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Cervical Cancer: From Etiology to Prevention

Cervical Cancer: From Etiology to Prevention - Springer978-1-4020-2016-2/1.pdf · V111 5. Measurement of Exposure to Human Papillomaviruses 119 Patti E. Gravitt, M.S., Ph.D. and Raphael

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Page 1: Cervical Cancer: From Etiology to Prevention - Springer978-1-4020-2016-2/1.pdf · V111 5. Measurement of Exposure to Human Papillomaviruses 119 Patti E. Gravitt, M.S., Ph.D. and Raphael

Cervical Cancer: From Etiology to Prevention

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Cancer Prevention - Cancer Causes

Volume2

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Cercival Cancer: From Etiology to Prevention

Edited by

Thomas E. Rohan, M.B.B.S., Ph.D. Professor Chairman, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, U.S.A.

and

Keerti V. Shah, M.D., Dr.P.H. Professor, Departments of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, U.S.A.

Foreword by Harald zur Hausen, M.D., D.Sc.

Springer-Science+Business Media, B.V.

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A C.I.P. Catalogue record for this book is available from the Library of Congress.

Printed on acid-free paper

ISBN 978-90-481-6336-6 ISBN 978-1-4020-2016-2 (eBook) DOI 10.1007/978-1-4020-2016-2

All Rights Reserved © 2004 Springer Science+Business Media Dordrecht Originally published by Kluwer Academic Publishers in 2004. Softcover reprint of the hardcover 1 st edition 2004

No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission from the Publisher, with the exception of any material supplied specifically for the purpose ofbeing entered and executed on a computer system, for exclusive use by the purchaser of the work.

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To Our Wives,

Rosa and F arida

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Contents

Contributors ix

Foreword xv

Introduction xxv

SECTION 1 -BIOLOGICAL BASIS 1

1. The Pathology of Cervical Neoplasia 3 Mark H. Stoler, M.D.

2. The Natural History of Cervical Cancer 61 Anthony B. Miller, M.B., F.R.C.P.

SECTION 2- HUMAN PAPILLOMA VIRUS 79

3. The Biology of Human Papillomavirus Infections 81 Patti E. Gravitt, M.S., Ph.D. and Keerti V. Shah, M.D., Dr.P.H

4. The Molecular Pathogenesis of HPV -Associated Cancer 101 Stephen T. Oh, Ph.D. and Laimonis A. Laimins, Ph.D.

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V111

5. Measurement of Exposure to Human Papillomaviruses 119 Patti E. Gravitt, M.S., Ph.D. and Raphael P. Viscidi, M.D.

6. The Epidemiology of Human Papillomavirus Infections 143 Rachel L. Winer, M.P.H. and Laura A Koutsky, Ph.D.

SECTION 3 - ETIOLOGY 189

7. The Etiology of Squamous Cell Cervical Cancer 191 F. Xavier Bosch, M.D., M.P.H.

8. The Epidemiology of Adenocarcinoma of the Cervix 217 Thomas E. Rohan, M.B.B.S., Ph.D.

SECTION 4- PREVENTION 235

9. Educational Strategies for the Prevention of Cervical Cancer 237 Electra D. Paskett, Ph.D., Mary Ellen Wewers, Ph.D., R.N., M.P.H., and Mack T. Ruffin IV, M.D., M.P.H.

10. Screening for Cervical Cancer 261 Jack Cuzick, Ph.D.

11. Chemoprevention of Cervical Cancer 301 Michele Pollen, M.D., Ph.D., FrankL. Meyskens, Jr., M.D., E. Neely Atkinson, Ph.D., and David Schottenfeld, M.D.

12. Preventive Human Papillomavirus Vaccines 325 John T. Schiller, Ph.D. and Douglas R. Lowy, Ph.D.

13. Therapeutic Human Papillomavirus Vaccines 345 Morris Ling, B.A. and T.-C. Wu, M.D., Ph.D.

14. Policies for Implementing Cervical Cancer Preventive and Control Strategies 3 77

Robert A. Hiatt, M.D., Ph.D. and Jon F. Kerner, Ph.D.

