Notice: The authors and publisher have made every effort to ensure that the patient care recommended herein, including choice of drugs and drug dosages, is in accord with the accepted standard and practice at the time of publication. However, since research and regulation constantly change clinical standards, the reader is urged to check the product information sheet included in the package of each drug, which includes recommended doses, warnings, and contraindications. This is particularly important with new or infrequently used drugs.

CONTRIBUTORS

Paul Abrams, MD, FRCS Bristol Urological Institute Southmead Hospital Bristol, United Kingdom Peter C. Albertsen, MD, MS Division of Urology University of Connecticut School of Medicine University of Connecticut Health Center Farmington, Connecticut George A. Alexander, MD Office of Special Populations Research National Cancer Institute National Institutes of Health Bethesda, Maryland

John J. Bauer, MD Uniformed Services University of the Health Sciences Urology Telemedicine and Advanced Technology Walter Reed Army Medical Center Washington, DC

Peter R. Carroll, MD Department of Urology University of California San Francisco University of California San Francisco/Mt. Zion Cancer Center San Francisco, California

Ronald M. Benoit, MD Allegheny University of the Health Sciences Allegheny General Hospital Pittsburgh, Pennsylvania

Culley C. Carson, MD Department of Surgery University of North Carolina Chapel Hill, North Carolina

Gerald L. Andriole, MD Division of Urology Washington University School of Medicine

Mitchell C. Benson, MD Department of Urology Columbia University, College of Physicians and Surgeons Squier Urologic Clinic New York Presbyterian Hospital— Columbia Presbyterian Campus New York, New York

John G. Anema, MD Department of Urology Brooke Army Medical Center Fort Sam Houston, Texas

Michael L. Blute, MD Department of Urology Mayo Clinic Rochester, Minnesota

Christopher J. Austin, MD Department of Urology University of Iowa Iowa City, Iowa

Otis W. Brawley, MD Office of Special Populations Research National Cancer Institute National Institutes of Health National Institutes of Health Clinical Center and National Naval Medical Center Bethesda, Maryland

Chris H. Bangma, MD, PhD Academic Hospital Rotterdam Erasmus University Rotterdam Rotterdam, The Netherlands David M. Barrett, MD Mayo Medical School Department of Urology Mayo Clinic Rochester, Minnesota

Reginald C. Bruskewitz, MD Department of Surgery Division of Urology University of Wisconsin Hospital and Clinics Madison, Wisconsin

H. Ballentine Carter, MD Department of Urology The Johns Hopkins University School of Medicine The Johns Hopkins Hospital Baltimore, Maryland R. Duane Cespedes, MD University of Texas Health Sciences Center Female Urology and Urodynamics Wilford Hall Medical Center San Antonio, Texas Jeffrey K. Cohen, MD Allegheny University of the Health Sciences Allegheny General Hospital Pittsburgh, Pennsylvania Charles A. Coltman, MD The Cancer Therapy and Research Foundation of South Texas San Antonio, Texas E. David Crawford, MD University of Colorado Health Sciences Center University Hospital Denver, Colorado

vi / Contributors

Daniel J. Culkin, MD Department of Urology University of Oklahoma Health Science Center Oklahoma City, Oklahoma Rodney Davis, MD Section of Urologic Oncology Tulane University New Orleans, Louisiana Nancy A. Dawson, MD University of Chicago Cancer Research Center Chicago, Illinois Todd H. Doyle, MD Radiation Oncology Hospital of the University of Pennsylvania University of Pennsylvania Health System Philadelphia, Pennsylvania George W. Drach, MD Division of Urology University of Pennsylvania Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Mario A. Eisenberger, MD Professor of Oncology and Urology The Johns Hopkins University Baltimore, Maryland Daniel S. Elliott, MD Mayo Graduate School of Medicine Department of Urology Mayo Clinic Rochester, Minnesota Rod J. Ellis, MD Department of Radiation Oncology Case Western Reserve University School of Medicine Cleveland, Ohio L. Andrew Eskew, MD Piedmont Urological Association High Point Regional Hospital High Point, North Carolina

Scott A. Fengler, MD, FACS, FASCRS Department of Surgery, Uniformed Services University of the Health Sciences St. Francis Hospital Tulsa, Oklahoma

S. Larry Goldenberg, MD, FRCSC Department of Surgery University of British Columbia Prostate Centre at Vancouver General Hospital Vancouver, British Columbia

Robert C. Flanigan, MD Department of Urology Loyola University Medical Center Stritch School of Medicine Maywood, Illinois

Gary D. Grossfeld, MD Department of Urology University of California San Francisco University of California San Francisco/Mt. Zion Cancer Center San Francisco, California

John P. Foley, MD Division of Urology University of Texas Health Sciences Center at San Antonio Brooke Army Medical Center Fort Sam Houston, Texas Jack Geller, MD University of California San Diego Clinical Medicine Anticancer Inc. San Diego, California Valal George, MD, PhD Wayne State University Harper & Childrens Hospital of Detroit Detroit, Michigan Glenn S. Gerber, MD Department of Surgery University of Chicago Pritzker School of Medicine Chicago, Illinois Edward L. Gheiler, MD Wayne State University Harper Hospital Detroit, Michigan Cynthia J. Girman, Dr.PH Clinical Epidemiology Mayo Clinic Department of Epidemiology Merck Research Laboratories Blue Bell, Pennsylvania Frank E. Glover Jr, MD Memorial Hospital Bainbridge, Georgia

Gerald E. Hanks, MD Radiation Oncology Temple University School of Medicine Department of Radiation Oncology Fox Chase Cancer Center Philadelphia, Pennsylvania Javier Hernandez, MD Department of Surgery University of Texas Health Science Center San Antonio, Texas Celestia Higano, MD Division of Medical Oncology Department of Medicine University of Washington Seattle, Washington Eric M. Horwitz, MD Radiation Oncology Fox Chase Cancer Center Philadelphia, Pennsylvania Maha Hussain, MD, FACP Wayne State University Barbara Ann Karmanos Cancer Institute Harper Hospital Detroit, Michigan Christopher W. Johnson, MD Department of Urology Columbia University, College of Physicians and Surgeons Squier Urologic Clinic New York Presbyterian Hospital— Columbia Presbyterian Campus New York, New York

Contributors / vii

John N. Kabalin, MD, FACS Section of Urologic Surgery University of Nebraska College of Medicine Regional West Medical Center Scottsbluff, Nebraska Fernando J. Kim, MD Department of Urology Loyola University Medical Center Stritch School of Medicine Maywood, Illinois Hines Veterans Administration Hospital Hines, Illinois Eric A. Klein, MD Section of Urologic Oncology Department of Urology Cleveland Clinic Foundation Cleveland, Ohio Barnett S. Kramer, MD, MPH Uniformed Services University of the Health Sciences Division of Cancer Prevention National Cancer Institute Bethesda, Maryland John N. Krieger, MD Department of Urology University of Washington VA Puget Sound Health Care System Seattle, Washington Rasmus H. Krogh, MD Department of Surgery Division of Urology University of Wisconsin Hospital and Clinics Madison, Wisconsin Menachem Laufer, MD The Johns Hopkins University Baltimore, Maryland Tel Aviv Medical Center Tel Aviv, Israel Gary E. Leach, MD Department of Urology University of Southern California Tower Urology Institute for Continence Cedars-Sinai Medical Center Los Angeles, California

Wendy W. Leng, MD Department of Urology University of California San Francisco San Francisco, California

Brian J. Miles, MD Scott Department of Urology Baylor College of Medicine Houston, Texas

Mark R. Licht, MD Department of Urology Cleveland Clinic Florida Fort Lauderdale, Florida

David C. Miller, BS Division of Urology Washington University School of Medicine

Scott A. MacDiarmid, MD, FRCSC Department of Urology University of Arkansas for Medical Sciences Little Rock, Arkansas

Gary J. Miller, MD, PhD Professor of Pathology and Urology University of Colorado Health Sciences Center Denver, Colorado

Gregory T. MacLennan, MD Department of Pathology Case Western Reserve University University Hospitals of Cleveland Cleveland, Ohio

Ralph J. Miller Jr, MD Allegheny University of the Health Sciences Allegheny General Hospital Pittsburgh, Pennsylvania

Susan R. Marengo, PhD Urology Research Laboratory Case Western Reserve University Cleveland, Ohio

Allen F. Morey, MD, FACS Brooke Army Medical Center Fort Sam Houston, Texas

David L. McCullough, MD Department of Urology Wake Forest University School of Medicine North Carolina Baptist Hospital Wake Forest University Baptist Medical Center Winston-Salem, North Carolina Edward J. McGuire, MD Department of Urology University of Texas Houston Health Science Center Houston, Texas Winston K. Mebust, MD Section of Urology, Department of Surgery University of Kansas Medical Center Kansas City, Kansas Lori Merlotti Allegheny University of the Health Sciences Allegheny General Hospital Pittsburgh, Pennsylvania

Judd W. Moul, MD Department of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland Edward J. Mueller, MD University of Texas Health Science Center St. Luke’s Baptist Hospital San Antonio, Texas Perinchery Narayan, MD Division of Urology University of Florida Gainesville, Florida Durwood E. Neal Jr, MD Division of Urology Southern Illinois University School of Medicine Springfield, Illinois

viii / Contributors

Robert J. Nejat, MD Department of Urology Columbia University, College of Physicians and Surgeons Squier Urologic Clinic New York Presbyterian Hospital— Columbia Presbyterian Campus New York, New York Ajay Nehra, MD Department of Urology Mayo Clinic and Mayo Foundation Rochester, Minnesota Peter Nelson, MD Division of Medical Oncology Department of Medicine University of Washington Seattle, Washington Brian E. Nicholson, MD Department of Urology Loyola University Medical Center Stritch School of Medicine Maywood, Illinois Mark J. Noble, MD Department of Urology Cleveland Clinic Foundation Cleveland, Ohio Keith J. O’Reilly, MD Section of Urology Madigan Army Medical Center Tacoma, Washington David K. Ornstein, MD Urologic Oncology Branch National Cancer Institute Manoj Patel, MD Division of Urology University of Florida Gainesville, Florida Rashmi I. Patel, MD Case Western Reserve University University Hospitals of Cleveland Cleveland, Ohio David F. Paulson, MD Duke University Duke Medical Center Durham, North Carolina

Michael Perrotti, MD Robert Wood Johnson Medical School Cancer Institute of New Jersey Robert Wood Johnson University Hospital New Brunswick, New Jersey Paul K. Pietrow, MD Vanderbilt University Medical Center Nashville, Tennessee J. Edson Pontes, MD Wayne State University Harper Hospital Wertz Cancer Institute Detroit, Michigan Isaac J. Powell, MD Department of Urology Wayne State University Karmanos Cancer Institute Detroit, Michigan Theresa P. Pretlow, MD Departments of Pathology, Oncology, and Environmental Health Sciences Case Western Reserve University Medical Center Cleveland, Ohio Thomas G. Pretlow, MD Departments of Pathology, Urology, Oncology, and Environmental Health Sciences Case Western Reserve University Medical Center Cleveland, Ohio Farhang Rabbani, MD, FRCSC Urology Service Department of Surgery Memorial Sloan-Kettering Cancer Center New York, New York Martin I. Resnick, MD Department of Urology Case Western Reserve University University Hospitals of Cleveland Cleveland, Ohio

Jerome P. Richie, MD, FACS Harvard Medical School Harvard Program in Urology Brigham and Women’s Hospital Boston, Massachusetts Mack Roach III, MD Radiation Oncology, Medical Oncology and Urology University of California San Francisco San Francisco, California Andrew C. Roberts, BS, MD Department of Urology The University of Oklahoma Health Science Center Oklahoma City, Oklahoma Steven G. Roberts, MD Department of Urology Mayo Clinic Rochester, Minnesota Thomas A. Rozanski, MD Uniformed Services University of the Health Sciences Brooke Army Medical Center San Antonio, Texas Oliver Sartor, MD Louisiana State University Medical School Stanley S. Scott Cancer Center New Orleans, Louisiana Anthony J. Schaeffer, MD Department of Urology Northwestern University Medical School Northwestern Memorial Hospital Chicago, Illinois Richard A. Schoor, MD Department of Urology Northwestern University Medical School Northwestern Memorial Hospital Chicago, Illinois Fritz H. Schröder, MD, PhD Academic Hospital Rotterdam Erasmus University Rotterdam Rotterdam, The Netherlands

Contributors / ix

Claude C. Schulman, MD, PhD Department of Urology University Clinics of Brussels Brussels, Belgium Thomas M. Seay, MD, LTCOL, USAF, MC, FS Department of Urology Wilford Hall Medical Center Lackland AFB, Texas San Antonio Uniformed Services Health Education Consortium San Antonio, Texas Allen D. Seftel, MD Department of Urology Case Western Reserve University University Hospitals of Cleveland and Cleveland VA Medical Center Cleveland, Ohio Moshe Shalev, MD Scott Department of Urology Baylor College of Medicine Houston, Texas Joseph A. Smith Jr., MD Vanderbilt University Medical Center Nashville, Tennessee Graeme S. Steele, MBBCh, FCS Harvard Medical School Division of Urology Brigham and Women’s Hospital Boston, Massachusetts Marcos V. Tefilli, MD Wayne State University Karmanos Cancer Institute Detroit, Michigan Ashutosh Tewari, MD Division of Urology University of Florida Gainesville, Florida Alun W. Thomas, BSc, MBBS, FRCS Bristol Urological Institute Southmead Hospital Bristol, United Kingdom

Ian M. Thompson, MD Department of Surgery University of Texas Health Sciences Center Uniformed Services University of the Health Sciences Brooke Army Medical Center San Antonio, Texas J. Brantley Thrasher, MD, FACS University of Kansas Medical Center Kansas City, Kansas Eric Vigneault, MD Department of Radiation Oncology Laval University CHUQ, Pavillon L’Hôtel-Dieu de Québec Quebec City, Quebec Nicholas J. Vogelzang, MD University of Chicago Cancer Research Center Chicago, Illinois Joanne Waldstreicher, MD Clinical Research, Endocrinology, and Metabolism Merck Research Laboratories Rahway, New Jersey Patrick C. Walsh, MD Department of Urology The Johns Hopkins University School of Medicine The Johns Hopkins Hospital Baltimore, Maryland William Bedford Waters, MD Loyola University Medical Center Stritch School of Medicine Maywood, Illinois Hines Veterans Administration Hospital Hines, Illinois

John D. Wegryn, MD Department of Urology Case Western Reserve University University Hospitals of Cleveland and Cleveland VA Medical Center Cleveland, Ohio Richard Whittington, MD Department of Radiation Oncology Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Richard D. Williams, MD Department of Urology The University of Iowa Iowa City, Iowa Timothy J. Wilt, MD, MPH Minneapolis VA Center for Chronic Diseases Outcomes Research Minneapolis VA Medical Center Minneapolis, Minnesota David P. Wood Jr, MD Department of Urology Wayne State University Department of Urologic Oncology Karmanos Cancer Institute Detroit, Michigan Ali M. Ziada, MD University of Colorado Health Sciences Center University Hospital Denver, Colorado Horst Zincke, MD, PhD Professor of Urology Mayo Clinic Rochester, Minnesota Alexandre R. Zlotta, MD Department of Urology University Clinics of Brussels Brussels, Belgium

PREFACE

It is well known that prostate cancer is the leading malignancy in aging men in the United States, and equally well known that it is the second leading cause of cancer-related death of American men. Benign prostatic hyperplasia is a common problem affecting the aging male; more than a third will experience symptoms requiring some form of therapy. Finally, prostatitis, another common disorder, occurs in younger men but is also seen in all ages, and both diagnosis and treatment can be problematic. Over the past decades, there have been many monographs, publications, and research efforts expended on these disorders and a marked increase has occurred in the 1990s. Why then is another book needed and what is its purpose? Because the diseases of the prostate are multi-faceted and because there have been significant changes over the past few years, an update by experts addressing the more controversial issues should be of value. For instance, there have been marked changes in the concepts regarding treatment modalities for patients with localized and regionally advanced carcinoma of the prostate. Additionally, the use of PSA and the wide introduction of screening and early detection though common remains controversial. We have also witnessed many changes in the management of benign prostatic hyperplasia in that past options related primarily to transurethral resection, while today many new less invasive techniques plus pharmacologic therapy are readily available. The field of prostatitis is also changing markedly with not only a redefinition of the disease itself, but reassessment of the treatment options available, as well. Our hope is that Advanced Therapy of Prostate Disease will address many of these issues. Experts in the field were chosen and in all instances the chapters are concise, to the point, and should provide the reader with practical, up-to-date information. We expect this text will be outdated in several years; hopefully, if it is well received and the many changes that we have seen in the past continue in the future, further editions will continue to update physicians in the latest evaluation-treatment trends of these disorders. MIR IMT

Dedicated to investigators throughout the world who are working tirelessly to prevent and cure prostate disease, and to our patients with prostate disease who have participated in studies to help develop those strategies for prevention and a cure. To our families, Laura, Ian III, and Donna, Vicki, Andy, Jeff, Missy, and Katelin, who have tolerated our absences and late nights at work with our patients. Martin I. Resnick, MD Ian M. Thompson, MD

CONTENTS

1

Epidemiology of Prostate Cancer: an Overview Peter C. Albertsen, MD, MS

1

2

Epidemiology of Prostate Cancer in African Americans Isaac J. Powell, MD

6

3

Epidemiology of Prostate Cancer in Africa George A. Alexander, MD, and Otis W. Brawley, MD

14

4

Prostate Cancer among the Chinese: Pathologic, Epidemiologic, and Nutritional Considerations Gary J. Miller, MD, PhD

18

5

Epidemiology of Prostate Cancer in Jamaicans Frank E. Glover Jr, MD, Patrick C. Walsh, MD, and H. Ballentine Carter, MD

28

6

Epidemiology of Prostate Cancer in Hispanic Americans Javier Hernandez, MD, and Ian M. Thompson, MD

31

7

Assessment of Risk of Prostate Cancer: Algorithms for Diagnosis, Staging, and Prognosis John J. Bauer, MD, and Judd W. Moul, MD

34

8

Molecular Factors in the Assessment of Prostate Cancer Risk Oliver Sartor, MD

44

9

Screening for Prostate Cancer: an Overview David C. Miller, BS, David K. Ornstein, MD, and Gerald L. Andriole, MD

50

10

The Optimal Diagnostic Tool: Assessment of Diagnostic Modalities to Detect Early Prostate Cancer Chris H. Bangma, MD, PhD, and Fritz H. Schröder, MD, PhD

60

11

Screening for Prostate Cancer: the Case for Screening Robert J. Nejat, MD, Christopher W. Johnson, MD, and Mitchell C. Benson, MD

73

12

Screening for Prostate Cancer: the Argument for Caution Barnett S. Kramer, MD, MPH, and Otis W. Brawley, MD

80

xiv / Contents

13

Natural History of Localized Adenocarcinoma of the Prostate John P. Foley, MD, and Ian M. Thompson, MD

86

14

Prostate Physiology and Regulation Susan R. Marengo, PhD

92

15

Pathobiology of Prostate Diseases: an Update Gregory T. MacLennan, MD

118

16

Models of Prostate Cancer Thomas G. Pretlow, MD, and Theresa P. Pretlow, MD

138

17

Diagnosis of Prostate Cancer L. Andrew Eskew, MD, and David L. McCullough, MD

154

18

Staging of Prostate Cancer Rashmi I. Patel, MD, and Martin I. Resnick, MD

159

19

Radical Prostatectomy: Patient Preparation Paul K. Pietrow, MD, and Joseph A. Smith Jr, MD

177

20

Stage T1a Prostate Cancer: the Case for Treatment Gary D. Grossfeld, MD, and Peter R. Carroll, MD

184

21

T1b-T2NxM0: the Case for Observation Fernando J. Kim, MD, and William Bedford Waters, MD

195

22

Radical Retropubic Prostatectomy for Clinical Stage T1b-T2 Prostate Cancer Moshe Shalev, MD, and Brian J. Miles, MD

202

23

Radical Perineal Prostatectomy David F. Paulson, MD

210

24

Continence-Enhancing Modifications for Radical Prostatectomy Mark R. Licht, MD, and Eric A. Klein, MD

219

25

T1-T2NxM0: the Case for External Radiotherapy Eric Vigneault, MD, and Mack Roach III, MD

229

26

Permanent Low-Dose-Rate Interstitial Brachytherapy Rod J. Ellis, MD

241

27

T1b-T2NxM0: a Case for Hormonal Therapy? Farhang Rabbani, MD, FRCSC, and S. Larry Goldenberg, MD, FRCSC

253

Contents / xv

28

Role of Cryosurgery in the Treatment of Prostate Cancer Ronald M. Benoit, MD, Jeffrey K. Cohen, MD, Ralph J. Miller Jr, MD, and Lori Merlotti

258

29

Should T1c Disease Be Treated Differently from T2 Disease? Keith J. O’Reilly, MD, and J. Brantley Thrasher, MD, FACS

267

30

T3-T4NxM0: the Case for Observation Thomas A. Rozanski, MD, and Rodney Davis, MD

275

31

T3-T4NxM0: the Case for Radiotherapy Eric M. Horwitz, MD, and Gerald E. Hanks, MD

284

32

Clinical-Pathologic T3NxM0 Prostate Cancer: the Case for Surgery Marcos V. Tefilli, MD, and David P. Wood Jr, MD

291

33

Node-Positive Prostate Cancer: the Case for Observation Daniel J. Culkin, MD, and Andrew C. Roberts, BS, MD

300

34

TxN+M0: the Case for Radiotherapy Richard Whittington, MD, and Todd H. Doyle, MD

304

35

TxN+M0 Disease: the Case for Early Hormonal Therapy and Surgery Thomas M. Seay, MD, LTCOL, USAF, MC, FS, and Horst Zincke, MD, PhD

311

36

TxNxM1: the Case for Monotherapy Menachem Laufer, MD, and Mario A. Eisenberger, MD

317

37

TxNxM1: the Case for Total Androgen Deprivation Ali M. Ziada, MD, and E. David Crawford, MD

324

38

Is Early Hormonal Therapy Preferable? Valal George, MD, PhD, and Maha Hussain, MD, FACP

332

39

Staging Failures of Initial Therapy J. Christopher Austin, MD, and Richard D. Williams, MD

340

40

Management of Prostate-Specific Antigen Failure after Definitive Therapy for Clinically Localized Prostate Cancer Marcos V. Tefilli, MD, Edward L. Gheiler, MD, and J. Edson Pontes, MD

353

41

Management of Local Failure following Treatment of Localized Prostate Cancer Graeme S. Steele, MBBCh, FCS, and Jerome P. Richie, MD, FACS

365

42

Secondary Hormonal Therapy Nancy A. Dawson, MD, and Nicholas J. Vogelzang, MD

378

xvi / Contents

43

Management of Hormone-Refractory Prostate Cancer: Chemotherapy and Immunotherapy Peter Nelson, MD, and Celestia Higano, MD

385

44

The Artificial Genitourinary Sphincter Daniel S. Elliott, MD, and David M. Barrett, MD

405

45

Collagen Therapy for Postprostatectomy Incontinence Wendy W. Leng, MD, R. Duane Cespedes, MD, and Edward J. McGuire, MD

410

46

Management of Complications of Therapy: Erectile Dysfunction Allen D. Seftel, MD, John D. Wegryn, MD, and Ajay Nehra, MD

416

47

Anorectal Complications of Prostate Surgery Scott A. Fengler, MD, FACS, FASCRS

423

48

Chemoprevention of Cancer of the Prostate Ian M. Thompson, MD, and Charles A. Coltman, MD

428

49

Prostate Cancer: Management of Complications of the Disease and Its Therapy Michael Perrotti, MD

446

50

Randomized Clinical Trials in Prostate Cancer Timothy J. Wilt, MD, MPH

452

51

Hormonal and Cellular Aspects of Benign Prostatic Hyperplasia R. Duane Cespedes, MD

463

52

Need for Urodynamics and Other Testing Gary E. Leach, MD, and Scott A. MacDiarmid, MD, FRCSC

471

53

Minimal Essential Diagnostic Testing Rasmus H. Krogh, MD, and Reginald C. Bruskewitz, MD

481

54

Pathophysiology of Bladder Outlet Obstruction and Voiding Dysfunction R. Duane Cespedes, MD

491

55

Prevention of the Progression and Long-Term Complications of Benign Prostatic Hyperplasia Cynthia J. Girman, Dr.PH, and Joanne Waldstreicher, MD

498

56

Benign Prostatic Hyperplasia: When to Intervene Steven G. Roberts, MD, and Michael L. Blute, MD

508

57

Preprocedural Evaluation/Preparation Alun W. Thomas, BSc, MBBS, FRCS, and Paul Abrams, MD, FRCS

515

Contents / xvii

58

Options for Treatment of Benign Prostatic Hyperplasia: Alpha-Blockers Perinchery Narayan, MD, Manoj Patel, MD, and Ashutosh Tewari, MD

531

59

5 Alpha-Reductase Inhibitors Jack Geller, MD

543

60

Transurethral Needle Ablation of the Prostate for Treatment of Benign Prostatic Hyperplasia Claude C. Schulman, MD, PhD, and Alexandre R. Zlotta, MD

552

61

Options for Treatment: Contact Edward J. Mueller, MD

562

62

Free Beam Laser Prostatectomy John N. Kabalin, MD, FACS

568

63

Transurethral Resection of the Prostate Mark J. Noble, MD, and Winston K. Mebust, MD

584

64

Transurethral Incision of the Prostate John G. Anema, MD, Allen F. Morey, MD, FACS, and John P. Foley, MD

593

65

Open Prostatectomy in the Management of Benign Prostatic Hyperplasia Fernando J. Kim, MD, Brian E. Nicholson, MD, and Robert C. Flanigan, MD

600

66

Phytotherapy in the Treatment of Benign Prostatic Hyperplasia Glenn S. Gerber, MD

607

67

Prostatitis: Pathophysiology George W. Drach, MD

615

68

Prostatitis: Diagnosis Culley C. Carson, MD

621

69

Prostatitis: Differential Diagnosis, Classification, and Conventional Treatment Strategies John N. Krieger, MD

627

70

Prostatitis: Factors Influencing Prognosis Richard A. Schoor, MD, and Anthony J. Schaeffer, MD

643

71

Prostatitis: Advanced Therapy Durwood E. Neal Jr, MD

650

Index

659

CHAPTER 1

EPIDEMIOLOGY OF PROSTATE CANCER: AN OVERVIEW PETER C. ALBERTSEN, MD, MS and four counties in the San Jose-Monterey region south of San Francisco, were added. Information concerning cancer deaths in the United States is derived from data provided by death certificates filed with state health departments and vital statistics offices. Each state collects mortality information that is processed and consolidated into a national database by the National Center for Health Statistics. The underlying cause of death is selected for tabulation following the procedures specified by the World Health Organization in the relevant Manual of the International Classification of Diseases, Injuries, and Causes of Death.

Adenocarcinoma of the prostate is the most common nonskin cancer among American men. The American Cancer Society estimates that 184,500 new cases of prostate cancer will be diagnosed in the United States in 1998 and that 39,200 men will die from the disease.1 The rate of new prostate cancer diagnoses has increased exponentially over the past three decades.2 During the 5 years preceding 1992, there has been an even more dramatic surge in prostate cancer incidence following the introduction of widespread testing for serum prostate-specific antigen (PSA).3 Since 1992, however, the annual incidence rate has declined by 11% and continues to decline.4 The mortality rate from prostate cancer has also changed during the past two decades. After increasing steadily from 1973 to 1990, the mortality rate from prostate cancer fell by 6.3% from 1991 to 1995.5 The rate for men under 75 years fell by 7.4% while the rate for men aged 75 years and older, a group accounting for twothirds of all prostate cancer deaths, fell by 3.8%. This is the first recorded fall in the mortality rate from this type of cancer since the 1930s when cancer statistics were first collected. Whether the decline in prostate cancer mortality can be attributed to early diagnosis and screening is the subject of much controversy and debate.

How Is Information Reported? Cancer incidence rates are often reported either as actual counts at a given point in time or are expressed as ageadjusted rates. Simply reporting the raw number of new cases annually provides some information concerning the magnitude of the disease incidence within a population. Unfortunately, this approach does not take into account the number of patients at risk for developing cancer. The age distribution of populations changes over time. Western countries, for example, generally have a greater number of elderly people compared to most developing nations. As more people live longer, the risk of developing prostate cancer increases. This will be especially true when the large “baby boom” generation enters its seventh and eighth decades. As a consequence, the absolute number of new cancer cases may increase but the relative incidence rate may increase, decrease, or remain constant. Epidemiologists often express incidence rates as an age-adjusted rate when they need to determine whether the number of new cases of prostate cancer is increasing faster or slower than the growing population at risk, or if they wish to make meaningful comparisons between different populations separated by geography or time. To correct for the age distribution of the population at risk, new cases must be weighted to reflect the pool of potential patients. Normally, the Bureau of Vital Statistics adjusts incidence rates to fit the United States population age distribution present during a census year. The standard used by the SEER program is the age distribution recorded in the 1970 census of the United States. The incidence and mortality data quoted earlier were adjusted

How Is Information Collected? Information concerning newly diagnosed cancer cases occurring in the United States is derived from data collected by the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.5 The SEER program was created following passage of the National Cancer Act in 1971 and is mandated to collect, analyze, and disseminate information that is useful in preventing, diagnosing, and treating cancer. The geographic areas comprising the SEER program’s database include approximately 13.9% of the United States’ population. Nine population-based registries including five states (Connecticut, Hawaii, Iowa, New Mexico, and Utah) and four standard metropolitan statistical areas (Atlanta, Detroit, San Francisco-Oakland, and SeattlePuget Sound) comprise the core regions of the SEER program. In 1992, the SEER program was expanded to increase coverage of minority populations, especially Hispanics. Two new areas in California, Los Angeles County 1

2 / Advanced Therapy of Prostate Disease

to the 1970 United States standard population and are expressed as an age-adjusted rate per 100,000 men.

How Have the Incidence Rates of Prostate Cancer Changed during the Past Two Decades? During the two decades spanning 1973 to 1992, the ageadjusted prostate cancer incidence rate for all men increased dramatically (Figure 1–1).3 The rate increased linearly between 1973 and 1986 but accelerated between 1987 and 1992. During the 5 years preceding 1992, the age-adjusted incidence rate of prostate cancer increased 84% from 102.9 cases per 100,000 men to 189.4 cases per 100,000 men. The two largest increases were observed in 1990 and 1991. Since 1992, there has been a precipitous drop in the number of new cases so that by 1994, the most current year for which accurate data are available, the incidence rates appear to be returning to the rates present before the introduction of widespread testing for PSA4 (Figure 1–2). The shape of the incidence curves are similar for African Americans and Caucasians although the peak incidence for African Americans was 1 year later. The incidence of prostate cancer in African Americans continues at a rate almost double that among Caucasians.

How Do Incidence Rates Vary by Patient Age at Diagnosis? Despite widespread screening efforts targeted at men aged 50 to 65 years, the age-adjusted incidence rates still

FIGURE 1–1. Prostate cancer incidence by stage for all ages. Data are from four Surveillance, Epidemiology, and End Results areas. From Potosky AL, Miller BA, Albertsen PC, Kramer BS. The role of increasing detection in the rising incidence of prostate cancer. JAMA 1995;273:548–52.

suggest that prostate cancer is a disease of older men. For the two decades leading up to 1993, the age-adjusted incidence rates were highest for men aged 75 years and older, followed by that for men aged 65 to 74 years.5 Since 1993, the age-adjusted rate has decreased sharply among men aged 75 years and older, so that the highest age-adjusted rate of prostate cancer now occurs among men aged 65 to 74 years. Prostate cancer is still relatively uncommon among men under the age of 65, but the annual ageadjusted rate among this group has more than tripled between 1989 and 1992. The rate has decreased slightly since 1992. For much of the 1980s, the mean age of diagnosis was approximately 72 years for Caucasians and 70 years for African Americans.5 Since the introduction of PSA testing, the mean age at diagnosis has fallen. As of 1994, the mean age at diagnosis among Caucasians was 69 years and 67 years among African Americans. These statistics suggest that prostate cancer is being diagnosed in the late 1990s approximately 2.5 years earlier than it was a decade ago. Because of this abrupt increase in the lead time of diagnosis, patients can expect to live an additional 2.5 years after their diagnosis compared to reports from a decade ago. To attribute improvements in longevity to aggressive intervention with either surgery or radiation, researchers must allow for a 2.5-year lead time when making comparisons with historic series.

How Has the Stage of Incident Prostate Cancers Changed Over the Past Decade? Before 1986, the diagnosis of localized prostate cancer accounted for the majority of the increase in incident cases. Only modest increases were detected for regional and distant-stage cases. After 1986, the stage-specific incidence rates began to increase exponentially for all stages except distant-stage disease. From 1986 to 1991, the incidence of localized disease increased 75% while incidences of regional and unstaged disease rose 144% and 161%, respectively.3 The incidence of distant disease remained essentially unchanged. The age-adjusted incident rates for distant disease have fallen dramatically since 1991, and are now approximately half what they were at the beginning of the decade. Decreasing rates of distant disease most likely reflect widespread use of PSA testing. While decreasing rates of distant disease are a significant indicator that early detection may subsequently lead to decreased mortality, this fact alone is not sufficient to demonstrate the efficacy of aggressive prostate cancer screening and treatment. Currently available mortality estimates have not demonstrated a convincing decline in prostate cancer deaths. Given the long natural history of prostate cancer, increased treatment of localized disease will not yield large population-based improvements until early in the next century.

Epidemiology of Prostate Cancer: an Overview / 3

How Has the Grade of Incident Cases Changed Over the Past Decade? Since the introduction of widespread PSA testing, the number of new cases of moderately differentiated disease has increased dramatically. Between 1974 and 1984, the number of incident cases of well-, moderately, and poorly differentiated disease were roughly comparable. Between 1984 and 1989, the age-adjusted incidence of well- and poorly differentiated tumors continued to increase slowly while the age-adjusted incidence of moderately differentiated tumors grew more rapidly. After 1989, there was a dramatic increase in the number of moderately differentiated tumors, such that the number of these new cases was two to three times higher than the number of well- and poorly differentiated tumors. Since 1991, moderately differentiated tumors have represented over half of the newly diagnosed cases while well- and poorly differentiated tumors each accounted for approximately 20% of new cases. Coding rules utilized by the SEER program may explain some of these changes. According to SEER conventions, the most accurate pathology grade is utilized when recording the grade of newly diagnosed cancers. For patients undergoing radiation therapy or conservative management, the grade of their tumor is based on the needle biopsy or transurethral resection specimen that resulted in a diagnosis. For patients undergoing radical prostatectomy, the results of the surgical pathology report replace the results obtained on biopsy. As a result, some of

the well-differentiated tumors may be upgraded to moderately differentiated tumors. These changes, however, do not likely account for the majority of new cases of moderately differentiated disease.

How Are the American Cancer Society Projections of Cancer Incidence and Mortality Calculated? Every year the American Cancer Society (ACS) prepares estimates for all major cancers. They publish statistics concerning the number of newly-diagnosed cancer cases and the number of cancer deaths occurring within the United States.1 These widely quoted estimates are calculated from data available from the United States Bureau of the Census and the cancer incidence rates collected by the National Cancer Institute’s SEER program. Estimates of new cancer cases are calculated using a three-step procedure. First, the annual age-specific cancer incidence rates for a 15-year period are multiplied by the age-appropriate United States Census Bureau population projections for the same years to estimate the number of cancer cases diagnosed annually for a 15-year period. These annual cancer case estimates are then fitted to an autoregressive quadratic model. This model is used to predict the following year’s rate. Although the American Cancer Society projections are based on SEER data, the projections are extrapolated 3 to 4 years into the future. For example, the ACS estimates of new prostate cancer cases published for 1997 were based

FIGURE 1–2. Prostate cancer incidence rates by age group at diagnosis and race. Rates are age-adjusted to the 1990 United States standard population. From Merrill RM, Potosky AL, Feuer EJ. Changing trends in U.S. prostate cancer incidence rates. J Natl Cancer Inst 1996;88:1683–5.

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on SEER public-use data available only through 1993. Because of the rapid rise in the number of incidence cases reported during the early 1990s, the ACS projections initially underestimated and then over-estimated the estimates derived from SEER data (Figure 1–3).6 As a consequence, the ACS published an adjustment to the 1997 estimates in the July/August issue of CA: A Cancer Journal for Clinicians that reduced the projected number of cases for 1997 from 334,500 to 209,900.4 These new estimates are based on an assumption that incidence rates will decline during the period 1993 to 1995 and will then resume the annual increase in incidence rates documented before the widespread use of prostate-specific antigen screening. Whether these assumptions are correct remains to be determined. The use of ACS projections has led to incorrect perceptions and inflated concern about prostate cancer trends in the PSA era. In hindsight, the recent changes in prostate cancer incidence rates do not appear to reflect an epidemic of new prostate cancers but rather a “cull” phenomenon that can result when a new, more sensitive test becomes available for disease detection. Such a cull phenomenon occurs when a large number of previously unsuspected cases are detected, resulting in fewer detectable cases in the remaining population. This cull effect should show the greatest declines in incidence among the men most extensively tested. This theory is supported by the observation that since 1992 incidence 350

Number of Cases (x 1,000)

300 American Cancer Society adjusts projection in July 1997 to n = 209,900

250

200

150 SEER Estimate 100 American Cancer Society Projection

50

0

81

83

85

87 89 91 Year of Diagnosis

93

95

97

FIGURE 1–3. United States men with prostate cancer: SEER estimates and American Cancer Society projections by year of diagnosis. SEER estimates obtained by multiplying the age-specific incidence for the SEER registries by the United States population. From Stephenson RA. Population-based prostate cancer trends in the PSA era: data from the Surveillance, Epidemiology, and End Results (SEER) program. Monogr Urol 1998;19:3–19.

rates for older men have fallen more rapidly than for younger men. Furthermore, Stephenson has reported that PSA testing appears to be related to age. The fraction of men undergoing PSA testing increases as a function of their age, from 17% of men in their fifth decade to 75% of men in their ninth decade.6

How Have Prostate Cancer Mortality Rates Changed during the Past Decade? Mortality from prostate cancer has gradually increased among both Caucasians and African Americans during the past two decades. In absolute terms, 33,565 men died of prostate cancer in 1991 and 34,901 men in 1994.5 When viewed in relative terms, however, the data suggest a different trend. Among Caucasian men, the ageadjusted mortality rate rose from 20.3 deaths per 100,000 men in 1973 to 24.7 deaths per 100,000 men in 1991. Rates among African Americans were more than twice as high. Since then the rates have declined. The National Cancer Institute recently reported data showing that the prostate cancer death rate in the United States fell between 1991 and 1995, from 26.5 to 17.3 deaths per 100,000 men in the overall population.7 The percentage decline was greatest for young Caucasion males and smallest for older men and African American men (Figure 1–4). The differences between absolute and relative age-adjusted rates are explained by the increasing number of men dying from prostate cancer but the even greater increase in the number of older men still alive in the United States population. The increase in the size of the population at risk (the denominator) has been proportionally more rapid than the increase in the number of men dying from prostate cancer (the numerator). This has resulted in a recent small age-adjusted decline during the past year.

What Is the Significance of the Recent Decline in Prostate Cancer Mortality Rates? Epidemiologists are uncertain how to explain the recent decline in prostate cancer mortality rates. It may be an All ages

50 ng per mL, 66% had microscopic lymph node invasion and 90% had seminal vesicle invasion. However, the majority of clinicians do not find the value of PSA alone sufficiently reliable for predicting the final pathologic stage for the individual patient. For example, Oesterling et al.16 found that the diagnostic accuracy of an elevated PSA value was 55% for capsular perforation and 50% for seminal vesicle invasion and lymph node involvement. Clinical stage determination by DRE is also notoriously inaccurate as a single staging marker. Zinke17 found in a large study that 40% of clinical stage C prostate cancer patients were understaged and had pathologic stage D1 disease, and 20% were overstaged with pathologic stage B2 disease. Kramer et al.18 found tumor grade to correlate with pathologic stage—93% of patients with biopsy Gleason score of 8 or higher had metastatic nodal disease and those patients with a score of 4 or less had no nodal disease. Despite this distinction between local and advanced disease at the lower and upper ends of Gleason scoring, the majority of patients are found to have a Gleason score between 5 and 7, making this a suboptimal marker when used alone. Kleer et al.19 at the Mayo Clinic evaluated the use of clinical stage and tumor grade in augmenting the predictive capability of pretreatment PSA. They found that the combination of clinical stage and tumor grade when used with pretreatment PSA significantly increased the predictive power of these pretreatment prognostic variables. Unfortunately, the Mayo Clinic tumor grading system used in this study is not a routinely employed pathologic grading system and therefore makes this model less useful for the community physician. Another example of the utility of combined predictive variables is a study by Wolf et al.20 that added TRUS findings to the algorithm of a grade-stratified PSA scale. With evidence from others describing the correlation of PSA to tumor grade,21 the authors stratified PSA values by grade to produce more accurate staging. The addition of TRUS to the staging algorithm, necessary only in patients with negative predictions using the grade-stratified PSA scale (46% of patients), increased sensitivity to 86% and the negative predictive value to 79%, while positive predictive value remained unchanged at 77%. Wolf found that this algorithm was especially useful in a subset of patients with a PSA < 4 ng per mL or > 15.9 ng per mL. The algorithm predicted an 85 and 88% likelihood of organconfined and nonorgan-confined disease, respectively. Wolf ’s evaluation of PSA-density grade-stratified method

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did not demonstrate better predictive capability over the grade-stratified PSA scale. Unfortunately, TRUS is highly operator-dependent, and extensive experience with this technique is required to reproduce results reported by academic centers. Badalament et al.22 combined pretreatment PSA and results obtained from sextant core biopsies to develop an algorithm for predicting nonorgan-confined prostate cancer. Their technique had a sensitivity of 85.7%, specificity of 71.3%, positive predictive value of 72.9%, negative predictive value of 84.7%, and an area under the receiver operating characteristic curve of 85.9%. Data obtained from the sextant core biopsies included multiple variables: quantitative nuclear grade, total percent tumor involvement, number of positive sextant cores, biopsy Gleason score, involvement of more than 5% of a base and/or apex biopsy, and DNA ploidy. Both quantitative nuclear grade and DNA ploidy were determined using an image analysis system and computer software that is commercially available (Dr. Robert W. Veltri, UroCor Inc., Oklahoma City, OK). This computer assisted image analysis technique is able to calculate 38 quantitative nuclear grading descriptors including size, shape, DNA content, and Markovian chromatin texture features.23 The authors provide a cautionary note regarding the use of the quantitative nuclear descriptors to predict tumor stage or aggressiveness. Specifically, the tissue processing methods, cell analysis and sampling techniques, patient sample training set size and composition, and stringency parameters for statistical analysis or neural network configurations will affect any feature-based algorithm. Therefore, it is imperative to train and test such feature-based algorithms on different populations using the same criteria for sample selection and processing. There should be a prospective multicenter trial of this technology performed. This novel approach is commercially available and is called Uro-score.24 The nomograms developed by Partin et al.25 in 1993 represent a more practical approach incorporating commonly used clinically obtained variables. These nomograms have recently been added to the 1996 prostate cancer practice guidelines of the National Comprehensive Cancer Network.26 They use a combination of pretreatment PSA, clinical stage, and biopsy Gleason score to predict the pathologic stage for men with clinically localized prostate cancer undergoing radical prostatectomy. Specifically, probabilities of organ-confined disease, established capsular penetration, seminal vesicle involvement, and lymph node involvement are displayed in an easy-to-use tabular format. This original set of nomograms was evaluated at a separate institution on a different patient population by Kattan et al.27 Their results suggested that the nomograms did discriminate quite well between organconfined and nonorgan-confined disease but had difficulty predicting high probabilities of seminal vesicle invasion and lymph node metastasis, pathologic features

known to have the most profound impact on prognosis. For example, when the nomograms predicted a 75% chance of positive lymph nodes, less than 20% of the patients in the Kattan data set actually had pathologically confirmed lymphatic involvement. The performance of the nomograms in the low probability areas, especially for seminal vesicle invasion, was quite good. Kattan and colleagues concluded that despite the accuracy of the nomograms in the Johns Hopkins University data set they may not be applicable to general clinical practice until further validations and modifications are performed. Deficiencies in the earlier published nomograms led to a larger multi-institutional study of a combined cohort of 4133 men by Partin et al.28 published in 1997. In the validation analyses of this much larger multi-institutional study, the nomograms correctly predicted the probability of a pathologic stage 72.4% of the time to within 10% (organ-confined disease, 67.3%; isolated capsular penetration, 59.6%; seminal vesicle involvement, 79.6%; and pelvic lymph node involvement, 82.9%). These new nomograms also included the 95% confidence intervals for all predicted probabilities, items not included in the earlier 1993 study. Using the same preoperative variables of pretreatment PSA, clinical stage, and Gleason score, Bishoff et al.29 analyzed a cohort of 481 men to predict the probability of lymph node involvement. This study was conducted to identify patients at low risk for nodal involvement so that a perineal prostatectomy could be safely performed without pelvic lymph node sampling prior to the procedure. Depending on the estimated probability of positive lymph nodes ranging from 2 to 10%, pelvic lymphadenectomy could be omitted in 20 to 63% of patients. Similarly, Roach et al.,30 Harris et al.,31 Narayan et 32 al., and Bluestein et al.33 developed algorithms or modeling equations to predict the probability of positive lymph nodes. The models by Harris et al., Narayan et al., and Roach et al. are based strictly on PSA and Gleason score. These studies suggested little additional benefit of incorporating the clinical stage because of the difficulty in reproducibility.30–32 Conversely, Bluestein et al. found the clinical stage to be reproducible and included it in their model.33 Roach et al.30 developed an equation based on data from Partin et al. (1993 nomograms):25 N+ (risk of positive nodes) = 2/3 PSA + (Gleason score – 6) × 10

If N+ is less than 15%, the patient is identified as at low risk for lymph node metastasis. If N+ is 15% or greater, then the patient is considered at high risk and a staging pelvic lymphadenectomy is recommended. The model by Harris et al.31 is based on experience with 484 patients presenting for radical prostatectomy. Narayan et al.32 used records from eight medical centers, including 932 patients with presumed localized prostate cancer who

Assessment of Risk of Prostate Cancer: Algorithms for Diagnosis, Staging, and Prognosis / 39

had undergone lymphadenectomy. Limits of PSA to ≤ 10 ng per mL and a biopsy Gleason score ≤ 6 were used. The false negative rate was 1% and the 95% confidence interval raised this to 2%. The authors considered a falsenegative rate under 3% to be an acceptable risk. The model by Bluestein et al.,33 which included the clinical stage, was developed from a cohort of 1632 patients who had undergone lymph node dissections. The authors also accepted a false-negative rate of < 3%. Spevack et al.34 reviewed records of 214 patients with a 14% positive lymph node rate and compared the four models by Roach et al.,30 Harris et al.,31 Narayan et al.,32 and Bluestein et al.33 This study revealed the following results respectively: 78%, 50%, 76%, and 42% of the patients were identified as low risk and could be spared a pelvic lymph node dissection. The false-negative rates were 13 (7.8%), 5 (4.6%), 14 (8.6%), and 1 (1.1%). Sensitivities were 56.7, 83.3, 53.3, and 96.7%. This study identified the model by Bluestein et al.33 to be the most sensitive. While this model identified a smaller number of patients at low risk for nodal disease (42%), it had the highest negative predictive value (98.9%) and the lowest false negative rate.

Algorithms for Prognosis The prediction of preoperative pathologic stage is important in counseling a patient before proceeding with radical prostatectomy. Despite these predictions, many patients, even those without organ-confined disease, are long-term disease-free survivors and surgical therapy is appropriate. Once surgical intervention is completed, a new set of predictive algorithms and statistical equations predicting recurrence and progression are now available to adequately inform the patient of future expectations. Approximately 65% of prostate cancers are clinically localized at the time of diagnosis and despite improved preoperative pathologic stage prediction, between 40 to 60% of men are found to have extracapsular disease after radical prostatectomy.35–37 Of these patients, the reported 5-year progression-free survival rate is 93% for PSA between 4.1 to 9.9 ng per mL and 71% for patients with a PSA greater than 10.0 ng per mL.38 Overall, approximately 25 to 40% of patients will have evidence of biochemical recurrence 10 years after radical prostatectomy for clinically localized prostate cancer.39–41 Lerner et al.42 evaluated 904 patients with multivariate statistical analysis, using the variables of pretreatment PSA, clinical stage, pathologic grade (Gleason score), pathologic stage, and DNA ploidy. They found that PSA, pathologic grade, and DNA ploidy were independent predictors of disease progression. The authors then developed two prognostic scoring systems, one with DNA ploidy and one without, to identify five distinct patient risk groups. Those patients with the lowest score had a 92% progression-free survival rate at 5 years, compared to only 39% for those patients with the highest scores. The systems were defined as follows:

System 1—add 0.8 if PSA is greater than 10 ng per mL, and add 0.8, 1.2, or 1.9 if Gleason score is 6, 7, 8 or more, respectively. Progression-free survival rate for those with a score of “0” was 90%, whereas only 41% with a score greater than 2.0 were free of cancer at 5 years. System 2 included DNA ploidy—add 0.7 if PSA is greater than 10 ng per mL, add 0.7, 1.1, or 1.7 if Gleason score is 6, 7, 8 or more, respectively, and add 0.4 or 0.8 if DNA ploidy is tetraploid or aneuploid, respectively. For the patients with the lowest score of “0,” 92% were free of cancer at 5 years, compared to only 39% with prognostic scoring system scores of 2.0 or more. Similar discrete risk groups were identified with both systems. Both systems identified intermediate groups between 0 and 2.0 (0.1 to 0.9, and 1.0 to 1.9), with different statistically significant 5-year progression-free survival rates. Veltri et al.43 performed a similar study on 70 patients that combined postoperative Gleason score and a novel variable termed the Quantitative Nuclear Grade (QNG). Multivariate statistical analysis of age, clinical stage, capsular penetration, surgical margins, postoperative Gleason score, and the QNG revealed that with a stepwise backward elimination of nonsignificant variables at a high stringency (p = .05), only Gleason score and QNG remained in the final predictive model. Quantitative Nuclear Grade can be determined by using a commercially available product. The computer-generated QNG is an evaluation of 38 nuclear morphometric descriptors that develops a QNG based on those descriptors that are statistically significant in the proposed data set. In this data set, 11 nuclear morphometric descriptors were found to be independently significant at a cutoff point of p < .05. The combination of Gleason score and QNG separated these patients into three distinct risk groups with respect to progression-free survival: low, moderate, and high. The model showed a sensitivity of 89%, specificity of 84%, positive predictive value of 78%, negative predictive value of 92%, and a receiver operator characteristic area under the curve of 92%. Partin et al. 44 developed a simple biostatistical model equation that categorized 216 clinical stage B2 postradical prostatectomy patients into three risk groups for likelihood of serologic failure. Many preoperative and pathologic variables were analyzed but after multivariate regression analysis only three variables were included in the final model to adequately select for high-risk patients after surgery. These consisted of a sigmoidal transformation of PSA (PSAST), prostatectomy Gleason score, and specimen confinement (margin status), which were incorporated into an equation that calculated the log relative risk of recurrence (Rw) as follows: Rw = (0.061 × PSAST) + (0.54 × postop Gleason) + (1.87 × specimen confined)

40 / Advanced Therapy of Prostate Disease

The sigmoidal transformation of PSA was defined as follows: PSAST = 10/(1 + exp6.8704–0.9815 × PSA)

This transformation of PSA was used to decrease the weighting toward low and high PSA levels (< 4.0 ng per mL and > 10.0 ng per mL) and to increase the predictive value of the intermediate levels of PSA (4.0 to 10.0 ng per mL). The constants used in this transformation were chosen to compress the upper and lower ends of PSA. Levels less than 4.0 ng per mL (in which early PSA recurrence is rare) would yield PSAST values between 0 and 0.5, and PSA levels > 10.0 ng per mL (in which early PSA recurrence is most common) would yield PSAST values between 9.5 and 10.0. Depending upon the calculated value for Rw, these patients could be stratified into three risk groups. Recurrence risk categories were determined to be low risk if Rw was less than 4.0, intermediate risk if from 4.0 to < 5.75, and high risk if Rw was more than 5.75. This model was validated using a separate cohort of 214 men treated at another institution by multiple urologists. Traditional variables were employed that are commonly and accurately determined at most institutions, making this form of risk assessment a practical clinical tool that can be used in decisions concerning adjuvant therapy. This model allows those patients at high risk for recurrence to be identified shortly after surgery, while their tumor burden is minimal. These may be ideal patients to benefit from adjuvant therapy or investigational therapies. Despite the obvious clinical utility of this type of risk assessment modeling, the Johns Hopkins model did not evaluate race as a potential variable and included only patients with clinically-palpable stage B2 disease. Ethnicity has been shown to be a significant predictor of recurrence after radical prostatectomy.45 Unfortunately, Partin’s study included only 8.5% African American patients. Subsequently, the current authors and colleagues46 evaluated 378 patients who had undergone radical prostatectomy at their institution, and developed a modeling equation similar to Partin’s. All stages of clinically organ-confined prostate cancer (T1a, b, c and T2a, b, c) were incorporated and a race variable was added (African American versus non-African American) as the patient population was approximately 25% African American. In the analysis, age, race, prostatic acid phosphatase (PAP), and nuclear grade as well as the established prognostic variables of pretreatment PSA, postoperative Gleason score, and other various pathologically determined stage variables were evaluated. This study also included a validation cohort of 91 patients treated by multiple surgeons at a separate medical center. By expanding the patient base to include all patients that are likely candidates for curative radical surgery and by adding the race variable, a more representative model

was formulated to calculate the relative risk of recurrence after surgery. The final model calculated the relative risk of recurrence (Rr) as follows: Rr = exp[(0.51 × race) + (0.12 × PSAST) + (0.25 × postop Gleason score) + (0.89 × organ confinement)]

Race was defined as “1” if the patient was African American or “0” if Caucasian or other. The sigmoidal transformation of PSA (PSAST) is defined as: PSAST = 10/(1 + exp6.8704–0.9815 × PSA)

Postoperative Gleason score (2 to 10) was defined as a continuous integer value. The organ-confined term (no capsular penetration) was defined as “0” whereas the nonorganconfined term (capsular extension and/or positive margins) was defined as “1.” The Rr values allowed stratification of patients into low-, intermediate-, and high-risk groups. The men at lowest risk of serologic recurrence after a radical prostatectomy were those with an Rr less than 10.0 (86% 5-year Kaplan-Meier disease-free survival rate [KM-DFSR]), intermediate risk when Rr was between 10.0 and 30.0 (59.0% 5-year KM-DFSR), and at highest risk if the Rr was greater than 30.0 (30.3% 5-year KM-DFSR). These cut-off values were defined by natural breaks in the numerical listing of Rr for each patient. This equation is extremely useful in predicting postoperative risk of recurrence but requires information obtained only after the prostate has been removed and evaluated pathologically. The development of these relative risk equations by Partin et al.44 and the current authors and colleagues46 spurred interest in developing a similar equation that could predict both the probability of extracapsular extension and the relative risk of recurrence after surgery using only pretreatment variables. By using this type of equation, the clinician can more thoroughly counsel patients about the expected outcome after radical prostatectomy even before the surgery is completed. The current authors and colleagues47 collected data on 260 radical prostatectomy patients for whom data for the following variables were available: age, race, biopsy Gleason score, biopsy nuclear grade, biopsy glandular differentiation, and clinical stage. These pretreatment variables were analyzed to predict recurrence using a Cox regression model with backward elimination of nonstatistically significant variables (p > .20). The traditional variables that significantly correlated with recurrence were incorporated into a model equation that calculates the relative risk of recurrence (Rr) as follows: Rr = exp[(0.47 × Race) + (0.14 × PSAST) + (0.13 × worst biopsy Gleason score) + (1.03 × stage T1c) + (1.55 × stage T2b,c)]

Assessment of Risk of Prostate Cancer: Algorithms for Diagnosis, Staging, and Prognosis / 41

FIGURE 7–3. Preoperative nomogram for prostate cancer recurrence. From Kattan MW, Eastham JA, Stapleton AMF, et al. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 1998;90:766–71.

Race was defined as “1” if the patient was African American or “0” if Caucasian, Hispanic, or Asian. Sigmoidal transformation of PSA (PSAST) was calculated using the following equation: PSAST = 10/(1 + exp6.8704–0.9815 × PSA)

Biopsy Gleason score (2 to 10) was defined as a continuous integer value. Stage T1c and T2b,c were defined as “1” if that was the patient’s clinical stage and “0” if that was not the patient’s stage. If “0” in this equation, the variable is effectively dropped. The Rr values allowed stratification of patients into low-, intermediate-, and high-risk groups. The men at lowest risk of serologic recurrence after a radical prostatectomy were those with an Rr less than 8.0 (94.7% 3-year KM-DFSR), intermediate risk when Rr was between 8.0 and 40.0 (65.4% 3-year KM-DFSR), and at highest risk if the Rr was greater than 40.0 (0.0% 3-year KM-DFSR). These cutoff values were defined by natural breaks in the numerical listing of Rr for each patient. The same variables (race, clinical stage, biopsy Gleason score, and sigmoidal transformation of PSA [PSAST]) that were used in the relative risk of recurrence equation were then analyzed with respect to the capsular status, using logistic regression. The fitted regression equation

was used to estimate the probability of extracapsular extension (PECE) as follows: PECE = 1/[1+ exp (–Z)] where Z= –2.47 + 0.15 (PSAST) + 0.31 (worst biopsy × Gleason score) + 0.18 (Race) + 0.16 (stage T1c) + 0.38 (stage T2b,c)

The variables in this equation were defined in the same manner as the preoperative relative risk equation presented earlier. Three probability groups were formed (low PECE < 0.43, medium PECE = 0.43 to 0.77, high PECE > 0.77). These cut-off values were defined by natural breaks in the numerical listing of the PECE for each patient. Specificity for the high PECE group was 97.2% and the sensitivity for the low PECE group was 87.0%. This model equation was validated using a validation cohort from a separate institution. Within this validation cohort, the probability group of low PECE (p < .43), 4 of 11 patients (36.5%) actually had positive capsular penetration. Conversely, the high PECE (p > .77) group had 20 of 25 patients (80.0%) with positive capsular penetration. The current authors’ modeling equations47 for estimating the probability of extracapsular disease and the relative risk of recurrence after radical prostatectomy for clinically

42 / Advanced Therapy of Prostate Disease

confined prostate cancer are based on easily obtained and widely accepted traditional preoperative prognostic variables. The equations, despite their complexity, can be easily automated on a personal computer for simultaneous calculation of both the probability of extracapsular disease and the estimated outcome of surgical intervention. These attributes may make these model equations more practical for use by the community-based urologist. Kattan and colleagues have also recently developed an algorithm in the form of a nomogram employing preoperative variables to predict disease recurrence after radical prostatectomy48 (Figure 7–3). This nomogram uses pretreatment PSA, clinical stage, and biopsy Gleason score on a scale and assigns points that are used to determine the 60-month recurrence-free probability. This nomogram was developed based on 983 radical prostatectomy patients treated at Baylor University. The developers are careful to point out that it is only applicable to the patient who has selected radical prostatectomy. Similar algorithms to predict recurrence after radiation and/or brachytherapy will no doubt be developed over the next few years.

5.

6. 7.

8.

9.

10.

11.

Summary The use of algorithms to predict the likelihood, stage, and outcome of prostate cancer is still in its infancy. Over the last few years, however, investigators have used traditional statistical methods and neural network computer programs to develop nomograms, probability tables, and computer-based equations to improve patient care. The simplest algorithms such as age-specific reference ranges for PSA and the Partin nomograms for predicting pathologic stage are already in widespread clinical use. As researchers and clinicians become more sophisticated in this area, more complex equations and algorithms will be available on office computers, local area networks (LAN), and the Internet, and will be widely used. As with many other aspects of prostate cancer, prospective, multicenter trials are needed to determine the clinical utility of diagnostic, staging, and prognostic algorithms.

References 1. Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6630 men. J Urol 1994;151:1283–90. 2. Benson MC, Whang IS, Pantuck A, et al. Prostate-specific antigen density: a means of distinguishing benign prostatic hypertrophy and prostate cancer. J Urol 1992; 147:815–6. 3. Oesterling JE, Jacobson SJ, Chute CG, et al. Serum prostate specific antigen in a community based population of healthy men: establishment of age-specific reference ranges. JAMA 1993;270:860–4. 4. Morgan TO, Jacobson SJ, McCarthy WF, et al. Age-specific

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reference ranges for prostate-specific antigen in black men. N Engl J Med 1996;335:304–10. Optenberg SA, Clark JY, Brawer MK, et al. Development of a decision-making tool to predict risk of prostate cancer: the Cancer of the Prostate Risk Index (CAPRI) test. Urology 1997;50:665–72. Douglas TH, Moul JW. Applications of neural networks in urologic oncology. Semin Urol Oncol 1998;16(1):35–9. Snow PB, Smith DS, Catalona WJ. Artificial neural networks in the diagnosis and prognosis of prostate cancer: a pilot study. J Urol 1994;152:1923. Snow P, Crawford ED, DeAntoni EP, et al. Prostate cancer diagnosis from artificial neural networks using the Prostate Cancer Awareness Week (PCAW) database [abstract]. J Urol 1997;157:365. Stamey TA, Barnhill SD, Zhang Z, et al. Effectiveness of ProstAsure in detecting prostate cancer and benign prostatic hyperplasia in men age 50 and older [abstract]. J Urol 1996;155 Suppl 5:436A. Stamey TA, Barnhill SD, Zhang A, et al. A neural network (ProstAsure) with high sensitivity and specificity for diagnosing prostate cancer (Pca) in men with a PSA < 4.0 ng per mL [abstract]. J Urol 1997;157:364. Loch T, Leuschner I, Brüske T, et al. Neural network analysis of subvisual transrectal ultrasound data: improved prostate cancer detection [abstract]. J Urol 1997;157 Suppl 4:364. Moul JW, Snow PB, Fernandez EB, et al. Neural network analysis of quantitative histological factors to predict pathological stage in clinical stage I nonseminomatous testicular cancer. J Urol 1995;153:1574. Niederberger CS. Commentary on the use of neural networks in clinical urology. J Urol 1995;153:1362. Stamey TA, Kabalin JN. Prostate-specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. I. Untreated patients. J Urol 1989;141:1070–5. Stamey TA, Kabalin JN. Prostate-specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. II. Radical prostatectomy treated patients. J Urol 1989;141:1076–83. Oesterling JE, Chan DW, Epstein JI, et al. Prostate-specific antigen in the preoperative and postoperative evaluation of localized prostatic cancer treated with radical prostatectomy. J Urol 1988;139:766–72. Zinke H. Combined surgery and immediate adjuvant hormonal treatment for stage D1 adenocarcinoma of the prostate: Mayo Clinic experience. Semin Urol 1990;8: 175–83. Kramer SA, Sphar J, Brendler CB, et al. Experience with Gleason’s histopathology grading in prostatic cancer. J Urol 1980;124:223–5. Kleer E, Larson-Keller JJ, Zinke H, Oesterling JE. Ability of preoperative serum prostate-specific antigen value to predict pathological stage and DNA ploidy. Influence of clinical stage and tumor grade. Urology 1993;41: 207–16. Wolf JS, Shinohara K, Carroll PR, Narayan P. Combined role of transrectal ultrasonography, Gleason score, and prostate-specific antigen in predicting organ-confined prostate cancer. Urology 1993;42(2):131–7.

Assessment of Risk of Prostate Cancer: Algorithms for Diagnosis, Staging, and Prognosis / 43 21. Partin AW, Carter HB, Chan DW, et al. Prostate-specific antigen in the staging of localized prostate cancer: influence of tumor differentiation, tumor volume, and benign hyperplasia. J Urol 1990;143:747–52. 22. Badalament RA, Miller MC, Peller PA, et al. An algorithm for predicting nonorgan confined prostate cancer using the results obtained from sextant core biopsies with prostate-specific antigen level. J Urol 1996;156:1375–80. 23. Veltri RW, Partin AW, Epstein JI, et al. Quantitative nuclear morphometry, Markovian texture descriptors, and DNA content captured on a CAS-200 image analysis system, combined with PCNA and HER-2/neu immunohistochemistry for prediction of prostate cancer progression. J Cell Biochem 1994;Suppl 19:249. 24. Veltri RW. Algorithms vie for diagnostic role in prostate cancer. J Natl Cancer Inst 1997;89:13–5. 25. Partin AW, Yoo J, Carter HB, et al. The use of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 1993;150:110–4. 26. Baker LH, Hanks G, Gershenson D, et al. National Comprehensive Cancer Network prostate cancer guidelines. Oncology 1996;Suppl 11:265–88. 27. Kattan MW, Stapelton AM, Wheeler TM, Scardino PT. Evaluation of a nomogram used to predict the pathologic stage of clinically localized prostate cancer. Cancer 1997;79:528–37. 28. Partin AW, Katten MW, Eric NP, et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage on localized prostate cancer. JAMA 1997;277:1445–51. 29. Bishoff JT, Reyes A, Thompson IM, et al. Pelvic lymphadenectomy can be omitted in selected patients with carcinoma of the prostate: development of a system of patient selection. Urology 1995;45:270–4. 30. Roach M, Marquez C, Hae-Sook Y, et al. Predicting the risk of lymph node involvement using pretreatment prostate-specific antigen and Gleason score in men with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 1993;28:33–7. 31. Harris MJ, Bishoff JT, Reyes A, Thompson IM. Preoperative PSA and prostate biopsy Gleason’s grade predictive of benign pelvic lymph nodes in men with prostate cancer [abstract 340A]. J Urol 1994;151:451. 32. Narayan P, Fournier G, Gajendran V, et al. Utility of preoperative serum prostate-specific antigen concentration and biopsy Gleason score in predicting risk of pelvic lymph node metastasis in prostate cancer. Urology 1994;44:519–24. 33. Bluestein DL, Bostwick DG, Bergstralh EJ, Oesterling JE. Eliminating the need for bilateral pelvic lymphadenectomy in selected patients with prostate cancer. J Urol 1994;151:1315–20. 34. Spevack L, Killion LT, West JC, et al. Predicting the patient at low risk for lymph node metastasis with localized prostate cancer: an analysis of four statistical models. Int J Radiat Oncol Biol Phys 1996;34:543–7.

35. D’Amico AV, Whittington R, Malkowicz SB, et al. A multivariate analysis of clinical and pathological factors that predict for prostate-specific antigen failure after radical prostatectomy for prostate cancer. J Urol 1995;154: 131–8. 36. Partin AW, Oesterling JE. The clinical usefulness of prostate-specific antigen: update 1994. J Urol 1993;152: 1358–68. 37. Lu-Yao GL, Potosky AL, Albertsen PC, et al. Follow-up prostate cancer treatments after radical prostatectomy: a population-based study. J Natl Cancer Inst 1996;88: 166–72. 38. Catalona WJ, Smith DS. 5-year tumor recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 1994;152:1837–42. 39. Frazier A, Robertson JE, Humphrey PA, Paulson DF. Is prostate-specific antigen of clinical importance in evaluating outcome after radical prostatectomy? J Urol 1993;149:516–8. 40. Stein A, deKernion JB, Dorey F. Prostate-specific antigen related to clinical status 1 to 14 years after radical prostatectomy. Br J Urol 1991;67:626–31. 41. Epstein JI, Carmichael MJ, Pizov G, Walsh PC. Influence of capsular penetration on progression following radical prostatectomy: a study of 196 cases with long-term follow up. J Urol 1993;150:135–41. 42. Lerner SE, Blute ML, Bergstralh EJ, et al. Analysis of risk factors for progression in patients with pathologically confined prostate cancers after radical retropubic prostatectomy. J Urol 1996;156:137–43. 43. Veltri RW, Miller MC, Partin AW, et al. Ability to predict biochemical progression using Gleason score and a computer-generated quantitative nuclear grade derived from cancer cell nuclei. Urology 1996;48:685–91. 44. Partin AW, Piantadosi S, Sanda MG, et al. Selection of men at high risk for disease recurrence for experimental adjuvant therapy following radical prostatectomy. Urology 1995;45:831–8. 45. Moul JW, Douglas TH, McCarthy WF, McLeod DG. Black race is an adverse prognostic factor for prostate cancer recurrence following radical prostatectomy in an equalaccess health care system. J Urol 1996;155:1667–73. 46. Bauer JJ, Conelly RA, Sesterhenn IA, et al. Biostatistical modeling using traditional preoperative and pathological prognostic variables in the selection of men at high risk for prostate cancer recurrence after radical prostatectomy for prostate cancer. J Urol 1998;159: 929–33. 47. Bauer JJ, Conelly RA, Sesterhenn IA, et al. Statistical modeling using preoperative prognostic variables in predicting extracapsular extension and progression after radical prostatectomy for prostate cancer. Mil Med 1998;163:615–9. 48. Kattan MW, Eastham JA, Stapleton AMF, et al. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 1998;90:766–71.

CHAPTER 8

MOLECULAR FACTORS IN THE ASSESSMENT OF PROSTATE CANCER RISK OLIVER SARTOR, MD Adenocarcinoma of the prostate is by far the most common visceral malignancy in men. In the past, prediction of adenocarcinoma of the prostate was linked to wellestablished clinical risk factors such as age, race, and family history. Over the past several years, a series of studies have begun to address the molecular markers that might add additional insights into the understanding of prostate cancer risk. In the future, there is hope that clinicians can use these (as yet undiscovered) molecular measurements to more accurately predict prostate cancer risk in individual men. In this chapter, recent progress toward that goal will be reviewed. Any molecular risk factors for prostate cancer will be evaluated in concert with well-established clinical risk factors; thus, a brief discussion of clinical risk factors is warranted as part of the background discussion for this chapter (Table 8–1). Age is the most dramatic and least understood of the conventional factors implicated in prostate cancer risk. For reasons that are unknown, the risk of prostate cancer rises more than 1000-fold during the natural aging process. Prostate cancer is rare prior to the age of 40 years and common in 80-year-old men, regardless of their ethnic or geographic origin. Race is another poorly understood but well-described clinical risk factor. African Americans have both an increased incidence and mortality from prostate cancer as compared to other ethnic groups. Conversely, Asian Americans are at lower risk as compared to other ethnic groups, both in the United States and in Asia. Family history is also a well-described risk factor. Men with a first-degree relative with prostate cancer are at increased risk relative

to men without such a history, particularly if the firstdegree relative was diagnosed at less than 65 years of age. Several areas of molecular investigation are preliminarily linked to prostate cancer risk and warrant further discussion (see Table 8–1). First, a series of polymorphisms have been described in the molecules involved both in the signal transduction and metabolism of androgenic hormones (Table 8–2). Second, a collection of recent experiments have clearly implicated insulin-like growth factor-I (IGF-I) in prostate cancer risk. Third, the well-accepted tumor marker prostate-specific antigen (PSA) has many uses, one of which is the ability to predict future prostate cancer risk. Though the molecular genetics of hereditary prostate cancers are an increasingly important topic, this subject will not be emphasized secondary to coverage in other chapters. Prior to analyzing studies of risk factors for prostate cancer, it is prudent to discuss those factors that influence the probability of finding cancer and that are not risk factors in the usual sense of the term. First and foremost, it is essential to understand that the probability of finding cancer is dependent on the diligence of the search as well as the population under study. Any series in a comparable population which evaluates sextant biopsy results will find more cancer than a series which examines only single biopsy specimens. It is also critically important to understand that the probability of detecting prostate cancer is dependent on the population examined. Series performed in the pre-PSA era cannot readily be compared to studies in the post-PSA era, and cohorts of patients with advanced disease cannot readily be compared to cohorts with localized cancers. Similarly, comparisons of studies examining a high proportion of African American men cannot readily be compared to studies that virtually exclude this population. Concurrent control populations are preferable to historic controls. Thus, when reviewing studies of prostate cancer risk, one should evaluate both the methodology of cancer detection and the particular population examined prior to making definitive conclusions.

TABLE 8–1. Established Clinical and Putative Molecular Risk Factors for Prostate Cancer Established clinical factors Age Race Family history Putative molecular factors Androgen receptor polymorphisms Cytochrome P-450 promoter variants Insulin-like growth factor-I Prostate-specific antigen

Androgen Receptor CAG Repeats Surprisingly, consistent mutations in genes associated with the androgen signaling pathway have yet to be described as a risk factor for prostate cancer. However, 44

Molecular Factors in the Assessment of Prostate Cancer Risk / 45

several polymorphisms in this pathway have been described as potentially important in this regard, and this section will examine these issues in some detail. The androgen receptor is part of a highly conserved family of steroid hormone receptors. Each of these family members is a protein containing three structural regions, a hormone-binding domain, a deoxyribonucleic acid (DNA)-binding domain, and a transactivation domain that modulates transcriptional activity (Figure 8–1). The androgen receptor gene is located on the X chromosome (Xq11-q12); thus, only one allele is responsible for gene expression in males. The first exon of the androgen receptor gene contains a region of CAG repeats which encode for a series of glutamine residues located in the middle of the receptor’s transactivation domain.1 Several populationbased studies indicate that this region is highly variable. Normal men may have anywhere between 11 and 31 CAG repeats in the androgen receptor gene with a corresponding number of glutamines in the androgen receptor protein.2 Androgen receptor function has been linked to CAG repeat length. A marked increase in CAG repeat length (40 to 60 range) has been detected in patients with Kennedy’s syndrome,3 an X-linked neurodegenerative disease accompanied by varying degrees of androgen insensitivity. Men with Kennedy’s have a blunted luteinizing hormone (LH)- and follicle-stimulating hormone (FSH)-suppression response after androgen administration, indicating impairment of androgen-mediated action.4 In vitro studies demonstrate that androgen-induced transcriptional activity is dependent on the number of CAG repeats in exon one. Transfection experiments with a series of androgen receptor genes containing a variable number of CAG repeats indicate that lower ligand-induced transcriptional activity is present in receptors with an increased number of CAG repeats.5 Furthermore, deletion of the CAG repeat region results in increased transcriptional activity.5 Additional studies have indicated that a higher number of androgen receptor CAG repeats is associated with a reduction in cellular messenger ribonucleic acid (mRNA) and protein levels.6 Thus, multiple mechanisms may abrogate androgen-receptor-mediated signal transduction in men with an increased number of CAG repeats. Several studies indicate that prostate cancer risk may be linked to germline androgen receptor gene CAG repeat length. In a preliminary study, Ingles and colleagues7 noted approximately a twofold increased risk of prostate cancer in men having a CAG repeat length of less than 20. Giovannucci et al.8 reported that the risk for developing prostate cancer was inversely proportional to CAG repeat length. In this report, 587 prostate cancer patients and 588 controls from the Physician’s Health Study were examined using a nested case-control design. Men with a repeat length of less than 19 had a 1.5-fold relative risk of prostate cancer compared to men with a repeat length of greater than 25. In addition to being at higher risk for prostate cancer, men

TABLE 8–2. Selected Polymorphisms Potentially Linked to Prostate Cancer Risk Androgen receptor Exon one CAG repeat length Exon one GGC repeat length Cytochrome P-450 (CYP) CYP3A4 upstream promoter variant

with shorter CAG repeats were also more likely to have poor prognostic markers such as advanced stage and/or poorly differentiated disease. When examining the subset of men with low-grade or low-stage cancers, CAG repeat length was not noted to be a risk factor. In a study by Hakimi and colleagues9 examining only patients undergoing radical prostatectomy for clinical stage B prostate cancer, men with lymph-node-positive prostate cancer were more likely to have a CAG repeat length of less than 18 compared with (literature controls) men with no history of prostate cancer. The odds of having a CAG repeat length of less than 18 were eightfold higher in Caucasian men with lymph-node-positive cancer compared to men with lymph-node-negative cancer. Taken together both the Giovannucci and Hakimi studies are consistent in that men with a shorter CAG repeat length have increased risk of nonorgan-confined prostate cancer. Another study, published by Stanford et al.10 did not demonstrate a statistically significant correlation between CAG length and prostate cancer risk when analyzing all subjects but did find increased risk for men who had both a CAG repeat length of < 22 and a GGN (a distinct polymorphism) repeat length of ≤ 16. Detailed studies of the family history of patients with prostate cancer indicate the possibility of an X-linked component to prostate cancer risk.11 The age-adjusted

A

B FIGURE 8–1. A, A schematic of the androgen receptor protein showing the regions of amino acid variability and the functional domains common to all steroid receptors. B, A schematic of the androgen receptor gene showing the CAG and GGN repeats in the first exon as well as the regions encoding the various functional domains in the androgen receptor protein.

46 / Advanced Therapy of Prostate Disease

prostate cancer risk in those with affected brothers exceeds that of those men with affected fathers, a finding consistent with (but not diagnostic of) an X-linked disease. Whether or not this risk is related to androgen receptor CAG repeat length or other recently described X-linked loci12 is not clear. Hardy et al.13 analyzed data from 109 Caucasian men with prostate cancer and concluded from a multivariate analysis that age of onset was linked to CAG repeat length (shorter repeats were linked to earlier onset of disease). The Hardy et al. report examined primarily patients originally diagnosed with advanced-stage disease. The Hakimi et al.9 report specifically examined this question as well and did not find an age-related association with CAG repeat length. As noted above, however, only patients undergoing radical prostatectomy were used in their data set. Comparison of data is hampered because of differences in the patient populations under investigation. Racial variation in CAG repeat length has been noted in several studies examining men with no known prostate cancer.2,14 These studies and other studies indicate that African American men have a statistically significant shorter number of CAG repeats as compared to nonHispanic Caucasians (mean 19 versus 21). A recent study indicates that approximately 57% of African American men have < 20 CAG repeats as compared to only 28% of non-Hispanic Caucasians in the United States.15 These differences could potentially explain the increased risk and earlier onset of prostate cancer in African American men compared with other ethnic groups. Because African Americans are consistently diagnosed with more advanced disease, CAG repeat length could potentially be a contributory factor for this observation as well. Additional studies are currently being conducted to specifically examine this hypothesis.

Androgen Receptor GGC Repeats In addition to containing a polymorphic CAG repeat in the transactivation domain, exon one of the androgen receptor also contains a polymorphic GGC repeat. The GGC repeat encodes for a variable number of glycines and is located approximately 1.1 kilobases 3' of the CAG repeat. The variable GGC repeat (4 to 24 triplets) follows an invariant (GGT)3GGG(GGT)2 repeat that also encodes for six consecutive glycines. The median and mean GGC repeat length are both approximately 16.9,10 Unpublished observations by Barrack and colleagues indicate that the GGC repeat length is shorter in African Americans as compared to Caucasians. Functional consequences, if any, have yet to be ascertained for variations in androgen receptor GGC length. Hakimi and colleagues9 report that men with prostate cancer are 4.6-fold more likely to have GGC repeats of < 15. Stanford and colleagues,10 in a study of 281 cases and

266 controls, reported that men with < 17 repeats have a 1.6-fold relative risk of prostate cancer compared to men with 17 or more repeats. Platz et al.,16 in the largest reported study of 582 cases and 794 controls, presented data suggesting that both increases and decreases above the mean were associated with slight elevations of risk. Taken together, these studies suggest modest increases in risk for men with a less-than-average number of GGC repeats. Interactions between the two androgen receptor exon one polymorphisms have also been evaluated. Stanford and colleagues10 examined the interaction between the two polymorphisms and concluded that men with both GGC of < 17 and CAG repeats of < 22 were at increased risk compared with men having longer GGC and CAG repeats.

Polymorphisms in the 5 Alpha-Reductase Gene The 5 α-reduction of testosterone to the potent androgen dihydrotestosterone (DHT) is catalyzed by the 5 α-reductase enzymes. Two forms of the 5 α-reductase enzyme have been described; current nomenclature designates these as type I and type II enzymes. A TA repeat is present in the 31 untranslated region of the type II gene. After examination of appropriate data sets, Kantoff et al.17 concluded that there was no relationship between type II 5 αreductase TA repeat length and prostate cancer risk.

Hormone Levels The androgen sensitivity of prostate cancer has been well described over the past five decades. Androgen withdrawal is clearly recognized as one of the cornerstones of management in patients with advanced prostate cancer disease. In addition, androgens are necessary for normal prostatic growth and development during puberty. Interestingly, however, data suggesting that variations in serum testosterone or DHT are a risk factor for prostate cancer in normal men are minimal or contradictory. A variety of studies measuring these potent androgens in both typical case-control and prospective studies indicate no significant elevation in risk associated with alterations in circulating testosterone levels.18–21 Low DHT levels have been associated with elevations in prostate cancer risk in some19 but not all20,21 studies. Low DHT/testosterone ratios have also been implicated as a prostate cancer risk factor in some18 but not all studies. Taken together, studies of hormones and prostate cancer are more compatible with a model in which serum androgen levels play a permissive rather than causative role. It is also readily conceivable that serum hormonal measurements may or may not correlate with intraprostatic hormonal measurements.

Molecular Factors in the Assessment of Prostate Cancer Risk / 47

Androgen Metabolism The cytochrome P-450 (CYP) enzyme system is involved in the metabolism of xenobiotics, pharmaceuticals, and a variety of endogenous and exogenous steroids including testosterone.22 The CYP3A enzyme subfamily is particularly important, being the predominant CYP expressed in both the liver and intestine.23 The CYP3 subfamily members catalyze the 2-, 6-, and 15-β hydroxylation of testosterone (in addition to a variety of other reactions). In liver microsomal preparations, the CYP3-dependent 6-β hydroxylation reaction accounts for 75 to 80% of testosterone’s oxidative metabolism.24 CYP3A activity is expressed in both normal and malignant prostatic tissue, however interindividual variation is high;25 only 61% of prostate cancers express the protein.26 This variability in expression has been hypothesized to result from a polymorphism within the 5' regulatory promoter.27 Approximately 14% of white men are heterozygotic and 3% homozygotic for an allele containing an A to G transition (CYP3A4-V) approximately 290 base pairs upstream from the CYP3A4 transcriptional start site in a region known to bind nuclear proteins and known to regulate CYP3A4 transcription rates.28 When examining a cohort of prostate cancer patients, men carrying a CYP3A4-V allele were more likely to present with advanced-stage disease as compared to men carrying the wild type (CYP3A4-W) allele.27 The authors of this study hypothesize that individuals expressing CYP3A4-V may have more bioavailable testosterone as a consequence of expressing less CYP3A4 enzyme. Whether or not men with or without this polymorphism are subject to an increased risk of prostate cancer awaits additional and appropriately controlled studies. Interestingly, this polymorphism in the CYP3A4 promoter region has also recently been linked to treatment-related leukemias.29

Insulin-Like Growth Factor-I Insulin-like growth factor-I has recently been linked to prostate cancer risk in a series of studies. The initial observation was a relatively small case-control study noting increased IGF-I in men with prostate cancer but not benign prostate hyperplasia.30 A much larger nested case-control study using data derived from the Physicians’ Health Study cohort has confirmed and extended this initial report.31 In the Chan et al.31 report, increasing plasma levels of IGF-I were directly linked to increasing prostate cancer risk. Importantly, this increased risk was detected in men with both normal and elevated PSA measurements, suggesting that these risk factors were independent of one another. When examining men with the highest quartile of IGF-I, the prospective risk of prostate cancer was increased 2.4-fold, relative to those with an IGF-I in the lowest quartile. In a multivariate

analysis adjusting for PSA and the major circulating IGF-I binding protein (IGFBP-3), men with a PSA ≤ 4 ng per mL and highest quartile PSA had a 4.3-fold prostate cancer risk. After a similar IGFBP-3 adjustment, men with a PSA > 4 ng per mL in combination with the highest quartile of IGF-I had a 17.5-fold risk of prostate cancer. On the basis of the findings of this study, a combination of PSA and IGF-I determinations could be used to construct a prospective risk-factor profile considerably more powerful than race or family history. Another large case-control study performed in Sweden has confirmed the association between IGF-I and prostate cancer32 and found this association to be particularly strong in men < 70 years old. In the Swedish study, no association was found between IGF-I level and stage at presentation, and no association was found between IGF-binding protein-3 (IGFBP-3) concentration and prostate cancer risk. The mechanism whereby IGF-I might contribute to prostate cancer risk may involve several potential pathways. Studies in prostatic tumor cell lines indicate that IGF-I can stimulate androgen-receptor-mediated gene transcription in the absence of exogenous androgen.33 Interestingly, this effect is blocked by antiandrogens. Experiments in animal models demonstrate that tumor growth can be inhibited by strategies designed to disrupt IGF-I signaling pathways. Overexpression of the inhibitory IGF-binding protein-4 (IGFBP-4) delays onset of prostate tumor formation.34 Furthermore, a dominant negative mutant of the IGF-I receptor inhibits prostate cancer growth in both soft-agar and animal models.35 Growth is stimulated by IGF-I in stromal as well as epithelial cells.36 These experiments indicate that disruption of IGF-I signaling pathways can inhibit prostatic tumor growth under a variety of modeled conditions. Interestingly, the secreted serine protease PSA can catalyze IGFBP-3 fragmentation.37 After PSA-induced cleavage, this binding protein has a markedly reduced IGF-I binding affinity. Thus, it is conceivable that PSA-secreting cells could increase “free” IGF-I concentrations in the local cellular microenvironment, thereby increasing the amount of IGF-I available to interact with its cell surface receptor. In the clinical setting, acromegalics have a marked increase in prostate volume that reverses with successful acromegalic treatment.38 Taken together, a variety of basic and clinical data support the concept that IGF-I can stimulate prostatic growth, and clinical studies clearly support the concept that increasing plasma IGF-I levels are associated with a substantially increased prostate cancer risk in men.

Prostate-Specific Antigen Prostate-specific antigen is a serine protease normally secreted by the prostatic epithelial cells during the ejaculatory process. Control of PSA transcription is, in part,

48 / Advanced Therapy of Prostate Disease

regulated by a typical androgen-response element located in the 5' regulatory region of the gene.39,40 Numerous studies indicate that PSA production is dependent on androgens. The role of PSA in the early detection and management of prostate cancer patients is well defined and well discussed in other aspects of this publication. Often overlooked, however, is the role of PSA in assessing the future risk of prostate cancer. In the provocative Physicians’ Health Study, serum and data were collected from 22,071 men (age 40 to 84 years) enrolled in the study beginning in 1982. After a decade of follow-up, 366 men diagnosed with prostate cancer were compared to 1098 age-matched controls for PSA measurements at the time of initial study enrollment.41 As anticipated, elevations in PSA (> 4.0 ng per mL) were associated with increased risk of prostate cancer (with a sensitivity and specificity of 73% and 91%, respectively). The estimated lead time between elevation of PSA and clinical diagnosis of prostate cancer was 5.5 years. These data support what numerous other publications have concluded: elevations in PSA are associated with individuals having an increased prostate cancer risk and PSA testing can lead to an earlier diagnosis of disease. Often overlooked in this study, however, is the fact that differences in PSA within the “normal” range were predictive of prostate cancer being diagnosed in the ensuing decade. This implies that PSA does not simply function as a tumor marker (as widely appreciated) but, rather, PSA can serve as a marker for future prostate cancer risk. In this study, men with a serum PSA between the range of 1.0 and 1.5 ng per mL had a 2.2-fold increased risk compared to men with a PSA of < 1.0 ng per mL. Men with a PSA in the 1.5 to 2.0 ng per mL range had a 3.4-fold risk and men with a PSA between 2.0 and 3.0 ng per mL had a 5.5-fold increased risk of prostate cancer (compared to men with a PSA of < 1.0 ng per mL). Though many interpretations of these data are possible, they are consistent with the hypothesis that PSA may function as a surrogate marker for androgen-mediated effects on prostatic gene transcription, which, in turn, is linked to prostate cancer risk. Alternatively, PSA, in and of itself, may have a procarcinogenic action. As noted above, interactions between PSA and IGF-I, a generally acknowledged prostatic growth factor, are consistent with the latter hypothesis.37 Clearly, more studies are warranted to explore both these hypotheses (and others) in more detail.

Summary Accumulated data over the past decade has considerably increased our understanding of molecular risk factors associated with prostate cancer. Many of these studies link alterations of androgen-signaling efficiency (or markers thereof) to prostate cancer risk. A series of polymorphisms in the androgen receptor (both CAG and

GGC repeat length) and androgen-metabolizing enzymes such as CYP3A4 are promising in terms of predicting future risk of prostate cancer; however, the levels of risk associated with these polymorphisms are considerably less than those associated with serum PSA and plasma IGF-I. Considerable future efforts are necessary to further define and explore these putative molecular risk factors and to devise methods of intervention that best capitalize on the information provided by their measurement.

References 1. Chang C, Kokontis J, Liao S. Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science 1988;240:324–6. 2. Edwards A, Hammond HA, Jin L, et al. Genetic variation at five trimeric and tetrameric tandem repeat loci in four human populations. Genomics 1992;12:241–53. 3. La Spada AR, Wilson EM, Lubahn DB, et al. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991;352:77–9. 4. Sobue G, Doyu M, Morishima T, et al. Aberrant androgen action and increased size of tandem CAG repeat in androgen receptor gene in X-linked recessive bulbospinal neuronopathy. J Neurol Sci 1994;121:167–71. 5. Chamberlain NL, Driver ED, Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 1994;22:3181–6. 6. Choong CS, Kemppainen JA, Zhou ZX, Wilson EM. Reduced androgen receptor gene expresssion with first exon CAG repeat expansion. Mol Endocrinol 1996;10: 1527–35. 7. Ingles SA, Ross RK, Yu MC, et al. Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J Natl Cancer Inst 1997;89:166–70. 8. Giovannucci E, Stampfer MJ, Krithivas K, et al. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci U S A 1997;94:3320–3. 9. Hakimi JM, Schoenberg MP, Rondinelli RH, et al. Androgen receptor variants with short glutamine or glycine repeats may identify unique subpopulations of men with prostate cancer. Clin Cancer Res 1997;3:1599–608. 10. Stanford JL, Just JJ, Gibbs M, et al. Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk. Cancer Res 1997;57:1194–8. 11. Monroe KR, Yu MC, Kolonel LN, et al. Evidence of an Xlinked or recessive component to prostate cancer risk. Nat Med 1995;1:827–9. 12. Xu J, Meyers D, Freije D, et al. Evidence for a prostate cancer susceptibility locus on the X chromosome. Nat Genet 1998;20:175–9. 13. Hardy DO, Scher HI, Bogenreider T, et al. Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset. J Clin Endocrinol Metab 1996;81: 4400–5. 14. Irvine RA, Yu MC, Ross RK, Coetzee GA. The CAG and

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GGC microsatelilites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res 1995;55:1937–40. Sartor O, Zheng Q, Eastham JA. Androgen receptor gene CAG repeat length varies in a race-specific fashion in men without prostate cancer. Urology. [In press] Platz EA, Giovannucci E, Dahl DM, et al. The androgen receptor gene GGN microsatellite and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 1998;7:379–84. Kantoff PW, Febbo PG, Giovannucci E, et al. A polymorphism of the 5 alpha-reductase gene and its association with prostate cancer: a case-control analysis. Cancer Epidemiol Biomarkers Prev 1997;6:189–92. Hsing AW, Comstock GW. Serological precursors of cancer: serum hormones and risk of subsequent prostate cancer. Cancer Epidemiol Biomarkers Prev 1993;2:27–32. Signorello LB, Tzonou A, Mantzoros CS, et al. Serum steroids in relation to prostate cancer risk in a case-control study. Cancer Causes Control 1997;8:632–6. Gann PH, Hennekens CH, Ma J, et al. Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst 1996;88:1118–26. Dorgan JF, Albanes D, Virtamo J, et al. Relationships of serum androgens and estrogens to prostate cancer risk: results from a prospective study in Finland. Cancer Epidemiol Biomarkers Prev 1998;1069–74. Cupp MJ, Tracy TS. Cytochrome P450: new nomenclature and clinical implications. Am Fam Physician 1998;57: 107–16. Lown KS, Ghosh M, Watkins PB. Sequences of intestinal and hepatic cytochrome P450 3A4 cDNAs are identical. Drug Metab Dispos 1998;26:185–7. Draper AJ, Madan A, Smith K, Parkinson A. Development of a non-high pressure liquid chromatography assay to determine testosterone hydroxylase (CYP3A) activity in human liver microsomes. Drug Metab Dispos 1998;26: 299–304. Agundez JA, Martinez C, Olivera M, et al. Expression in human prostate of drug- and carcinogen-metabolizing enzymes: association with prostate cancer risk. Br J Cancer 1998;78:1361–7. Murray GI, Taylor VE, McKay JA, et al. The immunohistochemical localization of drug-metabolizing enzymes in prostate cancer. J Pathol 1995;177:147–52. Rebbeck TR, Jaffe JM, Walker AH, et al. Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 1998;90:1225–9. Hashimoto H, Toide K, Kitamura R, et al. Gene structure of CYP3A4, an adult-specific form of cytochrome P450 in human livers, and its transcriptional control. Eur J Biochem 1993;218:585–95.

