History of cervical cancer and the role of the human papillomavirus, 1960-2000 : the transcript of a witness seminar held by the Wellcome Trust Centre for the History of Medicine at UCL, London, on 13 May 2008

HISTORY OF CERVICAL CANCERANDTHE ROLE
OFTHE HUMAN PAPILLOMAVIRUS, 1960-2000

The transcript of a Witness Seminar held by the Wellcome Trust Centre
for the History of Medicine at UCL, London, on 1 3 May 2008

Edited by LA Reynolds and E MTansey

Volume 38 2009

©The Trustee of the Wellcome Trust, London, 2009

First published by the Wellcome Trust Centre
for the History of Medicine at UCL, 2009

The Wellcome Trust Centre for the History of Medicine
at UCL is funded by the Wellcome Trust, which is
a registered charity, no. 210183.

ISBN 978 085484 123 3

All volumes are freely available online at: www.histoiy.qmul.ac.uk/research/modbiomedlwelkome_witnesses/

Please cite as : Reynolds L A, Tansey E M . (eds) (2009) History of Cervical Cancer and the Role of the Human
Papillomavirus, 1960-2000. Wellcome W itnessesto Twentieth Century Medicine, vol. 38. London: W ellco me Trust.

CONTENTS

Illustrations and credits v

Abbreviations vii

Witness Seminars: Meetings and publications; Acknowledgements

E MTansey and LA Reynolds ix

Introduction

Anne Johnson xix

Transcript

Edited by LA Reynolds and E MTansey 1

Appendix 1

The emergence of the natural history of cervical cancer

From Professor Leopold G Koss, Montefiore Medical Center and
Albert Einstein College of Medicine, Bronx, New York, NY 83

Appendix 2

Reminiscences on cervical screening

From Dr Arthur Spriggs (written 12 September 2009) 88

From Dr Nasseem Husain (written 2 April 2001, 16 and

31 May 2008) 89

References 93

Biographical notes 129

Glossary 145

Index 153

ILLUSTRATIONS AND CREDITS

Figure 1 Presidents of the British Society for Clinical Cytology

(BSCC), 1962-83. Reproduced by permission
oftheBSCC. 9

Figure 1 Mrs Marilyn Symonds, cytology laboratory,

Stoke Mandeville Hospital, Aylesbury, 1964.
Provided by and reproduced by permission of
Mrs Marilyn Symonds. 1 3

Figure 3 Contributors to the 1985 Banbury Center, conference

on 'The origins of female genital cancer'. (Peto and
zur Hausen (eds) (1986): frontispiece). Reproduced
by permission of the Banbury Center of Cold Spring
Harbor Laboratory, Long Island, New York. 20

Figure 4 Koilocytes, cells infected with HPV, 2009.

Image provided by and reproduced with permission
of Ms Beth Moore (www.flickr.com/photos/
moorepix4u2c). 35

Figure 5 Dr Jian Zhou in Dr Lionel Crawford's Cambridge

laboratory, c. 1989. Provided by and reproduced with
permission of Dr Lionel Crawford. 44

Figure 6 Three Aylesbury spatulas and one Ayre spatula, 2009.

Provided by and reproduced with permission
of Mrs Marilyn Symonds. 54

Figure 7 Dr George N Papanicolaou at the microscope, 1954.

Provided by and reproduced with permission of
Professor Leopold G Koss. 85

Table 1 Outline programme for 'The History

of Cervical Cancer and the Role of the Human
Papillomavirus, 1960-2000' Witness Seminar. 4

Table 2 Standardized mortality ratios (SMR) for cervical

cancer in married women, by social class and
occupation of husband, England and Wales, 1959—63.
Adapted from Beral (1974): 1039. 32

ABBREVIATIONS*

ABC 'Achievable standards, Benchmarks for reporting, Criteria

for evaluating cervical cytopathology' (Herbert (ed.) (1995);
Johnson (ed.) (2000))

AIDS acquired immune deficiency syndrome or acquired

immunodeficiency syndrome

ARTISTIC A Randomized Trial In Screening To Improve Cytology
(Sargent et al. (2008))

BECC British Empire Cancer Campaign (Cancer Research Campaign

from 1970)

BMS biomedical scientists

BPV bovine papillomavirus

BSCC British Society for Clinical Cytology (1961)

BSCCP British Society for Colposcopy and Cervical Pathology (1972)

CIN cervical intraepithelial neoplasia

CIS carcinoma in situ

CRPV cotton-tail rabbit papillomavirus

CSP NHS Cervical Screening Programme

DNA deoxyribonucleic acid

GVS Gynaecological Visiting Society of Great Britain and Ireland

(1911)

HART HPV in addition to routine testing study (Cuzick et al. (2003))

HPV human papillomavirus

HSV herpes simplex virus

IARC International Agency for Research on Cancer

IBMS Institute of Biomedical Science (formerly the Institute of

Medical Laboratory Technology/Science)

Details in parentheses refer to previous name, date of foundation or reference to classic paper

ICRF Imperial Cancer Research Fund

LBC liquid-based cytology

MRC Medical Research Council

NHS CSP NHS Cervical Screening Programme

NICE Nadonal Institute for Health and Clinical Excellence (formerly
National Institute for Clinical Excellence)

p53 protein 53 or tumour protein 53

PCR polymerase chain reaction

RCGP Royal College of General Practitioners

RCOG Royal College of Obstetricians and Gynaecologists

RCPath Royal College of Pathologists

RLU relative light units

RNA ribonucleic acid

SCMR standardized cohort mortality ratios

SMR standardized mortality ratio

STI sexually transmitted infection

TOMBOLA Trial of Management of Borderline and Other Low-Grade
Abnormal smears (Cotton et al. (2006))

VLPs virus-like particles

WITNESS SEMINARS:

MEETINGS AND PUBLICATIONS 1

In 1990 the Wellcome Trust created a History of Twentieth Century Medicine
Group, associated with the Academic Unit of the Wellcome Institute for the
History of Medicine, to bring together clinicians, scientists, historians and others
interested in contemporary medical history. Among a number of other initiatives
the format of Witness Seminars, used by the Institute of Contemporary British
History to address issues of recent political history, was adopted, to promote
interaction between these different groups, to emphasize the potential benefits
of working jointly, and to encourage the creation and deposit of archival sources
for present and future use. In June 1999 the Governors of the Wellcome Trust
decided that it would be appropriate for the Academic Unit to enjoy a more
formal academic affiliation and turned the Unit into the Wellcome Trust Centre
for the History of Medicine at UCL from 1 October 2000. The Wellcome
Trust continues to fund the Witness Seminar programme via its support for
the Centre.

The Witness Seminar is a particularly specialized form of oral history, where
several people associated with a particular set of circumstances or events are
invited to come together to discuss, debate, and agree or disagree about their
memories. To date, the History of Twentieth Century Medicine Group has held
more than 50 such meetings at the time of publication, most of which have
been published, as listed on pages xiii— xvii.

Subjects are usually proposed by, or through, members of the Programme
Committee of the Group, which includes professional historians of medicine,
practising scientists and clinicians, and once an appropriate topic has been
agreed, suitable participants are identified and invited. This inevitably leads to
further contacts, and more suggestions of people to invite. As the organization
of the meeting progresses, a flexible outline plan for the meeting is devised,
usually with assistance from the meeting's chairman, and some participants are
invited to 'set the ball rolling' on particular themes, by speaking for a short
period to initiate and stimulate further discussion.

The following is the standard introductoty text to the Wellcome Witnesses to Twentieth Century
Medicine series.

Each meeting is fully recorded, the tapes are transcribed and the unedited transcript
is sent to every participant. Each is asked to check his or her own contributions and
to provide brief biographical details. The editors turn the transcript into readable
text, and participants' minor corrections and comments are incorporated into that
text, while biographical and bibliographical details are added as footnotes, as are
more substantial comments and additional material provided by participants. The
final scripts are then sent to every contributor, accompanied by forms assigning
copyright to the Wellcome Trust. Copies of all additional correspondence received
during the editorial process are deposited with the records of each meeting in
archives and manuscripts, Wellcome Library, London.

As with all our meetings, we hope that even if the precise details of some of the
technical sections are not clear to the non-specialist, the sense and significance
of the events will be understandable. Our aim is for the volumes that emerge
from these meetings to inform those with a general interest in the history of
modern medicine and medical science; to provide historians with new insights,
fresh material for study, and further themes for research; and to emphasize to
the participants that events of the recent past, of their own working lives, are of
proper and necessary concern to historians.

Members of the Programme Committee of the
History ofTwentieth Century Medicine Group, 2009-10

Professor TilliTansey - professor of the history of modern medical sciences,
WellcomeTrust Centre for the History of Medicine at UCL (WTCHM) and chair

Dr Sanjoy Bhattacharya - reader in the history of medicine, WTCHM

Sir Christopher Booth - former director, Clinical Research Centre,
Northwick Park Hospital, London

Dr John Ford - retired general practitioner; Tonbridge

Professor Richard Himsworth - former director of the Institute of Health,
University of Cambridge

Professor Mark Jackson - professor of the history of medicine and director;
Centre for Medical History Exeter

Professor John Pickstone -Wellcome research professor; University of Manchester

Mrs Lois Reynolds - senior research assistant, WTCHM, and organizing secretary

Professor Lawrence Weaver - professor of child health, University of Glasgow, and
consultant paediatrician in the Royal Hospital for Sick Children, Glasgow

ACKNOWLEDGEMENTS

'History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000'
was suggested as a suitable topic for a witness seminar by Professor David Jenkins,
who assisted us in planning the meeting. We are very grateful to him for that input
and to Professor Glenn McCluggage for his excellent chairing of the occasion. We
are particularly grateful to Professor Anne Johnson for writing the Introduction to
the published proceedings. Our additional thanks go to Professor Leopold Koss, Dr
Arthur Spriggs and Dr Nasseem Husain, who have allowed us to reproduce some
of their reminiscences in Appendices 1 and 2. We thank the participants for their
help with the Glossary and Dr Lionel Crawford, Professor Leopold G Koss and
Mrs Marilyn Symonds for help with photographs. For permission to reproduce
other images included here, we thank the Banbury Center of Cold Spring Harbor
Laboratory Archives, the British Society for Clinical Cytology and Ms Beth Moore.
Professor Valerie Beral did not assign copyright for the use of her contribution and
thus it is included as reported speech.

As with all our meetings, we depend a great deal on staff of the Wellcome Trust
to ensure their smooth running: especially the audiovisual, catering, reception
and security departments and Wellcome Images. Mr Akio Morishima supervised
the design and production of this volume; Ms Liza Furnival provided the index;
and Mrs Sarah Beanland and Mr Simon Reynolds read the transcript for sense
and consistency; and Ms Stefania Crowther has given editorial and marketing
assistance. Mrs Jaqui Carter transcribed the tapes, and Mrs Wendy Kutner and
Ms Stefania Crowther assisted in running the meeting. Finally we thank the
Wellcome Trust for supporting this programme.

77///' Tansey

Lois Reynolds

WellcomeTrust Centre for the History of Medicine at UCL

VOLUMES IN THIS SERIES*

1. Technology transfer in Britain: The case of monoclonal antibodies
Self and non-self: A history of autoimmunity

Endogenous opiates

The Committee on Safety of Drugs (1997)

ISBN 1 86983 579 4

2. Making the human body transparent: The impact of NMR and MRI
Research in general practice

Drugs in psychiatric practice

The MRC Common Cold Unit (1998)

ISBN 1 86983 539 5

3. Early heart transplant surgery in the UK (1999)*

ISBN 1 84129 007 6

4. Haemophilia: Recent history of clinical management (1999)

ISBN 1 84129 008 4

5. Looking at the unborn: Historical aspects of
obstetric ultrasound (2000)

ISBN 1 84129 011 4

6. Post penicillin antibiotics: From acceptance to resistance? (2000)

ISBN 1 84129 012 2

7. Clinical research in Britain, 1950-1980 (2000)*

ISBN 1 84129 016 5

8. Intestinal absorption (2000)*

ISBN 1 84129 017 3

9. Neonatal intensive care (2001)

ISBN 85484 076 1

*Volumes in print and freely available from Dr Carole Reeves,
see page xvi.

1 0. British contributions to medical research and education in Africa
after the Second World War (2001)

ISBN 85484 077 X

1 1 . Childhood asthma and beyond (2001)*

ISBN 85484 078 8

1 2. Maternal care (2001)

ISBN 85484 079 6

1 3. Population-based research in south Wales: The MRC Pneumoconiosis
Research Unit and the MRC Epidemiology Unit (2002)

ISBN 85484 081 8

14. Peptic ulcer: Rise and fall (2002)*

ISBN 85484 084 2

15. Leukaemia (2003)*

ISBN 85484 087 7

1 6. The MRC Applied Psychology Unit (2003)*

ISBN 85484 088 5

1 7. Genetic testing (2003)*

ISBN 85484 094 X

18. Foot and mouth disease: The 1967 outbreak and its aftermath
(2003)*

ISBN 85484 096 6

1 9. Environmental toxicology: The legacy of Silent Spring (2004)*

ISBN 85484 091 5

20. Cystic fibrosis (2004)

ISBN 85484 086 9

21 . Innovation in pain management (2004)

ISBN 978 85484 097 7

22. The Rhesus factor and disease prevention (2004)

ISBN 978 85484 099 1

23. The recent history of platelets in thrombosis and other disorders
(2005)

ISBN 978 85484 103 5

24. Short-course chemotherapy for tuberculosis (2005)

ISBN 978 85484 104 2

25. Prenatal corticosteroids for reducing morbidity and mortality
after preterm birth (2005)

ISBN 978 85484 102 8

26. Public health in the 1980s and 1990s: Decline and rise? (2006)

ISBN 978 85484 106 6

27. Cholesterol, atherosclerosis and coronary disease in the UK,
1950-2000 (2006)

ISBN 978 85484 107 3

28. Development of physics applied to medicine in the UK, 1945-1990
(2006)

ISBN 978 85484 108

29. Early development of total hip replacement (2007)

ISBN 978 85484 1110

30. The discovery, use and impact of platinum salts as
chemotherapy agents for cancer (2007)

ISBN 978 85484 112 7

31 . Medical ethics education in Britain, 1963-1993 (2007)

ISBN 978 85484 113 4

32. Superbugs and superdrugs: The history of MRSA (2008)

ISBN 978 85484 114 1

33. Clinical pharmacology in the UK, c. 1950-2000: Influences and
institutions (2008)

ISBN 978 85484 117 2

34. Clinical pharmacology in the UK, c. 1950-2000: Industry and
regulation (2008)

ISBN 978 85484 118 9

35. The resurgence of breastfeeding, 1975-2000 (2009)

ISBN 978 85484 119 6

36. The development of sports medicine in twentieth-century Britain
(2009)

ISBN 978 85484 121 9

37. History of dialysis, c. 1950-1980 (2009)

ISBN 978 85484 122 6

38. History of cervical cancer and the role of the human papillomavirus,
1960-2000 (2009)

ISBN 978 85484 123 3 (this volume)

39. Clinical genetics in Britain: Origins and development (2010)

ISBN 978 85484 127 1 (in press)

40. The medicalization of cannabis (2010)

ISBN 978 85484 129 5 (in press)

All volumes are freely available online at www.ucl.ac.uk/histmed following
the links to Publications/Wellcome Witnesses.

* Volumes freely available, while stocks last, from Dr Carole Reeves at:
c.reeves@ucl.ac.uk

Hard copies of volumes 21-38 can be ordered from www.amazon.co.uk;
www.amazon.com; and all good booksellers for £6/$10 each plus postage,
using the ISBN.

UNPUBLISHED WITNESS SEMINARS

1 994 The early history of renal transplantation

1 994 Pneumoconiosis of coal workers

(partially published in volume 13, Population-based research
in south Wales)

1 995 Oral contraceptives

2003 Beyond the asylum: Anti-psychiatry and care in the community

2003 Thrombolysis

(partially published in volume 27, Cholesterol, atherosclerosis and
coronary disease in the UK, 1950—2000)

2007 DNA fingerprinting

The transcripts and records of all Witness Seminars are held in archives
and manuscripts, Wellcome Library, London, at GC/253.

OTHER PUBLICATIONS

Technology transfer in Britain: The case of monoclonal antibodies

Tansey E M, Catterall P P. (1993) Contemporary Record*): 409-44.

Monoclonal antibodies: A witness seminar on contemporary medical history

Tansey E M, Catterall P P. (1994) Medical History 38: 322-7.

Chronic pulmonary disease in South Wales coalmines: An eye-witness
account of the MRC surveys (1937-42)

P D'Arcy Hart, edited and annotated by E M Tansey. (1998)
Social History of Medicine 11: 459—68.

Ashes to Ashes — The history of smoking and health

Lock S P, Reynolds L A, Tansey E M. (eds) (1998) Amsterdam: Rodopi BV,
228pp. ISBN 90420 0396 (Hfl 125) (hardback). Reprinted 2003.

Witnessing medical history. An interview with Dr Rosemary Biggs

Professor Christine Lee and Dr Charles Rizza (interviewers). (1998)
Haemophilia 4: 769-77.

Witnessing the Witnesses: Pitfalls and potentials of the Witness Seminar
in twentieth century medicine

Tansey E M, in Doel R, Soderqvist T (eds) (2006) Writing Recent Science:
The historiography of contemporary science, technology and medicine. London:
Routledge: 260-78.

The Witness Seminar technique in modern medical history

Tansey E M, in Cook H J, Bhattacharya S, Hardy A. (eds) (2008) History
of the Social Determinants of Health: Global Histories, Contemporary Debates.
London: Orient Longman: 279-95.

Today's medicine, tomorrow's medical history

Tansey E M, in Natvig J B, Sward ET, Hem E. (eds) (2009) Historier om
helse [Histories about Health, in Norwegian). Oslo: Journal of the Norwegian
Medical Association : 166-73.

INTRODUCTION

It took nearly 150 years from Rigoni-Stern's observation that 'cancer of the
uterus' might be related to sexual lifestyle (page 83), for Human Papilloma
Virus (HPV) to be established as the cause of cervical cancer in the 1980s. His
observation that cancer was more common in married women than virgins and
nuns in nineteenth-century Verona gave the first clue to aetiology. A century
later epidemiological studies identified the sexual behavioural risks for cervical
cancer in both women and their male partners. In parallel, gynaecologists,
virologists and cytologists were making rapid advances in their understanding
of the natural history of cervical cancer, the detection through cervical cytology
of preinvasive stages of cervical cancer, and we're beginning to explore the
possibility of a viral cause.

This Witness Seminar volume gives fascinating insights into the science,
serendipity, and dogged commitment of a generation of clinicians, virologists,
cytologists, epidemiologists, and public health specialists in establishing cervical
screening as a sensitive, specific and effective tool to reduce cancer mortality.
Papanicolaou developed his smear test for early cancer detection in 1943 but
it took until 1988 for a properly organised population-based service to be
established in England.

The witnesses here trace the work leading to the discovery of HPV as a cause of
cervical cancer through advances in detection methods which identified oncogenic
viral types and thus paved the way for development of HPV vaccines.

But with the evolution of the science comes the determined and tireless effort of
those who drove screening policy (such as Muir Gray, Jocelyn Chamberlain and
Catherine Pike), those gynaecologists who were early adopters (such as Stanley
Way and later Albert Singer) and the army of major contributors (mainly
women) who led and executed the programmes of screening, read the smears,
improved the accuracy and standardization of methods of sample collection,
cytological protocols, call and recall and clinical follow-up over the course of
several decades.

I have not been directly involved in cervical cancer research but have followed
the unfolding story of aetiology and control from the sidelines over the last
30 years with gratitude for what has been achieved. It is my generation who
were among the first to benefit from cervical cancer screening and it will be
my daughter's generation who will be the first hopefully to benefit from the

introduction of HPV vaccination. But like the cervical screening programme
before it, population benefit will only be achieved through high uptake and
efficacy against all the predominant circulating oncogenic viruses.

I first became aware of the beginnings of cervical screening in the 1960s. Both
my parents were gynaecologists and worked for Stanley Way in Newcastle in the
1940s and 1950s. My mother recounts details of the radical surgery undertaken
by Way for advanced case of cancer and the early experiments comparing
outcomes of surgery and radium treatment, but mortality was high.

Accounts of the 1960s and 1970s abound with tales of the uncertainty
about effectiveness of screening and the disorganization, inconsistency and
opportunistic nature of much screening. Lamentably much of that uncertainty
might have been circumvented if Archie Cochrane's calls for randomized clinical
trials had been heeded (pages 18 and 59, notes 44 and 162).

My mother, along with many women doctors of her generation, was in part-
time work in family planning and cervical cytology clinics. She lamented the
poor technique used by many doctors and recalls teaching the importance
of visualization of the cervix to local GPs in Manchester, and the days of
undertaking screening of women in factories around Manchester in a mobile
unit. But she felt her efforts detected more ovarian than cervical pathology. Too
often they were screening the low-risk women.

Her account resonates with the report here. The 1960s and 1970s were the
years of concerted effort to improve the specificity and consistency of tests and
the coverage of screening by those who were the product champions of the day.
While attempts had been made by the then Ministry of Health to establish a
smear testing programme in 1964, it was not until 1988 that the current NHS
Cervical Screening Programme was established, largely as an outcome of the
efforts of the 1987 Intercollegiate Working Party (pages 26-9). An impassioned
editorial in the Lancet, attributed to George Knox, is testimony to the frustration
felt about the lack of substantial impact on cancer mortality between 1964
and 1984 at least in part, because of the lack of an organised population-based
approach: No-one knows what proportion of women have been screened at
different ages, and what proportion have not.' 3

My mother still has an unpublished report of Way's travels to Canada and the US in the early 1950s, where
he recounts some of the early cytology being carried out there. These documents, along with other records
of the meeting, will be deposited at GC/253 in archives and manuscripts, Wellcome Library, London.

3 Anon (1985): 363.

There are parallels with another sexually transmitted infection, Chlamydia
trachomatis, in which an 'opportunistic' screening programme is currently being
'rolled-out', among young men and women, without randomized controlled trial
(RCT) evidence of effectiveness, and without population coverage or defined
screening interval. In the week in which I write, a report for the National Audit
Office raised concerns about lack of uptake or evaluation of outcomes and poor
value for money.

Assessing effectiveness of the programme relied on observational data of rates
of cervical cancer and cancer deaths. But as Sasieni set out (page 64), it was
difficult to assess impact because it was known that cervical cancer incidence
and cervical intraepithelial neoplasia (CIN) 3 were increasing in those born
after 1940. Beral described this in her Lancet article of 1974. In an elegant
analysis based on standardized cohort mortality ratios (SCMRs), she was able
to demonstrate that SCMRs at age 20 in successive birth cohorts from 1902—
47 rose and fell in parallel with changing incidence of gonorrhoea. Risk was
highest among women whose husbands were in occupations associated with
higher sexually transmitted infection (STI) risk (pages 31-2).'

The putative changes in sexual behaviour driving the growing gonorrhoea
epidemic from the 1960s to the mid-1980s (when AIDS resulted in a rapid
decline in incidence) were not documented in population studies until 1 990. The
first National Survey of Sexual Attitudes and Lifestyles (Natsal), of which I was
principal investigator, was famously banned from public funding by Margaret
Thatcher and later funded by the Wellcome Trust. The study documented the
rapid decline in age at first intercourse from the 1950s onwards, the rising rate
of sexual partner change driving the observed increase in STI incidence and,
as we now know, the underlying silent epidemic of oncogenic HPV infection.
No wonder, with incidence of the underlying cause rising, that it was difficult
to demonstrate any major impact of incomplete screening on cervical cancer
mortality. But mortality rates did decline substantially after 1988. 7

National Audit Office (2009). Summaries available atwww.nao.org.uk/publications/0809/young_peoples_
sexualhealth.aspx. For news coverage of the report, see http://news.bbc.co.Uk/l/hi/health/8354932.stm
(both sites visited 24 November 2009).

5 Beral (1974).

Johnson et al. (1992, 1994). A Witness Seminar on 'The history of the National Sexual Attitudes and
Lifestyles Survey' will be held on 14 December 2009 and will be published as volume 41 in the Wellcome
Witnesses to Twentieth Century Medicine series.

7 Sasieni and Adams (1999).

The idea that cervical cancer was associated with some aspect of sexual lifestyle
was not new in the 1960s and Stanley Way and later Albert Singer and others
were among those who studied the 'male factor' in the aetiology of cervical
cancer. The idea that it might be related to a specific viral infection was gathering
strength (pages 29-32).

In retrospect, the initial suggestion of Herpes Simplex Virus (HSV) as a cause of
cervical cancer by Rawls et al. in 1968 diverted attention from HPV, a classical
case of association being confused with causality. A range of STIs could be
associated with cervical cancer because they shared the common route of sexual
transmission. But the HSV hypothesis held sway through much of the 1980s,
despite the failure to demonstrate viral DNA in malignant tissue (page 34).

This Witness Seminar report has something of the air of a detective story, with
strands of evidence from different disciplines all contributing to the identification
of the aetiological role of HPV. The recognition that the koilocytes were similar
to cells from histological condylomata contributed to the identification of HPV
in these cells. The development ofvirological methods in the 1970s identified the
different types of HPV, followed by the discovery by Gissman and zur Hausen
of HPV16 and 18 in 1980. 9 Methods of hybrid capture assays and polymerase
chain reaction all revolutionized detection, characterization, and quantification
of infectious organisms, and knowledge of their role in health and disease. As
Patrick Walker attests, it took some time before the 'received wisdom' that HSV
had a role in cervical cancer aetiology could be put to rest (pages 33—4). It seems
that only in the last decade with the successful development of HPV vaccines,
that HPV has been generally accepted as a cause.

The importance of the work of the late Jian Zhou with Ian Frazer in developing
the underlying virological work which made the production of a vaccine possible
is given due emphasis in the transcript (pages 43—6). It has arguably been a
gratifyingly short time between the discovery of HPV as a cause of cervical cancer
and the implementation of a vaccination programme in young women. The
debate will continue about the scientific and economic factors underpinning the
choice in the UK of a bivalent rather than quadrivalent vaccine as in the US and
Europe, 10 and thus will likely extend to the value of vaccinations in males. 11

8 Rawls etal (1968).

Gissmann and zur Hausen (1980).
10 Kmietowicz (2008).

Castle and Scarinci (2009).

It will need another generation to measure the population uptake of vaccine and
impact on cervical cancer, since the vaccine will not protect against all oncogenic
viruses. The cervical screening programme will in turn need to be re-evaluated
in successive cohorts. It is too early to measure the longer term acceptability
and uptake of the current vaccine, which has had its proponents and detractors.
Public concerns about vaccine safety will always cause nervousness among
policy and programme leaders. The death of a young woman in 2009 shortly
after receiving HPV vaccination was subsequently shown to be unrelated to the
vaccine, but was sufficient to suspend the UK programme for a few days until
the cause of death was known. 12

The well organized population-based cervical screening programme established
since 1988 has demonstrated its impact through secondary prevention of
cervical cancer. The impact of the primary prevention programme through HPV
vaccination on future generations is the culmination of a fascinating scientific
story and one for future historians to recount.

Anne M Johnson

Division of Population Health and Institute for Global Health, UCL

O'Dowd (2009).

HISTORY OF CERVICAL CANCERANDTHE ROLE
OFTHE HUMAN PAPILLOMAVIRUS, 1960-2000

The transcript of a Witness Seminar held by the Wellcome Trust Centre
for the History of Medicine at UCL, London, on 1 3 May 2008

Edited by LA Reynolds and E MTansey

HISTORY OF CERVICAL CANCER AND THE ROLE
OF THE HUMAN PAPILLOMAVIRUS, 1960-2000

Participants

ProfessorValerie Beral

Professor Saveria Campo

Professor Jocelyn Chamberlain

Professor Dulcie Coleman

Dr Lionel Crawford

Professor Heather Cubie

Professor Jack Cuzick

Dr Ian Duncan

Dr Winifred Gray

Dr Amanda Herbert

Professor David Jenkins

Dr Elizabeth Mackenzie

Drjoan Macnab

Professor Glenn McCluggage (chair)

Professor Anthony Miller

Professor Julian Peto

Dr Catherine Pike

Professor Peter Sasieni

Professor Albert Singer

Drjohn Smith

Professor Margaret Stanley

Mrs Marilyn Symonds

Dr Anne Szarewski

DrTilliTansey

Professor Leslie Walker

Mr Patrick Walker

Dr Margaret Wolfendale

Professor Ciaran Woodman

Among those attending the meeting: Mr Ken Campbell, Professor Steve
Gallivan, Ms Rosemary Sowerby Dr Elizabeth Toon, Dr David Wright

Apologies include: Dr Malcolm Anderson, Professor Leszek Boryseiwicz,

Professor Xavier Bosch, Dr Peter Boyle, Professor Linda Bryder, Dr Blanche

Butler, Professor Nicholas Day, Drjohn Doorbar, Professor Harold Fox,

Dr Sylvia Franchesci, Professor Dr Lutz Gissmann, Sir Muir Gray

Professor Sir Andrew Haines, Dr O A N (Nasseem) Husain, Dr Jane Johnson,

Professor Joe Jordan, Professor Henry Kitchener, Professor liana Loewy,

Professor Attila Lorincz, Mr Michael Palmer, Mrs Julietta Patnick,

Professor Frank Sharp, Professor Peter Stern, Professor Sir James Underwood,

Professor David Whynes, Mr Dennis Williams

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

DrTilliTansey:I would like to begin by welcoming you to this Witness Seminar
on cervical cancer and the human papillomavirus from I960 to 2000. These
Witness Seminars were started by the Wellcome Trust about 15 years ago and
they are designed to get together a group of people who have been involved in
a particular event or discovery, or people who have seen a lot of changes in their
professional lives, to get them together to talk and discuss among themselves,
sometimes disagree quite drastically, about what happened and why did things
happen. We all know that if we read conventional scientific papers and medical
accounts, it doesn't always tell us how things happened and why. So that is the
purpose of these meetings. The entire meeting is recorded and transcribed and
then the transcript is edited and published.

