Table Of ContentHuman Papillomavirus
Proving and Using a Viral Cause for
Cancer
Human Papillomavirus
Proving and Using a Viral Cause for
Cancer
Edited by
David Jenkins
Emeritus Professor of Pathology, University of Nottingham, United Kingdom
Consultant in Pathology to DDL Diagnostic laboratories, Rijswijk, The Netherlands
F. Xavier Bosch
Cancer Epidemiology Research Program, Catalan Institute of Oncology,
Barcelona, Spain
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Contents
List ofContributors...........................................................................................................................xvii
Preface..............................................................................................................................................xxiii
GeneralIntroduction—The Background toHuman Papillomavirus andCancer Research............xxv
CHAPTER 1 A Brief History of Cervical Cancer.......................................................1
David Jenkins
Understanding Cervical Cancer—From Paleopathology tothe 19th Century..........2
Transforming WesternMedicine andthe Rise ofMedical Science..........................3
The Idea ofPrevention...............................................................................................6
Cervical Cancer Preventionby Cervical Cytology Screening..................................8
Encouraging Participation inCervical Cancer Screening.........................................9
Evolution ofIdeason the Causes ofCervicalCancer, Male Role, and
Transmission ofa CausativeAgent.........................................................................10
Further Reading........................................................................................................11
SECTION 1 PROVING THE ROLE OF HUMAN PAPILLOMAVIRUS
IN CERVICAL CANCER: STUDIES IN THE LABORATORY, CLINIC,
AND COMMUNITY
CHAPTER 2 Linking Human Papillomavirus to Human Cancer and
Understanding Its Carcinogenic Mechanisms...................................17
Magnus von Knebel Doeberitz,HeatherCubie, Thomas R.Broker
and David Jenkins
Animal Papillomaviruses:From Papillomas toCancers.........................................18
The Search for Infectious Agents AssociatedWith Cervical Cancer.....................19
The Failure of the Herpes Hypothesis.....................................................................19
Molecular Tools........................................................................................................19
The Human Papillomavirus Hypothesis...................................................................20
SouthernBlotting......................................................................................................21
Cloning Human Papillomavirus DNAs....................................................................22
Epidermodysplasia Verruciformis............................................................................22
Identifying HPV 11,HPV 16,and HPV 18.............................................................22
Extending the Range ofHPV Types........................................................................23
The Advent ofPCR..................................................................................................24
Studying HPV GeneExpression inLesions............................................................24
HPV 16 and18 inNeoplastic Transformation: E6 andE7 Genes..........................25
v
vi Contents
Additional Pioneering StudiesofImmortalizationand
Transformation..........................................................................................................26
Recapitulation ofThree-Dimensional EpithelialTissues inRaft Cultures
as anExperimental Model for Investigations of HPV-Host Tissue
Interactions andMechanisms of Carcinogenesis.....................................................27
Conclusion................................................................................................................28
A Vignette:EarlyClinicalExperience WithHuman Papillomavirus
AlbertSinger
References.................................................................................................................31
CHAPTER 3 Demonstrating the Importance of Different HPVs in Cervical
Cancer and Other HPV-Related Cancers............................................41
NuriaGuimera, LaiaAlemany, LaiaBruniand NubiaMun˜oz
Introduction...............................................................................................................41
Human Papillomavirus asEtiologicalAgent ofCervical Cancer...........................42
Human Papillomavirus Association With Cervical Cancer: Case-Control
Studies.......................................................................................................................43
Human Papillomavirus Prevalence andDistribution inCervical Cancer
and Other Human Papillomavirus-Associated Carcinomas.....................................44
Human Papillomavirus-Type Distributionof OncogenicHuman
PapillomavirusTypes Across the Full Spectrum of Cervical Disease....................46
Human Papillomavirus Classification andIts Association With
Carcinogenicity.........................................................................................................46
Implications..............................................................................................................49
References.................................................................................................................50
CHAPTER 4 Finding How Human Papillomaviruses Alter the Biochemistry
and Identity of Infected Epithelial Cells............................................53
SharonC. Wu, Veronica Canarte, Harshita Beeravolu,MirandaGrace,
SurendraSharma and Karl Munger
Parasitic Lifestyles....................................................................................................53
TheEnigmatic, Illogical Life Cycle ofHigh-RiskHuman
Papillomaviruses.......................................................................................................54
Inhibition ofInnateImmune Signaling....................................................................55
Mechanisms That MinimizeHuman Papillomavirus Genome Loss During
CellDivision.............................................................................................................56
High-Risk HPV E6 andE7 Trigger and SubvertCell-Intrinsic Defense
Mechanisms..............................................................................................................58
Human Papillomavirus Infections Render HostCells Genomically Unstable........59
Concluding Remarks................................................................................................60
References.................................................................................................................61
Contents vii
CHAPTER 5 Biology of the Human Papillomavirus Life Cycle: The Basis
for Understanding the Pathology of PreCancer and Cancer.............67
John Doorbar, David Jenkins, MarkH. Stoler and Christine Bergeron
ProductiveInfection Facilitates the Assembly and ReleaseofVirus
