Human Papillomavirus

Alberto Rosenblatt
Homero Gustavo de Campos Guidi

Human Papillomavirus
A Practical Guide for Urologists
Alberto Rosenblatt, MD Homero Gustavo de Campos Guidi, MD, PhD
Hospital Israelita Albert Einstein Rua Teodoro Sampaio 744
Av. Albert Einstein 627/701 São Paulo-SP
São Paulo-SP 14th Floor
Brazil Brazil
[email protected] [email protected]

ISBN: 978-3-540-70973-2     e-ISBN: 978-3-540-70974-9

DOI: 10.1007/978-3-540-70974-9

Library of Congress Control Number: 2008944023

© Springer-Verlag Berlin Heidelberg 2009

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is
­concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting,
reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication
or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965,
in its current version, and permission for use must always be obtained from Springer. Violations are liable
to prosecution under the German Copyright Law.

The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply,
even in the absence of a specific statement, that such names are exempt from the relevant ­protective laws
and regulations and therefore free for general use.

Product liability: The publishers cannot guarantee the accuracy of any information about dosage and
application contained in this book. In every individual case the user must check such information by
consulting the relevant literature.

Cover design: estudioCalamar, Figueres/Berlin

Printed on acid-free paper

springer.com
This book is dedicated to our beloved parents
Agostinha and Mayer Rosenblatt
Isaura Guidi and Domingos Guidi
and to Sophie and Fernanda
for their constant support in every step of our lives.
 Foreword

The award of the Nobel Prize in Medicine to Professor Harald zur Hausen in 2008
represented one of the most auspicious recognitions in the field of cancer prevention.
Zur Hausen’s pioneer work unleashed an entire domain of research on the molecular
biology of human papillomavirus (HPV) and on its interaction with the human host.
His work permitted the characterization of HPV infection as the cause of the vast
majority of cervical cancers and of a large proportion of anogenital and upper aero-
digestive tract malignancies. Understanding the unequivocal role of HPV infection in
carcinogenesis led to two new fronts in cervical cancer prevention, namely, (i) the
development of diagnostic assays for HPV DNA, which are now being incorporated
into cervical cancer screening programs worldwide, and (ii) the regulatory approval
of the first prophylactic HPV vaccines to prevent HPV infections with the genotypes
of HPV that cause most cases of cervical cancer.
The burden of morbidity and mortality from cancers associated with HPV infec-
tion is greatest in developing cancers. Cervical cancer is the second most common
cancer in women worldwide and the most common in many developing countries in
Latin America, equatorial Africa, and in Southeast Asia. These countries now have a
renewed hope in controlling a disease that has been very difficult to prevent via tradi-
tional Pap cytology screening, an undertaking that has worked well only in high-
resource countries. One of the new vaccines also prevents the HPV types that cause
the majority of genital warts and low-grade lesions of the lower genital tract. Such
HPV types are also responsible for laryngeal papillomatosis. Collectively, these dis-
eases, albeit classified as benign, are responsible for much suffering and loss of qual-
ity of life throughout the world. In all, the spectrum of malignant and benign diseases
that can be prevented by the new prophylactic HPV vaccines affects women, men,
and children everywhere, and leads to major healthcare expenditures related to diag-
nosis, management, and treatment.
In this book, Drs. Alberto Rosenblatt and Homero Gustavo de Campos Guidi
have devoted considerable care in providing a comprehensive overview of the patho-
genesis, diagnosis, treatment, and prevention of diseases causally associated with
HPV infections. In many chapters, the authors also summarize the literature about
diseases in which HPV seems to be an incidental finding and whose specific role has
not yet been elucidated. As experienced, practicing urologists, Drs. Rosenblatt and
Guidi provided a richly illustrated guide that clinicians will find very useful as an
easy to navigate, yet authoritative reference to the diagnosis and treatment of HPV-
associated diseases. Although the emphasis is on the urologist’s approach to disease
­management, this book will also be appreciated by gynecologists, dermatologists,

vii
viii Foreword

pediatricians, and infectious disease specialists. The authors also enlisted the
­contribution of two renowned colleagues, Drs. Luisa Villa and Simon Horenblas, for
two chapters on laboratory detection methods and penile neoplasia, respectively.
Clinical and sub-clinical HPV infections are the most common sexually transmit-
ted diseases. Although there is justifiable enthusiasm in the public health community
with the novel prophylactic vaccines and sensitive screening tools, many challenges
lie ahead. The science on preventive and therapeutic approaches to curb the burden of
HPV diseases has grown exponentially in recent years. Clinicians need a practical
guide to allow them to sift through the new methods that have passed the scrutiny of
evidence-based medicine and can thus be used in the care of their patients. The
authors, Drs. Rosenblatt and Guidi, and Springer, the publisher, are to be commended
for Human Papillomavirus – A Practical Guide for Urologists, a contribution that
fills this need with high scholarly value.

Montreal, Canada Eduardo L. Franco

 Preface

We are what we repeatedly do. Excellence, then, is not an act, but a habit.
Aristotle

Human papillomavirus infection is a globally widespread disease that affects young

people and adults without sexual distinction. The sexually transmitted virus is respon-
sible for the development of benign anogenital lesions as well as several premalig-
nant and malignant anogenital and nongenital disorders.
Although obstetricians/gynecologists, urologists, and dermatologists are the med-
ical specialists most often involved in the management of HPV-related diseases, prac-
titioners in general ought to have a comprehensive understanding of the challenges
caused by this infective agent.
The interested reader will find in the chapters of this practical guide all the current
information concerning HPV and associated anogenital diseases, with particular
emphasis on the management of the infected male.
Premalignant and malignant penile neoplasias as well as current management of
anal and cervical intraepithelial disease are also reviewed in this book, providing the
readers with an authoritative wealth of updated data. The addition of practically
­oriented tables and numerous colored figures provides quick access to the objective
information, which is supported with over 800 references.
It is expected that the burden of HPV infection and associated diseases will cer-
tainly be reduced with the advent of current prophylactic vaccines. However, HPV
infection is a recurrent disorder and this book will enable practitioners in general to
understand and manage the male’s most common genital-related disorders.

São Paulo, Brazil Alberto Rosenblatt

Homero Gustavo de Campos Guidi

ix
 Acknowledgments

The authors acknowledge with deep appreciation Prof. Simon Horenblas and
Dr. Luisa Lina Villa for their valuable contribution to this book. Prof. Horenblas’s vast
expertise in penile cancer and Dr. Villa’s acclaimed investigative work with human
papillomavirus provide us with two key chapters where updates on penile neoplasia
and the current laboratory investigation of human papilloma virus are presented.

We express our gratitude to Dr. Carlos Walter Sobrado Jr., Dr. Sidney Roberto Nadal,
Dr. Maricy Tacla, Dr. Marcia Jacomelli, Dr. Reinaldo J. Gusmão, Dr. Toshiro
Tomishige, Dr. Monica Stiepcich, Dr. Rubens Pianna de Andrade, Dr. Libby Edwards,
Prof. Robert A. Schwartz, Prof. Gerd Gross, and Prof. Gino Fornaciari for their
­generous contribution providing the innumerous and valuable figures that illustrate
the chapters of the book.

We also specially thank Prof. Filomena Marino Carvalho for her significant insights
regarding the nomenclature of genital squamous intraepithelial lesions as well as the
illustrative cytology and histopathology slides, and Dr. Nadir Oyakawa, a pioneer in
the field of HPV-related diseases in women and who prematurely left us at the height
of her scientific career.

We thank the publishers who kindly gave us copyright permissions for the use of
figures in this book.

Finally, we are deeply grateful to all the staff at Springer involved in the creation of this
book, in particular, Ute Heilmann (Editorial Director, Clinical Medicine), Annette
Hinze (Editor, Clinical Medicine), Wilma McHugh (Project Coordinator), and Dörthe
Mennecke-Bühler (Assistant Editor, Clinical Medicine) for their professionalism, friend­
ship, and guidance along the path to publication. We also thank Nandini Loganathan
and the staff at SPi for their excellent job with the production of this book.

xi
 Contents

Part I Human Papillomavirus Facts and Novel Detection Methods

1 Human Papillomavirus History and Epidemiology . . . . . . . . . . . . . . . . 3

1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.2 Historical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.3 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.4 HPV in Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
1.5 HPV in Men . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
1.6 HPV Transmission Modes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.7 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

2 Laboratory Methods for Detection

of Human Papillomavirus Infection . . . . . . . . . . . . . . . . . . . . . . . . . . .  23
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.2 HPV DNA Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2.3 HPV RNA Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2.4 Serological Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.5 Detecting HPV Infection in Men . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Part II Human Papillomavirus and Urological-Associated Diseases

3 Human Papillomavirus and External Genital Lesions . . . . . . . . . . . . .  33

3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
3.2 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
3.3 Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
3.4 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.5 Detection Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.6 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
3.7 Other Treatment Modalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
3.8 Management of Latent and Subclinical HPV Infection . . . . . . . . . . . 66
3.9 Circumcision and HPV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
3.10 Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
3.11 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

xiii
xiv Contents

4 Human Papillomavirus-Associated Lesions

of the Urinary Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  73
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
4.2 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
4.3 Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
4.4 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
4.5 Detection Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
4.6 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
4.7 Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
4.8 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
4.9 The Role of HPV in Urethral, Bladder,
Renal, and Prostate Cancer Development . . . . . . . . . . . . . . . . . . . .  91
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
5 Human Papillomavirus and Penile Intraepithelial Neoplasia . . . . . . 97
5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
5.2 Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
5.3 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
5.4 Multifocal Intraepithelial Neoplasia (Bowenoid Papulosis) . . . . . . . 102
5.5 Bowen’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
5.6 Erythroplasia of Queyrat (Unifocal Intraepithelial Neoplasia) . . . . . 107
5.7 Penile Lichen Sclerosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
5.8 Penile Horn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
5.9 Genital Paget’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
5.10 Kaposi’s Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
5.11 PIN Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
6 Human Papillomavirus and
Squamous Cell Carcinoma of the Penis . . . . . . . . . . . . . . . . . . . . . . . .  121
6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
6.2 Natural History of HPV in Male Subjects . . . . . . . . . . . . . . . . . . . . . 122
6.3 Etiology of Squamous Cell Cancer of the Penis . . . . . . . . . . . . . . . . 122
6.4 Molecular Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
6.5 Prevention of HPV Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
6.6 HPV as a Prognostic Indicator in Penile Cancer . . . . . . . . . . . . . . . . 126
6.7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Part III Human Papillomavirus and Other Anogenital Premalignant Diseases
7 Human Papillomavirus and Anal Intraepithelial Neoplasia . . . . . . . .  133
7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
7.2 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
7.3 Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
7.4 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
7.5 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
7.6 Treatment for Anogenital Warts and AIN . . . . . . . . . . . . . . . . . . . . . 140
7.7 Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
7.8 Anal Disease Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
7.9 Prevention of HPV-Related Anal Warts and AIN . . . . . . . . . . . . . . . . 145
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
xv Contents

8 Human Papillomavirus and Cervical Intraepithelial Neoplasia . . . .  149

8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
8.2 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
8.3 Terminology and Grading of Cervical Dysplastic Lesions . . . . . . . . 150
8.4 Risk Factors for Cervical Cancer Development . . . . . . . . . . . . . . . . . 152
8.5 Natural History of Cervical Dysplastic Lesions . . . . . . . . . . . . . . . . 152
8.6 Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
8.7 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
8.8 Treatment for HSIL and CIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
8.9 Treatment Modalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
8.10 Post-treatment Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
8.11 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
8.12 Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Part IV Human Papillomavirus Infection and Immunosuppression
9 Human Papillomavirus Infection
in HIV-Infected Individuals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  163
9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
9.2 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
9.3 HPV Infectious Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
9.4 Effects of Host Immune Status on the Risk of HPV Infection . . . . . 166
9.5 Host Immune Evasion Methods of HPV . . . . . . . . . . . . . . . . . . . . . . 166
9.6 HPV Infection in Immunosuppressed Individuals . . . . . . . . . . . . . . . . 167
9.7 Relationship Between Declining CD4+ Levels,
HPV Infection, and Anogenital Cancers . . . . . . . . . . . . . . . . . . . . . .  168
9.8 Relationship Between HIV/HPV
Coinfection and CIN/Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . .  168
9.9 Relationship Between HIV/HPV
Coinfection and AIN/Anal Cancer . . . . . . . . . . . . . . . . . . . . . . . . .  169
9.10 HAART in HPV-Associated Neoplasias . . . . . . . . . . . . . . . . . . . . . . 171
9.11 HAART in HPV-Associated Cervical Disease . . . . . . . . . . . . . . . . . 171
9.12 HAART in HPV-Associated Anal Disease . . . . . . . . . . . . . . . . . . . . 171
9.13 HAART in HPV-Associated Oral Disease . . . . . . . . . . . . . . . . . . . . 172
9.14 Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
9.15 Considerations Regarding HPV Prophylactic and
Therapeutic Vaccines in HIV-Infected Individuals . . . . . . . . . . . . .  172
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Part V Human Papillomavirus - Laser Treatment and Prevention
10 Human Papillomavirus and CO2 Laser Treatment . . . . . . . . . . . . . . .  181
10.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
10.2 Historic Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
10.3 CO2 Laser Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
10.4 CO2 Laser Beam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
10.5 CO2 Laser Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
10.6 Personal Laser Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
11 Human Papillomavirus Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  195
11.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
11.2 HPV: An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
xvi Contents

11.3 A Short Introduction to Papillomavirus Biology . . . . . . . . . . . . . . . . 197

11.4 Significance of HPV Proteins in the Generation of
Prophylactic and Therapeutic HPV Vaccines . . . . . . . . . . . . . . . . . . 197
11.5 Natural History of HPV Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . 198
11.6 Prophylactic HPV Vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
11.7 HPV Vaccination: Issues to Be Addressed . . . . . . . . . . . . . . . . . . . . . 205
11.8 Prophylactic HPV Vaccines in Men . . . . . . . . . . . . . . . . . . . . . . . . . . 207
11.9 Therapeutic HPV Vaccination and
Future Vaccine Developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  208
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
 Human Papillomavirus History
and Epidemiology 1
Alberto Rosenblatt and Homero Gustavo de Campos Guidi

Contents According to a recent Centers for Disease Control

and Prevention (CDC) analysis (Forhan et al., 2008),
1.1 Introduction........................................................... 3 one in four American women between the ages of
1.2 Historical Perspective............................................ 5 14 and 19 (approximately 3.2 million young girls) is
1.3 Epidemiology......................................................... 6 infected with at least one of the most common STDs
(i.e., HPV, Chlamydia trachomatis, trichomoniasis, and
1.4 HPV in Women...................................................... 8
1.4.1 Risk Factors............................................................. 8
herpes simplex virus type 2). While genital chlamydia
is the most commonly reported condition in the United
1.5 HPV in Men........................................................... 9
States (Satterwhite, 2008), HPV is by far the most
1.5.1 Risk Factors............................................................. 11
1.6 HPV Transmission Modes.................................... 12
1.6.1 HPV Transmission in Children............................... 12
1.6.2 Considerations Regarding Unusual
Transmission Routes............................................... 14
1.7 Prevention.............................................................. 14
1.7.1 Condoms.................................................................. 14
1.7.2 Vaccines................................................................... 14
1.7.3 Antiviral Microbicides............................................ 15

References.............................................................. 15

1.1 Introduction

Human papillomavirus (HPV) infection is a significant

source of morbidity and mortality among the young pop-
ulation and, together with HIV, is considered the most
costly sexually transmitted disease (STD) in terms of esti-
mated direct medical expenses (Chesson et al., 2004).

A. Rosenblatt ()
Albert Einstein Jewish Hospital, Sao Paulo, Brasil
e-mail: [email protected] Fig. 1.1. Electron micrograph of HPVs

A. Rosenblatt, H. G. de Campos Guidi, Human Papillomavirus, 3

DOI: 10.1007/978-3-540-70974-9-1, © Springer-Verlag Berlin Heidelberg 2009
 4 1 Human Papillomavirus History and Epidemiology

Fig. 1.2. Nasal cavity papillomas. (Source: Photograph courtesy

of Reinaldo J. Gusmão, MD, PhD , São Paulo, Brazil)

Fig. 1.4. Epidermodysplasia verruciformis. (Source: Barrasso and

Gross (1997). Reproduced with permission from Prof. Gross G)

Fig. 1.3. HPV-related laryngeal papilloma. (Source: Photograph

courtesy of Reinaldo J. Gusmão, MD, PhD , São Paulo, Brazil) Fig. 1.5. Periungual wart. (Source: Photograph courtesy of Libby
Edwards, MD, PhD, North Carolina, USA)

prevalent (18.3% in the CDC study compared to 3.9% According to their molecular biological data and
for chlamydia). epidemiological association with anogenital cancers,
HPV is considered more transmissible than other mucosal HPV types are categorized into high-risk and
viral STDs (Burchell et al., 2006a), and Barnabas et al. low-risk types (zur Hausen, 1986, 2000).
(2006) estimated the per-partner male-to-female trans- High-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51,
mission probability of high-risk (oncogenic) type HPV 52, 56, 58, 59, 68, 73, and 82) have been implicated in the
16 to be 60%. pathogenesis of genital and nongenital carcinomas
HPV is a nonenveloped DNA virus with carcino- (including their high-grade precursor lesions).
genic properties (Fig. 1.1). There are approximately Low-risk HPV types (6, 11, 42, 43, 44, 54, 61,
200 different HPV types, of which nearly 100 have 70, 72, 81, and CP6108 (candHPV89)) cause benign
been fully sequenced (de Villiers et al., 2004). anogenital lesions (warts) and low-grade squamous
1.2 Historical Perspective 5

intraepithelial lesions of the cervix. Low-risk types 6

and 11 are also responsible for the development of
papillomas in the oral/nasal cavity (Fig. 1.2) or the
larynx (Fig. 1.3) that afflict individuals worldwide.
Therefore, although classified as low-risk types,
HPV 6 and 11 have also been categorized as possibly
carcinogenic (Cogliano et al., 2005; IARC Working
Group on the Evaluation of Carcinogenic Risks to
Humans, 2007).
HPV types 26, 53, and 66 are considered high-risk
mucosal lesions, although they can also be found in
benign lesions.
Cutaneous HPV genotypes are responsible for the
development of the rare hereditary dermatological dis-
ease epidermodysplasia verruciformis (EV) (Fig. 1.4),
and HPV 5 and 8 are the types most frequently detected.
Moreover, plantar (HPV 1) and common warts (HPV 2,
Fig. 1.6. Thymus capitatus
4, 26, 27, 29) (Fig. 1.5) are also caused by cutaneous
genotypes.
This chapter reviews historical aspects of the HPV
infection from the ancient Hellenic-Roman era to the
present. In addition, current epidemiologic data related
to the HPV infection are discussed, with a focus on the
burden on men. The most recent population preva-
lence, the dynamics of transmissibility (including
nonsexual routes in children and adults), and novel
prevention strategies are also detailed.
The biology and life cycle of HPV are discussed
in Chaps. 9 and 11. Prophylactic HPV vaccines are
reviewed in detail in Chap. 11.

1.2 Historical Perspective

The concept of sexual contact as a factor in causing

­disease was recognized as early as the ancient Hellenic Fig. 1.7. Ficus sycomorus
and Roman times. HPV-related genital lesions (also
known as genital warts, veneral warts, and condyloma the Latin word for “pointed.” Perianal warts were
acuminata) have been described in ancient writings as ­usually associated with homosexual activity and, in the
“morbid outgrowths” or “genital excrescences.” Genital late first and early second centuries, the roman poet
warts were referred to as “thymus” by Hippocrates Decimus Junius Juvenalis (also known as Juvenal) wrote
(Adams, 1886) and as “ficus” (figs) by Roman physi- about this correlation in his Satires (Bafverstedt, 1967).
cians (Routh et al., 1997), because of the similarity with Ancient Greek and Roman physicians used to
the plant Thymus capitatus (Fig. 1.6) and Ficus sycomo- treat condylomata with alum and surgical excision
rus (Fig. 1.7), respectively. (McDonagh, 1920; Buret, 1891), burning (Kelsey,
The word condyloma is derived from the Greek 1882), and Hippocrates recommended using the herb
“round tumor,” suggesting that anal warts might resem- Parthenium parviflorum for lesions located in the glans
ble a knob, while the term “acuminata” comes from (Adams, 1886).
 6 1 Human Papillomavirus History and Epidemiology

Fig. 1.8. (a) Italian Renaissance mummy. (b) Wart-like lesion in the right inguinal region. (Source: Fornaciari (2003). Reproduced
with permission from Elsevier)

During the syphilis epidemics that emerged in carcinogenesis (Schwarz et al., 1985; Durst et al.,
Europe in 1492, STDs (including genital condyloma) 1987; zur Hausen, 1991).
were considered manifestations of a veneral poison
and thus associated with syphilis, and even influenced
the terminology of specific lesions of this disease (i.e.,
condyloma lata) (Wikstrom, 1995). However, by the 1.3 Epidemiology
end of the eighteenth century, genital warts and gonor-
rhea began to be recognized as distinct diseases unre-
lated to syphilis (Bell, 1793), with further confirmation HPV is the world’s most common STD (Trottier and
occurring only in the next century (Ricord, 1838). Franco, 2006), and the global prevalence is estimated
One of the first instances of documented evidence at 291 million women (Burchell et al., 2006b). In the
of a historical HPV infection was found in an Italian United States, an estimated 6.2 million persons are
Renaissance mummy recovered from the Basilica of S. newly infected with the virus every year (Weinstock
Domenico Maggiore in Naples, Italy. Maria d’Aragona, et al., 2004), and epidemiologic studies predict that
Marquise of Vasto (1503–1568), exhibited a wart-like approximately 100 million women worldwide will be
lesion in the right inguinal region (Fig. 1.8a, b). Histo­ infected with the oncogenic types HPV 16 or HPV 18
logical examination of the lesion suggested condyloma at least once in their lifetime.
acuminatum and additional molecular studies per- Although recent data showed a reduction in sexual
formed revealed the presence of oncogenic type HPV intercourse acts and an increase in condom use among
18 (Fornaciari, 2006). The same mummy exhibited a U.S. high school students during 1991–2007, HIV- and
cutaneous ulcerated lesion in the left arm containing a STD-related risky behaviors are still prevalent in this
large number of treponemal filaments, which clearly group of young individuals (Centers for Disease
demonstrates the spread of multiple sexually transmit- Control and Prevention, 2008).
ted infections (STIs) over time. HPV affects more than two-thirds of North Amer­
The infectious nature of the condyloma acuminata icans aged 15–49 years, and molecular evidence of cur-
was first established in 1919 (Wiley et al., 2002; Kingery, rent or prior HPV infection is present in 20 million
1923), and Strauss et al. (1949) detected viral particles individuals (Koutsky, 1997; Koutsky et al., 1988).
in human warts by electron microscopy in 1949. However, Dunne et al. (2007) recently reported that
HPV DNA physical properties were described by the HPV infection prevalence in American women
Crawford and Crawford in 1963 (Crawford and aged 14–59 years is 26.8%, which corresponds to
Crawford, 1963), and the isolation of low-risk HPV almost 25 million individuals using the 2000 Census
6 and 11 from genital warts occurred in 1980 (Gissmann data. The same study showed that HPV prevalence was
and zur Hausen, 1980). highest in sexually active women aged 20–24 years
An association between HPV and the development (49.3%) with a gradual decline up to age 59.
of cervical cancer was initially proposed by zur Hausen Epidemiologic evidence confirming the sexual
in 1976 (zur Hausen 1976), and further studies later transmission of the disease appeared in 1954, when
confirmed the role of high-risk HPV types in human a cohort of women exhibited vulvar warts after 4–6
1.3 Epidemiology 7

100000 Males
Male 800
Number of diagnoses

Female
80000 700

Rate per 100,000 population

60000 600
500
40000
400
20000 300

0 200
19 2
19 4
19 6
19 8
19 0
19 2
19 4
19 6
19 8
19 0
19 2
19 4
19 6
20 8
20 0
20 2
20 4
06
100
7
7
7
7
8
8
8
8
8
9
9
9
9
9
0
0
0
19

Year 0

04

05

06
96

97

98

99

00

01

02

03
Fig. 1.9. Diagnoses of genital warts seen in genitourinary clinics

20

20
19

19

19

19

20

20

20

20

20
in England, Wales, and Scotland: 1971–2006. (Source: Health Year
Protection Agency (2007). Reproduced with permission)
Age (years)
>44y 35-44y 25-34y
20-24y 16-19y <16y
weeks of their spouse’s return from the Korean War.
Medical records of the male partners demonstrated Fig. 1.10. UK rates of male diagnoses of genital warts and age-
recently acquired penile warts in all of the involved group: 1996–2006. (Source: Health Protection Agency (2007).
Reproduced with permission)
soldiers (Barrett et al., 1954).
In the United Kingdom, HPV incidence in men
increased almost 400% from 1971 to 1994 (Simms and Females
Fairley, 1997). In 2006, 83,745 new cases of anogenital 800
warts were diagnosed in genitourinary clinics through-
700
Rate per 100,000 population

out the United Kingdom (Fig. 1.9), with a predominance

600
of male infections (Health Protection Agency, 2007).
Moreover, diagnoses of HPV-related warts in male sub- 500
jects increased by 34%, with the highest rates seen in 400
the 20–24-year age-group (CDR, 2006) (Fig. 1.10). 300
However, rates of genital warts and numbers of diag- 200
noses in women in the United Kingdom were particu- 100
larly high in the under-20-year age-group (<16 years:
0
55/100,000 and 16–19 years: 767/100,000) (Fig. 1.11).
96 997 998 999 000 001 002 003 004 05 006
Koshiol et al. (2004) reported an increase in the 19 1 1 1 2 2 2 2 2 20 2
rates of genital warts from 117.8 cases per 100,000 Year
Age (years)
person-years at risk in 1998 to 205 cases per 100,000
>44y 35-44y 25-34yy
person-years at risk in 2001. 20-24 16-19y <16y
In a retrospective analysis assessing the U.S. preva-
lence of genital warts in 18- to 59-year-old individuals, Fig. 1.11. UK rates of female diagnoses of genital warts and
Dinh et al. (2008) found that 5.6% have had genital age-group: 1996–2006. (Source: Health Protection Agency
(2007). Reproduced with permission)
warts in the past. Genital warts are more prevalent
among 20- to 39-year-old subjects (Fleischer et al.,
2001), with a reported higher prevalence of the disease
in female (7.2%) than in male subjects (4%) (Dinh
Genital warts have been estimated to be as com-
et al., 2008).
mon as breast and prostate cancers, with an approx-
The economic burden of HPV-related diseases has
imate annual rate of 100 per 100,000 (Franco,
also been analyzed. The treatment of an incident (new)
1996).
case of genital warts involved costs of U.S. $436
 8 1 Human Papillomavirus History and Epidemiology

(Insinga et al., 2003), and the U.S. annual medical cost prevalence of oncogenic HPV types has increased from
1 associated with the disease reached U.S. $200 million 19.2% in women with normal cytology to 100% in those
in 2004 (Insinga et al., 2005). Cervical cancer costs presenting with cervical intraepithelial neoplasia grade
ranged between U.S. $300 million and $400 million, 3 (CIN 3)/cervical cancer. In addition, HPV 16 has been
according to the same report. the most common type found (Kjaer et al., 2008).
Corresponding studies performed in Europe have
estimated the mean direct cost per patient with new
genital warts at €378 and for resistant genital warts at The biological mechanisms likely involved for the
€1,142 (Hillemanns et al., 2008). increased susceptibility of young female subjects
to HPV infection are cervical immaturity, inade-
quate production of protective cervical mucus, and
increased cervical ectopy (Kahn et al., 2002).
1.4 HPV in Women
Postmenopausal women in selected groups have
an increased prevalence of low-risk and unclassified
HPV infection is highly contagious with a per-partner HPV types (Herrero et al., 2000), which is likely
transmission probability of genital warts estimated related to the negative effect in host immune response
at 60% (Oriel, 1971). Coinfection with multiple HPV that is associated with the persistent HPV infection
types and sequential infection with phylogenetically (Garcia-Pineres et al., 2006).
related types and novel types are a common occurrence
(Thomas et al., 2000). Reactivation of previously undetectable infections
In a recent cross-sectional study assessing the inci- acquired earlier in life as a result of diminished
dence of genital warts in Germany, Hillemanns et al. immunity caused by hormonal influences, and/or
(2008) found new and recurrent cases in 113.7 and novel HPV infections acquired with different
34.7 per 100,000, respectively, for women aged 14–65 ­sexual partners is another explanation for the
years. The highest incidence for new and recurrent increased prevalence of HPV in postmenopausal
cases was observed in women aged 14–25 years (171.0 women (Bosch et al., 2008).
per 100,000) and in those aged 26–45 years (53.1 per
100,000), respectively.
The prevalence of HPV infection is increased in Recent multicountry data show that men and women
younger women and usually decreases through the aged 40–80 years regard sex as an important part of life
fourth and fifth decades of life (de Villiers et al., 1987; and continue to engage in sexual activity (Nicolosi
Meisels, 1992; Herrero et al., 2000; Garcia-Pineres et al., 2004; Moreira et al., 2006). Moreover, studies
et al., 2006). However, in a cross-sectional study eval- also demonstrate that older men are still involved in
uating sexually active women in four continents, risky sex, and the use of drugs for erectile dysfunction
Franceschi et al. (2006) observed that HPV infection likely contributes to the high-risk sexual behavior. In a
was high across all age-groups in low-resource settings recent cross-sectional analysis, Cooperman et al. (2007)
in Asia and Africa. reported that less than 20% of HIV-negative individuals
Cervical intraepithelial neoplasia (low-grade aged 49–80 used condoms with their sexual partners.
squamous intraepithelial lesion (LSIL) or high-grade
SIL (HSIL)) develops in 4% of infected women
(Mougin et al., 2001), and high-risk HPV presence and 1.4.1 Risk Factors
persistence is a required condition for HSIL develop-
ment and progression to cervical cancer (Liaw et al., The sexual behavior of men (the so-called male factor)
1999; Ylitalo et al., 2000; Schlecht et al., 2001; Kjaer can influence the risk of HPV infection and related
et al., 2002) (see also Chap. 8). diseases in their female sexual partners (Brinton
A recent large population-based study performed in et al., 1989).
Denmark has found an HPV prevalence of 26.4%, with The risk of infection is related to the reported life-
a peak of 50.2% in young women aged 20–24 years. The time number of male partners (Dillner et al., 1996;
1.5 HPV in Men 9

Carter et al., 1996), although in a recent cross-sectional A longitudinal study performed in a cohort of
study that evaluated a large group of Danish females, former university students that were examined 4–12
Nielsen et al. (2008) found that an increased number of years after their initial HPV diagnosis has shown that
recent sexual partners was associated with a higher nearly 1 in 5 women (16.3%) exhibited one or more of
risk of infection with oncogenic HPV types in younger the same previously detected HPV types. The long-
women. term HPV persistence was only 5%, but correlated
Age is another determining factor for HPV infection, positively with an abnormal Pap test result, presence of
and several studies show that the risk of acquiring inci- genital warts, and detection of the same HPV type dur-
dent infection is increased in young women (Jamison ing the course of the infection (Sycuro et al., 2008).
et al., 1995; Rousseau et al., 2000; Giuliano et al, 2002;
Sellors et al., 2003; Trottier and Franco, 2006).
Other reported risk factors associated with the
­disease are failure to use condoms, having intercourse 1.5 HPV in Men
with uncircumcised men, and a history of herpes
­simplex virus or chlamydia infections (Castellsague
et al., 2002; Moscicki et al., 2001). The majority of HPV infections in men are symptom-
HPV infection can be acquired even without vagi- less and unapparent, and detection is only possible
nal penetration, since any genital skin contact is suffi- when molecular diagnostic techniques are used (see
cient for virus transmission (Moscicki, 2005). Dunne also Chap. 2).
et al. (2007) recently detected HPV DNA in 5.2% of Prevalence rates in men (Table 1.1) appear to be
females who reported they had never experienced similar to those in women when HPV DNA detection
­sexual intercourse. techniques are used (Baken et al., 1995; Hernandez
The risk of female subjects acquiring HPV with et al., 2006; Dunne et al., 2006; Giuliano et al., 2008b),
a first heterosexual experience has been assessed as with (prevalence) rates as high as 73% being reported
28.5% and 50% at 1 and 3 years after the monogamous (Bleeker et al., 2005a).
episode, respectively (Winer et al., 2008). A recent meta-analysis has shown that HPV sero-
Data from several studies indicate that HPV 16 is prevalence of specific anti-HPV antibodies is lower in
usually the most common type acquired (Giuliano men than in women (Dunne et al., 2006).
et al., 2002; Richardson et al., 2003), although HPV Stone et al. (2002) analyzed the seroprevalence of
18, 39, 84, 51, 58, 31, and 52 have also been regularly oncogenic HPV 16 infection in the United States and
detected (Allen and Siegfried, 2000; Munoz et al., found it significantly higher in women (17.9%) than in
2003; Munoz et al., 2004). men (7.9%). Moreover, Hariri et al. (2008) analyzed
In the prevalence study performed by Dunne et al. the U.S. seroprevalence of low-risk HPV 11 infection
(2007), high-risk HPV 16 and low-risk HPV 6 was and reported that women have higher prevalence rates
detected in 1.5% and 1.3% of women, respectively, than men (5.7% vs 3.6%, respectively).
and the detection of the HPV types included in the Age has not been significantly associated with HPV
quadrivalent prophylactic vaccine (HPV 6, 11, 16, and prevalence, incidence, and duration of infection in men
18) was 3.4%. However, none of the females studied (Giuliano et al., 2008a, b). However, Giuliano et al.
was simultaneously infected with all four HPV vac- (2008a) observed a bimodal distribution with age for
cine types. oncogenic infections, with decreased prevalence of
Furthermore, it is estimated that HPV 16 and/or high-risk HPV types found in younger and older male
HPV 18 is present in 32% of women presenting nor- subjects. The prevalence peak occurred at ages 30–34
mal cytology (de Sanjose et al., 2007), and both types years for oncogenic HPV types, while the prevalence
are detected in 95–100% of cervical carcinomas. of nononcogenic infections peaked among men aged
However, despite the high infection rates, approxi- 45–70 years. Furthermore, Stone et al. (2002) showed
mately 90% of HPV infections are usually cleared that the overall prevalence peak occurred among men
(eliminated) within 24 months of the initial contact aged 30–39 years.
(Ho et al., 1998; Giuliano et al., 2002; Richardson et al., Duration of HPV infection in men seems to be shorter
2003; Brown et al., 2005; Rodriguez et al., 2007). than in women, suggesting that a more expeditious viral
 10 1 Human Papillomavirus History and Epidemiology

Table 1.1 Estimates of the prevalence of HPV infection by study (Source: Adapted from Partridge and Koutsky, 2006. Reproduced
1 with permission from Elsevier)

References No. Age (years) HPV prevalence (%)

DNA Warts High-risk Low-risk

HPV types HPV types

Baken et al. (1995) 48 >17 63 ~18 ~12

Van Doornum et al. (1994) 85 U/NR 28.2 U/NR U/NR U/NR
Hippelainen et al. (1993) 432 U/NR 23.6 5.6 U/NR U/NR
Bosch et al. (1996) 354 45.4 a
4.9 2.1 b
9.0
Wikstrom et al. (2000) 235 18–54 20.4 U/NR U/NR U/NR
Lazcano-Ponce et al. (2001) 120 14–55 42.7 19.8 17.7
Franceschi et al. (2002) 533 19–82 16.0 U/NR U/NR 0.5
Svare et al. (2002) 216 >18 44.9 25b
U/NR U/NR
Baldwin et al. (2003) 436 18–70 28.2 12.0 14.8
Weaver et al. (2004) 318 18–25 35.0 U/NR U/NR U/NR
Shin et al. (2004) 381 U/NR 8.7 U/NR 4.2 2.6
Bleeker et al. (2005a) 181 22–67 72.9 U/NR 58.6 27.1
Nicolau et al. (2005) 50 19–53 70.0 U/NR U/NR U/NR
Kjaer et al. (2005) 337 19–22 33.8 U/NR U/NR U/NR
Lajous et al. (2005) 1030 16–40 44.6 5.8 34.8 23.9
Rombaldi et al. (2006) 99 18–56 54.5 9.3 HPV 16 (3.5) HPV 6 (56.1)
Hernandez et al. (2006) 136 18–63 42.8–41.3 U/NR U/NR U/NR
Nielson et al. (2007) 463 18–40 65.4 (at any U/NR 10.6 22.0
site)
Giuliano et al. (2008b) 290 18–44 52.8 U/NR 31.7 30.0
Giuliano et al. (2008a) 1,160 18–70 65.2 None 12.0 20.7

U/NR unknown/not reported

a
Mean age
b
Percentage of men who reported previous history of genital warts

clearance occurs in the male partner (Hippelainen et al., (Winer et al., 2003), which could be related to the
1993), with most infections resolving after 1 year (Van shorter duration of HPV infection in men.
Doornum et al., 1994; Lajous et al., 2005; Giuliano Conversely, HPV incidence rates in men are
et al., 2008b). However, in a prospective follow-up study reported to be higher when compared with age-matched
among Danish soldiers, Kjaer et al. (2005) found that women. In a recent study that evaluated incidence and
infection with multiple HPV types strongly correlated risk factors of genital HPV among heterosexually
with viral persistence and the presence of oncogenic active male university students 18–20 years of age,
HPV types increased the persistence risk. Partridge et al. (2007) found that the cumulative inci-
Monogamous intercourse with a male partner for dence of new HPV infection was 62.4% at 2 years,
more than 8 months has been associated with a lower with low-risk HPV 84 and high-risk HPV 16 the most
risk of HPV infection acquisition among women frequent types detected.
1.5 HPV in Men 11

Prevalence rates in immunosupressed patients Reported data from studies performed in Spain and
(Halpert et al., 1986) and HIV-positive men who have Colombia have demonstrated a higher HPV DNA preva-
sex with men (MSM) are even higher, with reported lence in the male partner of women with cervical cancer
rates of HPV DNA detected in 64.7% of the anal speci- than in women not presenting the disease (Castellsague
mens of Dutch homosexual men (van der Snoek et al., et al., 1997). Nicolau et al. (2005) reported a high preva-
2003). lence of HPV DNA (70%) in male partners of HPV-
Several studies have investigated the prevalence of infected women, and the internal surface of the prepuce
type-specific HPV infection and the virus anatomic was the most affected site.
distribution in men. High-risk HPV 16 has been the Hernandez et al. (2008b) recently evaluated HPV
most prevalent type detected (Bosch et al., 1996; transmission in 25 heterosexual, monogamous couples.
Wikstrom et al., 2000; Lazcano-Ponce et al., 2001; In this prospective study, male-to-female transmission
Franceschi et al., 2002; Baldwin et al., 2003; Weaver (i.e., from the penis to the cervix) was substantially
et al., 2004; Nielson et al., 2007; Giuliano et al., 2008b); lower than transmission from the female to the male
however, a predominance of low-risk types (36.3% partner.
low-risk vs. 29.2% high-risk types) was found in a Studies evaluating HPV type prevalence in sex part-
recent anogenital and semen sampling analysis of 463 ners have shown that concordance is high and it is
men aged 18–40 years (Nielson et al., 2007), as well as associated with increased viral load (Bleeker et al.,
in another prospective study of male sexual partners of 2005a) and with recent sexual intercourse (Baken
women with CIN (Rombaldi et al., 2006). et al., 1995).
Giuliano et al. (2008a) also reported an increased In addition, Giovannelli et al. (2007) showed that a
prevalence of nononcogenic types (20.7% nononco- combination of penile and urethral brushing was the
genic types only vs. 12.0% oncogenic types only) most adequate approach in men to evaluate HPV type
among 1,160 men from Brazil, Mexico, and the United concordance in sexual couples.
States, with HPV 6 being detected in 6.6% of cases. In a recent multicountry analysis of HPV preva-
In addition, there has been a predominance of low- lence and type distribution among heterosexual males,
risk HPV types in studies that evaluated genital wart Giuliano et al. (2008a) reported that HPV types varied
HPV typing (Yun and Joblin, 1993; Boxman et al., widely across the countries studied. Among high-risk
1999; Hadjivassiliou et al., 2007). types, HPV 16 was the most common type detected in
Data from several investigators show that the penis Brazil and the United States, whereas HPV 59 was
shaft harbors most of the HPV DNA detected (Nielson commonly detected in Mexico. Among the nononco-
et al., 2007, Giuliano et al., 2007; Nicolau et al., 2005). genic types, HPV 62 was most commonly detected
However, a recent analysis performed by Smith et al. in Brazil, whereas in Mexico and the United States
(2007) in African male subjects reported a high HPV HPV 84 was the most common. Prevalence rates of the
DNA prevalence in the glans/coronal ­sulcus (39%). HPV types that are prevented by the current prophy-
Furthermore, the study concluded that urethral sam- lactic HPV vaccines were 6.5% for HPV 16, 1.7% for
pling in men added no sensitivity for HPV detection. HPV 18, 6.6% for HPV 6, and 1.5% for HPV 11.
Intriguing results from a recent study have shown Furthermore, according to the study, the prevalence of
that the glans penis and scrotum were the most frequent HPV infection and quadrivalent vaccine-related HPV
targets of infection from women (Hernandez et al., types (6, 11, 16, and 18) was highest in Brazil.
2008b). However, data from several reports have dem-
onstrated a low incidence of scrotal lesions (Nicolau
et al., 2005; Giuliano et al., 2007; Weaver et al., 2004; 1.5.1 Risk Factors
Flores et al., 2008). Therefore, one may speculate that
although the scrotal region is not usually subjected to Significant risk factors associated with HPV infection
microabrasive trauma during intercourse, contamina- in men are related to sexual behavior, particularly life-
tion can still occur through anogenital skin contact and time sexual behavior and recent number of sexual part-
vaginal secretions. ners (Hippelainen et al., 1993; Franceschi et al., 2002;
The prevalence of HPV DNA in the male partners Svare et al., 2002; Vaccarella et al., 2006; Nielson
of HPV-infected women has also been analyzed. et al., 2007). Condom use and cigarette smoking
 12 1 Human Papillomavirus History and Epidemiology

(ten or more cigarettes per day) have also been identi- The increased risk of HPV-related tonsillar squamous
1 fied as modifiable risk factors. cell carcinoma in patients presenting with HPV-
Studies that have analyzed HPV infection in circum- associated anogenital cancers suggests that genital–
cised individuals show conflicting results (Castellsague oral transmission is likely (Frisch and Biggar, 1999;
et al., 2002; Baldwin et al., 2004; Shin et al., 2004; Hemminki et al., 2000).
Weaver et al., 2004; Vaccarella et al., 2006), although In addition, a recent case-control study has found
Hernandez et al. (2008a) recently demonstrated a lower that a high (i.e., 26 or more) lifetime number of vaginal-
HPV prevalence in the glans/corona of circumcised men. sex partners and six or more lifetime oral-sex partners
In addition, the same study reported that infection with were associated with oropharyngeal cancer (D’Souza
high-risk and multiple HPV types was more prevalent in et al., 2007).
uncircumcised men, suggesting a protective effect of cir- However, in a prospective Finnish study, Rintala
cumcision against prevalent HPV infection (see also et al. (2006) failed to show an association between
Sect. 3.9 in Chap. 3). sexual habits and oral HPV infection. In addition, the
role of saliva as a vector transmitter is yet unknown.

1.6 HPV Transmission Modes HPV infection and HPV-related diseases occur
even in women in monogamous relationships and
Pap test screening should be regularly performed
Genital HPV transmission occurs through direct skin in these individuals (Marrazzo, 2000, 2001).
contact between sexual partners, and several studies
have shown that transmission is likely even without
vaginal and/or anal penetration (Tay et al., 1990; Winer
et al., 2003; Frega et al., 2003). 1.6.1 HPV Transmission in Children
The recent report of HPV transmission between the
female anus and the scrotum with nonpenetrative sex- Perinatal HPV transmission has been shown to occur
ual contact (Hernandez et al., 2008b) and the data con- in the external genital mucosa, oral cavity, nasal
firming that the perianal area is a frequent site of HPV mucosa, and particularly in the larynx of prepubertal
contamination support this observation. In addition, children (Fig. 1.12), although there is no evidence to
the occurrence of male self-transmission involving the support transmission to the cervix (see also Sect. 11.6
scrotum and other proximate genital sites (i.e., penis) in Chap. 11).
could suggest the scrotum as a viable infection reser- HPV DNA has been detected in 37–73% of nasopha-
voir (Hernandez et al., 2008b). However, additional ryngeal aspirates or buccal swabs of newborn babies
studies are needed to confirm this finding (see also
Sect. 3.2 in Chap. 3; Sects. 7.3 and 7.4 in Chap. 7).
Yet, Puranen et al. (1996) showed that transmission
through moist seats and floors is unlikely in locations
with adequate sanitary conditions.
Genital HPV types have been detected in the fingers
and fingernail tips of individuals with genital warts, and
a finger-genital route has been suggested (Sonnex et al.,
1999). In addition, Hernandez et al. (2008b) reported
that viral transmission from the woman’s hands to the
male partner’s genitals occurred in four cases of a pro-
spective transmission study that evaluated heterosexual,
monogamous couples. The investigators concluded that
HPV self-inoculation is a likely event in both genders,
particularly in men.
Studies suggest that oral HPV infection is sexually
acquired (D’Souza et al., 2007; Schwartz et al., 1998), Fig. 1.12. HPV-related laryngeal papilloma. (Source: Photograph
although auto- and hetero-inoculation can also occur. courtesy of Marcia Jacomelli, MD, PhD, São Paulo, Brazil)
1.6 HPV Transmission Modes 13

(Sedlacek et al., 1989; Fredericks et al., 1993; Pakarian

et al., 1994; Puranen et al., 1997).
In a recent study evaluating a possible hemato­
genous (i.e., transplacental) transmission route of
HPV, Rombaldi et al. (2008) showed HPV-associated
placental infection in 23.3% of the patients and trans-
placental transmission of the virus in 12.2%. These
results suggest that transplacental transmission of HPV
can occur, and the potential consequences of fetal
exposure to the virus should be further investigated.
Vertical transmission (from an infected mother to the
child) is increased when maternal genital HPV DNA is
present or high viral loads are detected at the time of
delivery (Alberico et al., 1996; Kaye et al., 1994).
Studies analyzing concordance of HPV types detected
in newborn babies and their mothers have shown concor-
dance results of 57–69% (Syrjanen and Puranen, 2000).
This finding suggests that postpartum HPV contamina-
tion of infants may occur from a variety of sources, Fig. 1.13. Vulvar and perianal condyloma in a 16-month-old girl.
including breast milk (Sarkola et al., 2008), from sib- (Source: Photograph courtesy of Nadir Oyakawa, MD, PhD, São
lings or caretakers via skin contact (Obalek et al., 1990; Paulo, Brazil)
Handley et al., 1997), or even through exposure to con-
taminated fomites (Syrjanen and Puranen, 2000).
A prospective analysis evaluating HPV infection in
infants showed that oral HPV infection had been
acquired by 42% and it had cleared and persisted in
11 and 10% of the children enrolled in the study,
respectively. In contrast, genital HPV had persisted in
only 1.5% of the infants during their first 26 months of
life (Rintala et al., 2005), suggesting that genital infec-
tion persistence in early age is an infrequent event
(Moscicki, 1996).
However, Cason et al. (1995) detected high rates
(73%) of perinatal transmission of oncogenic HPV 16
and HPV 18 in contaminated infants 24 h after deliv-
ery, with persistent HPV 16 DNA and HPV 18 DNA
detected in 83.3 and 20% of cases at 6 months of age,
respectively.
HPV seropositivity to low-risk HPV 6 and high-risk
HPV 16 types is noticeably more prevalent in children
and adolescents than in adults, suggesting that infec-
tion with these types is common (Muller et al., 1995;
Cason et al., 1995).
HPV-related lesions (genital warts) in boys are usu-
ally located in the perianal area, although the penis can
also be affected (Copulsky et al., 1975; Kumar et al.,
1990; Oriel, 1992). HPV lesions in young girls occur
Fig. 1.14. Anal and perianal condyloma in a 2-year-old girl.
in the vulvar (Fig. 1.13), vaginal, urethral, and perianal (Source: Photograph courtesy of Nadir Oyakawa, MD, PhD, São
areas (Fig. 1.14). Paulo, Brazil)
 14 1 Human Papillomavirus History and Epidemiology

HPV 6 and HPV 11 are detected in the majority of for HPV places the surgeon, as well as other members
1 anogenital lesions in children (Gibson et al., 1990; of the operating team and room staff, at risk of devel-
Obalek et al., 1993). However, anogenital HPV in chil- oping respiratory tract papillomatosis (Hallmo and
dren can also be associated with nonmucosal HPV Naess, 1991) (Fig. 1.15). Therefore, appropriate pre-
types, and cutaneous HPV 2 has been the usual type ventive measures should be adopted to avoid this occu-
detected (Obalek et al., 1990; Obalek et al., 1993; pational health hazard (see Chaps. 3 and 10).
Handley et al., 1997).
In addition to this finding, several studies have con-
firmed the low prevalence of sexual abuse as the cause
of anogenital warts in children (Sinclair et al., 2005; 1.7 Prevention
Jones et al., 2007). The investigators suggest that auto-
or hetero-inoculation from cutaneous warts may be the
usual nonsexual transmission route of anogenital warts 1.7.1 Condoms
in prepubertal children (Handley et al., 1997; Jones
et al., 2007). Studies suggest that condom use offers limited or no
protection against HPV infection, because the virus
can still be transmitted through contact with areas of
1.6.2 Considerations Regarding Unusual unprotected genital skin. However, there is some evi-
Transmission Routes dence that condom use may be associated with regres-
sion of CIN lesions (Hogewoning et al., 2003), as well
1.6.2.1 Transmission from CO2 Plume as with a reduced risk of developing genital warts, CIN
2 or 3, and invasive cervical carcinoma (Manhart and
Experimental studies have confirmed the presence of Koutsky, 2002; Winer et al., 2006). Furthermore,
clinically active HPV particles within the plume of smoke Bleeker et al. (2003) demonstrated that condom use
emanated from laser equipment and electrocautery was associated with regression of HPV-related penile
(Ferenczy et al., 1990). The inadvertent inhalation of lesions in men (see also Chap. 3).
noxious viral particles while performing laser surgery
Condom use should be strongly recommended
(particularly among young individuals), because
it offers effective protection against several other
sexually transmitted infections (STIs), including
HIV (Holmes et al., 2004).

1.7.2 Vaccines

Prophylactic HPV vaccines are highly immunogenic

and have shown safety and efficacy in preventing HPV
infection and related diseases in young women.
Recently licensed Gardasil (Merck & Co., Whitehouse
Station, NJ, USA) and Cervarix (GlaxoSmithKline,
Rixensart, Belgium) target a subset of oncogenic
HPV genotypes regarded as the most common disease-
causing HPV types. In addition, Gardasil prevents
against infection with low-risk HPV types largely
associated with genital warts.
Fig. 1.15. HPV-related tracheal papilloma. (Source: Photograph However, protection is not afforded against all
courtesy of Marcia Jacomelli, MD, PhD, São Paulo, Brazil) cancer-associated HPV types, and current vaccines are
References 15

not effective for individuals already infected with the be used as an ingredient of next-generation, broad-
HPV types contained in the vaccine formulation. spectrum topical microbicide candidates being devel-
Currently, indications for vaccine administration oped (Buck et al., 2006).
favor young female subjects, and clinical trials evalu- In contrast, several studies have shown that non-
ating vaccine efficacy in different target groups (older oxynol-9 (COL-1492) vaginal gel, an over-the-counter
women and male subjects) are underway. Furthermore, spermicide, provides no protection against HPV and
the majority of cervical cancer deaths worldwide occur other STDs, and could even potentiate HPV infection
in developing countries, where current vaccine charac- and persistence (Van Damme et al., 2002; Marais et al.,
teristics (e.g., need for refrigeration, three separate 2006; Roberts et al., 2007).
doses administered by injection, and particularly the
high cost of the vaccine) might not facilitate a compre-
hensive global implementation.
Therefore, the production of multivalent second- References
generation vaccines that would be administered as a
single dose orally or via a nasal spray rather than by Adams F (1886) The genuine works of Hippocrates: Translated
injection are long awaited. And preferably, vaccines from the Greek with a preliminary discourse and annota-
targeting diseases that are highly prevalent in low- tions, vol 2. William Wood, New York
resource countries should have low production costs Alberico S, Pinzano R, Comar M, Toffoletti F, Maso G, Ricci G,
Guaschino S (1996) [Maternal-fetal transmission of human
and no need for a cold chain. papillomavirus]. Minerva Ginecol 48: 199–204
Allen AL, Siegfried EC (2000) What’s new in human papilloma-
virus infection. Curr Opin Pediatr 12: 365–369
1.7.3 Antiviral Microbicides Bafverstedt B (1967) Condylomata acuminata-past and present.
Acta Derm Venereol 47: 376–381
Baken LA, Koutsky LA, Kuypers J, Kosorok MR, Lee SK,
The development of antiviral compounds that might be Kiviat NB, Holmes KK (1995) Genital human papillomavi-
used as topical microbicides to block HPV transmis- rus infection among male and female sex partners: Prevalence
sion by sexual contact is a promising cost-effective and type-specific concordance. J Infect Dis 171: 429–432
Baldwin SB, Wallace DR, Papenfuss MR, Abrahamsen M,
strategy. Vaught LC, Giuliano AR (2004) Condom use and other fac-
Carrageenan (Carraguard), a sulfated polysaccha- tors affecting penile human papillomavirus detection in men
ride extracted from red algae, has been described as an attending a sexually transmitted disease clinic. Sex Transm
effective HPV genital infection inhibitor (Buck et al., Dis 31: 601–607
Baldwin SB, Wallace DR, Papenfuss MR, Abrahamsen M,
2006; Roberts et al., 2007). Carrageenan works by pre- Vaught LC, Kornegay JR, Hallum JA, Redmond SA,
venting HPV attachment to cells and it resembles hep- Giuliano AR (2003) Human papillomavirus infection in men
aran sulfate, an HPV cell-attachment factor. In addition, attending a sexually transmitted disease clinic. J Infect Dis
carrageenan blocks HPV infection through a second, 187: 1064–1070
Barnabas RV, Laukkanen P, Koskela P, Kontula O, Lehtinen M,
postattachment heparan sulfate-independent effect (Buck Garnett GP (2006) Epidemiology of HPV 16 and cervical
et al., 2006). Carragard has failed to protect against cancer in Finland and the potential impact of vaccination:
HIV in a recent phase-III study, but HPVs demonstrate Mathematical modelling analyses. PLoS Med 3: e138
enhanced susceptibility to the product. Further clinical Barrasso R, Gross GE (1997) External genitalia: Diagnosis.
In: Gross GE, Barrasso R (eds) Human papillomavirus infec-
studies are needed to assess the potential of carra- tion, a clinical atlas. Ullstein Mosby, Berlin, pp 296–331
geenan as a topical microbicide against HPV. Barrett TJ, Silbar JD, Mc GJ (1954) Genital warts-a venereal
Defensins are proteins associated with innate anti- disease. J Am Med Assoc 154: 333–334
viral immunity (Selsted and Ouellette, 2005; Klotman Bell B (1793) Treatise on gonorrhoea virulenta and lues venerea,
vol 1. Watson Mudie, Edinburgh
and Chang, 2006). Bleeker MC, Hogewoning CJ, Berkhof J, Voorhorst FJ, Hesselink
Studies suggest that human a-defensins (human AT, van Diemen PM, van den Brule AJ, Snijders PJ, Meijer
a-defensins 1–3 [known as human neutrophil peptides CJ (2005a) Concordance of specific human papillomavirus
(HNPs) 1–3] and particularly, human a-defensin 5 types in sex partners is more prevalent than would be
expected by chance and is associated with increased viral
[HD-5]), may contribute to host defenses against infec- loads. Clin Infect Dis 41: 612–620
tion with sexually transmitted HPV types. These obser- Bleeker MC, Hogewoning CJ, Voorhorst FJ, van den Brule AJ,
vations raise the possibility that a-defensins could Snijders PJ, Starink TM, Berkhof J, Meijer CJ (2003) Condom
 16 1 Human Papillomavirus History and Epidemiology

use promotes regression of human papillomavirus-associated Centers for Disease Control and Prevention (2008) Trends in
1 penile lesions in male sexual partners of women with cervical HIV- and STD-related risk behaviors among high school
intraepithelial neoplasia. Int J Cancer 107: 804–810 students–United States, 1991-2007. MMWR Morb Mortal
Bosch FX, Burchell AN, Schiffman M, Giuliano AR, de Sanjose Wkly Rep 57: 817–822
S, Bruni L, Tortolero-Luna G, Kjaer SK, Munoz N (2008) Chesson HW, Blandford JM, Gift TL, Tao G, Irwin KL (2004)
Epidemiology and natural history of human papillomavirus The estimated direct medical cost of sexually transmitted
infections and type-specific implications in cervical neopla- diseases among American youth, 2000. Perspect Sex Reprod
sia. Vaccine 26(Suppl 10): K1–K16 Health 36: 11–19
Bosch FX, Castellsague X, Munoz N, de Sanjose S, Ghaffari Cogliano V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi
AM, Gonzalez LC, Gili M, Izarzugaza I, Viladiu P, Navarro F (2005) Carcinogenicity of human papillomaviruses. Lancet
C, Vergara A, Ascunce N, Guerrero E, Shah KV (1996) Oncol 6: 204
Male sexual behavior and human papillomavirus DNA: key Cooperman NA, Arnsten JH, Klein RS (2007) Current sexual
risk factors for cervical cancer in Spain. J Natl Cancer Inst activity and risky sexual behavior in older men with or at
88: 1060–1067 risk for HIV infection. AIDS Educ Prev 19: 321–333
Boxman IL, Hogewoning A, Mulder LH, Bouwes Bavinck JN, Copulsky J, Whitehead ED, Orkin LA (1975) Condyloma acum-
ter Schegget J (1999) Detection of human papillomavirus inata in a three-year-old boy. Urology 05: 372–373
types 6 and 11 in pubic and perianal hair from patients with Crawford LV, Crawford EM (1963) A comparative study of
genital warts. J Clin Microbiol 37: 2270–2273 polyoma and papilloma viruses. Virology 21: 258–263
Brinton LA, Reeves WC, Brenes MM, Herrero R, Gaitan E, D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch
Tenorio F, de Britton RC, Garcia M, Rawls WE (1989) The WM, Westra WH, Gillison ML (2007) Case-control study of
male factor in the etiology of cervical cancer among sexu- human papillomavirus and oropharyngeal cancer. N Engl J
ally monogamous women. Int J Cancer 44: 199–203 Med 356: 1944–1956
Brown DR, Shew ML, Qadadri B, Neptune N, Vargas M, Tu W, de Sanjose S, Diaz M, Castellsague X, Clifford G, Bruni L,
Juliar BE, Breen TE, Fortenberry JD (2005) A longitudinal Munoz N, Bosch FX (2007) Worldwide prevalence and gen-
study of genital human papillomavirus infection in a cohort otype distribution of cervical human papillomavirus DNA
of closely followed adolescent women. J Infect Dis 191: in women with normal cytology: A meta-analysis. Lancet
182–192 Infect Dis 7: 453–459
Buck CB, Day PM, Thompson CD, Lubkowski J, Lu W, Lowy de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen
DR, Schiller JT (2006) Human alpha-defensins block H (2004) Classification of papillomaviruses. Virology 324:
papillomavirus infection. Proc Natl Acad Sci U S A 103: 17–27
1516–1521 de Villiers EM, Wagner D, Schneider A, Wesch H, Miklaw H,
Burchell AN, Richardson H, Mahmud SM, Trottier H, Wahrendorf J, Papendick U, zur Hausen H (1987) Human
Tellier PP, Hanley J, Coutlee F, Franco EL (2006a) Modeling papillomavirus infections in women with and without abnor-
the sexual transmissibility of human papillomavirus infec- mal cervical cytology. Lancet 2: 703–706
tion using stochastic computer simulation and empirical data Dillner J, Kallings I, Brihmer C, Sikstrom B, Koskela P, Lehtinen
from a cohort study of young women in Montreal, Canada. M, Schiller JT, Sapp M, Mardh PA (1996) Seropositivities to
Am J Epidemiol 163: 534–543 human papillomavirus types 16, 18, or 33 capsids and to
Burchell AN, Winer RL, de Sanjose S, Franco EL (2006b) Chlamydia trachomatis are markers of sexual behavior.
Chapter 6: Epidemiology and transmission dynamics of J Infect Dis 173: 1394–1398
genital HPV infection. Vaccine 24(Suppl 3): S3/52–S3/61 Dinh TH, Sternberg M, Dunne EF, Markowitz LE (2008) Genital
Buret F (1891) Syphilis to-day and among the ancients, vol 1: warts among 18- to 59-year-olds in the United States, National
Syphilis in ancient and prehistoric times. F.A. Davis, Health and Nutrition Examination Survey, 1999–2004. Sex
Philadelphia, pp 124–154 Transm Dis 35: 357–360
Carter JJ, Koutsky LA, Wipf GC, Christensen ND, Lee SK, Dunne EF, Nielson CM, Stone KM, Markowitz LE, Giuliano
Kuypers J, Kiviat N, Galloway DA (1996) The natural history AR (2006) Prevalence of HPV infection among men: A
of human papillomavirus type 16 capsid antibodies among a ­systematic review of the literature. J Infect Dis 194:
cohort of university women. J Infect Dis 174: 927–936 1044–1057
Cason J, Kaye JN, Jewers RJ, Kambo PK, Bible JM, Kell B, Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC,
Shergill B, Pakarian F, Raju KS, Best JM (1995) Perinatal Patel SS, Markowitz LE (2007) Prevalence of HPV infection
infection and persistence of human papillomavirus types 16 among females in the United States. JAMA 297: 813–819
and 18 in infants. J Med Virol 47: 209–218 Durst M, Croce CM, Gissmann L, Schwarz E, Huebner K (1987)
Castellsague X, Bosch FX, Munoz N, Meijer CJ, Shah KV, de Papillomavirus sequences integrate near cellular oncogenes
Sanjose S, Eluf-Neto J, Ngelangel CA, Chichareon S, Smith in some cervical carcinomas. Proc Natl Acad Sci U S A 84:
JS, Herrero R, Moreno V, Franceschi S (2002) Male circum- 1070–1074
cision, penile human papillomavirus infection, and cervical Ferenczy A, Bergeron C, Richart RM (1990) Carbon dioxide
cancer in female partners. N Engl J Med 346: 1105–1112 laser energy disperses human papillomavirus deoxyribonu-
Castellsague X, Ghaffari A, Daniel RW, Bosch FX, Munoz N, cleic acid onto treatment fields. Am J Obstet Gynecol 163:
Shah KV (1997) Prevalence of penile human papillomavirus 1271–1274
DNA in husbands of women with and without cervical neo- Fleischer AB, Jr., Parrish CA, Glenn R, Feldman SR (2001)
plasia: a study in Spain and Colombia. J Infect Dis 176: Condylomata acuminata (genital warts): Patient demograph-
353–361 ics and treating physicians. Sex Transm Dis 28: 643–647
References 17

Flores R, Abalos AT, Nielson CM, Abrahamsen M, Harris RB, papillomavirus infections: The Young Women’s Health
Giuliano AR (2008) Reliability of sample collection and Study. J Infect Dis 186: 462–469
laboratory testing for HPV detection in men. J Virol Methods Giuliano AR, Lazcano-Ponce E, Villa LL, Flores R, Salmeron J,
149: 136–143 Lee JH, Papenfuss MR, Abrahamsen M, Jolles E, Nielson
Forhan SE, Gottlieb SL, Sternberg MR, Xu F, Datta SD, Berman CM, Baggio ML, Silva R, Quiterio M (2008a) The human
S, Markowitz LE (2008) Prevalence of sexually transmitted papillomavirus infection in men study: Human papillomavi-
infections and bacterial vaginosis among Female adolescents rus prevalence and type distribution among men residing in
in the United States: Data from the National Health and Brazil, Mexico, and the United States. Cancer Epidemiol
Nutritional Examination Survey (NHANES) 2003–2004. In: Biomarkers Prev 17: 2036–2043
National STD Prevention Conference, Chicago, IL Giuliano AR, Lu B, Nielson CM, Flores R, Papenfuss MR, Lee
Fornaciari G (2006) [The Aragonese mummies of the Basilica JH, Abrahamsen M, Harris RB (2008b) Age-specific preva-
of Saint Domenico Maggiore in Naples]. Med Secoli 18: lence, incidence, and duration of human papillomavirus infec-
843–864 tions in a cohort of 290 US men. J Infect Dis 198: 827–835
Fornaciari G, Zavaglia K, Giusti L, Vultaggio C, Ciranni R Giuliano AR, Nielson CM, Flores R, Dunne EF, Abrahamsen M,
(2003) Human papillomavirus in a 16th century mummy. Papenfuss MR, Markowitz LE, Smith D, Harris RB (2007)
Lancet 362: 1160 The optimal anatomic sites for sampling heterosexual men
Franceschi S, Castellsague X, Dal Maso L, Smith JS, Plummer for human papillomavirus (HPV) detection: The HPV detec-
M, Ngelangel C, Chichareon S, Eluf-Neto J, Shah KV, tion in men study. J Infect Dis 196: 1146–1152
Snijders PJ, Meijer CJ, Bosch FX, Munoz N (2002) Hadjivassiliou M, Stefanaki C, Nicolaidou E, Bethimoutis G,
Prevalence and determinants of human papillomavirus geni- Anyfantakis V, Caroni C, Katsambas A (2007) Human
tal infection in men. Br J Cancer 86: 705–711 papillomavirus assay in genital warts – correlation with
Franceschi S, Herrero R, Clifford GM, Snijders PJ, Arslan A, symptoms. Int J STD AIDS 18: 329–334
Anh PT, Bosch FX, Ferreccio C, Hieu NT, Lazcano-Ponce Hallmo P, Naess O (1991) Laryngeal papillomatosis with human
E, Matos E, Molano M, Qiao YL, Rajkumar R, Ronco G, de papillomavirus DNA contracted by a laser surgeon. Eur
Sanjose S, Shin HR, Sukvirach S, Thomas JO, Meijer CJ, Arch Otorhinolaryngol 248: 425–427
Munoz N (2006) Variations in the age-specific curves of Halpert R, Fruchter RG, Sedlis A, Butt K, Boyce JG, Sillman
human papillomavirus prevalence in women worldwide. Int FH (1986) Human papillomavirus and lower genital neo­
J Cancer 119: 2677–2684 plasia in renal transplant patients. Obstet Gynecol 68:
Franco EL (1996) Epidemiology of anogential warts and cancer. 251–258
In: Reid R, Lorincz A (eds) Human papillomaviruses I. W.B. Handley J, Hanks E, Armstrong K, Bingham A, Dinsmore W,
Saunders, Philadelphia, pp 597–623 Swann A, Evans MF, McGee JO, O’Leary J (1997) Common
Fredericks BD, Balkin A, Daniel HW, Schonrock J, Ward B, association of HPV 2 with anogenital warts in prepubertal
Frazer IH (1993) Transmission of human papillomaviruses children. Pediatr Dermatol 14: 339–343
from mother to child. Aust N Z J Obstet Gynaecol 33: Hariri S, Dunne EF, Sternberg M, Unger ER, Meadows KS,
30–32 Karem KL, Markowitz LE (2008) Seroepidemiology of
Frega A, Cenci M, Stentella P, Cipriano L, De Ioris A, Alderisio human papillomavirus type 11 in the United States: Results
M, Vecchione A (2003) Human papillomavirus in virgins from the third National Health and Nutrition Examination
and behaviour at risk. Cancer Lett 194: 21–24 Survey, 1991–1994. Sex Transm Dis 35: 298–303
Frisch M, Biggar RJ (1999) Aetiological parallel between tonsil- Health Protection Agency (2006) Trends in anogenital warts and
lar and anogenital squamous-cell carcinomas. Lancet 354: anogenital herpes simplex virus infection in the United
1442–1443 Kingdom: 1996 to 2005. CDR Wkly 16: 1–4
Garcia-Pineres AJ, Hildesheim A, Herrero R, Trivett M, Williams Health Protection Agency (2007) Trends in genital warts
M, Atmetlla I, Ramirez M, Villegas M, Schiffman M, and genital herpes diagnoses in the United Kingdom. In:
Rodriguez AC, Burk RD, Hildesheim M, Freer E, Bonilla J, Health Protection Weekly Report, vol 1. Health Protection
Bratti C, Berzofsky JA, Pinto LA (2006) Persistent human Agency, UK
papillomavirus infection is associated with a generalized Hemminki K, Dong C, Frisch M (2000) Tonsillar and other
decrease in immune responsiveness in older women. Cancer upper aerodigestive tract cancers among cervical cancer
Res 66: 11070–11076 patients and their husbands. Eur J Cancer Prev 9: 433–437
Gibson PE, Gardner SD, Best SJ (1990) Human papillomavirus Hernandez BY, McDuffie K, Goodman MT, Wilkens LR,
types in anogenital warts of children. J Med Virol 30: Thompson P, Zhu X, Wong W, Ning L (2006) Comparison
142–145 of physician- and self-collected genital specimens for detec-
Giovannelli L, Bellavia C, Capra G, Migliore MC, Caleca M, tion of human papillomavirus in men. J Clin Microbiol 44:
Giglio M, Perino A, Matranga D, Ammatuna P (2007) HPV 513–517
group- and type-specific concordance in HPV infected sex- Hernandez BY, Wilkens LR, Zhu X, McDuffie K, Thompson P,
ual couples. J Med Virol 79: 1882–1888 Shvetsov YB, Ning L, Goodman MT (2008a) Circumcision
Gissmann L, zur Hausen H (1980) Partial characterization of and human papillomavirus infection in men: A site-specific
viral DNA from human genital warts (Condylomata acumi- comparison. J Infect Dis 197: 787–794
nata). Int J Cancer 25: 605–609 Hernandez BY, Wilkens LR, Zhu X, Thompson P, McDuffie K,
Giuliano AR, Harris R, Sedjo RL, Baldwin S, Roe D, Papenfuss Shvetsov YB, Kamemoto LE, Killeen J, Ning L, Goodman
MR, Abrahamsen M, Inserra P, Olvera S, Hatch K (2002) MT (2008b) Transmission of human papillomavirus in
Incidence, prevalence, and clearance of type-specific human ­heterosexual couples. Emerg Infect Dis 14: 888–894
 18 1 Human Papillomavirus History and Epidemiology

Herrero R, Hildesheim A, Bratti C, Sherman ME, Hutchinson M, papillomavirus infection in younger men: A prospective
1 Morales J, Balmaceda I, Greenberg MD, Alfaro M, Burk RD, follow-up study among Danish soldiers. Cancer Epidemiol
Wacholder S, Plummer M, Schiffman M (2000) Population- Biomarkers Prev 14: 1528–1533
based study of human papillomavirus infection and cervical Kjaer SK, van den Brule AJ, Paull G, Svare EI, Sherman
neoplasia in rural Costa Rica. J Natl Cancer Inst 92: 464–474 ME, Thomsen BL, Suntum M, Bock JE, Poll PA, Meijer CJ
Hillemanns P, Breugelmans JG, Gieseking F, Benard S, Lamure (2002) Type specific persistence of high risk human papillo-
E, Littlewood KJ, Petry KU (2008) Estimation of the inci- mavirus (HPV) as indicator of high grade cervical squamous
dence of genital warts and the cost of illness in Germany: intraepithelial lesions in young women: Population based
A cross-sectional study. BMC Infect Dis 8: 76 prospective follow up study. BMJ 325: 572
Hippelainen M, Syrjanen S, Koskela H, Pulkkinen J, Saarikoski Klotman ME, Chang TL (2006) Defensins in innate antiviral
S, Syrjanen K (1993) Prevalence and risk factors of genital immunity. Nat Rev Immunol 6: 447–456
human papillomavirus (HPV) infections in healthy males: Koshiol JE, Laurent SA, Pimenta JM (2004) Rate and predictors
A study on Finnish conscripts. Sex Transm Dis 20: 321–328 of new genital warts claims and genital warts-related health-
Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD (1998) care utilization among privately insured patients in the
Natural history of cervicovaginal papillomavirus infection in United States. Sex Transm Dis 31: 748–752
young women. N Engl J Med 338: 423–428 Koutsky L (1997) Epidemiology of genital human papilloma­
Hogewoning CJ, Bleeker MC, van den Brule AJ, Voorhorst FJ, virus infection. Am J Med 102: 3–8
Snijders PJ, Berkhof J, Westenend PJ, Meijer CJ (2003) Koutsky LA, Galloway DA, Holmes KK (1988) Epidemiology
Condom use promotes regression of cervical intraepithelial of genital human papillomavirus infection. Epidemiol Rev
neoplasia and clearance of human papillomavirus: A ran- 10: 122–163
domized clinical trial. Int J Cancer 107: 811–816 Kumar B, Gupta R, Sharma SC (1990) Penile condylomata
Holmes KK, Levine R, Weaver M (2004) Effectiveness of con- acuminata in a male child: A case report. Genitourin Med
doms in preventing sexually transmitted infections. Bull 66: 226–227
World Health Organ 82: 454–461 Lajous M, Mueller N, Cruz-Valdez A, Aguilar LV, Franceschi S,
Insinga RP, Dasbach EJ, Myers ER (2003) The health and eco- Hernandez-Avila M, Lazcano-Ponce E (2005) Determinants
nomic burden of genital warts in a set of private health plans of prevalence, acquisition, and persistence of human papil-
in the United States. Clin Infect Dis 36: 1397–1403 lomavirus in healthy Mexican military men. Cancer
Insinga RP, Dasbach EJ, Elbasha EH (2005) Assessing the Epidemiol Biomarkers Prev 14: 1710–1716
annual economic burden of preventing and treating anogeni- Lazcano-Ponce E, Herrero R, Munoz N, Hernandez-Avila M,
tal human papillomavirus-related disease in the US: Analytic Salmeron J, Leyva A, Meijer CJ, Walboomers JM (2001)
framework and review of the literature. Pharmacoeconomics High prevalence of human papillomavirus infection in
23: 1107–1122 Mexican males: Comparative study of penile-urethral swabs
IARC Working Group on the Evaluation of Carcinogenic Risks and urine samples. Sex Transm Dis 28: 277–280
to Humans (2007). Human papillomaviruses. IARC Monogr Liaw KL, Glass AG, Manos MM, Greer CE, Scott DR, Sherman
Eval Carcinog Risks Hum 90: 1–636 M, Burk RD, Kurman RJ, Wacholder S, Rush BB, Cadell
Jamison JH, Kaplan DW, Hamman R, Eagar R, Beach R, DM, Lawler P, Tabor D, Schiffman M (1999) Detection of
Douglas JM, Jr. (1995) Spectrum of genital human papillo- human papillomavirus DNA in cytologically normal women
mavirus infection in a female adolescent population. Sex and subsequent cervical squamous intraepithelial lesions.
Transm Dis 22: 236–243 J Natl Cancer Inst 91: 954–960
Jones V, Smith SJ, Omar HA (2007) Nonsexual transmission of Manhart LE, Koutsky LA (2002) Do condoms prevent genital
anogenital warts in children: A retrospective analysis. HPV infection, external genital warts, or cervical neoplasia?
Scientific WorldJournal 7: 1896–1899 A meta-analysis. Sex Transm Dis 29: 725–735
Kahn JA, Rosenthal SL, Succop PA, Ho GY, Burk RD (2002) Marais D, Carrara H, Kay P, Ramjee G, Allan B, Williamson AL
The interval between menarche and age of first sexual inter- (2006) The impact of the use of COL-1492, a nonoxynol-9
course as a risk factor for subsequent HPV infection in ado- vaginal gel, on the presence of cervical human papillomavi-
lescent and young adult women. J Pediatr 141: 718–723 rus in female sex workers. Virus Res 121: 220–222
Kaye JN, Cason J, Pakarian FB, Jewers RJ, Kell B, Bible J, Raju Marrazzo JM (2000) Genital human papillomavirus infection in
KS, Best JM (1994) Viral load as a determinant for transmis- women who have sex with women: A concern for patients
sion of human papillomavirus type 16 from mother to child. and providers. AIDS Patient Care STDS 14: 447–451
J Med Virol 44: 415–421 Marrazzo JM, Koutsky LA, Kiviat NB, Kuypers JM, Stine K
Kelsey CB (1882) Diseases of the rectum and anus. William (2001) Papanicolaou test screening and prevalence of genital
Wood, New York human papillomavirus among women who have sex with
Kingery LB (1923) The etiology of common warts: Their pro- women. Am J Public Health 91: 947–952
duction in second generation. JAMA 76: 440 McDonagh JER (1920) Venereal diseases. Mosby, St. Louis
Kjaer SK, Breugelmans G, Munk C, Junge J, Watson M, Iftner T Meisels A (1992) Cytologic diagnosis of human papillomavirus.
(2008) Population-based prevalence, type- and age- Influence of age and pregnancy stage. Acta Cytol 36: 480–482
specific distribution of HPV in women before introduction Moreira ED, Jr., Kim SC, Glasser D, Gingell C (2006) Sexual
of an HPV-vaccination program in Denmark. Int J Cancer activity, prevalence of sexual problems, and associated help-
123: 1864–1870 seeking patterns in men and women aged 40–80 years in
Kjaer SK, Munk C, Winther JF, Jorgensen HO, Meijer CJ, van Korea: Data from the Global Study of Sexual Attitudes and
den Brule AJ (2005) Acquisition and persistence of human Behaviors (GSSAB). J Sex Med 3: 201–211
References 19