Because we are going to record everything, we would like people to contribute
informally as the meeting goes on. Nothing will be published without your
permission, so we will ask you to assign legal copyright to the Wellcome Trust.
This meeting was suggested by Professor David Jenkins, who is now an affiliated
worker in the Wellcome Trust Centre for the History of Medicine at UCL, where
he is working on this subject. We are delighted that Professor Glenn McCluggage
from Belfast, who is a consultant pathologist there, has agreed to be our chairman
for this meeting. So without further ado, I will hand over to Glenn.

Professor Glenn McCluggage: Good afternoon everyone, and welcome to this
Witness Seminar. Probably most of you in this audience don't know me, but I
am a gynaecological histopathologist in Belfast and I suspect everybody in this
audience knows more about HPV than myself. My interest in HPV started
quite a few years ago. I started off in gynaecological pathology by reporting a lot
of cervical punch and loop biopsies' from colposcopy clinics and so I see a lot
of disease related to human papillomavirus and it is certainly a very important
topic to be discussed. Hopefully, my role will be limited. It is either making sure
that the discussion keeps going or, on occasions, to stop people talking who are
going on for too long.

You have a list of topics that we will try to discuss and the format is going
to be fairly open regarding each of these (Table 1). Without further ado, I
am going to introduce Professor David Jenkins, who is going to set the scene.
David worked in the University of Nottingham for many years and had a very

See Glossary, page 145.

A general draft outline of each Witness Seminar is circulated among all participants prior to the meeting.
The outline is flexible and not all the topics listed are covered in depth. See Table 1 , page 4.

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

Cervical cytology and colposcopy

How did cervical cytological screening develop
Who became a cytologist and why
Life and interactions in a cervical screening laboratory
The impact of colposcopy in the 1980s

The discovery of HPV and development of HPV research

The unknown male factor'

Finding HPV 16 and 18

The mechanisms and genes of HPV

p53andVLPs

Immune responses to HPV

Epidemiology and the natural history and importance of HPV

The UK national screening programme

Evidence on when screening works and when not

The organization of a national programme and the screening centers

The public health impact of screening reorganization

Later developments in applying understanding of HPV

HPV testing

HPV testing in triage and screening

The personal dimension

Table 1. Outline programme for The History of Cervical Cancer and
the Role of the Human Papillomavirus, 1960-2000' Witness Seminar

firm interest in preinvasive cervical lesions, and latterly he has been working in
Brussels, helping to organize clinical trials with one of the new HPV vaccines.
So David, could you start us off?

Professor David Jenkins: First of all, may I welcome everybody. It's great that
people have come. The gestation of this meeting has been around about two
years, so it's taken a while to contact everybody, to get everything established
and to actually be able to hold this meeting. Thanks to Tilli Tansey and the
Wellcome Trust for sponsoring and organizing the meeting and to Professor
McCluggage for chairing it. It's very important that the chairman is not an
HPV person, because we need somebody, who is not too deeply involved as a
protagonist in HPV, to be a neutral chairman for this session.

My interest in this subject goes back a long way, and one of the attractions
of HPV and cervical cancer for me is that it is a microcosm of relationships
between science, medicine and society. A lot of key issues that are involved in the
interactions between these different worlds are brought out in the study of HPV
and cervical cancer, in the development of cervical screening and more recently

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

now with the vaccines for preventing HPV infection and thus cervical cancer.
We have decided to cut this discussion off at 2000 because we don't really want
to get too much into the current controversies in which many people are still
involved, and the areas where there are still big decisions to make.

We want to look at how two parallel stories have developed: one is the evolution
of cervical cancer prevention through screening, and the second is the HPV
story since the early 1960s, since cervical screening was first introduced then,
and how these two have become intertwined in relation to attempts to prevent
cervical cancer. This has also had a lot of spin-offs. It has meant that it has been
a very multidisciplinary activity, there are a lot of different people involved,
and I am glad that we have been able to get a good mixture of cytologists,
pathologists, clinicians, epidemiologists, psychologists, as well as a few medical
historians involved in this meeting.

It is a really interesting area, and one of the fascinating parts of it is the way
in which it has grown up as an area in the era of sex, drugs, and rock and roll.
Certainly we all know that sex has been heavily involved in HPV transmission,
but it is a different sexually transmitted disease from the conventional ones.
Some of the issues that have happened and affected HPV have seen people trying
to draw parallels with traditional sexually transmitted diseases and particularly
with HIV, as another new disease, but a very different one.

The history that we want to get today, as Tilli has said, is a bit of the unofficial
history, as well as people's role in the official history of the development of both
screening and HPV. We don't want to indulge in conventional hagiography of
some kinds of medical history. When I was researching this, I looked through
what was available on the web about George Papanicolaou and there's some stuff
which really amounts to almost canonization of the guy. He was born in the same
town as an ancient physician, Diodes (who was second only to Hippocrates),
and he looked after a leper colony, arrived penniless in the US and, in order to
begin to fund his academic activities, worked as a rug salesman, while his wife
worked as a tailor. That's wonderful, and may or may not be totally true, but we
want to get to some of the more ordinary stories, and some of the actual ways
in which this admittedly important initial step with screening was translated
into the huge success of cervical screening by thousands of people — doctors,

The UK national programme to vaccinate girls aged 12—13 years began in September 2008, along with
some girls aged 17 years, using the bivalent vaccine Cervarix (GSK) giving protection against HPV subtypes
16 and 18; girls aged 16—18 years were eligible from September 2009; and those aged 15—17 years of age
from September 2010. See Anon (2008); Gilman etal (2009).

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

public health workers, technicians and screeners in many countries and very
successfully in the UK. We also know that the HPV story has expanded from
very small numbers of people in the 1970s and 1980s, up to the International
Papillomavirus Conferences and International Papillomavirus Society meetings,
which regularly attract over 1000 people every 18 months.

McCluggage: Shall we consider how cervical cytology screening developed?

Dr Elizabeth Mackenzie: It is good to see so many of my colleagues from the
past here, the great, the good and the not so good. It does give me great pleasure
to be here.

I had an interesting beginning: I trained at Bart's in the dim and distant past,
qualified in 1957, and when we got back to England from Malta in 1961, I
think it was my husband, Campbell, who decided that there was no way that I
was ever going to get a job and that I ought to do public health, which is what
I duly did. I am eternally grateful, because I think that's the thing that made me
understand what screening was all about.' It wasn't taking smears and forgetting
about them. From there I got up to Glasgow, with five sessions a week. The
gynaecologist in Glasgow asked: 'Would I like to do a closed community survey
of the women in Campbeltown?', which is where Campbell came from and
it certainly is closed. I went to get trained and my first mentor was Helena
Hughes. 7 So I trained and set up the beginnings of the screening programme
in the Southern General Hospital in Glasgow, but then, like all dutiful wives,
moved down to London in 1967. I was introduced to Dr Nasseem Husain,

For an evaluation of the early history of cytodiagnosis, and the final page of Papanicolaou's 1928 paper,
see Spriggs (1977): 1094. See also Papanicolaou and Traut (1943); Traut and Papanicolaou (1943);
Fremont-Smith and Graham (1952). Dr Margaret Wolfendale wrote: 'To make the historical context more
comprehensive it might be worth mentioning that as a result of Aureli Babes independently recognizing that
cervical cancer could be recognized in cervical smears in Bucharest in 1927, this test was routinely used on
a large scale by Kermauner and Schiller (Spriggs (1977)).' Note on draft transcript, 26 November 2008. See
Babes (1931); see also note 239.

Dr Elizabeth Mackenzie wrote: 'Mr James Mair, one of the more enlightened gynaecologists, suggested
that it would be useful to train in cytology with Helena Hughes at the Glasgow Royal Infirmary and set up
a screening programme in the small isolated town of Campbeltown in Kintyre. Dr Elizabeth Macgregor
had already established a very successful well-organized screening programme covering the population of
Aberdeen.' Note on draft transcript, 26 November 2008.

Dr Elizabeth Mackenzie wrote: 'This remained a paper exercise only, as we returned south to England.'
E-mail to Mrs Lois Reynolds, 13 September 2009.

' See, for example, Evans etal. (1986, 1987).

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

my second mentor, in a very busy laboratory at St Stephen's Hospital, Chelsea,
who I thought was going to be here today. It was the first time I learned about
automatic screening. He seemed to think that a bit of kit from Cambridge
Instruments — a densitometer — was going to automatically screen the smears,
which was absolute nonsense, because they were not monolayered cells. It was
terrific fun and I had some lovely papers out of that.

I then moved to Bristol in 1969, and the one thing about being a trained
cytologist was that you got a job anywhere. The hospitals were desperately short.
I then started up in Bristol, which was a moderate sized town of about 400 000,
and there the beginnings of my interest in screening programmes started. This
business about 'you can't take smears and forget about it,' is not possible.

We had the chief accountant of the South West Electricity Board as chairman
of Southmead Hospital board, who was interested in computers. We were then
taken over by the area health authority, and, I must say, it was really interesting
persuading our colleagues that women didn't need to be screened at five-minute

Dr Husain was unable to attend the Witness Seminar on 13 May 2008. Dr Elizabeth Mackenzie wrote:
'Dr Nasseem (O A N) Husain was experimenting with automated screening using normally prepared
smears, but attempting to identify malignant cells by their staining densities. Unfortunately it took some
years for this to progress and it wasn't until the introduction of the preparation of monolayered samples that
this was successful. It is interesting to note that in contrast to Scotland, England was training non-medical
staff to undertake primary screening. Despite having no previous scientific training, many of them provided
the major staffing in the screening laboratories and their contribution was later recognized by the British
Society for Clinical Cytology (BSCC) with a diploma and, for the more senior, membership of the society'
Note on draft transcript, 26 November 2008. See, for example, Husain (1972).

See, for example, Husain et al. (1970); Spriggs (1969). Further details of the Quantimet image analyser
with densitometer can be found at www.computerhistory.org/brochures/companies.phpPalpha-g-
i&company=com-42bclcecl37d6 (visited 30 April 2009).

Dr Elizabeth Mackenzie wrote: 'I worked with Dr Frank Lewis in Bristol and it is interesting to note
that none of my mentors started out with an interest in gynaecological cytology; Helena Hughes, Nasseem
Husain and Frank Lewis were a gynaecologist and two haematologists, respectively' Note on draft transcript,
26 November 2008.

Dr Elizabeth Mackenzie wrote: 'Interestingly, the development of the computer programme in Bristol
was supported by the chairman of Southmead Hospital board. His son persuaded his firm, IBM, to provide
us with computer expertise and suitable software to screen the Avon population of 250 000 women between
the ages of 20 and 64 every five years. The five-year interval programme in Bristol proved to be successful
and it prevented unnecessary interval smears from overloading the laboratory, as we returned them to the
sender unread if there were no clinical signs or symptoms. This policy was unpopular to begin with until it
was realized that it was effective and there was a finite amount of money supporting the service.' Note on
draft transcript, 26 November 2008.

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

intervals; you could have a reasonable sort of screening service at five-yearly
intervals, although I might add that several people here will disagree with
me, and certainly at that stage it was quite a miracle to get a regular screening
interval. The other thing was to get it into proper records, so that wherever
these women went, their screening histories followed them.

Jenkins: That's a good introduction, because, I think, it raises a lot of important
points about the start of screening, mainly how disorganized it was.

Mackenzie: May I say one thing about screening in Scotland? What was
interesting about Scotland is that they trained doctors to screen, and the only
good thing that I got out of it was that you knew exactly what screening was
all about, you didn't treat it lightly. Your colleagues who were screeners and
eventually everyone in the screening service deserved enormous support and
pats on the back. It was a very different set-up in Scotland, which was all
doctor-led, which was a so-called 'waste of expertise'. I think the combination
of screeners and medical people in the screening service made a huge difference
to what went on.

Jenkins: So when did you start using screeners in the screening service?

Mackenzie: We had screeners from day one when I got to Bristol in 1969. I
think it was quite a while before they started using screeners in Scotland.

Dr Ian Duncan: The initial screeners in Scotland in the early 1960s were, as Liz
Mackenzie has pointed out, enthusiastic female doctors. There was Elizabeth
Macgregor in Aberdeen, Helena Hughes in Glasgow, and Helen Duguid in
Dundee. They employed part-time female doctors largely, and this was
because, of course, the nature of screening meant that you had to do it part-
time. You couldn't spend all day screening, because you can't maintain that

For further discussion about the Lancet 1985 editorial, see pages 14 and 19. See also Threlfall et al.
(1997).

13 See also notes 8, 21, 24 and pages 8—9, 22—23.

Dr Euphemia McGoogan set up the BSCC national certificate of competence in cytology
screening examination (end-of-training exam for cytology screeners) in 1988 and ran it for three
years. She co-authored the NHS Cervical Screening Programme (NHSCSP) training logbook for
cytology screeners and designed a logbook and training programme for trained cytology screeners
wishing to gain competence in reading liquid-based cytology cervical samples. See www.csi.org.nz/
proceedings/mcgoogan.pdf (visited 30 September 2009).

See Dr Elizabeth (Betty) Macgregor's Biographical note, page 136.

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

PAST PRESIDENTS OF THE BSCC

PRESIDENT OF THE BSCC

Or. J. Bamfonh (1962-19641

Cvonasy at St Thamta tiaieical McdtE&t School

Professor £ Wactilsl (1 868-1 971 1

Couft&fY ot Mrs Pat Chapman

Dr. C.W. Taylor (1965-1968]

Pralessor K.R. Hill (1 971-1973)

Cvunasv ol World Muttic'fw

Dr, J.E. Maccjregor 1 1980-19831

Dr. A.I. Spngos [1974-1 977)

Dr. OAN. Husam (1977-1980)

Figure 1: Presidents of the British Society for Clinical Cytology (BSCC), 1962-83.

BSCC (1983): 2-3.

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

level of concentration. It very much suited the individual who didn't want to
devote the whole day to medical work. I think that the cytoscreeners then were
laboratory technicians, and that was the way that they trained, as laboratory
technicians. They then became screeners themselves, again, very much on a
part-time basis, and that happened in the late 1960s-early 1970s.

Dr Margaret Wolfendale: I started in cytology in 1962 and there are quite a
few parallels, because I became a cytologist as I had moved with my husband.
In those days there was very, very little open to women in medicine, unless
they were going to dedicate their whole life to it, full-time. The only part-time
work was either as an assistant in general practice, or else in family planning. I
was working at the Royal Marsden Hospital, Fulham, as a junior registrar with
Dr Humphrey Kay in the Fetal Tissue Bank and I didn't want to move when
my husband moved to the country. At the time there was an article written
by Geoffrey Crabbe and Mary Egerton in the BMJ, talking about cytology 8 I
went to my old hospital, the Royal Free, to train and then wrote round, it was
an awful cheek really, saying I had done some cytopathology and did anybody
want a cytopathologist in the Northampton, Aylesbury, Luton or Bedford
areas. At the time, it was the Oxford region, which was one of the forefront
regions employing married women, that took me on as a cytopathologist and
my mentor was Arthur Spriggs. I started a lot of the district general hospital
cytopathology in the Oxford region under his supervision.

Jenkins: One of the things that intrigues me about the very early days of cytology
is that it really wasn't organized in any national sense, or in any sense above
that which was generated by the consultants themselves. It would be nice to

See also Dr Elizabeth Mackenzie's discussion on page 6.

17 Lawler (1981).

Dr Margaret Wolfendale wrote: 'Crabbe and Egerton (1961) was one of a spate of publications on this
topic in 1961.' Note on draft transcript, 26 November 2008.

See Biographical note on page 140—1; see also Figure 1, page 9.

Dr Margaret Wolfendale wrote: 'Arthur Spriggs aptly pointed out that the "emergence of a body of
trained exfoliative cytologists" resulted in population screening becoming an accepted practice before the
general introduction of randomized controlled trials with the result that it became "a football between
public health authorities, epidemiologists, lay pressure groups, politicians and clinical cytologists" (Spriggs
(1977): 1095, 1096). Max Wilson, who worked at the DHSS at the time and was a great proponent of
cervical screening, was of the opinion that "in the early 1960s mainly on the evidence of pathology. . .
the time when a (randomized controlled) trial... could be considered ethical had by then passed" (Wilson
(1971): 71).' Note on draft transcript, 26 November 2008.

10

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

hear a bit more about that: how people organized their own local screening
programmes.

Professor Dulcie Coleman: I would like to talk a little bit about that and how
disorganized it was. In about 1964 the then Ministry of Health agreed that
cervical smear tests should be offered, to be available, to every woman. There
were really no formal plans of how this should be done, but every pathologist
became responsible for this. I think there were four or five training schools set
up, and that's important to record, because these were very important. I know
there was Erica Wachtel 23 and Chandra Grubb in London, Betty Attwood in
Birmingham 2 and Blanche Butler in Manchester. One sort of offered oneself
to these schools for training; there seemed to be no special funding for it, but

The Ministry of Health's 1964 circular announced the introduction of a series of training courses in
exfoliative cytology open to pathologists and medical laboratory technicians, as a result of the Standing
Medical Advisory Committee recommendation that revision of cytological facilities in hospital pathology
should be accelerated. The cervical cytology service was established in 1965, offering five-yearly smears to
all women over the age of 35 years. The National Archives, Kew, holds files on the early development of
screening (MH 154/46-48). For further discussion of the efficacy of the training courses, see Wilson (1967);
for later reports, see Farmery and Gray (1994); House of Commons, Committee of Public Accounts (1992).
See also note 33.

Five training schools to teach cytodiagnosis were set up in 1964 at the Hammersmith Hospital, London,
the Royal Free Hospital, London, Birmingham, Manchester and Newcastle. For current arrangements, see
www.cancerscreening.nhs.uk/cervical/training.html (visited 29 July 2009). The BSCC included training
sessions in their scientific meetings, description of which can be found in BSCC (1983): 25—62.

Dr Erica Wachtel (d. 1980) was at the Postgraduate Medical School, Hammersmith Hospital in 1961.
See also Wachtel and Plester (1952, 1954); Figure 1.

Mrs Marilyn Symonds wrote: 'In 1952 a meeting at the Royal College of Obstetricians and Gynaecologists,
attended by Birmingham gynaecologist Professor Hugh McLaren, suggested sending two medics to visit Dr
Papanicolaou in the US to study his technique for cervical cancer detection. Miss M E Attwood (Betty),
a young technician working in the university department in Birmingham, was sent instead, as Professor
McLaren and Dr Claude Taylor (pathologist) thought a technical person would be more appropriate to
learn the technique. Betty left six weeks later by boat from Southampton and worked for 18 months
with Papanicolaou in New York. She then worked at the Free Hospital in Boston followed by time in
Florida working with Ayre (of the Ayre spatula). She returned to Birmingham and set up a research cervical
screening routine, screening 2500 women. The results of this study were written up (Attwood etal (1956);
McLaren et ah (1958)), but no-one took much notice. They continued to screen women and eventually
obtained funding to set up one of the first UK cytology training schools in Birmingham in the early 1960s.
It was part of the medical school and eventually moved to the maternity hospital. Betty continued to run
the training school together with Dennis Williams until her retirement. As a result of her early work she
was often invited to speak at meetings all over the world and has been involved in writing several research
papers.' E-mail to Mrs Lois Reynolds, 1 1 September 2009; see also Figure 2, page 13.

11

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

that was the way to get your training, and that was the way that I got mine,
with Erica Wachtel. It was fairly basic training, because you were shown slides,
and told: 'This is abnormal and this isn't'. There was no one to explain to
you what you were looking at or to explain that the aim of the exercise was to
detect a precancerous condition. This was in the early days of training. That was
one aspect.

Another aspect was that there was a preponderance of women in cervical
cytology. Many of the pathologists, who were responsible for offering or
arranging screening in their own hospitals, really were not in a position to cope
with the job because it is very time-consuming, and they were willing to take
on anyone. I remember saying: 'Well, I have been to a training school', like
Margaret had, and 'I know how to do it.' They said: 'All right, we will take you
on a trial basis.' You were put in a little hole in the corner to get on with it on
your own. I remember I actually sat in a fireplace, my feet were in the fireplace,
and my microscope was on the mantelpiece and I had a suitably high stool
to sit on. ' Until I proved my worth, I wasn't given an office or a proper desk
or anything. This is the way it started up. But it evolved from there and now
there is a very well-organized training programme and training is very carefully
monitored, and, I am proud to say, there is even academic training offered, an
MSc course which started in 1990, at St Mary's Hospital Medical School (now
part of Imperial College London) and continues to be offered today 27 We have
come a long way from those early days.

Professor Albert Singer: You mentioned exclusively female screeners: well, it
wasn't all women. The great Stanley Way in Newcastle started off many years
ago and I used to go and work with him, and he would tell me of the early days
when he had been trained by Ruth Graham, who had worked with George
Papanicolaou. Way came back to Gateshead and to Newcastle in the late
1950s— early 1960s and for many years used to do all the work to prepare the

2 ' A later handbook was Bloch et al. (eds) (1995).

Professor Dulcie Coleman wrote: 'My first appointment was at the Hillingdon Hospital, London.
Pathology was located in the former sitting room of an old Victorian house on the hospital site. I think the
building has been torn down now.' Letter to Mrs Lois Reynolds, 8 October 2009.

For details of the current MSc in clinical cytology, see wwwl.imperial.ac.uk/medicine/teaching/
shortcourses/teaching/clinicalcytology/ (visited 23 June 2009).

See, for example, Way (1963); Stening (1950). Dr James Andrew reflected that Mr Way described
colposcopy as 'the biggest confidence trick ever perpetrated in the name of gynaecology', although Newcastle
later acquired a colposcope (Andrew (1975): 4).

12

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

Figure 2: Mrs Marilyn Symonds, cytology laboratory,
Stoke Mandeville Hospital, Aylesbury, 1964.

slides and read them himself. One day he told me this story of how it came to be
that there was a five-year screening interval — the Government used to say it was
five years — and he said, 'Well, they asked me one day down to a meeting and
they said how many years do you think there should be for an interval?' and he
said: 'Well, I really didn't know, there was no evidence, so I thought five -yearly
was a reasonable target.' He would still read his own cytology until he retired;
he was one of the originators.

Mackenzie: May I say that the other mentor I must not forget is Elizabeth
Macgregor in Aberdeen [Figure 1] . She was formative as far as screening in this
country was concerned, and when you think she was at the top of Great Britain
— we in Scotland are still part of GB, I presume, tucked away up there — and her
work was exemplary, proper screening, properly managed. It took the rest of the
UK about 30 years to catch up with her.

Glucksmann et al. ( 1 964) suggested that mortality increased between the fifth and tenth years of follow-
up of patients treated between 1952 and 1962 (page 200); Way (1954, 1962, 1969); Guthrie et al. (1981).
See also DHSS, Committee on Gynaecological Cytology (1981).

30 See also notes 5, 38, 163, 164 and 174; Figure 1, page 9.

13

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

Dr Catherine Pike: I was going to say that Elizabeth Macgregor was my colleague
at university, we got to know each other very well. I got into cytology when I
came back from Africa, where I had been for ten years with my husband, and
the phone rang one day and it was Elizabeth Macgregor saying: 'What are you
going to do? What about doing cytology?' The next thing was that I arrived at St
Thomas' Hospital with Professor John Tighe, who took an interest in cytology.
I was trained there, but also went to other training sessions and trained others
as well. In a very busy south London area, we were taught from the word go
to follow up women with abnormal smears, and that it was most important;
you didn't let them slide through the system. We started a card system, always
following up women with abnormal smears, making sure that they were seen by
a gynaecologist for assessment and treatment.

Dr Amanda Herbert: Can I say something further about Stanley Way, because
back in those days it was very often gynaecologists who were encouraging
screening, whereas pathologists were woefully apathetic about it. When he was
the chairman of the BSCC, he wrote a brilliant letter in the BMJ, saying how
hopeless Kenneth Robinson's proposal was for setting up the 1967 programme,
largely because it wasn't adequately funded. He went through the press release
bit by bit, in a beautifully written letter, pointing out that it wasn't going to
work if it wasn't properly funded — and if cytologists didn't have long enough
to train. 33 Nearly 20 years later the Lancet editorial, 'Death by incompetence'
fulfilled his prediction. 3

McCluggage: I am going to move to a related topic, that is, who became a
cytologist and why, and ask Dr Gray, because this leads on very nicely from
what we have just been talking about.

Dr Winifred Gray: I think a lot has already been said by previous speakers about
their own experience in this particular area. Throughout the 1960s women

See, for example, Tighe (1961); Fruin and Tighe (1967).

Dr Catherine Pike wrote: 'I received additional training at the Royal Free Hospital with Dr Chandra
Grubb in a few informal sessions, as far as I remember. I always attended the well-organized workshops at
the annual scientific meetings of the BSCC, at first relating to gynaecological cytology but soon covering all
aspects of non-cervical cytology. 1 Note on draft transcript, 29 August 2009. For a list of scientific meetings
and the papers given, see BSCC (1983).

Mr Kenneth Robinson's press conference on 21 October 1966 was reported in the BMJ (Anon. (1966));
Way's ripost appeared the following February (Way (1967)). See also Glossary, pages 149—50. For later
details of screening programme, see Spratley (1990).

34 Anon. (1985).

14

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

doctors needing part-time work for domesdc reasons were often responsible
for the reporting of abnormal smears. Some worked within a gynaecology
department, where an individual gynaecologist had a special interest in the work.
Others became involved at the time of establishing the BSCC in 1961, as already
mentioned, such as Dr Arthur Spriggs, who was a haematologist originally. He
was responsible for gynaecological and non-gynaecological cytology in Oxford
and played a significant part in attempts at automating the screening of cervical
smears. ' He also investigated the impact of the failure to follow up abnormal
smears, with an elaborate tracing of women across the country whom his laboratory
had found to have abnormal smears, but who hadn't returned for treatment.

Another factor that hasn't come into the discussion so far is the role of the
College of Pathologists in the training of histopathologists in cytology, and
encouraging them to take the area of gynaecological cytology seriously. It was
really completely separate from histology in the department in Oxford where
I worked. It was referred to as the 'dregs' by those who weren't involved at all,
and it was certainly not looked upon as a very prestigious area to be working
in as a histopathologist. I think the college did eventually acknowledge that
training was required, that an examination in cytology should be included in the
college exams. Certainly, when I took the MRCPath final in 1971, cytology was
beginning to be included. I think when I had my finals viva, the two examiners
were more nervous than I was, because here was this cytopathologist and they
didn't quite know what on earth to ask me. They got their own back in the
afternoon by giving me an amputated penis for a histological specimen.

Gradually, through the 1970s and 1980s, the college has become more and
more aware of the need to have a proper qualification that involves cytology and
particularly gynaecological cytology, along with histology. It's interesting that

Dr Winifred Gray wrote: 'I was one of the first to have a full training in pathology at the Radcliffe
Infirmary, starting in 1969, under the married women's retraining scheme which was started by Dr
Rosemary Rue, public health consultant in the Oxford NHS administration. This scheme enabled women
with family commitments to have a part-time training post in a teaching hospital. It led to several other
women qualifying for consultant posts where before they remained as clinical or medical assistants.' Letter
to Mrs Lois Reynolds, 12 September 2009. See Rue (1967); see also Colville and Wenban (1972); Duncan
(ed.) (1992); Anon. (1968).

For details of Dr Arthur Spriggs' work, see note 19, Appendix 2 and his Biographical note on
pages 140—1.

7 Kinlen and Spriggs (1978); Spriggs and Boddington (1980). Dr Winifred Gray wrote: 'This study
provided convincing evidence of the ability of cervical cytology to prevent the development of cervical
cancer.' Note on draft transcript, 26 August 2009.

15

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

in 1998, at an international meeting held in Oxford, the then president of the
college apologized for the lack of support that had been given to proper training,
particularly in cervical cytology, so I do think that has now been addressed.

McCluggage: Certainly, cervical cytology is much more important now. The
people who started off doing cervical cytology, were they mainly specializing in
that, or were they also doing non-gynaecological cytology and histopathology?

Gray: No, it was usually both. With the sub-specialization that is now so
prevalent, some pathologists are specializing solely in gynaecological cytology
and histology. But in most district general hospitals, pathologists still have to be
responsible for all aspects of cytology. That's what I understand.

Jenkins: If I can join in here? When I was training in histopathology, cervical
cytology was certainly despised in some of the institutions in the 1970s where
I was trained and in others there was great enthusiasm. Catherine Pike and
John Tighe were probably the people who trained me most in cytology at St
Thomas', but other institutions really didn't take it seriously at all. I think the
examination (MRCPath) was simply six slides that were carefully selected, so
that they were either normal or cancerous. It was very much a token effort.

[Professor Valerie Beral raised the question of international perspective,
as it wasn't clear from the discussion whether the meeting was concerned
solely with the cervical screening programme in the UK or elsewhere.
She suggested that Jocelyn Chamberlain, Tony Miller and others could
discuss what is going on in Scandinavia, British Columbia and elsewhere.