29. Felix CA, Walker AH, Lange BJ, et al. Association of CYP3A4 genotype with treatment-related leukemia. Proc Natl Acad Sci U S A 1998;95:13176–81. 30. Mantzoros CS, Tzonous A, Signorello LB, et al. Insulin-like growth factor-I in relation to prostate cancer and benign prostatic hyperplasia. Br J Cancer 1997;76:1115–8. 31. Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 1998;279:563–6. 32. Wolk A, Mantzoros CS, Andersson SO, et al. Insulin-like growth factor I and prostate cancer risk: a populationbased, case-control study. J Natl Cancer Inst 1998;90: 911–5. 33. Culig Z, Hobisch A, Cronauer MV, et al. Androgen receptor activation in prostatic tumor cell lines by insulinlike growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res 1994;54: 5474–8. 34. Damon SE, Maddison L, Ware JL, Plymate SR. Overexpression of an inhibitory insulin-like growth factor binding protein (IGFBP), IGFBP-4, delays onset of prostate tumor formation. Endocrinology 1998;139: 3456–64. 35. Burfeind P, Chernicky CL, Rininsland F, et al. Antisense RNA to the type I insulin-like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cell in vivo. Proc Natl Acad Sci U S A 1996;93:7263–8. 36. Grant ES, Ross MB, Ballard S, et al. The insulin-like growth factor type I receptor stimulates growth and suppresses apoptosis in prostatic stromal cells. J Clin Endocrinol Metab 1998;83:3252–7. 37. Cohen P, Graves HC, Peehl DM, et al. Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. Clin Endocrinol Metab 1992;75:1046–53. 38. Colao A, Marzullo P, Ferone D, et al. Prostatic hyperplasia: an unknown feature of acromegaly. J Clin Endocrinol Metab 1998;83:775–9. 39. Cleutjens KB, van Eekelen CC, van der Korput HA, et al. Two androgen response regions cooperate in steroid hormone regulated activity of the prostate-specific antigen promoter. J Biol Chem 1996;271:6379–88. 40. Zhang J, Zhang S, Murtha PE, et al. Identification of two novel cis-elements in the promotor of the prostatespecific antigen gene that are required to enhance androgen receptor-mediated transactivation. Nucleic Acids Res 1997;25:3143–50. 41. Gann PH, Henneckens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific antigen for detection of prostate cancer. JAMA 1995;273:289–94.

CHAPTER 9

SCREENING FOR PROSTATE CANCER: AN OVERVIEW DAVID C. MILLER, BS; DAVID K. ORNSTEIN, MD; GERALD L. ANDRIOLE, MD more slow growing or benign cancers.3 This occurs because tumors that grow rapidly and are more aggressive typically produce symptoms and are primarily identified by routine diagnostic procedures rather than screening tests. Length-time bias occurs when there is an impression of improved survival due to screening programs, based solely on the preferential detection of slowly progressive disease.6 These biases must be taken into account when assessing the value of any screening program.3

Prostate cancer is the most commonly diagnosed noncutaneous malignancy in American men and is exceeded only by lung cancer as a cause of cancer death among United States males.1 Estimates for 1998 indicated that over 180,000 men would be diagnosed with carcinoma of the prostate in the United States and more than 39,000 would die from this disease.1 In addition, a substantial fraction of United States health care dollars are allocated to diagnosis and treatment of this disease.2 The identification of serum prostate-specific antigen (PSA) measurements as a valuable tool for early diagnosis of prostate cancer has resulted in widespread implementation of early detection as a means to reduce the morbidity and mortality of this cancer. The importance of improving diagnosis and treatment for men with prostate cancer is unchallenged; however, the most efficient way of accomplishing this has been debated.

Screening for Prostate Cancer Proponents of widespread screening argue that current screening protocols result in detection of medically important prostate cancers while they are still organconfined and curable.5,7 To date, however, screening has not been proven to reduce morbidity and mortality.8 Critics of widespread screening therefore contend that the financial, emotional, and physical burdens of screening and subsequent diagnostic and therapeutic interventions may outweigh presumed benefits from screening.3 Given these conflicting viewpoints, it is not surprising that screening recommendations issued by various professional organizations have been highly variable and even contradictory. The American Cancer Society and the American Urological Association are in agreement in recommending that annual prostate cancer screening with digital rectal examinations (DRE) and PSA levels should be offered to all men starting at age 50 and for younger men who are at increased risk for prostate cancer.9 This protocol was approved by the Food and Drug Administration (FDA) in 1997.10 Recent recommendations from the American College of Physicians, however, do not endorse routine screening of all men but instead advocate an approach whereby physicians outline the potential benefits and known harms of screening, diagnosis, and treatment, discuss the patient’s concerns, and then allow the screening decision to be made on an individual basis.11 The United States Preventive Services Task Force does not currently recommend any routine screening for prostate cancer.9 Although disagreement on its appropriate use persists, screening for prostate cancer is widespread in the United States. Prostate Cancer Awareness Week, which was instituted in 1989, is now the largest cancer screening program in the nation and has attracted more than 3 million

General Principles of a Screening Test Screening tests are used to identify asymptomatic individuals with early stage, potentially curable disease. The ultimate goal of screening is to alter the prognosis of a given condition by identifying patients early and instituting effective therapy. For a screening program to be worthwhile, the disease of interest must fulfill a number of criteria including, but not limited to, the following: the disease must be common; it must be accompanied by significant morbidity and mortality if not treated; therapy must alter its natural history; and there must be some benefit in terms of outcome or associated morbidity when the disease is treated in the presymptomatic versus the symptomatic stage.3 Based on these criteria, prostate cancer screening is unquestionably appropriate,3 but the question of whether or not current screening programs have been successful in altering the natural history of this disease or improving outcomes for patients remains controversial.4,5 Two factors confounding interpretation regarding results of screening programs are “lead-time bias” and “length-time bias.” Lead-time bias may occur if early diagnosis results in patients living longer with a disease without ultimately affecting mortality.6 With lead-time bias, the apparent improvement in survival occurs only because of a shift in the date of diagnosis, and intervention produces no real prolongation of life. Length-bias sampling refers to the tendency of screening programs to preferentially detect 50

Screening for Prostate Cancer: an Overview / 51

participants.12 In addition, efforts are well underway to recruit over 300,000 men to participate in randomized, controlled trials in both the United States and Europe that may determine whether screening for prostate cancer improves mortality. The United States component of this international group, the National Cancer Institute’s Prostate, Lung, Colorectal, Ovarian (PLCO) screening trial, has already enrolled over 50,000 men.13 Given the highly promising data on screening currently available as well as the enormous public interest, it is clear that screening programs will remain prevalent for years to come.

Screening Tools Digital Rectal Examination Historically, the DRE was considered the first-line approach to screening for carcinoma of the prostate. Digital rectal examination has long been a component of routine health screening examinations for middle-aged and older men and is not associated with any additional risks or extra financial cost.11 Abnormalities on DRE associated with cancer and thereby indicating the need for prostate biopsy include induration, asymmetry, or nodules.14,15 While the true sensitivity and specificity of DRE remain undetermined, the positive predictive value of DRE for detecting prostate cancer has been estimated by various studies to be between 15 and 30%.11 Using the presence of nodules as criteria for biopsy, Thompson et al.16 reported a positive predictive value (PPV) of 26% while Chodak and associates detected 36 malignancies in 144 biopsies (PPV of 25%) that were performed based on detection of induration, asymmetry, or nodules on examination.14 In addition, DRE appears to have a low negative predictive value in that the absence of abnormalities on DRE does not appear to considerably reduce the patient’s odds of having a clinically significant cancer. Coley et al. suggest that this low negative predictive value is likely due to the low sensitivity of DRE for the detection of prostate cancer.11 Another confounding factor limiting widespread use of DRE alone as a screening tool is limited interexaminer reliability, even among urologists. This is demonstrated by a study by Smith and Catalona showing that DRE findings were disconcordant among examiners for half of cancers.17 Digital rectal examination by itself is a poor screening modality since cancers detected by DRE tend to be advanced and incurable.6 In a study by Thompson et al., 15 of 17 cancers detected by DRE revealed no evidence of metastases based on clinical staging; subsequent pathologic examination, however, resulted in upstaging to advanced, noncurable disease in 66% of cases.16 In addition, Chodak and associates reported that 50% of patients diagnosed with clinical stage B disease based on DRE findings were upgraded to stage C or D1 following pathologic examination of surgical specimens.14

There is a also a lack of data from controlled studies to indicate that screening with DRE alone alters survival from carcinoma of the prostate. In fact, when Gerber and associates examined prostate cancer mortality in men undergoing routine screening with DRE, they found that disease-specific survival was lower for men whose cancer was detected on a subsequent screening DRE than for men whose disease was diagnosed on the initial examination.18 Despite its ease of performance and low cost, therefore, DRE alone has limited, if any, utility in screening for prostate cancer. Recent data indicate that DRE may be complementary to PSA testing,3 however. When used together this combination represents the most effective screening tool for detecting prostate cancer in its earliest stages.15,19 In a community screening study, Bretton reported that 50% of men with both an abnormal DRE and PSA were found to have cancer at the time of biopsy. This represented a higher positive predictive value than for abnormalities in DRE or PSA alone.19 Similarly, Catalona et al. showed in a study of over 6000 men that the combination of PSA and DRE resulted in a greater than 80% improvement in cancer detection rates over DRE alone.15 More specifically, for patients with a PSA between 4.1 and 9.9 ng per mL, the presence of an abnormality on DRE increased the PPV of the PSA elevation to 49% from 24% with a normal DRE. Moreover, among patients with a total PSA higher than 10.0 ng per mL, the presence of a positive DRE resulted in a 69% PPV versus the 42% PPV seen in patients with a similar degree of PSA elevation but with normal physical exams.15 Similar findings were reported by Brawer and associates.20 In addition, a study by Babaian et al. reported a PPV of 75% for DRE and PSA in combination, compared to 59% and 51%, respectively, for PSA and DRE alone.21 These findings indicate that screening by digital rectal examinations enhances detection of early prostate cancer when performed in conjunction with PSA measurements. Prostate-Specific Antigen Prostate-specific antigen is the best single test for early diagnosis of prostate cancer and, along with DRE, has recently received FDA approval as an aid in the detection of prostate cancer in men 50 years of age and older.10 Since its introduction as a clinical marker nearly two decades ago, PSA has had a profoundly favorable impact on diagnosis and treatment of prostate cancer. The PSA produced by prostatic epithelial cells is not only secreted into prostatic fluid but enters the systemic circulation.3 In serum, PSA is primarily bound to the protease inhibitor α1-antichymotrypsin, and only a small fraction exists in an unbound or free form.22 Currently, the most frequently used assays measure total serum PSA, including both PSA bound to α1-antichymotrypsin and unbound PSA. The findings from six PSA-based prostate cancer screening studies15,20,23–26 are shown in Table 9–1. These results indicate that 8 to 15% of men who are older than

52 / Advanced Therapy of Prostate Disease

50 years of age will have an abnormal total serum PSA (> 4.0 ng per mL) on initial screening and that cancer will be detected in 1.5 to 4.1% of these patients. Based on followup biopsy results, the PPV of an elevated total PSA ranges from 11 to 34%. The false-positive elevations in serum PSA may have been due to one of a number of benign prostatic conditions or prostatic manipulations that have been shown or are speculated to produce elevations in total serum PSA to levels exceeding the threshold for suspicion of malignancy. Benign prostatic hyperplasia (BPH) is a common condition in men over 50 years of age and has been demonstrated in several studies to produce elevations in total serum PSA that overlap with levels associated with malignancy.27,28 In fact, Nadler et al. reported that prostate volume was the most important benign contributor to PSA elevation.28 The authors also reported that both acute and chronic prostatic inflammation accounted for some elevation in total PSA.28 Reports on the effects of ejaculation on PSA levels have been conflicting to date. Herschman et al. reported a statistically significant elevation in total PSA for up to 24 hours following ejaculation and concluded that PSA measurements within this interval may lead to inaccurate interpretation of both total and free PSA levels.29 In contrast, Stenner and associates found an initial postejaculation fall in PSA levels followed by a return to baseline over 12 hours. These authors concluded that ejaculation has no clinically significant impact on PSA levels and that patients need not abstain from sexual activities prior to PSA screening.30 The effect of finasteride on PSA levels is better defined, as several studies have shown that it lowers total serum PSA levels by 50% on average.31 Recently, Andriole et al. reported data demonstrating that doubling the total PSA level for men receiving finasteride preserves the sensitivity and specificity of PSA testing.32 Although false-positive results are possible, the risk of prostate cancer has been clearly and consistently shown to rise with total serum PSA levels, making this an efficacious test for prostate cancer screening.20,33 In a large multicenter trial reported by Catalona et al., the PPV for prostate cancer when the PSA was between 4.1 and 9.9 ng per mL was 26%

TABLE 9–1. Results from Prostate-Specific Antigen–Based Prostate Cancer Screening Trials Author Catalona23 Mettlin24 Brawer20 Labrie25 Catalona15 Catalona26

Initial PSA Elevation (%)

Cumulative Cancer Detection Rate (%)

8.34 14 15 12.4 9.4 15

2.2 1.5 2.6 4.1 3.1 3.3

Adapted from Arcangeli CG, Ornstein DK, Keetch DW, Andriole GL. Prostate-specific antigen as a screening test for prostate cancer: the United States experience. Urol Clin North Am 1997;24:299–306.

but this increased to over 50% when PSA levels were higher than 10.0 ng per mL.15 Although 4.0 ng per mL has traditionally been designated as the upper limit of normal, total PSA is not always above this level in men with clinically detectable and potentially dangerous prostate cancers. In a study by Brawer and Large, 32% of men with biopsyproven cancer had PSA levels of < 4.1 ng per mL.34 Further, Catalona et al. reported a cancer incidence of 18% in men with a “nonelevated PSA” who participated in a multicenter trial.15 In addition, a study by Gann et al. demonstrated that men with a baseline total PSA between 2.0 and 4.0 ng per mL have a 12-fold increased risk of prostate cancer after 10 years of follow-up when compared with patients whose baseline PSA was < 1.0 ng per mL.35 Smith et al. evaluated longitudinal data from a PSA-based screening program and found that men whose initial PSA was > 2.5 ng per mL had a 13-fold increased risk of being diagnosed with prostate cancer over 4 years of follow-up than those patients whose initial PSA was < 2.6 ng per mL.36 In a large prospective study by Catalona et al. of patients with a normal DRE and serum PSA between 2.6 and 4.0 ng per mL, 22% of the 322 men who underwent biopsy were found to have cancer and more than 80% of these lesions were pathologically localized and therefore potentially curable. Only 17% of surgically-staged tumors in this series were classified as clinically unimportant.37 Currently available evidence thus convincingly demonstrates that the risk of prostate cancer is minimal in patients whose total PSA is < 2.6 ng per mL but increases dramatically as PSA rises above 10.0 ng per mL. Given the sensitivity and specificity of these cutoffs for the detection of prostate cancer and the current practice of prostate biopsy for all patients whose PSA is > 10.0 ng per mL, it appears that measurement of total PSA alone may be sufficient to achieve optimal initial evaluation of these distinct cohorts. However, the apparent limitation in specificity of total PSA measurements in the “diagnostic gray zone” has led to the search for other tests to help stratify cancer risk among patients with total PSA levels of 2.5 to 10.0 ng per mL. Specifically, studies have evaluated the ability of selected PSA derivatives to improve the specificity of PSA screening. Several PSA transformations including PSA density, slope, age-specific PSA, and free PSA levels have been investigated. Prostate-Specific Antigen Density Prostate-specific antigen density is calculated by dividing the serum PSA level (in ng per mL) by the transrectal ultrasonography (TRUS)-determined prostate volume (in cubic centimeters). The PSA density has been promoted by some authors as a method of improving the specificity and PPV of PSA testing.38 Most studies that have evaluated PSA density report higher values in men with prostate cancer than in those without.38 Recommendations for PSA density cutoffs in men with total PSA levels between 4.0 and 10.0 ng per mL have ranged from 0.09 to 0.15 with

Screening for Prostate Cancer: an Overview / 53

variable effects on sensitivity, specificity, and number of biopsies performed.39,40 The variability in these findings may be a reflection of the practical limitations involved in determining PSA density, including the invasive nature and limited reliability of TRUS-determined prostatic volumes.10 The utility of PSA density in early detection protocols and the appropriate cutoff for improvement of specificity have yet to be fully elucidated. Prostate-Specific Antigen Slope The rate of change in total serum PSA over time (PSA slope or velocity) has been reported to be higher among men with prostate cancer than those with benign prostatic enlargement or no prostatic pathology.41 Several investigators have proposed a PSA slope of 0.75 ng per mL per year as a cutoff to enhance specificity for prostate cancer detection in PSA-based screening programs.41,42 Accurate determination of PSA slope, however, requires measurements over an 18-month time period and is therefore not useful in the short term but may be helpful in determining the need for repeat biopsy. Age-Specific Prostate-Specific Antigen Reference Range Age-specific PSA reference ranges have been proposed in the past as a means of improving the sensitivity of cancer detection in younger men (who would most benefit from aggressive diagnosis and treatment) and to enhance specificity of PSA screening among older men. In two separate studies, Oesterling et al. defined a set of age-specific PSA reference ranges and reported that their use in PSA-based screening studies resulted in an increased specificity (11%) and PPV (5%) for cancer detection, associated with a 9% decrease in sensitivity. In addition, the authors classified 95% of the missed cancers as clinically unimportant.43,44 These results were not confirmed, however, in a prospective, multi-institutional trial by Catalona et al. showing that the use of age-specific reference ranges would have prevented detection.45 While the use of age-adjusted PSA reference ranges does improve specificity of cancer detection in elderly men, this occurs at the expense of missing a substantial number of medically important tumors. The clinical use of this reference range has fallen out of favor.

prospective, multicenter clinical trial by Catalona et al. suggest that a free PSA cutoff of 25% or less is optimal for patients with total PSA values between 4.0 and 10.0 ng per mL and a benign DRE, irrespective of their age or prostate size. Using this cutoff, improvement in specificity over total PSA alone was evident in that 20% of unnecessary biopsies were avoided. Moreover, there was only a minimal loss of sensitivity as 95% of cancers identified by total PSA alone were also detected when a free PSA cutoff of 25% was employed.48 Thus, free PSA measurements may prove highly effective in limiting the number of unnecessary biopsies in screening programs, while preserving the sensitivity of cancer detection (Table 9–2).48 The ProstAsure index has recently been introduced. This index represents the product of a neural networkderived, nonlinear algorithmic procedure that is based on input variables including age, total PSA, and serum creatine phosphokinase and prostatic acid phosphatase levels.49 Preliminary studies suggest that ProstAsure may have an improved sensitivity and specificity for cancer detection when compared with free PSA at a cutoff value of 15%.49 The authors, however, emphasize that these findings will require confirmation in prospective clinical trials.

Effects of Prostate-Specific Antigen–Based Early Detection on Prostate Cancer Incidence While the optimal use of PSA and its derivatives continues to evolve, it is undeniable that screening for cancer with prostate-specific antigen has had a profound impact on incidence patterns for carcinoma of the prostate in the United States. Based on data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, the age-adjusted incidence rate of prostate cancer increased 84% between 1987 and 1992 from 102.9 cases per 100,000 to 189.4 cases per 100,000.50 Pototsky et al. also analyzed data collected by the SEER program and reported that the age-adjusted incidence rate of prostate cancer for men over 65 years of age in four SEER areas rose by 82% from 1986 to 1991, with the most dramatic annual increases occurring in 1990 (20%) and

Free Prostate-Specific Antigen Free PSA represents the small fraction of PSA that is unbound in serum. Several recent studies have shown that the percent serum free PSA (free PSA/total PSA × 100) is lower in patients with malignant prostatic disease than in those with benign prostates.45–47 These studies have demonstrated that free PSA measurements improve the specificity of prostate cancer detection in PSA-based screening trials without dramatically reducing sensitivity, and that the utility of free PSA may be greatest for patients whose total PSA falls in the diagnostic gray zone of 2.5 to 10.0 ng per mL. Results from a recently completed

TABLE 9–2. Probability of Prostate Cancer According to Free Prostate-Specific Antigen Cutoff* Free PSA Cutoff (%)

CaP (%)

0–10 10–15 15–20 20–25 > 25

56 28 20 16 8

*Among men with total PSA levels of 4.1 to 10.0 ng per mL and benign DRE. Adapted from Catalona WJ, Partin AW, Slawin KM, et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease. JAMA 1998;279:1542–7.

54 / Advanced Therapy of Prostate Disease

1991 (19%).51 When SEER sites in Connecticut and Minnesota were independently studied, changes in the incidence rates in these individual geographic locations were consistent with nationwide trends.52,53 The nearly universal explanation for the dramatic rise in the incidence of prostate cancer over this 5- to 10-year period is that it is a manifestation of widespread implementation of serum PSA testing.51,52 More specifically, Wingo et al. contend that when a screening test such as PSA is rapidly introduced and widely accepted by the population, the incidence rate for the disease of interest will invariably increase because cancers which would otherwise have been diagnosed at a later time will now be detected at an earlier stage, thereby increasing the incidence of the disease of interest.50 Moreover, Pototsky and colleagues commented that there is little evidence to suggest that the increased incidence of prostate cancer during this interval was linked to changes in the prevalence of theoretic risk factors such as prior vasectomy or increased consumption of dietary fat.51 While PSA-based screening did result in an initial rise in incident cases, subsequent epidemiologic data has revealed a decline in the age-adjusted incidence of prostate cancer since 1992. In his analysis of incidence data from the population-based Connecticut Tumor Registry, Polednak reported that for men in the age ranges 65 to 74, 75 to 84, and 85-plus years, the peak prostate cancer incidence in 1992 was followed by a decline such that in 1994 incidence rates in the 75 to 84 and 85-plus age groups had returned to or dropped below pre-PSA “baseline” rates dating from 1988.53 Significantly, this same study did not demonstrate a decline in prostate cancer incidence rates after 1992 in men between 45 to 54 and 55 to 64 years of age. The author hypothesized that the absence of such a decline in this population may be due to increased detection of cancers with long lead times.53 Stephenson et al., reporting on data from the Utah Cancer Registry, also described a decrease in the prostate cancer incidence rates from a peak of 236.2 cases per 100,000 in 1992 to 195.0 and 164.0 per 100,000 in 1993 and 1994, respectively.54 Merrill and associates reported similar declines after analyzing incidence data from eight different SEER locations.55 In addition, it was demonstrated in two large-scale studies that the cancer detection rate decreases to approximate the prostate cancer detection rate in the absence of screening after 3 to 4 years of serial PSA-based screening.36,56 Finally, evidence of this continued decline in the incidence of prostate cancer since 1992 led the American Cancer Society to make a midyear adjustment in their projections for the number of new cases in 1997, from 334,500 to fewer than 210,000 cases.50 Therefore, a more longitudinal evaluation of prostate cancer incidence in the PSA era indicates that the concern that widespread screening with PSA would lead to detection of a large number of possibly incidental carcinomas of the prostate was without foundation.

Effects of Prostate-Specific Antigen–Based Early Detection on Prostate Cancer Stage Prostate-specific antigen-based screening has also resulted in a dramatic stage migration among newly diagnosed prostate cancers and has increased the number of tumors that are organ-confined at the time of diagnosis twofold compared to the pre-PSA era. Historically, only 33% of cancers were pathologically organ-confined at the time of diagnosis.26,57 In contrast, cancers detected through PSAbased screening programs are much more likely to be organ-confined. In a study of 24,346 men by Smith and Catalona, 69% of tumors detected by initial PSA screening and 74% of those detected through serial screening were shown to be pathologically organ-confined when surgical staging was available.58 Similar findings were described by Catalona and associates who reported that pathologically organ-confined cancers were found in 63% and 71% of men undergoing initial or serial PSA-based screening, respectively.26 Mettlin et al. reported on a cohort of 2999 asymptomatic men between 55 and 70 years of age who participated in a multimodality early-detection program involving PSA, DRE, and TRUS; 64% of cancers detected in this series were proven to be pathologically organconfined.57 Finally, in the Hybritech study of 6630 men, the use of PSA in combination with DRE produced a 78% increase in the detection of organ-confined disease, and 71% of patients undergoing radical prostatectomy had prostate cancer that was pathologically organ confined.15

Characteristics of Prostate-Specific Antigen–Detected Cancers The preceding data demonstrates rather robustly that screening with PSA improves our ability to detect early, pathologically organ-confined carcinoma of the prostate. However, some have questioned whether this downward stage migration will improve mortality from prostate cancer and have suggested that many of the cancers detected through PSA screening are indolent and clinically unimportant. The controversy surrounding this question arises from the fact that, historically (in the pre-PSA era), there has been a discrepancy between the incidence of clinical prostate cancer and the high prevalence of the disease found at autopsy. Specifically, it has been reported that 30% of men over 50 years of age with no clinical evidence of disease are found to have adenocarcinoma of the prostate at the time of autopsy.59 To appropriately address this question, a number of studies have examined whether screening with PSA successfully detects cancer at an earlier stage without identifying an increased proportion of incidental or clinically insignificant cancer. The aggressiveness of a prostate carcinoma depends on its grade, volume, and PSA level, the latter of which

Screening for Prostate Cancer: an Overview / 55

increases in proportion to tumor volume.60 Consequently, the criteria that have traditionally been associated with medically important cancer include such clinicopathologic features as palpable tumor, multifocal or diffuse involvement, and moderately or poorly differentiated histology (Gleason score [GS] 4 or higher). In contrast, features of tumors that are more likely to be medically unimportant include those that are microfocal or have well-differentiated histology.58,59 In a Washington University study, only 3% of men with PSA-detected prostate cancer who underwent surgical staging were determined to have clinically insignificant disease based on the findings of impalpable, pathologically confined, well-differentiated (GS ≤ 4), minimal (≤ 0.5 cc) tumors.58 Moreover, Ohori and colleagues examined radical prostatectomy (RP) specimens from 306 cancers detectable by PSA, DRE, or TRUS and compared these to 90 cancers that were detected incidentally in cystoprostatectomy specimens. In this series, only 9% of the clinically detected tumors were classified as clinically unimportant versus 78% of the incidental cancers from the cystoprostatectomy specimens. In this same study, PSAdetected cancer was no more likely to be clinically unimportant than cancers detected by abnormal findings on DRE.59 Humphrey et al. assessed the pathologic features of 100 consecutive RP specimens from men in PSA-based screening programs and found that 94% of carcinomas had a clinically significant Gleason score of 5 to 8 and that in 68% of cases the tumor volume exceeded the clinically significant threshold of 0.5 cc.61 In addition, in a study of patients with elevated PSA and no palpable abnormalities on DRE, 65% of carcinomas examined following RP had a tumor volume greater than 1.0 cc and were therefore considered medically important.62 Finally, in a recent study, Douglas et al. analyzed 67 patients with stage T1c disease who underwent RP. They found that multifocal disease was present in 96% of specimens and, by study criteria, insignificant tumors were reported in only 4 cases.7 It seems that an overwhelming majority of the evidence indicates that most carcinomas detected by PSA elevation are medically important tumors deserving of early diagnosis and treatment (Table 9–3).

Effects of Early Detection on Cancer Mortality Although PSA-based screening has not been proven to reduce mortality in a randomized prospective trial, several pieces of evidence are highly suggestive that it will. As described previously, implementation of PSA-based screening produced a downward shift in cancer stage, with an increased incidence of organ-confined disease at the time of diagnosis and a decrease in the number of newly detected advanced cases.56,58,61 Most investigators, in turn, view this stable stage migration as actual evidence for a

reduction in mortality based on the ability of currently available therapy, particularly radical prostatectomy, to cure organ-confined disease.6,63 It is argued, therefore, that continued detection of early-stage disease through PSA-based screening protocols is the most effective strategy for ultimately achieving decreased mortality.6 In addition, there is significant indirect epidemiologic evidence suggesting that screening may indeed have a profoundly beneficial effect on survival and mortality. For instance, data from the SEER program indicates that the 5-year relative survival rates from prostate carcinoma have improved from 66.7% between 1974 and 1976 to 79.6% in the interval from 1983 to 1990.64 In a separate analysis of SEER data, a 20% increase in relative survival from carcinoma of the prostate from 1985 to 1993 compared to the period 1973 to 1980 was revealed.65 In addition, a decision model developed by the American College of Physicians suggests that, with appropriate treatment, the use of screening to detect organ-confined cancers in men between the ages of 50 and 69 years may increase life expectancy by up to 3 years.11 Finally, in 1996, the National Center for Health Statistics reported an estimated 6.3% decrease in mortality from prostate cancer in the United States from 1991 to 1995.66 Therefore, while the results of prospective, randomized trials are not yet available, the initial interpretation of data from the PSA era is highly promising with regard to impact on long-term survival. There are, however, alternate interpretations of the above data. Consistent with a decrease in mortality from prostate cancer, for example, these data may represent a manifestation of the lead-time bias and length bias associated with screening.67 More specifically, the present author suggests that the improved survival data may simply be due to prolonged awareness of the cancer’s existence without actual prolongation of the patient’s life. Also screening may merely be detecting slow-growing, less aggressive cancers which are nonlethal and would never require treatment.67 Others question whether early-stage prostate cancer can be cured by any means, citing the absence of controlled trials.8 It is clear that while most of the evidence is favorable, some disagreement remains concerning the interpretation

TABLE 9–3. Comparison of the Clinical and Pathologic Features of Prostate Adenocarcinomas Discovered by Prostate-Specific Antigen Screening* Median tumor volume Mean Gleason score % extra-capsular % < 0.5 cc and Gleason score ≤ 4

Autopsy

Cystoprostatectomy

T1c

0.05–0.15 4.8 0

0.02–0.17 5.1 2

0.5–2.4 6.8 20–48

94

78

5–15

*In cystoprostatectomy specimens, and at autopsy. Adapted from Ohori et al.,59 Smith and Catalona,58 Humphrey et al.,61 Scaletscky et al.,62 Douglas et al.7

56 / Advanced Therapy of Prostate Disease

of survival data from PSA-based studies as well as the true impact of early detection on mortality from carcinoma of the prostate. However, there appears to be an unwavering consensus, both within the urologic and the greater medical community, that the question of whether screening actually reduces prostate cancer mortality can only be answered by prospective, randomized controlled studies such as the National Cancer Institute PLCO screening study13 and the European Randomized Study of Screening for Prostate Cancer,68 both currently underway. The already widespread dissemination of prostate cancer screening will hopefully not compromise the completion or validity of these landmark trials. In summary, total serum PSA is the best single screening test for detecting prostate cancer. It is prostatespecific but not cancer-specific, as it may be elevated by a number of benign prostatic conditions as well as physical or pharmacologic manipulation of the prostate gland. The overlap of PSA elevations occurring in these various conditions makes the specificity of PSA as a cancer screening tool less than ideal. Nevertheless, widespread implementation of PSA-based screening has resulted in a dramatic increase in the detection of medically important, organ-confined prostate cancer and has greatly enhanced the potential for curative intervention and decreased mortality in men with this disease.

Economics of Prostate Cancer Screening Since prostate cancer is the most common visceral neoplasm in American men, the costs associated with its diagnosis and treatment represent a not insignificant component of United States health care expenditures. In a 1990 analysis by Optenberg and Thompson, it was estimated that the annual cost for clinical management of prostate cancer for men between 50 and 70 years of age prior to the widespread implementation of PSA-based screening programs was $255 million.69 However, as screening with PSA has become widely accepted in the past decade, estimates of health care expenditures related to prostate cancer have increased dramatically. Numerous studies have attempted to predict the actual costs associated with a single year of screening for prostate cancer in men between the ages of 50 and 70 years. In an updated analysis, Lubke, Optenberg, and Thompson estimated that the first-year cost of screening with PSA and DRE would be $25.7 billion in a scenario where organ-confined disease was managed with radical prostatectomy and more advanced tumors were treated with either radiotherapy or bilateral orchiectomy.70 This estimate was reduced to $17.6 billion when no treatment was undertaken for low-grade (GS 2–4), high-grade (GS 8–10), or T3 and T4 disease and all intermediate-grade disease was treated with radical prostatectomy.70 Kramer and colleagues proposed a similar exponential cost increase when they estimated an $11.9 billion price tag for the first year of screening in men from 50 to 74 years of age.71 This figure

includes the cumulative costs of screening, diagnosis, treatment, and any associated complications. Although there is little disagreement that widespread screening for prostate cancer has driven a profound increase in the share of health care dollars devoted to this disease, many authors have argued convincingly that this is money well spent. For instance, in a model developed by Benoit and Naslund, the cost per year-of-life saved by screening with DRE and PSA was estimated to be under $5000, which is significantly lower than the figures assigned to other medical interventions including mammography, liver transplantation, and control of hypertension.72 However, critics of this study contend that the authors’ consideration of a number of factors was incomplete, possibly altering their results, including their failure to figure time lost from work and lost productivity into estimates of societal costs of disease.73 In a separate analysis, Littrup estimated the cost of prostate cancer screening per quality-adjusted life year to be $14,200 to $51,267. Thus, the author concluded that screening for prostate cancer was cost effective when compared with the cost per quality-adjusted life year for breast cancer screening ($20,000 to $50,000) and fecal occult-blood screening for colon cancer ($35,054).74 The validity of these figures is limited, however, because many of the variables contributing to the estimates are subjective. As yet there is no truly accurate method to quantify the cost of each year of life saved by early detection of prostate cancer. In the context of these conflicting data and opposing viewpoints, the dramatic rise in expenditures associated with aggressive screening for carcinoma of the prostate will only be validated when it has been unequivocally demonstrated in appropriately designed trials that early detection and treatment reduce morbidity and increase disease-specific survival from prostate cancer.

Summary Serum PSA-based screening has been extensively studied for the past several years. It appears that we can comment with some certainty on the relative performance of serum PSA and DRE in detecting early-stage prostate cancer. We can also state that initial screening clearly improves detection of pathologically organ-confined, clinically significant cancers and has decreased the incidence of advanced disease. Moreover, epidemiologic data strongly suggests that annual, serial screening does not overdetect incidental carcinomas. Further, the specificity of prostate cancer screening may be enhanced as the optimal use of such PSA derivatives as PSA density, PSA velocity, and percent-free PSA are better defined. As these advances in diagnostic capability are coupled with an increased ability to predict the behavior and clinical significance of individual tumors, the already powerful argument for widespread PSA-based screening will become even more compelling. Currently, both the American Cancer Society and the American Urological Association recommend that

Screening for Prostate Cancer: an Overview / 57

annual DRE and total serum PSA measurements be offered to men older than 50 years of age and younger men at high risk for prostate cancer. The benefits of screening should be realized in men whose life expectancy exceeds 10 years and who are willing to undergo curative therapy for prostate cancer. Among younger men, PSA levels over 2.5 ng per mL should be considered suspicious and require further investigation. In men older than 65 years of age, a slightly higher PSA threshold of 4.0 ng per mL may be appropriate, and biopsy is indicated when total PSA exceeds this level. In addition, it appears that a free PSA cutoff of 25% improves specificity while maintaining sensitivity of PSA screening for patients whose total PSA is between 4.0 and 10.0 ng per mL. Finally, while the impact of prostate cancer screening on disease-specific mortality will not be fully defined until the completion of randomized, prospective clinical trials, PSA screening is undoubtedly the most effective current method for detecting organconfined disease, thereby affording patients a realistic chance to be cured of a potentially devastating disease.

References 1. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin 1998;48:6–29. 2. Kramer BS, Brown ML, Prorok PC, et al. Prostate cancer screening: what we know and what we need to know. Ann Intern Med 1993;119:914–23. 3. Goldstein MM, Messing EM. Prostate and bladder cancer screening. J Am Coll Surg 1998;186:63–74. 4. Brawley OW. Prostate carcinoma incidence and patient mortality: the effects of screening and early detection. Cancer 1997;80:1857–63. 5. Smith DS, Catalona WJ. The nature of prostate cancer detected through prostate-specific antigen-based screening. J Urol 1994;152:1732–6. 6. Andriole GL, Catalona WJ. Using PSA to screen for prostate cancer: the Washington University experience. Urol Clin North Am 1993;20:647–51. 7. Douglas TH, McLeod DG, Mostofi FK, et al. Prostate-specific antigen-detected prostate cancer (stage T1c): an analysis of whole mount prostatectomy specimens. Prostate 1997;32:59–64. 8. Collins MM, Barry MJ. Controversies in prostate cancer screening: analogies to the early lung cancer screening debate. JAMA 1996;276:1976–9. 9. Stein B, Lindenmayer JM. Proposed prostate cancer screening recommendations. Med Health RI 1997;80:343–5. 10. Arcangeli CG, Ornstein DK, Keetch DW, Andriole GL. Prostate-specific antigen as a screening test for prostate cancer: the United States experience. Urol Clin North Am 1997;24:299–306. 11. Coley CM, Barry MJ, Mulley AG. Early detection of prostate cancer. Part III: screening for prostate cancer. Ann Intern Med 1997;126:480–4. 12. DeAntoni EP. Eight years of “Prostate Cancer Awareness Week”: lessons in screening and early detection. Cancer 1997;80:1845–51.

13. Vanchieri C. Prostate cancer screening trials: fending off critics to recruit men. J Natl Cancer Inst 1998;90:10–2. 14. Chodak GW, Keller P, Schoenberg HW. Assessment of screening for prostate cancer using the digital rectal examination. J Urol 1989;141:1136–8. 15. Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal examination and serum prostate-specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6630 men. J Urol 1994;151:1283–90. 16. Thompson IM, Ernst JJ, Gangai MP, Spencer CR. Adenocarcinoma of the prostate: results of routine urological screening. J Urol 1984;132:690–2. 17. Smith DS, Catalona WJ. Interexaminer variability of digital rectal examination in detecting prostate cancer. Urology 1995;45:70–4. 18. Gerber GS, Thompson IM, Thisted R, Chodak GW. Disease-specific survival following routine prostate cancer screening by digital rectal examination. JAMA 1993;269:61–4. 19. Bretton PR. Prostate-specific antigen and digital rectal examination in screening for prostate cancer: a community-based study. South Med J 1994;87:720–3. 20. Brawer MK, Chetner MP, Beatie J, et al. Screening for prostatic carcinoma with prostate-specific antigen. J Urol 1992;147:841–5. 21. Babaian RJ, Dinney CP, Ramirez EI, Evans RB. Diagnostic testing for prostate cancer detection: less is best. Urology 1993;41:421–5. 22. Christensson A, Laurell C, Lilja H. Enzymatic activity of the prostate-specific antigen and its relation with extracellular serine protease inhibitors. Eur J Biochem 1990;194:755–63. 23. Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 1991;324:1156–61. 24. Mettlin C, Lee F, Drago J, Murphy JP. Findings on the early detection of prostate cancer in 2425 men. Cancer 1991; 67:2949–58. 25. Labrie F, Dupont A, Suburu R, et al. Serum prostate-specific antigen as a pre-screening test for prostate cancer. J Urol 1992;147:846–52. 26. Catalona WJ, Smith DS, Ratliff TL, Basler JW. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993;270:948–54. 27. Stamey TA, Yang N, Hay AR, et al. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987;317:909–16. 28. Nadler RB, Humphrey PA, Smith DS, et al. Effect of inflammation and benign prostatic hyperplasia on elevated serum prostate-specific antigen levels. J Urol 1995;154:407–13. 29. Herschman JD, Smith DS, Catalona WJ. Effect of ejaculation on serum total and free prostate-specific antigen concentrations. Urology 1997;50:239–43. 30. Stenner J, Holthaus K, Mackenzie SH, Crawford ED. The effect of ejaculation on prostate-specific antigen in a prostate cancer-screening population. Urology 1998; 51:455–9.

58 / Advanced Therapy of Prostate Disease 31. Guess HA, Gormley GJ, Stoner E, Oesterling JE. The effect of finasteride on prostate-specific antigen: review of available data. J Urol 1996;155:3–9. 32. Andriole GL, Walsh PC, Epstein JI, et al. Treatment with finasteride preserves the usefulness of PSA in prostate cancer (CaP) detection. J Urol 1998;159 Suppl: 277. 33. Catalona WJ, Hudson MA, Scardino PT, et al. Selection of optimal prostate-specific antigen cutoffs for early detection of prostate cancer: receiver operating characteristic curves. J Urol 1994;152:2037–42. 34. Brawer MK, Lange PH. Prostate-specific antigen: its role in early detection, staging, and monitoring of prostatic carcinoma. J Endourol 1989;3:227–36. 35. Gann PH, Hennekens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer. JAMA 1995;273:289–94. 36. Smith DS, Catalona WJ, Herschman JD. Longitudinal screening for prostate cancer with prostate-specific antigen. JAMA 1996;276:1309–15. 37. Catalona WJ, Smith DS, Ornstein DK. Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng per mL and benign prostate examination: enhancement of specificity with free PSA measurements. JAMA 1997;277:1452–5. 38. Benson MC, Whang IS, Olsson CA, et al. The use of prostate-specific antigen density to enhance the predictive value of intermediate levels of serum-prostate specific antigen. J Urol 1992;147:817–21. 39. Seaman E, Whang M, Olsson CA, et al. PSA density: role in patient evaluation and management. Urol Clin North Am 1993;20:653–63. 40. Smith DS, Catalona WJ, Keetch DW. Comparison of percent free PSA and PSA density as methods to enhance the specificity of PSA screening. J Urol 1996;155 Suppl: 422A. 41. Carter HB, Pearson JD, Metter EJ, et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA 1992;267:2215–20. 42. Smith DS, Catalona WJ. Rate of change of serum prostatespecific antigen levels as a method for prostate cancer detection. J Urol 1994;152:1163–7. 43. Oesterling JE, Jacobsen SJ, Cooner WH. The use of agespecific reference ranges for serum prostate-specific antigen in men 60 years old or older. J Urol 1995;153:1160–3. 44. Oesterling JE, Jacobsen SJ, Chute CG, et al. Serum prostate-specific antigen in a community-based population of healthy men: establishment of age-specific reference ranges. JAMA 1993;270:860–4. 45. Catalona WJ, Smith DS, Wolfert RL, et al. Evaluation of percentage of free serum prostate-specific antigen to improve specificity of prostate cancer screening. JAMA 1995;274:1214–20. 46. Woodrum DL, Brawer MK, Partin AW, et al. Interpretation of free prostate-specific antigen clinical research studies for the detection of prostate cancer. J Urol 1998;159:5–12. 47. Luderer AA, Chen Y, Soriano TF, et al. Measurement of the proportion of free to total prostate-specific antigen improves diagnostic performance of prostate-specific

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antigen in the diagnostic gray zone of total prostatespecific antigen. Urology 1995;46:187–94. Catalona WJ, Partin AW, Slawin KM, et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease. JAMA 1998;279:1542–7. Babaian RJ, Fritsche HA, Zhang Z, et al. Evaluation of ProstAsure index in the detection of prostate cancer: a preliminary report. Urology 1998;51:132–6. Wingo PA, Landis S, Ries LAG. An adjustment to the 1997 estimate for new prostate cancer cases. Cancer 1997;80: 1810–3. Pototsky AL, Miller BA, Albertsen PC, Kramer BS. The role of increasing detection in the rising incidence of prostate cancer. JAMA 1995;273:548–52. Jacobsen SJ, Katusic SK, Bergstralh EJ, et al. Incidence of prostate cancer diagnosis in the eras before and after serum prostate-specific antigen testing. JAMA 1995; 274:1445–9. Polednak AP. Trends in prostate carcinoma incidence in Connecticut (1988 to 1994) by age and race. Cancer 1997;79:99–103. Stephenson RA, Smart CR, Mineau GP, et al. The fall in incidence of prostate carcinoma: on the downside of a prostate-specific antigen induced peak in incidence— data from the Utah cancer registry. Cancer 1995;77: 1342–8. Merrill RM, Potosky AL, Feuer EJ. Changing trends in U.S. prostate cancer incidence rates. J Natl Cancer Inst 1996;88:1683–5. Labrie F, Candas B, Cusan L, et al. Diagnosis of advanced or noncurable prostate cancer can be practically eliminated by prostate-specific antigen. Urology 1996;47:212–7. Mettlin C, Murphy GP, Lee F, et al. Characteristics of prostate cancers detected in a multimodality early detection program. Cancer 1993;72:1701–8. Smith DS, Catalona WJ. The nature of prostate cancer detected through prostate-specific antigen-based screening. J Urol 1994;152:1732–6. Ohori M, Wheeler TM, Dunn JK, et al. The pathological features and prognosis of prostate cancer detected with current diagnostic tests. J Urol 1994;152:1714–20. Stamey TA, Kabalin JN, McNeal JE, et al. Prostate-specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. II. Radical prostatectomy-treated patients. J Urol 1989;141:1076–83. Humphrey PA, Keetch DW, Smith DS, et al. Prospective characterization of pathological features of prostatic carcinomas detected via serum prostate-specific antigen-based screening. J Urol 1996;155:816–20. Scaletscky R, Koch MO, Eckstein CW, et al. Tumor volume and stage in carcinoma of the prostate detected by elevations in prostate-specific antigen. J Urol 1994;152: 129–31. Gann PH. Interpreting recent trends in prostate cancer incidence and mortality. Epidemiology 1997;8:117–20. Smart CR. The results of prostate carcinoma screening in the U.S. as reflected in the Surveillance, Epidemiology, and End Results program. Cancer 1997;80:1835–44.

Screening for Prostate Cancer: an Overview / 59 65. Smart CR. Prostate cancer facts and fiction. J Surg Oncol 1997;66:223–9. 66. Shalala DE. Cancer death rate decline for the first time ever in the 1990s [press release]. Bethesda (MD): National Cancer Institute; 1996. 67. Brawley OW. Prostate carcinoma incidence and patient mortality: the effects of screening and early detection. Cancer 1997;80:1857–63. 68. Standaert B, Denis L. The European randomized study of screening for prostate cancer: an update. Cancer 1997; 80:1830–4. 69. Optenberg SA, Thompson IM. Economics of screening for carcinoma of the prostate. Urol Clin North Am 1990; 17:719–37.

70. Lubke WL, Optenberg SA, Thompson IM. Analysis of the first-year cost of a prostate cancer screening and treatment program in the United States. J Natl Cancer Inst 1994;86:1790–2. 71. Kramer BS, Brown ML, Prorok PC, et al. Prostate cancer screening: what we know and what we need to know. Ann Intern Med 1993;119:914–23. 72. Benoit RM, Naslund MJ. The economics of prostate cancer screening. Oncology 1997;11:1533–43. 73. Chodak GM. The Benoit and Naslund article reviewed. Oncology 1997;11:1543. 74. Littrup PJ. Future benefits and cost-effectiveness of prostate carcinoma screening. Cancer 1997;80:1864– 70.

CHAPTER 10

THE OPTIMAL DIAGNOSTIC TOOL: ASSESSMENT OF DIAGNOSTIC MODALITIES TO DETECT EARLY PROSTATE CANCER CHRIS H. BANGMA, MD, PHD; FRITZ H. SCHRÖDER, MD, PHD Screening for prostate cancer (PCa) is feasible due to the availability of diagnostic tools to detect prostate malignancy at an early and asymptomatic stage. None of the current diagnostic modalities, however, will detect cancer at an initial stage in which only molecular changes have occurred, or a stage in which only a few cells show histologic features of malignancy. Histologic studies of whole mount sections of prostate glands at autopsy have shown that the true incidence of prostate cancer at death is far more common than any early detection study with current diagnostic tools has ever indicated.1 The incidence of histologic cancer increases with age, as shown in populationbased early detection studies. This illustrates the lack of sensitivity of current screening modalities. What defines an “optimal” diagnostic tool? In terms of detection, this could be the tool (or combination of tools) that maximizes the number of detected cancers. The biologic behavior of prostate cancer shows, however, that not all men detected with a cancer will become symptomatic, or even ultimately die of it. It may therefore be desirable to diagnose the majority of cancers as harmless, or not diagnose them at all. In this sense, the optimal diagnostic tool should be able to inform about the aggressiveness of the detected cancer. Even better, it should inform about the pathologic stage of the disease so that decisions can be made as to whether the patient should undergo radical resection or other forms of available curative treatment. Diagnostic tools currently lack these qualities. Ongoing analysis of detected cancers may in the future enable clinicians to correlate diagnostic tests to some of the histologic and molecular qualities expected to be of prognostic value. The optimal diagnostic tool might be further defined in terms of patient comfort and financial and time effectiveness. These aspects can be summarized for most detection programs as the lowest number of biopsies (Bx) needed to detect one cancer, or Bx per PCa. In line with this, minimalizing the complications caused by the application of the screening modalities should be another goal of the optimal tool. Within the sequence of events from selecting participants from the population to undergo the screening protocol until death of a participant, several diagnostic steps

may be taken (Figure 10–1). The application of the diagnostic tools can be related to each of these events. Several of these events have been analyzed in the literature, such as the relationship between diagnostic tools and the frequency of prostate biopsy or the detection rate of cancers. More recently, the relationship between diagnostic testing and the histologic characteristics of radical prostatectomy specimens has been reported. Future studies will likely reveal the relationship between diagnostic tools and the characteristics of cancers found at death. It is clear that no single answer is to be expected in seeking the optimal diagnostic tool. Various aspects of detection, prognosis, and nondisease-related efficacy need to be combined. The question becomes even more complicated on the level of statistical comparison. Studies describing different populations with regard to age, race, geography, and selection for participation must be examined, any number of which may be defective in the presentation of their material and use of statistical methods. The underlying impossibility of proper comparison might restrict this investigation to a mere description of study results. This, however, does not diminish the value of the individual studies, which will shed light on forthcoming analyses of diagnostic tools.

Statistical Aspects It is important to discuss some of the statistical terms and methods used in evaluating diagnostic tools before examining specific modalities. Comparing different methods as diagnostic tools requires reproducibility of each method and agreement between different methods on the same item of diagnosis. Reproducibility of a tool, or test, can be expressed in intraobserver or assay variability (by the same observer), or interobserver (by two or more observers) variability. When measuring prostate-specific antigen (PSA), for example, it is possible to relate the numeric values of various determinations of the same serum sample at different closely related time points, and calculate the coefficient of variation by the ratio of the mean and its standard variation. This variation is theoretically dependent on the batch of chemicals and stan60

The Optimal Diagnostic Tool: Assessment of Diagnostic Modalities to Detect Early Prostate Cancer / 61

dards used, for which the term “lot-to-lot” variation is used, calculated similarly. Determination of the variation between different assays (interassay variation) is not very current as it is not justifiable to use different assays within the concept of one study, for frequently discussed reasons of assay design and the presence of PSA isoforms. The determination of reproducibility is less easy for digital rectal examination (DRE). The observer is usually not blinded to the patient and examination performed, and the examination result is at best semiqualitative, for example, “normal,” “suspicious,” or “cancer.” Analysis of the quality of DRE can only be performed as interrater agreement, for which “kappa” is calculated.2 Total agreement corresponds with a kappa of 1.00; in practice, a kappa value of below 0.50 is associated with poor agreement. The value of kappa depends on the proportion of subjects (prevalence) in each category and the number of categories. This makes the already small number of studies even less likely to be comparable. To improve the methods of diagnosis, intense research has been carried out to compare different diagnostic tools or tests, or their combinations, and seek agreement on the outcome. Up to the level of diagnosis, the endpoints are usually straightforward and dichotomous: to biopsy (yes or no); having cancer (yes or no). When the test is designed in such a way that its result is dichotomous, DRE suspect/not suspect, for example, or PSA above or below the cutoff level, simple terms can be used to describe the test. The quality of such a test can be expressed in its sensitivity and specificity in illustrating the proportion of men positive or negative that are correctly diagnosed by the test. This assumes, however, that the true prevalence of the disease is known; in this case, the true prevalence of prostate cancer in the population. Since this value is unknown for PCa, the test’s ability to predict the diagnosis or biopsy result must be evaluated, rather than the patient’s true disease status. Terms such as sensitivity and specificity can therefore only be used in patient populations with an expected similar prevalence of disease. Such information in most geographic areas is unknown. As a result, only studies assuming that disease prevalence is somewhat comparable due to the similarity in the distribution of race, diet, and migration between those areas can be compared. With the progression of large-scale screening programs, the age-adjusted cancer incidence will probably decrease,3 which may change the relative value of screening tools. Second-round screening tools may differ from those used in the first round. The use of the screening result and diagnosis as the gold standard of tumor incidence has led to unrealistically high estimates of the sensitivity of diagnostic tests in screening, especially in those groups where not every man is subjected to a diagnostic biopsy. From the incidence of cancers diagnosed in groups of screening participants in

which all men underwent PSA-driven biopsies, the “a priori prevalence” was extrapolated for men with a PSA below the cutoff value.4 This method gives a more realistic outcome of sensitivity calculations for tests applied in that PSA range. In practice, it is often more useful to know the number of patients with positive and negative tests that are correctly diagnosed. This is described by the positive predictive and negative predictive values of the test, both of which illustrate its accuracy. These predictive values are also unfortunately dependant upon prevalence, and therefore cannot be universally employed. The statistical method becomes more complicated whenever the test or endpoint is based on continuous rather than dichotomous measurements. Predicting cancer by the level of serum PSA (without the use of a cutoff), or the free to total PSA ratio (FT ratio), requires discriminant analysis based on logistic regression to assess the test. For the simplest dichotomous outcome (cancer yes/no), this means that sensitivity and specificity are calculated for every value of the test. Put together in a graph, this defines a receiver operator characteristic curve (ROC), originally based on signal detection by radar. Since such curves are used frequently, several aspects of this type of graphic representation are described below. Receiver operator characteristic curves help illustrate cutoff values and compare different tests in identical populations. They do not prove superiority of a clinical test

FIGURE 10–1. Diagnostic events (in squares) in the sequence of screening and follow-up for prostate cancer. The size and darkness of the curved arrows indicate the current knowledge regarding diagnostic tools. Block arrows indicate the function of diagnostic modalities regarding the outcome of events.

62 / Advanced Therapy of Prostate Disease

method, as decisions on choosing a method are based on more than statistical differences. The most favorable outcome of a test is represented by the upper left corner of the graph, in which the sensitivity and specificity of the test are both 100%. There are no false-negatives and false-positives at that point, and the test completely correlates with the gold standard of the specific diagnosis. Fitting a curve through that point would follow the lines of the axes, and the area under that curve would comprise the whole surface of the square lined by the axes. Compromise is necessary with every other graph because of the chance of false test results. The line x = y represents “sensitivity = 1 – specificity,” or “sensitivity + specificity = 100%.” This line shows the test result as if a coin is being tossed: the outcome of the test is correct in 50% of cases and the area under the curve is 50% of the surface, comprising 100%. To do better than chance, the test characteristic curve must shift above this line. The area under the curve then illustrates how often the test will predict a true outcome, given any cutoff value. This information might not be relevant, as clinically the point with a 10% sensitivity is not interesting. Curves with a higher predictive value, however, are usually shifted to the left into the clinically interesting areas. This “area under the curve” information is used as an argument in favor of differing testing procedures. Any point of the curve can be considered as a cutoff value for the test. The test result will be predicted by reading the sensitivity and specificity of the test on the x and y axes. Such a curve will always have a confidence interval that is smaller if the number of results used is larger. Often the desired sensitivity is high, occasionally 90 to 95%. The interesting portion then lies in the upper right corner of the graph, where the curve is almost horizontal. In that area, only a small change in the sensitivity based on its confidence interval will result in a considerable variation of the specificity. Unless such confidence intervals are mentioned, reports on improved specificity may be misleading when comparing sets of tests. Studies based on a small number of participants result in considerable confidence intervals, since charateristics other than those tested for, such as age and race, will influence the prediction of the test outcome of the group. In such cases, as a rule of thumb the standard error (SE) of quoted sensitivity and specificity of a dichotomous system may be calculated by the square root of the product of the studied frequencies of each group, divided by the number of participants. The 95% confidence interval can be estimated by plus or minus two times the standard error. This can also be regarded as the minimum significant difference needed to distinguish one sensitivity value from that of another curve. For example, assume that 300 biopsies are being studied, 60 of which are malignant. The diagnostic tool used detects 55 cancers correctly, and 200 benign cases correctly; sensitivity = 55/60 = 92%, with SE = (SqrRt [60 × 55 × 5])/60 = 2.1%; specificity = 200/240 = 83%, with SE

= 5.8%. In this scenario, an over 11.6% (related to 28 individuals) reduction of biopsies is required to significantly improve on the specificity of this method at this level of sensitivity. The point on the ROC curve nearest to the upper lefthand corner is frequently indicated as the optimal value of sensitivity and specificity. This point indicates merely the cutoff value where it would “cost” as much to have a false negative result as it would cost to have a falsepositive result, equalizing sensitivity and specificity. As mentioned before, the optimal cutoff value is determined by clinical decision.

Diagnosis by Biopsy: the Gold Standard Biopsy represents the gold standard of prostate cancer diagnosis. There is no better proof of the presence of a cancer than the histologic evidence. It is clear that the incidence of PCa is influenced by the method of prostate sampling. The real incidence of prostate cancer is unknown, as is the natural history concerning size and location within the prostate. In a small series of radical cystoprostatectomy specimens, removed for urothelial carcinoma, small volume prostate cancers were found in the absence of clinical symptoms.5 Prostate biopsies on autopsy specimens could provide data on the accuracy of prostate biopsies, permitting some extrapolation to a younger screening group. The biopsy procedure is a sampling procedure, and therefore PCa cannot be excluded with complete certainty. To assess the qualities of the sampling procedures, several attempts have been made to relate the technical aspects of taking biopsies (such as number, location, and direction) with histologic outcome (cancer-core length, tumor volume and location). The chance of hitting a carcinoma by random sextant biopsy decreased with increasing prostate gland size in computer simulations of a series of imaginative prostate glands harboring various sizes of cancer.6 Directing the sextant biopsies especially toward the lateral parts of the peripheral zone improved cancer detection.7 Not surprisingly, more cancers were found when the number of biopsies was increased in a clinical series.8 In this study, sampling with 7 to 11 additional biopsies in newly defined lateral and midline regions more than doubled the total number of detected tumors from 49 to 119. It was found that 83% of the cancers had a Gleason score of 6 or more; remarkably, the tumors appeared to be the same size as those in a sextant biopsy series. Computerized biopsy simulations on a series of mapped whole mount sections of radical prostatectomy specimens with PCa showed that the chance of missing a cancer with random sextant biopsies is considerable, estimated at about 25%.9 In a population of men diagnosed with prostate cancer, a second set of biopsies did not show malignancy in 27% of cases.10 There is a question whether the performance of an increased number of prostate biopsies will not only

The Optimal Diagnostic Tool: Assessment of Diagnostic Modalities to Detect Early Prostate Cancer / 63

increase the number of cancers but also influence the qualities of the cancers. Will the number of larger cancers increase (as they are easier to detect), or will a larger number of minor and clinically insignificant cancers be detected? In Terris’ series of sextant biopsies of 442 cancers detected in 816 patients, 10% of cancers had a tumor volume of < 0.5 mL.11 This arbitrary tumor volume of 0.5 mL has become a commonly cited threshold over the years for minimal or insignificant disease, especially when combined with a well-differentiated histology. The location of tumors, for example close to the prostate capsule, and features such as microvessel density, were not taken into account. Roughly 10 to 15% of tumors detected in various other series had the features of those detected at autopsy.12 Chen calculated that 18% of tumors with a volume < 0.5 mL (incidence in that series of 18%) carried a more than 90% chance of being identified by biopsy while this number in larger tumors was at least 73% and proportional to tumor size.13 Similar computer simulations were performed in 59 mapped autopsy prostates (derived from a series of consecutive autopsies) with clinically undetectable prostate cancers, in 25% of which PCa was found. The detection of multifocal cancers and cancers of larger volume increased compared to low-volume cancers.14 More important, single foci of well-differentiated cancers smaller than 0.5 mL went undetected by random sextant biopsies in 80% of specimens. Such volumetric and histologic criteria are used to define the significance of cancers but are subject to discussion, and various groups will report differently. Crawford came to a definition of insignificant cancer having a tumor volume of ≤ 0.25 mL with a maximum Gleason score of 7.14 The model detected 58% of asymptomatic significant and 20% of insignificant cancers. In Chen’s computer biopsy series, the number of detected smallvolume cancers doubled when the number of biopsies increased to 10 while that of the larger tumors detected increased from 107 to 147 (from 73% to 96%).13 This means that the number of small-volume cancers in screening will likely increase proportionally to the number of larger cancers, if the distribution of cancers is comparable to the population described by Chen. The proof of this will be demonstrated in those screening studies in which an adjustment of the protocol regarding biopsy indications alters the number of smaller cancers found. The effect of performing repeated series of biopsies may be questioned. Will the chance of detecting a cancer by performing two sets of random sextant biopsies be different than obtaining 12 at one time? Will a second round of screening detect the larger cancers missed in the first round, or will it only detect the less important small volume cancers? Not surprisingly, there was a 10% increase in the number of cancers detected in a series of men from a screening population biopsied for an increased PSA over 4 ng per mL after one previous series of negative biop-

sies.15 In the Rotterdam series, a similar result in rescreening by PSA, DRE, and transrectal ultrasonography (TRUS) after 1 year was reported. This series showed that the cancers detected during the second round of screening had similar histologic characteristics as those found during the first round of screening.16 Tumor volume appeared smaller but not significantly so. The second-round tumors were detected predominantly in prostates of larger total gland volume, suggesting that these had been missed during the first-round screening. This indicates that the number of biopsies may need to be adjusted to gland volume. Likewise, adjustment to age to decrease the risk of finding clinically unimportant disease may be of benefit for the elderly subset of men.17 This once again stresses the sampling nature of the current method for prostate biopsies. Assuming a second or third set of biopsies is justifiable in certain men with persistent abnormal screening tests, various authors have sought a way to predict a positive outcome and restrict the number of men who undergo rebiopsy. When performed on the indication of an increased PSA, an increased PSA density or a decreased FT ratio correlated to finding prostate cancer.18,19 There are a minority of cancers diagnosed in the transition zone of the prostate. These cancers are often confined but of larger volume, thereby increasing serum PSA. To detect these cancers, sextant biopsies with two additional transition-zone biopsies have been advocated in the case of an elevated PSA after a negative set of sextant biopsies.15 Carcinoma was detected in 19 of 166 participants (12%), and in 10% of men with cancer these were found in the transition-zone biopsies only. Some of the transition-zone cancers may still escape diagnosis, presenting an argument that some urologists should consider a diagnostic transurethral resection in the case of persistently elevated PSA.20 In a screening setting, 340 men with normal DRE and elevated PSA levels (using age reference values) underwent a biopsy regimen that included two transitionzone biopsies in addition to sextant biopsies.21 In 28 of 98 diagnosed prostate carcinomas (29%), only the transitionzone biopsies were positive for PCa. In 20 men (71%), these cancers were pathologically organ-confined. We are restricted to the diagnosis made on biopsies as the gold standard. Screening by biopsy only may be the best diagnostic tool presenting minimal complications.22 This approach, however, is not feasible due to the enormous costs involved. Also, overdiagnosis and overtreatment of insignificant cancers is a major concern and presents an argument that biopsies should be performed only after prescreening by modalities discussed below. More than 90% of cancers detected in the first round of screening by PSA and DRE are pathologically localized,23–25 and 10 to 15% of these are well-differentiated cancers of small volume (< 0.5 mL).16,26 Only our limited understanding of their natural history, with the possibility that they could be or become aggressive, life-threaten-

64 / Advanced Therapy of Prostate Disease

ing cancers, provides a rationale in retrospect for active removal of even small tumors. Adequate tools to predict insignificant tumors are lacking. In general, series of ultrasound guided sextant biopsies demonstrate adequate sensitivity. It is clear that the number of biopsies influences the chance of detecting PCa, and thus a strict comparison with sextant biopsy is not possible when the number of cases is limited to four. In a series of sextant biopsies plus TRUS lesion biopsies (seven or eight biopsies in total) the value of the extra biopsies increased the detection frequency minimally by 5%.27 Transrectal ultrasonography appeared to be better than DRE as a tool to direct biopsies.6 In Rotterdam, Rietbergen confirmed that the seventh biopsy uniquely detected only 5% of visible cancers (DRE normal and PSA < 4 ng per mL), that is, 19 of 298 cancers in 6533 men.4 Transrectal ultrasonography, however, appeared to be an excellent guidance tool, as 79% of the biopsies directed at hypoechogenic lesions showed malignancy.

The Classic Three: Prostate-Specific Antigen, Digital Rectal Examination, Transrectal Ultrasonography Various diagnostic modalities are discussed below, starting with the “classic” three: PSA, DRE, and TRUS. Most early detection efforts focused on these modalities, and each of them was at some time thought to be useful as an independent screening tool. In these studies, younger age was excluded from analysis, based on the clinical presentation of prostate cancer. Age, however turned out to be a valuable tool, especially in relation to PSA, and will be discussed in the section on prostate volume and age-related PSA adjustments. Prostate-specific antigen isoforms are discussed as well as tools for repeat screening. Prostate-Specific Antigen Determination of PSA in serum has become a major part of current urologic practice. Its importance as an indicator for prostatic disease, especially malignancy, is illustrated by the tremendous volume of literature referring to it and the presence of over 40 commercially available biochemical assays worldwide. Rapidly increasing interest in comparable serum PSA determinations has streamlined efforts to develop international biochemical standards.28 This development has been slowed by discrepancies between assays based on the existence of PSA isoforms in the serum29 and lack of understanding the physiologic variation of PSA in the serum. Assays for determining total PSA, hereafter referred to as PSA, currently show a low variation within and between batches, expressed as the coefficient of variation (CV). This CV is minimally dependent on the PSA range but is usually around 5 to 6%. Even for “ultrasensitive” assays developed especially for PSA ranges below 0.1 ng per mL, a good CV is obtained.30 These assays will not be discussed in this

chapter as they have no value for PCa screening. The low CV and the relatively low costs have made serum PSA an attractive instrument for mass screening. Variation between PSA assays is based on the design of the individual tests, in which the antibodies used bind to the various epitopes of the PSA molecule are of predominant importance. The oft-quoted PSA values determined by the Hybritech assay as reference material are mainly of historic interest and are commercially driven. The high quality of the biochemical performance of PSA assays is in sharp contrast to the physiologic variation observed in various studies. The difference between individual PSA determinations of healthy persons may be as large as 30% within 1 month30 and up to 55% over 1 year.31 Comparison between studies analyzing PSA variation is difficult due to the influence of the number of determinations, the time period between them, and the population studied. The number of reports of screening populations showing time-based PSA variation have been limited. The PSA variation over time, often referred to in terms of PSA velocity, has so far not shown any benefit for detecting PCa at a follow-up or second-round screening visit. More reports are expected in coming years. Prostate-specific antigen is a physiologic product of normal prostatic epithelial cells and not a tumor marker in itself. Various studies have claimed a significant and independent effect of age (r = .37 to .43) and of prostate volume (r = .55 to .56) on the serum PSA level.33–35 Others showed age and prostate size to be dependent factors, likely due to the higher age of the men analyzed.36 Up to 5 to 6% of the variation of serum PSA could be explained by age, and 30 to 34% by prostate size.34,36 It soon became evident that serum PSA concentration is relatively higher in men with PCa compared to those without. This is most likely due to increased “leaking” of the PSA into the abundantly available tumor capillaries rather than into the lumen of prostatic ducts at the apical side of the epithelial cell. The tumor-related contribution of serum PSA appears to correlate to tumor volume and, to a lesser extent, to its degree of differentiation.37 To distinguish healthy individuals from those with prostatic disease, and to select men at risk for PCa to undergo prostate biopsies, it became necessary to define normal reference values. The overlapping distributions of PSA values for healthy men and for those with PCa did not allow for a single PSA value discriminating both groups, and the extent of overlap was dependent on the population analyzed. In most screening programs, the initial goal was to maximize the number of cancers detected at an acceptable cost and morbidity, determine the incidence and characteristics of these cancers, and treat them accordingly. Subsequently, in order not to miss detectable and treatable cancers, a relatively low cutoff value of 3 to 4 ng per mL was chosen. Gradually it became evident that in the intermediate PSA range of 4 to 10 ng per mL, five to six biopsy pro-

The Optimal Diagnostic Tool: Assessment of Diagnostic Modalities to Detect Early Prostate Cancer / 65

cedures were performed to detect one carcinoma.38–41 To reduce the number of negative biopsies for psychologic and financial reasons, methods were designed to correct the slightly elevated PSA values for influences other than malignancy. It was therefore logical to normalize these PSA values to the other most evident measurable factors of increase: age and prostatic size. Age-Related Prostate-Specific Antigen Reference Values The concept of age-related PSA reference values is similar to that of the initially recommended PSA cutoff value of 4 ng per mL, based on the distribution of PSA values in a subset of the general population. Age-related reference values were defined for 5- or 10-year intervals as those including the lower 95% range of PSA values in clinically healthy individuals (Table 10–1). These age-adjusted reference values were aimed at increasing the sensitivity of cancer detection for individuals aged less than 60 years and to increase specificity in the elderly age group. In the latter group, various agerelated factors such as prostate size, infarction, and subclinical inflammation increase the serum PSA. This concept would theoretically have worked well for screening populations, as it appeared to do for clinical populations, if the distribution of PSA values (their median value and standard deviation) of men with PCa had not overlapped considerably with benign values. Catalona compared the age-specific PSA reference values with the use of a uniform PSA cutoff value for all ages in a multicentered screening study of 6630 men aged 50 years or older.42 In the age group under 60 years, 48 tumors were found in 256 biopsies indicated by an abnormal DRE or PSA over 4 ng per mL. An extrapolated increase of 15% in cancer detection at the cost of a 45% increase in the number of biopsies was calculated. In the older age groups actual observations showed that 8% of pathologically organ-confined cancers would have been missed by application of reference values for men aged 60 to 69 years, and up to 47% for men older than 70 years of age. As the number of quadrant biopsies needed to detect one carcinoma (Bx/PCa) remained constant across age groups, a uniform PSA cutoff of 4.0 ng per mL was advocated. To improve specificity in the older age group, Oesterling applied his recommended reference ranges in 2988 men aged 60 years or older.43 He found that 92 (5.5%) of the 1686 biopsies could have been avoided, of which 19 (21%) harbored a malignancy. Only one of those 19 cancers was histologically advanced. Cancer was detected in 20% of the remaining 94% of biopsies. The Bx/PCa ratio would therefore have changed from 2.8 to 2.7, a very limited gain. In the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rietbergen reported that the application of these reference values as a prescreen test would have led to the loss of 22

(13%) of all detectable cancers while avoiding 138 (14%) of all biopsies.22 This analysis was performed in a subset of men aged 55 to 76 years, all of whom underwent biopsies because of an elevated PSA of 4 ng per mL or more. To improve sensitivity in the older age group, Reissigl performed a screening study based on the PSA reference values as an initial screening test in men aged 45 to 75 years.44 Of 11,595 men, 8% had a PSA level of 4 ng per mL or more while 9% had an elevated PSA based on age reference values. Impalpable tumors were found in 16 men under 60 years of age with a PSA < 4.0 ng per mL. The number of biopsies increased by 66 (8%), from 778 to 844, and the number of detected carcinomas increased by 16 (8%), from 197 to 213. The Bx/PCa ratio remained at 3.9. All 16 cancers in this younger age group were pathologically organ-confined and none was reported to be “insignificant.” Overall, the readily applicable age reference values as prescreen values appear to have minimal additional benefit for cancer detection in a screening setting; too many detectable cancers are missed in the older age groups. Conversely, in the younger age group, the sensitivity for detecting significant tumors appears to increase, but the number of biopsies needed to detect these tumors increases significantly. It would be appropriate in future studies to re-evaluate the characteristics of lost tumors. It is possible that the loss of detected but relatively less harmful cancers is worth the gain in the number of organ-confined cancers in the younger age group, while leaving the overall Bx/PCa ratio unchanged. Prostate-Specific Antigen Density To normalize PSA values to prostate size, TRUS volumetry has been used to calculate the mean serum level of PSA related to 1 mL of prostatic tissue, or the PSA density (PSAD).45 Of all volumetric methods, step-section planimetry appears to be the most accurate and reproducible,46 but calculating prolate spheroid volume using caliper measurements is more time efficient and automatically available on most ultrasonic equipment. The application of PSAD was intended to add value to PSA alone, especially in the intermediate PSA range in which a relative indication for PSA-driven biopsy existed. Various studies addressing PSAD in screening populations are referenced in Table 10–2.42,47,48 The choice of a cutoff value is based on two studies. In a clinical population, Benson used 0.15 ng per mL per cc of prostate tissue as a cutoff value to discriminate between benign and malignant disease.45 Lee et al. altered their iniTABLE 10–1. Age-Related PSA Cutoff Values (ng per mL) Author

PSA Correlation to Age

Oesterling34

0.43

PSA = prostate-specific antigen.

N

40–49 Years

50–59 Years

60–69 Years

70–79 Years

471

2.5

3.5

4.5

6.5

66 / Advanced Therapy of Prostate Disease TABLE 10–2. PSAD as Indicator for Biopsies in the Intermediate and High PSA Range Author, Year

PSA

N

Cutoff (ng/mL/cc)

Bx/PCa

Reduction in Number of Bx (%)

Missed PCa(%)

Littrup, 199447 Catalona, 199442

4–10 4–10

154 161 DRE negative 1202

0.12 0.10 0.15 0.10 0.12 0.15

2.3 2.5 2.3 2.8 2.6 2.3

12 58 75 19.6 28.6 40.7

0 21 48 5 8.6 14.1

Rietbergen, 199848

≥4

PSAD = prostate-specific antigen density; PSA = prostate-specific antigen; Bx = biopsy; PCa = prostate cancer; DRE = digital rectal examination.

tial cutoff of 0.20 to 0.12 ng per mL per cc as a result of their analysis of the screening population from the American Cancer Society–National Prostate Cancer Detection Project (ACS-NPCDP) study.49 In their subsequent analysis they argued for the use of PSAD and DRE as selection tools following the application of serum PSA, leading to a cost-effective biopsy protocol.47 Their analysis showed that among 2558 participants, 60 cancers in 154 biopsies would have been detected due to an elevated PSA level while PSAD required only 136 biopsies to yield the same number of cancers. The study, however, was marred by a low biopsy compliance, and its multicenter design does not guarantee high consistency in ultrasonic procedures and indications for biopsy. Catalona objected to the use of PSAD based on the data of his multicentered screening study of nearly 5000 men.42 Reasoning that PSAD would be used to detect unpalpable carcinomas in the PSA range between 4 and 10 ng per mL, Catalona analyzed PSAD in a group of 734 men, of whom 161 had a normal DRE and who consented to random quadrant biopsies. In these 161 participants, 33 cancers were detected. Using a PSAD of 0.150 ng per mL per cc or more, 16 of 33 impalpable cancers were missed, 9 of which were organ-confined. Reducing the number of biopsies performed by 75% obviously did not outweigh the loss of detectable and confined carcinomas, even when the PSAD cutoff level was lowered to 0.100. These numbers are less dramatic when related to the total number of biopsies performed for an elevated PSA of > 4 ng per mL. The number would be reduced from 464 (with 151 cancers) to 344 (with 135 cancers), improving the overall Bx/PCa ratio from 770/192 (= 4.0) to 650/176 (= 3.7). In a further attempt to correct for benign changes of prostate size and PSA elevations, the size of the ultrasonically visible transition zone representing benign prostatic hyperplasia was used to adjust serum PSA values. Some studies claim a higher correlation between the transition zone volume and PSA compared to that involving total prostate volume.50 The PSA transition zone density (PSAT) is calculated by the ratio of PSA and TRUSdetermined transition zone volume.51 These ultrasonic measurements are more susceptible to observer variation compared to volumetry of the entire prostate gland.46 Applied to a screening population, Rietbergen found no better performance of PSAT compared to PSAD in his

analysis of 1202 biopsied participants with a PSA of > 4 ng per mL.48 At a PSAT cutoff of 0.16 ng per mL per cc, a reduction of 20.0% of biopsies would have been obtained at the cost of missing 5.8% (21 of 361) of detectable cancers. Reissigl claimed in 380 screened men between 45 and 75 years of age with an elevated PSA according to age-reference values in the PSA range between 2.5 and 10 ng per mL, that 24% of negative biopsies (n = 77) could have been avoided without missing any of the 58 prostate cancers (Bx/PCa = 5.3), using a cutoff value for the PSAT of 0.22 ng per mL per cc.21 These results are impressive, but from the data published it is impossible to say whether this biopsy reduction occurred mainly in younger men in the screening population (aged 45 to 59 years [55%]). These men were healthy volunteers, 22% of whom had biopsies, resulting in a 0.9% cancer incidence. For some reason, PSAD was not analyzed. Although Reissigl announced a prospective study using PSAT, it seems reasonable to conclude at this time with available data that PSAT has limited value in reducing the number of unnecessary biopsies in screening programs. Digital Rectal Examination Although DRE was used as the sole screening tool up to only one decade ago, this concept belongs now to the urologic history books. Results of studies on DRE, often case finding series, relate the incidence of palpable tumors only to age. The average detection rate with DRE alone appeared to be 1.4% between 51 and 70 years of age. Bentvelsen and Schröder provide a worthwhile overview of an era when larger screening efforts by PSA and DRE had just been started.52 From the introduction of PSA onward, incidence analysis of tumors detected by DRE has been influenced by the higher biopsy frequency for men with a serum PSA above the cutoff level for prostate biopsies. The value of DRE should be considered separately for men with and for those without an additional biopsy indication but a suspicious finding on DRE. The value of DRE in men with an extra biopsy indication, such as an elevated PSA, is not for detection but for staging and prognosis. Digital Rectal Examination with Prostate-Specific Antigen Less than 4 ng per mL Several screening studies that employed DRE as the sole biopsy indicator in PSA ranges lower than 4 ng per mL

The Optimal Diagnostic Tool: Assessment of Diagnostic Modalities to Detect Early Prostate Cancer / 67

are summarized in Table 10–3. Early detection in a community setting, involving 148 clinical centers, found 322 cancers in almost 32,000 participants over 50 years of age screened by PSA and DRE in the first screening round.53 Unfortunately, 46% of men with suspicious findings refused further investigations by biopsy. In the Rotterdam screening program of the ERSPC for men between 55 and 70 years of age, a similar positive predictive value (PPV) of 13% was found for men with a suspicious DRE and a PSA < 4 ng per mL.4 Whole mount sectioning of 15 prostates of the men operated on showed that all of them had a tumor volume < 1 mL (median < 0.41 mL) and a Gleason score of 7 or less. Since biopsies are not performed in men with a normal DRE and a PSA < 4 ng per mL, a negative predictive value (NPV) for DRE cannot be adequately calculated. Only a few studies provide such information in a screening setting by performing a biopsy in all study participants. Smith compared two screening arms of a study involving 30,000 men over 50 years old, screened by DRE and PSA. Biopsies were performed in 2466 men on the indication of a suspicious DRE and/or a PSA > 4 ng per mL in the one arm, and in 198 men with a similar indication but a PSA of > 2.5 ng per mL in the other arm.25 Remarkably, the PPV of DRE in both groups was identical at 28%. Response rates of participants to undergo prostate biopsies were approximately 33% in the combined arm versus 80% in the second arm, a difference which may have influenced the results. The predictive value of DRE in the lower PSA ranges appears to be small and is correlated to the serum PSA level.4 The tumor characteristics of these DRE-detected cancers do not show aggressive features such as unfavorable tumor size or pathologic grade. The DRE-detected tumors were not larger compared to the size of tumors detected by ultrasonography, and had similar histologic features. The low PPV and restricted reproducibility of DRE suggest that the results of a digital examination are influenced by serendipity. The DRE indicated a tumor by chance alone in 20 to 30% of cases, as was calculated from the correlation between palpability and the location of a histologic tumor at the side of the palpable lesion.4 Studies analyzing DRE as an aid to direct prostate biopsy also showed that contralateral tumor detection often occurred in the biopsies remote to the palpable lesion (on the side), illustrating that no additional help was provided by DRE for this purpose.52 Therefore, in the low PSA range below 3 or 4 ng per mL, DRE appears to be a poor screening tool. Nevertheless, it would be unrealistic to say that DRE does not play any role at all in screening in the low PSA range. The DRE does detect a number of carcinomas that are almost always confined to the prostate and therefore curable. Tailoring a screening approach might be feasible.

In the ERSPC screening population of 8367 participants, only four cancers were found by DRE or TRUS in the 1702 (20%) men with a PSA of ≤ 1 ng per mL. These welldifferentiated cancers had a volume of < 0.5 mL. This means that 20% of the population can be safely screened by PSA only. Detection of cancers on the indication of DRE only with a PSA between 1 and 3 ng per mL showed 43 cancers in 4619 men (55% of the screening population) at the cost of a Bx/PCa ratio of 10.4 Above a value of 3 ng per mL, the PPV of DRE and PSA might be compared in groups in which the biopsies are driven by a PSA cutoff of 3 ng per mL. Lodding calculated a PPV of 19% for DRE between 3 and 4 ng per mL PSA in 243 men, all biopsied, among whom 32 cancers were found.55 Five of the tumors were palpable and their histology appeared similar to the T1c cancers. Digital Rectal Examination with ProstateSpecific Antigen Greater than 4 ng per mL In the PSA range indicating biopsies (usually 4 ng per mL Hybritech and higher) the value of DRE initially has been analyzed to restrict the number of biopsies indicated by PSA only. With the maturation of screening data, however, it has become clear that a large number of detectable cancers were impalpable and classified as T1c according to the 1992 TNM classification. In the PSA range of 4 to 10 ng per mL, DRE detected 115 of 249 cancers correctly (PPV = 45%) while 123 detectable cancers in the same group of 1095 screening participants were impalpable.4 These T1c cancers did not differ in their histologic features from palpable lesions classified as T2a-b in the intermediate PSA ranges, nor were they different in tumor volume.16 They may therefore be regarded as equally significant for prognosis. This implies that at present DRE is important mainly in the clinical staging of detected tumors. Transrectal Ultrasonography The value of TRUS for screening has not always been analyed from a purely scientific point of view. Transrectal ultraTABLE 10–3. Cancers Found by DRE Below a PSA Cutoff Value of 4 ng per mL Author, Year Crawford, 199653 Smith, 199725 Mettlin, 199341 Lodding, 199855 Schröder, 19984

PSA < 4

DRE+

PCa

PPV (%)

28,846

3032

78

14.6

16,926

1433

143

12.4

2999

260

29

11

243

55

11

20

7055

639

82

12.8

Remark Low biopsy compliance Low biopsy compliance DRE and/or TRUS positive PSA range 3.0–4.0 Mean tumor volume 0.5 mL

DRE = digital rectal examination; PCa = prostate cancer; PPV = positive predictive value; PSA = prostate-specific antigen; TRUS = transrectal ultrasonography.

68 / Advanced Therapy of Prostate Disease

sonography is time consuming and therefore of considerable cost; two adverse factors for a screening program. Furthermore, TRUS is operator-dependent, and its interpretation learning curve is considerable. Though studies for intra- and interobserver reproducibility have been limited to volumetry of the prostate gland, most experts on TRUS will agree that only larger lesions are readily recognizable. Cancers will be most frequently heralded by hypoechogenic lesions, and fewer than half the biopsied hypoechogenic lesions in clinical series will show histologic malignancy.56 Evaluation of TRUS for detection of PCa in a screening setting is limited to a small number of studies. Mettlin reported on the multicentered screening effort of the ACS-NPCDP, in which the use of TRUS led to twice the number of biopsies compared to DRE in the first screening round (14.1 versus 6.7%).57 The PPV of TRUS by itself was 6% compared to 7.8% for DRE only. In the Rotterdam component of the ERSPC, TRUS was performed on all 3963 participants during the period 1992 to 1997, independent of DRE or PSA results.4 As biopsies were indicated on abnormal DRE or a raised PSA level (> 4 ng per mL), the results of TRUS-driven biopsies differ among those with one or more biopsy indications. With TRUS as sole indicator (PSA < 4 ng per mL), a PPV of 6.7% was shown, to that of DRE (8.1%) as sole indicator, approximating Mettlin’s results. The number of biopsies required to detect one cancer was 11.2 for TRUS and 10.0 for DRE. Remarkably, biopsies indicated by a combination of an abnormal TRUS and DRE in this low PSA range showed cancer in approximately 20% of men biopsied, which is similar to biopsies indicated by an increased PSA of more than 4 ng per mL. The apparent efficacy of cancer detection by the TRUS/DRE combination, however, is flawed by the characteristics of the detected tumors, as the mean tumor volume was 0.5 mL while the mean tumor volume in the PSA range between 4 and 10 ng per mL was 1.22 mL. These results motivated the change of the Rotterdam screening protocol in 1996 to screening with PSA only. The TRUS procedure has always been regarded as an important adjunct in guiding prostate biopsy. In protocols in which TRUS was not incorporated as a primary screening tool, application of TRUS during the biopsy procedure revealed suspicious lesions that were biopsied in addition to or instead of the usual random biopsies. The value of these extra biopsies appeared to be minimal, as discussed above. Currently, TRUS is considered by few to be of additional value in staging prostate cancers. Ongoing efforts to establish automated interpretation of gray-scale images may improve its diagnostic performance. Intravenous administration of ultrasonic contrast agents for the application of color-Doppler ultrasonography enhances tumor recognition for experienced clinicians.57 In screening for prostate cancer, however, TRUS currently has no role apart from its value of visualizing the prostate gland.

Prostate-Specific Antigen Isoforms With the discovery of PSA isoforms in the serum, a new era in tumor markers began. Prostate-specific antigen was found to circulate as a free, uncomplexed molecule in the blood or to bind to a number of serum proteins, of which α-antichymotrypsin (ACT) and α2-macroglobulin appeared predominant.58 The complexing process influenced some of the normally available antigenic sites on the free PSA molecule in such a way that various antibodies could no longer detect the PSA molecule. This phenomenon offered the opportunity to measure free and complexed forms, as complexing differed in men with prostate malignancies compared to those without.29 No obvious metabolic explanation for this phenomenon has yet been found. As ACT is abundantly available in the circulation but ACT production is increased within some prostate cancer cells as well as in cells found in hyperplastic nodules,59 research is ongoing to find an intracellular mechanism for complex formation.60 New assays for determining different forms of complexed PSA and for other members of the kallikrein family, such as the human glandular kallikrein hK2, are on the horizon. The binding of PSA to ACT was the first complex studied. Assays were developed measuring the free fraction compared to the total serum PSA concentration. This was expressed as a percentage, or as the free-to-total ratio (FT ratio). The FT ratio of men with PCa was on average lower compared to those without PCa but a considerable overlap between the distribution of these values existed in clinical series.61 Further, it became evident that due to the specific affinity of antibodies for their antigenic site, the total PSA value could be influenced. Assays were reported to be equimolar when the affinity of the antibody used for total PSA determination was equal between free and complexed PSA forms, resulting in the same total PSA value for any FT ratio. Although total PSA determinations theoretically may decrease due to this “skewed response,” these alterations are most likely of minor importance compared to the previously discussed physiologic changes of PSA. The mean variation of the FT ratio appears to be 15% over several weeks and not influenced by age or total PSA level.62 The determination of a useful cutoff level for the FT ratio has remained an obstacle. Although the FT ratio does not change significantly with age,63 it does increase with prostate volume. An extensive review of primarily clinical studies analyzing the application of the FT ratio concluded that specificity can be increased by use of the FT ratio. It remains unclear, however, how to use it (for what patient group, at which cutoff level), necessitating extensive multicentered studies for further assessment.64 Initial optimism that the FT ratio would improve cancer detection and reduce the number of negative biopsies has thus been tempered. The above article shows a figure of Van Cangh illustrating the dependency of the cancer

The Optimal Diagnostic Tool: Assessment of Diagnostic Modalities to Detect Early Prostate Cancer / 69

probability predicted by the FT ratio in different populations with variable cancer prevalence.65 In a number of reports the improved specificity of a test is based on a significantly larger area under the ROC curve. This indicates an overall quality of the test while the curves may assist in illustrating and choosing a cutoff level. Unfortunately, the statistical significance does not imply a clinically important advantage. In well-defined subsets of men, the use of the FT ratio in addition to PSA might be safe and justified when it has been assessed ultimately in connection with the characteristics of the cancers detected. In screening settings, the application of the FT ratio appeared potentially valuable when used in the intermediate PSA range between 4 and 10 ng per mL although it remained unclear which cutoff value to use. The reduction of the number of biopsies, however, may not be outweighed by the loss of the number of detectable cancers. Moreover, the cancers lost for detection were all histologically confined to the prostate.66 In the lower PSA range, no study has been performed in which the FT ratio was used as an indication for biopsy in all participants. For the PSA range from 2.5 to 4 ng per mL, Catalona found enhanced cancer detection in 332 men with normal DRE when biopsies would be indicated by the FT ratio.67 Catalona recommended performing biopsies when the FT ratio was below the cutoff value of 27%. This suggests, however, that too many false-positive indications for biopsy would be indicated by the FT ratio.68 In the PSA range above 10 ng per mL, the FT ratio appears universally low, and its use to exclude men from biopsy with a high FT ratio does not seem to be justified due to the strong probability of cancer suggested by PSA alone. Only a few studies exist that attempt to compare the use of the FT ratio to other additional modalities, such as PSAD or age reference values. For the PSA range between 3 and 4 ng per mL, Lodding calculated that the use of the optimal combination of FT ratio and PSAD in men with normal DRE would have reduced the number of biopsies indicated by a PSA > 3 ng per mL by 21% (from 217 to 172), resulting in a sensitivity for PCa of 93%.55 This was better than use of a single modality, as they each reduced the number of biopsies 10 to 12% at the same level of sensitivity. Bangma reported that the combined use for men from a screening population with a PSA between 4 and 10 ng per mL would reduce the number of biopsies by 40% at a cost of missing 12% of cancers.66 Of the cancers detected by FT ratio, 85% were the same as those detected by PSAD. It remains an intriguing question whether there is a fundamental relationship between the different concepts of PSAD and the FT ratio. The effect of a decreased FT ratio or an elevated PSAD is theoretically higher when the partial tumor volume in the prostate is larger compared to that of the normal tissue. So far, reports about the improved specificity of the FT ratio for prostate cancer in specific volumetric ranges of the prostate gland are

clinically based and no additional value has been found in screening populations.