Moscicki AB (1996) Genital HPV infections in children and Koutsky LA (2007) Genital human papillomavirus infection
adolescents. Obstet Gynecol Clin North Am 23: 675–697 in men: Incidence and risk factors in a cohort of university
Moscicki AB (2005) Impact of HPV infection in adolescent students. J Infect Dis 196: 1128–1136
populations. J Adolesc Health 37: S3–S9 Partridge JM, Koutsky LA (2006) Genital human papillomavi-
Moscicki AB, Hills N, Shiboski S, Powell K, Jay N, Hanson E, rus infection in men. Lancet Infect Dis 6: 21–31
Miller S, Clayton L, Farhat S, Broering J, Darragh T, Puranen M, Syrjanen K, Syrjanen S (1996) Transmission of
Palefsky J (2001) Risks for incident human papillomavirus genital human papillomavirus infections is unlikely through
infection and low-grade squamous intraepithelial lesion the floor and seats of humid dwellings in countries of high-
development in young females. JAMA 285: 2995–3002 level hygiene. Scand J Infect Dis 28: 243–246
Mougin C, Dalstein V, Pretet JL, Gay C, Schaal JP, Riethmuller Puranen MH, Yliskoski MH, Saarikoski SV, Syrjanen KJ,
D (2001) [Epidemiology of cervical papillomavirus infec- Syrjanen SM (1997) Exposure of an infant to cervical human
tions. Recent knowledge]. Presse Med 30: 1017–1023 papillomavirus infection of the mother is common. Am
Muller M, Viscidi RP, Ulken V, Bavinck JN, Hill PM, Fisher SG, J Obstet Gynecol 176: 1039–1045
Reid R, Munoz N, Schneider A, Shah KV, et al. (1995) Richardson H, Kelsall G, Tellier P, Voyer H, Abrahamowicz M,
Antibodies to the E4, E6, and E7 proteins of human papilloma- Ferenczy A, Coutlee F, Franco EL (2003) The natural his-
virus (HPV) type 16 in patients with HPV-associated diseases tory of type-specific human papillomavirus infections in
and in the normal population. J Invest Dermatol 104: 138–141 female university students. Cancer Epidemiol Biomarkers
Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Prev 12: 485–490
Shah KV, Snijders PJ, Meijer CJ (2003) Epidemiologic clas- Ricord P (1838) Traité pratique des maladies vénériennes.
sification of human papillomavirus types associated with J. Rouvier and E. le Bouvier, Paris
cervical cancer. N Engl J Med 348: 518–527 Rintala M, Grenman S, Puranen M, Syrjanen S (2006) Natural
Munoz N, Mendez F, Posso H, Molano M, van den Brule AJ, history of oral papillomavirus infections in spouses: A
Ronderos M, Meijer C, Munoz A (2004) Incidence, dura- ­prospective Finnish HPV Family Study. J Clin Virol 35:
tion, and determinants of cervical human papillomavirus 89–94
infection in a cohort of Colombian women with normal Rintala MA, Grenman SE, Jarvenkyla ME, Syrjanen KJ,
cytological results. J Infect Dis 190: 2077–2087 Syrjanen SM (2005) High-risk types of human papillomavi-
Nicolau SM, Camargo CG, Stavale JN, Castelo A, Dores GB, rus (HPV) DNA in oral and genital mucosa of infants during
Lorincz A, de Lima GR (2005) Human papillomavirus DNA their first 3 years of life: Experience from the Finnish HPV
detection in male sexual partners of women with genital Family Study. Clin Infect Dis 41: 1728–1733
human papillomavirus infection. Urology 65: 251–255 Roberts JN, Buck CB, Thompson CD, Kines R, Bernardo M,
Nicolosi A, Laumann EO, Glasser DB, Moreira ED, Jr., Paik A, Choyke PL, Lowy DR, Schiller JT (2007) Genital transmis-
Gingell C (2004) Sexual behavior and sexual dysfunc- sion of HPV in a mouse model is potentiated by nonoxynol-9
tions after age 40: The global study of sexual attitudes and and inhibited by carrageenan. Nat Med 13: 857–861
behaviors. Urology 64: 991–997 Rodriguez AC, Burk R, Herrero R, Hildesheim A, Bratti C,
Nielsen A, Kjaer SK, Munk C, Iftner T (2008) Type-specific Sherman ME, Solomon D, Guillen D, Alfaro M, Viscidi R,
HPV infection and multiple HPV types: prevalence and risk Morales J, Hutchinson M, Wacholder S, Schiffman M (2007)
factor profile in nearly 12,000 younger and older Danish The natural history of human papillomavirus infection and
women. Sex Transm Dis 35: 276–282 cervical intraepithelial neoplasia among young women in
Nielson CM, Flores R, Harris RB, Abrahamsen M, Papenfuss the Guanacaste cohort shortly after initiation of sexual life.
MR, Dunne EF, Markowitz LE, Giuliano AR (2007) Human Sex Transm Dis 34: 494–502
papillomavirus prevalence and type distribution in male Rombaldi RL, Serafini EP, Mandelli J, Zimmermann E,
­anogenital sites and semen. Cancer Epidemiol Biomarkers Losquiavo KP (2008) Transplacental transmission of human
Prev 16: 1107–1114 papillomavirus. Virol J 5: 106
Obalek S, Jablonska S, Favre M, Walczak L, Orth G (1990) Rombaldi RL, Serafini EP, Villa LL, Vanni AC, Barea F, Frassini
Condylomata acuminata in children: frequent association R, Xavier M, Paesi S (2006) Infection with human papillo-
with human papillomaviruses responsible for cutaneous maviruses of sexual partners of women having cervical intra-
warts. J Am Acad Dermatol 23: 205–213 epithelial neoplasia. Braz J Med Biol Res 39: 177–187
Obalek S, Misiewicz J, Jablonska S, Favre M, Orth G (1993) Rousseau MC, Franco EL, Villa LL, Sobrinho JP, Termini L,
Childhood condyloma acuminatum: Association with geni- Prado JM, Rohan TE (2000) A cumulative case-control
tal and cutaneous human papillomaviruses. Pediatr Dermatol study of risk factor profiles for oncogenic and non-oncogenic
10: 101–106 cervical human papillomavirus infections. Cancer Epidemiol
Oriel JD (1971) Natural history of genital warts. Br J Vener Dis Biomarkers Prev 9: 469–476
47: 1–13 Routh HB, Bhowmik KR, Parish LC (1997) Myths, fables and
Oriel JD (1992) Sexually transmitted diseases in children: Human even truths about warts and human papillomavirus. Clin
papillomavirus infection. Genitourin Med 68: 80–83 Dermatol 15: 305–307
Pakarian F, Kaye J, Cason J, Kell B, Jewers R, Derias NW, Raju Sarkola M, Rintala M, Grenman S, Syrjanen S (2008) Human
KS, Best JM (1994) Cancer associated human papillomavi- papillomavirus DNA detected in breast milk. Pediatr Infect
ruses: Perinatal transmission and persistence. Br J Obstet Dis J 27: 557–558
Gynaecol 101: 514–517 Satterwhite CL (2008) Up, up, and away? Trends in chlamydial
Partridge JM, Hughes JP, Feng Q, Winer RL, Weaver BA, Xi LF, infections in the U.S. In: National STD Prevention
Stern ME, Lee SK, O’Reilly SF, Hawes SE, Kiviat NB, Conference, Chicago, IL
 20 1 Human Papillomavirus History and Epidemiology

Schlecht NF, Kulaga S, Robitaille J, Ferreira S, Santos M, Syrjanen S, Puranen M (2000) Human papillomavirus infections
1 Miyamura RA, Duarte-Franco E, Rohan TE, Ferenczy A, in children: The potential role of maternal transmission. Crit
Villa LL, Franco EL (2001) Persistent human papillomavi- Rev Oral Biol Med 11: 259–274
rus infection as a predictor of cervical intraepithelial neopla- Tay SK, Ho TH, Lim-Tan SK (1990) Is genital human papillo-
sia. JAMA 286: 3106–3114 mavirus infection always sexually transmitted? Aust N Z
Schwartz SM, Daling JR, Doody DR, Wipf GC, Carter JJ, J Obstet Gynaecol 30: 240–242
Madeleine MM, Mao EJ, Fitzgibbons ED, Huang S, Thomas KK, Hughes JP, Kuypers JM, Kiviat NB, Lee SK, Adam
Beckmann AM, McDougall JK, Galloway DA (1998) Oral DE, Koutsky LA (2000) Concurrent and sequential acquisi-
cancer risk in relation to sexual history and evidence of tion of different genital human papillomavirus types. J Infect
human papillomavirus infection. J Natl Cancer Inst 90: Dis 182: 1097–1102
1626–1636 Trottier H, Franco EL (2006) The epidemiology of genital human
Schwarz E, Freese UK, Gissmann L, Mayer W, Roggenbuck B, papillomavirus infection. Vaccine 24(Suppl 1): S1–S15
Stremlau A, zur Hausen H (1985) Structure and transcrip- Vaccarella S, Lazcano-Ponce E, Castro-Garduno JA, Cruz-Valdez
tion of human papillomavirus sequences in cervical carci- A, Diaz V, Schiavon R, Hernandez P, Kornegay JR, Hernandez-
noma cells. Nature 314: 111–114 Avila M, Franceschi S (2006) Prevalence and determinants of
Sedlacek TV, Lindheim S, Eder C, Hasty L, Woodland M, human papillomavirus infection in men attending vasectomy
Ludomirsky A, Rando RF (1989) Mechanism for human clinics in Mexico. Int J Cancer 119: 1934–1939
papillomavirus transmission at birth. Am J Obstet Gynecol Van Damme L, Ramjee G, Alary M, Vuylsteke B, Chandeying V,
161: 55–59 Rees H, Sirivongrangson P, Mukenge-Tshibaka L, Ettiegne-
Sellors JW, Karwalajtys TL, Kaczorowski J, Mahony JB, Lytwyn Traore V, Uaheowitchai C, Karim SS, Masse B, Perriens J,
A, Chong S, Sparrow J, Lorincz A (2003) Incidence, clear- Laga M (2002) Effectiveness of COL-1492, a nonoxynol-9
ance and predictors of human papillomavirus infection in vaginal gel, on HIV-1 transmission in female sex workers: A
women. CMAJ 168: 421–425 randomised controlled trial. Lancet 360: 971–977
Selsted ME, Ouellette AJ (2005) Mammalian defensins in the van der Snoek EM, Niesters HG, Mulder PG, van Doornum GJ,
antimicrobial immune response. Nat Immunol 6: 551–557 Osterhaus AD, van der Meijden WI (2003) Human papilloma-
Shin HR, Franceschi S, Vaccarella S, Roh JW, Ju YH, Oh JK, virus infection in men who have sex with men participating in
Kong HJ, Rha SH, Jung SI, Kim JI, Jung KY, van Doorn LJ, a Dutch gay-cohort study. Sex Transm Dis 30: 639–644
Quint W (2004) Prevalence and determinants of genital Van Doornum GJ, Prins M, Juffermans LH, Hooykaas C, van den
infection with papillomavirus, in female and male university Hoek JA, Coutinho RA, Quint WG (1994) Regional
students in Busan, South Korea. J Infect Dis 190: 468–476 ­distribution and incidence of human papillomavirus infections
Simms I, Fairley CK (1997) Epidemiology of genital warts in among heterosexual men and women with multiple sexual
England and Wales: 1971 to 1994. Genitourin Med 73: partners: A prospective study. Genitourin Med 70: 240–246
365–367 Weaver BA, Feng Q, Holmes KK, Kiviat N, Lee SK, Meyer C,
Sinclair KA, Woods CR, Kirse DJ, Sinal SH (2005) Anogenital Stern M, Koutsky LA (2004) Evaluation of genital sites and
and respiratory tract human papillomavirus infections among sampling techniques for detection of human papillomavirus
children: Age, gender, and potential transmission through DNA in men. J Infect Dis 189: 677–685
sexual abuse. Pediatrics 116: 815–825 Weinstock H, Berman S, Cates W, Jr. (2004) Sexually transmit-
Smith JS, Moses S, Hudgens MG, Agot K, Franceschi S, ted diseases among American youth: Incidence and preva-
Maclean IW, Ndinya-Achola JO, Parker CB, Pugh N, Meijer lence estimates, 2000. Perspect Sex Reprod Health 36: 6–10
CJ, Snijders PJ, Bailey RC (2007) Human papillomavirus Wikstrom A (1995) Clinical and serological manifestations of
detection by penile site in young men from Kenya. Sex genital human papillomavirus infection. Acta Derm Venereol
Transm Dis 34: 928–934 Suppl (Stockh) 193: 1–85
Sonnex C, Strauss S, Gray JJ (1999) Detection of human papil- Wikstrom A, Popescu C, Forslund O (2000) Asymptomatic
lomavirus DNA on the fingers of patients with genital warts. penile HPV infection: A prospective study. Int J STD AIDS
Sex Transm Infect 75: 317–319 11: 80–84
Stone KM, Karem KL, Sternberg MR, McQuillan GM, Poon Wiley DJ, Douglas J, Beutner K, Cox T, Fife K, Moscicki AB,
AD, Unger ER, Reeves WC (2002) Seroprevalence of human Fukumoto L (2002) External genital warts: Diagnosis, treat-
papillomavirus type 16 infection in the United States. ment, and prevention. Clin Infect Dis 35: S210–S224
J Infect Dis 186: 1396–1402 Winer RL, Feng Q, Hughes JP, O’Reilly S, Kiviat NB, Koutsky LA
Strauss MJ, Shaw EW, et al. (1949) Crystalline virus-like parti- (2008) Risk of female human papillomavirus acquisition asso-
cles from skin papillomas characterized by intranuclear ciated with first male sex partner. J Infect Dis 197: 279–282
inclusion bodies. Proc Soc Exp Biol Med 72: 46–50 Winer RL, Hughes JP, Feng Q, O’Reilly S, Kiviat NB, Holmes
Svare EI, Kjaer SK, Worm AM, Osterlind A, Meijer CJ, van den KK, Koutsky LA (2006) Condom use and the risk of genital
Brule AJ (2002) Risk factors for genital HPV DNA in men human papillomavirus infection in young women. N Engl
resemble those found in women: a study of male attendees at J Med 354: 2645–2654
a Danish STD clinic. Sex Transm Infect 78: 215–218 Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky
Sycuro LK, Xi LF, Hughes JP, Feng Q, Winer RL, Lee SK, LA (2003) Genital human papillomavirus infection:
O’Reilly S, Kiviat NB, Koutsky LA (2008) Persistence Incidence and risk factors in a cohort of female university
of genital human papillomavirus infection in a long-term students. Am J Epidemiol 157: 218–226
­follow-up study of female university students. J Infect Dis Ylitalo N, Josefsson A, Melbye M, Sorensen P, Frisch M,
198: 971–978 Andersen PK, Sparen P, Gustafsson M, Magnusson P, Ponten
References 21

J, Gyllensten U, Adami HO (2000) A prospective study zur Hausen H (1986) Genital papillomavirus infections. In:
showing long-term infection with human papillomavirus 16 Rigby PW, Wilkie NM (eds) Viruses and cancer. Cambridge
before the development of cervical carcinoma in situ. Cancer University Press Cambridge, pp 83–90
Res 60: 6027–6032 zur Hausen H (1991) Human papillomaviruses in the pathogen-
Yun K, Joblin L (1993) Presence of human papillomavirus DNA in esis of anogenital cancer. Virology 184: 9–13
condylomata acuminata in children and adolescents. Pathology zur Hausen H (2000) Papillomaviruses causing cancer: Evasion
25: 1–3 from host-cell control in early events in carcinogenesis.
zur Hausen H (1976) Condylomata acuminata and human geni- J Natl Cancer Inst 92: 690–698
tal cancer. Cancer Res 36: 794
 Laboratory Methods for Detection
of Human Papillomavirus Infection 2
Luisa Lina Villa

Contents viral proteins. Antibodies generated against bovine

papillomavirus (BPV) late proteins have been widely
2.1 Introduction........................................................... 23 used because of the observed cross-reaction with HPV
2.2 HPV DNA Methods............................................... 24 late proteins; however, they have low sensitivity and
2.3 HPV RNA Methods............................................... 26 fail to discriminate between HPV types, which is
essential for disease risk determination. Detection of
2.4 Serological Assays................................................. 27
HPV early proteins is even more complicated due to
2.5 Detecting HPV Infection in Men.......................... 28 the low expression levels generally observed in cells or
References.............................................................. 28 tissues derived from HPV-positive lesions. Antibodies
against E6 or E7 are available but their use is mostly
restricted to in vitro assays including the direct visual-
ization in cells or tissues (immunohistochemistry) or
in protein extracts (Western blots and immune precipi-
2.1 Introduction tation assays), not always with consistent results.
HPV cannot be propagated in tissue culture and
hence in most cases its accurate identification relies on
The diagnosis of human papillomavirus (HPV) infec- molecular biology techniques. With a double-stranded
tion can be inferred from morphological, serological, DNA genome of about 8,000 base pairs (bp) in length
and clinical findings. In productive infections, such as and a well-known physical structure and gene organiza-
warts, virus particles of about 50 nm diameter can be tion, tests of choice for detecting HPV from clinical
detected by electron microscopy and by immune detec- specimens are based on nucleic acid probe technology.
tion of the virus capsid proteins (L1, L2). Immuno­ Direct detection of HPV genomes and its transcripts can
logical detection of HPV in human cells or tissues has be achieved with hybridization procedures that include
been hindered by three main factors: (a) the late, capsid Southern and Northern blots, dot blots, in situ hybrid-
proteins are only expressed in productive infections; ization (ISH), Hybrid Capture (HC; formerly DIGENE
(b) the early proteins are often expressed in low Co., now QIAGEN, MA, USA), and DNA sequencing
amounts in infected tissues; and (c) the lack of high- (reviewed in Iftner and Villa, 2003). A variety of signal-
quality, sensitive, and specific antibodies against the detection procedures are available that can further
increase the sensitivity of these assays. The only proce-
dure potentially capable of recognizing all HPV types
L.L. Villa
and variants present in the biological specimen is DNA
Ludwig Institute for Cancer Research,
São Paulo, Brazil sequencing of the viral genome, either after cloning into
e-mail: [email protected] plasmids or by direct sequencing of a polymerase chain

A. Rosenblatt, H. G. de Campos Guidi, Human Papillomavirus, 23

DOI: 10.1007/978-3-540-70974-9-2, © Springer-Verlag Berlin Heidelberg 2009
 24 2 Laboratory Methods for Detection of Human Papillomavirus Infection

reaction (PCR) fragment. This method, however, is and Koutsky, 2006). Moreover, the natural history
2 presently labor-intensive and requires expensive equip- of HPV-related diseases and transmission of HPV
ment. Moreover, direct sequencing of specimens con- between individuals cannot be fully understood with-
taining multiple HPVs awaits further developments. out the establishment of proper measures of the preva-
For HPV genome analysis, hybridization in solid lence and incidence of HPV infections in male subjects.
phase, such as Southern blot for DNA and Northern The dynamics of HPV infection in special popula-
blot for RNA molecules, is an excellent procedure that tions, including immune-deficient individuals, can also
can generate information with quality, but is time-­ be improved with precise measures of HPV exposure
consuming and requires large amounts of highly puri- including both HPV DNA and serology. This chapter
fied nucleic acids. Moreover, it requires well preserved, discusses the different technologies available for detect-
ideally full-size molecules, and therefore cannot be ing HPV infections. Moreover, the differences in ana-
done with any biological specimen, particularly those tomical sites and types of specimen collection in men
derived from fixed tissues in which DNA degradation are highlighted.
is often observed. It is also technically cumbersome
and time-consuming, not being amenable to large-
scale population studies. ISH is a technique by which
specific nucleotide sequences are identified in cells or 2.2 HPV DNA Methods
tissue sections with conserved morphology, thereby
allowing the precise spatial localization of the target
genomes in the biological specimen. One great advan- Presently, the two methodologies most widely used for
tage of ISH is that it can be applied to routinely fixed genital type detection that have equivalent sensitivities
and processed tissues, which overcomes the relatively and specificities are Hybrid Capture version 2 (HC2)
low analytical sensitivity of this method. This can be and PCR with generic primers. Both assays are ­suitable
increased by combining PCR to ISH, a procedure for high-throughput testing, with automated execution
known as in situ PCR (Nuovo et al., 1992). ISH has and reading, which is a necessary step to be considered
been used to detect messenger RNA (mRNA) as for use in large epidemiological studies and in clinical
a marker of gene expression, where levels of viral settings.
­proteins are low (Stoler et al., 1997). The major limita- HC2 is based on hybridization in solution of long
tions of the method are the potential for error in HPV synthetic RNA probes complementary to the genomic
typing because of probe cross-hybridization. How­ sequence of 13 high-risk (16, 18, 31, 33, 35, 39, 45, 51,
ever, recent improvements have made it possible for 52, 56, 58, 59, and 68) and five low-risk (6, 11, 42, 43,
this method to be widely used for HPV DNA and 44) HPV types, which are used to prepare high (B) and
RNA detection in tissues, with high sensitivities and low (A) probe cocktails that are used in two separate
­specificities. Viral DNA and RNA can also be detected reactions. DNA present in the biological specimen is
by a series of assays based on PCR. In this case, the then hybridized in solution with each of the probe
viral genomes are selectively amplified by a series of cocktails allowing the formation of specific HPV
­polymerization steps, which result in an exponential DNA-RNA hybrids. These hybrids are then captured
and reproducible increase in the HPV nucleotide by antibodies bound to the wells of a microtiter plate
sequences present in the biological specimen (Iftner that specifically recognize RNA-DNA hybrids. The
and Villa, 2003). A summary of the characteristics and immobilized hybrids are detected by a series of reac-
usefulness of different HPV detection assays is pre- tions that generate a luminescent product that can be
sented in Table 2.1. measured in a luminometer. The intensity of emitted
Studies conducted during the last two decades have light, expressed as relative light units, is proportional
clearly demonstrated the role of HPV infections and to the amount of target DNA present in the specimen,
risk of cervical neoplasia in women (Bosch et al., providing a semiquantitative measure of the viral load.
2008). In men, however, this knowledge is just starting HC2 is currently available in a 96-well microplate for-
to accumulate. An accurate definition of infection and mat, is easy to perform in clinical settings, and is suit-
identification of HPV-associated diseases in the male able for automation (Lorincz and Anthony, 2001).
genital tract is critical (Dunne et al., 2006; Partridge Furthermore, HC2 does not require special facilities to
2.2 HPV DNA Methods 25

Table 2.1 Characteristics of HPV test technologies

Test Analytical Clinical Comments

Sensitivity/ Sensitivity/specificity for

specificity CIN3/cervical cancer

Based on cell Pap smear/tissues Not applicable Low/high

morphology Limited because of their
Colposcopy Not applicable Moderate/low low-sensitivities
Visual inspection Not applicable Low/low Highly dependent on
sampling and tissue
Detection of HPV Immunocito/ Low/high Low/low
preservation
proteins histochemistrya
Low/high Low/low
Electron Cannot type HPV
microscopya Low/high Low/moderate

Western blotsa
Detection of HPV genomes
Direct methods Southern blota, b Moderate/high Moderate/high
ISH a, b
Moderate/moderate Moderate/moderate
Dot blot Low/high Low/high
Signal amplification HC c, d, e
High/high High/high
Target amplification PCR c, d, e
High/high Very high-high/
high-moderate
Real-time PCR d, e
Very high/high
Very highf
Detection of anti-HPV antibodies
ELISA peptides Low/low Low/low
VLP Moderate/high Low/low
Fused E6/E7 High/moderate Low-moderate/high

a
Technically cumbersome and/or time-consuming
b
Requires DNA and tissue preservation
c
Less dependent on sampling; can be done in crude samples
d
Suitable for high-throughput testing and automation
e
Provides viral load information
f
No data available

avoid cross-contamination, because it does not rely on and can be performed outside a specialized laboratory
target amplification to achieve high sensitivity, as do by staff with minimal training. The ability of the
PCR protocols. Often only the high-risk cocktail is careHPV test to detect premalignant lesions was found
used, and this reduces the time and cost of the test. The to be 90% in a large study conducted in the rural area of
U.S. Food and Drug Administration recommended China (Qiao et al., 2008).
cutoff value for test-positive results is 1.0 relative light The sensitivity and specificity of PCR-based meth-
unit (equivalent to 1 pg HPV DNA per 1 ml of sam- ods can vary, depending mainly on the primer set, the
pling buffer). size of the PCR product, the reaction conditions and
A newly developed HC assay uses RNA probes as in performance of the DNA polymerase used in the
HC2, but has been developed to be used in low-­resource ­reaction, the spectrum of HPV types amplified and the
settings (careHPV, QIAGEN NV). It is designed to be ­ability to detect multiple types, and the availability of a
a rapid test, able to detect 14 HPV types in about 2.5 h, type-specific assay. PCR can theoretically produce one
 26 2 Laboratory Methods for Detection of Human Papillomavirus Infection

billion copies from a single double-stranded DNA Recently, PCR protocols based on a 5¢-exonuclease
2 ­molecule after 30 cycles of amplification. There­fore, care assay and real-time detection of the accumulation of
must be taken to avoid false-positive results de­rived fluorescence were developed and named real-time
from cross-contaminated specimens or re­­a­gents. Several PCR. Compared to other assays, such as HC, this is
procedures are available to avoid this potential problem considered to be an accurate method of estimating
in using PCR protocols for HPV DNA detection. viral load, while controlling for variation in the cellu-
The most widely used PCR protocols employ con- lar content of the sample by quantification of a nuclear
sensus primers that are directed to a highly conserved gene. Several studies have shown that the risk of devel-
region of the L1 gene, since they are potentially capable oping cervical neoplasia is associated with higher copy
of detecting all mucosal HPV types. Among these are numbers of different HPV types (Gravitt et al., 2003;
the single pair of consensus primers GP5/6 and its Moberg et al., 2004; Schlecht et al., 2003). However,
extended version GP5+/6+ (de Roda Husman et al., there are inherent differences in the assays to deter-
1995; Jacobs et al., 1995) as well as the MY09/11 degen- mine viral load that could obscure the interpretation
erate primers and its modified version, PGMY09/11 and clinical relevance of the results obtained. Further
(Gravitt et al., 2000). Full distinction of more than 40 studies to evaluate the clinical relevance of viral load
types can be achieved by hybridization with type-­ are warranted.
specific probes that can be performed in ­different for- Testing for the presence of more than one HPV type
mats, and restriction fragment length polymorphism in the biological specimen is preferentially done by
analysis by gel electrophoresis (Bernard et al., 1994), PCR-based methods, since HC2 does not discriminate
dot blot hybridization, line strip assays, and microtiter between HPV types. In general, it seems that PCR sys-
plates that are amenable to automation. Recent develop- tems using multiple primers such as PGMY09/11 and
ments include the Amplicor HPV test kit (Roche SPF-PCR are more robust for detecting multiple infec-
Diagnostics, CA, USA) designed to amplify with non- tions than systems using single consensus primers such
degenerate primers a short fragment (170 bp) of the L1 as GP5+/6+. This may especially be true in cases of
gene of 13 high-risk genotypes. A PCR-based linear mixed infections where one type is present in large
array HPV product, which exploits the pGMY09/11 amounts, but all types present could be identified by
amplification system and is capable of identifying 37 very sensitive reverse line blot assays or linear arrays,
HPV genotypes, including all high- and low-risk geno- as described above.
types in the human anogenital region, is also commer-
cially available (Linear Array HPV Genotyping Test,
Roche Diagnostics). 2.3 HPV RNA Methods
Another pair of consensus primers is available that
amplifies a smaller fragment (65 bp compared to 150
bp for the GP primers and 450 bp for MY09/11) of the HPV RNA is being considered as an important target
L1 gene. This short PCR fragment (SPF)-PCR is for the molecular diagnosis of HPV infections. Testing
designed to discriminate between a broad spectrum of for viral RNA aims to evaluate the HPV genome
HPVs in a reverse line blot hybridization (LiPA) expression (and hence their activity in the infected
(Kleter et al., 1999). Tests that rely on shorter frag- cells), unlike HPV DNA assays that detect only the
ments of the viral genome are considered to be more presence of viral genomes. The rationale is that the
sensitive and amenable for less-preserved specimens. presence of transcripts of the HPV oncogenes E6 and
The SPF and GP5+/6+ systems are widely used in epi- E7 is a more accurate and specific marker of cells at
demiological studies and have being adapted to for- risk or already transformed by high-risk HPVs. HPV
mats amenable for high-throughput testing. A fast and 16 E6 and E7 transcripts can be detected with high sen-
reliable HPV typing method has been developed using sitivity in clinical specimens by employing PCR-based
nonradioactive reverse line blotting (RLB) of GP5+/6+ methods including reverse transcriptase PCR (RT-PCR)
PCR-amplified HPV genotypes. In this way 40 HPV- (Sotlar et al., 1998), quantitative RT-PCR, and real-
positive clinical samples can be simultaneously typed time PCR (Lamarcq et al., 2002). Recent studies have
for 37 HPV types (14 HR and 23 LR types) (van den shown that testing for E6/E7 transcripts of HPV
Brule et al., 2002). types 16, 18, 31, 33, and 45 with an RNA-based
2.4 Serological Assays 27

r­ eal-time nucleic acid sequence-based amplifi­cation Standardized methodologies that measure total
assay (NASBA; PreTect HPV-Proofer; Norchip, serum antibody, neutralizing antibody, and type-specific
Norway) was more specific in detecting individuals antibody concentrations will be necessary. Not all of
that developed high-grade cervical disease than HPV these assays will be routine, but if and when employed
DNA detection by PCR with GP5+/6+ consensus they must be standard and consistent. These assays
primers (Molden et al., 2005). Moreover, detection of will require the establishment of an International
such oncogenic transcripts identified which HPV high- Standard(s) with an arbitrarily assigned unit measure
risk infections persisted without having to perform or international units (IU). These issues were recog-
repeat testing (Cuschieri et al., 2004). Another impor- nized by the World Health Organization (WHO), who
tant application for HPV RNA studies has been sug- established collaborative studies to evaluate reference
gested by Klaes et al. (1999), who developed a method reagents for type-specific HPV serologic assays (http:
(APOT, amplification of papillomavirus oncogene //whqlibdoc.who.int/hq/2004/WHO_IVB_04.22.pdf
transcripts) to differentiate between episomal and inte- and Ferguson et al., 2006). Importantly, about half of the
grated HPV oncogene transcripts. The rationale behind individuals exposed to HPV never develop measurable
this method is that in cervical cancers HPV genomes titers of antibodies, although this scenario will change
are often integrated into the host chromosomes, while drastically as HPV prophylactic vaccination is imple-
in normal and premalignant tissues the viral DNA is mented in different areas around the world. This infor-
usually kept as episomes. Using this assay, they were mation is and will be predominantly known in women,
able to show a strong correlation between detection of which underscores the need to better understand the
integrated high-risk HPV transcripts and presence of natural course of HPV infection and corresponding
high-grade cervical neoplasia. The main problem with immune responses to HPV in men (Svare et al., 1997).
these techniques is that RNA is a much more labile It is very important to stress that the analytical sen-
molecule than DNA, and therefore less available in sitivities and specificities of HPV tests vary largely,
most biological specimens depending on the time and depending on the assay characteristics, the type and
type of storage conditions. Therefore, there is great quality of the biological specimen, and the type and
interest in collection media capable of preserving quality of the reagents employed, including the use of
both DNA and RNA molecules. These include collec- different DNA polymerases that affect test perfor-
tion media which contain methanol, shown to preserve mance. Moreover, caution should be used to interpret
both the cell morphology and integrity of DNA, such comparisons, because the assays differ in their
RNA, and proteins (Cuschieri et al., 2005; Nonogaki ability to detect different HPV types either as single or
et al., 2004). multiple infections. In general, there are good to excel-
lent agreement rates between tests performed with
HC2 and generic-PCR employing MY09/11 and
GP5+/6+ systems. This emphasizes the availability of
2.4 Serological Assays several robust HPV tests. Nevertheless, standardized
methods and validated protocols, reagents, and refer-
ence samples should be available to assure the best test
At present there is no agreed standard methodology performance in different settings.
for serological assays that measure antibody acquired Although the analytical sensitivities of some HPV
in a present or past HPV infection, although virtually detection assays can be very high, and therefore valu-
all reported studies employ enzyme immunoassays able for addressing the burden of HPV infections epi-
(Konya and Dillner, 2001). Before neutralizing anti- demiologically, their corresponding clinical significance
body assays were made available (Pastrana et al., 2004), is not so evident (Snijders et al., 2003). This is because
most serological assays were type-specific HPV VLP several HPV infections do not persist and therefore do
ELISA (Carter et al., 2001). More recently, an auto- not lead to clinically relevant disease. Anogenital HPV
mated multiplex assay based on the use of Luminex infections are very common in young, sexually active
beads was developed for the detection of different populations, including both women and men. However,
serotypes with the same sensitivity and specificity in the latter, the natural history of persistence and dis-
achieved in the single-type assays (Dias et al., 2005). ease development is largely unknown.
 28 2 Laboratory Methods for Detection of Human Papillomavirus Infection

2.5 Detecting HPV Infection in Men In summary, several methods to detect HPV infec-
2 tions are available. The choice of a particular method is
very much dependent on its analytical as well as its
Results from different studies of HPV infections in men clinical sensitivities and specificities. In the male geni-
are not always consistent and vary considerably accord- talia, HPV detection is further complicated by the low
ing to the anatomical site sampled, the type of collec- amount of DNA obtained from exfoliated skin cells,
tion, and the HPV DNA test used to ascertain HPV which highlights the importance of validating the col-
presence and type (Baldwin et al., 2003; Dunne et al., lection and detection method of choice. There are suf-
2006; Giuliano et al., 2008b, c; Nielson et al., 2007). ficient and validated tools for performing studies of
Among a series of clinical and histopathological tech- anogenital HPV infections in men, and results are rap-
niques, PCR has emerged as the most sensitive method idly accumulating. This experience should contribute to
to define HPV infection in men. Indeed, this is the accelerate our knowledge about the natural history of
methodology being used in large cohort studies of the HPV infection and risk of anogenital disease in men.
natural history of HPV infection and risk of neoplasia
in men (Giuliano et al., 2008a; Svare et al., 2002) (see
also Chaps. 1, 5, and 6).
Specimen Collection Site: Single and multiple ana-
References
tomical sites of the male genitalia are often sampled.
They include the penile shaft, coronal sulcus/glans Aguilar LV, Lazcano-Ponce E, Vaccarella S (2006) Human pap-
illomavirus in men: Comparison of different genital sites.
(including the prepuce in uncircumcised men), scro- Sex Transm Infect 82(1): 31–33
tum, urethra, as well as urine and semen (Aguilar Baldwin SB, Wallace DR, Papenfuss MR, et al. (2003) Human
et al., 2006; Benevolo et al., 2008; Fife et al., 2003; papillomavirus infection in men attending a sexually trans-
Giuliano et al., 2008a; Nielson et al., 2007). It has mitted disease clinic. J Infect Dis 187(7): 1064–1070
Benevolo M, Mottolese M, Marandino F, et al. (2008) HPV
been shown that specimens from the urethra and semen prevalence among healthy Italian male sexual partners of
contribute little toward the analysis of HPV DNA women with cervical HPV infection. J Med Virol 80(7):
prevalence and that specimens should be collected from 1275–1281
the shaft, glans, and scrotum in a combined sample Bernard H, Chan S, Manos MM, et al. (1994) Identification and
assessment of known and novel human papillomavirus by
(Giuliano et al., 2007). polymerase chain reaction amplification, restriction frag-
Collection Method: Another most important aspect ment polymorphisms, nucleotide sequence, and phylogeny
when analyzing HPV infection in men is the variability algorithms. J Infect Dis 170: 1077–1085
attributable to the collection method. Several methods Bosch FX, Burchell AN, Schiffman M, et al. (2008) Epidemiology
and natural history of human papillomavirus infections and
to obtain samples from the male genitalia have been type-specific implications in cervical neoplasia. Vaccine 26
described. They include the removal of exfoliated cells (Suppl 10): K1–K16
from the penis surface either by direct scraping with a Carter JJ, Madeleine MM, Shera K, et al. (2001) Human papil-
swab or brush (dry or pre-wetted in saline) (see also lomavirus 16 and 18 L1 serology compared across anogeni-
tal cancer sites. Cancer Res 61(5): 1934–1940
Sect. 3.5 in Chap. 3) or by first abrading the skin with Cuschieri KS, Beattie G, Hassan S, et al. (2005) Assessment of
a nail file followed by removal of cells with a swab human papillomavirus mRNA detection over time in cervi-
(Weaver et al., 2004). This in fact is the method that is cal specimens collected in liquid based cytology medium.
being applied to collect cells from the penis of men J Virol Methods 124: 211–215
Cuschieri KS, Whitley MJ, Cubie H (2004) Human papillomavi-
included in a large clinical trial for the quadrivalent rus type specific DNA and RNA persistence – implications
HPV L1 VLP prophylactic vaccine (Giuliano, 2007). for cervical disease progression and monitoring. J Med Virol
Recently, a systematic study has shown that skin cells 73: 65–70
exfoliated with a swab can be used reliably for HPV de Roda Husman AM, Snijders PJ, Stel HV, et al. (1995)
Processing of long-stored archival cervical smears for human
testing (Flores et al., 2008). Moreover, HPV preva- papillomavirus detection by the polymerase chain reaction.
lence results obtained from self-collected samples in Br J Cancer 72: 412–417
men show good agreement with clinician-­collected Dias D, Van Doren J, Schlottmann S, et al. (2005) Optimization
samples, which may be considered a suitable alterna- and validation of a multiplexed luminex assay to quantify
antibodies to neutralizing epitopes on human papillomavi-
tive for studies on HPV transmission (Hernandez et al., ruses 6, 11, 16, and 18. Clin Diagn Lab Immunol 12(8):
2006; Ogilvie et al., 2008). 959–969
References 29

Dunne EF, Nielson CM, Stone KM, et al. (2006) Prevalence of Konya J, Dillner J (2001) Immunity to oncogenic human papillo­
HPV infection among men: A systematic review of the lit- maviruses. Adv Cancer Res 82: 205–238
erature. J Infect Dis 194(8): 1044–1057 Lamarcq L, Deeds J, Ginzinger D, et al. (2002) Measurements
Ferguson M, Heath A, Johnes S, et al., Collaborative Study of human papillomavirus transcripts by real time quantita-
Participants (2006) Results of the first WHO international tive reverse transcription-polymerase chain reaction in sam-
collaborative study on the standardization of the detection of ples collected for cervical cancer screening. J Mol Diagn
antibodies to human papillomaviruses. Int J Cancer 118(6): 4(2): 97–102
1508–1514 Lorincz A, Anthony J, (2001) Advances in HPV detection by
Fife KH, Coplan PM, Jansen KU, et al. (2003) Poor sensitivity hybrid capture. Papillomavirus Rep 145: 154
of polymerase chain reaction assays of genital skin swabs Moberg M, Gustavsson I, Gyllensten U (2004) Type-specific
and urine to detect HPV 6 and 11 DNA in men. Sex Transm associations of human papillomavirus load with of ­developing
Dis 30(3): 246–248 cervical carcinoma in situ. Intl J Cancer 112(5): 854–859
Flores R, Abalos AT, Nielson CM, et al. (2008) Reliability of Molden T, Kraus I, Skomedal H, et al. (2005) Comparison of
sample collection and laboratory testing for HPV detection human papillomavirus messenger RNA and DNA detection:
in men. J Virol Methods 149(1): 136–143 A cross-sectional study of 4,136 women >30 years of age
Giuliano AR (2007) Human papillomavirus vaccination in with a 2-year follow-up of high-grade squamous intraepi­
males. Gynecol Oncol 107(2 Suppl 1): S24–S26 thelial lesion. Cancer Epidemiol Biomarkers Prev 14(2):
Giuliano AR, Lazcano-Ponce E, Villa LL, et al. (2008a) The 367–373
human papillomavirus infection in men study: Human papil- Nielson CM, Flores R, Harris RB, et al. (2007) Human papillo-
lomavirus prevalence and type distribution among men mavirus prevalence and type distribution in male anogenital
residing in Brazil, Mexico, and the United States. Cancer sites and semen. Cancer Epidemiol Biomarkers Prev 16(6):
Epidemiol Biomarkers Prev 17(8): 2036–2043 1107–1114
Giuliano AR, Lu B, Nielson CM, et al (2008b) Age-specific Nonogaki S, Wakamatsu A, Longatto Filho A, et al. (2004)
prevalence, incidence, and duration of human papillomavi- Hybrid capture II and polymerase chain reaction for identi-
rus infections in a cohort of 290 US men. J Infect Dis 198(6): dying HPV infections in samples collected in a new collec-
827–835 tion medium. A comparison. Acta Cytol 48(4): 514–520
Giuliano AR, Nielson CM, Flores R, et al. (2007) The optimal Nuovo GJ, Moritz J, Walsh LL, et al. (1992) Predictive value of
anatomic sites for sampling heterosexual men for human human papillomavirus DNA detection by filter hybridization
papillomavirus (HPV) detection: The HPV detection in men and polymerase chain reaction in women with negative
study. J Infect Dis 196(8): 1146–1152 results of colposcopic examination. Anatom Pathol 98(5):
Giuliano AR, Tortolero-Luna G, Ferrer E, et al. (2008c) 489–492
Epidemiology of human papillomavirus infection in men, Ogilvie G, Taylor D, Krajden M, et al. (2008) Self collection of
cancers other than cervical and benign conditions. Vaccine genital human papillomavirus in heterosexual men. Sex
26(Suppl 10): K17–K28 Transm Infect Dec 9 [Epub ahead of print]
Gravitt PE, Peyton C, Wheeler C, et al. (2003) Reproducibility Partridge JM, Koutsky LA (2006) Genital human papillomavi-
of HPV 16 and HPV 18 viral load quantitation using TaqMan rus infection in men. Lancet Infect Dis 6(1): 21–31
real-time PCR assays. J Virol Methods 112(1–2): 23–33 Pastrana DV, Buck CB, Pang YY, et al. (2004) Reactivity of
Gravitt PE, Peyton CL, Alessi TQ, et al. (2000) Improved ampli- human sera in a sensitive, high-throughput pseudovirus-
fication of genital human papillomaviruses. J Clin Microbiol based papillomavirus neutralization assay for HPV16 and
38: 357–361 HPV18. Virology 321(2): 205–216
Hernandez BY, McDuffie K, Goodman MT, et al. (2006) Qiao YL, Sellors JW, Eder PS, Bao YP, Lim JM, Zhao FH, Weigl
Comparison of physician- and self-collected genital speci- B, Zhang WH, Peck RB, Li L, Chen F, Pan QJ, Lorincz AT
mens for detection of human papillomavirus in men. J Clin (2008) A new HPV-DNA test for cervical cancer screening
Microbiol 44(2): 513–517 in developing regions: A cross sectional study of clinical
Iftner T, Villa LL (2003) Chapter 12: Human papillomavirus accuracy in rural China. Lancet Oncology 9(10): 926–936
technologies. J Natl Cancer Inst Monogr 31: 80–88 Schlecht N, Trevisan A, Duarte-Franco E, et al. (2003) Viral load
Jacobs MV, de Roda Husman AM, van den Brule AJ, et al. as a predictor of the risk of cervical intraepithelial neoplasia.
(1995) Group-specific differentiation between high- and Int J Cancer 103: 519–524
low-risk human papillomavirus genotypes by general primer- Snijders PJ, van den Brule AJ, Meijer CJ (2003) The clinical rel-
mediated PCR and two cocktails of oligonucleotide probes. evance of human papillomavirus testing: relationship between
J Clin Microbiol 33: 901–905 analytical and clinical sensitivity. J Pathol 1(1): 1–6
Klaes R, Woerner SM, Ridder R, et al. (1999) Detection of Sotlar K, Selinka H-C, Menton M, et al. (1998) Detection of
high-risk cervical intraepithelial neoplasia and cervical human papillomavirus type 16 E6/E7 oncogene transcripts
cancer by amplification of transcripts derived from inte- in dysplastic and nondysplastic cervical scrapes by nested
grated papillomavirus oncogenes Cancer Res 59(24): RT-PCR. Gynecol Oncol 69: 114–121
6312–6316 Stoler MH, Wolinsky SM, Whitbeck A, et al. (1997)
Kleter B, van Doorn LJ, Schrauwen L, et al. (1999) Development Differentiation-linked human papillomavirus types 6 and 11
and clinical evaluation of a highly sensitive PCR-reverse transcription in genital condylomata revealed by in situ
hybridization line probe assay for detection and identifica- hybridization with message-specific RNA probes. Virology
tion of anogenital human papillomavirus. J Clin Microbiol 172: 331–340
37: 2508–2517
 30 2 Laboratory Methods for Detection of Human Papillomavirus Infection

Svare EI, Kjaer SK, Nonnenmacher B, et al. (1997) Seroreactivity Van den Brule AJ, Pol R, Fransen-Daalmeijer N, Schouls LM,
2 to human papillomavirus type 16 virus-like particles is lower et al. (2002) GP5+/6 PCR followed by reverse line blot anal-
in high-risk men than in high-risk women. J Infect Dis ysis enables rapid and high-throughput identification of
176(4): 876–883 human papillomavirus genotypes. J Clin Microbiol 40(3):
Svare EI, Kjaer SK, Worm AM, et al. (2002) Risk factors for 779–787
genital HPV DNA in men resemble those found in women: Weaver BA, Feng Q, Holmes KK, et al. (2004) Evaluation of
a study of male attendees at a Danish STD clinic. Sex Transm genital sites and sampling techniques for detection of human
Infect 78(3): 215–218 papillomavirus DNA in men. J Infect Dis 189(4): 677–685
 Human Papillomavirus and External
Genital Lesions 3
Alberto Rosenblatt and Homero Gustavo de Campos Guidi

Contents 3.6.2 Destructive Therapy................................................ 57

3.6.3 Immunotherapy....................................................... 61

3.1 Introduction........................................................... 33 3.7 Other Treatment Modalities................................. 63

3.7.1 Chemical Destruction.............................................. 63
3.2 Overview................................................................ 34 3.7.2 Novel Therapies...................................................... 64
3.3 Clinical Manifestations......................................... 35 3.8 Management of Latent and Subclinical
3.3.1 Subclinical Infection............................................... 35 HPV Infection........................................................ 66
3.3.2 Clinical Disease....................................................... 35
3.3.3 HPV-Related Flat Penile Lesions............................ 40 3.9 Circumcision and HPV......................................... 67

3.4 Differential Diagnosis............................................ 42 3.10 Follow-Up............................................................... 67

3.4.1 Benign Penile Pearly Papules 3.11 Prevention.............................................................. 67
(Hirsutoid Papillomas) ........................................... 42
3.4.2 Fibroepithelial Polyps ............................................ 42 References.............................................................. 67
3.4.3 Prominent Sebaceous Glands (Ectopic Sebaceous
Glands, Fordyce Spots) .......................................... 43
3.4.4 Sebaceous Glands . ................................................. 43
3.4.5 Seborrheic Keratoses............................................... 43
3.4.6 Angiokeratoma (Fordyce Angiokeratoma) . ........... 43 3.1 Introduction
3.4.7 Verrucous Epidermal Nevi and
Pigmented Nevi ...................................................... 44
3.4.8 Molluscum Contagiosum........................................ 45
Genital lesions associated with human papillomavirus
3.4.9 Lichen Nitidus......................................................... 45
3.4.10 Syphilitic Condylomata Lata . ................................ 46 (HPV) infection affect children and adults of both gen-
3.4.11 Verrucous carcinoma (Buschke- ders and are a medical problem worldwide.
Löwenstein tumor)................................................. 46 According to Fleischer et al. (2001), obstetricians/
3.4.12 Squamous Intraepithelial Lesions (SILs)/
gynecologists, urologists, and dermatologists are the spe-
Penile Intraepithelial Neoplasia (PIN)/ Penile
Squamous Cell Carcinomas (SCCs)........................ 47 cialists most involved with the disease and the ones that
HPV-infected patients usually seek for counseling and
3.5 Detection Methods................................................. 47
3.5.1 Clinical Diagnosis................................................... 47 treatment. Because of the increasing number of individuals
3.5.2 Laboratory Diagnosis.............................................. 48 that are being infected by the virus and the burden inflicted
3.6 Treatment............................................................... 52 by the disease, it is imperative that every medical practitio-
3.6.1 Antimitotic Therapy................................................ 53 ner and particularly specialists in these fields acquire the
necessary expertise in the management of HPV.
This chapter discusses the management of subclini-
cal infection and clinical disease, including novel
A. Rosenblatt ()
Albert Einstein Jewish Hospital, Sao Paulo, Brasil ­therapeutic options for HPV-related external genital
e-mail: [email protected] lesions. In addition, it reviews current concepts ­regarding

A. Rosenblatt, H. G. de Campos Guidi, Human Papillomavirus, 33

DOI: 10.1007/978-3-540-70974-9-3, © Springer-Verlag Berlin Heidelberg 2009
 34 3 Human Papillomavirus and External Genital Lesions

circumcision and HPV infection, as well as preventive

3 measures against the disease (see also Chap. 11).

3.2 Overview

Although HPV infection in the male population has

not received as much attention as in its female counter-
part, Weaver et al. (2004) reported that both genders
have similar infection rates.
Furthermore, young male and female adults are
most likely to seek medical treatment for the disease,
mainly because of the stigma attached to a sexually
transmitted disease (STD) (Koshiol et al., 2004; Insinga
et al., 2003).
HPVs are classified as the Papillomaviridae family
and approximately 200 different HPV types have cur-
Fig. 3.1. Schematic representation of HPV-related benign lesion
rently been identified. According to their tissue tro-
formation
pism, HPVs can be also subdivided into mucosatropic
and cutaneotropic, with a predilection for squamous
epithelial cells rather than columnar, cuboidal, or tran- and was described by Pao et al. (1993), Tay et al. (1990),
sitional epithelial cells (Gillison and Shah, 2003). and Sonnex et al. (1999) (see also Sect. 1.6 in Chap. 1).
HPV infection occurs by direct inoculation of the HPV type-specific concordance between specimens
virus into the epidermal layers, and skin trauma may obtained from heterosexually active couples occurs
play an important role, causing epithelial microdefects often and confirms the contagious nature of the disease
that facilitate virus invasion (Mansur, 2002). (Baken et al., 1995; Bleeker et al., 2005a; Giovannelli
Following invasion, the virus undergoes a variable et al., 2007; Hernandez et al., 2008b).
period of latency with limited viral DNA replica- Moreover, Brown et al. (1999b) estimated the infec-
tion occurring in the basal layers of the epithelium. tivity rate between sexual partners at 60%, although
Expression of HPV nonstructural proteins (E6 and E7) Van Doornum et al. (1994) reported that men have
delays cell-cycle arrest and differentiation, causing fewer persistent infections than women. Available data
epithelial cells to proliferate. The ensuing process will from a study of a large group of Finnish male subjects
then result in the production of a clinically apparent also suggest that spontaneous viral clearance may
lesion (Doorbar and Sterling, 2001). occur more rapidly in men (Hippelainen et al., 1993).
As the virus migrates into differentiating keratino- The prevalence of HPV infection ranges from 2.3 to
cytes, HPV DNA replication is amplified, with final virus 34.8% for high-risk types and from 2.3 to 23.9% for
assembly occurring in the superficial squames. Highly low-risk types (Weaver et al., 2004; Lazcano-Ponce
infectious virions are then shed into the environment and et al., 2001; Kataoka et al., 1991; Wikstrom et al.,
viremia is nonexistent, since only superficial epithelial 2000; Franceschi et al., 2002; Baldwin et al., 2003;
cells are infected (Tseng et al., 1999) (Fig. 3.1) (see also Lajous et al., 2005). HPV 16 is the most pre­valent
Sect. 9.3 in Chap. 9 and Sect. 11.3 in Chap. 11). high-risk type detected, although variability exists
According to Gonçalves and Donadi (2004), viral among different geographic areas. However, Partridge
activity is likely to depend on the host immune status. In and Koutsky (2006) reported the possibility of reduced
immunocompetent patients, most genital HPV infections penile skin receptivity toward oncogenic HPV types.
are cleared spontaneously by the body’s defenses through Genital warts are common among sexually active
a cell-mediated immune mechanism (see also Chap. 9). young men, occurring in approximately 1% of the U.S.
HPV infection is thought to be acquired predomi- sexually active group aged 15–49 years.
nantly through sexual contact in adolescents and adults, The peak incidence of genital warts occurs in the
although transmission by nonsexual routes is possible 20–24-year age-group and the lifetime cumulative risk
3.3 Clinical Manifestations 35

of developing genital warts is almost 10%, according Mucosal fissuring

to Franco (1996). Moreover, there has been a predomi- Superficial moist desquamation, unpleasant odor
nance of low-risk HPV types in several studies that and white thick secretion when associated with
evaluated genital wart HPV typing (Yun and Joblin, ­fungal infection
1993; Boxman et al., 1999; Hadjivassiliou et al., 2007),
with a U.S. seroprevalence of low-risk HPV 11 esti-
mated at 4.7%. However, since the introduction of the 3.3.1.2 Symptoms
quadrivalent HPV vaccine, genital warts have become
a vaccine-preventable disease. Mostly asymptomatic
Pruritus
Current U.S. Centers for Disease Control Burning sensation and increased skin sensitivity
(CDC) Recommendation to Patients with (even to water)
Genital Warts (Workowski and Berman, 2007) Dyspareunia
HPV infection and recurrence are common among
sexually active individuals.
Incubation period can be long and variable. 3.3.2 Clinical Disease
Duration of infection and methods of prevention
are not definitively known.
Condyloma Acuminatum (Anogenital Warts)

3.3 Clinical Manifestations Incidence – 2.4 cases per 1,000 per year
Estimated annual incidence in individuals aged 20–24
Following contamination, HPV infection may follow years – 1.2%, according to Persson et al. (1996)
one of three paths:
Condyloma acuminatum is the most common and
(a) Latent infection – The virus remains in a quies- classical clinical presentation of genital HPV infection
cent state, without producing any gross or micro- (excluding subclinical or latent infection), and 70–100%
scopic evidence of disease (asymptomatic) of exophytic genital warts are usually associated with
(b) Subclinical infection HPV 6 or HPV 11 infections, with a small risk of malig-
(c) Clinical disease nant transformation (Brown et al., 1999a; Coleman
Asymptomatic et al., 1994; Greer et al., 1995; Li et al., 1995).
Symptomatic
Most HPV infections in men are symptomless and
3.3.2.1 Presentation
unapparent (Mao et al., 2003).
The classic acuminate condylomata (Fig. 3.2a, b) are
Expert Advice
pointed, cauliflower-like lesions with a fleshy, vascular
Persistence (i.e., HPV DNA genes are being detected appearance, usually found on moist surfaces, although
regularly) and latency (i.e., HPV DNA is detectable they can also be found outside the genital area.
although not replicating) are usually synonymous The lesions range in size from a few millimeters to
with long-term infections, regardless of symptoms. several centimeters (Fig. 3.3a, b), and individual warts
may coalesce forming large exophytic masses.

3.3.1 Subclinical Infection Keratotic lesions have a thickened, rough surface

and are usually found on dry surfaces, such as the
penile shaft (Fig. 3.4).
3.3.1.1 Presentation
Lesions appear as single or multiple well-­circum­
Normal appearance of skin or mucosa scribed verrucous or keratotic papules and plaques
Mild hyperemia (Fig. 3.5a, b).
 36 3 Human Papillomavirus and External Genital Lesions

Fig. 3.2. (a) Condyloma acuminatum on the penis shaft. (b) Viral
condyloma acuminatum (histology) (Source: Photo­graph cour-
tesy of Filomena Marino Carvalho MD, PhD, São Paulo, Brazil)

Fig. 3.3. (a) Small subcoronal warty lesions. (b) Condylomatous

Smooth papular warts are dome-shaped lesions, lesions around the coronal sulcus
usually found in relatively dry locations such as the
keratotic lesions (Fig. 3.6). Expert Advice
They may appear in clusters and the color ranges
Condyloma lesions are rare in the glans penis (except
from flesh-colored to pink to reddish-brown.
in the coronal sulcus) (Fig. 3.7), and occur frequently
When located in the glans penis and coronal sulcus,
in immunosuppressed and HIV-infected individuals.
the nonpigmented papules and small warts are trans-
In these patients, glans penis lesions are associated
lucent and show a clear vascular punctuation on the
with high-risk HPV types (Fig. 3.8a, b) and more
top, allowing their distinction from pearly papules
aggressive histological findings (Fig. 3.9).
(Barrasso and Gross, 1997) (see below Sect. 3.4).
3.3 Clinical Manifestations 37

Fig. 3.6. Papular warts located on the penis shaft

Fig. 3.4. Single, well-circumscribed verrucous lesion on the

shaft of the penis

Fig. 3.7. Glove finger-type lesion located on the glans penis

3.3.2.2 Multifocality

HPV-related lesions in the male population can develop

anywhere on the penis (Fig. 3.10), urethral meatus
(Fig. 3.11), and urethra (see Chap. 4). They can also be
found in the pubic area and the inguinal crease
(Fig. 3.12), but the scrotum (Fig. 3.13a, b) and perineum
are infrequent locations. The perianal area and
parti­cularly the intra-anal region is a common location
among men who have sex with men (MSM), but non-
sexual transmission routes (i.e., finger–genital) are
also implicated. Exotic presentations (Fig. 3.14a–c)
can also occur, particularly in immunosuppressed
patients.
Data from several studies show that the penis shaft
harbors most of the HPV DNA detected (Cook et al.,
Fig. 3.5. (a) Well-circumscribed keratotic shaft papules. (b) HPV- 1993; Nielson et al., 2007; Giuliano et al., 2007;
related keratotic lesions at the base of the penis Nicolau et al., 2005). However, in a recent analysis
 38 3 Human Papillomavirus and External Genital Lesions

Fig. 3.10. HPV-related lesion in the frenulum recessus

Fig. 3.8. (a) Glans papular lesion in HIV-positive patient; virol-

Fig. 3.11. Wart at the hypospadic meatus
ogy HPV 16. (b) Glans penis lesion in HIV-positive patient;
virology HPV 18

Fig. 3.9. Rapidly progressing glans penis lesion Fig. 3.12. Condyloma acuminatum in the inguinal crease
3.3 Clinical Manifestations 39

Fig. 3.13. (a) “Kissing” lesions (scrotal lesion developing through contact of the HPV-related penis lesion). (b) Small, HPV-related,
scrotal pigmented papule (arrow)

Fig. 3.14. (a) Exotic presentation – ear. (b) HPV-associated esophageal lesion (Source: Tomishige Photograph courtesy of Toshiro
Tomishige MD, PhD, São Paulo, Brazil). (c) Esophageal lesion – severe dysplasia (HPV-positive) (Source: Photograph courtesy of
Monica Stiepcich MD, PhD, São Paulo, Brazil)
 40 3 Human Papillomavirus and External Genital Lesions

performed on African men by Smith et al. (2007), a

3 high HPV DNA prevalence was detected in the glans/
coronal sulcus (39%).
The proximal penile area is a common location of
HPV-related lesions among men who routinely use
condoms, because the virus can still be transmitted
through contact with areas of unprotected genital skin
(Fig. 3.15). Besides, microabrasions caused by the
friction of the rolled portion of the condom are com-
mon at the base of the penis.

In uncircumcised men
Distal warts are more prevalent. Fig. 3.16. HPV-related vulvar intraepithelial neoplasia 1 (VIN 1).
The preputial cavity (glans penis, coronal sulcus, (Source: Photograph courtesy of Nadir Oyakawa, MD, PhD, São
inner aspect of the foreskin and frenulum) is Paulo, Brazil)
­particularly affected (Buechner, 2002).
In circumcised men the shaft of the penis is often
involved. 3.3.2.3 Symptoms

Often asymptomatic
Among women, frequent locations are the posterior
Pruritus
introitus, the labia majora and minora (Fig. 3.16), and
Mild burning
the clitoris. Less common locations are the vagina, cer-
Bleeding and pain (usually associated with large
vix, perineum, anus, and urethra.
lesions or secondary infection)

3.3.3 HPV-Related Flat Penile Lesions

Flat condyloma is frequently associated with subclini-

cal infection and this lesion is difficult to detect with-
out special techniques. The clinical findings resemble
a chronic inflammatory condition causing intermittent
episodes of balanoposthitis, with or without visible flat
lesions. However, flat condyloma can also be present
in totally asymptomatic individuals.
Bleeker et al. (2005b) recently evaluated the male
sexual partners of women with cervical intraepithelial
neoplasia (CIN). These individuals presented a higher
Fig. 3.15. Condyloma located at the base of the penis prevalence of HPV-related flat penile lesions, as well
3.3 Clinical Manifestations 41

Fig. 3.17. Glans lesion; virology HPV 16

Fig. 3.18. Hyperemic mucosa and fissuring

as a larger size of these lesions, when compared with a

male population from a non-STD clinic.
Moreover, recent data (Bleeker et al., 2006) have
shown that flat penile lesions are usually associated
with increased viral copy numbers of particularly high-
risk HPV types (Fig. 3.17), and the investigators have
further suggested that these lesions contribute to the
Fig. 3.19. (a) Flat condyloma (glans penis and inner aspect of
viral spread.
the foreskin). (b) Condyloma and flat condyloma lesions. (c) Flat
condyloma

3.3.3.1 Presentation
3.3.3.2 Symptoms
Normal appearance of the mucosa
Hyperemia and/or fissuring (Fig. 3.18) Asymptomatic
Visible slightly raised or macular lesions (Fig. Itching and burning
3.19 a–c) Dyspareunia
 42 3 Human Papillomavirus and External Genital Lesions

3.4 Differential Diagnosis

3

3.4.1 Benign Penile Pearly Papules

(Hirsutoid Papillomas) (Fig. 3.20)

Asymptomatic.
Usually appear at puberty and are present in 20%
of young adult males without racial predilection.
More commonly found in uncircumcised men.
Flesh-colored or pink papules with rounded tips and
discrete bases.
They are located primarily around the coronal sulcus
and presenting one or more rows around this structure
(“hirsute corona” (Fig. 3.21a, b)), although also found
on the distal penile shaft lateral to the frenulum, or on
the posterior aspect of the glans penis.
Histology shows angiofibroma.
No treatment is required but reassurance given of
benign condition.

3.4.2 Fibroepithelial Polyps (Fig. 3.22)

Asymptomatic.
Occasionally inflammatory symptoms secondary to
local trauma.
Soft, skin-colored, pedunculated lesions resembling
warts.
Fig. 3.21. (a) Large and exuberant pearly papules around coro-
nal sulcus (b) detail of “hirsute corona”

Fig. 3.20. Pearly papules Fig. 3.22. Fibroepithelioma

3.4 Differential Diagnosis 43

No treatment is required but reassurance given of 3.4.4 Sebaceous Glands (Fig. 3.24)
benign condition.
Excision is indicated if lesion is subjected to fre- Asymptomatic
quent trauma. Large, normal sebaceous glands usually located on
the proximal third of the penile shaft, especially on
the ventral surface
3.4.3 Prominent Sebaceous Glands No treatment required
(Ectopic Sebaceous Glands,
Fordyce Spots) (Fig. 3.23)
3.4.5 Seborrheic Keratoses (Fig. 3.25a, b)
Asymptomatic
Asymptomatic.
Small, raised, flesh-colored-to-yellow papules with a
Usually appears in individuals older than 30 years
smooth surface located on the shaft of the penis
of age.
No treatment required
Brown macules, plaques, and papules that may be
confused with warts or even melanoma when hyper-
pigmented (Pierson et al., 2003).
Waxy, “stuck-on” appearance; sometimes lesions may
drop off spontaneously and reappear.
Usually no treatment required but excision or
destruction with liquid nitrogen can be performed
for cosmetic reasons.

3.4.6 Angiokeratoma (Fordyce
Angiokeratoma) (Fig. 3.26a–c)

Asymptomatic.
Small, blue-to-red papules, usually located on the
scrotum, shaft of penis, or lower abdomen; glans can
occasionally be affected.

Fig. 3.24. Sebaceous glands of the penis shaft mimicking mol-

Fig. 3.23. Fordyce spots luscum contagiosum
 44 3 Human Papillomavirus and External Genital Lesions

Fig. 3.25. (a) Seborrheic keratoses mimicking genital warts. (b)

Seborrheic keratoses (histology) (Source: Photograph courtesy
of Filomena Marino Carvalho MD, PhD, São Paulo, Brazil)

Histology shows ectatic thin-walled vessels in the

superficial dermis with overlying epidermal hyper­
plasia.
No treatment required.

3.4.7 Verrucous Epidermal Nevi and

Pigmented Nevi (Fig. 3.27 a–d)

Verrucous epidermal nevi typically occur at birth or Fig. 3.26. (a) Angiokeratoma of the penis shaft. (b) Angiokeratoma
infancy, but in rare occasions lesions develop at of the glans. (c) Angiokeratoma of the scrotum
puberty.
Single or multiple warty papules of any size that
coalesce to form well-defined keratotic plaques usu-
ally in a linear fashion.
Extragenital location is usual but lesions have been Histology shows circumscribed hamartomatous les­
described in the perianal area (Bandyopadhyay and ions composed almost exclusively of keratino­cytes.
Sen, 2003) and penis (Narang and Kanwar, 2006). No treatment required.
3.4 Differential Diagnosis 45

Fig. 3.27. (a) Verrucous epidermal nevus. (Source: Narang and Kanwar (2006). Reproduced with permission from Medknow
Publications). (b) Verrucous nevus in the pubic area. (c) Pigmented nevus mimicking wart. (d) Nevus (histology) (Source: Photograph
courtesy of Filomena Marino Carvalho MD, PhD, São Paulo, Brazil)

3.4.8 Molluscum Contagiosum (Fig. 3.28 a, b) Treatment with lesion destruction is indicated to

reduce transmission.
Increasing prevalence in young adults.
Can be initially confused with folliculitis and Expert Advice
furunculosis.
Asymptomatic or discrete pruritus. Cryptococcosis in HIV/AIDS patients may produce
Firm, flesh-colored, dome-shaped papules with clas- lesions that mimic those of molluscum contagiosum.
sic central umbilication in the majority of cases. Therefore, biopsy is recommended in these patients.
Usually located in the pubic area, penile shaft, proxi-
mal and medial thighs.
A waxy central core (rich in viral particles) is extracted 3.4.9 Lichen Nitidus
when the lesion is incised.
Tzanck smear is a useful diagnostic method. Inflammatory condition (granulomatous nodules).
Spontaneous resolution is frequent. Penis is preferentially affected.
 46 3 Human Papillomavirus and External Genital Lesions

Fig. 3.28. (a) Molluscum contagiosum. (b) Molluscum contagiosum (histology) (Source: Photograph courtesy of Filomena Marino
Carvalho MD, PhD, São Paulo, Brazil)

Fig. 3.29. (a) Syphilitic condylomata lata. (b) Syphilitic condylomata lata in the axilla

Pruritus may be present. Highly infectious

Follicular-like pattern with a regular distribution, Distinguished by darkfield microscopy or serology
shiny papules smaller than 1–2 mm, ­skin-colored to
pink, dome shaped.

3.4.11 Verrucous carcinoma
(Buschke-Löwenstein tumor)
3.4.10 Syphilitic Condylomata Lata
(Fig. 3.29 a, b)
Verrucous carcinoma (giant condylomata or
Buschke-Löwenstein tumor) (Fig. 3.30) is consid-
Characteristic lesions of secondary syphilis
ered a penile neoplastic lesion with a locally inva-
Moist, raised nodules or plaques, often seen in warm,
sive behavior and it is usually associated with
moist areas such as the buttocks, genitals, and upper
high-risk HPV 16.
thighs
3.5 Detection Methods 47

Expert Advice

Male patients and partners presenting with high-risk

type HPV infection should be evaluated with genital
and anal examinations, including high-resolution
anoscopy when:
Perianal lesions are present.
There is a history of unprotected receptive anal
intercourse.
Moreover, female partners should also be tested
with:
Pap smear.
Colposcopy when cervical lesions are present.
High-resolution anoscopy when there is associ-
ated multifocal genital intraepithelial neoplasia.
Fig. 3.30. Verrucous carcinoma (Buschke-Löwenstein tumor)
See also Sect. 8.7 in Chap. 8 and Sect. 7.2.2 in
Chap. 7.

3.4.12 Squamous Intraepithelial
Lesions (SILs)/ Penile
Intraepithelial Neoplasia (PIN)/
Penile Squamous Cell 3.5.1.2 Acetic Acid Solution Test
(Acetowhite Test)
Carcinomas (SCCs)
The acetowhite test is associated with a high number
See Chap. 5, 6. of false-negative and false-positive results (Mansur,
2002). False-positive results are common when coex-
isting inflammatory conditions are present (i.e., can-
didiasis) (Fig. 3.31 a, b).
3.5 Detection Methods The acetowhite test sensitivity for hyperplastic
warts is very high, but for pigmented papules the test
sensitivity is very low.
3.5.1 Clinical Diagnosis Detection of unapparent subclinical HPV-infected
areas using the acetowhite test is not simple (Kumar
3.5.1.1 Physical Examination and Gupta, 2001); however, according to the CDC
treatment guidelines (Workowski and Berman, 2007),
Anogenital warts are primarily diagnosed by their the acetowhite test can be useful for identifying flat
characteristic appearance on clinical examination. genital warts (Fig. 3.32 a, b).
 48 3 Human Papillomavirus and External Genital Lesions

Fig. 3.31. (a) Candidal balanitis. (b) Candidal balanitis (histology). (Source: Photograph courtesy of Filomena Marino Carvalho
MD, PhD, São Paulo, Brazil)

How to Perform the Acetowhite Test

The warts and adjacent normal penile skin/mucosa

(as well as scrotal, perineal, and perianal area) are
wrapped in gauze soaked in 5% acetic acid solution
for about 3–5 min (Fig. 3.33).
The whole area is subsequently examined with a
magnifying hand lens or microscope/colposcope
(between 8× and 40×) (Fig. 3.34 a–c).
Highlighted HPV-related lesions develop a white
color (Fig. 3.35 a–c), which is attributed to an
overexpression of cytokeratin 10 in the HPV-
infected suprabasal cells. These are undifferenti-
ated cells rich in protein content and the whitening
might be caused by protein denaturation.
HPV lesions often exhibit well-demarcated punc-
tuated capillary patterns.
Acetowhite test in inflammatory conditions (i.e.,
Candida infection) usually presents with a more
irregular and diffuse pattern (Fig. 3.31a).

Fig. 3.32. (a) Flat condyloma (after acetowhite test). (b) Flat
lesions after acetowhite test
3.5.2 Laboratory Diagnosis
Expert Advice
Although the acetowhite test is not recommended See also Chap. 2.
for screening purposes, it is useful for:
Visualizing subclinical HPV-related anogenital 3.5.2.1 Cytology
lesions
Identifying lesions for targeted biopsy Bar-Am and Niv (2007) recently recommended that
Demarcating lesions during surgical therapy male sexual partners of females with CIN 3 (severe dys-
(Hadway et al., 2006; Bandieramonte et al., 2008) plasia) undergo peniscopy and cytology (Fig. 3.36 a, b)
of abnormal areas detected on colposcopic exami­
See also Sects. 5.3.1 and 5.6.4.7 in Chap. 5.
nation.
3.5 Detection Methods 49

Fig. 3.33. Penile/scrotal area is wrapped in gauze soaked in 5%

acetic acid solution

3.5.2.2 Histological Techniques

Histological techniques for the detection of HPV infec-

tion in men have low sensitivity and low specificity
(Strand et al., 1996; Krebs and Schneider, 1987).
Pathological findings (Fig. 3.37 a, b):
Papillomatosis
Hyperkeratosis
Acanthosis, associated with elongation and branching
of the rete ridges into the underlying vascular dermis
Large, vacuolated keratinocytes with an eccentric
pyknotic nucleus surrounded by a perinuclear halo
(koilocytes) (Fig. 3.38)

The presence of koilocytes (Fig. 3.39) is a morpho-

logical indication of HPV infection.
Each koilocyte contains approximately 50–100 viri-
ons, and Bryan and Brown (2001) showed that the
desquamation of cornified cells shedding koilocytes
successfully transmitted HPV type 11 infection.
Fig. 3.34. (a) Area is examined with microscope/colposcope.
(b) Video camera is attached to microscope. (c) Examination can
be fully documented
Expert Advice

Flat penile warts reveal acanthosis and hyperk­

eratosis and do not contain parakeratosis or papillo­
matosis; however, these lesions usually exhibit an
abundance of koilocytes.

When to Recommend Lesion Biopsy and Lesions that undergo a sudden growth, ulcerate,
­His­tological Evaluation or are fixed to underlying planes
Long-lasting penile lesion Sudden change in lesion pigmentation
Lesions that are unresponsive to classic medical Atypical lesions in immunocompromised indivi­
treatments duals
 50 3 Human Papillomavirus and External Genital Lesions

Fig. 3.36 (a) Penile brushing cytology. (b) Saline drops increase
cellularity

Detection of antibody response to viral capsid pro-

teins usually produces conflicting results and these
tests are currently used only in research settings.
Antibody responses to HPV may persist for several
years or resolve with the clearance of the infection.
Therefore, there is no current clinical indication for
the use of HPV serology.

3.5.2.5 Molecular Tests

There are no currently accepted recommendations for

HPV DNA testing of specimens obtained from men in
Fig. 3.35. (a) Warty lesions before acetic acid solution applica- clinical settings. Nevertheless, HPV infection in both
tion. (b) Warty lesions develop a white color after solution use. genders can only be accurately confirmed using molec-
(c) Acetowhite test of HPV-related glans lesions ular detection methods for the presence of HPV DNA
in the collected specimens (de Carvalho et al., 2006)
3.5.2.3 Culture (Fig. 3.40a, b).

HPV cannot be efficiently propagated in most culture Expert Advice

systems.
Flores et al. (2008) recently confirmed that male
specimens collected with the swab method (i.e., using
3.5.2.4 Serological Testing
exfoliated skin cells) can be used for molecular HPV
testing, and they concluded that PCR-based HPV
Serological testing for HPV antibodies has relatively
detection is a reliable diagnostic method in men.
low sensitivity (Dillner, 1999; Carter et al., 2000).
3.5 Detection Methods 51

a b

Fig. 3.37. (a) Condyloma acuminatum (Source: Photograph courtesy of Filomena Marino Carvalho MD, PhD, São Paulo, Brazil).
(b) Normal epithelium

Fig. 3.38. Vacuolated keratinocytes exhibiting eccentric nucleus

surrounded by a perinuclear halo (koilocytes) (Source: Photo­ Fig. 3.39. Koilocytes (Source: Photograph courtesy of Monica
graph courtesy of Monica Stiepcich MD, PhD, São Paulo, Stiepcich MD, PhD, São Paulo, Brazil)
Brazil)

Fig. 3.40. (a) Glans brushing HPV DNA-positive (in situ hybridization 10×). (b) Glans brushing HPV DNA-positive (koilocyte) (in
situ hybridization 40×) (Source: Photograph courtesy of Monica Stiepcich MD, PhD, São Paulo, Brazil)
 52 3 Human Papillomavirus and External Genital Lesions

3.6 Treatment
3 Expert Advice

Pictures or schematic representations of HPV-

HPV-related lesions often inflict considerable psycho- associated lesions recorded at each visit are a useful
logical and psychosexual distress and frustration on tool for evaluating treatment response and follow-up.
patients. These negative emotional feelings occur not
only because of the cosmetic problem but mainly
Treatment methods (Table 3.1) are categorized
because of the stigma of the lesions being sexually
according to their mode of action:
transmitted.
Studies show that HPV can persist latently in tissue Antimetabolic therapy (podophyllin, podophyllo-
that appears macroscopically normal (Ferenczy et al., toxin, and 5-fluorouracil (FU))
1985; Macnab et al., 1986). Therefore, because of this Immunomodulation and antiviral therapy (imiqui-
possible association with subclinical infection, every mod, interferons (IFNs), BCG, and polyphenon E)
treatment method for HPV infection is associated with Cytodestructive methods (surgical excision, cryo-
a high rate of recurrence. therapy, laser therapy, trichloroacetic acid)
The primary goal of treatment is to remove symptom-
Recommended therapeutic modalities can also be
atic visible lesions. Although there is no current evidence
classified as:
that treatment of genital warts has a favorable impact on
the incidence of cervical and genital cancer, treatment of
visible lesions may reduce HPV DNA ­tissue persistence Home-Applied Therapy
and infectivity (Workowski and Berman, 2007).
Podophyllotoxin solution or gel
Imiquimod 5% cream
A thorough review of the literature through a data- 5-FU cream
base search of Medline and Lilacs has revealed innu- Polyphenon E
merous controlled studies, historical reviews, and
case reports evaluating distinct treatment modalities
for genital warts and HPV-associated diseases. Physician-Applied Therapy
Reported results varied widely across studies, mainly
because of the use of different analytical methods. Surgical excision and/or electrosurgery
Thus, great effort has been made in this book to Cryotherapy
mostly consider high-quality randomized controlled Carbon dioxide (CO2) laser
trials on which to base clinical decisions. Photodynamic therapy (ALA-PDT)
IFN-a
Bacille Calmette-Guérin (BCG)
Therapy choice is based on lesion: Podophyllin solution
Number Trichloroacetic acid
Size and morphology
Location
Expert Advice
Additional factors that define therapy choice include:
The treatment method should be changed if:
Physician experience
Treatment cost (Table 3.1), efficacy (Table 3.1), con- Improvement is not documented after three
venience, and adverse effects ­physician-administered treatment sessions
Patient choice Already treated lesions reappear throughout the
course of therapy
Factors that might influence response to therapy Patient is not tolerating current treatment
include:
However, no treatment change is required for patients
Patient immunologic status whose original lesions have responded well to treat-
Treatment compliance ment but fresh lesions are occurring at new sites.
Age (de Sanjose et al., 2003)
3.6 Treatment 53

Table 3.1 Treatment methods currently available for external genital warts (see also text) (Adapted from: Kodner and Nasraty
(2004). Reproduced with permission from American Family Physician. Copyright © 2004 American Academy of Family Physicians.
All Rights Reserved)

Treatment Clearance rates (%) Risk of recurrence (%) Cost (U.S. $)/(package)

Podophyllin 17–45a (Stone et al., 1990) 23–65 (Scheinfeld and 385b (Alam and Stiller, 2001)
Lehman, 2006)
Podophyllotoxin 68–88 (Beutner and 16–34 334b (Alam and Stiller, 2001)
Ferenczy, 1997)
5-Fluorouracil (5-FU) 30–95 (Beutner and 0–8 40 (tube 15 g)
Ferenczy, 1997)
Surgical excision/ 61–94c (Wiley et al., 2002) 26–40 (Beutner and 210–415b (Alam and Stiller,
electrofulguration Ferenczy, 1997) 2001)
Cryotherapy 79–88 (Scheinfeld and 25–39d (Beutner and 482b (Fine et al., 2007)
Lehman, 2006) Ferenczy, 1997)
CO2 laser 69–88 (Padilla-Ailhaud, 25–33e 200–535b (Alam and Stiller,
2006) 2001)
Trichloroacetic acid 70–81f (Abdullah et al., 36 264b (Fine et al., 2007)
(TCA) 1993)
5-Aminolaevulinic acid 95–100 (Chen et al., NA NA
photodynamic therapy 2007)
(ALA-PDT)
Aldara (Imiquimod) 51g (Moore et al., 2001) 16h (Vexiau et al., 2005) 153–291b (12–24 sachets)
Interferon 36–53 (Beutner and 21–25 2.744–5.083b (Alam and
Ferenczy, 1997) Stiller, 2001)
Bacille Calmette-Guérin 80i (Metawea et al., 2005) NA 140–160 (per vial)
(BCG)
Veregen/Polyphenon E 50 (Stockfleth et al., 2008) 10.6–11.8 (Gross et al., 2007) 227–250b (15 g)
(sinecatechins 15%
ointment)
Cidofovir 50j (Matteelli et al., 2001) 35.29 (Orlando et al., 2002) NA

a
At 3 months
b
Total estimated costs
c
Within 3–6 weeks
d
Despite multiple sessions
e
After 16 months’ follow-up
f
After six applications
g
16-week therapy
h
At 6 months (low recurrence risk after 3 months)
i
Maximum of six applications
j
Lesion reduction
NA Data not available

3.6.1 Antimitotic Therapy

HPV treatment options in pregnant patients com­
prise: 3.6.1.1 Podophyllin
Surgical excision
Podophyllin resin is derived from the rhizomes of the
Cryotherapy
May apple or Mandrake plant (Podophyllum peltatum
Trichloroacetic acid
Linné), a perennial species of the northern and middle
 54 3 Human Papillomavirus and External Genital Lesions

states of the United States. It is still used as first-line Advantages

3 therapy in developing countries, but some authors
­suggest the drug should be removed from clinical Easily available
treatment protocols because of its low efficacy, high Inexpensive in some geographical areas (at least
toxicity, and a serious mutagenicity profile. when assessed by weight)
Cost per treatment in the U.S. – U.S. $385 (approxi-
mate price of podophyllum resin 25% – U.S. $150
per 30 ml)
Mechanism of Action
Efficacy – Clearance rate of 17–45% at 3 months and
73% at 9 months, according to the comparative analy-
Podophyllin is a cytotoxic agent that arrests mitosis in
sis using podophyllin, cryotherapy, and electrofulgu-
metaphase. The drug promotes local tissue necrosis
ration performed by Stone et al. (1990)
and consequently disrupts viral activity. In 1944, Culp
and Kaplan (1944) were the first to report the use of
topical podophyllin resin for the treatment of HPV- Disadvantages
related anogenital lesions.
Unstandardized preparation
Physician-applied treatment (highly recom­mended)
How to Use Less effective than surgery (Khawaja, 1989; Jensen,
1985), podofilox (Lacey et al., 2003), and cryother-
A thin layer of a 10–25% podophyllin suspension
apy (Stone et al., 1990)
in tincture of benzoin should be applied to each
High recurrence rates – 23–65%, according to a
lesion and allowed to air-dry completely.
recent evidence-based review of medical and surgical
Lesions covered by the prepuce should be
treatments of genital warts performed by Scheinfeld
allowed to dry for several minutes before the pre-
and Lehman (2006)
puce is returned to its usual position.
Mutagenic properties (Petersen and Weismann, 1995)
The treated area should be thoroughly washed
1–4 h after application to avoid local irritation.
Contraindicated in pregnancy
Treatment may be repeated weekly, but if
lesions persist after five weekly sessions, alterna-
tive ­therapy should be considered.
Adverse Effects
Important
Local
Uninvolved skin should be protected with petro-
leum jelly, such as Vaseline, to avoid irritation. Burning sensation
Drug application should not exceed 0.5 ml per Pain
session or an area of warts >10 cm2 per session. Ulceration
No open lesions or wounds should exist in the
affected area. Systemic
Podophyllin can be absorbed systemically and toxicity
increases when it is applied to mucosal surfaces or
Indications areas greater than 110 mm2.
Very rare side effects:
Moist warts with a large surface area and lesions
Bone marrow suppression
with many surface projections
Liver dysfunction
Neurological disturbances – podophyllin hallucina-
tions, psychosis
Podophyllin is not recommended for intraurethral
Gastrointestinal disturbances – nausea, vomiting,
warts.
diarrhea, abdominal pain
3.6 Treatment 55

Combination Therapy
Application to uninvolved skin should be mini-
mized. Treatment should be limited to no more
Podophyllin 25% Used in Combination
than 0.5 g of the gel per day.
with Cryotherapy

Efficacy – 75% of patients required only two weekly Indications

treatments to become wart free, in the recent com- In a recent medical survey, it was elected as the treat-
parative study performed by Sherrard and Riddell ment of choice for multiple small penile lesions
(2007) that evaluated commonly used therapies for (Sonnex and Vrotsou, 2007).
external genital warts
Podofilox is not recommended for anal or urethral
warts.
3.6.1.2 Podophyllotoxin (Podofilox Solution
0.5%; Condylox Gel and Solution 0.5%)
Advantages
Podophyllotoxin is an antimitotic agent derivative of Patient-applied solution and cream.
podophyllin. Purified solution exhibits low clinical toxicity and is
mutagenic free.
Mechanism of Action Can be used as first-line therapy.
Efficacy – More effective than podophyllin; in addi-
Podophyllotoxin, chemically synthesized or purified tion, podophyllotoxin solution is more effective than
from the plant families Coniferae and Berberidaceae podophyllotoxin cream when both are compared
(species of Juniperus and Podophyllum hexandrum), with podophyllin (Lacey et al., 2003).
acts primarily by binding to microtubule subunits and Cost per treatment – Extensive warts: U.S. $334
arresting cell division in mitosis (Wilson et al., 1974). (Alam and Stiller, 2001) (approximate price of
The effect of the drug on HPV may also be related to Podofilox gel 0.5% – U.S. $234 per 3.0 g/tube).
local immunomodulating effects.