Dr Margaret Wolfendale wrote: 'The part played by the BSCC was inadvertently omitted in the Witness
Seminar. Following the first International Meeting on Cytology in 1961 held in Vienna, a meeting was
convened by a small number of enthusiasts who were already practising cytology and the BSCC was founded
to promote the growth and development of clinical cytology in the UK. It proceeded to play a crucial role
in promoting cervical screening by bringing together individuals struggling in comparative isolation, by
sharing scientific information at their annual meetings, laying down standards of practice, encouraging the
setting up of training schools and setting up a "certificate of competence" for screeners, headed by Michael
Boddington. From the start there was a small non-medical membership which was expanded to 10 per
cent, then 20 per cent, an innovative move that was looked down on by many medical colleagues in other
specialties. In further recognition of the vital need for continuing education of the whole of the laboratory
team, the setting up of regional societies was supported and by 1973 the whole of the country was covered
by affiliated societies holding regular scientific meetings. A prime example of an initiative to raise standards
was the publication in 1981 ofaguide, Taking Uterine Cervical 5mf^rj (Macgregor (1981)), the first 10000
copies rapidly sold out. A new second edition was published in 1989 (revised edition 1995) accompanied
by a video, sales of which were also extremely successful.' Note on draft transcript, 26 November 2008. The
BSCC Report for 1961-83 notes that 15 000 copies were initially sold (BSCC (1983): 14).

16

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

She asked whether it was from these programmes that people in the UK
began to understand how screening worked.]

Professor Jocelyn Chamberlain: During the same period, in Sweden and Finland
and to a lesser extent in Denmark, but not Norway, screening was introduced
as a coordinated public health programme, aiming to reach the whole eligible
population. 39 Elizabeth Macgregor in Aberdeen, as far as I know was the only person
in Britain who really succeeded in doing that prior to the re-organization of the
UK screening programme in the late 1980s. There's very convincing and positive
evidence when you compare the incidence and mortality rates of invasive cervical
cancer in Sweden and Finland with those in Norway, where there was no organized
screening, during the 1970s, the rates come straight down in the two countries that
were doing it in a systemic, organized way. ' Their eligibility criteria were such that
to be invited to be screened a woman should, I think, be aged between 25 and 69,
and should not have had a normal test within the previous five years — between 70
per cent and 80 per cent of women accepted their invitations.

Professor Anthony Miller: I want to thank the organizers for bringing me here.
I have spent all my life in terms of cervical screening in Canada and I happen
to be visiting at the moment, although the first part of my life was spent in the
UK. In fact I was in the Medical Research Council (MRC) tuberculosis research
unit in 1970 - to link up with something that was said earlier — when, as I
was going to a conference in New York, I was invited to look at an automated
cytology set-up there. I did and came back to report to the MRC and also to
O A N Husain — normally known as Nasseem — with whom I discussed this,
although they didn't think that particular mechanism worked. 2

Professor Jocelyn Chamberlain wrote: 'In the 1960s and 1970s, as we have seen, cervical screening
developed here in a haphazard way, with decisions on who should be screened and how often, being taken
on the whim of individual clinicians working without guidance, and the cytology laboratories responding
as best they could to this uncoordinated demand.' Note on draft transcript, 31 July 2008. See, for example,
Hakama (1982).

Macgregor et al. (1971); for a discussion of the data, see Wilson et al. (1971). For background of the
policy changes concerning cervical screening, see note 155; Glossary, pages 148—51.

IARC Working Group on evaluation of cervical cancer screening programmes (1986). See also Hill and
Adelstein (1967).

A combined research group of Drs N Jankey, H Ferreira, C B Cameron and O A N Husain (Chelsea
Hospital for Women, Royal Marsden and St Stephens Hospital, Chelsea) gave a preliminary account of the
use of the Coulter counter in cancer screening at the fourth annual scientific meeting of the British Society
for Clinical Cytology in October 1965 (Anon (1965)); see also pages 90-1.

17

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

A bit more history, because people haven't given much history: in terms of the
perception internationally over cervical cytology, many of you will know the paper
of H S Ahluwalia and Sir Richard Doll, which effectively looked at the decline in
cervical cancer mortality in a number of countries, including Canada, and concluded
that cervical screening was not working. In my MRC links, before I went to the
National Cancer Institute of Canada, I used to interact with Archie Cochrane,
and Archie was very much of the belief that it didn't work and he told me that I
had to go to Canada to show that it didn't work. When I went to Canada, the
National Cancer Institute of Canada, together with the American Cancer Society,
had started funding an evaluation of the British Columbia programme at that
time. The British Columbia programme was established in 1949 by Herb Fidler,
a pathologist, who brought David Boyes into his programme. Boyes, originally a
family physician who trained as a pathologist and a gynaecologist, became a leader
in Canada in terms of cervical cancer screening. They kept meticulous records. So
when a group of us, including George Knox from Birmingham, started evaluating
these records at the beginning of the 1 970s, it became clear that there was a good
resource for evaluating the natural history of cervical cancer, and that resource was
eventually published. The data were published and incorporated into something
that Professor Nicholas Day was doing — unfortunately he can't be here today —
who was working in the International Agency for Research on Cancer (IARC) in
Lyons at that time in the mid-1980s. He evaluated the data in terms of models,
and demonstrated that you didn't have to screen annually, that you got almost the
maximum benefit by three-yearly or five-yearly screening, and, of course, this has
been replicated subsequently. ' Perhaps Peter Sasieni will talk about some of his
studies in the UK.

We were challenged nationally in Canada to try to demonstrate that screening
worked, and we set up a study to evaluate the extent to which mortality had

43 Ahluwalia and Doll (1968).

Dr Archie Cochrane wrore: Apart from the immunization programme the record of the NHS is
patchy. There are sins of omission and commission. Of the latter the introduction of the programme of
cervical smears in the hope of preventing carcinoma of the cervix is the saddest. It illustrates so clearly the
consequences of assuming a hypothesis is correct, and translating the consequences into routine clinical
practice before testing it by an RCT.' Cochrane (1972): 26—7. See also note 162.

Boyes et til. (1982); see also Shun-Zhang et al. (1982). For questions arising from the natural history of
carcinoma in situ, see Knox (1966).

46 Hakama <*,*/. (eds) (1986).

18

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

fallen in different parts of the country. We had to use cancer of the uterus
because there was a changing certification of whether you certify as cancer of
the cervix specifically or the uterus unspecified, so we took the whole of uterine
cancer, did a correlation analysis, and it was extremely clear: no matter what
factors you took into consideration, the areas which had the greatest intensity of
screening had the greatest reduction in mortality. This was very influential for
convincing people in Canada that this worked. It was the Walton Committee in
1976 that built on that. Eventually I think the Americans were persuaded, and
even Archie Cochrane was eventually persuaded that it worked.

One last point relates to the fact that very much later, through Jan Ponten, who
was chairman of the Swedish Cancer Society, we were able to evaluate historical
records in the Karolinska Institute. It became very clear that the introduction of
radiotherapy, basically radium therapy, had a major impact on mortality from
cancer of the cervix in Sweden before screening came in. So Richard Doll (Figure
3, top row, right) in many respects was right, there was a reduction going on,
largely because of improvements in treatment, but that had come to an end, and
then when screening came in and people began to find precursors and incidence
fell, then mortality fell not long after. So history sometimes is quite right.

Professor Jack Cuzick: I remember — I think, very much based on George Knox's
wonderful editorial 'Death by incompetence" — in 1973 we set up the Imperial
Cancer Research Fund (ICRF) coordinating committee on cervical screening,
and very much with Husain's strong leadership, managed to put together some
statements about what was needed, and the fact that, although Nick Day had
shown clearly that screening could reduce mortality, it wasn't happening in the
UK at that time. 52 We published a position paper in the BMJ in 1985 and
then subsequently another paper, which I think was very much the basis of the

47 Miller e tal (1976).

48 See, for example, Walton et al. (1976, 1982); Kassirer (1980).

49 Ponten et al. (1995).

50 Anon (1985).

ICRF, Coordinating Committee on cervical screening (1984). Members of the committee were: Walter
Bodmer, Jocelyn Chamberlain, Gary Cook, Jack Cuzick (secretary), Gerald Draper, Stephen Erskine, Hugh
Fisher, Rod Griffiths, David Haran, Christine Havelock, O A N Husain, E G Knox, Ann McPherson,
Alwyn Smith, Arthur Spriggs, David Innes Williams (chair) and Margaret Wolfendale.

IARC Working Group on evaluation of cervical cancer screening programmes (1986).

19

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

Figure 3: Contributors to the 1985 Banbury Center conference on

'The origins of female genital cancer'.

L to R from top row:J R Schlehofer, Elke-lngrid Grussendorf-Conen, Harald zur Hausen,

Richard Doll; row 2:Thomas Broker, J Cairns, Richard Peto, P M Howley; row 3: Erich Burghardt;

Attila Lbrincz, Martin Vessey, Richard Reid; bottom row: Albert Singer, Louise Brinton, Richard

Doll, Leopold Koss. (Peto and zur Hausen (eds) (1986): frontispiece).

20

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

national programme that was set up here, identifying the requirements for that
national programme and I think that's an important landmark as well.'

McCluggage: I think we are going to talk more about this later. We are going to
move on now to something we have already touched on, life and interactions in
a cervical screening laboratory.

Mrs Marilyn Symonds: I am speaking from the cytotechnology angle, from
the technicians' side. I also started in cytology a very long time ago with Dr
Margaret Wolfendale in 1963. It was absolutely unheard of for student medical
laboratory technicians to be employed solely in a cytology laboratory, because
there were no formal qualifications to become associates and fellows of what is
now the Institute of Biomedical Science (IBMS). So you had to qualify along
the histology route and, just to let you know, that the cytology question in my
histology final was to take a buccal smear (a sample of cells from inside of the
cheek) from myself and stain it, using a Papanicolaou technique. I don't think
that stood me in very good stead to actually be able to diagnose abnormalities
in cervical smears.

I heard from all of you pioneers in cervical cytology that very soon you wanted
to pass over all that boring screening stuff to some technical people. To start
with, the type of people who worked in a cytology department technically were
histology technicians, mainly female again, except for one very well-known
exception, Dennis Williams, who I am sorry is not here to support me today.
He started with the Birmingham crew and has done an enormous amount of
work to help recognize the important role of the non-medical person working
in cytology. To start with, we had people who were formally training to be
laboratory technicians and then I think it was probably in the 1970s that we
took on a group of women, mainly part-time, who became cytoscreeners. They
were different to the people who were qualified with the IBMS; they didn't have
any formal qualifications, and they were often derided and called shopping-bag
screeners, but they were absolutely fantastic at what they did. They were able
to sit down quietly and concentrate and look at every cell that was being passed
under the microscope, and I can say that that group of women now are nearly
all retired, and it's extremely difficult to replace them. The IBMS now think that

53 Cuzick etal. (1998); Cuzick and Sasieni (2001).

For a history of the Institute, see www.ibms.org/index. cfm?method=science.history_zone&subpage=
IBMSJiistory (visited 13 August 2009).

21

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

we should have biomedical sciendsts with degrees, and formal qualifications in
cytology, but I can honestly say that on the whole they are not nearly as good at
screening as those women from the 1960s and 1970s.

One of the most exciting things for me was the interaction, together with my
medical colleagues, with the pathologists, and also with the GPs, because we
were talking about setting up a screening programme in Aylesbury, Dr Margaret
Wolfendale, myself, and a couple of other people. We set up a screening
programme based on the electoral roll, so we wrote out invitation cards, little
postcards, and we went round the villages in the rural district of Aylesbury, and
delivered these personally ourselves to try to encourage the women to come to
clinics and have their smears done. Then there were a few very, very enthusiastic
GPs who were supporting us and they used to come in, deliver the smears they
had taken, and meet us in the laboratory and we felt part of this wider team.
And I think this is what cytology still is, within pathology medicine, that we all
know our GPs, we have a lot of interaction with the practice nurses who now
take all the smears, and we are quite different from the other laboratories.

Jenkins: One of the questions that has always intrigued me was what made
cytoscreeners, the women who weren't trained as technicians, become
cytoscreeners, because as you say it is a tremendously difficult job, it involves
enormous patience and is something that a lot of us couldn't do. Why did
people take up this job?

Symonds: One of the things was that we offered them part-time working, so it
fitted in very well with the ethos of our medical pathologists. They were mainly
married women with children, who wanted an interesting job to fit around
their home commitments. A lot of them had had some scientific background of
working within perhaps research, before they had their children, or perhaps had
worked in school laboratories.

Coleman: I wanted to add one thing that I think is not always appreciated
and which we found — because I was very much involved in teaching — that
you think of screening as being very dreary and routine. In fact every smear is
different and is a challenge, and I think only screeners, people who do it every
day, really appreciate that, and I think that's what keeps me going.

Wolfendale: We are really talking about the backbone of the cytology laboratory,
where these were almost all married screeners who worked part-time — they
were paid peanuts, absolute peanuts — and the only way that we managed to
keep them was making it teamwork, making them feel really worthwhile and

22

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

wanted, and they felt that it was something interesting that they could do to get
away from their family routines.' I think, it was an almost pastoral care that we
gave, supporting each other through all sorts of troubles. Last year I was invited
back, ten years after I had retired, and there were really a large number of the
people who had worked during the 40 years that the laboratory had been going
and had come back because it was a team effort. And I am sure many, many
other people in laboratories would say the same.

McCluggage: I have always heard anecdotally that it is very difficult to get people
to go into screening. Is it still difficult? And are the problems getting better
or worse?

Miller: I would like to make the comment that Dave Boyes in British Columbia
went out of his way to find people who couldn't find jobs elsewhere — some of
them, in fact, were in wheelchairs, were paraplegic — and there were many men
who fell into that category employed in his very large laboratory that served the
whole of the province. So it is sometimes possible, if you look, to find people
who really need employment and are prepared to spend the time.

Symonds: I think the answer to the question whether it is easy to recruit staff
now is 'no', it's impossible. Everybody who has worked in cytology labs for
many years is retiring, the people who are replacing them are not prepared to
sit down quietly in the same way, and I think there are so many more demands
on them. Especially in the south of England, it's virtually impossible to recruit
staff. So I would say thank goodness for liquid-based cytology (LBC). I know
that is not what we are talking about today, but with LBC comes the possibility
of automation, which will help reduce the staffing crisis. 5

Herbert: We don't find it impossible to recruit staff, especially now we have
biomedical scientists (BMS), who don't only do cervical cytology. They have
quite a lot of other things to do and cytology screening is part of the general
BMS qualification. We haven't employed cytology screeners as such for some

55 Wolfendale (1991).

Mrs Marilyn Symonds wrote: 'My hospital, Stoke Mandeville, was involved in a five-site research project
in 1996 comparing conventional screening to the PAPNET automatic screening method. The outcome was
that cytoscreeners were as effective at detection of abnormalities as the machines. Twelve years later, trials
using automated assisted screening are still taking place.' Note on draft transcript, 28 August 2008.

See 'Qualifications and training for non-medical laboratory staff in the UK cervical screening
programmes' (January 2000) at www.cancerscreening.nhs.uk/cervical/publications/nhscspl2.pdf (visited
30 April 2009).

23

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

time and we seem to have been able to recruit people reasonably easily in
London. We have had times when it was difficult, but not impossible.

McCluggage: We will move on to another very important subject: given the
expansion in cervical screening, obviously colposcopy has increased as well.

Duncan: Yesterday I went into the old byre and dug out stuff that had been
in a wheelbarrow since I retired at the end of March 2007. I found something
I thought was quite interesting; it was published in an obscure thing called
Colposcopy and Gynaecological Laser Surgery, published in 1987, and it was my
observations as the then president of the British Society for Colposcopy and
Cervical Pathology (BSCCP). You have asked me specifically to look at the
1980s, rather than the 1970s when it all began. I was reflecting, if you like,
following the annual meeting of the BSCCP. The BSCCP really was established
in the 1970s. Albert Singer was one of the original protagonists in 1972 when
the society was founded. The founding trio, Joe Jordan, Albert Singer and Archie
Crompton - that was it - met in 1972. 1 was training in the US at the time, came
back in 1974 and the society was formed in 1975. " From humble beginnings, it
grew in leaps and bounds, and by 1987 the membership was over 500. We used
to meet annually. The BSCCP met twice a year, once on our own, and once with
the BSCC and then we separated because there was more to talk about. The first
problem that I was addressing in this publication was who should be undergoing
colposcopic examination. 60 We had found out that the smears themselves did not
actually tell you what the underlying problem was. Yes, high-grade smears tended
to indicate high-grade cervical intraepithelial neoplasia (CIN) — as we were calling
it then — and low-grade smears tended to indicate low-grade lesions. However,
when the patient with a low-grade smear was examined with a colposcope, she
often had a high-grade lesion, usually, much smaller, but a high-grade lesion was
visible also. So it was a question of should we be seeing women with originally
positive smears? Suspicious smears? These were the class IVs and the Ills.' But
then the class II smears and mild atypia, should we be seeing them? What we were
saying at that time was that there seemed to be justification for doing it, but it

Duncan (1987); see also note 59.

For the history of the BSCCP, see www.bsccp.org.uk/index.asp?PageID=15 (visited 13 August 2009).

60 Duncan (ed.) (1992). See also Anon (1968).

These classes refer to the guidelines for the interpretation of smears proposed by Papanicolaou. See Koss
and Melamed (2006).

24

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

could increase our workload dramatically, and until the supply met the demand,
patients would have to be seen on a priority basis. The question was then whether
you should do follow-up colposcopy, or reserve your colposcopy for the primary
problem. And then who should be carrying out colposcopy? It's very much like
the cytologists. At that time the vice-president of the BSCCP was a pathologist,
so he wasn't a gynaecologist, and at the annual scientific meeting that year, a
general practitioner colposcopist addressed us in Aviemore, Scotland, on how
she was operating a successful practice here in London. Then we were discussing
what treatment was appropriate. What we agreed in the end, after quite a bit of
work, was that it didn't matter whether you treated them with local destruction
using extremes of heat or cold, or whether you used some method of excision,
these had all been shown to be equally effective. As long as you didn't overdo the
cervical treatment, then there was no injury to future cervical function. We all
agreed to disagree, if you like, and found all methods were acceptable. We had
also encountered in situ adenocarcinoma of the cervix. This was something that
had come out of cytology, and we were wondering exactly what we should be
doing with that. What we had also found was that women who had vulvar warts,
about 30 per cent of them were harbouring CIN as well, and so the question
arose should women with vulvar warts actually be seen, and should their partners
who had penile warts, should they be examined colposcopically as a routine?
And should they be treated as well? So these were the things that were perplexing
us, and the last paragraph of this publication said:

I have attempted to highlight the main problems facing us. There are, of
course, many others, from the particular (eg, what is the true significance of
HPV1 6?) to the more general (eg, what public health measures are necessary
to stem the flood of CIN?). We live in a world where the fear of pregnancy
has been removed by the contraceptive pill, where the protective effect of
the sheath against sexually transmitted infection has been lost due to the
fall in popularity of barrier methods. Sexual liberty and gratification are
regularly portrayed on television and used unashamedly by the advertising
industry. It should come as little surprise to us that we are seeing more and
more cases of CIN just as we are seeing more genital warts, chlamydia and
more cases of unwanted pregnancy. It is ironic that it may take something
like the government education programme engendered by a fear of an
AIDS epidemic to alter public opinion and sexual practice in such a way as
to provide primary prevention of invasive cervical cancer. ' 2

62 Duncan (1987).

25

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

I had attempted to highlight the main problems facing us, there were, of course,
many others: from the particular, for example, what is the true significance
of HPV16, to the more general, such as whether public health measures were
necessary to stem the flood of CIN.' I said that perhaps the government
education programme as then being applied to the AIDS epidemic might be
beneficial to us, but meanwhile the BSCCP would continue to have its say in
the setting and maintaining of standards for the present-day colposcopists and
the continued quest for tomorrow's knowledge. And that's really carried on in
the same way since then. So that was the 1980s.

McC luggage: Anybody else want to comment on that?

Coleman: I can recall one important meeting, I think it was called the
Intercollegiate Working Party on cervical cytology screening, which I think
Albert Singer drew together and perhaps he could comment on that. ' That was
1988 and I remember the results of that meeting were published in the BMJ
and that seemed to transform cytology from the desperate confused situation
into a more directive programme, and laid the foundation I thought, for what,
in my view, is the first-class cervical screening programme that we have today.
Perhaps Albert could comment on that.

Mr Patrick Walker: I'm from the Royal Free Hospital, London. I started
working with Albert Singer in 1981 as a research fellow interested in HPV.
To throw a little bit of light on a question that has never really been fully
understood: why was colposcopy very slow to get off the ground in the UK?
Hans Hinselmann's first paper was in October 1925 and from then on it became
reasonably popular on the mainland continent of Europe. "The Gynaecological
Visiting Society of Great Britain and Ireland (GVS) was founded by Blair-Bell
in 1911, who later went on to found the Royal College of Obstetricians and

63 Duncan (ed.) (1997).

Dr Ian Duncan wrote: 'It was not Albert Singer who was the chairman, but Frank Sharp from the Royal
College of Obstetricians and Gynaecologists.' Note on transcript, 2 September 2008. The brief was to
look at the clinical aspects of cervical cytopathology screening programme in the UK, see Royal College of
Obstetricians and Gynecologists, Royal College of Pathologists, Royal College of General Practitioners and
Faculty of Community Medicine, Intercollegiate Working Party (1987).

65 Havelock et al. (1988).

66 Hinselmann (1925); for the early history, see O'Dowd and Philipp (1994): 30-1; 550-1; 531-4;
543-70; 640-1.

26

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

Gynaecologists.' The society was a travelling group; they were the elite
travelling group of the professors from the British medical schools and they
travelled in 1937 to Berlin, stopping off on the way in Hamburg. They were
greeted by Professor Hinselmann who took them to his home for tea and then
the following day took them to his colposcopy unit in Altona, the hospital
where he practised colposcopy. These were difficult times in Europe and it is
alleged that Hinselmann — I think it is probably true — was quite a prominent
member of the National Socialist Party at the time. What the GVS used to
do was to assess surgical procedures, see how to do things slightly differently,
and as the convenor of the GVS at the moment, I have the records going back
to that meeting. One of the operations that they saw was a sterilization at a
time that forced sterilizations were allowed in Germany. So when they came
back from Germany, there was no enthusiasm for either Hinselmann or his
technique, although Fletcher Shaw arranged for one colposcope to be delivered
to the UK, and Dr James Andrew found one in the outpatients at Bart's in the
1950s. By then Andrew was running a monthly colposcopy clinic there through
the 1960s. 68

A personal remembrance: when I was a medical student at Bart's in 1972,
Gordon Bourne was the senior gynaecologist and there was an afternoon
tutorial. We were all trying to rush off to the bar or somewhere else, and he
said: 'No, please stay behind. There's a very nice man called Dr James Andrew
who is coming to talk to you about a German instrument called a colposcope,
which none of us feels has any value, but he's an awfully nice man, why don't
you stay and listen to him'. And I did and I didn't know then that later on
in my life it would mean something. I think that until Albert Singer came
from Coppleson's unit, Joe Jordan had been with Per Kolstad and Archie
Crompton with Professor Ernst Navratil, they came together to form the
British Colposcopy Group in 1972, the previous hiatus actually had something
of a medico— political dimension.'

Shaw (1950, 1954a and b). Sir William Fletcher Shaw was the first honorary secretary of the Royal
College of Obstetricians and Gynaecologists in 1929, later president (1938-43).

Dr James Andrew described his first Zeiss colposcope and setting up his regular colposcopy clinic at Bart's
in 1954 in a paper, 'British colposcopy before the 1960s' (Andrew (1975)). A copy of the paper will be
deposited along with other records of the meeting in archives and manuscripts, Wellcome Library, London,
in GC/253. See also Jordan (1975); Burghardt etaL (eds) (1978).

69 See also Kolstad (1970).

27

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

Herbert: One of the things that colposcopy did for cytology in the 1980s was
to focus laboratories on quality control, which greatly improved when the real
programme started in 1988. Colposcopists were seeing patients with borderline
smears and persistent mild abnormalities and finding they had CIN3. Obviously
not all of them, but it made cytologists focus on quality control.

The other thing — and Jocelyn Chamberlain is here — was her excellent article
on the reasons why screening may fail to prevent cancer, which was very
important. Among those reasons were false negative cytology, low-grade
abnormalities that were high-grade on review, and failure to follow up after
treatment. When colposcopists were seeing women with what were thought
to be minor abnormalities on cytology, it became a bit of a bone of contention
between pathologists and cytologists. I think that was one of the reasons why
the two organizations split and held different meetings.

Duncan: Dulcie was speaking about this Intercollegiate Working Party, which
Albert has passed on to me, because I don't think Albert was involved. It was
under the chairmanship of Frank Sharp, who along with myself, represented
the Royal College of Obstetricians and Gynaecologists. Dr D M D Evans
and Professor Harold Fox represented the Royal College of Pathologists; Dr
P B Havelock and Dr Ann McPherson from the Royal College of General
Practitioners; and Dr Jocelyn Chamberlain and Professor Alwyn Smith from
the Faculty of Community Medicine. 73 What it did was to publish a report in
November 1987 and it actually set out who should have smears, how often and
when, putting together what was happening in the Department of Health in
Scotland, which had issued a statement, and the DHS which had also issued

70 Chamberlain (1986).

See, for example, Cuzick et al. (1994).

Dr Amanda Herbert wrote: 'The BSCCP met during the BSCC annual meeting until 1982 and I think
not thereafter.' Note on draft transcript, 23 July 2009.

Although the BSCC were not officially represented on the Intercollegiate Working Party, the society
provided two appendices to the Report (RCOG et al. (1987)): 'Recommended code of practice for
laboratories providing a cytopathology service' and 'Terminology in gynaecological cytopathology, report
of the working party of the BSCC, the members of which were D M D Evans (chairman), E A Hudson
(secretary), C L Brown, M M Boddington, H E Hughes, E F Mackenzie and T Marshall, and had been
published in the Journal of Clinical Pathology (Evans et al. (1986)).

Scottish Health Service Planning Council, Scientific Services Advisory Group, Subcommittee on
Histopathology (1977). See Glossary, pages 150—1.

28

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

a statement. And that led one year later to the founding of the NHS Cervical
Screening Programme national coordinating network which was basically the
14 English health regions, the three Celtic nations, and the private sector (the
big 18). And, up until devolution, then it worked and produced a series of
documents and Amanda Herbert edited some, I edited some, Catherine Pike
did some as well. So that really got us all together, and it became a quality-
assured service with quality control and fail-safe mechanisms and all of that.
That is where Euphemia McGoogan came in, the missing link, the Edinburgh
one, who was, if you like, a second-generation cytologist, and then she took a
lead role as well. 77

McCluggage: I think we will probably touch on this later on, but we are going
to move on to the discovery of the HPV and the development of HPV research.
Albert Singer is going to make a few brief comments about the unknown
male factor.

Singer: In four minutes. It is certainly a privilege and rather humbling after
40 years to go back and look at — as you say — the unknown male factor, and
especially working with so many colleagues after all those years. I started off in the
mid-1960s, in Sydney, Australia, joining up with Professor Malcolm Coppleson
who has already been mentioned — he was a colposcopist and a gynaecological
oncologist — and Bevan Reid who was a cell biologist, a brilliant scientist; and
in the early 1960s they were studying the process of squamous metaplasia, the
process by which columnar epithelium changes to squamal and during that
time the observation was made that sperm heads were found in the regenerating
cells. They believed that the stromal cells underneath the epithelium were the
progenitor cells of the new squamous epithelium, and they absorbed the sperm
DNA. That culminated in the classic pictures by Bevan Reid in the Lancet of a
sperm fragment in a cervical cell. 78 1 was taken on as a research fellow in 1966,

5 Department of Health and Social Security (DHSS) (1986a), later consolidated as DHSS (1988). It
recommended that all women between the ages of 20 and 64 should be invited for screening within five
years of 31 March 1988. For details of the narrowing of the age range in 2004, see note 155.

Dr J A Muir Gray, as chairman of the National Coordinating Network (NCN), convened a group
of regional contacts and professional associations in cervical cancer screening about their training and
educational needs. The resulting report, 'Education and training needs of programme managers' was
published in 1989 and is no longer in print. See www.cancerscreening.nhs.uk/cervical/publications/pm-01.
html (visited 3 September 2009).

See Biographical notes, pages 137—8.

" 8 Reid (1964); see also Coppleson and Reid (1969); Singer and Reid (1976).

29

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

and the only other research fellow was my good friend Margaret Stanley, but she
was 700 miles away in Adelaide. Both of us worked on the cervix and my first
task was to imitate squamous metaplasia.

What I did was to take women who were down for cervical cauterization, which
destroyed the cervical epithelium and then watched the regeneration. When
they would say to us: 'Can I go with my husband or partner?' we said to them,
'That's all right', because the reason was to see if we could imitate Bevan Reid's
original findings, and sure enough, in many of the women the regenerating
cervical cells (we published this in publications in 1967) showed that sperm
was taken up. And that led us to the concept that maybe it was the sperm DNA
mixing with the endogenous DNA. But for all the tissue culture work we could
not go much further with it. I then left in 1970 to come here; Reid continued.
He moved away from DNA, worked mainly on basic proteins protamine and
histones in sperm, and in 1978, in a rather contentious and controversial paper
in the Lancet, showed that men from social class five whose wives had a very
high rate of cervical disease, also had very high levels of sperm basic protein,
especially protamine, and that men in social class one and two had low levels.
The paper was accepted in the Lancet, raised obviously a lot of ethical problems,
but he did show that there was a profound difference between the social classes
on that subject. These substances profoundly influence cell surface function in
vitro. He then went ahead and in 1987 showed indeed in tissue culture work
that you could imitate most of the morphological features of malignant cells.
He did time-lapse photography and showed that adding protamine, which is
a basic protein to the cell structures, when added to the cell cultures, induced
these changes. During the 1970s, many of us still believed that DNA in some
form, be it in viral form or in the actual virus or indeed sperm, was responsible,
and I wrote a letter to the BMJ on the 1 1 October 1969, which is 39 years ago,
to an article on contraceptives and cervical cancer, and said that these steroids
could prevent the entry of the proposed genital mutagen, be it in the form of
'spermatozoal or viral DNA. 80 Then Rawls and Melnick published their work
on herpes simplex virus 2 (HSV-2) in Houston in 1968. 8 ' But again we pointed
out that probably there was more DNA from sperm origin than there was from
viral. So there was quite a lot of activity in that field on the male.