Sequential Screening The performance of diagnostic tests has thus far been highlighted for first-round screening only. Several largescale screening protocols have included follow-up visits for participants with negative results during initial evaluation. Some of these studies have reported on intermediate results.48,57,69 Clearly, the composition of the screened population changes after filtering out detectable cancers with each screening round.57 Therefore, subsequent results of the application of screening tools will change. One modality adequate for first-round screening might be worthless for further screening. On the other hand, newly applied tools may be useful. Prostate-specific antigen velocity might be such a tool. In small retrospective studies, an exponential increase in the PSA level was observed during the 5-year period previous to cancer diagnosis. This PSA change correlated roughly with the cancer stage at the time of diagnosis. Increase in PSA, often expressed for reasons of simplicity in ng per mL per yr (PSA velocity), has been analyzed in several screening settings.57,70,71 The cutoff value of 0.75 ng per mL per year, proposed by Carter and based on observations in a selected group of patients with PCa, did not have any discriminatory value over a study period of 1 year.71 In Mettlin’s study57 extending over 5 years, men with PCa appeared to have, in almost 50% of cases, a PSA increase of more than 0.5 ng per mL per year compared to 12% of men with benign prostates. It is not clear from this study how many observations were involved or the mean observation period until the diagnosis of cancer. It is obvious, however, that an increase of 0.5 ng per mL per year cannot be justified as a biopsy indication when 12% of participants without disease show the same increase. The correlation between the risk of carcinoma and an increasing serum PSA has been observed, but biologic variation of serum PSA is the main obstacle to the clinical application of these changes. Kadmon confirmed the considerable biologic variation of PSA in men without prostate cancer in a screening population. He advised at least three annual PSA measurements before an increase in PSA should be considered abnormal.72 In 327 men aged 50 years or older who had previous negative biopsies in a screening setting, PSAD or a PSA increase of more than 0.75 ng per mL annually (measured over a variable time period) in the presence of an elevated PSA or abnormal DRE could not stratify adequately between benign and malignant disease.73 In general, it should be expected that the cancer detection rate decreases after the first screening and levels off after several evaluations. Tumors may become smaller and more difficult to detect by palpation and ultrasonography unless they are of a fast-growing character. Further, some of the detected tumors will be those that had been

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missed by previous biopsies due to sampling error. This general trend of decreasing incidence has been observed by Stephenson3 as well as by the ACS-NPCDP.57 In this multicentered study, the first round incidence of 2.8% decreased to a value of 1.1 to 2.1% during subsequent years. During the 5 years of follow-up, 203 cancers were detected with DRE, TRUS, and PSA in 2999 men aged 55 to 70 years, of which 1575 completed five visits. The PSA level, PSAD, and PSA change were all related to the presence of cancer, but due to the mixed screening designs of participating centers the exact value and optimal use of the various screening modalities is difficult to assess. It was reported that TRUS and DRE became less effective indicators for positive biopsies over time. In the primary screening round of the Rotterdam section of the ERSPC, 1875 of 8013 men had been biopsied for suspicious findings on DRE or TRUS or an elevated PSA, of which 374 (20%) harbored a malignancy.4 Those with negative biopsy results were screened again after 1 year, and 442 biopsy procedures were performed in 984 men. Prostate cancer was found in 49 men (11%). The pathologic tumor characteristics and tumor volumes after radical prostatectomy of 11 of these rescreened men were not significantly different from those found in the first screening round. The fraction of well-differentiated smaller sized tumors appeared to be equal in both screening rounds. The average size of the prostate glands in which they were detected, however, was significantly larger (53.4 mL versus 43.6 mL) than those in which PCa was diagnosed during the first screening. This suggests that they were the result of sampling error at the first biopsy, rather than the presence of a rapid growing or aggressive type of PCa.

Choosing the Best Screening Tools The choice of optimal screening tools depends on the population characteristics and attitudes toward participant comfort, scientific goals, local opportunities, and costs. These factors may differ worldwide and may change with maturation of screening data. Adjustments to screening protocols should be based firmly on data obtained from our own or comparative studies,22 rather than on gradual changes made by individual contributors within multicentered projects.57 Multivariate analysis of factors involved and subsequent statistical simulations based on significant risk factors are important steps in evaluating and redesigning screening strategies. Until screening endpoints in terms of mortality and quality of life are evaluable, intermediate endpoints such as tumor detection followed by pathologic and prognostic characteristics of detectable cancers should be used to evaluate and determine optimal screening modalities. Limitations of current screening tools may be summarized as follows:

• The drawbacks of the gold standard, which is a set of ultrasound-guided sextant prostate biopsies, are known, but it is not known whether a change of method or technique will be advantageous. • Simple and excellent serum tools (PSA and FT ratio) are available, but biologic variation limits their serial application. • Cancers can be identified much better than 10 years ago, but it is not known to what extent screening tools correlate with the clinical significance of the disease. • There may be enough information about the various screening tools to design nomograms to increase specificity in the prediction of prostate cancer, but their application is restricted due to considerable confidence ranges. It is likely that in the very near future, information will become available that will force project managers to tailor protocols to subgroups of specific age, race, or participants for follow-up. It has already become clear that positive family history, African American origin, or the histologic finding of prostatic intraepithelial neoplasia are conditions representing an increased risk of harboring or developing prostate cancer. One of the major goals for PCa detection programs is to distinguish the bad from the relatively benign cancers. Regardless of screening tools, numerous cancers are found, enough to determine the differences in mortality in screened and unscreened populations. Whenever randomized screening studies prove that prostate screening is at all justified, accurate current and future data will be indispensable to formulate optimal screening regimens.

References 1. Sakr WA, Grignon DJ, Crissman JD, et al. High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20 to 69: an autopsy study of 249 cases. In Vivo 1994;8:439–43. 2. Smith DS, Catalona WJ. Interexaminer variability of digital rectal examination in detecting prostate cancer. Urology 1995;45:70–4. 3. Stephenson RA, Smart CR, Mineau GP, et al. The fall in incidence of prostate carcinoma. On the down side of a prostate specific antigen induced peak in incidence— data from the Utah Cancer Registry. Cancer 1996;77: 1342–8. 4. Schröder FH, van der Maas P, Beemsterboer P, et al. Evaluation of the digital rectal examination as a screening test for prostate cancer. Rotterdam section of the European Ranomized Study of Screening for Prostate Cancer [see comments]. J Nat Cancer Inst. 1998;90: 1817–23. 5. Stamey TA, Freiha FS, McNeal JE, et al. Localized prostate cancer. Relationship of tumor volume to clinical significance for treatment of prostate cancer. Cancer 1993; 71:933–8. 6. Stricker HJ, Ruddock LJ, Wan J, Belville WD. Detection of nonpalpable prostate cancer. A mathematical and laboratory model. Br J Urol 1993;71:43–6. 7. Hodge KK, McNeal JE, Terris MK, Stamey TA. Random

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25. Smith DS, Humphrey PA, Catalona WJ. The early detection of prostate carcinoma with prostate-specific antigen: the Washington University experience. Cancer 1997;80:1852–6. 26. Humphrey PA, Keetch DW, Smith DS, et al. Prospective characterization of pathological features of prostatic carcinomas detected via serum prostate-specific antigen-based screening. J Urol 1996;155:816–20. 27. Hodge KK, McNeal JE, Stamey TA. Ultrasound guided transrectal core biopsies of the palpably abnormal prostate. J Urol 1989;142:66–70. 28. Stamey TA, Prestigiacomo AF, Chen Z. Standardization of immunoassays for prostate-specific antigen. A different view based on experimental observations. Cancer 1994;74:1662–6. 29. Stenman UH, Leinonen J, Alfthan H, et al. A complex between prostate-specific antigen and alpha 1-antichymotrypsin is the major form of prostate-specific antigen in serum of patients with prostatic cancer: assay of the complex improves clinical sensitivity for cancer. Cancer Res 1991;51:222–6. 30. Fritsche HA, Babaian RJ. Analytical performance goals for measuring prostate-specific antigen. Clin Chem 1993; 39:1525–9. 31. Prestigiacomo AF, Stamey TA. Physiological variation of serum prostate-specific antigen in the 4.0 to 10.0 ng per mL range in male volunteers. J Urol 1996;155:1977–80. 32. Riehmann M, Rhodes PR, Cook TD, et al. Analysis of variation in prostate-specific antigen values. Urology 1993;42:390–7. 33. Babaian RJ, Miyashita H, Evans RB, Ramirez EI. The distribution of prostate-specific antigen in men without clinical or pathological evidence of prostate cancer: relationship to gland volume and age. J Urol 1992;147:837–40. 34. Oesterling JE, Jacobsen SJ, Chute CG, et al. Serum prostate-specific antigen in a community-based population of healthy men. Establishment of age-specific reference ranges. JAMA 1993;270:860–4. 35. Collins GN, Lee RJ, McKelvie GB, et al. Relationship between prostate-specific antigen, prostate volume, and age in the benign prostate. Br J Urol 1993;71:445–50. 36. Bosch JL, Hop WC, Bangma CH, et al. Prostate-specific antigen in a community-based sample of men without prostate cancer: correlations with prostate volume, age, body mass index, and symptoms of prostatism. Prostate 1995;27:241–9. 37. Stamey TA, Kabalin JN, McNeal JE, et al. Prostate-specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. II. Radical prostatectomy-treated patients. J Urol 1989;141:1076–83. 38. Mettlin C, Lee F, Drago J, Murphy GP. The American Cancer Society National Prostate Cancer Detection Project. Findings on the detection of early prostate cancer in 2425 men. Cancer 1991;67:2949–58. 39. Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer [published erratum appears in N Engl J Med 1991;325(18):1324]. N Engl J Med 1991; 324:1156–61. 40. Labrie F, Dupont A, Suburu R, et al. Serum prostate-specific antigen as prescreening test for prostate cancer. J Urol 1992;147:846–52. 41. Mettlin C, Murphy GP, Ray P, et al. American Cancer Society: National Prostate Cancer Detection Project. Results from multiple examinations using transrectal

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58. Lilja H, Cockett AT, Abrahamsson PA. Prostate-specific antigen predominantly forms a complex with alpha 1antichymotrypsin in blood. Implications for procedures to measure prostate-specific antigen in serum. Cancer 1992;70:230–4. 59. Bjork T, Bjartell A, Abrahamsson PA, et al. Alpha 1antichymotrypsin production in PSA-producing cells is common in prostate cancer but rare in benign prostatic hyperplasia. Urology 1994;43:427–34. 60. Bjartell A, Bjork T, Matikainen MT, et al. Production of alpha-1-antichymotrypsin by PSA-containing cells of human prostate epithelium. Urology 1993;42:502–10. 61. Christensson A, Bjork T, Nilsson O, et al. Serum prostatespecific antigen complexed to alpha 1-antichymotrypsin as an indicator of prostate cancer. J Urol 1993;150:100–5. 62. Ornstein DK, Smith DS, Rao GS, et al. Biological variation of total, free, and percent-free serum prostate-specific antigen levels in screening volunteers. J Urol 1997;157: 2179–82. 63. Oesterling JE, Jacobsen SJ, Klee GG, et al. Free, complexed, and total serum prostate-specific antigen: the establishment of appropriate reference ranges for their concentrations and ratios. J Urol 1995;154:1090–5. 64. Woodrum DL, Brawer MK, Partin AW, et al. Interpretation of free prostate-specific antigen clinical research studies for the detection of prostate cancer. J Urol 1998;159:5–12. 65. Van Cangh PJ, De Nayer P, De Vischer L, et al. Free-to-total prostate-specific antigen (PSA) ratio improves the discrimination between prostate cancer and benign prostatic hyperplasia (BPH) in the diagnostic gray zone of 1.8 to 10 ng per mL total PSA. Urology 1996;48:67–70. 66. Bangma CH, Rietbergen JB, Kranse R, et al. The free-tototal prostate-specific antigen ratio improves the specificity of prostate-specific antigen in screening for prostate cancer in the general population. J Urol 1997; 157:2191–6. 67. Catalona WJ, Smith DS, Ornstein DK. Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng per mL and benign prostate examination. Enhancement of specificity with free PSA measurements. JAMA 1997;277:1452–5. 68. Bangma CH, Kranse R, Blijenberg BG, Schröder FH. The value of screening tests in the detection of prostate cancer. Part II: Retrospective analysis of free/total prostate-specific analysis ratio, age-specific reference ranges, and PSA density. Urology 1995;46:779–84. 69. Smith DS, Catalona WJ, Herschman JD. Longitudinal screening for prostate cancer with prostate-specific antigen. JAMA 1996;276:1309–15. 70. Brawer MK, Beatie J, Wener MH, et al. Screening for prostatic carcinoma with prostate-specific antigen: results of the second year. J Urol 1993;150:106–9. 71. Carter HB, Epstein JI, Chan DW, et al. Recommended prostate-specific antigen testing intervals for the detection of curable prostate cancer. JAMA 1997;277: 1456–60. 72. Kadmon D, Weinberg AD, Williams RH, et al. Pitfalls in interpreting prostate-specific antigen velocity. J Urology 1996;155:1655–7. 73. Keetch DW, McMurtry JM, Smith DS, et al. Prostatespecific antigen density versus prostate-specific antigen slope as predictors of prostate cancer in men with initially negative prostatic biopsies. J Urol 1996;156: 428–31.

CHAPTER 11

SCREENING FOR PROSTATE CANCER: THE CASE FOR SCREENING ROBERT J. NEJAT, MD; CHRISTOPHER W. JOHNSON, MD; MITCHELL C. BENSON, MD The American Cancer Society (ACS) estimates that there will be 179,300 new cases of prostate cancer diagnosed in 1999, making it the most commonly diagnosed malignancy among men in the United States. In addition, a projected 37,000 men will die this year secondary to prostate cancer. As a result, the ACS and the American Urological Association (AUA) have put forth guidelines recommending that annual serum prostate-specific antigen (PSA) testing and digital rectal examination (DRE) be offered to men aged 50 and older who have at least a 10-year life expectancy. The PSA and DRE should also be offered to younger men at high risk for developing prostate cancer, such as African American men or men with a strong family predisposition to the disease (two or more affected first-degree relatives, e.g., father, brother). Information should be provided to patients regarding the risks and benefits of intervention.1 In order for prostate cancer screening to be deemed a successful and worthwhile endeavor, three separate and distinct goals must be satisfied. First, we have to demonstrate that screening increases the diagnosis of earlier stage prostate cancer. Second, we have to prove that patient survival is prolonged, and lastly, a decrease in the prostate cancer–specific mortality rate has to be demonstrated. There is a large body of evidence to support the theory that prostate cancer screening increases the diagnosis of earlier stage prostate cancer.2–5 The incidence of newly diagnosed, organ-confined prostate cancer has risen significantly since the introduction of PSA testing. Conversely, the diagnosis of previously untreated, metastatic prostate cancer has plummeted.4–6 To fulfill our second goal, we must provide evidence that patient survival is prolonged by screening. Earlier diagnosis leads to prolonged survival by definition. Leadtime bias is the expected increase in survival related to earlier diagnosis. If a patient undergoes screening for prostatic disease and is diagnosed 3 years before he would have presented clinically, the screening test would have increased the patient’s life from time of diagnosis to an endpoint (e.g., death) by 3 years, thereby prolonging survival. Gann and colleagues, in a prospective study of frozen serum samples, estimated that PSA testing pro-

vided an average 5.5-year lead time in the diagnosis of clinically significant prostate cancer.7 Therefore, the first two prerequisites of any screening program have been satisfied by the use of serum PSA and DRE. The last objective of screening is to decrease the prostate cancer death rate and this remains to be definitively proven. However, there is a body of evidence amassing that leads us to conclude that this prerequisite will be satisfied. Given current technology, screening for prostate cancer will always be associated with error. This is because the only way one can exclude a diagnosis of prostate cancer with 100% certainty is to remove the entire prostate and to step section the entire gland with histologic examination. This is clearly both impractical and excessively invasive. However, anything short of total evaluation of the entire prostate will have a reduced sensitivity, that is, some cancers will be missed owing to sampling error. The issue of whether or not to screen American men for prostate cancer has been a subject of debate.8–13 Opponents argue that screening only benefits a select group of patients with clinically aggressive, organconfined disease, and they believe that treatment of most cases of prostate cancer detected by screening is either ineffective (i.e., tumor not organ-confined) or unnecessary (i.e., tumor not biologically significant). They further maintain that screening results in substantial economic cost, morbidity, and anxiety that are not justified by an increased detection of disease. Finally, and the most valid argument, is the fact that no prostate cancer screening program has been demonstrated to decrease mortality in a prospective, randomized, controlled trial. Those in favor of screening, including the authors, argue that prostate cancer is a major illness killing about as many men as breast cancer kills women, and that only through screening can this disease be brought under control. Waiting until the benefits of screening have been definitively proven could cost thousands of men their lives. The morbidity of treating early disease is in many instances less than the morbidity of treating advanced disease. Lastly, the economic considerations of screening should not weigh against this endeavor unless screening is proven to be of no benefit. Given the current data, the economic onus is on those who are against, rather than those who are in favor of screening. 73

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Screening by Digital Rectal Examination Before the widespread clinical use of PSA, DRE was the most common initial test for the diagnosis of prostate cancer. While several earlier reports have concluded that annual screening using DRE leads to improved early detection of disease and prolonged survival,14,15 other studies contradicted these findings.16,17 The limitation of DRE as a screening test appears to be its poor sensitivity in detecting curable (i.e., pathologically organ-confined) disease. In fact, approximately 40 to 60% of men with clinically localized prostate cancer detected by annual DRE have local or systemic spread of disease when pathologic staging is available.14,16,18 In addition, a study by Gerber and colleagues that evaluated disease-specific survival following routine screening by DRE in over 4000 men suggests that this approach will not decrease the mortality rate from prostate cancer.17 The investigators compared cancers diagnosed during the initial screen (prevalence group) with those identified during subsequent screens (the incidence group). It was hypothesized that the cancer-specific mortality would be lower in the incidence group. In fact, the cancer-specific mortality was significantly higher in this group. These findings led to the conclusion that routine screening by annual DRE may be insufficiently frequent and/or sensitive to prevent significant mortality from prostate cancer. The limitations of DRE as a sole screening modality have been further clarified by Flanigan and colleagues.19 In a multicenter study, more than 6000 men underwent screening by DRE and PSA. An abnormal result in either screening test led to a recommendation of transrectal ultrasonography (TRUS) with four-quadrant prostate biopsy. Of the 624 men who underwent biopsy, 1002 quadrants were suspicious by DRE, and 110 (11%) contained cancer. The positive biopsy rate for nonsuspicious quadrants was 9% (p = .97) and was statistically no different from that of a suspicious quadrant. In fact, 74% of cancers were diagnosed in prostate quadrants normal to palpation. In summary, it is clear that more clinically localized cancers can be detected through the use of annual screening by DRE. Unfortunately, a significant percentage of these tumors have already spread beyond the prostatic capsule at the time of diagnosis, rendering a cure unlikely. Therefore, although we are strongly in favor of prostate cancer screening and recognize that DRE is an extremely inexpensive screening tool, we do not believe that DRE alone will satisfy the three necessary prerequisites of successful screening.

Screening by Transrectal Ultrasound Following the introduction of transrectal ultrasonography of the prostate, there was a great deal of enthusiasm regarding its use in the early detection of prostate cancer. It was felt that TRUS would be able to detect many non-

palpable small tumors that were missed by DRE alone.20 However, studies have shown that TRUS has several limitations with regard to its use as a screening test for prostate cancer. Most importantly, TRUS has low positive and negative predictive values, which were reported to be 36 and 89%, respectively, in one study.21 Cooner and colleagues reported the positive predictive value of TRUS to be only 16% in men with a palpably benign prostate.22 This number drops to 9.8% when both DRE and PSA are normal. Additional limitations of TRUS as a screening tool include the procedure’s invasiveness, cost, and limited detection rate when the less invasive DRE and PSA are normal. It is the authors’ belief that the major value of TRUS is its ability to allow for anatomic sampling of the prostate when other screening tests are abnormal.

Screening by Prostate-Specific Antigen Since the late 1980s there has been an unquestionable increase in the detection of prostate cancer and the diagnosis of curable disease.4 Since DRE and TRUS have been shown to be ineffective screening tools, most epidemiologists relate this dramatic rise to PSA-based screening. Regarding PSA’s ability to improve detection of curable disease, one may compare stage at time of diagnosis. According to Jacobsen and colleagues, the incidence of clinically organ-confined prostate cancer increased from 61% in the pre-PSA era (i.e., DRE-detected cancers) to more than 90% in the post-PSA era.23 The incidence of pathologically organ-confined disease showed a similar upturn from an average of 33% before the widespread use of PSA testing, to as high as 70% following the introduction of PSA into community medical practice.3,16 In large PSA-based prostate screening trials involving thousands of men, cancer detection rates have ranged from 1.5% to 4%. The positive predictive value of PSA testing in these trials has varied between 11 and 34%. The false-negative PSA values were felt to be due to the relatively high incidences of benign prostatic hyperplasia (BPH) and subclinical prostatic inflammation in the screening population.24–27 Brawer and associates screened 1249 men over the age of 50 with serum PSA levels.25 Men with a PSA value greater than 4.0 ng per mL were further evaluated by DRE and TRUS-guided biopsy. A total of 187 men (15%) had an elevated PSA. In the 105 men who underwent biopsy, a total of 32 carcinomas were identified (31%). Mettlin and colleagues reported on a series of 2999 men aged 55 to 70 years who were screened for prostate cancer using PSA, DRE, and TRUS.28 Of the 164 patients that were found to have tumors, 103 underwent radical prostatectomy and 64 (62%) had pathologically organ-confined disease. In 1994, Catalona and colleagues published a multicenter study involving 6630 men aged 50 and above who underwent testing with serum PSA and DRE.27 Of the 14.8% of men

Screening for Prostate Cancer: the Case for Screening / 75

with a PSA greater than 4 ng/mL, 32% were found to have prostate cancer. Thus, the cancer detection rate for PSA was 4.6%. Again, PSA played a primary role in the diagnosis of pathologically localized disease. Of the 160 patients who underwent radical prostatectomy, 114 (71%) had pathologically organ-confined disease. In fact, the use of PSA and DRE in combination increased detection of organ-confined disease by 78% over DRE alone. In summary, it is the belief of the authors that PSA plays a vital role in the detection of early-stage curable prostate cancer. Serum PSA determinations should be the central modality of prostate cancer detection at this time. However, cancer detection rates, positive predictive value of PSA testing, and the possibility of false-positive results need to be discussed with patients prior to PSA-based screening.

PSA Derivatives The sensitivity of PSA has never been questioned. It is the test’s lack of specificity (i.e., the number of false-positives that result in invasive evaluations) that has caused most concern. In an attempt to improve specificity, several investigators have tried to modify the interpretation of PSA values. These modifications have been termed PSA derivatives. Numerous PSA derivatives have been developed and tested clinically with the purpose of optimizing the use of PSA as a screening tool. This can only be achieved by increasing the test’s specificity while preserving its sensitivity. PSA Density PSA density (PSAD) is one such variation and is defined mathematically as total PSA (ng/mL) divided by the volume of the prostate gland (cc). The concept of PSAD is based on the assumption that the PSAD calculation would standardize the amount of PSA produced per cubic centimeter of prostate tissue. A volume occupied by cancer will result in a higher serum PSA than a volume occupied by benign tissue. It was postulated that PSAD would be able to identify which patients had an elevated PSA secondary to benign enlargement, BPH, versus those with elevations secondary to prostate carcinoma.29 The concept of PSAD was introduced at ColumbiaPresbyterian Medical Center by the authors in collaboration with Dr. William Cooner of Mobile, Alabama. The objective was to derive a means of decreasing the number

TABLE 11–1. Age- and Race-Specific Reference Ranges for Prostate-Specific Antigen Serum PSA (ng/mL) Age 40–49 50–59 60–69 70–79

Caucasian

Japanese

African American

0–2.5 0–3.5 0–4.5 0–6.5

0–2.0 0–3.0 0–4.0 0–5.0

0–2.0 0–4.0 0–4.5 0–5.5

of false-positive PSA results and thus the number of unnecessary biopsies. An analysis of 773 patients with a normal DRE and a PSA between 4 to 10 ng per mL who subsequently underwent TRUS led to the proposal of a PSAD cutoff value of 0.15 mg per mL. In this preliminary study, only patients with an abnormal TRUS (hypoechoity or asymmetry) underwent an initial biopsy. The positive prostate biopsy rate in this group was 6% for patients with a PSAD less than 0.15 versus 18% for patients with a PSAD greater than 0.15.30 Another investigation by Bazinet and colleagues confirmed these findings.31 In their study, 142 patients with a negative DRE and a PSA between 4 to 10 ng per mL underwent prostate biopsy. They noted that only 2 patients who had a PSAD less than 0.15 biopsied positive, while 20 patients had positive biopsies with a PSAD greater than 0.15. Despite these encouraging initial data, other studies have failed to confirm improved cancer detection rates using PSAD compared with total serum PSA.32,33 Factors responsible for the conflicting results and conclusions may involve anatomic and technical difficulties in determining prostate volume, lack of uniformity regarding the statistical analysis applied to the different studies, and the fact that the epithelial-stromal ratio differs considerably from patient to patient. Differences in the amount of epithelium versus stroma in an individual’s prostate allow for a wide range of PSA production in prostates of similar volume. Because of these observations, PSAD as a means of increasing the specificity of serum PSA testing is not universally accepted. Age-Specific PSA An age-specific reference range for serum PSA is a variation of total PSA which was designed to increase sensitivity in younger men and to increase specificity in older men. The concept of age-specific PSA follows that as most men get older they develop BPH, with a resultant increase in their prostate size and an increase in their serum PSA. In a community-based study, Oesterling and colleagues enrolled 537 men aged 40 to 79 into a screening protocol that included serum PSA, DRE, and TRUS.34 Of the 537 men, 471 had all three tests performed without any evidence of prostate cancer. Utilizing this subset of patients, they correlated serum PSA with age and prostate volume. The results indicated that PSA increased by 0.04 ng per mL (3.2%) per year. From these data, using 95th percentile confidence limits, age-specific reference ranges for serum PSA were developed (Table 11–1). Several investigators have tested this hypothesis and examined its clinical usefulness in lowering the normal PSA value in younger men and raising the normal value in older men. It appears that lowering the normal range in younger men is valid and appropriate. In a multiinstitutional study, Catalona and colleagues utilized a patient population base consisting of 6630 men undergo-

76 / Advanced Therapy of Prostate Disease

ing PSA and DRE screening followed by TRUS, with prostate biopsy for those with abnormal results.35 They reported that a cutoff of 3.5 ng per mL in men 50 to 59 years old resulted in a 15% increase in cancer detection versus a cutoff of 4.0 ng per mL. Partin and colleagues studied a population of clinical stage T1c prostate cancer who had undergone radical prostatectomy.36 The authors concluded that in men younger than 60 years, a significant number of additional tumors would be detected by using age-specific ranges. Thus, it appears that the PSA cutoff of 4.0 ng per mL may be too high for younger men. However, it must be taken into consideration that the added sensitivity of a lower PSA cutoff would be at the cost of decreased specificity and the resultant added morbidity (more falsepositive results leading to more negative biopsies). The validity of increasing the normal PSA range in older men is less established. Had age-adjusted reference ranges been used in the Catalona study, men aged 60 to 69 would have undergone 15% fewer biopsies.35 However, 8% of organ-confined tumors would have been missed in this age group. In men older than 70, 44% fewer biopsies would have been performed with 47% of organconfined cancers missed. Partin and colleagues also made the observation that raising the PSA range for older men would result in decreased sensitivity, but they also raised the question of clinical significance and clinical consequence of the missed tumors.36 In summary, investigators support the theory that the use of age-specific reference ranges would improve the sensitivity of PSA in younger men, allowing for the diagnosis of more organ-confined prostate cancer. For now, most experts are unwilling to raise the upper limit of normal in older men. Race and Age-Specific PSA The database that led to the development of age-specific ranges for PSA was composed almost entirely of Caucasian men. It has been known for a long time that Asian men generally have smaller prostates and a lower incidence of prostate cancer than Caucasian or African American men. African American men have the highest incidence of prostate cancer in the world.37 These facts led investigators to evaluate the effect of race on age-specific ranges. Oesterling and colleagues performed a study similar to the one outlined above in an attempt to clarify age-specific reference ranges in Japanese men.38 The resulting age-specific ranges for Japanese men are posted in Table 11–1. Morgan and colleagues completed a study examining age-specific reference ranges in African American men.39 This study confirmed that the PSA concentration correlates with age, and that the upper limit of normal serum PSA should also be age dependent in African Americans. Morgan determined that if traditional age-specific reference ranges were used as outlined by Oesterling for Caucasian men, 41% of cancers in their African American

cohort would have been missed. The age-specific reference ranges for African Americans are also listed in Table 11–1. The differences appear minor, but they have tremendous clinical significance because it is in African Americans that prostate cancer is more prevalent; it occurs at an earlier age, and it has the highest mortality rate. PSA Velocity Another derivative used to improve PSA screening is known as PSA velocity (PSAV). Utilizing data and frozen serum from the Baltimore Longitudinal Study of Aging, Carter and colleagues were able to plot the PSA values of 73 men, aged 60 or older, over a 7-year period.40 They observed that men without prostate symptoms or prostate cancer had little change in their PSA value over time. Patients with BPH had a linear slope of PSA velocity, while patients with prostate cancer had an initial linear component that became exponential. Investigators calculated PSAV with an equation utilizing at least three separate points and suggested that a PSAV greater than 0.75 ng per mL per year was suspicious for prostate cancer. The “normal” PSAV was examined by several studies including one by Smith and Catalona, which prospectively enrolled 982 men to examine the efficacy and utility of PSAV.41 This study calculated that for patients with a PSA less than 4.0 ng per mL, the cutoff PSAV predictive of cancer was 0.75 ng per mL per year. However, for patients with PSA greater than 4.0 ng per mL, the cutoff point which predicts cancer was 0.4 ng per mL per year. The major question surrounding PSAV is how many serum measurements are required and how far apart they should be spaced. Carter and colleagues addressed these issues by retrospectively examining serial PSA measurements in 806 men.42 They focused on the number of PSA determinations, the time interval between PSA measurements, and the effect on the calculated PSAV. The authors concluded that three or more values with time intervals greater than 6 months between readings are necessary to determine velocity. This severely limits the clinical utility of PSAV, in that it is of greatest value retrospectively, and of least value when the PSA determinations occur within 1 year of each other. Therefore, at a minimum, 2 years of PSA determinations are required to accurately stratify patients by PSAV. With this lengthy time frame, patient anxiety and the possibility of disease progression become issues which push toward an early biopsy. As a result, PSAV would appear to be of greatest utility in men who have already undergone a biopsy which proved negative for cancer. Free to Total PSA Ratio One of the more recent PSA derivatives is the comparison of unbound (free) PSA to the total amount of PSA in the serum. The PSA can exist as free PSA and as PSA bound to α1-antichymotrypsin (ACT) or α2-macroglobulin

Screening for Prostate Cancer: the Case for Screening / 77

(A2M).43,44 The PSA bound to A2M (PSA-A2M) is antigenically shielded and not measurable by any PSA assay. The PSA-ACT complex, however, is immunoreactively unique and can be measured in the serum as a separate moiety. As a result, it is possible to compare the amount of free PSA to the total amount of PSA (free + PSAACT). Lilja and colleagues documented that the majority of PSA in the serum is complexed to ACT, accounting for approximately 85% of the total serum PSA.44 They later compared the ratio of free:total (FT) PSA in men with BPH to the FT PSA of men with prostate cancer. They found that the FT ratio was significantly lower in men with prostate cancer than men with BPH (18 versus 28%, respectively, p < .0001).45 Importantly, this difference was present for PSA values above and below 10 ng per mL. They concluded that the use of FT PSA ratio would allow for a differentiation of elevated PSA levels secondary to BPH and prostate cancer without decreasing the sensitivity of PSA. The explanation of why PSA secreted from BPH is less likely to be bound to ACT (higher FT ratio) may be found within prostate cancer cells. Bjork and colleagues found that prostate cancer cells produce not only PSA, but also ACT. This coexpression of PSA and ACT may allow for an increased likelihood of a PSA-ACT complex when PSA is expressed from a cancer cell as opposed to a benign cell.46 However, this is only speculative and the reason or reasons behind the observed FT differences remain unknown. Regardless of the explanation for the increased PSAACT complex in PSA expressed from prostate cancer cells (lower FT ratios), FT PSA ratios improve PSA specificity for patients with serum PSA levels in the 4 to 10 ng per mL range (Table 11–2). The use of Hybritech’s FT PSA has been granted approval from the Food and Drug Administration, and FT ratios from other companies are expected to be approved in the near future. However, FT PSA, like the other PSA derivatives, is not without controversy. A universal FT PSA cutoff has yet to be established, and it appears that like PSAD and age- and race-specific PSA, the resultant increases in specificity are at the cost of decreases in sensitivity.

The Status of Screening There are reports that support the notion that since the introduction of PSA in the late 1980s, PSA-based prostate cancer screening has led to dramatic changes in the epidemiology of the disease, which are suggestive of effective screening.4,23 Data supplied by the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 1994 have shown a substantial increase in the number of newly diagnosed cases of prostate cancer. This trend accelerated when PSA use became widespread in the late 1980s. New prostate cancer

TABLE 11–2. Percent of Free to Total PSA Ratio and Cancer Probability Ratio (%) 0–10 10–15 15–20 20–25 > 25

Probability of Cancer (%) 56 28 20 16 8

cases peaked in 1992 and have since declined. However, the incidence has not fallen back to pre-PSA screening levels. In addition to the drastic changes in the number of cases of prostate cancer during the PSA-testing era, there has been a downward shift in the age at which the disease is diagnosed.4 Perhaps more significant, however, is the increased proportion of tumors that are organ-confined at the time of diagnosis.4 Tumors diagnosed by PSA have a 70 to 80% chance of being organ-confined compared to only 20 to 30% in the pre-PSA era.2–4 A trend toward the diagnosis of moderately differentiated tumors has also become apparent. Indeed, organ-confined moderately differentiated disease now comprises 36% of tumors being diagnosed today. This is a significant increase from 22% prior to the PSA era. Also consistent with, but not definite proof of, the introduction of effective screening is the reduction of mortality secondary to prostate cancer. In 1996, the National Center for Health Statistics reported a 6.3% decrease in prostate cancer mortality in the United States.47 This was the first time such a decline had been reported. Since then, the data coming out of Quebec and Canada have confirmed this trend.48 After 1991, prostate cancer mortality rates declined moderately until 1995, and then more dramatically in 1996. Age-standardized prostate cancer mortality rates declined by 23% in Quebec between 1991 and 1997, and by 9.6% in Canada between 1991 and 1996. There are currently large well-designed, randomized, controlled trials underway both in the United States and Europe. The National Cancer Institute is running the Prostate, Lung, Colorectal, Ovarian (PLCO) screening trial that will last 16 years and involve 74,000 men who will be screened for prostate cancer with PSA and DRE at more than 10 screening centers across the country.49 The European Randomized Study of Screening for Prostate Cancer (ERSPC) will follow 172,000 men over 15 years.50 Preliminary data from these studies will not be available for 10 years, but they are anxiously awaited. A recent study by Labrie and colleagues was the first prospective, randomized, controlled prostate cancer screening trial published to date.51 The study enrolled 46,193 male voters from Quebec City aged 45 to 80. Screening invitations were mailed by random selection to 30,956 (67%) men. The remaining one-third of patients served as nonscreened controls. Prostate cancer screening consisted of a

78 / Advanced Therapy of Prostate Disease

serum PSA determination and DRE at the patient’s first visit with subsequent annual PSA tests. The TRUS with prostate biopsy was performed if PSA exceeded 3.0 ng per mL or if DRE was suspicious. Appropriate treatment was initiated if prostate cancer was diagnosed. The prostate cancer death rates during the 8-year period were 48.7 and 15 per 100,000 man-years in the unscreened and screened groups, respectively (p < .01), a 69% difference in favor of screening and early treatment. The authors were criticized for selection bias because only 23% of men randomized to undergo screening actually agreed to undergo testing. A second point of contention was that the intent-to-screen analysis only revealed a 6% decrease of the prostate cancer death rate in favor of the group initially invited to be screened. These criticisms, however, do not completely invalidate the results of the study. The authors pointed out that there was a noncompliance rate of 77% in the original invited group and a contamination rate of 7% of the uninvited men. When statistical adjustments were made to account for these levels of noncompliance and contamination, the effect of screening was estimated to reduce the death rate from prostate cancer by 54 to 100%. Therefore, the authors felt the 69% benefit of screening shown in their report was consistent with the results of the intent-to-screen analysis. Randomized, controlled trials currently taking place will all certainly be subject to some degree of selection bias. Additionally, any potential lack of survival differences in these ongoing trials will undoubtedly be influenced by the penetration of PSA determinations into the control unscreened populations. It will be difficult, if not impossible, to prevent these men from having PSA determinations performed by their primary care practitioners. As a result, men undergoing PSA screening outside of the study will infiltrate the nonscreened arm in any of these studies to various degrees.

Conclusion The introduction of routine serum PSA determinations into the annual health physical of older men has dramatically influenced the demographics of prostate cancer diagnosis. In general, prostate cancer is being diagnosed in younger men with a normal DRE. They are often found to have clinically localized disease of lower grade. Many of these men are seeking the potentially curable therapies of radical prostatectomy and radiation therapy (external beam and brachytherapy). In the past, these patients would have escaped diagnosis owing to a lack of symptoms and a normal DRE. Accordingly, their tumors would have progressed to the advanced disease so common in the 1980s. Given these facts, it is impossible for the authors to conclude that PSA screening will not satisfy the three tenets of a successful screening modality. The decreased death rate for prostate cancer now being evidenced in

preliminary results and SEER studies will be validated. The naysayers who refuse to accept screening will be left to ponder how many lives could have been saved had the widespread use of PSA been universally accepted sooner.

References 1. von Eschenbach A, Ho R, Murphy GP, et al. American Cancer Society guideline for the early detection of prostate cancer: update 1997. CA Cancer J Clin 1997; 47:261–4. 2. Smith DS, Catalona WJ. The nature of prostate cancer detected through prostate specific antigen based screening. J Urol 1994;152:1732–6. 3. Catalona WJ, Smith DS, Ratliff TL, Basler JW. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993;270:948–54. 4. Farkas A, Schneider D, Perrotti M, et al. National trends in the epidemiology of prostate cancer, 1973 to 1994: evidence for the effectiveness of prostate-specific antigen screening. Urology 1998;52:444–9. 5. Stephenson RA. Population-based prostate cancer trends in the PSA era: data from the Surveillance Epidemiology and End Results (SEER) program. Monogr Urol 1998;19:3–19. 6. Labrie J, Candas B, Cusan L, et al. Diagnosis of noncurable prostate cancer can be practically eliminated by prostate-specific antigen. Urology 1996;47:212–6. 7. Gann PH, Hennekens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific antigen for detection of prostate cancer. JAMA 1995;273:289–94. 8. Arcangeli CG, Ornstein DK, Keetch DW, Andriole GL. Prostate-specific antigen as a screening test for prostate cancer. Urol Clin North Am 1997;24:299–321. 9. Brawer MK. Screening and early detection of prostate cancer will decrease morbidity and mortality from prostate cancer: the argument for. Eur Urol 1996;29 Suppl 2:19–23. 10. Gerber GS, Chodak GW. Value of prostate cancer screening. Eur Urol 1993;24:161–5. 11. Denis LJ. To screen or not to screen? Prostate 1992;Suppl 4:63–70. 12. Jacobson JO. Can screening for early-stage prostate cancer be rationalized? Hematol Oncol Clin North Am 1996; 10:549–64. 13. Albertsen PC. Screening for prostate cancer is neither appropriate nor cost effective. Urol Clin North Am 1996;23:521–30. 14. Thompson IM, Rounder JB, Teague JL, et al. Impact of routine screening for adenocarcinoma of the prostate on stage distribution. J Urol 1987;137:424–6. 15. Jenson CB, Shahon DB, Wangensteen OH. Evaluation of annual examinations in the detection of cancer. Specific reference to cancer of the gastrointestinal tract, prostate, breast and female reproductive tract. JAMA 1960;174:1783–8. 16. Chodak GW, Keller P, Schoenberg HW. Assessment of screening for prostate cancer using the digital rectal examination. J Urol 1989;141:1136–8. 17. Gerber GS, Thompson IM, Thisted R, Chodak GW. Disease-specific survival following routine prostate cancer screening by digital rectal examination. JAMA 1993;269:61–4.

Screening for Prostate Cancer: the Case for Screening / 79 18. Mueller EJ, Crain TW, Thompson IM, Rodriguez FR. An evaluation of serial digital rectal examinations in screening for prostate cancer. J Urol 1988;140:1445–7. 19. Flanigan RC, Catalona WJ, Richie JP, et al. Accuracy of digital rectal examination and transrectal ultrasonography in localizing prostate cancer. J Urol 1994;152(5 Pt 1): 1506–9. 20. Lee F, Torp-Pedersen S, Littrup PJ, et al. Hypoechoic lesions of the prostate: clinical relevance of tumor size, digital rectal examination and prostate-specific antigen. Radiology 1989;170:29–32. 21. Chodak GW, Wald V, Palmer E, et al. Comparison of digital rectal examination and transrectal ultrasonography for the diagnosis of prostate cancer. J Urol 1986;135: 951–4. 22. Cooner WH, Mosley BR, Rutherford CL, et al. Prostate cancer detection in a clinical practice by ultrasonography, digital rectal examination and prostate specific antigen. J Urol 1990;143:1146–52. 23. Jacobsen SJ, Katusic SK, Bergstralh EJ, et al. Incidence of prostate cancer diagnosis in the eras before and after serum prostate-specific antigen testing. JAMA 1995; 274:1445–9. 24. Mettlin C, Lee F, Drago J, Murphy GP, and members of the American Cancer Society National Prostate Cancer Detection Project. Findings on the detection of early prostate cancer in 2,425 men. Cancer 1991;67:2949–58. 25. Brawer MK, Chetner MP, Beatie J, et al. Screening for prostate carcinoma with prostate-specific antigen. J Urol 1992;147:841–5. 26. Labrie F, Dupont A, Suburu R, et al. Serum prostate specific antigen as pre-screening test for prostate cancer. J Urol 1992;147:846–51. 27. Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. J Urol 1994;151:1283–90. 28. Mettlin C, Murphy GP, Lee F, et al. Characteristics of prostate cancer detected in the American Cancer Society-National Prostate Cancer Detection Project. J Urol 1994;152:1737–40. 29. Benson MC, Whang IA, Olsson CA, et al. The use of prostate specific antigen density to enhance the predictive value of intermediate levels of serum prostatespecific antigen. J Urol 1992;147:817–21. 30. Seaman E, Whang M, Olsson CA, et al. PSA density (PSAD): role in patient evaluation and managment. Urol Clin North Am 1993;20(4):653–63. 31. Bazinet M, Mashref AW, Trudel C, et al. Prospective evaluation of prostate-specific antigen density and systematic biopsies for early detection of prostatic carcinoma. Urology 1994;43:44–51. 32. Catalona WJ, Richie JP, DeKernion JB, et al. Comparison of prostate specific antigen concentration versus prostate-specific antigen density in the early detection of prostatic carcinoma: receiver operating characteristic curves. J Urol 1994;152:2031–6. 33. Brawer MK, Aramburu EAG, Chen GL, et al. The inability of prostate specific antigen index to enhance the predictive value of prostate-specific antigen in the diagnosis of prostate cancer. J Urol 1993;150:369–73.

34. Oesterling JE, Jacobsen SJ, Chute CG, et al. Serum prostate-specific antigen in a community based population of healthy men: establishment of age-specific reference ranges. JAMA 1993;270:860–4. 35. Catalona WJ, Hudson MA, Scardino PT, et al. Selection of optimal prostate-specific antigen cutoffs for early detection of prostate cancer: receiver operating characteristics curves. J Urol 1994;152(part 1);2037–42. 36. Partin AW, Criley SR, Subong EN, et al. Standard versus age-specific antigen reference ranges among men with clinically localized prostate cancer: a pathologic analysis. J Urology 1996;155:1336–9. 37. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, 1997. CA Cancer J Clin 1997;47:5–27. 38. Oesterling JE, Kumamoto Y, Tsukamoto T, et al. Serum prostate-specific antigen in a community-based population of healthy Japanese men: lower values than for similarly aged white men. Br J Urol 1995;75:347–53. 39. Morgan TO, Jacobsen SJ, McCarthy WF, et al. Age specific reference ranges for prostate-specific antigen in black men. N Engl J Med 1996;335:304–10. 40. Carter HB, Pearson JD, Metter EJ, et al. Longitudinal evaluation of prostate-specific antigen in men with and without prostate disease. JAMA 1992;267:2215–20. 41. Smith DS, Catalona WJ. Rate of change in serum prostatespecific antigen levels as a method for prostate cancer detection. J Urol 1994;152:1163–7. 42. Carter HB, Pearson JD, Waclawiw Z, et al. Prostate-specific antigen variability in men without prostate cancer: effect of sampling interval on prostate-specific antigen velocity. Urology 1995;45:591–6. 43. Christensson A, Lilja H. Complex formation between protein C inhibitor and prostate-specific antigen in vitro and in human semen. Eur J Biochem 1994;220:45–53. 44. Lilja H. Structure, function, and regulation of the enzyme activity of prostate-specific antigen. World J Urol 1993; 11:188–91. 45. Prestagiacomo AF, Lilja H, Pettersson K, et al. A comparison of the free fraction of serum prostate-specific antigen in men with benign and cancerous prostates: the best case scenario. J Urol 1996;156:350–4. 46. Bjork T, Bjartell A, Abrahamsson PA, et al. Alpha 1-chymotrypsin production in PSA producing cells is common in prostate cancer but rare in benign prostatic hypertrophy. Urology 1994;43:427–34. 47. Smith CR. The results of prostate carcinomas screening in the U.S. as reflected in the Surveillance, Epidemiology, and End Result program. Cancer 1997;80:1835–44. 48. Meyer F, Moore L, Bairati I, Fradet Y. Downward trend in prostate cancer mortality in Quebec and Canada. J Urol 1999;161:1189–91. 49. Gohagan JK, Prorok PC, Kramer BS, et al. The prostate, lung, colorectal, and ovarian cancer screening trial of the National Cancer Institute. Cancer 1995;75:1869– 73. 50. Schroder FHG, Bangma CH. The European randomized study of screening for prostate cancer (ERSPC). Br J Urol 1997;79 Supp:68–71. 51. Labrie F, Candas B, Dupont A, et al. Screening decreases prostate cancer death: first analysis of the 1988 Quebec prospective randomized controlled trial. Prostate 1999;38:83–91.

CHAPTER 12

SCREENING FOR PROSTATE CANCER: THE ARGUMENT FOR CAUTION BARNETT S. KRAMER, MD, MPH; OTIS W. BRAWLEY, MD For years, the public has been told that the key to curing cancer is early detection. This simplified soundbite has created, without rigorous evaluation, widespread support for screening efforts in a number of cancers. In fact, the public is not well prepared to accept negative results from randomized trials designed to rigorously test the efficacy of screening strategies such as chest radiography for lung cancer1 or breast self-examination for breast cancer.2 The medical community has not successfully conveyed the complexities of screening and the potential downside of widespread acceptance of screening without evidence of net benefit.3,4 The American medical community, more so than the medical communities of other developed countries and countries with organized health care systems, has recently embraced prostate cancer screening without rigorous evaluation. Indeed, prostate cancer screening may be done without the patient’s knowledge or consent and even more frequently is done without advising the patient of the uncertain efficacy of prostate cancer screening and treatment.5 In a real sense, the country has embarked upon a large uncontrolled clinical experiment.6 Though as yet unproven, screening for and aggressive treatment of localized prostate cancer may well be beneficial in that it may decrease prostate cancer mortality and save lives. However, it does have a definite cost of human suffering. At this point, we must weigh proven risks against unproven benefits. Ten years into the prostate-specific antigen (PSA) screening era, evidence shows that PSA screening still needs definitive evaluation. Many have concluded that an average increase in survival time after diagnosis and a shift toward lower stage disease at diagnosis will necessarily translate into saved lives. However, screening is capable of detecting disease of little or no medical significance (overdiagnosis), artificially increasing survival time after diagnosis, and triggering unnecessary treatment. While there has been a recent decline in prostate-cancer-specific mortality, it is not certain that the decline is due to screening. Indeed, there is evidence that screening is not causally related to the decline. Whether prostate cancer screening saves lives and at what human cost remains a cogent question. It is a question far more easily addressed by definitive randomized trials than by uncontrolled observations or

assumptions based on limited study design. The randomized prospective clinical trial ushered in the era of modern clinical medicine, and its power to answer pressing medical questions, cannot be overestimated.

Clinical Significance or Insignificance of Prostate Cancer Length bias is a well-described phenomenon associated with many tests used to screen asymptomatic individuals. It arises because asymptomatic disease processes, cancer included, are on average less biologically aggressive than symptomatic diseases. The phenomenon is illustrated in Figure 12–1, where, the length of each horizontal line represents the duration of the disease’s natural history in its recognizable states. Short lines represent a faster, more aggressive clinical behavior. A screening test is more likely to pick up prevalent indolent cases (left of Figure 12–1) than more life-threatening cases (right), thereby increasing the ratio of indolent to aggressive cancers in the pool of detected cases. The illustration shows that 5 of 5indolent cancers are picked up, compared with 1 of 5 aggressive cancers. Length bias has been documented in randomized trials of mammography for breast cancer and chest radiography with sputum cytology for lung cancer. More recently, it has been associated with digital rectal examination (DRE) screening for prostate cancer.7 There are consistently more cases detected in the screened group than in the control group. In the case of lung cancer, virtually all these excess cases of lung cancer were localized surgically operable lesions; yet, in the randomized screening trials for lung cancer, virtually identical numbers of lung cancer deaths were observed in the screened arms versus the controlled arms. In two of these studies, there was an increased but not statistically significant number of deaths in the screened group. This illustrates that length biases do exist and do matter in terms of quality of life. An extreme form of length bias, known as overdiagnosis, occurs when lesions are detected that never would have come to medical attention at all, were it not for screening. There are two forms of overdiagnosis: (1) detection of lesions with virtually no potential for progression, and (2) detection of indolent lesions with potential to progress but 80

Screening for Prostate Cancer: the Argument for Caution / 81

not within the remaining “natural” lifespan of the individual. The latter form of overdiagnosis can be substantial in a disease such as prostate cancer, in which the average age of diagnosis is in the eighth decade of life. The most significant question in a man with diagnosed prostate cancer is, “Is this specific cancer of clinical significance to this particular patient?” Half of all American men diagnosed with prostate cancer are 71 years of age or older and over 80% are 65 years or older. For years, it has been known that prostate cancer is unusual among malignancies in that more than a third of men over age 50 years dying of causes unrelated to prostate cancer are found at autopsy to have one or more foci of prostate cancer.8,9 A smaller but substantial proportion of men in their 30s and 40s also harbor prostate cancer.10 Many of these tumors fulfill the histologic and size criteria of clinically significant cancer. These criteria take into account tumor volume, differentiation, and capsular penetration.11,12 Such tumors by definition, however, did not contribute to the patient’s death. Studies of cystoprostatectomy specimens from men with bladder cancer also demonstrate that the reservoir of undetected slow-growing tumors is large. These studies suggest that the more we look for prostate cancer, the more we will find it. Reports of men diagnosed and treated with T1c prostate cancer should be interpreted in light of the fact that a number of tumors found at autopsy actually fulfill histologic criteria for clinically significant disease but are obviously not clinically significant.13 In one recent case series, pathologists estimated that 15% of men with T1c stage cancers had tumors that did not fulfill histologic criteria for clinically significant prostate cancer.14 The T1c tumors are those identified by needle biopsy after an elevated serum PSA. In other words, pathologists, looking at a group of men diagnosed through screening and treated with radical prostatectomy believe that at least 1 in 7 received unnecessary treatment based on histologic criteria for malignancy and aggressiveness. Given the additional considerations of competing causes of death in an elderly population, this is likely to be a minimum rather than maximum proportion. The autopsy data showing disease that is “histologically clinically significant” but not truly clinically significant would only raise this estimate. Several clinical observational studies have demonstrated that a number of diagnosed tumors can be observed and do not need definitive therapy.15–17 In a Swedish study of men diagnosed with clinically stage A and B prostate cancer, after 10 years of follow-up, only 8.5% had died of prostate cancer. Ultimately, only 15% of the deaths in the series were due to prostate cancer. Even clinical stage C disease can be indolent. In a series of 50 patients, Adolfsson reported that 12% had died at 5 years and 30% at 9 years with observation.15

FIGURE 12–1. The length bias phenomenon: length of horizontal lines depicts duration of disease natural history; a screening test, depicted by the vertical lines, enriches the sample for detection of biologically less aggressive tumors.

Effectiveness of Therapy for Localized Prostate Cancer Willet Whitmore’s famous statement “when cure is possible, is it necessary; when cure is necessary, is it possible?” is as pertinent today as when he first made it years ago. It is well established that survival after definitive treatment of organ-confined prostate cancer is relatively good. It is also clear that treatment cures some cancers that do not need to be cured. The efficacy of screening is a crucial but unresolved question. The American Urological Association convened the Prostate Cancer Clinical Guidelines Panel to analyze the literature regarding available methods for treating locally confined prostate cancer. The panel concluded that outcomes data are inadequate to make valid comparisons of treatment. In a similar literature review, Wasson et al.18 were unable to find definitive evidence concerning the efficacy of treatment of localized disease. Both groups cited the large number of weak study designs that allowed selection biases affecting choice of treatment and patient selection. Only one small randomized prospective trial has been completed assessing radical prostatectomy.18–20 This trial involved 111 men with early stage prostate cancer randomized to radical prostatectomy and placebo versus placebo alone. This trial with small size and low power showed a statistically indistinguishable life expectancy in both arms. Only recently has the question of treatment efficacy been re-addressed. The Prostate Intervention Versus Observation Trial, started in 1993, compares radical prostatectomy to palliative expectant management for clinically localized prostate cancer. The study will ultimately enroll approximately 1050 men, and is expected to have 90% power to detect a 15% reduction in all-cause mortality.19 Similar trials are underway in Europe, assessing the efficacy of radiation therapy as well as radical prostatectomy.21–26 Unfortunately, the results of these trials will not be available for several years.

82 / Advanced Therapy of Prostate Disease

Does treatment of localized prostate cancer save lives? Screening efficacy rests upon treatment efficacy. If treatment is ineffective at saving lives, screening will not save lives. But the very existence of such randomized trials with a “watchful waiting” control arm is evidence of the underlying uncertainties—uncertainties which are, oftentimes, not transmitted to men facing the decision regarding screening for prostate cancer.

Prostate Cancer Screening: Results of Screening Trials No randomized clinical trial in prostate cancer screening has been completed and analyzed on an intention-totreat or intention-to-screen (i.e., as randomized) basis. Recently, Labrie et al.27 have publicly presented interim results of a trial, but it was not analyzed on the basis of intention to treat. When analyzed by randomization allocation, the relative risk of death from prostate cancer in the screened group was 1.16 times greater than in the control group. Only about a third of men randomized to be screened were actually screened, and thus the inclusion of the unscreened men in the analysis of the group randomized to be screened would dilute any potential efficacy of screening. However, their inclusion should not have raised the risk of prostate cancer death above that of the control group if screening is truly efficacious. In the recent past, DRE of the prostate was assumed to be an effective screening technique, and many major health organizations recommended it be done as a prostate cancer screen. There are no completed clinical trials of DRE. However, DRE has been assessed in case-control studies that suggest no effect on preventing metastatic prostate cancer or disease-specific survival.28,29

Screening at the Population Level: Trends in Incidence and Mortality Prostate cancer screening, especially screening with serum PSA in the late 1980s and early 1990s, has profoundly increased the age-adjusted incidence of diagnosed prostate cancer in the United States. Steady rises in the 1970s and early l980s can be attributed to an increase in the number of transurethral resections of the prostate (TURPs) for benign prostatic hyperplasia.2 The subsequent acceleration of incidence can be attributed to increasing use of PSA.3 It should be noted that the use of TURP actually decreased during the late 1980s. A more recent decline in the incidence of prostate cancer may be due to a clearing of the prevalent cases. It may also be due to the fact that several organizations began recommending against prostate cancer screening in the early 1990s. By 1993, a number of American organizations that publish screening recommendations recommended against screening for prostate cancer or took the

position that it was unproven.4 Medicare data indicate that the rate of PSA testing in men aged 65 years and over rose 12-fold from 1988 to 1991, and the proportion of men getting a PSA for the first time peaked in 1991 and 1992. Incidence trends track with first-time PSA utilization rates.30,31 Prostate cancer mortality rates have increased over the past 20 years for both African American and Caucasian men although they have declined slightly during the past few years. From 1991 to 1995, there has been a 6.3% decrease in mortality rates. The Surveillance, Epidemiology, and End Results (SEER) mortality rate has not gone below the baseline mortality rate of the late 1970s and early 1980s. While mortality rates rose from 1973 to 1991, the increase is not as dramatic as those for prostate cancer incidence and provides some evidence of length bias (the diagnosis of tumors with relatively less life-threatening potential than symptomatic cancer). An increased rate of rise in prostate cancer mortality in the late 1980s may be related to the increase in incidence. As diagnostic abilities improved slightly, more deaths are attributed to the disease, a form of attribution bias. Curiously, at the very same time, when prostate cancer incidence in the United States began to fall so precipitously, prostate cancer mortality also began to fall slightly. Some have taken this mortality fall as a priori evidence of a benefit from nationwide screening.32 However, in addition to the fact that changes in treatment practice have occurred in recent years, shifts in mortality may also be due, at least in part, to fewer diagnoses of prostate cancer prior to death. If, in fact, the recent decrease in mortality is due to screening efficacy, it has occurred much more quickly than most would have guessed; and mortality benefits should occur much more quickly in the ongoing randomized screening trials in the United States and Europe than initially estimated. The data clearly demonstrate that length bias and overdiagnosis may be important confounders in analyzing prostate cancer incidence and mortality trends in the PSA screening era. Prostate cancer screening and treatment patterns vary widely throughout the United States. An assessment of the age-adjusted incidence patterns among Caucasian men in nine American populationbased cancer registries from the early 1970s to 1994 showed widely varying incidence of diagnosed cancers as well as use of radical prostatectomy. The regional data also suggest caution in attributing recent declines in mortality to screening. There is no geographic correlation between incidence and mortality rate (Figure 12–2). Indeed, the area with the greatest decrease in mortality, Connecticut, had the lowest rate of screening and lowest incidence during this period from 1973 to 1995. International comparisons of rates are also useful. Comparisons of age-adjusted prostate cancer rates in Caucasian men in the United States and United Kingdom show a widely varying incidence but similar mortality. Prostate

Screening for Prostate Cancer: the Argument for Caution / 83

cancer screening is not as widespread in the United Kingdom as it is in the United States. Moreover, a smaller proportion of men diagnosed with localized disease are treated with radical prostatectomy. Despite consistently higher incidence rates in the United States, with a more recent dramatic rise and fall in incidence, compared to the United Kingdom, mortality rates are extremely similar from the 1960s to the 1990s (Figure 12–3). This again suggests that greater detection efforts in the United States find a higher proportion of tumors that are not clinically significant.33 Likewise, the uncertainty about the efficacy of treatment of localized prostate cancer has led to a 20-fold difference in prostatectomy rates per 100,000 among Medicare beneficiaries in the states of Rhode Island versus Alaska.34 Nevertheless, the age-adjusted mortality rates for Caucasian males in the states of Rhode Island and Alaska are very similar.35

Potential Adverse Consequences of Treatment Morbidity Much of the enthusiasm for screening stems from the desire to avoid the suffering from advanced prostate cancer that screening and treatment could, in theory, prevent. Screening and subsequent treatment, however, cause considerable morbidity. All those who receive treatment are at risk for the morbidities of therapy, including those who are cured unnecessarily and those who need to be cured but are not. The men in these two categories experience all the morbidities of local therapy but none of the benefits. In fact, they experience them sooner and for a longer time since screening advances their date of diagnosis without extending lifespan. A recent study of Medicare beneficiaries36 notes that of 3173 undergoing radical prostatectomy from l985 to 1991, less than 60% were found to have organ-confined disease. Five years after surgery, the proportion of men receiving additional therapy for cancer recurrence or persistence was about 35%. Even in men with pathologically confined cancer after radical prostatectomy, the cumulative incidence of additional prostate cancer treatment at 5 years was 25%. The morbidities of prostate cancer treatment are better defined than the efficacy of the treatment itself. All forms of localized prostate cancer therapy have side effects but those for radical prostatectomy and external beam radiation are best described. Both are known to cause impotence, rectal injury, urinary incontinence, and urethral stricture. Literature reviews from physicians at major medical centers give impotence rates of 25 to 40%, rectal injury rates of 1 to 3%, urinary incontinence rates of 3 to 6%, and urethral stricture rates of 8 to 18%, with radiation therapy at the lower range compared to surgery.37 Morbidity is a highly subjective factor, and patientreported morbidities from surveys are substantially

higher than physician-reported morbidity rates. In a survey of Medicare patients38 undergoing radical prostatectomy from 1988 to 1992, 30% reported the chronic need for pads and urinary clamps. More than 60% reported a problem with wetting, 60% reported having no erections since surgery, and 90% reported no erections sufficient for intercourse in the month prior to answering the survey. Twenty-eight percent reported receiving follow-up treatment for recurrence of prostate cancer within 4 years of prostatectomy. It is not clear if the newer “nerve-sparing” or anatomic prostatectomy has solved the problem of postsurgical sexual impotence. In a study of patients treated with the newer procedure, the self-reported frequency of impotence and urinary incontinence was similar to that found in the survey of Medicare patients, even though the average age of those in the nerve-sparing study was younger than that in the Medicare survey.39 Although statistical power was limited, sexual dysfunction and urinary dysfunction did not seem to differ substantially between men who had undergone standard versus nerve-sparing radical prostatectomy. Radiation therapy also confers significant risk of morbidity.40 Clearly, more information is needed in this area. Prostatectomy incurs a higher risk of treatmentrelated death than radiation therapy.38 While individual surgeons have reported death rates of less than 0.5% depending on patient selection and the surgeon’s skill, the surgical mortality rate was 2% in a national sample of Medicare beneficiaries. Unfortunately this study included only men aged 65 years and over, but this age group does include more than 80% of all men with prostate cancer. In that same series, 8% of men suffered major cardiopulmonary complications after radical prostatectomy. Economic Costs It has been estimated that PSA screening for all men aged 50 to 74 years without pre-existing cardiac disease would add $12 to $26 billion in the first year of a nationwide screening campaign.41–43 Such a cost would divert the finite health care budget from interventions of proven and known effectiveness. If prostate cancer screening is not of substantial benefit, this would result in a net loss in the overall health of the nation. If screening is proven effective, therefore, it would be important to compare its

FIGURE 12–2. Prostate cancer incidence and mortality comparisons showing no correlations.Pcancer. JAMA 1995;273:548–52.

84 / Advanced Therapy of Prostate Disease

cost-effectiveness to that of other beneficial medical interventions in men.

Conclusion The medical community is in a very unfortunate position because it has taken so long to put its assumptions about prostate cancer screening and treatment to definitive testing. Lead-time bias and length bias cloud interpretation of previous prostate cancer screening data. Radical prostatectomy series demonstrate that a substantial number of men treated for localized disease ultimately relapse; autopsy, observation, and epidemiologic studies suggest that many men diagnosed with prostate cancer do not have clinically significant disease given their risk for competing causes of death. Indeed, if there is some benefit, it may be counterbalanced by harm to many more. The only way to demonstrate that screening saves lives and gauge the net benefits and harms is through a welldesigned randomized trial with an “intention-to-screen” analysis of men as randomized. A randomized trial of prostate cancer screening began in the United States in 1993.37 Several other trials are underway in Europe.44 In addition, trials of definitive surgery and radiation have also begun.19 If such trials had been launched just 5 years earlier, we would likely have results by now. The current state of knowledge does not permit a fully informed decision with regard to routine prostate cancer screening and subsequent management. Ongoing trials should inform the disagreements over screening effectiveness. Organizations taking a skeptical view of prostate cancer screening include the United States Preventive Ser-

FIGURE 12–3. Prostate cancer incidence and mortality trends in the United States and the United Kingdom (1968–1995).

vices Task Force, the American College of Physicians, and the Canadian Task Force on the Periodic Health Examination.45–49 While most organizations issuing screening recommendations have not advocated prostate cancer screening, recently the major American organizations that had previously suggested that men be screened evaluated the more recent data and moved away from a recommendation that “screening should be done” and toward informed education as to the benefits and risks of screening and patient choice. The National Cancer Institute does not have a position for or against prostate screening and is currently conducting a large prospective randomized trial testing the value of DRE and PSA testing in the screening setting. In the meantime, while results of this and other randomized trials are pending, health professionals should inform each man about the current state of knowledge, detail the known risks and theoretic benefits, encourage participation in clinical trials whenever possible, and reassure the individuals that for now there is no clear-cut right or wrong choice regarding their decision to be screened or not.

References 1. Eddy DM. Screening for lung cancer. Ann Intern Med 1989;111:232–7. 2. Thomas DB, Gao DL, Self SG, et al. Randomized trial of breast self-examination in Shanghai: methodology and preliminary results. J Natl Cancer Inst 1997;89:355–65. 3. Taube A. Screening with PSA (prostate specific antigen) raises ethical questions. Lakartidningen 1996;93:3341. 4. Brown V. Informed consent for PSA testing. J Fam Pract 1996;43:234–5. 5. Glode LM. Prostate cancer screening: a place for informed consent? Hosp Pract 1994;29:8,11–8. 6. Mandelson MT, Wagner EH, Thompson RS. PSA screening: a public health dilemma. Annu Rev Public Health 1995;16:283–306. 7. Gerber GS, Thompson IM, Thisted R, Chodak GW. Disease-specific survival following routine prostate cancer screening by digital rectal examinations. JAMA 1993;269:61–4. 8. Breslow N, Chan CW, Dhom G, et al. Latent carcinoma of prostate of autopsy in seven areas. Int J Cancer 1977; 20:680–8. 9. Stemmermann GN, Nomura AM, Chyou PH, Yatani R. A prospective comparison of prostate cancer at autopsy and as a clinical event: the Hawaii Japanese experience. Cancer Epidemiol Biomarkers Prev 1992;1:189–93. 10. Sakr WA, Haas GP, Cassin BF, et al. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol 1993;150:379–85. 11. Sakr WA, Grignon DJ, Haas GP, et al. Epidemiology of high grade prostatic intraepithelial neoplasia. Pathol Res Pract 1995;191:838–41. 12. Albertsen PC. Screening for prostate cancer is neither appropriate nor cost-effective. Urol Clin North Am 1996;23:521–30.

Screening for Prostate Cancer: the Argument for Caution / 85 13. Saxena S, Mohanty NK, Jain AK. Screening of prostate cancer in males with prostatism. Indian J Pathol Microbiol 1997;40:441–50. 14. Albertsen PC. Defining clinically significant prostate cancer: pathologic criteria versus outcomes data. J Natl Cancer Inst 1996;88:1177–8. 15. Adolfsson J. Deferred treatment of low grade stage T3 prostate cancer without distant metastases. J Urol 1993;149:326–8. 16. Pontes JE. Issues on early diagnosis and treatment of localized prostate cancer. Urol Int 1996;56 Suppl 1:1–5. 17. Brawley OW. Prostate carcinoma incidence and patient mortality: the effects of screening and early detection. Cancer 1997;80:1857–63. 18. Wasson JH, Cushman CC, Bruskewitz RC, et al. A structured literature review of treatment for localized prostate cancer. Prostate Disease Patient Outcome Research Team. Arch Fam Med 1993;2:487–93. 19. Moon TD, Brawer MK, Wilt TJ. Prostate Intervention Versus Observation Trial (PIVOT): a randomized trial comparing radical prostatectomy with palliative expectant management for treatment of clinically localized prostate cancer. PIVOT Planning Committee. Monogr Natl Cancer Inst 1995;19:69–71. 20. Graversen PH, Nielsen KT, Gasser TC, et al. Radical prostatectomy versus expectant primary treatment in stages I and II prostatic cancer. A fifteen-year followup. Urology 1990;36:493–8. 21. Gann PH. Interpreting recent trends in prostate cancer incidence and mortality. Epidemiology 1997;8:117–20. 22. Chodak GW. Carcinoma of the prostate. Lancet 1997;350: 592. 23. Thompson IM, Coltman CAJ, Crowley J. Chemoprevention of prostate cancer: the Prostate Cancer Prevention Trial. Prostate 1997;33:217–21. 24. Nijs HG, Tordoir DM, Schuurman JH, et al. Randomised trial of prostate cancer screening in the Netherlands: assessment of acceptance and motives for attendance. J Med Screen 1997;4:102–6. 25. Wang TT, Sathyamoorthy N, Phang JM. Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis 1996;17:271–5. 26. Schröder FH. The European Screening Study for Prostate Cancer. Can J Oncol 1994;4 Suppl 1:102–9. 27. Labrie F, Candas B, Dupont A, et al. Screening decreases prostate cancer death: first analysis of the 1988 Quebec prospective randomized controlled trial [see comments]. Prostate 1999;38(2):83–91. 28. Friedman GD, Hiatt RA, Quesenberry CPJ, Selby JV. Casecontrol study of screening for prostatic cancer by digital rectal examinations. Lancet 1991;337:1526–9. 29. Gerber GS, Thisted R, Chodak GW, Thompson IM. Disease-specific survival following routine prostate cancer screening by digital rectal examination: corrected patient classification. JAMA 1993;270:2437. 30. Potosky AL, Miller BA, Albertsen PC, Kramer BS. The role of increasing detection in the rising incidence of prostate cancer. JAMA 1995;273:548–52. 31. Legler JM, Feuer EJ, Potosky AL, et al. The role of

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prostate-specific antigen (PSA) testing in the recent prostate cancer incidence decline in the U.S.A. Cancer Causes Control 1998;9:519–27. Smart CR. The results of prostate carcinoma screening in the U.S. as reflected in the Surveillance, Epidemiology, and End Results program. Cancer 1997;80:1835–44. Shibata A, Ma J, Whittemore AS. Prostate cancer incidence and mortality in the United States and the United Kingdom. J Natl Cancer Inst 1998;90:1230–1. Lu-Yao GL, McLerran D, Wasson J, Wennberg JE. An assessment of radical prostatectomy. Time trends, geographic variation, and outcomes. The Prostate Patient Outcomes Research Team. JAMA 1993;269:2633–6. Lu-Yao GL, Greenberg ER. Changes in prostate cancer incidence and treatment in USA. Lancet 1994;343:251–4. Lu-Yao GL, Potosky AL, Albertsen PC, et al. Follow-up prostate cancer treatments after radical prostatectomy: a population-based study. J Natl Cancer Inst 1996;88: 166–73. Kramer BS, Brown ML, Prorok PC, et al. Prostate cancer screening: what we know and what we need to know. Ann Intern Med 1993;119:914–23. Fowler FJJ, Barry MJ, Lu-Yao G, et al. Patient-reported complications and follow-up treatment after radical prostatectomy. The National Medicare Experience: 1988–1992. Urology 1993;42:622–9. Litwin MS, Hays RD, Fink A, et al. Quality-of-life outcomes in men treated for localized prostate cancer. JAMA 1995;273:129–35. Jonler M, Ritter MA, Brinkmann R, et al. Sequelae of definitive radiation therapy for prostate cancer localized to the pelvis. Urology 1994;44:876–82. Optenberg SA, Thompson IM. Economics of screening for carcinoma of the prostate. Urol Clin North Am 1990; 17:719–37. Lubke WL, Optenberg SA, Thompson IM. Analysis of the first-year cost of a prostate cancer screening and treatment program in the United States. J Natl Cancer Inst 1994;86:1790–2. Woolf SH. Public health perspective: the health policy implications of screening for prostate cancer. J Urol 1994;152:1685–8. Schröder FH, Bangma CH. The European Randomized Study of Screening for Prostate Cancer (ERSPC). Br J Urol 1997;79 Suppl 1:68–71. Rose VL. ACP issues guidelines on the early detection of prostate cancer and screening for prostate cancer. Am Fam Physician 1997;56:1674–5. Woolf SH. Should we screen for prostate cancer? BMJ 1997;314:989–90. Shröder FH, Damhuis RA, Kirkels WJ, et al. European randomized study of screening for prostate cancer—the Rotterdam pilot studies. Int J Cancer 1996;65:145–51. Denis LJ, Murphy GP, Schröder FH. Report of the consensus workshop on screening and global strategy for prostate cancer. Cancer 1995;75:1187–207. Ramsey EW. Early detection of prostate cancer. Recommendations from the Canadian Urological Association. Can J Oncol 1994;4 Suppl 1:82–5.

CHAPTER 13

NATURAL HISTORY OF LOCALIZED ADENOCARCINOMA OF THE PROSTATE JOHN P. FOLEY, MD; IAN M. THOMPSON, MD An intimate knowledge of the natural history of adenocarcinoma of the prostate is essential for any physician who treats patients with this disease. As prostate cancer can be a relatively slow-growing tumor associated with a long asymptomatic and latent period and usually occurs in men who are at risk of dying from other causes (effectively eliminating the “opportunity” of the tumor to manifest itself clinically), decision making by both clinicians and patients is often based on the disease’s natural history. In this chapter, we will examine the experience of published series of patients in whom no treatment was provided for localized disease to develop an understanding of what appears to be the natural history. We will further examine how the behavior of the disease has “changed” over time (as methods of detection, diagnosis, and staging have changed) as well as a number of tumor and host features that can modulate tumor behavior. Specifically excluded from this review are those studies that have reported the results of observation alone for patients with T1a (A1) prostate cancer—focal, low-volume, welldifferentiated disease diagnosed at the time of transurethral resection of the prostate. Evidence is substantial that except in rare circumstances (very young patients), the majority of these patients will have excellent outcomes without treatment.1

have other competing causes of death. These two factors tend to exaggerate the “efficacy” of surveillance. The other bias is that historically detected tumors may not be similar to tumors detected contemporarily. Examples of this phenomenon include the virtual disappearance of lowgrade tumors, currently constituting less than 15% of tumors, compared to over twice as many 10 years ago. A recent evaluation at our institution has found that this phenomenon is probably due to the dramatic fall-off in the number of transurethral resections of the prostate (TURPs), the method by which most well-differentiated tumors are detected.2 This change may have led to an increased detection of more biologically active tumors, making a comparison with historic surveillance series more problematic. Nevertheless, an understanding of the historic experience with surveillance remains key to the evaluation of the impact of treatment on the natural history of the disease. A total of 17 series of surveillance have been published in which some element of tumor staging has been presented. Table 13–1 displays the results of these series, in the order of the final date of patient accession (for example, the first series of Hanash3 included patients diagnosed between 1934 and 1942 while the second series of Cook4 included patients diagnosed between 1939 and 1961). This ordering of outcomes is important due to the phenomenon of “stage migration.” While it is indeed possible that the natural history of prostate cancer has changed in the last 30 years, this change is more likely to be due to improved staging. As such, 30 to 40 years ago, patients considered to have localized prostate cancer were staged only with skeletal surveys (radiography of long bones) and acid phosphatase while patients in more contemporary series have been staged by computed tomography, transrectal ultrasonography, and bone scans. Additionally, previous series of patients often were diagnosed on the basis of symptoms while patients in more recent series may have been diagnosed by digital rectal examination (DRE) screening. For these reasons, earlier series undoubtedly included patients with metastatic disease. As a result, their failure over time was likely to be much greater than current series of patients who were staged more assiduously and accurately.

Results of Surveillance for Localized Prostate Cancer Perhaps the best method to evaluate the natural history of carcinoma of the prostate is to review series of patients without treatment who were followed up. These results then become the “floor” for any treatment of the disease. For example, if 10-year data from a surveillance series finds that the risk of development of metastatic disease is 20%, the treatment series must improve upon that figure, and any cost and morbidity arising from treatment must be compared directly with gains in such outcomes. Unfortunately, such comparisons suffer greatly from patient selection biases. Two of these are extremely important. First is the bias that surveillance series have generally enrolled patients with low-risk (well-differentiated, lowvolume, low-stage) tumors as well as older patients who 86

Natural History of Localized Adenocarcinoma of the Prostate / 87

Perhaps the earliest series of note, a total of 1000 patients from the Mayo Clinic, suffered from serious problems with tumor staging.5 The first series with more reliable staging was that of Hanash and colleagues.3 This series of 200 patients included patients of all stages—A, B, C, and D. While staging did not include any of the currently available modalities, the authors made several important observations. First, the risk of death was inversely proportional to the age at diagnosis. As such, the relative survival (actual survival divided by the expected survival of a similar-aged man) of the 50- to 59-year-old cohort was less than that for the 60- to 69-year-old cohort. Of interest, men over age 80 diagnosed with prostate cancer actually had a better survival than expected for the population. The authors also observed that patients with higher-grade tumors had a substantially worse prognosis than those with low-grade tumors. Finally, they observed that controlling for tumor grade, a patient with clinical symptoms of his disease had a significantly worse prognosis. A small series of 20 untreated prostate cancer patients was found in Cook and Watson’s review of 367 prostate cancer patients at Ellis Fischel State Cancer Hospital between 1939 and 1961.4 In this population of patients, the mean age was 74 years; the mean age of all other patients was 67 years. While overall survival at 5 and 10 years was 36% and 20%, respective cancer-specific survivals were 55% and 52%. A substantial experience with 233 patients (118 with stage A and 115 with stage B disease) was reported by Barnes et al. in 1976.6 Unlike prior reports, the authors noted that the majority of patients had been treated hormonally (orchiectomy or estrogens) either immediately or on a delayed basis. Some patients also required transurethral resection of the prostate for symptoms but none were treated for cure. As can be seen in Table 13–1, the authors had the first group of patients with longer survivals at 10 and 15 years for both stage A and stage B disease. They made the additional observation that patients with focal and diffuse disease had different outcomes—an observation that would be made later with better estimates of tumor volume using whole mount techniques. For example, while focal stage A disease had 5-, 10-, and 15-year survivals of 58%, 56%, and 35%, the respective survivals for diffuse stage A disease were 58%, 26%, and 14%. The authors again found that tumor grade and outcome were intimately linked, finding 5-, 10-, and 15-year survivals in grades I and II stage B disease of 81%, 70%, and 42% compared with 53%, 43%, and 15% for grade III and IV disease. A most interesting study was published in its last iteration by Madsen et al. in 1988.7 This publication provided full 15-year follow-up on 142 patients with T1 or T2 prostate cancer, who were randomized to either undergo radical prostatectomy or to receive surveillance alone. Unfortunately, the study was much too small to reach any

conclusions regarding the relative efficacy of the two forms of disease management. (For example, the current PIVOT trial is expected to accrue 1000 patients to address the same question with sufficient statistical power.) Nevertheless, the outcomes of the patients randomized to observation are illustrative of the natural history of prostate cancer diagnosed between 1967 and 1975. As can be seen from Table 13–1, survivals of almost 40% were reported for patients with stage B disease. The authors also

TABLE 13–1. Results of Surveillance for Localized Prostate Cancer Reference Number (Year) Stage 3 (1942) 4 (1961) 6 (1970) 7 (1975) 8 (1976)

9 (1979) 11 (1982) 14 (1984) 15 (1984)

16 (1985) 17 (1985)

18 (1986)

19 (1986) 20 (1991)

A B B A B A B Gleason 2–4 Gleason 5–7 Gleason 8–10 T1b-T2 T1b-T2 T1-2 T1-2 T1-2 T1-2 TxNxM0† 55–59 yr, Gleason 2–4 55–59 yr, Gleason 2–4 55–59 yr, Gleason 7 55–59 yr, Gleason 7 70–74 yr, Gleason 7 70–74 yr, Gleason 7 55–59 yr, Gleason 8–10 T1-2 (75% of patients) T1a T1b T2 B1‡ B2‡ B3‡ TxM0 T1-4M0

Percent Survival No. of Patients 50 129 20 118 115 30 20 44 160 130 279 279 122 122 223 223 767

5 10 15 Years Years Years 86 19 36 62 71 59 85 100* 88* 63* 88 95* 82 99* NS NS 92 98* 70 75* 60 84* 58*

278 13 53 28 29 37 9 120 301

40 100* 93.7* 70* 95 86 86 70 90§ 80*

52 4 20 43 51 49 59 95* 75* 52* 61 80* 50 84* 40.8 85.6*

22 1 NS 27 28 15 39 92* 66* 47* NS NS NS NS 20.7 80.9*

84 96* 35 48* 24 48* 23*

72 95* 16 30* 9 60* 14*

NS NS NS NS 90 60 66

NS NS NS NS 62 36 66

NS 50*

NS 30*

NS = not stated. *Prostate-cancer-specific survival (likelihood of not dying of prostate cancer within time period). †Staging in this study was haphazard. Bone scans were performed on only 30% of patients, acid phosphatase was performed in 53%, and there was no testing for the presence of metastatic disease in between 15% (Gleason 8 to 10) and 33% (Gleason 2 to 4) of patients. Estimates of overall survival and cancer-specific survival are obtained from the figures in the text and are approximate. ‡See text for explanation of staging definitions. §90% represents cancer-specific survival including only those deaths that were definitely due to prostate cancer. Seventy percent represents cancer-specific survival, including those deaths that were possibly due to prostate cancer.

88 / Advanced Therapy of Prostate Disease

commented on the relationship of tumor grade and outcome. They found that the 10-year survival for Gleason score ≤ 4 (24 patients) was 76%, for Gleason score 5 to 6 (92 patients) 48%, and 26% for Gleason score ≥ 7. The first of two analyses of patients from the Connecticut Tumor Registry was performed by Albertsen et al. in 1995.8 An analysis of patients originally diagnosed between 1971 and 1976 identified 451 patients who (1) had no evidence of metastatic disease (using acid phosphatase, bone scan, or metastatic survey); (2) were untreated; (3) had histologic evidence of prostate cancer, independent of autopsy or in association with bladder cancer diagnosis (e.g., prostate cancer diagnosed at the time of radical cystoprostatectomy); and (4) had sufficient clinical information to compute a comorbidity index score. The mean age of these patients was 70.9 years, and 14% were stage A1 (T1a), 24% were A2 (T1b), 49% were stage B (T2), and 13% were classified as T1x (due to inadequate pathologic material to classify the tumor as either T1a or T1b). The authors did not report overall survival but, of much greater value, reported cumulative mortality from prostate cancer itself, on the basis of initial tumor grade. These data are noted in Table 13–1. As the authors classified the patients’ cause of death, they were able to determine the impact of prostate cancer on survival. For men ages 65 to 75 years, they found that a Gleason 2 to 4 prostate tumor had minimal to no impact on life expectancy. However, this same age group, diagnosed with a Gleason 5 to 7 tumor, had a 4- to 5-year reduction in life expectancy. For men unfortunate enough to have a poorly differentiated tumor, the reduction in life expectancy was 6 to 8 years. The authors also noted that in those patients with a higher comorbidity score (i.e., sicker patients), the impact of their tumor on life expectancy was, as would be expected, less. A novel review by Lerner et al. from Baylor College of Medicine analyzed a group of 360 patients with T1b-T3a prostate cancer who were treated with staging pelvic lymphadenectomy and a combination of interstitial radiotherapy with 198Au seeds and external beam radiotherapy.9 The authors’ purpose in the review was to investigate the risk of prostate cancer death among men treated with brachytherapy using open implantation techniques—a procedure that had lost favor because of poor seed placement and resultant poor dosimetry. This less-than-adequate treatment modality would then provide a window on the potential mortality from “contemporary” prostate cancer (1966 to 1979) left untreated. Two sets of results are displayed in Table 13–1, both overall survival as well as prostate-cancer-specific survival, only summarizing the 279 patients with T1-T2 disease. The large number of patients also allowed the authors to calculate the actuarial risk of cancer death by age group. At 5 years, the risk of cancer death in men < 60, 60 to 70, and > 70 years of age was 8%, 9%, and 5%, respectively. At 10 years, the respective rates were 25%, 31%, and 34%.

Adolfsson et al. from the Karolinska Hospital in Stockholm have presented two reviews of patients with localized prostate cancer followed up without therapy.10,11 The most recent update11 included 122 patients diagnosed between 1978 and 1982 with T1-T2 tumors, who had well- or moderately differentiated disease. All patients underwent bone scans and acid phosphatase determinations prior to study inclusion. The median patient age was 68 years and the median follow-up was 91 months. The majority (109) of patients were diagnosed with T2 disease. During follow-up, 55% of patients developed disease progression to T3, 14% developed metastatic disease, and 7% died due to prostate cancer (compared to 38% who died of other causes). Using lifetable analyses, the risk of developing metastatic disease at 5 and 10 years was 8% and 28%, respectively. During follow-up 45% of patients required subsequent treatment due to local and/or distant disease progression. Johansson et al. from the Orebro Medical Center in Orebro, Sweden, have updated a series of patients with clinically localized prostate cancer, at different periods.12–14 Their most recent update14 summarized 223 patients with tumor confined to the prostate (T0-T2) who received no initial treatment for their disease. The mean age of these patients was 72 years, and the average follow-up was 168 months. Of these patients, 13% developed metastatic disease, 11% died of prostate cancer, and in 2%, prostate cancer was a contributing cause of death. Prostate-cancerspecific survival (reported as corrected survival by the authors) at 10 and 15 years was 85.6% and 80.9%, respectively. The risk of disease progression was substantial— 45% at 10 years and 57% at 15 years of follow-up. Albertsen’s second review of the Connecticut Tumor Registry comprised 767 men with localized prostate cancer who were managed without treatment between the years 1971 and 1984.15 Although the series included men without evidence of metastases, the staging of the patients was relatively haphazard (see footnote to Table 13–1). Nevertheless, the authors’ review had a number of strengths, including long follow-up, complete re-review of pathology by Dr. Gleason, and assignment of cause of death. By doing so, the authors were able to create a series of figures that displayed the patients’ overall survival and disease-specific survival, on the basis of age at diagnosis and biopsy Gleason score. A report of 278 patients with prostate cancer managed by surveillance alone was presented by Handley et al. from Newcastle upon Tyne.16 Staging information was sparse at best in this report with no T-stage reported, no mention of use of bone scans, and no patient undergoing lymph node staging—all this despite the fact that the patients were diagnosed between 1978 and 1985. The follow-up period was short (mean 41 months) and the average patient age was 73.1 years. While 54 patients (19.4%) were known to have metastases, prostate cancer was cited as the cause of

Natural History of Localized Adenocarcinoma of the Prostate / 89

death in 42% of the total number of patients. Additionally, 49% of patients required treatment during follow-up, of whom 83% received hormonal therapy. Although the authors reported that 75% of patients had T0-2 disease at diagnosis, the results of this series are distinctly different from almost all contemporary series of prostate cancer and probably reflect substantial understaging bias. Another series of patients from Scandinavia (the Norwegian Radium Hospital in Oslo) was the subject of the report of Waaler and Stenwig.17 Of 94 patients, 66 were T0NxM0, and 28 were T1-T2NxM0, with an average age of 73.3 and 74.5 years, respectively. Unfortunately, due to the short period of follow-up, only 5-year data were available regarding outcomes. One of the few United States series of untreated patients with localized prostate cancer hailed from Memorial Sloan-Kettering Cancer Center (MSKCC).18 Illustrating the degree of patient selection, the 75 patients reported in the series were a small fraction of the more than 4000 patients evaluated at MSKCC during that same period. Patients were staged in accordance with Whitmore’s staging system of that time (the same system used by the American Joint Commission on Cancer in their 4th edition of the staging manual): B1—palpable tumor ≤ 2 cm in diameter, B2—palpable unilateral tumor > 2cm in diameter, B3—palpable bilateral disease. The mean patient age for the three groups was somewhat lower than in previous series: 65, 67, and 69 years, respectively. The mean follow-up was extremely long— 133, 130, and 108 months. During follow-up, metastatic disease developed in 21% of patients with B1 disease, 46% of patients with B2 disease, and 22% of patients with B3 disease. Nevertheless, the median survival was substantial: > 200 months in B1 disease, > 125 months in B2 disease, and 190 months in B3 disease. Survival at 5, 10, and 15 years is displayed in Table 13–1. In a series of 120 patients without metastatic disease diagnosed between 1980 and 1986 from the University of South Manchester, United Kingdom, George noted a mean age of 74.8 years and had a follow-up of between 1 and 7 years.19 While palpable local progression was noted in 84% of patients, metastases developed in 11%, and death from prostate cancer was noted in 4% (compared with the rate of death from other causes of 40%). A unique study of a large number of patients from Göteborg, Sweden, was reported in 1995 by Aus et al.20 Of the 514 patients, 301 had no evidence of metastases at diagnosis. Unfortunately, it is difficult to determine the number of men who were T1-T2 as 158 of 301 were classified as T2b-T3 at diagnosis. Additionally, the authors selected patients who had prostate cancer and died between 1988 and 1991. As such, a death endpoint was reached in all patients. By using this methodology, the authors reported that they had completed the evaluation of cause of death in all patients and therefore could

report complete prostate-cancer-specific survival in all patients. A close evaluation of their Kaplan-Meier survival curves notes that all curves go to zero at 25 years of follow-up. From this projection, the authors concluded that ultimate cancer mortality rate in patients with M0 disease was 50% and among 65 patients who survived at least 10 years, mortality was 63%. The techniques of analysis used by the authors in this study have been called into question by a number of investigators. Of first concern is the attribution of prostate cancer death. We have demonstrated that such attribution is often extremely difficult and that survival curves can change dramatically, on the basis of individual interpretations of cause of death.21 Additionally, the act of censoring patients who die of other causes should prevent disease-specific survival curves from “going to zero,” as is seen in virtually all displays in Aus’ paper.20 As such, the accuracy of the authors’ estimates is of some concern.

Meta-analysis of Outcomes Data In 1994, Chodak published the results of a by-patient meta-analysis of six surveillance series comprising 828 patients.22 The principal conclusion of the authors was the impact of tumor grade on outcome. At 10 years, disease-specific survival for well-differentiated and moderately differentiated tumors was 87% and was 34% for poorly differentiated tumors. Of note, the authors also conducted an analysis of metastatic disease-specific survival, finding 10-year results of 81% for welldifferentiated tumors, 58% for moderately differentiated tumors, and 26% for poorly differentiated tumors. This second analysis is extremely important as it must be recalled that (1) the median age for most surveillance series is approximately 72 years, and (2) the evidence is compelling that the median survival for patients with metastatic prostate cancer is 2 years. Thus, if surveillance is offered to younger men, the likelihood of death from prostate cancer is extremely high within 10 to 12 years of follow-up.