INDEX 403

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Contributors

E. Neely Atkinson, Ph.D. Department of Biomathematics, The University of Texas M D. Anderson Cancer Center, Houston, TX

F. Xavier Bosch, M.D., M.P.H. Servei d'Epidemiologia i Registre del Cancer Institut Catala d'Oncologia, Barcelona, Spain

Jack Cuzick, Ph.D. Cancer Research UK , Dept. of Epidemiology, Mathematics and Statistics, Wolfton Institute of Preventive Medicine, London, UK

Patti E. Gravitt, M.S., Ph.D. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

Michele Pollen, M.D., Ph.D. Center for Biomedical Engineering, The University of Texas MD. Anderson Cancer Center, Houston, TX

Robert A. Hiatt, M.D., Ph.D. Division of Cancer Control and Population Sciences, National Cancer Institute, NIH, Bethesda, MD

IX

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X Contributors

Harald zur Hausen, M.D., D.Sc. Deutsches Krebsforschungszentrum, Heidelberg, Germany

Jon F. Kerner, Ph.D. Division of Cancer Control and Population Sciences, National Cancer Institute, NIH, Bethesda, MD

Laura A. Koutsky, Ph.D. Department of Epidemiology, University of Washington, Seattle, WA

Laimonis A. Laimins, Ph.D. Department of Microbiology- Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL

Morris Ling, B.A. Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD

Douglas R. Lowy, Ph.D. Laboratory of Cellular Oncology, National Cancer Institute, NIH, Bethesda, MD

FrankL. Meyskens, Jr., M.D. Chao Family Comprehensive Cancer Center, University of California­Irvine, Irvine, CA

Anthony B. Miller, M.B., F.R.C.P. Division of Clinical Epidemiology, Deutsches Krebsforschungszentrum, Heidelberg, Germany

Stephen T. Oh, Ph.D. Department of Microbiology- Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL

Electra D. Paskett, Ph.D. School of Public Health/Comprehensive Cancer Center, Ohio State University, Columbus, OH

Thomas E. Rohan, M.B.B.S., Ph.D. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY

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Contributors Xl

Mack T. Ruffin IV, M.D., M.P.H. Department ofF amily Medicine, University of Michigan, Ann Arbor, MI

John T. Schiller, Ph.D. Laboratory of Cellular Oncology, National Cancer Institute, NIH, Bethesda, MD

David Schottenfeld, M.D. Department of Epidemiology, School of Public Health, The University of Michigan, Ann Arbor, MI

Keerti V. Shah, M.D., Dr.P.H. Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

Mark H. Stoler, M.D. Robert E. Fechner Laboratory of Surgical Pathology, Department of Pathology, University of Virginia Health System, Charlottesville, VA

Raphael P. Viscidi, M.D. Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD

Mary Ellen Wewers, Ph.D., R.N., M.P.H. College of Nursing and School of Public Health/Comprehensive Cancer Center, Ohio State University, Columbus, OH

Rachel L. Winer, M.P.H. Department of Epidemiology, University of Washington, Seattle, WA

T.-C. Wu, M.D., Ph.D. Departments of Pathology, Oncology, Obstetrics and Gynecology, and Molecular Microbiology and Immunology, The Johns Hopkins Medical Institutions, Baltimore, MD

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Preface

In the last few years there has been enormous progress in terms of our understanding of the etiology and pathogenesis of cervical cancer, particularly with respect to the role of human papillomaviruses. These advances have opened up new avenues for the prevention of this disease, one of the most common cancers in women, both through the refinement of existing technologies for cervical cancer control and through the development and evaluation of new technologies. This book was motivated by the perceived need to make knowledge of these advances accessible to a wide audience. To this end, we have been assisted by scientists working in a wide range of disciplines that are pertinent to the epidemiology and prevention of cervical cancer, and who have contributed reviews of its descriptive and analytical epidemiology, and of approaches to cervical cancer prevention and control through public health policy, education, screening, chemoprevention, and vaccine development.