9 The data from Reid et al. (1978a) were re-cast in Reid et al, (1978b) as a result of the suggestions from
Cameron and Jones (1978): 366, and showed a higher degree of significance than reported in the earlier paper.

80 Singer et al. (1969).

81 Rawls etal. (1968).

30

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

I came to England and was influenced by the lady sitting on my left (Valerie Beral).
We had both been residents in Australia at the same hospital many years before
and she published a classic paper in 1 974 on the standardized mortality ratio for
cervical cancer by social class and husbands' occupation in married women. If
you were a fisherman, your wife would have had a standardized mortality ratio
(SMR) of 257, or the wife of a driver of road goods vehicles of 168; compared
to the Oxford clergyman's wife who was 12, or a scientist's wife who was 17
(Table 2, page 32). And on the basis of that and knowing what we knew about
some of the basic work, Bevan Reid and Malcolm Coppleson joined me in writing
a hypothesis published in the American Journal of Obstetrics and Gynecology on
the role of the high-risk male in the aetiology of cervical cancer, a correlation of
epidemiology and molecular biology. Certainly Stanley Way gave me some of
his anecdotal comments to add to that. The high-risk male as we suggested was
determined by occupation, as Valerie had pointed out: sexual behaviour, cigarette
smoking, sexually transmitted infection (STI), and genital HPV infection.

I came down to London from Sheffield in 1 980 and met David Oriel at University
College Hospital (UCH), who was a world expert on genital condyloma, and
over the next few years he allowed a team comprised of Michael Campion and
other research fellows to study the relationship between cervical and penile
condyloma. Jack Cuzick and Dennis McCance also helped us and we published
a number of papers showing that the women whose partners had penile HPV
were at a very increased risk of cervical disease. So that is really the unknown
male factor. It started off being unknown, because the only work before the
1960s dated back to 1842 to Rigoni-Stern, who showed that nuns had a low
rate of cervical cancer, and married and widowed women had a high rate of
cervical cancer. Very little occurred in the 1950s. Isadore Rotkin wrote on
female behaviour, on the early age of first intercourse; 8 ' but it wasn't until the
sperm work and the HSV work developed that we started looking at the male
and then eventually at warts in the 1980s.

82 Beral (1974): data on page 1039, see Table 2, page 32; see also Wakefield etal (1973); Anon. (1973).

83 Singer etal. (1976).

84 Campion et al. (1985); McCance etal, (1985).

85 Rigoni-Stern (1842, 1988); Griffiths (1991); Scotto and Bailar (1969); see also note 236.

86 Rotkin (1962, 1973).

87 Singer and Stevenson (1972); Singer (1983); Walker etal. (1983a).

31

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

Social class

Husband's occupation

SMR

I

All occupations

clergymen
scientists
civil engineers

34

12
17
60

II

All occupations

teachers

senior government officials
publicans & innkeepers
lodging house & hotelkeepers

64

30

40

120

150

III

All occupations

clerks of works

clerks

crane & hoist operators

drivers of road goods vehicles

100

40

64

159

168

IV

All occupations

shopkeepers & assistants

gardeners & groundsmen

fishermen

deck & engineroom ratings, barge & boatmen

116

71

98

257

263

V

All occupations

office & window cleaners
labourers

181

95
222

Table 2: Standardized mortality ratios (SMRs) for cervical cancer in married women,
by social class and occupation of husband, England and Wales, 1959-63. Beral (1974): 1039.

McCluggage: Well, that was a very complete summary of the unknown male
factor. Has anybody any comments about the unknown male factor?

Dr Anne Szarewski: I wanted to emphasize, perhaps, the role that Albert Singer
played in this. I think that women in general should be very grateful that he
highlighted the role of the male in cervical cancer, I think because there was so
much stigma attached to it all being a 'female thing'. 88 It was really Albert's unit,
which I joined in 1986, that was greatly responsible for the shift in emphasis to
say that: Actually this is a joint problem, it's not the fault of the woman'. I think
that a lot of the research that went on in our unit helped that shift a great deal.

M il ler : I wanted to comment that the epidemiologists had identified a male factor.
There was a case control study published in the UK, I think Buckley was the
first author, which showed this and there were several studies of epidemiologists

88 Singer et al. (1976).

32

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

which showed that husbands whose wives had died of cervical cancer, their
second wife was at a greater risk. So there was a fair amount coming in the
epidemiology area. Rotkin and various others were pointing out the importance
of the male. While I am talking, could I point out that it was Alex Meisels, the
cytopathologist in Montreal, who identified some of the cytological changes
that later were found to be due to HPV.

Professor Margaret Stanley: There was no doubt that there was a male factor.
The epidemiology that had been done in the first part of the century and in the
1950s showed that. 90 There were some very amusing reports in the literature.
One of my favourites was of a guy in the US whose wife had cervix cancer and
whose other partners lived within a relatively short distance also had cervix
cancer. 91 My boss, James Kirkland — the best gynaecological pathologist I have
ever known, who had trained as a cytopathologist under Elizabeth Macgregor
and went to Hans Hinselmann where he was trained as a colposcopist — had a
very wicked sense of humour and said: 'He didn't even need a bike.' So the male
factor was known and it's about the sociological and cultural attitudes of the
time that you would always blame women.

I remember being on a radio programme in Australia, where we were talking
and I was being asked questions about cervical cancer. I trotted out the usual
risk factors — early age of sex, usually more partners — and one lady phoned up
in absolute fury, and she said that she had been married since she was 16, she
had never had another partner, she had had five children, but her husband was
a merchant seaman. I rest my case.

Patrick Walker: Before we move on to the science and the next bit, it is
worthwhile remembering what it was like and how much HSV had actually
dominated the agenda through the 1970s. I started working with Albert Singer
in 1981 and he sent me along to Dulcie Coleman to work in the lab there,
and HSV was very much 'it'. It was intriguing at the time, I went to a meeting
where Laura Aurelian and Irvine Kessler came over to speak, and Ralph Richart
was there as well. 92 By the very tail end of the meeting, they were struggling to

89 Buckley et al. (1981).

90 Rotkin (1967).

Professor Margaret Stanley wrote: 'It was in the American Journal of Obstetrics and Gynecology, but the
precise reference is not in my records.' Note on draft transcript, 1 September 2009.

Richart (1964) introduced the terminology of cervical intraepithelial neoplasia (CIN).

33

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

keep the hypothesis of HSV going, and the difficulty was that they couldn't
find the DNA of the virus in the malignant tissue. They found the RNA and
therefore they developed something, I think McDougall called it 'the hit and
run hypothesis' (the virus got in, did the damage and then ran away again).
As our colleague (Anthony Miller) mentioned, Meisels, Fortin and Roy's
paper at the same time as Eva Savia and E Purola in Finland were identifying
cytopathological changes that could be HPV. 93

It always seemed strange to me as a young man entering the field at the time
that now we see koilocytosis and dyskeratosis everywhere, what were people
looking at in the 1970s during the HSV era that all of this so obviously became
true later?

Stanley: Cytologists did recognize these funny cells, but we called them halo
cells, we didn't know what they were. They weren't regarded, and Dulcie
Coleman may wish to comment. But I want to reinforce what Patrick Walker
said, HSV utterly dominated the agenda, and it was very much based —
and Joan Macnab may want to comment here — on the serology and the
relationship between antibody levels to HSV-2, but the thing that really should
have killed it was that nobody could transform human cells in tissue culture,
or primary cells other than rodent cells with HSV DNA or any fragment of
HSV, and one has to remember that the transformation assays that were used
to support the idea of HSV involvement were all done on Syrian hamster or
mouse fibroblasts. Anybody who works on those knows you only have to spit
at these cells and they will obligingly transform for you. So, that was the basis
of the science. 95

Dr John Smith: About the koilocyte: those of you who know the Papanicolaou
Atlas of Exfoliative Cytology from 1954, will know that it contains these
marvellous coloured pen-and-ink drawings of abnormal cells. There is a most
fantastic illustration of a koilocyte there, though its significance, of course, was
not realized at the time.

Purola and Savia (1977); Meisels et al. (1977); see also Nieminen et al. (1991).

Dr Joan Macnab wrote: 'I would like to record that the molecular analyses of cervical tumours in
Glasgow confirmed that HSV DNA could be retained. Furthermore, HSV was re-activable from rat
transformed cells using genetic techniques of analyses (Park et al. (1980, 1983)).' Note on draft transcript,
2 September 2008.

See, for example, Galloway et al. (1980); Stern and Stanley (eds) (1994).

34

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

Figure 4: Koilocytes, cells infected with HPV

96

(400* magnification), stained with the Papanicolaou stain.

McC luggage: That leads us on very nicely to the discovery of HPV16 and -18 as a
major cause of cervical cancer and precancerous lesions, so again, Albert Singer.

Singer: I feel rather humbled talking on this topic that everyone here is so
involved with. But again I start with Coppleson and Reid in 1966. It was
obvious to us that age of first intercourse and of 'promiscuous adolescence' were
very important as behavioural characteristics.

The first thing they got me to do was to start looking at the cervix of virginal
girls and those of sexually active girls. Well, you will say, how can you look at
virginal girls? In the 1960s it was usual for what was called the 'strip and stretch
of the hymen to be done under anaesthetic before a young woman married.
And working in a big hospital in Sydney, Val Beral knows it well, many of

'Their form indicates a transition from the navicular to the superficial type. Cells exhibiting dyskaryotic
changes. ..affect chiefly the nucleus and consist in enlargement, irregularity in form, hyperchromasia and
bi- or multinucleation. In the superficial and navicular dyskaryotic cells a perinuclear "cavitation" is often
present' (Papanicolaou (1954): A. VI. 9, pages al4— a!5).

35

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

the gynaecologists had huge private practices and every time a young woman
came in for this procedure, I would ask for permission and run along with my
colposcope, and in the space of about ten seconds was allowed to get a picture.
So I had a library of the cervix of virginal women, and then the sexually active
young women, and we published this and showed that the cervix of the sexually
active girls was smaller, but that squamous metaplasia was very active, about
three or four times more active, but the important thing was there was atypical
abnormal epithelium present. We then started to biopsy the cervix. Now, the
population we studied was a group of women whom Coppleson had been able
to observe, and these were young women in an institution who were offered a
bacterial examination to exclude STI of the vagina, and during that examination
we photographed. They were all sexually active, and I brought some of the
original photographs taken at the time with me. We have Miss H, aged 14,
sexual intercourse age 12. They had the most unusual changes in the cervix; we
had never seen these. Coppleson couldn't work it out, and he was an experienced
colposcopist. We took biopsies of these and I remembered photos from Koss and
Durfee's pathology book. So I sent him some of these black-and-white pictures.
'Dear Professor Koss, In your book you call these warty atypia. What are they?'
And he wrote back — I still have the letter and Leo Koss has mine — and we had
a correspondence. He said these are 'warty atypia'; this was 1968.

Then we had to work out these changes, and Coppleson said that indeed these were
obviously very profound changes and held the key to the whole abnormal process
in the cervix. At the time the pathologists really didn't recognize it. I have a book
from 1973 by Fred Langley and Archie Crompton on epithelial abnormalities. 100
There are four lines devoted to 'warty atypia', which were cells similar to these
cells, which were obvious HPV. Koilocytes were noted in the condyloma, thus
suggesting a possible relationship to infection. However, Patten considered these

97 Singer (1975).

Koss (1961) was a 'Citation Classic' in Current Contents: Life sciences (1989) 32: 15, having been cited in
over 1260 publications. See also Koss and Durfee (1956); Koss et al. (1963); Koss (1975).

99 Coppleson (1970).

The lines read: 'Cells similar to these are seen in condyloma acuminatum, thus suggesting a possible
relation to virus infection. Indeed Koss (1968) terms these changes 'warty atypia'. However, Patten (1969)
states that the perinuclear clear zone has been attributed to shrinkage and Sagiroglu (1963) considers it an
artefact.' Langley and Crompton (1973): page opposite Fig.5.3a and b.

Langley and Crompton (1973): Figure 5.2.

36

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

changes to be artefact and Langley himself said these were degenerative cells. But
we believed that these changes all were related to viral infections.

An offshoot of the work was that we wanted to know how the virus, or what it was
that was causing it, got into the cervix? Reid asked if the young woman ovulated
soon after she starts having her periods? The answer was: 'No, young women
don't ovulate for a few years after.' He said: 'Maybe there are structures in the
mucus that allows the entry at that time.' Again we examined the structure on
an electromicroscopy of cervical mucus and again the original picture showed,
as you would expect, that at mid-cycle if you are not ovulating, you have very
clear channels, and when you ovulate these channels are blocked. So, here was a
possible mechanism by whatever it was 'got into'.

We then went on from that and really I wanted to see what happened to these
girls as they got older. I came to this country and managed to link up with
Sir Richard Doll, who directed two young research fellows, Martin Vessey and
Peter Smith, to help me in a study at Holloway Prison (1970-73). I managed,
and it's another whole story, to get into Holloway Prison, set up the colposcopy
clinic and examine 768 women, 38 per cent of whom had CIN and for whom
18 per cent had CIN or cancer and the biopsy showed exactly the same result
as we had previously.

Jenkins: I think one of the key things, Albert, was when the probes began to
arrive, with the setting up of Southern blotting techniques.

Singer: If I may have ten seconds. Dulcie Coleman was helping me and we set
up a study with Patrick Walker. The main study that we did was in 1983 and
Jack Cuzick was also involved. We wanted to know what happened to women
with mild changes in smears, most of whom had an HPV infection. We followed
these women for three years with no biopsy, and showed that 26 of the 100 with
mild changes (CIN1) turned into severe disease (i.e. CIN2/3) and 85 per cent
of these had HPV16. Dennis McCance at Guy's Hospital did the hybridization
and, as far as HPV16 was concerned, that was really the turning point. 105

Subjects were from King George V Memorial Hospital, Sydney, Australia, and HM Prison, Holloway,
London, with financial support from the National Health and Medical Research Councils in Australia and
a project grant from the Medical Research Council, London (Singer (1975)). See also Singer (1973).

103 Melchers etal. (1991); Tidy etal (1989). See note 108.

104 Walker etal. (1983a and b).

105 Campion etal. (1986).

37

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

Professor Heather Cubie: I wondered if I could give a slight virologist's
perspective and go back a little bit, too, because there was quite a lot of
virology happening, looking at papillomaviruses in the 1960s, particularly
in the Institute of Virology in Glasgow, and we were doing quite a bit in
Edinburgh. Albert Singer has referred to what I actually think still is one of the
sentinel differentiations, which was David Oriel and June Almeida's electron
microscopy work, coupled with what Marie Ogilvie did in Edinburgh, to
separate out genital wart virus from the virus causing cutaneous warts. ' That
was the first indication that perhaps there were different kinds of this virus,
and through the second half of the 1960s, and the early 1970s, lots of work
was done trying to find in vitro models, as Margaret Stanley has mentioned
too, and cell culture systems which didn't work. I was much involved in those
animal models, which were jolly hard to do. 107 Then molecular techniques
came along, starting with things like hybridization with the most cumbersome
of techniques, coupled with Southern blotting — again an Edinburgh discovery
and yet hugely influential in being able to move forward to eventually produce
knowledge about different types of HPV- and that was the late 1970s.

I wonder if I could make one more interesting point? The first international
papillomavirus meeting was in 1975 and was held in Lyons, organized by the
Institute Pasteur dermatologists. And, there was the beginning of an association
of papillomavirus with cervical disease in terms of the virology at that stage. 109

Professor Saveria Campo: I wish to point out that the discovery of HPV16
and HPV18 was made in the laboratory of Harald zur Hausen in Heidelberg,
and it was made possible because Lutz Gissmann cloned HPV6 from a genital
condyloma and used that molecular clone of HPV6 as a probe. They were
the ones that found HPV16 and -18 in SiHa and CaSki cells, and then they
found them in several biopsies of cervical cancer, so we mustn't forget that they
actually found for the first time HPV viral DNA in cervical cell lines and in
cervical cancer specimens.

106 Dunn and Ogilvie (1968); Oriel and Almeida (1970). See also note 84.

107 Cubie (1976).

108 Southern (1975).

105 Prunieras (ed.) (1976).

110 Gissmann and zur Hausen (1980); Durst etal. (1983); Boshart et al. (1984).
zur Hausen et at (1974); Gissmann and zur Hausen (1976).

38

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

Stanley: I want to reinforce that and to also point out that zur Hausen had
published a paper early in the 1 970s, where he had been looking for papillomavirus
DNA in cervical cancer biopsies. And the problem was that the molecular
technologies were not advanced enough at that point for him to do it, and it
wasn't until 1978, when Gissmann cloned HPV1 1 . This was absolutely critical,
because without that, then the actual cloning out of HPV16 and HPV18 would
not have happened and that was crucial. Lionel, who knows more about this
perhaps than anyone else in the room, might want to comment.

Dr Lionel Crawford: I think the main comment is that I wish that Lutz
Gissmann was here because I think he could really fill us in on the logic of
what they did and the technology behind it. Certainly zur Hausen's lab was
extremely important in all of this and continued to be for a long period. So
his is a name which should be very prominent in all of these studies. If I could
make a perverse comment at the same time: zur Hausen's generosity in giving
everybody clones so that they could do searches with his cloned material had
an unfortunate effect. This turned out to be a standard that everyone was using
and the standard had in it a mutation which was effectively an assembly minus
lesion which made it more difficult to assemble LI into virus particles. In a
way people would have been better off to isolating their own strains and later
on it was found in my lab and Gissmann's lab that most of the natural isolates
differed from zur Hausen's clone in a position in LI which is critical, because
LI is the major coat protein. 11

McCluggage: Thank you for that. We are going to move on to Dr Campo, who
is going to talk about the mechanisms and genes of HPV.

Campo: I work in Glasgow, and the reason I work there is because at the end
of 1978 I read a review by Bill Jarrett, who was a veteran pathologist, on the
fact that BPV, bovine papillomavirus, was the cause of upper gastrointestinal
tract cancer. And I thought, 'Hey, this is a real cancer virus'. I was working
on SV40 and was absolutely fed up with working on SV40 because I couldn't
see where this was going to lead me. I wrote Jarrett a letter saying: 'You have a

zur Hausen et al. (1974).

113 Dartmann et al. (1986).

Dr Lionel Crawford wrote: 'I learned at this meeting that the sequence of the LI gene in the patent
application is not that of the zur Hausen HPV 16 clone, so this point may be irrelevant to VLP production
mentioned later.' Note on draft transcript, 16 July 2008.

115 Jarrett et al. (1978a and b); Jarrett (1978).

39

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

system and I have the molecular techniques, so why don't I come and work with
you?' And he said: 'Yes, sure, come on.' And the rest of it is history. I went to
Glasgow and stayed there.

To go back to HPV. As I have said, HPV was discovered later. In fact BPV
was one of the first cancer viruses, papillomavirus-induced cancer. It was found
along with CRPV, the cotton-tail rabbit papillomavirus, and these were the
days when, as has been said, nothing was known about HPV16 or HPV18.
It was really thought that these were different viruses from genital condyloma
and all the studies were being done on the rabbit and the bovine virus. Anyway,
talking about the mechanisms of HPV: if we take HPV16 as the paradigm,
then this virus has three transforming proteins that contribute to cervical cancer
formation and these are: E5, E6 and E7. It is now accepted that E6 and E7 are
the major transforming proteins and E5 is an auxiliary transforming protein.
The thing that fascinates me is that there are viruses, a whole lot of HPV
viruses, that do not have E6, like BPV4, and they are perfectly good at inducing
tumours and inducing cancer. And there are viruses that do not have E5, so
whatever E5 does — and we can talk about what E5 does later — these viruses
can do without E5 altogether. There is a whole class of bovine viruses again, in
which E7 does not bind the protein pRB, which is what HPV16 E7 does. So
whereas all these proteins undoubtedly do their thing in the transformation of
cervical keratinocytes, there are an awful lot of viruses that can do without one
or the other of these proteins. So I find this is actually quite interesting and
perhaps these viruses should be studied more. These proteins that operate on
cell transformation by pushing the accelerators, disabling the brakes, preventing
apoptosis, these very same proteins are those that disable the immune response.
They interfere with the immunomolecules of the host and they practically make
the infected cell, the HPV cell, invisible to the host lymphocytes. So, it's a very
clever system for such a small virus, it encodes two or three proteins that can do
multiple things: one is to put the cells into proliferation and at the same time
prevent the host's immune system from recognizing cells that are proliferating
when they shouldn't.

Dr Joan Macnab: I think that's interesting, but in my lab Henry Kitchener,
John Murdoch and Steve Walkinshaw did a lot of work on cervical cancer with
me. One of the issues we found — perhaps not common to the whole of the

116 Shope (1933, 1937); Syverton (1952).

117 Munger et al. (2004); Stoppler et al. (1996).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

UK, but certainly to the west of Scotland — was the high incidence of HPV16
in normal samples. Initially HPV16 was found in cytologically normal tissue
distant from a tumour, but later in CIN and in tissue from normal controls
with no evidence of cytological abormality. That made it very difficult for us
as workers on HSV-2. We were in the position of having found HPV16 in a lot
of circumstances that were difficult to explain. I think that HPV depends on
other factors and has other aetiology in the patients in which it forms tumours.
Co-factors could include HSV-2, which has proved to be present in cervical
tumours, transformed cells and also to have the ability to increase expression of
tumour-specific proteins such as the mitochondrial aspartate amino transaminase
and up-regulate the oestrogen receptor.

Crawford: May I speak up from the virus' point of view? There is no reason why
the virus should care at all about transformation; it only cares about making
more virus. It is perverse to only take the patient's point of view, whereas all
the virus wants is to produce more and more virus. So the fact that it appears
in normal cells, produces virus progeny, goes on to infect and everything else,
that is fine. If occasionally there is transformation, it doesn't matter to the virus,
but it matters a lot to the patient and to the doctor in charge. But I think one
has to look at things from a different point of view to understand the way the
virus works. So a lot of the things we have been talking about would not have
interested the virus at all.

Jenkins: This issue of HPV in normal women is one of the things that has caused
immense confusion, hasn't it? In terms of the development of the understanding
and the impact of the papillomavirus, the finding of virus everywhere did for
a while lead to considerable doubts about the oncogenic role of HPV and had
a big impact on the whole research activity, research programmes, going on at
that time in the 1980s.

Campo: I absolutely agree with every word that Lionel Crawford has said: the
virus wants to make more of itself, and it doesn't care about cancer, which
is a dead-end. Also, viruses are 'latent', can be latent, and papillomavirus has
been found in normal margins of lesions; it has been found in epithelia away
from lesions; it's been found in clinically normal people; and this is particularly
problematic for skin cancer. I know that we are not talking about skin cancer

118 Macnab et al. (1986); Kitchener etal (1991).

119 Lucasson etal. (1994); Offord etal. (1989).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

at this meeting, but non-melanoma skin cancer is a point of controversy as far
as HPV is concerned, precisely because the cutaneous squamous cell or basal
carcinomas are also found so frequently in clinically normal skin. But that
doesn't mean to say that once in a while an accident happens which is not good
for the virus, it's not good for the host, but it's good for the transformed cell that
gets selected then moves on.

Professor Julian Peto:I slightly disagree with Lionel. HPV16 is so extraordinary
compared with other HPVs, in terms of its transformation power that something
approaching half of all untreated women with HPV16 may develop CIN3.
The consequence is that they remain infectious for much longer, so in the case
of HPV16, you could argue that there has been selection for transformation,
because it substantially increases the time that the carrier remains infectious in
an unscreened, untreated population.

Jenkins: A lot of this has taken a long time to be understood, hasn't it? We are
going back to the early days of looking at HPV. We were really unaware of a lot
of these complications and the discovery of HPV in normal tissue as well as in
cancerous and precancerous tissue did cause quite a stir and a lot of concern at
the time, against the importance of HPV as an oncogenic agent.

Stanley: The problem with HPV was that infectious disease physicians and
microbiologists were not much involved with it. It was gynaecologists and
histopathologists, who really had very little understanding of infection and
infectious disease, and that has always been a problem in the HPV field. The
idea that with pathogens, with viruses, with any form of microbe, lots of
people are exposed, lots of people are infected, relatively few actually show any
clinical symptoms and really very few show the most severe and acute form of
disease caused by the pathogen. That is as true of HPV as it is of even polio, for
goodness sake.

Professor Ciaran Woodman:Somebody has to disagree with you, with thesoundbite
that 50 per cent of women with HPV16 develop CIN3; it's too large, much too
large. We started on our own longitudinal studies which attempted to define a
cohort in which we could measure the incidence of HPV16 and -18 infection, and
the proportion of those who acquired the HPV16 infection soon after the onset of
sexual intercourse was of an order of magnitude less than 50 per cent. 120

Tierney et al. (1993).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

Crawford: p53 is a whole meeting on its own, so I will only talk about it
very briefly. It has a very interesting history and came out of confusion,
misunderstanding and SV40. m

But I will talk about virus-like particles (VLPs) and I find myself in the minority
again, not speaking about the virus, but about prevention at a much earlier
stage than detecting early lesions and removing them. My position, for the
sake of argument, is that we could do without all of this if we had a decent
vaccination system, and the basis of that has to be the virus coat protein and
virus-like particles. 123 You see them in all sorts of wart virus, you see them in
sections and in negative staining, they are particles which lack DNA, and, of
course, you want anything that you are going to use to put into people to be
devoid of DNA, because that removes all the worries about actually causing
the disease, rather than preventing it. VLPs have been around for a long time,
but producing them in quantity was felt by experts to be almost impossible.
Even harmless sorts of warts, like the ones you get on your hands or your feet,
couldn't be reproduced in the sort of quantity of virus required and then the
empty particles separated out from the full particles, on a scale that would allow
you to do anything useful. For the important viruses like HPV16 and -18,
it was even more ridiculous, you couldn't get anywhere near it. There were
certainly people who felt that the infection of epithelial cells in the state of
terminal differentiation was essential for the production of virus particles, but
this was not true.

The name I want to emphasize here is Jian Zhou (1957-99). u He felt that if
you hooked up the virus coat protein gene (LI) to a strong enough promoter
in vaccinia virus you could actually get it expressed in quantity in cells, not
in terminal differentiation. He had survived the cultural revolution in China
(1966—69) and when he came over to the UK he was able to show that not
only could he produce decent quantities of HPV16 LI but he could also show
that in mice there was a tissue-mediated immune response. When he went to

For an overview, see Thomas et al. (1999).

122 Levine (1976, 1990); Basilico (1984); Matlashewski (1989).

123 See, for example, Zhou et al. (1990, 1992, 1994).

Dr Jian Zhou discovered the HPV VLPs (Zhou et al. (1991)) that enabled the development of the
cervical cancer vaccines Gardasiland Cervarix. See Figure 5, note 127 and Biographical note on page 144.

125 See, for example, Unschuld (1985); Ebrey (1996).

43

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

Figure 5:DrJian Zhou (1957-99) in Dr Lionel Crawford's
laboratory, Cambridge, c. 1 989.

Australia he continued this work and was able to produce VLPs. Admittedly
they were sloppy for the reason that I have already mentioned, because we were
generously given the HPV isolate from zur Hausen and that was the one being
used. But I think this was very much where the whole vaccination story begins
and I wish that Jian was here.

[Professor Valerie Beral asked about Zhou and Ian Frazer. She had
thought VLPs were first produced by Ian Frazer].

Crawford: Jian had been out picking melons in the fields during the cultural
revolution in China, and when he was allowed back into the lab he started to
put together vaccinia constructs in which various proteins were expressed, in
positions within the vaccinia genome where the promoter activity was extremely
strong. One of those was LI from HPV, and he wrote to me and asked if he
could come to the lab. After a lot of coming and going — it was also the time
of the general postal strike in 1971, which didn't make life any easier — he
came over to my lab and continued this work. Jian and his wife, Xiao-yi Sun,

44

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

were used to working extremely hard and doing everything for themselves, they
worked like crazy and moved fast. So, to my mind, Jian was the person who was
able to generate substantial amounts of LI, although not at this stage as virus-
like. He also felt that the important thing was not to get humoral immunity,
which you can get with bacterially produced LI, but also to put it into mice to
get cytotoxic T cells, which he did.

Ian Frazer was in Margaret Stanley's lab next door during this time and we were
having great difficulty in getting any sort of guarantee that we were going to get
a passport for Jian since the Home Office wouldn't do anything. They said he
could apply after several years' residence and that they would think about it. With
the state of politics in China, he really needed a passport. Because the Australian
authorities were much more flexible about this, he felt that he should get himself
an Australian passport and be free to go wherever the good science was. When
he got to Brisbane he continued that work and was able to produce pictures of
VLPs, which sedimented in about the right region. They were clearly sloppy;
they weren't really nice. Papillomaviruses are extremely pretty, they are beautiful
things, but his were far from beautiful. They had all the main requirements,
and as soon as you changed over the system, used a different sequence, without
the assembly lesion, then you started getting good quantities of good particles.
Other groups in the US also did similar things with papillomaviruses in all sorts
of other systems. 12 I think the important breakthrough was the idea that if you
put the LI gene behind a really strong promoter, all the other requirements
could be forgotten. And that turns it into a practical possibility. My feeling is —
again I suppose I am disagreeing — that screening and everything else is all very
well when you can afford it, but the vaccination of boys and girls worldwide
seems to me to be the way to go in the long term, to get herd immunity at the
stage of not being virus-infected, rather than becoming virus infected and then
catching it at the eleventh hour or so.