Particles.....................................................................................................................68
Genome Maintenance andthe Replication of HPV Genomesin
the EpithelialBasal Layer...................................................................................68
ProductiveInfection and Virus Synthesis Occurs inthe Differentiated
Layersof the Epithelium.....................................................................................70
Nonproductive InfectionLeads to the Development of Neoplasia.........................71
The Role of HPV Gene Products inthe Progression From Neoplasia
toCancer...................................................................................................................72
Understanding the Cervix and Other Vulnerable EpithelialSite
inthe DevelopmentofCancer.................................................................................74
Understanding HPV Biology inRelation tothe Pathological Classification
ofHPV-Associated Cancersand Precancer, andthe Selection ofTreatment
Regimes....................................................................................................................77
Conclusion................................................................................................................80
Acknowledgement....................................................................................................80
References.................................................................................................................80
CHAPTER 6 The Pathology of Cervical Precancer and Cancer
and its Importance in Clinical Practice.............................................85
Mark H. Stoler, David Jenkins and Christine Bergeron
Introduction: Framingthe Problem..........................................................................85
Terminology:Historical Perspective........................................................................85
DiagnosticProcess andSpecimen Types.................................................................87
Cytologic Specimens (“Pap Smears”).................................................................87
Cervical Biopsy...................................................................................................88
Cone Biopsy.........................................................................................................89
Hysterectomy.......................................................................................................89
Gross Morphology(cid:1)ColposcopicFeatures..............................................................89
Morphology (Histology andCytology)....................................................................90
NormalSquamousEpithelium............................................................................90
Low-Grade SquamousIntraepithelialLesions/CIN1..........................................93
High-Grade IntraepithelialSquamous Lesion: CIN2.........................................94
High-Grade IntraepithelialSquamous Lesion Variants......................................96
SquamousCell Carcinoma..................................................................................98
Glandular Neoplasia...............................................................................................100
Samplingof the Endocervical Epithelium........................................................102
AtypicalGlandular Cells...................................................................................102
Endocervical Adenocarcinoma InSitu.............................................................103
Adenocarcinoma................................................................................................103
viii Contents
Using Our Molecular Understanding ofDiseaseProgression toImprove
Diagnosis: Detectionof HPV DNA and Biomarkers ofInfection........................103
Biomarkers.........................................................................................................103
Biomarkers onCytology Samples..........................................................................105
Triageof HPV-Positive Women.......................................................................105
p16/ki-67 Dual Stain.........................................................................................105
Clinical Course andManagement ofCervical Neoplasia.....................................105
Low-Grade Squamous Intraepithelial Lesions Behavior/Management............106
High-Grade Intraepithelial Squamous Lesion Behavior/Management.............106
Further Reading......................................................................................................107
CHAPTER 7 Developing and Standardizing Human Papillomavirus Tests.........111
Attila Lorincz, CosetteMarieWheeler, Kate Cuschieri,Daan Geraets,
Chris J.L.M. Meijer and WimQuint
Historical Development..........................................................................................111
Discovery of Human Papillomavirus................................................................111
CloningofHuman Papillomavirus....................................................................112
First Wave of Human PapillomavirusDNA Tests...........................................113
Spectrum ofAnogenital Human Papillomavirus Types...................................116
First Commercial Human Papillomavirus DNA Tests.....................................116
TargetAmplification for Detection ofHuman Papillomavirus DNA..............118
Broad-Spectrum Polymerase Chain Reaction...................................................118
Type-SpecificPolymerase Chain Reaction.......................................................118
Detection ofHuman Papillomavirus mRNA....................................................119
Polymerase ChainReaction Read-Out Methods...............................................119
Designand Performance Assessmentof Human Papillomavirus Tests................119
Intended Use......................................................................................................119
Clinical Specimen, Collection, andProcessing................................................120
TargetSelection and Amplification..................................................................120
Human Papillomavirus DNA Detection Tests With Partialand Full
Spectrum Genotyping........................................................................................120
Performance Assessment ofHPV Testsand Requirements for Ongoing
Quality Assurance...................................................................................................121
Analytical Versus Clinical Performance...........................................................121
Proficiency Panels.............................................................................................122
Internal/Endogenous Control.............................................................................122
BriefSummary ofSelected Commercial Human Papillomavirus Tests...............123
The Hybrid Capture 2HumanPapillomavirusDNA Test...............................123
GP51/61 System...........................................................................................123