Disadvantages
How to Use Highly effective for short-term treatment but does
Podophyllotoxin 0.5% Solution or Gel not provide a long-term cure (Kirby et al., 1990)

The solution and gel should be applied with a cot- Contraindicated during pregnancy
ton swab and with a finger, respectively, and allowed
to air-dry. The involved area should be thoroughly
washed if excessive pain, burning, ­itching, or swell- 3.6.1.3 5-Fluorouracil Cream (Efudex®)
ing occurs.
Podophyllotoxin should be applied to warts 5% Fluorouracil (5-FU) is an antimetabolite agent that
twice daily for three consecutive days, and then has been used topically for HPV-related genital lesions.
discontinued for four consecutive days.
Alternative regimen – applied every other day
for 3 weeks. Mechanism of Action
This 1-week cycle of treatment may be repeated
until warts are no longer visualized or for a maxi- FU, a pyrimidine analog, is a widely used chemothera-
mum of four cycles. peutic agent that belongs to a group of drugs known as
antimetabolites. The drug is incorporated into RNA in
If response to podophyllotoxin is incomplete after
preference to the natural substrate uracil, and it inhibits
four weekly cycles, discontinue treatment and
cell growth and promotes apoptosis by targeting the
consider alternative therapy.
enzyme thymidylate synthetase.
 56 3 Human Papillomavirus and External Genital Lesions

3 How to Use

5-FU Cream
5-FU cream should be applied to the whole penile
surface with clean fingertips and after 1–3 h the
drug should be completely washed off the treated
area. Treatment is repeated 3–5 days a week for
a maximum of 4 weeks.
Hands should be washed immediately after con-
tact with the cream.

Important
The scrotum should be protected from the cream.
In case of contact, the area should be washed with
soap and water.

Indications

5-FU cream is more effective for intraurethral warts

(see Chap. 4).
Alternative option in recalcitrant external lesions.

Advantages

Inexpensive – approximate price U.S. $40/15 g (generic)

Patient-applied therapy (pretreatment orientation is
highly advised to avoid treatment complications)
Efficacy – reported cure rates of 30–95%

Disadvantages

Severe local side effects can occur.

Contraindicated during pregnancy (possible ter­

atogenic risks).

Side Effects

Pain Fig. 3.41. (a) Severe penile ulceration caused by Efurix.

Ulceration (Fig. 3.41 a, b) (b) Ulceration nearly affecting the entire penile circumference
3.6 Treatment 57

3.6.2 Destructive Therapy Widely available and cost effective – Surgical exci-
sion of simple warts: U.S. $210; extensive lesions:
3.6.2.1 Surgical Excision/Electrosurgery U.S. $318; electrofulguration of extensive lesions:
U.S. $415 (Alam and Stiller, 2001).
Surgical excision alone or in combination with elec-
trofulguration may be used in the treatment of genital Disadvantages
warts. The heat that is produced in the tissue at the
point of entry of high-frequency currents leads to the Office procedure for small lesions but larger lesions
destruction of the lesion. need an operating room setting.
Local/regional or general anesthesia required depend-
ing on the size/location of the lesion and the patient’s
Surgical Technique age.
High recurrence rates when method is used against
Simple lesion excision with a scalpel or scissors fol-
flat acetowhite HPV-associated lesions (Wikstrom
lowed by electrocautery of the remaining affected
and von Krogh, 1998).
tissue down to the skin surface, or alternatively,
In a recent randomized study that compared ablation
complete destruction of HPV-related lesions by
alone vs. imiquimod 5% cream and a combination of
means of electrofulguration.
the two treatments, Schofer et al. (2006) found recur-
rences at 6 months in 26.4% of cases treated with
excision and in 6.3% of patients treated with imiqui-
Important mod monotherapy.
Intensive coagulation should be avoided as it can Healing time – around 2 weeks.
result in slow wound healing, bleeding, and scarring. Electrosurgery plume hazards from released viral
organisms (see Sect. 10.4.1.2 in Chap. 10).

Expert Advice
Adverse Effects
Use of a topical anesthetic is recommended. EMLA
cream (a eutectic mixture of lidocaine 2.5% and Postoperative pain
prilocaine 2.5%) applied 30 min before the surgical Scarring
procedure is indicated for patients who do not toler-
ate the pain of the 1% lidocaine injection. Expert Advice

Important Postectomy (circumcision) is not a treatment modal-

ity for extensive preputial warts and should not be
A solution of 1% lidocaine without epinephrine recommended. However, the procedure can be per-
should be used for procedures involving the penis formed, if necessary, after the complete clearance of
and distal urethra. HPV-associated genital lesions (Fig. 3.42).

Indications 3.6.2.2 Cryotherapy

Small isolated warts on the shaft of the penis Cryotherapy involves the application of nitrous oxide
Large exophytic lesions in the anogenital area or liquid nitrogen (−196 °C) to anogenital lesions.

Advantages Mechanism of Action

The method produces immediate results. The freeze-thaw cycle produces dermal and vascular
Efficacy – 61–94% clearance within 3–6 weeks of damage and edema, leading to both epidermal and
treatment, according to Wiley et al. (2002). ­dermal cytolysis.
 58 3 Human Papillomavirus and External Genital Lesions

Disadvantages
3
Office procedure.
Optimal number of freeze – thaw cycles is not
established.
Healing time – usually 1–2 weeks following treat­
ment.
Recurrences – 25–39% despite multiple treatments.

Adverse Effects

Mild discomfort, swelling, and erythema.

Fig. 3.42. Penile condyloma and associated phimosis Preputial lesions, particularly flat genital warts, are
prone to scarring and fibrosis after treatment.
How to Use Pigmentary changes in the short term.

Liquid nitrogen may be applied directly to the lesion

Combination Therapies
with a cotton-tipped swab or sprayed onto
it for about 20 s.
Cryotherapy + Podophyllotoxin
Lesion turns white (frozen) and subsequent thaw
A combination of cryotherapy and podophyllotoxin is
produces cell damage.
the most common first-line treatment for HPV-related
Two freeze-thaw cycles are usually performed.
anogenital lesions in the United Kingdom, regardless
safety margin is included by letting the white border
of site (McClean and Shann, 2005).
extend approximately 1–2 mm beyond the periph-
ery of the lesion.
3.6.2.3 CO2 Laser
Treatment can be repeated every 2–4 weeks, if
necessary. Mechanism of Action

Indications Thermal tissue ablation (vaporization) using focused

infrared light energy (Fig. 3.43a, b).
Smaller, flatter genital lesions on the shaft of the penis
Grouped lesions Laser Technique
Lesions on hair-bearing areas (Scheinfeld and
Lehman, 2006) See also Chap. 10.

Advantages Power Settings

4–10 W in continuous or pulsed mode (promotes

Anesthesia usually not required for small lesions
tissue vaporization with a shallow penetration
(EMLA cream is recommended).
depth).
Cost per successful treatment – approximately U.S.
CO2 laser is coupled to the operating microscope/
$482 (Fine et al., 2007).
colposcope for enhanced visualization (focal dis-
Ease of application.
tance: 250 mm) and lesions are vaporized under
Rapid destructive effect.
direct colposcopic guidance.
Efficacy – clearance rates range from 79 to 88%,
It is important to focus the beam over the lesion
according to the review of Scheinfeld and Lehman
and move the laser beam as quickly as possible.
(2006). Most used method in a recent U.S. survey (cry-
Lesions are vaporized along with a 2–5-mm ­border
otherapy employed in 38% of cases, no ­treatment in
of normal-appearing epithelium (Fig. 3.44 a–d).
21% and podophyllin in 17%) (Newman et al., 2008).
3.6 Treatment 59

Fig. 3.43. (a) CO2 laser vaporization of penile shaft lesions (see laser plume). (b) Final result

Fig. 3.44. (a) Laser excision of penis base lesion. (b) A 2–3-mm security margin around the lesion. (c) Penis shaft lesion. (d) A 2–3- mm
security margin around the lesion
 60 3 Human Papillomavirus and External Genital Lesions

Indications Efficacy – complete clearance of warts was reported

3 in 52% of patients treated with laser and INF-
Primary and recurrent HPV-related anogenital lesions a-2b subcutaneously vs. clearance of 22% among
Extensive and exophytic lesions patients treated with laser and placebo (Petersen
et al., 1991).
Advantages
3.6.2.4 Photodynamic Therapy
Fast and precise treatment modality.
Bloodless surgical field. Photodynamic therapy (PDT) was introduced in the
Safe – water is the endogenous target absorber. 1990s. In this technique, light of a specific wavelength
Efficacy – Padilla-Ailhaud (2006) showed clearance is absorbed by certain photosensitizing molecules that
rates of 69% and 88% after first and ­second CO2 laser are exogenously administered to a target tissue. The
sessions, respectively. Moreover, in a recent study agent commonly used is 5-aminolaevulinic acid
evaluating persistence and recurrence rates of ano- (ALA), a prodrug that is selectively absorbed by tumor
genital condyloma and HPV-related intraepithelial cells and rapidly proliferating cells and that stimulates
neoplasias after CO2 laser treatment, Aynaud et al. porphyrin accumulation in the tissue (Casas and
(2008) reported that after 1.4 laser sessions 83% of Batlle, 2002). Porphyrins will then act as the photo-
patients were in remission at 6 – month follow-up. sensitizing agent.
Promotes rapid healing – usually 2 weeks following
treatment.
Minimal or no scar formation in most cases. Mechanism of Action
Probable elimination of the infective agent.
Following activation by red light, ALA is ­transformed
to protoporphyrin IX (PpIX). This induces the
Disadvantages ­formation of singlet oxygen, which leads to the death
or destruction of the involved cells (Loh et al., 1993).
Cost per treatment - approximately U.S. $200 (single Furthermore, Smetana et al. (1997) demonstrated that
lesions) to U.S. $535 (extensive lesions) (Alam and ALA–PDT could also inactivate viral particles.
Stiller, 2001).
Laser therapy training.
How to Use (Chen et al., 2007)
Day clinic or office procedure under local anesthesia.
Large lesions in female and pediatric patients may 20% ALA solution is prepared by dissolving ALA in
require general anesthesia. sterile saline immediately prior to its application.
CO2 laser plume hazards from released viral organ-
isms (see Sect. 10.4.2.2 in Chap. 10). An absorbent cotton ball is soaked in the solution
Recurrence rates ranged from 25 to 33%, with an and is applied over the lesions and adjacent
average follow-up of 16 months in the study per- healthy skin (5-mm border).
formed by Padilla-Ailhaud (2006). Small amounts of the solution are dropped onto
the surface of the cotton ball every 30 min and,
after a 3-h interval, the lesions are occluded with
Adverse Effects
cling film and thick gauze for light protection.
Light irradiation of the involved area is performed
Postoperative pain
using a cylindrical helium-neon laser fiber.
Scarring less pronounced when compared with
If lesions are not totally eradicated, treatment can
electrofulguration
be repeated once a week for a maximum of 3
weeks.
Combination Therapy

Laser therapy followed by postoperative systemic INF- Indications

a-2b in patients presenting with recalcitrant genital
warts. Lesions in sensitive mucosal tissues (penis and urethra)
3.6 Treatment 61

Advantages INF use for the management of HPV-associated

lesions can be administered:
Efficacy – Chen et al. (2007) have found complete
Intralesionally
response rates of 95 and 100% after one and two ses-
Topically
sions of ALA-PDT treatment, respectively.
Compared with conventional CO2 laser therapy, topi-
cal application of ALA-PDT is more ­effective and
has a lower recurrence rate (Chen et al., 2007). 3.6.3.2 Intralesional Injection of -INF-a
Minimal or absent scarring.
The photosensitizers have fluorescence properties, How to Use
assisting in the pretreatment visualization of the
lesions. Intralesional INF Injection
INF-a-n3 (Alferon N injection; available in 1-ml
vials).
Disadvantages
0.05 ml per lesion administered twice a week for
Physician-applied therapy up to 8 weeks.
Expensive, although probably cost-effective when
INF-a-2b, recombinant (Intron-A; vial of 10 mil-
multiple lesions are treated in one irradiation field
lion IU should be used for HPV lesions).
0.1 ml of reconstituted Intron-A vial is injected
Adverse Effects into each lesion three times a week on alternate
days for 3 weeks.
Mild burning and/or stinging sensation during
irradiation
Advantages

Efficacy – Friedman-Kien et al. (1988) reported com-

3.6.3 Immunotherapy plete clearance of lesions in 62% of INF-a-treated
patients compared to 21% of placebo-treated patients.
3.6.3.1 Interferons (INF-a) Reduced systemic side effects with intralesional
treatment.
IFN-a, the most widely used INF, is a cytokine pro-
duced primarily by leukocytes and it is approved by
the U.S. Food and Drug Administration (FDA) for the Disadvantages
treatment of condyloma acuminata in patients 18 years
of age or older. Physician-applied therapy
High-cost treatment – simple warts: U.S. $2,744;
extensive warts: U.S. $5,803 (Alam and Stiller, 2001)
Mechanism of Action Not recommended for routine clinical practice
Not effective in immunosuppressed individuals
The main functions of IFN-a are immunomodulatory
and antiproliferative, and it also has the ability to
­interfere with viral replication (Isaacs and Lindenmann,
1987). Side Effects

Local
Indications
Painful injections (Trizna et al., 1998)
Recurrent or recalcitrant lesions Hyperemia and edema at the injection site
 62 3 Human Papillomavirus and External Genital Lesions

Systemic
3 How to Use
Influenza-like symptoms (usually clear within 24 h
Imiquimod cream comes in single-use packets. Open
of treatment)
packets with unused cream should be discarded.
Autoimmune reactions
A thin layer of imiquimod 5% cream should be
Cardiovascular symptoms
applied and rubbed to external visible warts at bed-
Depression
time. The area is then washed with soap and water
6–10 h after application. Treatment is executed every
other day three times per week, and the weekly
Combination Treatment
cycles can be repeated until all of the warts disap-
pear, up to a maximum of 16 weeks.
Intralesional INF-a-2b (1.5 × 106 IU) plus topical 25%
podophyllin resin compared to topical podophyllin
resin alone (Douglas et al., 1990) Important

Efficacy – complete clearance of lesions in 67% of Imiquimod may weaken condoms and diaphragms,
patients receiving combination therapy vs. 42% in and sexual contact is not recommended while the
those receiving monotherapy with podophyllin cream is on the skin.
Recurrence rate – 67% in the combination treatment
arm, and 65% in the podophyllin-only arm after 11
Indications
weeks of follow-up
Not suitable for the treatment of long-standing,
fibrotic warts (von Krogh, 2001).
3.6.3.3 Topical INF Ointment Circumcised men have better responses than uncir-
cumcised men (Carrasco et al., 2002).
Topical INF treatment is tolerated much better than the In a recent medical survey, it was elected predomi-
injections, although it is less effective (Syed et al., 1994). nantly for large or bulky lesions (Sonnex and Vrotsou,
2007).

3.6.3.4 Imiquimod 5% Cream (Aldara®)

Advantages
Aldara cream is the first topical FDA-approved immu-
Patient-applied cream.
nomodulator for the treatment of external anogenital
Efficacy – Complete clearance of warts occurred in
warts.
51% of patients within 16 weeks of therapy, according
to the review performed by Moore et al. (2001).
Moreover, in a recent meta-analysis of 5% imiquimod
Mechanism of Action and 0.5% podophyllotoxin, Yan et al. (2006) reported
clinical cure rates of 50.34% with imiquimod and
The topically applied drug imidazoquinoline is an 56.41% with the podophyllotoxin ­treatment, but more
immunomodulator that acts stimulating toll-like recep- serious adverse effects were associated with the latter.
tors (i.e., TLR 7) on antigen-presenting cells, which
enhances the local production of Th1 cytokines and T
cell-mediated cytotoxic immune response. Disadvantages
Imiquimod also showed an antiangiogenic effect
through a possible promotion of INF-g production, an Expensive – Approximate cost U.S. $153,99 (12
effect mediated by IL-18 (Majewski et al., 2005). sachets) and U.S. $291,99 (24 sachets).
3.7 Other Treatment Modalities 63

Average treatment length – 9.5 weeks. in men. However, the exact mechanism of the immune
Recurrence rate – In a recent study, Vexiau et al. response to HPV infection has not been elucidated.
(2005) observed recurrences at 6 months in 16% of
the patients. In addition, the investigators reported How to Use
that most of the recurrences (86.6%) were already
Topical BCG (81 mg/ml suspension containing via-
present at 3 months, suggesting that after this period
ble bacteria of the BCG Connaught strain) applied
the recurrence risk is low.
weekly to the lesions for six consecutive weeks.
Exposure to healthy penile skin should be avoided
Adverse Effects and areas in contact with the BCG mixture should
be washed thoroughly 2 h after treatment.
Local
Mild and transient local inflammatory reaction reported Advantages
in 31% of patients.
Efficacy – Metawea et al. (2005) reported that com-
Hyperemia, swelling, pruritus, bleeding plete response was achieved in 80% of the patients
Blisters, flaking, scaling, dryness, or thickening of after a maximum of six applications.
the skin
Burning, stinging, pain in the treated area
Disadvantages

Systemic High cost (U.S. $140–160 per vial)

Headache Physician-applied therapy
Diarrhea
Back pain Adverse Effects
Fatigue
Fever Transient erythema
Mild fever
Expert Advice
Combination Treatment
If response to imiquimod is less than 50% by 6
weeks of treatment, discontinue use and consider
Laser vaporization and adjuvant BCG
alternative therapy.
Efficacy – the annual recurrence rate in patients with
refractory/recurrent HPV-related genital lesions
Combination Treatment decreased significantly after BCG therapy, accord-
ing to Bohle et al. (1998).
Imiquimod use following laser treatment:
Effective in reducing recurrences (Hoyme et al., 2002).
Cream should only be applied when wound healing
3.7 Other Treatment Modalities
is completed.

3.7.1 Chemical Destruction

3.6.3.5 Bacille Calmette-Guérin
3.7.1.1 Trichloroacetic Acid
Application of viable bacille Calmette-Guérin (BCG)
induces a cytotoxic immune response against malig- Trichloroacetic acid (TCA) produces protein coagula-
nant and virally transformed cells, and may also tion, leading to cell lysis and destruction of the affected
increase the immunological ability to eliminate HPV tissue.
 64 3 Human Papillomavirus and External Genital Lesions

Adverse Effects
3 How to Use
TCA in a Solution Concentration of 60–90% Burning sensation following TCA application that
Lidocaine gel (and not EMLA, to avoid mucosal may last for up to 10 min
edema) is initially spread over the involved area. A Pain
small amount of TCA is then applied to each lesion Ulceration
with a cotton tip applicator and is allowed to dry Crust formation
until a white frosting develops.
Usual regimen – once a week for four consecu-
tive weeks. 3.7.2 Novel Therapies
The dry end of the cotton tip can be used to remove
the destroyed tissue. 3.7.2.1 Cidofovir
Application to uninvolved skin should be mini-
mized, but if it occurs the area should be washed Cidofovir is a nucleotide analog of deoxycytidine
with liquid soap or a neutralizing agent should be monophosphate (dCMP), which is converted to the
used (talcum powder or sodium bicarbonate). active cidofovir diphosphate that inhibits viral DNA
polymerases (Ho et al., 1992). Cidofovir is an antiviral
Indications agent currently FDA approved for the treatment of
cytomegalovirus (CMV) retinitis in HIV patients, but
Particularly effective for treating small, moist, acum- the topical formulation has been effective in treating
inate or papular lesions. refractory HPV-related anogenital lesions (Hengge
Recommended for post-treatment control of small and Tietze, 2000; Schurmann et al., 2000).
papular warts (Fig. 3.45 a–d).
Less efficacious for keratinized or large lesion.
In the medical survey performed by Sonnex and How to Use
Vrotsou (2007), TCA was infrequently chosen as a
treatment option (<6% of respondents). Cidofovir 1.5% gel and 1% cidofovir cream is topi-
cally applied to the lesions once daily, and repeated
Advantages 3–5 days a week for 2 weeks followed by 2 weeks
of observation.
Easily available.
Efficacy – In a comparative study that evaluated cry-
otherapy (liquid nitrogen) and TCA, Abdullah et al. Indications
(1993) reported clearance rates of 70–81% after six
applications. Recurring or recalcitrant anogenital warts, particu-
larly in HIV-infected patients

Disadvantages
Advantages
Physician-applied therapy
Recurrence rates of 36% Patient-applied therapy.
Longer time to wart clearance and increased lesion Efficacy – Recent data reported by Matteelli et al.
persistence when used as single therapy (Sherrard (2001) showed a reduction of more than 50% of
and Riddell, 2007) lesions in 58% of HIV-infected patients.
Cost per successful treatment –approximately U.S. Recurrence – 35.29% in the study performed by
$264 (Fine et al., 2007) Orlando et al. (2002) using topical 1% cidofovir gel.
3.7 Other Treatment Modalities 65

Fig. 3.45 (a) Small wart 6 weeks after laser treatment. (b) Tiny amount of TCA is applied with a cotton tip. (c) Lesion is destroyed —
immediate result. (d) Visual aspect 1 day after TCA use

Disadvantages No systemic side effects.

Expensive
Not FDA approved for this indication Combination Treatment
Unstandardized preparation
Cidofovir vs. electrocautery excision vs. combination of
both treatments:
Adverse Effects Efficacy – complete resolution observed in 100% of
HIV-infected patients treated with combination ther-
Local mucosal erosion is a common and sometimes apy (Orlando et al., 2002)
severe event. Recurrence – 27% with electrocautery-cidofovir com-
Pain. bination treatment
 66 3 Human Papillomavirus and External Genital Lesions

3.7.2.2 Veregen™ (Sinecatechins 15% Efficacy – Stockfleth et al. (2008) showed clearance

3 Ointment) rates of 50% or higher in 78% of patients enrolled in
the randomized controlled trial that evaluated topical
Veregen was originally developed under the name of Polyphenon E efficacy on external genital and peria-
Polyphenon E ointment.1 nal warts.
Sinecatechins 15% ointment is a proprietary extract Better responses reported in women (complete wart
of green tea (Camellia sinensis) leaves, and green tea clearance in 60% of women vs. 45% of men)
catechins have demonstrated antiviral, antioxidative, (Stockfleth et al., 2008).
antiproliferative, and immunostimulatory activity.

Mechanism of Action Disadvantages

The exact mechanism of action of sinecatechins oint- Recurrence rates – 10.6% and 11.8% for Polyphenon
ment is unknown, although epigallocatechin gallate E 15% or 10% cream, respectively, 12 weeks after
(a major component of both green tea and sinecate- end of treatment, according to Gross et al. (2007)
chins ointment) has been shown to suppress the growth Expensive – approximate monthly cost: US $227–250/
of HPV-infected cervical cancer cell lines (Ahn et al., 15 g tube (based on 2008 average wholesale price)
2003).

How to Use Adverse Effects

Veregen 15% ointment is applied to all warts three Mild or moderate local site reactions, with a reported
times daily up to a maximum of 16 weeks. decline during continued use

Important

Sinecatechins may weaken condoms and dia- 3.8 Management of Latent and

phragms, and sexual contact is not recommended Subclinical HPV Infection
while the cream is on the skin.

Expert Advice
Indications
Management of Latent and Subclinical HPV Infection
Veregen is FDA approved for the topical treatment
Asymptomatic Patients
of external genital and perianal warts.
Observation alone is recommended, mainly because
Further clinical studies are recommended to evalu- currently there are no treatments available that can
ate use of sinecatechins in intra-anal, intravaginal, completely eliminate HPV from infected cells.
and cervical condylomas, as well as other intraepi-
Symptomatic Patients with Predominance of
thelial lesions.
Balanoposthitis Symptoms
Short treatment course of a systemic and/or topi-
Advantages
cal antifungal therapy.
Short course of a topical cicatrizant and/or antibi-
Safe.
otic ointment application.
Patient-applied therapy.
Symptomatic Patients with Predominance of Flat
Visible Lesions
Approval of the drug in Europe under the name of Polyphenon®
1
Should be managed by the same treatment meth-
E ointment is expected from the second half of 2008 (MediGene ods used for external lesions.
AG, http://www.medigene.com/englisch/ProjektPE.php).
References 67

3.9 Circumcision and HPV Delay the onset of sexual activity.

Reduce the number of sex partners (Kjaer et al.,
2005).
The studies assessing HPV infection risk and circum- Promote condom use on a regular basis – Condoms
cision status yield conflicting results (Shin et al., 2004; may not provide complete protection against HPV
Castellsague et al., 2002). transmission, yet Bleeker et al. (2003) reported that
However, recent data from a randomized controlled condom use promoted regression of HPV-related flat
trial that evaluated male circumcision for the preven- penile lesions in male sexual partners of women with
tion of HIV and other sexually transmitted infections CIN.
in Africa showed a significantly reduced prevalence of Circumcision – according to Tobian et al. (2009), the
high- and low-risk HPV genotypes among the circum- procedure can significantly reduce the incidence of
cised group of men (Tobian et al., 2009). several STIs and confer partial protection against
Moreover, in another recent study Hernandez et al. HPV infection.
(2008a) showed that uncircumcised men have an Immunization with prophylactic HPV vaccines.
increased risk of HPV infection, including with onco-
genic (high risk) as well as multiple HPV types.
The prevalence of any HPV infection in the glans/ According to a recent phase-III study that evaluated
corona was significantly higher in uncircumcised men, the efficacy of the prophylactic quadrivalent HPV
possibly due to the close contact with the foreskin, a vaccine in preventing HPV-related lesions in men
putative vulnerable site for HPV infection. naïve to all four vaccine HPV types (6, 11, 16, and
18), Gardasil was 89.4% effective in preventing
external anogenital warts (Giuliano and Palefsky,
2008). Efficacy against individual vaccine HPV
3.10 Follow-Up types 6 and 11 (usually responsible for the develop-
ment of genital warts) was 84.3 and 90.9%, respec-
tively, and against high-risk types 16 and 18 it was
Follow-up evaluation 3 months after topical therapies 100%. Furthermore, persistent viral infection and
is indicated, since external genital wart recur most fre- HPV DNA detection rates were reduced in 85.6%
quently during this period and can be difficult to iden- and in 44.7% of the vaccinated individuals, respec-
tify. Earlier follow-up visits may be beneficial in tively (Palefsky and Giuliano, 2008) (see Sect. 11.8
relapsing and immunosuppressed patients. in Chap. 11).
Following surgical treatments, patients return on
postoperative day 12 for monitoring of the cicatriza-
tion, treatment of possible complications, and check- References
ing for any early signs of recurrence (Workowski and
Berman, 2007). Subsequently, follow-up evaluation Abdullah AN, Walzman M, Wade A (1993) Treatment of exter-
3–4 weeks after the end of treatment is recommended, nal genital warts comparing cryotherapy (liquid nitrogen)
and then every 2–3 months for half a year if control and trichloroacetic acid. Sex Transm Dis 20: 344–345
Ahn WS, Huh SW, Bae SM, Lee IP, Lee JM, Namkoong SE,
examinations yield negative results. Kim CK, Sin JI (2003) A major constituent of green tea,
Patients should be oriented to self-refer if lesions EGCG, inhibits the growth of a human cervical cancer cell
reappear. line, CaSki cells, through apoptosis, G(1) arrest, and regula-
tion of gene expression. DNA Cell Biol 22: 217–224
Alam M, Stiller M (2001) Direct medical costs for surgical and
medical treatment of condylomata acuminata. Arch Dermatol
3.11 Prevention 137: 337–341
Aynaud O, Buffet M, Roman P, Plantier F, Dupin N (2008) Study
of persistence and recurrence rates in 106 patients with con-
dyloma and intraepithelial neoplasia after CO2 laser treat-
Strategies should be aimed at reducing the risk of ment. Eur J Dermatol 18: 153–158
acquiring HPV infection. Baken LA, Koutsky LA, Kuypers J, Kosorok MR, Lee SK, Kiviat
NB, Holmes KK (1995) Genital human papillomavirus infec-
Abstinence from sexual activity, including skin-to- tion among male and female sex partners: prevalence and
skin contact – the most reliable prevention method. type-specific concordance. J Infect Dis 171: 429–432
 68 3 Human Papillomavirus and External Genital Lesions

Baldwin SB, Wallace DR, Papenfuss MR, Abrahamsen M, Buechner SA (2002) Common skin disorders of the penis. BJU
3 Vaught LC, Kornegay JR, Hallum JA, Redmond SA, Int 90: 498–506
Giuliano AR (2003) Human papillomavirus infection in men Carrasco D, van der Straten M, Tyring SK (2002) Treatment of
attending a sexually transmitted disease clinic. J Infect Dis anogenital warts with imiquimod 5% cream followed by sur-
187: 1064–1070 gical excision of residual lesions. J Am Acad Dermatol 47:
Bandieramonte G, Colecchia M, Mariani L, Lo Vullo S, S212–S216
Pizzocaro G, Piva L, Nicolai N, Salvioni R, Lezzi V, Stefanon Carter JJ, Koutsky LA, Hughes JP, Lee SK, Kuypers J, Kiviat N,
B, De Palo G (2008) Peniscopically controlled CO2 laser Galloway DA (2000) Comparison of human papillomavirus
excision for conservative treatment of in situ and T1 penile types 16, 18, and 6 capsid antibody responses following
carcinoma: report on 224 patients. Eur Urol 54: 875–882 incident infection. J Infect Dis 181: 1911–1919
Bandyopadhyay D, Sen S (2003) Perianal verrucous epidermal Casas A, Batlle A (2002) Rational design of 5-aminolevulinic
naevus mimicking perianal warts. Sex Transm Infect 79: 424 acid derivatives aimed at improving photodynamic therapy.
Bar-Am A, Niv J (2007) The role of HPV DNA in the evaluation Curr Med Chem Anticancer Agents 2: 465–475
and follow-up of asymptomatic male sexual partners of Castellsague X, Bosch FX, Munoz N, Meijer CJ, Shah KV, de
females with CIN3. Eur J Gynaecol Oncol 28: 207–210 Sanjose S, Eluf-Neto J, Ngelangel CA, Chichareon S, Smith
Barrasso R, Gross GE (1997) External genitalia: diagnosis. In: JS, Herrero R, Moreno V, Franceschi S (2002) Male cir-
Gross GE, Barrasso R (eds) Human papillomavirus infec- cumcision, penile human papillomavirus infection, and cer-
tion, a clinical atlas. Ullstein Mosby, Berlin, pp 296–331 vical cancer in female partners. N Engl J Med 346:
Beutner KR, Ferenczy A (1997) Therapeutic approaches to geni- 1105–1112
tal warts. Am J Med 102: 28–37 Chen K, Chang BZ, Ju M, Zhang XH, Gu H (2007) Comparative
Bleeker MC, Hogewoning CJ, Berkhof J, Voorhorst FJ, Hesselink study of photodynamic therapy vs. CO2 laser vaporization in
AT, van Diemen PM, van den Brule AJ, Snijders PJ, Meijer treatment of condylomata acuminata: a randomized clinical
CJ (2005a) Concordance of specific human papillomavirus trial. Br J Dermatol 156: 516–520
types in sex partners is more prevalent than would be Coleman N, Birley HD, Renton AM, Hanna NF, Ryait BK,
expected by chance and is associated with increased viral Byrne M, Taylor-Robinson D, Stanley MA (1994)
loads. Clin Infect Dis 41: 612–620 Immunological events in regressing genital warts. Am J Clin
Bleeker MC, Hogewoning CJ, Voorhorst FJ, van den Brule AJ, Pathol 102: 768–774
Berkhof J, Hesselink AT, Lettink M, Starink TM, Stoof TJ, Cook LS, Koutsky LA, Holmes KK (1993) Clinical presentation
Snijders PJ, Meijer CJ (2005b) HPV-associated flat penile of genital warts among circumcised and uncircumcised het-
lesions in men of a non-STD hospital population: less fre- erosexual men attending an urban STD clinic. Genitourin
quent and smaller in size than in male sexual partners of Med 69: 262–264
women with CIN. Int J Cancer 113: 36–41 Culp OS, Kaplan IW (1944) Condylomata acuminata: Two hun-
Bleeker MC, Hogewoning CJ, Voorhorst FJ, van den Brule AJ, dred cases treated with podophyllin. Ann Surg 120:
Snijders PJ, Starink TM, Berkhof J, Meijer CJ (2003) 251–256
Condom use promotes regression of human papillomavirus- de Carvalho JJ, Syrjanen KJ, Jacobino M, Rosa NT, Carvalho
associated penile lesions in male sexual partners of women LZ (2006) Prevalence of genital human papillomavirus
with cervical intraepithelial neoplasia. Int J Cancer 107: infections established using different diagnostic techniques
804–810 among males attending a urological clinic. Scand J Urol
Bleeker MC, Snijders PF, Voorhorst FJ, Meijer CJ (2006) Flat Nephrol 40: 138–143
penile lesions: the infectious “invisible” link in the transmis- de Sanjose S, Bosch FX, Tafur LA, Nascimento CM, Izarzugaza
sion of human papillomavirus. Int J Cancer 119: I, Izquierdo A, Barricarte A, Shah KV, Meijer CJ, Munoz N
2505–2512 (2003) Clearance of HPV infection in middle aged men and
Bohle A, Doehn C, Kausch I, Jocham D (1998) Treatment of women after 9 years’ follow up. Sex Transm Infect 79: 348
recurrent penile condylomata acuminata with external appli- Dillner J (1999) The serological response to papillomaviruses.
cation and intraurethral instillation of bacillus calmette- Semin Cancer Biol 9: 423–430
guerin. J Urol 160: 394–396 Doorbar J, Sterling JC (2001) The biology of human papilloma-
Boxman IL, Hogewoning A, Mulder LH, Bouwes Bavinck JN, viruses. In: Sterling JC, Tyring SK (eds) Human papilloma-
ter Schegget J (1999) Detection of human papillomavirus viruses: Clinical and scientific advances. Arnold, London,
types 6 and 11 in pubic and perianal hair from patients with pp 10–23
genital warts. J Clin Microbiol 37: 2270–2273 Douglas JM, Jr., Eron LJ, Judson FN, Rogers M, Alder MB,
Brown DR, Schroeder JM, Bryan JT, Stoler MH, Fife KH Taylor E, Tanner D, Peets E (1990) A randomized trial of
(1999a) Detection of multiple human papillomavirus types combination therapy with intralesional interferon alpha 2b
in Condylomata acuminata lesions from otherwise healthy and podophyllin versus podophyllin alone for the therapy of
and immunosuppressed patients. J Clin Microbiol 37: anogenital warts. J Infect Dis 162: 52–59
3316–3322 Ferenczy A, Mitao M, Nagai N, Silverstein SJ, Crum CP (1985)
Brown TJ, Yen-Moore A, Tyring SK (1999b) An overview of Latent papillomavirus and recurring genital warts. N Engl
sexually transmitted diseases. Part II. J Am Acad Dermatol J Med 313: 784–788
41: 661–677; quiz 678–680 Fine P, Ball C, Pelta M, McIntyre C, Momtaz M, Morfesis J,
Bryan JT, Brown DR (2001) Transmission of human papilloma- Cullins V, Rash RM (2007) Treatment of external genital
virus type 11 infection by desquamated cornified cells. warts at Planned Parenthood Federation of America centers.
Virology 281: 35–42 J Reprod Med 52: 1090–1096
References 69

Fleischer AB, Jr., Parrish CA, Glenn R, Feldman SR (2001) and human papillomavirus infection in men: a site-specific
Condylomata acuminata (genital warts): Patient demograph- comparison. J Infect Dis 197: 787–794
ics and treating physicians. Sex Transm Dis 28: 643–647 Hernandez BY, Wilkens LR, Zhu X, Thompson P, McDuffie K,
Flores R, Abalos AT, Nielson CM, Abrahamsen M, Harris RB, Shvetsov YB, Kamemoto LE, Killeen J, Ning L, Goodman
Giuliano AR (2008) Reliability of sample collection and MT (2008b) Transmission of human papillomavirus in het-
laboratory testing for HPV detection in men. J Virol Methods erosexual couples. Emerg Infect Dis 14: 888–894
149: 136–143 Hippelainen M, Syrjanen S, Koskela H, Pulkkinen J, Saarikoski
Franceschi S, Castellsague X, Dal Maso L, Smith JS, Plummer S, Syrjanen K (1993) Prevalence and risk factors of genital
M, Ngelangel C, Chichareon S, Eluf-Neto J, Shah KV, human papillomavirus (HPV) infections in healthy males: a
Snijders PJ, Meijer CJ, Bosch FX, Munoz N (2002) study on Finnish conscripts. Sex Transm Dis 20: 321–328
Prevalence and determinants of human papillomavirus geni- Ho HT, Woods KL, Bronson JJ, De Boeck H, Martin JC,
tal infection in men. Br J Cancer 86: 705–711 Hitchcock MJ (1992) Intracellular metabolism of the anti-
Franco EL (1996) Epidemiology of anogential warts and cancer. herpes agent (S)-1-[3-hydroxy-2-(phosphonylmethoxy)pro-
In: Reid R, Lorincz A (eds) Human papillomaviruses I. W.B. pyl]cytosine. Mol Pharmacol 41: 197–202
Saunders, Philadelphia, pp 597–623 Hoyme UB, Hagedorn M, Schindler AE, Schneede P, Hopfenmuller
Friedman-Kien AE, Eron LJ, Conant M, Growdon W, Badiak H, W, Schorn K, Eul A (2002) Effect of adjuvant imiquimod 5%
Bradstreet PW, Fedorczyk D, Trout JR, Plasse TF (1988) cream on sustained clearance of anogenital warts following
Natural interferon alfa for treatment of condylomata acumi- laser treatment. Infect Dis Obstet Gynecol 10: 79–88
nata. JAMA 259: 533–538 Insinga RP, Dasbach EJ, Myers ER (2003) The health and eco-
Gillison ML, Shah KV (2003) Chapter 9: Role of mucosal nomic burden of genital warts in a set of private health plans
human papillomavirus in nongenital cancers. J Natl Cancer in the United States. Clin Infect Dis 36: 1397–1403
Inst Monogr: 57–65 Isaacs A, Lindenmann J (1987) Virus interference. I. The inter-
Giovannelli L, Bellavia C, Capra G, Migliore MC, Caleca M, feron. By A. Isaacs and J. Lindenmann, 1957. J Interferon
Giglio M, Perino A, Matranga D, Ammatuna P (2007) HPV Res 7: 429–438
group- and type-specific concordance in HPV infected sex- Jensen SL (1985) Comparison of podophyllin application with
ual couples. J Med Virol 79: 1882–1888 simple surgical excision in clearance and recurrence of peri-
Giuliano A, Palefsky J (2008) The efficacy of quadrivalent HPV anal condylomata acuminata. Lancet 2: 1146–1148
(types 6/11/16/18) vaccine in reducing the incidence of HPV Kataoka A, Claesson U, Hansson BG, Eriksson M, Lindh E
infection and HPV-related genital disease in young men In: (1991) Human papillomavirus infection of the male diag-
European Research Organization on Genital Infection and nosed by Southern-blot hybridization and polymerase chain
Neoplasia – EUROGIN Nice, France reaction: Comparison between urethra samples and penile
Giuliano AR, Nielson CM, Flores R, Dunne EF, Abrahamsen M, biopsy samples. J Med Virol 33: 159–164
Papenfuss MR, Markowitz LE, Smith D, Harris RB (2007) Khawaja HT (1989) Podophyllin versus scissor excision in the
The optimal anatomic sites for sampling heterosexual men treatment of perianal condylomata acuminata: a prospective
for human papillomavirus (HPV) detection: The HPV detec- study. Br J Surg 76: 1067–1068
tion in men study. J Infect Dis 196: 1146–1152 Kirby P, Dunne A, King DH, Corey L (1990) Double-blind ran-
Goncalves MA, Donadi EA (2004) Immune cellular response to domized clinical trial of self-administered podofilox solu-
HPV: Current concepts. Braz J Infect Dis 8: 1–9 tion versus vehicle in the treatment of genital warts. Am
Greer CE, Wheeler CM, Ladner MB, Beutner K, Coyne MY, J Med 88: 465–469
Liang H, Langenberg A, Yen TS, Ralston R (1995) Human Kjaer SK, Munk C, Winther JF, Jorgensen HO, Meijer CJ, van
papillomavirus (HPV) type distribution and serological den Brule AJ (2005) Acquisition and persistence of human
response to HPV type 6 virus-like particles in patients with papillomavirus infection in younger men: a prospective fol-
genital warts. J Clin Microbiol 33: 2058–2063 low-up study among Danish soldiers. Cancer Epidemiol
Gross G, Meyer KG, Pres H, Thielert C, Tawfik H, Mescheder A Biomarkers Prev 14: 1528–1533
(2007) A randomized, double-blind, four-arm parallel- Koshiol JE, Laurent SA, Pimenta JM (2004) Rate and predictors
group, placebo-controlled Phase II/III study to investigate of new genital warts claims and genital warts-related health-
the clinical efficacy of two galenic formulations of care utilization among privately insured patients in the
Polyphenon E in the treatment of external genital warts. United States. Sex Transm Dis 31: 748–752
J Eur Acad Dermatol Venereol 21: 1404–1412 Krebs HB, Schneider V (1987) Human papillomavirus-­associated
Hadjivassiliou M, Stefanaki C, Nicolaidou E, Bethimoutis G, lesions of the penis: colposcopy, cytology, and histology.
Anyfantakis V, Caroni C, Katsambas A (2007) Human pap- Obstet Gynecol 70: 299–304
illomavirus assay in genital warts-correlation with symp- Kumar B, Gupta S (2001) The acetowhite test in genital human
toms. Int J STD AIDS 18: 329–334 papillomavirus infection in men: what does it add? J Eur
Hadway P, Corbishley CM, Watkin NA (2006) Total glans resur- Acad Dermatol Venereol 15: 27–29
facing for premalignant lesions of the penis: initial outcome Lacey CJ, Goodall RL, Tennvall GR, Maw R, Kinghorn GR,
data. BJU Int 98: 532–536 Fisk PG, Barton S, Byren I (2003) Randomised controlled
Hengge UR, Tietze G (2000) Successful treatment of recalci- trial and economic evaluation of podophyllotoxin solution,
trant condyloma with topical cidofovir. Sex Transm Infect podophyllotoxin cream, and podophyllin in the treatment of
76: 143 genital warts. Sex Transm Infect 79: 270–275
Hernandez BY, Wilkens LR, Zhu X, McDuffie K, Thompson P, Lajous M, Mueller N, Cruz-Valdez A, Aguilar LV, Franceschi S,
Shvetsov YB, Ning L, Goodman MT (2008a) Circumcision Hernandez-Avila M, Lazcano-Ponce E (2005) Determinants
 70 3 Human Papillomavirus and External Genital Lesions

of prevalence, acquisition, and persistence of human papil- Orlando G, Fasolo MM, Beretta R, Merli S, Cargnel A (2002)
3 lomavirus in healthy Mexican military men. Cancer Combined surgery and cidofovir is an effective treatment for
Epidemiol Biomarkers Prev 14: 1710–1716 genital warts in HIV-infected patients. AIDS 16: 447–450
Lazcano-Ponce E, Herrero R, Munoz N, Hernandez-Avila M, Padilla-Ailhaud A (2006) Carbon dioxide laser vaporization of
Salmeron J, Leyva A, Meijer CJ, Walboomers JM (2001) condyloma acuminata. J Low Genit Tract Dis 10: 238–241
High prevalence of human papillomavirus infection in Palefsky J, Giuliano A (2008) Efficacy of the quadrivalent HPV
Mexican males: comparative study of penile-urethral swabs vaccine against HPV 6/11/16/18-related genital infection in
and urine samples. Sex Transm Dis 28: 277–280 young men In: European Research Organization on Genital
Li HX, Zhu WY, Xia MY (1995) Detection with the polymerase Infection and Neoplasia – EUROGIN, Nice, France
chain reaction of human papillomavirus DNA in ­condylomata Pao CC, Tsai PL, Chang YL, Hsieh TT, Jin JY (1993) Possible
acuminata treated with CO2 laser and microwave. Int J non-sexual transmission of genital human papillomavirus
Dermatol 34: 209–211 infections in young women. Eur J Clin Microbiol Infect Dis
Loh CS, MacRobert AJ, Bedwell J, Regula J, Krasner N, Bown 12: 221–222
SG (1993) Oral versus intravenous administration of 5-amin- Partridge JM, Koutsky LA (2006) Genital human papillomavi-
olaevulinic acid for photodynamic therapy. Br J Cancer 68: rus infection in men. Lancet Infect Dis 6: 21–31
41–51 Persson G, Andersson K, Krantz I (1996) Symptomatic genital
Macnab JC, Walkinshaw SA, Cordiner JW, Clements JB (1986) papillomavirus infection in a community. Incidence and
Human papillomavirus in clinically and histologically nor- clinical picture. Acta Obstet Gynecol Scand 75: 287–290
mal tissue of patients with genital cancer. N Engl J Med 315: Petersen CS, Bjerring P, Larsen J, Blaakaer J, Hagdrup H, From
1052–1058 E, Obergaard L (1991) Systemic interferon alpha-2b
Majewski S, Marczak M, Mlynarczyk B, Benninghoff B, increases the cure rate in laser treated patients with multiple
Jablonska S (2005) Imiquimod is a strong inhibitor of tumor persistent genital warts: a placebo-controlled study.
cell-induced angiogenesis. Int J Dermatol 44: 14–19 Genitourin Med 67: 99–102
Mansur CP (2002) Human papillomaviruses. In: Tyring SK, Petersen CS, Weismann K (1995) Quercetin and kaempherol: an
Yen-Moore A (eds) Mucocutaneous manifestations of viral argument against the use of podophyllin? Genitourin Med
diseases. Marcel Dekker, New York, pp 247–294 71: 92–93
Mao C, Hughes JP, Kiviat N, Kuypers J, Lee SK, Adam DE, Pierson D, Bandel C, Ehrig T, Cockerell CJ (2003) Benign epi-
Koutsky LA (2003) Clinical findings among young women thelial tumors and proliferations. In: Bolognia JL, Jorizzo
with genital human papillomavirus infection. Am J Obstet JL, Rapini RP (eds) Dermatology. Mosby, Edinburgh, pp
Gynecol 188: 677–684 1697–1720
Matteelli A, Beltrame A, Graifemberghi S, Forleo MA, Gulletta Scheinfeld N, Lehman DS (2006) An evidence-based review of
M, Ciravolo G, Tedoldi S, Casalini C, Carosi G (2001) medical and surgical treatments of genital warts. Dermatol
Efficacy and tolerability of topical 1% cidofovir cream for Online J 12: 5
the treatment of external anogenital warts in HIV-infected Schofer H, Van Ophoven A, Henke U, Lenz T, Eul A (2006)
persons. Sex Transm Dis 28: 343–346 Randomized, comparative trial on the sustained efficacy of
McClean H, Shann S (2005) A cross-sectional survey of treat- topical imiquimod 5% cream versus conventional ablative
ment choices for anogenital warts. Int J STD AIDS 16: methods in external anogenital warts. Eur J Dermatol 16:
212–216 642–648
Metawea B, El-Nashar AR, Kamel I, Kassem W, Shamloul R Schurmann D, Bergmann F, Temmesfeld-Wollbruck B, Grobusch
(2005) Application of viable bacille calmette-guerin topically MP, Suttorp N (2000) Topical cidofovir is effective in treat-
as a potential therapeutic modality in condylomata acumi- ing extensive penile condylomata acuminata. AIDS 14:
nata: A placebo-controlled study. Urology 65: 247–250 1075–1076
Moore RA, Edwards JE, Hopwood J, Hicks D (2001) Imiquimod Sherrard J, Riddell L (2007) Comparison of the effectiveness of
for the treatment of genital warts: a quantitative systematic commonly used clinic-based treatments for external genital
review. BMC Infect Dis 1: 3 warts. Int J STD AIDS 18: 365–368
Narang T, Kanwar A (2006) Verrucous epidermal naevus on Shin HR, Franceschi S, Vaccarella S, Roh JW, Ju YH, Oh JK,
penis. In: Indian J Dermatol vol 51, pp 222–223 Kong HJ, Rha SH, Jung SI, Kim JI, Jung KY, van Doorn LJ,
Newman L, Datta D, Ahrens K, Bissette J, Kerani R, Klinger E, Quint W (2004) Prevalence and determinants of genital
Kohn R, Rietmeijer K, Weinstock H (2008) Monitoring gen- infection with papillomavirus, in female and male university
ital wart disease in STD clinics through the STD Surveillance students in Busan, South Korea. J Infect Dis 190: 468–476
Network (SSuN). In: National STD Prevention Conference, Smetana Z, Malik Z, Orenstein A, Mendelson E, Ben-Hur E
Illinois, Chicago (1997) Treatment of viral infections with 5-aminolevulinic
Nicolau SM, Camargo CG, Stavale JN, Castelo A, Dores GB, acid and light. Lasers Surg Med 21: 351–358
Lorincz A, de Lima GR (2005) Human papillomavirus DNA Smith JS, Moses S, Hudgens MG, Agot K, Franceschi S,
detection in male sexual partners of women with genital Maclean IW, Ndinya-Achola JO, Parker CB, Pugh N, Meijer
human papillomavirus infection. Urology 65: 251–255 CJ, Snijders PJ, Bailey RC (2007) Human papillomavirus
Nielson CM, Flores R, Harris RB, Abrahamsen M, Papenfuss detection by penile site in young men from Kenya. Sex
MR, Dunne EF, Markowitz LE, Giuliano AR (2007) Human Transm Dis 34: 928–934
papillomavirus prevalence and type distribution in male ano- Sonnex C, Strauss S, Gray JJ (1999) Detection of human papil-
genital sites and semen. Cancer Epidemiol Biomarkers Prev lomavirus DNA on the fingers of patients with genital warts.
16: 1107–1114 Sex Transm Infect 75: 317–319
References 71

Sonnex C, Vrotsou K (2007) Treatment of ano-genital warts: the Van Doornum GJ, Prins M, Juffermans LH, Hooykaas C, van
effect of an educational event on practitioner choice. Int den Hoek JA, Coutinho RA, Quint WG (1994) Regional dis-
J STD AIDS 18: 531–537 tribution and incidence of human papillomavirus infections
Stockfleth E, Beti H, Orasan R, Grigorian F, Mescheder A, among heterosexual men and women with multiple sexual
Tawfik H, Thielert C (2008) Topical Polyphenon E in the partners: a prospective study. Genitourin Med 70: 240–246
treatment of external genital and perianal warts: a random- Vexiau D, Decuypere L, Moyse D, Aractingi S (2005) [Efficacy
ized controlled trial. Br J Dermatol 158: 1329–1338 and safety of 5% imiquimod cream in external genital warts:
Stone KM, Becker TM, Hadgu A, Kraus SJ (1990) Treatment of a 6 month follow-up evaluation]. Ann Dermatol Venereol
external genital warts: a randomised clinical trial comparing 132: 845–851
podophyllin, cryotherapy, and electrodesiccation. Genitourin von Krogh G (2001) Management of anogenital warts (condylo-
Med 66: 16–19 mata acuminata). Eur J Dermatol 11: 598–603; quiz 604
Strand A, Rylander E, Wilander E, Zehbe I, Kraaz W (1996) Weaver BA, Feng Q, Holmes KK, Kiviat N, Lee SK, Meyer C,
Histopathologic examination of penile epithelial lesions is Stern M, Koutsky LA (2004) Evaluation of genital sites and
of limited diagnostic value in human papillomavirus infec- sampling techniques for detection of human papillomavirus
tion. Sex Transm Dis 23: 293–298 DNA in men. J Infect Dis 189: 677–685
Syed TA, Lundin S, Cheema KM, Kahlon BM, Cheema R, Wikstrom A, Popescu C, Forslund O (2000) Asymptomatic
Ahmad SA, Ahmad M (1994) Human leukocyte interferon- penile HPV infection: a prospective study. Int J STD AIDS
alpha in cream, for the treatment of genital warts in Asian 11: 80–84
women: a placebo-controlled, double-blind study. Clin Wikstrom A, von Krogh G (1998) Efficacy of surgical and/or
Investig 72: 870–873 podophyllotoxin treatment against flat acetowhite penile
Tay SK, Ho TH, Lim-Tan SK (1990) Is genital human papillo- human papillomavirus associated lesions. Int J STD AIDS 9:
mavirus infection always sexually transmitted? Aust N Z 537–542
J Obstet Gynaecol 30: 240–242 Wiley DJ, Douglas J, Beutner K, Cox T, Fife K, Moscicki AB,
Tobian AA, Serwadda D, Quinn TC, Kigozi G, Gravitt PE, Fukumoto L (2002) External genital warts: diagnosis, treat-
Laeyendecker O, Charvat B, Ssempijja V, Riedesel M, Oliver ment, and prevention. Clin Infect Dis 35: S210–S224
AE, Nowak RG, Moulton LH, Chen MZ, Reynolds SJ, Wilson L, Bamburg JR, Mizel SB, Grisham LM, Creswell KM
Wawer MJ, Gray RH (2009) Male circumcision for the pre- (1974) Interaction of drugs with microtubule proteins. Fed
vention of HSV-2 and HPV infections and syphilis. N Engl J Proc 33: 158–166
Med 360: 1298-1309 Workowski KA, Berman SM (2007) Centers for Disease Control
Trizna Z, Evans T, Bruce S, Hatch K, Tyring SK (1998) A ran- and Prevention sexually transmitted diseases treatment
domized phase II study comparing four different interferon guidelines. Clin Infect Dis 44 Suppl 3: S73–S76
therapies in patients with recalcitrant condylomata acumi- Yan J, Chen SL, Wang HN, Wu TX (2006) Meta-analysis of 5%
nata. Sex Transm Dis 25: 361–365 imiquimod and 0.5% podophyllotoxin in the treatment of
Tseng CJ, Pao CC, Lin JD, Soong YK, Hong JH, Hsueh S (1999) condylomata acuminata. Dermatology 213: 218–223
Detection of human papillomavirus types 16 and 18 mRNA Yun K, Joblin L (1993) Presence of human papillomavirus DNA
in peripheral blood of advanced cervical cancer patients and in condylomata acuminata in children and adolescents.
its association with prognosis. J Clin Oncol 17: 1391–1396 Pathology 25: 1–3Fig. 3.20. (Continued)
 Human Papillomavirus-Associated Lesions
of the Urinary Tract 4
Alberto Rosenblatt and Homero Gustavo de Campos Guidi

Contents 4.1 Introduction

4.1 Introduction........................................................... 73
4.2 Overview................................................................ 73 Human papillomavirus (HPV) infection can affect the
4.3 Clinical Manifestations......................................... 74 urethra of male and female individuals causing symp-
4.3.1 Symptoms................................................................ 74 toms and concern. Urethral lesions (warts) may occa-
4.3.2 Presentation............................................................. 74 sionally develop and the urethra can also be a source of
4.4 Differential Diagnosis............................................ 76 HPV infection, contributing to the spread of infection
4.5 Detection Methods................................................. 76
between partners.
4.5.1 Clinical Diagnosis................................................... 76 This chapter reviews updated concepts concerning
4.5.2 Laboratory Diagnosis.............................................. 77 urethral HPV, including new detection methods, treat-
4.6 Treatment............................................................... 82 ment options, and prevention. In addition, the role of
4.6.1 Medical Therapies................................................... 82 HPV in the development of urethral, bladder, prostate,
4.6.2 Surgical Therapies................................................... 86 and kidney cancer is also discussed.
4.6.3 Treatment Failures – What to do?........................... 90
4.7 Follow-Up............................................................... 91
4.8 Prevention.............................................................. 91
4.9 The Role of HPV in Urethral, Bladder, Renal 4.2 Overview
and Prostate Cancer Development...................... 91
4.9.1 Urethral Cancer....................................................... 91
4.9.2 Bladder Cancer........................................................ 92
The prevalence of urethral involvement among genital
4.9.3 Prostate Cancer........................................................ 92
4.9.4 Renal Cancer........................................................... 93 HPV-associated lesions is 4–25% (von Krogh, 2001)
and the prevalence of HPV detection in the urethra, in
References.............................................................. 93
the absence of clinical lesions, ranges from 3 to 50%
(Rosemberg et al., 1988; Katelaris et al., 1988; Cecchini
et al., 1988; Aynaud et al., 2003).
Chuang et al. (1984) reported that the male ­urethra is
affected more often than the female urethra, and recent
analysis by von Krogh (2001) reported HPV-related
meatal lesions in 20–25% of male and 4–8% of female
A. Rosenblatt ()
individuals. Meatal warts have also been observed in
Albert Einstein Jewish Hospital, Sao Paulo, Brasil children, and Takatsuki et al. (1993) described a relaps-
e-mail: [email protected] ing meatal condyloma in a 4-year-old boy.

A. Rosenblatt, H. G. de Campos Guidi, Human Papillomavirus, 73

DOI: 10.1007/978-3-540-70974-9-4, © Springer-Verlag Berlin Heidelberg 2009
 74 4 Human Papillomavirus-Associated Lesions of the Urinary Tract

HPV-related lesions are usually found at the distal

4 2–3 cm of the urethra, and the proximal urethra is usu-
ally not involved without previous or simultaneous
lesions in the distal portion (Culp and Kaplan, 1944;
Gartman, 1956; von Krogh, 2001). Rothman et al. (1994)
showed that of 90 men with external meatal warts, 15
(16.7%) also had more proximal lesions and only 5
(5.6%) had lesions at or beyond the pendulous urethra.
Detection studies using cytological analysis of ure-
thral brushings as well as hybridization techniques
applied to urethral brushings have shown evidence to
support the urethra as a reservoir for HPV (Cecchini
et al., 1988; Zderic et al., 1989).
The association of HPV and urethral carcinoma in
both sexes has been described by several investigators
(Wiener et al., 1992; Wiener and Walther, 1994; Sumino Fig. 4.1. HPV-related lesion obstructing the urethral meatus
et al., 2006). However, bladder involvement is rare in
immunocompetent individuals and although high- and
low-risk HPV types can be detected in bladder speci-
mens, there is ongoing controversy on the role of HPV
in bladder carcinogenesis (Noel et al., 1994; Olsen
et al., 1995; Aynaud et al., 1998; Griffiths and Mellon,
2000; Chrisofos et al., 2004; Youshya et al., 2005).

4.3 Clinical Manifestations

4.3.1 Symptoms

Asymptomatic in the majority of cases

4.3.1.1 Less Frequent

Itching sensation usually preceding the appearance

of the lesion
Light bleeding or spotting following masturbation or
coitus
Hemospermia (Jones, 1991)
Urethral discharge and dysuria
Urethritis (significantly associated with HPV detec- Fig. 4.2. Meatal “rouge lips”
tion, according to recent data presented by de
Carvalho et al. (2006)
Secondary infection resulting in pyuria 4.3.2 Presentation

4.3.1.2 Atypical Occurrence Meatal lips can exhibit hyperemia and edema (“rouge
lip” appearance) (Fig. 4.2). Fralick et al. (1994)
Urinary retention due to meatal obstruction (Kilciler reported that “rouge lip” was associated with ure-
et al., 2007) (Fig. 4.1) thral HPV infection in 30% of cases.
4.3 Clinical Manifestations 75

Fig. 4.3. Urethral lesion extending through the meatus

Fig. 4.5. (a) Fleshy appearance of urethral condyloma. (b)

Broad-based lesion, friable and vascular

HPV-associated lesions can rarely extend to the

proximal urethra and bladder in immunosuppressed
individuals.
Lesions are usually single and rarely multiple
(Fig. 4.4).
Classic flesh appearance, soft, friable, and vascular
(Fig. 4.5a, b).
Meatal sentinel lesions may indicate presence of
urethral involvement (Fig. 4.6a–c).
Fig. 4.4. HPV-related lesion protruding through the female meatus
Urethral lesions can coexist with external warts (in
up to 36% of cases, according to Huguet Perez et al.,
Lesions are usually found on the moist surface of the 1996) (Fig. 4.7a, b).
fossa navicularis and extend through the meatus HPV-related urethral lesions can exhibit a hyperpig-
(Fig. 4.3). mented appearance (Fig. 4.8).
 76 4 Human Papillomavirus-Associated Lesions of the Urinary Tract

4.4 Differential Diagnosis

4
Normal anatomic variance
Urethral caruncle
Urethral polyp in young female patients
Other sexually transmitted diseases (STDs), if ure-
thral discharge is the main symptom
Urethral malignancy (may also be associated with
HPV-related lesions)

Expert Advice

If urethral discharge is the only symptom, further

investigation is necessary to determine the exact
­etiology of the discharge, because different STDs
may coexist.

4.5 Detection Methods

4.5.1 Clinical Diagnosis

4.5.1.1 Physical Examination of the Meatus

and Fossa Navicularis

Despite its reduced sensitivity, clinical examination is

the reference standard for detecting HPV infection of
the male urethra (Aynaud et al., 2003).
Gentle manual eversion of the meatal lips allows for
the visual inspection of the urethral meatus and fossa
navicularis (Fig. 4.10).

Expert Advice

Meatal lip eversion should be performed on every

patient and particularly in those presenting with
genital condyloma (Fig. 4.11a, b).

Expert Advice
Fig. 4.6 (a) Sentinel lesion. (b) Meatal sentinel lesion. (c) Meatal
sentinel and urethral lesion Urethral malformations (hypospadias and epispa-
dias) (Fig. 4.12a–c) and anatomic variance (Fig. 4.13)
should be carefully examined for genital warts.

115 4.3.2.1 Lesion Base Visual inspection using a magnifying glass, sur­gical
microscope, or an articulated microscope (Fig. 4.14a, b),
116 Individually on a stalk and using three magnifications (3.5×, 5.4×, 8×) or
117 Broad-based and coalescent (Fig. 4.9) five magnifications (2×, 3.5×, 5.4×, 8×, 13.3×).
4.5 Detection Methods 77

Fig. 4.7. (a) Flat condyloma (glans penis) associated with urethral lesion. (b) Urethral lesion (black arrow) and frenular lesion
(white arrow)

Meatoscopy. Expert Advice

−−The use of a meatal spreader (Hartmann nasal
speculum) allows visualization of the first 2 cm of Thin (1992) recommends that meatoscopy should
the urethra (Aynaud, 1992). be performed on all patients with meatal warts to
−−An otoscope is useful for the adequate visualiza- correctly assess the lesion base and extension.
tion of lesions in the fossa navicularis and first
3 cm of urethra (Fig. 4.15). 4.5.2 Laboratory Diagnosis
How to Perform Meatoscopy Using the
4.5.2.1 Brushing Cytology
Otoscope

Aqueous chlorhexidine solution is used to clean the To improve the quality of the specimen, saline ­solution
glans and urethral meatus, and a small amount of lido- drops are instilled into the meatus before “brushing”
caine gel is applied to the meatal area. A sterile and of the fossa navicularis and meatal area (Fig. 4.16).
disposable otoscope cone is gently introduced through −−The weak adherence of HPV-related lesions in the
the meatus while the patient exerts penile traction. urethra usually yields high cellularity samples.
−−Lubricant or anesthetic gel is usually not used as it
The procedure is asymptomatic.
might influence smear quality.
 78 4 Human Papillomavirus-Associated Lesions of the Urinary Tract

Fig. 4.10 Meatal lip eversion

Urethral cytology as a single screening method may

lead to a high number of false-positive findings.

4.5.2.2 Biopsy and Histopathological

Evaluation

Specimens can be removed for histopathological eval-

uation with:
Cold cup biopsy using a suitable instrument for
meatal warts (Fig. 4.17a, b)
Fig. 4.8. Hyperpigmented HPV-related urethral lesion (arrow) Endoscopic resection for urethral and bladder
lesions

Histopathological Findings

Koilocytosis (Fig. 4.18), the hallmark histopatho-

logical feature of HPV infection, can lead to false-
positive and false-negative results and its use as a
pathognomonic sign of HPV infection is not recom-
mended (Strand et al., 1996).
HPV DNA can be detected in biopsy specimens that
lack the classic histological features of HPV infec-
tion, although the detection rate is much lower than
for condylomata (Nuovo et al., 1990).

Fig. 4.9. Broad-based lesion Biopsy Indications

−−The use of a soft plastic bacteriological loop If lesion appearance is equivocal or atypical
(Fig. 4.16) is preferred to avoid urethral trauma To rule out malignancy, particularly in immuno-
and pain during specimen collection. compromised patients
According to Aynaud et al. (2003): If lesion is unresponsive or worsens during clini-
In the absence of clinical lesions in the urethra, cal treatment
­cytology is nonspecific for urethral HPV infection. If lesion exhibits irregular dyschromia
4.5 Detection Methods 79

4.5.2.3 Molecular Tests

See also Chap. 2.

Urethral Meatus/Fossa Navicularis (Fig. 4.19)

1. Specimens are collected by brushing the urethral

meatus and fossa navicularis.
In a survey evaluating HPV prevalence in Mexican
soldiers performed by Aguilar et al. (2006), HPV
DNA was detected more frequently in external
­genitalia samples (46.4%) than in the urethra
(20.8%) or meatus samples (12.1%).

Can HPV Detection Be Improved by

Adding Urethral Samples?

Although urethral sampling provides adequate cell

counts, the HPV DNA testing does not markedly
increase overall HPV positivity beyond that found
in the glans penis and coronal sulcus due to its low
sensitivity for HPV detection.
Furthermore, the discomfort caused by the col-
lection method could be a barrier for its generalized
use (Aguilar et al., 2006).

Urine/Semen

HPV DNA is present in the urine of patients with

urethral condylomata, as urine may wash infected
cells from the urethral epithelium (Iwasawa et al.,
1997). However, in a recent study evaluating the
presence of HPV DNA in first-voided urine (FVU)
and urethroglandular brushed samples, D’Hauwers
et al. (2007) reported that HPV-PCR tested positive
in 60% of the male brushed samples and negative in
all of the male FVU specimens.
High-risk HPV DNA has been detected at variable
percentages in semen (8–64%), but the conse-
quences of this finding are yet unknown (Green
et al., 1991).
HPV DNA has been found in samples from the vas
deferens (possibly eliminating the issue of urethral
Fig. 4.11. (a) Meatal lip eversion disclosing small fossa navicu- contamination), and thus raising the question of HPV
lar lesion. (b) Small fossa navicular lesion (arrow) transmission through sperm donation (Rintala et al.,
2002).
 80 4 Human Papillomavirus-Associated Lesions of the Urinary Tract

Fig. 4.13. Lacuna magna (also known as Guérin’s sinus)

At present, there is no consensus about the real value

of urethral and semen samples when the overall HPV
male infection is considered. In a recent HPV detec-
tion study, Giuliano et al. (2007) reported that the
exclusion of these two sites, plus the scrotal and
perianal areas, resulted in a prevalence reduction of
less than 5%.

4.5.2.4 Urethroscopy

Urethroscopy using a 0-degree lens should be per-

formed on all patients with distal penile (glans,
corona, or frenulum) or meatal lesions (Kaplinsky
et al., 1995).

Urethroscopy – When to Perform

Urethroscopy should not be performed until all

meatal condylomata have been eradicated to avoid
the potential risk of seeding disease into the prox-
imal urethra, prostate, or bladder during retro-
Fig. 4.12. (a) Balanic epispadia (arrow). (b) Careful examina-
tion of epispadic urethral meatus. (c) HPV-related lesion (arrow)
grade passage of the cystoscope (Sumino et al.,
protruding through the hypospadiac meatus 2004).
Urethral instillation of 5-fluorouracil (5-FU) prior
However, Rintala et al. (2004) found no significant to instrumentation of the involved distal urethra is
associations between seminal HPV DNA and altered recommended.
semen parameters in HPV-positive semen, except for
borderline lower pH values.
4.5 Detection Methods 81

Fig. 4.15. An otoscope is used for distal urethra inspection

Fig. 4.14. (a) HPV-related lesion protruding through the female Fig. 4.16. Meatal and fossa navicularis cytology using a plastic
urethral meatus. (b) Condyloma located in the female urethra bacteriological loop and saline drops

Fig. 4.17. (a) Hartman-Herzfeld Ear Forceps. (b) Cup-shaped jaws

 82 4 Human Papillomavirus-Associated Lesions of the Urinary Tract

to urethroscopy to screen for and follow the ­treatment

4 response of urethral HPV, minimizing the risk of
virus dissemination.
Antegrade and retrograde urethrography are useful
examinations in cases of multiple condylomata and
large lesions, but false-negative results are common
in small or flat urethral lesions.
−−The use of catheters for radiological contrast
medium instillation is contraindicated to prevent ret-
rograde seeding of disease into the proximal urethra
or bladder.

Ultrasonography and Computed Tomography

Pelvic US and CT Can Be Performed

Fig. 4.18. Koilocyte (detailed in blue) (Source: Photo­graph
courtesy of Monica Stiepcich MD, PhD, São Paulo, Brazil) To rule out bladder involvement in immunosuppressed
patients presenting with distal urethral lesions
As a screening examination prior to cystoscopy

4.6 Treatment (Table 4.1)

Therapy choice is based on lesion:

Number
Size and morphology
Location
Additional factors that define therapy choice:
Physician experience
Treatment cost, convenience, and adverse effects
Patient choice
Fig. 4.19. Urethral brushing HPV DNA-positive (in situ hybrid- Meatal anatomy
ization 40×) (Source: Photograph courtesy of Monica Stiepcich
MD, PhD, São Paulo, Brazil)
Expert Advice
Expert Advice Pictures or a schematic representation of lesions at
each visit is a useful tool for evaluating treatment
A simplified “waterless” urethroscopy can be per-
response and follow-up.
formed using a pediatric cystoscope with a 0-degree
lens and lidocaine 2% gel as an alternative to con-
ventional urethroscopy. 4.6.1 Medical Therapies

4.6.1.1 Cytotoxic Agents

4.5.2.5 Image Diagnosis
Podophyllotoxin
Antegrade and Retrograde Urethrography
Podophyllotoxin contains purified podophyllin in a
Sawczuk et al. (1983) recommended the use of ante- standardized concentration in cream (not available in
grade and retrograde urethrography as an alternative the United States), gel, or solution preparation.
4.6 Treatment 83

Table 4.1 Treatments for urethral warts (Adapted from: Kodner and Nasraty (2004). Reproduced with permission from American
Family Physician. Copyright © 2004 American Academy of Family Physicians. All Rights Reserved)

Treatment Clearance rates (%) Risk of recurrence (%) Adverse effects

Cryotherapy Female proximal urethra: 25–39 (Beutner and Pain or blisters at application site
75 with one treatment and Ferenczy, 1997)
25 with two treatments
(Sand et al., 1987)
Imiquimod (Aldara) ‡ ‡ Erythema; irritation, ulceration, and pain;
Contra-indicated in burning, erosion, flaking, edema, indura-
urethral lesions tion, and pigmentary changes at applica-
tion site; minimal systemic absorption
Interferon 64 (Levine et al., 1996) ‡ None
CO2 laser treatment 50–86.6 (Rosemberg et al., 5–50 Similar to surgical excision; risk of
1982; Graversen et al., spreading HPV via smoke plumes; low risk
1990; Krogh et al., 1990) of urethral stricture, meatal stenosis and
frequency (Krogh et al., 1990)
Nd:YAG laser treatment 30–40 (Volz et al., 1994); 35.7 (Zaak et al., 2003) Reduced risk of meatal stenosis; less
100 (Bloiso et al., 1988) plumes with reduced risk of HPV spreading
Podofilox (condylox) ‡ ‡ Burning at application site, pain, meatitis;
Contra-indicated in low risk of systemic toxicity
urethral lesions
Podophyllin resin ‡ ‡ Local irritation, erythema, burning, and
Contra-indicated in soreness at application site; possibly
urethral lesions mutagenicity, oncogenicity
Endoscopic ‡ 14–35.2 (Gonzalvo Pain, bleeding, scarring and meatal
electrocoagulation Perez et al., 1994; stenosis; risk of burning and allergic
Huguet Perez et al., reaction from local anesthetic
1996)
5-FU cream and 25–95 (Dyment, 1996) 53 (Carpiniello et al., Risk of severe local side effects (scrotal
solution 1990) irritation or meatitis)
BCG ‡ Reduced from 3.2 with Mild dysuria, penile edema, fever of short
standard therapy to duration
0.75 (Bohle et al., 1998)
5-ALA photodynamic 95 (Wang et al., 2004) 6.3 (Chen et al., 2007) Mild burning and/or stinging sensation;
therapy erythema, mild edema, and skin erosion
following treatment
Transurethral resection ‡ ‡ Bleeding, dysuria, frequency; risk of
urethral stricture, meatal stenosis

Time until recurrence varied across studies, but recurrence rates typically are measured at 3 months after treatment. ‡- insuffi-
cient data; 5-FU 5-fluorouracil; BCG bacille Calmette-Guérin
 84 4 Human Papillomavirus-Associated Lesions of the Urinary Tract

4 Expert Advice How to Use

Podofilox is not recommended for intraurethral Podophyllin 10–25% in a compound tincture of

warts. Although it can be used to treat meatal lesions benzoin should be applied to meatal lesions with a
(Clinical Effectiveness Group, 2007), caution should cotton-tipped swab once weekly.
be taken with the urethral mucosa. The affected area should be clean and dry before
application and, after use, podophyllin should be
allowed to air dry. The involved area should be thor-
How to Use
oughly washed 1–4 h after application.
Podophyllotoxin 0.15% cream is applied once daily Stop use if signs of local irritation persist.
with a cotton-tipped swab for 3–4 days, and then
discontinued for four consecutive days (von Krogh, Advantages
2001).
The 1-week cycle of treatment may be repeated Efficacy – data for meatal warts: No evidence-based
until there is no visible wart tissue or for a maximum data available
of four cycles.
Stop use if signs of local irritation persist. Disadvantages
Recurrence rate: No evidence-based data available
Advantages
Patient-applied medication. Adverse Effects
Cream or gel formulations are easier to use for per-
imeatal and meatal lesions. Meatitis
Inexpensive. Burning and pain at application site
Meatal stenosis and adhesions
Disadvantages Systemic side effects due to higher absorption of
podophyllin by moist surface of urethral mucosa
Limited data evaluating use of podophyllotoxin for
the treatment of meatal warts Contraindicated during pregnancy (potential risk
Recurrence rate for meatal warts: Insufficient evi- of mutagenicity and oncogenicity)
dence-based data
Contraindicated during pregnancy 5-Fluorouracil Cream (Efudex®)

Adverse Effects Fluorouracil, a fluoropyrimidine, is a widely used che-

Pain and burning sensation at application site motherapeutic agent that belongs to a group of drugs
Meatitis known as antimetabolites. It is incorporated into RNA
Low risk of systemic toxicity in preference to the natural substrate uracil and the
drug inhibits cell growth and promotes apoptosis by
targeting the enzyme thymidylate synthetase.
Podophyllin

Expert Advice Advantages

Patient-applied medication.
Podophyllin is not recommended for intraurethral
Inexpensive: U.S. $40.99/15 g (generic).
warts. Although it can be used to treat meatal lesions
Painless.
(Workowski and Berman, 2007), caution should be
Efficacy: 5-FU efficacy ranged from 25 to 95%,
taken with the urethral mucosa.
according to the study performed by Dyment (1996).
4.6 Treatment 85

Disadvantages 4.6.1.2 Immune-Response Modifiers

Risk of severe local side effects (scrotal irritation or
Imiquimod (Aldara®)
meatitis (Fig. 4.20)) if not correctly used.
Recurrence rate: Carpiniello et al. (1990) reported
recurrences in 53% of the patients in a long-term Expert Advice
follow-up of subclinical HPV infection treated with Not approved for use against cervical, vaginal,
5-FU. intraurethral, or rectal warts (3M Pharmaceuticals,
Aldara, package insert), although treatment can be
How to Use recommended in selected patients with recurring
disease.
5-FU cream is applied with a cotton swab or injected Imiquimod use for urethral meatal lesions can be
(1 ml) into the urethra 3–4 times a week and washed recommended if the lesion base is visualized (Clinical
away after 30–60 min. Effectiveness Group, 2007).
Treatment duration is approximately 3–4 weeks.

How to Use
Important
Imiquimod is applied to urethral meatal warts at
The scrotum should be protected to avoid possible bedtime and washed off in the morning.
skin erosion. It should be repeated three times per week for 16
weeks.
Stop use if signs of local irritation persist.
Expert Advice
Advantages
In a recent case report of an HIV-infected patient
presenting with pan-urethral warts, Wen et al. Patient-applied medication
(2006) demonstrated good results using intraure- May stimulate a cell-mediated immune response
thral instillation of 5-FU solution (500 mg in nor- against HPV
mal saline 50 ml) once a week for 7 weeks, and then Efficacy rate: Insufficient data for urethral warts
once a month until urethral lesions were no longer
detected at urethroscopy. Disadvantages
Expensive: U.S. $153.99 (12 sachets) and U.S.
$291.99 (24 sachets) (2008-based costs)
No direct antiviral activity
Therapeutic effects may take up to 4 weeks to occur
Limited data evaluating use of imiquimod for the
treatment of urethral meatal warts (Workowski and
Berman, 2007)
Prolonged treatment duration
Contraindicated during pregnancy

Adverse Effects
Frequent
Mild to severe erythema
Localized erosions
Fig. 4.20. Meatitis after intraurethral 5-FU application Itching or burning sensations
 86 4 Human Papillomavirus-Associated Lesions of the Urinary Tract

Less Frequent
4 Expert Advice
Local irritation
Use of a topical anesthetic is recommended. EMLA
Induration
cream (AstraZeneca, Wilmington, Delaware), a
Crust formation
eutectic mixture of lidocaine 2.5% and prilocaine
Tenderness
2.5%, should be applied in the urethral meatus for a
minimum of 15 min before the procedure to mini-
mize pain from local anesthetic injection (a solution
4.6.2 Surgical Therapies of 1% lidocaine without epinephrine should be used
for procedures involving the penis and distal ure-
4.6.2.1 Excision thra) (see also Sect. 10.6.3.4 in Chap. 10).