[Professor Valerie Beral asked Dr Lionel Crawford for clarification about
who discovered VLPs, which was the breakthrough that led to the HPV
vaccine.]

Crawford: Jian Zhou.

Cubie: I am so delighted that you have said all those things about Jian. He
certainly was a very important person and I was privileged to be the person
who was chairing a session, again at one of the international meetings, where

University of Rochester, Georgetown University and the National Cancer Institute. See also note 127.

45

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

Jian presented his first revelation in 1991 in Seattle. Indeed, I have often been
chased by the patent attorneys to give the exact timing of that presentation, and
therefore from the historical point of view it was a very important thing to be
associated with.

Crawford: It was brilliant and that's why I have made such a point of it. Because,
I think, one needs to acknowledge the people - in spite of all the difficulties and
all the interference, political and otherwise — who knew what was important,
and did it.

Stanley: Lionel is absolutely right. I have come back from Australia where we
held the ninth anniversary of Jian's death (2008), and we really talked a lot
about this. I think Jian did something incredibly important and he drove
it; he showed the particle and that there was activity. People had made VLPs
for other viruses; in fact, the hepatitis B vaccine, which was developed and is
being administered, is actually a VLP-like structure. So there were other people
thinking about it and doing it. The baculovirus expression system for HPV
was started in a PhD by Bob Rose in Rochester in the late 1980s, 125 but Jian
was the first person to actually publish and show a VLP I think it needs to be
recognized that the intellectual discussion and drive originated in Lionel's lab,
and perhaps that hasn't been given the recognition it should.

McCluggage: Can we move on to immune responses to HPV?

Stanley: Immune responses to HPV languished for a long time and it's
important to say that pretty well everything we could understand about the
immune response to papillomaviruses came from animal viruses. If you think
about it, the first demonstration that a vaccine would work was done in 1937

127 For the 2007 decision of the US Coutt of Appeals fot fedetal circuit 2006-1154, interference no.
104,776, see www.cafc.uscourts.gov/opinions/06-1154.pdf (visited 6 October 2009). The work of
Zhou etal. (1991) was not disputed. See also McNeil (2006).

A memorial volume from that meeting is freely available at www.scribd.com/doc/2740521/zhou-
jianprefaces-Etc (visited 23 April 2009).

129 Rose etal. (1994a and b).

130 Zhou etal. (1992).

Dr Lionel Crawford FRS was made an honorary member of the Biochemical Society in 2004 and awarded
the Royal Society's Gabor medal in 2005 for his work on the small DNA tumour viruses, specifically the
papova virus group, papilloma, polyoma and SV40. For a description of his work, see www.biochemist.org/
bio/02606/0063/026060063.pdf (visited 27 October 2009).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

by Richard Shope, with the cotton-tail rabbit papillomavirus (CRPV). 132 The
reason why Shope could do it was that you make a lot of virus in the cotton-tail
rabbit, and so you could always extract the virus, which was pure, so you could
challenge animals and show that the virus was infectious and would generate
lesions. You could do the classic neutralization assays, which are the meat and
drink of the virologist. In other words, have you generated an antibody response
which will neutralize the virus and prevent it from infecting? You could do
that in rabbits and cows. In 1937 Shope did a classic experiment. He took
cotton-tail rabbit papillomavirus and he immunized the animal systemically In
other words, he infected intramuscularly. Not surprisingly, the animals didn't
develop papillomaviruses, because you have to infect the skin if you are going
to generate a papillomavirus lesion or wart. Even though the animals didn't
make warts, they generated antibodies and Shope could show that this was
neutralizing antibody in a classic method. What he then did was to take his
immunized animals and tried to challenge them with virus. The immunized
animals did not get warts, the non-immunized animals did. Now that is a classic
experiment. It shows that if you can generate a neutralizing antibody, you will
prevent infection with the virus.

You had to wait for the VLPs before the production of properly folded protein,
because you have to have the protein folded to generate neutralizing antibodies.
It took from 1937 to 1991 before the reagents were around to be able to test,
if you like, the Shope experiment with HPV. The serology of HPV was useless
until 1991, because we didn't have the proper reagents to measure circulating
antibodies, so we couldn't do the standard things you would expect to do:
looking at serum responses, antibody responses, to HPV. The other arm of
the immune system, of course, cell-mediated immunity, was easier to attack,
in the sense that we could make the proteins, we could make peptides and
so we could start to ask questions about whether there were cytotoxic T-cell
responses, whether it was a standard type of cell-mediated immune response
to viruses, in other words mediated by CD8 T-cells. Here again, the virus was
very difficult, because systemic responses to papillomaviruses turned out to be
almost undetectable. Everybody struggled like mad in the 1980s, particularly to
demonstrate that you could have a systemic response to HPV, either in terms of
antibody, or in terms of T-cell. The antibody story took off as soon as we had
VLPs, because you then had the right thing to measure. We are still struggling

Shope (1937).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

in 2008 with the cell-mediated response to HPV. We know it's important, we
know the clearance of lesions is regulated by CD4 THl-type responses, we still
don't know what the primary cellular immune response to the virus-infected
cell is. There are only two things you can say: that prophylactic vaccination
works, because it has been demonstrated, but immunotherapy — which is the
other thing that people want to generate — is very difficult because we don't
understand how you clear the virus.

Campo: If I can take up this last point and continue with it. The strange thing
is that therapy, therapeutic vaccination, works in the animal system: it works
in the rabbit, it works in the cow, it works in the dog. There is something
that we do not know about HPV in humans, which has prevented an effective
therapeutic vaccination in humans. Every time we hear of a new trial: 'Yes, it
works; it's very promising.' We have to continue. But still it is nothing like a
preventive vaccine, the prophylactic vaccine which we are talking about that
is 100 per cent effective. Any therapeutic vaccine against HPV is not as good
as therapeutic vaccines against animal papillomaviruses, would you say? You
[Margaret Stanley] have done therapy in the dog, we have done therapy in the
cow and it works. 133

Stanley: The trouble is that the therapeutic approach in humans is always
targeted to precancerous lesions and therefore it becomes an anticancer vaccine
rather than a therapeutic vaccine against a virus infection.

Cubie: There's another dimension to looking at immune responses, and that's
clearly in epidemiological studies in large numbers. As we go towards the
introduction of the vaccination and a lot of what we were talking about earlier,
about the cytology and the colposcopy, I think it's really important to know
how ubiquitous these papillomaviruses are, and, as Margaret said, once the
VLPs were available we could do some extended serological work. Margaret
and I worked on a group of children and found an incidence of antibodies to
HPV16, not a very high incidence, about 7 per cent, compared with about 50
per cent of the kids having antibodies to the skin types. Now, to me, that
is a really important thing, because although the viruses that we are talking
about in relation to cervical disease are being considered as sexually transmitted
viruses, and the virus is undoubtedly usually sexually transmitted, it is possible
to pick up that infection — whether it ever progresses to pathological disease —

133 Campo etal, (1993); Moore et al. (2003).

134 Cubie et al. (1998).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

by nonsexual routes. It was serology as well as DNA detection that was able to
show that.

McCluggage: We are going to move on to Professor Peto, who is going to talk
about the epidemiology, natural history and importance of HPV.

Peto: It was clear to everybody who was interested in HPV by about 1985 or
1986, that this was the cause of cervical cancer. It took us ten years to persuade
the rest of the world, and a lot of clinicians were still sceptical until quite recently.
It's extraordinary how suddenly things changed. Dulcie Coleman and I set up a
cohort of 50 000 women in Manchester, and similar studies were done by many
other people. These large, population-based studies of women undergoing
routine screening showed that about 20 per cent of women aged 20—24 had
oncogenic HPV, not HPV6/HPV1 1, but the oncogenic types. It really was rather
extraordinary. And it also became clear from such studies that most of these were
transient infections, implying that something of the order of 50 per cent of the
British female population were being infected with the virus that causes cervical
cancer by the time they were 30. Everybody in this room knew this for 20 years,
but it didn't become generally known until five years ago. Those studies also
showed the relationship between HPV and CIN3, although the relationship
between HPV and cancer is more difficult to demonstrate in prospective studies
because you have to wait so long and have so many people in the study. Ciaran
Woodman described it as a soundbite, but in our cohort, the cumulative risk
of CIN3 in women with high-risk HPV and normal cytology was 28 per cent
after 14 years. That's why I questioned Lionel's comment that transformation
is irrelevant to natural history, at least for HPV16. At that level I think it could
appreciably affect viral evolution. Anyway, studies of that sort demonstrated the
prevalence of HPV, but the fact that most infections disappear within two or

Professor Heather Cubie wrote: 'Probably the most relevant work came from Drs Jenny Best and John
Cason working at St Thomas' Hospital in studies on primary school children. Also work done in South
Africa by Dr Dianne Marais, and by Dr Stina Syrjanen in Finland on family transmission studies, would
also be useful.' Letter to Mrs Lois Reynolds, 9 September 2009. See Rice etal (1999); Marais etal (1997);
Syrjanen and Puranen (2000).

136 See also Wakefield etal. (1973).

137 Zimet etal. (2006); Savard (2006).

138 Peto etal (2004b).

139 Professor Julian Peto wrote: 'The CIN3 risk is much higher for HPV16 than for other high-risk types
and the 28 per cent doesn't include CIN3 diagnosed at entry in cytologically abnormal women.' E-mail to
Mrs Lois Reynolds, 5 November 2009.

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

three years is still slightly mysterious. Everybody has always had the idea that
these were underlying chronic infections and nothing to worry about.

Something which has emerged quite recently is that the progression to high-grade
disease appears to happen much more rapidly than was previously assumed. It
may actually develop within two or three years, or not at all, as a consequence
of recent infection. As we are only going up to 2000 in this Witness Seminar
and this evidence has appeared in the last eight years, I think that the defects in
cytology historically were really very considerable. The progressive improvement
in cytology, particularly with re-training together with the introduction of LBC,
has raised the sensitivity of cytology to about 95 per cent for detecting CIN3. It
used to be less than 50 per cent in a lot of places. In the surveys that Jack Cuzick
did in various centres around Europe, the sensitivities varied from about 30 per
cent to 80 per cent not so long ago. Now it is over 90 per cent and there's very
little difference between the sensitivity of HPV testing and cytology. CIN3s
were often missed by screening, so you used to have to screen women again and
again so that they were picked up eventually. Modern cytology is extraordinarily
sensitive. We detected about 300 CIN3s at entry in 'A Randomized Trial In
Screening To Improve Cytology' (ARTISTIC) trial, and we only detected ten
extra CIN3s by testing everybody for HPV and colposcoping women still
positive a year later. So my view of the natural history of HPV has changed
quite dramatically in the last five years. The improvements in cytology that have
taken place quite recently have revealed a very different pattern from what we
thought.

Professor Peter Sasieni: Rather than debating the natural history with you,
here is an anecdote on the history. I was asked to give a talk at the Royal College
of Obstetricians and Gynaecologists in the mid-to-late 1990s, I don't remember
exactly when. I think it was David Luesley who was chairing it and decided at the
end of it to say: 'Let's take a vote to see who believes that human papillomavirus
is the cause of cervical cancer?' I lost the vote. It wasn't overwhelming, but I
think about 60 per cent of the obstetricians and gynaecologists in the audience
did not believe then that HPV was the cause of cervical cancer. It's interesting,
because you were saying earlier, Albert, about koilocytes and HPV morphological
changes, and I think that for that audience it was one of the reasons why they
didn't believe that HPV was the cause. Because they were so used to seeing
reports of HPV changes on smears, and knowing that it wasn't particularly
relevant to high-grade disease, high-grade CIN, so although it was important,

140 Sargent etal. (ARTISTIC study group) (2008).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

the actual labelling of koilocytes as HPV changes could have had a detrimental
effect, in terms of convincing most gynaecologists that HPV was the cause.

Jenkins: I think it is only since vaccination has begun to be studied clinically
and to be promoted that the general public has really begun to accept, and I
would include in that the vast majority of medical professionals, outside the
small number of cognoscenti, that HPV is the causal agent of cervical cancer.
Again, another personal statement: my daughter was taught in medical school,
about five years ago, that HPV was thought by some people to be associated
with cervical cancer, but nobody was sure about it. She came and questioned
me on this, about what I had been doing for the last 20 years. These things did
go on.

Singer: Patrick Walker failed to remember that we, along with Dennis McCance,
wrote an editorial for the BMJ, 'Genital wart virus infection: nuisance or
potentially lethal?' That was more than 20 years ago, and, like you, I was
ambushed at the Royal College of Obstetrics and Gynaecology in a 1988 debate
entitled 'More people live off than die from HPV. 142 That was less than 20 years
ago, and 75 per cent of the audience believed that more people lived off HPV
than died from it.

Peto: If you want to mention heroes in the history of HPV, Jan Walboomers,
who unfortunately is also dead, was another extraordinary man. In the study
which we initiated with the International Agency for Research on Cancer
(IARC, part of the WHO), we collected cervical cancer specimens from nearly
1000 people in 22 different countries. They were looked at using the standard
techniques for HPV detection and 93 per cent contained it. Jan re-analysed the
negative samples and demonstrated that they all contained HPV. We finished
up with only two out of 930 cancers that HPV was not isolated from. Jan's
analysis was absolutely decisive in showing that HPV is present in essentially
100 per cent of cancers.

McCluggage: The next session is about the UK national screening programme.
I know there are several people from overseas and we would be very glad if they
were able to comment on screening in other countries, but first Tony Miller will
talk about evidence as to when screening works and when it does not.

Singer et at (1984); see also Singer and McCance (1985).

142 Kitchener (1988).

143 Walboomers et d. (1999).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

Miller: Screening works when you get a high proportion of the at-risk
population involved in screening. That, indeed, had been one of the big issues
in this country (from our perception outside of the country). We were looking
at this, as Jocelyn said earlier, in relation to the fact that Finland had initiated
a programme in women aged 30 to 54 and achieved very high compliance, a
most successful programme. Five-yearly screening had as much impact as in the
US and Canada, where we had largely annual screening — and the reduction in
mortality has been the same, 80 per cent in the US and Canada, 80 per cent in
Finland, contrasting also with other Scandinavian countries, and with Norway
particularly. I think what became clear from outside as well as from what was
done here, is that if you made a big impact on the population and invited the
right sort of people to come in — and in fact I believe that the genius in this
country was to use the NHS register for that purpose — it called in the women
and you had the impact. I don't know how many people have looked at the
international contrasts, but the contrasts between Finland, Canada, the US and
the UK is the separation that occurred in the reduction, and the area between
the curves, when the UK finally got its act together and the mortality came
down. So you had this great gap between these countries, when mortality had
not fallen in the UK, and when essentially a lot of women died as a result of not
bringing forward screening.

I would like to come back to this issue of cytology sensitivity. It may well be true
that there were some laboratories in the US, and maybe in the UK, which had
30 per cent sensitivity. In British Columbia, where we made some very good
estimates, it was 75 per cent. Now 75 per cent is not what Julian said, he was
talking about 95 per cent. But 75 per cent in the context of the amount of
screening that was done clearly resulted in detecting the majority of the disease,
which is progressive. The only other point I think I need to make is about when
screening did not work, that there is still in every country this great divide between
those whom we are able to bring to screening, and those we are not. The fact
that we have a plateau in nearly all countries in terms of reduction of mortality,
particularly in North America, has been because we haven't been able to bring
recent migrants and people in the lower social classes into the programme. That's
a lesson that I think has got to be borne in mind in terms of vaccination. When
you hear in reports, as we have recently, that you only get 70 per cent compliance,
that is 70 per cent of the 70 per cent effectiveness, and you are then below 50 per
cent. So, I think we have to be extremely cautious when we look at this.

Hakama (1982); see also note 39.

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

I know we are not meant to go beyond 2000, but I want to make the point that
we all have to bear in mind — and we are thinking about this very hard at the
moment in Canada — that we have to set out our programmes for the future,
ensuring that the vaccinated women get screened appropriately, and ensuring
that the unvaccinated women still continue to get screened. So screening works
when the women at risk are screened. And that is what you have got to do to
ensure a successful programme.

Duncan: The Walton Report came out in 1976, and, of course, it was slightly
counter-productive, because the women could select themselves whether they
were high-risk or low-risk and be screened with a frequency which was different
for the two categories. There was a slight blip because all screening went down,
because nobody wanted to point a finger at themselves, and say: 'I am "high-
risk".' We have had difficulties in Scotland recently with younger women who
are not coming for screening. It's a bit like HIV and all the protection for that.
It's almost like wanton risk-taking when it is not due to ignorance. So, younger
women are not coming for screening.

We did look at a rural population and an urban population several years ago,
trying to identify why women were not being screened. These were women
who were approached up to eight times to find out why they were not coming.
Many of them had been informed, or were well informed, and decided that they
themselves were not at any significant risk. And so it's quite interesting how
people absent themselves from the screening programme.

Sasieni: Of course, if you don't screen a woman, you are not going to do any
good in terms of preventing cancer, but it's not enough to do a screening test.
As has been seen all over the world, it has to be an integrated programme. You
have got to make sure that the women get the results of the smear, which doesn't
happen in many cases. You have got to make sure that treatment is available,
which doesn't always happen. In parts of Latin America, something like 80 per
cent of women had a smear in the last three years. But if they have an abnormal
smear, there is no treatment facility for them. They would have to fly to a major
city to get treatment, which they can't do, so it's a total waste of time doing the
smear tests. The quality of the smears is really poor, particularly because there
are high rates of infection. So when you are looking on a global scale, there

145 See note 48.

'*' Cockcroft (2009).

147 Sasieni et aL (1996).

53

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

Figure 6:Three Aylesbury spatulas and oneAyre spatula, 2009.

The Ayre was the Department of Health spatula, replaced as the spatula of choice

by the Aylesbury from 1984 onwards.

are a lot of reasons, a lot of factors, which are critical to making a screening
programme work.

As Margaret Wolfendale is here we should think about the smear-taking
device. The extended tip spatula made a big difference in terms of the quality
of the smears, and what you could detect: the Aylesbury spatula and a good
laboratory.

I think that there are a lot of other factors. Of course, when you are not covering
the whole population you cannot have a big impact. That was the big difference
between Norway and Finland because, I think, they were taking a similar
number of smears, but in Norway it was the same women who were being
screened every year and in Finland they were making sure that they had very
high coverage with five-yearly screening. So that is important. There is so much
more to cervical screening than doing a smear test.

Herbert: I quite agree with what Peter Sasieni said. If there isn't good quality in
all parts of the programme, it won't be effective. May I say two things: the first
about Finland. Screening every five years from age 30—55 was always attractive
to people organizing programmes elsewhere, but in Finland they do not register
opportunistic smears — more than 50 per cent of smears were taken outside
the organized programme. So a lot of women would have been screened in

Wolfendale et al. (1987); see in particular page 33 and Figure 6 above.
149 Hakama (1990).

54

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

their twenties and might have had CIN3 treated. You can't assume from the
programme in Finland that screening every five years between the ages of 30— 55
is enough, because that was not what happened in practice.

The other point I want to make is that people may think that screening has had
no effect when the risk of disease had changed. All through the 1970s and
1980s, there were around 4000 cancers and 2000 deaths in England and Wales,
and people said that screening hadn't made any difference at all. But if you look at
CIN3 rates, there were increasing numbers of women being successfully treated
and those women were at lower risk of getting cancer later in life. Because there
was a younger birth cohort at greater risk and an older one in whom screening
was to some extent working, it looked as though there was no effect. That is still
happening in some places in Eastern Europe. Recently I showed the English
figures for cancer incidence with the Czech figures superimposed over them and
they are very similar to ours in 1985, when incidence was increasing. ' Screening
may appear not to be working because the cancer rates are unchanged, but its
effect depends on whether the risk of disease was changing.

Chamberlain: I wanted to take up something that Peter Sasieni said about
the lack of adequate treatment. I am quite surprised at this historical meeting
that nobody has mentioned the New Zealand experience, where there was a
gynaecologist called Herbert Green, who believed that screening was unnecessary
because he maintained that precancerous changes did not progress, and so he
set out to prove it by not treating women with what was then called cervical
carcinoma in situ. I actually met him once when I was working as a very
junior assistant to Max Wilson, whom some of you will remember as one of the
Department of Health people who argued early on for screening — Wilson of
Wilson and Jungner's 'ten principles of screening', this spelled out the criteria
needed for screening to be successful and was published way back in the early
1960s or maybe late 1950s. Anyway, Herbert Green came to see Max Wilson
to tell him about his plans, and Max said: 'That's fine, so long as you do it as
a randomized controlled trial comparing your untreated group with a treated
group as the controls, with stopping rules and a data monitoring committee,
so that everything is above board.' Had this actually happened, we would have

150 Draper and Cook (1983).

Data from Rob (2007). See also cancer registration statistics at: www.statistics.gov.uk/StatBase/Product.
asp?vlnk=7720 (visited 23 July 2009).

152 Cartwright (1988); Jones (2009).

55

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

known the natural history of carcinoma in situ and of all CIN much, much
sooner and more clearly than we do even today. Unfortunately Green didn't
have a control group, and lots of women in New Zealand went on to develop
cervical cancer unnecessarily because of this.

Peto: David Skegg in New Zealand has updated the follow-up on that cohort,
and it is about to be published."

[Professor Valerie Beral said a major paper on the natural history of
cervical neoplasia was published in Lancet Oncology in April.]

Peto: Forty per cent of untreated women with CIN3 develop cancer. So it is
going to be shown at last.

Miller: I agree absolutely with what Peter Sasieni said; I should have said it
myself. I want to come back though to the Finnish experience. The Finns have
done quite a lot of good, looking at the impact of opportunistic screening versus
their organized programme and there's no question that the opportunistic
screening is not very important, because it's largely given to women who are
outside the age range you want to get at. Let's face it, there's absolutely no
point in starting screening at the age of 18, 19, 20. And they published this. 15 '
So, it is the organized programme which has had the impact, rather than the
opportunistic screening. In terms of how far you can get away with five-yearly
versus three-yearly or more frequent screening, I think the natural history we
gathered from British Columbia was useful; Nick Day essentially looked at this
and gave an answer to that many years ago. " There's no question that three-
yearly screening was optimal and five-yearly screening still highly effective. I
hope we don't go away with another impression, and some recent models done
by Sue Goldie essentially confirm that.

153 For discussion often US surveys, see Wilson (1961); Wilson and Jungner (1968). For the ten principles
of screening, see Glossary, pages 151—2.

154 McCredie et al. (2008).

155 Anttila etal. (2004); Barnabas et al. (2006). England withdrew cervical screening to the age range 20— 24
in 2004, as a result of Sasieni et al. (2003), although screening of this age range continues in Scotland and
Wales. See also Law et al. (1999); McGahan et al. (2001). Professor Anthony Miller wrote: 'There is not
a direct Finnish assessment of age of start, it is just that they started at age 35 and this was as effective as
programs in North America starting at 18-20.' E-mail to Mrs Lois Reynolds, 5 September 2009.

See IARC Working Group on evaluation of cervical cancer screening programmes (1986).

157 Stout etal. (2008); Garnett etal. (2006); Goldie etal. (2001, 2004).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

Wolfendale: May I come back to what Amanda Herbert was saying about the
risk? If you want to stop the growth of cervical cancer and if there is a higher risk
of cervical cancer in the younger age group, then if the risk of cervical cancer
in younger women is increasing, it is then very difficult in the early years of
screening to reduce the overall incidence of cervical cancer. In the 1970s Martin
Usherwood and I saw a very large increase in CIN3 in our patients in Aylesbury,
in a population we had studied and screened since the early 1960s. We showed
a tremendous increase in CIN3 very clearly and we felt that, although we were
having great trouble in actually reducing the cervical cancer rate, we were in fact
holding back what could essentially have been an epidemic. 158

Cuzick: Coming back on the question of when screening works: I think it
emphasizes the need for continual monitoring of the screening programmes
and not process monitoring of the detection of cytological abnormalities, but,
like any large-scale process, monitor it by actually looking at the failures. That
means going back and carefully looking at every case who gets cervix cancer
and determining why the programme failed. Was it lack of coverage? Was it
an abnormality that was not picked up? Or was there a normal screening and
the test did not detect any abnormality? Any programme that's going to be
successful has to maintain this long-term monitoring function.

Herbert: We are doing a great deal of monitoring now. We should face the
fact that peak incidence of invasive cancer is now in women aged between
35—39; 2005 was the first year when it was higher than in women over 60. In
my experience, something like 70 per cent of those cancers in women in their
twenties and thirties are screen-detected early cancers, which is an additional
benefit of screening. I quite agree with Peter Sasieni that most of these young
women have already been screened. Most of them are interval cancers. There
are fewer opportunities for preventing a cancer that develops at age 35 than at
age 50, and a single smear may not detect every abnormality. If you go back over
the history of the women with cancer who have previously been screened, there
are quite a number with evidence of CIN3 fairly recently. It might have been

158 Wolfendale et al. (1983); Peto et al. (2004a) calculated that cervical screening costs about £150 million
per year in England and would prevent about 4500 deaths per year. The overall cost was thus about £36 000
per life saved and £18 000 per cancer prevented, comparing all screening against none.

159 Dr Amanda Herbert wrote: 'Sasieni et al. (2003) and Herbert et al. (2009) both show that cancers in
young women are often "interval cancers". Herbert et al. (2009) also show a strong association between
interval cancers, younger age groups and early stage screen-detected cancers.' Note on draft transcript,
1 September 2009.

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

missed on a smear — while others had inadequate smears, or had failed to have
their latest smear or had one six years rather than three years before. Some did
not attend for a biopsy, or had treatment and didn't come back for follow-up. It
tends to be CIN3 rather than CIN2 that was missed or not treated, often within
the previous three or four years' diagnosis. So I don't think in a community like
ours, when we have got to a stage when we are detecting early cancer and saving
these young women's lives, we can possibly not screen them in the preceding
decade of life without increasing the rate of more advanced cancer.

[Professor Valerie Beral commented that cervical screening in the UK
today is working very well.]

Sasieni: I agree that the UK screening programme is extremely effective, working
very well, but to say that it is preventing 90 per cent of cervical cancer in the
UK is not really realistic, if coverage is only 80 per cent. If you look at the
proportion of women aged 25 to 64 screened at least once within the last ten
or 15 years it goes up to over 90 per cent, but that's only for those aged 25 to
64 years. There isn't huge evidence that it is preventing cancer in the over-70s.
I think, realistically, cervical cancer incidence would be two and a half times
higher than it is, and mortality would probably be three or four times higher,
but not ten times higher. It is very, very effective.

Herbert: If you look at the incidence in one of those first high-risk cohorts,
born, say, in 1950, the ones who had increasing cancer rates during the 1980s,
incidence was more than 30 per 100 000 at age 35-39. Their incidence had gone
down 15 years later by about 70 per cent, to something like 10 per 100 000, when
it would be expected to have increased towards a plateau, as Julian was saying.
Peter has published a graph of mortality in different birth cohorts showing
much the same thing. 1 ' 1 Treating CIN3 and early cancer prevents invasive or
more advanced cancer later in life. Women in their fifties and sixties now, who
were screened when they were younger, have got a very low risk of disease.

McCluggage: We are now going to talk about the organization of a national
programme and the screening centre.

Herbert: May I go back to when it started? As we have already heard, it was
extremely haphazard in the 1960s, with arguments about whether it was going
to work or not, and some of the people who were promoting screening probably

Sigurdsson and Sigvaldason (2007).
Sasieni and Adams (1999).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

thought it was going to be more effective than it was. I think that's undoubtedly
true, because the enthusiasts exaggerate the benefits and there was a certain
amount of acrimony about anybody who suggested that it wouldn't work. That
was said to be Cochrane's experience, when he suggested that it might not be
so successful and people thought he was saying something terrible. Of course,
we all know now that it's not quite as effective as it might be if every case of
CIN3 was immediately detected and effectively treated and are well aware of the
problems and disadvantages of screening. While in England enthusiasts were
trying to get it going and the Department of Health was distributing circulars
without enough money attached to them, in Aberdeen, Macgregor and Baird
got on with setting up their own programme. In their 1963 article they made
the comment that it was past the stage of needing a controlled trial. They went
out with balloons for the children and took smears from the women. As has
already been said, they achieved good population coverage, monitored the
outcome (using punch cards rather than computers), published a case-control
study in 1985 and provided evidence in the UK that screening worked. 1 '

Meanwhile, back in England, where the government was reluctant to pay, some
highly effective screening was being carried out. CIN3 rates show how much
the likes of Liz Mackenzie, Erica Wachtel and Dulcie Coleman were achieving,
although many of the smears were taken opportunistically from young women.
We shouldn't only look at mortality and incidence rates, we should also look
at CIN3 rates, which were available from 1971 and went up at a much higher
rate than the additional number of women screened. ' Margaret Wolfendale
showed an increase in severe dyskaryosis on smears in young women, 1 '' which
was similar to the increases that were being reported in CIN3 as well as invasive
cancer incidence and mortality, which gave us among the highest mortality

Professor Archie Cochrane wrote: 'I remember giving a lecture in Cardiff on screening in 1967 into
which I introduced the (as I thought) innocuous phrase "I know of no hard evidence, at present, that cervical
smears are effective". To my surprise I was pilloried in the local Welsh press, who quoted many anonymous
colleagues who thought me a "dangerous heretic" and I received many abusive letters, some from colleagues.'
Cochrane (1972): 26—7; see also Bryder (2008); note 44. For a review of screening procedures, see Cochrane
and Holland (1971); Wilson et al. (1971); Macgregor and Teper ( 1 974) .