The book is divided into 5 sections. Section 1 lays the foundation for the remainder of the book with chapters that address the histological classification of cervical neoplasia (i.e., cervical cancer and its precursors) and the natural history of the disease. Section 2 focuses on infection with human papillomaviruses. It commences with chapters on the biology and molecular basis of the effects of human papillomavirus infections, and concludes with chapters on methods for the detection of human papillomaviruses and on the epidemiology of infection with these viruses. Section 3 describes the etiology of the two main histological types of cervical neoplasia, namely squamous cell carcinoma and adenocarcinoma. Section 4 considers approaches to cervical cancer prevention, including risk reduction through educational means; screening using Pap smears, HPV detection, and other methods; chemoprevention; and preventive and

Xlll

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XIV Preface

therapeutic vaccination. The final section of the book, Section 5, contains a chapter addressing policy issues relevant to the implementation of preventive measures, and it also considers barriers to the implementation of such measures and strategies to surmount those barriers.

Given its scope, the book should appeal not only to oncologists, primary care practitioners, and public health professionals working on the policy implications of scientific developments, but also to basic scientists, pathologists, epidemiologists, and graduate students in cancer-related fields who want to gain an understanding of the topic.

We are grateful to Professor Harald zur Hausen, a major contributor to the understanding at a fundamental level of the role of human papillomaviruses in causing cervical cancer, for writing the foreword for the book, and we thank our colleagues whose excellent contributions made the book possible. We were helped enormously with the myriad tasks associated with production of the book by our assistants, Olga Mendoza and Joy Mays. We appreciate the contribution of Jaime Stone and Angela Coraccio at Harvard, who prepared the camera-ready versions of the chapters, and we also appreciate the help and advice that we received from the editorial staff at Kluwer, namely Cristina Miranda Alves dos Santos, Melania Ruiz, and Marianne Janssen.

Thomas E. Rohan, MB.B.S., Ph.D. Bronx, New York

Keerti V. Shah, MD., Dr.P.H. Baltimore, Maryland

September, 2003

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Foreword A Brief History of Human Papillomavirus Research

Harald zur Hausen, M.D., D.Sc. Deutsches Krebsforschungszentrum, Heidelberg, Germany

We are presently looking back to more than 100 years of papilloma and papillomavirus research. It is still relatively poorly recognized that McFadyean and Hobday in England started tumorvirus research in 1896 by demonstrating the cell-free transmission of canine warts. In 1907 this was followed by the more frequently quoted cell-free transmission of human warts by Ciuffo in Italy. Warts of course were not considered as authentic tumors at that time. It is therefore not too surprising that the subsequent cell-free transmission of chicken leukemia by Ellermann and Bang in Copenhagen (1908) and of chicken sarcoma by Rous in New York (1911) received much more attention by the scientific community.

In spite of a limited number of studies on papillomas and their viral etiology in subsequent decades, it took almost 80 more years before this field found broad interest, particularly in medicine. This resulted from the demonstrated relationship between specific papillomavirus infections and cancer of the cervix. It is, however, fair to say that the recent surge in activities in papillomavirus research has four (initially relatively independent) historical roots: (i) studies on papilloma development in cattle, (ii) in rabbits, (iii) in a rare human hereditary condition ( epidermodysplasia verruciformis ), characterized by an extensive verrucosis and the subsequent development of cancer in warts located at sun-exposed sites, and (iv) from the search for a viral etiology of cancer of the cervix. Although started from different initial observations, all four types of studies fertilized the

XV

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XVI Foreword

subsequent progress and stimulated specific experimental approaches. In a brief outline of pioneering work performed in these four areas, I will briefly try to characterize some of the early major advances made in these fields:

The infectious origin of bovine warts was initially demonstrated in Brazil (Magelhaes, 1920). Interest in these types of frequently giant papillomas developed from early studies of Olson and Crook who showed that transmission of these viruses to another species, horses, resulted in the induction of sarcoids. These invasively growing, but non-metastasizing tumors were also noted in domestic horses under natural conditions. Thus, their experimental induction suggested an origin from transspecies transmission of bovine papillomavirus, much later proven by molecular analyses (Lancaster et al., 1978). The Olson group made another striking observation, namely the induction of bladder tumors in cattle by bovine papillomavirus (BPV) infection (Olson et al., 1959). Only four years later two additional publications by Black et al. (1963) and Thomas and colleagues (1963) demonstrated the transforming activity of BPV preparations for bovine fetal and murine cells. This permitted for the first time the application of tissue culture studies to papillomavirus research and profoundly influenced progress in subsequent years.