Excision of meatal warts can be performed using scis-

sors, scalpel, or electrocautery. 4.6.2.2 Endoscopic Electrosurgical Techniques

Advantages

Indications Widely available and cost effective.

Office procedure.
Usually recommended for large lesions that involve Bleeding can be easily controlled.
the urethral meatus and cause obstruction (Scheinfeld Efficacy rate: Huguet Perez et al. (1996) reported
and Lehman, 2006). clearance of lesions after two sessions in nearly all
Excision is the preferred option when histopathologi- of the 24 patients treated with the method.
cal examination is needed to rule out malignancy.

Disadvantages
Advantages
Anesthesia is required (local, regional, or general).
Development of meatal stenosis resulting from cir-
Efficacy rate: 35–70% for urethral meatal lesions
cumferential thermal injury of the meatus (McKenna
and McMillan, 1990; Zheng et al., 2000). However,
a novel technique to avoid meatal stenosis described
Disadvantages by Shaw and Payne (2007) reported good short-term
results.
Anesthesia is required (local, regional, or general).
Scarring.
Pain.
Meatotomy may be required for fossa navicular
lesions (Gartman, 1956) (Fig. 4.21).
Recurrence rate: 20% for urethral meatal lesions.

Complications

Excessive bleeding can occur as urethral warts are

highly vascular.
Allergic reaction risk from local anesthetic. Fig. 4.21. Urethral lesion and a difficult meatus
4.6 Treatment 87

Postoperative pain (usually controlled with simple Can be used for any meatal wart that is accessible to
analgesics). treatment.
Recurrence rate: Available data report recurrences in Efficacy for proximal urethral lesions in female
14–35.2% of patients (Gonzalvo Perez et al., 1994; patients: 75% with one treatment session and 25%
Huguet Perez et al., 1996), with no differences with two sessions, according to the study performed
observed between subjects submitted to electroco- by Sand et al. (1987).
agulation and those patients treated by Nd:YAG laser Healing usually occurs 1–2 weeks after treatment.
photocoagulation (Huguet Perez et al., 1996).
Disadvantages

Complications Recurrence rate: 25–39% (Beutner and Ferenczy,

1997)
Pain
Adverse Effects
Bleeding
Scarring
Pain or blisters at application site
Burning risk
Risk of allergic reaction from local anesthetic
4.6.2.4 CO2 Laser Vaporization

4.6.2.3 Cryotherapy See Chap. 10.

Indications
Cryotherapy involves application of nitrous oxide or
liquid nitrogen (−196°C) to HPV-related lesions. It Lesions located in the urethral meatus and fossa
induces dermal and vascular damage and edema, caus- navicularis
ing cellular destruction by thermal-induced cytolysis.
CO2 Laser Technique
How to Use
See Chap. 10.
Liquid nitrogen is applied directly to meatal warts Carbon dioxide (CO2) laser is coupled to the oper-
with a cotton-tipped swab for about 10–20 s until a ating microscope for enhanced visualization.
white halo appears around the circumference of the Lesions are vaporized under direct colposcopic
lesion (indicating that it is frozen). Subsequent thaw guidance.
produces cell lysis. Power settings of 4–5 W in continuous or pulsed
Treatment is repeated every 2 weeks until the mode are used in urethral meatus and fossa navic-
lesion disappears. ularis for depth destruction not exceeding 1 mm.
According to Dyment (1996), it is important to It is important to focus the beam over the lesion
treat a small margin of normal-appearing tissue and move the laser beam as quickly as possible.
surrounding the lesion because HPV DNA has Lesions are vaporized along with a 2–3-mm border
been found as far out as 5-10 mm from the visible of normal-appearing epithelium (Fig. 4.22a. b).
wart.

Following vaporization of the lesion(s), the unfo-

Advantages
cused laser beam should be quickly “flashed” over
the remaining epithelium of the urethral meatus
Relatively inexpensive.
and fossa navicularis. The brief thermal effect cre-
Ease of application.
ated will likely destroy any latent virus contained
Rapid destructive effect.
within the area.
Injected anesthesia is not usually required, but topi-
Bleeding is controlled with the unfocused laser
cal anesthesia with lidocaine (spray or gel) or EMLA
beam.
cream may facilitate therapy.
 88 4 Human Papillomavirus-Associated Lesions of the Urinary Tract

Fig. 4.22. (a) Laser treatment of female meatal lesion. (b) A 2–3-mm safety margin

Expert Advice Disadvantages

Urologists are frequently consulted for the diagno- Expensive and not widely available.
sis and treatment of female urethral lesions associ- Experience with the technique required.
ated with HPV. Gentle traction exerted on the lesion Recurrence rate: 5–50%, usually developing within
exposes its pedicle, and the urethral mucosa around 3 months after treatment.
the lesion is minimally affected in the majority of HPV DNA may be released during the procedure
cases. and a smoke evacuation system must always be used
(see Sect. 10.4.1.2 in Chap. 10).
Important
Urethroscopy should be performed at a later stage
to avoid the potential risk of seeding disease into Complications
the proximal urethra and bladder.
(See above, Urethroscopy – When to Perform) Urethral stricture (less than 2%), meatal stenosis
(8%), and frequency (3%) (Krogh et al., 1990)
Advantages

Sharply precise
4.6.2.5 Neodymium:YAG Laser/Holmium:
Shallow depth of penetration with above settings
YAG Laser
Fast and usually bloodless technique
Good cosmetic results
Mechanism of Action
Office procedure
Efficacy: 86.6% after single treatment (Rosemberg
Phototermic mechanism causing protein denaturation,
et al., 1982); 50% after single treatment, and 86%
coagulative necrosis, and a minimal amount of carbon-
after three treatments (Graversen et al., 1990); 78%
ization and vaporization
after single treatment of isolated meatal lesion
(Krogh et al., 1990) Zone of thermal injury: 0.5–1.0 mm
4.6 Treatment 89

Indications
Expert Advice
External lesions Intraurethral 5-FU cream application following
Intraurethral lesions located proximally of the fossa laser procedures to prevent recurrence is highly rec-
navicularis ommended (see 5% Fluorouracil Cream above).
Bladder lesions
4.6.2.6 Transurethral Resection of HPV-Related
Technique Lesions of the Urethra and Bladder
“Side fire” or “end fire” laser fibers are introduced
through the urethrocystoscope when treatment is See also Sect. 4.6.2.2.
directed to anterior urethral and bladder lesions.
 Neodymium (Nd):YAG laser settings: Power:
Indications
10–20 W
 Holmium (Ho):YAG laser settings: Pulse rate:
Isolated intraurethral lesions proximal to the fossa
13–15 W/Pulse energy 1.0–1.5 J
navicularis
Bladder lesions
Advantages

Nd:YAG and Ho:YAG lasers can be used to treat Complications

intraurethral and bladder lesions.
Coagulates tissue causing less plume. Risk of urethral stricture, particularly for lesions
Outpatient procedure. affecting the whole urethral circumference
Efficacy: Among the 20 cases of meatal and/or ure- Bladder and urethral perforation
thral condyloma treated with Nd:YAG laser, Volz
et al. (1994) reported cure rates of 30% after one treat-
ment and 40% after up to five separate treatments. 4.6.2.7 5-Aminolaevulinic Acid Photodynamic
However, Bloiso et al. (1988) found 100% efficacy Therapy
with no recurrences with an average follow-up of 13
months. 5-Aminolaevulinic acid photodynamic therapy (ALA-
Recurrences following Nd:YAG laser: Zaak et al. PDT) is a new technique introduced in the 1990s for
(2003) detected recurrences in 35.7% of 168 patients the treatment of superficial epithelial skin tumors.
presenting with urethral condylomata (recurrences Wang et al. (2004) recently described the method for
were mainly on the meatus and in the distal the treatment of urethral condylomata.
urethra).
Reduced incidence of urethral stricture.
Meatotomy is not required in most cases. Mechanism of Action

Disadvantages Following the exogenous application of the photosen-

sitizer ALA to HPV-related lesions, it is selectively
Laser experience required. absorbed by the hyperplastic tissue and transformed
Eye protection is needed. to endogenous protoporphyrin IX (PpIX).
Cost. The PpIX is then activated by red light leading to the
Not worldwide applicable. formation of singlet oxygen, causing necrosis and
apoptosis of the HPV-infected cells.
Complications Smetana et al. (1997) postulated that ALA-PDT
could also inactivate viral particles by binding to
Bladder and urethra perforation (laser fiber tip should virion surface glycoproteins and preventing the early
not touch lesion to avoid perforation risk). steps of the HPV infection cycle.
 90 4 Human Papillomavirus-Associated Lesions of the Urinary Tract

Advantages 4.6.3 Treatment Failures – What to do?

4
Chen et al. (2007) reported that the application of 4.6.3.1 Immune-Response Modifiers
ALA-PDT is simpler, more effective, and safer com-
pared with conventional CO2 laser therapy. Bacille Calmette-Guérin
Efficacy: 95% after a follow-up of 6–24 months
(Wang et al., 2004). The combination of surgical ablative methods and
Recurrence: 6.3% in the comparative study of PDT immunomodulative agents seems to be a promising
vs. CO2 laser vaporization performed by Chen treatment modality for recurrent HPV infection. Bohle
(2007). et al. (1998) demonstrated that local application of
No scarring or urethral stricture. bacille Calmette-Guérin (BCG) is effective in the
Fluorescence of the photosensitizers can assist in the adjuvant treatment of recurrent urethral condylomata
localization of lesions. acuminate.

How to Use (Bohle et al., 1998)

Adverse Effects
BCG Preparation
Mild burning and/or stinging sensation during
treatment 81 mg Connaught strain is dissolved in 2 ml sterile
Erythema, mild edema, and skin erosion following saline for direct instillation into the urethra at low
treatment pressure.
Solution is instilled once a week for 6 weeks and
is maintained intraurethrally for a minimum of 2
How to Use (Chen et al., 2007) h (a dressing can be taped over the meatus to avoid
inadvertent emptying).
20% ALA solution under occlusive dressing for 3 h, After 2 h the dressing is removed and the patient
followed by irradiation with helium-neon laser at a is allowed to void spontaneously.
dose of 100 J cm2 and a power of 100 mW.
A cotton swab soaked in the solution is gently
Advantages
inserted into the meatus or, alternatively, a cotton
ball is placed over the glans penis covering the Office procedure.
meatus and adjacent normal mucosa (5-mm bor- Efficacy: It is suggested that the annual recurrence
der). The solution is dropped over the cotton ball rate is decreased using intraurethral BCG instillation
every 30 min. Lesions are then occluded with food- as an adjuvant to laser therapy. According to Bohle
grade cling film and covered with thick gauze for et al. (1998), recurrence rate was reduced from 3.2
light protection. with standard therapy to 0.75 with BCG therapy.
After a 3-h interval, irradiation with helium-neon
laser is performed.
Disadvantages
Treatment can be repeated once a week for a
maximum of 3 weeks. High cost (U.S. $140–$160 per vial) may prevent
extended treatment.
ALA Solution Preparation
Adverse Effects
20% ALA (Fudan Zhangjiang Bio-Pharm,
Mild dysuria
Shanghai, China) is dissolved in sterile saline imme­
Penile edema
diately before its application.
Fever of short duration
4.9 The Role of HPV in Urethral, Bladder, Renal, and Prostate Cancer Development 91

Interferon Follow-up tests for urethral lesions:

Urethral brushing polymerase chain reaction (PCR)
How to Use (Levine et al., 1996)
2 months after treatment.
Interferon Urethrocystoscopy is performed 3 months after treat-
ment and every 3 months thereafter for a period of
25 millions units of interferon-a-2b (Intron A, 1 year.
Schering-Plough, Kennilworth, NJ) in 5–7 cm3 US/CT is performed 4 weeks after therapy for HPV-
­sterile saline related lesions in the proximal urethra or bladder.
The solution is instilled intraurethrally once a
week for 6 weeks.
In case of recurrence, retreatment with an addi-
tional 6-week course of 50 million units of inter- 4.8 Prevention
feron-a-2b is recommended.

See also Chap. 3.

Advantages A recent phase-I/II clinical trial using a therapeutic
vaccine for male intraurethral flat condyloma showed
Interferon appears to eradicate subclinical disease by promising results (Albarran et al., 2007). The vaccine
antiviral (Friedman-Kien et al., 1988; Agarwal et al., was administered into the urethra once a week over a
1994), antiproliferative (Salmon et al., 1983), and 4-week period. The immune response after MVA E2
immunomodulative activity (Herberman et al., 1982). treatment was determined by measuring the antibodies
Efficacy rate: 9 of 14 (64%) patients were disease- against the MVA E2 virus and by analyzing the lym-
free for an average of 11.8 months, in the study per- phocyte cytotoxic activity against cancer cells bearing
formed by Levine et al. (1996). oncogenic papillomavirus. Lesion changes were moni-
No adverse effects were described in the same study. tored by colposcopy and brush histological analysis,
whereas viral presence was determined by the Hybrid
Disadvantages capture® method. In 28 of 30 patients that received the
MVA E2 vaccine, the flat condyloma in the urethra was
Expensive completely eliminated and absence of the papillomavi-
Prolonged treatment duration rus was confirmed by brush histologic examination. In
addition, patients treated with MVA E2 did not show
any lesion recurrence after 1 year of treatment and all
4.7 Follow-Up patients developed antibodies against the MVA E2
­vaccine and E2 viral protein, generating a specific cyto-
toxic response against papilloma-transformed cells.
Recurrences occur most frequently during the first 3
months following treatment.
Closer follow-up is advisable for patients with
intraurethral warts, particularly for those harboring
high-risk HPV and/or those who have not responded to
4.9 The Role of HPV in Urethral,
other treatment modalities. Bladder, Renal, and Prostate Cancer
Following laser treatment, patients return on post- Development
operative day 12 to monitor cicatrization, treat possible
complications, and check for early recurrences. A fol-
low-up evaluation is advised 3–4 weeks after the end 4.9.1 Urethral Cancer
of treatment, and every 2–3 months thereafter for half
a year if control examinations yield negative results. Detection studies using cytological analysis of urethral
Patients should be instructed to watch for recur- brushings as well as hybridization techniques applied
rences and self-refer whenever lesions reappear. to urethral brushings showed evidence to support the
 92 4 Human Papillomavirus-Associated Lesions of the Urinary Tract

urethra as a reservoir for HPV (Cecchini et al., 1988; et al., 1988). This finding prompted investigators to
4 Zderic et al., 1989). explore a link between HPV colonization of the urinary
Moreover, several studies have shown that HPV is tract and the development of urothelial malignancy.
associated with urethral carcinoma in both sexes However, methods used to detect the virus have often
(Wiener et al., 1992; Wiener and Walther, 1994; been associated with false-positive results and although
Sumino et al., 2006; Mevorach et al., 1990). condylomatous bladder lesions attributable to HPV
Tumors of the anterior urethra are mostly squamous infection have been described in immunocompetent and
cell carcinoma (SCC) arising in the bulbar and penile immunosuppressed patients, the etiological role of HPV
portion. Although transitional cell carcinoma (TCC) in bladder TCC is still a matter of discussion (Chetsanga
usually occurs in the posterior urethra, Sumino et al. et al., 1992; Anwar et al., 1992a; Shibutani et al., 1992;
(2006) recently reported TCC of the navicular fossa Knowles, 1992; Furihata et al., 1993; Sinclair et al.,
that was associated with low-risk and high-risk HPV 1993; Agliano et al., 1994; Chang et al., 1994; Sano
infection. et al., 1995; Olsen et al., 1995; Mvula et al., 1996).
Youshya et al. (2005) suggested that HPV is unlikely Furthermore, immunohistochemical assay (IHA)
to play an etiological role in the development of TCC and PCR tests were used to investigate HPV in TCC,
but, according to Noel et al. (1994), the virus could act with very different results (Aynaud et al., 1998;
as an oncogenic agent in immunosuppressed patients. Chetsanga et al., 1992; Chan et al., 1997; De Gaetani
In addition, the iatrogenic seeding of HPV into the et al., 1999).
urethral lumen could also play a role in the develop- The disparity of theses results suggests that the
ment of urethral SCC and TCC in immunocompro- association of HPV with bladder TCC may be influ-
mised or elderly patients (Steele et al., 1997; Bans enced by geographical location, owing to the fact that
et al., 1983). most studies reporting a high incidence of HPV-positive
samples were performed in Asia (Yu et al., 1999;
Barghi et al., 2005; Wiwanitkit, 2005; Smetana et al.,
4.9.2 Bladder Cancer 1995), in strong contrast to the extremely low rate of
HPV positivity that was found in northern European,
The majority of bladder cancers detected in the Western American, and even African studies (Aynaud et al.,
world are TCCs, while SCCs represent the second most 1998; Simoneau et al., 1999; Sur et al., 2001). In addi-
common morphological type identified (Young, 1996). tion, the highly sensitive PCR technique was unable to
HPV-related papillomatous lesions are commonly disclose HPV DNA sequences in most studies.
found on the anogenital mucosa (zur Hausen, 1996), In contrast, data from a preliminary study performed
and in immunosuppressed patients these benign lesions by Moonen et al. (2007) that recently evaluated an
may involve the urothelial mucosa (Fig. 4.23) (Benoit association between HPV DNA, p53 status, and clini-
cal outcome in bladder cancer patients suggest a likely
correlation between tumor grade/stage and infection
with oncogenic HPV types.
Therefore, while available data appear not to sup-
port the etiological role of HPV in the development of
TCC and SCC of the bladder in immunocompetent
patients (Maloney et al., 1994; Lu et al., 1997; Gutierrez
et al., 2006), further studies are definitely required.

4.9.3 Prostate Cancer

Owing to the fact that HPV is sexually transmitted and

is commonly detected in anogenital cancers, many
Fig. 4.23. Vulvar neoplasia (virology HPV 16/18) invading ure- studies investigate the possible etiologic role of HPV
thra and bladder in immunosuppressed patient in prostate cancer.
References 93

Rabkin et al. (1992) reported that the risk of pros- References

tate cancer is increased in men who develop anal can-
cer, an HPV-related tumor. Agarwal C, Hembree JR, Rorke EA, Eckert RL (1994) Interferon
According to Choo et al. (1999), HPV E6 and E7 and retinoic acid suppress the growth of human papillomavi-
proteins can affect human prostate cells in vitro through rus type 16 immortalized cervical epithelial cells, but only
interferon suppresses the level of the human papillomavirus
their effects on the cellular tumor suppressor gene
transforming oncogenes. Cancer Res 54: 2108–2112
products p53 and Rb, respectively. However, studies Agliano AM, Gradilone A, Gazzaniga P, Napolitano M, Vercillo
on the detection of the virus in prostate tissues have R, Albonici L, Naso G, Manzari V, Frati L, Vecchione A
yielded conflicting results (McNicol and Dodd, 1990; (1994) High frequency of human papillomavirus detection
in urinary bladder cancer. Urol Int 53: 125–129
Anwar et al., 1992b; McNicol and Dodd, 1991; Ibrahim
Aguilar LV, Lazcano-Ponce E, Vaccarella S, Cruz A, Hernandez
et al., 1992; Dodd et al., 1993; Wideroff et al., 1996; P, Smith JS, Munoz N, Kornegay JR, Hernandez-Avila M,
Masood et al., 1991; Effert et al., 1992). Franceschi S (2006) Human papillomavirus in men: Compar­
Strickler et al. (1998) suggested that HPV DNA is ison of different genital sites. Sex Transm Infect 82: 31–33
Albarran YCA, de la Garza A, Cruz Quiroz BJ, Vazquez Zea E,
uncommon in the prostates of older men and is not
Diaz Estrada I, Mendez Fuentez E, Lopez Contreras M,
associated with prostate cancer. Andrade-Manzano A, Padilla S, Varela AR, Rosales R (2007)
In contrast, several studies also suggest that HPV MVA E2 recombinant vaccine in the treatment of human
type 16 antibodies may predict the development of papillomavirus infection in men presenting intraurethral flat
condyloma: A phase I/II study. BioDrugs 21: 47–59
future prostate cancer (Hisada et al., 2000; Dillner
Anwar K, Naiki H, Nakakuki K, Inuzuka M (1992a) High fre-
et al., 1998), and seropositivity against HPV 18 has quency of human papillomavirus infection in carcinoma of
been associated with a 2.6-fold increased risk of devel- the urinary bladder. Cancer 70: 1967–1973
oping prostate cancer (Dillner et al., 1998). Anwar K, Nakakuki K, Shiraishi T, Naiki H, Yatani R, Inuzuka
M (1992b) Presence of ras oncogene mutations and human
In conclusion, the association between HPV and/or
papillomavirus DNA in human prostate carcinomas. Cancer
other viral infections has not been substantiated by Res 52: 5991–5996
current studies and yet, if validated, the association Aynaud O (1992) Meatal spreader. J Urol 147: 409
would likely account for a small subset of prostate can- Aynaud O, Ionesco M, Barrasso R (2003) Cytologic detection of
human papillomavirus DNA in normal male urethral sam-
cers (Strickler and Goedert, 2001).
ples. Urology 61: 1098–1101
Aynaud O, Tranbaloc P, Orth G (1998) Lack of evidence for a
role of human papillomaviruses in transitional cell carci-
noma of the bladder. J Urol 159: 86–89; discussion 90
4.9.4 Renal Cancer Bans LL, Eble JN, Lingeman JE, Maynard BR (1983)
Transitional cell carcinoma of the fossa navicularis of the
male urethra. J Urol 129: 1055–1056
There are few studies and conflicting results regarding Barghi MR, Hajimohammadmehdiarbab A, Moghaddam SM,
the influence of HPV in the development of renal cell Kazemi B (2005) Correlation between human papillomavi-
carcinoma (RCC) (Rotola et al., 1992; Kamel et al., rus infection and bladder transitional cell carcinoma. BMC
Infect Dis 5: 102
1994). Benoit G, Orth G, Vieillefond A, Sinico M, Charpentier B, Jardin
Grce et al. (1997) using snap-frozen samples and A, Fries D (1988) Presence of papilloma virus type 11 in
PCR technology failed to detect HPV in both RCC condyloma acuminatum of bladder in female renal trans-
specimens and samples of corresponding normal renal plant recipient. Urology 32: 343–344
Beutner KR, Ferenczy A (1997) Therapeutic approaches to geni-
tissue. tal warts. Am J Med 102: 28–37
However, Kuwahara et al. (1998) analyzed the pres- Bloiso G, Warner R, Cohen M (1988) Treatment of urethral dis-
ence of HPV DNA and overexpression of the p53 protein eases with neodymium:YAG laser. Urology 32: 106–110
in 31 patients with carcinoma of the renal pelvis and ure- Bohle A, Doehn C, Kausch I, Jocham D (1998) Treatment of
recurrent penile condylomata acuminata with external appli-
ter. The investigators reported that HPV DNA 16 or 18 cation and intraurethral instillation of bacillus Calmette
was present in 9 of 28 patients with renal/ureteral TCC Guerin. J Urol 160: 394–396
and p53 expression was found in 7 of the TCC cases, Carpiniello VL, Schoenberg M, Malloy TR (1990) Long-term
suggesting that high-risk HPV types and p53 protein are followup of subclinical human papillomavirus infection
treated with the carbon dioxide laser and intraurethral 5-flu-
involved in the pathogenesis of urothelial tumors. orouracil: A treatment protocol. J Urol 143: 726–728
Additional research is needed before any causal Cecchini S, Cipparrone I, Confortini M, Scuderi A, Meini L,
relationship can be defined. Piazzesi G (1988) Urethral cytology of Cytobrush speci-
 94 4 Human Papillomavirus-Associated Lesions of the Urinary Tract

mens. A new technique for detecting subclinical human pap- Effert PJ, Frye RA, Neubauer A, Liu ET, Walther PJ (1992)
4 illomavirus infection in men. Acta Cytol 32: 314–317 Human papillomavirus types 16 and 18 are not involved in
Chan KW, Wong KY, Srivastava G (1997) Prevalence of six human prostate carcinogenesis: Analysis of archival human
types of human papillomavirus in inverted papilloma and prostate cancer specimens by differential polymerase chain
papillary transitional cell carcinoma of the bladder: an eva­ reaction. J Urol 147: 192–196
luation by polymerase chain reaction. J Clin Pathol 50: Fralick RA, Malek RS, Goellner JR, Hyland KM (1994)
1018–1021 Urethroscopy and urethral cytology in men with external
Chang F, Lipponen P, Tervahauta A, Syrjanen S, Syrjanen K genital condyloma. Urology 43: 361–364
(1994) Transitional cell carcinoma of the bladder: Failure to Friedman-Kien AE, Eron LJ, Conant M, Growdon W, Badiak H,
demonstrate human papillomavirus deoxyribonucleic acid Bradstreet PW, Fedorczyk D, Trout JR, Plasse TF (1988)
by in situ hybridization and polymerase chain reaction. Natural interferon alfa for treatment of condylomata acumi-
J Urol 152: 1429–1433 nata. JAMA 259: 533–538
Chen K, Chang BZ, Ju M, Zhang XH, Gu H (2007) Comparative Furihata M, Inoue K, Ohtsuki Y, Hashimoto H, Terao N, Fujita Y
study of photodynamic therapy vs CO2 laser vaporization in (1993) High-risk human papillomavirus infections and over-
treatment of condylomata acuminata: A randomized clinical expression of p53 protein as prognostic indicators in transi-
trial. Br J Dermatol 156: 516–520 tional cell carcinoma of the urinary bladder. Cancer Res 53:
Chetsanga C, Malmstrom PU, Gyllensten U, Moreno-Lopez J, 4823–4827
Dinter Z, Pettersson U (1992) Low incidence of human pap- Gartman E (1956) Intraurethral verruca acuminata in men.
illomavirus type 16 DNA in bladder tumor detected by the J Urol 75: 717–718
polymerase chain reaction. Cancer 69: 1208–1211 Giuliano AR, Nielson CM, Flores R, Dunne EF, Abrahamsen M,
Choo CK, Ling MT, Chan KW, Tsao SW, Zheng Z, Zhang D, Papenfuss MR, Markowitz LE, Smith D, Harris RB (2007)
Chan LC, Wong YC (1999) Immortalization of human pros- The optimal anatomic sites for sampling heterosexual men
tate epithelial cells by HPV 16 E6/E7 open reading frames. for human papillomavirus (HPV) detection: The HPV detec-
Prostate 40: 150–158 tion in men study. J Infect Dis 196: 1146–1152
Chrisofos M, Skolarikos A, Lazaris A, Bogris S, Deliveliotis C Gonzalvo Perez V, Ramada Benlloch F, Blasco Alfonso JE,
(2004) HPV 16/18-associated condyloma acuminatum of Donderis Guastavino C, Pallas Costa Y, Navalon Verdejo P,
the urinary bladder: First international report and review of Zaragoza Orts J (1994) [Endoscopic electrofulguration of
literature. Int J STD AIDS 15: 836–838 intraurethral condylomata acuminata]. Actas Urol Esp 18:
Chuang TY, Perry HO, Kurland LT, Ilstrup DM (1984) 234–236
Condyloma acuminatum in Rochester, Minn., 1950–1978. I. Graversen PH, Bagi P, Rosenkilde P (1990) Laser treatment of
Epidemiology and clinical features. Arch Dermatol 120: recurrent urethral condylomata acuminata in men. Scand J
469–475 Urol Nephrol 24: 163–166
Clinical Effectiveness Group BAfSHaHB (2007) United Grce M, Furcic I, Hrascan R, Husnjak K, Krhen I, Marekovic Z,
Kingdom national guideline on the management of anogeni- Zeljko Z, Pavelic K (1997) Human papillomaviruses are not
tal warts. In: British Association for Sexual Health and HIV associated with renal carcinoma. Anticancer Res 17:
(BASHH), London (UK) 2193–2196
Culp OS, Kaplan IW (1944) Condylomata acuminata: Two hun- Green J, Monteiro E, Bolton VN, Sanders P, Gibson PE (1991)
dred cases treated with podophyllin. Ann Surg 120: Detection of human papillomavirus DNA by PCR in semen
251–256 from patients with and without penile warts. Genitourin Med
de Carvalho JJ, Syrjanen KJ, Jacobino M, Rosa NT, Carvalho 67: 207–210
LZ (2006) Prevalence of genital human papillomavirus Griffiths TR, Mellon JK (2000) Human papillomavirus and uro-
infections established using different diagnostic techniques logical tumours: II. Role in bladder, prostate, renal and tes-
among males attending a urological clinic. Scand J Urol ticular cancer. BJU Int 85: 211–217
Nephrol 40: 138–143 Gutierrez J, Jimenez A, de Dios Luna J, Soto MJ, Sorlozano A
De Gaetani C, Ferrari G, Righi E, Bettelli S, Migaldi M, Ferrari (2006) Meta-analysis of studies analyzing the relationship
P, Trentini GP (1999) Detection of human papillomavirus between bladder cancer and infection by human papilloma-
DNA in urinary bladder carcinoma by in situ hybridisation. virus. J Urol 176: 2474–2481; discussion 2481
J Clin Pathol 52: 103–106 Herberman RB, Ortaldo JR, Mantovani A, Hobbs DS, Kung HF,
D’Hauwers K, Depuydt C, Bogers JP, Stalpaert M, Vereecken A, Pestka S (1982) Effect of human recombinant interferon on
Wyndaele JJ, Tjalma W (2007) Urine versus brushed sam- cytotoxic activity of natural killer (NK) cells and monocytes.
ples in human papillomavirus screening: Study in both gen- Cell Immunol 67: 160–167
ders. Asian J Androl 9: 705–710 Hisada M, Rabkin CS, Strickler HD, Wright WE, Christianson
Dillner J, Knekt P, Boman J, Lehtinen M, Af Geijersstam V, RE, van den Berg BJ (2000) Human papillomavirus anti-
Sapp M, Schiller J, Maatela J, Aromaa A (1998) Sero- body and risk of prostate cancer. JAMA 283: 340–341
epidemiological association between human-papillomavirus Huguet Perez J, Errando Smet C, Regalado Pareja R, Rosales
infection and risk of prostate cancer. Int J Cancer 75: Bordes A, Salvador Bayarri J, Vicente Rodriguez J (1996)
564–567 [Urethral condyloma in the male: Experience with 48 cases].
Dodd JG, Paraskevas M, McNicol PJ (1993) Detection of human Arch Esp Urol 49: 675–680
papillomavirus 16 transcription in human prostate tissue. Ibrahim GK, Gravitt PE, Dittrich KL, Ibrahim SN, Melhus O,
J Urol 149: 400–402 Anderson SM, Robertson CN (1992) Detection of human
Dyment PG (1996) Human papillomavirus infection. Adolesc papillomavirus in the prostate by polymerase chain reaction
Med 7: 119–130 and in situ hybridization. J Urol 148: 1822–1826
References 95

Iwasawa A, Hiltunen-Back E, Reunala T, Nieminen P, Paavonen Mvula M, Iwasaka T, Iguchi A, Nakamura S, Masaki Z, Sugimori
J (1997) Human papillomavirus DNA in urine specimens of H (1996) Do human papillomaviruses have a role in the
men with condyloma acuminatum. Sex Transm Dis 24: pathogenesis of bladder carcinoma. J Urol 155: 471–474
165–168 Noel JC, Thiry L, Verhest A, Deschepper N, Peny MO, Sattar
Jones DJ (1991) Haemospermia: A prospective study. Br J Urol AA, Schulman CC, Haot J (1994) Transitional cell carci-
67: 88–90 noma of the bladder: Evaluation of the role of human papil-
Kamel D, Turpeenniemi-Hujanen T, Vahakangas K, Paakko P, lomaviruses. Urology 44: 671–675
Soini Y (1994) Proliferating cell nuclear antigen but not p53 Nuovo GJ, Hochman HA, Eliezri YD, Lastarria D, Comite SL,
or human papillomavirus DNA correlates with advanced Silvers DN (1990) Detection of human papillomavirus DNA
clinical stage in renal cell carcinoma. Histopathology 25: in penile lesions histologically negative for condylomata.
339–347 Analysis by in situ hybridization and the polymerase chain
Kaplinsky RS, Pranikoff K, Chasan S, DeBerry JL (1995) reaction. Am J Surg Pathol 14: 829–836
Indications for urethroscopy in male patients with penile Olsen S, Marcussen N, Jensen KM, Lindeberg H (1995) Urethral
condylomata. J Urol 153: 1120–1121 condylomata, due to human papilloma virus (HPV) type 6/11.,
Katelaris PM, Cossart YE, Rose BR, Thompson CH, Sorich E, associated with transitional cell tumors in the bladder and ure-
Nightingale B, Dallas PB, Morris BJ (1988) Human papil- ter. A case report. Scand J Urol Nephrol Suppl 172: 51–55
lomavirus: The untreated male reservoir. J Urol 140: Rabkin CS, Biggar RJ, Melbye M, Curtis RE (1992) Second pri-
300–305 mary cancers following anal and cervical carcinoma:
Kilciler M, Bedir S, Erdemir F, Coban H, Erten K, Ors O, Ozgok Evidence of shared etiologic factors. Am J Epidemiol 136:
Y (2007) Condylomata acuminata of external urethral 54–58
meatus causing infravesical obstruction. Int Urol Nephrol Rintala MA, Grenman SE, Pollanen PP, Suominen JJ, Syrjanen
39: 107–109 SM (2004) Detection of high-risk HPV DNA in semen and
Knowles MA (1992) Human papillomavirus sequences are not its association with the quality of semen. Int J STD AIDS 15:
detectable by Southern blotting or general primer-mediated 740–743
polymerase chain reaction in transitional cell tumours of the Rintala MA, Pollanen PP, Nikkanen VP, Grenman SE, Syrjanen
bladder. Urol Res 20: 297–301 SM (2002) Human papillomavirus DNA is found in the vas
Krogh J, Beuke HP, Miskowiak J, Honnens de Lichtenberg M, deferens. J Infect Dis 185: 1664–1667
Nielsen OS (1990) Long-term results of carbon dioxide laser Rosemberg SK, Jacobs H, Fuller T (1982) Some guidelines in
treatment of meatal condylomata acuminata. Br J Urol 65: the treatment of urethral condylomata with carbon dioxide
621–623 laser. J Urol 127: 906–908
Kuwahara M, Fujisaki N, Kagawa S, Furihata M, Ohtsuki Y Rosemberg SK, Reid R, Greenberg M, Lorincz AT (1988)
(1998) Determination of p53 protein and high-risk human Sexually transmitted papillomaviral infection in the male: II.
papillomavirus DNA in carcinomas of the renal pelvis and The urethral reservoir. Urology 32: 47–49
ureter. Int J Mol Med 1: 703–707 Rothman I, Berger RE, Kiviat N, Navarro AL, Remington ML
Levine LA, Elterman L, Rukstalis DB (1996) Treatment of sub- (1994) Urethral meatal warts in men: results of urethroscopy
clinical intraurethral human papilloma virus infection with and biopsy. J Urol 151: 875–877
interferon alfa-2b. Urology 47: 553–557 Rotola A, Monini P, Di Luca D, Savioli A, Simone R, Secchiero
Lu QL, Lalani el N, Abel P (1997) Human papillomavirus 16 P, Reggiani A, Cassai E (1992) Presence and physical state
and 18 infection is absent in urinary bladder carcinomas. Eur of HPV DNA in prostate and urinary-tract tissues. Int J
Urol 31: 428–432 Cancer 52: 359–365
Maloney KE, Wiener JS, Walther PJ (1994) Oncogenic human Salmon SE, Durie BG, Young L, Liu RM, Trown PW, Stebbing
papillomaviruses are rarely associated with squamous cell N (1983) Effects of cloned human leukocyte interferons in
carcinoma of the bladder: Evaluation by differential poly- the human tumor stem cell assay. J Clin Oncol 1: 217–225
merase chain reaction. J Urol 151: 360–364 Sand PK, Shen W, Bowen LW, Ostergard DR (1987) Cryotherapy
Masood S, Rhatigan RM, Powell S, Thompson J, Rodenroth N for the treatment of proximal urethral condyloma acumina-
(1991) Human papillomavirus in prostatic cancer: No evi- tum. J Urol 137: 874–876
dence found by in situ DNA hybridization. South Med J 84: Sano T, Sakurai S, Fukuda T, Nakajima T (1995) Unsuccessful
235–236 effort to detect human papillomavirus DNA in urinary blad-
McKenna JG, McMillan A (1990) Management of intrameatal der cancers by the polymerase chain reaction and in situ
warts in men. Int J STD AIDS 1: 259–263 hybridization. Pathol Int 45: 506–512
McNicol PJ, Dodd JG (1990) Detection of papillomavirus DNA Sawczuk I, Badillo F, Olsson CA (1983) Condylomata acumi-
in human prostatic tissue by Southern blot analysis. Can J nata: Diagnosis and follow-up by retrograde urethrography.
Microbiol 36: 359–362 Urol Radiol 5: 273–274
McNicol PJ, Dodd JG (1991) High prevalence of human papil- Scheinfeld N, Lehman DS (2006) An evidence-based review of
lomavirus in prostate tissues. J Urol 145: 850–853 medical and surgical treatments of genital warts. Dermatol
Mevorach RA, Cos LR, di Sant’Agnese PA, Stoler M (1990) Online J 12: 5
Human papillomavirus type 6 in grade I transitional cell car- Shaw MB, Payne SR (2007) A simple technique for accurate
cinoma of the urethra. J Urol 143: 126–128 diathermy destruction of urethral meatal warts. Urology 69:
Moonen PM, Bakkers JM, Kiemeney LA, Schalken JA, Melchers 975–976
WJ, Witjes JA (2007) Human papilloma virus DNA and p53 Shibutani YF, Schoenberg MP, Carpiniello VL, Malloy TR
mutation analysis on bladder washes in relation to clinical (1992) Human papillomavirus associated with bladder can-
outcome of bladder cancer. Eur Urol 52: 464–468 cer. Urology 40: 15–17
 96 4 Human Papillomavirus-Associated Lesions of the Urinary Tract

Simoneau M, LaRue H, Fradet Y (1999) Low frequency of Wang XL, Wang HW, Wang HS, Xu SZ, Liao KH, Hillemanns P
4 human papillomavirus infection in initial papillary bladder (2004) Topical 5-aminolaevulinic acid-photodynamic ther-
tumors. Urol Res 27: 180–184 apy for the treatment of urethral condylomata acuminata. Br
Sinclair AL, Nouri AM, Oliver RT, Sexton C, Dalgleish AG J Dermatol 151: 880–885
(1993) Bladder and prostate cancer screening for human Wen YC, Wu HH, Chen KK (2006) Pan-urethral wart treated
papillomavirus by polymerase chain reaction: Conflicting with 5-fluorouracil intraurethral instillation. J Chin Med
results using different annealing temperatures. Br J Biomed Assoc 69: 391–392
Sci 50: 350–354 Wideroff L, Schottenfeld D, Carey TE, Beals T, Fu G, Sakr W,
Smetana Z, Keller T, Leventon-Kriss S, Huszar M, Lindner A, Sarkar F, Schork A, Grossman HB, Shaw MW (1996)
Mitrani-Rosenbaum S, Mendelson E, Smetana S (1995) Human papillomavirus DNA in malignant and hyperplas-
Presence of human papilloma virus in transitional cell carci- tic prostate tissue of black and white males. Prostate 28:
noma in Jewish population in Israel. Cell Mol Biol (Noisy- 117–123
le-grand) 41: 1017–1023 Wiener JS, Liu ET, Walther PJ (1992) Oncogenic human papil-
Smetana Z, Malik Z, Orenstein A, Mendelson E, Ben-Hur E lomavirus type 16 is associated with squamous cell cancer of
(1997) Treatment of viral infections with 5-aminolevulinic the male urethra. Cancer Res 52: 5018–5023
acid and light. Lasers Surg Med 21: 351–358 Wiener JS, Walther PJ (1994) A high association of oncogenic
Steele GS, Fielding JR, Renshaw A, Loughlin KR (1997) human papillomaviruses with carcinomas of the female ure-
Transitional cell carcinoma of the fossa navicularis. Urology thra: Polymerase chain reaction-based analysis of multiple
50: 792–795 histological types. J Urol 151: 49–53
Strand A, Rylander E, Wilander E, Zehbe I, Kraaz W (1996) Wiwanitkit V (2005) Urinary bladder carcinoma and human
Histopathologic examination of penile epithelial lesions is papilloma virus infection, an appraisal of risk. Asian Pac J
of limited diagnostic value in human papillomavirus infec- Cancer Prev 6: 217–218
tion. Sex Transm Dis 23: 293–298 Workowski KA, Berman SM (2007) Centers for Disease Control
Strickler HD, Burk R, Shah K, Viscidi R, Jackson A, Pizza G, and Prevention sexually transmitted diseases treatment
Bertoni F, Schiller JT, Manns A, Metcalf R, Qu W, Goedert guidelines. Clin Infect Dis 44(Suppl 3): S73–S76
JJ (1998) A multifaceted study of human papillomavirus and Young R (1996) Usual variants of primary bladder lesions and
prostate carcinoma. Cancer 82: 1118–1125 secondary tumours of the bladder. In: Pathology of bladder
Strickler HD, Goedert JJ (2001) Sexual behavior and evidence cancer. Williams and Wilkins, Baltimore, pp 326–337
for an infectious cause of prostate cancer. Epidemiol Rev 23: Youshya S, Purdie K, Breuer J, Proby C, Sheaf MT, Oliver RT,
144–151 Baithun S (2005) Does human papillomavirus play a role in
Sumino Y, Emoto A, Satoh F, Nakagawa M, Mimata H (2006) the development of bladder transitional cell carcinoma? A
Transitional cell carcinoma of the navicular fossa detected comparison of PCR and immunohistochemical analysis.
human papillomavirus 16. Int J Urol 13: 645–647 J Clin Pathol 58: 207–210
Sumino Y, Mimata H, Nomura Y (2004) Urethral condyloma Yu Z, Xia T, Xue Z (1999) [The detection of high risk human pap-
acuminata following urethral instrumentation in an elderly illomaviruses in papillary transitional cell carcinoma of uri-
man. Int J Urol 11: 928–930 nary bladder]. Zhonghua Wai Ke Za Zhi 37: 369–371; 322
Sur M, Cooper K, Allard U (2001) Investigation of human papil- Zaak D, Hofstetter A, Frimberger D, Schneede P (2003)
lomavirus in transitional cell carcinomas of the urinary blad- Recurrence of condylomata acuminata of the urethra after
der in South Africa. Pathology 33: 17–20 conventional and fluorescence-controlled Nd:YAG laser
Takatsuki K, Kamiyama Y, Sato S, Amemiya H, Iizumi T, Yazaki treatment. Urology 61: 1011–1015
T, Umeda T (1993) [A case report of condyloma acuminatum Zderic SA, Carpiniello VL, Malloy TR, Rando RF (1989)
of urethral meatus in a boy]. Hinyokika Kiyo 39: 479–481 Urological applications of human papillomavirus typing
Thin RN (1992) Meatoscopy: A simple technique to examine the using deoxyribonucleic acid probes for the diagnosis and
distal anterior urethra in men. Int J STD AIDS 3: 21–23 treatment of genital condyloma. J Urol 141: 63–65
Volz LR, Carpiniello VL, Malloy TR (1994) Laser treatment of Zheng W, Vilos G, McCulloch S, Borg P, Denstedt JD (2000)
urethral condyloma: A five-year experience. Urology 43: Electrical burn of urethra as cause of stricture after transure-
81–83 thral resection. J Endourol 14: 225–228
von Krogh G (2001) Management of anogenital warts (condylo- zur Hausen H (1996) Papillomavirus infections - a major cause
mata acuminata). Eur J Dermatol 11: 598–603; quiz 604 of human cancers. Biochim Biophys Acta 1288: F55–F78
 Human Papillomavirus and Penile
Intraepithelial Neoplasia 5
Alberto Rosenblatt and Homero Gustavo de Campos Guidi

Contents 5.7.3 Treatment................................................................. 112

5.7.4 Follow-Up............................................................... 113
5.1 Introduction........................................................... 97 5.8 Penile Horn............................................................ 113
5.2 Terminology........................................................... 98 5.8.1 Predisposing Factors............................................... 113
5.2.1 Differentiated PIN................................................... 98 5.8.2 Pathogenesis............................................................ 114
5.2.2 Undifferentiated PIN............................................... 99 5.8.3 Clinical Manifestations........................................... 114
5.8.4 Diagnosis................................................................. 114
5.3 Overview................................................................ 99 5.8.5 Treatment................................................................. 114
5.3.1 Natural History of PINs........................................... 101 5.8.6 Follow-Up............................................................... 114
5.3.2 Incidence................................................................. 101
5.3.3 Risk Factors............................................................. 102 5.9 Genital Paget’s Disease......................................... 114
5.3.4 Differential Diagnosis............................................. 102 5.9.1 Clinical Manifestations........................................... 115
5.9.2 Treatment................................................................. 115
5.4 Multifocal Intraepithelial Neoplasia
(Bowenoid Papulosis)............................................ 102 5.10 Kaposi’s Sarcoma.................................................. 115
5.4.1 Clinical Manifestations........................................... 103 5.10.1 Clinical Manifestations........................................... 116
5.4.2 Diagnosis................................................................. 104 5.10.2 Treatment................................................................. 116
5.4.3 Treatment................................................................. 104
5.4.4 Follow-Up............................................................... 104 5.11 PIN Prevention...................................................... 116
5.5 Bowen’s Disease..................................................... 105 References.............................................................. 116
5.5.1 Risk Factors............................................................. 105
5.5.2 Clinical Manifestations........................................... 105
5.5.3 Diagnosis................................................................. 105
5.5.4 Treatment................................................................. 105 5.1 Introduction
5.5.5 Follow-Up............................................................... 107
5.6 Erythroplasia of Queyrat (Unifocal
Intraepithelial Neoplasia)..................................... 107 Following the increase in the investigation of the male
5.6.1 Clinical Manifestations........................................... 107 partner for human papillomavirus (HPV), along with
5.6.2 Differential Diagnosis............................................. 107
novel detection methods and organ-confined nomen-
5.6.3 Diagnosis................................................................. 107
5.6.4 Treatment................................................................. 109 clature, a multitude of diagnoses of penile intraepithe-
5.6.5 Follow-Up............................................................... 110 lial neoplasias (PINs) are now being presented to
5.7 Penile Lichen Sclerosus......................................... 110 medical practitioners involved in the treatment of
5.7.1 Clinical Manifestations........................................... 111 HPV-related diseases.
5.7.2 Diagnosis................................................................. 111 PIN is the term presently used to describe a precan-
cerous lesion of the penis.
A. Rosenblatt (*) HPV infection is associated with PIN development,
Albert Einstein Jewish Hospital, Sao Paulo, Brasil and PIN progression to penile invasive disease is an
e-mail: [email protected] uncommon but possible event.

A. Rosenblatt, H. G. de Campos Guidi, Human Papillomavirus, 97

DOI: 10.1007/978-3-540-70974-9-5, © Springer-Verlag Berlin Heidelberg 2009
 98 5 Human Papillomavirus and Penile Intraepithelial Neoplasia

This chapter reviews current concepts of PINs,

5 including distinctive clinical findings, grading and ter-
minology, diagnosis, and therapeutic options.

5.2 Terminology

The generic term “penile intraepithelial neoplasia”

(“Tis” in the TNM classification) is a histological
entity equivalent to penile dysplasia. Squamous intra-
epithelial lesion (SIL) is another recommended term
to describe atypical lesions of the penile epithelium.
According to the level of dysplastic abnormalities
(i.e., morphologic criteria and tissue architecture, where
the level of epithelial involvement by disorderly growth
and cytologic atypia are analyzed), penile squamous
intraepithelial lesions (or PIN) may be divided into
low-grade (PIN 1) (Fig. 5.1a, b) and high-grade (PIN 3/
in situ) lesions (Fig. 5.2a–c) (see also Chaps. 7 and 8).

What Happened to PIN 2?

The categorization of SILs into low- and high-grade

depends mainly on the degree of koilocytosisa
found, since koilocytosis translates into significant
cellular differentiation (albeit associated with HPV
infection). Like cervical intraepithelial neoplasia 2
Fig. 5.1. (a) Penile intraepithelial neoplasia 1 (PIN 1). (b) PIN 1
(CIN 2), vaginal intraepithelial neoplasia 2 (VaIN with HPV-positive cell stained in red (immunohistochemistry)
2), and anal intraepithelial neoplasia 2 (AIN 2), PIN (Source: Photograph courtesy of Monica Stiepcich MD, PhD,
2 constitutes a group of lesions exhibiting variable São Paulo, Brazil)
degrees of koilo­cytosis, and therefore subjected to
different interobserver interpretations (Fig. 5.3a, b). PIN and vulvar intraepithelial neoplasia (VIN)
Therefore, the utilization of a Bethesda-type cate- share clinical and histological similarities and, accord-
gorization (low- and high-grade) is recommended ing to Aynaud and Bergeron (2004), PIN can be cate-
until more sensitive and less subjective risk markers gorized according to the same criteria recommended
for grading are available (Carvalho, personal com- by the International Society for the Study of Vulvar
munication, 31 October 2008). Disease (ISSVD) (Bergeron, 2008). Based on the eti-
ology and natural history of the penile lesion, PIN can
a
The presence of koilocytes (Fig. 5.4) is a morphological be characterized as differentiated and undifferentiated
indication of HPV infection. (Aynaud and Bergeron, 2004).

Moreover, according to Cubilla et al. (2000), low-

and high-grade SILs can be further classified into:
5.2.1 Differentiated PIN
Squamous or simplex (the most frequent types)
Warty (condylomatous) (Fig. 5.5) and basaloid The atypia of differentiated PIN is confined to the infe-
(Fig. 5.6a, b) rior layers of the epithelium and usually originates
from chronic benign balanopreputial lesions, such as
Both warty and basaloid types are associated with
penile lichen sclerosus (LS), extramammary Paget’s
HPV infection, whereas the typical squamous type
disease (EMPD) involving the genital region, and
is not related to HPV.
Kaposi’s sarcoma (KS).
5.3 Overview 99

Fig. 5.2. (a) Transition PIN 3 and normal epithelium (Source: Photograph courtesy of Filomena Marino Carvalho MD, PhD, São
Paulo, Brazil). (b) PIN 3 – severe ­dysplasia (Source: Photograph courtesy of Rubens Pianna de Andrade MD, PhD/ Monica Stiepcich
MD, PhD São Paulo, Brazil). (c) PIN 3 detailed (Source: Photograph courtesy of Monica Stiepcich MD, PhD, São Paulo, Brazil)

5.2.2 Undifferentiated PIN associated with squamous cell carcinoma (SCC) of the
penis. However, Porter et al. (2002) describe BP as a
Undifferentiated PIN is currently been used to describe low-grade SCC in situ, although clinically distinct
the premalignant conditions of the penis formerly from BD and EQ.
referred to as Bowen’s disease (BD) and erythroplasia Furthermore, BP can also be categorized as a form
of Queyrat (EQ). The dysplasia found in undifferenti- of cutaneous dysplasia (Micali et al., 2006).
ated PIN involves more than two-thirds of the mucosa BD and EQ are probably the same entity, as they
thickness and the lesions usually present a higher his- share similar clinicopathological features.
tological grade (PIN 3/in situ). High-risk HPV infec-
SCC in situ presenting on the shaft of the penis is
tion is usually associated with undifferentiated PIN
known as BD.
(Fig. 5.7), but koilocytosis (the pathognomonic feature
SCC in situ presenting on the mucous membranes of
of HPV infection) is not ­frequently observed.
the glans penis, prepuce, coronal sulcus, frenulum,
and urethral meatus is referred to as EQ.
These premalignant skin disorders display the same
5.3 Overview microscopic features of SCC in situ, such as epithelial
proliferation, hyperkeratosis, and marked parakerato-
sis. The cell nuclei are hyperchromatic, clumped, and
The classification of bowenoid papulosis (BP) is still a show lack of organization, maturation, and cohesion.
matter of debate among authors. According to Solsona Mitotic figures are prominent throughout the layers
et al. (2004), BP is a disorder that is sporadically and abnormal forms are regularly found.
 100 5 Human Papillomavirus and Penile Intraepithelial Neoplasia

Fig. 5.5. Warty (condylomatous) type. (Source: Photograph

courtesy of Filomena Marino Carvalho MD, PhD, São Paulo,
Brazil)

Fig. 5.3. (a)(b) Moderate dysplasia. (Source: Photo­graph cour-

tesy of Monica Stiepcich MD, PhD, São Paulo, Brazil)

Fig. 5.4. Koilocytes. (Source: Photograph courtesy of Filomena Fig. 5.6. (a)(b) Basaloid type. (Source: Photograph courtesy of
Marino Carvalho MD, PhD, São Paulo, Brazil) Filomena Marino Carvalho MD, PhD, São Paulo, Brazil)
5.3 Overview 101

Expert Advice

The importance of the acetowhite test in the diagno-

sis and treatment of PIN is paramount. It allows for
the exact location of the lesion and delimitates the
area to be excised. Although the correlation between
peniscopic images and histology is still not well
defined (Horenblas, 2008), the execution of the ace-
towhite test during laser surgery performed with the
operating microscope has been shown to increase
the efficacy of conservative approaches for the treat-
ment of in situ and superficial penile cancers
(Bandieramonte et al., 2008). Moreover, it is also
used as an adjunct to modern surgical techniques
employed for the treatment of premalignant lesions
of the penis (Hadway et al., 2006) (see Sect. 5.6.4.8).
(See also How to Perform the Acetowhite Test in
Chap. 3).

to these results, the investigators recommend that

patients presenting with low-grade PIN should be reas-
sured of the benign behavior of these lesions. The same
affirmative attitude should be given to patients present-
ing with PIN 3, although treatment and surveillance
Fig. 5.7. PIN 3 – in situ hybridization showing HPV 16. (Source: are required in these cases.
Photograph courtesy of Monica Stiepcich MD, PhD, São Paulo, Bandieramonte et al. (2008) recently performed a
Brazil)
retrospective analysis of 106 patients with penile car-
cinoma in situ treated with CO2 laser excision under
Progression to frankly invasive SCC can occur if peniscopic control. The authors reported that in only
lesions are left untreated, but it is a rare event. three cases could the resection margins not be clearly
PINs comprising BD, EQ, and BP are considered evaluated because of thermal artifacts. Lesion recur-
precursor lesions of basaloid and warty carcinomas of rences (22 in 12 patients) were in situ mostly and
the penis, which are frequently associated with HPV occurred in both treated and untreated areas.
infection (Gross and Pfister, 2004). The distinct epidemiology and the variable clinical
characteristics presented by premalignant penile enti-
ties must be fully understood so as to avoid diagnostic
5.3.1 Natural History of PINs inaccuracies that may impact on prognosis.

The majority of PINs are completely asymptomatic.

Expert Advice
These premalignant penile disorders generally appear
as clinically suspicious flat acetowhite lesions that Any long-lasting penile lesion that is unresponsive
mandate biopsy; hence, the correct diagnosis is made to classic medical treatments should be biopsied
histologically. Furthermore, oncogenic HPV types 16, and sent for histological examination to exclude a
18, and 33 are usually associated with these lesions. possible SCC in situ (PIN) or invasive SCC.
In a preliminary analysis that evaluated the natural
history of PIN lesions, Guidi et al. (2007) reported no
malignant progression in all 17 patients with untreated 5.3.2 Incidence
PIN 1/2. In addition, no evidence of disease was found
in six patients with PIN 3 treated with CO2 laser during PIN is considered a rare disorder, although its real inci-
a mean follow-up of 51 months. Therefore, according dence is unknown.
 102 5 Human Papillomavirus and Penile Intraepithelial Neoplasia

The association of PIN with distinct HPV types that

5 carry oncogenic potential may possibly influence future
epidemiologic data, but evidence-based prospective
studies are still needed to correctly define the natural
history of this disorder.

5.3.3 Risk Factors

Lack of circumcision – According to Schoen et al.

(2000), circumcision at birth has a protective effect
for SCC in situ, but protection is less evident than for
invasive SCC.
Chronic inflammatory dermatologic diseases of the Fig. 5.8. Nevus at the penile shaft
penis such as lichen sclerosus (LS) (Nasca et al.,
2003; Barbagli et al., 2006).
HPV infection.
Immunosuppression.

5.3.4 Differential Diagnosis

Pigmented warts (see Expert Advice below (Fig.

5.14a, b))
Seborrheic keratosis
Nevi (Fig. 5.8) and melanoma
Lentigo (Fig. 5.9)
Angiokeratoma (Fig. 5.10)
Lichen planus (Fig. 5.11)
Psoriatic lesions (Fig. 5.18)
Fig. 5.9. Penile lentigo

5.4 Multifocal Intraepithelial Neoplasia

(Bowenoid Papulosis)

Bowenoid papulosis (BP) is a dermatological term

coined by Wade, Kopf, and Ackerman (Wade et al.) in
1978. BP lesions have been described in young men
and women (usually at the vulva), and gynecologists
still refer to the disease as multifocal VIN.
BP is considered a low-grade SCC in situ, although
it can also be categorized as a form of cutaneous
dysplasia.
BP, BD, and EQ can occur concurrently (Porter
et al., 2002). Fig. 5.10. Penile shaft angiokeratoma
5.4 Multifocal Intraepithelial Neoplasia (Bowenoid Papulosis) 103

5.4.1.2 Presentation

Multiple, small, darkly pigmented flat papules

(Fig. 5.12) or patches mainly located on the penis
shaft (Fig. 5.13), but glans penis, foreskin, and peria-
nal area can also be affected.
Lesions range in color from brown to pink (flesh-
colored) and red.
Lesions sometimes may coalesce and form large
plaques.

Expert Advice

Fig. 5.11. Lichen planus – white geographical annular plaques BP lesions are less papillomatous than common
genital viral condyloma lesions and usually present
a smooth-topped brown aspect (Fig. 5.14a, b).
BP mainly occurs in sexually active young men
(average age – 30 years).
It is highly prevalent in uncircumcised patients
(Porter et al., 2002), despite the original report by
Wade et al. (1978) of a higher BP prevalence in cir-
cumcised patients.
Several HPV DNA genotypes have been dete­cted by
Hama et al. (2006), particularly high-risk type 16.
Female sexual partners of affected men have a higher
risk of developing cervical neoplasia (Obalek et al.,
1986).
The full-blown lesion may evolve over a period of
weeks or months.
Spontaneous regression of the lesions may occur
within several months and, according to Yoneta et al.
(2000), progression to invasive disease is an uncom-
mon event. Fig. 5.12. Bowenoid papulosis – multiple, small, darkly pig-
However, immunocompromised individuals and mented flat papules
elderly patients are at higher risk of disease progres-
sion (Schwartz and Janniger, 1991).
Feldman et al. (1989) recommend that the immuno-
logic status should always be evaluated in patients
with persistent BP lesions.

5.4.1 Clinical Manifestations

5.4.1.1 Symptoms

Mostly asymptomatic.
Pruritus (usually present in 30–50% of women).
BP lesions may occasionally show inflammatory
signs. Fig. 5.13. Bowenoid papulosis located on the penis shaft
 104 5 Human Papillomavirus and Penile Intraepithelial Neoplasia

5 Expert Advice

The finding of inclusion-like bodies associated with

the presence of innumerous mitoses in metaphase
(“star-shaped” figures) may help differentiate BP
from BD. However, correlation with clinical find-
ings is essential for the correct diagnosis of BP.

5.4.3 Treatment

The main objective is the complete destruction of the

lesions without the need for wide surgical margins. BP
lesions can be adequately treated by surgical removal,
electrosurgery, and cryosurgery, in much the same way
as HPV-related lesions (see Chap. 3).

5.4.3.1 CO2 Laser

Advantages

Recurrence rate: 0–33%, according to a study per-

formed by von Krogh and Horenblas (2000)

5.4.3.2 5-Fluorouracil Cream

There are few evidence-based reports using 5-fluorou-

racil (5-FU) for the treatment of BP.
Therapeutic regimen – 5-FU cream applied twice
daily for 3 weeks (Porter et al., 2002).
Fig. 5.14. (a) Bowenoid papulosis lesions – smooth-topped
brown aspect. (b) Keratotic shaft papules, HPV-related

5.4.3.3 Imiquimod Cream (Aldara®)

5.4.2 Diagnosis
Advantages
Physical examination
Biopsy and histopathological examination Efficacy – Complete clearance of the lesions reported
on a small number of patients (Wigbels et al., 2001;
Goorney and Polori, 2004). Additional studies are
5.4.2.1 Histological Findings required to assess efficacy.
Therapeutic regimen – Imiquimod cream is applied on
Epidermal thickening.
alternate days for up to 3 months (Porter et al., 2002).
Small and scattered atypical basaloid keratinocytes
with large, hyperchromatic, pleomorphic nucleus,
and frequent mitoses. 5.4.4 Follow-Up
The dermal-epidermal border is preserved.
Inclusion-like bodies may be found in the stratum Patients should be instructed for self-examination and
corneum and granular cell layer. self-referral if a suspicious lesion is found.
5.5 Bowen’s Disease 105

A routine follow-up visit 3–6 months after treatment

is recommended to check for recurrences, but immuno-
suppressed patients should be carefully screened for
possible progression to penile SCC.

5.5 Bowen’s Disease

SCC in situ presenting on the shaft of the penis is

known as Bowen’s disease (BD).
BD of the penis most often affects elderly (>50 years)
uncircumcised white men and, if untreated, progression
to invasive disease has been reported in approximately
5% of cases (Cox et al., 2007; Lucia and Miller, 1992).
Fig. 5.15. Bowen’s disease - nodular presentation

5.5.1 Risk Factors

Presence of foreskin BD diagnosis is usually delayed for weeks or

Poor genital hygiene months because of the insidious onset and gradual
Lichen sclerosus progression of the lesion.
Preceding or concurrent papillomavirus infection (HPV
types 16, 18, and 57b), according to studies per­formed
by Ikenberg et al. (1983) and Ohnishi et al. (1999) 5.5.3.1 Histological Findings

Epidermal acanthosis and parakeratosis.

5.5.2 Clinical Manifestations Replacement of mature keratinocytes with dysplas-
tic cells showing nuclear atypia.
5.5.2.1 Symptoms Involvement of follicle-bearing epithelium by atypi-
cal cells.
Asymptomatic The dermis presents an inflammatory infiltrate but
Pruritus (the most common reason to seek medical basal cells are normal.
care and usually present in about 50% of women)
Pain
Crusting, scaling, or bleeding 5.5.4 Treatment
Difficulty in retracting the foreskin
Surgical excision is the best treatment option for small
lesions, according to von Krogh and Horenblas (2000).
5.5.2.2 Presentation
BD recurrences from secondary progression of
atypical cells in the epidermal lining of the hair follicle
Isolated and well-defined reddish scaly plaque with
occur frequently, particularly when using treatment
surface fissures and sometimes presenting foci of
modalities such as topical 5-FU or electrosurgery.
pigmentation located on the shaft of the penis.
Treatment should be applied to the visible lesion and
BD lesions grow slowly and may eventually ulcerate
to the bordering normal tissue, but a penis-preserving
or develop a nodular appearance (Fig. 5.15), sug-
strategy is strongly recommended.
gesting progression to malignant disease.

5.5.4.1 Surgical Excision and Electrosurgery

5.5.3 Diagnosis
Indication
Physical examination
Biopsy and histopathological examination Small lesions
 106 5 Human Papillomavirus and Penile Intraepithelial Neoplasia

Advantages 5.5.4.4 Imiquimod Cream (Aldara®)

5
Efficacy – regarded by Cox et al. (2007) as an effec- Indication
tive treatment with low recurrence rates, although
evidence-based results are limited Large lesions
Therapeutic regimen – Topical imiquimod can be
applied on alternate days for up to 3 months, according
5.5.4.2 Cryotherapy to Porter et al. (2002).

Advantages
Advantages
Good evidence of efficacy (Cox et al., 2007; Dawber
and Colver, 1992) Efficacy – complete response in few reported cases
with short follow-up (3–18 months) (Schroeder and
Sengelmann, 2002; Arlette, 2003; de Diego Rodriguez
Disadvantages et al., 2005; Taliaferro and Cohen, 2008)

Prolonged healing time Disadvantages

Expensive
Side Effects Not FDA-licensed for this indication
Ideal regimen not yet established
Pain
Inflammation
Spontaneous bleeding 5.5.4.5 CO2 Laser
Infection
Meatal stenosis Advantages

Excellent cosmetic and functional results

Considered an acceptable indication for both ­initial
5.5.4.3 5-Fluorouracil Cream
treatment and disease recurrences (van Bezooijen
et al., 2001)
Indications
Efficacy – good long-term results (follow-up up to
24 months) for PIN associated with HPV infection
Noninvasive lesions in unhairy locations (Tolia et al.,
(Malek, 1992)
1976; Porter et al., 2002)
Large and multiple lesions (in the latter case, Cox
et al. (2007) recommended that 5-FU should be Disadvantages
used for disease control, rather than for cure)
van Bezooijen et al. (2001) reported a high incidence
Therapeutic regimen – 5-FU cream may be applied
of recurrences
twice a day for 3 weeks (Porter et al., 2002), but ideal
Patient compliance for follow-up control required
regimen has not been established.

5.5.4.6 Photodynamic Therapy with Methyl

Side Effects Aminolevulinate

Irritative symptoms may limit efficacy because of Indication

treatment interruption.
Erosion and superficial necrosis. Large lesions
5.6 Erythroplasia of Queyrat (Unifocal Intraepithelial Neoplasia) 107

Advantages EQ lesions often evolve insidiously but, if untreated,

the risk of progression to invasive SCC is 5–33%
Excellent cosmetic and functional results. (Malek, 1992). Lesions occurring on keratinized areas
Efficacy – Photodynamic therapy (PDT) has demon- appear less prone to progression than mucosal-located
strated superior efficacy when compared to topical lesions.
5-FU or cryotherapy, according to a study performed According to Porter et al. (2002), LS is more preva-
by Morton et al. (2006). lent in patients with EQ and the association with low-
European Medicines Authority-approved therapy for and high-risk HPV has been demonstrated by Wieland
BD. et al. (2000).

Disadvantages Wieland et al. (2000) also suggested that the pres-

ence or absence of the rare HPV type 8 may help
Residual disease – In the study that evaluated PDT differentiate between penile EQ and BD.
with methyl aminolevulinate (MAL) for atypical
carcinoma in situ of the penis, Axcrona et al. (2007)
reported histological residual disease in 30% of 5.6.1 Clinical Manifestations
patients after median follow-wup of 20 months.
5.6.1.1 Symptoms
Side Effects
Pain (uncommon)
Pruritus
Pain in the immediate week following treatment
Bleeding
Difficulty in retracting the foreskin
5.5.4.7 Circumcision

Indication 5.6.1.2 Presentation

Lesions limited to the foreskin (Mikhail, 1980) Single, well-demarcated and slightly raised, bright
red, moist plaque (Fig. 5.16a, b).
Lesion modification to a verrucous, nodular, or ulcer-
5.5.5 Follow-Up ated aspect is a sign of invasion (Graham and Helwig,
1973) (Fig. 5.17).
Patients should be instructed for self-examination and
self-referral if a suspicious lesion is found.
Routine follow-up visits 3–6 months follo­wing 5.6.2 Differential Diagnosis
treatment are advised to check for early recurrences.
Since clinical inspection can be unreliable, biopsies Candidal balanitis
are often required for proper evaluation of lesion pro- Psoriasis (Fig. 5.18)
gression to invasive disease. Zoon’s balanitis (Fig. 5.19)
Erosive lichen planus
Inflammatory granuloma
5.6 Erythroplasia of Queyrat (Unifocal Reiter syndrome (rare)
Intraepithelial Neoplasia) Lupus erythematosus (very rare)

EQ is a penile intraepithelial neoplasia that mainly 5.6.3 Diagnosis

affects the mucous membranes of the glans surface,
inner aspect of the foreskin, or the urethral meatus of Physical examination
elderly men. Biopsy and histopathological examination
 108 5 Human Papillomavirus and Penile Intraepithelial Neoplasia

Fig. 5.18. Glans penis psoriasis

Fig. 5.16. (a) Erythroplasia of Queyrat (EQ)/PIN 3 located at

the glans penis. (b) EQ – slightly raised, bright red, moist
plaque

Fig. 5.19. Plasma cell balanitis (Zoon’s balanitis)

Expert Advice

Early biopsy to better define diagnosis is recom-

mended by Porter et al. (2002).
Excisional biopsy can be performed for a small
lesion located in the prepuce or in an accessible
area.
Incisional biopsy, tissue core biopsy, fine-needle
aspiration, or brush biopsy can be used for larger
lesions.

Fig. 5.17. Erythroplasia of Queyrat – discrete nodular 5.6.3.1 Histological Findings

presentation

BD and EQ share histological features but, compared

to the former, EQ displays more epithelial hypoplasia,
fewer dyskeratotic multinucleated cells, and increased
plasma cells numbers (Graham and Helwig, 1973).
5.6 Erythroplasia of Queyrat (Unifocal Intraepithelial Neoplasia) 109

5.6.4 Treatment 5.6.4.5 CO2 Laser

The recurrence rate in patients with EQ is lower than Laser CO2 vaporization should extend beyond the
in patients with BD, reflecting the absence of hair fol- lesion borders and an 8–10-mm safety margin is rec-
licles in the penile mucosa (see also BD Treatment). ommended by Conejo-Mir et al. (2005).
Topical treatment regimens for EQ are similar to
BD regimens (see above), but in a recent analysis
Porter et al. (2002) reported more difficulties with the Advantages
management of EQ lesions or a combination of PIN
disorders. Excellent cosmetic and functional results
Moreover, a penis-preserving strategy is strongly rec- Alternative to topical therapy in patients with penile
ommended when using surgical treatment approaches. SCC in situ (Rosemberg and Fuller, 1980)
Effective for EQ with urethral involvement in young
immunocompetent patients (Del Losada et al., 2005)
5.6.4.1 5-Fluorouracil Cream
Disadvantages
There are only a few evidence-based reports (Tolia
et al., 1976; Goette and Carson, 1976), but 5-FU cream
Recurrence rates following CO2 laser ablation –
is the preferred first-line option of Hadway et al.
10–26%, according to the study performed by Porter
(2006).
et al. (2002)

5.6.4.2 Imiquimod Cream (Aldara) 5.6.4.6 Nd:YAG Laser

Advantages Disadvantages

Efficacy – complete clearance of EQ lesions associ- Recurrence rates – Recent data by Frimberger et al.
ated or not with high-risk HPV (Kaspari et al., 2002; (2002) showed that 1 of 17 patients with CIS treated
Micali et al., 2006) with Nd:YAG laser had several recurrences and
Therapeutic regimen – further studies required. another developed nodal metastases from an ­apparent
missed invasive disease.

5.6.4.3 Local Excision

5.6.4.7 Photodynamic Therapy with Methyl
Aminolevulinate
Indications
Stables et al. (1999) and Lee and Ryman (2005) treated
Small or large lesions located on the foreskin
very few cases with PDT and reported good results
Not suitable for large glans penis lesions or perime-
for limited EQ lesions, but observed that extensive
atal and urethral location, because of functional and/
­disease is less responsive to PDT. Further studies are
or cosmetic results
recommended.

5.6.4.4 Circumcision Side Effects

Indication Pain
Local swelling
Lesions limited to foreskin Redness
 110 5 Human Papillomavirus and Penile Intraepithelial Neoplasia

5.6.4.8 Total Glans Resurfacing 5.6.5 Follow-Up

5
Total glans resurfacing (TGR) is a novel surgical tech- Patients should be instructed for self-examination and
nique developed by Bracka et al. (Depasquale et al., self-referral if a suspicious lesion is found.
2000) that completely denudes the glans and subco- Long-term follow-up is advised by Mikhail (1980),
rona of the penis down to the corpus spongiosum and because the risk of progression to invasive SCC is
Buck’s fascia at the coronal sulcus, respectively. The higher in EQ than in other PIN variants.
bare surface is then covered with a healthy extragenital Biopsies are often required for proper evaluation of
skin graft. lesion progression to invasive disease, as clinical
In selected cases, TGR is a promising treatment inspection can be unreliable.
modality that offers good functional and cosmetic
results without compromising oncologic control; how-
ever, additional studies and longer follow-up are needed 5.7 Penile Lichen Sclerosus
to confirm early good results.

Lichen sclerosus (LS) is a relatively common hypopig-

Indications (Hadway et al., 2006) mented skin disorder, with a large incidence on genital
skin.
Relapsing disease following topical therapy with According to new proper terminology initially pro-
5-FU and imiquimod posed by Friedrich (1976) and later adopted by Ridley
Extensive glans penis lesions (1992), the term atrophic and dystrophy must be
Severe dysplasia avoided when referring to LS because not all cases are
SCC in situ lesions in young men (relapses and long histologically atrophic.
treatment modalities are avoided with faster return to Penile LS, traditionally known as balanitis xerotica
normal activities) obliterans (BXO), is a chronic, progressive, and scar-
ring dermatologic disease that may result in significant
voiding complications.
Optional Indication
It mostly affects uncircumcised middle-aged white
men; however, LS has been described in 4-year-old
Patients who do not comply with regular follow-up
boys (Rickwood et al., 1980) and according to Chalmers
et al. (1984), it affects the young male population more
Advantages often than previously assumed. In a recent long pro-
spective study performed by Kiss et al. (2005), the peak
The specimen obtained allows for a thorough histo- incidence of LS occurred between the ages of 9 and 11,
logical assessment of the disease. and nearly all affected boys had secondary phimosis.
Minimal chance of recurrence. The exact etiology of LS is unknown, but immune
Normal anatomy is restored with acceptable cos- dysregulation is considered the factor most strongly
metic and functional results (Hadway et al., 2006). associated with the disease (Regauer, 2005).
No evidence of recurrence with follow-up of 32–45 Recent data have shown a higher prevalence of
months (Palminteri et al., 2007; Hadway et al., infection with high-risk HPV types in patients with
2006). penile LS (Nasca et al., 2006; Prowse et al., 2008).
Together with low- and high-grade PIN and
squamous hyperplasia, LS may be considered a pre-
Disadvantages cursor lesion of penile cancer (Powell et al., 2001;
Cubilla et al., 2004; Velazquez and Cubilla, 2007),
Surgeon experienced with the technique necessary with a 6% risk of progression to SCC. According to
Hospitalization and regional or general anesthesia Nasca et al. (2006), infection with oncogenic HPV
required types may enhance the risk of penile cancer develop-
Immobilization for 3–4 days following the procedure ment in patients with genital LS.
5.7 Penile Lichen Sclerosus 111

In a recent clinicopathologic analysis performed by

Cubilla et al. (2004), LS was specifically related to
well-differentiated, SCC of the penis with pseudohy-
perplastic features. These multicentric tumors are usu-
ally present in older patients and preferentially involve
the inner mucosal surface of the foreskin.

5.7.1 Clinical Manifestations

5.7.1.1 Symptoms

Asymptomatic at early stages

Recurrent inflammatory symptoms (balanitis)
Pruritus
Glans penis hypoesthesia
Dyspareunia
Dysuria
Urethritis and voiding problems because of meatal
stenosis
Difficulty or inability to retract the foreskin in uncir-
cumcised individuals

5.7.1.2 Presentation
Fig. 5.20. (a) Lichen sclerosus – multiple erythematous papules
Single or multiple erythematous papules or macules or macules at the glans penis. (b) Lichen sclerosus – erythema-
usually affecting the glans penis and foreskin at the tous papules or macules at the glans penis
early stages of the disease (Fig. 5.20a, b); in a study
performed by Depasquale et al. (2000), LS was involvement and spongiofibrosis can progress proxi-
found limited to the foreskin and glans in 57% of mally as far back as the posterior urethra (Fig. 5.21).
patients. The perianal region is not affected in male
individuals.
Thin patches or plaques affecting the frenulum and 5.7.2 Diagnosis
foreskin (penile shaft is rarely involved).
Presence of a typical white sclerotic ring at the tip of Physical examination.
the foreskin. Biopsy and histological examination.
Mucosal fissures, petechiae, telangiectasias, and Urethroscopy and retrograde urethrography are man-
hemorrhagic lesions may occur, leading to glans datory to determine the proximal extent of disease if
penis adhesion to the prepuce at advanced stages. urethral involvement is suspected.
The urethral meatus and fossa navicularis may be
affected resulting in urethral involvement in 20% of Expert Advice
patients (Depasquale et al., 2000); urinary obstruc-
Biopsy is recommended in all patients suspected of
tion as a result of meatal stenosis was reported in 47%
having LS (Pugliese et al., 2007); however, the
of the patients studied by Bainbridge et al. (1971).
biopsy of chronically hyperplastic or ulcerated
The urethra is initially affected at the level of the
lesions of LS is mandatory to rule out SCC.
meatus, but with long-standing disease the mucosal
 112 5 Human Papillomavirus and Penile Intraepithelial Neoplasia

Fig. 5.21. Lichen sclerosus affecting the urethral meatus

5.7.2.1 Histological Findings (Fig. 5.22a, b)

Hyperkeratosis
Basal cells hydropic degeneration
Sclerosis of the subepithelial collagen
Collagen homogenization at the upper layer of the
dermis
Dermal lymphocytic infiltration
Atrophic epidermis with loss of rete pegs
Fig. 5.22. (a) Lichen sclerosus. (b) Lichen sclerosus (LS) exhib-
iting marked epithelial hyperplasia (increased risk of malignant
progression) (Source: Carvalho. Photograph courtesy of
5.7.3 Treatment Filomena Marino Carvalho MD, PhD, São Paulo, Brazil)

5.7.3.1 Medical Side Effects

Steroids Cutaneous atrophy

Hypopigmentation
Indication Contact sensitivity
Adrenal suppression
Mild disease limited to the foreskin in young indi-
viduals with minimal scar formation Expert Advice

The use of potent steroids should be avoided in

Advantages
pediatric and in HPV-infected patients.
Efficacy – Steroids may improve initial symptoms
and slow disease progression (Kiss et al., 2005).
5.7.3.2 Hormones
Clobetasol propionate (Temovate ) 0.05% cream or
ointment is the topical steroid most commonly used, Efficacy – There are no recent studies performed on
although it is not FDA approved for this indication; male subjects (Pasieczny, 1977). In a recent compara-
relapses may occur when treatment is discontinued. tive study of steroids and testosterone propionate ther-
Therapeutic regimen – Once or twice daily for 2–3 apy for vulvar LS, clobetasol resulted in higher remission
months with gradual dose reduction. and lower recurrence rates than hormonal therapy;
5.8 Penile Horn 113

however, according to Ayhan et al. (2007) the results Meatoplasty

obtained were not statistically different.
There may be recurrences when ventral meatotomy
is performed for meatal stenosis correction in LS
5.7.3.3 Tacrolimus Topical (Protopic) patients.
Technique of extended meatoplasty for complex or
Tacrolimus ointment, a topical calcineurin inhibitor, is reoperative strictures showed successful results in
a highly selective immune modulator agent. 87% of the patients treated by Morey et al. (2007).

Advantages Urethral Reconstruction

Efficacy – lower relapse rate when compared with Nongenital skin should preferably be used for ure-
topical betamethasone (Ebert et al., 2007) throplasty because LS will likely recur using genital
Therapeutic regimen – A small amount of tacrolimus skin for reconstruction (Venn and Mundy, 1998).
ointment is applied twice a day to the affected area. Despite use of buccal mucosal graft urethroplasty
techniques, the recurrence rate of LS-related stric-
Tacrolimus ointment 0.03% is prescribed to chil- tures is high in the short and long term.
dren and young boys between 2 and 15 years old. The effectiveness of one-stage buccal mucosal graft
urethroplasty vs. multistage reconstruction of LS­-
related urethral strictures is not yet established
Expert Advice (Levine et al., 2007).
Tacrolimus use in anogenital LS may reactivate
HPV infection (Bilenchi et al., 2007).
5.7.4 Follow-Up
5.7.3.4 Surgical Long-term follow-up is advised to detect possible pro-
gression to premalignant disease or SCC.
Circumcision

Indication
Early disease limited to the glans penis and foreskin 5.8 Penile Horn
(Depasquale et al., 2000)
Penile horn is considered an unusual disorder as it is
Expert Advice rarely seen in areas not exposed to sunlight.
The etiology is unclear but it usually affects individ-
It is highly recommended to send all tissue removed uals who had undergone adult circumcision because of
at circumcision or meatotomy (including in the a long-standing phimosis and chronic balanoposthitis.
pediatric population) for pathological analysis. It may also appear on the surface of preexisting
penile lesions such as nevi or warts or in areas exposed
to traumatic abrasions (Lowe and McCullough, 1985).
CO2 Laser
According to Solsona et al. (2004), penile horn is
sporadically associated with SCC of the penis and the
Advantages
potential for malignant degeneration is increased in
Efficacy – A recent study performed by Windahl cases of recurrent disease (Cruz Guerra et al., 2005;
(2006) showed good long-term results (80% of Fields et al., 1987). A recent study performed by de la
patients asymptomatic and without visible lesions) Pena Zarzuelo et al. (2001) found penile SCC arising
following CO2 laser treatment. at the base of the cutaneous horn in 37% of cases.
 114 5 Human Papillomavirus and Penile Intraepithelial Neoplasia

5 Expert Advice

Malignant change should be suspected in a rapidly

growing penile horn lesion.