Macgregor and Baird (1963).

164 Macgregor et al. (1985).

165 Herbert (2000).

166 Wolfendale et al. (1983).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

anywhere in the world in women under 35. " All that happened in the 1980s
when it seemed as though screening wasn't working at all; hence Knox's article
in the Lancet. It was terribly badly organized and quality control was poor.
I remember doing a small study in 1988 when I had always been told that 90
per cent of women with cancer had never been screened (it was a sort of old
cytologist's tale). I looked at our cases and saw that, yes, that was true if they
were over 50, but if they were under 50, about half of them had been screened.
When we looked back at the smears, there were all these small dyskaryotic
cells, glandular abnormalities and things that were not being picked up. We
massively improved our quality control, which Muir Gray facilitated before the

I 170

screening programme began.

I think much of the success of screening since 1988 was due to quality control.
Of course, there was the introduction of a computerized national register, so
that all women aged 20—64 could be invited every five years, including those
who had never been screened. With the old system there was no way of 'calling'
women, it was only 'recall', so you never got the ones who didn't turn up in the
first place. But particularly we started re-screening negative smears, improved
training of cytologists, BMS and pathologists and, for the first time, had
standards for comparing practice between laboratories, as well as guidelines
for 'fail-safe' follow-up of women with abnormalities. The colposcopists
and cytologists got together and discussed discrepancies and, in Southampton
where I was working, the critical thing for us was to look back at the smears of
the women who had got cancer and CIN3 and that's when we saw what had
been missed.

167 Peto etaL (2004a): 252.

168 Anon. (1985); see also Knox (1966).

169 Herbert etaL (2009).

Dr Elizabeth Mackenzie wrote: 'These local programmes were properly coordinated finally by the
Department of Health, first by the charismatic Dr Muir Gray prior to becoming part of Julietta Patnick's
breast and cervical screening empire. It is now, in my humble opinion, the most successful national screening
programme. My choice of specialty was enjoyable and fulfilling and was ideally suited to a peripatetic
existence. My only regret, however, was that it was a struggle to get our specialty recognized in the early days
and, as a consequence, promotion to a consultant post was often pitifully slow.' Note on draft transcript,
26 November 2008. See Gray (1990).

171 Chaired by Dr Amanda Herbert and together with Dr Jane Johnson and Mrs Julietta Patnick, led a
Royal College of Pathologists, BSCC, NHSCSP working party (RCPath etal. (1995), also known an ABC).

172 Pike and Chamberlain (1992).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

There is a well-known graph in a BMJ article by Quinn et al. showing that
suddenly in 1988, the coverage went up and the incidence went down, but we
know from Macgregor's work in Aberdeen that it takes seven years for incidence
to go down. It didn't magically go down because the screening programme
was launched. It was because of all the things that happened during the 1980s:
the gradual increase in coverage and quality control, so that incidence eventually
started going down. It went down in all the age groups eligible for screening,
in what Bray called a 'period-specific change', seen in countries such as the UK
when organized screening started, which was enough to cope with the cohort-
specific change. 175 In the US and Canada they didn't see an increase in cancer;
it was only in places like Norway, New Zealand and England that there was an
increase in invasive cancer in the 1980s. In Canada and the US, Finland and
Scandinavia, there may have been an increase in CIN3, but not in cancer, because
they were controlling it. So, I think that Julietta Patnick's group and Muir Gray
need credit, particularly for quality control, and for improving communication,
so that colposcopists, histopathologists, everybody got together and discussed
the problems. ' I think that cancer audit, as Jack has said, is probably one of
the most important things to show us where things have gone wrong. I think
that with what is happening now, we probably have one of the best screening
programmes in the world.

McCluggage: Do you think anything useful will come out of the National
Cervical Cancer Audit, which is now up and running?

Herbert: I am working on our own cases at Guy's and St Thomas' at the
moment. We are seeing two things in particular: first, that most of the cancers
in young women are screen-detected and not all of those are microinvasive, and
second — an interesting finding that was the same as in Southampton — that it's
the early screen-detected cancers that are more likely to be interval cancers. The

173 Quinn etal. (1999).

174 Macgregorrta/. (1994).

175 Bray etal. (2005a).

176 See Patnick (ed.) (2008b).

Dr Amanda Herbert wrote: 'Robertson and Woodend (1993) were among tbe first to look back at
smears from women who developed cancer and pointed out that what has more recently been introduced
as "rapid review" of negative and inadequate smears might allow many of these abnormalities to be noticed
by a second screener.' Note on draft transcript, 1 September 2009.

178 The National Cervical Cancer Audit was introduced in 2007. See Patnick (ed.) (2006).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

audit is showing, as Valerie Beral says, that we are down to rock bottom. We
are down to the ones which you can't prevent, but may detect.

Chamberlain: I agree with what Amanda said about the importance of quality
control and its contribution to the success of our present programme. But,
even more important than laboratory-based quality control monitoring — and
I don't think Amanda gave quite enough emphasis to this — is the fact that
all women in the whole country, or at least those registered with a GP, are
now routinely invited for screening. It is this that achieves the high level of
population coverage, which is vital.

The template for using the NHS Central Register for cancer screening was,
in fact, developed in the context of breast, not cervical cancer, as the method
used in the UK Trial of Early Detection of Breast Cancer starting in 1978. IS1
And subsequently in the Forrest Committee report on implementing national
breast screening, which came out in 1986, a year before the Intercollegiate
Cervical Screening Report, we recommended that this system be introduced
nationally. In comparing the introduction of national screening for breast
and cervical cancer in the late 1980s, Muir Gray made an amusing but very
pertinent analogy, in which health authorities were likened to a person being
told to knit a garment. In the case of breast cancer screening, they were given
a clear knitting pattern, a new ball of wool and some needles, and even some
money to pay the knitters, so all they had to do was get on with it. Whereas
with cervical cancer screening they were presented with a worn-out 20-year-
old cardigan full of holes and they first of all had to unravel the whole thing,
then roll up the wool, find the needles and start knitting, all without any extra

Dr Amanda Herbert wrote: 'Incidence of invasive cancer now (2005—06: figures from www.statistics.
gov.uk/StatBase/Product. asp?vlnk-7720 (visited 1 September 2009)) "peaks" in women aged 30—34 years,
incidence in older women having declined steadily in all age groups screened. According to our experience
in London (unpublished) and Southampton (Herbert et al. (2009)), cancers in these young women tend to
be early-stage screen-detected interval cancers in women little older than the 20-fold higher peak (aged 25—
29 years) of incidence of CIN3, which is recorded on the same statistics website.' Note on draft transcript,
1 September 2009.

Professor Jocelyn Chamberlain wrote: 'Indeed, Catherine Pike and I wrote one of the guidelines on this
put out by the NHS Cervical Screening Programme in 1991.' Note on draft transcript, 31 July 2008. See
Pike and Chamberlain (1992).

See, for example, UK Trial of Early Detection of Breast Cancer Group (1981).

Department of Health and Social Security (1986b); NHS Breast Screening Programme (1991). See also
Sutton (1997).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

resources. It is to the great credit of all the disciplines involved that it is now
so successful.

Cuzick: A brief comment: I think a crucial issue was this transformation from
a policy to a programme before this reorganization. Screening was a policy
and not a programme. In our 1984 paper we outlined the requirements for a
programme, including that somebody needs to be in charge of a fail-safe system
and monitor overall performance. 184 This, I think, did actually outline in print
the issues that many other people had enunciated in the early 1970s and laid
down the important requirements for a programme, which I think did have an
effect on this restructuring.

[Professor Valerie Beral said that there was evidence that screening did
work. The CMO, Donald Acheson, had suggested putting the case for
the prediction of cervical cancer incidence and mortality in England
and Wales.] 185

Sasieni: Historically, Julietta Patnick did not become involved in the start of
this programme. For a number of years it was Elaine Farmery, who chaired
the National Coordinating Committee with Muir Gray 186 It's very difficult to
know what was most important in improving coverage, but at the time, in the
early 1990s, I believed, and I still believe, that the GP payments were extremely
important. They had a payments system whereby there were much greater
payments per smear in the practice that had at least 50 per cent coverage and
greater still with over 80 per cent coverage. And, cynically, it's amazing how
very few people got much higher than 80 per cent, but virtually everywhere —
well, lots and lots of places — 80 per cent was achieved, and it had a knock-on

'Developing a breast screening programme was like knitting a cardigan at terrific speed. Developing a
cervical screening programme will be like unravelling a cardigan, writing the pattern, knitting it again at
terrific speed, while still wearing it.' Dr Muir Gray talking about the late 1980s in NHS CSP (2003): 5.

ICRF Coordinating Committee on Cervical Screening (1984).

185 Beral and Booth (1986).

ICRF Coordinating Committee on Cervical Screening (1984); Sasieni et al. (1996).

GPs are paid to encourage patients to participate in the cervical screening programme. The basic-
payment target, under the GP contract of 1990, was 50 per cent or more of eligible patients screened in the
previous five-and-one-half years and a higher payment if 80 per cent or more were screened (Department
of Health (1989)). Between April 1990 and October 1993 the percentage of general practitioners reaching
the 80 per cent target rose from 53 per cent to 83 per cent, while the percentage achieving neither target
decreased over the same period from 15 per cent to 3 per cent. Austoker (1994).

63

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

effect of actually removing people who didn't exist from GP lists, because they
realized that they could get paid more from reaching these screening targets,
than from having dead people on their lists. So I think the GP payment was
actually critical.

Coleman: I would like to dwell on that and say: 'Yes, it did'; and one can be
cynical about GPs responding to this system of payment, but on the other
hand, there was tremendous cooperation from the people on the ground
who were actually involved in the cytology service. The pathologists and the
screeners were willing to subject themselves to testing twice a year and they still
do this today. They have assessors who come round and test one's competence
to screen, right from the consultant down to the lowest level of cytoscreener.
You have to pass that test before you are allowed to screen. But I think that
cooperation is quite extraordinary, because I don't think it occurs in any other
specialist field.

Herbert: The cancer audit shows that it isn't all about reviewing the smears.
I agree with Jocelyn Chamberlain that you have to look at the quality of the
call-and-recall and also at what the GPs are saying to the patients, and not focus
only on the lab.

Sasieni: We have heard quite a lot about this. The public health impact was
perhaps first seen from the Finnish data. What was happening in the UK
in the 1980s was that although cervical cancer mortality (the standardized
mortality rate in this country) was falling by about 1.5 per cent per year and
had been since the late 1950s, cervical cancer incidence was fairly static overall
and was increasing rapidly in young women. That was mostly due to this
epidemic of HPV infections with a knock-on effect on cervical cancer, which
we have heard about, and it made it very difficult to determine what effect
cervical screening that was being done outside of any organized programme
was having. However you interpret that, there was a dramatic change: if you
look at the trends around 1988 to 1990, the mortality within a few years was
falling by something like between 4—6 per cent a year and it continued to fall
at that sort of rate, really accelerating the decline. For the first time we were
seeing a fall in the incidence and there was this phenomenon, which people
have alluded to — which we called the 'hockey stick. If one followed a cohort

See, for example, 'Evaluation of Clinical Events (ECE): Guidance fot assessors and trainees in
histopathology' from the Royal College of Pathologists (2008), freely available online at www.rcpath.org/
resources/pdf/histopathologyeceguidance.pdf (visited 5 August 2009).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

of women, one had seen incidence increase with age at least until aged 50.
After 1990, instead of their incidences increasing with age, in every single
cohort, as the women aged, their cervical cancer rates came down. So some
dramatic effects could be seen.

The initial emphasis with the reorganization of the programme had been to
monitor the process, which made sense because you can look at process measures
very soon after starting a programme. In about 1989 or 1990, Jack Cuzick,
Jocelyn Chamberlain and Muir Gray decided that we needed to look at the
effectiveness of screening and we introduced these audits, to see where screening
was failing. In other words, why were women getting cancer despite the fact
that there was this screening programme. We did not want to attribute blame
but to try to understand why these things were happening: how many deaths
were inevitable? How many might be prevented by modifications? As people
began to see what was going on, and why some of the cancers were occurring,
greater emphasis was on quality assurance throughout the programme. 190
Historically, I don't think we should be debating exactly how much cancer,
and how many deaths were prevented by the screening programme. The exact
numbers depend on agreeing what would have happened in the absence of
screening and in the presence of an epidemic of HPV infection that is very
difficult to determine accurately. Nevertheless, we all agree that there were
substantial numbers and the UK screening programme became among the
best in the world; it was as effective as any other, I think, and probably more
cost-effective than most.

Patrick Walker: There were important collaborations and publications in the
1990s. The first were by Ian Duncan in 1992 and 1997 with the publication
of Guidelines for Clinical Practice and Programme Management, which brought
together cytologists and colposcopists, and then David Luesley's publication,
Standards and Quality in Colposcopy, which for the first time started to give some
evidence base to the quality of care. I think the other important thing about
that time is that the programme became more woman-centred. It was realized

For details of the ICRF committee members, see note 51; ICRF Coordinating Committee on Cervical
Screening (1986); see also Sasieni et al. (1996).

190 NHS CSP (1996).

See notes 60 and 63. See also Luesley (ed.) (1996).

192 Marteau rt <z/. (1990).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

for the first time that a lot of unnecessary anxieties were experienced by women
involved in the screening programme.

Gray: I was actually going to touch upon the question of the anxiety. It played
a very big part in the public perception of the screening programme, and in
the way the press reported aspects of the screening programme. Anxiety was
heightened by the increase in litigation that took place as we started looking
back at smears and found that abnormalities had been missed. Lawyers became
well aware that they could actually get very successful compensation through
the courts. This whole aspect, I think, should be recorded as part of the history
of the programme in the late 1980s and early 1990s. It had quite an impact on
laboratories and on women.

McCluggage: It's something I have thought about with the National Cervical
Cancer Audit, looking back at all cancers, the potential for more litigation
coming out of this. Is this something that we are going to be faced with?

Sasieni: There are different views. I think there is going to be more litigation
generally. But there are two audit activities going on. One is that any woman
who gets cervical cancer, and even breast cancer, is entitled to know everything
about her screening history, and that's been mandated by the Minister, so that's
the one that could potentially be used for litigation.

I wanted to say two things historically. One is how the improvement in quality
assurance led to more bad stories about cervical screening, and in the 1990s it
seemed that every six months there was another story about a doctor taking a
smear with his finger and about a lab that binned all the results. These things
were happening because they had been happening for years and now they were
being discovered. Quality assurance put a stop to those bad practices, you
don't get such stories very often nowadays. The other media-type issue, I am
not so certain it was in the 1990s — Dr Szarewski could correct me — but
the Coronation Street story, in terms of wanting to know what can be done
with publicity, when Alma got cervical cancer, there was an increase in smears
taken. In all these poster campaigns and other campaigns that many PCTs

193 Wilson (2000); see also Bryder (2008).

See, for example, BBC News, UK Health: Thousands call cancer scare hotline, Wednesday, July 29,
1998 Published at 17:03 GMT 18:03, freely available at http://news.bbc.co.Uk/l/hi/health/l4l391.stm
(visited 6 October 2009).

Alma Halliwell, a character in the television soap opera, was diagnosed with cervical cancer in June 200 1
and died six weeks later. See Howe et al. (2002); Richardson et al. (2002).

66

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

did, no-one ever monitored any detectable effect on screening uptake. The
invitations had a huge effect on coverage, but the only publicity about screening
which had been shown to have an impact was the Alma episode.

Szarewski: It was a double-edged sword this, because we spent all of our time
trying to make women less anxious about going for cervical screening. But, as
Peter has said, the single most effective intervention in getting women to turn
up for smears was the death of Alma in Coronation Street, which scared women
out of their wits and attendance at screening shot up. It was written up in the
5A//and they concluded that it there was a demonstrable effect of that massive
increase in anxiety caused by Alma's death. ' In fact, the whole Alma story was
extremely poorly done, because it actually couldn't have been attributed to a
failure of screening. But nevertheless, all of that went by the board, the women
were scared stiff and turned up.

McC luggage: We are going to move on to later developments and applying
understanding of HPV.

Cubie: We started to talk earlier about some of the molecular techniques
that had been developed in the 1980s and used in basic science and research
situations. It's still a jump to think of using tests and technology in a clinical
situation and that had to wait a little bit longer. I think we owe quite a lot to
someone who isn't here, Attila Lorincz, who in the early 1990s was developing
HPV hybridization methods that could be applied to clinical samples, both
to sections and to smears. Attila very kindly shared his HPV protocols in
1984/5, so I am not sure when he started doing this on clinical material, and
I certainly went down the route of in situ hybridization for a while, because I
am a diagnostic virologist, and basically we do cytology too. The difference was
that we were looking for proteins in other viruses, and that's not so different
from looking for the nucleic acid of specific viruses by in situ hybridization.
There were things coming together in the early 1980s which linked virology
and pathology but also led to developments in tests that could be suitable for
diagnostic situations. The in situ hybridization unfortunately was not sensitive
enough and perhaps put a lot of our gynaecologist colleagues off the results that
could be obtained from mass HPV testing. Attila worked to produce the hybrid
capture assays that have been used widely in recent years in studies around

196 Howe rta/. (2003).

See, for example, Lorincz et al. (1986).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

the world. Actually, the technology for the hybrid capture assay is very good
technology. It's a hybridization system that detects nucleic acid by amplifying
the detection signal rather than the molecular tests we all hear about every day,
polymerase chain reaction (PCR), which amplifies the nucleic acid directly. So,
I guess hybrid capture first hit the market in the late 1980s, version 1 (HC-I),
which was not that sensitive, but actually probably clinically quite relevant,
because we then worked out that you could have a test that was too sensitive if
you were trying to relate it to clinical needs. That moved on to hybrid capture
version 2 (HC-II), which everyone knows of or has read studies about. I guess
the first randomized controlled trial using HC-II in the UK was the 'HPV
in addition to routine testing' (HART) study, which Jack Cuzick set up with
Anne Szarewski — I was involved as were others — that was reported in 2003 in
the Lancet. In parallel with hybrid capture, other people were developing the
PCR technique, particularly Jan Walboomers in the Amsterdam lab, and his
colleague may talk more about this. They linked the PCR to a hybridization
system which allowed them to type the virus. Those typing systems went
beyond the screening possibilities of the hybrid capture assay and have given
us tools that have been adapted by lots of companies, with commercial interest
in competition now being fierce for different technologies, but that's in the last
decade, not before 2000.

Peto: A technical point on hybrid capture: it does have a false positive rate,
something between 1—3 per cent. This is quite a serious problem in older
women, because in older women the prevalence of HPV is only a few per cent.
It's a technical problem that still needs sorting out.

McCluggage: For those of us who don't know, does HC-II pick up all
HPV types?

Peto: It picks up all types. All the ones that matter.

Cubie: It's a screening test. It uses a pool of probes which cover many high-
risk genital types, and Julian is right to say that there is some cross-reactivity.
It is not a false positive result though: these results are real HPV detection
results, they are just not so clinically relevant. But a screening test — whether it

198 See, for example, Castle etal. (2003); Cope et al. (1997).

199 Chvel etal. (1998).

See Glossary, page 148; (2003); also note 216.
201 Cuzick etal. (2003).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

is cytology, HPV, breast screening — will never be completely effective. You will
always have an element of assessing sensitivity versus specificity, which is why it
is very useful to have a range of other tests that allow us to go further and look at
specific types of HPV. This happens in virology all the time — there's a difference
between a screening test and a diagnostic test — and whatever we do, we usually
have both available.

Jenkins: I think one of the important messages is that you can't really over-
estimate the impact of HC-II in this field, can you? It's had such a huge impact,
not just in the US where it was introduced, but in the UK and globally, and
I think, perhaps, its major contribution in many ways is bringing HPV into
the market place and then bringing it out into public awareness, particularly
through some of the rather aggressive marketing techniques that are being
used. It is one of the ways in which HPV has been brought to the attention
of the general public and I think these are important historical contributions,
whereas the other testing systems have tended to remain much more research-
based, much more restricted to the laboratories and to the experts.

Duncan: With regard to HPV testing, perhaps its greatest contribution has not
actually been put into practice yet, and that is the negative predictive value,
because if you are cytologically negative and you are HPV-negative, then you
really are negative. Now, that allows us to discharge older women, who are
never going to develop cervical cancer, from the screening programme early.
And that's another aspect of the screening, because we at Dundee and Aberdeen
have argued that it's unethical to subject women to screening if they are not at
any significant risk.

Wolfendale:Avery quick comment. You say older women don't need screening.
What about those who have new partners?

Duncan: It's all about fertile fields and in the older woman the cervix has
matured. We wondered about the question of hormone replacement therapy
and whether it would rejuvenate the cervix and create a transformation zone

Professor David Jenkins wrote: 'One of the main methods used was direct-to-consumer advertising in
journals and television, as is allowed in the US, aimed at focusing women's attention on sexually acquired
HPV infection as an issue, encouraging women to ask for HPV testing at a clinic and to seek this additional
test for extra reassurance about freedom of risk from cervical cancer. This was combined with active
promotion among doctors in many countries at a time when the evidence remained inconclusive.' Note on
draft transcript, 1 1 September 2009.

203 Duncan (2004).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

again, but that does not appear to be the case. The cervix has matured and is no
longer the fertile ground for malignant transformation.

[Professor Valerie Beral reiterated the point that older women with new
partners could be at risk.]

Jenkins: Can I make one comment here before we go off on to what is still a very
active debate and certainly one which those of us who have been involved a lot
in vaccination have to face almost every time we have to speak at any meeting.
One intriguing issue is that we are only beginning to disclose the extent of
natural protection against HPV in women who have successfully cleared an
infection 30 years after the basic story of HPV was defined. We are still a long
way from answering some of these key questions.

Duncan: In the same population, we kept publishing the number of cases of
CIN that we would have failed to detect if we had stopped screening women at
the age of 50. And that's without HPV testing. I think that if HPV testing were
brought in above the age of 35, in conjunction with cytology, this would allow
us to reduce the frequency of screening and stop earlier.

Szarewski: Scotland, of course, is a more Presbyterian society perhaps, and it
may be that sexual activity is less frequent there, but I think when we are talking
about new partners, with respect to Margaret Wolfendale's question, I think we
should mention that it's more likely that the 55-year-old man decides to have
a younger female partner, and, because he feels obliged to have sex occasionally
with his wife, he passes on the HPV from the younger partner he's having on
the side to his older wife, who knows nothing about it for several years.

Peto: A point on the natural history: up to the age of c. 45 or 50, the probability
of finding CIN2 or CIN3 is pretty much the same; if you detect HPV, it is
lower above the age of 50. It depends what you mean by older women.

Sasieni: On the natural history: all the models looking at the time from CIN3
to progression of cancer showed that CIN3 is more likely to progress in older
women, and the older you get the more likely it is to progress. I suspect that is
because it's been persistent longer, and it's the persistent CIN3 that's most likely
to progress. The importance of CIN3 in a woman in her fifties is probably
much greater than the importance of CIN3 in a woman in her twenties.

See also discussion on page 33.
205 Jenkins (2006).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

Herbert: But what about women of 65 who are HPV-positive? Do they go
on being screened for ever? If they are positive and cytology is negative, what
happens to them?

Cuzick: There are a lot of cancers found in women over the age of 65; it is still a
major unmet need. So, I think we need to be very cautious about dropping off
screening too early, when there are so many cancers still occurring in these older
women, and we are doing very little about it.

Peto: HPV testing really does solve an awful lot of problems, particularly in
older women where a lot of abnormal smears have nothing to do with HPV or
cervical cancer risk.

McCluggage: We are going to move on to talk about HPV testing in triage and
screening.

Cuzick: Triage and screening is still a very active topic, so I will try to confine
myself primarily to some historical comments, and I think much of the work
in this area really owes a big debt to Albert Singer, who was one of the first to
recognize the clinical potential of all of this early work, discovering that HPV is
the cause of cervix cancer and looking for ways in which this could be used in a
clinical context. ' I have been fortunate to work with a number of his scholars,
starting with Michael Campion, Tony Hollingworth and Anne Szarewski (who
is here today), on a range of studies, going back to the first study with Michael
Campion in which it was found that women with low-grade smears that were
HPV16-positive were more likely to have CIN3 on biopsy. In retrospect, I
think that was done with very old technology, before we had PCR, before we
had hybrid capture, low specified dot blots, and probably one of the reasons
that study was so successful was there was a lot of cross-hybridization. HPV16
detection would then be associated with all of these other types. Probably those
early tests cross-hybridized with many different other high-risk types.

I think the field has very much benefited from improvements in technologies as
we have moved on. With PCR and hybrid capture and discoveries from some of
the studies, we have moved away from the triage concept of this work (originally
done with the Campion studies) and begun to move forward, to think: 'Can

206 See, for example, Campion et al. (1988); Mould etal. (2000).

207 Campion etal. (1986).

Professor Jack Cuzick wrote: 'High-risk HPV types are now thought to include 16, 18, 31, 35, 39, 45,
51, 52, 58 and 68.' Note on draft transcript, 4 September 2009.

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

this really be used in primary screening?' The first study of screening in normal-
risk women with HPV, was the Margaret Pyke study, and again it was early
technology. We screened for only four types (HPV16, -18, -31, and -33) and
again were surprised at the first clear evidence that a lot of women were actually
harbouring high-grade lesions that were negative on cytology. The only way
we found out about it was to have another test that was positive that led to a
colposcopy. That was the first indication that cytology was not as good as we
had thought, because we had another test which was actually saying we needed
to do colposcopy as well. That moved on then to a larger study in older women,
the Hammersmith study, then the multi-centre HART study 210 So it's still a
very, very active area. We still don't have HPV-introduced testing, even in triage,
although I think the evidence for that is overwhelming. But if we are looking
historically, I think a lot of that came out of the early work of Albert Singer.

McC luggage: This story seems to have been going on for an awfully long time
now, this argument for HPV testing in the cervical screening programme. Is
some decision going to be made in the near future, or what is happening at
the moment?

Cuzick: I am probably the last one to answer that, because I spent ten years
trying to get HPV considered for primary screening, and yet it is still a research
question. I am also perplexed by the fact that we have been so slow to take
this forward. I think it is a finding of major importance, and we do need to
take these new technologies and evaluate them thoroughly, but not slowly; we
need to be moving much more quickly on this. Again, cytology was a little bit
its own worst enemy to some extent. Clearly cytology was a good screening
test, and it did a substantial amount of good, and we must fully acknowledge
that, but sometimes, we do need to move on. It is an old technology and there
probably are better ways of doing what cytology is able to achieve. 211 I think
that has been a difficult issue. We have something that works pretty darn well,
but can we improve it with something that works a lot better? That's always a
hard sell.

Smith: Mr Chairman, I think I can partly answer your question. The NHS
Cervical Screening Programme (CSP) has recently instituted what is known
as sentinel sites, of which there are six sites in England, including my own

209 Cuzick etal. (1995).

210 Cuzick etal. (2008); Cuzick etal, (HART) (2003).
See for example, Schiffman and Castle (2006).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

laboratory, the Sheffield Cervical Cytology Service. There they are looking at
practical implementation of HPV testing for triage of low-grade abnormality
and test of cure and that study commenced a few months ago.

McCluggage: So this was triage of what?

Smith: Low-grade abnormalities.

Jenkins: So why was the decision taken to have sentinel sites rather than to
implement triage?

Smith: It is a pilot to look at the practical implementation, particularly the
relationship of HPV with cytology.

Herbert: Can I say something about poor old cytology here? Most of the places
that are implementing clinical trials of HPV as a primary screening test are
using cytology triage. They still need cytology — because HPV may indicate a
risk of CIN in the future, but cytology shows that an abnormality is present
now. So, they do still need us; we don't need to hand in our resignations yet.

Sasieni: To try to answer the question about 'why' they are operating sentinel
sites rather than rolling it out nationwide. I was on the advisory committee
looking at the results from the three primary pilots, two of which looked at
HPV triage, and the results were not as clearcut as in the research studies.
There was a big question as to who was going to pay for the HPV testing.
The Department of Health was saying: 'There's no extra money, the screening
programme already costs us £170 million a year or something in that region,
and that's it'. It was Henry Kitchener's idea, 24 1 think, to get a little bit of money
in order to be able to do triage, continuing in the pilot sites and add Manchester
and Liverpool. To make sure that it continued, everyone agreed that HPV triage

The NHS CSP introduced HPV sentinel sites at six laboratories in autumn 2007 at Bristol, Northwick
Park (Harrow), Liverpool, Manchester, Norwich and Sheffield. See www.cancerscreening.nhs.uk/cervical/
hpv-sentinel-sites.html (visited 22 July 2009).

213 See Legood et al. (2006); Moss et al. (Liquid-based Cytology/Human Papillomavirus Cervical Pilot
Studies Group) (2006).

Professor Henry Kitchener, Manchester, led a trial in 2001 to investigate HPV as a primary screening
test funded by the Health Technology Assessment (HTA) programme, at Manchester, Stockport, Wigan and
Leigh and Salford andTrafford (Sargent et al. (2008)). The Medical Research Council (MRC) and NHS in
England and Scotland funded 'Trial of Management of Borderline and Other Low Grade Abnormal smears'
(TOMBOLA) study, headed by Professor Norman Waugh, which began in 1999. See Patnick (ed.) (2008a);
see also note 228.