The development of molecular biology and of DNA cloning techniques in the 1970s and application of this technology to the BPV system resulted in the characterization of parts of the BPV genome as responsible elements for tissue culture transformation (Lowy et al., 1980). Shortly thereafter BPV 1 represented the first fully sequenced papillomavirus type (Chen et al., 1982).

The interest in bovine papillomavirus studies continues until today. This is mainly based on the ease of using some of the most prevalent BPV types (BPV 1 and 2) in tissue culture studies to understand the mechanisms of viral genome persistence, as well as the expression pattern of specific viral genes. In addition, the use of viral BPV DNA in shuttle vectors and the episomal persistence of this DNA greatly increased the number of studies of these virus types.

Retrospectively, the impact of BPV research on the papilloma virus field originated mainly from analysis of BPV -caused cell transformation, from the dissection of the viral genome and from the structural and functional characterization of individual viral genes and gene products. The obtained data facilitated in particular early studies on human papillomavirus infections.

A second root of papillomavirus research, substantially influencing cancer research in general terms, goes back to the identification of papillomas and their infectious origin in wild cottontail rabbits in the early 1930s by Shope (1933). After successful transmission of this infection to domestic rabbits, Rous and Beard (1934) soon noted that in the latter animals the initial papillomas frequently converted into squamous cell carcinomas. Occasionally malignant

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Foreword xvn

conversion occurred also in the natural host, the cottontail rabbit. In a number of ingenious studies by the Rous group, synergistic effects between viral and chemical carcinogens were observed. Rous developed the concept of tumor initiation by analyzing this system (e.g., Rous and Kidd, 1938; Rous and Friedewald, 1944). He conceptually preceded his contemporaries by several decades, but the importance ofhis work was only acknowledged in 1966, when he received the Nobel award. In 1961, Ito and Evans showed that purified DNA of the cottontail rabbit papillomavirus (CRPV) was able to induce squamous cell carcinomas in rabbits, thus directly revealing the carcinogenicity of a viral genome.

The research by Peyton Rous was not specifically driven by his interest in the infectious agent of rabbit papillomas. He wanted to understand the mechanisms of cancer induction. The frequent progression of rabbit papillomas into squamous cell carcinomas provided him with a most useful model to analyze steps in cancer development and to understand the synergistic effects of different classes of carcinogens. Interestingly, the rabbit papillomavirus system found comparatively little attention in the subsequent period. The PubMed bibliography today lists only 189 titles for the cottontail rabbit papilloma virus, in contrast to 1085 titles for bovine papillomaviruses, 389 for epidermodysplasia verruciformis, and 5895 for genital papillomavirus infections.

The analysis of human papillomatous lesions and their relationship to virus infections and carcinogenesis had a much slower start. Since the cell­free transmission of human warts, their infectious etiology was clearly established. Yet, warts were mainly regarded as a cosmetic nuisance and not considered to be of significant medical interest.

A gradual change of this view originated from the description of a syndrome published in 1922 by Lewandowsky and Lutz in Basel. They described a hereditary condition, characterized by an extensive verrucosis, which they named epidermodysplasia verruciformis. At sun-exposed sites of those patients, at the forehead, the face, the back of the hands and arms some of these papillomatous lesions converted into squamous cell carcinomas. In 1946 Lutz and subsequently Jablonska and Millewsky (1957) proved the viral etiology of these warts in autoinoculation experiments. Schellender and Fritsch (1970) and Ruiter and van Mullem (1970) were particularly intrigued by the restriction of squamous cell carcinoma development to sun-exposed sites. It was mainly the merit of Stefania Jablonska in Warsaw, Poland, to point to a possible role of the papilloma virus particles seen in these warts as causal factors for the subsequent development of squamous cell cancers of the skin (Jablonska et al., 1972). In collaboration with the Paris group of Gerard Orth, both groups successfully demonstrated the presence of novel types ofpapillomaviruses, most frequently HPV 5, within epidermodysplasia

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xviii Foreword

verruciformis lesions and within squamous cell carcinoma biopsies of those patients (Orth et al., 1978; 1979).