5.8.1 Predisposing Factors

Chronic preputial inflammation and phimosis

Poor hygiene
Traumatic abrasions
Previous or concurrent HPV infection with onco-
genic type 16 (Solivan et al., 1990)

Fig. 5.23. Penile horn and condylomatous lesion at the glans

5.8.2 Pathogenesis penis

Abnormal overgrowth of dry keratinized epithelium

that probably occurs in response to chronic preputial 5.8.5 Treatment
inflammation and epithelial cornification.
Wide surgical excision including a margin of normal
tissue at the base of the lesion
5.8.3 Clinical Manifestations
Careful histological examination of the lesion base
to exclude underlying carcinoma or a malignant
5.8.3.1 Symptoms
transformation of the penile horn
Asymptomatic
Chronic penile discomfort 5.8.6 Follow-Up

Close follow-up of the excision site is recommended,

5.8.3.2 Presentation as these lesions have a potential to recur and become
malignant.
Single and occasionally multiple hard, exophytic,
hyperkeratotic lesions of variable size (Fig. 5.23)
Color ranges from white to yellow with an erythema-
tous lesion base (Agarwalla et al., 2000) 5.9 Genital Paget’s Disease

5.8.4 Diagnosis EMPD involving the penis and scrotum is exceedingly

rare, with only small series or case reports described
Physical examination in the literature (Park et al., 2001; van Randenborgh
Biopsy and histopathological examination et al., 2002; Yang et al., 2005). EMPD is a cutaneous
­adenocarcinoma of epidermal origin and glandular
­differentiation is usually involved. Chanda (1985) sug-
5.8.4.1 Histological Findings gests that EMPD is a cutaneous marker of internal
malignancy.
Acanthosis This slow-growing intraepithelial neoplasia affects
Papillomatosis elderly men (between the ages of 60 and 70), and
Intense hyperkeratosis and dyskeratosis there may be an association of penoscrotal EMPD
Chronic inflammatory infiltrate with genitourinary cancer. The association with distant
5.10 Kaposi’s Sarcoma 115

internal organ malignancy has been reported (Kim

et al., 2005; Im et al., 2007), although it is a rare event
with penoscrotal EMPD (Park et al., 2001). The disease
may also spread to the regional lymph nodes, and lymph
node metastasis is associated with a poor prognosis.

Expert Advice

Patients presenting with EMPD should be system-

atically evaluated for an underlying carcinoma.

5.9.1 Clinical Manifestations

5.9.1.1 Symptoms Fig. 5.25. Paget’s disease. (Source: Photograph courtesy of

Filomena Marino Carvalho MD, PhD, São Paulo, Brazil)
Mostly asymptomatic
Pruritus or burning pain may also occur

5.9.1.2 Presentation

Red, moist, eroded plaque with a sharp border

between normal and affected skin of the anogenital
region (Fig. 5.24).

5.9.1.3 Histological Findings (Fig. 5.25)

Presence of Paget’s cells in the epidermis

Positive immunohistochemical staining for glandular
cytokeratins (Fig. 5.26), epithelial membrane anti­
gen, and carcinoembryonic antigen (Wojnarowska and Fig. 5.26. Paget’s disease – Immunohistochemical staining for
Cooper, 2003) glandular cytokeratins. (Source: Photograph courtesy of
Filomena Marino Carvalho MD, PhD, São Paulo, Brazil)

5.9.2 Treatment

Wide local excision and immediate reconstruction

with skin grafting or a local skin flap is the preferred
treatment. Intraoperative frozen-section analysis is
highly recommended to reduce positive margins.

5.10 Kaposi’s Sarcoma

Kaposi’s sarcoma (KS) is a neoplastic vascular lesion of

multifocal origin occurring primarily on the extremi-
ties. KS is frequently seen in HIV-infected patients with
Fig. 5.24. EMPD involving the scrotum. (Source: Bolognia advanced immune impairment (Tappero et al., 1993),
et al., 2003. Reproduced with permission from Elsevier) and it is the most frequent neoplasm found in
 116 5 Human Papillomavirus and Penile Intraepithelial Neoplasia

homosexual and bisexual men with AIDS. Moreover,

5 almost 20% of patients with KS present genital lesions,
but initial lesions at this region occur in only 3% of KS
cases.
Primary penile KS is a relatively uncommon disor-
der in HIV-negative men, and histologic evaluation is
necessary to establish the correct diagnosis.
The association of all types of KS with the infection
caused by a virus of the Epstein-Barr family, human
herpesvirus 8 (HHV-8), was recently demonstrated by
Chang et al. (1994). Furthermore, according to Mendez
et al. (1998), HHV-8 DNA load correlates with the
severity and staging of this disease.

5.10.1 Clinical Manifestations

5.10.1.1 Symptoms

Mostly asymptomatic
Fig. 5.27. Kaposi’s sarcoma lesions at the coronal sulcus.
(Source: Schwartz et al., 2008. Reproduced with permission
from Elsevier)
5.10.1.2 Presentation

Minimal glans penis or preputial lesion with nondis- pattern, and the immune status of the patient. Local
tinctive clinical features. therapies such as surgical excision, laser treatment,
Single or multiple, red-to-purple macular lesion or cryotherapy, imiquimod, or intralesional injection of
skin-colored nodule (Fig. 5.27). chemotherapeutic agents (i.e., vinblastine) may be
Slowly growing pigmented macules are usually employed (Chun et al., 1999; Heyns and Fisher, 2005;
found in immunocompetent individuals with clas­ Schwartz et al., 2008). Systemic therapies are reserved
sical KS. for patients with documented disseminated disease.
Solitary genital lesion may be the first manifestation
of KS associated with AIDS (Lowe et al., 1989).
5.11 PIN Prevention
5.10.1.3 Histological Findings
A recent study that evaluated the efficacy of the pro-
Endothelial cell proliferation phylactic quadrivalent HPV vaccine in young men
Fibroblastic proliferation, spindle cell bundles, and reported that PIN was not detected in vaccinated indi-
collagen dissection viduals, but PIN 3 cases were observed in the placebo
Progression from an early inflammatory or patch stage group. Moreover, penile cancer was not reported in the
to nodular lesions of endothelialized vessels and non- vaccinated or in the placebo group (Giuliano and
endothelialized slit-like spaces (Schwartz et al., 2008) Palefsky, 2008) (see also Sect. 11.8 in Chap. 11).

5.10.2 Treatment References

Patients should be informed that KS is a multicentric
Agarwalla A, Agrawal CS, Thakur A, Garg VK, Joshi A, Agrawal
disease. Management of penile KS is usually based on S, Jacob M (2000) Cutaneous horn on condyloma acumina-
the number and location of the lesions, the progression tum. Acta Derm Venereol 80: 159
References 117

Arlette JP (2003) Treatment of Bowen’s disease and erythropla- Dawber R, Colver G (1992) Premalignant lesions. In: Dawber R,
sia of Queyrat. Br J Dermatol 149 Suppl 66: 43–49 Colver G, Jackson A (eds) Cutaneous cryosurgery. Martin
Axcrona K, Brennhovd B, Alfsen GC, Giercksky KE, Warloe T Dunitz, London, pp 77–93.
(2007) Photodynamic therapy with methyl aminolevulinate de Diego Rodriguez E, Villanueva Pena A, Hernandez Castrillo
for atypial carcinoma in situ of the penis. Scand J Urol A, Gomez Ortega JM (2005) [Treatment of Bowen’s disease
Nephrol 41: 507–510 of the penis with imiquimod 5% cream]. Actas Urol Esp 29:
Ayhan A, Guven ES, Guven S, Sakinci M, Dogan NU, Kucukali 797–800
T (2007) Testosterone versus clobetasol for maintenance of de la Pena Zarzuelo E, Carro Rubias C, Sierra E, Delgado JA,
vulvar lichen sclerosus associated with variable degrees of Silmi Moyano A, Resel Estevez L (2001) [Cutaneous horn
squamous cell hyperplasia. Acta Obstet Gynecol Scand 86: of the penis]. Arch Esp Urol 54: 367–368
715–719 Del Losada JP, Ferre A, San Roman B, Vieira V, Fonseca E
Aynaud O, Bergeron C (2004) [Penile intraepithelial neoplasia]. (2005) Erythroplasia of Queyrat with urethral involvement:
Prog Urol 14: 100–104 treatment with carbon dioxide laser vaporization. Dermatol
Bainbridge DR, Whitaker RH, Shepheard BG (1971) Balanitis Surg 31: 1454–1457
xerotica obliterans and urinary obstruction. Br J Urol 43: Depasquale I, Park AJ, Bracka A (2000) The treatment of balani-
487–491 tis xerotica obliterans. BJU Int 86: 459–465
Bandieramonte G, Colecchia M, Mariani L, Lo Vullo S, Ebert AK, Vogt T, Rosch WH (2007) [Topical therapy of balani-
Pizzocaro G, Piva L, Nicolai N, Salvioni R, Lezzi V, Stefanon tis xerotica obliterans in childhood. Long-term clinical
B, De Palo G (2008) Peniscopically controlled CO2 laser results and an overview]. Urologe A 46: 1682–1686
excision for conservative treatment of in situ and T1 penile Feldman SB, Sexton FM, Glenn JD, Lookingbill DP (1989)
carcinoma: Report on 224 patients. Eur Urol 54: 875–882 Immunosuppression in men with bowenoid papulosis. Arch
Barbagli G, Palminteri E, Mirri F, Guazzoni G, Turini D, Lazzeri Dermatol 125: 651–654
M (2006) Penile carcinoma in patients with genital lichen Fields T, Drylie D, Wilson J (1987) Malignant evolution of
sclerosus: A multicenter survey. J Urol 175: 1359–1363 penile horn. Urology 30: 65–66
Bergeron C (2008) [New histological terminology of vulvar Friedrich EG, Jr. (1976) Lichen sclerosus. J Reprod Med 17:
intraepithelial neoplasia]. Gynecol Obstet Fertil 36: 74–78 147–154
Bilenchi R, Poggiali S, De Padova LA, Pisani C, De Paola M, Frimberger D, Hungerhuber E, Zaak D, Waidelich R, Hofstetter A,
Fimiani M (2007) Human papillomavirus reactivation fol- Schneede P (2002) Penile carcinoma. Is Nd:YAG laser therapy
lowing topical tacrolimus therapy of anogenital lichen scle- radical enough? J Urol 168: 2418–2421; discussion 2421
rosus. Br J Dermatol 156: 405–406 Giuliano A, Palefsky J (2008) The efficacy of quadrivalent HPV
Chalmers RJ, Burton PA, Bennett RF, Goring CC, Smith PJ (1984) (types 6/11/16/18) vaccine in reducing the incidence of HPV
Lichen sclerosus et atrophicus. A common and distinctive infection and HPV-related genital disease in young men In:
cause of phimosis in boys. Arch Dermatol 120: 1025–1027 European Research Organization on Genital Infection and
Chanda JJ (1985) Extramammary Paget’s disease: Prognosis Neoplasia – EUROGIN Nice, France
and relationship to internal malignancy. J Am Acad Dermatol Goette DK, Carson TE (1976) Erythroplasia of Queyrat: Treatment
13: 1009–1014 with topical 5-fluorouracil. Cancer 38: 1498–1502
Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles Goorney BP, Polori R (2004) A case of Bowenoid papulosis of
DM, Moore PS (1994) Identification of herpesvirus-like the penis successfully treated with topical imiquimod cream
DNA sequences in AIDS-associated Kaposi’s sarcoma. 5%. Int J STD AIDS 15: 833–835
Science 266: 1865–1869 Graham JH, Helwig EB (1973) Erythroplasia of Queyrat. A
Chun YS, Chang SN, Park WH (1999) A case of classical Kaposi’s clinicopathologic and histochemical study. Cancer 32:
sarcoma of the penis showing a good response to high-energy 1396–1414
pulsed carbon dioxide laser therapy. J Dermatol 26: 240–243 Gross G, Pfister H (2004) Role of human papillomavirus in
Conejo-Mir JS, Munoz MA, Linares M, Rodriguez L, Serrano A penile cancer, penile intraepithelial squamous cell neoplasias
(2005) Carbon dioxide laser treatment of erythroplasia of and in genital warts. Med Microbiol Immunol 193: 35–44
Queyrat: A revisited treatment to this condition. J Eur Acad Guidi HGC, Stiepcich M, Andrade Z (2007) Estudo por biologia
Dermatol Venereol 19: 643–644 molecular de 17 neoplasias intraepiteliais penianas (Analyzis
Cox NH, Eedy DJ, Morton CA (2007) Guidelines for management of 17 penile intraepithelial neoplasias by molecular biology
of Bowen’s disease: 2006 update. Br J Dermatol 156: 11–21 techniques) [article in portuguese]. In: 31th Brazilian
Cruz Guerra NA, Saenz Medina J, Ursua Sarmiento I, Zamora Congress of Urology vol 33. Braz J Urol, Salvador, Brazil
Martinez T, Madrigal Montero R, Diego Pinto D, Tarroc Hadway P, Corbishley CM, Watkin NA (2006) Total glans resur-
Blanco A (2005) [Malignant recurrence of a penile cutane- facing for premalignant lesions of the penis: Initial outcome
ous horn]. Arch Esp Urol 58: 61–63 data. BJU Int 98: 532–536
Cubilla AL, Meijer CJ, Young RH (2000) Morphological fea- Hama N, Ohtsuka T, Yamazaki S (2006) Detection of mucosal
tures of epithelial abnormalities and precancerous lesions of human papilloma virus DNA in bowenoid papulosis,
the penis. Scand J Urol Nephrol Suppl 215–219 Bowen’s disease and squamous cell carcinoma of the skin.
Cubilla A L, Velazquez E F, Young RH (2004) Pseudohyperplastic J Dermatol 33: 331–337
squamous cell carcinoma of the penis associated with lichen Heyns CF, Fisher M (2005) The urological management of the
sclerosus. An extremely well-differentiated, nonverruciform patient with acquired immunodeficiency syndrome. BJU Int
neoplasm that preferentially affects the foreskin and is fre- 95: 709–716
quently misdiagnosed: A report of 10 cases of a distinctive Horenblas S (2008) Editorial comment on: Peniscopically con-
clinicopathologic entity. Am J Surg Pathol 28: 895–900 trolled CO2 laser excision for conservative treatment of in
 118 5 Human Papillomavirus and Penile Intraepithelial Neoplasia

situ and T1 penile carcinoma: Report on 224 patients. Eur Nasca MR, Innocenzi D, Micali G (2006) Association of penile
5 Urol 54: 883; discussion 883–884 lichen sclerosus and oncogenic human papillomavirus infec-
Ikenberg H, Gissmann L, Gross G, Grussendorf-Conen EI, zur tion. Int J Dermatol 45: 681–683
Hausen H (1983) Human papillomavirus type-16-related Nasca MR, Panetta C, Micali G, Innocenzi D (2003) Microinvasive
DNA in genital Bowen’s disease and in Bowenoid papulosis. squamous cell carcinoma arising on lichen sclerosus of the
Int J Cancer 32: 563–565 penis. J Eur Acad Dermatol Venereol 17: 337–339
Im M, Kye KC, Kim JM, Lee JH (2007) Extramammary Paget’s Obalek S, Jablonska S, Beaudenon S, Walczak L, Orth G (1986)
disease of the scrotum with adenocarcinoma of the stomach. Bowenoid papulosis of the male and female genitalia: Risk
J Am Acad Dermatol 57: S43–S45 of cervical neoplasia. J Am Acad Dermatol 14: 433–444
Kaspari M, Gutzmer R, Kiehl P, Dumke P, Kapp A, Brodersen JP Ohnishi T, Kano R, Nakamura Y, Hasegawa A, Watanabe S (1999)
(2002) Imiquimod 5% cream in the treatment of human pap- Genital Bowen disease associated with an unusual human
illomavirus-16-positive erythroplasia of Queyrat. Dermatology papillomavirus type 57b. Arch Dermatol 135: 858–859
205: 67–69 Palminteri E, Berdondini E, Lazzeri M, Mirri F, Barbagli G
Kim KJ, Lee DP, Lee MW, Choi JH, Moon KC, Koh JK (2005) (2007) Resurfacing and reconstruction of the glans penis.
Penoscrotal extramammary Paget’s disease in a patient with Eur Urol 52: 893–898
rectal cancer: Double primary adenocarcinomas differenti- Park S, Grossfeld GD, McAninch JW, Santucci R (2001)
ated by immunoperoxidase staining. Am J Dermatopathol Extramammary Paget’s disease of the penis and scrotum:
27: 171–172 Excision, reconstruction, and evaluation of occult malig-
Kiss A, Kiraly L, Kutasy B, Merksz M (2005) High incidence of nancy. J Urol 166: 2112–2116; discussion 2117
balanitis xerotica obliterans in boys with phimosis: Pasieczny TA (1977) The treatment of balanitis xerotica obliter-
Prospective 10-year study. Pediatr Dermatol 22: 305–308 ans with testosterone propionate ointment. Acta Derm
Lee MR, Ryman W (2005) Erythroplasia of Queyrat treated with Venereol 57: 275–277
topical methyl aminolevulinate photodynamic therapy. Porter WM, Francis N, Hawkins D, Dinneen M, Bunker CB
Australas J Dermatol 46: 196–198 (2002) Penile intraepithelial neoplasia: clinical spectrum
Levine LA, Strom KH, Lux MM (2007) Buccal mucosa graft and treatment of 35 cases. Br J Dermatol 147: 1159–1165
urethroplasty for anterior urethral stricture repair: Evaluation Powell J, Robson A, Cranston D, Wojnarowska F, Turner R (2001)
of the impact of stricture location and lichen sclerosus on High incidence of lichen sclerosus in patients with squamous
surgical outcome. J Urol 178: 2011–2015 cell carcinoma of the penis. Br J Dermatol 145: 85–89
Lowe FC, Lattimer DG, Metroka CE (1989) Kaposi’s sarcoma Prowse DM, Ktori EN, Chandrasekaran D, Prapa A, Baithun S
of the penis in patients with acquired immunodeficiency (2008) Human papillomavirus-associated increase in
syndrome. J Urol 142: 1475–1477 p16INK4A expression in penile lichen sclerosus and
Lowe FC, McCullough AR (1985) Cutaneous horns of the penis: squamous cell carcinoma. Br J Dermatol 158: 261–265
an approach to management.Case report and review of the Pugliese JM, Morey AF, Peterson AC (2007) Lichen sclerosus:
literature. J Am Acad Dermatol 13: 369–373 Review of the literature and current recommendations for
Lucia MS, Miller GJ (1992) Histopathology of malignant lesions management. J Urol 178: 2268–2276
of the penis. Urol Clin North Am 19: 227–246 Regauer S (2005) Immune dysregulation in lichen sclerosus. Eur
Malek RS (1992) Laser treatment of premalignant and malig- J Cell Biol 84: 273–277
nant squamous cell lesions of the penis. Lasers Surg Med 12: Rickwood AM, Hemalatha V, Batcup G, Spitz L (1980) Phimosis
246–253 in boys. Br J Urol 52: 147–150
Mendez JC, Procop GW, Espy MJ, Paya CV, Smith TF (1998) Ridley CM (1992) Lichen sclerosus. Dermatol Clin 10:
Detection and semiquantitative analysis of human herpesvi- 309–323
rus 8 DNA in specimens from patients with Kaposi’s sar- Rosemberg SK, Fuller TA (1980) Carbon dioxide rapid super-
coma. J Clin Microbiol 36: 2220–2222 pulsed laser treatment of erythroplasia of Queyrat. Urology
Micali G, Nasca MR, De Pasquale R (2006) Erythroplasia of 16: 181–182
Queyrat treated with imiquimod 5% cream. J Am Acad Schoen EJ, Oehrli M, Colby C, Machin G (2000) The highly
Dermatol 55: 901–903 protective effect of newborn circumcision against invasive
Mikhail GR (1980) Cancers, precancers, and pseudocancers on penile cancer. Pediatrics 105: E36
the male genitalia.A review of clinical appearances, histopa- Schroeder TL, Sengelmann RD (2002) Squamous cell carci-
thology, and management. J Dermatol Surg Oncol 6: noma in situ of the penis successfully treated with imiqui-
1027–1035 mod 5% cream. J Am Acad Dermatol 46: 545–548
Morey AF, Lin HC, DeRosa CA, Griffith BC (2007) Fossa Schwartz RA, Janniger CK (1991) Bowenoid papulosis. 24:
navicularis reconstruction: Impact of stricture length on out- 261–264
comes and assessment of extended meatotomy (first stage Schwartz RA, Micali G, Nasca MR, Scuderi L (2008) Kaposi
Johanson) maneuver. J Urol 177: 184–187; discussion 187 sarcoma: a continuing conundrum. J Am Acad Dermatol 59:
Morton C, Horn M, Leman J, Tack B, Bedane C, Tjioe M, Ibbotson 179–206; quiz 207–178
S, Khemis A, Wolf P (2006) Comparison of topical methyl Solivan GA, Smith KJ, James WD (1990) Cutaneous horn of the
aminolevulinate photodynamic therapy with cryotherapy or penis: its association with squamous cell carcinoma and
Fluorouracil for treatment of squamous cell carcinoma in situ: HPV-16 infection. J Am Acad Dermatol 23: 969–972
Results of a multicenter randomized trial. Arch Dermatol 142: Solsona E, Algaba F, Horenblas S, Pizzocaro G, Windahl T
729–735 (2004) EAU Guidelines on Penile Cancer. Eur Urol 46: 1–8
References 119

Stables GI, Stringer MR, Robinson DJ, Ash DV (1999) Wade TR, Kopf AW, Ackerman AB (1978) Bowenoid papulosis
Erythroplasia of Queyrat treated by topical aminolaevulinic of the penis. Cancer 42: 1890–1903
acid photodynamic therapy. Br J Dermatol 140: 514–517 Wieland U, Jurk S, Weissenborn S, Krieg T, Pfister H, Ritzkowsky
Taliaferro SJ, Cohen GF (2008) Bowen’s disease of the penis A (2000) Erythroplasia of queyrat: coinfection with cutane-
treated with topical imiquimod 5% cream. J Drugs Dermatol ous carcinogenic human papillomavirus type 8 and genital
7: 483–485 papillomaviruses in a carcinoma in situ. J Invest Dermatol
Tappero JW, Conant MA, Wolfe SF, Berger TG (1993) Kaposi’s 115: 396–401
sarcoma. Epidemiology, pathogenesis, histology, clinical Wigbels B, Luger T, Metze D (2001) [Imiquimod: A new treat-
spectrum, staging criteria and therapy. J Am Acad Dermatol ment possibility in bowenoid papulosis?]. Hautarzt 52:
28: 371–395 128–131
Tolia BM, Castro VL, Mouded IM, Newman HR (1976) Bowen’s Windahl T (2006) Is carbon dioxide laser treatment of lichen
disease of shaft of penis. Successful treatment with 5-fluo- sclerosus effective in the long run? Scand J Urol Nephrol 40:
rouracil. Urology 7: 617–619 208–211
van Bezooijen BP, Horenblas S, Meinhardt W, Newling DW Wojnarowska F, Cooper SM (2003) Anogenital (non-venereal)
(2001) Laser therapy for carcinoma in situ of the penis. disease. In: Bolognia JL, Jorizzo JL, Rapini RP (eds)
J Urol 166: 1670–1671 Dermatology. Mosby, Edinburgh, pp 1099–1113
van Randenborgh H, Paul R, Nahrig J, Egelhof P, Hartung R Yang WJ, Kim DS, Im YJ, Cho KS, Rha KH, Cho NH, Choi YD
(2002) Extramammary Paget’s disease of penis and scrotum. (2005) Extramammary Paget’s disease of penis and scrotum.
J Urol 168: 2540–2541 Urology 65: 972–975
Velazquez EF, Cubilla AL (2007) Penile squamous cell carci- Yoneta A, Yamashita T, Jin HY, Iwasawa A, Kondo S, Jimbow K
noma: anatomic, pathologic and viral studies in Paraguay (2000) Development of squamous cell carcinoma by two
(1993–2007). Anal Quant Cytol Histol 29: 185–198 high-risk human papillomaviruses (HPVs), a novel HPV-67
Venn SN, Mundy AR (1998) Urethroplasty for balanitis xerotica and HPV-31 from bowenoid papulosis. Br J Dermatol 143:
obliterans. Br J Urol 81: 735–737 604–608
von Krogh G, Horenblas S (2000) The management and preven-
tion of premalignant penile lesions. Scand J Urol Nephrol
Suppl 220–229
 Human Papillomavirus and Squamous Cell
Carcinoma of the Penis 6
Simon Horenblas

Contents 6.1 Introduction

6.1 Introduction........................................................... 121
6.2 Natural History Of HPV In Male Subjects......... 122 The notion that human papillomavirus (HPV) plays an
6.3 Etiology of Squamous Cell Cancer important role in the etiology of cervical cancer and
of the Penis............................................................. 122 the sexual transmission of HPV has led to further
6.4 Molecular Pathogenesis........................................ 123 assessment of the role of HPV in the etiology of
6.4.1 HPV-Mediated Penile Carcinogenesis.................... 125 squamous cell carcinoma of the penis. While risk fac-
6.4.2 HPV-Independent Penile Carcinogenesis................ 125 tors for penile cancer, such as number of sex partners
6.4.3 Common Molecular Events in Penile and a history of genital warts or other sexually trans-
Carcinogenesis........................................................ 125
mitted diseases, have been known for a long time, it is
6.5 Prevention of HPV Infection................................ 126 becoming clear that some of these risk factors can be
6.5.1 HPV Vaccination..................................................... 126
6.5.2 Condom Use............................................................ 126
related to the presence of HPV (Daling et al., 2005;
Bleeker et al., 2008). Several studies have shown that
6.6 HPV as a Prognostic Indicator
an infection with high-risk HPV, mainly type 16, is
in Penile Cancer..................................................... 126
causally involved in the pathogenesis of penile carci-
6.7 Conclusion.............................................................. 127 noma (Rubin et al., 2001; McCance et al., 1986;
References.............................................................. 127 Heideman et al., 2007; Gregoire et al., 1995). The pub-
lished overall prevalence of high-risk HPV DNA in
penile carcinomas ranges from 30 to 100%, depending
on methods of HPV detection, geographical variance,
and subtype (Rubin et al., 2001; McCance et al., 1986;
Maden et al., 1993). An association of a small subset
of penile cancers with low-risk HPV types has also
been suggested, and DNA of cutaneous HPV 8 has
occasionally been detected in penile lesions (Heideman
et al., 2007; Dorfman et al., 2006; Senba et al., 2006;
Wieland et al., 2000).

S. Horenblas
Chief department of urology, Netherlands Cancer Institute-Anton
van Leeuwenhoek Hospital, Plesmanlaan121, 1066 CX,Amsterdam,
The Netherlands
e-mail: [email protected]

A. Rosenblatt, H. G. de Campos Guidi, Human Papillomavirus, 121

DOI: 10.1007/978-3-540-70974-9-6, © Springer-Verlag Berlin Heidelberg 2009
 122 6 Human Papillomavirus and Squamous Cell Carcinoma of the Penis

6.2 Natural History of HPV 6.3 Etiology of Squamous Cell

6
in Male Subjects Cancer of the Penis

The distribution of HPV in the penis is as following, Penile cancers are thought to arise from the progres-
according to two studies: prepuce 28%, shaft 24%, sion of precursor lesions and can be subdivided into
scrotum 17%, glans 16%, and urethra 6% (Morris, HPV-positive and HPV-negative cases. Similar to vul-
2007; Weaver et al., 2004). HPVs, most notably high- var and head and neck carcinomas, squamous cell car-
risk types, are more common in uncircumcised male cinomas of the basaloid and warty type display the
subjects (Castellsague et al., 2002). A large multina- strongest association with high-risk HPV (ranging
tional study found HPV in 19.6% of 847 uncircumcised from 70 to 100%) and their etiological relationship
men, but only 5.5% of 292 circumcised men; this differ- with high-risk HPV infection is most plausible (Cubilla
ence was statistically significant (Castellsague et al., et al., 1998, 2000). The remaining penile squamous
2002). High-risk HPVs often produce clinically occult cell carcinomas demonstrate about 30–50% positivity
lesions, in contrast to low-risk HPVs that usually pres- for high-risk HPV DNA. In the HPV-positive cases,
ent as visible warts (Katelaris et al., 1988). These lesions HPV 16 is the predominant type found (Gregoire et al.,
include flat penile lesions (FPLs), which become visible 1995; Bezerra et al., 2001; Ferreux et al., 2003).
only by application of dilute acetic acid to the penis Despite the similarities between penile and vulvar can-
(Barrasso, 1997; Hippelainen et al., 1991; Bleeker et al., cer, including their presence of HPV (mainly HPV 16)
2002). FPLs are predominantly found at the mucosal and their precursor lesions, a clear bimodal age distri-
site of the penis. Histological evaluation of FPLs gener- bution as is found for vulvar cancer is not clearly seen
ally shows mild changes such as squamous hyperplasia for penile cancer (Canavan and Cohen, 2002). Cubilla
or low-grade penile intraepithelial neoplasia (PIN). et al. observed a lower age of patients with basaloid or
High-grade PIN is uncommon, being present in about warty types (i.e., average 55 years) of cancer compared
5% of cases. FPLs are found in about 50–70% of the to other types of penile squamous cell carcinomas
male sexual partners of women with cervical intraepi- (Bleeker et al., 2002, 2006; Cubilla et al., 2004).
thelial neoplasia (CIN) vs. about 10–20% in men who However, in another study, including a large series of
do not have a partner with CIN (Bleeker et al., 2006). penile cancer cases, no age difference was found
Even higher prevalence rates (up to 36%) have been between HPV-positive and -negative cases (i.e., aver-
found in young male populations (Kataoka et al., 1991). age 64 years) (Lont et al., 2006).
Beside the association with HPV, it is important to real- Cubilla et al. presented cross-sectional data of 288
ize that, in the case of HPV positivity, FPLs display rela- invasive penile cancers and studied the presence of
tively high viral load levels. The presence of high viral associated epithelial lesions (Cubilla et al., 2004). His­
loads in these lesions is clinically meaningful as it indi- tological evaluation showed that squamous hyperpla-
cates a potential increased risk for HPV transmission. sia, low-grade PIN, and high-grade PIN were present in
The majority of infections are subclinical (Kohn et al., 83, 59, and 44% of the cases, respectively. The observed
1999). associated lesions suggested a sequence of squamous
Although the clinical course is generally benign, hyperplasia to low-grade PIN to high-grade PIN. In this
showing healing within 1–2 years in the majority of study a more common association was observed
cases, a small percentage of FPLs remain persistently between squamous hyperplasia and the usual squamous,
HPV-positive and do not heal. These persistent HPV- papillary, and verrucous squamous cell carcinomas
positive FPLs might progress to high-grade PIN and than with warty or basaloid carcinomas. Con­versely,
subsequent penile cancer. high-grade PIN was present in two-thirds of the warty,
Consistent with HPV sexual transmission, varying basaloid, or mixed warty-basaloid tumor subtypes, in
amounts of men whose female partner had a squamous half of the usual squamous cell carcinomas, and absent
intraepithelial lesion (SIL) had PIN (Aynaud et al., 1994). in papillary and verrucous tumors. In fact, despite the
High-risk HPV was present in 75% of patients with PIN lack of a clear identification of the clinical counterparts,
grade I, 93% with PIN grade II, and 100% of PIN grade corresponding histopathologic features between the
III, which is one step removed from overt penile cancer. precursor lesion and its associated tumor type were
6.4 Molecular Pathogenesis 123

shown. Apparently, nondysplastic or mildly dysplastic very high-risk type HPV 16. Since not all HPV types
lesions may directly progress into invasive cancer in at were tested for, the rate of HPV is undoubtedly higher.
least a substantial subset of penile cancer cases. In con- Condom use lowers HPV infection only slightly. The
clusion, although there are several clear-cut differences reported HPV prevalence rates of 43–100% are based
between the types of penile squamous cell carcinoma on relatively small numbers (Wieland et al., 2000; Hahn
and their precursor lesions (i.e., histomorphological et al., 1988; Ikenberg et al., 1983).
features and HPV status), their clinical distinction and
the underlying molecular pathogenesis for progression
into invasive cancer are not clear-cut and merit further 6.4 Molecular Pathogenesis
investigation. An overview of the different histopatho-
logical lesions, the presence of high-risk HPV, their
clinical phenotype, and their putative transformation to Although the etiology of penile cancers is not yet fully
penile cancer are presented in Fig. 6.1. understood, penile carcinoma is recognized to be het-
Multiple studies have consistently shown that there erogeneous. A proportion of penile carcinomas is
is a high prevalence of HPV in PIN (60–100%) attributable to high-risk HPV infection, while in the
(Barrasso et al., 1987; Porter et al., 2002). In the gen- remaining penile cancers molecular mechanisms inde-
eral population, PIN has been found in 10% of uncir- pendent of HPV are likely to represent the more com-
cumcised men compared with 6% of circumcised men. mon underlying events. An overview of the molecular
Most cases of PIN are cleared naturally. HPV has pathogenesis is presented in Fig. 6.2, and will be dis-
been found in 80% of tumor specimens, 69% having the cussed below.
hyperplasia/low grade PIN high grade PIN lichen sclerosus

Histopathology

*
Clinical
manifestations

flat penile lesion Bowenoid papulosis Erythroplasia of Queyrat* lichen sclerosus

Genital Bowen’s disease
hrHPVpositivity(%) 70-80% >95% 40-100% no association with HPV

Progression to unkown <1% 5-30% 5%

cancer
80-100% warty/ penile cancer keratinizing/ 65-70%
HPVpos basaloid verrucous HPVneg

Fig. 6.1. Relationship between histology, HPV presence, clinical manifestation, and putative transformation of penile precursor
lesions into penile cancer (hrHPV high-risk HPV) (Published with permission from Bleeker (2009))
 124 6 Human Papillomavirus and Squamous Cell Carcinoma of the Penis

HPV-mediated non-HPV mediated

6 Different (early)
molecular events: Intervention in p16INK4a/cyclinD/Rb Alternative modes of intervention in
and p14ARF/MDM2/p53 pathways by p16INK4a/cyclinD/Rb and
hrHPV E6 and E7 proteins: p14ARF/MDM2/p53 pathways:

p16 promoter methylation

BMI-1 ↑

p16 p14
p14 gene mutation

CyclinD/CDK MDM 2
MDM 2 ↑

Rb p53 p53 gene mutation

hrHPV E7
others
(to be identified)
hrHPV E6

cell cycle arrest

apoptosis

dysregulated
control of the
cell cycle and
apoptosis

Common (late)
molecular events: alterations in:
ras
myc
E-cadherin
MMPs
COX
PGE2 synthase
host cell (epi)genome
others (to be identified)

immortalization
angiogenesis
Ti:me

invasion
metastasis

Fig. 6.2. Concept of penile molecular pathogensis. Schematic overview of modes of intervention in cellular pathways involved in
early and late stages of penile carcinogenesis, and their net effect (Published with permission from Bleeker (2009))
6.4 Molecular Pathogenesis 125

6.4.1 HPV-Mediated Penile Carcinogenesis 2002). This may infer that penile epithelium represents
a less favorable environment for virus-induced trans-
High-risk HPV-associated penile cancers arise from formation compared to the epithelium of the cervical
the progression of precursor lesions caused by a high- transformation zone, in which cervical cancers arise.
risk HPV infection. The penile carcinogenic pathway Furthermore, the peak incidence of cervical cancer is
is thought to be equivalent to high-risk HPV-mediated around the age of 35–45 years, while the incidence of
cervical carcinogenesis (Snijders et al., 2006). ­High-risk high-risk HPV-associated penile cancer simply increases
HPV-induced carcinogenesis is multistep in nature: a with age. These findings suggest that there exist tissue-
persistent infection with high-risk HPV is the initiating and/or hormonal-specific variables that influence the
causative event, and subsequent (epi)genetic alterations course of the high-risk HPV-mediated carcinogenic pro-
are necessary for a high-risk HPV-infected cell to cess that merit further attention.
become fully malignant. High-risk HPVs exert their
oncogenic effect by expressing the oncoproteins E6
and E7, which bind to and inactivate the p53 and Rb 6.4.2 HPV-Independent Penile
tumor suppressor gene products, respectively (zur Carcinogenesis
Hausen, 2002; Scheffner et al., 1994). The E6 and E7
gene products of the oncogenic HPV types are required Several studies have focused on the genetic and molec-
for induction and maintenance of the transformed phe- ular changes associated with HPV-independent penile
notype of the infected cells. By disturbance of the carcinogenesis, and they have identified nonviral
p14ARF/MDM2/p53 and p16INK4a/cyclin D/Rb pathways, mechanism(s) leading to disturbance of the p14ARF/
oncogenic HPV types interfere with control of the cell MDM2/p53 and/or p16INK4a/cyclin D/Rb pathways in
division cycle and apoptosis. The functional inactiva- this subset of penile carcinomas (Rubin et al., 2001;
tion of pRb by hrHPV E7 results in the reciprocal over- Martins et al., 2002; Leis et al., 1998; Couturier et al.,
expression of p16INK4a, due to a negative feedback loop 1991; Sastre-Garau et al., 2000; Campos et al., 2006;
between retinoblastoma tumor suppressor protein Golijanin et al., 2004; Kayes et al., 2007). Findings
(pRb) and p16INK4a. Therefore, overexpression of from Ferreux et al., revealed that there are at least two
p16INK4a may be used as a marker of viral involvement plausible mechanisms by which the p16INK4a/cyclin D/
(Kohn et al., 1999). Subsequent host-cell (epi)genetic Rb pathway can be disrupted during penile carcino-
events involved in high-risk HPV-induced penile car- genesis in the absence of hrHPV, i.e., silencing of the
cinogenesis are not well studied, but may include those p16INK4a gene by promoter hypermethylation in 15% of
identified for high-risk HPV-mediated cervical carcino- cases and overexpression of the polycomb group (PcG)
genesis, e.g., promoter methylation of CADM-1, an gene BMI-1, which targets the INK4A/ARF locus,
immunoglobulin (Ig)-like cell surface protein involved encoding both p16INK4a and p14ARF, in 10% of cases
in cell–cell adhesion, and a change in the composition (Kohn et al., 1999). Also, alternative high-risk HPV-
of the AP-1 complex, a transcription factor consisting independent mechanisms of p14ARF/MDM2/p53 path-
of different proteins (e.g., c-Jun, c-Fos, or Fra-1) in way inactivation in penile carcinogenesis have been
homo- or heterodimer complexes (Steenbergen et al., described including somatic mutations of the p53 gene,
2001; Sastre-Garau et al., 2000). Whether the same overexpression of MDM2, and mutation of p14ARF. An
(epi)genetic alterations are involved in high-risk HPV- inverse correlation between high-risk HPV presence
mediated penile carcinogenesis as in cervical carcino- and p53 stabilization, a feature of mutated, inactive
genesis warrants further research. It should be realized p53, has been reported in penile carcinoma (Castren
that despite a common causative event, differences et al., 1998; Pilotti et al., 1993; Ranki et al., 1995).
exist between high-risk HPV-associated cervical and
penile carcinoma, which are reflected by the different
incidence rates and time-span of development. While 6.4.3 Common Molecular Events
penile high-risk HPV infections are as equally com- in Penile Carcinogenesis
mon as those of the cervix, the incidence of HPV-
associated penile carcinoma is very rare as compared to Several other molecular events associated with penile
cervical cancer (Ikenberg et al., 1983; Franceschi et al., cancer include alterations in the ras and myc genes,
 126 6 Human Papillomavirus and Squamous Cell Carcinoma of the Penis

E-cadherin expression, matrix metalloproteinase (MMP- expected in the prevention of HPV-associated penile
6 2, MMP-9) expression, cyclo-oxygenase-2 (COX) path- lesions, to date the efficacy of HPV vaccination in men
way, and prostaglandin E2 synthase (66–70). These is unknown and the first results are awaited in the
alterations have been described in both HPV-positive near future. To study the efficacy of a prophylactic
and -negative penile cancers, and are suggested HPV vaccine in men, the presence of HPV-associated
to ­represent late events in penile carcinogenesis FPLs should not be ignored in the evaluation. This is
including disease progression, invasion, metastasis, and particularly important because their existence reflects
angio­genesis. the presence of high viral load, indicating their poten-
Evidence exists for multiple independent molecular tial increased risk for viral spread to sex partners
pathways of penile carcinogenesis, with a subgroup ­compared to those not having FPL, being either HPV-
known to be etiologically related to high-risk HPV negative or carrying very low copy numbers of HPV
infection. The most common disrupted pathways, both that are clinically irrelevant.
in HPV-mediated and HPV-independent penile car-
cinogenesis, involve the p14ARF/MDM2/p53 and/or
p16INK4a/cyclin D/Rb pathways. To date, the etiology of 6.5.2 Condom Use
penile cancers is not completely understood and addi-
tional research is necessary to fully delineate the Although there is not 100% protection, condom use is
sequence of molecular events involved in both HPV- effective in the prevention of sexually transmitted
mediated and non-HPV-associated pathways leading infections (STIs), including HPV (Holmes et al., 2004;
to penile cancer. A better understanding of the molecu- Vaccarella et al., 2006; Winer et al., 2006; Nielson
lar mechanisms beyond the development and progres- et al., 2007). To study whether viral shedding among
sion of penile cancer and its precursor lesions will aid sex partners might have consequences for viral persis-
the prevention, early detection, and development of tence and the natural history of genital lesions, a ran-
novel therapeutic agents to reduce morbidity and mor- domized clinical trial was performed. In this study, sex
tality from penile cancer. partners were randomized for condom use, and it was
shown that healing of HPV-associated genital lesions
was considerably shortened in condom-using couples
(Hogewoning et al., 2003; Bleeker et al., 2003). The
6.5 Prevention of HPV Infection healing time of high-risk HPV-associated FPLs was
7.4 months in male partners of the condom group com-
pared to 13.9 months in the noncondom group.
6.5.1 HPV Vaccination

To date, two prophylactic HPV vaccines, i.e., a biva-

lent HPV 16/18 vaccine Cervarix (GlaxoSmithKline 6.6 HPV as a Prognostic Indicator
Biochemicals S.A.) and a quadrivalent HPV 16/18/6/11 in Penile Cancer
vaccine Gardasil (Sanofi Pasteur MSD), have been
registered by the European Medicines and Evaluation
Agency (EMEA) and the Federal Drug Administration Although studies have found that HPV infection is
(FDA). A high prophylactic efficacy of these vaccines related to the tumor subtype, the correlation with prog-
for persistent HPV infection and incident high-grade nostic variables is still unclear.
cervical lesions has been observed in HPV-negative Bezerra et al. analyzed tissue from 82 patients
women in large multicentric trials (Harper et al., 2004, treated for penile carcinoma using PCR (Bezerra et al.,
2006; Villa et al., 2005). Evidence to date also suggests 2001). Of these, 42 patients had lymph node metasta-
the safety and immunogenicity of HPV vaccines in ses. HPV DNA was detected in 30.5% (25/82) samples,
men (10–15 years of age) and thus the vaccines have of which 13 were positive for HPV 16, four contained
been licensed for men in some countries (Villa et al., HPV 18, with the remaining samples positive for a vari-
2005). The EMEA license for the quadrivalent vaccine ety of HPV DNA including HPV 45, 6/11, 31, 33, and
includes both sexes. Although similar effects might be 35. There was no correlation between HPV DNA status
References 127

and 10-year survival. With a mean follow-up of 88.7 in sexual partners of women with cervical intraepithelial
months (range, 0.1–453 months), the study concluded ­neoplasia. N Engl J Med 317(15): 916–923
Bezerra AL, Lopes A, Santiago GH, Ribeiro KC, Latorre MR,
that HPV status was related only to lymphatic embo- Villa LL (2001) Papillomavirus as a prognostic factor in car-
lization and had no correlation with the prognosis. cinoma of the penis: Analysis of 82 patients treated with
Disease-specific survival was only significantly related amputation and bilateral lymphadenectomy. Cancer 91(12):
to the lymph node status. 2315–2321
Bleeker MC, Heideman DA, Snijders PJ, Horenblas S, Dillner J,
In contrast, Lont et al. investigated the survival out- Meijer CJ (2009) Penile cancer: Epidemiology, pathogenesis
come in 176 patients with SCC of the penis with a and prevention. World J Urol 27(2): 141–150
mean follow-up of 95 months (Lont et al., 2006). HPV Bleeker MC, Hogewoning CJ, van den Brule AJ, Voorhorst FJ,
DNA detection was performed using PCR with geno- Van Andel RE, Risse EK, Starink TM, Meijer CJ (2002)
Lesions and human papillomavirus in male sexual partners
typing for all the high-risk HPV subtypes. The study of women with cervical intraepithelial neoplasia. J Am Acad
showed the presence of high-risk HPV DNA in 50 of Dermatol 47(3): 351–357
the 171 patients (29%), of which 38 (76%) harbored Bleeker MC, Hogewoning CJ, Voorhorst FJ, van den Brule AJ,
HPV 16. Multiple logistic regression analysis found Snijders PJ, Starink TM, Berkhof J, Meijer CJ (2003)
Use promotes regression of human papillomavirus-­associated
that the only factor related to the HPV status was mor- penile lesions in male sexual partners of women with ­cervical
phea-like growth, whereby HPV-positive tumors showed intraepithelial neoplasia. Int J Cancer 107(5): 804–810
less morphea-like growth. The 5-year disease-specific Bleeker MC, Snijders PF, Voorhorst FJ, Meijer CJ (2006) Penile
survival was 92% in the HPV-positive group com- lesions: The infectious “invisible” link in the transmission of
human papillomavirus. Int J Cancer 119(11): 2505–2512
pared to 78% in the HPV-negative group, indicat- Campos RS, Lopes A, Guimaraes GC, Carvalho AL, Soares FA
ing a survival advantage for patients who are HPV (2006) E-Cadherin, MMP-2, and MMP-9 as prognostic
DNA-positive. markers in penile cancer: Analysis of 125 patients. Urology
67(4): 797–802
Canavan TP, Cohen D (2002) Cancer. Am Fam Physician 66(7):
1269–1274
Castellsague X, Bosch FX, Munoz N, Meijer CJLM, Shah KV,
6.7 Conclusion et al. (2002)circumcision, penile human papillomavirus
infection and cervical cancer in female partners. N Engl
J Med 346: 1105–1112
Castren K, Vahakangas K, Heikkinen E, Ranki A (1998) Absence
In almost half of the patients with squamous cell can- of P53 mutations in benign and pre-malignant male genital
cer, a clear association with high-risk HPV has been lesions with over-expressed P53 protein. Int J Cancer 77(5):
found. Based on research in cervical cancer, similar 674–678
Couturier J, Sastre-Garau X, Schneider-Maunoury S, Labib A,
pathophysiological factors in the etiology of squamous Orth G (1991) Integration of papillomavirus dna near myc
cell cancer of the penis were found. Additionally, more genes in genital carcinomas and its consequences for proto-
insight has been gained in the non-HPV-related penile oncogene expression. J Virol 65(8): 4534–4538
cancers. Nevertheless, for a complete understanding, Cubilla AL, Reuter VE, Gregoire L, Ayala G, Ocampos S,
Lancaster WD, Fair W (1998) Squamous cell carcinoma: A
even more insight is necessary, especially in the differ- distinctive human papilloma virus- related penile neoplasm:
ences of natural clearance between HPV infection in a report of 20 cases. Am J Surg Pathol 22(6): 755–761
men and women. However, true prevention is at hand Cubilla AL, Velazquez EF, Young RH (2004) Lesions associated
with HPV vaccination. with invasive penile squamous cell carcinoma: a pathologic
study of 288 Cases. Int J Surg Pathol 12(4): 351–364
Cubilla AL, Velazquez EF, Young RH (2004) Squamous cell car-
cinoma of the penis associated with lichen sclerosus. An
extremely well-differentiated, nonverruciform neoplasm that
References preferentially affects the foreskin a report of 10 cases of a
distinctive clinicopathologic entity. Am J Surg Pathol 28(7):
895–900
Aynaud O, Ionesco M, Barrasso R (1994) Penile intraepithelial Cubilla AL, Velazques EF, Reuter VE, Oliva E, Mihm MC, Jr.,
neoplasia – specific clinical features correlate with histo- Young RH (2000) Warty (Condylomatous) squamous cell
logic and virologic findings. Cancer 74: 1762–1767 carcinoma of the penis: A report of 11 cases and proposed
Barrasso R (1997) Latentand subclinical HPV external anogeni- classification of ‘verruciform’ penile tumors. Am J Surg
tal infection. Clin Dermatol 15(3): 349–353 Pathol 24(4): 505–512.
Barrasso R, de Brux J, Croissant O, Orth G (1987) Prevalence of Daling JR, Madeleine MM, Johnson LG, Schwartz SM, Shera
papillomavirus-associated penile intraepithelial neoplasia KA, Wurscher MA, Carter JJ, Porter PL, Galloway DA,
 128 6 Human Papillomavirus and Squamous Cell Carcinoma of the Penis

McDougall JK, Krieger JN (2005)Cancer: Importance of Ikenberg H, Gissmann L, Gross G, Grussendorf-Conen EI, zur
6 circumcision, human papillomavirus and smoking in in situ Hausen H (1983) Papillomavirus Type-16-related dna in
and invasive disease. Int J Cancer 116(4): 606–616 genital bowen’s disease and in bowenoid papulosis. Int
Dorfman S, Cavazza M, Cardozo J (2006) Cancer associated J Cancer 32(5): 563–565
with so-called low-risk human papilloma virus. report of five Kataoka A, Claesson U, Hansson BG, Eriksson M, Lindh E
cases from rural venezuela. Trop Doct 36(4): 232–233 (1991) Papillomavirus infection of the male diagnosed by
Ferreux E, Lont AP, Horenblas S, Gallee MPW, Raaphorst FM, southern-blot hybridization and polymerase chain reaction:
Doeberitz MV, Meijer CJLM, Snijders PJF (2003) Evidence Comparison between urethra samples and penile biopsy
for at least three alternative mechanisms targeting the samples. J Med Virol 33(3): 159–164
P16(INK4A)/cyclin D/Rb pathway in penile carcinoma, one Katelaris PM, Cossart YE, Rose BR, Thompson CH, Sorich E, et
of which is mediated by high-risk human papillomavirus. al. (1988) Human papillomavirus: The untreated male reser-
J Pathol 201(1): 109–118 voir. J Urol 140: 300–305
Franceschi S, Castellsague X, Dal Maso L, Smith JS, Plummer Kayes O, Ahmed HU, Arya M, Minhas S (2007) Molecular and
M, Ngelangel C, Chichareon S, Eluf-Neto J, Shah KV, genetic pathways in penile cancer. Lancet Oncol 8(5):
Snijders PJ, Meijer CJ, Bosch FX, Munoz N (2002) Prevalence 420–429
and determinants of human papillomavirus genital infection Kohn F-M, Pflieger-Bruss S, Schill W-B (1999) Penile skin
in men. Br J Cancer 86(5): 705–711 ­diseases. Andrologia 31: 3–11
Golijanin D, Tan JY, Kazior A, Cohen EG, Russo P, Dalbagni G, Leis PF, Stevens KR, Baer SC, Kadmon D, Goldberg LH, Wang
Auborn KJ, Subbaramaiah K, Dannenberg AJ (2004) XJA (1998) C-RasHa mutation in the metastasis of a human
Cyclooxygenase-2 and microsomal prostaglandin E syn- papillomavirus (HPV)-18 positive penile squamous cell car-
thase-1 are overexpressed in squamous cell carcinoma of the cinoma suggests a cooperative effect between HPV-18 and
penis. Clin Cancer Res. 10(3): 1024–1031 C-RasHa activation in malignant progression. Cancer 83(1):
Gregoire L, Cubilla AL, Reuter VE, Haas GP, Lancaster WD 122–129
(1995) Association of human papillomavirus with high- Lont AP, Kroon BK, Horenblas S, Gallee MP, Berkhof J, Meijer
grade histologic variants of penile-invasive squamous cell CJ, Snijders PJ (2006) Presence of high-risk human papil-
carcinoma. J Natl Cancer Inst 87(22): 1705–1709 lomavirus dna in penile carcinoma predicts favorable out-
HahnA, Loning T, HoosA, Henke P (1988) Immunohistochemistry come in survival. Int J Cancer 119(5): 1078–1081
(S 100, KL 1) and human papillomavirus dna hybridization on Maden C, Sherman KJ, Beckmann AM, Hislop TG, Teh CZ,
morbus bowen and bowenoid papulosis. Virchows Arch A Ashley RL, Daling JR (1993) Importance of circumcision,
Pathol Anat Histopathol 413(2): 113–122 medical conditions, and sexual activity and risk of penile
Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, cancer. J Natl Cancer Inst 85(1): 19–24
Schuind A, Zahaf T, Innis B, Naud P, De Carvalho NS, Martins AC, Faria SM, Cologna AJ, Suaid HJ, Tucci S Jr. (2002)
Roteli-Martins CM, Teixeira J, Blatter MM, Korn AP, Quint Immunoexpression of P53 protein and proliferating cell
W, Dubin G (2004) Sustained efficacy up to 4.5 yearsof a nuclear antigen in penile carcinoma. J Urol 167(1): 89–92.
bivalent L1 virus-like particle vaccine in prevention of infec- McCance DJ, Kalache A, Ashdown K, Andrade L, Menezes F,
tion with human papillomavirus types 16 and 18 in young Smith P, Doll R (1986) Papillomavirus types 16 and 18 in car-
women: a randomised controlled trial. Lancet 364(9447): cinomas of the penis from Brazil. Int J Cancer 37(1): 55–59
1757–1765 Morris, BJ (2007) Why circumcision is a biomedical imperative
Harper DM, Franco EL, Wheeler CM, Moscicki AB, Romanowski for the 21th century. Bioessays. 29(11): 1147–1158.
B, Roteli-Martins CM, Jenkins D, Schuind A, Costa Clemens Nielson CM, Harris RB, Dunne EF, Abrahamsen M, Papenfuss
SA, Dubin G (2006) Efficacy up to 4.5 years of a bivalent l1 MR, Flores R, Markowitz LE, Giuliano AR (2007) Factors
virus-like particle vaccine against human papillomavirus for anogenital human papillomavirus infection in men.
types 16 and 18: Follow-up from a randomised control trial. J Infect Dis 196(8): 1137–1145.
Lancet 367(9518): 1247–1255 Pilotti S, Donghi R, D’Amato L, Giarola M, Longoni A, Della
Heideman DA, Waterboer T, Pawlita M, Delis-van Diemen P, X, Torre G, De Palo G, Pierotti MA, Rilke F (1993) Detection
Nindl I, Leijte JA, Bonfrer JM, Horenblas S, Meijer CJ, and P53 alteration in squamous cell verrucous malignancies
Snijders PJ (2007) Papillomavirus-16 is the predominant of the lower genital tract. Diagn Mol Pathol 2(4): 248–256.
type etiologically involved in penile squamous cell carci- Porter WM, Francis N, Hawkins D, Dinneen M, Bunker CB
noma. J Clin Oncol 25(29): 4550–4556 (2002) Intraepithelial neoplasia: Clinical spectrum and treat-
Hippelainen M, Yliskoski M, Saarikoski S, Syrjanen S, Syrjanen ment of 35 cases. Br J Dermatol 147(6): 1159–1165
K (1991) Human papillomavirus lesions of the male sexual Ranki A, Lassus J, Niemi KM (1995) Relation of P53 tumor sup-
partners: The diagnostic accuracy of peniscopy [See pressor protein expression to human papillomavirus (HPV)
Comments]. Genitourin Med 67(4): 291–296 DNA and to cellular atypia in male genital warts and in pre-
Hogewoning CJ, Bleeker MC, van den Brule AJ, Voorhorst FJ, malignant lesions. Acta Derm Venereol. 75(3): 180–186
Snijders PJ, Berkhof J, Westenend PJ, Meijer CJ (2003) use Rubin MA, Kleter B, Zhou M, Ayala G, Cubilla AL, Quint WG,
promotes regression of cervical intraepithelial neoplasia and Pirog EC (2001) Detection and typing of human papilloma-
clearance of human papillomavirus: A randomized clinical virus dna in penile carcinoma: evidence for multiple inde-
trial. Int J Cancer 107(5): 811–816 pendent pathways of penile carcinogenesis. Am J Pathol
Holmes KK, Levine R, Weaver M (2004) Effectiveness of con- 159(4): 1211–1218
doms in preventing sexually transmitted infections. Bull Sastre-Garau X, Favre M, Couturier J, Orth G (2000) patterns of
World Health Organ 82(6): 454–461 alteration of Myc genes associated with integration of human
References 129

papillomavirus type 16 or type 45 DNA in two genital Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano
tumours. J Gen Virol 81(Pt 8): 1983–1993 AR, Wheeler CM, Koutsky LA, Malm C, Lehtinen M,
Scheffner M, Romanczuk H, Munger K, Huibregtse JM, Mietz Skjeldestad FE, Olsson SE, Steinwall M, Brown DR,
JA, Howley PM (1994) Functions of human papillomavirus Kurman RJ, Ronnett BM, Stoler MH, Ferenczy A, Harper
proteins. Curr Top Microbiol Immunol 186: 83–99 DM, Tamms GM, Yu J, Lupinacci L, Railkar R, Taddeo FJ,
Senba M, Kumatori A, Fujita S, Jutavijittum P, Yousukh A, Jansen KU, Esser MT, Sings HL, Saah AJ, Barr E
Moriuchi T, Nakamura T, Toriyama K (2006) Prevalence of (2005)Quadrivalent human papillomavirus (Types 6, 11, 16,
human papillomavirus genotypes in penile cancers from and 18) L1 virus-like particle vaccine in young women: A
Northern Thailand. J Med Virol 78(10): 1341–1346 randomised double-blind placebo-controlled multicentre
Snijders PJ, Steenbergen RD, Heideman DA, Meijer CJ (2006) phase ii efficacy trial. Lancet Oncol 6(5): 271–278
HPV-mediated cervical carcinogenesis: concepts and clini- Weaver BA, Feng Q, Holmes KK, Kiviat N, Lee SK et al. (2004)
cal implications. J Pathol 208(2): 152–164 Evaluation of genital sites and sampling techniques for
Steenbergen RD, Kramer D, Meijer CJ, Walboomers JM, Trott detection of human papillomavirus DNA in men. J Infect
DA, Cuthbert AP, Newbold RF, Overkamp WJ, Zdzienicka Dis 189: 677–685
MZ, Snijders PJ (2001) Suppression by chromosome 6 in a Wieland U, Jurk S, Weissenborn S, Krieg T, Pfister H, Ritzkowsky
human papillomavirus type 16-immortalized keratinocyte A (2000) Erythroplasia of Queyrat: coinfection with cutane-
cell line and in a cervical cancer cell line. J Natl Cancer Inst ous carcinogenic human papillomavirus type 8 and genital
93(11): 865–872 papillomaviruses in a carcinoma in situ. J Invest Dermatol
Vaccarella S, Franceschi S, Herrero R, Munoz N, Snijders PJ, 115(3): 396–401
Clifford GM, Smith JS, Lazcano-Ponce E, Sukvirach S, Shin Winer RL, Hughes JP, Feng Q, O’Reilly S, Kiviat NB, Holmes
HR, de Sanjose S, Molano M, Matos E, Ferreccio C, Anh KK, Koutsky LA (2006) Use and the risk of genital human
PT, Thomas JO, Meijer CJ (2006) Behavior, condom use, papillomavirus infection in young women. N Engl J Med
and human papillomavirus: pooled analysis of the iarc 354(25): 2645–2654
human papillomavirus prevalence surveys. Cancer Epidemiol zur Hausen H (2002) Papillomaviruses and cancer: From basic
Biomarkers Prev 15(2): 326–333 studies to clinical application. Nat Rev Cancer 2(5): 342–350
 Human Papillomavirus and Anal
Intraepithelial Neoplasia 7
Alberto Rosenblatt and Homero Gustavo de Campos Guidi

Contents 7.1 Introduction

7.1 Introduction........................................................... 133
7.2 Overview................................................................ 133 Human papillomavirus (HPV)-associated malignan-
7.2.1 Anal HPV Infection and Associated cies other than cervical cancer have increased in recent
Diseases in Men...................................................... 134
7.2.2 Anal HPV Infection and Associated decades and one of the most challenging is squamous
Diseases in Women.................................................. 134 cell carcinoma of the anus (SCCA).
7.3 Clinical Manifestations......................................... 136
This chapter reviews and discusses the recent find-
7.3.1 Symptoms................................................................ 136 ings related to anal intraepithelial neoplasia (AIN), the
precursor lesion of anal SCC, including grading, ter-
7.4 Differential Diagnosis............................................ 136
7.4.1 Benign Conditions................................................... 136 minology, and management of anal dysplastic lesions.
7.4.2 Malignant Conditions.............................................. 137 A complete discussion of anal carcinoma is beyond the
7.5 Diagnosis................................................................ 137
scope of this book, and readers interested in the subject
7.5.1 Anal Cytology and Histology.................................. 137 should refer to the specialized literature (Abbasakoor
7.5.2 AIN Grading and Terminology............................... 137 and Boulos, 2005; Shepherd, 2007).
7.5.3 Anal and Perianal Brush
Samples for Molecular Tests................................... 138
7.5.4 High-Resolution Anoscopy and
Targeted Biopsies.................................................... 138 7.2 Overview
7.5.5 Anoscopic Changes Associated with HSIL............. 140
7.5.6 Cellular Markers...................................................... 140
7.6 Treatment for Anogenital Warts and AIN.......... 140 Squamous cell carcinoma of the anus (SCCA) and
7.6.1 Topical Treatments.................................................. 141
perianal skin is relatively uncommon, accounting for
7.6.2 Ablative Treatments................................................ 143
about 4% of all lower gastrointestinal cancers in the
7.7 Surveillance............................................................ 145 United States. However, evidence shows that the inci-
7.8 Anal Disease Screening......................................... 145 dence of both anal SCC and AIN is increasing in both
7.9 Prevention of HPV-Related genders, particularly in high-risk groups such as indi-
Anal Warts and AIN............................................. 145 viduals infected with the human immunodeficiency
References.............................................................. 145
virus (HIV) and immunosuppressed patients.
The prevalence of AIN in surgically removed peria-
nal/anal warts is higher than previously reported. In a
recent retrospective analysis, McCloskey et al. (2007)
A. Rosenblatt ()
Albert Einstein Jewish Hospital, Sao Paulo, Brasil found an overall AIN rate of 33% (with 20% high-
e-mail: [email protected] grade AIN) in men without HIV infection and 78%

A. Rosenblatt, H. G. de Campos Guidi, Human Papillomavirus, 133

DOI: 10.1007/978-3-540-70974-9-7, © Springer-Verlag Berlin Heidelberg 2009
 134 7 Human Papillomavirus and Anal Intraepithelial Neoplasia

(52% high-grade AIN) in HIV-infected men. In HIV-

7 negative female subjects, the overall rate of AIN in
perianal/anal warts was 8.3%, with high-grade AIN
present in 2.8% of specimens. According to the inves-
tigators, the presented data support the judicious path-
ological analysis of all HPV-related lesions removed
from the anogenital region.
The anal squamocolumnar junction is anatomically
very similar to the squamocolumnar junction of the
cervix. This active transformation zone is particularly
vulnerable to HPV infection and its related oncogenic
effects, particularly in women where the anal squamo-
columnar junction is more exteriorized than in men. It
is currently believed that basal cell invasion by the
virus occurs in a period of approximately 24 h, and the
HPV life cycle and infection are initiated when viruses
reach this cell layer.
AIN shares many disease characteristics with cervi-
cal intraepithelial neoplasia (CIN) and is considered a
precursor lesion of anal invasive disease.
However, as opposed to CIN lesions, the natural
Fig. 7.1. Anal condyloma. (Source: Photograph courtesy of
history of AIN is still not completely understood. The Carlos Walter Sobrado Jr MD, PhD, São Paulo, Brazil)
regression rate is questionable in low-grade AIN, as it
could simply reflect inconsistent pathologic reporting Nyitray et al. (2008) reported that the overall prevalence
or poor clinical follow-up. Concerning high-grade of anal HPV infection (at the anal canal and/or perianal
AIN, Shepherd (2007) showed that these lesions may region) in men who acknowledged having had no prior
remain in a quiescent state for long periods of time in sexual intercourse with men was 24.8%, suggesting the
immunocompetent subjects, but have a tendency to possibility of distinct routes of HPV transmission (such
rapidly progress in HIV/AIDS patients. as spread from the penis or from sexual partners via fin-
Anal cancer is highly associated with HPV infec- gers or other objects). In the HIV-negative MSM group,
tion, particularly with oncogenic type 16, although Ching-Hong detected HPV DNA in the anal canal in
several other high-risk HPV types are also involved in 57% of 1,218 individuals aged 18–89 years, and the
the pathogenesis of this disease (Palmer et al., 1987; prevalence of low-grade squamous intraepithelial
Youk et al., 2001; Shroyer et al., 1995). lesions (LSILs) and high-grade squamous intraepithe-
lial lesions (HSILs) was 15% and 5%, respectively
(Chin-Hong et al., 2005).
7.2.1 Anal HPV Infection and Associated In addition, Palefsky et al. (1998c) showed that the
Diseases in Men relative risk of HIV-positive men developing incident
HSILs is 3.7 higher than HIV-negative men.
HIV-positive men, and particularly infected men who
have sex with men (MSM), are at increased risk of anal
HPV infection (Fig. 7.1), AIN, and anal cancer (Melbye 7.2.2 Anal HPV Infection and Associated
et al., 1994; Carter et al., 1995; Chin-Hong and Palefsky, Diseases in Women
2005; Chin-Hong et al., 2005; Kreuter et al., 2005)
(Table 7.1). The exact mechanism is still unknown, The prevalence of anal HPV infection in cytologically
but it is likely related to an immunosuppressive status. (cervical) normal and abnormal women has recently
However, the risk of acquiring anal HPV infection is been analyzed. Goodman et al. (2008) detected anal
also high in heterosexual men and in HIV-negative sex- HPV infection in 42% of women without cervical
ually active MSM (Chin-Hong et al., 2004) (Table 7.1). abnormalities at the time of study enrollment, and more
7.2 Overview 135

Table 7.1 Risk factors for anal HPV infection, AIN, and anal neoplasia

Risk factors associated with anal HPV infection in heterosexual male subjects (Nyitray et al., 2008)
 Lifetime number of female sex partners
 Frequency of sex with females during the preceding month
Risk factors associated with anal HPV infection in HIV-negative MSM (Chin-Hong et al., 2004)
 Receptive anal intercourse during the preceding 6 months
 >Five sex partners during the preceding 6 months
Most significant risk factors for anal HPV detection (Palefsky et al., 1998b)
 Presence of anal HPV infection
 History of receptive anal intercourse
 HIV infection
 Low CD4+ levels
Risk factors for developing low-grade SIL (LSIL) in HIV-negative MSM (Chin-Hong et al., 2005)
 >Five male receptive anal sex partners
 Use of poppers (alkyl nitrites) or injection drugs two or more times per month in the previous 6 months
 Older age at first receptive anal intercourse
 Infection with multiple HPV types
Risk factors for developing high-grade SIL (HSIL) (Palefsky et al., 1998a)
 HIV infection
 Low CD4 cell counts
 Persistent anal HPV infection
 Multifocal genital intraepithelial neoplasia in female subjects (Scholefield et al., 1992)
Risk factors associated with carcinoma of the anus (Ryan et al., 2000; Welton et al., 2004; Fagan et al., 2005)
 AIN 3 (HSIL)
 HPV infection
 HIV infection and immunosuppression
 Anoreceptive intercourse/multiple sexual partners
 History of cervical intraepithelial neoplasia (CIN)/cervical cancer
 Host genetic changes
 Other sexually acquired diseases
 Cigarette smoking

HPV human papillomavirus; HIV human immunodeficiency virus; MSM men who have sex with men; AIN anal intraepithelial
neoplasia; CIN cervical intraepithelial neoplasia; LSIL low-grade squamous intraepithelial lesion; HSIL high-grade squamous
intraepithelial lesion

than half of these were oncogenic types. But the risk of with multifocal genital intraepithelial neoplasia and
acquisition of an incident high-risk anal HPV infection the increased association of AIN, CIN, and vulvar
was increased significantly (91% greater risk) in women intraepithelial neoplasia (VIN) is probably related to
with a cervical HPV infection at baseline. Moreover, a the shared exposure to oncogenic HPV infections
significant inverse relationship was found for incident (Rabkin et al., 1992; Frisch et al., 1997; Frisch et al.,
oncogenic anal HPV infection and the women’s age. 1999; Fox, 2006) (Fig. 7.2a, b ). Furthermore, Holly
Anal intercourse and spread of HPV from the cervix/ et al. (2001) demonstrated that the risk of abnormal
vagina/vulva or even from sexual partners via fingers/ anal cytology is also higher in HIV-positive women
toys may play a causative role in viral transmission to than in HIV-negative women presenting high-risk
the anal region of women. behavior.
According to Scholefield et al. (1992), the inci- Nevertheless, anal carcinoma rates are not as high
dence of AIN is also high (16-fold increase) in women as the reported rates of anal dysplastic lesions.
 136 7 Human Papillomavirus and Anal Intraepithelial Neoplasia

Fig. 7.2. (a) Anal condyloma.

7 (b) Vulvar and perianal condy-
loma. (Source: Photograph
courtesy of Nadir Oyakawa,
MD, PhD, São Paulo, Brazil)

7.3 Clinical Manifestations

The majority of patients have no visible lesions, but

nonspecific macroscopic changes may occur in the
anal mucosa and/or perianal region:
Raised hyperemia or white desquamative lesions
Pigmentation (Fig. 7.3)
Ulceration or verrucous lesions (according to Kreuter
et al. (2005), the presence of the latter has been usu-
ally associated with increased risk of progression to
invasive disease)

7.3.1 Symptoms

Asymptomatic
Local symptoms such as, pruritus, irritation, pain,
tenesmus, and bleeding discharge

7.4 Differential Diagnosis

For further details (on the differential diagnosis), the

reader is referred to reports by Buechner and by
Wacker and Hartschuh (Buechner, (2002); Wacker and
Hartschuh, (2004)). Fig. 7.3. Anal intraepithelial neoplasia. (Source: Photograph
courtesy of Carlos Walter Sobrado Jr MD, PhD, São Paulo,
Brazil)
7.4.1 Benign Conditions

Essential pruritus
Chronic perianal dermatitis, contact urticaria, and
allergic contact dermatitis
Parasites and fungal infections
Seborrheic keratoses and hidradenitis suppurativa
7.5 Diagnosis 137

MSM. The investigators reported a higher sensitivity

of cytology in detecting AIN for clinician-collected
than for patient-collected specimens and for HIV-
positive vs. HIV-negative men. The specificity of
cytology in detecting AIN was higher in HIV-negative
than HIV-positive men.
However, given the high probability of AIN in a patient
with a negative cytology result (23% for HIV-negative
men and 45% for HIV-positive men with ­self-collected
specimen), anoscopy should still be considered in those
individuals with a single negative Pap test result.

Anal cytology is a useful screening method for

detecting premalignant anal lesions associated
with HPV, and the detection rate is increased with
repeated cytology screening (Jay et al., 1997;
Nadal et al., 2007).

7.5.2 AIN Grading and Terminology

AIN grading is based on anal cytology and histo-

pathologic confirmation (Jay et al., 1997).

AIN grading remains controversial. As for the cervix,

the grading of AIN is based on morphologic criteria
and tissue architecture, where the level of epithelial
Fig. 7.4. Perianal Buschke-Löwenstein tumor. (Source: Photo­
graph courtesy of Carlos Walter Sobrado Jr MD, PhD, São involvement by disorderly growth and cytologic atypia
Paulo, Brazil) are analyzed. In addition, the histological features of
AIN are usually combined with those associated with
HPV infection (i.e., presence of koilocytosis and dysk-
7.4.2 Malignant Conditions eratosis) (Shepherd, 2007):

Giant verrucous carcinoma of the perianal region AIN 1 – dysplasia involves less than one-third of the
(Buschke-Löwenstein tumor) (Fig. 7.4) squamous mucosa thickness.
Extramammary Paget’s disease AIN 2 – dysplasia involves more than one-third, but
Cutaneous T cell lymphoma less than two-thirds of the mucosa.
Basal cell carcinoma AIN 3 – dysplasia involves more than two-thirds of
Langerhans cell histiocytosis the mucosa thickness.
Anorectal melanoma (rare) Carcinoma in situ is now categorized as grade AIN 3.
Because of reported interobserver variations using the
“three-tiered” grading system, particularly for AIN grade
7.5 Diagnosis 1 and 2, the utilization of a Bethesda-type categorization
is recommended (i.e., low- and high-grade AIN), where:
Low-grade AIN encompasses AIN 1 and AIN 2.
7.5.1 Anal Cytology and Histology
High-grade AIN corresponds to AIN 3 (Scholefield,
1999).
Chin-Hong et al. (2008) analyzed patient- and clini-
cian-collected anal cytology samples to screen for AIN can also be referred to as anal squamous intra-
HPV-associated AIN in HIV-positive and -negative epithelial lesion (SIL); hence, low-grade anal squa­
 138 7 Human Papillomavirus and Anal Intraepithelial Neoplasia

mous intraepithelial lesion (LSIL) is equivalent to

7 histo­logic grade AIN 1 (Martin and Bower, 2001),
whereas ­high-grade anal squamous intraepithelial
lesion (HSIL) corresponds to AIN 2 or 3.

Specimens exhibiting insufficient abnormalities to

be interpreted as SIL, and those with rare atypical
squamous cells but without definitive cellular evi-
dence for SIL, should be classified as atypical
squamous cells of undetermined significance
(ASCUS) (see also Chap. 8).

7.5.3 Anal and Perianal Brush Samples Fig. 7.5. High-resolution anoscopy showing acetowhitening of the
for Molecular Tests anal mucosa. (Source: Photograph courtesy of Nadir Oyakawa,
MD, PhD, São Paulo, Brazil)

Perianal and anal canal specimens can be obtained by

brushing and then be analyzed for HPV DNA using How to Perform HRA
polymerase chain reaction (PCR) and genotyping.
Goldstone (2008) recently evaluated the use of the HRA is an office procedure and anesthesia is not
Hybrid Capture 2 test in HIV-positive and -negative required. A digital rectal examination (DRE) is also
MSM exhibiting ASCUS. The investigators reported performed at the time of the procedure.
that referring only patients with high-risk HPV types Initially, the perianal skin and perineum are
for high-resolution anoscopy (HRA) can reduce the examined under magnification following application
number of procedures by more than 50%. of acetic acid 5% (Fig. 7.6a, b). After introduction of
Studies show that HIV patients harbor different a disposable anoscope (Fig. 7.7), gauze wrapped
types of HPV DNA, including intermediate-risk and around a cotton-tipped swab soaked in 3% acetic
high-risk HPV types other than 16–18. Furthermore, acid solution is generously applied to the anal canal
regional differences in type prevalence have been also and perianal area. The solution is allowed to satu-
reported in these patients (Nyitray et al., 2008; Goodman rate the epithelium for a couple of minutes and the
et al., 2008; Tsai et al., 2008). swab is then removed. The whitening of the mucosa
(Fig. 7.8a, b) produced by the vinegar solution in
areas of abnormal transitional epithelium facilitates
examination with a magnifying instrument (colpo-
7.5.4 High-Resolution Anoscopy scope/ microscope). Lugol’s iodine solution is then
and Targeted Biopsies applied after the acetic acid, and the anus is exam-
ined once again with the magnifying instrument.
High-resolution anoscopy (HRA) is a minimally inva- HSILs do not take up the iodine solution and the
sive procedure (equivalent to cervical colposcopy) that suspected areas appear yellow-to-tan, whereas nor-
enables visualization and biopsy of abnormal lesions mal tissue or LSILs become dark brown or black.
(Fig. 7.5).
HRA should be performed if ASCUS, LSIL, or
HSIL is found on the anal Pap smear (Chin-Hong and
High-resolution anoscopy and targeted surgical
Palefsky, 2002).
destruction:
Moreover, since subclinical anal HPV infection
Suspected HSIL areas (Fig. 7.9) are then selec-
should be considered in the differential diagnoses of
tively destroyed under direct visualization (see
idiopathic anal pruritus, HRA can also be recom-
below - Anoscopic changes associated with HSIL
mended in individuals presenting this common disor-
(Sect. 7.5.5) and Sect 7.6).
der (Magi et al., 2003; Magi et al., 2006).
7.5 Diagnosis 139

Fig. 7.6. (a.b) Acetowhitening and condylomatous lesions in the anal/perianal area. (Source: Photograph courtesy of Sidney Roberto
Nadal MD, PhD, São Paulo, Brazil)

Fig. 7.7. HPV-related anal lesion identified after introduction of

a disposable anoscope. (Source: Photograph courtesy of Sidney
Roberto Nadal MD, PhD, São Paulo, Brazil)

Important
Normal mucosa in between treated areas should be
preserved, with an effort to prevent anal stenosis. Fig. 7.8. (a) High-resolution anoscopy showing acetowhite
lesions (Source: Nadal. Photograph courtesy of Sidney Roberto
Nadal MD, PhD, São Paulo, Brazil). (b) Acetowhite lesions of
the anal canal (Source: Photograph courtesy of Toshiro
Tomishige MD, PhD, São Paulo, Brazil)
 140 7 Human Papillomavirus and Anal Intraepithelial Neoplasia

7.5.6 Cellular Markers

7
Walts et al. (2006) and Bean et al. (2007) demonstrated
that the immunohistochemical expression of p16 and
Ki67 is a useful method to refine the diagnosis and
grading of AIN, particularly for high-grade disease.
Moreover, Kreuter et al. (2007) recently showed
that p16 may be a useful adjunct marker for the evalu-
ation of treatment response in HPV-associated AIN.