SPF10/DEIA/LiPA System............................................................................124
25
Contents ix
The LINEAR ARRAYHuman Papillomavirus Genotyping
System................................................................................................................124
The Cobas 4800HumanPapillomavirusTest (Roche Cobas).........................124
The APTIMA HumanPapillomavirusassay....................................................124
The BDOnclarity Human Papillomavirus Assay.............................................125
The Xpert Human Papillomavirus Assay..........................................................125
Future Perspectives.................................................................................................125
Vaccinology.......................................................................................................125
Human Papillomavirus Surveillance.................................................................126
Human Papillomavirus-Based Screening..........................................................126
Cervical Screening inVaccinated Women.......................................................126
Full Molecular-Based Screening.......................................................................127
Next Generation Sequencing.............................................................................127
Overview andSummary.........................................................................................128
References...............................................................................................................128
CHAPTER 8 Proving the Causal Role of Human Papillomavirus
in Cervical Cancer: A Tale of Multidisciplinary
Science..............................................................................................131
EduardoL. FrancoandF. Xavier Bosch
Avoidinga Clash Between Different Lines ofScientificEvidence......................131
LearningFrom Errors.............................................................................................133
ANew Beginningfor Molecular Epidemiology...................................................136
The Birth ofa New Paradigm inCancer Prevention.............................................137
Moving From Understanding Etiology toImprovingCervical Cancer
Screening................................................................................................................140
The Opportunity toPrevent Cervical Cancer With a Vaccine..............................141
From Discovery to aNobelPrize..........................................................................142
References...............................................................................................................144
CHAPTER 9 The Natural History of Human Papillomavirus Infection
in Relation to Cervical Cancer.........................................................149
Anna-Barbara Moscicki, Mark Schiffman and
Silva Franceschi
Key Bullet Points....................................................................................................149
Transmission ofHuman Papillomavirus................................................................152
Lack ofStrongEpidemiologic Indicators for Human Papillomavirus
Persistence (or Clearance)......................................................................................153
Roles of Parity, Female Hormones and Tobacco..................................................154
References...............................................................................................................156
x Contents
SECTION 2 HUMAN PAPILLOMAVIRUS BEYOND CERVICAL CANCER
CHAPTER 10 Low-risk Human Papillomavirus: Genital Warts, Cancer
and Respiratory Papillomatosis.......................................................165
Charles J.N. Lacey, NuriaGuimeraand Suzanne M. Garland
TheProblem:Genital Warts and Laryngeal Papillomatosis.................................165
Historical Aspectsof Genital Warts andLaryngeal Papillomatosis.....................166
Risk Factors, Natural History,and Treatment ofGenital Warts and
Laryngeal Papillomatosis.......................................................................................167
Pathology of Genital Warts and Laryngeal Papillomatosis...................................168
Human Papillomavirus inGenital Warts and Laryngeal Papillomatosis..............169
Low-Risk Human Papillomavirus Types andCancer...........................................172
Therapeutic andProphylactic Vaccines AgainstGenital Warts and Laryngeal
Papillomatosis.........................................................................................................173
Past, Present, and Future Epidemiology of Genital Warts andLaryngeal
Papillomatosis.........................................................................................................174
Conclusion..............................................................................................................175
Acknowledgements.................................................................................................175
References...............................................................................................................175
CHAPTER 11 Human Papillomavirus Infection and Related Diseases
Among Men.......................................................................................179
Anna R.Giuliano
Wherethe Story ofMale Human Papillomavirus Infection Among
HeterosexualMen Began: TheMaleFactorin Cervical Carcinogenesis.............179
Human Papillomavirus Natural History inHeterosexual Men—Past
and CurrentUnderstanding....................................................................................179
TheHIM Study: Population and Procedures..........................................................180
Genital Human Papillomavirus Infection..............................................................181
AnalHuman Papillomavirus Infection...................................................................181
Oral Human PapillomavirusInfection...................................................................182
Human Papillomavirus Serology............................................................................183
HeterosexualHuman PapillomavirusTransmission..............................................183
References...............................................................................................................184
CHAPTER 12 Anal HPV Infection and HPV-Associated Disease...........................195
Joel M. Palefsky
Studiesof Anal HPV Infection: Their Origins andInspirations...........................195
DevelopmentofTools toStudy Anal HPV Infection and HPV-associated
Diseases...................................................................................................................196
AnalCancer and Immune Suppression..................................................................198
AnalCancer in HIV-infectedMen andWomen inthe era of Antiretroviral
Therapy...................................................................................................................201