Characteristics of Prostate Cancers Currently Detected It is well known that prostate cancer is a ubiquitous disease among older men if autopsy data are used for analysis. Data from these autopsy series suggest that prostate cancer can be found in 34% of men in the fifth decade of life and in as many as 54% of men in their eighth decade.23,24 From these data, some have suggested that prostate cancer screening will detect many of these indolent, “autopsy” tumors. Evidence suggests otherwise. In the American Cancer Society–National Prostate Cancer Detection Project, 2999 men aged 55 to 70 years underwent DRE, transrectal ultrasonography, and prostate-specific antigen (PSA) determi-

90 / Advanced Therapy of Prostate Disease

nations on an annual basis for up to 5 years.25 In these men, a total of 164 tumors were detected, with 83 found during the first year (the so-called “harvest effect”). During the subsequent years, 2 to 5 prostate cancers were found in 38, 16, 21, and 6 patients. Similar findings were published by Catalona in a series of 10,251 men who underwent prostate cancer screening.26 During the initial examination, 174 prostate cancers were detected, and during follow-up screens, 165 tumors were detected. Thus, during both initial and follow-up examinations, 339 tumors were detected in 10,251 men (a total of 2.3%), far different from the 30 to 60% rate of autopsy tumors. It thus appears likely that screening for prostate cancer with DRE and PSA will result in the detection of only a fraction of the “autopsy” tumors. It remains to be determined, however, if these screening programs will detect tumors that are of no clinical significance. Evidence is compelling from a number of studies that the tumors detected using current techniques of screening are truly of clinical significance. Ohori et al. conducted a study of 306 patients treated with radical prostatectomy for clinically localized prostate cancer and compared them with 90 patients who underwent cystoprostatectomy for invasive bladder cancer and who had no evidence of prostate cancer.27 The authors characterized radical prostatectomy specimens by tumor volume, grade, and pathologic stage and applied these criteria to all prostate tumors found in cystoprostatectomy specimens. Tumors were categorized as “unimportant” (less than 0.5 cm3, confined to the prostate, and no Gleason 4 or 5 component), “clinically important and curable” (> 0.5 cm3 or Gleason 4 to 5 and organ-confined), or “clinically important and advanced” (extraprostatic disease). These three categories proved to be reliable predictors of outcome with 5-year progression-free survivals of 100%, 86%, and 45%, respectively. When these categories were applied to cystectomy specimens, 78% were unimportant, 22% were important-curable, and none were advanced. Conversely, radical prostatectomy specimens included only 9% of unimportant tumors but had 62% important-curable tumors and 29% advanced tumors. Similar findings were reported by Smith and Catalona.28 In a series of 24,346 men undergoing screening, 1059 prostate cancers were detected. Of these men, 816 underwent surgical staging, allowing a determination of pathologic tumor stage. Of this group, only 25 (3%) were found to have microfocal, well-differentiated disease. A similar analysis by Dugan and colleagues using PSA doubling time estimates and tumor volumes in radical prostatectomy specimens estimated that clinically insignificant disease was treated with radical prostatectomy in between 0.3 and 14.5% of patients.29 These data thus suggest that the prostate tumors currently diagnosed with PSA screening and contemporary methods of prostate biopsy closely resemble those tumors

that have proved to be of significance over the years of experience as illustrated in Table 13–1. Optimistic data have been presented by Catalona et al. that with serial screening, the likelihood of organ-confined (and therefore, curable) disease increases.26 The combination of these observations suggests that intervention with serial screening may indeed alter the natural history of the disease if a curative treatment is imposed.

Decision Analyses While not specifically designed to determine the natural history of localized prostate cancer, several decision analyses have been published over the past 5 to 6 years that have addressed a similar question: the impact and utility of prostate cancer screening or treatment for localized disease. Many of the conclusions reached from these decision analyses are based on estimates of the natural history of the disease and therefore will be discussed in this chapter. The first such analysis was performed by Fleming et al.30 The authors developed a series of outcomes for men 60 to 75 years of age, using estimates of the disutility of complications of treatment and of the disease and concluded that only with the most optimistic assumptions regarding treatment efficacy would treatment for prostate cancer affect patient outcomes. Unfortunately, for reasons that are inexplicable, of the five natural history studies of prostate cancer that the authors used to estimate what would happen to patients if tumors were left untreated, four studies reported on results of T1a disease. (As stated above, T1a disease unquestionably behaves in an indolent fashion and is undeniably different from T1b-T2 disease in all respects.) Additionally, the disutility of a variety of complications is very much at odds with the experience of any clinician who manages prostate cancer. For example, treatment-related impotence and incontinence were given disutility factors of 95% and 70%, respectively. While these indeed may seem reasonable, how it can be appropriate to give hormonally responsive metastatic prostate cancer a disutility rate of 90% is hard to understand. With these issues in mind, it is not surprising that the authors came to the conclusion that treatment had little effect on the natural history of the disease. A similar analysis of prostate cancer screening was conducted by Krahn et al.31 The authors in this study used only one estimate for the natural history of the disease, that of Johansson. In addition to the problems inherent in using data from 70-year-old men to develop a decision analysis applied to men 50 to 70 years of age is the issue concerning the initial exclusion of men with poorly differentiated disease from Johansson’s study. As can be seen from Table 13–1, while Johansson’s study provides one estimate, there is considerable variation in the estimates of these outcomes. Of note, the authors did find that screening with PSA alone was relatively cost effective with an

Natural History of Localized Adenocarcinoma of the Prostate / 91

incremental cost-utility ratio of $42,000 per qualityadjusted life-year gained in 50-year old men. While this may seem to be a relatively high cost, it is very much in line with other therapeutic and preventive interventions.

Conclusion With a change in how prostate cancer has been diagnosed and staged over the past five decades, a change in the anticipated natural history of the disease has been witnessed. Current data suggest that prostate cancer diagnosed in a man with a 10- to 15-year anticipated life expectancy places the patient at substantial risk for disease progression and metastatic disease as well as for death due to the disease. Outcome seems to be intimately related to tumor grade; while well-differentiated tumors have a small impact on life expectancy, moderately and poorly differentiated tumors may result in a 4- to 8-year reduction in a patient’s lifespan. The opinions expressed herein are those of the authors and do not necessarily reflect those of the Departments of the Army or Defense.

References 1. Sheldon CA, Williams RD, Fraley EE. Incidental carcinoma of the prostate: a review of the literature and critical reappraisal of classification. J Urol 1980;124:626–31. 2. Endrizzi J, Thompson IM. The disappearance of well-differentiated prostate cancer due to PSA screening and decrease in number of transurethral resections of the prostate. Proceedings of the Kimbrough Urological Seminar; San Antonio (TX): Society of Urologists: Government Service; 1998. 3. Hanash KA, Utz DC, Cook EN, et al. Carcinoma of the prostate: a 15-year followup. J Urol 1972;107:450–3. 4. Cook GB, Watson FR. Twenty single nodules of prostate cancer not treated by total prostatectomy. J Urol 1968; 100:672–4. 5. Bumpus HC. Carcinoma of the prostate: a comparative study of modes of treatment. J Urol 1940;44:169. 6. Barnes R, Hirst A, Rosenquist R. Early carcinoma of the prostate: comparison of stages A and B. J Urol 1976; 115:404–5. 7. Madsen PO, Graversen PH, Gasser TC, Corle DK. Treatment of localized prostatic cancer. Radical prostatectomy versus placebo. A 15-year followup. Scand J Urol Nephrol 1988;110 Suppl:95–100. 8. Albertsen PC, Fryback DG, Storer BE, et al. Long-term survival among men with conservatively treated localized prostate cancer. JAMA 1995;274:626–31. 9. Lerner SP, Seale-Hawkins C, Carlton CE, Scardino PT. The risk of dying of prostate cancer in patients with clinically localized disease. J Urol 1991;146:1040–5. 10. Adolfsson J, Carstensen J, Lowhagen T. Natural course of clinically localized prostate adenocarcinoma in men less than 70 years old. J Urol 1991;146:96–8. 11. Adolfsson J, Carstensen J. Deferred treatment in clinically localised prostatic carcinoma. Br J Urol 1992;69:183–7. 12. Johansson JE, Adami HO, Andersson SO, et al. Natural

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history of localised prostatic cancer. Lancet 1989;1: 799–803. Johansson JE, Adami HO, Andersson SO, et al. High 10year survival rate in patients with early, untreated prostatic cancer. JAMA 1992;267:2191–6. Johansson JE, Holmberg L, Johansson S, et al. Fifteen-year survival in prostate cancer. A prospective, populationbased study in Sweden. JAMA 1997;277:467–71. Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998;280:975–80. Handley R, Carr TW, Travis D, et al. Deferred treatment for prostate cancer. Br J Urol 1988;62:249–53. Waaler G, Stenwig AE. Prognosis of localised prostatic cancer managed by “Watch and Wait” policy. Br J Urol 1993;72:214–9. Whitmore WF, Warner JA, Thompson IM. Expectant management of localized prostatic cancer. Cancer 1991;67:1091–6. George NJR. Natural history of localised prostatic cancer managed by conservative therapy alone. Lancet 1988;1: 494–6. Aus G, Hugosson J, Norlen L. Long-term survival and mortality in prostate cancer treated with noncurative intent. J Urol 1995;154:460–5. Clark J, Lillis P, O’Rourke T, et al. Reliability of disease specific survival in prostate cancer trials. Mol Urol. [In press] Chodak GW, Thisted RA, Gerber GS, et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994;330:242–8. Woolf SH. Screening for prostate cancer with prostatespecific antigen: an examination of the evidence. N Engl J Med 1995;333:1401. Sakr WA, Haas GP, Cassin BF, et al. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol 1993;150:379. Mettlin C, Murphy GP, Lee F, et al. Characteristics of prostate cancer detected in the American Cancer Society—National Prostate Cancer Detection Project. J Urol 1994;152:1737–40. Catalona WJ, Smith DS, Ratliff TL, Basler JW. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993; 270:948–54. Ohori M, Wheeler TM, Dunn JK, et al. The pathological features and prognosis of prostate cancer detectable with current diagnostic tests. J Urol 1994;152:1714–20. Smith DS, Catalona WJ. The nature of prostate cancer detected through prostate specific antigen based screening. J Urol 1994;152:1732–6. Dugan JA, Bostwick DG, Myers RP, et al. The definition and preoperative prediction of clinically insignificant prostate cancer. JAMA 1996;275:288–94. Fleming C, Wasson JH, Albertsen PC, et al. A decision analysis of alternative treatment strategies for clinically localized prostate cancer. JAMA 1993;269:2650–8. Krahn MD, Mahoney JE, Eckman MH, et al. Screening for prostate cancer: a decision analytic view. JAMA 1994; 272:773–80.

CHAPTER 14

PROSTATE PHYSIOLOGY AND REGULATION SUSAN R. MARENGO, PHD ing by day 19.7,8 At birth, the rodent prostatic epithelium predominately expresses cytokeratins characteristic of basal cells.8,9 Differentiation of the basal epithelium into distinct luminal (cytokeratins 8, 18, 19) and basal epithelia (cytokeratins 5, 7, 14, and 19) begins during the first 7 to 10 days of life, concomitant with canalization of the prostatic ducts (proximal [urethra] then distal [acinus]).8,9 At birth, the mesenchyme is strongly androgen-receptor positive, with small amounts of androgen receptor being expressed in the basal epithelium.8,9 As differentiation proceeds, the luminal epithelial cells come to express the highest levels of androgen receptor, although some expression remains in the stroma.7–9 Five α-reductase types I and II are detectable in the undifferentiated urogenital sinus and in the developing prostate, with type I localized to the epithelium and type II to the mesenchyme.10,11 For a more detailed discussion of prostatic ductule development in the mouse, the reader is referred to a series of studies by Cunha and associates.11–13 The elegant studies of Cunha and Chung demonstrated that the urogenital sinus mesenchyme is responsible for the induction of a prostatic phenotype in the urogenital sinus.14 Subsequent studies demonstrated that this induction includes the induction of expressed prostatic proteins.15,16 In the fetal rat, the androgen receptors are largely localized in the stromal rather than the epithelial compartment, and a lack of androgen receptors in the mesenchyme, but not the epithelium, produces a vaginal rather than a prostatic phenotype (Figure 14–1).8,9,14,17 In the fetal human prostate, androgen receptors have been localized in the smooth muscle and epithelial cells by in situ hybridization and immunohistochemistry.3,18 Using the reconstituted prostate model, Hayward and associates19 demonstrated that stromal-epithelial crosstalk goes both ways, and that combining human epithelium with murine mesenchyme results in the development of a stroma phenotypically resembling the human prostatic stroma, with its high proportion and liberal distribution of smooth muscle fibers.

This chapter focuses on the normal physiology of the human prostate and its regulation. Because of the pronounced interspecies variation in the types of accessory sex glands present and the constitution of their secretions, this review cannot be considered a review of general prostatic physiology that can be extrapolated to other species. Since the rodent model (rats and mice) has been utilized extensively as a model for investigation of prostatic physiology and pathology, these species will be included where pertinent.

Development and Anatomy Development The prostate originates from five pairs of buds arising on the posterior side of the urogenital sinus on either side of the verumontanum, which then invade the mesenchyme of the urogenital sinus.1,2 The topmost buds arise from the inner mesoderm and eventually develop into the transition zone of the human prostate, while the lower buds arising from the endoderm ultimately form the peripheral zones of the prostate.1,2 Cannulation of ductules begins almost immediately.1 The period of development of the fetal prostate (10 to 12 weeks) roughly coincides with that of maximal testosterone production by the fetal testis (12 to 18 weeks). At about 17 weeks, prostatic acid phosphatase (PAP) can be detected within the fetal prostate. Androgen receptor protein can be detected in both the epithelium and stroma of the fetal prostate, while expression of 5 α-reductase protein is limited to the stroma.3 In humans, a distinct anterior lobe is present only until 16 weeks, after which it regresses totally.1 It has been postulated that the central zone arises from the wolffian ducts rather than from the urogenital sinus, which would make its origin mesodermal rather then endodermal.4 Anatomically, the central zone lies in close opposition to the ejaculatory ducts, and its epithelium more closely resembles that of the seminal vesicles than that of the peripheral and transition zones.4 Biochemically, the expression of lectins and pepsinogen II (which has an extremely limited distribution) in the central zone resembles that of the seminal vesicles rather than that of the peripheral zone.5,6 In mice, development of the urogenital structures begins at roughly day 14.7,8 There is a definitive urogenital sinus formed by day 17, with solid epithelial chords form-

Gross Anatomy The gross and microscopic anatomy of the human4,20–22 and rodent23–28 prostates have been described in detail and will be covered only briefly here. The gross anatomy of the human prostate is best described as a zonal arrangement consisting of the peripheral zone (70 to 92

Prostate Physiology and Regulation / 93

75%), central zone (20 to 25%), transitional zone (5 to 10%), and the periurethral zones (approximately 1%) (Figure 14–2).20,24,27 For a comparison of the original lobular nomenclature of prostatic anatomy with that of the currently used zonal nomenclature, the reader is referred to the 1980 work of McNeal.4 The human prostate has two unique features that contribute to the development of the obstructive symptoms of prostatic disease. First, the gland completely surrounds and envelops the urethra, which makes a 35-degree bend at the verumontanum. Second, a large fibrous capsule accounting for approximately one-third of the total prostatic mass covers the entire anterior and anterolateral surface of the gland.20 The capsule is composed primarily of smooth muscle fibers that infiltrate the parenchyma of the gland.20 Pathologically, the three zones have very different profiles. Prostatic cancer (PCa) is most common in the peripheral zone, followed by the transition zone (approximately 20%), and central zone (5 to 10%).20 Prostatic intraepithelial neoplasia (PIN) is limited to the peripheral and central zones in approximately two-thirds of cases.29 In the remaining third, PIN is distributed throughout the three zones.29 Traditionally, benign prostatic hyperplasia (BPH) has been considered a disease solely of the transitional and periurethral zones. Detailed studies, however, have revealed that a small proportion of BPH nodules are located in the peripheral and central zones.30 In contrast to the human prostate, the rodent prostate is clearly divided into three or four lobes26 (see Figure 14–2). The ventral lobe is the largest and rests on the ventral surface of the bladder. There has been discussion as to whether the dorsal and lateral lobes are actually one pair of lobes or two, although they are often harvested as one unit for dissection purposes.26 The final lobe is the coagulating gland or anterior prostate.26 Based largely on the observation that tumors induced in the rodent prostate generally arise in the dorsal-lateral lobe,31–33 it has been proposed that this lobe is analogous to the peripheral zone in the human. Definitive biochemical and anatomic evidence has not yet been obtained, however.

zone. The periurethral zone immediately surrounds the proximal urethra as a series of abortive, embryonic glands without their own periglandular muscularis.35 They do not invade the surrounding urethral muscularis. Although there is zonal variation in the anatomic details, the prototypical prostatic acinus is lined with a tall cuboidal or columnar epithelium connected by desmosomes at the apical pole (for a review of the comparative fine structure of the human and rodent prostate, see the studies by Brandes23 and Price24). The apical boarder is lined with highly variable numbers and sizes of microvilli. The Golgi apparatus and endoplasmic reticulum are located supranuclearly and are highly developed, as is consistent with the cells’ secretory function. Apocrine and merocrine (exocrine) secretion are widely observed in both species. Studies in rats suggest that the

Histology Histologically, the normal adult human prostate consists of three major compartments: stromal (45%), epithelial (21%), and acinar luminal (34%).34 The acini in the peripheral zone are compact and regularly shaped,35 lined by a uniform columnar epithelium, and surrounded by loose and irregularly arranged muscle bundles.35 In contrast, the acini of the central zone are heterogeneous in shape and size, are partially separated by intraluminal ridges, and are closely surrounded by compact stromal muscle bundles.35 The epithelium is crowded and of irregular height and nuclear placement. Surrounding the proximal urethra to the level of the verumontanum is the transitional zone, which histologically resembles the peripheral

FIGURE 14–1. Effects of tissue localization of the androgen receptor on differentiation of the urogenital sinus (UGS). Epithelium and stroma from the urogenital sinuses of wild-type (androgenreceptor positive) or Tfm (androgen-receptor negative) mice were recombined and grafted under the renal capsule. Prostatic epithelium was obtained when wild-type or Tfm epithelium was recombined with wild-type stroma. Recombination of wild-type or Tfm epithelium with Tfm stroma resulted in development of a vaginal morphology. Reproduced with permission from Cunha GR, Chung WK, Shannon JM, Reese BG. Stromal-epithelial interactions in sex differentiation. Biol Reprod 1980;22:19–42.

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FIGURE 14–2. Comparison of the gross anatomy of the human (left) and rat (right) prostate. PZ = peripheral zone; CZ = central zone; TZ = transition zone; fm = anterior fibromuscular stroma; UD = distal urethra; UP = proximal urethral segment; E = ejaculatory ducts; bn = bladder neck; s = preprostatic and distal striated urethral sphincters; C = coronal plane; OC = oblique coronal plane; BL = bladder; SV = seminal vesicles; CG = coagulating gland; V = ventral lobe of the prostate; L = lateral lobe of the prostate; D = distal lobe of the prostate; Bur G = bulbourethral gland; UR = urethra; PU = pubis; vas deferens; CE = cauda epididymis. Reproduced with permission from Price D. Comparative aspects of development and structure in the prostate. In: Vollmer EP, editor. Biology of the prostate and related tissues. Vol. XII. Bethesda (MD): Dept. of Health, Education, and Welfare (US); 1963. p. 1–27; and Jesik CJ, Holland JM, Lee C. An anatomic and histologic study of the rat prostate. Prostate 1982;3:81–97.

distal/acinar tips actively undergo mitosis while few, if any, mitotic figures are observed in the intermediate to proximal portions of the ductules.27 In contrast to the tall columnar epithelium observed in the distal and intermediate regions, the epithelium in the proximal region is low cuboidal and contains frequent apoptotic figures.27 Basal cells lie between the luminal epithelium and the basement membrane and do not communicate with the lumen. It has been hypothesized that these cells serve as precursors to the luminal epithelial cells and to replenish the epithelium in the event of androgen withdrawal (e.g., in seasonal breeders).9,36,37 The prostatic stroma is separated from the epithelium by a dense acellular basal lamina. It is composed of smooth muscle cells, fibroblasts, and an extracellular matrix and contains the nerves and vasculature of the organ. The primary cell type in the prostatic stroma is smooth muscle cells, which closely surround the ductules. In humans, the stromal smooth muscle infiltrates the entire stroma and is a major component of the prostate, constituting 22% of the gland.38 There is far less smooth muscle in the rodent prostate, largely limited to thin sheaths of smooth muscle cells enveloping the ductules and acini.38 Fibroblasts are loosely interspersed between the cells of the smooth muscle sheath and the glandular units.38 In both rodents and humans, smooth muscle

cells express the expected markers and are androgenreceptor positive.38 Prostatic neuroendocrine (endocrine-paracrine, amine precursor uptake and decarboxylation [APUD]) cells are believed to differentiate from the prostatic stem cell population. Their presence in the epithelial compartment of normal, hypertrophic, and cancerous prostates has been well documented.39,40 Neuroendocrine cells have been identified in the peripheral zone, the periurethral glands, and the prostatic ducts.41 Immunohistochemical studies of paraffin-embedded tissues have not revealed neuroendocrine cells in rats,42 although neurosecretory granules have been described in the prostate tumors in transgenic mice expressing the Gγ/T-15 viral oncogene. 43 Neuroendocrine cells have two major morphologic phenotypes: open and closed.39,44 Open neuroendocrine cells extend slender processes to the tubule lumen. Closed neuroendocrine cells do not communicate with the lumen but rather extend dendritic-like processes amongst the adjacent exocrine epithelial cells. Ultrastructurally, neuroendocrine cells are distinguished from luminal epithelial cells by heterogeneous, dense-core granules (neurosecretory granules).39,40 Androgen receptors have been reported to be both present45 and absent46 from neuroendocrine cells, although the disappearance of neuroendocrine cells from the acini of newborns shortly after

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birth and their reappearance at puberty41 argues for either direct or indirect (paracrine) androgen regulation. The function of neuroendocrine cells within the prostate is not known. Based on morphology, however, some type of secretion or monitoring of luminal contents by open neuroendocrine cells seems likely.39,40,44 The most common proteins identified within the cytoplasm granules are chromogranins A and B, secretogranin, neuron-specific enolase, and serotonin, although calcitonin, katacalin, somatostatin, and bombesin/gastrin-related peptide have also been detected.39,40 Frequently, a given tumor will express multiple peptides.40,47 Although neuroendocrine cells express a cytokeratin profile more characteristic of basal than luminal epithelial cells,39,48 both prostate-specific antigen (PSA) and prostatic acid phosphatase have been detected in neuroendocrine cells.47,49 Additionally, neuroendocrine cells have been observed to cluster around afferent and efferent nerves, posing the possibility that they may regulate this axis.44 Based on the frequent presence of neuroendocrine cells within clusters of proliferating cells in PCa and BPH, it is also possible that these cells are involved in paracrine regulation of prostatic growth.46,50 The neuroendocrine cells themselves are apparently postmitotic and do not express proliferation markers.51,52

Prostatic Function and Secretions Under natural mating conditions, the secretions of the accessory sex glands function to (1) dilute the caudal epididymal sperm to the appropriate concentration and volume; (2) remove urine and bacteria from the urethra; (3) provide appropriate buffering and energy sources for the sperm until they leave the site of deposition and begin their ascent up the female reproductive tract ; (4) remove the motility and capacitation inhibitors necessary in the epididymis to ensure a fresh product; and (5) in species exhibiting postejaculatory solidification of the semen, such as rats/mice and humans, provide the chemical components for solidification and, if appropriate, dissolution of the seminal clot. Sperm removed from the epididymis in humans and other species53,54 can fertilize ova, indicating that the secretions of the accessory sex glands are not essential for fertility, at least under laboratory conditions. However, under natural conditions fertility has not been optimized through genetics, management, or advanced reproductive technology and the secretions of the accessory sex glands are likely to play a larger role in maximizing the male’s fertility than is apparent under laboratory conditions. Ionic Composition The composition of human prostatic fluid and that of other mammalian species has been detailed in Aumuller2 and in Setchell et al.55 Little is known about the biochemical composition of rat prostatic fluid. In humans, the prostate contributes about 0.5 to 1 mL to the total

ejaculate (2 to 6 mL total ejaculate, 40 to 240 million sperm per mL).56,57 Due to the high concentration of citric acid (approximately 91 mM, range 45 to 176 mM), the pH is slightly acidic at 6.5. Compared to plasma and interstitial fluid, human prostate secretions contain extremely high levels of divalent cations, including Ca++, Zn++, and Mg++, roughly equivalent amounts of Na+, and relatively low amounts of Cl– and HCO3–. Protein averages about 24 mg per mL. The primary sugar present is inositol (8.2 mM), with low levels of glucose (0.9 mM) and virtually no fructose. Citrate In many species, the concentration of citrate in the semen (5 to 50 mM) greatly exceeds that of the blood (0.07 to 0.12 mM).21 In humans, the peripheral zone of the prostate is the primary source of seminal citrate, while in the rat, citrate is secreted by the lateral and ventral lobes of the prostate as well as by the seminal vesicles.21,55 Because of its key role in the tricarboxylic acid cycle (TCA) and in fatty-acid synthesis, citrate is conserved rather than secreted by most tissues. In contrast, the human prostate is able to concentrate citrate in the prostatic fluid to levels of 24 to 130 mM (making it the predominant anion), compared to plasma/extracellular concentrations of 0.1 mM.21 Mitochondrial aconitate hydratase activity (citrate catalyzed to isocitrate) is inhibited by chelation with Zn++; 21,58 the excess citrate then replaces Cl – as the primary anion utilized by the luminal sodium transporter (Figure 14–3).21,59 Replenishment of four carbon submits for the TCA cycle is accomplished by a citrate-stimulated sodium-aspartate pump on the basal surface of the epithelium and subsequent transamination of aspartate to oxaloacetate.59,60 Citrate is likely to act as a seminal buffering agent, a chelator of free Ca++ and Zn++,61,62 and possibly a scavenger of free radicals.63 Given the role of free Ca++ in inducing capacitation,64 it may be that citrate is acting to prevent premature capacitation in the female reproductive tract. Zinc Zinc is concentrated in the prostatic fluid and the apical and mitochondrial portions of the prostatic epithelium.65,66 Concentrations of Zn++ are highest in the lateral portions of the peripheral zone in humans65 and in the lateral lobes of the prostate of the rat, with little if any present in the dorsal and ventral lobes of the prostate.65,66 High levels of Zn++ in the prostatic fluid may inhibit the enzymatic activity of secreted proteases such as PSA.67 In semen, most of the Zn++ is bound to either citrate or metallothionein, both also secreted by the prostate.68,69 Zinc has been demonstrated to bind ejaculated sperm in its free and bound states70 and has been hypothesized to play roles in the inhibition of nuclear decondensation.68,71

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FIGURE 14–3. Aspartate transport and citrate production in prostate luminal epithelial cells. The low affinity L-aspartate transporter Na+-K+ ATPase and a citrate transporter are represented at the apical membrane. The high affinity L-aspartate transporter and glucose transporters are represented in the basal membrane. Reproduced with permission from Lao L, Franklin RB, Costello LC. High-affinity L-aspartate transporter in prostate epithelial cells that is regulated by testosterone. Prostate 1993;22:53–63.

Inositol Human and rat prostates have relatively high concentrations of myo-inositol.72–74 In the rat, 3-hydro-myo-inositol injected systemically is concentrated in the prostate, especially in the coagulating gland and prostatic fluid,72,73 and synthesis of myo-inositol from glucose has been demonstrated in the ventral prostate.75 Ejaculated human sperm have not been demonstrated to metabolize inositol,76 and its function in the seminal plasma is unknown. Polyamines Humans and rats (but not mice) are unique in that their prostates have very high levels of ornithine decarboxylase (ODC) (EC 4.1.1.17) activity, with the prostatic fluid containing high levels of polyamines.77,78 In human semen, concentrations of spermine are 10 times greater than putrescine or spermidine,77,78 while in the rat ventral prostate spermidine is the most abundant, followed by putrescine and cadaverine.79 Expression of ODC is localized to the luminal epithelium.80 In the rat, regulation of ODC activity differs with the lobe involved. In pubertal rats or in testosterone-supplemented castrates, ODC activity in the dorsal lateral prostate parallels that of lobe proliferation.81 In contrast, such a correlation has not been detected in the ventral prostate,

suggesting a differential regulation of this enzyme between lobes and regions of the prostate. It is believed that the primary function of ODC in the ventral prostate is to synthesize and secrete the polyamines spermine and spermidine into the prostatic fluid.77,78,82 The role of polyamines in the semen is not known, although they have been speculated to play a role in seminal clot formation, to act as bactericides, and to be involved in sperm motility or metabolism.55,78 Ornithine decarboxylase is a 54-kDa cytosolic protein that functions as a homodimer to catalyze the first and rate-limiting step in the polyamine cascade.83,84 Polyamines play a crucial but poorly defined role in progression from the G1 to S phase of the cell cycle; not unexpectedly, ODC expression is very tightly regulated, with three pathways (regulation of transcription and translation, of mRNA, and of protein degradation) employed to keep activity in check.83,84 Epithelial proliferation in the normal prostate as judged by any one of a number of proliferation indices is very low at 0.14 to 1.7% (Ki-67: 0.2 to 1.5%),85,86 with the cellular turnover of the organ being estimated to be in the neighborhood of 1.5 to 2 years.87 The prostate would therefore not be expected to express constitutively high levels of ODC. The mechanism by which the prostate avoids polyamine-induced downregulation of ODC,83,84 or ODC-induced tumorigenesis,88 is not known.

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Prostasomes Human prostatic secretions also contain 150 to 200 nm vesicles, typically coated with a trilaminar membrane and released by exocytosis from the prostatic epithelium.89 The prostasome membrane contains Mg++/Ca++ dependent adenosinetriphosphatase (ATPase), which may be responsible for the transport and concentration of Ca++ within the prostasome.89 Prostasomes have abundant enzymatic activity, including multiple ATPases,89 serine/ threonine kinase,89 alkaline phosphatase, 5'-nucleotidase, alkaline phosphodiesterase,90 and aminopeptidases.91 They also contain chromogranin B, neuropeptide Y, and vasoactive intestinal polypeptide.92 Prostasomes are unusual in that their membranes contain high levels of cholesterol and sphingomyelin and relatively low levels of phosphatidylcholine,93 resulting in a highly ordered, very fluid membrane.94 Sperm and prostasomes are able to fuse,94 and the transfer of lipids and proteins from prostasome to sperm has been reported.91,94,95 Prostasomes have been observed to stimulate sperm motility,89,96 increase sperm-membrane fluidity,94 and provide immunologic protection.95,97 Proteins Prostatic secretions include a variety of growth factors (epidermal growth factor [EGF]/transforming growth factor [TGF]-α;98 vascular endothelial growth factor;99 and hepatocyte growth factor/scatter factor100), proteases,101–104 phosphatases,105 and binding proteins.102,106–108 In humans, the primary secreted proteins are PSA, PAP, and βmicroseminoprotein (β-MSP or β-inhibin).102 In the rat, the primary secreted proteins are prostatic-binding protein (PBP) (30 to 50%)109and cystain-related protein (5 to 10%).107 Due to space limitations, discussion will be confined to those proteins that have been well characterized or exploited for diagnostic and experimental use. Prostatic-Binding Protein Prostatic-binding protein is secreted by both the rodent and human prostate and has been referred to variously as prostatein and estramustine-binding protein.110 It is a member of the uteroglobulin superfamily of proteins and is a serine protease.111 In the rat, PBP is the major secretory protein of the prostate, with its expression limited to the ventral lobe.16,112 In humans, PBP is a minor prostatic secretory product113 and is expressed in a variety of organs, including the liver and colon.114 Prostaticbinding/estramustine-binding protein has been detected in the normal and diseased human prostate.115,116 It is a tetramer with one subunit composed of C1-C3 submits and the other of C1-C2 submits.117 The function of PBP in vivo is not known. As well as binding estramustine, PBP binds lipids, steroids, and polyamines, and can prevent the androgen receptor from binding to deoxyribonucleic acid (DNA).112,118,119 It may

serve to traffic secretory products out of the cell, as 3-hydro-estramustine injected into rats is localized first in the prostate, then in the acinar lumens.120 The expression of PBP has been studied extensively, however, in gaining a better understanding of the regulation of the androgen-promoter and differentiation function of the ventral prostate.16,107,121 As radiolabeled PBP injected intraperitoneally has been shown to be taken up by the prostate,122 it is possible that PBP could act as a carrier for chemotherapeutic agents in PCa. Prostatic-binding/ estramustine-binding proteins act as a “ligand,” and estramustine phosphate is currently being investigated as neoadjuvant therapy in PCa,123,124 given its ability to arrest cells in the G2 to M phase of the cell cycle and its enhancement of the effectiveness of radiation therapy both in vitro and in vivo.125,126 Kallikreins The human kallikrein family of serine proteases currently consists of: (1) hK1, which is expressed in the pancreas, kidney, and submandibular salivary gland; (2) hK2, human glandular kallikrein; and (3) hK3, or PSA—the latter two are expressed by the prostatic epithelium.101,127,128 While the expression of PSA is highest in the prostate, it has been detected in a variety of tissues in both sexes, most notably in that of the normal and cancerous breast.101,128 Prostate-specific antigen is expressed by the prostates of other primates but has not yet been detected in the prostates of other genera.101 Rodent semen also coagulates, but the seminal clot forms a rigid copulatory plug which does not dissolve, thus preventing intercourse with rival males and backwash of the sperm out of the vagina.82 At ejaculation, enzymes secreted by the anterior prostate (coagulating gland) catalyze the crosslinking of proteins secreted by the seminal vesicles. Removal of the plug or coagulating glands substantially reduces the fertility of a given male. Prostate-specific antigen is a 33- to 34-kDa singlechain glycoprotein with chymotrypsin-like activity, as opposed to the trypsin-like activity displayed by the other human kallikreins.101,128 Like other proteases, PSA is initially secreted as a zymogen that is rapidly activated in the semen, possibly by a cascade including hK2.129 In the undiseased prostate, most if not all of the PSA is secreted luminally.101,128 At ejaculation, sperm are mixed with the secretions of the accessory sex glands (Figure 14–4). The major protein secreted by the seminal vesicles is semenogelin, which reversibly immobilizes the sperm and causes coagulation of the semen.130,131 Seminal coagulation is not required for sperm immobilization by semenogelin.131 Within 5 to 20 minutes of ejaculation, PSA enzymatically dissolves the clot,130 thus freeing the sperm to enter the cervical crypts and begin the ascent up the female reproductive tract. The purpose of the clot and sperm immobilization is not known. Indeed, immobile or

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dead sperm are rapidly expelled from the vagina, leaving those sequestered within the cervical crypts to fertilize the ova.57 Prostate-specific antigen also activates seminal α2-macroglobulin, a nonspecific protease inhibitor, which by exposing its binding sites allows sperm to bind to it.132 In the normal prostate, the vast majority of PSA is secreted apically into the prostatic fluid; serum levels of PSA are negligible. However, in patients with BPH and prostate cancer, substantial amounts of PSA are secreted basely, allowing the protein to be detected in the blood and utilized for diagnostic and follow-up purposes. It has been demonstrated in vitro133,134 that PSA is able to degrade insulin-like growth factor binding protein 3 (IGFBP-3), thus liberating insulin-like growth factors (IGF-I, IGF-II) to bind to receptors on the prostate cell membrane and stimulate growth.134,135 If PSA also plays a substantial role in liberating growth factors from their binding proteins in situ, then the presence of PSA in the stromal compartment under either natural or pathologic conditions could be an important mechanism regulating prostatic growth. Prostatic Acid Phosphatase For a detailed review of the structure of PAP and its properties in the human prostate, the reader is referred to Moss and colleagues136 and Chu and colleagues.137 Prostatic acid phosphatase is a member of the nonspecific orthophosphate monoesterase family, of which there are four distinct types: those with widespread distribution (erythrocytic and lysosomal), those that are largely organ/cell specific, and those that are prostatic and macrophagic. Prostatic acid phosphatase is a glycopeptide

of about 41 to 50 kDa, although dimers and trimers (enzymatically active form) held together by noncovalent bonds are common. Enzymatic activity is maximal at pH 5.0. The specific substrate for PAP or its discrete function has not yet been determined. Prostatic acid phosphatase is a general phosphatase that can dephosphorylate serine, threonine, or tyrosine;138 recent evidence indicates that PAP may regulate the phosphorylation of transmembrane growth factor receptors.139 Variable sialization results in at least three isoenzymes, with 2a comprising the majority (approximately 95%) of the enzyme and being the isoform detected in the blood during screening for the resurgence of PCa. The specific function of PAP within the prostatic secretions is not known. Following the identification of PAP in the serum of patients with PCa140 and the discovery that expression of the patient’s protein is positively regulated by androgens,105 PAP was utilized for the detection of disseminated prostatic carcinoma (capsular extravasation, or metastasis) using enzymatic and later immunologic assays. However, due to methodologic difficulties and the inability to detect PAP in the serum until after dissemination of the disease, its usefulness as a marker for PCa has been limited.136 Recently, it has been proposed that PAP may negatively regulate phosphorylation of membrane tyrosine kinases such as P185erbB-2.139 The epithelium of the ventral prostate of the rat also produces an acid phosphatase (P150), which has an approximate 75% homology to human PAP, a short signal sequence, lacks a membrane anchoring sequence, and is regulated by androgens.141,142 Unlike human PAP, rat PAP is not inhibited by tartrate.136,141

FIGURE 14–4. Proposed functions of prostate-specific antigen (PSA). IGF-I = insulin-like growth factor I; IGFBP-3 = insulin-like growth factor binding protein 3; IGFR-I = insulin-like growth factor receptor I. Adapted from Jones et al.,184 Cohen et al.,134 Lilja,130 and Robert et al.67

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Beta-Inhibin/Beta-Microseminoprotein Beta-Inhibin, or β-microseminoprotein, is a nonglycosylated heterodimer consisting of alpha and beta subunits of a roughly 18-kDa protein. It is related to the transforming growth factor/immunoglobulin-binding superfamilies143 and is expressed by the epithelia of both the rat and human prostates.102,144 In addition to its role as an ovarian/testicular-produced negative regulator of pituitary follicle-stimulating hormone (FSH) secretion,143 it is readily detected in the linings of the reproductive, respiratory, gastrointestinal, and urinary tracts, especially in the mucosal cells.145 It is also readily detected in human seminal fluid and binds to ejaculated sperm.146 Although one of the three major secretory proteins produced by the human prostate,102 the role of βinhibin/β-microseminoprotein in prostatic physiology and pathology has not been intensively researched. Probasin Probasin is a 20-kDa, single-chain, highly basic (pI approximately 11.5) nonhistone protein that localizes to the prostatic secretions, secretory granules, and epithelial nuclei.136,147 The differential localization appears to be due to multiple transcripts with and without a signal peptide for secretion.148 The primary site of expression is the dorsal lateral prostate, although small amounts are also expressed in the ventral prostate.149 Not surprisingly, the expression of probasin is regulated by androgens.147,149 Based on sequence homology, probasin is a member of the ligand-binding family,148 which includes retinol-binding protein and α2-macroglobulin.150 The function of probasin within the prostate is not known, although it is known to be a heparin-binding protein and to have little if any mitogenic effects on the prostatic epithelium in vitro.151 In research, it has been used as a marker of androgen-dependent differentiation of the dorsal lateral prostate,121,152 in elucidation of androgen regulation of gene expression,153,154and through its promoter to target androgen-dependent gene expression to the prostate.31

Regulation of Prostatic Function and Growth Although androgens play a key role in the regulation of prostatic growth, function, and disease, it is now clear that they act in concert with, or as a backdrop for, a host of other regulatory pathways. Prostatic growth and the development of differentiated function take place under the influence of increased expression of testosterone during puberty,1,2 although castration prior to puberty does not entirely prevent subsequent prostatic growth.155,156 Once its mature size is reached, however, the prostate and other accessory sex glands cease growing, even though testosterone levels remain elevated. Supraphysiologic doses of exogenous testosterone do not

stimulate additional growth.157,158 Withdrawal of testosterone results in massive involution of the gland, characterized by apoptosis of the secretory epithelium.105,159 At maturity, therefore, testosterone becomes responsible for survival of the prostate and maintenance of its differentiated functions. The mechanism for this switch from a growth stimulator to a maintenance factor is not known but could be of prime importance in understanding the renewal of testosterone’s ability to stimulate prostatic growth in PCa and BPH. From an evolutionary standpoint, the majority of mammals are seasonal breeders and show drastic decreases in testosterone levels during the nonbreeding season. Thus, there must be a mechanism to either maintain prostatic function during the nonbreeding season or reinitiate it during sexual recrudescence.36,37 It is not unreasonable to assume that vestiges of these mechanisms would be present in the prostates of nonseasonal breeders such as humans. It is not known if the androgen-independent cells of advanced prostatic carcinoma are originally derived from the stem cells that survive during the nonbreeding season or if they are androgen-dependent cells that have developed the capacity to utilize other mechanisms to support their growth in the absence of androgens. Endocrine Regulation Androgens The prostate is dependent on testicular-derived testosterone; despite the presence of the 3β-hydroxysteroid dehydrogenase-∆5-∆4 isomerase complex,160 the prostate has not been reported to synthesize testosterone de novo. It can reversibly metabolize testosterone to androstenedione (17β-hydroxysteroid dehydrogenase161) and, possibly irreversibly, to estrogens (see below). The prostate’s primary metabolite of testosterone is dihydrotestosterone (DHT), an irreversible reaction catalyzed by 5 α-reductase.162 This is a more potent ligand for the androgen receptor than is testosterone, as it binds the receptor with greater affinity, enhances translocation from the cytoplasm to the nucleus, and is more effective in activating many androgenresponse elements.163,164 Following 5 α-reduction, DHT and androstanedione are further metabolized by 3α/βhydroxysteroid dehydrogenase to 5 α-androstane-3α/β17β-diol and androsterone.165,166 The reader is referred to the work of Amann and colleagues167 for a review of nomenclature and metabolic pathways for androgens in the male. Two forms of 5 α-reductase have been cloned in humans and rats.162 Type I isozyme is active over a broad pH range on either side of neutral, while type II isozyme is active over a very narrow pH, centering at 4.5.162 The rat prostate expresses both isozymes, with type I being expressed by basal epithelial cells and type II predominating in the stroma of the regenerating ventral

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prostate.168,169 In the human prostate, type II isozyme predominates,162 however type I expression and activity have recently been reported.170,171 Immunohistochemistry and in situ hybridization have detected both isozymes in basal, epithelial, and stromal cells, with lesser amounts being detected in the luminal epithelial cells.3,170–173 Interestingly, type I isozyme appears to be preferentially localized to the nucleus, while type II isozyme is localized to the cytoplasm.170 In culture, freshly isolated epithelial cells express type II isozyme. As the time in culture increases, however, type II activity decreases and type I activity becomes predominant.174 The androgen receptor is a member of the steroid/ thyroid hormone superfamily of nuclear receptors.163,164,175 The androgen receptor is 110 to 112 kDa (910 to 919 amino acids) and can be divided grossly into the N-terminus (amino acids 1 to 559), the DNA-binding region (amino acids 559 to 625), the hinge region (amino acids 625 to 671), and the ligand-binding region (amino acids 671 to 919) (Figure 14–5).163,164,175 The N-terminus contains a transactivation domain and three homopolymeric regions: Gln, Pro, and Gly.163 The Gln (CAG) polymorphism is of particular interest due to its role in X-linked spinal and bulbar muscular atrophy (Kennedy’s disease).176 Normal individuals have 17 to 29 CAG repeats, but affected males have > 40 repeats.176 Receptors with high numbers of repeats have decreased ligand binding and transcriptional activation.176 Investigations are ongoing to determine if variations in the length of N-terminus repeats the length CAG polymorphisms and are associated with increased risk for

PCa177,178 or fertility.179 The DNA-binding region contains domains involved with dimerization and nuclear localization, two zinc fingers, and the dimerization domain, which continues into the hinge region.163,164 The ligand-binding region contains two hydrophobic pockets for the ligand, nuclear localization, dimerization, and transactivation region, and the Hsp90 protein-binding site.163,164 The qualitative affinity of androgens for the androgen receptor follow the sequence DHT to testosterone to androstenedione to 5 α-androstane-3α/β-17βdiol androsterone.163,164 Following ligand binding, the androgen receptor undergoes conformational changes resulting in the dissociation of the heat shock/chaperone proteins and homodimerization, nuclear translocation, and eventual association with the androgen-response element on the DNA and the appropriate transcriptional regulatory cofactors.163,164,175 In rats and humans, the androgen receptor is localized primarily in the luminal epithelium, with heterogeneous expression in the prostatic stroma and little or none in the basal epithelial cells.180–182 In addition to the classic steroid-receptor mechanism described above, the androgen receptor is able to interact with several other regulatory pathways (see Figure 14–5). Although receptor phosphorylation is classically thought of as being part of the signaling pathway of membranebound receptors (e.g., the epidermal growth factor receptor [EGFR] family,183 IGFR,184 and TGFR),185 it is now known that steroid receptor activity is also regulated by phosphorylation.175 Androgen receptors are phosphorylated predominately on Ser residues, at least three of which

FIGURE 14–5. Schematic diagram of the human androgen receptor gene. Black areas = transactivation domains; P = proline directed phosphorylated Ser residues; HSP = heat shock protein; pKC = protein kinase C; pKA = protein kinase A; MAPK = mitogen-activated protein kinase; DNADep Kin = DNA-dependent kinase; Ser-Pro = serine-proline directed kinase; Cas-Kin II = casein kinase II. Adapted from Wiener et al.,164 MacLean et al.,176 Blok et al.,175 and Zhou et al.186

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show Pro-directed phosphorylation.175,186 Unlike many of the membrane-bound receptors, steroid receptors cannot undergo autophosphorylation.175,187 This reliance on kinases not directly associated with the receptor provides a key opportunity for modulation of androgen-receptor activity by other signaling pathways. When exposed to androgens, the androgen receptor undergoes a two- to fourfold increase in apparent phosphorylation. This has been shown, however, to be due to increased receptor stabilization rather than to increased phosphorylation.188 While not essential for activity, phosphorylation increases androgenreceptor transcriptional activity and may affect ligand binding.175,186 The androgen-receptor ligand-binding domain also includes consensus recognition motifs for multiple protein kinases175 (see Figure 14–5), and both EGF and IGF-I increase transcriptional activation of the androgen receptor in the presence of ligand.189 Paradoxically, the androgen receptor can also be activated in the absence of ligand (as judged by reporter constructs) by several growth factors, including EGF, IGF, and keratinocyte growth factor (KGF).190 Protein kinase A agonists are also able to stimulate the androgen receptors in kidney and prostate cells cotransfected with androgen receptors and androgenresponsive reporter constructs.191 Recently, it has been reported that TGF-β1 is capable of inducing translocation of the androgen receptor from the nucleus to the cytoplasm in human and rat stromal cultures, by an as yet undetermined mechanism.192 The role played by phosphorylation in androgenreceptor function or its interactions with other signaling pathways is currently an emerging field. However, given the extensive use of phosphorylation/dephosphorylation cascades in membrane-bound receptor signaling and the fact that many key growth factors are tyrosine or serine/ threonine kinases (see below), androgen-receptor phosphorylation/dephosphorylation would appear to be an ideal mechanism for mutual regulation of paracrine factor–steroid hormone signaling pathways. The effects of androgens on the expression of paracrine factors and their receptors are listed in Table 14–1. Physiologically, DHT, rather than testosterone, is responsible for virilization of the urogenital sinus and external genitalia.162 Treatment of pregnant rats with 5 α-reductase inhibitors during differentiation of the reproductive tract inhibits prostate development, an effect that can be reversed by simultaneous treatment with DHT.193 In the human fetus, the type II isozyme is critical for differentiation of the male reproductive tract, as evidenced by the incomplete masculinization of infants and children with a type II 5 α-reductase deficiency.162 Individuals with a type I isozyme deficiency have not yet been detected.162 Underscoring the importance of DHT’s role in the prostate is the use of 5 α-reductase inhibitors (e.g., finasteride) in the treatment of BPH, resulting in a gradual decrease in prostate size and serum PSA levels.162 Chronic

finasteride use in rats also reduces prostatic size and DNA content and increases apoptosis, however these changes are neither as rapid nor as dramatic as those observed with castration.194 In contrast to the obvious superiority of DHT compared to testosterone in the development and maintenance of adult prostate morphology are the very modest differences in expression of messenger ribonucleic acid (mRNA)/protein in the prostates of rats treated with testosterone versus DHT or castration versus finasteride.195,196 Expression of most of the secretory products mentioned above and the growth factors listed below is regulated by androgens and is summarized in Table 14–1. In addition to upregulation, androgens frequently act as negative regulators of protein expression. Negative regulation falls into two categories: (1) an immediate and transient increase (hours to days) following castration, as exemplified by testosterrone-repressed prostate message (TRPM)-2 and TGFβ,197,198 which likely play a direct role in the regression process; and (2) a more gradual and sustained increase (weeks) in expression, exemplified by C-cell adhesion molecule (C-CAM) and cytokeratin 8.197,199 Additionally, androgen regulation of gene expression is to a degree organ-dependent, as has been shown for S-adenosylmethionine200 and EGFR; 201,202 these are clearly regulated by androgens in the prostate but are not necessarily regulated by androgens in the peripheral androgen-responsive tissues. Sensitivity to androgens also varies with the lobe of the prostate studied;197,203,204 presumably, this would also hold true for the different zones of the human prostate. Estrogens The ability of estrogens to induce prostatic dysplasia in rats205 and hyperplasia in dogs and cynomolgus monkeys206,207 has spurred the investigation of their role in prostatic physiology and disease in humans. As exogenous estrogens inhibit testosterone secretion via negative feedback at the hypothalamus-pituitary, most in vivo models include treatment with exogenous androgens. Estrogens have been reported to stimulate 3-hydro-thymidine incorporation208 and the expression of desmin in cultures of human prostatic stromal cells.209 Further, aromatase inhibitors have been reported to inhibit hyperplastic changes in animal models and patients with BPH.210,211 Aromatase activity has been reported in preparations of the ventral prostate in rats,212 and proteins immunoreactive with aromatase antibodies have been detected in the human prostate,213,214 although detection of aromatase activity has yielded mixed results.213–219 It is likely that the primary source of estrogens in sexually mature males is the testicular Leydig’s cells, which express substantial amounts of aromatase activity in many species, including rats and humans.220,221 In the human prostate, estrogen receptors are confined to the stromal elements (periacinar fibroblasts, myoblasts, smooth muscle cells).222,223 Per unit stroma,

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estrogen receptors are highest in the zone of the prostate that is susceptible to BPH, the transition zone.224 The precedent for steroid hormones to affect epithelial function and development via paracrine factors secreted by the stroma has been well established,14,225 but such a pathway has not yet been studied for estrogens in the prostate. Estrogen receptors can be detected in the rat prostate by immunohistochemical methods during the prenatal period and puberty but not in the adult (45 days).226 Both the α and β forms of the estradiol receptor in the adult rat prostate are detected by reverse transcriptase–polymerase chain reaction (RT-PCR) and

in situ hybridization.227–229 The β estradiol receptor is the major estrogen receptor expressed in the rat prostate, with approximately equal expression being detected in the ventral, dorsal, and lateral lobes of the adult prostate.227–229 While labeling in the stroma is predominant in the prenatal animal, in the pubertal and adult rat, it is most intense over the epithelial compartment.229 Expression of the α-estrogen receptor is much lower than that of the β form, being highest in the lateral lobe and lowest in the ventral lobe.228 The physiologic significance of these two receptor isotypes is not known, and although they differ in their ability to bind to certain androgens

TABLE 14–1. Regulation by Androgens of Prostatic Secretory Products and Signaling Pathways* Substance

Level of Regulation Examined

Assay Method

Effect†

Reference

Citrate

Precursor uptake Key synthetic enzymes Uptake by mitochondria Key synthetic enzymes Key synthetic enzymes Protein mRNA Serum protein mRNA Protein Serum protein

Uptake assay Western blot Atomic absorption Enzyme activity Enzyme activity Immunohistochemistry Transcriptional regulation RIA Northern blot Immunohistochemistry Enzyme activity RIA; enzyme activity SDS-PAGE Promoter—receptor interactions RIA Northern blot, in situ hybridization Ligand binding immunohistochemistry Immunohistochemistry Northern blot Enzyme activity Immunohistochemistry PCR Immunohistochemistry Northern blot Binding assay RT-PCR RIA Northern blot RT-PCR Immunohistochemistry Northern blot Binding assay Northern blot Affinity labeling Northern blot Immunohistochemistry

Positive

Lao,59 Costello367

Positive Positive Positive Positive

Liu203 Hasagawa75 Fjosne368 Page,369 Aumuller370

Positive 4.9 kB—no change 2.3, 1.5 kB—positive Positive Positive Positive

Rittenhouse,101 Clements128 Huggins,105 Moss,136 Chu,137 Terracio,141 Porvari371

No change Negative (transient) Positive Negative Positive

Risbridger144 Banerjee,265 Kumar,372 Prins,373,375 Quarmby,374 Takeda,376 Bentvelsen377 Miyamoto,169 George378

No change Negative Positive Negative

Lau,228 Kruithof-Dekker379

Positive Positive Negative

Nishi,267 Hiramatsu380

Zinc Myo-inositol Polyamines PBP/estramustine-binding protein PSA (human) PAP (rat) PAP (human) Probasin Inhibin Androgen receptor 5 α-reductase

Protein Promoter activity Protein mRNA Protein Protein mRNA Protein

Estrogen receptor (rat) Estrogen receptor (human) Prolactin receptor EGF receptor

mRNA Protein mRNA Protein

EGF

Protein mRNA mRNA Protein mRNA Protein mRNA Binding mRNA Protein (BP-5) Protein (BP-3) mRNA Protein mRNA Protein

TGF-α TGF-β TGF-β receptor IGF-I IGFR-I IGFBP2–5 α1-adrenergic receptors β2-adrenergic receptors Muscarinic receptors

RT-PCR Ligand binding Northern blot Ligand binding

Matuo,149 Kasper153

Nevalainen233 Traish,202 St-Arnaud263

Banerjee,265 Liu381

Negative Negative Negative → positive Negative → positive Negative Negative

Kyprianou198 Kyprianou292 Nickerson382 Nickerson382 Nickerson,382 Thomas383

No change

Auger-Pourmarin384

Positive Positive

Collins358 Shapiro365

PBP = prostatic-binding protein; PSA = prostate-specific antigen; PAP = prostatic acid phosphatase; EGF = epidermal growth factor; TGF-β = transforming growth factor beta; IGF = insulin-like growth factor; IGFR-I = insulin-like growth factor receptor-I; IGFBP = insulin-like growth factor binding protein; BP = binding proteins; RIA = radioimmunoassay; PCR = polymerase chain reaction; RT-PCR = reverse transcriptase-polymerase chain reaction; SDS-PAGE = sodium dodecyl sulfate–polyacrylamide gel electrophoresis. *Unless otherwise noted, data were obtained from adult rodents. †Positive/negative: decreased/increased expression following castration, or increased/decreased expression with supplemental testosterone to intact or castrated males. Experiments using 5 α-reductase inhibitors instead of castration are not included.

Prostate Physiology and Regulation / 103

and antiestrogens, both forms have similar affinities for the three common estrogens (estrone, estradiol-17β, and estrone).227 Androgens have not been reported to affect the expression of either receptor subtype.228 Recently, alternative mechanisms for estrogen stimulation of prostatic cells have been reported, raising the question whether estrogen receptors are even a requirement for estrogen-mediated action on the prostate. By binding to sex steroid–binding globulin (also known as androgen-binding protein), and interacting with receptors on the cell membrane, estradiol has been shown to stimulate cyclic adenosine monophosphate (cAMP) production and PSA secretion and arginine esterase in explants of human BPH tissue.230,231 Prolactin Prolactin receptors are present in the secretory epithelium of the human prostate232 and in the epithelium of the dorsal and lateral lobes of the rat prostate.233 The primary source of serum prolactin is probably the pituitary, however prolactin protein and message have been detected in the epithelium of the dorsal and lateral prostates of both rats234 and humans.232 Prolactin stimulates prostatic growth,21,235,236 mitochondrial zinc accumulation,203 and citrate metabolism.237,238 Although expression of prolactin protein234 and the message for its receptor233 are positively regulated by testosterone, at least some of prolactin’s effects are independent of testosterone’s effects on the prostate.236,238 In the rat, the lateral lobe of the prostate is the most sensitive to the mitogenic, transcriptional, and metabolic effects of prolactin.203,239 Paracrine and Autocrine Growth Factors In addition to hormonal regulation, the prostate is clearly under paracrine and autocrine regulation, as has been demonstrated by epithelial/mesenchymal recombination studies in vivo14,16,240,241 and coculture/conditioned media studies in vitro.242–244 Some growth factors such as nerve-growth factor (NGF)/trk and NGF-β receptors245,246 as well as hepatocyte growth factor/met receptors247–249 operate as classic paracrine mediators, with ligand produced by the prostatic stroma and the receptors present on the basal and/or luminal epithelial cells. In contrast, TGF-β250,251 and IGF-II134 have the necessary components to utilize both paracrine and autocrine (epithelial to epithelial or stromal to stromal) pathways. The role played by these growth factor pathways in prostatic physiology and disease as well as their integration into the other prostatic regulatory pathways are currently being actively researched. This review focuses on three of the better characterized systems in the prostate that represent two strictly local pathways: (1) EGFs (generally stimulatory to proliferation); (2) TGF-βs (generally inhibitory for proliferation); and (3) IGFs, which act by both endocrine and local pathways.

Epidermal Growth Factor Family Pathway The EGFR family of membrane-localized tyrosine kinases has to date four members: (1) erbB-1/EGFR (170 kDa); (2) erbB-2/neu/HER-2 (185 kDa); (3) erbB-3 (160 kDa); and (4) erbB-4 (170 kDa).183,252 Depending on the particular ligand bound and the complement of receptors present, homo- or heterodimers of receptor subunits are formed following ligand binding.183,252 To date, no ligand has been identified for P185erbB-2, and P60erbB-3 appears to not have an active tyrosine kinase domain.183 This forces these two receptors to form obligate heterodimers with other members of the EGFR family for ligand-directed intracellular signaling. In the human prostate, all four EGFR/erbB family members have been identified in the epithelial compartment, with all but P170erbB-4 being expressed primarily in the basal epithelium; P170erbB has been reported to be expressed in both the basal and secretory epithelium.253–257 There are also persistent reports of some EGFR expression in the prostatic stroma.258,259 Multiple ligands for the EGFR family have been detected in the normal human prostate, including EGF,260 and heparinbinding (HB)-EGF,261 which have been localized to the stroma. Immunoreactive TGF-α has been identified inconsistently in a small proportion of normal human prostatic epithelial cells.257,258 The presence or absence of TGF-α in the stroma of the normal human prostate is still uncertain.257,258 Together, these results suggest that the EGFR/erbB family acts as a paracrine pathway from the stroma to the epithelium. Unlike the other ligand of the EGFR/erbB family, neu differentiation factor (NDF/heregulin) has been localized in the stromal, basal, and secretory epithelium.254 In rats, EGFR P185erbB-2 and P160erbB-3 have been identified in normal prostates and cell lines.202,262,263 Both EGFR and TGF-α have been localized to the luminal epithelium of the ventral prostate in the rat; thus the EGFR–TGF-α axis may operate, unlike in the human prostate, as an autocrine rather than a paracrine pathway.264,265 There has been no TGF-α detected in the stroma of any of the three lobes.264 Epidermal growth factor is also expressed by the rat prostatic epithelium, with the highest levels of expression in the dorsal prostate, although some expression has also been detected in the ventral lobes.266,267 There has been no EGF detected in the rat prostatic stroma.266 Interest in EGF in relation to the prostate is in part due to its role in proliferation and its use as an additive to tissue-culture medium. Epidermal growth factor stimulates the proliferation of prostatic epithelial cells in vitro268,269 and following orthotopic injection.270 It has also been reported to stimulate the growth of fetal prostates and adult human fibroblasts.271 The EGFR family is also believed to play a role in PIN and PCa, as there are frequently changes in levels of expression and a shift of localization of expression with these conditions. Prob-

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ably the best documented change is the dramatic increase in P185erbB-2 expression seen in PCa.253 The P185erbB-2 is able to form active heterodimers with all three other EGFR/erbB receptors, and it can be activated by a variety of ligands, including NDF, EGF, and TGF-α.183,272 An upregulation of this receptor would therefore dramatically increase the activation pathways available to the cell. Experiments with nontumorigenic epithelial cells from the rat ventral prostate have demonstrated that increased expression of P185erbB-2 can induce tumorigenesis and metastasis.262 Each of P185erbB-2 EGFR, P160erbB-3, and TGF-α has been reported, albeit inconsistently, to show increased expression in the luminal epithelium in PIN or PCa as well as in human prostate epithelial cell lines derived from PCa.255,256,273–276 It is possible that acquisition of an autocrine loop for the EGFR/erbB pathway may be a key event in the progression of PCa. The decreased expression of EGF in PCa compared to the normal prostate has also led to speculation that a shift in available ligands (e.g., decreased EGF, increased TGF-α) may also play a role in the progression of PCa.256,274 Transforming Growth Factor-β Inhibition of prostatic growth and the subsequent induction of either differentiation or apoptosis also appear to be regulated by paracrine factors.133,277–283 Of these pathways, the TGF-β family (TGF-β1, -2, and -3) has been the most intensively studied. The TGF-βs are classically thought of as inhibitors of epithelial growth and inducers of apoptosis in epithelial cells from several organs.185,284 They are secreted in a latent form that must subsequently be activated.185,246,284–286 Activation can occur through several mechanisms, including integrins αvβ1,285 IGFR-II,287 and extracellular proteases.185 Based on the localization of receptors and ligand, TGF-β, at least in the human prostate, should be able to act by both paracrine and autocrine pathways. The receptor is a transmembrane heterodimer with serine/threonine kinase activity.185,284 In the human prostate, both TGFR-I and TGFR-II are present in the glandular epithelial cells and colocalize with cells coexpressing smooth muscle α-actin in the stroma.251,288 Immunoreactivity of the ligand, TGF-β1, has also been localized to both the epithelial and stromal compartments.250 Immunoreactivity of TGF-β2 and -3 is preferentially localized in the epithelium, with TGF-β3 localized to the basal epithelial cells.289 Both receptors as well as TGF-β1 and -3 have been detected in the ventral prostate of the rat.286,290,291 The TGF-βs and their receptors were one of the first proteins shown to be negatively regulated by androgens, as their expression was dramatically upregulated immediately following castration and downregulated with subsequent androgen replacement.180,198,291,292 Continuous perfusion with TGF-β1 in vivo reduces wet weights of the ventral prostate without reducing serum testosterone,

implying that the effects of TGF-βs are downstream of those of testosterone.293 In vitro, exposure to TGF-β1 induces apoptosis in NRP-154 cells and primary cultures of prostatic epithelial cells as well as inhibiting the growth of primary cultures of epithelial cells from the rat ventral prostate.294,295 However, it should be noted that in both studies results were found to be highly dependent on culture conditions. The TGF-βs also inhibit the proliferation of prostatic stromal cells296,297 and induce differentiation of primary stromal cultures from a fibroblastic phenotype (expression of fibronectin and vimentin) to the smooth muscle phenotype (expression of α–smooth muscle actin).185,296 Epidermal growth factor can attenuate the TGF-βs’ induction of smooth muscle phenotype,269 their ability to induce apoptosis,295 and their inhibition of proliferation.298 The TGF-βs are able to inhibit androgen and EGF-stimulated growth; treatment of castrated rats with EGF increases the expression of TGF-β1 mRNA in prostatic stromal cells, suggesting a feedback loop between growth stimulators and inhibitors.192,290 Paradoxically, the overexpression of TGF-βs in tumorigenic prostate cell lines has been shown to induce greater tumor growth, be associated with induction of carcinomas and hyperplasia in the myc+ras transgenic mice prostate model, and to possibly induce hyperplasia in murine recombinant prostates.241,284,299 The phenotypic changes by which TGF-β promotes tumorigenesis are likely to be multiple, including alterations in the expression of extracellular matrix components, integrins, protease inhibitors, and metalloproteases.185,300–302 Insulin-Like Growth Factor The IGF pathway in the prostate differs from that of other growth factors in that it has both endocrine (IGF-I) and paracrine (IGF-II) components.184,303 IGFR-I, which is activated by IFG-I > IGF-II >>> insulin, is present on human prostatic epithelial cells and adenoma cell lines.135,304 As judged by in situ hybridization and RTPCR, IGFR-I is present at low levels in the prostatic stroma.135,305 The IGFR-II component has been less well characterized and has been reported to be present only on the adenoma cell line DU 145278 and on benign human stromal cells.305 The primary source of serum and presumably prostatic IGF-I is the liver.184,303 The IGF-I protein has not been identified in the conditioned media of primary cultures of human prostate fibroblasts or epithelial cells134,305,306 or in prostatic carcinoma cell lines.279,307 In the rat, however, IGF-I has been identified in the prostatic stroma308,309 and IGF-II has been detected in the prostatic epithelium,135 stroma,306 and in the conditioned media of prostatic stromal and epithelial cells.306 It thus may act as an autocrine (epithelial to epithelial) or paracrine (stromal to epithelial) regulator in the rat. The activity of the IGF pathway is also modulated by binding proteins, originating both in the sera and

Prostate Physiology and Regulation / 105

locally.134,184 As judged by combinations of protein (immunohistochemistry, Western blot) and mRNA (Northern blot, in situ hybridization), both prostatic fibroblasts and epithelial cells express IGFBP-1 through IGFBP-7.134,306,310–314 The ability to liberate serumderived IGF-I from its carrier proteins (primarily IGFBP-3) is another mechanism by which this pathway is regulated. At least three prostatic enzymes—PSA,133 cathepsin D,315 and urokinase279—are capable of releasing IGF-I from IGFBP-3. Whether the basally secreted PSA or the increased expression of urokinase and cathepsin D in PCa101,128,316,317 actually liberate enough IGF-I to stimulate the growth of the tumor remains to be determined (see Figure 14–4). Several in vivo and in vitro experiments have demonstrated that the IGF pathway can have an effect on prostatic growth. The prostate is vestigial in IGF-I null mice,318 and systemic treatment of IGF-I in rats increases wet weight of the ventral and dorsal lateral prostate by increasing the proportion of epithelial cells.319 In vitro, both IGF-I and IGF-II increase growth of prostatic epithelial cells and PCa cell lines.134,320,321 Also, expression of antisense message to IGFR-I reduces tumor size and metastatic capabilities of the PA-III rat adenocarcinoma model.322 Using the Noble rat model, Wang and Wong308 reported that during the induction of adenoma, expression of IGF-I shifted from the prostatic stroma to the epithelium, suggesting, as has been demonstrated for EGFR/TGF-α, a shift from a paracrine to autocrine pathway for this growth factor during tumorigenesis. In contrast, IGFBPs are generally reported to inhibit growth in most but not all cases.133,278,279,323 Probably the best studied of the prostatic IGFBPs, IGFBP-3 has been reported to induce apoptosis of cell lines derived from PCa by both ligand-dependent and -independent pathways.282,324 Clinically, there has been a great deal of interest in determining if increased serum levels of IGF-I325,326 and altered IGFBP profiles327 can be used to predict, diagnose, or follow PCa. In vivo, IGF-I expression in the liver is regulated by growth hormone that acts at this level to increase IGF-I and somatostatin expression, both of which act at the anterior pituitary to inhibit the release of growth hormone. Similar to the use of luteinizing hormone–releasing hormone (LHRH) agonists to inhibit testosterone expression by the testis, somatostatin agonists are being explored as potential therapeutics for PCa.328,329 Neurogenic Regulation Traditionally, investigation of the role of neurogenic regulation in the prostate has been limited to the obstructive symptoms of BPH330,331and the addition of the prostatic secretions to the ejaculate.98,332 Its role in regulation of prostatic function has not been well studied, although evidence is accruing that it may play a broader role than previously suspected. The reader is referred to Walsh and

colleagues,333 Higgins and Gosling,334 and McVary and colleagues335 for descriptions of the gross distribution of nerves and ganglia within the human prostate. Synaptomenal complexes appear to be limited to the prostatic stroma.336,337 Alpha-adrenergic innervation predominates in both the rat and human prostate, although muscarinic335,338 and nonadrenergic noncholinergic pathways334,336,337,339–341 are also present. Alpha1-adrenergic receptors are localized primarily to the stromal compartment in both rats and humans.342–344 Alpha2-adrenergic receptors have also been identified in the prostate, particularly in the vicinity of blood vessels344 and in the prostatic capsule.345,346 Based on genetic and agonist/antagonist studies, three α1 subtypes have been identified: α1A (previously α1C), α1B, and α1D (previously α1A and α1A/D).347,348 Both RT-PCR and in situ hybridization studies have identified all three subtypes in the human prostate.349–351 Based on mRNA, protein expression, ligand-binding, and isometric contraction studies, the α1A subtype is by far the most predominant receptor in the human prostate.349,350,352–355 The role played by these receptors in prostatic contraction is illustrated by the clinical use of α1-adrenergic blockers in relieving the obstructive symptoms of BPH.330,331 The agonist/antagonist binding profile for prostatic α1A receptors differs from that found in several other tissues. It has been hypothesized that the prostatic α1A-receptor is a unique α1A subtype, another as yet uncharacterized receptor, or is subjected to unique regulatory pathways.352,354,355 The α1C-adrenergic receptors are localized predominantly, but not exclusively, within the stroma.349–351 Studies have found α1D (α1A/D) receptors in both the stromal and epithelial compartments.349,350 In contrast, the α1B receptors are predominately localized to the glandular epithelium.349 In addition to expelling the contents of the prostatic acini during ejaculation as has been found in the rat,98,332 the adrenergic pathway may also play a role in promoting prostatic smooth muscle differentiation356 and in survival of the prostate stroma and epithelium.335,357 Beta-adrenergic receptors are present in the prostatic capsule345,346 but, as judged by ligand-binding and contraction studies, are all but absent from the parenchyma of the human prostate.335,346 In contrast, β2 receptors are readily detectable in the rat ventral prostate.358 Beta2adrenergic agonists stimulate cAMP accumulation in epithelial-cell primary cultures359 and have been reported to upregulate the expression of PBP message and protein in denervated prostates and in recombinant prostatic graphs in the renal capsule.357,360 Unlike the α1-adrenergic agonists,98,332,361 β2-adrenergic agonists do not appear to regulate exocrine secretion.98 The muscarinic cholinergic receptor system is also present in both rats and humans species although this has been much less extensively studied.335,338 In human prostatic adenomas, the M1 subtype has been localized to the

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prostatic epithelium and is the predominant muscarinic receptor detected by immunoprecipitation and ligandbinding studies.344,362 The presence of muscarinic receptors in the stroma is still a matter of controversy,344,362 but the M2-receptor subtype has been detected primarily on cultures of prostatic smooth muscle.363 In the ventral prostate, the M3 subtype predominates,364 although the M1 subtype has also been detected on the prostatic epithelium.365 In humans, muscarinic agonists stimulate the contraction of the prostatic capsule but not of the parenchyma.346 Muscarinic receptors (M3 subtype) have also been reported to stimulate proliferation of primary cultures of epithelial cells obtained from radical prostatectomies.366 In rats, muscarinic agonists induce a sustained release of prostatic secretory products, which appears to occur by mechanisms other than smooth muscle contraction.98,332

Conclusion Historically, the prostate has functioned to enhance fertility by secreting buffers and protective agents that help keep the sperm in a quiescent and undamaged state until they have reached the ampulla of the oviduct, as well as by secreting PSA that releases the ejaculated sperm from the semenogelin coagulate. In the past, few men lived long enough for PCa or BPH to become clinically relevant, much less life threatening. The dramatic increase in life expectancy during the twentieth century has altered the role of the prostate in men’s health. The prostate is the only organ in the body that demonstrates abnormal growth (PIN, BPH, or PCa) in nearly 100% of American males by their sixth decade. Further, unlike the epithelium of the skin and colon, the prostatic epithelium is relatively protected from environmental assault and has a very low rate of turnover. Is there a basic regulatory mechanism in the prostatic housekeeping machinery that goes awry as men age? What are the physiologic differences between the transitional zone and peripheral zone such that the former is highly predisposed to benign disease while the latter demonstrates almost no benign disease but cancer instead? Given the unique attributes of abnormal prostatic growth, whether benign or malignant, future research must be directed toward understanding the basic developmental and regulatory pathways of the prostate so that appropriate preemptive measures and therapies can be developed.

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116 / Advanced Therapy of Prostate Disease prostate cancer cell proliferation by insulin-like growth factors and its interaction with the epidermal growth factor autocrine loop. Prostate 1994;24:167–75. 322. Burfeind P, Chernicky CL, Rininsland F, et al. Antisense RNA to the type I insulin-like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cells in vivo. Proc Natl Acad Sci U S A 1996;93:7263–8. 323. Damon SE, Maddison L, Ware JL, Plymate SR. Overexpression of an inhibitory insulin-like growth factor binding protein (IGFBP), IGFBP-4, delays onset of prostate tumor formation. Endocrinology 1998;139: 3456–64. 324. Gill ZP, Perks CM, Newcomb PV, Holly JMP. Insulin-like growth factor-binding protein (IGFBP-3) predisposes breast cancer cells to programed cell death in a nonIGF-dependent manner. J Biol Chem 1997;272:25602–7. 325. Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 1998;279:563–6. 326. Wolk A, Mantzoros CS, Andersson SO, et al. Insulin-like growth factor 1 and prostate cancer risk: a populationbased, case-control study. J Natl Cancer Inst 1998;90: 911–5. 327. Kanty H, Madjar Y, Dagan Y, et al. Serum insulin-like growth factor-binding protein-2 (IGFBP-2) is increased and IGFBP-3 is decreased in patients with prostate cancer: correlation with serum prostate-specific antigen. J Clin Endocrinol Metab 1993;77:229–33. 328. Lamharzi N, Schally AV, Koppan M, Groot K. Growth hormone-releasing hormone antagonist MZ-5-156 inhibits growth of DU 145 human androgen-independent prostate carcinoma in nude mice and supresses the levels and mRNA expression of insulin-like growth factor II in tumors. Proc Natl Acad Sci U S A 1998;95:8864–8. 329. Vainas G, Pasaitoi V, Galaktidou G, et al. The role of somatostatin in complete antiandrogen treatment in patients with prostatic carcinoma. J Exp Clin Cancer Res 1997;16:119–26. 330. Lepor H. Alpha blockade for the treatment of benign prostatic hyperplasia. Urol Clin North Am 1995;22:375–86. 331. Yamada S, Tanaka C, Kimura R, Kawabe K. Alpha1adrenoceptors in human prostate: characterization and binding characteristics of alpha1-anatagonists. Life Sci 1994;54:1845–54. 332. Wang JM, McKenna KE, Lee C. Determination of prostatic secretion in rats: effect of neurotransmitters and testosterone. Prostate 1991;18:289–301. 333. Walsh PC, Lepor H, Eggleston JC. Radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. Prostate 1983;4:473–85. 334. Higgins JRA, Gosling JA. Studies on the structure and intrinsic innervation of the normal human prostate. Prostate Suppl 1989;2:5–16. 335. McVary KT, McKenna KE, Lee C. Prostate innervation. Prostate Suppl 1998;8:2–13. 336. Vaalasti A, Hervonen A. Nerve endings in the human prostate. Am J Anat 1980;157:41–7. 337. Vaalasti A, Hervonen A. Innervation of the prostate of the rat. Am J Anat 1979;154:231–44. 338. Vaalasti A, Hervonen A. Autonomic innervation of the human prostate. Invest Urol 1980;17:293–7.

339. Hedlund P, Ekstrom P, Larsson B, et al. Heme oxygenase and NO-synthase in the human prostate—relation to adrenergic, cholinergic and peptide-containing nerves. J Auton Nerv Syst 1997;63:115–26. 340. Killam AL, Watts SW, Cohen ML. Role of alpha 1-adrenoceptors and 5-HT2 receptors in serotonin-induced contraction of rat prostate: autoradiographical and functional studies. Eur J Pharmacol 1995;273:7–14. 341. Juarranz MG, Guijarro LG, Bajo AM, et al. Ontogeny of vasoactive intestinal peptide receptors in rat ventral prostate. Gen Pharmacol 1994;25:509–14. 342. Kobayashi S, Demura T, Nonomura K, Koyanagi T. Autoradiographic localization of α1-adrenoceptors in human prostate: special reference to zonal difference. J Urol 1991;146:887–90. 343. Walden PD, Durkin MM, Lepor H, et al. Localization of mRNA and receptor binding sites for the alpha 1aadrenoceptor subtype in the rat, monkey and human urinary bladder and prostate. J Urol 1997;157:1032–8. 344. James S, Chapple CR, Phillips MI, et al. Autoradiographic analysis of alpha-adrenoceptors and muscarinic cholinergic receptors in the hyperplastic human prostate. J Urol 1989;142:438–44. 345. Lepor H, Gup DI, Baumann M, Shapiro E. Comparison of alpha 1 adrenoceptors in the prostate capsule of men with symptomatic and asymptomatic benign prostatic hyperplasia. Br J Urol 1991;67:493–8. 346. Caine M, Raz S, Zeigler M. Adrenergic and cholinergic receptors in the human prostate, prostatic capsule and bladder neck. Br J Urol 1975;47:193–202. 347. Michel MC, Kenny B, Schwinn DA. Classification of α1adrenoceptor subtypes. Naunyn Schmiedebergs Arch Pharmacol 1995;352:1–10. 348. Schwinn DA, Johnston GI, Page SO, et al. Cloning and pharmacological characterization of human alpha-1 adrenergic receptors: sequence corrections and direct comparison with other species homologues. J Pharmacol Exp Ther 1995;272:134–42. 349. Tseng-Crank J, Kost T, Goetz A, et al. The α1C-adrenoceptor in human prostate: cloning, functional expression, and localization to specific prostatic cell types. Br J Pharmacol 1995;115:1475–85. 350. Nasu K, Moriyama N, Kawabe K, et al. Quantification and distribution of alpha1-adrenoceptor subtype mRNAs in human prostate: comparison of benign hypertrophied tissue and non-hypertrophied tissue. Br J Pharmacol 1996;119:797–803. 351. Price DT, Schwinn DA, Lomasney JW, et al. Identification, quantification, and localization of mRNA for three distinct alpha1 adrenergic receptor subtypes in human prostate. J Urol 1993;150:546–51. 352. Marshall I, Burt RP, Chapple CR. Noradrenaline contractions of human prostate mediated by α1 A - (α1 C -) adrenoceptor subtype. Br J Pharmacol 1995;115:781–6. 353. Lepor H, Tang R, Shapiro E. The alpha-adrenoceptor subtype mediating the tension of human prostatic smooth muscle. Prostate 1993;22:301–7. 354. Chess-Williams R, Chapple CR, Verfurth F, et al. The effects of SB 216469, an antagonist which discriminates between the alpha1 A -adrenoceptor and the human prostatic alpha1-adrenoceptor. Br J Pharmacol 1996;119:1093–100. 355. Kenny BA, Miller AM, Williamson IJR, et al. Evaluation of

Prostate Physiology and Regulation / 117 the pharmacological selectivity profile of alpha1 adrenoceptor antagonists at prostatic alpha1 adrenoceptors: binding, functional and in vivo studies. Br J Pharmacol 1996;118:871–8. 356. Smith P, Rhodes NP, Beesley C, et al. Prostatic stromal cell phenotype is directly modulated by norepinephrine. Urology 1998;51:663–70. 357. Thompson TC, Zhau HY, Chung LW. Catecholamines are involved in the growth and expression of prostatic binding protein by rat ventral prostatic tissues. Prog Clin Biol Res 1987;239:239–48. 358. Collins S, Quarmby VE, French FS, et al. Regulation of the beta2-adrenergic receptor and its mRNA in the rat ventral prostate by testosterone. FEBS Lett 1988; 233:173–6. 359. Carmena MJ, Hueso C, Recio MN, Prieto JC. Beta-adrenergic stimulation of cyclic AMP accumulation in rat prostate epithelial cells during sexual maturation. Mech Ageing Dev 1990;52:79–86. 360. Guthrie PD, Freeman MR, Liao ST, Chung LW. Regulation of gene expression in rat prostate by androgen and beta-adrenergic receptor pathways. Mol Endocrinol 1990;4:1343–53. 361. Steidle CP, Cohen ML, Hoover DM, Neubauer BL. Comparative contractile responses among ventral, dorsal, and lateral lobes of the rat prostate. Prostate 1989; 15:53–63. 362. Ruggieri MR, Colton MD, Wang P, et al. Human prostate muscarinic receptor subtypes. J Pharmacol Exp Ther 1995;274:976–82. 363. Yazawa H, Saita Y, Iida E, et al. Characterization of muscarinic cholinoceptor in primary culture of smooth muscle cells from human prostate. J Urol 1994;152: 2173–7. 364. Pontari MA, Luthin GR, Braverman AS, Ruggieri MR. Characterization of muscarinic cholinergic receptor subtypes in rat prostate. J Recept Signal Transduct Res 1998;18:151–66. 365. Shapiro E, Miller AR, Lepor H. Down regulation of the muscarinic cholinergic receptor of the rat prostate following castration. J Urol 1985;134:179–82. 366. Rayford W, Noble MJ, Austenfeld MA, et al. Muscarinic cholinergic receptors promote growth of human prostate cancer cells. Prostate 1997;30:160–6. 367. Costello LC, Liu Y, Franklin RB. Testosterone stimulates the biosynthesis of m-aconitase and citrate oxidation in prostate epithelial cells. Mol Cell Endocrinol 1995; 112:45–51. 368. Fjosne HE, Strand H, Ostensen M-A, Sunde A. Ornithine decarboxylase and S-adenosylmethionine decarboxylase activity in the accessory sex organs of intact, castrated, and androgen-stimulated castrated rats. Prostate 1988;320:309–20. 369. Page MJ, Parker MG. Effect of androgen on the transcription of rat prostatic binding protein genes. Mol Cell Endocrinol 1982;27:343–55. 370. Aumuller G, Seitz J, Heyns W, Flickinger CJ. Intracellular

localization of prostatic binding protein (PBP) in rat prostate by light and electron microscopic immunocytochemistry. Histochemistry 1982;76:497–516. 371. Porvari K, Kurkela R, Kivinen A, Vihko P. Differential androgen regulation of rat prostatic acid phosphatase transcripts. Biochem Biophys Res Commun 1995;213: 861–8. 372. Kumar VL, Majumder PK, Kumar V. Androgen deprivation causes up-regulation of androgen receptor transcript in the rat prostate. Mol Cell Biochem 1997;171: 133–8. 373. Prins GS, Woodham C. Autologous regulation of androgen receptor messenger ribonucleic acid in the separate lobes of the rat prostate gland. Biol Reprod 1995; 53:609–19. 374. Quarmby VE, Yarbrough WG, Lubahn DB, et al. Autologous down-regulation of androgen receptor messenger ribonucleic acid. Mol Endocrinol 1990;4:22–8. 375. Prins GS, Birch L. Immunocytochemical analysis of androgen receptor along the ducts of the separate rat prostate lobes after androgen withdrawal and replacement. Endocrinology 1993;132:169–78. 376. Takeda H, Nakamoto T, Kokontis J, et al. Autoregulation of androgen receptor expression in rodent prostate: immunohistochemical and in situ hybridization analysis. Biochem Biophys Res Commun 1991;177:488–96. 377. Bentvelsen FM, McPhaul MJ, Wilson CM, et al. Regulation of immunoreactive androgen receptor in the adrenal gland of the adult rat. Endocrinology 1996;137:2659–63. 378. George FW, Russell DW, Wilson JD. Feed-forward control of prostate growth: dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5-alphareductase. Proc Natl Acad Sci U S A 1991;88:8044–7. 379. Kruithof-Dekker IG, Tetu B, Janssen PJ, Van-der-Kwast TH. Elevated estrogen receptor expression in human prostatic stromal cells by androgen ablation therapy. J Urol 1996;156:1194–7. 380. Hiramatsu M, Kashimata M, Minami N, et al. Androgenic regulation of epidermal growth factor in the mouse ventral prostate. Biochem Int 1988;17:311–7. 381. Liu X-H, Wiley S, Meikle W. Androgens regulate proliferation of human prostate cancer cells in culture by increasing transforming growth factor-alpha (TGFalpha) and epidermal growth factor (EGF)/TGF-alpha receptor. J Clin Endocrinol Metab 1993;77:1472–8. 382. Nickerson T, Pollak M, Huynh H. Castration-induced apoptosis in the rat prostate is associated with increased expression of genes encoding insulin-like growth factor binding proteins 2, 3, 4 and 5. Endocrinology 1998;139: 807–10. 383. Thomas LN, Cohen P, Douglas RC, et al. Insulin-like growth factor binding protein 5 is associated with involution of the ventral prostate in castrated and finasteride-treated rats. Prostate 1998;35:273–8. 384. Auger-Pourmarin L, Roubert P, Chabrier PE. Alpha1adrenoceptors in testosterone-induced prostatic hypertrophy. Eur J Pharmacol 1998;341:119–26.

CHAPTER 15

PATHOBIOLOGY OF PROSTATE DISEASES: AN UPDATE GREGORY T. MACLENNAN, MD

Prostatitis

spp. Another major grouping of rDNAs, found in 74% of patients, were distinct from previously reported sequences but were > 90% similar to known gram-negative bacteria. Minor rDNA groups showed similarities to Flavobacterium and Pseudomonas testosteroni; in addition, two patients had rDNAs < 70% similar to known rDNAs. The findings from these two studies suggest that microorganisms undetectable by traditional methods may be harbored within the prostate. In fact, most of these diverse sequences are not reported in environments outside the prostate; the sequences suggest the adaptation of limited groups of bacteria to the microenvironment of the prostate. The authors note that prostate tissue from asymptomatic volunteers also contained 16S rDNA sequences, although in a much lower percentage than that noted in the symptomatic patients reported in their studies. Their future studies will address such issues as the relationship between prostatitisassociated pain and the presence of rDNA sequences, and the question of whether the presence of infectious microorganisms may play a role in the development of prostate hyperplasia and/or prostate cancer.

Acute prostatitis and chronic recurrent prostatitis are clinical entities associated with readily documented single or multiple bacterial isolates. These entities are well accepted and relatively well understood. Chronic idiopathic prostatitis/prostatodynia, however, remains an enigma. A number of recent publications indicate that our knowledge of the processes underlying these difficult problems is increasing at an encouraging pace. Prokaryotic DNA Sequences in Prostate Tissue Krieger and colleagues evaluated 135 men with chronic prostatitis refractory to multiple previous courses of antibiotics.1 Standard investigations showed no evidence of lower urinary tract dysfunction or structural abnormalities, nor was there evidence of bacteriuria, bacterial prostatitis, urethritis, or urethral pathogens by optimal clinical and microbiologic techniques. Samples of prostate tissue from these patients were obtained, using double needle biopsy to limit skin contamination. Organismspecific and broad-spectrum polymerase chain reaction (PCR) assays were performed on these biopsies, taking precautions to ensure that their results could not represent contamination. Organism-specific assays detected Mycoplasma genitalium, Chlamydia trachomatis, or Trichomonas vaginalis in 8% of patients. The broad-spectrum assays detected sequences encoding 16S ribosomal ribonucleic acid (rRNA) in 77% of patients, about a third of whom also were noted to have tetracycline resistance–encoding genes (tetM-tetO-tetS). A strong correlation was noted between the presence of 16S rRNA sequences in prostate tissue and the presence of significant numbers of inflammatory cells in the patient’s expressed prostatic secretions (EPS). The prokaryotic gene sequences detected were distinct from those of common skin and gut flora. In a follow-up study reported by the same group of investigators, sequencing was carried out on 36 ribosomal deoxyribonucleic acid (rDNA) clones from 23 rDNApositive patients as well as phylogenetic studies comparing the detected sequences to those of known bacteria.2 Sequences from 35% of patients grouped with Aeromonas

Commensal and Difficult-to-Culture Bacteria Other lines of investigation have supported the notion that chronic idiopathic prostatitis may be caused by ascending infection of the prostate by bacteria, some of which are known uropathogens, and some of which are commensal organisms such as Staphylococcus epidermidis and Staphylococcus haemolyticus.3 It is postulated that such organisms possess virulence factors that become operative in the prostatic microenvironment, facilitating colonization. It is further postulated that these bacteria produce extracellular “slime substance,” which favors their persistence in spite of antibiotic therapy. A study by Berger and colleagues in 1997 addressed the relationship between genitourinary infection and inflammatory prostatitis in 85 patients without bacteriuria.4 Urine, urethral fluids, and transperineal prostate tissue samples were cultured, with particular emphasis on attempts to culture commensal and fastidious bacteria. Inflamed prostatic secretions were noted in 25 patients, and 60 patients had noninflamed prostatic secretions. The 118

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patients in the former group were found to have a significantly higher likelihood of any type of positive bacterial culture, positive culture for anaerobic bacteria, higher total bacteria counts, and more bacterial species isolated. A study by Domingue and colleagues in 1997 showed that careful microscopic examination and the use of enriched culture media could document the presence of difficult-to-culture coryneform bacteria in EPS, despite negative routine cultures, using blood agar.5 The organisms in question were identified as Corynebacterium group atrial natriuretic factor (ANF) and Corynebacterium minutissimum. A related study in 1995 by Riegel and colleagues reported the isolation of a newly described coryneform species, Corynebacterium seminale, from various sites (semen, urine, urethra, blood) in patients with genital infections.6 Further emphasis on the subject of difficult-toculture bacteria was placed by a report by Szoke and colleagues in 1998.7 These investigators isolated an average of 3.9 types of anaerobic bacteria from the urethral samples and EPS of 24 patients, using careful culture techniques. The roles of C. trachomatis and Ureaplasma urealyticum in the genesis of prostatitis remain controversial. Separate studies published in 1995 and 1996 produced opposing views of the significance of the former.8,9 One of the patients in the previously noted PCR assay study by Krieger and colleagues tested positive for C. trachomatis.1 Based on the results of their study of serum antichlamydial antibodies in groups of men with and without chronic prostatitis (subcategorized by the number of leukocytes in the EPS), Ostaszewska and colleagues concluded that C. trachomatis may be the causative organism in up to 30% of such cases.10 No studies supporting U. urealyticum as an etiologic agent in prostatitis have appeared since 1994.3 Granulomatous Prostatitis Several articles examining mycobacterial infection of the prostate were published in 1997. Galbis and colleagues described a patient suffering from acquired immunodeficiency syndrome (AIDS) who developed a tuberculous abscess of the prostate.11 LaFontaine and colleagues found granulomatous prostatitis in 9 of 12 radical cystoprostatectomy specimens from patients previously treated with intravesical bacillus Calmette-Guérin (BCG); in 7 of these cases, acid-fast bacilli (AFB) were identified with special stains.12 In 94 cases of granulomatous prostatitis diagnosed by needle biopsy in a study by Oppenheimer and colleagues, 18.1% were classified as infectious; in all cases in this subset, there was a history of intravesical BCG instillation.13 The remainder of the cases were categorized as nonspecific (77.7%) or indeterminate (4.3%) in etiology. An additional note of interest in the latter study was that two cases of nonspecific granulomatous prostatitis seen in consultation by the authors had previously been misdiagnosed as poorly differentiated carcinoma, resulting in radical prostatectomy and subsequent litigation.