7.6 Treatment for Anogenital

Warts and AIN

Treatment of anal and perianal warts is similar to HPV-

related genital lesions (see Chap. 3).
Fig. 7.9 HPV-related lesion in the rectal ampulla (Source:
Photograph courtesy of Toshiro Tomishige MD, PhD, São Paulo,
However, reliable treatment modalities for the man-
Brazil) agement of AIN are still lacking and good treatment
results are probably best achieved in centers with a
special interest in this disease.
7.5.5 Anoscopic Changes Associated with HSIL Recurrence rates are high, particularly in HIV-
positive patients, and likely reflect the multifocal nature
Anoscopic changes most often associated with HSIL of the disease. Some authors recommend close surveil-
are similar to those seen in cervical colposcopy and lance with HRA every 6 months as a treatment option
peniscopy: for extensive and multifocal high-grade AIN in the
Acetowhite lesions exhibiting specific vascular char- anal canal (Chin-Hong and Palefsky, 2002; Devaraj
acteristics such as punctuate vessels, ­mosaicism, or and Cosman, 2006; Scholefield et al., 2005).
honeycomb patterns (Pineda et al., 2006). However, (Pineda et al., 2008) recently reviewed
Papillation and ulceration. their 10-year experience with high-grade SIL treated
HSIL involved areas not displaying the characteristic with HRA-targeted surgical destruction. There was
vascular changes associated with acetic acid can also high-grade SIL persistence in 18.7% of patients and a
be identified by their lack of Lugol’s iodine uptake. planned staged therapy was performed. Recurrences
High-grade lesions tend to be flat, although a warty were reported in 57% of cases at an average of 19
or exophytic appearance can also occur. Furthermore, months and surgery was required in 23% of these
HSIL can also be present in the deeper portions of patients. Progression to invasive anal neoplasia occurred
typical condylomata and LSIL lesions (Goldstone in 1.2% of cases despite adequate treatment, and no
et al., 2001). evidence of disease was reported in 78% of patients at
the last follow-up visit. The authors concluded that
HRA-targeted destruction combined with office-based
Expert Advice surveillance and therapy is superior to close observa-
HRA in conjunction with anal cytology is an effec- tion or traditional mapping procedures. The study even
tive way to detect AIN. Moreover, HRA associated suggested that circumferential or near-circumferential
with anal cytology and DRE is an effective method high-grade SIL (reflecting a “field defect”) can still be
to prevent anal cancer and/or facilitate the early managed by this treatment modality.
diagnosis of anal neoplasia. However, even when the Moreover, contrary to previous findings by the same
infrastructure for the screening and treatment of AIN investigators, the high recurrence rates reported in pre-
is lacking, every individual at risk of anal HPV infec- vious studies (Chang et al., 2002) represented patients
tion should be screened for anal cancer by DRE. who had persistent disease after their initial operation.
With the aim of preserving normal mucosa and skin,
7.6 Treatment for Anogenital Warts and AIN 141

Table 7.2 Recommended treatment modalities for anal warts Advantages

and AIN
Topical treatments Efficacy – In a preliminary study, Tinmouth and
 Podophyllotoxin solution or gel Lytwyn (2005) showed that short-term clearance
 Trichloroacetic acid (TCA) results using TCA for high-grade AIN were similar
 Imiquimod 5% cream to infrared coagulation results.
 Cidofovir gel
 Photodynamic therapy (ALA-PDT)
Ablative treatments Disadvantages
 Infrared coagulation (IRC)
 Cryotherapy Physician-applied therapy
 Surgical excision
 Electrocautery
 Carbon dioxide (CO2) laser Adverse Effects

Burning sensation following TCA application that

HSIL was intentionally left behind, but lesion persis- lasts for up to 10 min
tence was mistakenly reported as recurrence. Pain
Therapeutic strategies can be divided into topical Ulceration
(podophyllotoxin, trichloroacetic acid, imiquimod, cido-
fovir, photodynamic therapy) and ablative (infrared
coagulation, cryotherapy, surgical excision, electro- 7.6.1.3 Imiquimod 5% Cream (Aldara)
cautery, or CO2 laser vaporization) (Table 7.2).
Topical 5% imiquimod use has been shown to be
safe and effective (including in reducing recurrences)
Expert Advice for the treatment of HPV-related anogenital lesions
(Fig. 7.10a–d). Herrera et al. (2007) reported imiqui-
Patients with large-volume, circumferential, or near-
mod cream efficacy in treating related lesions in HIV-
circumferential HSIL disease should be offered a
infected patients, especially when used for longer
staged procedure (usually performed 3 months after
periods (up to 20 weeks).
the previous surgery), to prevent excessive tissue
In a recent study evaluating the use of self-applied
destruction and anal stenosis (Pineda et al., 2008).
suppositories containing 5% imiquimod following sur-
gical ablation of intra-anal warts in a small group of
HIV-infected patients, Kreuter et al. (2006) reported
7.6.1 Topical Treatments
efficacy in reducing the viral load of low- and high-
risk HPV DNA. In addition, the same study showed
7.6.1.1 Podophyllotoxin (see Chap. 3).
regression of high-grade AIN lesions in three of seven
patients after the use of 5% imiquimod suppositories,
Disadvantages
suggesting a beneficial role of the decrease in onco-
genic HPV DNA load.
High recurrence rates have been observed by de Gois
et al. (2005) in HIV-infected patients.
Advantages

7.6.1.2 Trichloroacetic Acid Patient-applied cream

Trichloroacetic acid (TCA) can be used for individual,

small to medium-sized high-grade lesions (Fox, 2006). Disadvantages
However, controlled studies evaluating TCA for anal
dysplasia are limited. Not FDA approved for use at the anal canal
 142 7 Human Papillomavirus and Anal Intraepithelial Neoplasia

Fig. 7.10. (a) Anal and perianal

condyloma in a 2-year-old girl. (b)
Anal and perianal region after topical
imiquimod use (Source: Oyakawa).
(c) Anal and perianal condyloma in a
13-year-old girl. (d) Anal and peria-
nal region after topical Imiquimod
use (Source: Photograph courtesy of
Nadir Oyakawa, MD, PhD, São
Paulo, Brazil)

Side Effects Back pain

Fatigue
Local Fever
Hyperemia, swelling, pruritus, bleeding
Blisters, flaking, scaling, dryness, or thickening of the
skin
7.6.1.4 Cidofovir 1% Gel
Burning, stinging, pain in the treated area
Cidofovir 1% gel has been used for relapsing and mul-
tifocal HPV-related anogenital lesions in HIV-positive
Systemic
patients (Orlando et al., 2002). However, controlled
Headache studies evaluating cidofovir for anal dysplasia have not
Diarrhea been performed.
7.6 Treatment for Anogenital Warts and AIN 143

Advantages
How to Use

Cidofovir gel is applied topically 5 days a week for Efficacy – In a recent study evaluating PDT in HIV-
up to 6 weeks. positive patients with anal carcinoma in situ, Webber
and Fromm (2004) showed consistent downgrading of
cytologic findings during the 5 months of follow-up.
Advantages

Patient-applied gel. Adverse Effects

Efficacy – In a recent study that evaluated surgery
and topical cidofovir in HIV-infected patients with Mild burning and/or stinging sensation during
anogenital warts, Orlando et al. (2002) showed a irradiation
complete response in 76.2% of patients treated with Liver function test abnormalities (usually return to
cidofovir 1% gel and in 100% of subjects treated by baseline values within 2 weeks)
a combination of electrocautery–cidofovir.

Disadvantages 7.6.2 Ablative Treatments

Expensive. 7.6.2.1 Infrared Coagulation

Not FDA approved for this indication.
Unstandardized preparation. Pulsed irradiation in the infrared range is applied to the
Recurrence was observed in 35.29% of patients using dysplastic anal mucosa resulting in controlled tissue
cidofovir 1% gel and 73.68% of patients treated by destruction. Targeted procedures using HRA to identify
surgical excision using electrocautery (Orlando et al., and infrared coagulation (IRC) to destroy HSIL can be
2002). performed in the office with patients under local anes-
thesia (Goldstone et al., 2005). Both low-volume HSILs
and large-volume disease in a staged approach are ame-
Adverse Effects nable to IRC therapy (Pineda et al., 2008).

Local mucosal erosion is a common and sometimes

severe event. Advantages
Pain.
No systemic side effects. FDA approved for the treatment of anal warts and
hemorrhoids.
Response rate – 64% for biopsy-proven HSIL, in a
7.6.1.5 Photodynamic Therapy recent retrospective study performed by Cranston
et al. (2008) that evaluated infrared coagulation
Aminolevulinic acid (ALA) is the photosensitizer agent treatment of high-grade anal dysplasia in a cohort of
most commonly used in photodynamic therapy (PDT). HIV-positive MSM. Goldstone et al. (2007) reported
Early results show that PDT can be used as a successful cure rates of 72% for individual lesions in HIV-
alternative to surgical excision for anal carcinoma in positive MSM and 81% after the first treatment in
situ, but further prospective studies are still needed. HIV-negative MSM patients.

How to Use (Webber and Fromm, 2004) Disadvantages

Photosensitizer delta-ALA is given orally. Approxi­
Not approved for the treatment of ASIL.
mately 4 h later, the entire anal circumference is
Recurrence rate is high in HIV-infected patients,
submitted to photodynamic therapy.
according to Goldstone et al. (2005).
 144 7 Human Papillomavirus and Anal Intraepithelial Neoplasia

Adverse Effects Adverse Effects

7
Immediate or delayed bleeding Postoperative pain
Infection

7.6.2.4 CO2 Laser

7.6.2.2 Surgical Excision
Carbon dioxide (CO2) laser can be used for anal and
Excision of the affected skin and mucosa using Metzen­ perianal warts, but studies evaluating targeted proce-
baum scissors and a scalpel is performed in the operat- dures using HRA and CO2 laser treatment for anal dys-
ing room with the patient under anesthesia. plasia are limited.

Indication Disadvantages

Lesions greater than 1 cm2 CO2 laser is usually performed in the operating room
Noncircumferential lesions with the patient under anesthesia.

Disadvantages Adverse Effects

Incomplete excision Postoperative pain

Possible need for skin grafting
Permanent or temporary fecal diversion
Expert Advice

Adverse Effects Despite available ablative therapies, giant perianal

condyloma (Buschke-Löwenstein tumor) (Fig. 7.11)
Postoperative pain is a highly recurrent disease. Sobrado et al. (2000)
Bleeding reported that radiation therapy is an optional treat-
Anal stenosis ment, and it can be used in selected cases as an ini-
Fecal incontinence tial cytoreductive approach before other ablative
modalities (laser or surgical excision) are used.

Expert Advice

Targeted destruction of lesions guided by HRA is

safe and effective, avoiding the risk of anal inconti-
nence or stenosis (Pineda et al., 2006).

7.6.2.3 Electrocautery

Targeted procedures using HRA to identify HSIL and

destruction of involved lesions using needle-tip electro-
cautery are usually performed in the operating room.
In a prospective study that evaluated HRA-targeted
destruction of HSIL with needle-tip electrocautery in
29 HIV-positive and 8 HIV-negative MSM patients,
Fig. 7.11. Buschke-Löwenstein tumor involving the anogenital
Chang et al. (2002) reported recurrence rates of 79% in area. (Source: Photograph courtesy of Carlos Walter Sobrado Jr.
the former group and 0% in the HIV-negative subjects. MD, PhD, São Paulo, Brazil)
References 145

7.7 Surveillance sexuals and 600 MSM) aged 16–26 years reported that
AIN was not detected in vaccinated individuals.
Moreover, Gardasil was 89.4% effective in preventing
Surveillance for anal dysplastic lesions is performed
HPV-related anogenital warts (Giuliano et al., 2008)
with cytology, HRA, and DRE (Pineda et al., 2008).
(see also Sect.11.8 in Chap. 11)
In individuals exhibiting atypical squamous cells of
unknown significance (ASCUS) or low-grade squamous
intraepithelial lesions (LSILs) and no HRA evidence of References
HSIL:
Abbasakoor F, Boulos PB (2005) Anal intraepithelial neoplasia.
Cytology and HRA should be repeated every 6 Br J Surg 92: 277–290
months. Bean SM, Eltoum I, Horton DK, Whitlow L, Chhieng DC (2007)
Immunohistochemical expression of p16 and Ki-67 corre-
In patients exhibiting cytological findings of atypical lates with degree of anal intraepithelial neoplasia. Am J Surg
squamous cells "cannot rule out high-grade squamous Pathol 31: 555–561
intraepithelial lesion" (ASC-H), or HSIL cytology: Benson CA, Kaplan JE, Masur H, Pau A, Holmes KK (2004)
Treating opportunistic infections among HIV-infected adults
HRA is performed in less than 4 months, coupled and adolescents: recommendations from CDC, the National
with biopsies to confirm recurrent disease or when Institutes of Health, and the HIV Medicine Association/
Infectious Diseases Society of America. MMWR Recomm
induration or a mass is found during DRE. Rep 53: 1–112
Buechner SA (2002) Common skin disorders of the penis. BJU
Int 90: 498–506
Carter PS, de Ruiter A, Whatrup C, Katz DR, Ewings P, Mindel
7.8 Anal Disease Screening A, Northover JM (1995) Human immunodeficiency virus
infection and genital warts as risk factors for anal intraepithe-
lial neoplasia in homosexual men. Br J Surg 82: 473–474
Chang GJ, Berry JM, Jay N, Palefsky JM, Welton ML (2002)
Who should be screened for AIN? (For further details, Surgical treatment of high-grade anal squamous intraepithelial
the reader is referred to reports by Chin-Hong and lesions: A prospective study. Dis Colon Rectum 45: 453–458
Palefsky (2002), de Sanjose and Palefsky (2002) and Chin-Hong PV, Berry JM, Cheng SC, Catania JA, Da Costa M,
Benson et al (2004)). Darragh TM, Fishman F, Jay N, Pollack LM, Palefsky JM
(2008) Comparison of patient- and clinician-collected anal
High-risk groups such as: cytology samples to screen for human papillomavirus-asso-
ciated anal intraepithelial neoplasia in men who have sex
Men who have sex with men with men. Ann Intern Med 149: 300–306
HIV-infected individuals (regardless of the means of Chin-Hong PV, Palefsky JM (2002) Natural history and clinical
management of anal human papillomavirus disease in men
HIV acquisition) and women infected with human immunodeficiency virus.
Other groups who should be considered: Clin Infect Dis 35: 1127–1134
Chin-Hong PV, Palefsky JM (2005) Human papillomavirus ano-
Women with cervical cancer, high-grade vulvar dis- genital disease in HIV-infected individuals. Dermatol Ther
18: 67–76
ease, or vulvar cancer Chin-Hong PV, Vittinghoff E, Cranston RD, Browne L,
Individuals presenting with HPV-related perianal Buchbinder S, Colfax G, Da Costa M, Darragh T, Benet DJ,
lesions Judson F, Koblin B, Mayer KH, Palefsky JM (2005) Age-
Transplant recipients related prevalence of anal cancer precursors in homosexual
men: The EXPLORE study. J Natl Cancer Inst 97: 896–905
Chin-Hong PV, Vittinghoff E, Cranston RD, Buchbinder S,
Cohen D, Colfax G, Da Costa M, Darragh T, Hess E, Judson
7.9 Prevention of HPV-Related Anal F, Koblin B, Madison M, Palefsky JM (2004) Age-specific
prevalence of anal human papillomavirus infection in HIV-
Warts and AIN negative sexually active men who have sex with men: The
EXPLORE study. J Infect Dis 190: 2070–2076
Cranston RD, Hirschowitz SL, Cortina G, Moe AA (2008) A
retrospective clinical study of the treatment of high-grade
A recent study that evaluated the efficacy of the pro- anal dysplasia by infrared coagulation in a population of
phylactic quadrivalent HPV vaccine in a large group of HIV-positive men who have sex with men. Int J STD AIDS
HPV-naïve sexually active young men (3,400 hetero- 19: 118–120
 146 7 Human Papillomavirus and Anal Intraepithelial Neoplasia

de Gois NM, Costa RR, Kesselring F, de Freitas VG, Ribalta JC, squamous intraepithelial lesions: Relationship to histopa-
7 Kobata MP, Taha NS (2005) Grade 3 vulvar and anal intra- thology. Dis Colon Rectum 40: 919–928
epithelial neoplasia in a HIV seropositive child–therapeutic Kreuter A, Brockmeyer NH, Hochdorfer B, Weissenborn SJ,
result: Case report. Clin Exp Obstet Gynecol 32: 138–140 Stucker M, Swoboda J, Altmeyer P, Pfister H, Wieland U
de Sanjose S, Palefsky J (2002) Cervical and anal HPV infections (2005) Clinical spectrum and virologic characteristics of
in HIV positive women and men. Virus Res 89: 201–211 anal intraepithelial neoplasia in HIV infection. J Am Acad
Devaraj B, Cosman BC (2006) Expectant management of anal Dermatol 52: 603–608
squamous dysplasia in patients with HIV. Dis Colon Rectum Kreuter A, Brockmeyer NH, Weissenborn SJ, Wafaisade A,
49: 36–40 Pfister H, Altmeyer P, Wieland U (2006) 5% imiquimod sup-
Fagan SP, Bellows CF, 3rd, Albo D, Rodriquez-Barradas M, positories decrease the DNA load of intra-anal HPV types 6
Feanny M, Awad SS, Berger DH (2005) Length of human and 11 in HIV-infected men after surgical ablation of condy-
immunodeficiency virus disease and not immune status is a lomata acuminata. Arch Dermatol 142: 243–244
risk factor for development of anal carcinoma. Am J Surg 190: Kreuter A, Wieland U, Gambichler T, Altmeyer P, Pfister H,
732–735 Tenner-Racz K, Racz P, Potthoff A, Brockmeyer NH (2007)
Fox PA (2006) Human papillomavirus and anal intraepithelial p16ink4a expression decreases during imiquimod treatment
neoplasia. Curr Opin Infect Dis 19: 62–66 of anal intraepithelial neoplasia in human immunodeficiency
Frisch M, Fenger C, van den Brule AJ, Sorensen P, Meijer CJ, virus-infected men and correlates with the decline of lesional
Walboomers JM, Adami HO, Melbye M, Glimelius B (1999) high-risk human papillomavirus DNA load. Br J Dermatol
Variants of squamous cell carcinoma of the anal canal and 157: 523–530
perianal skin and their relation to human papillomaviruses. Magi JC, Rodrigues MRS, Guerra GMLSR, Costa ACL, Formiga
Cancer Res 59: 753–757 GJS (2003) Subclinical human papillomavirus in the differen-
Frisch M, Glimelius B, van den Brule AJ, Wohlfahrt J, Meijer tial diagnosis of the etiology of anal pruritus [O Papilomavirus
CJ, Walboomers JM, Goldman S, Svensson C, Adami HO, humano (HPV) na forma subclínica como diagnóstico difer-
Melbye M (1997) Sexually transmitted infection as a cause encial da etiologia do prurido anal] [article in portuguese].
of anal cancer. N Engl J Med 337: 1350–1358 Rev bras Coloproct 23: 273–277
Giuliano A, Palefsky J, Coutlee F (2008) The efficay of quadri- Magi JC, Rodrigues MRS, Guerra GMLSR, Costa MC, Costa
valent HPV (types 6/11/16/18) vaccine in reducing the inci- ACL, Villa LL, Formiga GJS (2006) Histopathological and
dence of HPV infection and HPV-related genital disease in PCR results for clinical and subclinical forms of HPV anal
young men. In: European Research Organization on Genital infection – Study of four groups of patients In: Rev bras
Infection and Neoplasia – EUROGIN, Nice, France Coloproct, vol 26, Rio de Janeiro, pp 406–413
Goldstone SE, Hundert JS, Huyett JW (2007) Infrared coagula- Martin F, Bower M (2001) Anal intraepithelial neoplasia in HIV
tor ablation of high-grade anal squamous intraepithelial positive people. Sex Transm Infect 77: 327–331
lesions in HIV-negative males who have sex with males. McCloskey JC, Metcalf C, French MA, Flexman JP, Burke V,
Dis Colon Rectum 50: 565–575 Beilin LJ (2007) The frequency of high-grade intraepithelial
Goldstone SE, Kawalek AZ, Goldstone RN, Goldstone AB (2008) neoplasia in anal/perianal warts is higher than previously
Hybrid Capture II detection of oncogenic human papillomavi- recognized. Int J STD AIDS 18: 538–542
rus: A useful tool when evaluating men who have sex with Melbye M, Cote TR, Kessler L, Gail M, Biggar RJ (1994) High
men with atypical squamous cells of undetermined signifi- incidence of anal cancer among AIDS patients. The AIDS/
cance on anal cytology. Dis Colon Rectum 51: 1130–1136 Cancer Working Group. Lancet 343: 636–639
Goldstone SE, Kawalek AZ, Huyett JW (2005) Infrared coagu- Nadal SR, Calore EE, Nadal LR, Horta SH, Manzione CR
lator: a useful tool for treating anal squamous intraepithelial (2007) [Anal cytology for screening of pre-neoplasic
lesions. Dis Colon Rectum 48: 1042–1054 lesions]. Rev Assoc Med Bras 53: 147–151
Goldstone SE, Winkler B, Ufford LJ, Alt E, Palefsky JM (2001) Nyitray A, Nielson CM, Harris RB, Flores R, Abrahamsen M,
High prevalence of anal squamous intraepithelial lesions and Dunne EF, Giuliano AR (2008) Prevalence of and risk fac-
squamous-cell carcinoma in men who have sex with men as tors for anal human papillomavirus infection in heterosexual
seen in a surgical practice. Dis Colon Rectum 44: 690–698 men. J Infect Dis 197: 1676–1684
Goodman MT, Shvetsov YB, McDuffie K, Wilkens LR, Zhu X, Orlando G, Fasolo MM, Beretta R, Merli S, Cargnel A (2002)
Ning L, Killeen J, Kamemoto L, Hernandez BY (2008) Combined surgery and cidofovir is an effective treatment for
Acquisition of anal human papillomavirus (HPV) infection genital warts in HIV-infected patients. AIDS 16: 447–450
in women: The Hawaii HPV Cohort study. J Infect Dis 197: Palefsky JM, Holly EA, Ralston ML, Jay N (1998b) Prevalence
957–966 and risk factors for human papillomavirus infection of the anal
Herrera S, Correa LA, Wolff JC, Gaviria A, Tyring SK, canal in human immunodeficiency virus (HIV)-positive and
Sanclemente G (2007) Effect of imiquimod in anogenital HIV-negative homosexual men. J Infect Dis 177: 361–367
warts from HIV-positive men. J Clin Virol 39: 210–214 Palefsky JM, Holly EA, Ralston ML, Jay N, Berry JM, Darragh
Holly EA, Ralston ML, Darragh TM, Greenblatt RM, Jay N, TM (1998c) High incidence of anal high-grade squamous
Palefsky JM (2001) Prevalence and risk factors for anal intra-epithelial lesions among HIV-positive and HIV-
squamous intraepithelial lesions in women. J Natl Cancer negative homosexual and bisexual men. AIDS 12: 495–503
Inst 93: 843–849 Palmer JG, Shepherd NA, Jass JR, Crawford LV, Northover JM
Jay N, Berry JM, Hogeboom CJ, Holly EA, Darragh TM, (1987) Human papillomavirus type 16 DNA in anal
Palefsky JM (1997) Colposcopic appearance of anal squamous cell carcinoma. Lancet 2: 42
References 147

Pineda CE, Berry JM, Jay N, Palefsky JM, Welton ML (2008) Sobrado CW, Mester M, Nadalin W, Nahas SC, Bocchini SF,
High-resolution anoscopy targeted surgical destruction of Habr-Gama A (2000) Radiation-induced total regression of
anal high-grade squamous intraepithelial lesions: A ten-year a highly recurrent giant perianal condyloma: report of case.
experience. Dis Colon Rectum 51: 829–835; discussion Dis Colon Rectum 43: 257–260
835–827 Tinmouth J, Lytwyn A (2005) Treatment of high grade anal
Pineda CE, Berry JM, Welton ML (2006) High resolution anos- dysplasia with trichloroacetic acid and infra red coagula-
copy and targeted treatment of high-grade squamous intra- tion [PosterP033]. In: 22nd International Papillomavirus
epithelial lesions. Dis Colon Rectum 49: 126 Conference, Vancouver, Canada
Rabkin CS, Biggar RJ, Melbye M, Curtis RE (1992) Second pri- Tsai TF, Kuo GT, Kuo LT, Hsiao CH (2008) Prevalence status
mary cancers following anal and cervical carcinoma: Evidence and association with human papilloma virus of anal
of shared etiologic factors. Am J Epidemiol 136: 54–58 squamous proliferative lesions in a patient sample in Taiwan.
Ryan DP, Compton CC, Mayer RJ (2000) Carcinoma of the anal Sex Transm Dis 35: 721–724
canal. N Engl J Med 342: 792–800 Wacker J, Hartschuh W (2004) [Differential diagnosis of chronic
Scholefield JH (1999) Anal intraepithelial neoplasia. Br J Surg perianal dermatitis. Premalignant and malignant disorders].
86: 1363–1364 Hautarzt 55: 266–272
Scholefield JH, Castle MT, Watson NF (2005) Malignant transfor- Walts AE, Lechago J, Bose S (2006) P16 and Ki67 immunos-
mation of high-grade anal intraepithelial neoplasia. Br J Surg taining is a useful adjunct in the assessment of biopsies for
92: 1133–1136 HPV-associated anal intraepithelial neoplasia. Am J Surg
Scholefield JH, Hickson WG, Smith JH, Rogers K, Sharp F Pathol 30: 795–801
(1992) Anal intraepithelial neoplasia: Part of a multifocal Webber J, Fromm D (2004) Photodynamic therapy for carci-
disease process. Lancet 340: 1271–1273 noma in situ of the anus. Arch Surg 139: 259–261
Shepherd NA (2007) Anal intraepithelial neoplasia and other Welton ML, Sharkey FE, Kahlenberg MS (2004) The etiology
neoplastic precursor lesions of the anal canal and perianal and epidemiology of anal cancer. Surg Oncol Clin N Am 13:
region. Gastroenterol Clin North Am 36: 969–987, ix 263–275
Shroyer KR, Brookes CG, Markham NE, Shroyer AL (1995) Youk EG, Ku JL, Park JG (2001) Detection and typing of human
Detection of human papillomavirus in anorectal squamous papillomavirus in anal epidermoid carcinomas: Sequence
cell carcinoma. Correlation with basaloid pattern of differ- variation in the E7 gene of human papillomavirus Type 16.
entiation. Am J Clin Pathol 104: 299–305 Dis Colon Rectum 44: 236–242
 Human Papillomavirus and Cervical
Intraepithelial Neoplasia 8
Alberto Rosenblatt and Homero Gustavo de Campos Guidi

Contents 8.1 Introduction

8.1 Introduction........................................................... 149
8.2 Overview................................................................ 149 This chapter reviews gynecological diseases ­associated
8.3 Terminology and Grading of
with human papillomavirus (HPV) infection, particu-
Cervical Dysplastic Lesions.................................. 150 larly the terminology and grading of premalignant cer-
vical lesions as well as general guidelines for the
8.4 Risk Factors for Cervical
Cancer Development............................................. 152 treatment of these disorders. The aim is to provide
updated information that will help urologists and med-
8.5 Natural History of Cervical
Dysplastic Lesions................................................. 152 ical practitioners understand the diagnosis (including
8.5.1 CIN 2 and 3............................................................. 152 the different grading systems currently in use) and
management of cervical intraepithelial neoplasia in
8.6 Clinical Manifestations......................................... 152
8.6.1 Symptoms................................................................ 152 the female partner. A full discussion of gynecological
malignancies is beyond the scope of this book, and the
8.7 Diagnosis................................................................ 152
8.7.1 Colposcopy with Acetowhite Test........................... 153 interested reader should refer to specific literature.
8.7.2 Biomarkers.............................................................. 153
8.8 Treatment for HSIL and CIN............................... 155
8.8.1 High-Grade Squamous Intraepithelial Lesions....... 155 8.2 Overview
8.8.2 CIN 1....................................................................... 155
8.8.3 CIN 2 and 3............................................................. 155
8.9 Treatment Modalities............................................ 155 Cervical cancer is the second most common cancer
8.9.1 Excisional Procedures............................................. 155
8.9.2 Ablative Procedures................................................ 156 among women worldwide and one of the leading causes
of women’s death in developing countries (Parkin
8.10 Post-Treatment Follow-Up.................................... 156
et al., 2005).
8.11 Prevention.............................................................. 157 Nevertheless, cervical premalignant conditions (also
8.12 Screening................................................................ 158 known as cervical intraepithelial neoplasia (CIN)) evolve
slowly and these precancerous lesions can be discovered
References.............................................................. 158
and treated before progression to invasive cervical carci-
noma (ICC) occurs.
Furthermore, in countries where organized cervical
A. Rosenblatt ()
cancer surveillance has been implemented with a routine
Albert Einstein Jewish Hospital, Sao Paulo, Brasil Papanicolaou (Pap) smear screening program, the ICC
e-mail: [email protected] incidence and mortality have seen a dramatic reduction.

A. Rosenblatt, H. G. de Campos Guidi, Human Papillomavirus, 149

DOI: 10.1007/978-3-540-70974-9-8, © Springer-Verlag Berlin Heidelberg 2009
 150 8 Human Papillomavirus and Cervical Intraepithelial Neoplasia

Sexually active young women are more susceptible cervical cancer (Wallin et al., 1999; Walboomers et al.,
8 to HPV infection and the peak age of infection is in 1999; Munoz et al., 2003).
the 20- to 24-year-old group. According to Moscicki Eventually, only a small percentage of all HPV-
(2008), abnormal cytology is frequently observed in associated lesions will ultimately progress to ICC if no
these young women, but most of these findings are intervention occurs.
related to the HPV infection and are transient. In addi-
tion, clearance of HPV infection is higher in young
female individuals. 8.3 Terminology and Grading
However, in a small number of adolescents and in of Cervical Dysplastic Lesions
older female groups, viral infection tends to persist.
There is enough evidence to support the fact that the
presence and persistence of high-risk HPV infection Different terminology systems can be used to report a
are necessary for the development of high-grade cytology (Pap smear) test (Table 8.1), but it is impor-
squamous intraepithelial lesions (HSILs) and invasive tant to differentiate between:

Table 8.1 Cervical diagnostic terminology. (Source: Safaeian

et al. (2007a). Reprinted with permission from Elsevier)

Dysplasia CIN Bethesda

Atypia Atypia ASCUS (Fig. 8.1)

HPV HPV
Mild dysplasia CIN 1 (Fig. 8.3)

Moderate dysplasia CIN 2 LSIL 

HSIL (Fig. 8.2)
Severe dysplasia CIN 3
CIS

ASCUS atypical squamous cells of undetermined significance;

CIN cervical intraepithelial neoplasia; HPV human papilloma-
Fig. 8.2. High-grade squamous intraepithelial lesion (HSIL).
virus; LSIL low-grade squamous intraepithelial lesion; HSIL
(Source: Photograph courtesy of Filomena Marino Carvalho
high-grade squamous intraepithelial lesion; CIS carcinoma in
MD, PhD, São Paulo, Brazil)
situ

Fig. 8.1. Atypical squamous cells of undetermined significance

(ASCUS). (Source: Photograph courtesy of Filomena Marino Fig. 8.3. CIN 1. (Source: Photograph courtesy of Filomena
Carvalho MD, PhD, São Paulo, Brazil) Marino Carvalho MD, PhD, São Paulo, Brazil)
8.3 Terminology and Grading of Cervical Dysplastic Lesions 151

b
Fig. 8.4. CIN 2 (histology report) after Lugol’s solution applica-
tion. (Source: Photograph courtesy of Nadir Oyakawa, MD,
PhD, São Paulo, Brazil)

Cytologic abnormalities
−− Low-grade intraepithelial squamous lesions
(LSILs)
−− High-grade intraepithelial squamous lesions
(HSILs)
Histologic abnormalities (CIN)
The CIN classification is based on morphologic cri-
teria and is widely used in cervical histopathology, but c
Pap test results are commonly reported using the
Bethesda system.
CIN 2 can be regarded as a combination of lesions
that may potentially regress or become premalignant
(Fig. 8.4)
Carcinoma in situ (CIS) is now encompassed under
the same category as severe dysplasia (CIN 3), and his-
tologic CIN 3 (Fig. 8.5a–c) is considered to be the “true
cancer precursor.”
In the Bethesda system, HPV-related cellular
changes are categorized under “squamous intraepithe-
lial lesion.”LSIL corresponds to acute HPV infection,
irrespective of type, resulting in mild and usually tran-
sient cytological abnormalities. HSIL is highly associ- Fig. 8.5. (a) CIN 3/CIS (histology report). (b) CIN 3/CIS
ated with persistent HPV infection, mostly caused by (­histology report) after Lugol’s solution application (Source:
oncogenic types. Photograph courtesy of Nadir Oyakawa, MD, PhD, São Paulo,
Brazil). (c) CIN 3 (Source: Photograph courtesy of Filomena
Marino Carvalho MD, PhD, São Paulo, Brazil)
Important
Treatment decisions are based on histology and not
on cytology grade.
 152 8 Human Papillomavirus and Cervical Intraepithelial Neoplasia

8.4 Risk Factors for Cervical Cancer Furthermore, Safaeian et al. (2007a) reported that
8 high-grade morphological abnormalities can appear
Development
de novo from persistent HPV infection without pro-
gressing from low-grade changes.
Early age at onset of sexual activity and multi-
ple sexual partners
High-risk sexual partner
Multiparity 8.5.1 CIN 2 and 3
History of sexually transmitted diseases (STDs)
Immunosuppression
CIN 2 is associated with significant spontaneous regres-
Cigarette smoking
sion (approximately 40% over 2 years). However:
High-grade dysplasia (HSIL or grade 2–3 CIN) is
8.5 Natural History of Cervical likely to progress to ICC, particularly in the group of
HIV-positive women where ICC behavior is likely to
Dysplastic Lesions
be more aggressive (Maiman et al., 1997).
Persistent high-risk HPV infection is necessary for
The natural history of CIN is linked to the presence of the development of almost all invasive cervical can-
high-risk HPV and, in a recent meta-analysis per- cers (Fig. 8.7).
formed by Koshiol et al. (2008), HPV persistence was
validated as a marker for cervical cancer risk.
Accordingly, the risk of cervical cancer is extremely 8.6 Clinical Manifestations
low in women not infected with oncogenic HPV types.
Only 15% of women with a negative Pap smear and
a positive HPV test result will develop abnormal 8.6.1 Symptoms
­cytology results within 5 years, and HPV infection is
Premalignant intraepithelial dysplasia is generally
required for CIN 3 promotion and maintenance.
asymptomatic, but local symptoms such as, pruritus,
Most LSILs are usually associated with HPV
irritation, dyspareunia, and abnormal vaginal discharge
­infection and have a tendency to regress spon­taneously
may occur.
(Moscicki et al., 2004) (Fig. 8.6).
Nobbenhuis et al. (2001) reported that high-risk
HPV clearance preceded regression of cervical lesions
8.7 Diagnosis
by an average of 3 months.

According to Goodman et al. (2008), the risk of

acquisition of an incident high-risk anal HPV infec-
tion is increased significantly (91% greater risk) in
women with cervical HPV infection. Moreover, the
incidence of anal intraepithelial neoplasia (AIN) is
also high (16-fold increase) in women with multi-
focal genital intraepithelial neoplasia (Scholefield
et al., 1992), and the increased association of AIN,
CIN, and vulvar intraepithelial neoplasia (VIN)
(Fig. 8.8a–d) is probably related to the shared expo-
sure to high-risk HPV types. Therefore, a thorough
investigation of the anogenital region for HPV
Fig. 8.6. CIN 1 associated with HPV 16/18 detection by in situ infection and associated ­premalignant diseases is
hybridization (ISH). (Source: Photograph courtesy of Monica recommended by some investigators.
Stiepcich MD, PhD, São Paulo, Brazil)
8.7 Diagnosis 153

Fig. 8.7. Steps in cervical carcinogenesis (Source: From Wright and Schiffman (2003). Reproduced with permission from Massachusetts
Medical Society)

8.7.1 Colposcopy with Acetowhite Test Negative cytological results associated with ­positive
high-risk HPV DNA test results (the risk of having
Colposcopy with acetic acid 5% application (Fig. 8.9) an undetected CIN 2 or greater is quite low, ranging
is performed when frank dysplasia (i.e., LSILs in pre- from 2.4 to 5.1%):
menopausal women and HSIL in all female subjects) −− Colposcopy is not routinely performed.
is found on cytology. Colposcopic-directed biopsy of −− HPV DNA testing in combination with a Pap test
suspicious lesions is done to assess histology. is repeated at 1 year, according to the 2006 con-
Women with persistent LSIL or presenting with sensus guidelines for the management of women
high-risk HPV infection should undergo multiple col- with abnormal cervical cancer screening test
poscopic examinations over time.­ results (Wright et al., 2007a).
ASCUS associated with a positive high-risk HPV
DNA testing (the risk of developing CIN 3 is 15.2%
Atrophic changes in postmenopausal women may
at 12-month follow-up, according to Safaeian et al.
result in the cytologic diagnosis of LSIL. Therefore,
(2007b)):
these women can be managed similarly to those
with a diagnosis of atypical squamous cells of −− Colposcopy with directed biopsy as needed is
­undetermined significance (ASCUS) (i.e., cytologic recommended.
evaluation repeated at 6 and 12 months and HPV
DNA testing). LSIL should be managed as ASCUS associated
with a positive high-risk HPV DNA test result
(studies show that the prevalence of CIN 2 or
greater identified at initial colposcopy among
8.7.2 Biomarkers women with LSIL is 12–16%).

8.7.2.1 HPV DNA Testing ASCUS associated with a negative high-risk HPV
DNA test result (low risk of developing CIN 2/3):
See also Chap. 2.
−− Cytology is repeated after 1 year or longer
Molecular HPV testing can now further refine depending on age and screening history (Safaeian
most cytologic findings of ASCUS. et al., 2007b).
 154 8 Human Papillomavirus and Cervical Intraepithelial Neoplasia

Fig. 8.8. (a) Vulvar and perianal condyloma. (b) HPV-associated vulvar intraepithelial neoplasia 1 (VIN 1) (histology). (c) Vaginal
carcinoma in situ (CIS) (histology) post-hysterectomy. (d) High-resolution anoscopy (HRA) showing acetowhitening of the anal
mucosa (Source: Photograph courtesy of Nadir Oyakawa, MD, PhD, São Paulo, Brazil)

Expert Advice

HPV DNA testing is not useful in adolescents and

should not be used. In addition, Spitzer (2007) rec-
ommended that colposcopic evaluation in this age-
group should be delayed in most cases, and should
be performed only if cytological abnormalities per-
sist or are of high grade (HSIL)

Fig. 8.9. Colposcopic findings after acetic acid 5% application

(Source: Photograph courtesy of Maricy Tacla MD, PhD, São
Paulo, Brazil)
8.9 Treatment Modalities 155

8.8 Treatment for HSIL and CIN Pregnant women with a histological diagnosis of
CIN 1 should not be treated and surveillance only
is the recommended management option.
8.8.1 High-Grade Squamous Intraepithelial
Lesions 8.8.3 CIN 2 and 3

Findings of HSIL on cytology carry a high risk of sig- Excision or ablation is recommended for nonpregnant
nificant cervical disease. Therefore, according to the women presenting with CIN 2 and 3. However, CIN 2
2006 consensus guidelines for the management of in adolescents should be managed as CIN 1, since
women with abnormal cervical cancer screening test there is a high rate of spontaneous lesion regression
(Wright et al., 2007a): and clearance in this group (Wright et al., 2007b).
Colposcopy and directed biopsy of visible lesions Treatment is recommended for adolescents presenting
are recommended, including endocervical assess- with CIN 3 or CIN 2/3 that persists for 24 months.
ment in nonpregnant women and thorough vaginal
visualization, particularly when a Pap scan-related
lesion is not found. 8.9 Treatment Modalities
In cases where a lesion consistent with CIN 2 or 3 is
found in nonpregnant women who may be at risk to 8.9.1 Excisional Procedures
be lost to follow-up, a loop electrosurgical excision
procedure (LEEP) (see Sect 8.9.1.1) at the same visit 8.9.1.1 Loop Electrosurgical Excision
as the colposcopy is recommended. In this “see and /Large Loop Excision of the
treat” modality, cervical biopsy is not performed and Transformation Zone
an endocervical assessment can be done after the LEEP
(Wright et al., 2007b). LEEP and large loop excision of the transformation
However, HSIL in adolescents should be managed zone (LLETZ) are safe and effective treatment
with colposcopy and observation for up to 24 months, options for CIN, with high cure rates reported at 1
using both colposcopy and cytology at 6-month inter- year (Spitzer, 2007).
vals. Immediate LEEP (i.e., “see and treat”) is not indi-
cated in this age-group.
Advantages

Outpatient procedure under local anesthesia.

More effective than cryotherapy for CIN 2 and 3
8.8.2 CIN 1
(Kleinberg et al., 2003).
Efficacy – Kjellberg and Tavelin (2007) reported that
Surveillance with Pap smear is recommended, particu- LEEP conization is a safe and timesaving “see and
larly in young women as most cases of CIN 1 sponta- treat” modality after an HSIL Pap smear result.
neously regress without the need for treatment (Wright
et al., 2007b). In a recent study, Moscicki (2008) sug-
Adverse Effects
gested that adolescents should be followed up with
yearly cytology indefinitely or until HSIL or CIN 2/3
Subsequent risk of pregnancy complications
develops.
Women with CIN 1 preceded by ASCUS, ASC-H,
In a recent study that evaluated data from the ASCUS-
or LSIL should be followed up with Pap tests repeated
LSIL Triage Study, Kreimer et al. (2007) reported
at 6 and 12 months, or preferably HPV testing at 12
that HPV types that are likely to persist or reappear
months (Wright et al., 2007b).
after LEEP treatment for CIN 2 or 3 are mostly HPV
Persistent CIN 1 should not be treated before 2
types in the alpha3 species, which are all noncarcino-
years and a longer surveillance is also preferred in
genic and therefore unlikely to cause disease.
women who are planning a pregnancy.
 156 8 Human Papillomavirus and Cervical Intraepithelial Neoplasia

8.9.1.2 Cold-Knife Conization Efficacy – In a recent large-series analysis, Luciani

8 et al. (2008) showed that 1 year after cryotherapy
Indications 70% of CIN 3 lesions were cured.

Cold-knife conization is usually performed in cases

where a more accurate pathologic interpretation of the Disadvantages
specimen is required, such as a suspected microinva-
sion or adenocarcinoma of the cervix. Considered the least effective strategy for CIN 2 and
3 (Kleinberg et al., 2003)

Disadvantages
Adverse Effects
General/peridural anesthesia required
Colic pain and occasionally a vasovagal reflex dur-
ing the procedure
Watery discharge that may last for several weeks
Adverse Effects
after cryotherapy
Risk of hemorrhage
Subsequent risk of pregnancy complications
8.9.2.2 CO2 Laser or Nd:YAG Laser

Advantages
8.9.2 Ablative Procedures
Efficacy – In a long follow-up study using Nd:YAG
laser conization, Ueda et al. (2006) showed that
Expert Advice incomplete CIN excision occurred in 12.3% of cases,
although a failure rate (persistence or recurrence)
Application of Lugol’s solution to the cervix may was found in only 1.2% of cases.
help define the area to be treated (Fig. 8.10a-d).
Because of the lack of glycogen in the dysplastic
cells, high-grade cervical lesions do not take up the Disadvantages
iodine solution (Lugol’s negative). Therefore, HSILs
appear yellow-to-tan, whereas normal tissue or Laser expertise is needed.
LSILs appear dark brown or black. General/peridural anesthesia is required.
Hospital-based procedure.
8.9.2.1 Cryotherapy

A vaginal probe is used and the 3–5–3 freeze technique

8.10 Post-treatment Follow-Up
is usually employed (freeze for 3 min twice, with a
5-min thaw interval between cycles).
Treatment of precancerous lesions of the cervix usually
results in clearance of HPV infection. However, the
risk of lesion recurrence after the treatment of CIN 2/3
Advantages
with LEEP is 2–3% when specimen margins are nega-
tive and 5–15% when margins are positive. In a recent
Considered the least expensive strategy for CIN 2 study, Xi et al. (2007) showed that 10% of women with
and 3 (Kleinberg et al., 2003). CIN 3 and baseline infection with HPV 16 who were
Office-based procedure. treated with LEEP developed CIN 2/3 in 2 years.
8.11 Prevention 157

Fig. 8.10. (a) Cervical acetowhite lesion. (b) Cervical lesion after Lugol’s solution application (Source: Photograph courtesy of
Maricy Tacla MD, PhD, São Paulo, Brazil). (c) CIN 3 (histology report). (d) CIN 3 (histology report) after Lugol’s solution applica-
tion (Source: Photograph courtesy of Nadir Oyakawa, MD, PhD, São Paulo, Brazil)

HPV DNA testing can be a helpful diagnostic tool UK guidelines recommend annual Pap tests for 9 years
in the follow-up of patients after treatment of precan- and colposcopy in cases of positive cytology. However,
cerous cervical lesions (Aerssens et al., 2008), and based on consistent observations that most recurrences
Cuzick et al. (2006) recently supported its use as the of CIN are in the first 2–3 years after treatment,
sole primary screening test. Kitchener et al. (2008) recommended a shorter follow-
In addition, Houfflin Debarge et al. (2003) sug- up before these women return to routine screening.
gested that the frequency of follow-up could be reduced
in patients presenting free margins and negative post-
treatment HPV test results.
Women should undergo cytology tests at 6 and 12 8.11 Prevention
months after treatment of CIN (Wright et al., 2007b).
HPV DNA testing at 6 and 12 months after treatment
is also recommended for women with CIN 2 and 3, and Sexual behavior changes such as initiating sexual life
colposcopy should be performed on those presenting at a later age, use of condoms, limiting the number of
with high-risk HPV type infection (Wright, 2007b). sexual partners, as well as avoiding high-risk partners
 158 8 Human Papillomavirus and Cervical Intraepithelial Neoplasia

are important measures aimed at reducing the risk of References

8 HPV infection and other STDs.
Avoidance of cigarette smoking is also recom- Aerssens A, Claeys P, Garcia A, Sturtewagen Y, Velasquez R,
mended, because tobacco is a known cofactor for the Vanden Broeck D, Vansteelandt S, Temmerman M, Cuvelier
development of cervical cancer. CA (2008) Natural history and clearance of HPV after treat-
ment of precancerous cervical lesions. Histopathology 52:
Prophylactic HPV vaccination should be offered to
381–386
girls before onset of sexual activity; however, the uni- Cuzick J, Clavel C, Petry KU, Meijer CJ, Hoyer H, Ratnam S,
versal vaccination of men and women may become Szarewski A, Birembaut P, Kulasingam S, Sasieni P, Iftner T
necessary to adequately control HPV infection and (2006) Overview of the European and North American stud-
ies on HPV testing in primary cervical cancer screening.
related cervical diseases, therefore complementing
Int J Cancer 119: 1095–1101
secondary screening programs (i.e., Pap smears) (see Goldhaber-Fiebert JD, Stout NK, Salomon JA, Kuntz KM,
also Chap. 11). Goldie SJ (2008) Cost-effectiveness of cervical cancer
screening with human papillomavirus DNA testing and
HPV-16,18 vaccination. J Natl Cancer Inst 100: 308–320
Goodman MT, Shvetsov YB, McDuffie K, Wilkens LR, Zhu X,
Ning L, Killeen J, Kamemoto L, Hernandez BY (2008)
8.12 Screening Acquisition of anal human papillomavirus (HPV) infection
in women: The Hawaii HPV Cohort study. J Infect Dis 197:
957–966
The first Pap smear should be performed 3 years from Houfflin Debarge V, Collinet P, Vinatier D, Ego A, Dewilde A,
initiation of sexual activity or at age 21 years (whichever Boman F, Leroy JL (2003) Value of human papillomavirus
testing after conization by loop electrosurgical excision for
comes first), and repeated subsequently at least every 3 high-grade squamous intraepithelial lesions. Gynecol Oncol
years (US Preventive Services Task Force. Screening for 90: 587–592
cervical cancer: recommendations and rationale). Kitchener HC, Walker PG, Nelson L, Hadwin R, Patnick J,
Women up to the age of 30 years should undergo Anthony GB, Sargent A, Wood J, Moore C, Cruickshank
ME (2008) HPV testing as an adjunct to cytology in the
either annual cytologic screening or biennial screening ­follow up of women treated for cervical intraepithelial neo-
if a liquid-based Pap test is used, according to the plasia. BJOG 115: 1001–1007
American Cancer Society guidelines (Smith et al., Kjellberg L, Tavelin B (2007) ‘See and treat’ regime by LEEP
2002); thereafter, the screening interval may be increased conisation is a safe and time saving procedure among women
with cytological high-grade squamous intraepithelial lesion.
to every 2–3 years based on previous cytology test Acta Obstet Gynecol Scand 86: 1140–1144
results and risk factors. Kleinberg MJ, Straughn JM, Jr., Stringer JS, Partridge EE (2003)
HPV testing or newer Pap test technologies for screen- A cost-effectiveness analysis of management strategies for
ing are not currently recommended (US Preventive cervical intraepithelial neoplasia grades 2 and 3. Am J Obstet
Gynecol 188: 1186–1188
Services Task Force. Screening for cervical cancer: rec- Koshiol J, Lindsay L, Pimenta JM, Poole C, Jenkins D, Smith JS
ommendations and rationale). However, in a recent (2008) Persistent human papillomavirus infection and cer­
analysis, Goldhaber-Fiebert et al. (2008) concluded that vical neoplasia: A systematic review and meta-analysis.
the use of HPV DNA testing as a triage test for equivo- Am J Epidemiol 168: 123–137
Kreimer AR, Katki HA, Schiffman M, Wheeler CM, Castle PE
cal results in younger vaccinated and unvaccinated (2007) Viral determinants of human papillomavirus persis-
women may be more cost-effective than current screen- tence following loop electrical excision procedure treatment
ing recommendations. for cervical intraepithelial neoplasia grade 2 or 3. Cancer
Women older than 65 years should not be routinely Epidemiol Biomarkers Prev 16: 11–16
Luciani S, Gonzales M, Munoz S, Jeronimo J, Robles S (2008)
screened for cervical cancer if recent Pap smears were Effectiveness of cryotherapy treatment for cervical intraepi-
normal and are not otherwise at high risk for cervical thelial neoplasia. Int J Gynaecol Obstet 101: 172–177
cancer (i.e., recent unprotected intercourse with new Maiman M, Fruchter RG, Clark M, Arrastia CD, Matthews R,
sexual partner). Gates EJ (1997) Cervical cancer as an AIDS-defining ill-
ness. Obstet Gynecol 89: 76–80
Moscicki AB (2008) Conservative management of adolescents
with abnormal cytology and histology. J Natl Compr Canc
Screening must be performed even in vaccinated Netw 6: 101–106
populations, since HPV infection and related dis- Moscicki AB, Shiboski S, Hills NK, Powell KJ, Jay N, Hanson
eases may also occur with other high-risk HPV EN, Miller S, Canjura-Clayton KL, Farhat S, Broering JM,
strains not covered by currently available vaccines. Darragh TM (2004) Regression of low-grade squamous intra-
epithelial lesions in young women. Lancet 364: 1678–1683
References 159

Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, U.S. Preventive Services Task Force. Screening for cervical can-
Shah KV, Snijders PJ, Meijer CJ (2003) Epidemiologic clas- cer: Recommendations and rationale [available at: http://
sification of human papillomavirus types associated with www.ahrq.gov/clinic/3rduspstf/cervcan/cervcanrr.htm]
cervical cancer. N Engl J Med 348: 518–527 (viewed on 14/09/2008)
Nobbenhuis MA, Helmerhorst TJ, van den Brule AJ, U.S. Preventive Services Task Force. Screening for cervical can-
Rozendaal L, Voorhorst FJ, Bezemer PD, Verheijen RH, cer: Recommendations and rationale In: Agency for
Meijer CJ (2001) Cytological regression and clearance of Healthcare R, and Quality, (ed). U.S. Department of Health
high-risk human papillomavirus in women with an abnormal and Human Services
cervical smear. Lancet 358: 1782–1783 Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer
Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer sta- JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Munoz N
tistics, 2002. CA Cancer J Clin 55: 74–108 (1999) Human papillomavirus is a necessary cause of inva-
Safaeian M, Solomon D, Castle PE (2007a) Cervical cancer sive cervical cancer worldwide. J Pathol 189: 12–19
prevention–cervical screening: Science in evolution. Obstet Wallin KL, Wiklund F, Angstrom T, Bergman F, Stendahl U,
Gynecol Clin North Am 34: 739–760, ix Wadell G, Hallmans G, Dillner J (1999) Type-specific
Safaeian M, Solomon D, Wacholder S, Schiffman M, Castle P ­persistence of human papillomavirus DNA before the devel-
(2007b) Risk of precancer and follow-up management strat- opment of invasive cervical cancer. N Engl J Med 341:
egies for women with human papillomavirus-negative atypi- 1633–1638
cal squamous cells of undetermined significance. Obstet Wright TC, Jr., Massad LS, Dunton CJ, Spitzer M, Wilkinson
Gynecol 109: 1325–1331 EJ, Solomon D (2007a) 2006 consensus guidelines for the
Scholefield JH, Hickson WG, Smith JH, Rogers K, Sharp F management of women with abnormal cervical cancer
(1992) Anal intraepithelial neoplasia: Part of a multifocal screening tests. Am J Obstet Gynecol 197: 346–355
disease process. Lancet 340: 1271–1273 Wright TC, Jr., Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ,
Smith RA, Cokkinides V, von Eschenbach AC, Levin B, Solomon D (2007b) 2006 consensus guidelines for the man-
Cohen C, Runowicz CD, Sener S, Saslow D, Eyre HJ (2002) agement of women with cervical intraepithelial neoplasia or
American Cancer Society guidelines for the early detection adenocarcinoma in situ. Am J Obstet Gynecol 197: 340–345
of cancer. CA Cancer J Clin 52: 8–22 Wright TC, Jr., Schiffman M (2003) Adding a test for human
Spitzer M (2007) Screening and management of women and papillomavirus DNA to cervical-cancer screening. N Engl
girls with human papillomavirus infection. Gynecol Oncol J Med 348: 489–490
107: S14–S18 Xi LF, Kiviat NB, Wheeler CM, Kreimer A, Ho J, Koutsky LA
Ueda M, Ueki K, Kanemura M, Izuma S, Yamaguchi H, (2007) Risk of cervical intraepithelial neoplasia grade 2 or 3
Nishiyama K, Tanaka Y, Terai Y, Ueki M (2006) Diagnostic after loop electrosurgical excision procedure associated with
and therapeutic laser conization for cervical intraepithelial human papillomavirus type 16 variants. J Infect Dis 195:
neoplasia. Gynecol Oncol 101: 143–146 1340–1344
 Human Papillomavirus Infection
in HIV-Infected Individuals 9
Alberto Rosenblatt and Homero Gustavo de Campos Guidi

contents 9.11 HAART in HPV-Associated Cervical Disease.... 171

9.12 HAART in HPV-Associated Anal Disease........... 171
9.1 Introduction........................................................... 163
9.13 HAART in HPV-Associated Oral Disease........... 172
9.2 Overview................................................................ 164
9.2.1 HPV-HIV Coinfection in Women............................ 164 9.14 Surveillance............................................................ 172
9.2.2 HPV-HIV Coinfection in Men................................ 164
9.15 Considerations Regarding HPV
9.3 HPV Infectious Cycle............................................ 165 Prophylactic and Therapeutic Vaccines
in HIV-Infected Individuals.................................. 172
9.4 Effects of Host Immune Status on 9.15.1 Prophylactic Vaccines.............................................. 172
the Risk of HPV Infection..................................... 166 9.15.2 Therapeutic Vaccines............................................... 173
9.5 Host Immune Evasion Methods of HPV............. 166
References.............................................................. 173
9.6 HPV Infection in Immunosuppressed
Individuals.............................................................. 167
9.7 Relationship Between Declining CD4+ Level,
HPV Infection, and Anogenital Cancers............. 168 9.1 Introduction
9.8 Relationship between HIV/HPV Coinfection
and CIN/Cervical Cancer..................................... 168 The body’s natural defenses are able to spontaneously
9.8.1 Natural History of CIN in the clear more than 90% of all human papillomavirus (HPV)
HIV-Infected Patient................................................ 168
9.8.2 Cervical Disease Screening for infections in healthy, immunocompetent individuals,
HIV-Infected Women.............................................. 169 but in human immunodeficiency virus (HIV)-positive
9.8.3 Treatment Considerations for Anogenital individuals the burden of the HPV infection and related
Warts and CIN in HIV-Infected Women................. 169 anogenital diseases is higher.
9.9 Relationship between HIV/HPV Coinfection In addition to the indirect effects of HIV-associated
and AIN/Anal Cancer........................................... 169 immune suppression, HPV has evolved to directly sub-
9.9.1 Natural History of AIN in the
HIV-Infected Patient................................................ 169
vert and evade immune responses, allowing the virus
9.9.2 Anal Disease Screening for HIV-Infected to replicate undetected by the host.
Individuals............................................................... 170 Failure of virus clearance with subsequent HPV infec-
9.9.3 Treatment Considerations for Anogenital tion persistence is associated with poor immunological
Warts and AIN in HIV-Infected Individuals............ 170
response and an increased risk of HPV-related diseases,
9.10 HAART in HPV-Associated Neoplasias.............. 171 including cancer.
This chapter reviews the most recent data related
A. Rosenblatt () to the effects of HIV infection and immune sup­
Albert Einstein Jewish Hospital, Sao Paulo, Brasil pression on HPV infection, with particular emphasis
e-mail: [email protected] on ­anogenital neoplasia. It briefly discusses the HPV

A. Rosenblatt, H. G. de Campos Guidi, Human Papillomavirus, 163

DOI: 10.1007/978-3-540-70974-9-9, © Springer-Verlag Berlin Heidelberg 2009
 164 9 Human Papillomavirus Infection in HIV-Infected Individuals

in­fectious cycle and its immune evasion methods,

9 and it also addresses anogenital screening, treatment
­considerations, and surveillance (anal intraepithelial
neoplasia (AIN) is detailed in Chap. 7).
The chapter ends with a short update on HPV
­vaccines in HIV-infected individuals, although a com-
plete discussion of HPV vaccines can be found in
Chap. 11.

9.2 Overview

9.2.1 HPV-HIV Coinfection in Women

The seroprevalence of oncogenic HPV type 16 among

HIV-positive women has been estimated at approxi-
mately 50%, according to a recent study that evaluated
immunoglobulin G response to HPV 16 capsids (Viscidi
et al., 2003a).
HPV DNA of multiple and concurrent HPV types is
more prevalent in cervicovaginal specimens of HIV-
positive women than in noninfected subjects (Sun
et al., 1995; Kreiss et al., 1992), and infection with
multiple HPV types has been associated with cervical
carcinogenesis.
The prevalence of squamous intraepithelial lesions
(SILs) among HIV-infected women ranges between 12
and 76% (Clark et al., 1993; Massad et al., 1999; Parham
et al., 2006), and Trottier et al. (2006) reported that
coinfection with oncogenic HPV types 16 and 58
increased the risk of developing SIL.
HPV infection, particularly with high-risk HPV 16
and 18, is associated with the majority of vulvar and
vaginal cancers (Hampl et al., 2006). Furthermore, the
risk of developing anogenital neoplasias is increased
in HIV-positive women (Fig. 9.1a, b) compared to
HIV-negative subjects (Frisch et al., 2000; Jamieson
et al., 2006).

9.2.2 HPV-HIV Coinfection in Men

HPV infection is common in HIV-infected male subjects Fig. 9.1. (a) Vulvar Bowen’s disease in an HIV-positive woman.
and, in a large study performed by Palefsky et al. (1998c), (b) Invasive cervical cancer (Source: Photograph courtesy of
HPV infection was found in 95% of HIV-positive men Nadir Oyakawa, MD, PhD, São Paulo, Brazil)
who have sex with men (MSM). Moreover, according to
a recent report (CDR, 2006), the number of cases of HPV DNA has been detected at different anatomic
anogenital warts occurring in MSM in the United locations in 50% of HIV-positive men, with a high
Kingdom increased by 76% between 1996 and 2005. prevalence of simultaneous HPV infection at different
9.3 HPV Infectious Cycle 165

Fig. 9.2. HPV-related lesion in the left nasal cavity of an HIV-

positive patient with anal intraepithelial neoplasia (Source:
Photograph courtesy of Carlos Walter Sobrado Jr., MD, PhD,
São Paulo, Brazil)

sites (penis, mouth, and anus) (Fig. 9.2) in the same

individual (Sirera et al., 2006).
According to a recent analysis performed by Hagensee
et al. (2004), HPV DNA detection in HIV-infected sub-
jects was highest in the anal and perianal regions.
In a retrospective study evaluating carbon dioxide
(CO2) laser treatment efficacy for HPV-associated ano-
genital lesions in immunocompetent and immuno­
suppressed patients (HIV-infected and therapeutically
immunosuppressed), Aynaud et al. (2008) found that
anogenital intraepithelial lesions were significantly more
common in HIV-positive patients (47.4%) than in immu-
nocompetent individuals (20.2%). The dysplastic lesions
exhibited a higher grade in 25% of cases and also cov- Fig. 9.3. (a) Glans lesions in an HIV-positive patient; virology
ered a larger surface area (see also Chaps. 5 and 7). HPV 18. (b) Glans papular lesion in an HIV-positive patient;
virology HPV 16
The risk of anal neoplasia in HIV-positive men is
reported to be two to six times higher than in HIV-
negative subjects (Ryan et al., 2000; Goedert et al., HPV infection in immunocompromised individuals
1998), and the reported prevalence of the putative anal may also affect atypical sites (Fig. 9.2) (Handisurya
cancer precursor high-grade squamous intraepithelial et al., 2007), with a high prevalence of oncogenic types
lesion (HSIL) is 52% in HIV-positive MSM (Palefsky (Kojic and Cu-Uvin, 2007).
et al., 2005) and 5% in immunosuppressed patients
(Ogunbiyi et al., 1994).
The prevalence of penile (Fig. 9.3a, b) and oral 9.3 HPV Infectious Cycle
HPV infection in HIV-infected men is 36 and 30%,
respectively. Moreover, Heideman et al. (2007) recently
See also Chap. 11.
reported that HPV 16 was the main type etiologically
involved in the development of penile squamous cell HPV infects basal keratinocytes and the viral life
carcinoma (SCC). Incidentally, the reported frequency cycle follows the differentiation stages of the host epithe-
of penile cancers in HIV-positive men is two to three lial cell. Expression of early gene products (E1, E2, E5,
times higher than the occurrence rate in their nonin- E6, and E7) is activated in the basal and suprabasal lay-
fected counterparts. ers of the epithelium. However, late gene expression of
 166 9 Human Papillomavirus Infection in HIV-Infected Individuals

Replication cycle of genital hr HPV Fig. 9.4. Replication cycle of

9 high-risk (hr) HVP (see also
Epithelium Dead superficial cells text for further explanation)
laden with virus (Source: Stanley, 2006.
Reproduced with permission
L1, L2 genes expressed from Elsevier)
Virus amplifies to 1000 genome
copies per cell in non dividing cells
E6, E7, E1, E2, E5, E4 genes expressed

Virus and cell replicate together

Very low expression of E6, E7, E1, E2

Virus infects basal epithelial

cells at about 10 virus genomes per cell
then amplifies to about 50 genomes per cell
E1, E2 ?E6, E7 genes expressed

high levels of capsid viral proteins (L1 and L2), the Long-lasting infection with high-risk HPV types
expression of protein responsible for HPV DNA replica- may increase the risk of progression to high-grade SILs
tion and encapsidation (E4), along with final viral assem- and invasive carcinoma (Remmink et al., 1995; Liaw
bly will only occur in the upper layers of the squamous et al., 1999).
epithelia (Sterling et al., 1993; Stanley, 1994; Middleton
et al., 2003). As virus-laden superficial cells desquamate,
HPVs are released into the environment (Fig. 9.4).
9.5 Host Immune Evasion
Methods of HPV
9.4 Effects of Host Immune Status The exclusively intraepithelial viral infectious cycle is
on the Risk of HPV Infection itself an efficient immune evasion mechanism, expos-
ing minimal amounts of replicating virus particles in a
The cell-mediated immunity is the main component noninflammatory milieu to the host immune surveil-
involved in clearing HPV infections. However, Shrestha lance cells.
et al. (2007) recently evaluated the effects of interleu- Viral gene expression is confined to cells with
kin-10 (IL-10) gene polymorphisms on the clearance squamous maturation potential, and the mature ­infectious
of high-risk HPV infection in a cohort of HIV-infected virus is released with the differentiating keratinocyte, a
young female subjects. The results of this study sup- cell already programmed to die and desquamate.
port the hypothesis that HPV clearance may be under As the virus is not involved in the cell death, the host
host genetic influence. immune system becomes unaware of the infection and,
In immunocompetent individuals, DNA from onco- as a result, there is little or no release of proinflamma-
genic HPV types is no longer observed (i.e., clearance tory cytokines that are important for squamous epithe-
of infection) after 8–14 months, and low-risk types are lial immune responses (Kupper and Fuhlbrigge, 2004).
usually cleared in 5–6 months (Giuliano et al., 2002; In addition, oncogenic HPV types encode proteins
Brown et al., 2005; Franco et al., 1999). (E6 and E7) that inhibit p53 and Rb1, important tumor
However, observing the long interval between HPV suppression proteins (Munger et al., 1989; Heck et al.,
infection and lesion manifestation, it appears that effi- 1992; Werness et al., 1990).
cient virus immune evasion methods seem to delay or HPV E6 and E7 proteins also downregulate inter-
prevent the host immune response mechanism from feron (IFN)-a gene expression (Chang and Laimins,
clearing or controlling the infection, resulting in a 2000; Nees et al., 2001) and directly interact with IFN
chronic and persistent viral presence. signaling pathways (Barnard and McMillan, 1999),
9.6 HPV Infection in Immunosuppressed Individuals 167

Fig. 9.5. Schematic repre­

sentation of HPV-associated
lesions and malignant trans-
formation (see also text)

inhibiting an important antiviral defense system. (Breese et al., 1995; van der Snoek et al., 2003; Strickler
According to Stern (2005), these oncoproteins are et al., 2005; Palefsky and Holly, 2003).
implicated in the mechanisms that promote viral
persistence and cancer progression (Fig. 9.5). Silverberg et al. (2006) recently demonstrated that
measurement of serial HPV 16 serum antibodies
In addition to its potent antiviral features, type-1 is a useful diagnostic tool for identifying HPV 16
IFNs (INF-a and INF-b) display immunos­timulatory, replication.
antiproliferative, and antiangiogenic properties.
According to these investigators, rising antibody
Studies have shown that high-risk HPV 16 may levels among HIV-positive female patients may
more efficiently evade host immune surveillance than reflect reactivation of a latent HPV infection,
other HPV types; consequently, progression to high- whereas among their HIV-negative counterparts, it
grade intraepithelial lesions and invasive carcinoma is may result from HPV reinfection.
likely if a cell-mediated immune response is not gener-
HIV-positive female patients have a greater ten-
ated during persistent HPV 16 infection.
dency to develop cervical SILs than HIV-negative
individuals.
A high quantitative HPV load has been associated
9.6 HPV Infection in with both histological severity and lesion size, and the
Immunosuppressed Individuals potential use of HPV load measurement as a risk
marker for cervical disease was lately suggested by
HPV infection flourishes, persists, and recurs in HIV- Lillo and Uberti-Foppa (2006).
positive patients as their local immune responses are Furthermore, female subjects with high HIV viral
usually unpredictable. load are at increased risk of developing cervical HPV
van Benthem et al. (2000) reported that HIV-infected infection with oncogenic types and cervical dysplasias
women have a significantly increased risk for HPV infec- (Massad et al., 1999).
tion occurrence. In addition, HIV-infected individuals Minkoff et al. (2008) found an increased risk of
usually harbor multiple HPV types and additional ones detection of both prevalent and incident high-risk HPV
can be detected over time, particularly among those with types and an increased risk of SIL in HIV-positive
lower CD4+ levels. They are more prone to long-lasting cocaine users, which may be related to the potential
infection or latent HPV infection reactivation rather immunosuppressive effect of the drug on HIV-infected
than acquisition of new infection through recent sexual patients. However, recent data by Syrjanen (2008)
contact, presumably as a result of immunosuppression showed that drug abuse itself is not a risk factor for
 168 9 Human Papillomavirus Infection in HIV-Infected Individuals

high-risk HPV infection, but rather it seems to be asso- The results showed that HPV 16 detection levels were
9 ciated with risky sexual behavior. not greatly affected by diminished CD4+ T cells. This
HIV-infected male patients have an increased could suggest that HPV 16 may evade host immune sur-
­incidence of anal HPV infection with oncogenic risk veillance more efficiently than other HPV types, contrib-
types (Critchlow et al., 1998), although infection with uting to its strong association with cervical neoplasia
multiple HPV genotypes is very common. A low CD4 cell count is a known risk factor for anal
In a histological assessment of anogenital HPV high-grade SIL (HSIL) development (Palefsky et al.,
infection in HIV-infected male patients, Aynaud et al. 1998c), but Fagan et al. (2005) reported that the inci-
(1998) demonstrated that penile exophytic lesions dence of anal cancer in HIV-positive individuals is not
were associated with low-grade intraepithelial neopla- related to low CD4+ levels or HIV viral load. This find-
sia and high-grade dysplastic lesions in 36% and 22% ing suggests that host genetic changes may play a more
of cases, respectively. The same study suggested that influential role in the progression from high-grade AIN
development of high-risk HPV-associated lesions is to invasive neoplasia (Gagne et al., 2005).
facilitated by immune suppression.

Recent analysis evaluating the effectiveness of

using urine samples as a noninvasive alternative 9.8 Relationship between HIV/HPV
for HPV testing showed that molecular biological Coinfection and CIN/Cervical
methods that detect HPV DNA in urine can be
Cancer
reliably used for screening genital HPV infection
in both HIV-infected men and women (Smits
See also Chap. 8.
et al., 2005; Jong et al., 2008).
A better understanding of the contribution of HIV
to the increased risk of HPV infection and CIN is still
9.7 Relationship Between Declining required. However, diminished HPV-specific immune
responses resulting from HIV infection may allow for
CD4+ Levels, HPV Infection, and viral and high-grade CIN persistence with the subse-
Anogenital Cancers quent accumulation of genetic changes that are influ-
ential in lesion progression to invasive disease.
HPV anogenital infections have been associated with a Invasive cervical carcinoma (ICC) became an acquired
declining CD4 cell count (Clark et al., 1993), and immunodeficiency syndrome (AIDS)-defining illness in
Fennema et al. (1995) reported that the risk for recurrent the early 1990s, and it is likely the most common AIDS-
genital warts was strongly associated with decreased related malignancy among HIV-positive women in coun-
CD4+ levels. tries with a high HPV prevalence (Maiman et al., 1997).
In a recent study in Africa, Yamada et al. (2008) Fortunately, the incidence and associated mortality rate
showed that cervical HPV infection was present in 49% of ICC is low in places with adequate cervical cytologi-
of HIV-positive women compared to 17% of HIV- cal screening.
negative counterparts. Moreover, the investigators found However, Massad et al. (1999) reported that the
that high-risk HPV infection and low CD4+ T cell counts prevalence and incidence of CIN was increased among
are risk factors for cervical cancer. HIV-positive individuals, with abnormal cervical cyto-
However, data suggest that lower CD4+ levels (i.e., logical results found in 38% of HIV-positive women
immunosuppression) may play a more important role compared with 16% of the HIV-negative subjects.
in the earlier stages of HPV-related disease (up to and
including high-grade cervical intraepithelial neoplasia
(CIN) and AIN), rather than in the progression from 9.8.1 Natural History of CIN
high-grade anogenital lesions to invasive disease in the HIV-Infected Patient
(Palefsky and Holly, 2003).
A recent study performed by Strickler et al. (2003) In the HIV-infected group, SILs have been shown to be
evaluated HPV DNA detection in cervicovaginal lavage more aggressive, multifocal, and extensive (Fruchter
specimens of HIV-infected patients with cervical cancer. et al., 1996).
9.9 Relationship between HIV/HPV Coinfection and AIN/Anal Cancer 169

Table 9.1 Known risk factors for cervical intraepithelial ities are needed. However, recurrence rates after treat-
neoplasia among HIV-infected women
ment are high in this group of patients.
 Decreased CD4 cell count

 High human immunodeficiency viral load (HIVL)

9.9 Relationship between HIV/HPV
 Human papillomavirus (HPV) infection Coinfection and AIN/Anal Cancer

Furthermore, Maiman et al. (1997) demonstrated

See also Chap. 7.
that high-grade dysplasia (HSIL or grade 2–3 CIN) is
likely to progress to ICC, particularly in HIV-positive AIN is considered a precursor lesion of anal SCC,
women where ICC behavior is more aggressive. and the progression of AIN lesions to anal neoplasia in
Risk factors for CIN among HIV-positive women immunosuppressed individuals was recently demon-
are listed in Table 9.1. strated by Scholefield et al. (2005).
However, Lehtovirta et al. (2008) recently demon- There is an increased incidence of anal HPV infec-
strated that the risk of developing CIN was not associ- tion in HIV-infected male patients (Kreuter et al.,
ated with decreased levels of CD4 lymphocytes, HIV 2005) and high-risk types are commonly detected
infection duration, antiretroviral treatment, or plasma (Critchlow et al., 1998).
HIVL (high human immunodeficiency viral load). In a study evaluating prevalence of AIN lesions in
According to these investigators, HIV-positive women HIV-positive and -negative homosexual and bisexual
have a higher risk of CIN in association with bacterial men, Palefsky et al. (1998b) showed that the incidence
vaginosis (BV), whereas parity lowered the risk. rate of AIN in HIV-positive homosexual men was
52%, compared to 17% in HIV-negative individuals.
Furthermore, HIV-positive men have a higher risk of
9.8.2 Cervical Disease Screening anal neoplasia than HIV-negative subjects (Ryan et al.,
for HIV-Infected Women 2000; Goedert et al., 1998).
Pineda et al. recently reviewed 246 patients (among
A Pap smear should be performed at the time of diag- those 182 HIV-positive and 12 immunocompromised)
nosis of HIV infection, and repeated in 6 months if with both HSIL and LSIL, who were managed with
results are normal. high-resolution anoscopy (HRA)-targeted surgical
Women with a previous history of normal cytologi- destruction. Recurrences were documented in 57% of
cal findings and at least two normal Pap smears can the 200 patients treated in a single-stage procedure,
then undergo an annual screening. and the authors reported that lesion recurrence corre-
The Pap smear should be repeated in 3 months if lated with extent of disease but not with HIV status
inflammation or atypia is demonstrated. (Pineda et al., 2008).
Colposcopic examination is recommended when
Pap smear results exhibit persistent atypia, SIL, or
Fagan et al. (2005) showed that HIV disease dura-
HPV findings.
tion was the most significant factor for the devel-
opment of invasive anal carcinoma in HIV-infected
9.8.3 Treatment Considerations individuals with HPV.
for Anogenital Warts and CIN
in ­HIV-Infected Women
9.9.1 Natural History of AIN
See also Chap. 8.
in the HIV-Infected Patient

HIV-positive female patients with cervical SIL The natural history of AIN is poorly understood, being
(regardless of grade) require more aggressive therapy the subject of current active investigation.
than HIV-negative subjects. Low-grade AIN (AIN 1 and 2) lesions may regress
Excisional procedures are recommended by Nappi in up to 30% of cases (Scholefield et al., 1992;
et al. (2005), and sometimes multiple treatment modal- Scholefield et al., 1994), but Palefsky et al. (1998a)
 170 9 Human Papillomavirus Infection in HIV-Infected Individuals

reported progression of LSIL to HSIL in more than of HPV-related anogenital lesions in HIV-infected
9 50% of HIV-positive homosexual men during a 2-year patients.
follow-up. The same authors showed that high-grade
lesions rarely regress in these patients.
Immunosuppressed patients seem to have multifo- 9.9.3.2 Cidofovir 1% Gel
cal disease and show an increased rate of progression
to invasive anal carcinoma (Scholefield et al., 2005; Cidofovir 1% gel has been found more effective than
Watson et al., 2006). surgery for HPV-related anogenital lesions in HIV-
positive patients (Orlando et al., 2002).

9.9.2 Anal Disease Screening

for HIV-Infected Individuals 9.9.3.3 Infrared Coagulation

HIV-positive MSM should have a Pap smear annually Cranston et al. (2008) reported efficacy rates of 64%
and patients with cytological results exhibiting atypi- for biopsy-proven HSIL in HIV-positive MSM.
cal squamous cells of undetermined significance Goldstone et al. (2007) using HRA and targeted surgi-
(ASCUS), high-grade change (ASC-H), LSIL, and cal destruction with infrared coagulation (IRC) in the
HSIL should be referred to HRA and biopsy. office reported cure rates of 72% for individual lesions
Cranston et al. (2007) recently reported that abnor- in HIV-positive MSM.
mal anal cytology was highly predicative of anal dys-
plasia on biopsy specimens.
In addition to the increased risk of developing AIN 9.9.3.4 Excisional Surgery and Electrocautery
and anal cancer, the risk of penile cancer is also mod-
erately increased in HIV-positive MSM. However, data Mapping of the lesions with punch biopsies associated
concerning the precursor lesion penile intraepithelial with intraoperative frozen section analysis and wide
neoplasia (PIN) in this group of patients are limited. local excision of involved areas is a nontargeted ther-
Kreuter et al. (2008) studied a large group of HIV- apy that is associated with high recurrence rates and
positive MSM patients and detected PIN in 4.2% and increased morbidity (Margenthaler et al., 2004; Brown
AIN in 59.3% of these patients. Furthermore, nearly et al., 1999).
all patients diagnosed with PIN had a concurrent AIN However, targeted procedures using HRA to iden-
lesion, and all PIN lesions showed immunohistochem- tify HSIL are safer and can be performed in the operat-
ical staining for p16(INK4a) that correlated both with ing room using needle-tip electrocautery to destroy the
the histological grade and with high-risk HPV DNA lesions (Pineda et al., 2008). In their recent 10-year ret-
load. These findings suggest that HIV-positive MSM rospective analysis of 246 patients (among them, 79%
should be screened for both PIN and AIN. HIV-positive or immunocompromised), Pineda et al.
showed that HRA and targeted surgical destruction of
anal HSIL offer excellent disease-free status and less
9.9.3 Treatment Considerations progression to invasive anal disease than expectant
for Anogenital Warts and AIN management (see below, Observation (“Watch and
in HIV-Infected Individuals Wait” Approach)).

See also Chap. 7.

9.9.3.5 CO2 Laser

9.9.3.1 Imiquimod 5% CO2 laser treatment can be an effective choice, even in

cases of repeated laser sessions if lesions recur or per-
Although topical 5% imiquimod is not licensed for use sist. Aynaud et al. (2008) evaluated remission and
in the anal canal, Herrera et al. (2007) recently demon- relapse rates in immunocompetent and immunosup-
strated that it is safe and effective for the treatment pressed individuals with condyloma and high-grade
9.12 HAART in HPV-Associated Anal Disease 171

intraepithelial neoplasms (IENs 3) treated with CO2 already in clinical trials (FDA Approved Drugs and
laser. The study showed clinical absence of lesions in Investigational Drugs, AIDSinfo).
81.2% of cases at 1 month, irrespective of immune sta- The introduction of current HAART regimens has
tus. IEN 3 lesions in remission at 1 month maintained contributed to the many advances seen in the man-
the remission status at 6 months. There was recurrence agement of HIV-infected patients. HAART has
in 12.6% of cases and persistence in 6.6% of cases. The decreased the incidence of opportunistic infections,
investigators reported that lesion persistence was more resulting in fewer hospital admissions and fewer
frequently observed in HIV-positive patients, while HIV-related deaths (Murphy et al., 2001; Vandamme
recurrences were found mainly in immunocompetent et al., 1998).
and therapeutically immunosuppressed patients.