73

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

shouldn't stop, it needed to be rolled out in a much more controlled fashion,
because the results were disappointing, and it was fairly easy to get enough
money to do HPV triage in just five sites.

McCluggage: What about the experiences in other countries? Is there anything
that we can learn from those? Has it been successful in other countries?

Miller: There's a randomized trial ongoing in Finland. Matti Hakama has been
very successful in arranging to evaluate new technology in a randomized fashion
and the preliminary results seem to suggest that the peak difficulties are the
specificity, the sensitivity in relation to the cytology is not greatly superior. 215 He
is beginning to look at the question of changing the relative light units (RLU)
cut-off level, raising the level at which you declare a positive, and believes that
in doing that he can achieve with HPV testing the relevant specificity associated
with cytology. In British Columbia the decision has been taken to run a trial
that has been initiated, comparing HPV testing every four years with a safety
net of two years in another group with the two-year cytology, which is their
standard. That trial has only just started; I don't think there's going to be much
reported on it for a while.

Singer: Historically, as clinicians, we recognized probably about eight or nine
years ago the enormous value of a negative HPV result with the negative
predictive value in many trials being 99 per cent. 27 Approximately 5—7 per
cent of all women in this country have a borderline smear. In the US they have
used it as a reflex test in women with a borderline smear or 'atypical squamous
cells of undetermined significance' (ASC-US, the US equivalent 218 ), and saved
an enormous amount of money by excluding women with a negative test. But,
more importantly, the anxiety of women patients is reduced and a negative
result really does mean negative.

13 Anttila et al. (2006); Kotaniemi-Talonen et al. (2008a).

Testing for HPV DNA with HC-II is a molecular biological method that tests for the presence of HPV
DNA through a chemoluminescent reaction based on hybridization. Viral presence is measured in relative
light units and reported as a ratio of relative light units (rlu ratio), a measure of luminescence. Samples with
a ratio of less than 1.0 are classified as negative for high-risk HPV DNA and those 1.0 or above are positive.
See Kotaniemi-Talonen et al. (2008b); Peyton et al. (1998).

217 Wrights al. (2004).

ASC-US is a classification of squamous intraepithelial lesions. For a discussion of UK and US grading,
see Slater et al. (2005).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

Cubie: Professor Sasieni asked: 'Who's going to pay?' Doesn't that sound familiar?
Isn't that what most of this story of cervical screening has been about? And how
cytology started? Who's going to pay? People did not know how they would fund
screening, but started getting on with it. And, what has been achieved since 1988
is but a series of tweaks, which are the things which Tony Miller was talking about,
the tweaks which will need to be put in place once we actually get down to it.

Sasieni: What is going on in other places? HPV in triage of borderline or, as
the Americans call it, ASC-US cytology, is routine in North America, I think,
and is used elsewhere. There's a new, fast HPV test, which is a hybrid capture
test, for developing countries, which I believe is going to be adopted as the
primary screening test in Colombia. So there is more HPV testing going on
elsewhere. In addition to the randomized trial in Finland, there are randomized
trials in Italy, Sweden and the Netherlands, and all four of them show higher
sensitivity for the detection of high-grade CIN on the first round, and those
that have published second-round results show lower detection of high grade
CIN in the HPV arm on the second round. Yes, more women will be sent
to colposcopy. The Finns have a very negative interpretation of the results, but
their results are pretty much the same as others, and the Italians have a very
positive interpretation of the same sort of results.

Szarewski: I think the problem with the HPV testing is the specificity to
which we have alluded. The trouble is that although we keep talking about
how wonderful it is to have a negative HPV test, in the pilot studies of triage
in the UK, it made no difference to the women themselves. When looking at
the anxiety levels in women with borderline smears and a negative HPV test, it
made no difference, because they didn't understand what it meant. So if we are
going to introduce HPV testing, which I do think is inevitable eventually, we
mustn't forget the real importance of education of the public, because otherwise
it's wasted. The patients are as anxious with a negative HPV test and a borderline
smear as they would have been with the borderline smear, or even, in fact, a
positive HPV test. What, then, is the point in doing it?

Professor Leslie Walker: To put this in historical perspective, in the 1970s and
1980s there was increasing interest in the psychosocial aspect of the diagnosis

219 See, for example, WHO (2002).

Ronco et al, New Technologies for Cervical Cancer Working Group (2006, 2008); Mayrand et at,
Canadian Cervical Cancer Screening Trial Study Group (2007); Kotaniemi-Talonen et al. (2008a and b);
Naucler et al. (2007); Bulkmans et al. (2007).

75

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

and the treatment of cancer, particularly in the disciplines of nursing, psychology
and psychiatry. In the early 1980s, when the British Psychosocial Oncology
Society was founded, I think it is fair to say that initial interest focused on
what one might call 'screening distress', the effect of getting an abnormal smear
result. One of the early studies by Beresford and Gervaize showed that all of
the women that they surveyed were afraid that they would have cancer. Many —
two-thirds — were afraid of the medical procedures involved in the investigation,
and this fear showed itself in a range of behavioural changes, including sleep
disturbance, irritability, relationship difficulties, including problems with sexual
relationships. It was also clear even then that there were other issues for these
women, including uncertainty about fertility and the possibility of transmission
of disease to their partners.

The second area of interest was investigational and procedural distress. Some
studies showed that anticipatory anxiety was similar, or equal to, that produced
by some types ofsurgery 223 Also, Campion and colleagues showed that, compared
with a comparison group of women, six months after colposcopy, biopsy and
laser vaporization, women had less sexual interest, less frequency of intercourse
and more negative feelings towards their partners. 22

People have studied several ways of attempting to ameliorate this distress,
particularly leaflets and booklets, and these have generally been of some help,
but not for all women. Counselling has also been investigated, although there
aren't many studies. ' Women usually say that it's helpful, but interestingly,
most studies show that there's no significant effect on objective measures of
health-related quality of life.

Then there's the issue of gynaecological intervention for an abnormal smear,
for example, the effects of 'see and treat' versus surveillance and, indeed, this
is how my interest in this field was stimulated. Stephen Bell and colleagues in
Aberdeen had shown that colposcopy was associated with persistent anxiety

For further details, see www.bpos.org/ (visited 29 April 2009).

Beresford and Gervaize (1986).

223 Rogstad (2002): particularly page 365.

Campion et al. (1988).

See, for example, www.womens-health.co.uk/smear.asp; www.womenshealthlondon.org.uk/leaflets/
cervical/cervab.html; www.bbc.co.uk/health/womens_health/issues_smeartest.shtml (visited 29 April 2009).

226 See, for example, Wolfe et al. (1992).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

following surveillance, but it wasn't a randomized trial. He came to see me
subsequently to seek advice on how to validate screening tests for clinically
significant anxiety and depression in a further study.

In 1998 I was very pleased to be invited by Julian Little to lead on the
psychosocial aspects of a randomized controlled trial subsequently funded
by the MRC (TOMBOLA). 228 This was a study of over 4000 women from
Grampian, Tayside and Nottingham, who had low-grade abnormal cytology
and were randomized either to cytological surveillance in primary care or to
colposcopy. Compared with surveillance, colposcopy was associated with less
clinically significant anxiety in the short term. However, in the longer term,
there was no difference in the levels of anxiety or depression between these
management policies. But, more specifically, women managed by surveillance
were more worried about the next smear being positive; they were more worried
generally about their health; and they were more worried about whether they
could have children in the future.

Turning to the issue of HPV specifically, McCaffery et al. showed, and we
have already heard a little bit about this, that women who were HPV-positive
were more anxious and felt more worried about sexual relationships than those
who were HPV-negative, regardless of whether their smears were normal or
abnormal.

Finally, there is the issue of non-participation in the screening programme.
Again, we have heard something about this. But in addition to socio-
demographic factors and ethnicity, there are a number of clinic-specific factors
and psychological factors which seem to be related to this. For example, non-
participation is associated with having a fear of cancer, not having a female
cytoscreener available, a worry about embarrassment and pain, the belief that
screening is not going to be of any benefit and the perception of being at low
risk of cervical cancer.

So, to conclude, over the last 20 years or so, people have become increasingly
aware that there is a personal cost and a psychosocial cost to cervical screening,
and more recently to HPV testing also. And clearly there is a continuing need
to develop ways to minimize that, and to encourage current non-participants to
attend for screening.

227 Bell etal. (1995).

For further details, see Cotton et al. (2006).
229 McCaffery etal. (2004).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

Szarewski: I am conscious that I am slipping beyond 2000 by saying this, but
coming back to the education aspect, I think it's ironic that the advent of the
HPV vaccines is providing an absolutely fantastic platform for educating the
public about HPV in general, because the press are really interested in the
vaccines, which they have never been in any other aspect of HPV. So ironically,
the vaccines are providing us with the opportunity to educate everybody about
HPV in general.

Singer: We know as a result of the vaccine and doing many pre-introduction
interviews in the form of an online questionnaire survey, which showed that
a substantial amount of ignorance was present at all levels, extending from
the administrators in the government all the way down to the actual women,
mothers, etc. The most important thing now is to get knowledge of HPV
passed on to all of them.

Mr Patrick Walker: Not to put too much of a down note on it, what we have
been looking at over the last three or four hours is the enormous success of
a population-based screening programme that came out of a disorganized
and under-funded programme. The keys for success that we have seen are a
consistent level of public investment in the organization of the programme, and
the high coverage of the population at risk. For all of the great opportunities that
vaccination offers for the 12- and 13-year-old women, partial implementation
of the vaccine programme, which doesn't have all of the viral types in a catch-up
group, might lead to false assurance of young vaccinated women who are still
at risk of the disease, reduced compliance with the programme, and reduced
coverage. Ironically, this could undermine the success of the programme we
have now, particularly if the cash-strapped primary care trusts having to invest
in the organization, particularly of the catch-up programme, are tempted to
reduce the budget that currently goes towards screening quality assurance.

Peto:The amount of money spent on the vaccine will be almost as much as on the
screening programme, and we'll have to go on screening as well until a polyvalent
vaccine against all the common HPV types is available and affordable. 232 Western

230 See, for example, Chan and Berek (2007); FUTURE II Study Group (2007).

231 ShemsetaL (2006).

For an economic evaluation of the two vaccines currently in use in the UK, see Jit et al. (2008): a769;
and other perspectives, see Franco et al. (2006). For estimates of the cost of screening compared with the
cost of a life saved, see Bryant and Stevens (1995); Waugh and Robertson (1996); Waugh et al. (1996a and
b); Peto etal. (2004a) and note 158.

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

governments should be collaborating to develop a cheap polyvalent vaccine as
rapidly as possible. That would save them hundreds of millions of pounds, and
would also prevent cervical cancer in developing countries where most of the
cases and deaths occur and where effective screening isn't viable.

Jenkins: I feel I have to say something on this, because that really is a gross
oversimplification of what's quite a complex development of vaccines, and the issue
of multivalent and polyvalent vaccines is unfortunately not as simple as you would
have us believe in that impassioned speech. I think if it were simple to generate
these polyvalent vaccines, then it would have been done, and certainly both the
vaccine companies are working on these currently. However, this is all going well
beyond 2000, we are now looking at probably 2010, 2011, 2012, before any of
these become anything like the possibility of reality, and we have to work with what
we have got. Having said that, it is the ultimate goal; there's no question that things
will continue to develop beyond what we have now. If I can get back to the point
that Anne Szarewski was making, I think one of the huge impacts of the vaccine,
apart from its potential clinical benefits, has been that it has opened up HPV to
the world in general, and meant that we are not a small community of eccentrics
exploring a rather exotic virus that most people have never even heard about.

Sasieni: To return to the personal, the screening programme in England - it
may have been after 2000 — started this new information, informed choice.
But there has certainly been a huge debate, some of it by Professor Peto, even
more passionate than he has been today, about the information that should be
provided. There were individuals whom I won't mention by name, who seemed
to emphasize the downside of screening the whole time, and were accused,
I think, of causing the deaths of thousands of women by putting them off
going for screening. Then there are people who felt that actually virtually all
you needed to do was to promote the positive side of screening. There was a
general agreement over time that we try to get a more balanced approach to the
information, although it's always very difficult because there is no agreement
among the experts about what is a balanced approach to the information.
Certainly, there was a huge change from 1988 until 1999, in terms of the
attitude of providing information and the general feeling in society that the

Professor David Jenkins wrore: 'The two companies currently working on a polyvalent vaccine for HPV
are GSK and Merck.' Comment on draft transcript, 1 1 August 2009.

23 Raffle et al. (2003); listen to Dr Angela Raffle and Mrs Julietta Patnick discussing changes in cervical
screening on Woman's Hour, 22 October 2003, at: www.bbc.co.uk/radio4/womanshour/2003_42_wed_02.
shtml (visited 4 September 2009).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000

medical profession should be less paternalistic. Women needed to be told the
downside of screening, even it if puts them off attending.

Campo: Three comments: the first is that the vaccine is type- specific, and
one thing that has, in my mind, not been extensively investigated is that L2
protein should have been incorporated in the vaccine. It induces cross-reactive
neutralizing antibodies, but it's not there. It's something that should be thought
about. The second thing is that it is not quite so easy in terms of adding VLPs
to the vaccine, because these are, surely, different HPV types, with a different
incidence in different parts of the world. So while HPV16 and HPV18 are global,
HPV58 is in Hong Kong but not in Brazil; and so on and so forth. If you want
to add more and more VLPs I think we should start adding them differentially
to the vaccine from Brazil, and the vaccine for Hong Kong, and I don't think
anybody is going to do that. My third comment is about education. Professor
Sasieni said that people should be educated from the administrators down, and
this is my own experience, that even doctors do not understand what the current
vaccine is about. Treating CIN2 with the current vaccine is like throwing money
down the drain; clearly there are doctors who do not know what the vaccine can
do. The vaccine is fantastic, but it has to be used properly.

Jenkins: I am very glad that everybody is discussing the vaccine, but we really
have to limit discussion on that at the moment. Certainly, the L2 vaccine has
been looked at. There are some issues around that; there is some recent work
that suggests perhaps some of the differences, geographical differences, that are
claimed in HPV types may not be as great as they appear to be and that some
of this is due to very small studies in very special populations. Like the HPV58
in Hong Kong, it is based on very small numbers.

Singer: We could only dream about the vaccine. There was an editorial from
23 years ago in the British Journal of Obstetrics and Gynaecology by Dennis
McCance and myself, talking about the association of HPV and cervical cancer
and we weren't sure whether the association was causal or casual. We said that
the most satisfactory evidence or proof would be if a vaccine were produced
against HPV in the future, which would show a reduction in the vaccinated
women at greatest risk. This, we said, would be a difficult task. 235 Thankfully, in
the end it wasn't as impossible as we thought it would be.

Singer and McCance wrote: 'The association of HPV infections and neoplasias of the lower genital tract,
but is this association causal or casual? The most satisfactory evidence would be if a vaccine were produced
against HPVs and show a reduction in the vaccinated women at greatest risk. This will be a difficult task 1
(Singer and McCance (1985): 1085).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000

McCluggage: Very true words. It remains for me to say that this has been a
very successful Witness Seminar and Dr Tansey will speak after I have finished.
I would like to thank all the audience for their participation. I have enjoyed
this very much and, as a non-HPV person, I have learned a lot, and I hope
everybody else has and has enjoyed the Witness Seminar.

Tansey: Yes, I would like to thank you all very much for coming. It's been a very
interesting, educational, informative, and at times very amusing and entertaining
afternoon. I also have learned an awful lot. As I mentioned at the beginning,
this meeting is the tip of the iceberg. We will now translate the transcript of this
Witness Seminar into readable text and we shall need your help in doing that.
On your way home tonight, many of you will think: 'Oh why didn't I say so and
so?' You will have the opportunity of putting that into the transcript at a later
date as a footnote. If you have any papers or references you would like us to have
or that we could copy, please get in touch with us and let us know.

I would like to offer the thanks of the History of Twentieth Century Medicine
Group to David Jenkins, whose idea this was originally, and who has worked
very closely with Lois Reynolds, Wendy Kutner and myself in planning this,
and also thank Lois and Wendy for all their hard work in rushing around with
the microphones, and especially to Glenn, whose timing of this meeting has
meant that we have finished right on the dot, and to invite you all to have a
glass of wine.

81

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 -Appendix 1

Appendix 1

The emergence of the natural history of cervical cancer
From Professor Leopold G Koss

Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York, NY

In 1842, an Italian physician, Domenico Rigoni-Stern, published a series of
mortality statistics of women dying of cancer in the city of Verona. 236 In this first
epidemiological analysis, Rigoni-Stern pointed out that 'cancer of the uterus' was
much more common in married women and widows than in virgins and nuns.
This was the first suggestion that 'cancer of the uterus' was somehow related to
sexual activity. It may be safely assumed that most of the women in Verona died
of cancer of the uterine cervix because that was, at that time and remained for
over 100 years, the most common form of cancer of the female genital tract.
In spite of many speculations, the nature of the sexually transmitted cancerous
agent remained a mystery.

The concept that cancer of the uterine cervix was preceded by precancerous
states limited to the epithelium must be attributed to a 1908 paper by an
Austrian gynaecologist, Walther Schauenstein. 23 " This concept was essential for
cervix cancer prevention programmes which were based on recognition and
elimination of precancerous states, thus preventing invasive cancer.

Cytologic screening became one method of recognition of precancerous states.
Although the method is attributed to George Papanicolaou, who presented a
paper on the use of vaginal smears in detection of uterine cancer in 1928, 238
he had a predecessor, a Romanian pathologist, Aureli Babes, who published
a beautifully illustrated paper on this topic in the French publication, Presse
Medicate, prior to Papanicolaou's presentation. 239 Babes, using direct cervical
samples, proposed that cancer of the cervix can be recognized in preinvasive
stages. Papanicolaou's primary interest was the sequence of events in the menstrual
cycle which he could study by means of vaginal smears. He did not pursue his

23 Rigoni-Stern (1842). See also note 85.
237 Schauenstein (1908).
Papanicolaou (1928).
239 Babes (1928); see also note 4.

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 -Appendix 1

observations on cancer for ten years, for lack of access to clinical material, until
a fortuitous association with the gynaecologist, Herbert Traut, in 1938. Traut
provided him with vaginal smears, the topic of the paper published in 1941. 240
This was the beginning of the 'Pap smear.' Papanicolaou never acknowledged
Babes' contribution. It is alleged that this omission cost him a Nobel award.

Direct sampling of the uterine cervix was rediscovered by a Canadian
gynaecologist/cytologist, J Ernest Ayre in 1949. 241 Among the many varieties of
cells observed in the cervical smears, there were some that were characterized
by large nuclei and large, clear perinuclear spaces. These cells were extensively
studied by Ayre, who called them 'halo cells' and considered them to be
precursors of cervical cancer. 242 In I960, Ayre proposed that the 'halo cells' may
represent a viral manifestation in premalignancy 243

The term, koilocytes, in common use today to describe these cells, was derived
from the term 'koilocytotic atypia' proposed by Koss and Durfee in 1 956. 244 The
term reflected the hollow nature of the clear perinuclear space (Greek: koilos =
cavity, kytos = cell). The histologic equivalent of koilocytes was named 'warty
atypia' because of its resemblance to warts or condylomas. The suggestion that
koilocytes were a specific manifestation of a viral infection became plausible
with the recognition that genital condylomas were a sexually transmitted
disease caused by a virus, as documented by Dunn and Ogilvie in 1968. 245
The cytologic similarity of condylomas to 'warty atypia' was noted in the first
edition of my book in 1961. 246 In two synchronous papers, Meisels and Fortin
from Canada and Purola and Savia from Finland proposed that the koilocytes
may be a link to condylomas, hence the viral origin of cervical cancer. 247 The
first documentation that the nuclei of koilocytes contained viral particles was

Papanicolaou and Traut ( 1 94 1 ) .

41 Ayre (1949).

42 Ayre and Ayre (1949).

43 Ayre (1960).

Koss and Durfee (1956); see also Figure 4, page 35.

45 Dunn and Ogilvie (1968).

46 Koss (1961); see also note 98.

47 Meisels and Fortin (1976); Purola and Savia (1977).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 -Appendix 1

Figure 7: Dr George N Papanicolaou at the microscope.
Photo inscribed to Leopold G Koss on 23 April 1954.

presented by Laverty et al. from Australia in 1978. 248 Presumably, it is this work
that generated the interest of virologists in papillomavirus in biopsies of the
uterine cervix and the beginning of classification of viral types, as shown by zur
Hausen and Gissmann. 249 There were many other contributors to this sequence
of events that led to subclassification of human papillomaviruses into low-risk
and high-risk types and to antiviral vaccines.

There are still many unanswered questions about the relationship of human
papillomavirus to cervical cancer. The mechanism of viral penetration into

Laverty et al. (1978).

zur Hausen (1987); Gissmann and zur Hausen (1976).

85

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 -Appendix 1

the epithelium is not known. The reason why, among many young women
infected with human papillomavirus, only a very few progress to cancer, is
not understood, in keeping with the unpredictable behaviour of precancerous
lesions of the cervix in a long-term follow-up study 250 The possibility of one or
more contributing factors explaining the relationship of viral infection to cancer
still needs to be explored. Some of the remaining mysteries have to do with
the presence of human papillomavirus in cancers of organs that are clearly not
related to sexual activity, such as the cornea of the eye and the oesophagus, the
latter particularly in China. 251

I had the rare privilege of knowing Dr Papanicolaou and working with him.
I also got to know personally most of the key participants in the sequence of
events briefly summarized above, stretching over the past half a century.

Having read the text of the discussions that took place during the Witness
Seminar, I realized that I know personally several of the participants and
knew many whom have either died or are no longer active. In the UK, as in
most other countries, cytological screening for cervical cancer was pioneered
by gynecologists, because pathologists had no interest in processing the time-
consuming and poorly rewarded Pap smears. Among the pathologists, there
were a few notable exceptions: Herbert Fidler organized a screening programme
in Vancouver, British Columbia; James Reagan of Cleveland and Stanley Patten
of Rochester, New York, wrote extensively about the correlation between cell
patterns and tissues in cervical material.

The true proponents of cervical screening in the US were gynaecologists and
the first major book on the subject was written by a cytotechnologist, Ruth
Graham. 252 Not surprisingly, the first American organization dealing with
cytological diagnosis of cancer was named the Intersociety Cytology Council
as it consisted of gynaecologists, cytologists and the few interested pathologists.
Today, the organization is known as the American Society of Cytopathology
In the UK, the proponents of cytologic screening for cervical cancer were the
gynaecologists, Stanley Way and Erica Wachtel. The latter was a refugee from
Vienna, Austria, another gift from Mr Hitler to the civilized world. She was the
mentor of Professor Dulcie Coleman. Nasseem Husain of London also played a

250 Koss etal. (1963).

For a summary, see Koss (1961).

The second edition (Graham (1963)) of a volume originally published from the Vincent Memorial
Hospital laboratory, Boston, published in 1950.

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 -Appendix 1

major role in these events. Although there is no doubt that Harald zur Hausen,
the recent Nobel Prizewinner, and his co-workers were instrumental in the study
of human papillomavirus as a factor in the genesis of carcinoma of the cervix, I
have little doubt that this work was influenced by cytological observations that
suggested a viral origin of cervical cancer. The story is more complicated than is
generally assumed and it was a privilege to have participated in it in some way.

I can only repeat the words of Michel de Montaigne (1 533-92) : 253

It might well be said of me that in this book I have only made up a
bunch of other men's flowers, providing of my own only the string that
ties them together.

Montaigne (1580).

87

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 -Appendix 2

Appendix 2

Reminiscences on cervical screening

From Dr Arthur SpriggS (written 12 September 2009)

I joined the pathology department at the Radcliffe Infirmary, Oxford. In the
haematology department under Gwyn Macfarlane I began studying the cells
of serous fluids, and started my DM thesis (1952) which became the basis of a
monograph 'The cytology of effusions' (1957). 254 With a grant provided by Dr A
HT Robb-Smith (pathology) and Professor John Chassar Moir (gynaecology),
I spent three months in the US and Canada studying the cytology of vaginal
and cervical smears using the Papanicolaou methods; 'cytodiagnosis' was
usually practised independently of the department of morbid anatomy. So
while learning from the leading cytologists, the variably sceptical opinions of
the local histopathologists were also sought. On my return, with the assistance
of Michael Boddington, I inaugurated the cytodiagnostic service in Oxford.
At first this was for gynaecological outpatients, but in the 1960s was extended
to screening of the local population. The expanding laboratory was transferred
to the Churchill Hospital. Grants were provided by the British Empire Cancer
Campaign (Cancer Research Campaign from 1970) for research into various
aspects of cytological diagnosis - in particular, cyto-histological correlation
in sputum and stomach washings, as well as cervical smears (1953—60);
identification of tumour cells in circulating blood, also in cerebrospinal fluid
(1959-61); and chromosomes of human malignant cells (1960-72). It became
apparent that each malignant tumour was a new unique clone of cells with an
altered chromosome complement. This was most easily demonstrated in the
cells of effusions, but from a small number of biopsy fragments from the cervix
when there was evidence of the same process in carcinoma in situ.™ From the
late 1960s, attempts were made to follow up cases in which a 'positive' cervical
smear had escaped from further recommended procedures over at least two
years. Some of these were found again, particularly with the collaboration of
Professor Richard Doll's department, and a picture could be presented showing
the proportion regressing or progressing over the years, evidently a positive smear

254 Spriggs (1957).
Spriggs et al. (1971).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 -Appendix 2

is dangerous to ignore. 256 Concerning automated cytodiagnosis in the 1970s,
the proposal which I thought achievable would be to pre-screen smears with
a machine capable of marking any large or hyperchromatic nuclei, so that the
screener could go at once to significant areas of the smear. We failed to achieve this
with the apparatus then available. Before my retirement in 1984, collaborative
studies were done with the histopathologists using immunochemical methods,
some of which appeared promising in the identification of malignant cells in
effusions. Following my retirement, I completed with M M Boddington a new
fully illustrated book on the cytology of serious effusions. 257

From Dr Nasseem Husain (written 2 April 2001, 16 and 31 May 2008)

I recognized the value of cytological screening both here and in many countries
elsewhere in the world when I went on lecture tours in the US, South America,
Europe, Asia and Japan to promote this concept. The need for a defined screening
programme which was argued by me through the central committees of the
Ministry of Health resulted in and the establishment of cytology screening units
in every hospital and by general practitioners. In this I was aided and strongly
supported by Marks and Spencers, whose medical staff I knew well and they
were the first to create mobile screening units in this country, where around 7000
tests per year were carried out on their female employees on a two-to-three year
recall, conducting field analysis of different techniques and follow-up programmes
(1967-89). Many of the smears went to local laboratories, but M&S also provided
a magnificent laboratory for me at St Stephen's Hospital along with the salaries of
three technicians and half of a clerk and provided many other assets, where, as well as
screening, we also looked at detailed morphology of chromatin patterns. Although
many doctors took up the practice of cytology, few of them were histopathologist
or haematologists and the practice sadly moved away from scientific cellular
pathology and a separate specialty of cytology developed. (31 May 2008)

I was the first NHS consultant in cytopathology in the UK, being appointed
in 1961, but was also very actively involved in the development of screening
programmes, training of pathologists and technicians, development of
automation techniques and in cytochemistry. (16 May 2008)

256 Kinlen and Spriggs (1978).

57 Spriggs and Boddington (1989). Excerpt from a letter to Dr Winifred Gray, 12 September 2009, which
will be deposited with the other records of the meeting in archives and manuscripts, Wellcome Library,
London, at GC/253.

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000 - Appendix 2

I was involved in research and development of a non-wettable swab, plastic
spatula and a more appropriately shaped knuckle-ended wooden spatula in
the mid-1970s which has ultimately resulted in the Aylesbury spatula ten
years later (see Figure 6, page 54).

Trials were undertaken of an irrigation cytopipette as a self-collecting instrument
to identify its 75-80 per cent accuracy compared with the spatula, but at about
one-fifth the cost, and the development of our own British model of the pipette,
to my specifications and an improved irrigation and preservative solution and
eventually, the greater acceptability as a screening procedure in a controlled trial
supported by the Ministry of Health (DHSS after 1968).

The development of cell preparatory techniques for automated scanners utilizing
cell dispersal systems of mucolytic, chemical, enzymic and physical methods,
which include a study of ultrasonics, disaggregation by sheer stress techniques
using syringes, vortex whistle, peristaltic pumps and cell 'spinners' on to film
strips and glass slides. Research into the cell coatings from 90.000 to 500.000
molecular weight with a cell spread utilizable for any subsequent staining process
and for use with cyst fluid, urine and fine needle aspirate samples.

An extensive study was made for use with automatic scanners to produce a
high signal-to-noise ratio and achieve a machine-blind stain. This involved a
review of a range of haematoxylins and DNA stains and the development of a
quantitative fast gallocyanin of 5— 10 minutes' duration, instead of the 18-hour
schedule of Einarson (1932), to which cytoplasmic stains could be added.

In 1 965 , 1 evaluated the claim that the Coulter cell counter with a size distribution
plotter would demonstrate secondary peaks of large cells in neoplastic cell
samples. This was examined in a joint venture with the Royal Marsden Hospital
to demonstrate that the large cell was in fact a cell cluster, probably polymorphs,
and often in association with malignancy, but that these secondary peaks would
disappear on cell cluster disaggregation.