Although HPV 5 represents the first human papillomavirus infection regularly detected in cutaneous squamous cell cancers of these patients, the rarity of the syndrome, the difficulties in obtaining sufficient clinical materials for extensive studies, and the absence of tissue culture lines from these carcinomas were probably the reasons for a limited interest in this condition. Even more than 25 years after the initial discovery of HPV 5 and related viruses most questions relating to their etiological role and to the mechanism of their interaction in infected host cells in the course of carcinogenesis still remain open. Only in more recent years the study of cutaneous papillomavirus infections and their relationship to non-melanoma skin cancer in immunosuppressed and immunocompetent patients is finding increasing attention.

A fourth track of papillomavirus research resulted in the identification of specific HPV types as causative agents for cancer of the cervix, other anogenital cancers, and a subset of oropharyneal carcinomas. Our group started these investigations in search for a viral etiology of cancer of the cervix. After fmding Epstein-Barr virus DNA in a 'virus-free' Burkitt lymphoma cell line (zur Hausen and Schulte-Holthausen, 1970) and in biopsies from Burkitt's lymphoma and nasopharyngeal cancer (zur Hausen et al., 1970), we used the same techniques in attempts to detect herpes simplex type 2 (HSV 2) DNA in biopsies from cervical cancer. By the end of the 1960s and during the 1970s serological studies suggested a role of HSV 2 in this cancer (Rawls et al., 1968; Naib et al., 1969). Our failure to find traces of HSV 2 DNA in these cancer biopsies prompted considerations to look for potential other infectious candidates causing this cancer, since its epidemiology provided good reasons to suspect an infectious etiology.

A number of anecdotal reports on malignant conversion of genital warts (condylomata acuminata), scattered in the medical literature of the preceding 100 years, caught our attention. This resulted in the speculation on a possible causal role of papillomavirus infections for cervical cancer and led to initial attempts to characterize the viral DNA in genital warts (zur Hausen et al., 1974; 1975; zur Hausen 1976; 1977). These and other studies had the early consequence of discovering the heterogeneity of the papillomavirus family (Gissmann and zur Hausen 1976; Orth et al., 1977; Gissmann et al., 1977), presently counting close to 100 fully sequenced genotypes (de Villiers, 1994; and personal communication). Although the eventual isolation ofHPV DNA from genital warts, labeled as HPV 6 (Gissmann and zur Hausen, 1980), and from laryngeal papillomas (HPV 11) two years later (Gissmann et al., 1982) did not yield positive data for these viruses in cervical cancer, the use of their DNA in hybridization experiments, performed under conditions of reduced stringency, permitted the subsequent

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Foreword XlX

cloning ofHPV 16 (Durst et al., 1983) and ofHPV 18 (Boshart et al., 1984), the two papillomavirus types most frequently found in cervical cancer. The following years resulted in a burst of activities. These included, among numerous other observations,

• the demonstration of a specific expression pattern of the viral E6 and E7 genes in the respective carcinoma tissue (Schwarz et al., 1985; Yee et al. 1985);

• the immortalization of human keratinocytes by high risk HPV, expressing the E6 and E7 genes (Durst et al., 1987; Pirisi et al., 1987);

• the interaction of E6 and E7 proteins with various cellular proteins, initially particularly with pRb and p53 (Dyson et al., 1989; Werness et al., 1990);

• the direct demonstration that E6 and E7 proteins are responsible for the malignant phenotype of cervical carcinoma cells (von Knebel Doeberitz et al., 1992; 1994);

• and large scale epidemiological studies identifying high-risk HPV types as the major risk factor for cervical cancer (Munoz et al., 1992; Bosch et al., 1995).

Today the practical consequences of these studies become more and more apparent: gaining an order of magnitude as diagnostic approaches to validate early precursor lesions of cervical cancer and the development of preventive vaccines with the potential to prevent one of the major cancers of women are no longer unrealistic fantasies (reviewed in zur Hausen, 2002). The recent demonstration of an effect of a virus-like particle vaccine preventing persistent infection by HPV 16 and early precursor lesions of cervical cancer (Koutsky et al., 2002) impressively underlines this potential. Thus, besides hepatitis B vaccine, another cancer-preventive vaccine will soon become available.