9.9.3.6 Observation (“Watch and Wait” 9.11 HAART in HPV-Associated

Approach) Cervical Disease

HIV-infected patients presenting with extensive and There are conflicting results in the literature regarding
multifocal anal squamous dysplasia can be followed the impact of HAART on the persistence of both HPV
up with physical examination surveillance only, since infection and cervical abnormalities (Heard et al.,
morbidity and recurrences are high using any of the 1998; Lillo et al., 2001).
current treatment modalities. Luque et al. (2001) reported a diminished detection
Patients should be instructed for self-referral if new of HPV DNA in cervical specimens of HIV-infected
anal symptoms or worsening of presenting symptoms women on antiretroviral therapy compared to subjects
develop, and close follow-up is recommended with without antiretroviral treatment.
HRA and repeated biopsies for new or suspicious In the long follow-up study performed by Soncini
lesions (Chin-Hong and Palefsky, 2002; Devaraj and et al. (2007), HAART significantly reduced the risk of
Cosman, 2006). developing CIN, while Minkoff et al. (2001) reported
Further studies regarding AIN treatment for HIV- that women on HAART were less likely to have cervi-
positive individuals are required. cal disease progression.
Sirera et al. (2008), in a recent retrospective analy-
sis, showed that when CD4 cell count was high, the
Expert Advice
incidence of cervical SIL in HIV-positive women
Visible lesions of the anal and perianal region in treated with HAART was similar to infected women
HIV-infected individuals should be carefully evalu- not on HAART. In addition, Moore et al. (2002)
ated, including with pathological studies, because reported that higher CD4+ levels at or following the
of the increased occurrence of low- and high-grade initiation of HAART appeared to have a positive effect
anal disease in this group of patients (Sanclemente on CIN regression.
et al., 2007).
HIV-positive women, whether or not on HAART,
should continue to be actively screened and treated
for CIN (Heard et al., 2006).
9.10 HAART in HPV-Associated
Neoplasias

Treatment of HIV has evolved from monotherapy to a 9.12 HAART in HPV-Associated

combination of three or more antiretroviral drugs Anal Disease
(HAART or highly active antiretroviral therapy).
More than 20 single anti-HIV drugs have been According to Palefsky et al. (2005), the detection of
approved by the U.S. Food and Drug Administration high-grade AIN has not been reduced since HAART
and new drugs are under active development or are introduction.
 172 9 Human Papillomavirus Infection in HIV-Infected Individuals

Hoffman et al. (1999) showed that CD4 count levels Surveillance of AIN in HIV patients is best achieved
9 previous to anal cancer treatment may determine the by HRA with multiple targeted biopsies every 4–6
response of HIV-positive patients to chemoradiation months, as long as dysplasia persists (Chang and Welton,
and their ability to tolerate potential therapy-related 2003; Chin-Hong et al., 2005) (see also Chap. 7).
toxicity. Furthermore, HIV-infected patients with CD4 Further studies of anal cytology screening methods
counts of more than 200 cells/ml should usually be are required.
treated with combined chemoradiation, similarly to
non-HIV-infected individuals (Berry et al., 2004).
HIV-positive patients with anal cancer on HAART 9.15 Considerations Regarding HPV
demonstrated an improved ability to sustain cancer
Prophylactic and Therapeutic
treatment using full chemoradiation and an improved
local tumor control (Cleator et al., 2000; Place et al., Vaccines in HIV-Infected
2001). Individuals

In summary, studies failed to demonstrate a clear 9.15.1 Prophylactic Vaccines

relationship between HPV-associated anal and cer-
vical neoplasia and diminished immunity as mea- Newly developed HPV prophylactic vaccines will
sured by low CD4+ T cell levels. Therapy with likely influence HPV-related diseases in immunocom-
highly active antiretroviral drugs is not effective petent individuals, including the prevention of cervical
for anal and cervical neoplasia in HIV-positive lesions caused by the high-risk HPV types 16 and 18
individuals, and the incidence of these cancers has (see Chap. 11).
not changed since HAART introduction (Chiao However, the influence that prophylactic vaccines
et al., 2005; Bower et al., 2006). will have in immunosuppressed individuals is still
unknown.
Natural immunity against HPV involves a strong
localized cell-mediated response and the subsequent
9.13 HAART in HPV-Associated generation of serum-neutralizing antibodies (Stanley,
Oral Disease 2006).
Viscidi et al. (2003b) recently evaluated serum
An increase in oral HPV infection has been reported immunoglobulin A (IgA) response to HPV 16 capsids
in white HIV-infected men on HAART (72%) as in a large group of HIV-positive and high-risk HIV-
compared with those not on HAART (29%) (Cameron negative women. IgA seropositivity was higher in
et al., 2005). HIV-positive female subjects and was associated with
progression of high-grade cytological abnormalities,
suggesting that IgA response to HPV 16 may be a
9.14 Surveillance marker of viral persistence.
HPV prophylactic vaccine induces the production of
neutralizing antibodies. Thus, since the immune response
HIV and HPV coinfected individuals require a close in HIV-infected individuals with well-preserved CD4
surveillance in order to detect early squamous cell can- count levels is still effective, HPV vaccines could also
cer transformation and progression in the penis, anus, benefit this particular group of individuals. In addition, it
cervix, vagina, vulva, and mouth. has been demonstrated that HIV-positive women are
Current data available reinforce a policy of contin- able to generate HPV antibodies (particularly against
ued screening and aggressive treatment of CIN in HIV- oncogenic HPV 16) even with a low CD4+ level (Strickler
infected women, and assessment of CD4+ levels and et al., 2003).
HPV DNA testing may be useful risk indicators (Nappi In a recent study, Goncalves et al. (2008) reported
et al., 2005). that infection with HPV 18 was commonly found in
References 173

both the anal and genital region of HIV-positive women, dyloma and intraepithelial neoplasia after CO2laser treat-
suggesting that current HPV vaccines may prevent anal ment. Eur J Dermatol 18: 153–158
Aynaud O, Piron D, Barrasso R, Poveda JD (1998) Comparison
HPV infection in immunocompromised individuals. of clinical, histological, and virological symptoms of HPV
Limited information is now available about the in HIV-1 infected men and immunocompetent subjects. Sex
safety and immune response of the quadrivalent HPV Transm Infect 74: 32–34
vaccine in young male subjects (Block et al., 2006; Barnard P, McMillan NA (1999) The human papillomavirus E7
oncoprotein abrogates signaling mediated by interferon-
Reisinger et al., 2007). In addition, a recent study alpha. Virology 259: 305–313
showed that the quadrivalent HPV vaccine was 100% Berry JM, Palefsky JM (2003) A review of human papillomavi-
effective in preventing AIN, PIN and penile cancer in rus vaccines: From basic science to clinical trials. Front
young immunocompetent male individuals (Giuliano Biosci 8: s333–s345
Berry JM, Palefsky JM, Welton ML (2004) Anal cancer and its
and Palefsky, 2008) (see also Sect. 11.8 in Chap. 11). precursors in HIV-positive patients: Perspectives and man-
Further clinical studies in both immunocompetent agement. Surg Oncol Clin N Am 13: 355–373
and immunosuppressed subjects are required. Block SL, Nolan T, Sattler C, Barr E, Giacoletti KE, Marchant
CD, Castellsague X, Rusche SA, Lukac S, Bryan JT,
Cavanaugh PF, Jr., Reisinger KS (2006) Comparison
of the immunogenicity and reactogenicity of a prophylactic
9.15.2 Therapeutic Vaccines quadrivalent human papillomavirus (types 6, 11, 16, and 18)
L1 virus-like particle vaccine in male and female adoles-
cents and young adult women. Pediatrics 118: 2135–2145
Therapeutic vaccines directed against HPV-infected Bower M, Palmieri C, Dhillon T (2006) AIDS-related malignan-
cells are likely to improve local immune responses, cies: Changing epidemiology and the impact of highly active
resulting in potential regression of associated anogeni- antiretroviral therapy. Curr Opin Infect Dis 19: 14–19
Breese PL, Judson FN, Penley KA, Douglas JM, Jr. (1995) Anal
tal dysplastic lesions. human papillomavirus infection among homosexual and
Therapeutic vaccines could particularly benefit HIV- bisexual men: Prevalence of type-specific infection and
infected individuals, because of the increased risk of association with human immunodeficiency virus. Sex
HPV infection occurrence in these patients and the Transm Dis 22: 7–14
Brown DR, Shew ML, Qadadri B, Neptune N, Vargas M, Tu W,
associated high rates of recurrence found after the treat- Juliar BE, Breen TE, Fortenberry JD (2005) A longitudinal
ment of anal squamous intraepithelial lesions (ASILs). study of genital human papillomavirus infection in a cohort
There are no commercially available licensed vac- of closely followed adolescent women. J Infect Dis 191:
cines intended for therapeutic use against ASILs, but 182–192
Brown SR, Skinner P, Tidy J, Smith JH, Sharp F, Hosie KB
clinical studies are being performed on HIV-positive (1999) Outcome after surgical resection for high-grade anal
and HIV-negative high-risk subjects. intraepithelial neoplasia (Bowen’s disease). Br J Surg 86:
Two vaccines have been evaluated and only data 1063–1066
from phase-I/II clinical trials for ASILs are available Cameron JE, Mercante D, O’Brien M, Gaffga AM, Leigh JE,
Fidel PL, Jr., Hagensee ME (2005) The impact of highly
(Berry and Palefsky, 2003). active antiretroviral therapy and immunodeficiency on human
A phase-I safety study of SGN-00101 (HspE7), papillomavirus infection of the oral cavity of human immu-
designed to treat high-grade AIN in HIV-positive indi- nodeficiency virus-seropositive adults. Sex Transm Dis 32:
viduals, showed regression of HSIL in about one-third 703–709
CDR W (2006) Trends in anogenital warts and anogenital herpes
of participants (Palefsky et al., 2006) and clearance of simplex virus infection in the United Kingdom: 1996 to
HPV infection in 60% of patients in whom anal lesions 2005. In: Communicable Disease Report Weekly (CDR
regressed. Weekly), vol 16. Health Protection Agency
Therapeutic vaccination may be useful at the early Chang GJ, Welton ML (2003) Anal neoplasia. Sem Colon Rectal
Surg 14: 111–118
stages of cervical and anal disease, but further evidence Chang YE, Laimins LA (2000) Microarray analysis identifies
for clinical efficacy is still needed. interferon-inducible genes and Stat-1 as major transcrip-
tional targets of human papillomavirus type 31. J Virol 74:
4174–4182
Chiao EY, Krown SE, Stier EA, Schrag D (2005) A population-
References based analysis of temporal trends in the incidence of
squamous anal canal cancer in relation to the HIV epidemic.
J Acquir Immune Defic Syndr 40: 451–455
Aynaud O, Buffet M, Roman P, Plantier F, Dupin N (2008) Study Chin-Hong PV, Palefsky JM (2002) Natural history and clinical
of persistence and recurrence rates in 106 patients with con- management of anal human papillomavirus disease in men
 174 9 Human Papillomavirus Infection in HIV-Infected Individuals

and women infected with human immunodeficiency virus. cogenic human papillomavirus infection at the United
9 Clin Infect Dis 35: 1127–1134 States-Mexico border. Cancer Epidemiol Biomarkers Prev
Chin-Hong PV, Vittinghoff E, Cranston RD, Browne L, 11: 930–934
Buchbinder S, Colfax G, Da Costa M, Darragh T, Benet DJ, Goedert JJ, Cote TR, Virgo P, Scoppa SM, Kingma DW, Gail
Judson F, Koblin B, Mayer KH, Palefsky JM (2005) Age- MH, Jaffe ES, Biggar RJ (1998) Spectrum of AIDS-
related prevalence of anal cancer precursors in homosexual associated malignant disorders. Lancet 351: 1833–1839
men: The EXPLORE study. J Natl Cancer Inst 97: 896–905 Goldstone SE, Hundert JS, Huyett JW (2007) Infrared coagula-
Clark RA, Brandon W, Dumestre J, Pindaro C (1993) Clinical tor ablation of high-grade anal squamous intraepithelial
manifestations of infection with the human immunodefi- lesions in HIV-negative males who have sex with males. Dis
ciency virus in women in Louisiana. Clin Infect Dis 17: Colon Rectum 50: 565–575
165–172 Goncalves MA, Randi G, Arslan A, Villa LL, Burattini MN,
Cleator S, Fife K, Nelson M, Gazzard B, Phillips R, Bower M Franceschi S, Donadi EA, Massad E (2008) HPV type infec-
(2000) Treatment of HIV-associated invasive anal cancer tion in different anogenital sites among HIV-positive
with combined chemoradiation. Eur J Cancer 36: 754–758 Brazilian women. Infect Agent Cancer 3: 5
Cranston RD, Hart SD, Gornbein JA, Hirschowitz SL, Cortina Giuliano A, Palefsky J (2008) The efficacy of quadrivalent HPV
G, Moe AA (2007) The prevalence, and predictive value, of (types 6/11/16/18) vaccine in reducing the incidence of HPV
abnormal anal cytology to diagnose anal dysplasia in a pop- infection and HPV-related genital disease in young men In:
ulation of HIV-positive men who have sex with men. Int J European Research Organization on Genital Infection and
STD AIDS 18: 77–80 Neoplasia – EUROGIN Nice , France
Cranston RD, Hirschowitz SL, Cortina G, Moe AA (2008) A Hagensee ME, Cameron JE, Leigh JE, Clark RA (2004) Human
retrospective clinical study of the treatment of high-grade papillomavirus infection and disease in HIV-infected indi-
anal dysplasia by infrared coagulation in a population of viduals. Am J Med Sci 328: 57–63
HIV-positive men who have sex with men. Int J STD AIDS Hampl M, Sarajuuri H, Wentzensen N, Bender HG, Kueppers V
19: 118–120 (2006) Effect of human papillomavirus vaccines on vulvar,
Critchlow CW, Hawes SE, Kuypers JM, Goldbaum GM, Holmes vaginal, and anal intraepithelial lesions and vulvar cancer.
KK, Surawicz CM, Kiviat NB (1998) Effect of HIV infec- Obstet Gynecol 108: 1361–1368
tion on the natural history of anal human papillomavirus Handisurya A, Rieger A, Bankier A, Koller A, Salat A, Stingl G,
infection. AIDS 12: 1177–1184 Kirnbauer R (2007) Human papillomavirus type 26 infec-
Devaraj B, Cosman BC (2006) Expectant management of anal tion causing multiple invasive squamous cell carcinomas of
squamous dysplasia in patients with HIV. Dis Colon Rectum the fingernails in an AIDS patient under highly active anti-
49: 36–40 retroviral therapy. Br J Dermatol 157: 788–794
Fagan SP, Bellows CF, 3rd, Albo D, Rodriquez-Barradas M, Heard I, Potard V, Costagliola D (2006) Limited impact of
Feanny M, Awad SS, Berger DH (2005) Length of human immunosuppression and HAART on the incidence of cervi-
immunodeficiency virus disease and not immune status is a cal squamous intraepithelial lesions in HIV-positive women.
risk factor for development of anal carcinoma. Am J Surg Antivir Ther 11: 1091–1096
190: 732–735 Heard I, Schmitz V, Costagliola D, Orth G, Kazatchkine MD
Fennema JS, van Ameijden EJ, Coutinho RA, van den Hoek AA (1998) Early regression of cervical lesions in HIV-
(1995) HIV, sexually transmitted diseases and gynaecologic seropositive women receiving highly active antiretroviral
disorders in women: Increased risk for genital herpes and therapy. AIDS 12: 1459–1464
warts among HIV-infected prostitutes in Amsterdam. AIDS Heck DV, Yee CL, Howley PM, Munger K (1992) Efficiency of
9: 1071–1078 binding the retinoblastoma protein correlates with the trans-
Franco EL, Villa LL, Sobrinho JP, Prado JM, Rousseau MC, forming capacity of the E7 oncoproteins of the human papil-
Desy M, Rohan TE (1999) Epidemiology of acquisition and lomaviruses. Proc Natl Acad Sci U S A 89: 4442–4446
clearance of cervical human papillomavirus infection in Heideman DA, Waterboer T, Pawlita M, Delis-van Diemen P,
women from a high-risk area for cervical cancer. J Infect Dis Nindl I, Leijte JA, Bonfrer JM, Horenblas S, Meijer CJ,
180: 1415–1423 Snijders PJ (2007) Human papillomavirus-16 is the predom-
Frisch M, Biggar RJ, Goedert JJ (2000) Human papillomavirus- inant type etiologically involved in penile squamous cell
associated cancers in patients with human immunodeficiency carcinoma. J Clin Oncol 25: 4550–4556
virus infection and acquired immunodeficiency syndrome. J Herrera S, Correa LA, Wolff JC, Gaviria A, Tyring SK,
Natl Cancer Inst 92: 1500–1510 Sanclemente G (2007) Effect of imiquimod in anogenital
Fruchter RG, Maiman M, Sedlis A, Bartley L, Camilien L, warts from HIV-positive men. J Clin Virol 39: 210–214
Arrastia CD (1996) Multiple recurrences of cervical intra- Hoffman R, Welton ML, Klencke B, Weinberg V, Krieg R (1999)
epithelial neoplasia in women with the human immunodefi- The significance of pretreatment CD4 count on the outcome
ciency virus. Obstet Gynecol 87: 338–344 and treatment tolerance of HIV-positive patients with anal
Gagne SE, Jensen R, Polvi A, Da Costa M, Ginzinger D, Efird cancer. Int J Radiat Oncol Biol Phys 44: 127–131
JT, Holly EA, Darragh T, Palefsky JM (2005) High-resolution Jamieson DJ, Paramsothy P, Cu-Uvin S, Duerr A, Group
analysis of genomic alterations and human papillomavirus HIVERS (2006) Vulvar, vaginal, and perianal intraepithelial
integration in anal intraepithelial neoplasia. J Acquir Immune neoplasia in women with or at risk for human immunodefi-
Defic Syndr 40: 182–189 ciency virus. Obstet Gynecol 107: 1023–1028
Giuliano AR, Papenfuss M, Abrahamsen M, Inserra P (2002) Jong E, Mulder JW, van Gorp EC, Wagenaar JK, Derksen J,
Differences in factors associated with oncogenic and nonon- Westerga J, Tol A, Smits PH (2008) The prevalence of
References 175

human papillomavirus (HPV) infection in paired urine and Lambert P, Coleman N, Doorbar J (2003) Organization of
cervical smear samples of HIV-infected women. J Clin Virol human papillomavirus productive cycle during neoplastic
41: 111–115 progression provides a basis for selection of diagnostic
Kojic EM, Cu-Uvin S (2007) Update: Human papillomavirus markers. J Virol 77: 10186–10201
infection remains highly prevalent and persistent among Minkoff H, Ahdieh L, Massad LS, Anastos K, Watts DH,
HIV-infected individuals. Curr Opin Oncol 19: 464–469 Melnick S, Muderspach L, Burk R, Palefsky J (2001) The
Kreiss JK, Kiviat NB, Plummer FA, Roberts PL, Waiyaki P, effect of highly active antiretroviral therapy on cervical
Ngugi E, Holmes KK (1992) Human immunodeficiency cytologic changes associated with oncogenic HPV among
virus, human papillomavirus, and cervical intraepithelial HIV-infected women. AIDS 15: 2157–2164
neoplasia in Nairobi prostitutes. Sex Transm Dis 19: 54–59 Minkoff H, Zhong Y, Strickler HD, Watts DH, Palefsky JM,
Kreuter A, Brockmeyer NH, Hochdorfer B, Weissenborn SJ, Levine AM, D’Souza G, Howard AA, Plankey M, Massad
Stucker M, Swoboda J, Altmeyer P, Pfister H, Wieland U LS, Burk R (2008) The relationship between cocaine use
(2005) Clinical spectrum and virologic characteristics of and human papillomavirus infections in HIV-seropositive
anal intraepithelial neoplasia in HIV infection. J Am Acad and HIV-seronegative women. Infect Dis Obstet Gynecol
Dermatol 52: 603–608 2008: 587082
Kreuter A, Brockmeyer NH, Weissenborn SJ, Gambichler T, Moore AL, Sabin CA, Madge S, Mocroft A, Reid W, Johnson
Stucker M, Altmeyer P, Pfister H, Wieland U (2008) Penile MA (2002) Highly active antiretroviral therapy and cervical
intraepithelial neoplasia is frequent in HIV-positive men intraepithelial neoplasia. AIDS 16: 927–929
with anal dysplasia. J Invest Dermatol 128: 2316–2324 Munger K, Werness BA, Dyson N, Phelps WC, Harlow E,
Kupper TS, Fuhlbrigge RC (2004) Immune surveillance in the Howley PM (1989) Complex formation of human papillo-
skin: Mechanisms and clinical consequences. Nat Rev mavirus E7 proteins with the retinoblastoma tumor suppres-
Immunol 4: 211–222 sor gene product. EMBO J 8: 4099–4105
Lehtovirta P, Paavonen J, Heikinheimo O (2008) Risk factors, Murphy EL, Collier AC, Kalish LA, Assmann SF, Para MF,
diagnosis and prognosis of cervical intraepithelial neoplasia Flanigan TP, Kumar PN, Mintz L, Wallach FR, Nemo GJ
among HIV-infected women. Int J STD AIDS 19: 37–41 (2001) Highly active antiretroviral therapy decreases mortal-
Liaw KL, Glass AG, Manos MM, Greer CE, Scott DR, Sherman ity and morbidity in patients with advanced HIV disease.
M, Burk RD, Kurman RJ, Wacholder S, Rush BB, Cadell Ann Intern Med 135: 17–26
DM, Lawler P, Tabor D, Schiffman M (1999) Detection of Nappi L, Carriero C, Bettocchi S, Herrero J, Vimercati A,
human papillomavirus DNA in cytologically normal women Putignano G (2005) Cervical squamous intraepithelial
and subsequent cervical squamous intraepithelial lesions. lesions of low-grade in HIV-infected women: recurrence,
J Natl Cancer Inst 91: 954–960 persistence, and progression, in treated and untreated
Lillo FB, Ferrari D, Veglia F, Origoni M, Grasso MA, Lodini S, women. Eur J Obstet Gynecol Reprod Biol 121: 226–232
Mastrorilli E, Taccagni G, Lazzarin A, Uberti-Foppa C Nees M, Geoghegan JM, Hyman T, Frank S, Miller L, Woodworth
(2001) Human papillomavirus infection and associated cer- CD (2001) Papillomavirus type 16 oncogenes downregulate
vical disease in human immunodeficiency virus-infected expression of interferon-responsive genes and upregulate
women: Effect of highly active antiretroviral therapy. J Infect proliferation-associated and NF-kappaB-responsive genes in
Dis 184: 547–551 cervical keratinocytes. J Virol 75: 4283–4296
Lillo FB, Uberti-Foppa C (2006) Human papillomavirus viral Ogunbiyi OA, Scholefield JH, Raftery AT, Smith JH, Duffy S,
load: A possible marker for cervical disease in HIV-infected Sharp F, Rogers K (1994) Prevalence of anal human papil-
women. J Antimicrob Chemother 57: 810–814 lomavirus infection and intraepithelial neoplasia in renal
Luque AE, Li H, Demeter LM, Reichman RC (2001) Effect of allograft recipients. Br J Surg 81: 365–367
highly active antiretroviral therapy (HAART) on human Orlando G, Fasolo MM, Beretta R, Merli S, Cargnel A (2002)
papillomavirus (HPV) infection and disease among HIV- Combined surgery and cidofovir is an effective treatment for
infected women. In: 8th Conference on retroviruses and genital warts in HIV-infected patients. AIDS 16: 447–450
opportunistic infections, Chicago Palefsky JM, Berry JM, Jay N, Krogstad M, Da Costa M,
Maiman M, Fruchter RG, Clark M, Arrastia CD, Matthews R, Darragh TM, Lee JY (2006) A trial of SGN-00101 (HspE7)
Gates EJ (1997) Cervical cancer as an AIDS-defining ­illness. to treat high-grade anal intraepithelial neoplasia in HIV-
Obstet Gynecol 89: 76–80 positive individuals. AIDS 20: 1151–1155
Margenthaler JA, Dietz DW, Mutch MG, Birnbaum EH, Kodner Palefsky JM, Holly EA (2003) Chapter 6: Immunosuppression
IJ, Fleshman JW (2004) Outcomes, risk of other malignan- and co-infection with HIV. J Natl Cancer Inst Monogr:
cies, and need for formal mapping procedures in patients 41–46
with perianal Bowen’s disease. Dis Colon Rectum 47: 1655– Palefsky JM, Holly EA, Efirdc JT, Da Costa M, Jay N, Berry
1660; discussion 1660–1651 JM, Darragh TM (2005) Anal intraepithelial neoplasia in the
Massad LS, Riester KA, Anastos KM, Fruchter RG, Palefsky highly active antiretroviral therapy era among HIV-positive
JM, Burk RD, Burns D, Greenblatt RM, Muderspach LI, men who have sex with men. AIDS 19: 1407–1414
Miotti P (1999) Prevalence and predictors of squamous cell Palefsky JM, Holly EA, Hogeboom CJ, Ralston ML, DaCosta
abnormalities in Papanicolaou smears from women infected MM, Botts R, Berry JM, Jay N, Darragh TM (1998a)
with HIV-1. Women’s Interagency HIV Study Group. Virologic, immunologic, and clinical parameters in the inci-
J Acquir Immune Defic Syndr 21: 33–41 dence and progression of anal squamous intraepithelial
Middleton K, Peh W, Southern S, Griffin H, Sotlar K, Nakahara lesions in HIV-positive and HIV-negative homosexual men.
T, El-Sherif A, Morris L, Seth R, Hibma M, Jenkins D, J Acquir Immune Defic Syndr Hum Retrovirol 17: 314–319
 176 9 Human Papillomavirus Infection in HIV-Infected Individuals

Palefsky JM, Holly EA, Ralston ML, Arthur SP, Jay N, Berry and high-risk HIV-negative women. Clin Vaccine Immunol
9 JM, DaCosta MM, Botts R, Darragh TM (1998b) Anal 13: 511–519
squamous intraepithelial lesions in HIV-positive and HIV- Sirera G, Videla S, Lopez-Blazquez R, Llatjos M, Tarrats A,
negative homosexual and bisexual men: prevalence and risk Castella E, Grane N, Tural C, Rey-Joly C, Clotet B (2008)
factors. J Acquir Immune Defic Syndr Hum Retrovirol 17: Highly active antiretroviral therapy and incidence of cervi-
320–326 cal squamous intraepithelial lesions among HIV-infected
Palefsky JM, Holly EA, Ralston ML, Jay N (1998c) Prevalence women with normal cytology and CD4 counts above 350
and risk factors for human papillomavirus infection of the anal cells/mm3. J Antimicrob Chemother 61: 191–194
canal in human immunodeficiency virus (HIV)-positive and Sirera G, Videla S, Pinol M, Canadas MP, Llatjos M, Ballesteros
HIV-negative homosexual men. J Infect Dis 177: 361–367 AL, Garcia-Cuyas F, Castella E, Guerola R, Tural C, Rey-
Parham GP, Sahasrabuddhe VV, Mwanahamuntu MH, Shepherd Joly C, Clotet B (2006) High prevalence of human papillo-
BE, Hicks ML, Stringer EM, Vermund SH (2006) Prevalence mavirus infection in the anus, penis and mouth in HIV-positive
and predictors of squamous intraepithelial lesions of the cer- men. AIDS 20: 1201–1204
vix in HIV-infected women in Lusaka, Zambia. Gynecol Smits PH, Bakker R, Jong E, Mulder JW, Meenhorst PL, Kleter B,
Oncol 103: 1017–1022 van Doorn LJ, Quint WG (2005) High prevalence of human pap-
Pineda CE, Berry JM, Jay N, Palefsky JM, Welton ML (2008) illomavirus infections in urine samples from human immunode-
High-resolution anoscopy targeted surgical destruction of ficiency virus-infected men. J Clin Microbiol 43: 5936–5939
anal high-grade squamous intraepithelial lesions: a ten-year Soncini E, Zoncada A, Condemi V, Antoni AD, Bocchialini E,
experience. Dis Colon Rectum 51: 829–835; discussion Soregotti P (2007) Reduction of the risk of cervical intraepi-
835–827 thelial neoplasia in HIV-infected women treated with highly
Place RJ, Gregorcyk SG, Huber PJ, Simmang CL (2001) active antiretroviral therapy. Acta Biomed 78: 36–40
Outcome analysis of HIV-positive patients with anal Stanley M (2006) Immune responses to human papillomavirus.
squamous cell carcinoma. Dis Colon Rectum 44: 506–512 Vaccine 24 Suppl 1: S16–22
Reisinger KS, Block SL, Lazcano-Ponce E, Samakoses R, Esser Stanley MA (1994) Replication of human papillomaviruses in
MT, Erick J, Puchalski D, Giacoletti KE, Sings HL, Lukac S, cell culture. Antiviral Res 24: 1–15
Alvarez FB, Barr E (2007) Safety and persistent immunoge- Sterling JC, Skepper JN, Stanley MA (1993) Immunoelectron
nicity of a quadrivalent human papillomavirus types 6, 11, microscopical localization of human papillomavirus type 16
16, 18 L1 virus-like particle vaccine in preadolescents and L1 and E4 proteins in cervical keratinocytes cultured in vivo.
adolescents: A randomized controlled trial. Pediatr Infect J Invest Dermatol 100: 154–158
Dis J 26: 201–209 Stern PL (2005) Immune control of human papillomavirus
Remmink AJ, Walboomers JM, Helmerhorst TJ, Voorhorst FJ, (HPV) associated anogenital disease and potential for vac-
Rozendaal L, Risse EK, Meijer CJ, Kenemans P (1995) The cination. J Clin Virol 32 Suppl 1: S72–S81
presence of persistent high-risk HPV genotypes in dysplas- Strickler HD, Burk RD, Fazzari M, Anastos K, Minkoff H,
tic cervical lesions is associated with progressive disease: Massad LS, Hall C, Bacon M, Levine AM, Watts DH,
Natural history up to 36 months. Int J Cancer 61: 306–311 Silverberg MJ, Xue X, Schlecht NF, Melnick S, Palefsky JM
Ryan DP, Compton CC, Mayer RJ (2000) Carcinoma of the anal (2005) Natural history and possible reactivation of human
canal. N Engl J Med 342: 792–800 papillomavirus in human immunodeficiency virus-positive
Sanclemente G, Herrera S, Tyring SK, Rady PL, Zuleta JJ, women. J Natl Cancer Inst 97: 577–586
Correa LA, He Q, Wolff JC (2007) Human papillomavirus Strickler HD, Palefsky JM, Shah KV, Anastos K, Klein RS, Minkoff
(HPV) viral load and HPV type in the clinical outcome of H, Duerr A, Massad LS, Celentano DD, Hall C, Fazzari M,
HIV-positive patients treated with imiquimod for anogenital Cu-Uvin S, Bacon M, Schuman P, Levine AM, Durante AJ,
warts and anal intraepithelial neoplasia. J Eur Acad Dermatol Gange S, Melnick S, Burk RD (2003) Human papillomavirus
Venereol 21: 1054–1060 type 16 and immune status in human immunodeficiency virus-
Scholefield JH, Castle MT, Watson NF (2005) Malignant trans- seropositive women. J Natl Cancer Inst 95: 1062–1071
formation of high-grade anal intraepithelial neoplasia. Br Sun XW, Ellerbrock TV, Lungu O, Chiasson MA, Bush TJ,
J Surg 92: 1133–1136 Wright TC, Jr. (1995) Human papillomavirus infection in
Scholefield JH, Hickson WG, Smith JH, Rogers K, Sharp F human immunodeficiency virus-seropositive women. Obstet
(1992) Anal intraepithelial neoplasia: Part of a multifocal Gynecol 85: 680–686
disease process. Lancet 340: 1271–1273 Syrjanen K (2008) New concepts on risk factors of HPV and
Scholefield JH, Ogunbiyi OA, Smith JH, Rogers K, Sharp F novel screening strategies for cervical cancer precursors.
(1994) Treatment of anal intraepithelial neoplasia. Br J Surg Eur J Gynaecol Oncol 29: 205–221
81: 1238–1240 Trottier H, Mahmud S, Costa MC, Sobrinho JP, Duarte-Franco
Shrestha S, Wang C, Aissani B, Wilson CM, Tang J, Kaslow RA E, Rohan TE, Ferenczy A, Villa LL, Franco EL (2006)
(2007) Interleukin-10 gene (IL10) polymorphisms and Human papillomavirus infections with multiple types and
human papillomavirus clearance among immunosuppressed risk of cervical neoplasia. Cancer Epidemiol Biomarkers
adolescents. Cancer Epidemiol Biomarkers Prev 16: Prev 15: 1274–1280
1626–1632 van Benthem BH, Prins M, Larsen C, Delmas MC, Brunet JB,
Silverberg MJ, Schneider MF, Silver B, Anastos KM, Burk RD, van den Hoek A (2000) Sexually transmitted infections in
Minkoff H, Palefsky J, Levine AM, Viscidi RP (2006) European HIV-infected women: incidence in relation to time
Serological detection of human papillomavirus type 16 from infection. European Study on the Natural History of
infection in human immunodeficiency virus (HIV)-positive HIV Infection in Women. AIDS 14: 595–603
References 177

van der Snoek EM, Niesters HG, Mulder PG, van Doornum GJ, A, Strickler H (2003b) Serum immunoglobulin A response
Osterhaus AD, van der Meijden WI (2003) Human papilloma- to human papillomavirus type 16 virus-like particles in
virus infection in men who have sex with men participating in human immunodeficiency virus (HIV)-positive and high-
a Dutch gay-cohort study. Sex Transm Dis 30: 639–644 risk HIV-negative women. J Infect Dis 188: 1834–1844
Vandamme AM, Van Vaerenbergh K, De Clercq E (1998) Anti- Watson AJ, Smith BB, Whitehead MR, Sykes PH, Frizelle FA
human immunodeficiency virus drug combination strategies. (2006) Malignant progression of anal intra-epithelial neo-
Antivir Chem Chemother 9: 187–203 plasia. ANZ J Surg 76: 715–717
Viscidi RP, Ahdieh-Grant L, Clayman B, Fox K, Massad LS, Werness BA, Levine AJ, Howley PM (1990) Association of
Cu-Uvin S, Shah KV, Anastos KM, Squires KE, Duerr A, human papillomavirus types 16 and 18 E6 proteins with p53.
Jamieson DJ, Burk RD, Klein RS, Minkoff H, Palefsky J, Science 248: 76–79
Strickler H, Schuman P, Piessens E, Miotti P (2003a) Serum Yamada R, Sasagawa T, Kirumbi LW, Kingoro A, Karanja DK,
immunoglobulin G response to human papillomavirus type Kiptoo M, Nakitare GW, Ichimura H, Inoue M (2008)
16 virus-like particles in human immunodeficiency virus Human papillomavirus infection and cervical abnormali-
(HIV)-positive and risk-matched HIV-negative women. ties in Nairobi, Kenya, an area with a high prevalence of
J Infect Dis 187: 194–205 human immunodeficiency virus infection. J Med Virol 80:
Viscidi RP, Ahdieh-Grant L, Schneider MF, Clayman B, Massad 847–855
LS, Anastos KM, Burk RD, Minkoff H, Palefsky J, Levine
 Human Papillomavirus
and CO2 Laser Treatment 10
Alberto Rosenblatt and Homero Gustavo de Campos Guidi

Contents Lasers containing carbon dioxide (CO2) gas are

called CO2 lasers (Fig. 10.1a–c). These devices emit an
10.1 Introduction........................................................... 181 invisible infrared light at a wavelength of 10,600 nm,
10.2 Historic Background............................................. 181 which is absorbed by intracellular and extracellular
10.3 CO2 Laser Components........................................ 182 water, the main constituent of human tissue. Heat is then
produced, which results in tissue vaporization and coag-
10.4 CO2 Laser Beam.................................................... 183
ulative necrosis of superficial epidermal layers.
10.4.1 Laser Safety............................................................ 184
This chapter briefly reviews CO2 lasers, with par-
10.5 CO2 Laser Indications........................................... 186 ticular focus on the use of CO2 lasers in the treatment
10.6 Personal Laser Technique..................................... 186 of HPV-related genital lesions.
10.6.1 Preoperative Care.................................................... 186
10.6.2 Settings.................................................................... 187
10.6.3 Procedure................................................................. 188
10.6.4 Postoperative Care................................................... 189 10.2 Historic Background
10.6.5 Complications.......................................................... 191
References.............................................................. 193
In the treatise On the Quantum Mechanics of Radiation,
published in 1917 by Albert Einstein (Einstein, 1917),
the fundamentals of light emission by an atom were
10.1 Introduction initially proposed. The basic principles of the laser
were described in “Infrared and Optical Masers,” pub-
lished in 1958 by the American physicists Arthur L.
The acronym LASER stands for “light amplification by
Schalow and Charles H. Townes (Schalow and Townes,
the stimulated emission of radiation” and it was coined
1958). The first MASER (microwave amplification
by the American physicist Gordon Gould, ­considered
through the stimulated emission of radiation, as the
by some as the “inventor of the laser.”
laser was called then) instrument was developed in
Medical lasers deliver the exact amount of energy
1959, and in the following year the first operational
to the target tissue, thus sparing contiguous structures,
laser using ruby as an active medium was devised by
a principle called selective photothermolysis.
American physicist Theodore Maiman (Maiman,
1960) at the Hughes Research Laboratories. Polanyi
(1961) wrote about the possibility of using molecular
A. Rosenblatt ()
Albert Einstein Jewish Hospital, Sao Paulo, Brasil vibrations for laser action in 1961, and Patel (1964)
e-mail: [email protected] described the laser action on the vibrational-rotational

A. Rosenblatt, H. G. de Campos Guidi, Human Papillomavirus, 181

DOI: 10.1007/978-3-540-70974-9-10, © Springer-Verlag Berlin Heidelberg 2009
 182 10 Human Papillomavirus and CO2 Laser Treatment

Fig. 10.1. (a) Cavitron (CO2

10 laser) used in 1980 (b) CO2
laser used in 1990 (c) CO2 laser
and microscope used in 2008

transitions of CO2 in an electrical discharge in 1964. Pump (power supply): In the pump the atoms are
High power and efficiency have been attained with the excited, creating a population inversion (i.e., all the
addition of nitrogen (N2) by Patel (1965) and helium atoms are directly and continuously excited from the
(He) by Moeller and Rigden (1965). ground state to the excited state).
Delivery system: Typically, delivery is through an
articulating arm containing mirrored joints (Fig. 10.2)
10.3 CO2 Laser Components to efficiently transmit the laser light through an output
device, such as a handpiece (Fig. 10.3), colposcope
(Fig. 10.4), or operating microscope (Fig. 10.5a, b).
Laser medium: CO2 gas However, waveguide or fiberoptic cables may be used
by some devices.
Optical cavity (also called resonator): The optical cav-
ity is where the laser medium is enclosed and the When using the laser connected to the operating micro-
amplification process takes place. scope or colposcope, a joystick ­micromanipu­lator is
10.4 CO2 Laser Beam 183

Fig. 10.2. Laser articu­lating

arm

Fig. 10.3. Laser

handpiece
Fig. 10.4. CO2 laser connected to colposcope

operated to change the laser beam position (Fig. 10.6a, b).

Each movement of the joystick is translated into the
inclination of a movable mirror (Fig. 10.7). The sur-
geon then shifts the point irradiated with the laser beam
by moving the joystick back and forth or right and left
while observing the operative field through a
microscope.

10.4 CO2 Laser Beam

The laser beam in focus mode can be used like a ­scalpel

to cut the tissue. Laser light is absorbed by blood, thus
deep penetration of the laser beam with subsequent tis-
sue damage is avoided.

Expert Advice

A dry operative field is required for effective CO2

laser action.
 184 10 Human Papillomavirus and CO2 Laser Treatment

10

Fig. 10.6. (a) Joystick assembled into colposcope (arrow).

(b) Joystick assembled into microscope (arrow)

Bleeding vessels can be coagulated by applying the

laser beam in defocused mode or by directing the beam
to the periphery of the lesion, causing the tissue (and
the vessel within) to retract.

10.4.1 Laser Safety

Appropriate laser training is required to avoid risks to

Fig. 10.5. (a) CO2 laser connected to surgical microscope patients and operating room personnel, including the
(b) Laser and operating microscope laser operator.
10.4 CO2 Laser Beam 185

Fig. 10.8. Bilateral vocal cord papillomas (Source: Photograph

courtesy of Reinaldo J. Gusmão, MD, PhD, São Paulo, Brazil)

Fig. 10.7. Joystick (black arrow) and movable mirror (white

arrow)

10.4.1.1 Eye Protection

Direct or reflected light from CO2 lasers may damage

the cornea, therefore special optically coated glasses
and goggles should be used by the patient and operat-
ing room personnel. Adequate signage identifying
laser usage should be displayed on the operating room
doors, and these should be kept closed while the CO2
laser is being used.

10.4.1.2 Laser Plume

Ferenczy and coworkers (1990) were the first to detect

clinically active HPV particles within the plume of
smoke that emanated from laser equipment, and Hallmo
and Naess (1991) reported the occurrence of HPV-
related laryngeal papillomatosis ­contracted by a laser
surgeon. Therefore, the inadvertent inhalation of viral
particles while performing laser surgery for HPV Fig. 10.9. (a) Laser plume/smoke evacuator with hose posi-
tioned close to the operative site. (b) Laser filter
places the surgeon and other members of the operating
team and room staff at risk of developing respiratory
tract papillomatosis (Fig. 10.8). A laser-specific plume/ site. In addition, maintaining appropriate room ventila-
smoke evacuator adapted with a filter (Fig. 10.9a, b) tion and wearing special mask protection should reduce
should be used and positioned close to the operative inhalation risks.
 186 10 Human Papillomavirus and CO2 Laser Treatment

10.5 CO2 Laser Indications

10
Extensive and exophytic lesions
Multifocal recurring lesions
Lesions unresponsive to other medical and/or surgi-
cal therapies
Urethral lesions (see Chap. 4)
Penile intraepithelial neoplasia (PIN) lesions (see
Chap. 5)
Perianal lesions associated with genital lesions

10.6 Personal Laser Technique

The CO2 laser should preferably be connected to the
operating microscope or colposcope (Fig. 10.10),
because enhanced magnification is important in order
to detect microscopic lesions. Lesions are then quickly
and precisely vaporized under microscopic ­guid­ance
using the laser joystick micromanipulator (Fig. 10.11).
However, the laser handpiece can also be used to
treat extensive and multiple lesions (Fig. 10.12). The
greater mobility of the device allows for the swift exci-
sion of exophytic lesions close to the base, which are
then completely vaporized. Fig. 10.11. Joystick micromanipulator is used to guide laser beam

10.6.1 Preoperative Care

The topical anesthetic cream EMLA (eutectic ­mixture

of lidocaine and prilocaine) is liberally applied to the
genital area involved, with or without occlusion 30–60
min before the procedure (Fig. 10.13). For localized

Fig. 10.12. Lesion is vaporized using the laser handpiece

lesions, local infiltration with lidocaine HCl 2% without

epinephrine (Fig. 10.14) is used, and for extensive penile
lesions a nerve block is preferred.
Acetic acid (5%) is applied to the genital area to
identify and map areas to be treated (Fig. 10.15a, b)
Fig. 10.10. Colposcope with connected laser is used to visualize (see also How to Perform the Acetowhite Test in
and treat lesions Chap. 3).
10.6 Personal Laser Technique 187

Fig. 10.13. EMLA is applied to involved area

Fig. 10.14. Local infiltration of scrotal and penile lesions with

lidocaine HCl 2%without epinephrine
Fig. 10.15. (a) Acetowhite test performed to map areas to be
treated (b) Acetowhite areas and diffuse hyperemic mucosa
A smoke evacuation system is always used and
placed close to the vaporized area.
Expert Advice
10.6.2 Settings
It is recommended to begin the laser procedure with
the lowest possible power output, particularly for
Power ranges between 4 W/cm2 (urethra) and 5 W/cm2
lesions located within the urethra, and power adjust-
(external genitalia) in continuous (Fig. 10.16) or
ments can be made accordingly during the laser ses-
pulsed-wave mode for tissue vaporization, and between
sion. This will reduce intraoperative complications
5 and 10 W/cm2 for excision of large exophytic lesions,
and postoperative patient discomfort.
are used.
 188 10 Human Papillomavirus and CO2 Laser Treatment

a
10

Fig. 10.16. Laser power 5 W/cm2 in continuous mode

10.6.3 Procedure
c
Tissue vaporization is best accomplished when laser
beam exposure times are shorter than 1 ms. Therefore,
the laser beam should be moved in small and continu-
ous movements until the area of interest is completely
vaporized (Fig. 10.17a–c). The laser vaporization depth
should not exceed 1 mm to prevent scarring and bleed-
ing (particularly in the urethra). A 3-mm border of
normal-appearing epithelium around the involv­ed area
is also vaporized to destroy any undetectable lesion
(Fig. 10.18a, b). Bleeding is usually controlled with the
defocused laser beam.

10.6.3.1 CO2 Laser Vaporization

of Penile Lesions
Fig. 10.17. (a) Laser directed to glans lesion. (b) Laser beam is
moved in small and continuous movements. (c) Glans lesion is
See Fig. 10.17a–c. vaporized
10.6 Personal Laser Technique 189

a b

Fig. 10.18. (a) Laser beam directed to scrotal lesion. (b) Scrotal lesion and normal-appearing epithelium around lesion being vapor-
ized (see laser plume)

10.6.3.2 CO2 Laser Vaporization the fossa navicularis and urethral meatus, with the aim
of Scrotal Lesions of destroying any clinically unapparent lesion contained
within the area (Fig. 10.24). HPV-associated external
See Fig. 10.18a, b. lesions are treated during the same laser session (Fig.
10.25a, b).
10.6.3.3 CO2 Laser Lesion Excision
Expert Advice
The laser beam can also be used as a scalpel to cut
the tissue and completely excise the affected area EMLA applied to the urethral meatus can produce
(Fig. 10.19a–d). The specimen obtained can be sent for mucosal edema (Figs. 10.22–10.24). This harmless
histological analysis (Fig. 10.20). side effect may cause undue difficulties during laser
treatment, particularly in patients with deeper
located lesions and/or narrow meatus. In these
10.6.3.4 CO2 Laser Vaporization patients, the use of lidocaine gel may be a better
of Urethral Lesions topical anesthetic alternative.

The urethral meatus is opened and the lesion is visualized

(Fig. 10.21). It is very important to identify the lesion
boundaries before vaporization begins, particularly at the 10.6.4 Postoperative Care
deepest level, to avoid mucosal edema and loss of lesion
margin definition. As soon as the lesion base is identified, Lidocaine gel is applied to all treated areas, which are
the laser beam is applied to the wart’s most exposed part then lightly covered with gauze mesh.
to completely vaporize it down to its base (Fig. 10.22a, b). A topical collagenase-based ointment (sometimes
The laser is also applied to the areas adjacent to the associated with topical antibiotic after extensive
urethral condyloma (Fig. 10.23). The unfocused beam is vaporization) is applied on the first postoperative day
then quickly “flashed” over the remaining epithelium of and repeated thereafter two times a day with an open
 190 10 Human Papillomavirus and CO2 Laser Treatment

10

Fig. 10.19 (a) HPV-related lesion at the base of the penis. (b) Laser beam incises the tissue at the base of the lesion. (c) Lesion at the
base of the penis being removed. (d) Final result

Fig. 10.20. Specimen obtained can be sent for histological and

viral analysis Fig. 10.21. Small urethral lesion
10.6 Personal Laser Technique 191

Fig. 10.23. Urethral mucosa adjacent to the lesion is also

vaporized

Fig. 10.22. (a) Laser beam directed to the lesion. (b) Urethral Fig. 10.24. The unfocused beam is quickly flashed over the
lesion is vaporized down to its base mucosa

dressing. Healing is usually completed in 2–3 weeks contact dermatitis, and the cicatrizant cream should be
(Fig. 10.26–10.27) and sexual intercourse is deferred removed or changed. Oral antifungal medications are
until complete healing occurs. occasionally required when erythema and pruritus
associated with white discharge and odor persist.
Infection is an unusual event after genital laser
treatment and topical and/or oral antibiotics are sel-
10.6.5 Complications dom recommended.
Pigmentary changes and scarring usually appear in
Postoperative swelling and ecchymosis usually subside areas where deep penetration of the laser beam has
in 2–5 days. Erythema and pruritus are usually due to oc­curred.
 192 10 Human Papillomavirus and CO2 Laser Treatment

10

Fig. 10.26. Glans penis and preputial area on postoperative day 12

Fig. 10.27. Base of the penis on postoperative day 12

Fig. 10.25. (a) Broad-based urethral lesion (black arrow) and

external lesions (white arrows). (b) Laser-treated areas
References 193

References Maiman T (1960) Stimulated optical radiation in ruby masers.

Nature 187: 493–494
Moeller G, Rigden J (1965) High-power laser action in CO2-He
Einstein A (1917) Zur Quantentheorie der Strahlung (on the mixtures. Appl Phys Lett 7: 274–276
quantum mechanics of radiation). Physikalische Zeitschrift Patel C (1964) Continuous-wave laser action on vibrational rota-
18: 121–128 tional transitions of CO2. Phys Rev 136: 1187–1193
Ferenczy A, Bergeron C, Richart RM (1990) Carbon dioxide laser Patel C (1965) High power N2-CO2 laser. Appl Phys Lett 7:
energy disperses human papillomavirus deoxyribonucleic acid 15–17
onto treatment fields. Am J Obstet Gynecol 163: 1271–1274 Polanyi J (1961) Proposal for an infrared Maser dependent on
Hallmo P, Naess O (1991) Laryngeal papillomatosis with human vibrational excitation. J Chem Phys 34: 347
papillomavirus DNA contracted by a laser surgeon. Eur Schalow A, Townes C (1958) Infrared and optical masers. Phys
Arch Otorhinolaryngol 248: 425–427 Rev 112: 1940–1949
 Human Papillomavirus Vaccines
11
Alberto Rosenblatt and Homero Gustavo de Campos Guidi

Contents 11.1 Introduction

11.1 Introduction........................................................... 195
11.2 HPV: An Overview................................................ 196 Human papillomavirus (HPV) infection and HPV-
11.3 A Short Introduction to associated anogenital diseases, such as warts, cancers
Papillomavirus Biology......................................... 197 precursors, as well as anogenital invasive cancers, are
11.3.1 HPV Life Cycle....................................................... 197 significant health care problems (Fig. 11.1). Current
11.4 Significance of HPV Proteins in the estimates of the worldwide prevalence of HPV indi-
Generation of Prophylactic and cate that approximately 10% of women in the general
Therapeutic HPV Vaccines................................... 197 population will harbor cervical HPV infection at a
11.5 Natural History of HPV Antibodies.................... 198 given time (de Sanjose et al., 2007).
11.5.1 Humoral Responses................................................. 198 Furthermore, estimates of human cancer incidence
11.5.2 Cell Immune Responses.......................................... 200
linked to infectious agents suggest that HPV infections
11.6 Prophylactic HPV Vaccination............................. 200 in female individuals presently contribute to more than
11.6.1 Gardasil................................................................... 204
51% of cancer cases, whereas infection in male indi-
11.6.2 Cervarix................................................................... 204
viduals accounts for slightly more than 4% of HPV-
11.7 HPV Vaccination: Issues to Be Addressed.......... 205 associated neoplasias (Hausen, 2008).
11.7.1 Duration of Protection............................................. 205
11.7.2 HPV Prophylactic Vaccine Cross-Protection.......... 205 Cervical cancer causes considerable morbidity and
11.7.3 Vaccination of HPV-Infected Individuals................ 205 mortality in the young female population and con­
11.7.4 HPV Vaccines in Developing Countries.................. 206 stitutes a significant economic burden to developing
11.7.5 Condoms vs. HPV Prophylactic Vaccines............... 207 countries. According to 2002 data from the International
11.8 Prophylactic HPV Vaccines in Men..................... 207 Agency for Research on Cancer (Parkin et al., 2005),
11.8.1 Nongenital HPV Infections in Men......................... 208 approximately half a million women worldwide develop
11.8.2 Cost-Effectiveness of Male Vaccination.................. 208
cervical cancer every year (Fig. 11.1), and over two-
11.9 Therapeutic HPV Vaccination and thirds of these cases are associated with HPV infection
Future Vaccine Developments.............................. 208
of either oncogenic type 16 (51.0%) or HPV type 18
References ............................................................. 209 (16.2%). Consequently, successful strategies that can
protect against HPV infection are expected to decrease
the rates of HPV-related diseases.
Sexual abstinence is the most effective preventive
measure against HPV infection and other sexually
A. Rosenblatt ()
Albert Einstein Jewish Hospital, Sao Paulo, Brasil transmitted diseases (STDs). Although Winer et al.
e-mail: [email protected] (2006) reported that the regular use of condoms may

A. Rosenblatt, H. G. de Campos Guidi, Human Papillomavirus, 195

DOI: 10.1007/978-3-540-70974-9-11, © Springer-Verlag Berlin Heidelberg 2009
 196 11 Human Papillomavirus Vaccines

Human Papillomavirus Infection and Associated

11 Diseases
Cervical cancer: 0,493 million in 20021
CIN 2+:
10 million2

Low-grade cervical lesions:

30 million2
es
typ

es
yp
PV

Genital warts:
Vt
H

HP
ic

30 million3
en

nic
og

ge
nc

co
o
by

Asymptomatic
-on
ed

HPV infection:
on
us

300 million2
by
Ca

ed
us
Ca

1.Parkin DM, Bray F, Ferlay J, Pisani P. CA Cancer J Clin 2005;55:74–108.

2.World Health Organization. Geneva, Switzerland: World Health Organization; Fig. 11.1. HPV infection and associ­
1999:1–22. 3. World Health Organization. WHO Office of Information. ated diseases.(Source: Merck Sharp &
WHO Features 1990;152:1–6. Dohme. Reproduced with permission)

reduce the risk of genital HPV infection, transmission There are more than 30 strains of HPV that can
to the unprotected perigenital skin can still occur. infect the mucosa and genital tract, and between 13 and
The interest in HPV immunology and vaccine devel-18 HPV strains have been associated with an increased
opment is not new. However, the practical obstacles carcinogenic risk (Munoz et al., 2003; Trottier and
involving the growth of papillomavirus in the labo­ratory
Franco, 2006).
and the oncogenic HPV proteins have been a ­hindrance According to the epidemiologic classification of
to the generation of live attenuated HPV vaccines. high-risk HPV types, 12 belong to the HPV species
The recent licensure of two prophylactic vaccines7 (HPV 18, 39, 45, 59, 68) and HPV species 9 (HPV 16,
against sexually transmitted HPV, developed with safe31, 33, 35, 52, 58, 67) (Munoz et al., 2003). However,
and effective recombinant DNA technology, has demon- strains that belong to the same species may differ bio-
strated that persistent HPV infection and more than 90%
logically, and Viscidi et al. (2004, 2005) recently dem-
of precancerous lesions associated with types 16 or 18
onstrated that natural infection with high-risk HPV 16,
among HPV-naive women can be effectively prevented. 18, and 31 is not associated with immune protection
This chapter begins with a brief introduction to the
from reinfection with homologous HPV strains or with
biology and life cycle of HPV, followed by a review genetically related types.
of current information regarding the newly licensed Evidence-based studies show that HPV infection
prophylactic vaccines, as well as future developmentswith oncogenic types and viral persistence are highly
in prophylactic and therapeutic strategies aimed at associated with cervical cancer and to a lesser extent
HPV-related diseases. with vulvar, anal, and penile cancer.
A recent meta-analysis released by the Pan American
Health Organization (2008) showed that the prevalence
11.2 HPV: An Overview of HPV 16 and HPV 18 among a cohort of Latin–
American women with invasive cervical cancer is
49.3% and 10%, respectively.
HPV belongs predominately to the genus alpha-­ HPV vaccines can offer protection against high-
papillomavirus, which can be further subdivided into risk HPV types responsible for approximately 70% of
species and then strains (de Villiers et al., 2004). cervical cancers. However, due to several reasons
11.4 Significance of HPV Proteins in the Generation of Prophylactic and Therapeutic HPV Vaccines 197

(such as economic, religious, logistic), HPV vaccine et al. (2007), heparan sulfate proteoglycan syndecan-3
introduction is a slow process. Therefore, for the pres- appears to be the initial cell surface attachment factor.
ent female population and particularly for those living It is currently believed that basal cell invasion occurs
in low-income countries, screening remains the pri- in a period of approximately 24 h, but viral gene
mary option for cervical cancer prevention (Bosch expression is only initiated 2–3 days thereafter.
et al., 2008). In the basal cells and their progeny, known as
­transit-amplifying cells, HPV DNA replication occurs
HPV vaccination is not a replacement for an effec- with minimal gene expression (early genes E1
tive screening program for cervical cancer, but and E2).
rather a complement to it. The expression of early viral proteins E6 and E7
delay cell-cycle arrest and differentiation, and support
the viral genome replication that occurs in the supra-
11.3 A Short Introduction basal epithelial layer cells (where some infected cells
to Papillomavirus Biology may persist for many years).

Papillomaviruses are nonenveloped DNA viruses (i.e., High-risk HPV E6 and E7 oncoproteins lack intrin-
the viral capsid (outer shell) lacks a lipid membrane). sic enzymatic activities, but interact with cellular
The HPV genome is a double-stranded circular DNA proteins that are known cellular tumor suppressors,
molecule that contains around 8,000 base pairs (bp), such as p53 and retinoblastoma tumor suppressor
and the virus genome is divided into three portions (pRB). Although p53 levels are unaffected by E6
(Munger and Howley, 2002; Munger et al., 2004): proteins of low-risk HPV, oncogenic HPV E6 pro-
tein induces the degradation of p53 (Streeck, 2002).
1. A region of approximately 4,000 bp that encodes
nonstructural early expressed (E) proteins primarily
involved in viral DNA transcription and replication In the differentiated keratinocyte, viral gene expres-
(E1, E2) and cell transformation (E5, E6, and E7) sion is upregulated and thousands of viral genomes are
2. A region containing around 3,000 bp that encodes generated. High levels of late capsid viral proteins (L1
the major late capsid protein (L1) and a minor and L2) and proteins responsible for HPV DNA replica-
capsid protein (L2) tion and encapsidation (E4) are expressed, with final
3. A noncoding region (around 1,000 bp) that regu- virus assembly occurring in the superficial squames.
lates viral DNA replication and gene expression Highly infectious virions are then shed into the
environment.
There is no E3 protein and the E4 protein is encoded
early but expressed late in infection, suggesting
that it may facilitate virus escape from infected Stanley et al. (2007) showed that the time interval
keratinocytes. from infection to viral release is approximately
3 weeks, which coincides with the complete cycle
11.3.1 HPV Life Cycle (see graphic of basal keratinocytes.
representation of HPV life cycle
in Fig. 11.2)
11.4 Significance of HPV Proteins
in the Generation of Prophylactic
HPV replication is restricted to the differentiated lay-
and Therapeutic HPV Vaccines
ers of the epidermis or mucosa (McMurray et al.,
2001; Munger et al., 2004). Viral penetration occurs
through microabrasions in the epithelium and HPV The major late capsid protein (L1) of HPV spontane-
receptors have been identified on the surface of basal ously assembles into virus-like particles (VLPs) when
cells (Evander et al., 1997). According to de Witte synthesized by recombinant expression vector systems
 198 11 Human Papillomavirus Vaccines

11

Fig. 11.2. HPV life cycle (see also text for further explanation). (Source: Frazer, 2004. Reproduced with permission from Macmillan)

(Zhou et al., 1991; Kirnbauer et al., 1992). Prophylactic 11.5 Natural History of HPV Antibodies
vaccines use these noninfectious but immunogenic
VLPs to generate neutralizing antibodies against HPV
It is well known that HPV infection clearance often
L1 protein (Wheeler, 2007).
occurs in immunocompetent individuals (Schiffman and
According to studies performed by Hagensee et al.
Kjaer, 2003), although the exact mechanisms involved
(1993), the minor viral capsid protein (L2) is not
remain uncertain. The regression, persistence, and pro-
required for assembly, but it is integrated into VLPs
gression of HPV-related lesions likely reflect the com-
when coexpressed together with L1. However, L2 pro-
bined action of nonspecific innate immunity and
tein is important for virus infectivity (Unckell et al.,
antigen-specific adaptive immune components.
1997) and it seems to play an essential role in viral
morphogenesis (Day et al., 1998). Furthermore, accord-
ing to some investigators the modification of current
prophylactic HPV vaccines by insertion of cross-reac- 11.5.1 Humoral Responses
tive L2-epitopes could be the basis for the production
of broad-spectrum vaccines (Gambhira et al., 2007; Since a bloodstream phase is not required in the life
Kondo et al., 2008). cycle of HPV, viral exposure to the systemic immune
Early expressed proteins (E6, E7), which are system is minimal. Consequently, host antibody levels
involved in uncontrolled proliferation and cellular following incident infection are very low and probably
transformation, have also been used as antigens for not sufficient to afford protection during the primary
therapeutic vaccination against HPV-related anogeni- event. However, de Gruijl et al. (1997) found increased
tal diseases (Klencke et al., 2002; Sheets et al., 2003; serum IgG antibody titers in patients with persistent
Davidson et al., 2003; Baldwin et al., 2003; Hallez HPV 16 infections and histologically confirmed high-
et al., 2004). grade lesions.
11.5 Natural History of HPV Antibodies 199

The main immunoglobulin present in the female that increased viral load and persistent HPV 16 infec-
genital tract is IgG, and these local neutralizing anti- tion may extend seropositivity duration.
bodies are the first line of defense against HPV infec- Bontkes et al. (1999) found that systemic IgG
tion. However, IgG antibodies are not produced locally, responses were more frequently detected in patients
and transudation or exudation from serum to the cervi- with persistent HPV 16 infection. However, in a study
cal mucus must occur before antigen-specific immune evaluating antibody responses following incident
components can exert their protective effects at the cer- HPV infection, Carter et al. (2000) reported that some
vical mucosa (Parr and Parr, 1997; Nardelli-Haefliger ­subjects with persistent HPV 16 infection failed to
et al., 2003; Kemp et al., 2008). In transudation, IgG is seroconvert.
transferred from the intravascular compartment into An epidemiologic analysis of mucosal immunoglob-
the genital tract through ultrafiltration, while exudation ulin IgA and IgG responses to oncogenic HPV capsids
involves the passage of fluid from damaged blood ves- has shown that IgA is associated with HPV infection,
sels (i.e., during intercourse) to the extravascular com- whereas IgG correlates with cervical squamous intra-
partment (Fig. 11.3). epithelial lesions (SIL) and invasive disease (Sasagawa
Most studies regarding antibody-mediated humoral et al., 2003).
immunity to naturally occurring HPV infection support Data evaluating the detection of HPV 16 antibody
the idea that minimal protection is exerted against HPV in HPV 16-associated cervical intraepithelial neopla-
persistence or related diseases. The delay in response sia (CIN) in Australian women reveal a more frequent
after infection suggests that HPV is able to efficiently seropositivity in women presenting HPV 16 DNA-
evade the host immune system (see Chap. 9). positive lesions than in women with no HPV DNA.
Ho et al. (2004) recently demonstrated that HPV However, Tabrizi et al. (2006) reported that in this
16-infected individuals elicited higher IgG and IgA selected patient population HPV 16 serology was a
antibodies titers than those infected with other HPV poor predictor of the presence of HPV 16-associated
strains. IgG seropositivity appeared in 56.7% of cases CIN 3.
within 8.3 months, and IgA appeared in 37% of sub- Mbulawa et al. (2008) recently demonstrated that
jects within 14 months after natural infection with serum and cervical HPV 16-neutralizing antibodies
HPV 16. Both IgG and IgA seroconversions lasted for correlated with HPV 16 infection, and Bierl et al.
approximately 36 months, and the same study showed (2005) suggested that cervical mucosal anti-HPV 16

Transudation Exudation
n

n
ne tio

ne tio
ix

Cervical
zo rma

zo rma

ix

Cervical
ix
ix

rv

rv
rv
rv

ce

mucus
ce

mucus
ce
ce

sfo

sfo
do

do
to

to
an

an
Ec

En

Ec

En
Tr

Tr

Intravascular Intravascular
compartment compartment

Normal blood vessel Damaged blood vessel as a result of microtrauma

Fig. 11.3. Transudation and exudation of serum antibodies to the cervical mucus and cervical mucosa. (Source: Schwarz and Leo
(2008). Reproduced with permission from Elsevier)
 200 11 Human Papillomavirus Vaccines

IgA and IgG antibodies may protect against HPV The targets of the cell immune response include the
11 infection and cervical disease. early HPV oncoproteins E6 and E7 as well as HPV
Therefore, it is likely that the primary mechanism gene E2 (Stanley, 2006). However, CD4(+) T cell
of protection against persistent oncogenic HPV infec- responses to HPV 16 oncoproteins are lacking or
tion is the transudation of anti-HPV IgG antibodies severely impaired in women presenting with CIN
from the serum to the cervical mucosa (Nardelli- recurrence and invasive cervical cancer (de Jong et al.,
Haefliger et al., 2003). However, the exact influence of 2004; Sarkar et al., 2005).
seropositivity to oncogenic HPV 16, HPV 18, or HPV These results demonstrate that HPV infection can
31 after incident infection and protection to subse- interfere with local immune surveillance mechanisms
quent infections with homologous or genetically and, according to Sheu et al. (2007), these interferences
related HPV types must be further elucidated (Viscidi are probably related to cytokine immunomodulating
et al., 2004). actions and host genetic susceptibility (see also Chap. 9).

11.5.2 Cell Immune Responses 11.6 Prophylactic HPV Vaccination

Cellular immunity plays a critical role in the eradica-

tion of HPV infection and related diseases, as well as The use of recombinant DNA technology to generate
in the protection against persistent viral infection and VLPs in 1991 (Zhou et al., 1991), and the subsequent
HPV-associated disease progression (Scott et al., 1999; improvements in VLPs assembly (Kirnbauer et al., 1992)
Welters et al., 2003; Piketty and Kazatchkine, 2005; (Fig. 11.4), contributed to the development of HPV vac-
van Poelgeest et al., 2006). cines. VLPs are noninfectious because the entire HPV
T cells in the cervical epithelium belong mainly genome is lacking, but they are readily recognized by the
to the CD8 suppressor/cytotoxic subgroup and to a immune system and are able to elicit both humoral and
lesser extent to the CD4 helper/inductor subgroup. cellular immune responses when injected into human
Stanley et al. (1994) demonstrated that HPV-related hosts (Harro et al., 2001; Brown et al., 2001).
lesions that regress spontaneously usually exhibit a The mechanisms involved in vaccine protection
cellular infiltration composed essentially of CD4 and against HPV infection have not been completely eluci-
macrophages. dated. However, several studies have demonstrated that
In addition, other investigators have demonstrated high levels of HPV-specific neutralizing serum anti-
that T helper 1 (Th1) responses are important in HPV bodies are essential for effective protection (Christensen
control (Scott et al., 1999; de Jong et al., 2004). et al., 1996; Suzich et al., 1995; Day et al., 2007).
HPV vaccines generate neutralizing antibodies
against HPV capsid antigen L1 (Fig. 11.5a–c). Since
Th 1 effector/memory cells secrete interferon-g viral neutralization is genotype-specific, HPV VLP
(IFN-g), interleukin-2 (IL-2), and lymphotoxin, pro­ vaccines need to be formulated with the most prevalent
moting a milieu in which important cytotoxic effec­ genital HPV types with the aim of inducing a broadly
tors (such as macrophages, natural killer cells, and protective immunity against genital HPV disease.
cytotoxic CD8+ T lymphocytes) are activated. This There are two vaccines against HPV currently avail-
cell-mediated immune response is directed against able (Table 11.1). Gardasil (Merck & Co., Whitehouse
intracellular pathogens (i.e., virus) and cancer cells. Station, NJ), the first vaccine to be licensed by the U.S.
Food and Drug Administration (FDA, 2008), offers
protection against high-risk HPV types 16 and 18, as
Lee et al. (2004), in a recent study, found a reduc- well as low-risk HPV types 6 and 11. The oncogenic
tion of Th1 cytokine production by activated CD4(+) T types 16 and 18 account for an estimated 70% of all
cells in female patients presenting with HPV-associated cervical cancers worldwide, and the two low-risk types
high-grade SIL, suggesting the deficient Th1 function included in the vaccine are responsible for approxi-
may impair cytotoxic CD8(+) T cells responses. mately 90% of genital warts.
11.6 Prophylactic HPV Vaccination 201

Fig. 11.4. Assembly of HPV

virus-like particles (VLP).
The rosette-like surface struc-
tures (black arrow) are pen-
tamers, each consisting of
five molecules of L1. (Source:
Adapted from Kirnbauer et al.,
1992; Syrjanen and Syrjanen,
2000; Reproduced with per-
mission from Merck, Sharp
& Dohme)

Cervarix (GlaxoSmithKline, Rixensart, Belgium), amorphous aluminum hydroxyphosphate sulfate adju-

recently licensed in Europe, offers protection against vant. However, no direct comparative studies have
oncogenic HPV types 16 and 18, and Paavonen et al. been performed to date between VLPs adjuvanted
(2007) recently demonstrated that the bivalent vaccine with AS04 and the aluminum salts of Gardasil.
may also prevent HPV infection with heterologous Both Gardasil and Cervarix have been extensively
HPV strains 31/45/52 by cross-protection. tested in several randomized, double-blind, placebo-
controlled phase-III clinical trials in North America,
The main target group for prophylactic vaccines is Latin America, Europe, and the Asia-Pacific region
young girls before sexual onset, because the preva- (Harper et al., 2004; Villa et al., 2005; Koutsky and
lence of HPV infection is dramatically increased Harper, 2006). Gardasil trials involved more than
thereafter (Brown et al., 2005). 30,000 women aged 16–26 who were seronegative and
DNA-negative for the vaccine HPV types at the time of
enrollment, and Cervarix phase-III trials are underway
Recent investigators have demonstrated that the biva- with more than 39,000 individuals planned to
lent and quadrivalent vaccine induce an enhanced and participate.
long-lasting immune response (Giannini et al., 2006; Results from the clinical trials published thus far have
Olsson et al., 2007). shown that prophylactic vaccines are safe and highly
Furthermore, Giannini et al. (2006) showed that immunogenic (Future II Study Group, 2007; Villa, 2007;
the adjuvant used in Cervarix (GSK AS04), a mixture Paavonen et al., 2007; Rambout et al., 2007).
of aluminum hydroxide and monophosphoryl lipid Gardasil showed sustained efficacy over 5 years
A, induced higher antibody responses than Merck’s (Villa et al., 2006) and it has reduced the combined

Fig. 11.5. (a) Model of papillomavirus capsid. The L1 pentamer is represented (gray arrow) and one molecule of L2 (not repre-
sented) fits into the central dimple of each pentamer ( yellow arrow). (b) Papillomavirus particles with full (i.e., containing DNA)
and empty particles represented. (c) HPV 16 L1 virus-like particles. (Source: Stanley et al., (2006). Reproduced with permission
from Elsevier)
 202 11 Human Papillomavirus Vaccines

Table 11.1 Current HPV vaccines

11
Quadrivalent vaccine Bivalent vaccine

Trade name (manufacturer) Gardasil® (Merck) Cervarix® (GlaxoSmithKline)

VLPs of genotypes 6, 11, 16, 18 16, 18
Composition 20 mg HPV 6, 40 mg HPV 11, 40 mg HPV 16, 20 mg HPV 16, 20 mg HPV 18
20 mg HPV 18
Adjuvant Proprietary aluminum hydroxyphosphate Proprietary aluminum hydroxide (500
sulfate (225ug) (Merck aluminum mg) plus 50 mg 3-deacylated monophos-
adjuvant) phoryl lipid A (GSK AS04 adjuvant)
Dosage Three 0.5-ml doses at 0, 2, 6 months Three 0.5-ml doses at 0, 1, 6 months
Administration route IM injections in the upper arm or thigh IM injections in the upper arm
Recommended 11–12 year-old girls (FDA ) 3
10–25-year-old female subjects
Licensed FDA – girls/women between ages 9 and 26 European Commission – girls/women
between the age of 10 and 25
Safety/immunogenicity bridging Girls and boys 9–15 years Girls 10–14 years
trialsa
Boys 10–18 years

Women 26–55 years

Cross-protection HPV 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) HPV 45 (88%)
(Brown et al., 2007)
HPV 31 (54.5%) (Harper et al., 2006)

HPV 33 and 52 (Paavonen et al., 2007)

Cost b
(United States) U.S. $360 (three-dose (United Kingdom) £240 (three-dose
regimen) regimen)
Current duration of protection 5 years 6.4 years (Schwarz and Leo, 2008)

IM intramuscular
a
Gardasil and Cervarix are not recommended for pregnant women (pregnancy category, B2 classification), although no greater
risk of spontaneous pregnancy or fetal abnormality has been observed
b
2008-based costs

incidence of HPV 6-, 11-, 16-, and 18-associated per- showed that these cells are important for the long-term
sistent infection or disease (CIN or adenocarcinoma in efficacy of vaccine-induced protection.
situ (AIS)) by 96% (Ault, 2007; Future II Study Group, Phase-II and phase-III clinical trial results have
2007). The vaccine also prevented HPV 6-, 11-, 16-, or shown that Cervarix-induced L1 VLP-specific antibody
18-related external genital lesions by 100% (Villa levels can be sustained for up to 6.4 years (Schwarz and
et al., 2006; Perez et al., 2008) (Table 11.2). Leo, 2008), with additional cross-protection against
In addition, HPV prophylactic vaccination with HPV 45, 31, and 52 (Gall and Teixeira, 2007; Paavonen
quadrivalent vaccine resulted in 100% efficacy against et al., 2007). In addition, interim phase-III results showed
HPV 16- and 18-related high-grade vulvar/vaginal vaccine efficacy in preventing 90.4% of CIN2+ lesions
neoplasias (VIN 2+/VaIN 2+) (Joura et al., 2007). and 80% efficacy against persistent infections associ-
Giannini et al. (2006) demonstrated that the biva- ated with HPV 16 and 18 (Paavonen et al., 2007).
lent vaccine induced high frequencies of HPV L1 The prophylactic HPV vaccines may also reduce
VLP-specific memory B cells, and Stanley et al. (2006) the incidence of other HPV-related anogenital
11.6 Prophylactic HPV Vaccination 203

malignant diseases, such as anal and penile cancer Table 11.2 Key results from phase-III trials of HPV vaccines
(Hampl et al., 2006; Prowse et al., 2008). Current esti- (Source: Bosch et al. (2008). Reproduced with permission from
Macmillan)
mates of HPV-associated cancers in the United States
showed that there were more than 3,000 HPV-
Vaccine name Gardasil® Cervarix®
associated anal cancers per year during the period
1998–2003 (Watson et al., 2008). In addition, Joseph Time of follow-up 36 months 15 months
et al. (2008) reported that the incidence rates of this (advanced) (interim)
disease increased 2.6% per year and women were more HPV types included 6, 11, 16, 18 16, 18
affected than men. Watson et al. (2008) also showed Efficacy HPV16 or 18 Yes Yes
that penile cancer is relatively rare in the United States, CIN 2+
with approximately 800 men affected each year, but
Efficacy HPV16 Yes Yes
the incidence of the disease can be as high as 17% of CIN 2+
all male ­neoplasias in some low-resource countries.
Efficacy HPV18 Yes Not yet provena
Moreover, in a recent study, Daling et al. (2005) CIN 2+
reported a strong association between HPV DNA and
Efficacy HPV16 or 18 Yes Yes
penile cancer development, particularly with the high-
CIN 2
risk HPV 16 strain.
Current HPV vaccines could also prevent HPV- Efficacy HPV16 or 18 Yes Not yet provena
CIN 3
associated benign and malignant neoplasms of the oral
cavity and aerodigestive tracts. Low-risk HPV types Therapeutic efficacy None None
6 and 11 are almost always responsible for the devel- Efficacy on VIN 2/3 Yes Not yet reported
opment of juvenile laryngeal papillomas and recurrent Efficacy on VaIN 2/3 Yes Not yet reported
respiratory papillomas (RRP) in adults. The former
Efficacy on genital Yes Not in target
typically develops between birth and age 7 in children warts
born to mothers with HPV-related genital lesions,
Safety at 6-year Safeb Safec
while the adult-onset disease most likely occurs as a follow-up
result of sexual transmission. Although both juvenile
Tolerability Acceptable Acceptable
and adult RRP are rare (arising in perhaps 0.1–0.2% of
exposed individuals), frequent surgeries are required Cross-protection 6 months 12 months
to control the disease which imposes a significant bur- (persistent HPV
infection)
den on patients. Moreover, infected cells can also
migrate down the airway causing tracheal, bronchial, Cross-protection Reported Not yet reported
(lesions)
and rarely pulmonary lesions.
Recently released data that evaluated HPV- Duration of 5–6 years 6.4 years
protectiond
associated cancers in the United States have shown
that nearly 5,700 men and about 1,700 women develop Immunogenicity in Yes Yes
cancers of the oral cavity and oropharynx per year preadolescents
(Watson et al., 2008). In addition, Ryerson et al. Immunogenicity in Yes Yes
(2008) reported that the incidence rates for tonsil can- older women
cers and neoplasia of the tongue base increased 3% Immune memory at Yes Not yet reported
per year during the period 1998–2003, with a higher 6 years
predilection for men. There is evidence to support a CIN cervical intraepithelial neoplasia; HPV human papilloma-
sexual transmission of HPV infection to the oral cav- virus; VIN vulvar intraepithelial neoplasia; VaIN vaginal intra-
ity (Frisch et al., 1999; Hemminki et al., 2000) and, in epithelial neoplasia
a systematic review of HPV types found in head and
a
Proven in combined analysis of phase-II/III trials
b
In postlicencing evaluation (http://www.who.int/vaccine_
neck squamous cell carcinomas, Kreimer et al. (2005) safety/en/)
reported that HPV 16 was associated with oropharyn- c
In clinical trials
geal carcinomas in more than 80% of cases. d
Corresponds to duration of trials in 2007/2008
 204 11 Human Papillomavirus Vaccines

11.6.1 Gardasil® 11.6.1.4 Side Effects

11
Injection site reactions such as pain (83.9%), swell-
11.6.1.1 Who Should Receive Gardasil?
ing (25.4%), and erythema (24.6%)
Low fever (13%)
Gardasil was approved by the U.S. Food and Drug
Nausea (6.7%)
Administration (FDA) and the European Medicines
Nasopharyngitis (6.4%)
Agency (EMEA), and is currently licensed for use
Arthralgia, myalgia
among female subjects aged 9–26 years.
Asthenia, malaise
The quadrivalent vaccine is currently recommended
Anaphylaxis (2.6 cases per 100,000 doses occurred
for 11–12-year-old girls, although HPV vaccination
in the Australian school-based program, according
can begin at the age of 9. It is also recommended for
to Brotherton et al., 2008)
13–26-year-old girls/women who have not yet received
or completed the three-dose vaccination regimen
(Centers for Disease Control and Prevention-CDC).
11.6.1.5 Cost
In a recent analysis evaluating the epidemiological
and economic impact of the quadrivalent HPV vaccine
On the basis of 2008 prices, in the U.S. market, the
for preventing HPV-related diseases, Dasbach et al.
cost of Gardasil per single dose is U.S. $120 (or U.S.
(2008) reported that vaccination at 12 years of age
$360 for a typical three-dose regimen), and in Europe
combined with a 12- to 24-year-old catch-up strategy
the average price is €360 for the three doses of the
was cost-effective.
vaccine.

According to Luna and Saah (2007), the efficacy of

Gardasil in HPV-naive women between the ages of
27 and 45 years is similar to that in younger 11.6.2 Cervarix“
women.
Cervarix was licensed in Australia and Europe, and is
currently awaiting U.S. FDA approval.
11.6.1.2 Indications

The quadrivalent vaccine is currently indicated for the 11.6.2.1 Who Should Receive Cervarix?
prevention of incident and persistent HPV infections,
external genital warts (condyloma acuminata), high- The EMEA has licensed Cervarix for girls and women
grade cervical dysplasia (precancerous cervical between the age of 10 and 25 years, and in Australia it
lesions), invasive cervical cancer, and high-grade vul- is licensed for use among female individuals aged
var and vaginal dysplastic lesions (precancerous vul- 10–45 years (Skinner et al., 2008).
var and vaginal lesions) that are caused by HPV 6, 11,
16, or 18. Schwarz and Dubin (2007) recently demonstrated
that the bivalent vaccine is safe and effective in
women up to the age of 55 years.
11.6.1.3 How to Administer

Gardasil is administered as three separate 0.5-ml intra- 11.6.2.2 Indications

muscular injections in the upper arm or thigh over a
6-month period. The initial dose is given anytime The bivalent vaccine is currently indicated for the pre-
between the ages of 9 and 26 years; the second and vention of incident and persistent infections, high-grade
third dose should be given 2 and 6 months, respec- cervical dysplasia (precancerous CIN 2 and 3) and inva-
tively, after the first injection. sive cervical cancer caused by HPV types 16 and 18.
11.7 HPV Vaccination: Issues to Be Addressed 205

Protection against persistent infections with HPV phase-IV studies using cervical carcinoma as end-
strains 45 and 31 (Harper et al., 2006; Paavonen et al., point are needed to demonstrate effective protection
2007) may broaden current indications. against the disease.
Population-based studies in Nordic countries are in
progress to evaluate the efficacy of HPV vaccination
11.6.2.3 How to Administer with regard to carcinoma in situ (Lehtinen et al., 2006a)
and invasive cervical cancer (Lehtinen et al., 2006b),
Cervarix is administered as three separate 0.5-ml intra- and definitive results are expected by the years
muscular injections in the upper arm over a 6-month 2015–2020.
period. The initial dose is given anytime between the
ages of 10 and 25 years, and the second and third dose Villa et al. (2006) reported that a booster (fourth)
should be given 1 and 6 months, respectively, after the dose of Gardasil at 5 years leads to a rapid increase
first injection. in antibody levels, consistent with the presence of
immune memory.