Fungal Prostatitis Isolated reports of this rare entity have appeared in recent years. A case of Aspergillus prostatitis in a man immunosuppressed by corticosteroid therapy was reported in 1997.14 Two cases of Cryptococcus neoformans prostatitis, in a patient with AIDS and a patient with Behçet’s disease, respectively, were reported in 1994 and 1995.15,16 Viral Prostatitis Herpes simplex and cytomegalovirus have been documented as infrequent causative organisms in the genesis of prostatitis from reports early in this decade.17–19 In 1996, Monini and colleagues reported that, using PCR techniques, they had identified DNA sequences derived from a novel herpesvirus, Kaposi’s-associated herpesvirus (KHSV), from prostate tissue and ejaculates (as well as other sites) of a large proportion of healthy immunocompetent men.20 Their findings suggested that this virus is ubiquitously present in healthy adults and is probably transmitted by sexual contact. Subsequent studies by Corbellino and colleagues21 and Tasaka and colleagues22 failed to confirm the findings of Monini and colleagues.20 Those authors stressed that the results of assays based on PCR studies are easily compromised by contamination of materials and instruments used in performing the tests. An analysis by Anderson and colleagues of DNA samples of prostate tissue from 24 patients failed to detect evidence of human papillomavirus.23 Although this study was primarily aimed at unraveling the etiology of prostate cancer, the results provide no support for the notion that this virus is a likely cause of prostatitis. Bacterial Urovirulence Factors in Prostatitis Although the urovirulence properties of Escherichia coli strains which cause acute or chronic urinary tract infections in women have been well characterized, studies of these properties in E. coli causing prostatitis in men were not reported until 1997. Andreu and colleagues studied E. coli isolates from men with acute and chronic prostatitis and compared urovirulence characteristics in these organisms with those of E. coli isolates from women with pyelonephritis, acute cystitis, and complicated urinary tract infection (UTI).24 They concluded that encapsulation, hemolytic activity, and the ability to produce cytotoxic necrotizing factor (CNF)-1 were features of E. coli which may enable it to colonize prostatic tissue and produce chronic prostatitis. Their findings minimized the importance of pap-encoded fimbriae in producing invasive prostate infection. In general, the urovirulence profiles of E. coli producing prostatitis are similar to those of strains from women with acute uncomplicated pyelonephritis. Terai and colleagues, in a similar study of men with acute prostatitis, concluded that the strains of E. coli involved in this process require several virulence factors to overcome inherent male genitourinary tract defense mechanims.25

120 / Advanced Therapy of Prostate Disease

Chemical Prostatitis Pursuant to the theory that inflammation associated with nonbacterial prostatitis is initiated by reflux of urine into prostatic ducts, Persson and Ronquist demonstrated a statistical relationship between prostatitis-associated pain estimated by a scoring scale questionnaire and the content of white blood cells, urate, and creatinine in EPS.26 These investigators believe that urate and possibly other purine and pyrimidine base–containing nitrogen metabolites are prime suspects in the initiation of nonbacterial chronic prostate inflammation. Autoimmunity and Prostatitis Two recent articles from Cordoba, Argentina, have addressed autoimmunity as a cause for prostatitis. Studies from Argentina dating back as far as 1981 have demonstrated that the intraperitoneal instillation of a saline extract of rat male accessory gland protein associated with liposomes (RAG) into rats can elicit both primary and secondary cellular immune responses to RAG as well as prostatitis.27 The observations of Correa and colleagues suggest that special antigen-presenting cells known as peritoneal dendritic cells (PDC), which comprise only about 1% of the normal population of peritoneal cells, are of greater importance in initiating this process than the much more numerous peritoneal macrophages.28 In an article from the same institution in 1998, Donadio and colleagues described initial prostate infiltration by macrophages, followed by an influx of lymphocytes as a consequence of immunization against the male accessory sexual gland homogenate.27 The infiltrates appeared under the epithelium and around blood vessels. The study showed more advanced changes including interstitial fibrosis, acinar enlargement, and flattening of acinar epithelium. Adoptive transfer techniques confirmed the autoimmune nature of the process. Disease transfer was antigen specific and could be accomplished by cells, but not by serum. The authors speculate that the infiltrating inflammatory cells produce their destructive effects by direct contact with target cells and/or by secretion of harmful substances such as proteases, free radicals, or cytokines. Further support for the concept that chronic prostatitis/ chronic pelvic pain syndrome may have an autoimmune etiology was presented by Alexander and colleagues.29 These investigators showed a significant proliferative response of CD4+ peripheral helper T lymphocytes drawn from patients with a history of chronic prostatitis/chronic pelvic pain syndrome, following exposure to seminal plasma. No significant response to the same antigen was elicited in similar T cells drawn from historically asymptomatic men. Seminal Markers of Inflammation Further information regarding cytokines and other products of inflammation has been provided in two recent

articles. Ludwig and colleagues studied the levels of several markers of seminal plasma inflammation in men with chronic prostatitis, men with significant leukocytospermia, and men with no known prostatic inflammation.30 Their findings indicate that polymorphonuclear (PMN) elastase and complement C3 correlate significantly with prostatic inflammation. The levels of the following markers did not achieve statistical significance as markers of prostatic inflammation in this study: C-reactive protein, α-glucosidase, PSA, and prostatic secretory protein (PSP) 94. Alexander and colleagues found significant elevations of the mean levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the semen of men with chronic prostatitis/pelvic pain syndrome as compared with levels in asymptomatic men.31 Levels of the noted cytokines did not correlate with the number of leukocytes per high power field in expressed prostatic secretions. The authors note that not all their symptomatic patients had elevated cytokine levels, in keeping with the notion that not all pelvic pain syndromes are secondary to prostatic inflammation. The diagnosis and treatment of prostatitis remains a difficult challenge for caregivers. In a recent survey of Canadian primary care physicians and urologists, prostatitis was perceived as being significantly more frustrating to treat than either benign prostatic hyperplasia (BPH) or prostate cancer, mainly due to a lack of confidence in accurately diagnosing and satisfactorily treating this condition.32

Benign Prostatic Hyperplasia Several excellent textbooks of urologic pathology have been published recently, and the reader is referred to them for comprehensive discussions of BPH and other aspects of prostate pathology.33–35 In the following sections, information which has become available since the publication of these fine textbooks will be reviewed. Recent studies have addressed such diverse topics as the role of estrogens in the induction of BPH and prostate cancer, the frequency of P53 mutations in BPH, the distribution of keratin 19 in benign and malignant prostate tissue, the role of peptide growth factors in the development of BPH and prostate cancer, the roles of different types of prostatic epithelial cells in the genesis of prostatic diseases, atypical adenomatous hyperplasia, prostatic atrophy, and prostatic crystalloids. Androgen Receptor Ligands in Prostate Tissue Previous studies have supported the concept that testosterone and dihydrotestosterone (DHT) function as ligands for androgen receptors (AR), which reside within the target cells in a nonactivated state. Binding of ligand to receptor results in a complex chain of events that ultimately influences the transcriptional apparatus of the cell with induction or repression of target gene expression. It is postulated that coactivators or corepressors may act as

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regulators in this process. Yeh and colleagues have isolated an AR coactivator, ARA70, and shown that it enhances AR transcriptional activity six- to 10-fold in human prostate cancer cells.36 Further studies by these investigators demonstrate that this enhancement of AR activity is even more pronounced (> 30-fold) in the presence of 17βestradiol (E2), but not in the presence of diethylstilbestrol. The elucidation of this new E2-AR-ARA70 pathway for activation of androgen target genes may have implications in our understanding of the development of the male reproductive system, BPH, and prostate cancer. P53 Tumor Suppressor Gene Mutations in Benign Prostatic Hyperplasia Noting that mutations and/or loss of heterozygosity in the tumor suppressor gene P53 have been shown to be strongly associated with the genesis and advancement of prostatic carcinoma and that most carcinomas develop in BPHbearing prostates, Schlecte and colleagues initiated a search for P53 mutations in transurethrally resected BPH tissue, using nonhyperplastic prostate tissue and samples of prostatic adenocarcinoma as controls.37 The P53 mutations were identified in 29 of 153 BPH specimens (19%) and in 26.2% of the tissue specimens from patients known to have prostate cancer. Two patients with P53 mutations developed prostate cancer 2 to 3 years after transurethral resection of BPH tissue, and one developed bladder cancer. None of the 118 patients with nonmutated DNA developed urologic cancer during the period of follow-up. The authors conclude that P53 mutation in BPH tissue may be a risk factor for the subsequent development of prostate cancer. Distribution of Keratin 19 in Adult Human Prostate Tissue It has been observed that the luminal cells lining acini of nonlactating mammary epithelium show variable expression of cytokeratin 19. It has been proposed that keratin 19–negative cells are precursors of keratin 19–positive cells. This is of interest because all invasive breast cancers are keratin 19 positive; furthermore, there are structural and functional similarities between breast and prostate tissue. With this in mind, Peehl and colleagues used immunohistochemical and immunoblot techniques to evaluate the expression of keratin 19 in normal, benign hyperplastic, dysplastic, and malignant epithelia in adult prostate tissue.38 These investigators were unable to discern any uniform pattern of keratin 19 expression in the noted tissues or cell cultures. Keratin 19 was commonly found in both basal and luminal cells in histologic preparations. Keratin 19 expression was observed in a minority of cancer cells, in marked contrast to the findings in invasive breast cancer. In short, keratin 19 expression does not appear to correlate with any epithelial cell lineage or phenotype in the human adult prostate.

Autocrine/Paracrine Influences on Normal and Abnormal Prostate Growth In the human adult prostate, androgen receptor is demonstrable in occasional mature smooth muscle cells and is strongly expressed by the nuclei of secretory epithelial cells. Furthermore, there is evidence that ARnegative basal cells are the source of benign epithelial proliferations. Consequently, it is postulated that epithelial proliferation is driven by the elaboration from ARpositive smooth muscle cells of peptide growth factor signals that interact with cognate receptors in AR-negative basal cells.39,40 One such peptide growth factor is transforming growth factor alpha (TGF-α), which binds to and activates its receptor, epidermal growth factor receptor (EGFR). Leav and colleagues undertook an extensive analysis of the immunohistochemical localization of TGF-α and EGFR in fetal, neonatal, prepubertal, and young adult prostate glands, and compared the findings with those in samples of BPH, high-grade prostatic intraepithelial neoplasia (HGPIN), and prostate carcinoma.39 These investigators noted persistent expression of EGFR exclusively in the proliferation-competent basal cells through the entire spectrum from fetal life through adulthood. In contrast, the ligand, TGF-α, became increasingly localized to smooth muscle cells as maturation proceeded, a finding which suggests that TGF-α acts as a paracrine mediator of proliferative signals arising from prostatic stromal cells and interacting with EGFRpositive basal cells. It is believed by these and other investigators that the mitogenic interactions of TGF-α and EGFR in the adult prostate are mediated by androgens.39 In the pathogenesis of BPH, androgen continues to regulate the TGF-α/EGFR pathway through stromal/epithelial interactions, a paracrine process which is markedly enhanced, for reasons which are presently undefined, during the development of BPH. The onset of carcinogenesis involves an autocrine process, according to these investigators; this is discussed separately in the section on prostatic adenocarcinoma. Prostatic Epithelial Cell Compartments: Their Roles in Proliferative Disorders Bonkhoff and Remberger have provided an extensive review of the relative roles of various types of prostatic epithelium in normal and abnormal prostatic growth.41 Prostatic epithelium is composed of three cellular phenotypes: secretory luminal cells, basal cells, and neuroendocrine cells. Secretory luminal cells express nuclear AR and PSA and require the support of circulating androgens. Basal cells lack AR and PSA expression, and proliferate under estrogen stimulation. They express specific cytoplasmic high-molecular-weight cytokeratin 34βE12 and may express nuclear estrogen and progesterone receptors. Neuroendocrine cells comprise the third epithelial cell type in prostate tissue.

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Although there is lack of consensus in this matter, it appears likely that the basal cell layer includes the prostatic stem cell population and that basal cells are pluripotential, capable of differentiating into secretory luminal cells and endocrine cells via intermediate phenotypes42,43 (Figure 15–1). The proliferation of basal cells is regulated by growth factor receptors (such as EGFR, p185, erbB-2 p180erbB-3) and is stimulated by estrogens. The protooncogene bcl-2 protects basal cells from apoptic cell death, and the telomerase gene imparts basal cells with immortality.44,45 The development of basal cell hyperplasia in response to estrogen stimulation suggests that estrogens block differentiation of basal cells to secretory luminal cells. This estrogen effect is balanced by androgens. Basal cells are “androgen independent,” in the sense that they are not induced to proliferate by androgen stimulation, and they do not require androgen for survival. Nevertheless, a proportion of basal cells are “androgen responsive”; it is believed that androgens are capable of inducing this population of basal cells to differentiate into an intermediate population of “amplifying cells.”45 These cells can undergo a limited number of doublings, ultimately generating a population of terminally differentiated, nonproliferating secretory luminal cells that require circulating androgens for their continued maintenance and undergo programmed cell death (apoptosis) when deprived of testosterone.44 Hence, the turnover (net gain versus stasis versus

net loss) of secretory epithelium is thought to be largely dependent on the proportion of androgen-responsive basal cells in the proliferative compartment. Previous studies have suggested that with aging, there is a diminution in 5 α-reductase activity and in DHT levels in prostatic epithelium; it is postulated that this results in increased AR gene expression in the basal cells, making them more responsive to the androgen effect. An alternative hypothesis is that growth factors elaborated by stromal cells increase the androgen sensitivity of basal cells. In either case, as the number of androgen-responsive basal cells increases, the net effect is an acceleration of differentiation to secretory luminal cells, that is, glandular hyperplasia. Cordon-Cardo and colleagues recently reported an apparent role for the P27KIP1 gene in the genesis of BPH.46 The protein product of this gene is a negative regulator of the cell cycle. Both P27KIP1 messenger RNA (mRNA) and P27 protein were found abundantly in stromal and epithelial cells of normal prostate tissue but both were virtually absent in BPH tissue, suggesting that the absence of this growth-suppressive protein may permit the development of BPH. In addition, mice genetically lacking the P27KIP1 gene were noted to develop hyperplastic glands. Because prostatic adenocarcinoma showed contrasting results when analyzed for the presence of P27KIP1 mRNA or P27 proteins, the authors believe that BPH is not a precursor to prostate cancer.

rine

doc

en euro

n

NE-cell

luminal cell

exo c

rine

STEM CELL

AMPLIFYING CELL

tumor cell TERMINAL CELL

keratin differential expression BASAL CELL

INTERMEDIATE CELL

LUMINAL CELL

FIGURE 15–1. Prostatic epithelial cells and their inter-relationship: a stem cell model. Horizontal lines indicate basal keratin expression, vertical lines indicate luminal keratin expression, and crossed lines indicate the transition in keratin expression signifying the transition of basal cells to luminal cells via intermediate cells (for details see discussion). With permission from Xue Y, Verhofstad A, Lange W, et al. Prostatic neuroendocrine cells have a unique keratin expression pattern and do not express bcl-2. Am J Pathol 1997;151:1759–65.

Pathobiology of Prostate Diseases: an Update / 123

The concept that BPH is not a precursor to prostate cancer was supported by De Marzo and colleagues, who noted that basal cells, which are the reservoir from which BPH is ultimately derived, express much higher levels of gene products that protect against genomic aberrations than do secretory cells (e.g., glutathione S-transferase PI [GSTPI], glyceraldehyde-3-phosphate dehydrogenase [GAPDH], and nuclear phosphoprotein 32 [pp32]). It is hypothesized that possession of these protective proteins prevents the acquisition of multiple genomic changes that result in neoplastic transformation.45 Neuroendocrine cells are capable of producing a wide assortment of regulatory peptides.41 They are distinctive by their expression of the neuroendocrine marker chromogranin A, and by their lack of detectable nuclear AR, an indication that they are androgen insensitive.47 These cells are considered terminally differentiated and nonproliferative, a concept supported by their lack of expression of bcl-2 (which protects against apoptosis) or MIB-1 (a proliferation marker).48 Despite their lack of bcl-2, they may be protected from apoptosis by other members of the same gene family, for example, MCL1.48 A study by Cockett and colleagues in 1993 suggested that neuroendocrine cells may play a role in the development of BPH.49 This hypothesis does not seem to have garnered further support. Atypical Adenomatous Hyperplasia of Prostate Atypical adenomatous hyperplasia (AAH) is an enigmatic small acinar proliferation reportedly observed in up to 23% of prostate specimens.50 Although the large majority of foci of AAH are confined to the transition zone, AAH may also be seen outside this region. It resembles well-differentiated prostatic adenocarcinoma in that it consists of aggregates of closely packed, uniform, smallto-medium-sized acini with variable degrees of circumscription.50,51 The age-peak incidence of AAH precedes that of adenocarcinoma, cells of AAH show increased nuclear area and diameter relative to benign epithelium, and there is a topographic relationship between AAH and small acinar carcinoma.51 In contrast to the findings in adenocarcinoma, however, prominent nucleoli and crystalloids are infrequent, and a patchy layer of basal cells can be identified either with routine hematoxylin and eosin stains or by employing immunohistochemical staining for 34βE12.51 The biologic behavior of AAH, specifically its potential as a precursor of prostatic adenocarcinoma, has been a subject of scrutiny and debate for some time.50,51 Grignon and Sakr reviewed all the available information in this regard in 1996.50 Atypical adenomatous hyperplasia has been reported to be more frequent in prostates with cancer than in the noncancerous glands. Intraluminal crystalloids are noted in up to 24% of AAH acini but are less common in AAH than in adenocarcinoma. Wispy intraluminal basophilic (acidic) mucin has been reported in acini of AAH with a fre-

quency comparable with that noted in adenocarcinoma. As noted above, AAH consistently shows varying degrees of disruption of the basal cell layer. Studies of the proliferation rate of the epithelial cells in AAH and the number of silver-staining nuclear organizing regions (AgNORs) in these cells have consistently shown values intermediate between BPH and adenocarcinoma. Studies of the DNA content of AAH epithelia have shown inconsistent results. Reports of increased expression of peanut agglutinin receptors and decreased expression of blood group isoantigens in AAH epithelia suggested a closer kinship to adenocarcinoma than to benign epithelium. Some findings were less supportive of the putative premalignant nature of AAH. In a study of the expression of the carbohydrate D-galactose-N-acetyl-D-galactosamine by the prostatic epithelium, no expression was noted in cases of AAH, in contrast to its expression in 95% of cases of adenocarcinoma. Attempts to identify chromosomal abnormalities using fluorescence in situ hybridization demonstrated a loss of chromosome 8 in 4% of cases. Allelic loss of 8p22 was noted in 6% of AAH compared with 56% of carcinoma cases. The cumulative findings were considered to be inconclusive. More recently, Cheng and colleagues reported the results of their search for allelic imbalances in five microsatellite polymorphic markers on chromosomes 7, 8, and 18, in 15 patients with AAH.51 Allelic imbalances were detected in 7 of 15 (47%) of AAH cases. More concisely, 47% of AAH foci included cells with genetic alterations characteristic of prostatic adenocarcinoma. These findings suggest that AAH may represent an early genetic phase in the evolution of prostatic adenocarcinoma. Morphologic Findings in Benign Prostates Two recent reports have examined prostatic atrophy (PA), a predominantly peripheral zone lesion sometimes mistaken for adenocarcinoma on histologic sections. It can be especially problematic in sections from needle biopsies. Billis studied step sections from the prostatic peripheral zone of 100 autopsies, noting that PA is present in 85% of men over 40 years of age, and that the incidence of PA increases with age.52 Morphologic observations suggested that the presence of PA correlates best with the presence of local atherosclerotic changes, suggesting ischemia as an etiologic factor. There appeared to be no consistent association with nodular prostatic hyperplasia, prostatitis, systemic atherosclerosis, HGPIN, or adenocarcinoma. Oppenheimer and colleagues reported 51 cases with a lesion which they designated partial atrophy, to denote foci of crowded benign glands lined by cells with relatively scant cytoplasm but lacking the distinctive acinar architecture and nuclear basophilia typically observed in atrophic foci at low magnification.53 Some lining cells contain readily visible nucleoli, and basal cells typically are difficult to identify without the use of an immunoperoxi-

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dase stain for 34βE12. These lesions create diagnostic uncertainty because they may be difficult to distinguish from low-grade adenocarcinoma. The authors point out that in partial atrophy there is lack of nuclear enlargement, conspicuous nuclear atypia is uncommon, and the cells lining the acini of partial atrophy exhibit a high nuclear (N):cytoplasmic (C) ratio. The acini in the focus of concern tend not to have an infiltrative appearance and, in fact, may blend with adjacent acini that are clearly benign. Foci of partial atrophy may lie directly adjacent to foci of fully developed atrophy. None of the foci of partial atrophy described in this report contained blue tinged mucinous secretions or crystalloids. Intraluminal crystalloids are enigmatic eosinophilic structures that have been linked to prostatic adenocarcinoma in publications dating back to 1977. They have subsequently been reported to occur in acini of benign glands and in foci of AAH. It has been proposed that crystalloids identified in benign glands on needle biopsy are a harbinger of concurrent carcinoma and thereby constitute an indication for repeat biopsy. Henneberry and colleagues examined follow-up biopsies and serum PSA levels in 31 men whose only unusual finding on initial biopsy was the presence of intraluminal crystalloids within benign glands and compared these results with the findings in a control population of men with a benign first biopsy not showing crystalloids.54 The incidence of cancer on subsequent biopsy was not significantly different in the two groups. The authors concluded that the isolated finding of intraluminal crystalloids in benign glands is not associated with an increased risk of concurrent carcinoma and does not constitute an indication for repeat biopsy.

Prostatic Neoplasia Carcinogenesis Where do prostate cancer cells come from? Why do they behave as they do? In general, prostate cancer is the net result of alterations in the regulatory control of cell proliferation, cell DNA repair, apoptosis, cell differentiation, cell/matrix interactions, angiogenesis, and senescence. These functions are influenced by oncogenes, tumor suppressor genes, hormones, growth factors, and growth factor receptors. De Marzo and colleagues maintain that an understanding of carcinogenesis requires an appreciation of the numerous differences between basal cells and their derivatives—the epithelial cells found in normal prostatic glands, in BPH, in HGPIN, and in adenocarcinoma. The theories of these investigators are based on their own observations and those of numerous other investigators, and are summarized below.41–45 First, it is informative to consider the attributes of basal cells. A subset of these cells is considered to be stem cell progenitors of normal luminal secretory cells and neuro-

endocrine cells41 (Figure 15–2). Stem cells possess abundant protective proteins (GSTPI, GADPH, pp32) that prevent the permanent acquisition of carcinogenic genomic alterations. The growth suppressive influence of P27KIP1 is intact in these cells, as is the cell death suppressive effect of bcl-2. In addition, stem cells are immortalized by their ability to express telomerase. Telomerase is a reverse transcriptase that provides a template for the synthesis of DNA telomeres—DNA repeat sequences found at the ends of eukaryotic chromosomes. Cells which lack telomerase lose telomere segments with each round of replication, and their descendants ultimately undergo senescence. As previously noted, stem cells differentiate into a pool of transiently proliferating “amplifying cells,” which under normal circumstances simply renew the supply of terminally differentiated luminal secretory cells. In BPH, it appears that an expanded pool of activated stem cells produces more than the usual number of amplifying and terminally differentiated luminal secretory cells. These stem cell descendants are no longer pluripotential, nor are they immortal or protected from apoptosis. Of critical importance, however, is that they retain the genome protective influence of GSTPI and therefore do not usually undergo malignant transformation. The epithelial cells observed in HGPIN and adenocarcinoma demonstrate a different set of molecular characteristics (Figure 15–3). It is hypothesized that these cells are derivatives of transiently proliferating (amplifying) secretory cells that have not yet undergone terminal differentiation. It is further hypothesized that downregulation of the P27KIP1 gene in these cells allows them to linger in the cell cycle (rather than undergo terminal differentiation and eventual senescence) and that loss of genome protective influences results in their acquisition of neoplastic genomic alterations through the practice of “unsafe replication.” In support of this hypothesis, it has been shown by Cheville and colleagues that prostate cancers with downregulation of P27 are more likely to display aneuploidy, higher grade, and involvement of seminal vesicles and regional lymph nodes.55 Neoplastic cells activate or maintain telomerase expression, facilitating immortality, and their survival is further enhanced by their expression of bcl-2, which prevents apoptosis and allows cell survival despite DNA damage. Their proliferative capacity is enhanced by their abnormal expression of growth factor receptors, and by loss of tumor suppressor genes.41 As the “unsafe replication” continues, additional genomic alterations accumulate that impart invasive and metastatic properties to the neoplastic cells.45 As noted by Bonkhoff, the invasive and metastatic properties of prostatic carcinoma are marked by the production of distinctive periacinar and pericellular basement membrane material and associated laminin and collagen receptors, accompanied by the loss of normal basement membrane–associated adhesion proteins and receptors.42

Pathobiology of Prostate Diseases: an Update / 125

Aspects of neuroendocrine differentiation in prostatic adenocarcinoma were also recently addressed by Bonkhoff and Remberger.41 Malignant cells expressing a neuroendocrine phenotype are believed to be descendents of the transiently proliferating “amplifying cells” derived from stem cells and are detectable in about 10% of all common adenocarcinomas.41,48 Surprisingly, these cells are not usually highly proliferative; in fact, neuroendocrine differentiation occurs exclusively in the G0 phase of cell proliferation. However, it is believed that neuroendocrine cells secrete growth-promoting peptides which enhance the proliferation of nearby malignant exocrine cells by a paracrine mechanism. It is further believed that these cells are intrinsically androgen insensitive and, thus, are refractory to hormonal therapy.47 Hence, they are triply troublesome: (1) they do not respond to hormonal manipulation themselves, (2) they are capable of promoting the growth of adjacent exocrine cells even in an androgendeprived milieu, and (3) their relative lack of proliferative activity suggests a probable resistance to radiation therapy and chemotherapy. Despite the troublesome nature of malignant neuroendocrine cells, a recent study indicates that focal neuroendocrine differentiation, which can be found by immunohistochemical studies in up to 25% of core needle biopsies of newly diagnosed prostate cancer, does not provide prognostic information independent of Gleason score or Ki-67 labelling index.56 Of considerable interest in this study was the finding of a significant increase in the frequency and density of neuroendocrine differentiation between the initial needle core biopsies and subsequent biopsy specimens taken from patients that had become refractory to hormonal therapy. This finding correlates nicely with the results of a study by Papandreou and colleagues concerning the loss of neutral endopeptidase 24.11 (NEP) by tumor cells of androgen-independent prostate cancers.57 Androgen-dependent prostate cancers express a cell-surface enzyme, NEP, which inactivates the neuropeptides involved in the growth of androgenindependent tumor cells. When antiandrogen therapy is instituted, with loss of androgen-dependent clones of tumor cells, there is a net loss of NEP, and a net gain in bioavailable neuropeptides. Androgen-independent tumor cells thus gain a growth advantage by using mitogenic neuropeptides as an alternate source of androgen in order to stimulate cell proliferation. The process of carcinogenesis appears to be dependent upon three cellular characteristics: (1) increased cell proliferation, (2) extended cell survival, and (3) diminished apoptosis. The role of apoptosis in carcinogenesis has been extensively clarified in recent years.58 It is known that prostate cancer typically is a mixture of androgendependent and androgen-independent clones. Upon androgen withdrawal, the androgen-dependent clones are induced to undergo apoptosis, whereas androgenindependent clones do not initiate this “cellular suicide.”

Even androgen-independent cells retain their apoptosis machinery and can be induced to undergo apoptosis by a wide spectrum of pharmacologic and biologic agents.58 Apoptosis is a complex event that is influenced by the relative effects of a host of cellular proteins, which can be characterized as proapoptotic (P53, Bax, Bad, Bak) or antiapoptotic (bcl-2, P21). Two roles are ascribed to P53: (1) arresting the cell cycle to allow DNA repair, and (2) triggering apoptosis to induce self-destruction of cells that

Normal Maturation Sequence

BASAL COMPARTMENT

Stem Stem Cell Features: Genome protection (e.g., GSTP1) Active proliferation capacity (e.g., decreased P27KIP1) Death suppression (e.g., bcl-2) Immortality (e.g., telomerase) Pluripotentiality

Other Features: Secretion Genetic instability Nuclear atypia Clonal Invasiveness Metastatic potential

Normal Stem

SECRETORY COMPARTMENT Transiently Proliferating Postmitotic

BPH

PIN

_

_

Cancer

_+/+

+

+

+ + +

_ /+ _ _

_ /+

+

_ _ _

+

_ _ _ _ _

_

+ +

+ + +

_/+

_/+

+ + +

+ + + + +

_ _

FIGURE 15–2. Stem cell model of BPH and cancer development. Although BPH and cancer develop often within the same patient, the target cells are different and the resultant abnormal cells retain or enhance different features of the normal stem cell and its maturing progeny. In BPH, there is an abnormal increase in the pool of basal cells with proliferative capacity. This basal TP cell maintains genome protection and, hence, resistance to transformation, which explains why BPH usually does not progress to cancer. Also, BPH partially retains the stem cell features of cell death capacity. In BHP, as in the normal epithelium, secretory cells become terminally differentiated (postmitotic). In high-grade prostatic intraepithelial neoplasia (PIN), the target TP cell is in the secretory compartment, which explains the lack of basal cell–specific marker expression (cytokeratins 5 and 14). Like other secretory compartment cells, these cells have lost genome protection activity, perhaps since they are normally programmed for the permanent exit of cell cycle terminal differentiation. These cells become blocked from full maturation, remaining in the cell cycle to a large degree by acquiring alterations in cell cycle control. Proliferating secretory type cells are subject to DNA damage from environmental factors and acquire genome alterations in oncogenes and tumor suppressor genes, resulting in clonal expansion. Cell immortality results from re-expression or increased expression of telomerase. Additional genetic changes in genes that control cell adhesion, angiogenesis induction, and motility result in invasion (carcinoma) and eventual metastasis. Dark nuclei = P27KIP1 positive; light nuclei = P27KIP1 negative. With permission from De Marzo AM, Nelson WG, Meeker AK, Coffey DS. Stem cell features of benign and malignant prostate epithelial cells. J Urol 1998;160:2381–92.

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are beyond repair. The relative contributions of the apoptotic proteins to carcinogenesis were evaluated by Tang and colleagues in a study of the effects of growth-factor deprivation on the survival properties of cell-culture populations derived from normal and hyperplastic prostate tissue and from primary and metastatic prostate carcinomas.58 Growth-factor deprivation led to rapid apoptosis in non-neoplastic cell lines. In contrast, malignant cell lines demonstrated enhanced cell proliferation and decreased apoptosis. Further analysis revealed that nonneoplastic cells upregulate proapoptotic proteins (wildtype P53, Bax, Bad, Bak), show little or no bcl-2 expression, and either no change or a decrease in P21 expression. The results of growth-factor deprivation and molecular changes in normal cells are a halt in cell proliferation and apoptosis leading to decreased cell number (Figure 15–4). In contrast, neoplastic cells continue to proliferate despite growth factor deprivation, probably due to autocrine growth factor production. In addition, they evade apoptosis by refraining from P53 upregulation, by a diminution or deletion of the apoptosis-inducing proteins Bax/Bad/ Bak, by upregulating P21 (which halts the proliferative machinery at a time when cancer cells would be prone to “mitotic catastrophe”), by upregulating bcl-2 (an antiapoptosis mechanism), and possibly by aberrant expression of immunoglobulin molecules unique to cancer cells (P25, P54/55) whose role is unknown but which may, in

some way, extend the survival of cancer cells. Sustained proliferation and evasion of apoptosis allows the prolonged survival of cancer cells. Sustained proliferation and evasion of apoptosis allow the prolonged survival of neoplastic cell lines; in vivo, this would account for the production of the lesion we recognize as carcinoma. Much information has accumulated concerning the influence of growth factors on prostatic proliferation, and interest continues because growth factor manipulation may be a realm of therapeutic intervention. This topic was reviewed by Culig and colleagues.40 The growth factors operative in physiologic and nonphysiologic prostatic conditions are EGF, TGF-α and -β, fibroblast growth factors (FGFs), and insulin-like growth factors (IGFs). All are believed to be positive growth factors, with the exception of TGF-β, which inhibits prostatic growth and antagonizes growth-promoting factors. Under normal physiologic conditions, they act in a paracrine fashion. Transformation to a neoplastic state is accompanied by a shift from paracrine control of growth to an autocrine state. Leav and colleagues demonstrated a rather abrupt appearance of both TGF-α and EGFR in dysplastic luminal secretory cells; ordinarily, EGFR is restricted to basal cells, and its ligand, TGF-α, is restricted to smooth muscle cells.39 In addition, they noted that the co-localization of AR, TGF-α, and EGFR in dysplastic cells is identical to the pattern of expression of these molecules in invasive carcinoma. This

FIGURE 15–3. Loss of genome protective function in high-grade prostatic intraepithelial neoplasia (HGPIN) based on proliferation compartment infidelity. With permission from De Marzo AM, Nelson WG, Meeker AK, Coffey DS. Stem cell features of benign and malignant prostate epithelial cells. J Urol 1998;160:2381–92.

Pathobiology of Prostate Diseases: an Update / 127

suggests two concepts: (1) that autocrine growth stimulation is an early phenomenon in carcinogenesis, and (2) that this autocrine loop is regulated by androgens during this phase of carcinogenesis. As carcinogenesis proceeds, the autocrine loop is believed to become progressively independent of androgen for continued growth.39 In addition, there is evidence to suggest that prostate carcinoma cells are also capable of endogenous production of FGFs.40,59 It is unclear whether neoplastic cells participate in endogenous IGF production. Studies on TGF-β support the concept that advanced prostate cancer escapes the inhibitory effects of TGF-β. A recent report by Cipriano and Chen offers an explanation for the lack of inhibition of prostate cancer cells by TFG-β.60 Normal progress of cell

A

replication through the G1 phase is permitted by several “cyclin-Cdk complexes.” When cyclin-Cdk complexes are associated with “cyclin-dependent kinase inhibitors” (CKIs), cell-cycle arrest occurs. The normal inhibitory effect of TGF-β is mediated through several CKIs. In prostate cancer cells, it appears that there is a failure of inhibition of Cdk2 activity by CKIs, and consequently cellcycle arrest is not accomplished. While much has been written about the importance of chromosomal alterations associated with carcinogenesis, less attention has been paid to the role of epithelial-stromal interactions in normal and abnormal prostatic growth. This subject was addressed in a recent review by Bonkhoff.61 It is well known that acinar structures har-

wt P53: P21: bcl-2: little/no bcl-XL: Bax/Bad/Bak:

wt P53: P21: bcl-2: little/no bcl-XL: Bax/Bad:

P53: null P21: wt P53: bcl-2: P21: bcl-XL: bcl-2: Bad/Bak: Bax: bcl-XL: Bax/Bad/Bak: P25/P54/55: yes

wt P53: P21: bcl-2: little/no bcl-XL: Bax/Bad/Bak: P25/P54/55: yes

P53: mutant P21: bcl-2: bcl-XL: Bad/Bak: Bax: deleted P25/P54/55: yes

Growth Apop +++

Growth Apop +++

Growth + Apop +++

Growth +++ Apop +

Growth +++ Apop +

BPH

NHP

LNCaP

Growth +++ Apop ++

PC3

PCA

DU 145

B Normal Prostate Epithelium Androgen dependence Growth factor dependence Long population doubling time Wild-type P53 Little/no bcl-2

Deprivation

Deprivation P53 upregulation P21: no change or decrease Bax/Bad/Bak upregulation bcl-2: little/no expression

No cell proliferation Apoptosis

Decreased cell number

Prostate Cancer Cells Androgen independence Autocrine growth factor production Short population doubling time Non-functional P53 High bcl-2 Low/no Bax

Deprivation

Cell proliferation

No P53 upregulation

Deprivation P21 upregulation

Bax/Bad/Bak: decrease or deletion bcl-2: upregulation Novel proteins: P25: P54/55(?)

Evasion of apoptosis

Extended survivability

FIGURE 15–4. A, The overall survivability of various prostate cells in the absence of trophic factors is presented: BPH < NHP < LNCaP < PCA < PC3 < PCA < DU 145. Shown above are changes in apoptosis proteins. (Refer to text for details.) No change; increase (upward arrowhead); decrease (downward arrowhead); little or no expression (little/no). Shown in the middle are the cell growth and apoptosis properties of various prostate cells in the absence of trophic factors, as deduced from preceding figures. (– = no growth;. + to +++ = different levels of apoptosis.) The BPH and NHP cells did not proliferate at all and demonstrated fast apoptotic kinetics. The LNCaP cells demonstrated a low level of proliferation and an intermediate level of apoptosis. The PC3 cells demonstrated very aggressive growth and intermediate levels of apoptosis. The PCA and DU 145 cells, in contrast, demonstrated a rapid cell proliferation as well as much delayed and decreased levels of apoptosis. B, Summary of molecular events leading to differential survivabilities of normal versus cancerous prostate epithelial cells in the absence of trophic factors. Note that there exist exceptions to this generalized scheme. For example, PCA cells possess wild-type P53 and express little/no bcl-2. With permission from Tang DG, Li L, Chopra DP, Porter AT. Extended survivability of prostate cancer cells in the absence of trophic factors: increased proliferation, evasion of apoptosis, and the role of apoptosis proteins. Cancer Res 1998;58:3466–79.

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boring benign epithelium are surrounded by basement membrane (BM) material. Normal BM is mainly composed of type IV collagen, laminins, heparin sulfate proteoglycans, and entactin. Prostatic basal cells possess receptors for laminins, collagen subunits, and a receptor associated with hemidesmosome formation. It is believed that the adhesive interactions between the epithelial cells and BM are predominantly mediated by laminin receptors, that epithelial BM are produced predominantly by basal cells, and that prostatic epithelial cells require BM components for growth and differentiation. It has been shown that the cells of HGPIN exhibit increasing transcriptional activity of genes encoding BM components, raising speculation that this abnormal expression of BM-encoding genes may modify the structure of the underlying BM, which in turn may alter cell/matrix adhesive interaction. Furthermore, the cells of HGPIN lose hemidesmosomeforming proteins and a host of adhesive molecules normally found in prostatic epithelial cells; this is accompanied by a progressive loss of basal-cell differentiation. Invasive prostate carcinomas continue to produce BM and to express integrin receptors, which facilitates attachment of tumor cells to the adjacent BM. This BM-forming function is maintained through all stages of the disease and appears to increase as tumor progression and metastasis supervene. However, the BM produced by cancer cells is abnormal. These cells lose a variety of hemidesmosomeforming proteins and associated adhesive molecules. In many if not all instances, there is complete loss of certain types of collagen chains.62 Furthermore, as the tumor grade increases, the number of cell/matrix receptors progressively diminishes. It is postulated that de novo synthesis of BM and maintenance of adhesion molecules may facilitate extracellular matrix penetration during the processes of invasion and metastasis.61,62 Clearly, this is an avenue which will receive continued scientific attention in the coming years, since future therapeutic endeavors may revolve around prevention of stromal invasion and metastasis. The first documentation of malignant transformation of human prostatic epithelial cells by exposure to the chemical carcinogen N-nitroso-N-methylurea (NMU) was reported by Rhim and colleagues.63 The process of carcinogenesis was observed in prostatic cells immortalized by DNA transfection with the HPV-18 genome and subsequently exposed repeatedly to NMU. Multiple chromosomal losses or gains were observed, the most frequent of which were loss of the short arms of chromosomes 8 and 10 and gain of the long arm of chromosome 8. Prognostic Indicators in Prostate Cancer Because there is such a large disparity between the autopsy prevalence of histologic prostate cancer and its clinical incidence, it is readily apparent that the mere presence of prostate cancer in needle biopsy or transurethral resection of the prostate (TURP) specimens may or may not alter or

threaten the individual’s life. It is the acquisition of the ability to metastasize that characterizes a life-altering or life-threatening prostate cancer. It is for this reason that ongoing efforts are being made to identify molecular changes associated with metastatic potential. Metastasis is the result of a sequence of events, including growth, local invasion, and destruction of extracellular matrix, angiogenesis, angiolymphatic invasion, survival in the circulation, adhesion at a metastatic site, exit from the circulation, and proliferation at the metastatic site.64 It is well known that there is an inverse correlation between tumor size (the result of tumor growth) and long-term survival.65 Hence, it seems sensible to examine the factors that may influence tumor growth, in relation to their prognostic value. Studies of these factors are most commonly done using immunohistochemical or molecular biologic techniques. The studies are usually performed on archival tissue from patients whose long-term outcome is known, to allow correlation of the prognostic marker with subsequent tumor behavior. Stapleton and colleagues evaluated the prognostic value of P53, Ki-67, and apoptotic index in cancers removed by radical prostatectomy.66 Of the three markers, only apoptotic index (the number of apoptotic bodies per 100 cancer cells) provided prognostic information independent of other parameters, that is, clinical stage, serum PSA, and Gleason score. These investigators speculate that high apoptotic activity establishes the conditions for the selection of subsets of aggressive tumor cell clones, on the basis of compromised function of the apoptotic pathway. In a similar study of archival radical prostatectomy specimens, Kim and colleagues evaluated the association between the immunohistochemical expression of TGF-β membrane receptor type I (TGFβRI) and a variety of pathologic and clinical parameters.67 They report that loss of expression of TGF-βRI significantly correlated with higher Gleason score, advanced clinical stage, decreased 4-year survival rate, and increased serologic recurrence rate. Insulin-like growth factor binding protein-3 (IGFBP-3) was reported to provide no useful prognostic information in a comparable study by Hampel and colleagues.68 Before a carcinoma cell can metastasize, it must first break free of the adhesive molecular bonds that normally anchor it to its neighboring cells and to the underlying matrix. In prostate tissue, the major cell-to-cell adhesion molecules are cadherins. Cadherin molecules of neighboring cells bind to one another in the extracellular space. The cadherin molecule also traverses the cell membrane to bind with members of the catenin family, which, in turn, link to cytoskeletal microfilaments such as actin.69 Several studies analyzing radical prostatectomy or TURP tissue have shown that aberrant expression of E-cadherin and/or α-catenin correlates with poor outcome, in terms of disease progression and overall survival.69,70 A problem arises, however, when trying to use markers such as

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E-cadherin or P53 to predict the prognosis, when the only tissue available is a prostate needle biopsy specimen. This difficulty was reported by Ruijter and colleagues, who found an alarmingly low sensitivity for detecting abnormal E-cadherin expression by needle biopsy, probably because of inherent sampling error but also because of the marked heterogeneity of all prostate cancers.71 After analyzing their results, these authors question the utility of E-cadherin and P53 expression as prognostic markers in needle biopsy specimens. Considerable research activity has centered recently on “metastasis regulation genes” such as KAI1, CD44, and thymosin (Figure 15–5). It has been observed that hybrid cancer cells derived from fusion of highly metastatic and nonmetastatic cells continue to be tumorigenic but demonstrate suppressed metastatic capability, provided they retain all the chromosomes from both parental cell lines. Subsequent chromosome loss re-establishes metastatic potential, suggesting that metastatic suppressor gene(s) have been inactivated by mutation, allelic loss, or biochemical inactivation.72 A gene on human chromosome 11, designated KAI1, has been isolated and has been shown to suppress metastatic capability when introduced into rat prostate cancer cells.73 Furthermore, diminished expression of KAI1 was consistently observed in metastatic human prostate cancer.73 Neither the exact manner in which metastasis is suppressed nor the mechanism of downregulation is known; downregulation in this case does not appear to involve either mutation or allelic loss. Also located on chromosome 11 is another metastasissuppressor gene, CD44, whose products are involved in cell-to-cell and cell-to-extracellular matrix interactions. Downregulation of CD44 expression appears to be involved in the progression of prostate cancer to metastasis.74,75 An additional factor which appears to be operative in allowing malignant cells to abandon their organ of origin is the apparent upregulation of thymosin β-15, a molecule which directly regulates cell motility in prostate cancer cells. According to Bao and colleagues, the expression of this gene product correlates with the Gleason score, and studies of its possible utility in predicting the metastatic potential of prostate cancer diagnosed by needle biopsy are underway.76

achieved with antibodies against PSA and prostatic acid phosphatase. The staining patterns were not prognostically useful. Their study confirms that hK2 is prostate localized, tumor associated, and expressed more intensely in high-grade carcinomas than PSA. Studies to evaluate the utility of serum hK2 as a marker for prostate cancer are planned; it is noted that this molecule may be useful as a target for reverse transcriptase–polymerase chain reaction (RT-PCR) in the detection of circulating cancer cells that express hK2. Sophisticated molecular techniques have been successfully employed to identify gene products that are unique to prostate cancer cells. A gene on chromosome 9, specific to prostate cancer cells, and its gene product have been identified by Bussemakers and colleagues.78 This gene has been designated DD3. A cell surface antigen uniquely produced by prostate cancer cells, labelled PTCA-1, has also been identified by Su and colleagues.79 Discovery of these unique genetic aberrations is tantalizing because they may be useful therapeutically, for example, in genetherapy regimens. Ornithine decarboxylase (ODC) is an enzyme involved in the biosynthesis of cellular polyamines. It has been observed that there is dysregulation of ODC activity in rodent tumors. It is known that the highest levels of ODC in humans are found in prostate tissue. Mohan and colleagues reported that ODC activity and protein expression are significantly higher in human prostate cancer than in paired benign prostate tissue controls. Furthermore, ODC activity in prostatic fluid obtained by digital rectal massage from prostate cancer patients was significantly higher than ODC levels in prostatic fluid from patients without prostate cancer.80 These authors suggest that measurement of ODC levels in prostatic fluid may be useful as a noninvasive test for prostate cancer and as a mechanism for monitoring the efficacy of treatment.

Thymosin β-15 (Activator) KAI1 (Suppressor) E-Cadherin

Recently Developed Molecular Diagnostic Modalities It is recognized that PSA has become the most important tumor marker for prostate cancer. However, the sensitivity and specificity of serum PSA leave room for improvement. Darson and colleagues reported their evaluation of human glandular kallikrein 2 (hK2) expression in a large series of pathologic stage T2 prostatic adenocarcinomas treated by radical prostatectomy.77 They found that the immunohistochemical expression of hK2 increased incrementally from benign epithelium to HGPIN to adenocarcinoma, and showed an inverse relationship to staining,

α-Catenin

MOTILITY

METASTASIS

Integrins

Extracellular Matrix FIGURE 15–5. Important steps in increasing tumor cell motility as part of the cascade to metastasis. With permission from Coffey DS. Prostate cancer metastasis: talking the walk. Nature Med 1996;2:1305–6.

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Studies of the Morphology of Prostate Neoplasms High-Grade Prostatic Intraepithelial Neoplasia This entity, now well established as the most likely precursor of prostatic adenocarcinoma, continues to be a topic of much research interest, as noted in prior references. The ultrastructural features of HGPIN were described comprehensively by Bostwick and colleagues in a study comparing the benign epithelium, HGPIN, and adenocarcinoma.81 This study was unique in that the tissue analyzed was fresh and optimally fixed for ultrastructural assessment. The ultrastructural features of HGPIN were found to be intermediate between those of benign epithelium and adenocarcinoma, providing further support for the hypothesis that HGPIN is a premalignant lesion. Animal models may prove valuable in assessing the utility of chemoprevention in halting or reversing the progression of HGPIN to prostate cancer. In a report by Waters and Bostwick, it is noted that HGPIN occurs spontaneously in the canine prostate and that there are numerous similarities between canine and human HGPIN.82 Canine HGPIN displays marked cytologic atypia and basal-celllayer disruption as well as proliferative index and microvessel density parameters intermediate between those of benign epithelium and adenocarcinoma. Furthermore, HGPIN was identified in the majority (66%) of canine prostate cancers. Prevalence data confirmed that HGPIN is found in 55% of elderly, sexually intact dogs and is infrequently found in young, sexually intact dogs and elderly, castrated dogs. In short, the prevalence of HGPIN in dogs is strongly influenced by age and testicular androgens. These authors propose that the canine prostate may be a useful model in assessing prostate carcinogenesis. The possibility that HGPIN is the precursor of relatively aggressive prostate cancers but not of indolent well-differentiated cancers was raised by Dawson and colleagues in a study of the expression of the RET protooncogene product by benign prostatic epithelium, HGPIN, and a variety of grades of prostate cancer.83 Higher RET expression was observed in HGPIN and in tumors with poorer histologic differentiation; weak expression was noted in the benign epithelium and welldifferentiated tumors. Obviously, more study will be needed to resolve this question. Morphologic Features and Prognosis As previously noted, there is considerable research underway using molecular and immunohistochemical techniques to identify factors that can be used clinically in the management of prostate cancer patients. The histologic evaluation of routinely processed pathologic specimens continues to provide helpful prognostic information, as evidenced by the following studies. In a large series of radical prostatectomies, McNeal and Yemoto evaluated vascular invasion as a prognostic

indicator.84 Vascular invasion was found in 7% of cancers < 4 cc in volume, and in 24% of cancers > 4 cc in volume. Vascular invasion, cancer grade, and cancer volume were all found to be statistically significant independent predictors of cancer progression. The significance of perineural invasion noted on prostate needle biopsy continues to be a subject of debate. The results of comprehensive studies by Egan and Bostwick,85 and by Epstein,86 have led them to conclude that this finding does not independently influence the likelihood of PSA recurrence following radical prostatectomy, when preoperative Gleason score, serum PSA, and clinical stage are also taken into account. Epstein also notes that excising the neurovascular bundle in cases with perineural invasion reduces the incidence of positive surgical margins by 17.5%. A different viewpoint was expressed by Stone and colleagues.87 These investigators assessed the significance of “extensive” perineural invasion and seminal vesicle involvement by cancer on prostate needle biopsies in relation to lymph node metastasis. Their results indicate that both factors are independent predictors of lymph node metastasis; they recommend that lymph node dissection should precede definitive therapy if either of these findings is observed on prostate needle biopsies. It appears that this is one debate that will require more evaluation. A study of the significance of capsular invasion and extracapsular spread of prostate cancer by Wheeler and colleagues yielded several interesting findings.88 These investigators found a strong association between the level of invasion by the cancer into or through the prostatic capsule and the volume, grade, pathologic stage, and recurrence rate after radical prostatectomy. Tumors that did not invade the capsule did not metastasize in this patient cohort, regardless of tumor volume or grade. There was a linear relationship between degree of capsular invasion and the occurrence of adverse findings, such as seminal vesicle or lymph node involvement and postoperative recurrence of tumor. In a related report, Sanwick and colleagues compared the frequency of extracapsular tumor extension with preliminary needle biopsy findings.89 In patients with cancer of Gleason score 3 or lower on one side and no cancer in at least three needle cores from the opposite side, there was rarely any extracapsular extension of tumor on the side thought preoperatively to be free of tumor. Their findings suggest that the neurovascular bundle can safely be preserved on the side without evidence of cancer, given the conditions specified above. The problem of unwarranted optimism among pathologists was addressed by Iczkowski and Bostwick.90 Comparing their grading of over 1400 needle biopsies and TURP specimens sent for consultation with the grades assigned by the referring pathologists, these authors observed a 2% incidence of “well-differentiated” cancers (Gleason score 2 + 2 = 4 or less) in these cases. The referring pathologists had labelled 56% of the cases

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as “well differentiated.” Steinberg and colleagues also noted a pronounced tendency on the part of pathologists in nonacademic settings to assign low Gleason scores (2 to 4) to cancers detected in needle biopsies.91 The point being made is that the common overdiagnosis of “welldifferentiated” cancer on needle biopsy may inadvertently (and inappropriately) influence choice of therapy to the patient’s detriment. Variants of Prostatic Adenocarcinoma Neoplastic glomeruloid structures exhibit a pattern of growth that mimics the renal glomerulus; these architectural oddities have been noted in Wilms’ tumor, gliomas, and, more recently, prostatic adenocarcinoma. Pacelli and colleagues noted glomerulus-like malignant epithelial aggregates in 9 of 202 radical prostatectomy specimens and in 3 of 100 needle biopsy cases.92 The finding is believed by these authors to be specific for malignancy since it was not observed in benign epithelia or in HGPIN. The significance of the entity is so far uncertain, although it seems most often to be a component of high-grade cancers that tend to exhibit extraprostatic extension. The cytoarchitectural changes in the morphology of prostatic adenocarcinoma induced by total androgen blockade therapy have been well characterized in numerous reports. Tran and colleagues have described an additional, previously unreported, alteration in prostate cancer morphology as a consequence of androgen ablation—the formation of lakes of extravasated mucin, with or without recognizable residual tumor.93 In 3 of 13 cases exhibiting this finding, no residual intact prostatic adenocarcinoma could be found; review of preoperative biopsies confirmed the diagnosis of adenocarcinoma. This study is important for at least two reasons. First, identification of these mucin lakes in a radical prostatectomy specimen may prompt the pathologist to search for the other more subtle findings that are typical of preoperative androgen ablation therapy. Secondly, pathologists need to be aware that these mucin lakes may be the only residual clue to the previous existence of adenocarcinoma in the gland to be examined. For several years, there has been controversy among pathologists concerning cytologically malignant solid, papillary, and cribriform cellular proliferations within prostatic ducts that retain a basal cell layer. The debate has centered on the question of whether such proliferations represent a premalignant lesion (HGPIN) or whether they represent intraductal extension of an established invasive cancer (intraductal carcinoma [IDCa]). Proponents of both viewpoints have presented compelling arguments.94–96 The practical difficulty of this uncertainty is that a pathologist confronted with these findings in a needle biopsy specimen must provide a guideline to the urologist for patient management. Most pathologists agree that intraductal comedo-necrosis is only seen in cases of established carcinoma. Wilcox and

colleagues have suggested that the debate may be unresolvable, that a cytologically malignant intraductal proliferation may represent either HGPIN or a fully established cancer invading the ductal spaces, and that there is presently no reliable way of distinguishing the two entities on needle biopsy specimens.97 Therefore, Wilcox and colleagues have proposed that aggregates of cytologically malignant cells within a duct with an intact basal cell layer and showing central comedo-necrosis should be considered to represent cancer; all other intraductal proliferations should be lumped together as HGPIN, with a recommendation to repeat biopsy. In an article closely related to the above discussion, Bock and Bostwick have questioned the existence of prostatic duct adenocarcinoma as a distinct pathologic entity with unique pathologic and clinical features.98 In 5% of 338 radical prostatectomy specimens, they found areas with microscopic features normally attributed to prostatic duct carcinoma within typical peripheral zone adenocarcinomas; the noted areas comprised up to 60% of total tumor volume. They believe that prostatic duct adenocarcinoma is simply a manifestation of typical adenocarcinoma with extension into accommodating large ducts. Diagnostic Pitfalls and Dilemmas in Prostate Pathology The problem of overdiagnosing prostate cancer has been discussed in a previous section. Several recent reports have described subtle alterations in prostatic adenocarcinoma morphology, which can be difficult to recognize as malignant. Foamy gland carcinoma, characterized by the presence of abundant xanthomatous cytoplasm within tumor cells, is a deceptively bland lesion described by Nelson and Epstein.99 Recognition of a malignant process is aided by the crowded and infiltrative architecture of the neoplastic glands and by the frequent presence of dense pink acellular secretions within smaller than normal acini (Figure 15–6). It is noteworthy that these neoplasms often do not display nucleomegaly or nucleolomegaly. The entity is considered by the authors to be of intermediate grade. Pseudohyperplastic prostatic adenocarcinoma, originally described by Epstein and revisited in a recent article by Humphrey and colleagues, can also be readily misinterpreted as a benign condition.100 The malignant glands in this condition can display nodular architecture, cystic change in larger acini, complex branching, luminal undulations, and true papillary projections with fibrovascular cores. The malignant epithelium is often columnar. Fortunately, the lining cells are cytologically malignant upon close inspection, with nucleomegaly and nucleolomegaly in all cases reported by Humphrey and colleagues; the diagnostic difficulty lies in the deceptively benign-looking architechture. Prostatic adenocarcinoma with atrophic features is a deceptively innocuous-looking lesion described by two groups of investigators in 1997.101,102

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A

B

FIGURE 15–6. Foamy gland carcinoma. A, At low power, there are crowded acini with abundant dense secretions. The acini are clearly different from the normal adjacent acini. B, At high power, there is a single layer of epithelial cells without nucleomegaly or nucleolomegaly; the cytoplasm is copious and ”foamy.“ The diagnosis of malignancy in these cases is based on recognition of abnormal architecture.

The diagnostic problems in this entity are both architectural and cytologic. The lesion resembles acinar atrophy on scanning magnification. The acinar spaces are either dilated and round to oval, or small with an irregular distorted outline (Figure 15–7). The lining cells appear attenuated, with scant cytoplasm and a high nucleus-to-

cytoplasmic ratio. A diagnosis of malignancy is facilitated if the atypical glands display clear-cut infiltration between adjacent benign acinar structures. The diagnosis of adenocarcinoma with atrophic features should only be made when there is convincing cytologic evidence of malignancy (nuclear and nucleolar enlargement) and

A

B

C

D

FIGURE 15–7. Adenocarcinoma with atrophic features. At low power, malignant acini are small, distorted, and angular (A), or dilated and round to oval (B); in either case, they mimic atrophy. At higher magnification (C, D), the malignant acini are lined by cytologically malignant cells.

Pathobiology of Prostate Diseases: an Update / 133

should be made with great caution when there is a background of inflammation. Cowper’s glands, normal residents of the urogenital diaphragm, may be sampled inadvertently during TURP, or occasionally in the course of prostate needle biopsy. They are composed of small tightly packed acini and can be misinterpreted as adenocarcinoma. Saboorian and colleagues addressed this problem and pointed out that the acinar epithelium of Cowper’s glands stains positively for mucin and negatively for PSA and PAP.103 The acinar units are lined by an attenuated layer of myoepitheial cells that show positive staining for smooth muscle actin but negative staining for protein S100 or 34βE12. The authors correctly emphasize that reliance on a negative 34βE12 stain for basal cells to diagnose cancer can be treacherous in instances such as this. The noted combination of staining characteristics helps to resolve the nature of the suspicious acinar units; however, the most critical factor is the initial recognition that the worrisome focus may be derived from a normal anatomic structure. Prostate needle biopsies often include atypical small acinar proliferations (ASAP) that are suspicious for but not diagnostic of malignancy because they lack the full complement of architectural and cytologic findings required for an unequivocal diagnosis of malignancy. The few atypical features they display may represent partial sampling of a host of “cancer mimics.” Considerable attention has been directed toward this problem recently, following assessment of the clinical significance of this biopsy finding.104,105 Factors that prevent a diagnosis of malignancy in these cases include paucity of abnormal acini for evaluation, disappearance of the worrisome focus on deeper levels, lack of convincing cytologic abnormality, crush artifact, associated inflammation, and nearby atrophic changes (Figure 15–8). Follow-up biopsies reveal adenocarcinoma in 45 to 60% of instances. Unlike HGPIN, ASAP is not a unique entity; however, it is a useful diagnostic category

A

that reflects the pathologist’s uncertainty but still reflects considerable risk of malignancy. Considering the high risk of subsequent detection of malignancy after an initial diagnosis of ASAP, routine follow-up needle biopsies in these cases would seem reasonable and prudent. Pathologists continue to refine existing techniques and develop new techniques designed to aid in resolving diagnostic dilemmas. The value of being able to demonstrate the presence of basal cells in a suspicious focus of prostatic acini is well recognized. In practice, however, it is widely acknowledged among pathologists that the immunohistochemical stain for 34βE12 is both temperamental and variable under routine conditions, despite considerable experience in its use. A substantial improvement in the use of 34βE12 to identify basal cells has been reported by Iczkowski and colleagues.106 Their technique involves the use of a combination of steam heat with EDTA buffer and protease digestion to enhance basal cell immunoreactivity in needle biopsy specimens. Furthermore, a new antibody has been developed for the immunohistochemical demonstration of A-80, a mucinous glycoprotein that is consistently and strongly upregulated in the overwhelming majority of cases of prostatic adenocarcinoma and HGPIN but not expressed by normal or hyperplastic prostatic epithelium.107 The anti–A-80 antibody has been employed to identify the relics of malignant acini in prostatic tissue examined after androgen ablation therapy and appears to be a very useful adjunct to routine diagnostic evaluation in this setting. Further studies are planned to evaluate the utility of this immunohistochemical stain in identifying residual malignancy following radiation therapy. Other Neoplasms of the Prostate Transitional cell carcinoma of the prostate in the absence of invasive bladder carcinoma was revisited by Cheville and colleagues, who reported the clinicopathologic features

B

FIGURE 15–8. An example of one of the entities that are included under the designation “atypical small acinar proliferation (ASAP)” at low and high power magnification (A, B). This single acinus is lined by cells with macronucleoli; however, one of the cells may be a basal cell. The acinus disappears in deeper levels. Because the focus raises concern for malignancy, but cannot be confidently diagnosed as adenocarcinoma, the appropriate appellation is “ASAP.”

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and outcome of 50 patients with this lesion, treated by radical cystoprostatectomy over a 30-year period at the Mayo Clinic.108 Involvement of the bladder by transitional cell carcinoma in situ (CIS) was observed in 64% of the pathologic specimens, but patients with current or prior invasive bladder carcinoma were excluded from the series. The overall 5-year disease-specific survival was 52%. Patients whose disease was limited to CIS had a 100% 5-year survival; in patients with urethral submucosal/prostatic stromal invasion, the 5-year survival fell to 45%. Survival rates were even lower in patients with extraprostatic extension of tumor or with lymph node metastases, but the limited number of patients with these findings precluded meaningful statistical analysis. The authors noted that 20% of their patients later developed urethral CIS, a finding that supports the notion of prophylactic urethrectomy in this patient group. The specialized prostatic stroma can give rise to sarcomas and other stromal proliferations. A series of 22 such lesions was analyzed by Gaudin and colleagues, who believe that these lesions represent a spectrum of neoplasms that can be grouped into two clinicopathologic categories: prostatic stromal sarcoma (PSS), and prostatic stromal proliferations of uncertain malignant potential (PSPUMP).109 On the basis of their observations and an extensive literature review, they note that patients range in age from the 3rd to the 9th decade of life (peak incidence in the 6th and 7th decades), and present with urinary retention, hematuria, rectal pain, and/or a palpable abdominal mass. The lesions may become as large as 58 cm; most appear to arise posteriorly with basal extension and compression of other pelvic organs. Microscopically, all lesions display hypercellularity, which is most marked in the sarcomatous lesions. Stromal sarcomas demonstrate mitotic figures, necrosis, and stromal overgrowth. The PSPUMP lesions lack necrosis and significant mitotic activity and can be further subdivided into four categories

on the basis of the degree and extent of cytologic atypia, the presence or absence of benign prostatic glands, and the presence or absence of a “leaf-like” architecture resembling phyllodes tumor of the mammary gland. Immunohistochemically, PSS and PSPUMP commonly express vimentin, CD34, and progesterone receptor; however, the expression of muscle markers is distinctly different between the groups. It is noted that immunohistochemical results allow a distinction between PSS and other sarcomas such as leiomyosarcoma and rhabdomyosarcoma. Both PSS and PSPUMP are prone to local recurrence, and occasionally PSPUMP lesions have shown behavior that suggests progression to PSS. The authors acknowledge that it is still unclear whether all of these lesions are necessarily neoplastic since some are reportedly focal and without evidence of recurrence or progression. The cumulative experience with malignant lymphoma involving the prostate was greatly enhanced by a report by Bostwick and colleagues of 62 additional cases from two large institutions, bringing the reported total to 158 cases.110 Sixty cases were of non-Hodgkin’s type and two were Hodgkin’s lymphoma. Mean age at diagnosis was 62 years, with a range of 5 to 89 years. Patients presented with obstructive voiding symptoms. About half the patients had previous documentation of lymphoma involving other sites, a third presented with primary extranodal lymphoma, and it was indeterminate whether the remainder of lymphomas were primary or secondary. A wide variety of histologic subtypes were represented in both the primary and secondary groups; not surprisingly, the majority of small lymphocytic lymphomas were secondary in the prostate (Figure 15–9). There was no significant difference in median survival after diagnosis of prostatic involvement by lymphoma between primary and secondary lymphoma or between histologic subtypes. Lymphoma-specific survival was 64% at 1 year, 50% at 2 years, 33% at 5 and 10 years, and 16% at 15 years of follow-up.

FIGURE 15–9. Malignant lymphoma involving the prostate. A normal prostatic acinus is engulfed in a sea of small atypical cells. Immunohistochemical stains confirmed the lymphoid nature of the abnormal infiltrate.

Many of the uncertainties concerning idiopathic chronic prostatitis/pelvic pain syndrome are being aggressively unravelled. It appears from the content of recent publications that syndromes included under this designation probably encompass a spectrum of disorders of infectious, chemical, and autoimmune origin, all of which produce similar symptomatology. Studies of cytokine levels in seminal plasma may provide additional clinical measurements that may be helpful in triaging individual cases. The molecular and cytogenetic aberrations which culminate in the development of BPH and prostatic adenocarcinoma are being intensely investigated. The goal of many investigators is to develop a diagnostic method which could be readily employed in combination with well-established parameters such as Gleason score and serum PSA to accurately predict the behavior of an indi-

Summary

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vidual cancer. Elucidation of molecular and cytogenetic pathways of disease will hopefully pave the way for innovative new preventive and therapeutic modalities. It appears that some promising advances have been made toward achieving these goals.

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Pathobiology of Prostate Diseases: an Update / 137 75. De Marzo AM, Bradshaw C, Sauvageot J, et al. CD44 and CD44v6 downregulation in clinical prostatic carcinoma: relation to Gleason grade and cytoarchitecture. Prostate 1998;34:162–8. 76. Bao L, Loda M, Janmey PA, et al. Thymosin β-15: a novel regulator of tumor cell motility upregulated in metastatic prostate cancer. Nature Med 1996;2:1322–8. 77. Darson MF, Pacelli A, Roche P, et al. Human glandular kallikrein 2 (hK2) expression in prostatic intraepithelial neoplasia and adenocarcinoma: a novel prostate cancer marker. Urology 1997;49:857–62. 78. Bussemakers MJG, van Bokhoven A, Debruyne FMJ, Isaacs WB. A new prostate-specific marker, overexpressed in prostatic tumors [abstract]. J Urol 1997;157:21. 79. Su ZZ, Lin J, Shen R, et al. Surface-epitope masking and expression cloning identifies the human prostate carcinoma tumor antigen gene PTCA-1, a member of the galectin gene family. Proc Natl Acad Sci U S A 1996;93: 7252–7. 80. Mohan RR, Challa A, Gupta S, et al. Overexpression of ornithine decarboxylase in prostate cancer and prostatic fluid in humans. Clin Cancer Res 1999;5:143–7. 81. Bostwick DG, Pacelli A, Lopez-Beltran A. Ultrastructure of prostatic intraepithelial neoplasia. Prostate 1997;33:32–7. 82. Waters DJ, Bostwick DG. The canine prostate is a spontaneous model of intraepithelial neoplasia and prostate cancer progression. Anticancer Res 1997;17:1467–70. 83. Dawson DM, Lawrence EG, MacLennan GT, et al. Altered expression of RET proto-oncogene product in prostatic intraepithelial neoplasia and prostate cancer. J Natl Cancer Inst 1998;90:519–23. 84. McNeal JE, Yemoto CEM. Significance of demonstrable vascular space invasion for the progression of prostatic adenocarcinoma. Am J Surg Pathol 1996;20:1351–60. 85. Egan AJM, Bostwick DG. Prediction of extraprostatic extension of prostate cancer based on needle biopsy findings: perineural invasion lacks significance on multivariate analysis. Am J Surg Pathol 1997;21:1496–500. 86. Epstein JI. The role of perineural invasion and other biopsy characteristics as prognostic markers for localized prostate cancer. Semin Urol Oncol 1998;16:124–8. 87. Stone NS, Stock RG, Parikh D, et al. Perineural invasion and seminal vesicle involvement predict pelvic lymph node metastasis in men with localized carcinoma of the prostate. J Urol 1998;160:1722–6. 88. Wheeler TM, Dillioglugil O, Kattan MW, et al. Clinical and pathological significance of the level and extent of capsular invasion in clinical stage T1-T2 prostate cancer. Hum Pathol 1998;29:856–62. 89. Sanwick JM, Dalkin BL, Nagle RB. Accuracy of prostate needle biopsy in predicting extracapsular tumor extension at radical retropubic prostatectomy: application in selecting patients for nerve-sparing surgery. Urology 1998;52:814–9. 90. Iczkowski KA, Bostwick DG. The pathologist as optimist. Am J Surg Pathol 1998;22:1169–70. 91. Steinberg DM, Sauvageot J, Piantadosi S, Epstein JI. Correlation of prostate needle biopsy and radical prostatectomy Gleason grade in academic and community settings. Am J Surg Pathol 1997;21:566–76. 92. Pacelli A, Lopez-Beltran A, Egan AJM, Bostwick DG. Prostatic adenocarcinoma with glomeruloid features. Hum Pathol 1998;28:543–6.

93. Tran TA, Jennings TA, Ross JS, Nazeer T. Pseudomyxoma ovarii-like posttherapeutic alteration in prostatic adenocarcinoma. Am J Surg Pathol 1998;22:347–54. 94. Bostwick DG, Amin MB, Dundore P, et al. Architectural patterns of high-grade prostatic intraepithelial neoplasia. Hum Pathol 1993;24:298–310. 95. McNeal JE, Yemoto CE. Spread of adenocarcinoma within prostatic ducts and acini: morphologic and clinical correlations. Am J Surg Pathol 1996;20:802–14. 96. Rubin MA, de La Taille A, Bagiella E, et al. Cribriform carcinoma of the prostate and cribriform prostatic intraepithelial neoplasia. Am J Surg Pathol 1998;22:840–8. 97. Wilcox G, Soh S, Chakraborty S, et al. Patterns of highgrade prostatic intraepithelial neoplasia associated with clinically aggressive prostate cancer. Hum Pathol 1998;29:1119–23. 98. Bock BJ, Bostwick DG. Does prostatic duct adenocarcinoma exist? Am J Surg Pathol 1999. [In press] 99. Nelson RS, Epstein JI. Prostatic carcinoma with abundant xanthomatous cytoplasm. Am J Surg Pathol 1997;20: 419–26. 100. Humphrey PA, Kaleem Z, Swanson PE, Vollmer RT. Pseudohyperplastic prostatic adenocarcinoma. Am J Surg Pathol 1998;22:1239–46. 101. Cina SJ, Epstein JI. Adenocarcinoma of the prostate with atrophic features. Am J Surg Pathol 1997;21:289–95. 102. Egan AJM, Lopez-Beltran A, Bostwick DG. Prostatic adenocarcinoma with atrophic features: malignancy mimicking a benign process. Am J Surg Pathol 1997;21: 931–5. 103. Saboorian MH, Huffman H, Ashfaq R, et al. Distinguishing Cowper’s glands from neoplastic and pseudoneoplastic lesions of prostate: immunohistochemical and ultrastructural studies. Am J Surg Pathol 1997;21:1069–74. 104. Cheville JC, Reznicek MJ, Bostwick DG. The focus of “Atypical glands, suspicious for malignancy” in prostatic needle biopsy specimens. Am J Clin Pathol 1997; 108:633–40. 105. Iczkowski KA, MacLennan GT, Bostwick DG. Atypical small acinar proliferation suspicious for malignancy in prostate needle biopsies. Clinical significance of 33 cases. Am J Surg Pathol 1997;21:1489–95. 106. Iczkowski KA, Cheng L, Crawford BG, Bostwick DG. Steam-EDTA optimizes immunohistochemical expression of basal cell-specific anti-keratin 34βE12 to discriminate cancer in prostatic epithelium. Mod Pathol 1999. [In press] 107. Gould VE, Doljansakai V, Gooch GT, Bostwick DG. Stability of the glycoprotein A-80 in prostatic carcinoma subsequent to androgen deprivation therapy. Am J Surg Pathol 1997;21:319–26. 108. Cheville JC, Dundore PA, Bostwick DG, et al. Transitional cell carcinoma of the prostate. Clinicopathologic study of 50 cases. Cancer 1998;82:703–7. 109. Gaudin PB, Rosai J, Epstein JI. Sarcomas and related proliferative lesions of specialized prostatic stroma. A clinicopathologic study of 22 cases. Am J Surg Pathol 1998; 22:148–62. 110. Bostwick DG, Iczkowski KA, Amin MB, et al. Malignant lymphoma involving the prostate. Report of 62 cases. Cancer 1998;83:732–8.

CHAPTER 16

MODELS OF PROSTATE CANCER THOMAS G. PRETLOW, MD; THERESA P. PRETLOW, MD The authors define a “model of prostate cancer (PCa)” as a system that can be manipulated in the laboratory without the active participation of a patient to better understand human PCa. Many kinds of model systems have been used to investigate the biochemistry, physiology, molecular biology, and experimental therapy of PCa. Different approaches have used human tissue for biochemical analysis, organ culture, tissue culture, and xenografts as well as prostates from several different experimental animals, including rodents and dogs. Using these models of PCa has involved a wide range of techniques. Those models that seem most relevant to the biology and pathogenesis of human prostate cancer will be emphasized. The authors agree with Gleave and Hsieh1 that “An ideal model for the study of human prostate cancer does not exist.” While studying human prostate tissue requires much more effort and interdisciplinary organization than studying many other models, it seems that studying human tissue has been and will continue to be the most relevant and meaningful approach. All extant laboratory models of PCa have much larger proliferative fractions and more rapid rates of growth than do most human PCas. As reviewed previously,2 whether investigators studied proliferation of PCa cells with tritiated thymidine incorporated into prostate cells in vitro,3 the expression of Ki-67,3 incorporation of bromodeoxyuridine injected into patients immediately before prostatectomy4,5 or added to cultured prostates after prostatectomy,6 or the expression of other markers of cell proliferation, most found that the mean proportion of cells in the proliferative fraction in PCas ranged from 0.68%3 to 3.3%7 of cells. More than 90% of patients with clinically evident PCa, that is, not just latent PCa, had fewer than 6% of cells in the proliferative fraction. As discussed,2 this stands in sharp contrast to most other human cancers. For example, the mean proliferative fraction includes 22% of cells in gastric carcinoma8 and 38.7% of cells in colorectal carcinoma.9 The low proliferative fraction and slow rate of growth are characteristics of human PCa that greatly complicate the design of models accurately reflecting the biology of human PCa. Sakr et al.10 have carried out a detailed histopathologic analysis of the prostates of 525 men who died from trauma and found that invasive PCas can be identified in 8% of men in their twenties and 31% of men in their thirties. The small proliferative fraction in PCas

suggests a very slow rate for growth of most PCas, which is quite credible in view of the several decades between the times when these cancers can be detected histopathologically, become sufficiently advanced to be diagnosed clinically, and kill patients. Unfortunately, all models of PCa depending on tissue culture or life expectancies of laboratory animals will involve much briefer periods than the several decades during which most human PCas remain small and undiagnosed. Except for the very limited number and variety of PCa tissue culture cell lines, models of benign and malignant prostatic tissue and cells placed directly in culture are very limited in their life expectancies.

Human Models Models for studying benign prostates and PCa include fresh, human prostatic tissue; prostatic tissue fixed and embedded in paraffin or other embedding media; prostatic fluid obtained by prostatic massage; fresh tissue placed in organ culture or prepared for tissue culture; tissue culture lines; and xenografts. Human Prostatic Tissues Procuring prostatic tissue to be studied fresh, fixed, and embedded in paraffin, in organ culture, in tissue culture, or as xenografts requires much more careful attention than does procuring most other human tissues. Based on personal experience in running National Cancer Institute– sponsored human tissue procurement programs in two universities over a span of two decades, the authors have found that prostatic tissues are among the first of many studied human tissues to lose their biochemical integrity and viability after removal from patients. It is important that they immediately be put into cold saline or culture medium in the surgical suite so that they are cooled en route to the surgical pathologist. Enzymatic activities that the authors have studied11–22 as well as many other biologic properties, such as the ability to grow in culture19,23 or as xenografts,24,25 decline rapidly if prostatic tissues are not promptly cooled after interruption of the blood supply. Benign and malignant prostatic tissue can be obtained from total prostatectomies. Benign hyperplastic prostatic tissue is abundantly available in medical centers from transurethral resections of prostatic tissues (TURPs) when they are carried out without cautery. Tissue from PCa is much less readily available, except in those centers where 138

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large PCas and/or nodal metastases are resected. In many centers, total prostatectomies are performed only for those patients with low levels of circulating prostate-specific antigen (PSA); these cancers are small and often difficult to locate grossly. Small cancers are often needed in their entirety for histopathologic documentation. In the authors’ experience, if transurethrally resected prostatic tissue is immediately placed in cold saline in an ice bath in the operating room, biochemical and biologic functions are often more intact than when tissues are obtained from total prostatectomy. This difference may be related to the fact that transurethrally resected prostatic tissues can be placed in cold saline within seconds of interruption of the blood supply. The blood supplies of whole prostates will have been interrupted for longer periods of time before the tissue is removed from the patient and can be cooled in cold liquid. If sagittal sections of all resected fragments (“chips”) from all transurethrally resected prostates with a preoperative clinical diagnosis of benign prostatic hyperplasia (BPH) were examined by cryostat section, at least 10% of patients would be found to have unsuspected carcinomas,26,27 some of them extensive. Pacelli and Bostwick28 found that 18.3% of transurethral resections from 698 patients with the clinical diagnosis of BPH contained adenocarcinoma. The authors found PCa in the transurethrally resected prostates of 19 of 100 similar patients. Many investigators are well served if they receive one-tenth of a gram of PCa, and some transurethral resections (3 to 5% in the authors’ experience) contain sufficient cancer in excess of that required for diagnosis to make fresh and/or frozen tissue available to dozens of investigators. Histopathologic documentation of sagittal sections of each chip provides diagnostic information and essential quality control necessary for work with this histopathologically heterogeneous tissue. In the authors’ laboratory, resected chips weighing less than 0.1 g were often biochemically altered; chips weighing more than 0.1 g, as most chips from most surgeons do, were excellent. This approach makes the lateral halves of each piece of resected tissue available for research. Prostatic Fluid In the early 1970s, the authors became aware of the importance of prostatic fluid when Grayhack et al. presented some novel findings, reported subsequently.29–33 He demonstrated that the ratios of lactic dehydrogenase isoenzymes V/I were different in prostatic massage fluids obtained from patients with diagnosed PCa compared to fluids from patients without diagnosed PCa. Grayhack et al. found other chemical differences between fluids from patients with and without diagnosed PCa. With prostatic massage, one can obtain prostatic fluid cells from a large proportion29,30,33–37 of PCa patients without using a knife or needle. Both Koss and Bologna et al.34–36 concur that cytologically identifiable PCa cells in prostatic massage fluid are

sufficiently uncommon to make cytologic examination of prostatic fluid an impractical approach to diagnosing PCa for most patients. Importantly, however, Bologna et al.35,36 have concluded, that the relatively small number of PCa cells in prostatic massage fluid usually expands rapidly in culture, and that the presence of PCa cells in the fluid of PCa patients observed during culture provides the basis for a diagnostically useful screening test that permits identification of at least 80% of PCa patients. The authors do not yet have sufficient data to confirm Bologna et al.’s observations in detail, but preliminary data are consistent with his conclusions. Specifically, the authors37 obtained over 1 million cells from prostatic fluids of 11 of 16 patients who had rectal massage immediately prior to total prostatectomy for PCa. One was infected and the remaining 10 contained cells that grew in soft agar. The soft agar culture system of Hamburger and Salmon et al.,38–42 as used by the authors previously,43–45 results in the formation of colonies by malignant cells and failure of benign cells to grow from tumors. Except for the work of Bologna et al. and Koss,34–36 the authors are not aware of any detailed characterization of prostatic fluids for their content of PCa cells. With qualitatively different approaches, data from Grayhack et al.,30 Bologna et al.,36 and the authors’37 laboratory suggest that prostatic fluid deserves investigation as a valuable source of PCa cells. Organ Culture Organ culture represents potentially one of the most useful modalities for the short-term (4 to 8 weeks) propagation of benign human prostatic epithelial cells. It is a method unknown to many “modern” PCa researchers. The organ culture of human prostatic tissues has been reviewed in detail.23 Commencing in the early 1950s, Ilse Lasnitzki46 conducted studies related to carcinogenesis with the organ culture of mouse prostate. Following a sabbatical year with Laznitzki, Heidelberger in collaboration with Iype,47 used organ culture followed by tissue culture. They were the first investigators to induce carcinomas of any kind in vitro followed by proving their tumorigenicity in vivo. This work, along with Heidelberger’s design and synthesis of 5-fluorouracil, were reviewed in Heidelberger’s Clowes Memorial Lecture48 and elsewhere.49 Lasnitzki’s early work46,50–53 was related to the study of carcinogens as they affected rodent prostates in organ culture and to methods for reversing or antagonizing the carcinogenic process with vitamins and other approaches.51,52,54,55 Her group50–52,56,57 and Franks’ group58,59 also studied the effects of many steroid hormones on rodent prostates in organ culture. Lasnitzki’s collaborations with others60,61 demonstrated that testosterone and metabolites of testosterone stimulated rodent prostatic epithelium in organ culture and eventually led her to the conclusion that dihydrotestosterone was the “principal

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intracellular androgen whether the hormone in the incubation medium was testosterone or dihydrotestosterone.”62 Work with the organ culture of human prostatic tissues closely resembled the work Lasnitzki conducted on the prostates of rodents. In 1971, two laboratories63,64 reported the successful maintenance of benign human prostatic tissue in organ culture. Stonington and Hemmingsen63 reported that small fragments of human prostatic tissue became “encapsulated” in 7 to 14 days with a layer of epithelial cells “in continuity with the glands on serial section,” that the supporting stromal cells were lost, and that the production of histochemically demonstrable acid phosphatase continued at 21 days in culture. They described the morphologic changes in these fragments in detail.65,66 Harbitz67 confirmed many of these findings. Stonington and Hemmingsen63 specifically mention that they initially fed their organ cultures so that “medium rises only half way up the explant mass.” This is an important point since growth is more vigorous and attachment and outgrowth of epithelial cells on plastic culture dishes are much more vigorous in shallow medium with the cultured tissue less than entirely submerged in medium. The best culture medium for this purpose contains supplements previously described by the authors et al.68 Encapsulation of the organ fragments by epithelial cells in their laboratory was seen in more than half of the fragments after 3 days in culture, 73% after 5 days, and 90% after 10 days in culture. While production of PSA and acid phosphatase remained significant at all time intervals examined, the contents of many other enzymes were rapidly modulated in organ culture.19,23 Incorporation of bromodeoxyuridine, assessed immunohistochemically, demonstrated continued vigorous growth of epithelial cells for more than a month and less vigorous growth for periods up to 2 months.23 Webber et al.69 noted the potential utility of organ culture as a step in purifying benign prostatic epithelial cells. Organ cultures of human prostates were used extensively to investigate the effects of different hormones on the prostate in organ culture.70–77 These studies often found small and inconsistent changes in organ cultures of prostates treated with different hormones. Ghanadian et al.70 have emphasized the enormous variability observed among samples of prostates obtained from different patients. Xenografts and Cell Lines in Culture Before separately addressing xenografts and cell lines in culture, two important differences between the results of the two techniques should be addressed. The first is illustrated in Table 1 of a 1996 paper by Ellis et al.78 The authors of this report stated that “At this time, only eight continuously passaged prostate cancer cell lines...and nine serially passable xenografts [sic] lines (both primary and metastatic)... currently exist (summarized in Table 1).” The authors then listed not 8 but 9 established

PCa cell lines in their table. While the most recently developed tissue culture cell lines and xenografts listed in the table were started in 1991, the table is important because the several other xenografts and tissue culture cell lines developed prior to publication of the paper, and subsequently, exemplify the generalizations flowing from the table. One of 9 listed culture lines and 6 of 9 listed xenografts resembled most human PCas in being sensitive to androgens. Similarly, 1 of the 9 culture lines produced PSA; another, designated ND-1, produced a “trace” of PSA. The other 7 listed cell lines produced none. The ND-1 culture line was originally described as producing “small amounts of prostate specific antigen” as assayed with the “Tandem PSA...assay.”79 In contrast, 4 of the 9 listed xenograft lines produced PSA, the largest single protein product of most benign and malignant prostatic epithelia in patients. Similarly, all the xenografts the authors started from three patients, (CWR31/91, CWR21, and CWR22) make both PSA and androgen receptors.25,44,80 In addition to the fact that most xenografts are more similar to PCas in patients than are tissue culture lines, initiating PCa xenografts has enjoyed a much higher success rate than initiation of tissue culture lines from PCas. In 1980, Gittes81 reviewed the attempts to establish PCa xenografts up to that time, and concluded that “the incidence of ‘take’ of prostate cancer has been close to zero.” It is not known with certainty why success rates have been higher recently. The authors, however, have established four xenografts from the primary PCas of 3 of 33 patients in their laboratory.25 Other laboratories have reported higher levels of success than those described by Gittes in 1980 in establishment of xenografts.81 Klein et al.82 obtained persistent growth of PCas as xenografts for more than 5 passages from 2 of 8 patients with metastatic PCa. One of these 2 xenografts resulted from transplantation of transurethrally resected prostatic tissue. One group83 from Europe has developed seven PCa xenografts. Based on currently available knowledge, the establishment of PCa xenografts appears to be much more readily feasible than direct establishment of tissue culture lines from PCas. In at least two instances, after being passaged several times as xenografts, cells from the xenografts have been used to establish PCa tissue culture lines.82,84 Human Prostate Cancers as Xenografts Xenografts as models of PCa have been reviewed in detail2,81,83,85 and summarized in the recent report of a workshop.86a In 1980, Mickey et al. reported growth of the DU 145 PCa tissue culture cell line as a xenograft.86b In 1980, Hoehn et al.87 reported establishment of the first human PCa xenograft to survive and continue to be used to the present time, PC-82, an androgen-dependent xenograft. Four years later, Hoehn et al.88 reported a

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second androgen-dependent xenograft, PC-EW. Both these xenografts regressed after hormonal manipulations of several kinds over the longest periods of observation reported (7 and 9 weeks); interesting differences in the histologies during regression were described.88 In 1984 and subsequently, Ito et al.89,90 described the HONDA tumor, another androgen-dependent PCa xenograft. Ito and Nakazato90 reported that they could identify viral particles in the HONDA tumor; however, the significance of these particles is unknown. Evidence of viral infection has been found in human PCas from different continents;91,92 the biologic and clinical significance of these infections, however, is unclear. Studies of papillomavirus infections were reviewed with different conclusions in a recent characterization93 of several new patients. While the review of this area was well referenced, the subjects studied were very different ethnically from those studied in the two earlier reports.91,92 Another investigation94 with an excellent review of the recent literature leads to the conclusion that infection of human PCas with papillomavirus is unusual. In 1985, Graham et al.95 obtained the “479” xenograft from tissue taken from a bone biopsy from a patient who had been treated with androgen ablation and several kinds of chemotherapy; the tumor was described95 as “estrogen and androgen insensitive.” In 1986, Harper et al.96 described another androgen-dependent xenograft, TEN/12. In 1987, Pittman et al.97 started a xenograft from primary, small-cell PCa. Csapo et al.98 described the PCEG, androgen-dependent xenograft in 1988. In a study of PC-82, PC-EW, and PC-EG, they found that both PSA and prostatic acid phosphatase (PAP) in the blood of nude mice increased with increasing tumor size; however, “the indicator value of PSA was 20 to 50 times higher than that of PAP.…”28 In 1991, Gingrich et al.99 described the DU 5683 xenograft which was started from a metastasis to a lymph node of a patient who had been treated earlier with orchiectomy; DU 5683 grew equally well in male and female nude mice. In 1990, Kleinman and her collaborators100 reported that the use of Matrigel as a vehicle for injecting small-cell lung cancer cells and MCF7 breast cancer cells greatly enhanced their tumorigenicity. Matrigel is often described as a “basement membrane–like substance” derived from the extraction of the Engelbreth-Holm Swarm (EHS) tumor, a transplantable tumor that arose approximately four decades ago. Several additional reports from Kleinman et al. confirmed these results with different kinds of cells.101–103 One of these, from 1992,103 was entitled “Malignant transformation of NIH-3T3 cells after subcutaneous co-injection with a reconstituted basement membrane.” While there were certainly behavioral and phenotypic changes in 3T3 cells injected in Matrigel, that is, they formed sarcomas and acquired other different phenotypic properties, it is important to recognize that Boone104 had

demonstrated over a decade earlier that very small numbers of 3T3 cells formed sarcomas when attached to microspheres and injected into mice. The word “transformation” might be subject to several different interpretations since 3T3 cells can form sarcomas when injected in the absence of Matrigel. Many other reports24,25,80,105–107 on the use of Matrigel to enhance the tumorigenicity of cell lines have been published. More important, Mehta et al.108 used Matrigel to approach a much more difficult problem that had been very refractory to many other approaches. They digested 28 primary human breast cancers in a mixture of enzymes and injected the cells into nude mice in Matrigel. Seventeen of the 28 cancers grew in nude mice, and 7 of these tumors gave rise to distant metastases spontaneously from the subcutaneous injection sites. Prior to this approach, breast cancer had been exceptionally refractory to growing as primary xenografts in immunologically deprived rodents. Kleinman et al.’s report100 led the authors to inject three PCa cell lines, PC-3, DU 145, and LNCaP, into nude mice with and without Matrigel.24 The tumorigenicity of PC-3 increased 25,000-fold in Matrigel; that of DU 145, 7000-fold. Tumors were obtained from LNCaP only when cells were injected in Matrigel. The authors were also excited at that time because 6 of 10 primary human PCas, minced and suspended in Matrigel, survived until the mice were sacrificed 70 to 123 days after transplantation. Subsequently, the authors have developed several serially transplantable xenografts with this system.25,44,80 For newer xenografts, the authors have always injected minced tumor with Matrigel into some animals and minced tumor without Matrigel into others. All minced tumors that have grown with Matrigel have also grown without Matrigel. The same is true of serially transplanted xenografts. If instead of injecting minced tissue one obtains cell suspensions from these same xenografts by enzymatic digestion, tumorigenicities of all the xenografts examined are at least 1000-fold enhanced when cells are injected in Matrigel.2,44 The authors have also found no detectable differences in tumorigenicity or biologic behavior between tumors that have been passaged serially for 10 successive passages with the vehicles being either consistently Matrigel or consistently culture medium. In the laboratory, Matrigel has enhanced the tumorigenicity of PCa xenografts as cell suspensions. The tumorigenicities of minced tissue from the same PCa xenografts, however, have not been affected by Matrigel. Starting with PCas resected from 3 patients, the authors’ laboratory25 has developed 4 xenografts that are phenotypically significantly different. It was originally believed that the 4 xenografts came from 4 patients. Subsequently, it was found that 2 of these 4 serially transplanted xenografts, CWR31 and CWR91, were cytogenetically complex and identical. Unexpectedly, CWR31 and