It is likely that papillomavirus research is still going to expand in the future: the role of these virus infections in at least some subsets of other anogenital and oropharyngeal cancers has substantially gained in substance during the past few years (IARC Report). In addition, an interesting mode of an indirect contribution to carcinogenesis (zur Hausen, 1999) by certain cutaneous papillomavirus types preventing apoptosis in UV -damaged cells becomes increasingly apparent (Jackson et al., 2000; 2002).

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XX Foreword

In this book, Drs. Rohan and Shah have produced a comprehensive treatment of the evidence relating to cervical cancer etiology and prevention. They have done so by assembling a team of leading cervical cancer researchers who have addressed the biology and natural history of human papilloma­virus infection and cervical cancer, as well as the etiology of cervical cancer, approaches to its prevention, and the policy issues relating to implementation of preventive strategies. The book is very timely in that it synthesizes the substantial advances in knowledge of these topics that have taken place in recent years, advances that put us on the threshold of a new era in cervical cancer prevention and control.

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XXII Foreword

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Introduction

Thomas E. Rohan, M.B.B.S., Ph.D. Department of Epidemiology and Population Health, Albert Einstein College of Medicine

Keerti V. Shah, M.D., Dr.P.H Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health

It is estimated that about 15.6% of all cancers worldwide, or about 1.45 million cases annually, are attributable to infections (Pisani et al 1997). A cancer of infectious origin may be preventable by immunization against the etiologic agent, as is already evident in the decreasing incidence ofhepatocellular carcinoma following immunization against the hepatitis B virus (Chang et al., 1997). Recent advances in our understanding of the causes of cervical cancer have raised the possibility that a reduction in the incidence of this disease might be accomplished through similar means.

Cervical cancer is a major cause of morbidity and mortality worldwide. Each year, approximately 470,000 women are diagnosed with the disease and about 230,000 die from it, making it the second most common cancer amongst women (Parkin et al., 2001). Given its importance, cervical cancer has been subjected to intensive investigation in order to identify its causes, and to develop and improve methods for preventing and controlling it.

Epidemiologic studies conducted several decades ago provided clues to the role of sexual activity in the etiology of cervical cancer. In particular, cervical cancer rates were noted to be low in Catholic nuns (Fraumeni et al., 1969) and in other religious groups (Boyd and Doll, 1964; Cross et al., 1968). Furthermore, risk of cervical cancer was observed to be increased in women who married at young ages (Boyd and Doll, 1964) and who therefore initiated sexual activity relatively early in life (Terris et al., 1967), and it was

XXV

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xxvi Introduction

also observed to be increased in association with the number of sexual partners that a woman had had (Terris et al., 1967). Attributes of the male partners of women who develop cervical cancer were found also to be related to risk, given the increased risk of cervical cancer observed in the wives of men with penile cancer (Martinez, 1969), the increased risk of cervical cancer in the wives of men previously married to cervical cancer patients (Kessler, 1977), and the higher number of sexual partners reported by the husbands of women with cervical cancer than by the husbands of women without the disease (Buckley et al., 1981). Observations such as these helped to generate the concept that a sexually transmitted agent might be involved in the etiology of cervical cancer.

Early efforts to identify a sexually transmissible agent focused on herpes simplex virus type 2 (Rawls et al., 1968). However, the case for a primary role for this virus was weakened considerably when cervical tumors failed to show consistent evidence ofHSV 2 DNA and protein (Park et al., 1983), and when the results of a large cohort study of Czechoslovakian women did not show a significantly increased risk of cervical neoplasia in association with HSV 2 serology at enrolment (Vonka et al., 1984; Schiffman et al., 1996).