11.6.2.4 Side Effects

11.7.2 HPV Prophylactic Vaccine
Headache
Cross-Protection
Myalgia
Mild soreness, hyperemia, and swelling around the
injection site Current prophylactic vaccines only protect against
Fatigue HPV types targeted by the quadrivalent and bivalent
Gastrointestinal symptoms vaccine (HPV 6, 11, 16, 18 and HPV 16, 18, respec-
Skin rash and itching tively). Individuals can still be infected by other low-
Low fever (occasionally) and high-risk types and secondary (screening) cancer
prevention should continue even in vaccinated
women.
11.6.2.5 Cost There are conflicting results regarding cross-­
protection from naturally occurring HPV infection
On the basis of 2008 prices, in the UK market, the cost (Viscidi et al., 2004); however, recent studies have
of Cervarix per single dose is approximately £80 (or shown that HPV vaccination is likely to induce neu-
£240 for a typical three-dose regimen). tralizing antibodies across HPV species (Slupetzky
et al., 2007; Gambhira et al., 2006).
Both HPV vaccines can be administered simulta- Preliminary data reported by Brown (2007) showed
neously with other vaccines routinely given to that Gardasil provided cross-protection against ten
individuals within this age-group, such as hepatitis HPV types (i.e., 31, 33, 35, 39, 45, 51, 52, 56, 58, and
B, quadrivalent meningococcal vaccine, and DTaP 59) associated with CIN2+ or adenocarcinoma in situ.
(Markowitz et al., 2007). Cross-protection has also been demonstrated against
persistent infections with HPV 45, 31, 33, and 52
­following Cervarix vaccination, with vaccine efficacy
11.7 HPV Vaccination: Issues against these types ranging from 31.6 to 59.9% at
to Be Addressed 6 months (Paavonen et al., 2007).

11.7.1 Duration of Protection

11.7.3 Vaccination of HPV-Infected
The duration of clinical trials that have evaluated the Individuals
efficacy of current vaccines against HPV infection and
SIL is approximately 6 years. Therefore, given the pro- Hildesheim et al. (2007) recently showed that the admin-
tracted natural history of HPV-related cervical cancer, istration of the prophylactic bivalent HPV vaccine to
 206 11 Human Papillomavirus Vaccines

women already infected with HPV 16 and 18 failed to

11 improve viral clearance. Therefore, bivalent HPV vac-
VLP vaccines are relatively expensive, and it is
predicted that vaccine cost will be one of the great-
cine immunization has not been recommended in these
est barriers to the introduction of HPV immuniza-
subjects.
tion programs in developing countries (Saxenian
However, the Future II Study Group (2007) recom-
and Hecht, 2006).
mended HPV immunization with the quadrivalent vac-
cine for women already infected with 1–3 vaccine-related
strains. The rationale is that the vaccine would still be
A recent economic report evaluating HPV vaccina-
effective against the remaining strain(s).
tion in Latin American countries has shown that, based
on current vaccine cost, cervical cancer screening was
Prevaccination HPV DNA testing is not necessary more cost-effective than vaccination as the main pre-
and is not recommended before vaccinating sexu- ventive measure against the disease (Pan American
ally active women. Health Organization, 2008).
In another recent analysis evaluating health and
economic outcomes of HPV 16 and 18 vaccination for
11.7.4 HPV Vaccines in Developing countries with a low GDP, Goldie, et al. (2008)
Countries reported that, to become cost-effective and affordable,
each HPV vaccine dose should cost around U.S. $2.
Techakehakij and Feldman (2008) recently per-
The strategy of broad dissemination of HPV vaccines
formed a systematic review of the literature regarding
has the potential to reduce the burden of HPV-related
cost-effectiveness of HPV vaccination programs com-
diseases on individuals and subsequently decrease
pared with Pap smear screening. Using guidelines of
government-related health costs. The extent of the
the World Health Organization to determine whether
benefit of a specific population will be determined by
nation-wide application of the HPV vaccine would be
the incidence rates of cervical cancer attributable to
cost-effective, they concluded that in only 46 high-
HPV 16 and 18, as well as the vaccine efficacy and
income countries (i.e., with a per capita GDP higher
coverage. Cervical cancer is a leading cause of can-
than U.S. $8,505 in 2004) would an HPV vaccination
cer among young women as well as a leading cause
program be cost-effective.
of cancer-related deaths in poor countries. Recent
It is expected that HPV vaccines could receive
data from the World Health Organization (WHO,
­subsidies from different public and private sectors,
2006) reported that approximately 80% of the
such as GAVI Alliance (Gavialliance), World Health
250,000 cervical cancer deaths in 2005 occurred in
Organization (WHO), UNICEF and others in a joint
poor-resource countries. Since this burden is pre-
effort to bring HPV immunization to where it is most
dicted to increase in the coming years (Agosti and
needed.
Goldie, 2007), the gains that can be obtained with
even a partially effective HPV vaccine are likely to
be substantial.
It has been reported that both HPV vaccine manu-
However, particularly in developing countries, the
facturers (Sanofi Pasteur MSD and Glaxo Smith
cost of the HPV vaccine and the cost-effectiveness of
Kline) have already submitted an application to
preventive vaccination relative to other established
seek WHO prequalification, an important step
programs directed to the health care of female adoles-
toward providing global access to vaccines (medi-
cents (the main vaccine target group) will greatly influ-
cal news today 2008b; The Henry J. Kaiser Family
ence government policy recommendations for HPV
Foundation, 2007a).
immunization.
11.8 Prophylactic HPV Vaccines in Men 207

11.7.5 Condoms vs. HPV Prophylactic effective in reducing HPV-related lesions in the vulva,
Vaccines suggesting that penile lesions could also be prevented
because of epithelial similarities.
Despite the high efficacy of current vaccines, vaccina- A recent phase-III study that evaluated the efficacy
tion does not offer 100% protection against HPV infec- of the quadrivalent vaccine in preventing HPV-
tion because HPV types not included in the formulation related lesions in a large group of sexually active
of Gardasil and Cervarix can also infect the anogenital young men (3,400 heterosexuals and 600 men who
region of both genders. Consistent condom use may have sex with men (MSM)), aged 16–26 and naïve
offer some additional protection, although variable, to all four HPV vaccine types, showed that Gardasil
against other low- and high-risk HPV types. In addi- was 89.4% effective in preventing external anogeni-
tion, condom use can protect against other common tal warts (Giuliano and Palefsky, 2008). Moreover,
sexually transmitted infections. HPV-related persistent infections were reduced in
85.6% of the cases, with higher vaccine efficacy
observed against persistent infection with HPV types
18 (96%) and 11 (93.4%) (Palefsky and Giuliano,
11.8 Prophylactic HPV Vaccines in Men 2008). HPV DNA detection was also decreased in
almost 45% of the vaccinated individuals.
Moreover, according to the investigators, the
Genital HPV infection is a sexually transmitted ­disease quadrivalent vaccine is safe to use in men with
and it is predictable that male immunization may help only minor injection site reactions reported (see
prevent HPV transmission and subsequently reduce the also Sect.3.11 in Chap. 3).
burden of HPV infection and HPV-related diseases in
women. Anal HPV infection, anal intraepithelial neoplasia
Studies show that HPV-infected men can transmit (AIN), and anal cancer are highly prevalent in MSM
HPV infection to women, contributing to the develop- and in immunosuppressed patients, especially those
ment of cervical premalignant lesions and cervical with HIV (see also Chap. 7). Available data have shown
cancer (Agarwal et al., 1993; Bosch et al., 1996). that HPV infection with oncogenic type HPV 16 is
According to Bosch et al. (1996), men with a his- closely involved in the development of AIN and anal
tory of multiple sexual partners are a known risk factor squamous cell carcinoma (Varnai et al., 2006; Kagawa
for cervical neoplasia, increasing by almost sevenfold et al., 2006), but a recent study showed that the quadri-
the risk of the disease in the female partner (Castellsague valent HPV vaccine was 100% effective in preventing
et al., 2002). AIN development in young male subjects (Giuliano
Although HPV-infected men appear to have a lower and Palefsky, 2008).
antibody prevalence of HPV types 6, 11, 16, and 18 com­ Recent studies also reported a strong association
pared with women, recent studies evaluating immune between HPV DNA and penile cancer development,
responses using the HPV quadrivalent vaccine in male particularly with the high-risk HPV 16 strain (Daling
and female adolescents showed high antibody responses et al., 2005; Pascual et al., 2007). However, in the study
in both genders (Block et al., 2006; Reisinger et al., that evaluated the efficacy of the quadrivalent HPV
2007). Seroprevalence in men peaks at an older age vaccine in men, there were no penile intraepithelial
(around 30–39 years) when compared with women neoplasia (PIN) cases in the vaccinated group, but
(20–29 years), and this biological difference might three PIN cases were observed in the placebo group.
reflect a lower viral load, transient infections, or even Penile cancer was not reported in both groups (Giuliano
decreased immunological responses in men compared and Palefsky, 2008).
with women (Partridge and Koutsky, 2006). Additional data from the ongoing Gardasil study
HPV-related lesions in men often present clinically in men will become available in the coming months
as anogenital warts, and the development of these and trials to evaluate Cervarix safety and immu­
lesions has been associated with HPV types 6 and 11 nogenicity in young males are also in progress
(Greer et al., 1995). The quadrivalent vaccine proved (ClinicalTrials.gov).
 208 11 Human Papillomavirus Vaccines

11.8.1 Nongenital HPV Infections in Men by about 4%, yet the preventive effect per vaccination
11 was reduced.
Current HPV vaccines could also prevent HPV-related Currently, only UK, Mexico, Australia, New Zealand
oropharyngeal infection and disease in men. and South Korea have licensed HPV vaccination for
Several studies suggest that oral HPV infection is both genders, where boys aged 9–15 years are able to
sexually acquired (Schwartz et al., 1998; D’Souza receive the quadrivalent vaccine (May, 2007).
et al., 2007) and HPV is considered an independent Although the European Union marketing authoriza-
risk factor for oral cancer. Low-risk HPV types 6 and tion for Gardasil has not excluded its use in male sub-
11 are the viral genotypes most frequently associated jects, at present only Austria opted to include boys aged
with benign squamous cell lesions of the oral mucosa 9–15 years into a government-based immunization pro-
and the aerodigestive tract, while high-risk HPV 16 gram. The main goal of this policy is prevention of
has been detected in up to 90% of HPV-related cases of infection with HPV 6 or 11 and, as a result, reduction of
head and neck squamous cell carcinomas (HNSCCs) the rate of genital warts in young male individuals.
(Gillison et al., 2000; Weinberger et al., 2006).
Moreover, Syrjanen (2005) reported that tonsillar car-
cinoma was associated with the highest nongenital
virus prevalence. 11.9 Therapeutic HPV Vaccination and
According to some investigators, there is a good Future Vaccine Developments
level of evidence in these findings to argue in favor of
the universal HPV vaccination of both boys and girls
(Laurence, 2008). The quadrivalent HPV vaccine can Antibody-generating prophylactic vaccines are not
be expected to significantly decrease HPV infection effective against preexisting and persistent HPV
and related diseases of the head and neck region and infections (Future II Study Group, 2007; Hildesheim
respiratory tract. et al., 2007); however, HPV oncogenic proteins E6
and E7 are promising targets for therapeutic strat­
egies aimed at these oncogenes, because they are the
only proteins maintained and expressed in HPV-
11.8.2 Cost-Effectiveness of Male
associated cancers (Bosch et al., 2002; Wentzensen
Vaccination et al., 2004). Therapeutic vaccines that elicit a
cytolytic T-cell immune response to premalignant and
In a recent analysis using a dynamic model to evaluate malignant cells expressing HPV E6 and/or E7 have
cost-effectiveness of the quadrivalent HPV vaccine in shown some degree of clinical efficacy against estab-
the Mexican population, Insinga et al. (2007) showed lished HPV-associated malignancies (Lin et al., 2007;
that vaccination of 12-year-old girls and boys with a Hung et al., 2008; Huh and Roden, 2008).
12 to 24 year-old “catch-up” program was the most Cellular immune responses directed against early
effective strategy to reduce HPV infection and related expressed HPV 16 E7 protein have been associated
diseases in female subjects. with CIN 2 and CIN 3 regression and clearance of
However, Kim et al. (2007), in another similar cost- HPV infection (Kadish et al., 2002), suggesting the
effectiveness analysis showed little advantage of therapeutic potential of HPV E7-targeted vaccines in
including boys in a preadolescent HPV vaccination CIN patients (Hallez et al., 2004).
program modeled in a low-resource setting. Viral vector vaccines can induce viral and recombi-
A Nordic modeling study to evaluate the optimal nant protein expression, promoting strong cellular host
vaccination strategies in the Swedish population has responses. A phase-II trial using a modified vaccinia
estimated the prevention of 5.8 million cumulative HPV virus Ankara (MVA) expressing modified HPV 16 E6
16 infections by the year 2055 with the vaccination of and E7 proteins and coexpressed with T-cell cytokine
female subjects starting at age 12 in 2008 (Ryding IL-2 reported regression of CIN 2+ in 47.6% of vacci-
et al., 2008). Moreover, the authors showed that vacci- nated female subjects after 6 months (Transgene,
nation of male subjects increased the protective effect 2006).
References 209

Although current HPV vaccines are comprised of Bontkes HJ, de Gruijl TD, Walboomers JM, Schiller JT, Dillner
L1 epitopes, Kondo et al. (2008) recently demonstrated J, Helmerhorst TJ, Verheijen RH, Scheper RJ, Meijer CJ
(1999) Immune responses against human papillomavirus
that vaccine modification by insertion of cross-reactive (HPV) type 16 virus-like particles in a cohort study of
L2 epitopes elicited antibodies that cross-neutralized women with cervical intraepithelial neoplasia II. Systemic
against related HPV strains. This could potentially but not local IgA responses correlate with clearance of HPV-
reduce the number of VLP types required for vaccine 16. J Gen Virol 80(Pt 2): 409–417
Bosch FX, Castellsague X, de Sanjose S (2008) HPV and cervi-
protection, suggesting it is a viable strategy for the cal cancer: Screening or vaccination? Br J Cancer 98: 15–21
generation of multivalent vaccines (Slupetzky et al., Bosch FX, Castellsague X, Munoz N, de Sanjose S, Ghaffari
2007; Xu et al., 2007). AM, Gonzalez LC, Gili M, Izarzugaza I, Viladiu P, Navarro
In addition, new strategies aimed at improving C, Vergara A, Ascunce N, Guerrero E, Shah KV (1996) Male
sexual behavior and human papillomavirus DNA: Key risk
HPV vaccine potency are being developed. The fusion factors for cervical cancer in Spain. J Natl Cancer Inst 88:
of HPV 16 recombinant proteins E6 and E7 with heat 1060–1067
shock protein (Hsp) 70 of Mycobacterium tuberculo- Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV (2002)
sis in an animal model study has elicited protection The causal relation between human papillomavirus and cer-
vical cancer. J Clin Pathol 55: 244–265
against challenge with transformed tumor cells (Qian Brotherton JM, Gold MS, Kemp AS, McIntyre PB, Burgess MA,
et al., 2006). In another research study, Xu et al. (2008) Campbell-Lloyd S (2008) Anaphylaxis following quadriva-
showed that the fusion of effec­tive adjuvant protein lent human papillomavirus vaccination. CMAJ 179: 525–533
into chimeric VLPs induced increased titers of HPV Brown D (2007) HPV type 6/11/16/18 vaccine: First analysis of
cross-protection against persistent infection, cervical intra-
16-specific long-lasting neutralizing antibodies. epithelial neoplasia (CIN), and adenocarcinoma in situ
(AIS) caused by oncogenic HPV types in addition to 16/18
In: 47th Interscience Conference on Antimicrobial Agents
and Chemotherapy, Chicago
References Brown DR, Bryan JT, Schroeder JM, Robinson TS, Fife KH,
Wheeler CM, Barr E, Smith PR, Chiacchierini L, DiCello A,
Jansen KU (2001) Neutralization of human papillomavirus
Agarwal SS, Sehgal A, Sardana S, Kumar A, Luthra UK (1993) type 11 (HPV-11) by serum from women vaccinated with
Role of male behavior in cervical carcinogenesis among yeast-derived HPV-11 L1 virus-like particles: correlation
women with one lifetime sexual partner. Cancer 72: with competitive radioimmunoassay titer. J Infect Dis 184:
1666–1669 1183–1186
Agosti JM, Goldie SJ (2007) Introducing HPV vaccine in devel- Brown DR, Shew ML, Qadadri B, Neptune N, Vargas M, Tu W,
oping countries – key challenges and issues. N Engl J Med Juliar BE, Breen TE, Fortenberry JD (2005) A longitudinal
356: 1908–1910 study of genital human papillomavirus infection in a cohort
Ault KA (2007) Effect of prophylactic human papillomavirus of closely followed adolescent women. J Infect Dis 191:
L1 virus-like-particle vaccine on risk of cervical intraepithe- 182–192
lial neoplasia grade 2, grade 3, and adenocarcinoma in situ: Carter JJ, Koutsky LA, Hughes JP, Lee SK, Kuypers J, Kiviat N,
A combined analysis of four randomised clinical trials. Galloway DA (2000) Comparison of human papillomavirus
Lancet 369: 1861–1868 types 16, 18, and 6 capsid antibody responses following
Baldwin PJ, van der Burg SH, Boswell CM, Offringa R, Hickling incident infection. J Infect Dis 181: 1911–1919
JK, Dobson J, Roberts JS, Latimer JA, Moseley RP, Coleman Castellsague X, Bosch FX, Munoz N, Meijer CJ, Shah KV, de
N, Stanley MA, Sterling JC (2003) Vaccinia-expressed Sanjose S, Eluf-Neto J, Ngelangel CA, Chichareon S, Smith
human papillomavirus 16 and 18 e6 and e7 as a therapeutic JS, Herrero R, Moreno V, Franceschi S (2002) Male circum-
vaccination for vulval and vaginal intraepithelial neoplasia. cision, penile human papillomavirus infection, and cervical
Clin Cancer Res 9: 5205–5213 cancer in female partners. N Engl J Med 346: 1105–1112
Bierl C, Karem K, Poon AC, Swan D, Tortolero-Luna G, Follen CDC HPV Vaccine Information for Clinicians. Centers for
M, Wideroff L, Unger ER, Reeves WC (2005) Correlates of Disease Control and Prevention, Atlanta
cervical mucosal antibodies to human papillomavirus 16: Christensen ND, Reed CA, Cladel NM, Han R, Kreider JW
Results from a case control study. Gynecol Oncol 99: (1996) Immunization with virus like particles induces long-
S262–S268 term protection of rabbits against challenge with cottontail
Block SL, Nolan T, Sattler C, Barr E, Giacoletti KE, Marchant rabbit papillomavirus. J Virol 70: 960–965
CD, Castellsague X, Rusche SA, Lukac S, Bryan JT, ClinicalTrials.gov In. U.S. National Institutes of Health
Cavanaugh PF, Jr., Reisinger KS (2006) Comparison of the Daling JR, Madeleine MM, Johnson LG, Schwartz SM, Shera
immunogenicity and reactogenicity of a prophylactic qua- KA, Wurscher MA, Carter JJ, Porter PL, Galloway DA,
drivalent human papillomavirus (types 6, 11, 16, and 18) L1 McDougall JK, Krieger JN (2005) Penile cancer: Importance
virus-like particle vaccine in male and female adolescents of circumcision, human papillomavirus and smoking in in
and young adult women. Pediatrics 118: 2135–2145 situ and invasive disease. Int J Cancer 116: 606–616
 210 11 Human Papillomavirus Vaccines

Dasbach EJ, Insinga RP, Elbasha EH (2008) The epidemiologi- Gall S, Teixeira J (2007) Substantial impact on precancerous
11 cal and economic impact of a quadrivalent human papilloma- lesions and HPV infections through 5.5 years in women vac-
virus vaccine (6/11/16/18) in the UK. BJOG 115: 947–956 cinated with the HPV-16/18 L1 VLPAS04 candidate vac-
Davidson EJ, Boswell CM, Sehr P, Pawlita M, Tomlinson AE, cine. In: Proceedings of the AACR Annual Meeting Los
McVey RJ, Dobson J, Roberts JS, Hickling J, Kitchener HC, Angeles
Stern PL (2003) Immunological and clinical responses in Gambhira R, Gravitt PE, Bossis I, Stern PL, Viscidi RP, Roden
women with vulval intraepithelial neoplasia vaccinated with RB (2006) Vaccination of healthy volunteers with human
a vaccinia virus encoding human papillomavirus 16/18 papillomavirus type 16 L2E7E6 fusion protein induces
oncoproteins. Cancer Res 63: 6032–6041 serum antibody that neutralizes across papillomavirus spe-
Day PM, Roden RB, Lowy DR, Schiller JT (1998) The papilloma- cies. Cancer Res 66: 11120–11124
virus minor capsid protein, L2, induces localization of the Gambhira R, Karanam B, Jagu S, Roberts JN, Buck CB, Bossis
major capsid protein, L1, and the viral transcription/replication I, Alphs H, Culp T, Christensen ND, Roden RB (2007) A
protein, E2, to PML oncogenic domains. J Virol 72: 142–150 protective and broadly cross-neutralizing epitope of human
Day PM, Thompson CD, Buck CB, Pang YY, Lowy DR, Schiller papillomavirus. L2J Virol 81: 13927–13931
JT (2007) Neutralization of human papillomavirus with Gavialliance In. GAVI Alliance
monoclonal antibodies reveals different mechanisms of inhi- Giannini SL, Hanon E, Moris P, Van Mechelen M, Morel S,
bition. J Virol 81: 8784–8792 Dessy F, Fourneau MA, Colau B, Suzich J, Losonksy G,
de Gruijl TD, Bontkes HJ, Walboomers JM, Schiller JT, Stukart Martin MT, Dubin G, Wettendorff MA (2006) Enhanced
MJ, Groot BS, Chabaud MM, Remmink AJ, Verheijen RH, humoral and memory B cellular immunity using HPV16/18
Helmerhorst TJ, Meijer CJ, Scheper RJ (1997) Immuno­ L1 VLP vaccine formulated with the MPL/aluminium salt
globulin G responses against human papillomavirus type 16 combination (AS04) compared to aluminium salt only.
virus-like particles in a prospective nonintervention cohort Vaccine 24: 5937–5949
study of women with cervical intraepithelial neoplasia. J Natl Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH,
Cancer Inst 89: 630–638 Wu L, Zahurak ML, Daniel RW, Viglione M, Symer DE,
de Jong A, van Poelgeest MI, van der Hulst JM, Drijfhout JW, Shah KV, Sidransky D (2000) Evidence for a causal associa-
Fleuren GJ, Melief CJ, Kenter G, Offringa R, van der Burg tion between human papillomavirus and a subset of head and
SH (2004) Human papillomavirus type 16-positive cervical neck cancers. J Natl Cancer Inst 92: 709–720
cancer is associated with impaired CD4 + T-cell immunity Giuliano A, Palefsky J (2008) The efficacy of quadrivalent HPV
against early antigens E2 and E6. Cancer Res 64: 5449–5455 (types 6/11/16/18) vaccine in reducing the incidence of HPV
de Sanjose S, Diaz M, Castellsague X, Castellsague X, Clifford infection and HPV-related genital disease in young men In:
G, Bruni L, Munoz N, Bosch FX (2007) Worldwide preva- European Research Organization on Genital Infection and
lence and genotype distribution of cervical human papillo- Neoplasia – EUROGIN Nice, France
mavirus DNA in women with normal cytology: A Goldie SJ, O’Shea M, Campos NG, Diaz M, Sweet S, Kim SY
meta-analysis. Lancet Infect Dis 7: 453 – 459 (2008) Health and economic outcomes of HPV 16,18 vac-
de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen cination in 72 GAVI-eligible countries. Vaccine 26:
H (2004) Classification of papillomaviruses. Virology 324: 4080–4093
17–27 Greer CE, Wheeler CM, Ladner MB, Beutner K, Coyne MY,
de Witte L, Zoughlami Y, Aengeneyndt B, David G, van Kooyk Liang H, Langenberg A, Yen TS, Ralston R (1995) Human
Y, Gissmann L, Geijtenbeek TB (2007) Binding of human papillomavirus (HPV) type distribution and serological
papilloma virus L1 virus-like particles to dendritic cells is response to HPV type 6 virus-like particles in patients with
mediated through heparan sulfates and induces immune acti- genital warts. J Clin Microbiol 33: 2058–2063
vation. Immunobiology 212: 679–691 Hagensee ME, Yaegashi N, Galloway DA (1993) Self-assembly
D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch of human papillomavirus type 1 capsids by expression of the
WM, Westra WH, Gillison ML (2007) Case-control study of L1 protein alone or by coexpression of the L1 and L2 capsid
human papillomavirus and oropharyngeal cancer. N Engl J proteins. J Virol 67: 315–322
Med 356: 1944–1956 Hallez S, Simon P, Maudoux F, Doyen J, Noel JC, Beliard A,
Evander M, Frazer IH, Payne E, Qi YM, Hengst K, McMillan Capelle X, Buxant F, Fayt I, Lagrost AC, Hubert P, Gerday
NA (1997) Identification of the alpha6 integrin as a candi- C, Burny A, Boniver J, Foidart JM, Delvenne P, Jacobs N
date receptor for papillomaviruses. J Virol 71: 2449–2456 (2004) Phase I/II trial of immunogenicity of a human papil-
FDA, (2008) Gardasil – Product Approval Information. U.S. lomavirus (HPV) type 16 E7 protein-based vaccine in
Food and Drug Administration, Rockville women with oncogenic HPV-positive cervical intraepithelial
Frazer IH (2004) Prevention of cervical cancer through papillo- neoplasia. Cancer Immunol Immunother 53: 642–650
mavirus vaccination. Nat Rev Immunol 4: 46–54 Hampl M, Sarajuuri H, Wentzensen N, Bender HG, Kueppers V
Frisch M, Fenger C, van den Brule AJ, Sorensen P, Meijer CJ, (2006) Effect of human papillomavirus vaccines on vulvar,
Walboomers JM, Adami HO, Melbye M, Glimelius B (1999) vaginal, and anal intraepithelial lesions and vulvar cancer.
Variants of squamous cell carcinoma of the anal canal and Obstet Gynecol 108: 1361–1368
perianal skin and their relation to human papillomaviruses. Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D,
Cancer Res 59: 753–757 Schuind A, Zahaf T, Innis B, Naud P, De Carvalho NS,
Future II Study Group (2007b) Quadrivalent vaccine against Roteli-Martins CM, Teixeira J, Blatter MM, Korn AP,
human papillomavirus to prevent high-grade cervical lesions. Quint W, Dubin G (2004) Efficacy of a bivalent L1 virus-like
N Engl J Med 356: 1915–1927 ­particle vaccine in prevention of infection with human
References 211

p­ apillomavirus types 16 and 18 in young women: A ran- Kemp TJ, Hildesheim A, Falk RT, Schiller JT, Lowy DR,
domised controlled trial. Lancet 364: 1757–1765 Rodriguez AC, Pinto LA (2008) Evaluation of two types of
Harper DM, Franco EL, Wheeler CM, Moscicki AB, sponges used to collect cervical secretions and assessment
Romanowski B, Roteli-Martins CM, Jenkins D, Schuind A, of antibody extraction protocols for recovery of neutralizing
Costa Clemens SA, Dubin G (2006) Sustained efficacy up to anti-human papillomavirus type 16 antibodies. Clin Vaccine
4.5 years of a bivalent L1 virus-like particle vaccine against Immunol 15: 60–64
human papillomavirus types 16 and 18: Follow-up from a Kim JJ, Andres-Beck B, Goldie SJ (2007) The value of ­including
randomised control trial. Lancet 367: 1247–1255 boys in an HPV vaccination programme: A cost-­effectiveness
Harro CD, Pang YY, Roden RB, Hildesheim A, Wang Z, analysis in a low-resource setting. Br J Cancer 97:
Reynolds MJ, Mast TC, Robinson R, Murphy BR, Karron 1322–1328
RA, Dillner J, Schiller JT, Lowy DR (2001) Safety and Kirnbauer R, Booy F, Cheng N, Lowy DR, Schiller JT (1992)
immunogenicity trial in adult volunteers of a human papil- Papillomavirus L1 major capsid protein self-assembles into
lomavirus 16 L1 virus-like particle vaccine. J Natl Cancer virus-like particles that are highly immunogenic. Proc Natl
Inst 93: 284–292 Acad Sci U S A 89: 12180–12184
Hausen HZ (2008) Papillomaviruses to vaccination and beyond. Klencke B, Matijevic M, Urban RG, Lathey JL, Hedley ML,
Biochemistry (Mosc) 73: 498–503 Berry M, Thatcher J, Weinberg V, Wilson J, Darragh T, Jay
Hemminki K, Dong C, Frisch M (2000) Tonsillar and other N, Da Costa M, Palefsky JM (2002) Encapsulated plasmid
upper aerodigestive tract cancers among cervical cancer DNA treatment for human papillomavirus 16-associated
patients and their husbands. Eur J Cancer Prev 9: 433–437 anal dysplasia: A Phase I study of. ZYC101Clin Cancer Res
Hildesheim A, Herrero R, Wacholder S, Rodriguez AC, Solomon 8: 1028–1037
D, Bratti MC, Schiller JT, Gonzalez P, Dubin G, Porras C, Kondo K, Ochi H, Matsumoto T, Yoshikawa H, Kanda T (2008)
Jimenez SE, Lowy DR (2007) Effect of human papillomavi- Modification of human papillomavirus-like particle vaccine
rus 16/18 L1 viruslike particle vaccine among young women by insertion of the cross-reactive L2-epitopes. J Med Virol
with preexisting infection: A randomized trial. JAMA 298: 80: 841–846
743–753 Koutsky LA, Harper DM (2006) Chap. 13: Current findings
Ho GY, Studentsov YY, Bierman R, Burk RD (2004) Natural from prophylactic HPV vaccine trials. Vaccine 24(Suppl 3):
history of human papillomavirus type 16 virus-like particle S3/114–S3/121
antibodies in young women. Cancer Epidemiol Biomarkers Kreimer AR, Clifford GM, Boyle P, Franceschi S (2005) Human
Prev 13: 110–116 papillomavirus types in head and neck squamous cell carci-
Huh WK, Roden RB (2008) The future of vaccines for cervical nomas worldwide: a systematic review. Cancer Epidemiol
cancer. Gynecol Oncol 109: S48–S56 Biomarkers Prev 14: 467–475
Hung CF, Ma B, Monie A, Tsen SW, Wu TC (2008) Therapeutic Laurence J (2008) HPV-linked oral cancer: another argument for
human papillomavirus vaccines: Current clinical trials and universal HPV vaccination of boys and girls. AIDS Read 18:
future directions. Expert Opin Biol Ther 8: 421–439 345–346
Insinga RP, Dasbach EJ, Elbasha EH, Puig A, Reynales-Shigematsu Lee BN, Follen M, Shen DY, Malpica A, Adler-Storthz K, Shearer
LM (2007) Cost-effectiveness of quadrivalent human WT, Reuben JM (2004) Depressed type 1 cytokine synthesis
­papillomavirus (HPV) vaccination in Mexico: A transmission by superantigen-activated CD4 + T cells of women with
dynamic model-based evaluation. Vaccine 26: 128–139 human papillomavirus-related high-grade squamous intraep-
Joseph DA, Miller JW, Wu X, Chen VW, Morris CR, Goodman ithelial lesions. Clin Diagn Lab Immunol 11: 239–244
MT, Villalon-Gomez JM, Williams MA, Cress RD (2008) Lehtinen M, Apter D, Dubin G, Kosunen E, Isaksson R,
Understanding the burden of human papillomavirus-associ- Korpivaara EL, Kyha-Osterlund L, Lunnas T, Luostarinen T,
ated anal cancers in the US. Cancer 113: 2892–2900 Niemi L, Palmroth J, Petaja T, Rekonen S, Salmivesi S,
Joura EA, Leodolter S, Hernandez-Avila M, Wheeler CM, Perez Siitari-Mattila M, Svartsjo S, Tuomivaara L, Vilkki M,
G, Koutsky LA, Garland SM, Harper DM, Tang GW, Ferris Pukkala E, Paavonen J (2006a) Enrolment of 22,000 adoles-
DG, Steben M, Jones RW, Bryan J, Taddeo FJ, Bautista OM, cent women to cancer registry follow-up for long-term
Esser MT, Sings HL, Nelson M, Boslego JW, Sattler C, Barr human papillomavirus vaccine efficacy: guarding against
E, Paavonen J (2007) Efficacy of a quadrivalent prophylactic guessing. Int J STD AIDS 17: 517–521
human papillomavirus (types 6, 11, 16, and 18) L1 virus- Lehtinen M, Idanpaan-Heikkila I, Lunnas T, Palmroth J, Barr E,
like-particle vaccine against high-grade vulval and vaginal Cacciatore R, Isaksson R, Kekki M, Koskela P, Kosunen E,
lesions: A combined analysis of three randomised clinical Kuortti M, Lahti L, Liljamo T, Luostarinen T, Apter D,
trials. Lancet 369: 1693–1702 Pukkala E, Paavonen J (2006b) Population-based enrolment
Kadish AS, Timmins P, Wang Y, Ho GY, Burk RD, Ketz J, He W, of adolescents in a long-term follow-up trial of human papil-
Romney SL, Johnson A, Angeletti R, Abadi M (2002) lomavirus vaccine efficacy. Int J STD AIDS 17: 237–246
Regression of cervical intraepithelial neoplasia and loss of Lin YY, Alphs H, Hung CF, Roden RB, Wu TC (2007) Vaccines
human papillomavirus (HPV) infection is associated with against human papillomavirus. Front Biosci 12: 246–264
cell-mediated immune responses to an HPV type 16 E7 pep- Luna J, Saah A (2007) Safety, efficacy, and immunogenicity of
tide. Cancer Epidemiol Biomarkers Prev 11: 483–488 quadrivalent HPV vaccine (Gardasil) in women aged 24–45.In:
Kagawa R, Yamaguchi T, Furuta R (2006) Histological features 24th International Papillomavirus Congress, Beijing
of human papilloma virus 16 and its association with the Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H,
development and progression of anal squamous cell carci- Unger ER (2007) Quadrivalent human papillomavirus
noma. Surg Today 36: 885–891 ­vaccine: Recommendations of the Advisory Committee on
 212 11 Human Papillomavirus Vaccines

Immunization Practices (ACIP). MMWR Recomm Rep 56: Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer sta-
11 1–24 tistics, 2002. CA Cancer J Clin 55: 74–108
May J (2007) HPV vaccination – a paradigm shift in public Parr EL, Parr MB (1997) Immunoglobulin G is the main protec-
health. Aust Fam Physician 36: 106–111 tive antibody in mouse vaginal secretions after vaginal
Mbulawa ZZ, Williamson AL, Stewart D, Passmore JA, Denny immunization with attenuated herpes simplex virus type 2.
L, Allan B, Marais DJ (2008) Association of serum and J Virol 71: 8109–8115
mucosal neutralizing antibodies to human papillomavirus Partridge JM, Koutsky LA (2006) Genital human papillomavi-
type 16 (HPV-16) with HPV-16 infection and cervical dis- rus infection in men. Lancet Infect Dis 6: 21–31
ease. J Gen Virol 89: 910–914 Pascual A, Pariente M, Godinez JM, Sanchez-Prieto R, Atienzar
McMurray HR, Nguyen D, Westbrook TF, McAnce DJ (2001) M, Segura M, Poblet E (2007) High prevalence of human
Biology of human papillomaviruses. Int J Exp Pathol 82: papillomavirus 16 in penile carcinoma. Histol Histopathol
15–33 22: 177–183
MediLexicon International Ltd (2008) Gardasil® applies for Perez G, Lazcano-Ponce E, Hernandez-Avila M, Garcia PJ,
WHO certification to reinforce global access to the vaccine – Munoz N, Villa LL, Bryan J, Taddeo FJ, Lu S, Esser MT,
Approval would qualify Gardasil® for procurement by Vuocolo S, Sattler C, Barr E (2008) Safety, immunogenicity,
United. medicalnewstoday. and efficacy of quadrivalent human papillomavirus (types 6,
Munger K, Baldwin A, Edwards KM, Hayakawa H, Nguyen CL, 11, 16, 18) L1 virus-like-particle vaccine in Latin American
Owens M, Grace M, Huh K (2004) Mechanisms of women. Int J Cancer 122: 1311–1318
human papillomavirus-induced oncogenesis. J Virol 78: Piketty C, Kazatchkine MD (2005) Human papillomavirus-
11451–11460 related cervical and anal disease in HIV-infected individuals
Munger K, Howley PM (2002) Human papillomavirus immor- in the era of highly active antiretroviral therapy. Curr HIV/
talization and transformation functions. Virus Res 89: AIDS Rep 2: 140–145
213–228 Prowse DM, Ktori EN, Chandrasekaran D, Prapa A, Baithun S
Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, (2008) Human papillomavirus-associated increase in
Shah KV, Snijders PJ, Meijer CJ (2003) Epidemiologic clas- p16INK4A expression in penile lichen sclerosus and
sification of human papillomavirus types associated with squamous cell carcinoma. Br J Dermatol 158: 261–265
cervical cancer. N Engl J Med 348: 518–527 Qian X, Lu Y, Liu Q, Chen K, Zhao Q, Song J (2006) Prophy­
Nardelli-Haefliger D, Wirthner D, Schiller JT, Lowy DR, lactic, therapeutic and anti-metastatic effects of an HPV-
Hildesheim A, Ponci F, De Grandi P (2003) Specific anti- 16mE6Delta/mE7/TBhsp70Delta fusion protein vaccine in
body levels at the cervix during the menstrual cycle of an animal model. Immunol Lett 102: 191–201
women vaccinated with human papillomavirus 16 virus-like Rambout L, Hopkins L, Hutton B, Fergusson D (2007) Prophy­
particles. J Natl Cancer Inst 95: 1128–1137 lactic vaccination against human papillomavirus infection
Olsson SE, Villa LL, Costa RL, Petta CA, Andrade RP, Malm C, and disease in women: A systematic review of randomized
Iversen OE, Hoye J, Steinwall M, Riis-Johannessen G, controlled trials. CMAJ 177: 469–479
Andersson-Ellstrom A, Elfgren K, von Krogh G, Lehtinen M, Reisinger KS, Block SL, Lazcano-Ponce E, Samakoses R, Esser
Paavonen J, Tamms GM, Giacoletti K, Lupinacci L, Esser MT, Erick J, Puchalski D, Giacoletti KE, Sings HL, Lukac S,
MT, Vuocolo SC, Saah AJ, Barr E (2007) Induction of immune Alvarez FB, Barr E (2007) Safety and persistent immunoge-
memory following administration of a prophylactic quadriva- nicity of a quadrivalent human papillomavirus types 6, 11,
lent human papillomavirus (HPV) types 6/11/16/18 L1 virus- 16, 18 L1 virus-like particle vaccine in preadolescents and
like particle (VLP) vaccine. Vaccine 25: 4931–4939 adolescents: A randomized controlled trial. Pediatr Infect
Paavonen J, Jenkins D, Bosch FX, Naud P, Salmeron J, Wheeler Dis J 26: 201–209
CM, Chow SN, Apter DL, Kitchener HC, Castellsague X, de Ryding J, French KM, Naucler P, Barnabas RV, Garnett GP, Dillner
Carvalho NS, Skinner SR, Harper DM, Hedrick JA, J (2008) Seroepidemiology as basis for design of a human pap-
Jaisamrarn U, Limson GA, Dionne M, Quint W, Spiessens illomavirus vaccination program. Vaccine 26: 5263–5268
B, Peeters P, Struyf F, Wieting SL, Lehtinen MO, Dubin G Ryerson AB, Peters ES, Coughlin SS, Chen VW, Gillison ML,
(2007) Efficacy of a prophylactic adjuvanted bivalent L1 Reichman ME, Wu X, Chaturvedi AK, Kawaoka K (2008)
virus-like-particle vaccine against infection with human Burden of potentially human papillomavirus-associated can-
papillomavirus types 16 and 18 in young women: An interim cers of the oropharynx and oral cavity in the US, ­1998–2003.
analysis of a phase III double-blind, randomised controlled Cancer 113: 2901–2909
trial. Lancet 369: 2161–2170 Sarkar AK, Tortolero-Luna G, Follen M, Sastry KJ (2005)
Palefsky J, Giuliano A (2008) Efficacy of the quadrivalent HPV Inverse correlation of cellular immune responses specific to
vaccine against HPV 6/11/16/18-related genital infection in synthetic peptides from the E6 and E7 oncoproteins of HPV-
young men In: European Research Organization on Genital 16 with recurrence of cervical intraepithelial neoplasia in a
Infection and Neoplasia – EUROGIN, Nice, France cross-sectional study. Gynecol Oncol 99: S251–S261
Pan American Health Organization (2008) Burden of Human Sasagawa T, Rose RC, Azar KK, Sakai A, Inoue M (2003)
Papillomavirus (HPV) Infection and HPV-Related Disease in Mucosal immunoglobulin-A and -G responses to oncogenic
Latin America and the Caribbean, and Health and Economic human papilloma virus capsids. Int J Cancer 104: 328–335
Outcomes of HPV Vaccination in Selected Countries in Saxenian H, Hecht R (2006) HPV vaccines: Costs and financing.
LatinAmerica, Executive Summary. Pan American Health In: Stop Cervical Cancer: Accelerating Global Access to
Organization, Washington HPV vaccines, London
References 213

Schiffman M, Kjaer SK (2003) Chapter 2: Natural history of Tabrizi SN, Frazer IH, Garland SM (2006) Serologic response to
anogenital human papillomavirus infection and neoplasia. human papillomavirus 16 among Australian women with
J Natl Cancer Inst Monogr (31): 14–19 high-grade cervical intraepithelial neoplasia. Int J Gynecol
Schwartz SM, Daling JR, Doody DR, Wipf GC, Carter JJ, Cancer 16: 1032–1035
Madeleine MM, Mao EJ, Fitzgibbons ED, Huang S, Techakehakij W, Feldman RD (2008) Cost-effectiveness of
Beckmann AM, McDougall JK, Galloway DA (1998) Oral HPV vaccination compared with Pap smear screening on a
cancer risk in relation to sexual history and evidence of human national scale: A literature review. Vaccine 26(49):
papillomavirus infection. J Natl Cancer Inst 90: 1626–1636 6258–6265
Schwarz TF, Dubin G (2007) Human papillomavirus (HPV) The Henry J. Kaiser Family Foundation (2007a) Public Health &
16/18 L1 AS04 virus-like particle (VLP) cervical cancer Education | GSK Applies for WHO Prequalification of HPV
vaccine is immunogenic and well-tolerated 18 months after Vaccine Cervarix. kaisernetwork.org.
vaccination in women up to age 55 years. J Clin Oncol 25: Transgene (2006) Sustained response at month 12 for trans-
abstract 3007 gene’s TG 4001 in HPV-induced precancerous lesions of the
Schwarz TF, Leo O (2008) Immune response to human cervix and next clinical development steps. http://www.
­papillomavirus after prophylactic vaccination with AS04- transgene.fr/us/pdf/communique_presse/communiques_
adjuvanted HPV-16/18 vaccine: Improving upon nature. divers_2006/PR-US_TG4001-HPV_13-11-2006.pdf
Gynecol Oncol 110: S1–S10 Trottier H, Franco EL (2006) The epidemiology of genital human
Scott M, Stites DP, Moscicki AB (1999) Th1 cytokine patterns papillomavirus infection. Vaccine 24(Suppl 1): S1–S15
in cervical human papillomavirus infection. Clin Diagn Lab Unckell F, Streeck RE, Sapp M (1997) Generation and neutral-
Immunol 6: 751–755 ization of pseudovirions of human papillomavirus type 33.
Sheets EE, Urban RG, Crum CP, Hedley ML, Politch JA, Gold J Virol 71: 2934–2939
MA, Muderspach LI, Cole GA, Crowley-Nowick PA (2003) van Poelgeest MI, Nijhuis ER, Kwappenberg KM, Hamming IE,
Immunotherapy of human cervical high-grade cervical intra- Wouter Drijfhout J, Fleuren GJ, van der Zee AG, Melief CJ,
epithelial neoplasia with microparticle-delivered human Kenter GG, Nijman HW, Offringa R, van der Burg SH
papillomavirus 16 E7 plasmid DNA. Am J Obstet Gynecol (2006) Distinct regulation and impact of type 1 T-cell immu-
188: 916–926 nity against HPV16 L1, E2 and E6 antigens during HPV16-
Sheu BC, Chang WC, Lin HH, Chow SN, Huang SC (2007) induced cervical infection and neoplasia. Int J Cancer 118:
Immune concept of human papillomaviruses and related 675–683
antigens in local cancer milieu of human cervical neoplasia. Varnai AD, Bollmann M, Griefingholt H, Speich N, Schmitt C,
J Obstet Gynaecol Res 33: 103–113 Bollmann R, Decker D (2006) HPV in anal squamous cell
Skinner SR, Garland SM, Stanley MA, Pitts M, Quinn MA carcinoma and anal intraepithelial neoplasia (AIN). Impact
(2008) Human papillomavirus vaccination for the preven- of HPV analysis of anal lesions on diagnosis and prognosis.
tion of cervical neoplasia: Is it appropriate to vaccinate Int J Colorectal Dis 21: 135–142
women older than 26? Med J Aust 188: 238–242 Villa LL (2007) Overview of the clinical development and
Slupetzky K, Gambhira R, Culp TD, Shafti-Keramat S, results of a quadrivalent HPV (types 6, 11, 16, 18) vaccine.
Schellenbacher C, Christensen ND, Roden RB, Kirnbauer R Int J Infect Dis 11(Suppl 2): S17–S25
(2007) A papillomavirus-like particle (VLP) vaccine dis- Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano
playing HPV16 L2 epitopes induces cross-neutralizing anti- AR, Wheeler CM, Koutsky LA, Malm C, Lehtinen M,
bodies to. HPV11Vaccine 25: 2001–2010 Skjeldestad FE, Olsson SE, Steinwall M, Brown DR,
Stanley M (2006) Immune responses to human papillomavirus. Kurman RJ, Ronnett BM, Stoler MH, Ferenczy A, Harper
Vaccine 24(Suppl 1): S16–S22 DM, Tamms GM, Yu J, Lupinacci L, Railkar R, Taddeo FJ,
Stanley M, Coleman N, Chambers M (1994) The host response Jansen KU, Esser MT, Sings HL, Saah AJ, Barr E (2005)
to lesions induced by human papillomavirus. Ciba Found Prophylactic quadrivalent human papillomavirus (types 6,
Symp 187: 21–32; discussion 32–44 11, 16, and 18) L1 virus-like particle vaccine in young
Stanley M, Lowy DR, Frazer I (2006) Chapter 12: Prophylactic women: A randomised double-blind placebo-controlled
HPV vaccines: Underlying mechanisms. Vaccine 24(Suppl 3): multicentre phase II efficacy trial. Lancet Oncol 6:
S3/106–S3/113 271–278
Stanley MA, Pett MR, Coleman N (2007) HPV: From infection Villa LL, Costa RL, Petta CA, Andrade RP, Paavonen J, Iversen
to cancer. Biochem Soc Trans 35: 1456–1460 OE, Olsson SE, Hoye J, Steinwall M, Riis-Johannessen G,
Streeck RE (2002) A short introduction to papillomavirus biol- Andersson-Ellstrom A, Elfgren K, Krogh G, Lehtinen M,
ogy. Intervirology 45: 287–289 Malm C, Tamms GM, Giacoletti K, Lupinacci L, Railkar R,
Suzich JA, Ghim SJ, Palmer-Hill FJ, White WI, Tamura JK, Bell Taddeo FJ, Bryan J, Esser MT, Sings HL, Saah AJ, Barr E
JA, Newsome JA, Jenson AB, Schlegel R (1995) Systemic (2006) High sustained efficacy of a prophylactic quadriva-
immunization with papillomavirus L1 protein completely lent human papillomavirus types 6/11/16/18 L1 virus-like
prevents the development of viral mucosal papillomas. Proc particle vaccine through 5 years of follow-up. Br J Cancer
Natl Acad Sci U S A 92: 11553–11557 95: 1459–1466
Syrjanen KJ, Syrjanen SM (2000) Papillomavirus infections in Viscidi RP, Schiffman M, Hildesheim A, Herrero R, Castle PE,
human pathology. Wiley & Sons, Chichester, pp 11–51. Bratti MC, Rodriguez AC, Sherman ME, Wang S, Clayman
Syrjanen S (2005) Human papillomavirus (HPV) in head and B, Burk RD (2004) Seroreactivity to human papillomavirus
neck cancer. J Clin Virol 32(Suppl 1): S59–S66 (HPV) types 16, 18, or 31 and risk of subsequent HPV infec-
 214 11 Human Papillomavirus Vaccines

tion: Results from a population-based study in Costa Rica. Wheeler CM (2007) Advances in primary and secondary inter-
11 Cancer Epidemiol Biomarkers Prev 13: 324–327 ventions for cervical cancer: human papillomavirus prophy-
Viscidi RP, Snyder B, Cu-Uvin S, Hogan JW, Clayman B, Klein lactic vaccines and testing. Nat Clin Pract Oncol 4: 224–235
RS, Sobel J, Shah KV (2005) Human papillomavirus capsid WHO In. World Health Organization (WHO)
antibody response to natural infection and risk of subsequent WHO (1990) Sexually transmitted infections increasing – 250
HPV infection in HIV-positive and HIV-negative women. million new infections annually. WHO Feature 152: 1–6
Cancer Epidemiol Biomarkers Prev 14: 283–288 WHO (1990) The current status of development of prophylactic
Watson M, Saraiya M, Ahmed F, Cardinez CJ, Reichman ME, vaccines against human papillomavirus infection. Report of a
Weir HK, Richards TB (2008) Using population-based technical meeting, Geneva, 16–18 February 1999, pp 1–22
­cancer registry data to assess the burden of human WHO (2006) Comprehensive cervical cancer control: a guide to
­papillomavirus-associated cancers in the United States: essential practice. World Health Organization p284
Overview of methods. Cancer 113: 2841–2854 Winer RL, Hughes JP, Feng Q, O’Reilly S, Kiviat NB, Holmes
Weinberger PM, Yu Z, Haffty BG, Kowalski D, Harigopal M, KK, Koutsky LA (2006) Condom use and the risk of genital
Brandsma J, Sasaki C, Joe J, Camp RL, Rimm DL, Psyrri A human papillomavirus infection in young women. N Engl J
(2006) Molecular classification identifies a subset of human Med 354: 2645–2654
Papillomavirus – associated oropharyngeal cancers with Xu Y, Wang Q, Han Y, Song G, Xu X (2007) Type-specific and
favorable prognosis. J Clin Oncol 24: 736–747 cross-reactive antibodies induced by human papillomavirus
Welters MJ, de Jong A, van den Eeden SJ, van der Hulst JM, 31 L1/L2 virus-like particles. J Med Microbiol 56: 907–913
Kwappenberg KM, Hassane S, Franken KL, Drijfhout JW, Xu Y, Zhang H, Xu X (2008) Enhancement of vaccine potency
Fleuren GJ, Kenter G, Melief CJ, Offringa R, van der Burg by fusing modified LTK63 into human papillomavirus type
SH (2003) Frequent display of human papillomavirus type 16 chimeric virus-like particles. FEMS Immunol Med
16 E6-specific memory T-helper cells in the healthy popula- Microbiol 52: 99–109
tion as witness of previous viral encounter. Cancer Res 63: Zhou J, Sun XY, Stenzel DJ, Frazer IH (1991) Expression of
636–641 vaccinia recombinant HPV 16 L1 and L2 ORF proteins in
Wentzensen N, Vinokurova S, von Knebel Doeberitz M (2004) epithelial cells is sufficient for assembly of HPV virion-like
Systematic review of genomic integration sites of human particles. Virology 185: 251–257
papillomavirus genomes in epithelial dysplasia and invasive
cancer of the female lower genital tract. Cancer Res 64:
3878–3884
 Index

A screening, 170, 172

Acanthosis, 49, 114 squamocolumnar junction, 134
Acetic acid solution. See also Acetowhite test squamous cell carcinoma (See Anal cancer)
test, 138, 186 squamous intraepithelial lesion (See Anal Intraepithelial
Acetowhite lesions, 57, 101 Neoplasia (AIN))
Acetowhite test, 46, 48, 101, 122, 153 stenosis, 144
AIDS, 45, 115, 134, 168 warts, 5
ALA-PDT. See Photodynamic therapy prevention, 145
Aldara. See Imiquimod Anesthesia. See EMLA, Lidocaine
Alferon N. See Interferon alfa Angiofibroma, 42
Alkyl nitrites, 135 Angiokeratoma, 45, 102
Aluminum salts. See Cervarix; Gardasil; adjuvant, Human Anogenital
papillomavirus; vaccine cancer(s) (See also Specific organ carcinoma/cancer/
Aminolaevulinic acid. See Photodynamic therapy (PDT) neoplasia)
Amplicor in children, 14
HPV test kit, 26 condyloma (See Condyloma)
Anal diseases, 28, 168, 198, 203
canal, 134 HPV infection (See also Human papillomavirus;
cancer, 135, 196, 203, 207 infection)
carcinoma in situ, 143 infection, 27, 28
cytology, 138, 170, 172 (See also Pap smear) intraepithelial lesions, 165, 173 (See also Specific
dysplasia, 141, 170, 171 intraepithelial lesion)
dysplastic lesions lesions, 47, 54, 57, 58, 60, 64, 165, 168, 170, 173
surveillance, 145 lichen sclerosus, 113 (See also Lichen Sclerosus)
histology, 137 mucosa, 92
HPV infection (See Human papillomavirus (HPV); neoplasia (See specific organ carcinoma/neoplasia/cancer)
anal infection) region, 26, 207
intercourse, 135 skin, 11
intraepithelial lesion, 134, 137 (See also Intraepithelial warts, 4, 35, 47, 62, 64, 67, 164, 168, 169, 171
neoplasia) Anoscope, 138
in HIV infected, 165 Anoscopy. See High-resolution anoscopy
in immunosuppressed, 165 Antibody. See Human Papillomavirus; antibody
intraepithelial neoplasia (AIN), 98, 152, 207 Antigen. See Human papillomavirus; antigen
cellular markers, 140 Antiretroviral drugs. See HAART
grading, 137–138 APOT, 27
in HIV infected, 168 ASCUS, 145, 153, 155, 170
natural history, 134 Atypia, 98, 137, 150
prevalence, 134
prevention, 145
screening, 145 B
mucosa, 136 Bacille Calmette-Guérin (BCG), 63
neoplasia/cancer /carcinoma advantages, 63, 90
in HIV infected, 165 adverse-effects, 63, 90
in immunosuppressed, 165 disadvantages, 63, 90
pruritus, 138 efficacy, 63, 90

215
216 Index

mechanism of action, 63 protection, 205

preparation, 90 side-effects, 205
topical, 63 Cervical, 11, 125
use, 63, 90 antibodies (see Human papillomavirus; antibodies)
Balanitis, 111. See also Candidal balanitis, Zoon’s balanitis biopsy, 155
Balanitis xerotica obliterans, 110. See also Penile; cancer, 6, 27, 49, 66, 121, 125, 127, 135 (See also
lichen sclerosus carcinoma)
Balanoposthitis, 40, 66 detection
chronic, 113 in HIV infected, 168, 169, 171, 172, 207
Basal invasive, 196, 200
cell carcinoma, 137 precursor, 151
cells, 134, 197 prevention, 157–158, 172, 197
Bethesda risk factors, 152, 168, 169, 207
categorization, 98, 137 screening, 155, 158, 168, 169, 172, 206
system, 151 carcinogenesis, 125, 164
Bladder. See also Human papillomavirus (HPV); bladder lesions carcinoma (See also Cervical cancer) 9, 125
cancer, 92 condyloma (See Condyloma)
carcinogenesis, 74 colposcopy, 138
squamous cell carcinoma, 92 cytology
transitional cell carcinoma, 92 in follow-up, 156–157
Bowenoid papulosis (BP), 101, 103, 104 in HIV infected, 172
classification, 99 disease, 27, 167, 171, 173, 200
lesions, 102 dysplasia, 167, 169, 170, 204
Bowen’s disease (BD), 99, 101, 102, 104, 107–109 high-grade, 152 (See also Squamous; intraepithelial
diagnosis, 105 lesion)
lesions, 105 mild, 150
recurrences, 105 moderate, 150
Bronchial in premenopausal women, 153
HPV-related lesions, 203 severe, 151
Buck’s fascia, 110 ectopy, 8
Buschke-Löwenstein tumor, 137. See also Giant condylomata epithelium, 200
histopathology, 151
HPV infection (see Human papillomavirus; cervical
C infection)
Cancer. See Specific organ carcinoma/cancer/neoplasia immaturity, 8
Candida. See Candidiasis infection, 195
Candidal balanitis, 107 intraepithelial lesion, 151, 199 (See also Intraepithelial
Candidiasis, 47 neoplasia)
acetowhite test in, 47 follow-up, 156
Capsid. See Human papillomavirus; capsid prevention, 157–158
Carbon dioxide. See Laser screening, 155
Carcinoma. See Specific organ carcinoma/cancer/neoplasia intraepithelial neoplasia (CIN) 8, 40, 98, 122, 134, 135, 199
CareHPV test, 25 in adolescents, 155
Carrageenan, 15 natural history, 152
CD4 pregnancy and, 155
cell count(s), 135, 168, 171 risk factors, 169
level(s), 135, 167–169, 172 screening, 170
Cell lesions, 47, 149, 152, 156, 168, 172
apoptosis, 125 mucosa, 199
division cycle, 125 mucus, 8, 199
Cervarix, 126, 201, 202, 204, 205, 207. See also neoplasia (See Cervical cancer/carcinoma)
Human papillomavirus: vaccines; prophylactic precancerous lesions (See Intraepithelial neoplasia)
adjuvant, 201 premalignant lesions (See Cervical cancer; percursor)
clinical trials, 201 squamocolumnar junction, 134
costs, 205 squamous intraepithelial lesion, 8
cross-protection, 201 in HIV infected, 169, 171
dosage, 205 transformation zone, 125
efficacy, 205 warts, 85
indication, 204 Cervix. See Cervical
licensure, 204 Chlamydia trachomatis, 3
method of administration, 205 Cidofovir, 64, 65, 143, 170
Index 217

advantages, 64 DNA. See Human papillomavirus (HPV); DNA

adverse-effects, 65 Dyskeratosis, 137
cost, 65
disadvantages, 65
efficacy, 64 E
indications, 64 E-cadherin expression, 126
mechanism of action, 64 Efurix. See Fluorouracil
use, 64 Electrocautery, 57, 143, 144
CIN. See Cervical; intraepithelial neoplasia needle-tip, 170
Circumcision, 12, 34, 57, 67, 102, 107, 109, 113 Electrofulguration, 57
HPV and, 122 Electrosurgery, 57, 104, 105
Penile intraepithelial neoplasia (PIN) and, 122 EMLA, 57, 86, 87, 186, 189. See also Lidocaine/Prilocaine
Clobetasol Endoscopic electrosurgical techniques
propionate, 112 advantages, 86
Cold-knife conization, 156 complications, 87
Colposcope, 182, 186 (See also Microscope) disadvantages, 86
Colposcopy, 47, 153, 155, 157 Epidermodysplasia verruciformis, 5
Common warts, 5 Epispadia, 76
Computed tomography. See Human papillomavirus Erythroplasia of Queyrat (EQ), 99, 101, 102, 108, 110
(HPV); detection lesions, 107
Condom(s), 6, 8, 9, 11, 14, 62, 66, 123, 126, 195, 207 recurrences, 109
Condyloma, 73, 76, 78–80, 82, 89, 144, 170. Excision
See also Human papillomavirus (HPV); bladder, advantages, 57, 86
urethral, meatal lesions adverse-effects, 57
acuminata, 204 complications, 86
acuminatum, 5, 6, 35, 61 cost, 57
acuminate, 90 disadvantages, 57, 86
flat, 91 indication(s), 57, 86
flat lesions, 41 technique, 57
genital, 35 Exudation, 199
in HIV-infected, 37
lata, 6
papular, 36 F
viral, 103 Fibroepithelial polyps. See Fibroepithelioma
Condylomata. See also Condyloma Fibroepithelioma, 42
acuminate, 35 Ficus sycomorus, 5
lata, 46 Flat condyloma. See Condyloma; flat
Condylomatous Fluorouracil (5-FU), 55, 84
type, 98 advantages, 56, 84
Condylox. See Podophyllotoxin adverse-efects, 56
Corpus spongiosum, 110 contraindication, 56
Cryotherapy, 55, 57, 87, 106, 107, 116, 155, 156 cost, 56
advantages, 58, 87 cream, 106, 109
adverse effects, 58, 87 disadvantages, 56, 85
cost, 58 indication, 56
disadvantages, 58, 87 mechanism of action, 55,
indications, 58 side-effects, 85
mechanism of action, 57 use, 56, 85
use, 58, 87 Fordyce spots. See Sebaceous glands
Cryptococcosis, 46 Fossa navicularis. See also Human papillomavirus (HPV);
Cyclo-oxygenase pathway, 126 urethral lesions
Cystoscopy, 82. See also Urethrocystoscopy brushing, 77
Cytology, 48, 77, 78. See also Anal, Cervical, Urethral; cytology examination, 76
terminology, 150–151 HPV related lesions in, 77
Cytomegalovirus
retinitis, 64
G
Gardasil, 126, 145. See also Human papillomavirus
D (HPV); vaccine
Defensins, 13 adjuvant, 201
DIGENE, 23 booster dose, 205
218 Index

clinical trials, 201, 202 antibody titers, 27

costs, 204, 206, 208 antigens, 198
cross-protection, 201, 205 assembly, 34
dosage, 205 bladder lesions, 78
efficacy in men, 67, 207 capsid, 197–199, 201
indication, 204 capsid protein, 23
licensure, 204 cellular immunity, 200
method of administration, 204 cervical infection, 167, 168
protection, 201 clearance, 10, 12
recommendation concordance, 13
in men, 204 condom use and, 38, 67
side-effects, 204 culture, 50
Genital in circumcised men, 40
multifocal intraepithelial neoplasia, 135, 152 cutaneous, 5, 14
warts/condyloma, 5, 7, 34, 35, 76, 121, 168 detection, 23, 24, 27, 28, 79, 91, 200, 207
Genome. See Human papillomavirus (HPV); genome detection in men, 28
Giant condyloma, 35 DNA, 6, 9, 11–13, 121, 126, 127, 138
See Buschke-Löwenstein tumor detection, 26, 27, 35, 38, 165, 168
Glans in prostate, 93
total resurfacing in semen, 79
indications, 110 in urine, 79
Gonorrhea, 6 encapsidation, 166
Graft. See Urethroplasty load, 170
prevalence, 11
replication, 34, 166
H sequencing, 23
HAART testing, 153, 154, 157, 158
anal cancer and, 172 in men, 50
anal intraepithelial neoplasia (AIN) and, 171 early gene expression, 165
cervical intraepithelial neoplasia (CIN) and, 171 early protein detection, 23
HPV infection and, 171 early proteins, 23
oral HPV infection and, 172 economic burden, 7
regimens, 171 epidemiology, 6–8
Head and neck (carcinoma), 122, 203, 208 follow-up, 59
Hemospermia, 74 genital lesions, 4, 5
Herpes simplex virus, 3 genome, 23, 24, 26, 27, 197, 200
Herpesvirus, 116 genotypes, 26
Hidradenitis histological techniques, 49
suppurativa, 136 human immunodeficiency virus and, 11
High-resolution anoscopy (HRA) humoral immunity, 199
targeted destruction of lesions guided by, 144, 169, 170 intra-anal, 37
Honeycomb incidence, 7, 9–11
patterns, 140 incubation, 36
HSIL. See Anal, Cervical; intraepithelial neoplasia infection
Human immunodeficiency virus (HIV), 115, 116, 133, 152. in adolescents, 150
See also Human papilloma virus; in children, 13
and HIV coinfection clearance of, 50, 150, 156, 166, 198, 208
ilicit drugs and, 167 clinical disease, 35
Human papillomavirus (HPV), 23, 103, 104, duration of infection, 9–10
107, 109, 112, 196, 199 exotic presentation, 37, 39
anal infection koilocytes in, 49
in immunosuppressed, 169, 170 latency in, 34, 35
life cycle, 134 in MSM, 11, 37
in men, 134 in newborn, 13
prevalence, 133, 134 in older women, 150
risk factors, 135 in postmenopausal women, 8
subclinical, 138 in pre-pubertal children, 12
transmission routes, 135 risk, 8
in women, 134–135 subclinical, 35, 40, 66
anatomic distribution, 11 infectivity rate, 34
antibody(ies), 50, 167 infection reservoir, 12
Index 219

in immunosuppression, 11 vaginal cancer and, 164

late gene expression, 165 vulvar cancer and, 164
latent, 66, 167 Hybrid Capture, 23, 24
late proteins, 23 cutoff value, 25
life cycle, 165, 197, 198 test, 138
linear array genotyping test, 26 Hybridization
meatal lesions, 73 dot blot, 26
method of collection in men, 28 procedures, 23
methods of immune evasion, 166 reverse line blot, 26
molecular tests in situ, 23
PCR-based detection, 50 Hyperkeratosis, 49
mucosal, 4, 5 Hypospadia, 76
neutralizing antibody and, 199–201, 205, 209
non-mucosal types, 14
oncogenes, 26, 208 I
oncogenic types, 166 Interferons (INF-a), 61
oncoproteins, 125, 197, 200 antibodies titers, 199
oropharyngeal infection, 208 responses, 199
penile, 40, 42 seroconversions, 199
perianal, 37 Imiquimod, 85, 104, 141, 170
perinatal advantages, 62, 85
transmission, 12–13 adverse effects, 62, 85
persistence, 8–10, 13, 15, 35, 150, 171, 199 cost, 62, 85
prevalence, 6, 8, 9, 11, 14, 38, 67, 201, 207, 208 disadvantages, 62, 63, 85
prevention, 14–15, 35, 67 efficacy, 62, 85
protection, 201, 205, 207 indications, 62,
proteins, 34, 93, 166. See also oncogenes/oncoproteins mechanism of action, 62
reactivation, 8 use, 62, 85
receptors, 197 Immune precipitation assays, 23
risk factors, 8–10 Immunoglobulin, 199. See also Human
RNA detection, 24 papillomavirus (HPV)
role of immune status, 34 Immunoglobulin A (IgA)
scrotal lesion, 11 antibodies titers, 199
in scrotum, 37 responses, 172, 199
serology, 31 seroconversions, 199
seropositivity, 199, 200 seropositivity, 172
seroprevalence, 9 Immunoglobulin G (IgG), 164
sexual abuse and, 14 Immunohistochemistry, 23
species, 196, 205 Immunotherapy. See Interferons,
testing, 168 Bacille Calmette-Guérin
transcripts, 26, 27 Infrared coagulation, 141, 143, 170
transmission, 4, 8, 9, 11–14, 34, 37, 122, 196, Interferons, 91, 166, 200
203, 204, 207 advantages, 61, 91
nonsexual routes, 14 adverse effects, 91
treatment, 33, 82 cost, 61
in pregnancy, 53 disadvantages, 61, 91
type concordance, 34 efficacy, 91
type prevalence, 34 indications, 61
types, 4, 5, 9, 196 intralesional, 61
in anal cancer, 138 mechanism of action, 61
high-risk (oncogenic), 125 side-effects, 61, 62
low-risk, 121 topical, 62
typing, 24, 26 use, 91
in uncircumcised men, 40 Interleukin, 200
urethral infection, 37, 74, 78 Interleukin-10, 166
urethral lesions, 75 Intraepithelial neoplasia. See Specific organ neoplasia
vaccines, 35, 91, 126, 145, 172 (See also Intron-A. See Interferons
Cervarix; Gardasil)
in men, 35, 116
prophylactic, 5, 9, 11, 14 J
HPV types included in, 9, 14–15 Juvenal, 5
220 Index

K pump, 182
Kaposi’s sarcoma, 98, 115. See also Penile; Kaposi’s sarcoma safety, 184
Keratinocyte(s), 34, 49, 166, 197 smoke evacuator, 185
Keratoses training, 184
seborrheic, 43, 102, 136 vaporization, 187
Keratotic LEEP. See Loop electrosurgical excision procedure
lesions, 35 Lentigo, 102
papules, 35 Lichen
plaques, 44 nitidus, 45
Koilocytes, 49 planus, 102, 107
Koilocytosis, 78, 98, 99, 137 Lichen sclerosus, 98, 102, 105, 110
Lidocaine, 57, 186
LLETZ. See Large loop excision of the transformation zone
L Loop electrosurgical excision procedure (LEEP), 156
Langerhans cells histiocytosis, 137 conization, 155
Large loop excision of the transformation zone (LLETZ), 155 LSIL. See Anal, Cervical; intraepithelial neoplasia
Laryngeal papillomas, 4, 12 Lugol iodine solution, 138, 140, 156
juvenile, 203 Lupus erythematosus, 107
Laryngeal papillomatosis, 185 Lymph node, metastasis, 114
Laser, 87, 88 Lymphoma, cutaneous, 137
acronym, 181 Lymphotoxin, 200
beam, 183, 184, 188, 189, 191
carbon dioxide (CO2), 87, 101, 104, 106, 109, 113, 144,
156, 170 M
advantages, 60, 88 Macrophages, 200
adverse-effects, 60 MASER, 181
complications, 88, 187, 191 Matrix metalloproteinase expression, 126
cost, 60 Meatal. See also Human papillomavirus; urethral lesions
disadvantages, 60, 88 obstruction, 74
efficacy, 88 spreader, 77
indications, 60, 87, 186 stenosis, 84, 86, 88, 106, 111, 113
mechanism of action, 58 Meatoplasty, 113
postoperative care, 189 Meatoscopy, 76, 77
settings, 87, 186, 187 Meatotomy, 86, 89
technique, 58, 87 Melanoma, 102
therapy, 60 anorectal, 137
components, 182 Methyl aminolevulinate. See Photodynamic therapy
goggles, 185 Microbicides, 15
handpiece, 182 Microscope, 48, 49, 58, 76, 87, 101, 138, 182–184, 186
holmium Molecular biology
advantages, 89 techniques, 23
complications, 89 Molluscum contagiosum, 45
efficacy, 89 Tzanck smears in, 45
indications, 89 Mosaicism, 140
mechanism of action, 88
settings, 89
technique, 89 N
joystick, 182, 183, 186 Nasal cavity papilloma, 4
light, 181 Neck carcinoma. See Head and neck carcinoma
Nd:YAG, 88, 109, 156 Neoplasia. See Specific organ carcinoma/cancer/neoplasia
advantages, 89 Neutralizing antibody assays, 27
complications, 89 Nevi, 102, 113
conization, 156 pigmented, 44
disadvantages, 89 verrucous epidermal, 44
efficacy, 89 Nonoxynol-9, 15
indications, 89 Northern blot hybridization, 23
mechanism of action, 88
settings, 89
technique, 89 O
optical cavity, 182 Oncoproteins. See Human papillomavirus (HPV);
plumes, 14, 185 oncoproteins
Index 221

Oral (papilloma), 4–5, 12, 14 intraepithelial neoplasia (PIN), 107, 186

HPV infection (See Human Papillomavirus; classification, 98
oral infection) epidemiology, 101
Oropharyngeal high-grade, 122
cancer /carcinoma, 12, 204 HIV and, 170
HPV infection, 208 (See also Human papillomavirus; HPV prevalence in, 122
oropharyngeal infection; vaccine(s)) low-grade, 122
natural history, 101
quadrivalent HPV vaccine and, 207
P Kaposi’s sarcoma, 116
p53, 125, 197 lesions, 40, 168, 186, 188, 207
Paget’s (cells), 115 lichen sclerous (See Lichen sclerosus)
disease, 137 squamous cell carcinoma (SCC), 105, 109, 113, 165 (See
extramammary, 98 also Penile; cancer)
genital, 114–115 warts, 7
Pap Peniscopy. See Acetowhite test
smear, 149, 150, 152, 169, 170 Perianal (dermatitis)
Papanicolaou, 149. See also Pap dermatitis, 136
smear/ test, 9, 12, 47, 137, 138, 150, 151, 153, lesions, 145
155, 157, 158 region, 134, 136, 137
Papilloma. See also Organ specific papilloma skin, 133, 138
hirsutoid, 42 (See also Pearly penile papules) squamous cell carcinoma, 133
Papillomatosis, 49. See Laryngeal papillomatosis; warts, 5, 144
Organ specific papillomatosis Phimosis, 110, 113, 114
Papillomavirus. See also Human Photodynamic therapy (PDT), 60, 89, 107
papillomavirus (HPV) advantages, 61, 90
bovine, 23 adverse effects, 61, 90
capsid, 197–199, 201 aminolevulinic acid, 60, 89, 143
classification, 34 cost, 61
genus, 196 disadvantages, 61
replication, 197 efficacy, 90
strains, 196 indications, 60
transcription, 197 mechanism of action, 60, 89
Papular. See Condyloma; papular methyl aminolevulinate, 106, 109
Parakeratosis, 49 porphyrins in, 60
Parthenium parviflorum, 5 use, 60, 90
Pearly penile papules, 42 Photothermolysis, 181
Penile (cancer) Pigmented warts, 102
cancer, 101, 110, 116 Plantar warts, 5
basaloid type, 122 Podofilox. See Podophyllotoxin
clinical phenotype, 123 Podophyllin, 53, 84
etiology, 122 advantages, 54, 84
histopathological lesions, 123 adverse effects, 54, 84
HIV and, 170 contraindications, 54, 84
HPV prevalence in, 121–123 cost, 54
incidence, 125 disadvantages, 54, 84
molecular pathogenesis, 123 efficacy, 54
papillary type, 122 indications, 54
pathogenesis, 123 mechanism of action, 54
prophylactic HPV vaccine and, 203 use, 54, 84
risk factor, 121 Podophyllotoxin, 55, 82, 141
verrucous, 122 advantages, 55, 84
warty type, 122 adverse effects, 55, 84
carcinogenic pathway, 125 contraindication, 55
carcinoma in situ, 101 cost, 55
dysplasia, 98 disadvantages, 55, 84
epithelium, 98, 125 efficacy, 55
flat lesions (FPLs), 122 indications, 55
prevalence of, 122 mechanism of action, 55
flat warts (See Condyloma; flat) use, 55, 84
horn, 113–114 Podophyllum peltatum Linné, 53
222 Index

Polymerase chain reaction (PCR), 138 high-grade, 150, 151

real-time, 26 low-grade, 151
reverse transcriptase, 26 intraepithelial neoplasia (PIN), 122
in situ, 24 mucosa, 137
Polyphenon E. See Sinecatechins Steroids, 112
Poppers. See Alkyl nitrites Surgical
Postectomy. See Circumcision ablation/excision, 141, 143, 144
Prilocaine, 57 excision, 57, 105, 114, 116 (See also excision)
Prostaglandin, 126 Syphilis
Prostate cancer, 92–93 secondary, 46
Protopic, 113 treponemal, 6
Protoporphyrin, 89
Pruritus. See Anal; pruritus
Psoriasis, 107 T
Pulmonary Tacrolimus, 113
HPV-related lesions, 203 Targeted destruction. See High-resolution anoscopy (HRA)
T-cell. See Lymphoma
Temovate. See Clobetasol
Q Tenesmus, 136
QIAGEN, 23, 25 Testosterone
Queyrat. See Erythroplasia of Queyrat propionate, 112
Thymus capitatus, 5
Tissue culture, 23
R Tonsillar
Rectal digital examination (DRE), 138 carcinoma, 208
Reiter syndrome, 107 squamous cell carcinoma, 12
Renal (cell carcinoma), 93 Tracheal
pelvis carcinoma, 93 HPV-related lesions, 203
transitional cell carcinoma, 93 papilloma, 14. See also Human papillomavirus;
Respiratory (papillomas) oropharyngeal infection
recurrent, 203 Transformation zone. See Anal/Cervical squamocolumnar
Respiratory tract papillomatosis, 14 junction
Retinoblastoma tumor suppressor, 197 Transit-ampliflying cells, 197
Retinoblastoma tumor suppressor protein (pRB), 125 Transitional cell carcinoma. See Bladder, Urethral, Ureter
Rouge lip, 74 transitional cell carcinoma
Transudation, 199, 200
Transurethral resection, 89
S complication, 89
Sebaceous glands, 43 indications, 89
Serological assays, 27 Trichloracetic acid (TCA), 63, 141
Sexually transmitted disease (STD), 3 advantages, 64
Sexually transmitted infections (STIs), 6, 126 adverse-effects, 64
Sinecatechins, 66 disadvantages, 64
advantages, 66 efficacy, 64
adverse-effects, 66 mechanism of action, 64
cost, 66 use, 64
disadvantages, 66 Trichomoniasis, 3
efficacy, 66
indications, 66
mechanism of action, 66 U
use, 66 Ultrasonography, 82. See also Human papillomavirus
Southern blot hybridization, 23 (HPV); detection
Spongiofibrosis, 111 Ureter (carcinoma)
Squamous, 150, 151, 153 transitional cell carcinoma (TCC), 93
atypical cells, 153 (See also ASCUS) Urethra, 37. See also Human
cell carcinoma (See Anal cancer; Bladder/Urethra papillomavirus; urethral lesions
squamous cell carcinoma; Penile cancer) Urethral
cells, 138 carcinoma, 93
hyperplasia, 110, 122 caruncle, 76
intraepithelial lesions (SIL) (See also Anal intraepithelial condyloma, 189
neoplasia (AIN); Penile intraepithelial neoplasia) cytology, 78
Index 223

lesions, 37, 186, 189 oropharyngeal HPV infection and, 208

malformations (See Epispadia, Hypospadia) prevaccination testing, 206
meatus, 86 protection, 201, 207
squamous cell carcinoma, 92 quadrivalent (See Gardasil)
transitional cell carcinoma, 93 therapeutic
warts, 55, 85 chimeric virus-like, 209
Urethritis, 74, 111 viral vector, 208
Urethrocystoscopy, 91 Vaginal. See also Human papillomavirus (HPV);
Urethrography, 82 vaginal cancer and intraepithelial neoplasia.
Urethroplasty, 113 (VaIN), 98
Urethroscopy, 80, 82 cancer
Urticaria, 136 prophylactic HPV vaccine and, 203
Veneral warts, 5
Veregen. See Sinecatechins
V Verrucous carcinoma. See Buschke-Löwenstein tumor
Vaccine(s), 14–15, 126. See also Cervarix; Gardasil; Vinblastine, 116
Human papillomavirus; vaccines Virions, 197
antibody response in men, 207 Virus-like particles (VLPs), 197
antibody response in women, 207 Vulvar See also Human papillomavirus (HPV); vulvar cancer
bivalent (See Cervarix) and intraepithelial neoplasia, 135, 152
cost-efficacy cancer/neoplasia, 122
in men, 208 prophylactic HPV vaccine and, 202
in developing countries, 206 warts, 6
duration of protection, 205
efficacy
in men, 208 W
epitopes, 198, 209 Warts. See Specific organ/region warts
HPV genotypes in prophylactic, 14 Western blot hybridization, 23
in HPV-infected individuals, 205
multivalent, 209
neutralizing antibodies and, 201, 205, 209 Z
oropharyngeal cancer and, 204 Zoon’s balanitis, 107