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CWR91, despite their cytogenetic identity, have several biologic properties that are different, that is, the number of cells required to transplant the tumors and the frequency of spontaneous pulmonary metastases. After the 20 patients from whom tumor was transplanted prior to the authors’ first report of these tumors,25 tissue from 13 additional patients has been transplanted without the development of additional xenografts. That is, based on a very small sample (33 patients), the authors have had a 9% success rate in starting new xenografts. One of the authors’ androgen-dependent xenografts, CWR22,80 regresses after animals are castrated but has been the source of four cytogenetically different relapsed xenografts, CWR22R.44 There are several important variables likely to enhance the rate of success in starting new xenografts. Using Matrigel for serial transplantation of cell suspensions, not minced tissues, seems very important. Despite the use of Matrigel, the authors have lost some xenografts after the first and second serial transplantations. The marked heterogeneity among nude mice with respect to their circulating levels of testosterone makes the use of sustainedrelease testosterone very important for the growth of androgen-dependent tumors. While the authors’ laboratory has generated a smaller body of data consistent with the data of van Steenbrugge,109 the latter remains the best study of levels of circulating androgen in nude mice. The van Steenbrugge study showed that “natural” levels of circulating androgen in nude mice vary enormously among mice from a level approaching zero to significantly higher levels than those found in human adult males. Consistent with van Steenbrugge’s work,109 the authors’ laboratory has found that sustained-release testosterone administered to nude mice can produce levels of androgen consistent with human adult male levels. Failure to use sustained-release testosterone would likely result in (1) a lower success rate in initiating new xenografts because of the failure of androgen-dependent tumors to grow, and (2) selection, in an androgen-deprived environment, of subpopulations of cells not optimally representative of patients’ tumors. The authors do not believe that there are adequate data to support van Weerden et al.’s opinion that “Although the number of animals is small, it seemed that tumor take and growth at onset did not relate to androgen levels in the host animal as tumors developed in either intact male mice or in male and female mice supplemented with testosterone....”83 Of the 7 tumors reviewed by van Weerden et al., only 4 failed to grow in females. Generalization about hormonal supplementation of animals based on these 4 tumors in the absence of data seems hard to defend. The authors’ work suggests that androgen level in the host is important for androgen-dependent tumors; more data, however are needed. Unequivocally, CWR2124 and CWR2244 tumors regressed in castrated animals, and some male nude mice had levels of circulating androgen in the

range of castrated mice both in the authors’ laboratory [unpublished observation] and in a much larger study.109 Schröder and collaborators have made enormous contributions to our understanding of xenografts of prostatic tissues in nude mice. In 1976, they reported that transplantation of 19 PCas into 84 nude mice resulted in histologically confirmed survival of PCa from 17 of 19 tumors 10 to 142 days after transplantation; “continuous passaging of transplants in ‘nude’ mice was not attempted.”110 Similarly, 6 prostatic adenomas were transplanted into 26 nude mice; tissue from 5 of the 6 adenomas could be identified histologically after an average of “57.3 days (range 17 to 132 days).” In 1974, Okada and Schröder111 reported establishing, from a primary human PCa, a “reproducibly” transplantable xenograft110 and a PCa cell line which was subsequently shown not to be altered by androgen withdrawal.112 Unfortunately, this cell line was contaminated with HeLa cells and lost.113 Work from Schröder and his collaborators over the next two decades contributed significantly to our knowledge of PCa xenografts. They write in a very informative review in 1994 that “During a period of more than 10 years (1977 to 1990), almost 200 clinical specimens were transplanted in Balb/c nude mice, resulting in a very low number of permanent tumor models: the hormonedependent PC-82 model; 2 hormone-independent tumors, PC-133 and PC-135; and, more recently, the PC295 tumor.”85 Establishing these 4 xenografts from “almost 200” human PCas would appear to represent a success rate of 2%; 2 of the 4serially transplantable lines were derived from lymph node resections from patients with metastatic disease. None were developed from transurethrally resected tissue. In contrast, they developed “permanent tumor [xenograft] lines” during the next 3 years, from “6 out of 19 transplants.”85 Several of their lines, PC-295, PC-310, PC-324, PC-329, PC-339, PC-346, and PC-347, were described in detail 2 years later.83 Three of these xenografts were derived from transurethrally resected tissues; 1, from a skin metastasis; and 2, from “primary prostate tumor.” Two of the 3 transurethrally resected PCas that formed xenografts were from tumors that had “relapsed”83 after hormonal therapy. van Steenbrugge et al.85 suggest that the change in their rate of success related to their use of NMRI nude mice for the 19 most recent xenografts; they had used Balb/c nude mice in the earlier work with “almost 200” PCas. Using NMRI mice may be advantageous; it is equally possible, however, that the strain of mice previously used in Schröder’s institution presented a disadvantage. In work currently in progress in the authors’ laboratory, several strains of immunologically defective mice have been compared: 2 strains of NMRI mice imported from Europe, NMRI and HAN-NMRI; 2 strains of severe combined immunodeficiency (SCID) mice; 2 strains of nude mice; and beige mice. The NMRI nude mice and an

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unrelated strain of nude mice obtained from the genetics colony were similar in their ability to grow difficult xenografts. Surprisingly, SCID mice and beige mice offered no advantages. While the reported numbers of xenografts are too small to permit conclusions, the available data suggest that the success rate is highest when advanced PCas are transplanted. Klein et al.82 transplanted tissue from 8 patients with more advanced cancer (stages C and D disease). Two serially transplantable PCa xenografts were obtained, both from patients with stage D disease. One of these was from a metastasis; the other, from transurethrally resected tissue. All 3 of the xenografts in the authors’ laboratory originated from transurethrally resected tissue of patients with advanced disease. The PC-EW line from Hoehn et al.88 was from a metastasis. van Steenbrugge et al.85 identify the origins of the 10 xenografts started by their laboratories over two decades as follows: 4 are from metastases, 3 are from transurethrally resected prostatic tissues (2 after relapse following responses to hormonal therapy), and 3 are from “primary prostate tumor” (total prostatectomies?). That is, 6 (perhaps 7) of the 10 were from patients with advanced disease. Moreover, only 2 of the 3 from “primary prostate tumor” are described as being hormone dependent. There is a need for PCa xenografts that, like most PCas in patients, regress in response to castration of the host then subsequently relapse. There are a large number of human PCas that are androgen-sensitive, in that they respond to castration and/or pharmacologic attacks on their reactivities to androgen.114 These responses may last from a few months to a few years. The authors believe that the xenograft best exemplifying this pattern of hormonal responsiveness is the CWR22 androgen-dependent tumor and the CWR22R tumors, that is, tumors that developed in animals bearing CWR22 tumors that regressed after castration but subsequently recurred. For animals bearing 1-gram tumors, the tumors will disappear or almost disappear after castration of the host and PSA will disappear from the blood. This phenomenon, followed by relapse of the tumor in approximately half of animals 3 to 10 months after castration, has been reported.44 Data were also presented44 showing that some castrated animals could be free of measurable tumors and measurable serum PSA for more than a year and a half but experience recurrence when given sustained-release testosterone.44 Other xenografts have been suggested to be good models of hormonally responsive tumors. Concerning LNCaP, Gleave et al.115 remarked that “Following castration, PSA levels decreased rapidly up to 8-fold...no reduction in tumor volume occurred.” The LuCaP xenograft has responded to castration of the host116 by a two- to threefold decrease in circulating PSA and slight retardation of the growth rate of the tumor. van Steenbrugge et al.85 studied PC-346 and concluded that “Although not yet definite,

the PC-346 tumor might be the first established human xenograft model showing the clinically very important relapse phenomenon.” The graph they included to support this statement showed a slight shrinkage of tumor in 1 of 6 animals, with tumors in the other 5 animals showing a range of responses from no response to a slight retardation in rate of growth for a short period of time. Klein et al.82 felt “clearly...that LAPC-4 is an androgen-dependent xenograft” capable of “progression...to androgen independence” because it grows 4.3 weeks after transplantation in intact males but takes 13.4 weeks to grow in castrated males or females. It was subsequently reported117 that LAPC-4 expresses a newly discovered antigen, designated “prostate stem cell antigen,” that is reported to be a membrane antigen expressed by 88% of PCas. As described above, CWR22 tumors up to 1 gram in size routinely completely regress in castrated animals, recur in approximately half of animals, and often show > 1000-fold declines in circulating PSA after castration. Recently, Chen et al.118 described a very interesting study of the differences of several chemotherapeutic agents in CWR22, CWR22R, and CWR91 xenografts, leading them to conclude that these are “useful models for drug activity evaluation.” In 1992, Stephenson et al.119 reported that strains of PC-3 and LNCaP tumors grew more easily and metastasized more often when transplanted orthotopically in immunodeficient mice. Waters et al.120 subsequently raised serious questions about the specificity of the orthotopic location. In addition to following the lead of Stephenson et al.119 in injecting PC-3 cells orthotopically, Waters et al. injected PC-3 cells into the walls of the stomach and bladder and showed that these sites were as effective as the orthotopic site for the production of metastases. As reviewed previously,2 the current authors believe that there were weaknesses in the paper by Stephenson et al.119 and that their conclusions cannot be generalized generically to all PCa xenografts. For example, CWR22 does not grow well orthotopically. While neither LNCaP nor PC-3 metastasize frequently from the subcutaneous site, the 2272 strain of CWR22R, CWR21, and CWR91 all metastasize to lungs spontaneously from the subcutaneous site. There are many human prostate cancer cell lines that metastasize in nude mice. To the authors’ knowledge, Ware et al.121 was the first to report the metastasis of human prostate cancer cells in nude mice, a process that she characterized in detail and subsequently reviewed.122–124 Continuing studies of metastasis have been conducted on PC-3 tumors;125–127 this tumor has little in common phenotypically with most prostate cancers. With DU 145, Knox et al.128 found no differences between orthotopic and subcutaneous transplantation that affected biologic behavior, metastatic behavior, or the expression of several genes. They point out several experimental disadvantages of the orthotopic site, including urinary obstruction, increased animal mortality, and inac-

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cessibility of the site to convenient measurements of the tumors. Orthotopic transplantation has become in vogue recently. Like the work of Knox et al. with DU 145, the authors’ work80 in comparing many sites for transplanting of CWR22 found that orthotopic transplantation offered no advantages. Waters et al.’s120 demonstration that the pattern of metastasis for PC-3 is similar whether cells are transplanted orthotopically or in several other sites, and studies of other cell lines, raise important questions about the advantages of orthotopic transplantation. To date, most studies of orthotopic transplantation have been limited to work with a very limited number of tissue culture cell lines. It makes sense that, if seeking “optimal microenvironments,” many sites for transplantation would be tested. Waters et al.120 did test many sites for the transplantation of PC-3; the authors tested many sites for the transplantation of CWR22.80 Most studies that have found the orthotopic transplantation of prostate cancer tissue culture cell lines “best” have tested only two sites for transplantation. No new xenografts have resulted from the orthotopic transplantation of resected human PCas. The common usage of “androgen-independent” must be questioned. Data from work in progress in the authors’ laboratory show that some relapsed PCas that grow in female mice can be stimulated in vivo to grow faster when hosts have been treated with sustained-release androgen. There are also data in the authors’ laboratory demonstrating that cells from tumors showing no detected responses to androgens in vivo may respond to growth factors in vitro in a fashion that is augmented by the presence of androgen. Mouse sarcomas can result from transplantation of some human PCas. Specifically, CWR21, 1 of the 4 xenografts (CWR21, CWR31, CWR91, and CWR22) the authors started from 3 patients and have transplanted serially in their laboratory has been replaced by mouse sarcomas in slightly less than 10% of transplantations. These mouse sarcomas have monoclonal cytogenetic aberrations that differ from one sarcoma to the next. Often when CWR21 is not replaced by sarcomas the 15 to 20% of cells from this tumor that are stromal cells will show similar monoclonal, cytogenetic aberrations, that is, they are probably neoplastic despite the fact that they do not grow fast enough to replace the CWR21 tumors. From CWR31, CWR91, CWR22, and several CWR22R (relapsed CWR22) tumors, the authors have obtained only normal, diploid mouse stromal cells and have never observed sarcomas. Replacement of xenografted human tumors by mouse neoplasms appears to be an uncommon event for most human tumors; from the authors’ discussion of this problem with other researchers, however, it would appear that some human PCas frequently give rise to mouse sarcomas. In 1978, the replacement of a colon cancer xenograft by neoplastic cells with mouse karyotypes was reported.129

Subsequently, Beattie et al.130 reported that 2 of 50 serially passaged human tumor xenografts had been replaced by mouse sarcomas; the original human tumors were a hepatoma and an undescribed adenocarcinoma. Sparrow et al.131 later reported that 2 of 30 human tumor xenografts in their laboratory had been replaced by mouse sarcomas; these tumors were a small-cell carcinoma of the lung and an ovarian carcinoma. In 1997, Pathak et al.132 reported a subline of LNCaP and, from the same group, Ozen et al.133 reported 3 advanced human PCas that were replaced by mouse sarcomas. The authors’ laboratory has had communications from investigators who had been working with PC-82 but were requesting CWR22 xenografts since as many as half of their transplantations of PC-82 had been replaced by sarcomas. The authors have had first-hand reports of other PCas causing the same problems. From the literature, conversations with others, and the authors’ experience in their own laboratory, it would appear that there is a specific subgroup of human PCas that are susceptible to being replaced by mouse sarcomas. The authors have never encountered this phenomenon in studies of CWR31, CWR91, CWR22, or any of the CWR22R lines. At least one other group carrying 7 human PCa xenografts has found that only a specific minority of tumors shows this phenomenon. To date, the mechanisms are unclear. Human Prostate Cancer Tissue Culture Cell Lines As the authors134 discussed in a review of methods for obtaining cell suspensions from solid tissues, the first step for working with cell suspensions is to evaluate different means of obtaining cells in suspension in a viable, functional form. If the cells are to be representative of the tissues from which they are obtained, one would like to know what proportions of the different kinds of cells available in the tissue were obtained in the suspensions of cells. In 1976, Stone et al.135 described the use of collagenase to obtain cells in suspension for culturing human prostatic tissues. Yields, that is, cells per gram of tissue, were not given. At approximately the same time, the authors’ laboratory compared physical disaggregation, collagenase, Pronase, and trypsin for the dissociation of benign and malignant prostatic tissues and found that collagenase gave the lowest yield of viable cells, by a wide margin.136,137 Peehl,138 in a review of prostatic epithelial cultures, states that she has described the “most comprehensive methodologies for the procurement and culture of adult human prostatic epithelial cells from normal, benign prostatic hyperplasia (BPH) and malignant tissues....” She advocates using collagenase and has never given a quantitative description of the number of cells obtained per gram of tissue with this approach. While Peehl may well be correct in stating that her descriptions have been the “most comprehensive” and that she has worked for over 15 years at Stanford, a major prostate

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surgery center, with an excellent availability of human prostatic tissues,139,140 the question remains: are these not only the most comprehensively described but the most effective methods of the culturing of prostatic tissues? As reviewed below, Peehl has followed the lead of others in recent years in transforming prostate cells with a variety of vectors. In 15 years, however, her methods for culturing PCas and benign prostatic tissues in the absence of vectors has not resulted in a single cell line. The first of the PCa cell lines that are available today was described by a group at Duke University in 1977.141,142 This line was named DU 145 and was shown to grow both as a tissue culture line and a xenograft. In 1978 and subsequently, Kaighn and collaborators143,144 described the second PCa cell line, PC-3. These lines, and putative PCa cell lines that were subsequently lost, were reviewed in 1980.145 These two lines and LNCaP, a line described in 1980 and subsequently by Horoszewicz et al.,146,147 have been the basis for the overwhelming majority of work with PCa cell lines in the past two decades. If we exclude cell lines that have resulted from immortalization of prostate cells in tissue culture with various vectors, which to the authors’ knowledge is not related to any process that occurs in patients, DU 145, PC-3, and LNCaP are three of the four PCa cell lines that both (1) were derived from human tissues not altered by the introduction of foreign genes, and (2) are currently available from the American Type Culture Collection. The fourth, NCI-H660, is a neuroendocrine tumor that, according to the American Type Culture Collection, was established from metastatic tumor that was originally reported to be an extrapulmonary small-cell carcinoma of the lung.148 Recently, James Jacobberger’s laboratory84 has developed a cell line from a CWR22R strain. To our knowledge, this new CWR22R culture line, which Dr. Jacobberger makes available to anyone requesting it, and LNCaP are the only prostate cancer cell lines that make PSA, express androgen receptors, and respond to androgen to some degree. Having noted that most of the published work with PCa cell lines has been carried out with three cell lines, it should be pointed out that there are several other PCa cell lines, including the one from the authors’ institution (derived from the 2152 strain of CWR22R),84 that have been developed directly either from human PCas or PCa xenografts, and described with widely varying degrees of documentation. These include the ALVA lines,138,149–151 two of which, ALVA-31 and ALVA-41, show evidence of responsiveness to androgens.149–151 Other lines include EB-33,111,112 a line that became replaced by HeLa cells;113 DUPRO-1,99 JCA-1,152 ND-1,79 PC-93,153 and TSUPR1.154 As reviewed by Ellis et al.,78 LNCaP was the only one of these PCa cell lines available in 1996 that has been established to make both significant amounts of prostatespecific antigen and androgen receptors. The new line

from the Jacobberger laboratory84 from the relapsed CWR22R also makes both PSA and androgen receptors. In 1989, Kaighn et al.,155 the investigator in whose laboratory the PC-3 cell line was developed, reported the transformation of human neonatal prostatic epithelial cells by strontium phosphate transfection with a plasmid containing SV40 early-region genes. This was the first report of the transformation of human prostatic epithelial cells by the introduction of foreign genes into prostate cells. Numerous investigators have followed Kaighn et al.’s lead and developed a large and increasing number of PCa cell lines by the introduction of foreign or altered genetic material into cells.156–166 These lines have been used extensively in tissue culture and as xenografts; their relevance to naturally occurring PCa needs investigating.

Nonhuman Animal Models Animal models of PCa have been used widely and have influenced treatment of human prostatic diseases. In presenting their studies of the effects of castration on PCa and benign prostates both in man and dogs, Huggins et al.167–169 reviewed 19th and early-20th century studies in rodents and dogs in which the effect of castration on the prostate had been investigated. Huggin et al.’s work with man clearly indicated that androgens affect the behavior of both benign and malignant prostates in man. There has been extensive investigation of animal models since the work of Huggins et al., some relatively unique.170–172 Canine Model In 1916, Goodpasture and Wislocki173 reported that autopsies performed on 15 “very old” mongrel dogs showed that their prostates were “two or three times the normal size” and that 8 of 15 of the prostates contained “tumors” that were not further described. Later, Huggins and Clark167 described the functions of hyperplastic prostates in dogs. In 1968, Leav and Ling174 reviewed autopsies of 20 dogs that had died from PCa. They found that the cancers were found in older dogs, mean age of 10.1 years, and that the cancers commonly metastasized to the lung, urinary bladder, bone, mesentery, rectum, and pelvic muscle. Interestingly, in stark contrast to humans, PCa in 3 of the 10 dogs metastasized to their hearts. Leav and Ling174 cited a large number of papers reporting that PCa had not been found to be a common cancer in dogs at that time. Orgad et al.175 reported a detailed histochemical characterization of canine prostatic tissues, including 18 PCas with a variety of lectins. Canine PCa shared some features in common with PCa in man.176 More recently, Waters et al.177 reviewed the ages at death of 686 dogs that had died of PCa and concluded that the development of PCas in dogs is related to age. They have also described prostatic intraepithelial neopla-

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sia in dogs with many similarities to prostatic intraepithelial neoplasia in man.178,179 Of particular interest, elderly dogs with PCa have a high incidence of prostatic intraepithelial neoplasia.178 Rodents Rodents have been used to study carcinogenesis in the prostate for many years.180,181 In a very interesting review of tumors in experimental animals (primarily rodents), Bosland182 stated that “spontaneously occurring prostate tumors are rare in most species” except in the dog, the “ACI/SegHapBR (or ACI/Seg)” rat, and man. Following the earlier work of Shain et al.,183 the lesions in these rats are described in great detail by Ward et al.184 They report that carcinomas occur in 35 to 40% of this strain of rat by the age of 33 months; they also note, however, that “the majority of human tumors are morphologically different.”184 In fact, the majority of human tumors diagnosed clinically are different in many other ways. These very careful investigators184 studied 201 rats and did not observe a single metastasis. While these tumors may be called “cancer,” this model seems very marginal as a model of human PCas. There is a very large body of literature addressing the use of rodents as models for prostate carcinogenesis.185 Unlike many organs (colon, liver, etc.), rodent prostates are quite different from human prostates grossly, histologically, biochemically, and functionally.186 Without reviewing this area comprehensively, it should be noted that PCas have been produced in rodents by radiation,187–189 chemical carcinogens,190–193 and hormonal manipulations.194 Each of these approaches has been reviewed in detail recently.182 There are no models of autochthonous PCa in rodents, excluding transgenic animals, that metastasize spontaneously to bone, the most common organ system to which PCa metastasizes in humans.195,196 In evaluating the literature related to prostate carcinogenesis in the rodent, it is important to ascertain that investigators identified the cancers in stages sufficiently early to permit distinction between carcinomas of the seminal vesicles and PCas, that is, before carcinomas envelope and become confluent with both the seminal vesicles and prostate. One of the authors (TG Pretlow) has performed or supervised over 1000 autopsies on humans and has attended pathology conferences for over three decades but has not seen a single cancer of the seminal vesicle in man. There is only one study197 in the literature prior to the current decade describing cancer of the seminal vesicles in rodents. It appears that many investigators assumed large adenocarcinomas in the lower pelves of rats, like most adenocarcinomas in the lower pelves of man, were likely to be prostatic in origin. In 1994, two laboratories disproved this assumption. Cohen et al.198 examined in detail a previously used model of PCa in the Lobund-Wistar rat. After treating these animals with

N-methyl-N-nitrosourea and testosterone, they reported that “Seventy-three percent of the tumors involved only the seminal vesicle, 22% involved other portions of the prostatic complex as well as the seminal vesicle, and 5% were located in the coagulating gland (anterior prostate).”198 In that same year and subsequently, investigators from Michael Sporn’s laboratory199 reported that PCas were slightly more frequent than carcinomas of the seminal vesicles in the Lobund-Wistar rat treated with a regimen similar to that used by Cohen et al. The same regimen had been used in many earlier publications from other laboratories, with PCas as the only described malignant products. While it is clear that PCas do occur spontaneously in some strains of rats200 (as reported earlier201–203), it is clear that many of the earlier studies that did not adequately examine the seminal vesicles and prostates histopathologically did not detect the fact that a considerable proportion of the tumors termed “prostate cancer” in rodent models are likely to have originated in the seminal vesicles. While different strains of rodents differ with respect to the relative frequencies of carcinomas of the prostate and seminal vesicles, most rodents studied develop both kinds of tumors in the appropriate experimental environments.170–172,199,204,205 Rodent models have recently been reviewed in a workshop.170 The summary statement for the symposium of which this workshop was a part stated: “Rodent models are easy and economical to use....”206 While these models have been biologically interesting, the critical, unanswered question is: since the work of Huggins and Clark167 with dogs in 1940, have we learned anything unique that is significantly relevant to human PCa from the study of PCas originating in rodents? The Dunning Tumor The Dunning tumor, often called the “Dunning prostate cancer,” was first described by Dunning207 in 1963, and was perhaps best described by Aumuller’s group in 1992.208 The original tumor “occupied a large part of the lower abdominal cavity...[and]...measured 5.0 × 4.5 × 4.0 cm.”207 The gross pathology was never seen by a pathologist; without any allusion to specific data, however, it was “histologically and histochemically” thought to have originated from the prostate of the rat. In the absence of specific data, it is difficult to imagine what kinds of evidence would allow this conclusion about a 5.0-cm tumor in the pelvis of a rat. Surprisingly for a PCa, “heart blood...showed an acid phosphatase level of 9.5, which was not as high as has been observed (14.4, 16.2, and 20.9) in some of the rats bearing the transplanted squamous cell carcinomas of the prostate.”207 This tumor was declared an outstanding model of PCa by the National Prostate Cancer Project of the National Cancer Institute in the 1970s, which announced subsequently over several years that these “hormone-responsive prostatic adenocarcinomas are available” to investigators.209 The Dunning

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tumor continues to be used very widely without any convincing evidence that it was a PCa. In 1991, Aumuller et al.210 carried out immunohistochemical investigations refuting previous claims that basal cells might be found in the Dunning tumor. They also reported finding myoepithelial cells, cells that are foreign to rodent prostates. In 1992, Goebel et al.,208 in collaboration with Aumuller, reported new data and summarized several earlier papers from the Aumuller group that showed that the Dunning tumor has much more in common chemically with breast cancer than with PCa. It manufactures “milk fat globule membrane proteins, lactoperoxidase, and lactalbumin” while failing to manufacture proteins normally found in rat prostates.208 Transgenic Models The status of transgenic mice in the investigation of PCa was recently reviewed and will not be described in detail here.206,211 The authors would agree with Waters et al. and Green et al.206,211 that justified “concerns persist regarding the validation and correlation of these models with human prostate cancer.” On the other hand, the transgenic models represent a qualitatively different approach from the traditional approaches to the study of growth regulation in rodent PCas, and enjoy a high degree of interest because of this genetically and biologically different approach. In 1994, Maroulakou et al.212 reported observing both prostatic hyperplasia and PCa in transgenic mice. Since then, there have been several different heterologous genes used to develop transgenic models of PCa.213–218 This work was summarized in the report of a recent workshop.211

Summary There are many different ways of approaching the investigation of prostate cancer, a cancer which has increased markedly over the past three decades both in frequency of diagnosis and as a cause of death in men in the western world. Analyzing resected human tissues offers a unique opportunity to directly investigate human prostate cancer. Obtaining and preparing human prostatic tissue, however, is difficult because the chemical integrity of the tissue degrades rapidly if it is not promptly obtained and cooled in the operating room. Also, the tumors are often heavily mixed with benign tissue, making careful histopathologic control essential if data obtained from human prostatic tissues is to be interpreted accurately. The slow rates of growth and very small proportions of cells in the proliferative fractions in most human prostate cancers constitutes a very significant difference between most laboratory models and prostate cancers as they occur in humans. As discussed above, Sakr and colleagues10 have shown that prostate cancers can be found in relatively young men (for example, 8% of men in their twenties), and that many decades pass between the time when cancer can be detected in prostates and its clinical appearance. Except for resected human tissue, none of

the commonly employed models for the study of human prostatic carcinomas take decades to grow significantly. Tissue culture lines and xenografts represent two other approaches. There are limited numbers of cell culture lines established from human prostate cancers, and the overwhelming majority of these fail to make PSA, the most abundant protein product of human prostates. Many of the culture lines also fail to make androgen receptors. Much less than 1% of the prostate cancers that have been tested in culture have formed cell lines. In contrast, the majority of xenografts of prostate cancers make both PSA and androgen receptors. Approximately 5 to 10% of prostate cancers will grow as xenografts, given the knowledge that is currently available. Historically, much less effort has been devoted to establishing these xenografts than to tissue culture lines, and there is reason to speculate that improved technology in this area may facilitate a higher rate of success than the current 5 to 10%. The availability of serially transplantable xenografts makes a large amount of prostate cancer tissue available repeatedly over long periods of time. In some cases, this has aided the development of tissue culture lines from prostate cancer xenografts. Both rodents and dogs have been studied extensively as models for prostate cancer. Prostate cancers do not naturally occur in most rodents; there are some strains, however, from which some animals will develop prostate cancer when quite old. The literature in this area is a bit confusing because most of the work prior to the last decade was done under the assumption that most cancers in the pelves of rodents were prostate cancers. Many more recent studies have shown that many of the tumors previously viewed as prostate cancers were, in fact, cancers of seminal vesicles. Human prostates and rodent prostates are quite different with respect to their gross anatomy, histology, biochemistry, and function. An enormous amount of work has been done with carcinomas in rodents. It can only be speculated the extent to which carcinomas of the prostate or seminal vesicle in rodents will ever reveal important information about human prostatic carcinomas. The most recently developed models of prostate cancer are the transgenic models. In these models, exogenous genetic material is introduced into prostatic cells and facilitates their growth as cell lines, some of which are malignant. These models may be very useful for investigating biologic mechanisms of many kinds; the extent to which the products of such investigations will reveal anything important about human prostate cancers remains to be determined.

Acknowledgment This work was supported by grants CA57179 from the National Cancer Institute and DK51347 from the National Institute of Diabetes and Kidney and Digestive Diseases. The authors thank Dr. M. Edward Kaighn, Dr. Raymond B. Nagle, and Dr. Mark E. Stearns for their helpful comments and criticism.

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CHAPTER 17

DIAGNOSIS OF PROSTATE CANCER L. ANDREW ESKEW, MD; DAVID L. MCCULLOUGH, MD Historic Perspective

However, cancerous lesions can show up as hyperechoic, hypoechoic, or isoechoic lesions.4 Transrectal ultrasonography (TRUS) can show asymmetry of the gland, which may prompt a biopsy.

Diagnosing prostate cancer requires obtaining cancerous tissue from the prostate gland. The evolution of this now simple office-based procedure is interesting. Prostate biopsy began as an open transperineal aspiration of the prostate, originated by Ferguson around 1930.1 This method was refined until a prostate tissue recovery rate of 86% was attained. Over time, the open transperineal aspiration approach was abandoned for the transrectal aspiration approach. Transurethral resection of prostate was used to diagnose cancer of the prostate but proved to be less accurate than other forms of biopsy. With the advent of core biopsy needles, transperineal and transrectal digitally directed biopsies became a popular means of obtaining prostate tissue for diagnosis. Core biopsy needles also allowed for a histologic diagnosis as opposed to a cytologic diagnosis. The advent of transrectal ultrasound has revolutionized prostate biopsy and has greatly increased the diagnostic accuracy of this screening procedure. With over 200,000 cases of prostate cancer diagnosed every year in the United States and thousands of other men undergoing negative biopsies, the magnitude of this procedure can be appreciated.

Presence of High-Grade Prostatic Intraepithelial Neoplasia on Prior Biopsy While low-grade prostatic intraepithelial neoplasia (PIN) is not considered a precancerous lesion, high-grade PIN is considered a precancerous lesion of the prostate; approximately 35 to 38% of high-grade PIN eventually converts to prostate cancer.5,6 The current recommendation is to rebiopsy the prostate at 6-month intervals after a positive diagnosis of high-grade PIN has been established. Biopsy after Curative Therapy Palpable abnormality and/or rising PSA after curative therapy for cancer (radical prostatectomy, external beam radiation, or cryotherapy) is an indication for prostate biopsy. In this setting, a positive biopsy would dictate further treatment plans based on the individual clinical situation.

Indications for Prostate Biopsy

Patient Preparation

Elevated Prostate-Specific Antigen The most common current indication for prostate biopsy is an elevated serum prostate-specific antigen (PSA) level. The serum reference range is 0.0 to 4.0 ng per mL, with a level > 4.0 ng per mL considered elevated; age-adjusted normal PSA levels, however, have been established. Oesterling et al. demonstrated an 8% increase in the number of biopsies and organ-confined cancers detected in men aged 50 years or less (normal digital rectal examination) when agespecific PSA reference ranges were used (Table 17–1).2

Informed Consent Full, informed consent should be obtained from the patient prior to prostate biopsy, including alternatives, consequences, and complications of biopsy. Bowel Preparation Patients are started on a clear liquid diet at lunch time the day before biopsy. Laxatives are given the day prior to biopsy, followed by a cleansing enema before the biopsy session. Alternatively, a formal polyethylene glycol bowel preparation can be administered on the evening prior to the biopsy. The patient is given nothing by mouth on the day of biopsy.

Abnormal Digital Rectal Examination Abnormal or suspicious digital rectal examination of the prostate is an indication for prostate biopsy. If there is a prostate nodule, focal induration of the gland, or a diffusely hard prostate gland, biopsy should be promptly carried out regardless of PSA level.

Antibiotics There is a 3-day course of quinolone antibiotic administered commencing the day before biopsy and continued through to the day after biopsy. If preprocedure assessment reveals urinary tract infection, a longer course of antibiotics would be prescribed as indicated. Patients with valvular heart disease are administered parenteral

Abnormalities Seen on Transrectal Ultrasonography Classically, the echo pattern of prostate cancer seen on transrectal ultrasound was that of hypoechoic lesions.3 154

Diagnosis of Prostate Cancer / 155

antibiotics as outlined by the American Heart Association.7 Ampicillin 2 g and gentamicin 80 mg are administered intravenously or intramuscularly 30 minutes prior to biopsy, with amoxicillin 2 g given by mouth 6 hours after biopsy. Patients with penicillin allergies are given vancomycin 1 g intravenously in place of ampicillin. Due to the longer serum half-life of vancomycin, a delayed dose is not necessary. Discontinuation of Anticoagulants or Antiplatelet Drugs Patients are taken off anticoagulants or antiplatelet drugs prior to the biopsy session, if medically possible. Patients who require warfarin sodium for mechanical heart valves or heart arrhythmias are converted to heparin prior to procedure and are maintained on heparin following biopsy until adequately anticoagulated with warfarin. Aspirin and nonsteroidal anti-inflammatory drugs should be avoided prior to biopsy. Patients who have a recent history of using these drugs should have a bleedingtime preprocedure to rule out qualitative platelet defect. To reduce bleeding complications after biopsy, the biopsy session should be postponed until the bleeding time has normalized.

Technique of Transrectal Ultrasound-Guided Needle Biopsy Transrectal ultrasonography allows accurate imaging of the prostate and accurate biopsy needle placement. Transrectal ultrasound-guided needle biopsy of the prostate is an office procedure which can be accomplished quickly, without anesthesia, and is well tolerated by patients. Patient Positioning Patients are placed in either the knee-chest lateral decubitus position or the dorsal lithotomy position for biopsy, depending on the preference of the operator. Analgesia Transrectal ultrasound-guided needle biopsy can be performed without the use of anesthesia. Parenteral or oral analgesics may be administered, depending on operator and patient preferences. Anecdotally, intrarectal topical lidocaine jelly seems to reduce discomfort associated with prostate biopsy. Patient anxiety regarding biopsy can be reduced if patients are warned prior to the biopsy needle being inserted. This prepares the patient for the noise and discomfort associated with biopsy needle firing, which often will startle an unsuspecting patient. Imaging the Prostate and Obtaining Biopsies Once the patient has been positioned for biopsy, the lubricated transrectal ultrasound probe is inserted into the rectum. The probe is inserted with the tip aimed in a direction pointing toward the patient’s umbilicus until

TABLE 17–1. Age-Specific Reference Ranges for Serum PSA Concentration, Prostatic Volume, and PSA Density Age Group (Years) Parameter

40–49

50–59

60–69

70–79

Serum PSA concentration, ng/mL Prostatic volume, mL PSA density, ng/mL-cc

0.0–2.5

0.0–3.5

0.0–4.5

0.0–6.5

13–51 0.0–0.08

15–60 0.0–0.10

17–70 0.0–0.11

20–82 0.0–0.13

Reproduced with permission from Oesterling JE, Jacobsen SJ, Chute GG, et al. Serum prostate-specific antigen in a community-based population of healthy men: establishment of age-specific reference ranges. JAMA 1993;270:860–4.

the probe tip is past the anal verge, then the probe is directed along the direction of the rectum. The prostate is imaged from the bladder neck down through the apex. The seminal vesicles and periprostatic tissue are imaged. Images are obtained in the transverse and sagittal planes. If present, contour abnormalities and abnormal or asymmetric echo patterns are noted. The volume of the prostate can be measured.8 Biopsies are then taken with ultrasound guidance to aim the biopsy needles accurately. The biopsy needle is a spring-loaded 18-gauge automatic device for singlepatient use. The needles obtain a core of prostate tissue 15 mm in length. It must be remembered that the beveled needle tip is usually 5 mm in length. The biopsy core will thus be taken 5 mm proximal to the needle tip. Core biopsy needles should be oriented so that the point of the beveled needle rather than the flat side of the bevel strikes the prostate surface initially. This will minimize deflection of the needle by the prostate, enabling more accurate core sampling (Figure 17–1). Use of a sagitally oriented transducer allows a needle guide to be projected on the ultrasound machine so that the entire course of the needle through the prostate can be observed (Figure 17–2). Once the core biopsies are obtained, they are sent in formalin for microscopic interpretation or sent fresh for frozen section if an immediate diagnosis is required. Postbiopsy Care Patients are kept on quinolone antibiotics for 48 hours after biopsy. Patients are instructed to force fluids, especially in cases where gross hematuria is encountered. Patients are encouraged to maintain a sedentary lifestyle and avoid aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) for 72 hours to minimize postbiopsy bleeding. Patients are counseled that hematuria, hematochezia, and hematospermia may occur as a result of the biopsy and should be short lived. Prolonged bleeding is reported by some patients. Patients are instructed to report prolonged bleeding, fevers, or voiding difficulty after a biopsy session. Hematospermia may occur up to a month postbiopsy.

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FIGURE 17–1. Core biopsy needles should be oriented so that the point of the beveled needle rather than the flat side of the bevel strikes the prostate surface initially. This will minimize deflection of the needle by the prostate and more accurate core sampling is accomplished. Reproduced with permission from Cooner WM, Holt W. Needle biopsy of the prostate. In: Marshall F, editor. Textbook of operative urology. Philadelphia: WB Saunders; 1996.

Methods of Biopsy Sextant Prostate Biopsy Introduced by Hodge et al. in 1989, the sextant method of prostate biopsy is worldwide the “gold standard” method of prostate biopsy.9 As originally described, the sextant method of biopsy takes six biopsies of the prostate. The biopsies are obtained in the midlobe parasagittal plane at the apex, middle, and base of the prostate bilaterally (Figure 17–3). More recently, the sextant method of prostate biopsy has changed as originally described. The biopsies have been moved laterally instead of being located parasagitally.10

FIGURE 17–2. Transrectal ultrasound in sagittal plane shows angle of entry (arrows) of biopsy needles, allowing the entire course of the needle through the prostate to be observed. Reproduced with permission from Eskew LA, Bare RL, McCullough DL. Systematic fiveregion biopsy is superior to sextant method for diagnosing carcinoma of the prostate. J Urol 1997;157:199–203.

Five-Region Prostate Biopsy Concern arose that the standard sextant method of biopsy may not provide an adequate biopsy sample. Thus, a prospective study was performed comparing the sextant method of biopsy with a more extensive method called the five-region prostate biopsy.11 Using the five-region method, sextant biopsies as originally described are taken from the prostate gland. In addition, biopsies are taken from the far lateral aspects of the gland on each side and from the middle. There are a minimum of 13 biopsies routinely taken (Figure 17–4). By using the five-region biopsy, the diagnostic yield of prostate is increased by 35% over the standard sextant biopsy. In glands measuring over 50-cc volume, at least one additional core from each region is generally taken (total 18 cores). Prostate cancer diagnosed using the five-region technique has been shown to be significant in grade, volume, and ploidy, as has cancer diagnosed by the sextant technique.12 Other Forms of Biopsy Chen et al. analyzed prostate biopsy using a computergenerated biopsy model.13 Sectioned cancerous prostate specimens with tumor areas highlighted were digitized, and computer-simulated biopsy sessions were performed for 180 prostates. In this model, a biopsy scheme was reported which diagnosed cancers 96% of the time when cancer volume was > 0.5 cc.

Accuracy of Prostate Biopsy As with any screening test, prostate biopsy is not 100% accurate in identifying carcinoma when it is present. Several studies have investigated this phenomenon. Fleshner et al. repeated TRUS-guided needle biopsy of the prostate in 130 men and found 30% of these men to have cancer on repeat biopsy.14 Correlating risk factors including age, pathologic result of initial biopsy, interbiopsy interval, PSA, PSA density, and other factors, they concluded that baseline risk for positive repeat biopsy even in the lowest risk patients (PSA < 10 ng/mL) was sufficiently high to justify repeat biopsy in patients who continue to meet the criteria for biopsy in follow-up. Levin et al. performed a study in which patients underwent sextant prostate biopsy followed by a second sextant prostate biopsy at the same setting. They found a 30% discrepancy in biopsy results from the initial biopsy compared to final biopsy, indicating a potential 30% false-negative rate of sextant prostate biopsy.15 Authors often have reported significant rates of cancer detection after initial negative biopsies. Keetch et al. reported a 19% positive rebiopsy rate in a cohort with persistently elevated PSA.16 Ellis and Brawer reported a 20% positive rebiopsy rate in a cohort with negative initial TRUS-guided biopsy.17 Svetec et al. performed sextant biopsy of 90 prostates ex vivo immediately after these glands had been removed for clinically localized carci-

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der catheter insertion and continuous bladder irrigation until the bleeding subsides. Platelet count, bleeding time, and coagulation studies may be obtained to rule out medical causes of excessive hematuria after prostate biopsy. Hematochezia is encountered infrequently after prostate biopsy and is usually self-limited. Excessive or prolonged bleeding may be treated by first packing the rectum with lubricated gauze packing material. This usually stops the bleeding. If bleeding continues, anoscopy or rigid sigmoidoscopy is performed to localize the source of the bleeding. Once the bleeding point is localized on the anterior rectal wall, an absorbable suture may be placed to stop the bleeding. Patients with hemorrhoids or portal hypertension may be at increased risk for rectal bleeding after prostate biopsy. If an anterior rectal-wall hematoma develops after biopsy, expectant management with stool softeners and low-residue diet can be pursued.

FIGURE 17–3. Position of six biopsies in (A) transverse and (B) sagittal views. Biopsies are taken in midlobe parasagittal plane at apex, middle, and base of prostate bilaterally. TZ = transition zone; PZ = peripheral zone; CZ = central zone. Reproduced with permission from Terris MK, McNeal JE, Stamey TA. Detection of clinically significant prostate cancer by transrectal ultrasound-guided systematic biopsies. J Urol 1992;148:829–32.

noma of the prostate. All glands had pathologically confirmed adenocarcinoma. Using the sextant biopsy on the prostatectomy specimens, however, they found a 45.6% false-negative biopsy rate.18 Needless to say, a false-negative rate of sextant biopsy exists and most likely ranges from 20 to 30%, based on the above studies. These data suggest that some carcinomas exist at the time of intial biopsy but are undetected possibly due to inadequate sampling or operator-dependent error. The false-negative rate could possibly be reduced by a more thorough biopsy session. The optimal number of biopsies to take during a biopsy session is not known.

Complications of Prostate Biopsy Reported complications or consequences of prostate biopsies include hematuria, hematochezia, hematospermia, pain, urinary retention, prostate abscesses, urinary tract infections, tumor tracking of biopsy site, and anterior rectal-wall hematomas. Hematuria after prostate biopsy is usually self-limited and transient. Serious problems with hematuria are more likely to be encountered in patients who have a bleeding dyscrasia, or in patients who are on medication which would inhibit normal blood clotting mechanisms. Hematuria with clots after biopsy should be managed with blad-

FIGURE 17–4. Figure depicting cross-sectional and posterior view of prostate showing peripheral zone (PZ) and areas of biopsy (circles). Shaded areas represent additional regions of biopsy using 5-region method. Reproduced with permission from Eskew LA, Woodruff RD, Bare RL, McCullough DL. Prostate cancer diagnosed by the five-region biopsy method is significant disease. J Urol 1998;160:794–6.

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Hematospermia is common after prostate biopsy and is self-limited but may persist for up to 30 days. Patients should be warned of this phenomenon prior to biopsy to prepare them for it. It has been the authors’ experience that patients with significant obstructive voiding symptoms prior to prostate biopsy may develop transient urinary retention after a biopsy session. This may be treated conservatively with a few days of catheter drainage and oral α-blocking agents. If the prostate biopsy is negative for cancer, the patient with urinary retention after biopsy may declare himself as a candidate for long-term medical treatment for benign prostatic hyperplasia or as a candidate for surgery to relieve bladder obstruction, should medical treatments fail. Patients with a positive biopsy for prostate cancer who are not candidates for radical prostatectomy may require androgen ablation with or without other surgical treatments to alleviate bladder outlet obstruction. Infectious complications after prostate biopsy can be minimized with careful prebiopsy preparation, including prophylactic antibiotics and bowel preparation or cleaning enemas. Gustafsson et al. report a urinary tract infection rate of 62% when prophylactic antibiotics were not used in patients undergoing transrectal prostate biopsy. One-half of these infections required hospitalization and parenteral antibiotics.19 Thompson et al. reported previously a 100% rate of bacteremia and an 87% rate of urinary tract infection in a cohort of patients biopsied without antibiotic prophylaxis.20 Besides preparing the patient for the biopsy to prevent infection, the equipment used for biopsy should be one-time use equipment as much as possible. Keizur et al. report iatrogenic urinary tract infection with Pseudomonas species in 8.2% of prepared patients undergoing transrectal biopsy. The source of the infection was found to be ultrasound transmission gel colonized with Pseudomonas species.21 The authors have had no serious septic events with a preoperative bowel cleansing (polyethylene glycol) and 3 days (6 doses) of a quinolone antibiotic.

Summary Transrectal ultrasound-guided needle biopsy of the prostate has become the gold standard method of obtaining prostate tissue to rule out malignancy. This is an office-based procedure which is readily available and is well tolerated by patients. The false-negative biopsy rate which exists seems to be inversely related to the number of core biopsies taken at the time of biopsy. Patient complications are rare and usually minor and self limited. Infectious complications may be minimized by careful patient preparation.

References 1. Ferguson RS. Prostatic neoplasms: their diagnosis by needle puncture and aspiration. Am J Surg 1930;9:507–11.

2. Oesterling JE, Jacobsen SJ, Chute GG, et al. Serum prostate-specific antigen in a community-based population of healthy men: establishment of age-specific reference ranges. JAMA 1993;270:860–4. 3. Lee F, Gray JM, McLeary RD, et al. Prostatic evaluation by transrectal sonography: criteria for diagnosis of early carcinoma. Radiology 1986;158:91. 4. Rifkin MD, McGlynn ET, Choi H. Echogenicity of prostate cancer correlated with histologic grade and stromal fibrosis: endorectal ultrasound studies. Radiology 1989;170:549–52. 5. Davidson D, Bostwick DG, Qian J, et al. Prostatic intraepithelial neoplasia is a risk factor for adenocarconoma: predictive accuracy in needle biopsies. J Urol 1995;154: 1295–9. 6. Bemer A, Danielsen HE, Pettersen EO, et al. DNA distribution in the prostate. Normal gland, benign and premalignant lesions, and subsequent adenocarcinomas. Anal Quant Cytol Histol 1993;15:247–52. 7. Danjani AS, Bisno AL, Ching KJ, et al. Prevention of bacterial endocarditis: recommendations by the American Heart Association. JAMA 1990;264:2919. 8. Terris MK, Stamey TA. Determination of prostate volume by transrectal ultrasound. J Urol 1991;145:984–7. 9. Hodge KK, McNeal JE, Terris MK, et al. Random systematic versus directed ultrasound-guided transrectal core biopsies of the prostate. J Urol 1989;142:71. 10. Stamey TA. Making the most of six systematic sextant biopsies. Urology 1995;45:2. 11. Eskew LA, Bare RL, McCullough DL. Systematic five-region biopsy is superior to sextant method for diagnosing carcinoma of the prostate. J Urol 1997;157:199–203. 12. Eskew LA, Woodruff RD, Bare RL, McCullough DL. Prostate cancer diagnosed by the five-region biopsy method is significant disease. J Urol 1998;160:794–6. 13. Chen ME, Troncoso P, Johnston DA, et al. Optimization of prostate biopsy strategy using computer-based analysis. J Urol 1997;158:2168. 14. Fleshner NE, O’Sullivan M, Fair WR. Prevalence and predictors of a positive repeat transrectal ultrasoundguided needle biopsy of the prostate. J Urol 1997;158: 505. 15. Levin MA, Ittman M, Melamed J, et al. Two consecutive sets of transrectal ultrasound-guided sextant biopsies of the prostate for the detection of prostate cancer. J Urol 1998;159:471. 16. Keetch DW, Catalona WJ, Smith DS. Serial prostatic biopsies in men with persistently elevated serum prostate antigen values. J Urol 1994;151:1571. 17. Ellis WJ, Brawer MK. Repeat prostate needle biopsy: who needs it? J Urol 1995;153:1946. 18. Svetec D, McCabe K, Peretsman S, et al. Prostate rebiopsy is a poor surrogate of treatment efficacy in localized prostate cancer. J Urol 1998;159:1606. 19. Gustafsson O, Norming U, Nyman CR. Complications following combined transrectal aspiration and core biopsy of prostate. Scand J Urol Nephrol 1990;24:249. 20. Thompson PM, Pryor JP, Williams JP, et al. The problem of infection after prostate biopsy: the case for the transperineal approach. Br J Urol 1982;54:736. 21. Keizur JJ, Lavin B, Leidich RB. Iatrogenic urinary tract infection with Pseudomonas cepacia after transrectal ultrasound-guided needle biopsy of the prostate. J Urol 1993;149:523.

CHAPTER 18

STAGING OF PROSTATE CANCER RASHMI I. PATEL, MD; MARTIN I. RESNICK, MD As medical technology and diagnostic imaging techniques continue to advance and provide for increased longevity, a larger portion of the male population will be diagnosed with prostate carcinoma. An accurate assessment of the stage of prostate cancer (PCa) prior to definitive therapy represents a clinical challenge to the physician treating PCa. Ideally, staging should reliably reflect the natural history of cancer, describe the burden and extent of tumor at the time of diagnosis, and stratify patients into prognostically distinct groups. Pathologic staging is more useful than clinical staging for predicting prognosis because tumor volume and grade, surgical margin status, extent of extracapsular extension (ECE), and involvement of seminal vesicles and lymph nodes can be determined.1 Preoperative (clinical) stage should predict postoperative (pathologic) stage with a reasonable degree of accuracy, particularly when considering nonsurgical treatments such as radiation therapy that do not yield tissue for pathologic examination. From a practical standpoint, clinical stage is performed to distinguish those patients who would likely benefit from local ablative therapy, that is, radical prostatectomy, from those with more advanced cancer who are less likely to benefit from this type of treatment. Further, accurate tumor staging is essential to identify risk factors for ECE prior to radical surgery. It is well known that ECE often leads to positive surgical margins. This is clinically important in that the incidence of ECE tends to increase with advancing clinical stage and histologic tumor grade. For example, Van Den Ouden et al. showed that the incidence of positive surgical margins ranged from 15% (T1 disease) to 47% (T3 disease). High-grade lesions were associated with greater frequency of residual disease than were lowgrade lesions in radical prostatectomy specimens.2 Since the accurate assessment of clinical stage plays an integral role in choosing definitive treatment options and improving treatment outcomes, many new approaches have been developed to more accurately predict pathologic stage. Digital rectal examination (DRE), routine prostate-specific antigen (PSA) screening, and transrectal ultrasonography (TRUS) have been the traditional mainstays of detection, diagnosis, and noninvasive staging over the years. Similarly, both pelvic lymph node dissection and radionuclide bone scan play an important role in staging of many patients. New imaging modalities such as magnetic resonance imaging (MRI), positron emission

tomography (PET), and radioimmunoimaging are being evaluated as potential means of detecting and staging patients with asymptomatic disease. This chapter reviews different techniques and imaging modalities currently available for the preoperative staging of patients with prostate adenocarcinoma.

Current Staging Systems Several staging classification systems have been designed to categorize PCa with respect to location, size, degree of ECE, and presence or absence of metastatic disease. Whitmore developed one of the first staging classification systems, in 1956.3 This system was based on the results of DRE and radiographic studies and categorized the disease as: stage A, the presence of subclinical disease; stage B, organ-confined disease without evidence of metastases; stage C, local extraprostatic disease without metastases; and stage D, evidence of metastatic disease. This system was the most commonly used staging system in the United States until its modification by Jewett in 1975.4 Jewett subclassified stage A disease based on whether the disease was focal (A1) versus diffuse (A2) and on the histology of the cancer. Stage B disease was subclassified as B1, which identified focal unilateral involvement of the prostate (B1 nodule; “Jewett Nodule”) and B2, which diffusely involved both lobes, without capsular involvement.1 Stage C disease minimally involved the capsule (C1) as well as more extensive ECE-producing bladder outlet or ureteral obstruction (C2). Stage D implied metastatic disease. The tumor, node, metastasis (TNM) system developed in 1975 by the American Joint Committee for Staging and End Results Reporting (AJC), further subclassified PCa based on the amount of tumor burden from needle core biopsies (T1), palpable size of the lesion (T2), pathologic findings of capsular involvement (T3), as well as lymph node metastases (N4).5 In 1988, Whitmore et al., acting as the Organ Systems Coordinating Center (OSCC) of the National Institutes of Health, proposed a modified TNM staging system that would attempt to unify the clinical staging systems for PCa.6 Although this system did not achieve widespread acceptance, it did incorporate results from tumors detected by TRUS, serum PSA, and DRE. It also allowed for flexibility and adaptability to recent developments in evaluating patients with PCa by using MRI as well as radioimmunoimaging. 159

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Finally, the International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) proposed in 1992 another unifying revision of the TNM system for staging PCa.7,8 First, a new category (T1c) was introduced to recognize nonpalpable, noninvasive tumors identified by random biopsy after detection of an elevated serum PSA level. Second, T2 palpably organconfined cancers were subdivided into three groups based on relative involvement of the prostate rather than simply absolute size determined by DRE. Third, cancers with ECE (T3) were subdivided into three groups based on laterality and seminal vesicle invasion. Recently, von Eschenbach et al. compared the utility and prognostic power of this revised TNM system to that of the Whitmore-Jewett system.9 This study conclusively proved that the UICC/AJCC system allows for designation of a greater number of meaningful tumor categories that are prognostically superior to the Whitmore-Jewett system. The UICC/AJCC system is therefore now considered the international standard; it is the most applicable staging system for PCa, and it has become the staging system most frequently used today. The AJCC system was updated in 1997, dividing both stage T2 and T3 disease into two stages: T2a and T2b (one or both lobes involved with organ-confined disease) and T3a and T3b (extracapsular extension and seminal vesical invasion) (Table 18–1).10

Limitations of Current Staging Systems There are a number of clinical factors which limit current PCa staging systems, including: (1) preoperative understaging with DRE; (2) preoperative understaging with transurethral resection of the prostate (TURP); (3) limitations of various imaging modalities to evaluate presence and extent of tumor; and (4) variability in pathologic staging.1 The DRE is one of the traditional methods used for staging PCa. It relies on palpation of the prostate to differentiate confined from nonconfined disease, unilateral from bilateral disease, and small from large tumors. Studies indicate, however, that detection rates based solely on DRE rarely exceed 2.2%; the accuracy of clinical staging based on DRE alone is approximately 50% in men with palpable disease.11–13 Further, Bostwick et al. identified clinical understaging in 59% and clinical overstaging in 5% of 311 cases of prostatectomy specimens.1 Also, DRE lacks specificity, and studies have demonstrated false-negative rates as high as 36% for lesions thought to be suspicious based soley on palpation.14 In a recent multicenter study by Flanigan et al. evaluating patients with PSA > 4 ng per mL or with a suspicious DRE in a patient who had undergone TRUS-guided biopsies, 74% of the biopsies containing cancer were not considered suspicious based on DRE alone.15 While traditionally DRE has been the mainstay of PCa detection, studies have proven conclusively that DRE alone lacks

sensitivity and specificity and is not a reliable sole means of evaluating a patient at risk for PCa. Clinical understaging with TURP is a well-recognized dilemma in early carcinoma of the prostate. Since the majority of tumors arise in the periphery of the prostate gland, TURP is not used as a staging modality in over 70% of early cancers. The sensitivity of TURP in detecting stage T1(A) cancers is only 28%, and up to 60% of patients with stage T1a(A1) tumors who have repeat TURP have residual tumor, with 26% of these being upstaged.1 Walsh et al. found that 26% of the patients studied with clinical T1b(A2) stage tumors had higher final pathologic stages and that they all had residual tumor.16 These are only a few studies demonstrating that examining TURP specimens is not a reliable method of PCa staging. Imaging modalities that could accurately access volume and extent of ECE would be invaluable to preoperative staging. However, as is discussed later in this chapter, even with recent advances in imaging technology (MRI, PET, radioimmunoimaging), no single imaging modality can provide all the necessary information needed to reliably and accurately predict clinical stage. The variability of pathologic staging also limits current PCa staging systems. For instance, the processing of TURP specimens is not standardized, and numerous methods have been developed to measure tumor volume and define substages T1a(A1) and T1b(A2). The pathologist’s “eyeball” estimation of tumor volume includes TURP chip counting (fewer or more than three chips involved), tumor area ratio estimation (percentage of specimen area), TURP chip ratio (ratio of benign-tomalignant chips), and cancer foci counting (fewer or more than three microscopic foci of cancer).1 Pathologic understaging can also be caused by variability in the processing of radical prostatectomy specimens. Haggman et al. examined the results of limited sectioning of specimens (sections through palpable tumor plus two random sections of apex and base) versus complete sectioning (whole organ sections).17 They found a significant increase in positive surgical margins (12% versus 59%, respectively) and pathologic stage with the complete sectioning approach. Currently, there does not seem to be a standardized approach for processing prostatic pathologic specimens. Further, standardized terminology to describe tumor invasion is lacking. For instance, localized ECE has been variously referred to as capsular “invasion,” “penetration,” or “perforation.” There are clearly limitations to the current staging systems, as has been shown by recent data describing a significant tendency toward tumor understaging and a limited ability to define the true extent of the disease. For example, a review of 17 recent studies comparing clinical and pathologic staging data of radical prostatectomy specimens demonstrated an overall clinical staging accuracy of 52.4%.18 This underscores the need for refinement in tech-

Staging of Prostate Cancer / 161 TABLE 18–1. Comparison of TNM and Whitmore-Jewett Staging Systems for Clinically Localized Prostate Cancer Stage TNM TX T0 T1a T1b T1c T2a T2b T3a T3b T4

Whitmore-Jewett * * A1 A2 * B1 B2 C1 C2 *

Description Primary tumor cannot be assessed No evidence of primary tumor Impalpable tumor, not visible by imaging in ≤ 5% of resected tissue Impalpable tumor, not visible by imaging in > 5% of resected tissue Impalpable tumor, not visible by imaging identified with needle biopsy (e.g., because of elevated PSA) Tumor confined within the prostate involving one lobe Tumor confined within the prostate involving both lobes Extracapsular extension of tumor Invasion of the seminal vesicle(s) Tumor is fixed or invades adjacent structures other than seminal vesicles (e.g., bladder neck, external sphincter, rectum, levator muscles, and/or pelvic floor)

*No corresponding stage. From American Joint Committee on Cancer. AJCC cancer staging manual. 5th ed. Philadelphia: Lippincott-Raven; 1997.

nologies and standardization of pathologic evaluation of specimens so that both prognosis and management plans can be based on solid clinical and pathologic data.

Prostate Cancer Staging Techniques An accurate clinical staging assessment is essential following diagnosis of PCa to enable the physician to assess the prognosis of the patient and design a rational treatment strategy. Preoperative evaluation of patients with PCa begins with its initial diagnosis, which is generally made using a combination of modalities to maximize the sensitivity and specificity of the diagnostic process.19 In general, the techniques currently available to evaluate clinical stage and grade of disease can be divided into clinical indicators and radiologic indicators. Clinical indicators used in assessing PCa include history and physical examination, laboratory survey, PCa serum markers, prostate needle biopsy, and pelvic lymph node dissection. Radiologic studies used to evaluate PCa include TRUS, plain radiography, computed tomography (CT), bone scintigraphy, MRI, radioimmunoimaging, PET, and, rarely, lymphangiography. Clinical Indicators History and Physical Examination The history and physical examination should elicit signs or symptoms suggesting either localized or extensive disease. Generally speaking, patients with low-volume, lowgrade, localized tumors are asymptomatic with respect to malignancy. For these patients, the most common symptom prompting evaluation is related to bladder outlet obstruction secondary to concurrent benign prostatic hyperplasia (BPH), rather than PCa. These complaints may include both obstructive and irritative voiding symptoms. Recognizing them may prompt further investigations leading to diagnosis of the underlying malignancy. Other symptoms elicited from the history, such as an acute change in voiding habits or hematuria, while

commonly attributed to BPH, may represent an extension of tumor into the bladder neck, trigone, or bladder base. Also, locally extensive disease can obstruct or invade the ejaculatory ducts leading to hematospermia and/or a decrease in ejaculate volume. Prostate cancer may at times involve the pelvic plexus, which innervates the corpora cavernosa and may lead to impotence.20 In addition, nonspecific complaints such as suprapubic, pelvic, lower extremity, and perineal pain have been described in 20 to 40% of patients diagnosed with PCa.21 Finally, constitutional symptoms such as weight loss, fatigue, and diffuse bone pain, while occurring in < 15% of patients at initial presentation, should prompt an exhaustive search for metastases prior to considering aggressive local therapy.21 Digital Rectal Examination As stated previously, DRE may estimate the local extension of disease, but it lacks the sensitivity and specificity to determine either tumor volume or ECE of PCa. Based on 17 radical prostatectomy studies, the false-negative rate of DRE for nonorgan-confined disease was approximately 48%.18 The overall specificity of DRE for organconfined disease staging in one study was only 9% while the overall accuracy was 57.7%.18 The positive predictive value (PPV) for DRE in several studies ranged from 21 to 53%.20 Conversely, the negative predictive value (NPV) of DRE for organ-confined disease ranged from 80 to 90%, indicating that when DRE suggests extraprostatic disease, it is usually correct.22,23 The DRE can therefore be a useful adjunct in the staging process by allowing evaluation of the peripheral architecture of the gland, assessing the site, location, and laterality of regions of induration which may reflect tumor. Cooner et al. found that the sensitivity of DRE increases significantly when used in combination with TRUS and serum PSA.24 In an elegant, multicenter study, Smith et al. performed both transrectal ultrasonography and DRE on 386 patients who were candidates for radical prostatectomy. The authors

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used receiver operating characteristic curves (ROC) to compare the staging abilities of the two tests. An ideal test would have a ROC value of 1.0; that is, it would always be positive if the tumor was extraprostatic and would always be negative if the tumor was confined to the prostate. On the other hand, a coin toss would have a ROC value of 0.5. The ROC values for TRUS and DRE were 0.69 and 0.72 for predicting extracapsular tumor extension and 0.74 and 0.69 for predicting seminal vesicle invasion. Neither value was significantly different. This landmark study suggests that a well-performed DRE is as effective in local staging of prostate cancer as is transrectal ultrasound.25 Digital rectal examination is limited for several reasons, including failure to provide an accurate estimate of tumor volume and an inability to detect microscopic spread, which accounts for a large proportion of extraprostatic tumor sites. The findings on DRE may also be affected by some forms of benign prostatic diseases (chronic prostatitis, calculi) and after transurethral surgery or prior prostate needle biopsies. Nevertheless, DRE continues to remain an integral part of PCa staging, especially due to its low cost and ease of performance. Laboratory Survey The laboratory survey, including the complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), and serum creatinine will be within normal limits for most patients. However, patients with advanced disease may show alterations in hematologic or renal function. For instance, an elevation in BUN and serum creatinine due to ureteral or bladder outlet obstruction secondary to invasive PCa and anemia, or from chronic disease caused by either bone marrow involvement by tumor or renal failure leading to decreased erythropoietin production, may be features of newly diagnosed disease. The serum alkaline phosphatase can also be useful in preoperative staging. Although not specific for PCa, an elevated serum alkaline phosphatase may be a harbinger of bony metastases. One study showed that approximately 90% of patients with PCa metastases to bone had an increased serum alkaline phosphatase.26 Prostate Cancer Serum Markers The role of PCa serum markers has changed tremendously in helping clinicians more accurately predict clinical/pathologic stage. These markers include prostatic acid phosphatase (PAP), PSA and its derivatives, and reverse transcriptase–polymerase chain reaction (RT-PCR) for PSA. Prostatic acid phosphatase and PSA are two FDAapproved serum tumor markers for PCa. The former was discovered to be a component of human ejaculate and has been found in high concentrations in patients with bony metastases from PCa. Elevations in PAP and the response of PAP to castration therapy were first documented in

metastatic PCa patients more than 50 years ago.18 However, early enthusiasm for PAP as a screening test for PCa waned when several studies concluded that men with organ-confined cancer often had normal PAP levels.27 Stamey et al. demonstrated that PAP does not correlate with PCa stage as well as does total serum PSA.28 Similarly, another study showed that only 21 of 460 men (4.6%) with PCa had an elevated PAP.29 Clearly, several limitations preclude PAP from being a valuable screening or clinical staging technique for PCa. These limitations include a relative insensitivity for distinguishing periprostatic invasion from disseminated disease, a substantial variation in PAP levels over time, lack of specificity for PCa, and an inability to distinguish soft tissue (i.e., lymph node) involvement from metastatic disease.19,21 Since a negative serum PAP is diagnostically trivial and an elevated PAP provides negligible information beyond serum PSA and clinical staging, potential application of serum PAP is outdated. Most clinicians, therefore, consider serum PAP to have no practical role in clinically evaluating newly diagnosed PCa.18 Although controversial, some clinicians use the enzymatic acid phosphatase instead of the radioimmunoassay for PAP to stage patients with PCa. Chybowski et al. showed that 90% of patients with an elevation in enzymatic acid phosphatase who had a negative bone scan at the time of diagnosis will have metastatic PCa within two years.30 Therefore, some clinicians still obtain a serum enzymatic acid phosphatase to evaluate patients with clinically localized PCa. If elevated, radical prostatectomy is not recommended. This last waning indication for PAP has been disputed by a recent study by Brawn et al. showing enzymatic PAP to be unreliable for predicting metastatic disease.31 Total serum PSA is prostate-gland specific but not PCa specific.22,32,33 It was first isolated from seminal plasma in 1971 by Hara et al., and 8 years later this protease was isolated from the prostate by Wang et al. who demonstrated its specificity to prostate tissue.34,35 It is a chymotrypsin-like serine protease that functions to hydrolyze the coagulum of the ejaculate, thus enhancing sperm mobility. Stamey et al. calculated the half-life of PSA to be 2.2 days,28 while Oesterling et al. calculated it to be 3.2 days.36 Total PSA is the sum of all immunologically detectable forms of serum PSA, which includes the free (unbound) form, plus the predominant complexed (bound) form. Serum PSA, coupled with DRE and TRUS-guided prostate needle biopsy, has revolutionized the detection of PCa as well as monitoring the response to treatment of patients with PCa. One of the earliest PSA studies screened 1653 asymptomatic healthy men over the age of 50 years and found 92% to have PSA < 4.0 ng per mL. Six percent of the men had values ranging from 4 to 9.9 ng per mL; 22% of these men proved to have cancer. Only 2% of the

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total patient population had PSA levels > 10.0 ng per mL but the cancer detection rate among them was 67%.37 The conventional ranges of PSA levels optimizing detection of PCa while minimizing the false-positive rate are < 4.0 ng per mL for low probability of PCa, 4 to 10 ng per mL for intermediate, and > 10 ng per mL for high probability. Oesterling summarized several large studies showing a statistically significant difference in detection in these three ranges with organ-confined disease versus BPH38 (Table 18–2). Seventy-five percent of the patients with BPH had a PSA < 4 ng per mL while 57% of the patients with PSA > 4 ng per mL had organ-confined PCa. The level of serum PSA has also been shown to be predictive of metastatic PCa. Only 3 of 561 patients with PCa and a PSA < 10 ng per mL had an abnormal bone scan.39 The sensitivity of a preoperative serum PSA > 10 ng per mL in predicting ECE, seminal vesicle invasion, and nodal metastases has been found to be 20%, 61%, and 71%, respectively.36 Lange et al. determined the PPV of a PSA > 10 ng per mL to be 78% for ECE and the NPV to be 61%.40 Myrtle et al. found that serum PSA levels were elevated (> 4.0 ng per mL) in 81% of the patients they studied with PCa; moreover, the percentage of patients with a PSA value above the reference range increased progressively with advancing stage.41 In 1987, Stamey et al. found that the PSA level was elevated in all of the 115 patients they studied with advanced disease and that the elevation was proportional to the estimated volume of tumor.28 While extremely sensitive as a diagnostic screening tool and mechanism for identifying metastatic disease, the ability of serum PSA at levels < 20 ng per mL to discriminate localized versus locally extensive cancer and, therefore, to serve as a sole predictive staging modality, is limited. Specifically, Oesterling et al. showed that, while a strong correlation exists between increasing PSA levels and ECE of cancer, the sensitivity and specificity of this test across broad ranges of cutoff values (4 to 16 ng per mL) were inadequate to justify its use as sole predictor of locally advanced cancer.36 Lange et al. likewise concluded that PSA alone was not a sufficiently reliable tumor marker in staging PCa because of its poor predictive value.40 In 1994, Partin’s staging guidelines showed that a majority of men (70 to 80%) with a PSA < 4.0 ng per mL had pathologically organ-confined disease and that 50% with a PSA of > 10 ng per mL had ECE.42 Therefore, while the trend is clearly toward an increased risk of residual cancer after surgical treatment with higher levels of PSA, the relatively poor sensitivity and predictive value and the fact that almost one-quarter of the patients with positive surgical margins had a PSA level < 10 ng per mL suggest that PSA by itself cannot be used to define clinical stage or predict poor surgical outcomes.43 The reason for the inability of the serum PSA to predict locally advanced PCa appears to be threefold: (1) the lack of an accurate method of determining tumor volume

prior to surgery; (2) decreasing production of PSA by higher-grade tumors as a function of tumor volume; and (3) the relative contribution of benign conditions (BPH, prostatitis) in generating a leaky PSA syndrome, versus cancer-to-serum PSA level which renders the test unreliable in predicting clinical stage.44,45 To improve the predictive value of the serum PSA and enable better differentiation between BPH and PCa in patients with elevated PSA, several authors have studied PSA derivatives such as prostate-specific antigen density (PSAD), PSA velocity (PSAV), free versus complexed PSA, and age-specific PSA. Since PSA elevations from 4 to 10.0 ng per mL can be due to BPH in many men, Benson et al. suggested adjusting PSA for ultrasound-based prostate size by calculating PSAD, which represents the quotient of PSA and prostate volume.46,47 The focus on PSAD assumes that cancer results in a greater increase in serum PSA than does hyperplasia. It has been proposed that a PSAD of 0.15 or greater be the threshold for recommending prostate biopsies in men with PSA levels between 4 and 10 ng per mL and a normal DRE.48,49 Several studies, however, refute the usefulness of PSAD. Oesterling et al. showed that PSAD does not provide any additional clinical information over PSA when using age-specific reference ranges.50 Also, Catalona et al. found that in men with PSA levels between 4 and 10 ng per mL and a normal DRE and TRUS, 50% of cancers would have been missed using a PSAD of > 0.15 as a guide for biopsy.51 In a recent study, Presti et al. concluded that PSAD should not be used to determine the need for biopsy in men with normal DRE and/or TRUS due to the large number of missed clinically significant prostate cancers.52 Similarly, Lee and Oesterling concluded that “there is no significant role for PSAD in early detection of prostate cancer.”53 Prostate-specific antigen density seems to be an imperfect predictor of cancer primarily due to its poor reproducibility of volume determinations using TRUS and variations in normal prostate sizes. Prostate-specific antigen velocity, defined as the change in PSA over time, is another method developed to improve differentiation between benign and malignant prostate disease. Since PSA rises with increases in BPH and cancer volume, and it is assumed that welldifferentiated cancers produce more PSA than lessdifferentiated cancers, interpreting a single PSA value becomes difficult. Therefore, PSAV is the use of serial PSA levels to evaluate a patient, thus avoiding the interrelated variables of PSA concentration, BPH volume, cancer volume, and cancer differentiation.45 Carter et al. studied men with PCa, BPH, and normal prostates from the Baltimore Longitudinal Study of Aging. They found a significant difference in the ageadjusted rate of change in PSA among these groups, with PCa patients having the highest rate of change, followed

164 / Advanced Therapy of Prostate Disease TABLE 18–2. PSA Values for BPH versus Organ-Confined Prostate Cancer Percentage of Patients with PSA Values in Specified Range (No./Total) Number of Patients

0.0–4.0 ng/mL*

> 10.1 ng/mL*

Reference

BPH

Partin et al.45 Lange et al.40 Hudson et al.166

72 357 168

185 31 103

47 (34/72) 79 (282/357) 79 (133/168)

45 (83/185) 45 (14/31) 38 (39/103)

46 (33/72) 18 (64/357) 19 (32/168)

44 (82/185) 32 (10/32) 26 (27/103)

7 (5/72) 3 (11/357) 2 (3/168)

11 (20/185) 23 (7/31) 36 (37/103)

Totals

597

319

75 (449/597)

43 (136/319)

22 (129/597)

37 (119/319)

3 (19/597)

20 (64/319)

p value

BPH

Organ-Confined PCa

4.1–10.0 ng/mL*

Organ-Confined PCa

p < .0001

BPH

Organ-Confined PCa

BPH

Organ-Confined PCa

p < .0001

p < .0001

*Tandem-R PSA assay. Reproduced with permission from Oesterling JE. Prostate-specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate. J Urol 1991;145:907–10.

by BPH and control patients, respectively. They determined that a PSAV greater than 0.75 ng per mL per year identified prostate cancer patients, with a sensitivity of 72% and a specificity of 90%.54 However, Smith and Catalona showed a cancer detection rate of only 47% among men with PSAV > 0.75 while Oesterling et al. found tremendous variation in PSAV across all age ranges.55,56 In two separate studies, the minimal length of follow-up time to calculate PSAV has been determined to be 18 months.55,57 Further, an average rate of change in PSA between three repeated PSA measurements has been shown to optimize the accuracy of PSAV in helping detect PCa.54,58 Although not widely accepted, PSAV can be a helpful adjunct to PCa detection. Recently, the discovery that PSA exists in bound and unbound forms sparked another test to help in the diagnosis of PCa. The PSA primarily exists in a complexed form, bound to either α1-chymotrypsin (ACT) or α2macroglobulin (AMG). However, current immunoassays can detect only the free PSA and PSA-ACT. The AMG covers the epitopes of the free PSA which are needed for detection. It has been shown that men with PCa have an increased level of serum PSA complexed to ACT than they do of free PSA. Conversely, more free PSA exists in men with BPH than with PCa.59 In one of the earliest reports, Lilja et al. found a median of 18% free PSA in PCa and 28% in BPH.60 Stenman et al. reported 40% free PSA in cancer patients versus 60% in BPH patients.61 Several studies have found that a free/total PSA cutoff ranging from 18 to 23% improved the ability to distinguish between cancer and noncancer patients with intermediate total PSA levels (4.0 to 10.0 ng per mL).59,62 Currently, the role of free and complexed forms of PSA remains undefined but has the potential to categorize men with intermediate levels of PSA into high-risk and low-risk groups for prostatic carcinoma. The normal aging prostate undergoes hyperplasia, resulting in increased prostate size and PSA production. It has been shown that 1 g of BPH gives rise to 0.2 ng per mL of PSA in serum.28 Accounting for this size increase with age, Oesterling et al. adjusted the serum PSA reference ranges, hoping to increase detection of cancer in younger

patients most likely to benefit from treatment and to minimize unnecessary evaluation in older patients who may be less likely to benefit.63 They established the following normal, age-specific PSA references ranges: age 40 to 50, 0 to 2.5 ng per mL; age 50 to 60, 0 to 3.5 ng per mL; age 60 to 70, 0 to 4.5 ng per mL; age 70 to 80, 0 to 6.5 ng per mL.63 Other studies have shown that the age adjustment of PSA provided no advantage in cancer detection over the traditional PSA cutoff of 4.0 ng per mL, primarily due to an increased risk of missing tumors in older men by increasing the PSA threshold.64–66 Current data suggest that a cutoff of 4.0 ng per mL is an effective threshold to maximize PCa detection and minimize undue biopsy in men between 50 and 70 years of age. The optimal PSA cutoff is not known. However, greater suspicion is warranted when evaluating younger patients with levels < 4.0 ng per mL as these patients have the most to gain from a diagnosis of PCa, especially with accompanying risk factors such as family history or black race. Higher thresholds may be appropriate in older men to avoid costly or unnecessary evaluations which may be unlikely to benefit the elderly patient.20 Currently, even though PSA is the most accurate, important, and clinically useful tumor marker for PCa, it is not without its shortcomings. Prostate-specific antigen assays, therefore, will continue to evolve to better distinguish patients with and without PCa. Further attempts to enhance the predictive value of serum PSA in detecting PCa have centered on the RT-PCR for PSA technique. Many authors have postulated that it may be possible to “molecularly stage” the patient using a technique relying on RT-PCR detection of messenger RNA for PSA in circulating cells. This hypothesizes that these circulating cells represent PCa cells and impending metastatic disease. Katz et al. found RT-PCR PSA analysis to have a sensitivity of 83%, specificity of 76%, and a PPV of 80% in predicting positive surgical margins.67 In this study, RT-PCR PSA was used to assess the presence of capsular penetration and seminal vesicle involvement, along with the demonstrated absence of RT-PCR PSA in women, and in men without PCa. In a later study by Cama et al., the PCR assay for PSA was a stronger predictor of

Staging of Prostate Cancer / 165

pathologic stage than a PCR assay for prostate-specific membrane antigen (PSMA), a prostate epithelial transmembrane glycoprotein.68 Thus, RT-PCR PSA appears to be PCa-cell-specific and directly correlates with pathologic stage.20 Unfortunately, about 25% of patients with localized prostate cancer will have a positive RT-PCR, which presents a major limitation to this study, especially when the majority of patients will be low stage at diagnosis. An additional limitation of the test is that this assay can potentially identify both malignant and benign PSAproducing cells and “PSA-like” cells in the circulation.69 Since the ability of these detected systematic cells to establish a metastatic site is not known and long-term followup results are not currently available, the RT-PCR PSA technique should be used with caution, especially in the patient with low-stage disease. Prostate Needle Biopsy The prostate needle biopsy, while not included in traditional clinical staging, can provide important information to help predict the pathologic stage of PCa. Factors such as histologic grade (Gleason score), neovascularity of the tumor, the number of positive biopsies, biopsy core tumor volume, laterality, and percent involvement of the positive lesions reflect the biologic potential and relative aggressiveness of the tumor. Other histopathologic parameters that can be helpful but are inconsistently available include perineural invasion, pericapsular fibroadipose tissue involvement, and bilaterality of the tumor.70 The most commonly used histologic grading system for PCa is the Gleason system.71 Several authors have shown that the presence of a Gleason 4 or 5 grade or a Gleason sum greater than 7 portends a poorer prognosis.72–76 Badalament et al. demonstrated that a Gleason score of 7 or greater had a 58% accuracy in predicting organ-confined disease.77 Partin et al. showed that PSA, Gleason score, and clinical stage could independently predict ECE and that the combination of these elements has the greatest prognostic potential78 (Table 18–3). Gleason grade is also useful in predicting the risk of lymph node metastases. McNeal et al. noted that a high Gleason score in combination with large tumor volume conferred a significantly increased risk of lymph node metastases.79 Stamey and Grossman et al. independently confirmed this observation.80,81 Moreover, Partin et al. determined that the combination of localized disease on DRE, serum PSA ≤ 10 ng per mL, and a Gleason score ≤ 6 reflects a low likelihood of nodal metastases.78 The Gleason scoring system, however, is not without its limitations. These include: (1) the finding that preoperative Gleason score does not always correlate with final pathologic grade after surgery (a phenomenon resulting from limited tumor sampling);82,83 (2) the relatively infrequent occurrence of well-differentiated (Gleason score 2 to 4) and poorly differentiated (Gleason score 8 to 10)

cancers on biopsy specimens (20% in most large series);82,84 (3) the fact that the majority of men with PCa have intermediate Gleason scores (5 to 7), but the correlation between Gleason score and prognosis is accurate mostly on the extreme ends of the scale;82 and (4) the fact that intermediate Gleason scores may have different staging implications depending on the presence and percentage of the Gleason 4 or 5 component.78,79 In an effort to improve accuracy in predicting pathologic stage, Ackerman et al. found that pretreatment PSA level and the number of positive core biopsies correlated well with the risk of positive surgical margins.85 In particular, 15% of the patients in this study with only one positive biopsy each had evidence of positive margins while 47% of men with multiple positive biopsies had residual disease after radical prostatectomy.85 Hammerer et al. calculated the sensitivity and specificity of the number of positive sextant cores and the total linear percent involvement for predicting lymph node metastases.86 In this study, using 280% as the total linear percent involvement cutoff point, the sensitivity, specificity, and accuracy of percent involvement were 66%, 93%, and 87%, respectively. Also, of the patients with fewer than five positive scores, only 5.6% had positive lymph nodes.86 Similarly, Bostwick et al. accurately predicted ECE using percent cancer on biopsy, PSA, and Gleason score.87 Another attempt to improve the predictive value of prostate needle biopsies was performed by Daniels et al., correlating bilaterality of neoplastic disease to subsequent pathologic stage. The study showed that patients with bilateral disease had, on biopsy, an increased risk of margin positive disease (32%) compared to those with only unilateral disease(19%).70 Also, the site of origin appears to be a significant prognostic factor. Cancer arising in the transition zone of the prostate appears to be clinically less aggressive than the more common peripheral zone cancers.88–91 In addition, there are data to suggest that tumor volumes may predict local tumor stage. Villers et al. demonstrated seminal vesicle invasion in 6% of tumors < 4 cc in volume, versus 82% for lesions > 12 cc in volume.92 Similarly, Stamey and McNeal reported that cancer volumes of 4 cc or less are generally associated with a good prognosis whereas tumors of 12 cc or more are surgically incurable.19 Another study showed capsular penetration in only 7% of tumors < 4 cc in volume but in 86% of those tumors > 12 cc in volume.93 In general, capsular penetration is uncommon in tumors < 5 cc while seminal vesicle invasion or lymph node metastases are uncommon in tumors < 4 cc in volume.94 Clearly, tumor volume is a strong indicator of clinical stage and disease outcome. Unfortunately, there are no reliable methods of calculating tumor volume within the prostate gland prior to therapy. Although some investigators have advocated the use of seminal vesicle biopsies to improve preoperative staging of PCa,95–97 others have not found them useful when routinely performed.98 Stone et al. reported that 47.8% of

166 / Advanced Therapy of Prostate Disease TABLE 18–3. Partin Nomogram for Prediction of Final Pathologic Stage* 0.0– 4.0 Clinical Stage

4.1–10 Clinical Stage

10.1–20 Clinical Stage

Greater than 20 Clinical Stage

T1a T1b T1c T2a T2b Tsc T3a

T1a T1b T1c T2a T2b Tsc T3a

T1a T1b T1c T2a T2b Tsc T3a

T1a T1b T1c T2a T2b Tsc T3a

— — 42 — —

100 100 100 100 —

78 79 53 39 32

82 71 59 43 31

83 73 62 51 39

67 56 44 32 22

71 64 48 37 25

— 43 33 26 12

100 100 — — —

— 49 36 24 11

— 55 41 24 —

61 58 44 36 29

52 43 28 19 14

— 37 37 24 15

— 26 19 14 9

— — — — —

— 33 20 7 — — — 24 32 — 3 — — 22 14 11 4 5 — 7 18 4 5 3 — 3 3 1 2 2

Prediction of established capsular penetration 2–4 0 15 22 14 26 17 — 5 0 22 30 20 34 26 — 6 0 30 34 29 46 38 59 7 — 43 40 39 59 50 — 8–10 — — — 50 68 — —

0 0 0 0 —

22 29 45 58 64

29 34 38 44 48

19 28 38 49 59

34 45 56 68 77

27 34 49 59 71

— 58 68 75 87

0 0 — — —

— 49 62 73 87

— 40 45 52 —

40 43 56 64 70

49 58 73 81 86

— 61 59 73 82

— 75 82 86 92

— — — — —

— — — — —

— 97 96 95 97

— — 95 98 98

Prediction of seminal vesicle involvement 2–4 0 1 1 cm are not visualized by TRUS.112 Further, TRUS has demonstrated a 66% sensitivity and 46% specificity in its ability to correctly stage advanced and localized disease, in addition to identifying only 59% of tumors > 5 mm. The overall accuracy of TRUS in detecting extraprostatic PCa is only 58%.113 The ultrasono-

graphic finding suggestive for ECE is a large hypoechoic lesion with an overlying irregularity to the normal continuous hyperechoic boundary surrounding the prostate.114,115 To further confound the examination, several benign processes can also mimic the hypoechoic pattern of PCa, including hyperplastic nodules, cysts, inflammatory lesions, and postbiopsy hematomas. Clearly, TRUS alone is neither reliable nor accurate in the contemporary staging of PCa. It does, however, have significant value as an adjunctive study for evaluating patients with PCa, by guiding systematic sextant biopsies toward hypoechoic regions and directing accurate seminal vesicle biopsies.19 Radiography Bone radiography can also be a useful adjunct in clinically staging PCa, primarily in evaluating or confirming suspicious lesions found on bone scintigraphy. Plain radiographs are also useful in identifying osteoblastic (75% incidence) or mixed osteoblastic/osteolytic (15% incidence) lesions, which typify disseminated prostate metastases.21 The most common sites of prostatic bony metastases are the spine, followed by the femur, pelvis, rib cage, skull, and humerus. Computed Tomography The clinical utility of CT in PCa staging has generally been disappointing, with sensitivities ranging from 27% to 75% and specificities ranging from 66% to 100%.116–118 Although rarely seen, findings on CT suggestive of invasive disease include unilateral levator ani enlargement, rectal wall thickening, and loss of tissue fat planes between the prostate and seminal vesicle or bladder wall. Many of these findings will be noted on a properly performed DRE. One drawback of CT is its inability to distinguish between cancer and benign abnormalities of the prostate, and to demonstrate microscopic extracapsular involvement. Further, it can detect lymph node enlargement but cannot determine the cause of nodal enlargement (e.g., inflammation versus tumor). In clinical studies, the sensitivity of CT scanning for detecting pelvic lymphadenopathy varies from 25 to 93%119 (Figure 18–1). Because of this, Levran et al. concluded that given the current low incidence (3.7%) of positive nodes in a patient with a serum PSA ≤ 20 ng per mL and the resolution limits of the CT scan, this study is not indicated in the preoperative staging of these low-risk patients.120 Lee and Oesterling similarly do not recommend CT as a routine modality for staging newly diagnosed PCa in patients with PSA levels of 20 ng per mL or under.53 This very low risk of positive nodes along with the risk of a false-positive CT scan makes this test potentially more harmful than helpful as a staging test in a group of patients with newly diagnosed PCa.

168 / Advanced Therapy of Prostate Disease

Bone Scintigraphy Advanced PCa favors the axial skeleton for metastases; therefore, excluding bony involvement is essential in selecting appropriate treatment. The bone scintigram (radionuclide bone scan) is an extremely sensitive method to detect PCa metastases (0 to 8% false-negative rate),121 superior to bone radiographs, serum alkaline phosphatase level, and clinical evaluation122–124 (Figure 18–2). Of those men with negative bone radiographs, at least 25% will have skeletal metastases on bone scan.125 Unfortunately, the bone scan is so sensitive that it tends to have a high false-positive rate, detecting not only metastatic disease but also inflammatory lesions, Paget’s disease, healing fractures, degenerative bone disease, arthritis, and bony infections.21,124,126 In the past, the standard evaluation for a newly diagnosed PCa patient included a bone scan. It remains the gold standard for skeletal metastases detection since its development in 1963; recent data, however, call into question its routine use as a staging modality. For instance, Oesterling found that for patients with newly diagnosed PCa and a PSA ≤ 10 ng per mL, bone scans added little to pretreatment tumor staging.127 Further, Chybowski et al. showed that a PSA of < 20 ng per mL had a 99.7% NPV for finding metastatic lesions on the bone scan.30 The authors concluded that bone scans are unnecessary in staging untreated PCa patients who have no skeletal symptoms and a PSA value ≤ 10 ng per mL.30 Similarly, Vijayakumar et al. and Gleave et al. showed a 100% NPV for positive bone scans in patients with a PSA level ≤ 10 ng per mL and recommended ceasing bone scans for these patients.128,129 Although occasional exceptions to this rule will be seen, these studies suggest that PCa disseminated to bone may be accurately excluded in patients without bone pain and low PSA without incurring the added cost of bone scintigraphy. The role of bone scans in patients with known metastatic disease has also been studied with regard to the num-

FIGURE 18–1. Pelvic CT in a patient with stage T3 cancer of the prostate showing right-sided prostate cancer impinging on the bladder base (arrow).

ber and location of osseous metastases. Studies have shown that bone scintigraphy can provide prognostic information as well as predict the duration of response to hormonal ablative therapy. For instance, patients with metastases limited to the pelvis and lumbar spine, with few metastatic foci on bone scan, demonstrate a significantly better response to hormonal therapy and have a longer mean survival than patients with more extensive disease at presentation.130 These studies support the utility of bone scans in patients with metastatic disease found on presentation for staging and predicting response to therapy and overall survival. Although there are no absolute data on bone scan imaging in the patient with recurrent PCa following definitive therapy, Lee and Oesterling suggest that bone scans are unnecessary in postprostatectomy patients with a PSA level < 2.0 ng per mL.131 While bone scintigraphy is the most sensitive method of detecting bony involvement with PCa, current data suggest that it should be reserved for newly diagnosed PCa patients with symptomatic bone pain, a PSA level > 10 ng per mL, or evidence of local or distant metastases. If the bone scan is positive, especially in a weight-bearing location, or the patient has bone pain with a negative scan, plain radiographs of the area of interest are often indicated. If the plain films are equivocal or negative in the face of high clinical suspicion, an MRI of the area can help localize metastatic disease. Oesterling studied the economic implications of eliminating bone scans according to the above criteria and calculated a potential savings of $38 million annually.127 Magnetic Resonance Imaging Magnetic resonance imaging is an expensive imaging technique that produces images in all three planes without using ionizing radiation. Although it is not possible to discern the internal architecture of the prostate on T1-weighted images, PCa often appears as a high-intensity signal (Figure 18–3). The zonal anatomy of the prostate can be demonstrated on T2-weighted images.132 Prostate cancer appears as a low-intensity signal on T2-weighted images, contrasting sharply with the usual high intensity of the peripheral zone.133 Other abnormalities, however, such as adenoma, prostatitis, and corpora amylacea also produce low-intensity signals, making MRI not very accurate at identifying localized PCa. Unfortunately, MRI has proven to have an overall staging accuracy approximately equal to that of TRUS in local staging of PCa.132 Rifkin et al. compared body MRI to TRUS in staging of patients with early PCa and found that MRI correctly staged 77% of those with advanced disease and only 57% with localized disease, for an overall staging accuracy of 69%.113 It was able to identify only 60% of all malignant tumors measuring more than 5 mm on pathologic analysis.113 In an attempt to improve accuracy, a balloonmounted endorectal coil was developed to enhance imag-

Staging of Prostate Cancer / 169

ing details of the MRI scan for the prostate and periprostatic tissue. Tempany et al. performed MRI scans in patients using three different imaging techniques and compared the results of conventional body coil, body coil with fat suppression, and endorectal coil.134 The overall accuracy was 61%, 64%, and 54%, respectively, and the authors concluded that none of these techniques was sufficiently accurate for staging early PCa. Similarly, Perrotti et al. advised against the routine use of endorectal coil MRI to stage localized PCa.135 Further, contrast/gadolinium-enhanced MRI images did not improve overall staging accuracy for localized PCa.136,137 Some centers, though, are using MRI in patients with known PCa to confirm bony metastases on a routine basis. At the current time, due to the inaccuracy and high cost of the MRI, there is little justification for its use in the preoperative staging of PCa. Radioimmunoimaging The development of hybridoma technology in 1975 was an important breakthrough in monoclonal antibody (MoAb) technology, which revolutionized the field of immunoassays and in vitro diagnostics such as PSA testing.138 Radioimmunoimaging has contributed greatly to diagnosing and staging of both ovarian and colorectal carcinoma;139 the promise of MoAbs in the area of in vivo imaging for PCa, however, is just now being realized. Anatomic imaging modalities (CT, MRI, TRUS) are variously deficient in tumor detection, as stated earlier. Most of these modalities are organ-specific and may fail to recognize distant disease; radioimmunoimaging, however, localizes tumors using tumor-specific radiolabelled MoAbs. Consequently, functional imaging by radioimmunoscintigraphy can differentiate tumor recurrence from postoperative changes and can detect cancer in normal-sized lymph nodes. It can also evaluate the entire body in one session, thus allowing detection of distant metastases and local recurrences.139 Despite these advantages, immunoscintigraphy, as any imaging modality, does have its limitations. For instance, monoclonal scans are hampered by less spatial detail, making it less likely to detect ECE. While monoclonal antibodies have been found to be highly immunogenic, suggesting they cannot be used repeatedly,140 a recent study by Williams et al. concluded that the indium-111-labelled MoAb could be repeatedly administered without significant side effects.141 Previous antibody studies using radiolabelled antiPAP and antiPSA monoclonal antibodies have shown sites of metastases.142,143 These antigens are suboptimal, however, because elevated levels of antigens cross react with the antibody, reducing its availability to the target cells of interest. Also, these antigens have a propensity to be rapidly removed from the blood and subsequent sequestering by the liver.144,145 The most commonly used radiolabelled MoAb today is the indium-111 CYT-356 (ProstaScint, Cytogen

Corporation, Princeton, NJ) described by Horoszewicz et al., which is a murine immunoglobulin G monoclonal antibody to a glycoprotein localized on the cell membrane of benign and malignant prostate epithelium.145 This antibody is commercially available. Many recent preliminary studies using this MoAb have shown it to be superior to conventional imaging studies in detecting overt PCa metastases and recurrent PCa in post-therapy patients with rising PSA levels142,144–149 (Figures 18–4 and 18–5). Babaian et al., for instance, found indium-111 CYT-356 imaging to have a sensitivity of 44%, specificity of 86%, a PPV of 50%, and an NPV of 83%.150 Another study, by

FIGURE 18–2. Bone scan of a patient with stage T4 cancer of the prostate showing diffuse metastatic disease throughout the pelvic girdle and lumbar spine (arrow).