Interest in the possible role of human papillomaviruses (HPV) in the etiology of cervical cancer was spurred by the discovery of HPV DNA in cervical tumors (zur Hausen et al., 1974), and at about the same time, by the observation by pathologists that the earliest precursor lesion of cervical cancer, low grade cervical dysplasia, was associated with HPV infection (Meisels et al., 1982). Subsequently, the immortalizing ability ofHPV DNA and of the encoded viral oncogenes was demonstrated (Pirisi et al., 1987; Miinger et al., 1989; zur Hausen, 2002). Over the course of the last decade, epidemiologic studies have shown that the association between the presence of HPV DNA in cervical specimens and risk of cervical neoplasia (both squamous cell carcinoma and adenocarcinoma) is one of the strongest ever observed in the study of human cancer etiology (Bosch et al., 2002). In addition, experimental investigations have provided insight into the mechanisms underlying the association, thereby helping to confirm the causal role of HPV infection in the development of cervical cancer (zur Hausen, 2002). Indeed, HPV is considered to be a necessary cause of cervical cancer, the first etiological agent to be given this designation for a human cancer (Bosch et al., 2002). While necessary, HPV infection alone is not sufficient to cause cervical cancer, indicating that progression from persistent (rather than transient (Burk,1999)) HPV infection to cervical neoplasia is likely to require exposure to other factors (so-called cofactors). Candidate cofactors include cigarette smoking, use of oral contraceptives, high parity, and infection with other sexually transmitted diseases (Castellsague et al., 2002), but research in this area is still at a relatively early stage.

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Introduction xxvn

Identification of the causal role of HPV infection in cervical carcinogenesis has made prevention of the disease a real possibility. Prevention of HPV infection through modification of sexual behavior presents enormous challenges, although some sex and AIDS education programs have been shown to delay the initiation of intercourse and reduce its frequency, to reduce the number of sexual partners, and to increase the use of condoms (Kirby et al., 1994; Rock et al., 2000). However, current efforts directed towards the development of vaccines designed to prevent HPV infection (Koutsky et al., 2002) and to prevent progression of existing HPV infections and neoplastic lesions (Moniz et al., 2003) represent more realistic prospects. Chemopreventive agents which target HPV transcription (Rosl et al., 1997) or which operate by other means (Rock et al., 2000) might also find application eventually.

The natural history of cervical cancer is now reasonably well understood. Essentially, it begins with disruption of the normal maturation of the epithelium of the transformation zone of the cervix (Franco and Ferenczy, 2002) leading to progressively more advanced grades of pre-invasive cervical neoplasia, known as cervical intraepithelial neoplasia (Richart, 1980), or equivalently, squamous intraepithelial lesions (Solomon et al., 2002). If such lesions are not treated, some will progress to involve the full thickness of the cervical epithelium (carcinoma in situ), and subsequently will break through the basement membrane and become invasive. Progression from an initial HPV infection to carcinoma in situ has been estimated to take more than 17 years on average (Ylitalo et al., 2000), and progression from carcinoma in situ to invasive cancer has been estimated to take an average of about 13 years (Gustafsson and Adami, 1989).

The long time course required for the development of cervical cancer renders it amenable to secondary prevention by screening. Specifically, the Papanicolaou test, in which exfoliated cells collected from the cervical transformation zone are examined microscopically, allows detection of cervical lesions at a relatively early stage in the natural history of cervical cancer; if followed by appropriate treatment, the course of the disease can be arrested. However, the conventional Pap smear has relatively low sensitivity, so that a substantial proportion of women who develop cervical cancer have adequate recent screening histories (Sasieni et al., 1996). More recently, with identification of the central role of HPV infection in the development of cervical neoplasia, use of HPV testing as an adjunct to or replacement for Pap screening has been suggested as a means of improving detection (Kulasingam et al., 2002), and such approaches are currently undergoing active evaluation. Indeed, screening based on HPV testing alone may be particularly suitable in resource-poor settings (Kuhn et al., 2000).

The developments outlined above have led to considerable optimism that the public health burden of cervical cancer can be reduced substantially

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XXVlll Introduction

in the coming years. However, important health policy issues remain, and they differ between developed and developing countries (Goldie, 2002). In developed countries, the main issues relate to how to ensure that the clinical benefits of state-of-the-art technologies are maximized. In contrast, in developing countries, the main issue currently (in the absence of an established HPV vaccine) is how to establish effective cervical cancer screening programs where it has not been possible to implement cervical cytology-based screening, given that resources are limited and that there are many competing priorities.

Our aim in this book has been to expand upon the themes introduced here. It is our hope that in doing so we have assembled an up-to-date resource that will be of use to those interested in cervical cancer etiology and prevention.

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