170 / Advanced Therapy of Prostate Disease

Positron Emission Tomography While many techniques use noninvasive cross-sectional imaging to detect oncologic processes, only PET uses noninvasive in vivo biochemical and/or physiologic reac-

tions to detect cancer (Figure 18–6). Although PET has been in existence since the 1960s, it has experienced a prolonged period in gaining clinical acceptance.153 The procedure was first used to detect recurrent brain tumors. Its use in urology is just now being recognized. The basis of PET technology is the radiotracer, which is a positron emitting analogue of glucose that provides a means of measuring in vivo biochemical functions. The most commonly used PET tracer is the glucose analogue 18-fluoro-2-deoxyglucose (FDG). Following intravenous injection, FDG accumulates in tissue with a high rate of glycolysis (i.e., malignant neoplasms). The radiotracer emits a positron which collides with a negatively charged electron to form photons, which are then detected by photon detectors. This procedure has been shown to detect tumors of the thyroid, breast, lung, colon, and ovaries.154 Also, PET scans have shown alterations in tumor metabolism prior to any changes shown on CT or MRI, and can identify metastases in the presence of other normal imaging studies.155–157 The amount of radiation the patient receives from an FDG PET scan is roughly equal to that of CT.158 The value of PET scanning in PCa is still under investigation. Several studies have demonstrated difficulty in imaging prostate lesions secondary to the intense adjacent bladder activity and the high uptake of FDG in BPH.159–161 Laubenbacher et al. and Effert et al. both concluded that there was no significant difference in the activity of FDG uptake between PCa and BPH.159,161 Shreve et al. confirmed that the uptake of FDG in PCa is low, which may reflect the characteristics of a slow-growing tumor.160 The study concluded that “FDG PET can help identify osseous and soft tissue metastasis of prostate cancer with a high positive predictive value (98%) but is much less sensitive (65%) than bone scintigram in the identification of osseous metabolism.”160 One study reported a sensitivity of only 20% for osseous metastases.162

FIGURE 18–4. ProstaScint scan showing metastatic right iliac node disease in a patient with stage D prostate cancer (arrows).

FIGURE 18–5. ProstaScint scan showing recurrence of prostate cancer in the prostatic bed of a patient who has undergone radical prostatectomy (arrow).

FIGURE 18–3. Prostatic carcinoma. A T1-weighted MRI scan showing an area of increased signal posterolaterally on the right lobe.

Sodee et al., showed residual or metastatic disease in 14 of 15 patients with rising PSA levels after radical prostatectomy.149 In addition, multicenter studies with this MoAb revealed that the smallest foci of tumor visualized are 3 to 5 mm in size, which is far below that of other imaging modalities.151,152 The ProstaScint scan has received FDA approval and will most likely be used in patients with newly diagnosed PCa who are deemed to be at high risk for having lymph node involvement and in those patients who have an elevated PSA level following radical prostatectomy.140 With further refinements, it may be used to define the local extent of the primary tumor and may prove to be an adjunct in the clinical evaluation of patients before radical therapy.

Staging of Prostate Cancer / 171

FIGURE 18–6. A PET scan showing metastatic prostatic carcinoma in the periaortic, retrocrural, and pulmonary regions.

There may be a more feasible application for PET scanning in the detection of lymph node metastases to the pelvis and retroperitoneum, where bladder activity is less of a problem. Investigations are currently underway examining the use of PET in patients with PSA relapse after primary local therapy. Preliminary results show that in patients with a high PSA level (> 4.0 ng per mL) or a high PSA velocity (greater than 1.3 at 6 months), PET may be more sensitive than CT for detecting lymph node metastases.154 Additional studies have shown that a decrease in FDG uptake following therapy is an early predictor of chemo- or radiosensitivity.163–165 This ability to evaluate treatment efficacy and determine the presence, extent, and metabolic activity of metastatic disease may be important in clinical management decisions when considering early versus late hormonal or experimental therapy. Although intense FDG uptake can be interpreted as highly suspicious for tumor, lesions with mild uptake are equivocal. Therefore, in addition to the high cost of a scanner, poor resolution of images, and the need of a cyclotron to generate positron emitting tracers, PET scans have only a complementary role with other imaging modalities in contemporary staging of PCa. Lymphangiography Historically, pedal lymphangiography was a popular technique for evaluating the status of pelvic lymph nodes. By examining the internal architecture of lymph nodes, images can be produced that cannot be duplicated by other techniques. However, the technique is invasive, uncomfortable, time-consuming, and carries the risk of pulmonary embolism due to the lipid-based contrast medium. Fur-

ther, metastases must be at least 5 mm in diameter to be detectable by this technique. Although good images can be obtained of the common iliac, external iliac, and paraaortic nodes, the images of the hypogastric and obturator nodes, which become involved earliest in PCa, are not as clear. In a study of 40 patients with PCa, lymphangiography has produced a false-positive rate of 59% and a false negative rate of 36%.130 Today, with the advent of newer imaging modalities, lymphangiography has become essentially obsolete and most clinicians consider this technique to be of little value in staging PCa.

Conclusion There has been little impact on the natural history of PCa in the past, despite aggressive intervention. This has likely been due to the inability to select and treat patients most likely to benefit from aggressive treatment. Through continued research efforts, however, new data have been reported that have influenced the approach to PCa. As these data accumulate, the group of patients thought to benefit from aggressive intervention will most likely be redefined. Until then, PSA determination, TRUS-guided biopsies, and assessment of tumor grade, along with appropriate imaging studies, will continue to be the mainstay of PCa staging.

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154. Hoh CK, Seltzer MA, Franklin J, et al. Positron emission tomography in urological oncology. J Urol 1998; 159:347–9. 155. Wahl RL, Harney J, Hutchins G, et al. Imaging of renal cancer using positron emission tomography with 2-deoxy-2-(18F)-flouro-d-glucose: pilot animal and human studies. J Urol 1991;146:1470–3. 156. Harney JV, Wahl RL, Liebert M, et al. Uptake of 2-deoxy2-(18)-flouro-d-glucose in bladder cancer: animal and initial patient positron emission tomography. J Urol 1991;145:279–83. 157. Letocha H, Ahlstrom H, Malmstroms PU, et al. Positron emission tomography with L-methionine in the monitoring of therapy response in muscle invasive transitional cell carcinoma of the urinary bladder. Br J Urol 1994;74:767–70. 158. Jones SC, Alavi A, Christman D, et al. The radiation dosimetry of 2 [F-18]flouro-2-deoxy-D-glucose in man. J Nucl Med 1982;23:613–6. 159. Effert PJ, Bares R, Handt S, et al. Metabolic imaging of untreated prostate cancer by positron emission tomography with 18F-flourine-labeled deoxyglucose. J Urol 1996;155:994–9. 160. Shreve PD, Grossman HB, Gross MD, Wahl RL. Metastatic prostate cancer: initial findings of PET with 2-deoxy-2-[F-18]flouro-d-glucose. Radiology 1996; 199:751–9. 161. Laubenbacher C, Hofer C, Avril N, et al. F-18-FDG PET for differentiation of local recurrent prostate cancer and scar. J Nucl Med 1995;36 Suppl:198P–9P. 162. Yeh SDJ, Imbriaco M, Garza D, et al. Twenty percent of bony metastases of hormone resistant prostate cancer are detected by PETFDG whole body scanning. J Nucl Med 1995;36 Suppl:199P–200P. 163. Iosilevsky G, Front D, Bettman L, et al. Uptake of gallium67 citrate and [2-H] deoxyglucose in tumor model, following chemotherapy and radiotherapy. J Nucl Med 1985;26:278–81. 164. Minn H, Payl R, Ahonen A. Evaluation of treatment response to radiotherapy in head and neck cancer with flourodeoxyglucose. J Nucl Med 1988;29:1521–5. 165. Minn H, Soini I. I[18-F]Flourodeoxyglucose scintigraphy in diagnosis and follow up of treatment an advanced breast cancer. Eur J Nucl Med 1989;15:61–5. 166. Hudson MA, Bahnson RR, Catalona WJ. Clinical use of prostate-specific antigen in patients with prostate cancer. J Urol 1989;142:1011–2.

CHAPTER 19

RADICAL PROSTATECTOMY: PATIENT PREPARATION PAUL K. PIETROW, MD; JOSEPH A. SMITH JR, MD Patient Education

Successful treatment of localized carcinoma of the prostate is dependent upon appropriate patient selection and proper preparation. This not only influences ultimate treatment results but can have an impact on treatment and disease-related morbidity. Issues of patient preparation and perioperative management are often based more on custom and anecdotal experience than on solid, evidence-driven decision making. Nevertheless, growing data increasingly support various measures designed to produce the best outcome. This enabled construction of pathways for patient management that begin with patient preparation and can be carried through to discharge.

Patient preparation for treatment of prostate cancer often begins well before the doctor-patient relationship is established. Many patients present to a physician’s office with preconceived expectations developed from contact with friends, relatives, co-workers, literature, and, increasingly, the Internet. Therefore, by the time a diagnosis of prostate carcinoma is established, the patient may know a great deal about the various treatment options. Assuming that the patient has elected to undergo radical prostatectomy, it is important to help teach the patient what to expect in the various stages of his therapy. Each urologic surgeon should explain the basic course of the patient’s trip to the operating room and of the typical steps in his recovery. In the authors’ practice, every patient is seen by the Department of Anesthesia in the preoperative evaluation clinic, where a history and physical examination is performed to determine any increased anesthetic risks. There is no consensus in the anesthesia literature on the necessity of preoperative laboratory tests. For patients with no additional risk factors, however, a basic chemistry panel, including electrolytes and a complete blood count, are sufficient. Coagulation studies such as prothrombin time (PT) or partial thromboplastin time (PTT) are not required in the absence of an identified bleeding tendency. Chest radiographs are not ordered unless indicated by the patient’s medical history since only 0.1% of routine studies reveal an abnormality requiring a change in preoperative planning.5 Electrocardiograms are performed for all patients over the age of 50 years. Specific anesthetic risks should be explained to the patient at this point. At the authors’ clinic, patients are also instructed to discontinue all anticoagulants (aspirin, nonsteroidal antiinflammatory drugs, warfarin) for 7 days prior to operation. With the exception of diabetes medications, patients are instructed to continue all other routine morning medications on the day of their procedure, including antihypertensives. The nurse manager of the authors’ clinic also meets with each patient to arrange a scheduled date for the operation. This allows the nurse manager to reinforce important preparatory points brought up by the surgeon and anesthesiologist. In addition, each patient is given a

Selection of Therapy To achieve the greatest chance of therapeutic success, an appropriate course of action must be selected for each patient. The best treatment for localized prostate cancer is controversial and frequently debated in the medical literature. In addition, patients often form their own opinions based on information from multiple sources. The responsibility of the physician is to help guide the patient to a realistic plan by adequately assessing and synthesizing several factors, including tumor stage/grade, patient age and comorbidities, and patient preferences and expectations. The natural history of localized prostate cancer has led most clinicians to apply aggressive therapy to patients whose life expectancy is at least 10 to 15 years.1–3 The overall assessment of the patient and his coexisting medical condition is inherently subjective, based on physical examination, medical and family history, and clinical judgment. The authors assessed the accuracy of physician judgment of patient longevity by submitting the medical records of 261 consecutive radical prostatectomy patients to the actuarial division of a major life insurance company.4 By the insurance actuary’s projection, at least 80% of the patients had a life expectancy of greater than 10 years. Of note, 26 men were recognized preoperatively as having a projected life expectancy of under 10 years but underwent radical prostatectomy at their own insistence. It appears that even when compared to insurance actuaries, physicians select appropriate patients for treatment of localized prostate carcinoma in a highly practiced, if less structured, clinical manner. 177

178 / Advanced Therapy of Prostate Disease

printed instruction sheet describing preoperative diet restrictions (clear liquids the day before surgery with nothing by mouth after midnight), advice on what to bring to the hospital, and directions to the admitting office. The authors have not used a more extensive bowel preparation as the incidence of rectal injury is substantially less than 1%. This same pamphlet describes a typical postoperative course, including anticipated length of stay, dietary management, pain control, and the expected intravenous lines, drain, and Foley catheter. Discharge instructions are outlined as well as follow-up visit plans. In short, great efforts are taken to inform the patient of a typical hospital course and to help remove much of their anxiety about what will transpire. There is a great deal of overlap incorporated into this system as patients frequently have difficulty processing all the information presented at any one encounter.

Collaborative Care Pathways Patient education and preparation are critical in promoting a successful outcome of any surgical intervention. Collaborative care refers to the concept of delivery of care in an environment in which the goals are clearly defined.6 As such, it requires input and participation from all levels of the professional team, including the attending surgeons, operating room nurses, resident physicians, floor nurses, social workers, nurse specialists, and even ancillary staff. The tool of the collaborative care team is the creation of a clinical care pathway to help standardize patient management. The care pathway maps out goals and optimum daily care for the ideal patient (Figure 19–1). Practices considered wasteful or unsubstantiated in the medical literature are replaced by those supported by objective data. It is recognized, of course, that not all aspects of basic patient management have been scrutinized in current medical literature, but great efforts are taken to remove practices based purely on habit or custom. It is important to stress that each pathway is created to represent the course of an ideal patient. Care should be expanded as needed for more complex situations. The pathway should be developed with close supervision by the attending physician. The completed product should contain input of all members of the care team and address all steps of a patient’s stay, including preoperative, intraoperative, and postoperative care. Ideally, each institution, and each surgeon if feasible, should develop a unique pathway. Close observation of each patient while on the pathway is very important as the pathway assumes an ideal course. Deviation from the path is not considered a failure as long as such changes occur in response to an individual patient’s needs and not to a potential worst-case scenario. The impact of the pathway at the authors’ institution has been dramatic.7 While recognizing that nearly half of total patient costs are incurred in the operating room,

efforts were made to remove unnecessary supplies and equipment. Standardized trays and sutures were organized. The greatest savings in overall cost occurred in the operating room and in routine care. Operating room costs diminished as a result of a decrease in surgical supplies and surgical time, which decreased by an average of 52 minutes. Length of hospital stay also dropped to a median of 2.9 days (Figure 19–2). Total hospital costs and charges were reduced by 44% (Figure 19–3) while maintaining a high level of patient satisfaction. Overall, 99% of patients responding to a follow-up questionnaire were generally pleased with their hospital stay.

Bowel Preparation Rectal injury is a potential complication of pelvic surgery and can lead to significant morbidity and even mortality. Wound infection, fascial dehiscence, rectourethral fistula, and the need for a diverting colostomy are all acknowledged sequelae of rectal injury. While the reported incidence of rectal injury has ranged from 1 to 11%, most recent reports place the rate at the lower end of the spectrum.8–11 Several factors have been identified to predict those patients at increased risk for sustaining an injury, including previous transurethral surgery, prior pelvic radiation therapy, and a history of previous rectal surgery. High-stage local disease is another potential predisposing factor although the available data supporting this are inconsistent. In addition, the surgical approach influences injury rates. Radical perineal prostatectomy is associated with a higher incidence of rectal laceration than is retropubic surgery.9 To help prevent the serious sequelae of a rectal injury and reduce the need for diverting colostomy, many surgeons advocate using a preoperative bowel preparation. Mechanical bowel preparation can decrease the obvious soilage of the wound and may increase the success of a primary rectal closure. Indeed, several reports on the management of rectal injuries during radical prostatectomy state that primary closure without fecal diversion should not be attempted unless the patient has undergone some type of bowel preparation.8,10 Many variations on the standard Nichols-Condon preparation have been suggested, and multiple studies in the general surgical literature have searched for the ideal antibiotic regimen.12–16 None of these have proven superiority, however, and the “gold standard” remains a mechanical preparation combined with erythromycin and neomycin base, 1 g each given at 1:00 PM, 2:00 PM, and 11:00 PM the day before surgery. There are, however, drawbacks to bowel preparation. Many patients find a thorough mechanical preparation difficult and sometimes intolerable. Heavy preoperative use of antibiotics can lead to the development of resistant organisms, monilial overgrowth, diarrhea, or Clostridium difficile enterocolitis. The frequency with which rectal

Radical Prostatectomy: Patient Preparation / 179 Preop (Outpatient)

Day of Surgery (OR → Floor)

Postop: Day One (Floor)

Postop: Day Two (Floor → Home)

Postop: Day Three (Floor → Home)

F/U: 14 Days (Clinic)

Bowel sounds present, ± flatus Drain output < 100 cc/d Possible D/C if tolerate diet Remove drain if < 60 cc and D/C planned today

Bowel sounds present, passing flatus Follow up appt. w/MD D/C drain if < 60 cc/24° Discharge home with Foley catheter D/C teaching complete

Pt. to bring Depends undergarment to clinic visit

Goals

Preop testing completed WNL Patient/family teaching completed Consent signed

Bowel sounds present, no flatus Drain output < 150 cc/day UOP >150 cc over 4 hours

Labs

SMA 18 CBC w/plt T&S

Hct

Tests

H&P CXR EKG

Treatments

Consent signed

VS q4° x 24, then q8° I&O q4hr Foley catheter IMED Pump JP drain TED stockings Pulm. toilet: TCDB and IS q1hr WA

Activity

Ad lib

May be OOB tonight

Ambulate in hall TID

Diet

Clear liquid diet for supper, then NPO at 12 MN, night before surgery

NPO No ice chips

Full liquid evening meal

Consults

Anesthesia Case Manager

Equipment & Supplies

Meds/IV

OR supplies Anesthesia supplies IMED/IV tubing JP drain TED stockings Foley/Urine bag PCA pump 2 bisacodyl tabs PO in AM the day before surgery

Preop: Cefazolin IV 1 hr prior to surgery Postop: • IV (D5 1/2 NS with 20 mg KCL at 150 cc/hr • Ketorolac 30 mg IV in recovery, then 15 mg IVq6hr for 36 hr • PCA pain med • Promethazine IV q6hr PM nausea • Tylenol prn T >101° •

Teaching/ D/C Plan

Procedure Plan of care VUMC Orientation

Procedure Postop care Hospital routines

Patient Flow

Complete tests and labs

Admit EMA Usual surgery 1.5–2 hr Average blood loss 550 cc General anesthesia Lower abd. midline incision

D/C Possible D/C drain

D/C drain

Regular diet

Regular diet

Possible D/C drain

D/C drain

Hep-lock IV Dulcolax supp. if pt. hasn’t passed flatus

D/C Hep-lock

Foley remains in for 2 weeks after discharge

D/C IV fluid (decrease rate 100 cc/hr)

D/C D/C PCA Oxycodone and Tylenol pm pain

Begin home care instructions Instruct pt. in use of leg bag Complete home care instructions and give pt. HCI sheet Schedule F/U appt. w/attending MD in 14 d Pt. to bring urine protective (Depends undergarment) to follow-up appt.

FIGURE 19–1. Clinical care pathway for radical prostatectomy. OR = operating room; UOP = urine output; F/U = follow-up; ELOS = estimated length of stay.

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While some urologists keep patients on oral antibiotics as long as an indwelling Foley catheter is in place, there does not appear to be a difference in the rate of clinically significant infections compared to those patients not maintained on antibiotics. It has therefore been the authors’ practice to not recommend antibiotics at the time of discharge although an oral antibiotic may be given for 24 to 48 hours following catheter removal. Consecutive Cases

FIGURE 19–2. Radical prostatectomy hospital stay.

injury occurs often does not justify the use of a full, standard bowel preparation. Rectal injury has not occurred in the authors’ series of over 600 consecutive radical retropubic prostatectomies. Therefore, we routinely use a modified preparation consisting of a clear liquid diet the day prior to surgery, bisacodyl (Dulcolax) 10 mg by mouth the morning prior to surgery, and nothing by mouth after midnight. The individual surgeon must use his or her own judgment in deciding which patients require bowel preparation. Factors such as prior rectal/prostatic surgery or previous radiation therapy as well as the surgeon’s own complication rate should influence the decision whether an individual patient requires a bowel preparation.

Antibiotics Radical prostatectomy is considered a “clean contaminated” surgical procedure because of entry into a hollow viscus.17 Wound infection rates can be lowered in this category by the use of preoperative antibiotics, provided they are delivered in such a manner that peak serum levels will be achieved at the time of incision.18 One to two additional postoperative doses may also be given although the data proving the benefit of this are less clear. Extended use of antibiotics has not proven to be of benefit and may promote emergence of resistant organisms. First- or second-generation cephalosporins are frequently used as they provide good gram-positive (skin) coverage as well as activity against some of the gram-negative organisms commonly found in the urinary tract.

Consecutive Cases

FIGURE 19–3. Radical prostatectomy total hospital charges.

Deep Venous Thrombosis Prophylaxis Deep venous thrombosis (DVT) and its potential complications remain the leading cause of major morbidity and mortality following radical prostatectomy. Clinically recognized DVT occurs in 3 to 5% of patients while pulmonary embolism is observed in roughly 1% of cases, with an associated mortality rate of 0.3%.19 There are probably an equal number of unrecognized thromboembolic events. In fact, pulmonary embolism is clinically suspected in only 20 to 30% of those cases where it is the cause of death as determined by autopsy.19 It is equally important to recognize the less drastic sequelae of a DVT such as postphlebitis syndrome, chronic venous insufficiency, or even predisposition to recurrent thromboembolism. The economic consequences are also significant due to factors such as increased length of hospitalization and lost wages. Finally, it is important to realize that most episodes of pulmonary embolism do not occur until after the patient has been discharged.20 There have been multiple studies examining techniques for the prophylaxis of DVT in surgical patients and specifically in prostatectomy patients. Systemic anticoagulation with warfarin has been proposed but has not gained widespread popularity due to concerns about increased intra- and postoperative hemorrhage and increased lymphatic leak and lymphocele formation. Various forms of heparin, particularly unfractionated (UFH) versus low-molecular-weight (LMWH) versions, have been studied and compared. In a recent meta-analysis comparing LMWH to UFH in general surgery patients, both were found to have similar rates of thromboembolic events, with no clear advantage for either form of prophylaxis.21 The only noted statistical difference was a small advantage for LMWH in the incidence of “minor bleeding events” (defined as wound hematomas not requiring evacuation and injection site hematomas). Low-molecular-weight heparin does offer the practical advantage of a more convenient dosing schedule and decreased incidence of thrombocytopenia. The authors evaluated the use of LMWH in radical retropubic prostatectomy patients and have found it to be a safe method of thromboembolic prophylaxis.22 While there was no increase in intraoperative blood loss or postoperative drain output, there was an increased incidence of scrotal and pelvic hematomas. For this reason, the authors

Radical Prostatectomy: Patient Preparation / 181

have now restricted the use of anticoagulants to those patients with a higher risk of thromboembolic events, such as obese patients or those with a previous history of DVT. Pneumatic sequential compression devices (SCD) are often used for DVT prophylaxis, especially among the general surgery and orthopedic patient populations. Several studies have proven their benefit in these settings in lowering the rate of DVT.23,24 The urologic literature has been less persuasive. Strup et al. found that the use of SCDs in their radical prostatectomy patients led to increased intraoperative blood loss, presumably because the SCDs promoted venous return from the lower extremities.25 The authors’ data have failed to confirm an association between SCD use and blood loss with radical prostatectomy.26 Cisek and Walsh examined a large, nonrandomized series of consecutive radical prostatectomy patients and were unable to prove that the rate of DVT decreased with the use of SCDs beyond the immediate perioperative period.20

Blood Management Intraoperative blood loss is a potential source of morbidity for individuals undergoing radical prostatectomy, and the possible necessity of blood transfusion should be discussed with each patient. Due to the potential for transmission of bloodborne diseases, many patients fear the use of homologous blood. With current screening methods, the risk of infection by the human immunodeficiency virus (HIV) is estimated to range from 1 in 450,000 to 1 in 660,000,27 the risk for hepatitis C is 1 in 100,000,28 and the risk of hepatitis B is 1 in 60,00027 (Table 19–1). In addition, hemolytic reactions can result from improperly crossmatched or administered blood at a rate of 1 in 4000. The most common immediate complications are circulatory overload (1 in 100 to 200) and febrile transfusion reaction, occurring in 1 out of every 200 transfusion recipients. To avoid some of these potential problems, many surgeons recommend preoperative banking of autologous blood.29 While the risks of clerical error (the most common cause of transfusion reactions), improper blood storage, and bacterial contamination still exist, banking eliminates the risk of acquiring a new viral infection. Concern has been raised, however, that lowering the hematocrit through preoperative blood donation increases the likelihood that a patient will require a transfusion. Again, the risk of clerical and contamination error still exist, perhaps creating a net increase in risk for the patient. After reviewing expected blood loss and the perception that the majority of patients would not require a transfusion, the authors initiated a prospective study in which autologous blood was not collected prior to radical retropubic prostatectomy. Intraoperative blood loss, length of hospital stay, and, most important, transfusion requirements were analyzed and compared to prestudy practices.30 Only 2.4% of patients required blood trans-

fusion (homologous), compared to the previous transfusion rate of 60% when predonated autologous units were available. The average blood loss was 579 cc while the mean postoperative serum hematocrit was 33% at the time of hospital discharge. With further experience, fewer than 1% of the authors’ patients have required transfusion of any blood products. When combined with the knowledge that homologous transfusion currently has a very low rate of viral transmission, the authors no longer recommend preoperative autologous blood donation prior to radical prostatectomy. The Cell-Saver suction can capture red cells lost during the course of the operation for later return to the patient. Concerns about the return of malignant cells dislodged during manipulation of the prostate seem to be obviated by the use of proper filters to capture all cells larger than an erythrocyte. While this device is used frequently in cardiac and orthopedic surgery, it is probably not necessary when dealing with the volume of blood loss encountered by most urologic surgeons during a typical prostatectomy. This is especially true in the more recent era of anatomic dissections and greater understanding of the periprostatic and deep dorsal vein complexes. In addition to the expense of the equipment, the cost of the trained technician required to operate the devices makes routine use of it prohibitive. Exogenous erythropoietin is available for use to aid in stimulating bone marrow to produce red blood cells. There is a small risk of allergic reaction associated with its use. Experience with the use of erythropoietin for radical prostatectomy is limited. However, several weeks of administration can increase serum hematocrit by several percentage points and decrease transfusion requirements in some groups.

Anesthesia The method of anesthesia used for radical retropubic prostatectomy is mostly a matter of surgeon, anesthesiologist, and patient preference. There is no conclusive eviTABLE 19–1. Frequency of Adverse Events of Red Blood Cell Transfusion Adverse Event

Estimated Frequency per Unit of Blood

Death 2° hemolytic reaction Febrile transfusion reaction Allergic transfusion reactions Acute anaphylaxis Acute hemolysis Transfusion-induced immunosuppression Bacterial contamination Cytomegalovirus Hepatitis B virus Hepatitis C virus Human immunodeficiency virus

1:633,000 1:200 1:333 1:20,000–50,000 1:4000 Unknown 1:1,000,000 3–12 per 100 1:60,000 1:100,000 1:450,000–660,000

Adapted from Simon TL, Alverson DC, AuBuchon J, et al. Practice parameter for the use of red blood cell transfusions. Arch Pathol Lab Med 1998;122:130–8.

182 / Advanced Therapy of Prostate Disease

dence for the superiority of one method over another for this particular procedure. While some studies suggest that the use of epidural anesthesia can reduce intraoperative blood loss via vasodilatation of the lower body vasculature, others have failed to confirm this finding.31 The authors prefer general anesthesia as no adverse effect on blood loss or other parameters has been observed. The selection of patients with at least a 10- to 15-year life expectancy for radical prostatectomy inherently produces healthier individuals than those undergoing various other oncologic operations. In addition, improved understanding of the local venous systems and refinement of anatomic dissection of the prostate have helped dampen the massive fluid shifts associated with radical prostatectomy in the past. The need for invasive monitoring therefore seems to be diminished. In addition, the use of invasive vascular catheters is associated with potential morbidity. Arterial catheters can cause infection, thrombosis, or even nerve injury during placement. Central venous catheter insertion can lead to pneumothorax, hemothorax, arterial injury, infection, or hematoma formation. With this in mind, the authors discontinued using invasive lines for patients as part of the collaborative pathway. In subsequent evaluations of the hospital course of 247 consecutive patients, the authors have found that none of these patients required intraoperative placement of an invasive line. 32 In addition, none of these patients suffered an adverse event that would have been more appropriately treated if a line had been in place at the time of the event. It can therefore be concluded that invasive monitoring is not necessary during radical prostatectomy.

Pain Management Many options are available for postoperative pain control, including intermittent narcotics, patient-controlled devices (PCA), epidural catheters, and adjuvant agents (e.g., ketorolac). Multiple studies have proven the effectiveness of epidural anesthesia or patient-controlled narcotics in surgical patients. Some studies have shown a more rapid resolution of postoperative ileus and improved gastric emptying when epidural catheters are used. In addition, other authors have shown improved patient comfort with epidural narcotics compared to parenteral narcotics.33 Shir et al. recently looked at the use of epidural catheters versus general anesthesia in radical prostatectomy patients for delivering intraoperative anesthesia and postoperative analgesia.34 Patients were randomized to either method. No differences were noted in complication rates, return of bowel function, or length of hospitalization. Nonsteroidal anti-inflammatory drugs (NSAIDs), in particular ketorolac, are being used increasingly for perioperative pain relief and have proven to be safe and effective in radical prostatectomy patients.35 Data suggest a role

for these and other drugs administered preoperatively to achieve preemptive effects.36,37 The need for narcotics can be decreased if NSAIDs are used, thereby reducing side effects such as ileus.35 This has enabled earlier resumption of oral feeding and more rapid discharge from hospital. The authors currently recommend a 30-mg intravenous dose of ketorolac administered 30 minutes before surgical incision. Postoperative doses of 15 mg are repeated every 6 hours for 36 hours, at which time the patient is converted from a morphine PCA to long-acting oral narcotics. It is very important to adhere to strict dosing regimens and avoid prolonged use of this medication.38 Older patients, or those with underlying renal insufficiency (atypical prostatectomy candidates), are at increased risk of suffering adverse consequences from the use of this medication. Increased risks of gastrointestinal and operative site hemorrhage from inappropriate use of ketorolac are well documented.

Discharge Planning Effective discharge planning begins before the patient enters the hospital. There should be a system for followup developed, and the patient should be instructed on how to access this system. Specific, detailed home-care instructions should be established and provided to the patient in verbal and written form. Instructing patients in the care of their Foley and legbag has become a routine part of postoperative care for surgical floor nurses. In addition, warning signs and symptoms of potential complications such as wound infection, DVT, and pulmonary embolism are reviewed. The nurse practitioner working at the authors’ clinic visits each patient and reviews much of the same information. Home health care nurses can be arranged if necessary. The nurse practitioner performs a follow-up phone call 1 to 2 days after discharge to help answer any questions and avert potential complications.

References 1. Warner J, Whitmore WF Jr. Expectant management of clinically localized prostate cancer. J Urol 1994;152 (5 Pt 2):1761–5. 2. Studer UE. Radical prostatectomy or deferred treatment? Semin Surg Oncol 1995;11:46–9. 3. Chodak GW, Thisted RA, Gerber GS, et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994;330:242–8. 4. Koch MO, Miller DA, Butler R, et al. Are we selecting the right patients for treatment of localized prostate cancer? Results of an actuarial analysis. Urology 1998;51(2): 197–202. 5. Archer C, Levy AE, McGregor M. Value of routine preoperative chest X-rays: a meta-analysis. Can J Anaesth 1993;40:1022–7. 6. Koch MO, Smith JA Jr, Hodge EM, et al. Prospective development of a cost-efficient program for radical retropubic prostatectomy. Urology 1994;44:311–8.

Radical Prostatectomy: Patient Preparation / 183 7. Smith JA Jr, Koch MO. Collaborative care pathways— impact on treatment costs and quality of care after radical prostatectomy. J Managed Care 1997;1:36–9. 8. McLaren RH, Barrett DM, Zincke H. Rectal injury occurring at radical retropubic prostatectomy for prostate cancer: etiology and treatment. Urology 1993;42:401–5. 9. Lassen PM, Kearse WS. Rectal injuries during radical perineal prostatectomy. Urology 1995;45(2):266–9. 10. Harpster LE, Rommel FM, Sieber PR, et al. The incidence and management of rectal injury associated with radical prostatectomy in a community based urology practice. J Urol 1995;154:1435–8. 11. Borland RN, Walsh PC. The management of rectal injury during radical retropubic prostatectomy. J Urol 1992; 147:905–7. 12. Condon RE, Bartlett JG, Greenlee H, et al. Efficacy of oral and systemic antibiotic prophylaxis in colorectal operations. Arch Surg 1983;118:496. 13. Khubchandani IT, Karamchandani MD, Sheeb JA, et al. Metronidazole versus erythromycin, neomycin, and cefazolin in prophylaxis for colonic surgery. Dis Colon Rectum 1989;32:17. 14. Groner JI, Edmiston CE Jr, Krepel C, et al. The efficacy of oral antimicrobials in reducing aerobic and anaerobic colonic mucosal flora. Arch Surg 1989;124:281. 15. Gottrup F, Diederich P, Sorensen K, et al. Prophylaxis with whole gut irrigation and antimicrobials in colorectalsurgery: a prospective randomized double-blind clinical trial. Am J Surg 1985;149:317–22. 16. Wolff BG, Beart RW Jr, Dozois RR, et al. A new bowel preparation for elective colon and rectal surgery: a prospective, randomized clinical trial. Arch Surg 1988;123:895–900. 17. Cluver DH, Horan TC, Gaynes RP. Surgical wound infection rates by wound class, operative procedure, and patient risk index. Am J Med 1991;91:1525. 18. Carson CC III. Antimicrobial prophylaxis in genitourinary surgery. In: Mulholland SG, editor. Antibiotic therapy in urology. Philadelphia: Lippincott-Raven Publishers; 1996. p. 221–36. 19. Clagett GP. Prevention of postoperative venous thromboembolism: an update. Am J Surg 1994;168:515–22. 20. Cisek LJ, Walsh PC. Thromboembolic complications following radical retropubic prostatectomy: influence of external sequential pneumatic compression devices. Urology 1993;42:406–8. 21. Palmer AJ, Schram W, Kirchof B, Bergemann R. Low molecular weight heparin an unfractionated heparin for prevention of thrombo-embolism in general surgery: a meta-analysis of randomised clinical trials. Haemostasis 1997;27:65–74. 22. Koch MO, Smith JA Jr. Low molecular weight heparin and radical prostatectomy: a prospective analysis of safety and side effects. Prostate Cancer Prostatic Dis 1997;1:101–4.

23. Hull RD, Hirsch J. Preventing venous thromboembolism. J Cardiovasc Med 1984;1:63–77. 24. Nicolaides AN, Fernandes E, Fernandes J, Pollock AV. Intermittent sequential compression of the legs in the prevention of venous stasis and postoperative deep venous thrombosis. Surgery 1980;87:69–76. 25. Strup SE, Gudziak M, Mulholland SG, Gomella LG. The effect of intermittent pneumatic compression devices on intraoperative blood loss during radical prostatectomy and radical cystectomy. J Urol 1993;150:1176. 26. Koch MO, Brandell RA, Lin D, Smith JA Jr. The effect of sequential compression devices on intraoperative blood loss during radical prostatectomy. J Urol 1994; 152:1178–9. 27. Simon TL, Alverson DC, AuBuchon J, et al. Practice parameter for the use of red blood cell transfusions. Arch Pathol Lab Med 1998;122:130–8. 28. Donahue JG, Munoz A, Ness PM, et al. The declining risk of post-transfusion hepatitis C virus infection. N Engl J Med 1992;327:369–73. 29. Toy PT, Menozzi D, Strauss RG, et al. Efficacy of preoperative donation of blood for autologous use in radical prostatectomy. Transfusion 1993;33:721–4. 30. Koch MO, Smith JA Jr. Blood loss during radical retropubic prostatectomy: is preoperative autologous blood donation indicated? J Urol 1996;156:1077–80. 31. Shir Y, Raja SN, Frank SM, Brendler SB. Intraoperative blood loss during radical retropubic prostatectomy: epidural versus general anesthesia. Urology 1995;45:993. 32. Ead DN, Koch MO, Smith JA Jr. Is invasive anesthetic monitoring necessary during radical prostatectomy? [Submitted] 33. Yeager MP, Glass DD, Nee RK, Brinck-Johnsen T. Epidural anesthesia and analgesia in high-risk surgical patients. Anesthesiology 1987;66:729–36. 34. Shir Y, Frank SM, Brendler CB, Raja SM. Postoperative morbidity is similar in patients anesthetized with epidural and general anesthesia for radical prostatectomy. Urology 1994;44:232–6. 35. Grass JA, Sakima NT, Valley M, et al. Assessment of ketorolac as an adjuvant to fentanyl patient-controlled epidural analgesia after radical retropubic prostatectomy. Anesthesiology 1993;78:642–8. 36. Gottschalk A, Smith DS, Jobes DR, et al. Preemptive epidural anesthesia and recovery from radical prostatectomy. JAMA 1998;279:1076–82. 37. Michaloliakou C, Chung F, Sharma S. Preoperative multimodal analgesia facilitates recovery after ambulatory laparoscopic cholecystectomy. Anesth Analg 1996; 82(1):44–51. 38. Strom BL, Berlin JA, Kinman JL, et al. Parenteral ketorolac and risk of gastrointestinal and operative site bleeding. JAMA 1996;275:376–82.

CHAPTER 20

STAGE T1A PROSTATE CANCER: THE CASE FOR TREATMENT GARY D. GROSSFELD, MD; PETER R. CARROLL, MD Stage T1 prostate cancer is an incidentally discovered malignancy. The patient becomes aware that he has stage T1 prostate cancer following pathologic examination of tissue removed by transurethral resection or open enucleation for presumed benign prostatic hyperplasia (BPH). Approximately 10% (range 8 to 22%) of men undergoing such procedures will be diagnosed with incidental prostate cancer.1–6 This percentage has remained constant despite the introduction of serum prostate-specific antigen (PSA) screening for prostate cancer and the evolution of noninvasive treatment modalities for BPH. Monda et al. described the prevalence of stage T1 prostate cancer in 966 patients undergoing transurethral resection of the prostate (TURP) for presumed BPH.7 This population included 499 consecutive patients who underwent TURP prior to the introduction of serum PSA testing and 467 consecutive patients who underwent TURP after being screened for prostate cancer with serum PSA and transrectal ultrasound-guided biopsies. The prevalence of stage T1 prostate cancer was nearly equivalent in these two groups despite the use of PSA screening in the more recent cohort (stage T1 prostate cancer in 8.6% of unscreened patients versus 10.3% of screened patients). Since the diagnosis of stage T1 prostate cancer depends on tissue obtained at the time of surgery for BPH, the introduction of newer, less invasive treatment modalities would be expected to have a significant impact on the overall incidence of newly discovered stage T1 prostate cancers. This has indeed been the case. Many minimally invasive therapies for BPH, including medical treatment, intraurethral stenting, laser, and electrical or microwave ablation of the prostate, do not produce prostatic tissue for histologic diagnosis. As a result, the overall number of patients with stage T1 prostate cancer appears to have declined.3 Fowler et al. analyzed temporal trends in the diagnosis of stage T1 prostate cancer over a period of time that included the introduction of medical and minimally invasive treatments for BPH.3 While these authors found no change in the proportion of TURP patients diagnosed with stage T1 prostate cancer during this time period, they did find a marked decline in the absolute number of prostate cancers detected. This decline in prostate cancer detection closely paralleled the less frequent use of TURP in the treatment of BPH.

Stage T1 prostate cancers appear to represent a spectrum of disease. These tumors can be divided into two biologically meaningful groups based on tumor volume and grade. It is generally accepted that high-volume, high-grade disease possesses a significant risk for progression if left untreated.8 Low-volume, low-grade disease, however, (socalled stage T1a prostate cancer) may pursue an indolent course and therefore not require treatment. More recent studies describing the natural history of untreated stage T1a prostate cancer have challenged this long-held belief by reporting disease progression in patients with long-term follow-up. The appropriate treatment of patients with stage T1a prostate cancer has thus become a matter of debate in the literature. For younger patients diagnosed with stage T1a prostate cancer who have at least a 10-year life expectancy, some would recommend aggressive local treatment of the primary tumor to prevent disease progression. The purpose of this chapter is to provide evidence in support of an aggressive approach to the treatment of stage T1a prostate cancer. This will be accomplished by (1) defining stage T1a prostate cancer; (2) describing the pathologic findings associated with radical prostatectomy specimens removed for stage T1a prostate cancer; (3) summarizing recent literature concerning the biologic potential of untreated stage T1a prostate cancer; (4) describing the accuracy of clinical staging techniques used to define the risk of progression for patients with stage T1a prostate cancer; and (5) summarizing the results of definitive local treatment for patients with this stage of disease. Through the course of the chapter it will become increasingly obvious that select patients with untreated stage T1a prostate cancer may be at a substantial risk for disease progression. These patients should therefore be considered candidates for definitive local treatment of their disease.

Definition Stage T1 prostate tumors can be categorized into two separate groups based on tumor grade and stage. In 1975, Jewett proposed that stage T1 tumors be subdivided into those of low biologic potential that pursue an indolent course and rarely progress (low stage and low grade), and those with a more aggressive biologic potential and a high likelihood of progression if left untreated (high grade and/or high volume).9 Unfortunately, precise cut-points 184

Stage T1a Prostate Cancer: the Case for Treatment / 185

between low and high volume and low and high grade were not specified and have never been standardized. Consequently, the definition of focal (stage T1a) and diffuse (stage T1b) incidental prostate cancer has varied between different series in the literature. Low-volume disease has previously been defined based on the total number of chips involved with cancer (less than 3 or 5 chips containing cancer), the total volume of tumor resected (< 1 cm3 of cancer present in the specimen), and the percentage of the specimen involved with tumor (from < 5% involvement to < 50% involvement with cancer).6,10,11 Similarly, the distinction between low- and high-grade disease has varied between investigators. Some authors have included both well- and moderately differentiated tumors (Gleason 2 to 4 and 5 to 7) in the stage T1a category while others have included only well-differentiated tumors.6,10 Epstein and colleagues demonstrated that as long as the tumor occupied ≤ 5% of the TURP specimen, there was no difference in the progression rate at 8 years following diagnosis whether the tumor Gleason score was ≤ 4 or 5 to 6.12 The most recent American Joint Committee on Cancer staging system for prostate cancer categorizes stages T1a and T1b disease using a 5% volume cutoff without mention of tumor Gleason score.13 Percent of the TURP specimen involved with tumor is often estimated by circling all identifiable foci of carcinoma with a marking pen and then combining these foci to calculate the percentage of total tissue involvement with tumor.8,14,15 Although this seems to be a crude method of estimation which does not account for the total volume of resected tissue, it has been shown to be a reproducible technique. Cantrell et al. demonstrated that the pathologist’s estimate of tumor volume corresponded well with tumor progression, and that this estimate was an equally good predictor of progression when compared with the morphometrically determined percentage of tumor extent.8 Other measures of tumor burden, such as the total number of tumor foci present, were less accurate in predicting progression. Epstein and colleagues recently examined whether actual resected tumor volume was a better predictor of progression in stage T1 prostate cancer than percent involvement with tumor.14 These authors questioned whether 1% involvement of a 50-g specimen (0.5 g of tumor) would have a worse prognosis than 1% involvement of a 5-g specimen (0.05 g of tumor). This study demonstrated that while both actual tumor volume and percent involvement with tumor were highly associated with tumor progression, percent involvement with tumor had a stronger association with progression. Variability in the method by which TURP or open prostatectomy specimens are processed may potentially influence the distinction between stage T1a and T1b prostate cancer. Murphy et al. and Rohr have demonstrated that submission of eight cassettes of tissue (12 g) can detect nearly all stage T1b prostate cancers and approximately

90% of stage T1a tumors.16,17 Because high-grade tumors should extensively involve the TURP specimen, this method of analysis should not lead to mistaken classification of stage T1a versus T1b based on tumor grade. In contrast, Newman et al. reported a 65% increase in the occurrence of incidentally diagnosed prostate cancer when the total specimen was examined.18 In addition, areas of highgrade carcinoma were focally present in 7% of their stage T1b lesions. These foci may have been missed if the entire TURP specimen had not been submitted. McDowell et al. examined whether or not submission of remaining tissue after the initial processing of eight cassettes would change stage T1a prostate cancer to T1b or vice versa.15 In this study, the authors examined 34 cases of stage T1 prostate cancer in which the tumor involved ≤ 15% of the specimen and 10 or more cassettes were required for total submission. The first eight slides were initially reviewed then the remaining slides were reviewed to determine if the overall percent involvement or grade changed. It was interesting to note that review of the remaining slides did not result in restaging any of these cancers based on volume criteria. Thus, there appeared to be no benefit to resubmitting stage T1b tumors (≥ 5% involvement) because examination of the remaining tissue would not lower tumor stage. However, one T1a tumor was upstaged to T1b based on the discovery of a high-grade tumor focus in the remaining tissue after examination of the initial eight slides. Because of this finding, and the infrequency with which extra tissue would need to be submitted, these authors recommended resubmission of all remaining tissue in those few cases of stage T1a prostate cancer requiring more than eight cassettes for complete analysis.

Pathology Does stage T1a prostate cancer represent an incidental, low-volume, unifocal tumor with limited biologic potential, or does it actually represent the “tip of the iceberg” for a larger, peripherally based malignancy? To address this issue, several studies have examined radical prostatectomy specimens removed for clinical stage T1a prostate cancer and described the incidence and characteristics of any residual prostatic cancers (Table 20–1). Parfitt et al. analyzed radical prostatectomy specimens removed from 31 patients with clinical stage T1a prostate cancer.19 These authors reported that 52% of the specimens contained no evidence of residual tumor while focal residual disease (reclassified as stage T1a) was found in 35% of the remaining cases. Residual diffuse tumor was present in only 13% of these specimens. In contrast, Paulson et al. analyzed 18 radical prostatectomy specimens removed for clinical stage T1a disease and found no evidence of residual tumor in three specimens (17% only).20 Of the remaining cases, 22% demonstrated a

186 / Advanced Therapy of Prostate Disease

single microscopic focus of residual disease while 61% were upstaged to stage T1b or T3. At least 2 patients in this series demonstrated evidence of tumor extension into the seminal vesicles while 1 patient had evidence of bladder-neck invasion.20 Zincke et al. analyzed radical prostatectomy specimens obtained from 32 patients with clinical stage T1a disease and found no residual tumor in 25%, stage T1a disease in 41%, stage T1b disease in 22%, and extracapsular disease extension or pelvic lymph node involvement in 12% of cases.21 Two studies from the Johns Hopkins Hospital have also described the pathologic findings of radical prostatectomy specimens removed for clinical stage T1a prostate cancer.22,23 In their initial study, Epstein and colleagues analyzed radical prostatectomy specimens obtained from 21 such patients.22 In this series, 14% of patients had no residual tumor at the time of radical prostatectomy even though all of these specimens demonstrated histologic evidence of severe dysplasia on final pathologic analysis. Sixty-two percent of the remaining specimens demonstrated minimal residual disease while 24% demonstrated substantial residual tumor in the radical prostatectomy specimen. When minimal residual tumor was present, it was located at the prostatic apex or in the periphery of the gland, areas which are difficult to sample by repeat transurethral resection. Of the 5 cases with substantial residual tumor, 2 (40%) demonstrated focally positive surgical margins near the prostatic apex. Larsen et al. expanded on this initial study by analyzing radical prostatectomy specimens removed from 64 patients with clinical stage T1a disease.23 In this study, only 6% of specimens had no residual cancer while 74% had minimal and 20% had substantial residual cancer (defined as either >1 cm3 total tumor volume, capsular penetration, or high-grade tumor). Five cases (8%) demonstrated capsular penetration and 2 of these also had positive surgical margins. Residual tumors were distributed in a heterogeneous manner throughout the prostate, with 39% having a predominately apical location and 61% having a predominately peripheral location. Neither transurethral resection tumor volume, per-

cent involvement of the TURP specimen with tumor, nor tumor grade at TURP were significantly associated with radical prostatectomy tumor volume or the presence of minimal versus substantial residual disease.23 McNeal et al. compared the morphologic features of radical prostatectomy specimens obtained from 11 patients with clinical stage T1 prostate cancer to those of specimens obtained from 73 patients with clinical stage T2 disease.24 This study demonstrated that all stage T1 cancers were located anteromedially (commonly invading the anterior fibromuscular stroma) while most stage T2 cancers were located posteriorly. The stage T1 and T2 cancers were similar with respect to range of tumor volume and degree of differentiation. Both stages of tumor demonstrated progressive dedifferentiation with increasing tumor volume. These results strongly suggested that although differing in their sites of origin, stage T1 and T2 tumors were similar with respect to their biologic potentials. In a related study by Voges et al., morphometric analysis was performed on 44 radical prostatectomy specimens removed from patients with clinical stage T1 tumors (22 patients with stage T1a and 22 patients with stage T1b cancer).25 Six of the 22 specimens (27%) removed for clinical stage T1a disease demonstrated extracapsular disease extension on final pathologic analysis while 5 of the 22 specimens (23%) demonstrated positive surgical margins. Further, 90% of the specimens from patients with clinical stage T1a disease demonstrated unsuspected cancers apparently unrelated to the index tumor identified at the time of transurethral resection. Eighty-three percent of these unsuspected tumors were located outside of the transition zone and 26% measured > 0.2 cm3 in volume. Based on these morphometric studies, it was concluded that transurethral sampling cannot reliably predict total tumor volume, residual tumor volume, or cancer grade. Finally, Babaian et al. analyzed 8 stage T1a prostate cancers identified from 100 cystoprostatectomy specimens removed from patients with bladder cancer.26 Similar to the findings of Voges et al.,25 these authors demonstrated that 50% of the specimens with stage T1a prostate cancer demonstrated multifocal disease (3 specimens

TABLE 20–1. Analysis of Radical Prostatectomy Specimens from Patients with Clinical Stage T1a Prostate Cancer Author

N

Parfitt19 Paulson20

31 18

Epstein22 Larsen23 Zincke21 Voges25

21 64 32 22

No Residual Disease

Minimal Residual Disease

Substantial Residual Disease

52% 17%

35% 22%

13% 61%

14% 6% 25% 0

62% 74% 41% 14%*

24% 20% 34% 86%

ECE = extracapsular extension. *Total residual volume less than 0.2 cm3.

Comments 2 patients with seminal vesicle invasion, 1 patient with bladder neck invasion 10% margin positive 8% ECE, 3% margin positive 9% stage C, 3% positive lymph nodes 90% with unsuspected cancers

Stage T1a Prostate Cancer: the Case for Treatment / 187

with 2 tumor foci and 1 specimen with 3 tumor foci). In addition, 62.5% of these specimens contained foci of grade 3 prostatic intraepithelial neoplasia (PIN) which were distinct from any overt focus of cancer. It is evident from these radical prostatectomy studies that a significant percentage of patients with clinical stage T1a prostate cancer will have substantial residual tumor present after the initial transurethral resection. In many instances, these tumors may be multifocal and exhibit adverse pathologic characteristics (including extracapsular disease extension and positive surgical margins). Unfortunately, resected tumor volume, percent of TURP specimen involved with tumor, and tumor grade cannot accurately predict which patients will continue to harbor substantial disease following TURP. It is clear that some patients with clinical stage T1a prostate cancer will be at risk for disease progression with longterm follow-up and expectant management. These are the patients who may benefit from aggressive local therapy of their prostate cancer.

Natural History of Untreated Stage T1a Prostate Cancer Stage T1a prostate cancer is an incidental finding. Any patient with this diagnosis, therefore, will have no signs or symptoms referable to his underlying malignancy. In addition, stage T1a prostate cancer, by definition, represents low-volume, low-grade disease which may possess a limited potential for progression. Because this stage of disease is often diagnosed in elderly men, several important issues must be addressed before a recommendation can be made regarding aggressive treatment for a newly diagnosed patient. These issues include: (1) the natural history of untreated stage T1a prostate cancer; (2) the overall life expectancy of the patient; (3) serious complications that may be associated with treatment; (4) the ability to distinguish stage T1a tumors with a high likelihood of progression from those with a low biologic potential; and (5) the effectiveness of local treatment in eradicating disease. Due to its seemingly low biologic potential, most early studies suggested that stage T1a prostate cancer had little impact on either overall or prostate cancer-specific survival. Generally, a 10-year mortality rate of less than 5% was associated with expectant management of such patients, likely due to a high prevalence of comorbid conditions in this patient population leading to death from intercurrent illness.6 In a study of 847 consecutive patients undergoing suprapubic prostatectomy for BPH, Bauer et al. found that 28 patients had well-differentiated prostate cancer at the time of surgery.27 Overall survival for these patients at 5 and 10 years following diagnosis was 75% and 47%, respectively. Consequently, these authors suggested that small, well-differentiated, incidentally discovered prostate cancers may require no further

treatment. Confirming these results, Hanash et al. reported disease specific outcomes for 21 patients with incidentally discovered, low-grade prostate cancers who were managed expectantly.28 Overall survival 5 years after diagnosis was reported to be 100% for these patients, and survival in this group of patients continued to be superior to expected survival (based on life-table analysis) for up to 15 years after diagnosis. The high rate of intercurrent illness in this patient population has resulted in disease progression replacing overall survival as the end point for measuring the biologic potential of stage T1a prostate cancer. In 1981, Cantrell et al. examined the rate of disease progression in 49 patients with stage T1a disease and at least 4 years of follow-up after diagnosis.8 Disease progression was reported in only one patient (2%) during this follow-up period (Table 20–2), confirming the low biologic potential of this stage of disease. Due to increasing life expectancy, patients with stage T1a prostate cancer who are managed expectantly will spend more time alive with their prostate cancer. Consequently, the policy of expectant management for these patients has recently been challenged. Several studies have demonstrated not only the potential for disease progression but also for death due to disease in these patients.5,12,29 More recent studies, with long-term follow-up, suggest that disease progression can occur in 10 to 27% of patients with stage T1a prostate cancer who are managed expectantly for 7 to 10 years after diagnosis (see Table 20–2). Epstein et al. reported the results of 50 men with stage T1a prostate cancer who were managed expectantly and followed for at least 8 years after diagnosis.12 In this study 8 patients (16%) experienced disease progression, and 6 of these 8 patients died of prostate cancer within an average of 2 years after progression. Neither tumor volume on the TURP specimen nor tumor grade predicted which patients would ultimately progress. Thompson and Zeidman followed 60 patients with stage T1a prostate cancer for an average of 7.5 years after diagnosis.5 Although the overall rate of disease progression was low in this groups of patients (5%), 8% of patients at risk for at least 7 years demonstrated progressive disease, and all 3 patients who progressed died of disease within 1 year of progression. Similar to the findings of Epstein et al., these authors reported no correlation between tumor volume at TURP and disease progression. Blute et al. reported progressive disease in 27% of men with stage T1a prostate cancer managed expectantly with the median time to progression being 10.2 years.30 Three of the 4 patients who progressed in this study did so with systemic disease. Finally, Ingerman et al. reported disease progression in 13% of patients with stage T1a prostate cancer presumed to be at low risk due to a negative staging TURP.31 Of the 3 patients who progressed, 1 did so with metastatic disease.

188 / Advanced Therapy of Prostate Disease

Additional evidence in support of the observation that stage T1a prostate cancer may progress over time is found in a study by Brawn.32 In this study, TURP specimens were examined from 54 patients with prostate cancer who required two separate transurethral resections. The second procedure was performed from 3 to 11 years after the initial TURP. Of 26 patients with grade 1 prostate cancer at the time of initial TURP, 19 (73%) had higher grade tumors at repeat resection. In addition, 75% of grade 2 lesions and 88% of grade 3 lesions dedifferentiated into a higher grade at repeat TURP. All 8 poorly differentiated tumors (grade 4) remained poorly differentiated on both resections. Grade was unchanged in only 10 (19%) patients, and only 1 lesion demonstrated a lower grade at repeat resection (from grade 2 to grade 1). The presence of metastases in this study was associated with tumor grade. While no grade 1 tumors demonstrated metastases, 19% of the grade 2 lesions, 55% of the grade 3 lesions, and 80% of the grade 4 lesions were associated with metastatic disease. These data suggest that low-grade prostate cancers may have the ability to dedifferentiate over time and that progression of the disease may be a consequence of such dedifferentiation. Similar to the data obtained from the radical prostatectomy studies described above, studies examining the natural history of untreated stage T1a prostate cancer strongly suggest that a significant percentage of these tumors have the potential for progression with long-term follow-up. Not only can these tumors progress locally, but there is also evidence to suggest that systemic progression, leading to death from disease, may be possible. It does not appear that the likelihood of progression can be reliably predicted from the findings at TURP, but the major risk factor for progression appears to be extended follow-up. Thus, for patients with stage T1a disease and a long life expectancy (greater than 10 years), some form of local treatment does appear warranted.

Risk Assessment Tumor volume and grade have been the traditional measures used to categorize incidental prostate cancers into stages T1a or T1b. It is also clear, however, that while some clinical stage T1a tumors will progress, others will pursue a more indolent course. The ability to distinguish those tumors with a high likelihood of subsequent progression from those that will not progress is of obvious clinical importance in selecting appropriate patients for definitive local therapy. Several staging modalities have been studied for this purpose, including repeat TURP, transrectal ultrasound and prostate biopsy, and serial PSA measurement. Repeat Transurethral Resection of the Prostate Repeat TURP has been proposed as a staging procedure for patients with stage T1a prostate cancer. It has been hypothesized that the presence of residual cancer at the time of repeat resection should be useful in upstaging patients from T1a to T1b disease, thus identifying patients who require early, aggressive local therapy. Studies examining the use of repeat TURP in these patients, however, have not clearly demonstrated the benefit of this staging procedure. These studies have reported diffuse residual disease (resulting in clinical upstaging to T1b disease) in only 3.5 to 26% of patients (Table 20–3). Conversely, 63 to 82% of patients have demonstrated no evidence of residual disease at the time of repeat TURP.1,19,33–37 While tumor volume on the initial TURP specimen does not appear to be associated with the finding of diffuse residual disease at repeat TURP,19 an association between tumor grade and upstaging has been reported.36 In a study by Sonda et al., none of 12 patients with Gleason score 2 to 4 cancer on the initial TURP were upstaged by repeat resection, compared to 3 of 19 patients (16%) with Gleason score 5 to 7 tumors.36

TABLE 20–2. Natural History of Untreated Stage T1a Prostate Cancer Author

Year

N

Number with Progression (%)

Heaney52 Correa53 Cantrell8 Blute30 Epstein12 Thompson5 Lowe34 Roy29 Zhang37 Ingerman31

1977 1974 1981 1986 1986 1989 1990 1990 1991 1993

50* 39* 49 15 50 60 80 19 132 24‡

3 (6%) 3 (8%) 1 (2%) 4 (27%) 8 (16%) 3 (5%) 12 (15%) 3 (16%) 13 (10%) 3 (13%)

N/A = not specified; TURP = transurethral resection of the prostate. *Some patients in these series treated with radical prostatectomy or hormonal therapy. †Median time to progression. ‡All patients without residual carcinoma on repeat TURP.

Follow-Up

Definition of Stage T1a (Volume, Grade)

N/A N/A At least 4 years 10.2 years† At least 8 years 7.5 years 8.4 years N/A 8.2 years 7 years

Small and focal, well differentiated Focal, none poorly differentiated ≤ 5% of TURP, none poorly differentiated < 1 cm3, well differentiated ≤ 5% of TURP, Gleason 2–7 < 5 foci on TURP, well differentiated ≤ 5% of TURP, none poorly differentiated Low volume and grade < 5% of TURP, Gleason ≤ 4 < 5% of TURP, Gleason < 5

Stage T1a Prostate Cancer: the Case for Treatment / 189

While it is possible that residual disease at the time of repeat TURP may identify a subset of patients at a higher risk for disease progression, a negative repeat TURP does not appear to exclude this risk. Zhang et al. performed repeat TURP on 52 patients with clinical stage T1a disease.37 Fourteen patients (27%) demonstrated residual foci of well-differentiated disease, including 2 patients (4%) who were upstaged to T1b and underwent radical prostatectomy. Of the remaining 12 patients, progressive disease was eventually encountered in 3 patients (25%). Although the presence of residual disease did appear to identify a population of patients at increased risk for disease progression, a negative repeat TURP did not exclude the possibility of progression (8% of patients with a negative repeat TURP still progressed). These findings were confirmed in a study by Ingerman et al. in which 3 of 24 patients (13%) with clinical stage T1a prostate cancer and a negative repeat TURP developed progressive disease.31 This progression rate, which was similar to that reported for stage T1a patients not undergoing repeat TURP, caused these authors to conclude that repeat TURP does not effectively evaluate the risk of progression in these patients. The inability of repeat TURP to identify patients with a high likelihood of disease progression is not surprising given the anatomic location of residual prostate cancer. As described above, Epstein et al. reported that residual carcinoma in radical prostatectomy specimens removed for clinical stage T1a prostate cancer is often located at the prostatic apex or in the periphery of the gland, adjacent to the prostatic capsule.22 Tumor in these locations is usually not amenable to TURP. Further, Voges et al. reported that 90% of radical prostatectomy specimens removed for stage T1a disease contained unsuspected cancers and that 83% of these cancers were located in the peripheral zone.25 Repeat TURP therefore does not appear to be useful in distinguishing those patients with clinical stage T1a prostate cancer who require aggressive local therapy from those who can be managed expectantly. Transrectal Ultrasonography and Biopsy Although transrectal ultrasonography (TRUS) with ultrasound-guided biopsy of the prostate has been a welldescribed method of prostate cancer diagnosis and staging, few studies have examined the utility of TRUS and biopsy in risk assessment for patients previously diagnosed with stage T1a prostate cancer. Carroll et al. described the results of transperineal needle biopsy of the prostate in 26 patients with stage T1a prostate cancer, including 24 patients who had also undergone a staging TURP.33 Only 2 of these 26 patients (8%) had residual tumor identified by transperineal biopsy. Of the 24 patients undergoing both procedures, residual disease was identified in 6 patients on repeat TURP, with only 1 of these patients (17%) also demonstrating tumor by transperineal needle biopsy. These results suggest that

transperineal needle biopsy is not a reliable method for detection of residual disease following initial TURP. Several studies have examined the ability of TRUS to identify residual disease in patients with stage T1 prostate cancer following their initial TURP. Sheth et al. performed TRUS in 29 patients with stage T1 prostate cancer prior to radical prostatectomy.38 The sensitivity of TRUS for evaluating clinical stage T1 lesions was only 55%. The total extent of tumor was often underestimated by TRUS and was unreliable for detection of anterior cancers. The specificity of TRUS in this study was also low (37%), as 19 of the 30 hypoechoic lesions identified did not prove to be cancer. Egawa et al. performed TRUS in 38 patients with stage T1 prostate cancer approximately 3 weeks after initial TURP.39 The positive predictive value (PPV) of TRUS in this study ranged from 60 to 80%. The predictive ability of TRUS was correlated with both the amount and location of residual disease. Forty-seven percent of the hypoechoic lesions identified by TRUS and located in the transition zone, and 88% of those located in the peripheral zone, were positive for cancer on histologic examination. When considering stage T1a patients only, TRUS identified residual cancer in only 2 of 11 patients (18%). Zhang et al. examined the ability of TRUS and biopsy to correctly identify residual disease in 52 patients with stage T1a prostate cancer who had been followed for 1 to 15 years after initial TURP.40 Hypoechoic areas were identified in 29 patients (58%). All patients in the study subsequently underwent ultrasound-guided biopsies. Carcinoma was detected in 8 of the patients evaluated, including 7 who demonstrated abnormalities on ultrasound. The PPV for ultrasound for the early detection of prostate cancer in this series was 24% (7 of 29 patients). Terris et al. evaluated the ability of ultrasonography and biopsy to identify residual tumor in three groups of patients with stage T1 prostate cancer.41 The first group underwent ultrasound only. Of 37 patients with residual disease at the time of radical prostatectomy, only 9 (24%) demonstrated focal hypoechogenicity on ultrasonograTABLE 20–3. Results of Repeat TURP in Patients with Clinical Stage T1a Prostate Cancer

Author

N

No Residual Tumor

McMillen35 Bridges1 Lowe34 Carroll33 Sonda36 Zhang37 Parfitt19

27 40 44 40 31 52 55

63% 70% 84% 78% 71% 73% 82%

Minimal Residual Tumor (T1a)

Diffuse Residual Tumor (T1b)

11% 25% 16%* 15% 20% 23% 14.5%

26% 5% N/A 7%† 9% 4% 3.5%

*Amount of residual disease (minimal versus diffuse) not specified. †Patients upstaged based on increased tumor grade.

190 / Advanced Therapy of Prostate Disease

phy consistent with residual disease. The second group included 25 patients who underwent TRUS with routine sextant biopsy. Cancer detection was increased to 28% in this group. Finally, a third group of 47 patients underwent TRUS with modified systematic biopsies that included additional anterior transition-zone biopsies. This technique improved cancer detection to 47%. Because all patients in groups two and three did not undergo radical prostatectomy after ultrasonography and biopsy, the actual incidence and volume of residual cancer in these patients was unknown. These studies demonstrated that interpreting TRUS following TURP can be problematic. Prostate asymmetry secondary to prior resection, artifactual peripheral zone hypoechogenicity, and the natural hypoechogenicity of residual benign prostatic hyperplasia can make interpretation of TRUS challenging in this setting.41 Further, the anterior location of many incidental prostate cancers also makes accurate identification difficult. In an attempt to improve prostate imaging following TURP, Carroll et al. reported on the use of magnetic resonance imaging (MRI) following TURP.42 Although the sensitivity of MRI for detecting residual cancer in the peripheral zone was 81%, MRI was unable to detect any cancers confined to the transition zone. Serum Prostate-Specific Antigen Few studies have examined the ability of PSA to accurately predict residual disease or disease progression following initial TURP in patients with clinical stage T1a prostate cancer. Monitoring post-TURP PSA in these patients should prove useful given that: (1) PSA increases with increasing tumor volume; (2) the contribution of cancer to serum PSA is 10 times greater than that of BPH; (3) prostate cancer has a more rapid growth rate than BPH; and (4) removal of the hyperplastic epithelium by TURP might increase the correlation between PSA and tumor volume.2,43 In a study of 24 patients with clinical stage T1a disease and a negative repeat TURP, Ingerman et al. found that the mean serum PSA level in three patients with disease progression (7.1 ng per mL) was significantly higher than that of the 21 patients who did not have progressive disease (1.3 ng per mL).31 Voges et al. correlated post-TURP serum PSA levels with residual cancer volume in 44 patients undergoing radical prostatectomy for clinical stage T1 disease.25 They reported that post-TURP PSA levels increased with increasing residual cancer volumes. Nineteen of 20 patients (95%) with a residual cancer volume > 0.9 cm3 had a serum PSA level ≥ 2.5 ng per mL, while 7 of 8 patients (88%) with a residual cancer volume < 0.4 cm3 had a serum PSA level < 1.0 ng per mL. In patients with serum PSA levels between 1.0 and 2.5 ng per mL, residual volume varied between 0 and 1.88 cm3.25 Carter et al. also correlated serum PSA levels with residual tumor volume in 67 patients with stage T1

prostate cancer undergoing radical prostatectomy.43 Similar to the findings of Voges et al., this study demonstrated that serum PSA was able to reliably predict residual tumor volume only when levels were very low (< 1 ng per mL) or very high (> 10 ng per mL). All stage T1a patients with a serum PSA < 1 ng per mL following TURP had a residual tumor volume < 0.5 cm3, while all stage T1 patients with a serum PSA > 10 ng per mL had a residual tumor volume > 0.5 cm3. For the majority of patients with a serum PSA level between 1.0 and 10 ng per mL, however, there was no significant correlation between PSA level and tumor volume. More recently, Feneley et al. analyzed the use of serial PSA testing and TRUS in 48 patients with stage T1 prostate cancer who were followed for an average of 2.8 years.44 Thirty-six of these patients had stage T1a disease, including 11 (31%) who demonstrated evidence of residual disease. These authors examined whether absolute PSA level, PSA density, PSA velocity, or TRUS could accurately predict the presence of residual disease in those patients undergoing TRUS-guided biopsies 3 months after TURP. Serum PSA levels were significantly higher in those patients with residual disease than in those without residual disease. Using a cutoff of 4.0 ng per mL, the sensitivity of an elevated PSA in predicting residual disease in T1a patients was 82%. However, specificity using this cutoff was only 60%. Similarly, sensitivity and specificity for predicting residual disease using PSA density (cutoff 0.15 ng per mL per cm3) were 82 and 68%, respectively, while TRUS had the poorest sensitivity (56%) and specificity (52%). The best predictor of residual disease in this study was PSA velocity. An incremental rise in PSA of 20% per year in untreated stage T1a patients improved sensitivity to 86% and specificity to 80%. While these few studies have examined the ability of PSA to predict the presence of residual disease in stage T1a patients following initial TURP, no study has adequately addressed the predictive ability of serum PSA with respect to disease progression in this setting. Prostate-specific antigen velocity appears to be the most promising measure in this regard. Additional studies are needed, however, to define which value of PSA velocity would be most indicative of progressive disease and what threshold should be used to recommend treatment. In summary, although clinical stage T1 patients can be divided into those with a low risk for disease progression (T1a) and those with a high risk for disease progression (T1b) based on tumor volume and grade, it is clear that some patients with clinical stage T1a disease will progress over time. While repeat TURP, TRUS ultrasound-guided prostate biopsies, and post-TURP serum PSA monitoring may be useful in defining risk for some clinical stage T1a patients, these methods are neither sensitive nor specific enough to be used for routine clinical decision making. The ability to distinguish those clinical stage T1a patients

Stage T1a Prostate Cancer: the Case for Treatment / 191

at high risk for disease progression from those at low risk awaits improvements in these clinical staging modalities. While it appears prudent to followup untreated clinical stage T1a patients with periodic rectal examinations and serum PSA levels, indications for intervention as well as the proper timing of intervention cannot be determined based on these techniques.

Local Treatment Options for Patients with Stage T1a Prostate Cancer Similar to other stages of prostate cancer, there have been no well-designed, randomized prospective trials comparing definitive local treatment versus observation for patients with stage T1a prostate cancer. In addition, no study to date has adequately compared one local treatment modality with another. In fact, few studies have been reported which describe disease-specific outcomes following local treatment for patients with stage T1a disease. For those studies which do describe such outcomes, the results of treatment for stage T1a patients are often combined with those of stage T1b patients, even though the biologic potential of these two tumor types are clearly different. In a study examining local treatment for stage T1 patients with a high probability of disease progression, Lowe and Listrom retrospectively compared disease-free survival in patients treated with aggressive local therapy (either radical prostatectomy or radiotherapy) with those managed expectantly.45 Even though patients in this study were not categorized as T1a or T1b, the results are of interest. For 17 stage T1 patients undergoing radical prostatectomy with at least 4.5 years of follow-up after surgery, survival free of disease was 93%. For 31 stage T1 patients treated with radiotherapy, survival free of disease was 84%. These results were compared to those of control patients who were managed expectantly in both a matched pair and an unmatched analysis. These analyses demonstrated that stage T1 patients treated with either radical prostatectomy or radiotherapy had significantly better disease-free survival than patients managed expectantly.45 Due to the small sample size, however, differences between the radical prostatectomy and radiotherapy groups were not statistically significant. Radical Prostatectomy Several large series have examined the efficacy of radical prostatectomy as definitive local therapy for prostate cancer (Table 20–4). Only a small percentage of patients in any of these studies, however, were stage T1a patients. Catalona and Smith reported 5-year tumor recurrence rates in 925 patients undergoing radical retropubic prostatectomy using serum PSA as an end point for treatment failure.46 Twentyone patients (2%) in this series had clinical stage T1a disease prior to surgery. Actuarial 5-year disease-free survival

(serum PSA ≤ 0.6 ng per mL) was 90% for all patients with clinical stage T1a or T1b disease. Gerber et al. reported the results of radical prostatectomy from a multi-institutional pooled analysis of 2758 men undergoing radical prostatectomy from eight university medical centers.47 For patients with clinical stage T1, grade 1 (well-differentiated) disease, 10-year actuarial disease-specific survival was 100% while 10-year actuarial metastasis-free survival was 99%. Finally, Pound et al. described their results with radical prostatectomy in 1621 men.48 Fifty-five (3%) of these patients had clinical stage T1a disease prior to surgery. Disease recurrence was defined as a detectable serum PSA level (> 0.2 ng per mL) following surgery. Five- and 10-year actuarial disease-free survival for these 55 stage T1a patients undergoing radical prostatectomy was 100%. There are two studies examining outcome following radical prostatectomy that have included only patients with stage T1 prostate cancer (see Table 20–4). Paulson et al. reported 76 patients who underwent radical prostatectomy for stage T1 disease.20 Eighteen of these 76 patients (24%) had stage T1a disease while the remaining patients had stage T1b disease prior to surgery. When analyzing their results, Paulson et al. stratified patients based on pathologic findings at prostatectomy (i.e., organ-confined, specimen-confined, margin-positive) and not by clinical disease stage. Overall, 10 patients failed, including 5 who failed locally and 5 who failed with distant disease. Of these 10 patients, 3 had Gleason score 8 or 9 tumors and therefore would have certainly been classified as T1b. For all 76 patients, 5- and 10-year actuarial disease-free survival was estimated at 85% and 75%, respectively. Zincke et al. also described the results of radical prostatectomy in 148 patients with clinical stage T1 disease.21 Of these patients, 32 (22%) had clinical stage T1a cancer prior to surgery. No patient in the T1a group died of disease with a mean follow-up of 4.6 years after surgery. One of the 32 stage T1a patients (3%) experienced disease progression (local progression 3 years after surgery, distant progression 4 years after surgery). Actuarial progression-free survival was approximately 95% for clinical stage T1a patients at 5, 10, and 15 years after surgery. This continued to be true even if a detectable serum PSA level (> 0.2 ng per mL) was considered evidence of disease progression. An improved understanding of the mechanisms and anatomy of urinary continence and erectile function has led to better operative techniques with respect to radical prostatectomy. Given the excellent results that are possible for clinical stage T1a patients with respect to disease-free and overall survival and the reduced morbidity associated with surgery, several authors have recommended that radical prostatectomy be a treatment option that is offered to patients with clinical stage T1a disease.21,22 This appears to be especially true for younger patients with at least a 10-year life expectancy since their

192 / Advanced Therapy of Prostate Disease TABLE 20–4. Results of Definitive Local Therapy for Patients with Clinical Stage T1a Prostate Cancer Author

Modality

Catalona46 Gerber47 Pound48 Paulson20 Zincke21 Zagars49 Ragde50 Critz51

RP RP RP RP RP XRT Brachy Brachy + XRT

N (T1a only) 21 101 55 18 32 23 5 10

Results 5-yr PSA-free survival 90% for T1a/T1b 100% actuarial disease specific, 99% actuarial metastasis-free survival at 10 years for T1, grade 1 100% 5- and 10-year actuarial PSA-free survival 85% 5-year and 75% 10-year actuarial disease-free survival for clinical T1a/T1b Approximately 95% actuarial progression-free survival at 5, 10, and 15 years (including PSA) 100% actuarial 5-year relapse-free survival No progression at median follow-up of 69 months Clinical recurrence in 1 patient at median follow-up of 45 months

RP = radical prostatectomy; XRT = external beam radiotherapy; Brachy = brachytherapy; PSA = prostate-specific antigen.

risk of disease progression may be as high as 10 to 25% (see Table 20–2). However, any benefit of radical prostatectomy over expectant management in these patients can only be confirmed by properly designed clinical trials. Therefore, the decision of whether or not to proceed with aggressive local treatment can only be made based on retrospective evidence and the consideration of clinical factors such as patient age and overall health status. Radiation Therapy Little data are available concerning outcomes following radiotherapy for stage T1a prostate cancer (see Table 20–4). Zagars et al. described disease outcome in 707 patients treated with external beam radiotherapy.49 Of these patients, 23 (3%) had clinical stage T1a disease. No patient in this study with stage T1a cancer experienced disease relapse or a rising PSA following radiotherapy. Because prior TURP is a risk factor for urinary incontinence after seed implantation, few clinical stage T1a patients have been included in brachytherapy series. Ragde et al. treated 5 patients with clinical stage T1a disease using iodine-125 seed implantation. 50 After a median follow-up of 69 months for the entire study group, no patient with stage T1a cancer had experienced disease recurrence. Critz et al. treated 10 patients with clinical stage T1a prostate cancer using iodine-125 seed implantation followed by postimplant external beam radiotherapy.51 Mean follow-up for patients in this study was 45 months. Of these 10 patients, 1 experienced a PSA recurrence associated with clinical recurrence of disease.

Stage T1a Prostate Cancer: the Case for Treatment Stage T1 prostate cancer is diagnosed in approximately 10% of men undergoing TURP for BPH. Although the incidence of such tumors has declined since the introduction of minimally invasive treatments for BPH, the percentage of men undergoing TURP who are found to have stage T1 prostate cancer has remained relatively constant despite routine preoperative PSA testing.

Many stage T1a prostate cancers will behave in an indolent fashion, leading most authors to continue recommending conservative treatment for elderly patients with this stage of disease. This is due to the high rate of death from intercurrent illness. Life expectancy of the general population continues to increase, however, and the definition of “elderly” has changed since earlier studies examining the natural history of stage T1a prostate cancer. Many patients who are currently in their 60s and early 70s are in excellent health and without significant comorbid conditions These patients can expect more than 10 additional years of life expectancy. The data presented in this review suggest the following considerations with respect to managing patients with stage T1a prostate cancer: (1) while most radical prostatectomy specimens removed for stage T1a disease show minimal tumor, at least 20 to 30% may show substantial residual cancer; (2) most of these specimens also demonstrate multifocal disease; (3) there appears to be an approximate 16 to 25% chance of disease progression in patients with stage T1a disease managed expectantly and followed up for 7 to 10 years; (4) there are currently no reliable diagnostic methods upon which to base treatment decisions for stage T1a patients; and (5) excellent results can be achieved with respect to disease-free and overall survival in these patients with definitive local treatment (either radical prostatectomy or radiotherapy). As with definitive local therapy for all early stages of prostate cancer, the dilemma is whether to overtreat some patients in order to potentially cure the others who may subsequently experience disease progression and die as a result of disease.11 The data presented herein suggest that definitive local treatment should be considered for those patients with stage T1a disease who are likely to have a long life expectancy. In these patients, the possibility of disease progression appears to be significant, and excellent results, with minimal morbidity, can be achieved with definitive local therapy. However, treatment must be individualized for all patients. Treatment decisions must take into account not only disease characteristics and life expectancy but also the wishes and expectations of the patient and his family.

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20. Paulson DF, Robertson JE, Daubert LM, Walther PJ. Radical prostatectomy in stage A prostatic adenocarcinoma. J Urol 1988;140:535–9. 21. Zincke H, Blute ML, Fallen MJ, Farrow GM. Radical prostatectomy for stage A adenocarcinoma of the prostate: staging errors and their implications for treatment recommendations and disease outcome. J Urol 1991;146:1053–8. 22. Epstein JI, Oesterling JE, Walsh PC. The volume and anatomical location of residual tumor in radical prostatectomy specimens removed for stage A1 prostate cancer. J Urol 1988;139:975–9. 23. Larsen MP, Carter HB, Epstein JI. Can stage A1 tumor extent be predicted by transurethral resection tumor volume, percent or grade? A study of 64 stage A1 radical prostatectomies with comparison to prostates removed for stages A2 and B disease. J Urol 1991;146:1059–63. 24. McNeal JE, Price HM, Redwine EA, et al. Stage A versus stage B adenocarcinoma of the prostate: morphological comparison and biological significance. J Urol 1988;139:61–5. 25. Voges GE, McNeal JE, Redwine EA, et al. The predictive significance of substaging stage A prostate cancer (A1 versus A2) for volume and grade of total cancer in the prostate. J Urol 1992;147:858–63. 26. Babaian RJ, Troncoso P, Ayala A. Transurethral-resection zone prostate cancer detected at cystoprostatectomy. A detailed histologic analysis and clinical implications. Cancer 1991;67:1418–22. 27. Bauer WC, McGavran MH, Carlin MR. Unsuspected carcinoma of the prostate in suprapubic prostatectomy specimens. Cancer 1960;13:370–8. 28. Hanash KA, Utz DC, Cook EN, et al. Carcinoma of the prostate: a 15-year follow-up. J Urol 1972;107:450–3. 29. Roy CR, Horne D, Raife M, Pienkos E. Incidental carcinoma of prostate. Long-term follow-up. Urology 1990;36: 210–3. 30. Blute ML, Zincke H, Farrow GM. Long-term follow-up of young patients with stage A adenocarcinoma of the prostate. J Urol 1986;136:840–3. 31. Ingerman A, Broderick G, Williams RD, Carroll PR. Negative repeat transurethral resection of prostate fails to identify patients with stage A1 prostatic carcinoma at lower risk of progression: a long-term study. Urology 1993;42:528–32. 32. Brawn PN. The dedifferentiation of prostate carcinoma. Cancer 1983;52:246–51. 33. Carroll PR, Leitner TC, Yen TS, et al. Incidental carcinoma of the prostate: significance of staging transurethral resection. J Urol 1985;133:811–4. 34. Lowe BA, Barry JM. The predictive accuracy of staging transurethral resection of the prostate in the management of stage A cancer of the prostate: a comparative evaluation. J Urol 1990;143:1142–5. 35. McMillen SM, Wettlaufer JN. The role of repeat transurethral biopsy in stage A carcinoma of the prostate. J Urol 1976;116:759–60. 36. Sonda LP, Grossman HB, MacGregor RJ, Gikas PW. Incidental adenocarcinoma of the prostate: the role of repeat transurethral resection in staging. Prostate 1984; 5:141–6. 37. Zhang G, Wasserman NF, Sidi AA, et al. Long-term followup results after expectant management of stage A1 prostatic cancer. J Urol 1991;146:99–103.

194 / Advanced Therapy of Prostate Disease 38. Sheth S, Hamper UM, Walsh PC, et al. Stage A adenocarcinoma of the prostate: transrectal US and sonographicpathologic correlation. Radiology 1991;179:35–9. 39. Egawa S, Greene DR, Flanagan WF, et al. Transrectal ultrasonography in stage A prostate cancer: detection of residual tumor after transurethral resection of prostate. J Urol 1991;146:366–71. 40. Zhang G, Wasserman NF, Kapoor DA, Reddy PK. Early detection of local disease progression from stage A1 prostate carcinoma by transrectal ultrasonography. Cancer 1992;69:2300–5. 41. Terris MK, McNeal JE, Stamey TA. Transrectal ultrasound imaging and ultrasound guided prostate biopsies in the detection of residual carcinoma in clinical stage A carcinoma of the prostate. J Urol 1992;147:864–9. 42. Carroll PR, Sugimura K, Cohen MB, Hricak H. Detection and staging of prostatic carcinoma after transurethral resection or open enucleation of the prostate: accuracy of magnetic resonance imaging. J Urol 1992;147:402–6. 43. Carter HB, Partin AW, Epstein JI, et al. The relationship of prostate-specific antigen levels and residual tumor volume in stage A prostate cancer. J Urol 1990;144:1167–71. 44. Feneley MR, Webb JA, McLean A, Kirby RS. Postoperative serial prostate-specific antigen and transrectal ultrasound for staging incidental carcinoma of the prostate. Br J Urol 1995;75:14–20. 45. Lowe BA, Listrom MB. Management of stage A prostate cancer with a high probability of progression. J Urol 1988;140:1345–7.

46. Catalona WJ, Smith DS. Five-year tumor recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 1994;152:1837–42. 47. Gerber GS, Thisted RA, Scardino PT, et al. Results of radical prostatectomy in men with clinically localized prostate cancer. JAMA 1996;276:615–9. 48. Pound CR, Partin AW, Epstein JI, Walsh PC. Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control. Urol Clin North Am 1997;24:395–406. 49. Zagars GK, Pollack A, Kavadi VS, von Eschenbach AC. Prostate-specific antigen and radiation therapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 1995;32:293–306. 50. Ragde H, Blasko JC, Grimm PD, et al. Interstitial iodine125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer 1997;80:442–53. 51. Critz FA, Tarlton RS, Holladay DA. Prostate-specific antigenmonitored combination radiotherapy for patients with prostate cancer. I-125 implant followed by externalbeam radiation. Cancer 1995;75:2383–91. 52. Heaney JA, Chang HC, Daly JJ, Prout GR Jr. Prognosis of clinically undiagnosed prostatic carcinoma and the influence of endocrine therapy. J Urol 1977;118: 283–7. 53. Correa RJ, Anderson RG, Gibbons RP, Mason JT. Latent carcinoma of the prostate—why the controversy? J Urol 1974;111:644–646.

CHAPTER 21

T1B-T2NXM0: THE CASE FOR OBSERVATION FERNANDO J. KIM, MD; WILLIAM BEDFORD WATERS, MD Carcinoma of the prostate is “the” cancer of the 1990s. This disease has touched the lives of several high-profile public figures such as golfer Arnold Palmer, Senator Bob Dole, French President François Mitterrand, General Norman Schwarzkopf, and entertainers such as Frank Zappa and Bill Bixby.1 Prostate cancer (PCa) has become the most diagnosed cancer in America and the second leading killer of men.2–4 Moreover, deaths from PCa are increasing by 2 to 3% per year because men are living longer and fewer men are dying of other causes such as cardiovascular disease.5,6 The annual detection rate of PCa is increasing rapidly in the United States.5–9 This is largely due to widespread early detection of the disease using prostate-specific antigen (PSA), digital rectal examination (DRE), and prostate needle biopsy with transrectal ultrasonography (TRUS).10–19 Death from PCa is common. This year, over 184,500 men will be diagnosed with PCa and more than 39,200 men previously diagnosed will die because of it.5–7 Crucial questions arise as to whether it is possible to reduce the mortality of PCa with early diagnosis and aggressive treatment and whether localized PCa progresses at a rate fast enough to kill most men if left untreated. Studies have clearly demonstrated that PSA testing leads to increased detection of organ-confined tumors.13,20–23 Detection and treatment of such tumors may eventually lead to decreased mortality from PCa. Many authors, however, are concerned about aggressive early detection and treatment, particularly in older patients. In the United States, men diagnosed with early PCa are treated with curative intent using radiation therapy or radical prostatectomy.24–26 Conversely, elsewhere in the world watchful waiting or expectant observation with subsequent delayed hormonal therapy at disease progression is commonly recommended as a management strategy.27–31 Although efforts are being made to address the issues of early detection and treatment of clinically localized PCa (stages T1 and T2), these controversies are unlikely to be resolved in the near future. The role of expectant management is therefore likely to remain unsettled and prove one of the most important and controversial areas in genitourinary oncology. In this chapter, the published results of watchful waiting over the last decade are reviewed, and an attempt is made to place this approach in perspective in relation to men with clinically localized prostate cancer.

Natural History of Untreated Localized Prostate Cancer The long-term results of initial conservative management of clinically localized PCa have been investigated by a number of authors. Unfortunately, studies have been uncontrolled and retrospective or have suffered from questionable study design or methodologic problems. Results of Deferred Therapy In 1972, Byar and colleagues published the single clinical trial (VACURG) in which patients were randomized either to aggressive surgical therapy (radical prostatectomy) or observation alone.32 In this study, a total of 76 men with stage A disease and 66 men with stage B tumors were randomized although 22% (31 of 142) were omitted for a variety of reasons. The overall cancer progression rate was 14% (16 of 111), and there was no significant difference in survival or progression between the observation and surgically treated groups. The authors concluded that if radical prostatectomy has any value for patients with stage A or B PCa, it must not be very dramatic. Unfortunately, this study had a small number of patients and a median follow-up of only 7 years. To evaluate the differences in progression of the disease and especially survival rates, a minimum of 10 to 15 years of follow-up is required following diagnosis. Moreover, a disproportionate number of patients with stage A PCa were included; lacking complete information about the volume or grade of tumor, it is conceivable that these men had very low-grade localized disease that would not progress despite treatment. Finally, excluding the randomized patients omitted from the study from the group with palpable disease (stage B), only 30 men underwent radical prostatectomy, of which 20 men were observed. Moskovitz et al.33 reported on 101 men with clinical stages T1b to T3 PCa managed by subtotal prostatectomy. The actuarial 5-year survival rates were 91.3, 60.6, and 41.7% for stages T1b, T2, and T3 disease, respectively. Moskovitz and colleagues concluded that these survival rates “resemble those quoted in the literature” and that “these results justify a less aggressive approach to carcinoma of the prostate.” The mean age of the patients in this report was 72 years (range of 50 to 92 years), which is past the age at which most urologists in the United States would consider offering aggressive therapy. As in 195

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most watchful waiting series, many of the patients had low-grade, well-differentiated (57.4%) or moderately differentiated (21.8%) disease. At a mean follow-up of 58 months, 29% of the men had died of PCa, 23% of other causes, and 43% had PCa. Only 6% of men were alive without clinical evidence of prostate cancer.33,34 Whitmore et al.31 retrospectively reviewed the records of 75 men with clinical stage T2 PCa who received no therapy for at least 1 year following diagnosis. Actuarial survival at 15 years was 67%, 39%, and 63% in men with T2a, T2b, and T2c lesions, respectively. This is not a true watchful waiting series because definitive therapy was offered to all patients at the time of local progression. Again, the histology was favorable, including well- and moderately differentiated tumors in 48 and 39% of cases, respectively. Despite these favorable clinical features, 64% had local progression, 33% had distant metastases, and 22% died of PCa.31,34 Jones35 reported on 233 men with clinically localized PCa who were followed up conservatively for up to 25 years. The author concluded that “the overall survival of patients was not statistically different from the United States life-tables probability for men of similar ages” and that “it appears prudent that all patients with localized PCa should have this management option (deferred therapy) as well as radical prostatectomy or external irradiation.” This study has several flaws that were identified by Steinberg et al.34 The series was described as a long-term study of watchful waiting. However, 52 of the patients survived less than 3 years. Only 233 of the 306 patients were included in the data analysis. The treatment and outcome of the remaining 73 patients were not stated. The mean patient age, duration of follow-up, and rate of development of metastatic disease were not reported. When the data are examined closely, only 80 of the 233 men were followed expectantly. Brachytherapy was administered in 44 cases (19%), but treatment of the remaining 109 (47%) was not specified. In addition, of the 80 men followed expectantly, only 14 had survived more than 6 years, and 8 more than 11 years when the study was published.34,35 Adolfsson et al.36 reported on 122 men with well- or moderately differentiated clinically localized PCa that was diagnosed by needle aspiration cytology and then followed up conservatively. The mean follow-up was 91 months. Local tumor progression occurred in 55% of the patients and metastatic disease developed in 14%. The patients were carefully selected. The mean age at diagnosis was 68 years and all had well-differentiated (77%) or moderately differentiated (23%) tumors. Patients with poorly differentiated tumors were excluded from the study. The diagnosis of PCa in this series was established by needle aspiration cytology, a technique associated with a high incidence of false-positive results. Patients were also treated at the time of rapid local progression or

development of metastatic disease. The 5- and 10-year actuarial rates of progression to clinical stage T3 disease were 52% and 69%, respectively. The respective rates for metastatic disease were 10 and 26%.34,36 Johansson et al.37 reported on 223 patients with clinical stage T1 and T2 PCa for expectant therapy with delayed treatment. From 1977 through 1979, only patients with well-differentiated tumors were included. From 1979 through 1984, patients younger than 75 years of age who had moderately or poorly differentiated tumors were randomly allocated to receive local radiation or no treatment. No data were given on the patients treated with radiation therapy. There was also a subgroup of 58 patients younger than 70 years of age who met current indications for radical prostatectomy and had clinical T1 or T2 disease with moderately differentiated tumors. Local progression was noted in 21 patients (36%), distant progression in 7 (12%), and death from PCa in 5 (9%). The actual progression-free survival rate was 60% and 50% at 5 and 10 years, respectively. In the entire group, local progression was reported in 50 patients (22%), distant progression in 26 (12%), and death from PCa in 19 (9%). The actuarial progression-free survival rate was 68% and 53% at 5 and 10 years, respectively. Of the 47% of patients who showed progression at 10 years, 84% had undergone orchiectomy or treatment with estrogens. It can be assumed that the progression and death rates from PCa were even higher than reported.38 Again, this study was biased to include older men with early-stage, low-grade tumors. Although only 9% of the men died of PCa, 48% died of other causes during observation. Because of the older age of many patients, there were a number of deaths from other causes. Approximately 50% of patients who are over 70 years of age will die of a noncancer-related death after 10 years of observation. It is possible that many of the patients in the study did not live long enough for their prostate malignancy to be the primary cause of death. Also, there are questions about the method used by Johansson to diagnose PCa, aspiration biopsy technique, in these patients. The Swedish registry mandates that patients with atypia on fine-needle aspiration biopsy be classified as having cancer. There is a possibility that patients without cancer were classified as having grade I disease. Few studies correlate aspiration cytology and punch biopsy. Nakamura et al. showed that in 77 cases out of 102 patients diagnosed with PCa by needle biopsy, 90% were concordant with findings of aspiration cytology. Moreover, grading on aspiration cytology revealed only 60% agreement compared to tissue obtained with the histologic method.39 Chodak et al.40 summarized the results of six nonrandomized studies in a meta-analysis of 828 men with clinically localized prostate cancer who were treated conservatively with observation and delayed hormonal therapy. The 10-year disease-specific actuarial survival rate was 87% for those with grade I disease, 58% for those with grade II, and

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34% for those with grade III. The 10-year metastasis-free survival rate was 81% for those with grade I disease, 58% for those with grade II, and only 26% for those with grade III. Forty-two percent of patients with grade II disease developed metastatic disease at 10 years and 70% at 15 years. Actuarial survival statistics demonstrated that grade was the most significant variable in predicting survival.38 The aforementioned studies and the meta-analysis summary by Chodak have been severely criticized for selection bias (predominance of low-grade, low-stage tumors), no central pathologic review of the cases to confirm the diagnoses and grades of prostate cancer, and a median age of 69 years, suggesting that many men in the series died of other causes before being at risk of death from PCa. Albertsen et al.41 reported on 451 men diagnosed with clinically localized PCa between 1971 and 1976. The patients received no treatment or immediate or delayed hormonal therapy. The mean follow-up was 15.5 years. The age-adjusted survival of men with Gleason score 2 to 4 tumors was not significantly different from that of the general population. The maximum estimated lost life expectancy of men with Gleason score 5 to 7 tumors, however, comprising 80% of the study, was 4 to 5 years, and 6 to 8 years for patients with Gleason score 8 to 10 tumors. The authors concluded that “compared with the general population, men aged 65 to 75 years with conservatively treated low-grade PCa incur no loss of life expectancy.” They also stated that “men with higher grade tumors (Gleason scores 5 to 10) experience a progressively increased loss of life expectancy.” The former statement received much publicity but the latter statement received much less.34,41 The Albertsen study41 supports the treatment philosophy that older men with well-differentiated tumors do well with conservative treatment. Only 44 (9.8%), however, had well-differentiated tumors, including more than half with clinical stage T1a disease. Only 6 men (1.3%) had palpable stage T2 well-differentiated tumors. Further, almost half of the patients received immediate hormonal therapy. The 10- and 15-year survival rates for men with Gleason grades 5 to 7 were 32% and 15%, respectively, and 15% and 5% for those with Gleason grade 8 to 10. This compares with 10- and 15-year survival rates of 58% and 32%, respectively, in a healthy population. This study illustrates that even men older than 70 years with moderately or poorly differentiated PCa are at risk of losing several years of life with conservative therapy.34 Johansson et al.42 reported in 1997 on 642 men with PCa of any stage diagnosed between 1977 and 1984 in Sweden. The mean age of the patients was 72 years. Among 300 patients with a diagnosis of localized disease (T0-T2), 33 (11%) died of PCa. The corrected 15-year survival rate was similar in 223 patients with deferred treatment (81%) and in 77 patients who received initial treatment (81%). Johansson and colleagues concluded that “patients with localized PCa have a favorable outlook following watchful

waiting, and the number of deaths potentially avoidable by radical initial treatment is limited. Without reliable prognostic indicators, an aggressive approach to all patients with early disease would entail substantial overtreatment.” This study, too, has problems common to other watchful waiting series. The mean age of the patients was 72 years, diagnosis was made by fine-needle aspiration, and the patients who progressed to symptomatic disease were treated with estrogens or orchiectomy. More important, PCa accounted for a higher proportion of all deaths in patients younger than 61 years (44%) than in those older than 80 years (25%) at diagnosis. More patients with poorly differentiated tumors also died of the disease. From these data, observation would not seem appropriate for younger men with moderate and/or poorly differentiated tumors who have a longer life expectancy. Albertsen et al.43 reported on 767 men with localized PCa diagnosed between 1971 and 1984 who were aged 55 to 74 years at diagnosis, either treated or not treated with immediate or delayed hormonal therapy, and followed for up to 10 to 20 years after diagnosis. The primary objective of the analysis was to estimate the probability of dying from PCa or other competing causes given a patient’s tumor histology (Gleason score) and age at diagnosis. Men with Gleason scores of 2 to 4, 5, 6, 7, and 8 to 10 face a 4 to 7%, 6 to 11%, 18 to 30%, 42 to 70%, and 60 to 80% chance, respectively, of dying from PCa within 15 years of diagnosis depending on their age at diagnosis. The majority of the younger men with Gleason scores of 2 to 4 were still alive but face a possibility of death from PCa in the future. Most of the older men with low Gleason scores died from competing medical hazards rather than from PCa. The men with Gleason scores 5 and 6 had a somewhat higher risk of death from PCa when managed with observation. In contrast, men with Gleason scores 7 and 8 to 10 experienced a very high rate of death from PCa regardless of their age at diagnosis. Very few of these men are still alive. The above study had several limitations, as Albertsen et al. point out: many men had inadequate staging evaluations, many were excluded because of incomplete or absent records, the majority of diagnoses were made by transurethral resection (60%), and there is a lack of rationale behind the timing of hormonal therapy (immediate or delayed). The study does make clear that younger men are at risk longer of dying from untreated PCa if their Gleason score is greater than 5.43 Another study addressing the role of watchful waiting compared to aggressive initial therapy was published by Fleming et al. from the Prostate Patient Outcomes Research Team (PPORT).44 In this study, a decision analysis model was used to compare the outcomes of radical prostatectomy, external beam radiation, and observation in men with clinically localized PCa. Probabilities and rates of development of progressive disease and death from PCa were calculated from a review of the

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medical literature. The authors concluded that in patients with well-differentiated tumors, treatment provides limited benefit over watchful waiting in terms of “qualityadjusted life expectancy.” For those patients with moderately or poorly differentiated PCa, the results of the study indicated that surgery or radiation therapy may provide up to 3.5 additional years of quality-adjusted life. Finally, the PPORT group concluded that men over 75 years of age are not likely to benefit from aggressive treatment when compared with watchful waiting. Determination of quality-adjusted life expectancy is based on the anticipated morbidity associated with radical prostatectomy or radiation therapy. More important, the overall results of the decision analysis are based largely on the tumor grade-specific rates of progression to metastatic disease in men managed by observation, derived from five published studies of watchful waiting.45,46

rates in the observation group are not representative of modern series of men with clinically localized PCa. Marked changes in detection and treatment of PCa as well as changes in life expectancy and overall health care over the period of the studies have had the result that the men selected for observation have little relation to patients currently diagnosed with PCa. Further study is needed to adequately address these issues. The PIVOT trial should provide answers to these questions.

Prognostic Factors for Localized Disease Many factors and variables are used in making decisions on treatment options for patients with localized disease. These may be categorized as patient variables, tumor variables, and access to medical care.49

Current Studies of Deferred Therapy

Patient Variables

The Scandinavian Prostatic Cancer Group is conducting a study in which patients with stages Tlb, Tlc, T2a, and T2b tumors are randomized between observation and radical prostatectomy.47 All men must be under 75 years of age, preferably under 70, with diagnosis of well-differentiated or moderately differentiated tumors. Patients selected for radical prostatectomy initially undergo pelvic lymphadenectomy, and the prostate is removed only in the absence of nodal metastases. Men with positive pelvic lymph nodes are initially observed, and hormonal therapy is initiated if symptomatic disease manifests. Patients randomized to initial observation are managed by a similar strategy. In the United States, a similar ongoing study, the Prostate Cancer Intervention Versus Observation Trial (PIVOT),48 compares expectant management and radical prostatectomy. It is sponsored by the Veterans Administration Cooperative Studies Program, the National Cancer Institute, and the Agency for Health Care Policy and Research. It is expected that over 1000 men under the age of 75 years who are candidates for radical prostatectomy will be enrolled. The primary end point is all-cause mortality. Secondary outcomes include PCa and treatment-specific morbidity and mortality, health status, predictors of disease-specific outcomes, and cost effectiveness of care. In the first 3 years of enrollment, nearly 500 men have been randomized. Early results of participants’ baseline characteristics indicate that enrollees are representative of clinically localized PCa patients throughout the United States, allowing results from PIVOT to be generalized. This study is necessary to determine preferred therapy for localized prostate cancer.48 It is immediately evident that underestimating or overestimating the progression rate of untreated PCa will significantly bias results against or in favor of aggressive therapy. Unfortunately, the patients selected in these studies who have been used to determine progression

The age of the patient at diagnosis is of paramount importance. The studies noted above have shown that men with a relatively short natural life expectancy, that is, under 10 years, will have little risk of cancer-related death or morbidity from cancer progression.33,36,40,43,49 These risks, however, increase considerably after 10 years. Observation may not be appropriate for younger men. Age alone, however, is not an accurate predictor of life expectancy or treatment outcome.49,50 Family history, longevity, and coexisting illness such as hypertension, cardiovascular disease, pulmonary disease, diabetes, and other illnesses may add or subtract several years to the patient’s physiologic age. The psychologic characteristics of the patient are also important. Some men may not be emotionally equipped to tolerate an observation protocol. This must be assessed during the initial visit and in subsequent interactions with the patient and his family. The patient must be relied upon to return for follow-up if an observation course is selected. Tumor Variables The stage of the tumor at diagnosis is important. The volume of the tumor, location, evidence of extension beyond the gland, the initial serum level of prostate-specific antigen, Gleason score, deoxyribonucleic acid (DNA) ploidy, and the growth rate of the tumor are all important variables to be considered when deciding on active treatment or observation.49 Prostate volume may be determined by DRE or TRUS if the tumor is palpable or sonolucent; accurate measurement with these techniques, however, is not certain and is often inaccurate. More information may be gained from the location and extent of malignancy found on the ultrasound-guided biopsy specimens and the measurement of tumor length within the biopsy core.49,51,52 Several studies in recent years have focused on the use of PSA as an adjunct prognostic marker in patients with

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clinically localized PCa. Partin and colleagues have demonstrated the value of combined data analysis— including clinical stage, serum PSA level, and preoperative Gleason score—to predict pathologic stage in 4133 men who underwent radical prostatectomy with clinically localized PCa at three academic medical centers.53 Prostate-specific antigen levels at diagnosis and the subsequent rise in serial serum PSA levels provide useful information for estimating the rate of tumor growth.49,54 Increasing tumor volume is usually concomitant with development of higher tumor grade, extension beyond the confines of the prostate, and metastatic potential.49,51 Currently, tumor grade (Gleason score) remains the single most useful predictor of disease progression and cancer mortality. This was shown in the meta-analysis by Chodak et al.,40 and by Albertsen et al.43 Men with high-grade localized tumors managed by surveillance had a much higher chance of progression to metastatic disease and of death from PCa after 10 years of followup, regardless of age at diagnosis. The analysis of DNA ploidy has been evaluated as a tool to predict biologic PCa behavior.49,55–57 Adolfsson et al.55 prospectively analyzed DNA ploidy in correlation to tumor progression in men with grade I or grade II malignancy who opted for surveillance. Almost equal numbers of diploid and nondiploid tumors were found. The nondiploid tumors progressed more rapidly and frequently than did the diploid tumors.49,55 Access to Medical Care Managed care restrictions, lack of medical insurance, and the availability of adequate, modern treatment facilities with the technical expertise of physicians, radiation therapists, and urologists are all factors that must be taken into consideration when selecting treatment options. The results of radical prostatectomy and radiation therapy reported from academic medical centers seem to have less morbidity and mortality than those reported using Medicare and other data sources.49

Rationale for Watchful Waiting and Monitoring for Localized Prostate Cancer Over the past decade, there have been a number of major advances in diagnosing and treating PCa. It is now possible to diagnose the disease in more men at an earlier stage due to the use of DRE, PSA testing, and improved biopsy techniques.58 The rationale for observation of men with localized PCa is based on several premises. First, there has been no decline in the disease-specific mortality rate despite advances in surgical and medical therapy for PCa over the past 30 years. Second, since the prevalence of PCa far exceeds the clinical incidence of the disease, there

is concern that some detected malignancies are “indolent” or “latent” and will not be progressive during the patient’s lifetime. Treatment of such cancers not only exposes patients to the risks of therapy they will not benefit from but also favorably biases the results of uncontrolled clinical trials. Finally, an increasing number of largely retrospective, uncontrolled studies have suggested that untreated men with low-grade malignancies have limited progression rates and high survival figures with follow-up of 5 to 10 years.33,35,36,40 Long-term prospective, randomized trials comparing early diagnosis with active therapy versus no treatment (watchful waiting) are in progress, but data from these clinical trials will not be available for many years, long after most urologists currently practicing have retired. At the current time, clinicians counseling a patient on treatment options for clinically localized prostate cancer should assess the patient’s overall medical condition (including attitude, fear, and anxiety) and family history of longevity as well as his tumor status and access to medical care.49 Watchful waiting is probably the best treatment option for men with well- and perhaps moderately differentiated, low-volume prostate cancer who have a life expectancy less than 10 years, as estimated by chronologic age and general health status. The patient should be comfortable with the prospect of living with the presence of prostate malignancy and the almost certain prospect that progression (albeit usually slow) will occur. The physician and patient must agree on what follow-up tests will be performed, their frequency, and the treatment implications of test results, as outlined by Adolfsson et al.49 The physician should be knowledgeable concerning prostate cancer behavior, should be available to perform followup visits within a facility that is easily accessible to the patient, and should educate the patient as much as possible concerning the nuances of the disease and its treatment.49 Most men older than 70 years, particularly those with well-differentiated tumors, derive little survival benefit from radical prostatectomy. The morbidity of radical prostatectomy is greater in older men.34,59 Therefore, except for those in excellent health and those with poorly differentiated tumors, most men older than 70 years should probably be treated alternatively. The conclusions derived from watchful waiting studies in older men, however, cannot and should not be applied to younger, healthier men who face the possibility of death from prostate cancer in the future, or to those with more advanced or aggressive disease. These studies also demonstrate that, when treated ineffectively, many of these men die of prostate cancer. The actual survival benefit with aggressive treatment is unknown at the present time.34 Hopefully, these data will be forthcoming with the above-mentioned randomized trials. In the interim, the best treatment strategy for the individual patient can be chosen using the above recommendations.34,49

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19. Helzlsouer KJ, Newby J, Comstock GW. Prostate-specific antigen levels and subsequent prostate cancer: potential for screening. Cancer Epidemiol Biomarkers Prev 1992;1:537–40. 20. Hudson MA, Bahnson RR, Catalona WJ. Clinical use of prostate-specific antigen in patients with PCa. J Urol 1989;142:1011–7. 21. Humphrey PA, Walther PJ, Curtin SM, Vollmer RT. Histologic grade, DNA ploidy, and intraglandular tumor extent as indicators of tumor progression of clinical stage B prostate carcinoma. Am J Surg Pathol 1991;15:1165–70. 22. Kleer E, Oesterling JE. Prostate-specific antigen and staging of localized prostate cancer. Urol Clin North Am 1993;20:675–704. 23. Komatsu K, Wehner N, Prestigiacomo AF, et al. Physiologic (intraindividual) variation of serum prostate-specific antigen in 814 men from a screening population. Urology 1996;47:343–6. 24. Oesterling JE, Chan DW, Epstein JI, et al. Prostate-specific antigen in the preoperative and postoperative evaluation of localized prostatic cancer treated with radical prostatectomy. J Urol 1988;139:766–72. 25. Jewett HJ. The present status of radical prostatectomy for stages A and B prostatic cancer. Urol Clin North Am 1975;2:105–24. 26. Epstein JI, Walsh PC, Brendler CB. Radical prostatectomy for impalpable PCa: the Johns Hopkins experience with tumors found on transurethral resection (stages Tla and Tlb) and on needle biopsy (stage Tlc). J Urol 1994;152:1721–9. 27. Bakke A, Grong K, Hoisaetre PA. Should we treat localized prostatic cancer? Proceedings of the 1985 Finnish Urological Club Meeting; 1985 March 1; 58–65. 28. Larsson A, Norlen BJ. Five-year follow-up of patients with localized prostatic carcinoma initially referred for expectant treatment. Scand J Urol Nephrol 1985;19 Suppl:30. 29. Orestano R. Problems of the wait-and-see policy in incidental carcinoma of the prostate. In: Altwein JE, Faul P, Schneider W, editors. Incidental carcinoma of the prostate. Berlin: Springer-Verlag; 1991. p. 163–6. 30. Jones GW. Prospective, conservative management of localized prostate cancer. Cancer 1992;70 Suppl:307–10. 31. Whitmore WF Jr, Warner JA, Thompson IM. Expectant management of localized prostatic cancer. Cancer 1991;67:1091–6. 32. Byar DP, Mostofi FK, Veterans Administration Cooperative Urological Research Group. Carcinoma of the prostate: prognostic evaluation of certain pathological features in 208 radical prostatectomies examined by step-section technique. Cancer 1972;30:5–13. 33. Moskovitz B, Nitecki S, Richter Levin D. Cancer of the prostate: is there a need for aggressive treatment? Urol Int 1987;42(1):49–52. 34. Steinberg GD, Bales GT, Brendler CB. An analysis of watchful waiting for clinically localized prostate cancer. J Urol 1998;159:1431–6. 35. Jones GW. Prospective, conservative management of localized prostate cancer. Cancer 1992;70(1 Suppl):307–10.

T1b-T2NxM0: the Case for Observation / 201 36. Adolfsson J, Carstensen J, Lowhagen T. Deferred treatment in clinically localized prostate cancer. Br J Urol 1992;69 183. 37. Johansson JE, Adami HO, Andersson SO, et al. High 10-year survival rate in patients with early, untreated prostatic cancer. JAMA 1992;267:2191–6. 38. Partin AW, Walsh PC. Surgical management of localized prostate cancer. In: Raghavan D, Scher HI, Leibel SA, Lange PH, editors. Principles and practice of genitourinary oncology. Philadelphia (PA): LippincottRaven; 1997. p. 499. 39. Nakamura T, Akimoto S, Shimazaki J. Usefulness of fine needle aspiration cytology in the diagnosis of prostate cancer. Jpn J Urol 1995;86:853–9. 40. Chodak GW, Thistad RA, Gerber, G, et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994;330:242. 41. Albertsen PC, Fryback DG, Storer BE, et al. Long-term survival among men with conservatively treated localized prostate cancer. JAMA 1995;274:626–31. 42. Johansson JE, Holmberg L, Johansson S, et al. Fifteen-year survival in prostate cancer. A prospective, populationbased study in Sweden. JAMA 1997;277:467–71. 43. Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998;280:975. 44. Fleming C, Wasson JH, Albertsen PC, et al. A decision analysis of alternative treatment strategies for clinically localized prostate cancer. J Urol 1993;269:2650–8. 45. Zhang G, Wasserman NF, Sidi AA, et al. Long-term followup results after expectant management of stage Al prostatic cancer. J Urol 1991;146:99–103. 46. Haapiainen R, Rannikko S, Makinen J, Alfthan O. To carcinoma of the prostate: influence of tumor extent and histologic grade on prognosis of untreated patients. Eur Urol 1986;12:16–20. 47. Chodak GW, Gerber, G. Treatment of early stage prostate cancer. Comprehensive textbook of genitourinary oncology. Baltimore (MD): Williams & Wilkins; 1996. p. 734–41. 48. Wilt TJ, Brawer MK. The Prostate Cancer Intervention Versus Observation Trial. VHSJ 1998;3:60.

49. Adolfsson J, Austenfeld M, Thompson IM. The case for conservative therapy for localized prostate cancer. In: Rashavan D, Scher HI, Leibel SA, Lange PH, editors. Principles and practice of genitourinary oncology. Philadelphia (PA): Lippincott-Raven; 1997. p. 468–72. 50. Corral DA, Bahnson RR. Survival of men with clinically localized prostate cancer detected in the eighth decade of life. J Urol 1994;151:1326–9. 51. Stamey TA, Freiha FS, McNeal JE, et al. Localized prostate cancer. Relationship of tumor volume to clinical significance for treatment of prostate cancer. Cancer 1993; 71(3 Suppl):933–8. 52. Terris MK, McNeal JE, Stamey TA. Estimation of prostate cancer volume by transrectal ultrasound imaging. J Urol 1992;147(3 Pt 2):855–7. 53. Partin AW, Kattan MW, Subong EN, et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 1997;277: 1445–51. 54. Schmid HP, McNeal JE, Stamey TA. Observations on the doubling time of prostate cancer. The use of serial prostate-specific antigen in patients with untreated disease as a measure of increasing cancer volume. Cancer 1993;71:2031–40. 55. Adolfsson J, Ronstrom L, Hedlund PO, et al. The prognostic value of modal deoxyribonucleic acid in low-grade, low-stage untreated prostate cancer. J Urol 1991;144: 1404–6. 56. Montgomery BT, Nativ O, Blute ML, et al. Stage B prostate adenocarcinoma. Flow cytometric nuclear DNA ploidy analysis. Arch Surg 1990;125:327–31. 57. Greene DR, Rogers E, Wessels EC, et al. Some small prostate cancers are nondiploid by nuclear image analysis: correlation of deoxyribonucleic acid ploidy status and pathological features. J Urol 1994;151:1301–7. 58. Smart CR. The results of prostate carcinoma screening in the U.S. as reflected in the Surveillance, Epidemiology, and End Results program. Cancer 1997;80:1835–44. 59. Lu-Yao GL, McLerran D, Wasson J, Wennberg JE. An assessment of radical prostatectomy. Time trends, geographic variation, and outcomes. The Prostate Patient Outcomes Research Team. JAMA 1993;269:2633–6.

CHAPTER 22

RADICAL RETROPUBIC PROSTATECTOMY FOR CLINICAL STAGE T1B-T2 PROSTATE CANCER MOSHE SHALEV, MD; BRIAN J. MILES, MD

Radical prostatectomy is considered a very effective form of treatment for patients with localized prostate cancer and a life expectancy of 10 years or more. Until 1947, when Millin1 introduced the retropubic approach, this operation was performed perineally. The retropubic approach gained popularity in the late 1970s after the introduction by Walsh2 and associates of a series of technical modifications based on a precise definition of periprostatic anatomy. These modifications resulted in reduced blood loss and lower rates of incontinence and erectile dysfunction, transforming the radical retropubic prostatectomy into a safer operation with an acceptably low morbidity rate. However, radical prostatectomy is curative only if all cancer is removed. For this reason, only patients with clinically organ-confined disease should be selected for surgery. Due to the generalized use of prostate-specific antigen (PSA) testing and the growing public and physician awareness of this disease, more patients are diagnosed at an earlier stage than in the past, making more men eligible for this operation. In 1997, 52,000 men underwent a radical retropubic prostatectomy and a similar number of operations are estimated for 1998.3 The ideal candidates for surgery are men with biopsy Gleason scores of ≤ 7 and a PSA below 10 ng per mL, who therefore have a probability of lymph node involvement of less than 1% and seminal vesicle involvement of less than 3%.4,5

who have a greater than 10 years life expectancy, a clinical stage of T2a or less, a biopsy Gleason grade of < 4 (primary or secondary), or a Gleason score < 7 and PSA levels of less than or equal to 10 ng per mL.6–8 Carcinoma of the prostate invading the seminal vesicles (stage T3c) is recognized as a very poor prognostic feature. In general, radical prostatectomy is not indicated in these patients due to the poor long-term results. It is estimated that seminal vesicle invasion will be found in 14.6% of patients with clinically organ-confined cancer.9,10 The Kaplan-Meier actuarial likelihood of PSArecurrence-free survival 4 years after surgery in patients with localized prostate cancer and seminal vesicle invasion is less than 50%.11 Poorly differentiated tumors usually have significant extracapsular extension at the time of diagnosis but biopsy Gleason score should not be used alone for excluding patients from surgery as patients with poorly differentiated cancer confined to the prostate have been found to have an excellent prognosis, similar to those of lower-grade cancer. The 5-year nonprogression rates were 85 ± 18% and 92 ± 4%, respectively.12 In a multi-institutional study on a group of 4133 patients treated with radical prostatectomy, nomograms to predict pathologic stage were developed, which combined PSA level, clinical stage, and Gleason score. These nomograms correctly predicted the probability of a pathologic stage 72.4% of the time,8–10,13 and they can be used when counseling patients to make more informed treatment decisions. However, it is important to point out to patients that the final pathologic stage does not equate with ultimate prognosis, for example, a 50% chance of extracapsular extension does not equal a 50% chance of recurrence (especially if the margins are negative).

Preoperative Assessment Accurate preoperative staging requires digital rectal examination (DRE), measurement of serum PSA level, transrectal ultrasonography (TRUS), and ultrasoundguided biopsy of the prostate for histologic examination and assessment of biopsy Gleason grade and score. Staging of prostate cancer involves the judicious use of bone scan and computed tomography (CT)/magnetic resonance imaging (MRI) of the pelvis and/or abdomen to detect systemic or locoregional disease. The combination of these parameters can give a good prediction of tumor extent in the individual patient. The best long-term results in terms of PSA nonprogression rates and progression-free rates have been achieved in healthy patients

Technique Radical prostatectomy is generally preceded by modified bilateral pelvic lymph node dissection, encompassing the tissue located between the external iliac vein laterally, the obturator nerve medially, Cooper’s ligament distally, and the bifurcation of the common iliac vein proximally. These nodes are forwarded for gross evaluation by the patholo202

Radical Retropubic Prostatectomy for Clinical Stage T1b-T2 Prostate Cancer / 203

gist, who performs frozen section when there is suspicion of metastasis. At our institution, only 2% of patients have been found to have unsuspected nodal microscopic involvement. Some investigators have recently recommended abandoning routine pelvic lymph node dissection because of the increased ability to accurately predict the likelihood of lymphatic metastasis.14 The basis for this recommendation is to decrease costs and potential morbidity from this procedure. We, however, feel that this is an important part of a complete cancer operation. Carrying out lymph node dissection with radical prostatectomy allows the accurate assignment of final pathologic stage and helps in planning future management strategies should the patient develop a PSA recurrence. After the pelvic lymph node dissection is completed, the endopelvic fascia is identified and opened bilaterally. The levator ani muscle fibers that are invariably loosely adherent to the prostate are then gently swept laterally off the prostatic surface, exposing the apex of the prostate. We then minimally incise the puboprostatic ligaments, being careful not to carry the dissection of these ligaments distally under the pubis, where the chance of injuring the external sphincter and continence mechanism increases significantly. The dorsal vein complex must now be addressed. The work of Reiner and Walsh15 has greatly improved our understanding of the anatomy of dorsal vein and periprostatic venous complexes and, thus, our ability to manage it. Although back bleeding from these complexes has sometimes been minimal, we have found that it is usually significant and therefore warrants control. To this end, we place sutures of 0-Vicryl at the bladder neck, and midprostate (Figure 22–1A). The dorsal vein complex is then approached. An index finger is placed under the complex and the Foley catheter/urethra localized. With gentle pressure between the urethra and dorsal vein complex, against the underside of the contralateral symphysis pubis, the lateral pelvic fascia investing these structures is disrupted. One must be careful not to carry out this blunt manipulation excessively to avoid carrying the dissection distally into the sphincteric structures. A right-angle clamp is then passed under the dorsal vein complex, and a 22-gauge sternal wire is grasped and brought beneath it (Figure 22–1B). This wire pulls the complex into a very distinct bundle and serves as a guide for sharply transecting it while simultaneously minimizing the chances of inadvertently cutting into the anterior prostate (Figure 22–1C). Bleeding from the dorsal venous complex is then controlled by closing the edges of the lateral pelvic fascia over the complex with a running 2-0 Vicryl suture (Figure 22–1D). Finally, the divided portion of the dorsal vein complex on the surface of the prostate is oversewn with running sutures. It is important to not drift laterally over the surface of the prostate when controlling this back bleeding; the edges of the lateral pelvic fascia have to be

simply closed to control bleeding. Drifting further laterally will generally create bleeding from the venous plexus running laterally over the surface of the prostate. After gaining hemostasis of the dorsal venous complex, the pillars of the prostate must then be taken down to completely expose the apex of the prostate. Once this is accomplished, the lateral pelvic fascia over the neurovascular bundles is approached (Figure 22–2A). If a nerve-sparing procedure is being performed, the fascia is incised anterior to the neurovascular bundle; if not, it is incised posterior to the bundle (Figure 22–2B). During this dissection, the posterior layer of Denonvilliers’ fascia is incised to ensure that it is incorporated with the specimen. When the posterior layer of Denonvilliers’ fascia is included with the prostate, the anterior perirectal fat will be seen along the entire surface of the rectum and not the shiny white plane that is more comfortable for blunt dissection, and that is located between the leaves of the fascia (Figure 22–3A). If the bundles are being sacrificed, the distal end is ligated with 3-0 chromic ligatures for hemostasis. After appropriately handling the neurovascular bundles, the urethra is transected, and 6 sutures of 2-0 Monocryl are placed at the 1, 3, 5, 7, 9, and 11 o’clock positions, tagged, and draped for future placement in the corresponding positions of the bladder neck (see Figure 22–3A). In placing the posterior sutures, care must be exercised to ensure inclusion of the edge of the posterior layer of Denonvilliers’ fascia with the urethra and yet to avoid incorporating a portion of the neurovascular bundle in this suture. Once the sutures have been placed, the prostate is lifted off the anterior surface of the rectum, being certain to include both layers of Denonvilliers’ fascia (perirectal fat should be seen along the entire surface). Once the prostate is dissected to the level of the lateral pedicles of the seminal vesicles, the Foley catheter, which has been removed just prior to placement of the posterior urethral sutures, is reinserted, placing modest traction on the prostate. The lateral pedicles are then mobilized, clipped, and transected. The seminal vesicles are mobilized in the standard fashion, and the ampullae of the vasa identified and transected. The prostate is then removed by transecting the attachments to the bladder neck. Although some advocate a bladder neck-sparing approach, we believe the bladder neck should be widely resected to ensure clear margins at the base and easy, wide eversion of the bladder mucosa over the neobladder neck. Once the mucosa is everted with 3-0 Vicryl, a 2-0 figure-of-8 Vicryl is placed to define the inferior, 6 o’clock position of the bladder neck. The rest of the defect is closed in the standard tennis racket-fashion. At the end of bladder neck reconstruction, the new bladder neck should have a stoma-like appearance (Figure 22–3B). The urethral sutures are placed in the corresponding positions in the bladder neck, and the urethrovesical anastomosis completed.

204 / Advanced Therapy of Prostate Disease

A

B

C

D

FIGURE 22–1. Management of the dorsal venous complex.

Early Complications In the last decade, intraoperative complications and death secondary to radical retropubic prostatectomy have been significantly reduced. Major complications occur in 5.4 to 9.8% of the patients and death within 30 days from the operation in 0.3 to 0.4% of cases.16–18 The most frequent, major perioperative complications are hemorrhage, rectal injury, deep venous thrombosis, and pulmonary embolism (Table 22–1). Hemorrhage In 1979, after describing the anatomy of the male pelvis, Reiner and Walsh15 proposed the ligation of the dorsal vein complex early in the course of the operation to decrease

A

blood loss. Adopting this approach and by giving special attention to the major blood supply to the prostate and seminal vesicles, intraoperative blood loss can be reduced to 600 to 850 mL. For major control of prostatic vasculature, Mittemeyer19 proposed the antegrade (from bladder to prostatic apex) dissection of the prostate that, together with early dorsal vein ligation, has resulted in reduced intraoperative blood loss.18,20,21 Despite his success with this technique, it is infrequently used and not recommended by the authors. The reduced blood loss achieved in recent years has decreased the transfusion rate to 10% or less in patients who do not donate autologous blood.22 Because the transfusion rate is so low and the safety of the homologous blood pool has significantly improved, the preparation of autologous blood for transfusion is not cost effec-

B

FIGURE 22–2. Lateral approach to apex and neurovascular bundles.

Radical Retropubic Prostatectomy for Clinical Stage T1b-T2 Prostate Cancer / 205

A

B

FIGURE 22–3. Management of posterior layer of Denonvilliers’ fascia (A) and eversion of bladder neck (B).

tive and not recommended. Preoperative hemodilution is a less costly and more acceptable alternative to the autologous blood procurement technique for some patients, such as Jehovah’s Witnesses.23 Postoperative bleeding requiring acute transfusions is estimated to occur in 0.5% of the patients24 (Table 22–2). Rectal Injury Rectal injury is uncommon and estimated to occur in 0.6 to 1% of the patients.16,18,25 Factors predisposing patients to rectal injury during the operation are previous pelvic radiation therapy, rectal surgery, and transurethral resection of the prostate (TURP). Higher local tumor stage has not been associated with this complication.26 Injury to the rectal wall most often occurs during the apical dissection and division of the rectourethralis muscle. Rectal injury recognized during the operation can be successfully repaired after the prostatectomy has been completed by primary closure without a diverting colostomy. The injury is closed in two layers, and the anal sphincter is dilated. Some authors advocate the placement of the omentum between the rectum and the vesicourethral anastomosis to reduce the potential of fistula formation, although we have not found this necessary. Deep Venous Thrombosis and Pulmonary Embolism Deep venous thrombosis and pulmonary embolism are complications that frequently appear after patients are discharged from the hospital, with an incidence estimated to be approximately 2%.18,27,28 The inclusion of sequential pneumatic compression devices as a prophylactic measure during and after surgery are reported to have no influence on the incidence of this complication.29 Early ambulation is beneficial and essential, and should be encouraged in all patients. In a recent study, Heinzer and colleagues pointed out that lymphoceles and hematomas are important cofactors in the pathophysiology of thromboembolic complications after radical prostatectomy as

they compress the pelvic and lower extremity veins. Early diagnosis by pelvic ultrasonography and anticoagulant treatment can reduce the rate of this complication, especially in patients on heparin prophylaxis.28 The rate of venous thrombosis and pulmonary embolism can be effectively reduced after surgery by perioperative subcutaneous low-dose heparin injections but the increased risk of hemorrhage and lymphorrhea has decreased the frequency of its use in radical prostatectomy. The role of low-molecular-weight heparin as a prophylactic agent after radical prostatectomy, although not apparently associated with an increased risk of hemorrhage, has not been established.

Late Complications Anastomotic Strictures The cause (or causes) of anastomotic strictures is uncertain but is generally believed to be due to inadequate mucosa-to-mucosa apposition during urethrovesical reconstruction. Other contributing factors may be excessive intraoperative blood loss, prolonged anastomotic urine leakage, prior history of TURP, and excessive bladder neck reconstruction.30,31 The incidence of anastomotic contractures after radical retropubic prostatectomy has been reported to range from 1 to 22%.30 Preservation of the bladder neck reduced the incidence of strictures from 8.2 to 3.3% in Lowe’s study, with no statistically significant difference in the incidence of positive surgical margins when compared with a group of patients in whom the bladder neck was not preserved. We believe that wide eversion of the bladder neck mucosa and proper placement of the urethral sutures can further contribute to lower the rate of this complication31 (Table 22–3). Dribbling, weak urinary stream, or urinary overflow incontinence are suggestive of bladder neck contracture. The evaluation of these patients should include ultrasound measurement of postvoid residual urine and flexible cystoscopy to evaluate the anastomotic site. Treatment

206 / Advanced Therapy of Prostate Disease TABLE 22–1. Early Complications and Mortality Rate after Retropubic Radical Prostatectomy Complication

Zincke 199418 N = 1728

Hautmann 199432 N = 418

Gaylis 199816 N = 116

Andriole 199427 N = 1342

Dillioglugil 199717 N = 472

0.6 1.1 0.7 0

2.9 1.7 1.4 1.2

0.9 1.8 1.8 0

0.2 0.6 1.7 0.2

0.6 1.3 1 0.4

Rectal injury (%) Thrombophlebitis/deep vein thrombosis (%) Pulmonary embolism (%) Mortality within 30 days (%)

options include dilation, bladder neck incision, or bladder neck resection. Usually, one or two urethral dilations will suffice to eradicate the problem but for severe or persistent contractures, cold-knife incisions may be required. Correction of recalcitrant, excessively fibrotic contractures will infrequently require wide transurethral resection, and these are invariably associated with significant urinary incontinence. Incontinence Urinary incontinence is considered by many to be the complication with the most significant impact on quality of life following radical retropubic prostatectomy. There exists the belief in some quarters that fear of incontinence may cause many patients to seek alternative treatments. In the hands of surgeons with expertise in radical retropubic prostatectomy, incontinence requiring the use of pads is estimated to occur in less than 8% of cases. Fowler and associates, however, found that 31% of a Medicare population of patients reported some degree of wetness.37 These variations may be partially the result of patientreported versus physician-reported outcomes and the lack of a uniform definition of continence but they do point to a problem in interpreting published results describing quality-of-life changes due to radical prostatectomy. At our institution, physician-reported incontinence of any degree at 24 months after the operation is about 5%. Several modifications to the surgical technique have been proposed to enhance postoperative urinary control. Hollabaugh and colleagues have described techniques to avoid injury to the pelvic nerve and intrapelvic branch of the pudendal nerve, thereby achieving continence in 98% of patients, with a median time to “dryness” of 1 week and 95% of patients achieving dryness by 4 months.38 On the other hand, patients who are candidates for nervesparing surgery usually have a lower clinical stage and tend to be of a younger age. These parameters may have a

TABLE 22–2. Estimated Blood Loss (EBL) in Patients Undergoing Radical Retropubic Prostatectomy Series Meide et al.20 Zincke et al.18 Gaylis et al.16 Scardino33

No. of Patients

Mean EBL (mL)

Range (mL)

200 1728 116 100

748 600 872 850

340–1256 — 100–2500 250–2300

greater influence on the results than the nerve-sparing technique by itself. Others have suggested puboprostatic ligament sparing, bladder neck preservation, and proximal prostatic urethra and preprostatic sphincter preservation for improving continence and rapidity of return of urinary control.30,39,40 We believe that bladder neck sparing is not important and routinely employ wide resection to ensure clear margins at the base. Wide eversion of the bladder mucosa over the bladder neck is important, and the new bladder neck should have a stoma-like appearance after reconstruction. Not only does this reduce bladder neck contracture formation but also we believe that mucosal apposition at the new bladder neck created by this wide or exaggerated eversion contributes to continence, much as it does in the female urethra. Risk factors for postoperative incontinence include age over 65 years and bladder neck contracture. Incontinence may spontaneously improve in about 1 year after the operation; therefore, it is best to defer any invasive corrective treatment for at least this period. Impotence The most important factors which correlate with the return of erectile function after radical retropubic prostatectomy are age and preservation of the neurovascular bundles. Nerve-sparing surgery should be considered in relatively young patients at a low clinical stage, preferably stage T1c (in whom the nerves can be safely spared), with a Gleason score of ≤ 6 and normal sexual function before surgery. In one series, men under the age of 50 years preserved their potency in 90% of the cases if one or both neurovascular bundles were preserved but for older patients, sexual

TABLE 22–3. Incidence of Anastomotic Strictures (N) after Radical Retropubic Prostatectomy Series Shelfo et al.,30 1998 Tomschi et al.,34 1998 Popken et al.,35 1998 Lowe,31 1996 Lowe,31 1996 Eastham et al.,36 1996 * Series with bladder neck preservation.

No. of Patients

N (%)

365 239 340 91 99 360

5 (1)* 36 (15) 24 (7) 3 (3.3)* 8 (8.2) 23 (6)

Radical Retropubic Prostatectomy for Clinical Stage T1b-T2 Prostate Cancer / 207

function was better when both neurovascular bundles were preserved.41 Catalona reported retained potency in 63% and 41% when bilateral or unilateral neurovascular bundles were preserved, respectively42 (Table 22–4). In our institution, after November 1993 when a modified technique to the apical prostatic dissection was adopted (as described above), the postoperative potency rate is 71% at 17 months in men under the age of 65 years.

Positive Surgical Margins Positive surgical margins are defined as extension of the tumor to the inked surface of the resected specimen and suggests incomplete excision of the tumor. Positive margins may be a result of an inadvertent incision into the prostate or due to extraprostatic tumor extending beyond the prostatic capsule and the limits of resection. The overall rate of positive surgical margins in radical prostatectomy varies among surgeons and institutions but averages approximately 28%.43 In the last decade, there has been a shift in the patient population undergoing radical prostatectomy, with a distinct increase in patients with stage T1c disease. This fact, together with improved surgical technique, has led to a decrease in the rate of positive surgical margins at most centers with a broad expertise in radical prostatectomy. At Baylor College of Medicine, there has been a decline in positive surgical margins from 19% in the late 1980s to 8% after adopting the lateral approach to the neurovascular bundles.44 In general, the preservation of the neurovascular bundle by itself does not result in a higher rate of positive margins and does not adversely influence cancer control in carefully selected patients.45,46 The prostatic apex is a frequent site of positive surgical margins. It is estimated that up to 69% of the positive margins are found in the apical region of the prostate.47,48 This is attributed to the fact that the prostate apex is often a difficult area for exposure and dissection, leading to a higher rate of positive surgical margins. However, we have found that by using the lateral approach to the neurovascular bundles and the prostatic apex, the rate of surgical margins in this area can be significantly reduced. Klein and colleagues found this to be true and reported a decrease in positive margins from 37.4% to 15.8% using this technique.49 Positive surgical margins appear more frequently in patients with a PSA of 10 ng per mL or greater, biopsy Gleason score of ≥ 7, multiple positive biopsies, or clinical stages of T2b, T2c, or T3. TABLE 22–4. Potency Rate According to Age after Radical Retropubic Prostatectomy Age (Years)

Quinlan41

Catalona42

% of Patients

% of Patients

< 50 50–59 60–69 ≥ 70

90 82 69 22

60 84 57 33

In general, positive margins confer a significantly poorer prognosis. When combining Gleason score, pathologic stage, and surgical margin status, Walsh and colleagues2 demonstrated that positive margins did not significantly increase the recurrence rate in tumors with Gleason scores from 2 to 6 with focal capsular penetration.11 In contrast, positive surgical margins in tumors with established extracapsular penetration and/or a Gleason score of ≥ 7 had the same progression rate as tumors with seminal vesicle invasion. Neoadjuvant androgen ablation has been suggested to reduce the rate of positive surgical margins. Although this technique has been shown to reduce positive surgical margins, no benefit in progression rates or improved survival has been demonstrated.43,50

Surgical Efficacy Recently, the 10-year experience with radical retropubic prostatectomy was reviewed at Baylor College of Medicine. Using actuarial analysis at 5 and 10 years, the overall PSA nonprogression rate in this series of 1120 patients was 76% and 71%, respectively. These results are comparable with those from other centers of excellence (Table 22–5). The progression-free survival rate after radical retropubic prostatectomy is dependent on clinical stage, Gleason score, and preoperative PSA level. At our institution, PSA-based, 5-year nonprogression rates above 80% have been achieved in patients with clinical stage up to T2b, Gleason score up to 7, and preoperative PSA up to 10 ng per mL. However, the most powerful parameter in predicting progression is the pathologic stage of the cancer.45 In 92% of patients with pathologically organ-confined disease, PSA is undetectable and patients are clinically disease-free at 5 years of follow-up. The data collected from various institutions clearly show that radical prostatectomy can cure the majority of prostate cancer patients with acceptable morbidity.

Summary In the last decade, there have been several advances in the diagnosis and treatment of localized prostate cancer. These TABLE 22–5. Actuarial (PSA-based) 5- and 10-Year Nonprogression Rates in Patients after Radical Retropubic Prostatectomy for Clinical Stage T1 and T2 Prostate Cancer PSA Nonprogression Rate (%) Groups Johns Hopkins52 Washington University7 Mayo Clinic50 UCLA51 Baylor

No. of Patients

5 Years

10 Years

894 925 4774 610 1120

83 78 74 69 76

70 — — 47 71

208 / Advanced Therapy of Prostate Disease

have caused a shift toward a higher percentage of patients diagnosed at a low-stage disease who are candidates for surgery and who can be cured. The actuarial nonprogression rate at 10 years after surgery determined by an undetectable PSA level in patients at stage T1-T2 in modern series is approximately 70%46,53 (see Table 22–5). There are no other treatment options that have achieved these results, and therefore radical prostatectomy remains an ideal form of treatment for localized prostate cancer.

References 1. Millin T. Retropubic urinary surgery. London: Livingstone; 1947. 2. Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982;128:492–7. 3. National Center for Health Statistics. Detailed diagnosis and procedures. National Hospital Discharge Survey. Hyattsville (MD): Center for Disease Control; 1997. 4. Terris MK, McNeal JE, Freiha FS, Stamey TA. Efficacy of transrectal ultrasound-guided seminal vesicle biopsies in the detection of seminal vesicle invasion by prostate cancer. J Urol 1993;149:1035–9. 5. Weldon VE, Tavel FR, Neuwirth H. Continence, potency and morbidity after radical perineal prostatectomy. J Urol 1997;158:1470–5. 6. Partin AW, Yoo J, Carter HB, et al. The use of prostatespecific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 1993;150:110–4. 7. Catalona WJ, Smith DS. 5-year tumor recurrence rate after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 1994;152:1837–42. 8. Partin AW, Kattan MW, Subong EN, et al. Combination of prostate-specific antigen, clinical stage and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 1997;277: 1445–51. 9. Stone NN, Stock RC, Unger P. Indications for seminal vesicle biopsy and laparoscopic pelvic lymph node dissection. J Urol 1995;154:1392–6. 10. O’Dowd GJ,Veltri RN, Orozco R, et al. Update on the appropriate staging evaluation for newly diagnosed prostate cancer. J Urol 1997;158:687–98. 11. Pound CR, Partin AW, Epstein JI, Walsh PC. Prostatespecific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control. Urol Clin North Am 1997;24:395–406. 12. Ohori M, Goad JR, Wheeler TM, et al. Can radical prostatectomy alter the progression of poorly differentiated prostate cancer? J Urol 1994;152:1843–49. 13. Kattan MW, Eastham JA, Stapleton AM, et al. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 1998;90:766–71. 14. Bluestein DL, Bostwick DG, Bergstralh EJ, Oesterling JE. Eliminating the need for bilateral pelvic lymphadenectomy in select patients with prostate cancer. J Urol 1994;151:1315–20.

15. Reiner WG, Walsh PC. An anatomical approach to the surgical management of the dorsal vein and Santorini’s plexus during radical retropubic surgery. J Urol 1979; 121:198–200. 16. Gaylis FD, Friedel WE, Armas OA. Radical retropubic prostatectomy outcomes at a community hospital. J Urol 1998;159(1):167–71. 17. Dillioglugil O, Leibman BD, Leibman NS, et al. Risk factors for complications and morbidity after radical retropubic prostatectomy. J Urol 1997;157:1760–7. 18. Zincke H, Oesterling JE, Blute ML. Long-term (15 years) results after radical prostatectomy for clinically localized (stage T2c or lower) prostate cancer. J Urol 1994; 152:1850–7. 19. Mittemeyer BT, Cox HD. Modified radical retropubic prostatectomy. Urology 1978;12:313–20. 20. Meide G, Kleer GC, Kielczewski P, et al. Autologous blood donation prior to anatomical radical retropubic prostatectomy: is it necessary? Urology 1997;49:569–73. 21. Menon M, Voidyanathan S. The University of Massachusetts technique of radical prostatectomy. Eur J Surg Oncol 1995;21(1):66–8. 22. Goad JR, Scardino PT. Modifications in the technique of radical retropubic prostatectomy to minimize blood loss. Atlas Urol Clin North Am 1994;2:65–70. 23. Monk TG, Goodnough LT, Brecher ME, et al. Acute normovolemic hemodilution can replace preoperative autologous blood donation as a standard of care for autologous blood procurement in radical prostatectomy. Anesth Analg 1997;85:953–8. 24. Hedican SP, Walsh PC. Postoperative bleeding following radical retropubic prostatectomy. J Urol 1994;152: 1181–3. 25. Borland RN, Walsh PC. The management of rectal injury during radical retropubic prostatectomy. J Urol 1992; 147(3 Part 2):905–7. 26. McLaren RH, Barrett DM, Zincke H. Rectal injury occurring at radical retropubic prostatectomy for prostate cancer: etiology and treatments. Urology 1993;42:401–5. 27. Andriole GL, Smith DS, Rao G, et al. Early complications of contemporary anatomical radical retropubic prostatectomy. J Urol 1994;152:1858–60. 28. Heinzer H, Hammerer P, Graefen M, Huland H. Thromboembolic complication rate after radical retropubic prostatectomy. Impact of routine ultrasonography for the detection of pelvic lymphocele and hematomas. Eur Urol 1998;33(1):86–90. 29. Cisek LJ, Walsh PC. Thromboembolic complications following radical retropubic prostatectomy. Urology 1993;42:406–8. 30. Shelfo WS, Obek C, Soloway MS. Update on bladder neck preservation during radical retropubic prostatectomy: impact on pathologic outcome, anastomotic stricture and continence. Urology 1998;51(1):73–8. 31. Lowe BA. Comparison of bladder neck preservation to bladder neck resection in maintaining post prostatectomy urinary continence. Urology 1996;48:889–93. 32. Hautmann RE, Sauter TW, Wenderoth UK. Radical retropubic prostatectomy: moribidity and urinary continence in 418 consecutive cases. Urology 1994;43(2 Suppl):47–51.

Radical Retropubic Prostatectomy for Clinical Stage T1b-T2 Prostate Cancer / 209 33. Goad RJ, Eastham JA, Fitzgerald KB, et al. Radical retropubic prostatectomy: limited benefit of autologous blood donation. J Urol 1995;154:2103–9. 34. Tomschi W, Suster G, Holtl W. Bladder neck strictures after radical retropubic prostatectomy, still an unsolved problem. Br J Urol 1998;81:823–6. 35. Popken G, Sommerkamp H, Schultze-Seemann W, et al. Anastomotic stricture after radical prostatectomy. Incidence, findings and treatment. Eur Urol 1998; 33:382–6. 36. Eastham AJ, Kattan WM, Rogers E, et al. Risk factors for urinary incontinence after radical prostatectomy. J Urol 1996;156:1707–13. 37. Fowler FJ Jr, Barry MJ, Lu-yao G, et al. Effect of radical prostatectomy for prostate cancer on patient’s quality of life: results from a Medicare survey. Urology 1995; 45:1007–13. 38. Hollabaugh RS Jr, Dmochowski RR, Kneib TG, Steiner MS. Preservation of putative continence nerves during radical retropubic prostatectomy leads to more rapid return of urinary continence. Urology 1998;51:960–7. 39. Poore RE, McCullough DL, Jarow JP. Puboprostatic ligament sparing improves urinary continence after radical retropubic prostatectomy. Urology 1998;51(1): 67–72. 40. Kaye KW, Creed KE, Wilson GJ, et al. Urinary continence after radical retropubic prostatectomy. Analysis and synthesis of contributing factors: a unified concept. Br J Urol 1997;80:444–501. 41. Quinlan DM, Epstein JI, Carter BS, Walsh PC. Sexual function following radical prostatectomy: influence of preservation of neurovascular bundles. J Urol 1991; 145:998–1002. 42. Catalona WJ. Surgical management of prostate cancer. Cancer 1995;75:1903.

43. Wieder JA, Soloway MS. Incidence, etiology, location, prevention and treatment of positive surgical margins after radical prostatectomy for prostate cancer. J Urol 1998;160:299–315. 44. Ohori M, Wheeler TM, Kattan MW, et al. Prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol 1995;154:1818–24. 45. Epstein JI, Pizov G, Walsh PC. Correlation of pathologic findings with progression after radical retropubic prostatectomy. Cancer 1993;71:3582–93. 46. Walsh PC, Partin AW, Epstein JI. Cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years. J Urol 1994;152:1831–6. 47. Stamey TA, Villers AA, McNeal JE, et al. Positive surgical margins at radical prostatectomy: importance of the apical dissection. J Urol 1990;143:1166–72. 48. Gomez CA, Soloway MS, Civantos F, Hachiya T. Bladder neck preservation and its impact on positive surgical margins during radical prostatectomy. Urology 1993;42:689–93. 49. Klein EF, Kupelian PA, Tuason L, Levin HS. Initial dissection of the lateral fascia reduces the positive margin rate in radical prostatectomy. Urology 1998;51:766–73. 50. Abbas F, Scardino PT. Why neoadjuvant androgen deprivation prior to radical prostatectomy is unnecessary. Urol Clin North Am 1996;23:587–604. 51. Amling CL, Blute ML, Lerner SE, et al. Influence of prostate-specific antigen testing on the spectrum of patients with prostate cancer undergoing radical prostatectomy at a large referral practice. Mayo Clin Proc 1998;73:401–6. 52. DeKernion JB, Franklin JR, Belldegrun A, Smith RB. Surgery from a US perspective. Cancer Surv 1995;23:315–20. 53. Partin AW, Pound CR, Clemens JQ, et al. Serum PSA after anatomic radical prostatectomy. Urol Clin North Am 1993;20:713–25.

CHAPTER 23

RADICAL PERINEAL PROSTATECTOMY DAVID F. PAULSON, MD Anatomy

approached posterior to the urogenital diaphragm.2 Continuing the dissection into the urogenital diaphragm may damage the external sphincteric mechanism accompanying the membranous urethra as it pierces the urogenital diaphragm (Figure 23–2).

Understanding the anatomy of the male perineum allows the perineal surgeon to make appropriate preoperative, postoperative, and intraoperative decisions in patients with prostatic cancer. The perineum is defined as that area which exists between the thighs and extends from the coccyx to the pubis.1 It is the most external aspect of the pelvic outlet; the superior boundary is the levator ani. The lower or perineal surface of the levator ani is felt to form the upper boundary of the perineum. Both the anal and urogenital canal exit the levator ani to appear on the perineal surface. The perineal region can be divided into anterior and posterior triangular segments by a transverse line passing just anterior to the ischial tuberosities and in front of the anal canal. This chapter deals only with the anterior perineal triangle, which can be the “urogenital triangle” (Figure 23–1). The anterior urogenital triangle contains a fibromuscular septum, the urogenital diaphragm, that extends across the anterior portion of the pelvic outlet below the levator ani. This is of anatomic importance to the perineal surgeon as the prostate and associated structures are

Anterior and Posterior Triangles The anal and urogenital triangle of the perineum have the levator ani in common, forming the perineum’s uppermost boundary. The musculature existing in the perineum inferior to the levator ani has a common attachment in the midline between the two regions, with a blending of the two sets of muscles forming a fibromuscular mass referred to as the central tendon of the perineum (Figure 23–3). The central tendon is interposed between the anterior surface of the anal canal and the posterior surface of the urethra. This central tendon must be severed in a perineal prostatectomy to allow for posterior displacement of the anus and rectum. The ischiorectal fossa is a potential space lying lateral to the anus between the skin of the anal region and the levator ani and posterior to the transverse perineal musculature. This fossa is filled with fibrofatty tissue and as a potential space must be developed to access the prostate (Figure 23–4). After incision through the skin overlying the perineum, the surgeon cannot pass a finger directly into this potential space. Entrance must be made by an incision through an outer condensation of the fibrofatty tissue, the superficial perineal fascia. This fascia is classically described as being contiguous with Camper’s fascia (the fibrofatty tissue extending onto the abdomen and across the pubis). If this fibrofatty tissue is entirely removed, a muscular diaphragm and a series of muscular bands are exposed. The external or voluntary anal sphincter surrounding the anal canal and rectum for a distance of approximately 2 cm from the lower surface levator ani to the anal canal can thereby be well visualized. Two bands of muscle arise from the coccyx, separate to pass the rectum, and converge anteriorly to insert on the perineal body. These form a portion of the anal sphincter. Some fibers of the external anal sphincter are circular; they are termed the subcutaneous external anal sphincter, as opposed to the superficial external anal sphincter (those fibers described above that sweep from posterior to anterior, from coccyx to perineal body) (Figure 23–5). The urologic surgeon is concerned only with that portion

FIGURE 23–1. The dotted line drawn between the ischial tuberosities separates the anterior and posterior perineal triangles. The dissection carried out during radical perineal prostatectomy is conducted in the anterior urogenital triangle. The urogenital diaphragm fills a portion of the anterior urogenital triangle. The intent of the surgeon should be to approach the prostate beneath the posterior aspect of the urogenital diaphragm. 210

Radical Perineal Prostatectomy / 211

tum itself. Some of the longitudinal smooth muscle fibers from the anterior surface of the rectum leave the rectal wall to run on the upper surface of the levator ani. There they pass forward to attach to the urethra. These constitute the rectourethralis muscle (Figure 23–6). In approaching the prostate from the perineum, the fibers of the rectourethralis must be divided or separated in the midline (after the attachments of the external anal sphincter to the central tendon have been divided) to access the prostate. The fibers of the rectourethralis become contiguous with the neurovascular fascia surrounding the prostate.

FIGURE 23–2. The dotted line indicates the incorrect line of dissection through the prostate. Note that the correct line of incision is beneath the anal sphincter and beneath the posterior margin of the urogenital diaphragm. Dissection through the urogenital diaphragm risks injury to the membranous urethra and distal urethral sphincter.

of the anal sphincter that is anterior to the rectum. The fibers incised to gain access to the prostate are identified in Figure 23–5. They are termed the central tendon and insert on the perineal body (or the midpoint of the transverse perineal diaphragm). These fibers are cut at the point of their insertion into the perineal body.

Membranous Urethra and Urogenital Diaphragm The perineal surgeon must recognize the posterior aspect of the urogenital diaphragm and understand that the correct approach to the prostate is posterior to the transverse perineal musculature. The apex of the prostate is beneath the posterior aspect of the urogenital diaphragm (see Figure 23–2). Continence after prostatectomy is largely dependent on the intrinsic urethral mechanism that exists within the membranous urethra as it exits through the urogenital diaphragm. An improper approach to the prostate may cause the surgeon to dissect within, rather than beneath, the urogenital diaphragm. In so doing, it is easy to fragment the membranous urethra. Leaving the patient with this portion of the sphincteric mechanism damaged contributes to urinary incontinence. The membranous urethra is the shortest subdivision of the male urethra. It lies largely within the deep perineal space and is surrounded by the fibers of the sphincteric urethra. It may be no more than 1 cm in length, begin-

The Rectourethralis The rectum, as it passes through the muscles of the pelvic floor, becomes confluent with some fibers of the levator ani, which actually blend with the muscular wall of the rec-

FIGURE 23–3. The central tendon of the perineum is schematically represented here. This lies just beneath the subcutaneous tissues of the perineum, anterior to the rectum. With the patient in the exaggerated lithotomy position, it is defined as a fanlike fibromuscular structure extending from the anterior surface of the rectum.

FIGURE 23–4. The parasagittal section through the ischiorectal fossa. The broken line separating the major part of the ischiorectal fossa from its anterior recess represents the part of the so-called roof membrane sometimes described as separating the two parts of the fossa. From Hollingshead WH, editor. Anatomy for surgeons. 2nd ed. New York: Harper & Row; 1971.

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Summary An appreciation of each of these features of the perineal anatomy is important to properly carry out the perineal prostatectomy. The functional integrity of these structures must be preserved in reconstructive and extirpative procedures.

Radical Perineal Prostatectomy

FIGURE 23–5. Once the central tendon has been divided, the surgeon identifies the superficial and subcutaneous external anal sphincters. The superficial anal sphincter sweeps around the anus and inserts anteriorly. In the midportion of the perineum, beneath two muscle bundles, is a surgical space that is triangular in nature. By retracting the superficial external anal sphincter fibers superiorly and laterally, the surgeon may identify the glistening white fascia of the rectum and use this as a guide to the prostate.

ning above the urogenital diaphragm at the apex of the prostate and ending just below the diaphragm. Here, after exiting the perineum, it becomes continuous with the bulbar urethra. Fasciae of the Pelvis An understanding of the fascial sheaths in the perineum is important in properly conducted operative procedure in this area. The retrovesical septum is an important anatomic structure. It is attached to the peritoneum of the rectovesical pouch superiorly and has been called the “anterior layer” of Denonvilliers’ fascia. The anterior portion of the rectal fascia that is easily separable from the anterior layer of Denonvilliers’ fascia is commonly called the “posterior layer” of Denonvilliers’ fascia (Figure 23–7).3,4 The two layers of Denonvilliers’ fascia have been suggested to represent both anterior and posterior layers of the peritoneum of the rectovesical pouch, which, after development, has receded from its original contact with the pelvic floor. It is now felt, however, that the septum itself represents a local condensation of areolar tissue. The anterior surface of Denonvilliers’ or the rectovesical septum covers the posterior aspect of the prostate and the seminal vesicles. This must be incised if the seminal vesicles are to be approached from below (Figure 23–8). Similarly, the potential space between the posterior aspect of bladder and the seminal vesicles is sheathed by a fascial layer that must be incised if the seminal vesicles are to be approached anteriorly.

Radical perineal prostatectomy is growing in popularity as a surgical procedure. It has been used by few surgeons over the past three decades because most have been taught radical retropubic prostatectomy. Nevertheless, the procedure has recently become much more in vogue because of recognized advantages of the operative approach. The surgical conduct of perineal prostatectomy as originally described has been modified over the past 25 years. This chapter describes modifications in radical perineal prostatectomy developed by the author over the past two decades and compares them with modifications described by others. Patient Selection Surgical treatment of prostatic malignancy is appropriate only for those patients in whom the disease is confined to the prostate. Preoperative staging maneuvers should be designed to ensure that the disease is so confined. Most of the patients the author and colleagues currently operate on have had isotopic bone scanning to exclude metastatic skeletal disease at the time of initial consultation. Both preoperative bone scan and staging pelvic lymphadenectomy may be excluded, however, in patients who have Gleason scores of 7 or less and whose prostate-specific antigen (PSA) level is < 25 ng per mL. The incidence of metastatic disease is under 2% when these criteria are used. Preoperative Preparation The patient is provided an osmotic bowel preparation the day before surgery and nonabsorbable oral antibiotics the evening before the procedure. On the morning of surgery, a neomycin enema is given 2 to 3 hours before the scheduled operative procedure. Broad-spectrum antibiotics are given parenterally as required. Contraindications Patients with significant competing risks of death estimated to result in mortality 10 years from the projected date of surgery are not considered candidates for radical prostatectomy. In general, patients who have previously undergone an open transcapsular or transvesical prostatectomy should not be considered candidates for perineal prostatectomy since fixation of the prostatic capsule or bladder within the pelvis may compromise the urethrovesical anastomosis. The procedure may be safely carried out in these patients, however, if adequate care is

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taken. Previous transurethral resection of the prostate is not a contraindication and does not increase the risk of intraoperative or postoperative complications, nor does it increase the risk of postoperative incontinence. The author and colleagues routinely delay radical prostatectomy for 6 to 8 weeks after transurethral resection to allow healing of the prostatic fossa. The author, however, has operated as early as 3 to 4 days after transurethral resection without adverse outcome. Patients who are massively obese may not tolerate the exaggerated lithotomy position since the intra-abdominal contents may compromise diaphragmatic excursion and prevent adequate respiration, even with increased ventilatory pressures. Previous pelvic radiation, other pelvic surgery, and abdominal-perineal resection are not contraindications for perineal prostatectomy, except when previous therapy has compromised the bladder neck. Operative Procedure The procedure may be accomplished on a standard operating table with adequate leg support. The author prefers to use candy-cane stirrups, wrapping the feet to insure that the straps do not place excessive pressure on bony prominences (Figure 23–9).5 There is no need to wrap the legs or place them in alternating pressure stockings. The patient is positioned far from the head of the table, the small of the back being brought to the edge of the table with the buttocks extending approximately 20 to 30 cm over the table and the feet then rotated toward the head. It is not necessary to use shoulder braces to stabilize the patient. With the patient properly positioned, the weight of the patient is borne across the shoulder blades, and sandbags or folded towels are placed beneath the sacrum and the small of the back to maintain elevation of the pelvis. When legs and feet are rotated toward the head and the patient has been properly positioned, the perineum is parallel to the floor. The ischial tuberosities can be palpated and should lie in a line just posterior to the anus.

Urethra

Rectourethralis

Rectum

FIGURE 23–6. The rectourethralis is a condensation of muscular fibers that run from the rectum to the urethra anteriorly. It is variable in a cephalad-caudad direction and is always in the midline. The surgeon may create a space on each side of the rectourethralis all the way to the prostate itself. The rectourethralis may then be sharply divided without fear of injury to the rectum.

Surgical Procedure The procedure commences with a skin incision made approximately 1.5 cm anterior to the anal verge, extended posterolaterally on either side of the anus medial to the ischial tuberosities, and continued behind the anus on each side.5 To open the ischiorectal space, a defect using cutting cautery is created in the superficial perineal fascia on either side of the central tendon. The surgical space in the ischiorectal fossa is developed by placing a finger in this defect perpendicular to the floor and medial to the ischial tuberosities themselves (Figure 23–10).6 The finger is curved toward the operating surgeon and the overlying fibrofatty tissue is incised with cutting cautery. The next maneuver is designed to isolate the central tendon. Allis clamps are placed on the mucosa of the anus and the distal rectal segment placed on tension. The surgeon passes a finger beneath the central tendon and palpates

FIGURE 23–7. Schema of the fascial sheaths of the pelvic viscera in the male in sagittal section. Although essentially tubular condensations of connective tissue around the viscera, they receive contributions from or are continuous with the neurovascular sheaths, largely visible in sagittal section but represented here by puboprostatic ligament of the umbilicovesical fascia; from the fascia of the upper surface of the levator ani; and in the male from the rectovesical septum. From Hollingshead WH, editor. Anatomy for surgeons. 2nd ed. New York: Harper & Row; 1971.

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FIGURE 23–8. The central tendon is divided close to the skin margin.

the taut rectal surface. There is a defect just distal to the rectourethralis as it inserts on the rectum. The finger is passed just distal to the rectourethralis over the surface of the rectum and exits the contralateral side. The tissue superior to the finger represents the tissue of the central tendon. The central tendon itself is a fibromuscular tissue that arises on the tip of the coccyx, flows around the rectum, and inserts on the perineal body. This fibromuscular tissue must be divided so that the anus and rectum can be displaced posteriorly. Once the surgeon has passed a finger anterior to the rectum, distal to the rectourethralis, and beneath the central tendon, the central tendon is divided in its entirety with cautery. The line of incision is made close to the skin margin (see Figure 23–8). The rectum will drop posteriorly following division of the central tendon. With upper traction on the perineal

body, the rectourethralis is easily identified as is the glistening surface of the anterior rectal fascia. Using Metzenbaum scissors held so that the curve approximates the curve of the rectum, and by gently spreading the scissors on either side of the midline, with blunt dissection, the anterior surface of the rectum can be exposed and mobilized on either side of the rectourethralis to and beyond the level of the prostatic apex (Figure 23–11). The next maneuver is designed to place the rectourethralis under tension. To accomplish this, an examining finger is placed in the rectum to place downward pressure on it while an assistant elevates the perineal body in the opposite direction using the anterior retractor. The operating surgeon now places a finger on either side of the rectourethralis to further open the space by blunt dissection. Using Metzenbaum scissors, the rectourethralis is partially cut in the midline. As the tissue is divided with Metzenbaum scissors, the midportion of the rectourethralis is seen to be white and largely avascular. Gently spreading the Metzenbaum scissors in the midline will create a defect between the two lateral leaves of the rectourethralis. The rectourethralis can then be separated to the level of the prostate. To facilitate access to the prostate, an assistant can push the prostate into the operative field using the Lowsley retractor. This will immobilize the prostate while the surgeon separates the supporting fibers of the levator sling and the fibrofascial tissue surrounding the prostate, and through which the nerves of corporal innervation pass. Once identified in the midline, the next maneuver will fully expose the prostate posteriorly and laterally by dissecting beneath the neurovascular fascia. This is accomplished using either a sharp or blunt dissection lateral to the prostate. Once this fascia has been identified, the decision can be made to sacrifice the neurovascular fascia or maintain it. Baby Deaver retractors are then placed either medial or lateral to the neurovascular fascia, at the surgeon’s discretion (Figure 23–12). Attention is then focused on developing a plane between the rectum and prostate. After the prostate has been exposed in the manner described above, its posterior aspect will be covered with fibromuscular tissue that is seemingly continuous with the anterior rectal surface. By downward pressure on the rectum, easily maintained by use of a weighted vaginal speculum, the margin between the rectum and prostate can be identified. These fibers may be divided using Metzenbaum or Strully scissors. Once they have been divided, digital dissection is used to develop a surgical space between the prostate and seminal vesicles anteriorly, and the rectal surface posteriorly. Exposure of the Prostate Apex and Urethra

FIGURE 23–9. The patient is placed in exaggerated lithotomy.

Once the prostate has been exposed laterally and posteriorly, the next step is to expose the apex of the prostate and identify the urethra. With the prostate exposed and still

Radical Perineal Prostatectomy / 215

FIGURE 23–10. The ischial space is opened with cautery.

covered posteriorly at the apex with fibromuscular tissue, the surgeon may palpate the Lowsley retractor within the urethra at the apex of the prostate. With Strully scissors, the fibers overlying the apex of the prostate and the urethra are incised only in the midline. With blunt dissection using a bronchial dissector, the prostate apex is displaced inferiorly and the urethra exposed in the midline. The dissector may then be pushed on either side of the urethra medial to the vasculature exiting from the prostate.5 The lymphatics from the prostate flow in this tissue and apical disease may extend along this vasculature. This neurovascular tissue, however, is independent of the neural tissue providing innervation to the corpora and should be divided. These vascular structures are sharply incised, and the surgeon, with digital dissection to the right and left of the urethra, can separate prostatic substance from the overlying dorsal venous complex and carry this dissection to the detrusor musculature.

FIGURE 23–11. The rectourethralis is placed on tension.

FIGURE 23–12. The urethra is separated from the adjacent vascular tissue.

At this point, a right-angled clamp is placed around the urethra. The clamp is opened and the prostatic substance separated from the urethra at the apex of the prostate to establish as much urethral length as possible beneath the transverse perineal diaphragm (Figure 23–13). It is often possible to establish a urethral length of 1 to 1.5 cm beneath the transverse perineal diaphragm, and it is this portion of the urethra that is important in postoperative urinary control. (Having biopsied over 200 of the patient-side urethral segments and not identifying malignancy, the author does not believe this maneuver places the patient at increased risk for residual malignancy.) Once the urethra is fully mobilized, the Lowsley retractor is removed

FIGURE 23–13. The urethra is divided at the apex of the prostate.

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FIGURE 23–14. The vasculature to the prostate lies lateral to the seminal vesicles.

and the urethra divided at the apex of the prostate, with the patient-side margin being tagged with 2-0 suture to permit easy identification during reconstruction.

FIGURE 23–15. A direct urethrovesical anastomosis is supported by modified Vest suture anterior and posterior to the urethra.

Following division of the urethra, a Young prostatic tractor (or a straight Lowsley retractor) is passed through the urethra into the bladder and the blades extended. These permit the surgeon to identify the bladder wall and also manipulate the operative specimen. Allis clamps or a tenaculum may be placed on the prostate to draw it into the operative field and permit identification of the plane between prostate and detrusor fibers. With blunt dissection, the plane between the prostate and detrusor can be developed to the right and left of the bladder neck and the latter identified in the midline. Investing fibrous tissue between prostate and bladder laterally can be also identified and sharply divided. There is no significant vasculature in this tissue and, if vasculature is identified, it is not of a size to cause significant bleeding. Cut vessels can be easily cauterized to establish hemostasis. With the prostate under tension, the tissue extending from the bladder neck into the prostate is easily identified. This is then sharply divided using curved Metzenbaum scissors, then a large curved clamp is passed through the prostatic urethra from apex to bladder neck and a loop of soft rubber catheter brought through and used for manipulation of the specimen. With traction on the catheter and the tenaculi, the prostate is further mobilized on either side of the posterior bladder neck. Once it is maximally mobilized but still adherent to the posterior bladder neck, curved Metzenbaum scissors are passed behind the bladder neck to sharply divide the posterior bladder neck. Before doing this, however, a tagging suture should be placed on the bladder neck as the bladder will retract into the pelvis, possibly making it difficult to identify the bladder neck after removal of the prostate. With traction on the prostate to bring it further into the operative field, the surgeon should use scissors to incise the fibromuscular tissue overlying the vas deferens and seminal vesicles in the midline. This is largely an avascular fascia and the tissue may be divided with impunity. Once the vasa deferentia have been identified in the midline and the seminal vesicles lateral to the vasa deferentia, the physician can mobilize the lateral vascular pedicles to the prostate. This is accomplished using a right-angled clamp, passing it just lateral to the seminal vesicles but medial to the vascular pedicle to the prostate (Figure 23–14). Once this space has been developed, the vascular pedicles can be controlled using surgical clips, or they can be sharply divided and bleeding points subsequently controlled by electrocoagulation. Using the seminal vesicles as an anatomic marker, the seminal vesicles can be entirely encircled at the base of the prostate, all investing tissue being sharply divided to mobilize the prostate. Once the fibromuscular tissue and vascular pedicles have been severed, the specimen is held in place only by the seminal vesicles and vas deferens and by the fascia overlying the seminal vesicles posteriorly. The specimen may be elevated in the operative field and the fascia

Radical Perineal Prostatectomy / 217

the pelvis, separating the prostate and seminal vesicles from the rectal surface to the apex of the seminal vesicles and then controlling them. This is the methodology espoused by Harris and Thompson.6 When the vesicles are initially exposed, the pedicles at the base of the prostate are ligated and divided before exposure of the anterior prostate. The choice of surgical approach to the seminal vesicles, whether positive initially or anteriorly after division of the urethra, is purely physician preference. The current author finds it technically easier to approach the seminal vesicles and vas deferens as described.

Management of the Bladder Neck FIGURE 23–16. Kaplan-Meier projection of time-to-cancer-associated-death for patients with organ-confined, specimen-confined, or margin-positive disease.

divided. With the seminal vesicles identified, each vasa deferentia is isolated in the midline, controlled with a surgical clip, and divided. The seminal vesicles may be exposed either in their entirety or for a distance of 2 to 3 cm. If the surgeon elects not to remove the seminal vesicles in their entirety, they can be controlled at a distance of 2 to 3 cm from the prostate with surgical clips before division and the specimen then removed. There is no enhanced disease control established by removing the seminal vesicles in their entirety. This can be done but may be technically difficult. Also, there is concern that dissection to the tips of the seminal vesicles may compromise the neural innervation of the bladder and increase the probability of postoperative detrusor dysfunction. Alternatively, after the prostate has been exposed posteriorly, the prostate may be completely elevated within

FIGURE 23–17. Time to PSA failure as a function of disease extent.

There is much discussion surrounding “bladder neck preservation” versus excision of the bladder neck.6 Harris and Thompson6 advocate preservation. The current author, however, widely excises tissue at the bladder neck to ensure that all prostatic tissue has been removed. Preservation of the bladder neck fibers does not, the author believes, improve postoperative continence as this depends largely on that segment of urethra preserved at the level of the transverse perineal diaphragm. Wide excision of the bladder neck is accomplished by grasping the posterior bladder neck with an Allis clamp at the 6 o’clock position and cutting away the bladder neck from the 6 through 8 to 12 o’clock positions, and from the 6 through 4 to 12 o’clock positions. The surgeon then places a traction suture in the bladder neck at the 6 o’clock position, maintaining tension on the posterior bladder neck by weight of a Kelly clamp. Attention is then turned to covering the raw detrusor from the 9 through 12 to 3 o’clock segments with bladder mucosa. This is accomplished with 0000 Monocryl. The 6 to 9 o’clock and 6 to 3 o’clock segments need not be covered with mucosa since this portion will be closed in the subsequent racket-handle closure. Once the anterior bladder neck has been covered with vesicle mucosa, 0-strength absorbable sutures are placed outside-inside and inside-outside approximately 0.5 cm to either side of the 12 o’clock midline (Figure 23–15).

FIGURE 23–18. Time to continence.

218 / Advanced Therapy of Prostate Disease

These will later be brought through the perineal body and tied beneath the skin to support the direct urethrovesical anastomosis. An 18F Foley catheter is passed through the urethra. The previously placed 0-0 suture is used to identify the urethra as it penetrates the transverse perineal diaphragm. The surgeon then places 0-0 absorbable sutures in the urethra at the 2, 4, 8, and 10 o’clock positions. The two sutures placed at the 4 and 8 o’clock positions are driven in the mucosa-covered bladder neck approximately 0.5 cm from the 12 o’clock midline. An 18F Foley catheter is passed through the urethra and into the bladder and the balloon inflated. The bladder neck is closed from the 6 to 12 o’clock position with interrupted 0-strength absorbable sutures, the closure being made tight around the 18F Foley catheter. The two 0-0 urethral sutures that were placed at the 10 and 2 o’clock positions in the urethra are then brought into the reconstructed bladder neck approximately 0.5 cm on either side of the racket-handle closure. These four 0-0 absorbable sutures are snugly tied. Once the four direct anastomotic sutures have been secured, the two 0-strength absorbable sutures previously placed in the bladder neck near the 12 o’clock midline and the last two 0 sutures used in the racket handle posteriorly are brought through the transverse perineal body on the right and left side of the urethra with a No. 8 surgeon’s needle. These are tied beneath the skin. The wound is drained with a Penrose drain and the central tendon reconstructed using absorbable 0-0 sutures. Skin margins are closed with 0-0 strength absorbable vertical mattress sutures.

Postoperative Care The patient is mobilized within 6 to 8 hours after surgery, and oral intake is initiated within 4 to 8 hours after surgery. The patient is administered oral antibiotics plus a stool softener. Patients are routinely discharged 48 hours after the day of surgery. The catheter is left in place for 14 to 18 days and then removed by either the operating or referring surgeon. Although it is possible to remove the catheter earlier, the author and colleagues have found that difficulties in voiding after catheter removal are markedly reduced if the catheter is left in place for a longer period. Disease Control Benefit of Perineal Prostatectomy Although proponents of both perineal prostatectomy and retropubic prostatectomy vigorously maintain that their respective procedure provides superior cancer control, a rational assessment of the impact of disease control would indicate that equivalent outcome is achieved by either method. In a series of over 1200 patients subjected to radical prostatectomy at Duke University (segregated by local extent of disease—organ confined, specimen confined [microscopic T3 with negative margins], or margin positive [microscopic T3 with positive margins]), the PSA failure rates and cancer-associated death rates were equiva-

lent to other large single institution series using either perineal or retropubic surgery (Figures 23–16 and 23–17). The postoperative urinary control rate appears similar for patients subjected to radical perineal prostatectomy, even at geographically diverse sites. Weldon et al.7 from the University of California at San Francisco have reported a continence curve in 220 consecutive patients that closely approximates that reported by Frazier et al.8 (Figure 23–18). In the Duke University experience, 54 of 122 patients in this particular segment of the study were dry at the time of catheter removal. With the modifications described in this review, approximately 70% are dry at the time of catheter removal. The cumulative postoperative potency rate in 50 selected patients demonstrates a rate of approximately 75% for the California group, which is quite similar to the 77% potency rate in the Duke University experience. All three investigators reported a potency rate of 70%.6–8 Most adherents of perineal prostatectomy argue there is much less blood loss with the perineal approach than with the retropubic approach because the perineal dissection is conducted beneath rather than through Santorini’s venous plexus. The average operative blood loss reported by the San Francisco group was 600 cc.7 The average blood loss reported by the Duke University group was 565 cc.8 Harris and Thompson6 also reported low blood loss, though their exact figure is indeterminate. This blood loss figure should be compared to the blood loss reported by retropubic surgeons, which ranges from 1200 to 2000 cc per patient.

Conclusion It appears that perineal prostatectomy offers significant advantages over retropubic surgery with respect to surgical outcome. It is usually well tolerated by patients and surgeons.

References 1. Hollingshead WH, editor. Anatomy for surgeons. 2nd ed. New York: Harper & Row; 1971. 2. Paulson DF. The surgical technique of radical perineal prostatectomy. AUA Update Series. Vol.5 (lesson 38). Houston (TX): American Urological Association, 1986. 3. Paulson DF. Perineal prostatectomy. In: Marshall FF, editor. Operative urology. Philadelphia: WB Saunders; 1991. 4. Little NA, Paulson DF. Perineal radical prostatectomy. In: Whitehead ED, editor. Current operative urology. Philadelphia: JB Lippincott; 1989. 5. Paulson DF. Radical perineal prostatectomy. In: Marshall FF, editor. Textbook of operative urology. Philadelphia: WB Saunders; 1996. p. 545–54. 6. Harris MJ, Thompson IM. The anatomic radical perineal prostatectomy: a contemporary and anatomic approach. Urology 1996;48:762–8. 7. Weldon VE, Tavel FR, Neuwirth H. Continence, potency, and morbidity after radical perineal prostatectomy. J Urol 1997;158:1470–5. 8. Frazier HA, Robertson JE, Paulson DF. Radical prostatectomy: the pros and cons of the perineal versus retropubic approach. J Urol 1992;147:888–90.

CHAPTER 24

CONTINENCE-ENHANCING MODIFICATIONS FOR RADICAL PROSTATECTOMY MARK R. LICHT, MD; ERIC A. KLEIN, MD the prostatic urethra to the level of the verumontanum. These fibers are innervated by the autonomic nervous system. The distal sphincter is composed of an inner smooth muscle urethral layer combined with an outer periurethral arrangement of striated muscle fibers. The distal sphincter is innervated by both the autonomic nervous system via the pelvic plexus and somatic nerve branches from the pudendal nerve.8,9 The striated muscle of the distal sphincter is arranged in an approximate omega shape over the membranous urethra and the prostatic apex, with the bulk of the tissue oriented anteriorly beneath the dorsal vein complex. The distal sphincter is supported by the pelvic fascia, the puboprostatic ligaments, and the posterior midline fibrous tissue raphe, which is intimately associated with Denonvilliers’ fascia and the rectourethralis muscle. The overlap of fibers of the proximal and distal sphincter zones and the coordinated activity of each has led Myers to consider one unified continence mechanism as a continuum from bladder neck to membranous urethra.10 He describes this anatomic distance as the sphincteric functional urethral length. This concept is helpful in understanding how technical aspects of radical prostatectomy may influence urinary control. Factors contributing to normal continence in the male are summarized in Table 24–1.

In presenting the case for radical prostatectomy to patients with newly diagnosed, clinically localized prostate cancer, a discussion of postoperative urinary continence is mandatory. Most patients are already aware of the potential impact of surgery on urinary control and have access to often conflicting information regarding the risk of urinary incontinence. These data are confusing and can cause individuals to be concerned about choosing surgery over other forms of therapy. The medical literature also yields highly divergent results regarding continence following radical prostatectomy depending on the definition of incontinence, the mechanism of data collection, and modifications in surgical technique. Large contemporary series of radical prostatectomy report complete continence rates of 88 to 94%1–3 while the national Medicare experience4 found that 40% of men complained of stress incontinence and 30% wore pads or clamps to control urine leakage. Defining incontinence strictly as any amount of urine passing through the distal sphincter with an increase in intravesical pressure, Rudy et al.5 demonstrated with video urodynamics that 87% of patients studied were incontinent 6 months after surgery. Since the development of the anatomic approach to radical prostatectomy by Walsh,6 there have been numerous advances in the understanding of pelvic anatomy as it relates to urinary control in men. The mechanisms for urine loss following radical prostatectomy are also better understood. This expanded knowledge has led to modifications in surgical technique directed toward improving overall urinary continence and earlier return of postoperative urinary control.

Mechanisms of Postprostatectomy Incontinence Removal of the prostate causes a disruption in the normal anatomic configuration of the continence mechanism and its associated support structures (Table 24–2). The bladder neck following prostatectomy is directly anastomosed to the membranous urethra, with the bladder filling the space of the prostate in the pelvis. This results in a loss of overall urethral length. Dissection of the prostatic apex can further compromise both urethral length and support tissue. Portions of the distal sphincter may be destroyed or excised during the apical dissection. Damage to the smooth muscle fibers of the bladder neck can occur during dissection and reconstruction of the bladder neck, leading to impairment of function by loss of elasticity or scar tissue formation. Nerves supplying the distal bladder and urethra are often cut or injured as a result of surgery.

Anatomy of Male Continence The continence mechanism in men is commonly divided into two separate zones.7 The bladder neck and preprostatic sphincter have been considered together as the proximal sphincter while the distal sphincter includes tissue from the prostatic apex to the perineal membrane encompassing the membranous urethra. Urinary control can be maintained solely by one intact, functioning sphincter site. The proximal sphincter is composed of the circular smooth muscle fibers of the bladder neck which extend into 219

220 / Advanced Therapy of Prostate Disease TABLE 24–1. Factors Contributing to Normal Continence Bladder Compliance Competence of vesical neck Urethra Functional length Maximum closing pressure Striated urethral (external) sphincter Anatomic integrity Innervation

Scar tissue formation leading to poor urethral coaptation can occur at the vesicourethral anastomosis due to devascularization or postoperative urine leak. While loss of functional urethral length and sufficient sphincter action are the likely mechanisms for incontinence following prostatectomy, there has been significant debate in the literature as to which is most important. O’Donnell et al.11 showed radiographically that the functional level of continence after prostatectomy was approximately 1 cm distal to the vesicourethral anastomosis. They found urine in the proximal urethra at rest, with evidence of loss of closure pressure in incontinent patients. They therefore concluded that continence was maintained by a more distal sphincter mechanism. Presti et al.12 compared urodynamic studies in 24 incontinent patients and 13 continent patients who had undergone radical prostatectomy. They found a statistically significant difference between continent and incontinent patients in mean functional profile length, maximal urethral closure pressure, and maximal urethral closure pressure during voluntary contraction of the external sphincter. Continent patients had both increased functional urethral length as well as intact distal sphincter function. Fluoroscopically, continent patients were found to have tubularization of the bladder neck and proximal urethra above the level of the striated distal sphincter while incontinent patients did not. In flourourodynamic studies recently performed on 37 incontinent patients following prostatectomy, Gudziak et al.13 found that lack of functional coaptation of an intact proximal urethra alone and not loss of distal striated sphincter action was the cause of incontinence in all but one patient. They concluded that the volitional sphincter is not primarily responsible for postoperative urinary control. Similarly,

TABLE 24–2. Anatomic Changes following Radical Prostatectomy Decreased urethral length Loss of vesicourethral continuity Decreased elasticity of vesical neck and urethra Loss of fascia investing urethra Interruption of pelvic plexus innervation Changes in bladder compliance

Desautel et al.14 showed that of 26 incontinent patients in whom urethral scarring and anastomotic stricture was cystoscopically and radiographically demonstrated, all had urodynamic evidence of sphincteric incontinence as measured by abdominal leak point pressure. The contribution of bladder dysfunction to postprostatectomy incontinence is controversial. Incontinence could result from a poorly compliant, high pressure bladder with uninhibited detrusor contractions despite intact urethral and sphincteric function. By performing urodynamic studies on 162 incontinent patients, Leach et al.15 discovered bladder dysfunction alone in 14% and combined bladder dysfunction and sphincteric incontinence in 36% of patients. Conversely, Chao and Mayo16 reported bladder dysfunction alone as the cause of incontinence in only 4% of 76 patients, with sphincteric incontinence alone seen in 57%. They did, however, find combined bladder and sphincteric dysfunction in 43% of patients. Similarly, Presti et al.12 found that urethral and detrusor instability on urodynamics correlated poorly with incontinence, and Gudziak et al.13 concluded that bladder dysfunction is rarely the sole cause of postprostatectomy incontinence. While this issue has not been completely resolved, it does have important ramifications on the treatment algorithm for postprostatectomy incontinence. Incontinence following radical prostatectomy can be a complex issue influenced by many factors. To have the best chance of complete return of continence after surgery, however, patients most likely require a stable, compliant bladder, a functioning proximal sphincter unit free of scar tissue, and an intact distal sphincter mechanism. Based on this knowledge, specific