In 1966 we were the first to explore the use of a static cell scanner by the
conversion of the industrial Quantimet B imaging analysing computer using a
Vidicon television tube from an incidental light microscope to a transmission
light instrument. A study of cells from cervical smears demonstrated that there
were sufficient discrete neoplastic cells stained by haematoxylin which were over-
threshold, giving a raised integrated optical density, which could be registered
by virtue of sizing and density potentiometers and be recalled for interactive
visual assessment. These results were presented in the first automatic research

90

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 -Appendix 2

conference in 1968. A purpose-built scanner called the Imaco cytoscreen was
then constructed to my specifications and funded by the DHSS. This project
led the international field in conferences in Europe and the US for the next five
to ten years. The further development of this scanner failed to be adequately
supported by the DHSS and subsequently by the MRC, as I had to transfer our
energies to the Cervifip (Cytoscan 110), an offshoot of the metaphase finder
and chromosome analyser being developed by the MRC, first in London and
then at the Western General Hospital, Edinburgh, 1978-89. We were closely
involved in perfecting this diode array scanner over the last five to ten years of
my appointment, which resulted in a sophisticated instrument with a low false
negative signal rate achieved by the register of aneuploid and polyploidy nuclei,
with rejection of the false positive signals due to nuclear overlaps and cell debris,
by pattern recognition, but has not yet reached acceptable limits. Nevertheless,
this instrument compares well with the three to four instruments developed in
Europe and the US and can read and sort cells at the rate of about 150 000 per
two minutes.

I had considerable experience in flow cell instruments and our comparative trials
using flow cell analysers and microdensitometers does demonstrate the unique
advantage of our fast static cell scanner (Cervifip), working on both the rapid
cell detection of the rare event and also on analyzing disaggregated selective
archival material from tissue blocks in order to study the ploidy pattern of cells
of tumours and therefore to relate to the prognostic and the therapeutic effects
and able to achieve a valuable prospective dimension if fine needle aspirate
samples are used.

The limitation of morphological criteria for the diagnosis of malignancy
encourage me to pursue a study in depth of the biochemical and functional
parameters of neoplastic cells and it is here that our researches embraced both
biochemical and cytochemical fields. Our study of the glucose-6-phosphate
dehydrogenase enzyme in vaginal aspirates was based on a claim of raised
activity in neoplasia and a survey of some 5000 case samples tested against
traditional scrape smear cytology to confirm or disprove this thesis resulted in
the finding that although all invasive lesions showed high levels, only about half
the carcinoma in situ cases did so and there was an excessively high proportion of
false positive readings. It was later found that if potassium was used as a measure
of cellular content and therefore the source of enzyme rather than freeze dried
weight or cytochrome, the false positive rate dropped to less than 9 per cent.
Such a test could conceivably be used to screen for endometrial cancer.

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000 - Appendix 2

We were the first to study the state of the DNA in neoplasia by a slowed-down
Feulgen hydrolysis technique at room temperature to show that there was a
significant labile component, both in the neoplastic cell and also in the benign
cells in their vicinity, a feature that may make the detection of malignancy
possibly without encountering or identifying a neoplastic cell.

The combined output of the Charing Cross and St Stephen's cytology
departments was about 55 000 tests per year. An increasing proportion of these
were becoming non-gynaecological tests presenting a substantial workload in
the fields of gastrointestinal and pulmonary brush specimens and fine needle
aspirates. The gynaecological screening load used to come from a large area of
south-west London and from parts of Sussex where we served about 55 different
gynaecological screening clinics, 22 hospital clinics and about 130 general
practitioners. On the transfer of the district to North West Thames Regional
Health Board, the range of GPs and clinics was reduced but the volume of
throughout dropped only marginally, while problem cervical smears and non-
gynaecological specimens, including fine needle aspirates and AIDs specimens,
increased markedly. (2 April 2001)

I must finally congratulate you on your initiative to choose this field of
cytodiagnosis as a subject for a Witness Seminar, which has effectively spread
to many other parts of the body and is now a highly sophisticated and effective
method of early diagnosis. (31 May 2008)

92

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - References

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Biographical Notes

Biographical notes'

Professor Valerie Beral
FRCP FMedSci FRS (b. 1946),
epidemiologist, was born and
educated in Australia with
degrees in both medicine and
surgery from the University of
Sydney and a combined course in
epidemiology and statistics at the
London School of Hygiene and
Tropical Medicine, where she was
lecturer and reader. She has been
the head of cancer epidemiology
unit for Cancer Research UK since
1989. For further details on the
million women study, the largest
study of women's health, with
one in four UK women who were
aged 50-64 during the period of
recruitment (1996-2001), see
Beral (Million Women Study
Collaborators (2003)). and
http: //info, cancerresearchuk.
org/cancerandresearch/
ourcurrentresearch/
researchbygrantee/beral/ (visited
30 September 2009). See also
Green etal. (1988).

Professor Saveria Campo
PhD FRSE (b. 1947) studied at the
University of Palermo, Italy, where
she graduated summa cum laude in
1969. She obtained her PhD at the

University of Edinburgh in 1973
and worked in the department of
genetics (1973-76) and then in the
department of zoology (1976-81).
In 1980 she was awarded a Cancer
Research career development
fellowship and in 1982 she moved
to Glasgow to the Beatson institute
for cancer research where she
led the papillomavirus research
group. She obtained a Cancer
Research life fellowship in 1984
and achieved professorial status in
1992. She moved to the institute of
comparative medicine, University
of Glasgow, in 1999, where she is
professor of viral oncology. She was
elected a fellow of the Royal Society
of Edinburgh in 2006.

Professor Jocelyn Chamberlain
FRCP FFPH (b. 1932)
graduated in medicine in 1955
at St George's Hospital Medical
School, University of London and
pursued a career in epidemiology
at Guy's Hospital (1961-68), the
London School of Hygiene and
Tropical Medicine (1968-73),
and University College Hospital
Medical School (1973-78), before
moving to the Institute of Cancer
Research, University of London,
where she founded the cancer

* Contributors are asked to supply details; other entries are compiled from conventional
biographical sources.

129

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000 - Biographical Notes

screening evaluation unit, funded
by the Department of Health
(DoH) research division, and
directed it until her retirement in
1995, when she moved to Wales
and became chairman of the South
West Wales cancer institute until
2002. She served on numerous
national and international
committees, including the DoH
standing subcommittee on cancer,
the MRC molecular and cellular
medicine board, the UKCCCR
subcommittee on breast screening
research (chairman), the board of
the Faculty of Public Health, and
the International Union against
Cancer (UICC) core committee on
cancer screening.

Professor Dulcie Coleman
MD FRCPath FIAC (b. 1932)
qualified at St Bartholomew's
Hospital Medical School,
London, and trained in clinical
cytopathology there under the
supervision of Dr Gordon Canti
and with Professor Erica Wachtel at
Hammersmith Hospital(1962— 64).
She was appointed clinical
assistant in in the department of
pathology, Hillingdon Hospital,
London, in 1964; became clinical
assistant in the department of
pathology, St Mary's Hospital,
in 1965, appointed consultant
cytopathologist there in 1972
and professor of cytopathology,
Imperial College Faculty of

Medicine (1988-98) until her
retirement, later emeritus, and
remains engaged in teaching and
research.

Dr Lionel Crawford
PhD FRSE FRS (b. 1932) was
senior scholar, then research fellow
of Emmanuel College Cambridge
(1952-58). After two years as a
Rockefeller research fellow at the
Virus Laboratory, Berkeley, and the
California Institute of Technology,
Pasadena, he returned to the
Institute of Virology, University
of Glasgow. He was subsequently
head of the department of
molecular virology at the Imperial
Cancer Research Fund Laboratory,
London, and then set up the
ICRF tumour virus group in
Cambridge (1988). His interest in
papillomaviruses goes back to the
early 1960s and continues to the
present with forays into polyoma,
SV40 and extensively into p53. He
was awarded the Gabor medal of
the Royal Society in 2005.

Professor Heather Cubie
PhD FRCPath (b. 1946) graduated
in bacteriology in 1968, later
receiving an MSc and PhD, all
from University of Edinburgh.
She has worked in either the
University of Edinburgh (medical
microbiology and dermatology) or
NHS Lothian (Royal Hospital for
Sick Children, City Hospital and

130

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Biographical Notes

the Royal Infirmary of Edinburgh)
since then, becoming a consultant
clinical scientist in virology in
1993. Her specialist research
interest is human papillomavirus
(HPV). She is a member of the
Scottish HPV national steering
group and epidemiology and
surveillance subgroup and also
of the UK NCSP HPV special
interest group. She became
honorary professor of research and
research management, University
of Edinburgh, in 2006 and visiting
professor of virology, University of
Glasgow, in 2008.

Professor Jack Cuzick

PhD FMedSci (b. 1948) holds
a PhD in mathematics and has
been head of the Cancer Research
UK centre for epidemiology,
mathematics and statistics in
London and John Snow Professor
of Epidemiology at the Wolfson
Institute of Preventive Medicine at
Queen Mary, University of London
since 2004. His current interests
are in cancer epidemiology and
clinical trials, with special interest
in prevention and screening and
he is currently involved in studies
on the use of HPV assays for
cervical screening. He discovered a
method for sensing and processing
biopotentials for early diagnosis
of breast cancer (named on US
patent no. 6,351,666 Bl assigned
to the Biofield Corporation in

2003; for precursors, see Cuzick
etal. (1998b)); received the
Thomson's hottest research award
of 2005/06 for scientists with most
cited papers, the only UK-based
author of 17 scientists selected
worldwide; and has been president,
International Society of Cancer
Prevention since 2004.

Professor Nicholas Day
CBE FRSS FRCPath FMedSci
FRS (b. 1939) statistician, later
head of the unit of biostatistics
and field studies, epidemiology
section of the International Agency
for Research on Cancer, in Lyons
(1969-86), director of the MRC
biostatistics unit, Cambridge
(1986-89, honorary director 1989-
99), professor of public health,
University of Cambridge (1989-99)
and MRC research professor of
epidemiology there (1999-2004).
He was chairman of the MRC
committee on the epidemiology and
surveillance of AIDs (1988-92). See
Breslow and Day (eds) (1987).

Dr Ian Duncan
FRCOGFHEA(b. 1943)
graduated in medicine at the
University of St Andrews
and trained in obstetrics
and gynaecology in Dundee
(1969-72, 1974-8), specializing
in gynaecological oncology
at Duke University, Durham,
North Carolina (1972-74). He

131

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000 - Biographical Notes

was appointed senior lecturer,
University of Dundee, in 1978,
subsequently reader and honorary
consultant gynaecologist/
oncologist until his retirement
in 2007. He established one
of the first colposcopy services
in Scotland in 1974; has been
executive member and subsequently
president of the British Society
for Colposcopy and Cervical
Pathology (1985-88), the British
Gynaecological Cancer Society
(1988-91) and the International
Federation for Cervical Pathology
and Colposcopy (1993-96.) He has
also served on the Strong advisory
committee on the cervical cytology
service in Scotland (1985/6), the
intercollegiate working party on
cervical cytology screening in the
UK (1987), the NHS Cervical
Screening Programme national
coordinating network and its
successor the NHS CSP, editing,
drawing up and subsequent revision
of guidelines for clinical practice
and programme management
(1989-97). He was chairman of
the Scottish Cervical Screening
Programme national advisory group
(1998-2003).

Professor Ian Frazer
immunologist, jointly holds
the patent with his late research
partner, Dr Jian Zhou (1957-99),
and was the commercial driver in
the development of the vaccine for

cervical cancer ( Gardasit) by the
University of Queensland team.
He is head of the University of
Queensland Diamantina institute
for cancer, Princess Alexandra
Hospital and was honoured as
2006 Australian of the Year,
was inaugural winner of the
Queensland smart state premier's
fellowship (2006) and received
the Balzan prize for international
medicine. See interview by Robyn
Williams in 2008 at www.science.
org.au/scientists/if.htm; see also
www. di. uq. edu. au/news-archive
(both sites visited 23 April 2009).

Professor Lutz Gissmann

German Cancer Research
Center, Heidelberg, Germany,
was appointed to a postdoctoral
position, later assistant professor,
department of virology, University
of Freiburg (1977-83); head of
the German Cancer Research
Center, genome modifications and
carcinogenesis division, Heidelberg
Germany (1983- ); full professor
(1986); chairman, applied tumor
virology programme, German
Cancer Research Center (1991-93);
director of research, department
of obstetrics and gynecology,
programme leader for viral oncology
and full professor, Loyola University
Medical Center, Chicago, Illinois
(1993-97); vice president of research
and development, MediGene AG,
Martinsried, Germany (1998/9);

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Biographical Notes

honorary professor, King Saud
University, Riyadh, Saudi Arabia
(2008- ).

Sir Muir Gray

Kt CBE MD FRCP FRCPSGlas
FFPH (b. 1944) qualified at the
University of Glasgow and trained
in public health at Bristol. After
house jobs he joined the city of
Oxford as senior medical officer
(1972-74); public health specialist,
Oxfordshire HA (1974-91);
director, health policy and public
health, Oxford RHA (1991-94);
Director of R&D, Anglia and
Oxford RHA, then Anglia and
Oxford Regional Office, NHS
Executive, Department of Health
(DoH) (1994-98); director of
the Institute of Health Sciences,
University of Oxford (1999-2002).
He was co-ordinator of the national
breast cancer screening programme,
1988-91; national cervical
screening programme (1988-94);
and Adviser, WHO (1984-91).
He has been programmes director,
UK national screening committee,
since 1995, and director of clinical
knowledge, process and safety,
Department of Health, since 2004.
See Gray (1997, 2004).

DrWinifred Gray
FRCPath (b. 1937) qualified
in Adelaide and trained in
cytopathology with Dr Arthur
Spriggs in the cytology department

in Oxford. She took up a post
in cytology at the Northampton
and Kettering General Hospitals;
was one of the first to have a
full training in pathology at the
Radcliffe Infirmary, Oxford,
starting in 1969, under Dr
Rosemary Ruse's married women's
retraining scheme; was consultant
histo/cytopathologist, Wycombe
General Hospital (1974-88) and
John Radcliffe Hospital, Oxford
(1988-2002), where she set up
a cytology training school for
technical and medical staff, which
closed on her retirement. She
examined in cytopathology for
the Royal College of Pathologists
and served on their cytopathology
subcommittee; was editor of
Cytopathology (1998-2002) and
on the BSCC council. The third
edition of her textbook (Gray and
McKee (2003)) is in preparation.

Professor Matti Hakama
statistician and professor of
epidemiology at the University of
Tampere, Finland.

Professor Harald zur Hausen
MD (b. 1936) studied medicine at
the Universities of Bonn, Hamburg
and Diisseldorf, working as a post-
doctoral student at the Institute of
Microbiology in Diisseldorf, assistant
professor in the virus laboratories
of the Children's Hospital in
Philadelphia, Pennsylvania; senior

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000 - Biographical Notes

scientist at the Institute of Virology,
University of Wtirzburg and as
chairman and professor of virology at
the University of Erlangen-Niirnberg,
moving to a similar position at the
University of Freiburg in 1977;
and as scientific director of the
Deutsches Krebsforschungszentrum
(German Cancer Research Center)
in Heidelberg (1983-2003). His
special interest is in infection-induced
malignancies and he showed the role
of papillomaviruses in cervical cancer
and discovered a larger number of
novel virus types. He shared half
the 2008 Nobel prize in Medicine
or Physiology with Francoise Barre-
Sinoussi and Luc Montagnier,
recognized 'for his discovery of
human papilloma viruses causing
cervical cancer'. He has been editor-
in-chief of the International Journal
of Cancer since 2000. See also zur
Hausen (2006).

Dr Amanda Herbert
MRCS LRCP FRCPath
(b. 1943) qualified in medicine
at St Mary's Hospital, London in
1968. Appointed as consultant
cytopathologist and histopathologist
at Southampton University
Hospitals Trust (1982-98), she
held a similar post at Guy's and St
Thomas' NHS Foundation Trust
(1998-2008), since when she works
part-time in the same department.
She is an honorary senior lecturer
at Guy's, King's and St Thomas'

School of Medicine. She chaired
the Royal College of Pathologists
cytopathology subcommittee and
examination panel (1993-97) and
was a member of council and/
or officer of the BSCC almost
continually (1984-2004). She has
been editor of the Wiley-Blackwell
journal Cytopathology since 2008.

Dr O A N (Nasseem) Husain
MD FRCPath FRCOG (b. 1924)
qualified King's College Hospital
Medical School and military service
in the RAMC as a specialist in
pathology, training at Westminster
Hospital, London. He was the first
NHS consultant in cytopathology
in the UK in 1961 appointed to
the Chelsea and Kensington Group
pathological laboratories and in
charge of the cytodiagnostic unit at
St Stephen's Hospital, London, later
Chelsea and Westminster Hospital
(1961-91). He was co-founder
and secretary, then chairman and
ultimately president (1977-80)
of the British Society of Clinical
Cytology (BSCC). See Husain and
Butler (1999).

Professor David Jenkins
MA MD FRCPath (b. 1946)
studied at King's College,
Cambridge, and then at the Welsh
National School of Medicine,
Cardiff. He was assistant lecturer
in the department of pathology,
Cambridge University, and then
lecturer in pathology at Westminster

134

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Biographical Notes

and St Thomas' Hospitals, London.
He started clinical and laboratory
research on the role of HPV in
cervical and other cancers and
precancer in 1984 with Albert
Singer at the Whittington and
Royal Northern Hospitals and
continued at Nottingham as
professor in pathology. He was a
principal investigator on the MRC
TOMBOLA trial of management
of abnormal smears in cervical
screening and became director of
clinical research into prophylactic
HPV vaccines at GlaxoSmithKline
Biologicals based in Belgium
from 2003 until his retirement
in 2007. He remains an active
scientific consultant to this vaccine
programme and continuing
evaluation and publication of the
results of the large clinical trials he
established on the HPV vaccine.

Professor Anne Johnson
FRCP FFPH FRCGP FMedSci
(b. 1954) trained in medicine in
Cambridge and Newcastle and
specialized in epidemiology and
public health. She was in general
practice (1978-83), registrar in
community medicine, NE Thames
Regional Health Authority (1983/4),
lecturer, Middlesex Hospital Medical
School (part of University Hospital
Medical School since 1987, 1985-
88); senior lecturer in epidemiology
(1988-94), honorary consultant in
public health medicine since 1998,

reader in epidemiology 1994-96;
professor of epidemiology (1996—),
head of the department of primary
care and population sciences, Royal
Free and UCH Medical School
(2002-), and director of the Division
of Population Health, UCL (2007).
She was visiting professor at the
London School of Hygiene and
Tropical Medicine (1999-2006).
She co-directed the Medical
Research Council-UK Centre for
Co-ordinating Epidemiological
Studies of HIV and AIDS from
1985 until 1999 and was principal
investigator on the 1 990 Wellcome
Trust-funded first National Survey
of Sexual Attitudes and Lifestyles
(Natsal 1990) and on MRC Natsal
2000. She was a deputy chair of
the MRC infection and immunity
board (2004-07, a member of the
Department of Trade and Industry
expert advisory group, foresight
detection and identification of
infectious diseases project (2004—
07), a member of the Department of
Health specialist advisory committee
on antimicrobial resistance (2001-
07), a member of the working party
on public health: Ethical Issues
(Nuffield Council for Bioethics) in
2007. She is a member of the Board
of International Society of Sexually
Transmitted Diseases Research
(ISSTDR) and a non-executive
director of the Whittington NHS
Trust.

135

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000 - Biographical Notes

Professor Leopold Koss
MD HonFRCPath (b. 1920)
received his MD degree from the
University of Bern, Switzerland
in 1946. He was chief of the
cytology service and attending
pathologist of the Memorial Sloan-
Kettering Cancer Center, New
York (1952-70) and has been
professor and chairman emeritus
of the department of pathology,
Montefiore Medical Center, Albert
Einstein College of Medicine,
Bronx, New York since 1973. His
textbook, Diagnostic Cytology and its
Histopathologic Bases (Koss (1961))
was awarded a Citation Classic in
1989. He was made honorary fellow
of the Royal College of Pathologists
in 1996. See also Koss (2007).

Professor Attila Lorincz

PhD (b. 1954) molecular biologist,
inventor of the hybrid capture series
of tests for HPV while senior vice-
president and chief scientific officer
at the Digene Corporation (later
part of QIAGEN, Gaithersburg,
Maryland). He has been professor
of molecular epidemiology at the
Wolfson Institute of Preventive
Medicine, Queen Mary, University
of London, since 2007.

Dr Elizabeth (Betty) Macgregor
OBE MD FRCPath FRCOG
(1920-2005) qualified at Glasgow
with house jobs at Glasgow Royal
Infirmary and Western General

Hospital. In 1958 she became a
research assistant at Aberdeen in
the department of obstetrics and
gynaecology run by Sir Dugald
Baird, who wanted a screening
programme for cervical cancer
established in the then stable
population and she learned to
take and interpret smears and to
use the Papanicolaou staining
technique; she was awarded an MD
in 1963. The Aberdeen screening
programme was one of the first
in the UK and she established a
punchcard system for calling and
recalling patients. She visited GP
surgeries to take smears, started
to analyse them and study the
epidemiology, publishing evidence
after five years and encouraging
others to follow. She was president
of the BSCC (1980-83, Figure 1).
See Anon. (2005); Richmond
(2005); www.oxforddnb.
com/view/article/96184 (visited
16 September 2009).

Dr Elizabeth Mackenzie
FRCPath DPH (b. 1934) trained at
St Bartholomew's Hospital Medical
School, London, and was consultant
cytopathologist, Southmead
Hospital, Bristol (1986-94; and
head of the department of cytology,
1987-90, 1991-94); consultant
cytopathologist to BUPA screening
service, The Glen BUPA Hospital,
Bristol (1994-2007). She was
manager of the cervical cytology

136

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Biographical Notes

screening programme for Bristol &
Weston district, Frenchay district
and Southmead district (later
Bristol and district health authority
(1976-94)); was chairman of the
regional cytological committee
(1984); established the South West
regional cytology training centre for
cytoscreeners, medical laboratory
scientific officers (MLSOs) and
pathologists (1990); was secretary
(1983-86) and president of the
BSCC (1994-97); chairman of the
South West Association of Clinical
Pathologists (1987).

Drjoan Macnab
PhD FRCPath qualified and
trained at the University of
Glasgow. She worked as a research
assistant in infectious diseases
(1959/60), poliomyelitis (1960/1)
and a memorable spell as research
assistant to Professor Guido
Pontecorvo (1962—67) where she
later took up an MRC scientific
appointment. In 1967 she joined
Professor John Subak-Sharpe,
Director of the MRC Institute of
Virology, University of Glasgow. As
senior scientist and research team
leader she took early retirement in
1995. Her early love of genetics
influenced her approach to virology
research. She has been scientific
adviser to Medical Research
Scotland (formerly the Scottish
Hospital Endowments Research
Trust) since 1996.

Professor Glenn McCluggage
FRCPath (b. 1963) trained in
medicine at Queen's University
of Belfast (QUB) in 1987;
has worked as a trainee and
consultant in histopathology in
the Royal Group of Hospitals
Trust, Belfast, since 1988. He was
appointed an honorary professor
in pathology, QUB, in 2005; has
published approximately 250 peer-
reviewed articles and reviews in
gynaecological pathology; and is
president of the British Association
of Gynaecological Pathologists
(2007-10).

Dr Euphemia McGoogan
MPath qualified at Aberdeen
University Medical School
and trained at the University
of Edinburgh department of
pathology. She was a senior
lecturer there and honorary
consultant pathologist (1983-
2004); and was pathology patient
services director for the Lothian
University Hospitals NHS Trust
in Edinburgh, responsible for the
largest combined morbid anatomy,
histopathology and cytopathology
service in the UK. She was medical
director, Europe, for the Cytyc
Corporation (2004-08) and has
owned her own consultancy service
since 2008. She chaired an inquiry
into cervical cytopathology at
the Inverclyde Royal Hospital,
Greenock (1993). See www.

137

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000 - Biographical Notes

cancerscreening.nhs.uk/cervical/
publications/nhscsp22.pdf (visited
27 January 2009).

Professor Anthony Miller
MD FRCP FRCP(C) FACE
(b. 1931) qualified in medicine in
1955 and specialized in internal
medicine. He was a member of
the scientific staff of the Medical
Research Council's tuberculosis
and chest diseases unit, Brompton
Hospital, London (1962-71). He
directed the epidemiology unit
of the National Cancer Institute
of Canada (1971-86), and was
chairman of the department
of preventive medicine and
biostatistics, University of Toronto
(1992-96). He was senior scientist,
International Agency for Research
on Cancer, Lyons, France (1997-
99) and served as head of the
division of clinical epidemiology,
German Cancer Research Center,
Heidelberg, Germany (1999-
2003), and is currently associate
director of research at the Dalla
Lana School of Public Health,
University of Toronto, Canada.
He is principal investigator of
the Canadian national breast
screening study and he serves as a
consultant to the early detection
research programme, division of
cancer prevention, National Cancer
Institute, Bethesda, Maryland, and
to the World Health Organization's
programme in cancer control. He

chairs the cancer risk management
advisory committee of the Canadian
partnership against cancer and is a
member of its advisory committee
on cancer control.

Professor George Papanicolaou
MD PhD (1883-1962) qualified
in medicine at the University of
Athens, studied philosophy of
biologic sciences in Germany with
August Weisman, earned his PhD
in zoology in Munich and worked
in France as a physiologist. He was
appointed as a technical assistant
in the department of anatomy,
Cornell Medical School, at New
York (1913-61), and consultant
to the Strang Laboratory. While
preparing his 1933 monograph
on the human female sexual cycle
'as revealed by vaginal smear', he
noted abnormal cells from the
cervix and later re-evaluated the
vaginal smear for cancer detection
at the suggestion of Joseph Hinsey
in 1939. Dr Herbert Traut, from
the department of obstetrics and
gynecology at Cornell, collaborated
with Papanicolaou on the
diagnostic potential of the vaginal
smear, later called the Pap test,
published in 1943. Papanicolaou's
Atlas of Exfoliative Cytology,
appeared in 1954, with a revision
in 1960. See Hinsey (1962);
Michalas (2000); Sawin (2002);
www.papsociety.org/index.html
(visited 22 July 2009).

138

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Biographical Notes

Professor Julian Peto

DSc FMedSci (b. 1945) graduated in
mathematics from Oxford in 1967.
He was a research scientist with Sir
Richard Doll in Oxford (1974-83)
and chairman of the section of
epidemiology at the Institute of
Cancer Research (ICR, 1983-2004).
His Cancer Research UK chair is
now held jointly between the ICR
and the London School of Hygiene
and Tropical Medicine.

Dr Catherine Pike

(b. 1920) graduated in medicine
at the University of Glasgow in
1943; served in the Royal Air Force
medical service (1944-47); and
subsequently took medical house
and registrar posts followed by
marriage and life in Tanganyika
(Tanzania from 1964) until 1960.
She was a community physician
(child health and family planning)
at Guildford (1960-67) when
she retrained in cytology at St
Thomas' Hospital, London.
She was appointed consultant
cytopathologist, Royal Surrey
County Hospital (1978-85);
a member of the national
coordinating network for the UK
cervical screening programme; a
council member, BSCC. Following
retirement in 1985, she worked
on a screening programme with
Professor Jocelyn Chamberlain at
the Institute of Cancer Research,
Sutton until 1992.

Dame Rosemary Rue
DBE FRCP FFPHM FRCPsych
FRCS (1928-2004), physician and
regional medical officer (1973-84)
and regional general manager
(1984-88) of the Oxford Regional
Health Authority, who set up a
married women doctors' retraining
scheme. See Rue (1967); note 35.

Professor Peter Sasieni
PhD (b. 1963) studied
mathematics at Cambridge
University before going to the
department of biostatistics at the
University of Washington, where he
obtained a PhD. His post-doctoral
post was with Dr Jack Cuzick at
ICRF, Bart's, London, in 1989
and it was there that he started
studying cervical screening and
became involved in the National
Coordinating Committee. He
moved to Queen Mary, University
of London as professor of cancer
epidemiology and biostatiscs in
the Wolfson Institute of Preventive
Medicine in 2002.

Professor Albert Singer
PhD DPhil FRCOG (b. 1938)
attended Sydney University,
graduating in I960, specializing
in obstetrics and gynaecology
obtaining membership of the
Royal College in 1967. He had
joined Dr Malcolm Coppleson, a
clinical gynaecologist and expert
colposcopists, and Dr Bevan Reid,

139

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000 - Biographical Notes

an outstanding cellular biologist,
in 1966, obtaining a PhD from
Sydney University (Singer (1972)).
He moved to Oxford in 1 970
on a scholarship to continue his
work on high-risk women for the
development of cervical cancer
by studying women in a large
London prison where evidence of
clinical HPV as a aetiological factor
became evident and was awarded
an DPhil for this work (Singer
(1973)); worked in Sheffield
investigating possible genetic
markers in women with cervical
precancer while also building a
large colposcopy unit (1973-81)
and has been at the Whittington
Hospital NHS Trust since 1981 as
a gynaecologist as well as holding
chairs in gynaecological research
and molecular pathology at UCL.
His unit in collaboration with basic
science units at UCL has been
active in both basic and clinical
HPV research as well as examining
the role of genetic markers for
cervical neoplasia diagnosis.

Drjohn Smith

FRCPath MIAC (b. 1953) qualified
at the Middlesex Hospital Medical
School, London, and trained
in histopathology and cytology
at St Bartholomew's Hospital,
London, and in Bristol, where
he developed a particular interest
in cervical cytology. He has
been consultant histopathologist

and cytopathologist at the
Royal Hallamshire Hospital,
Sheffield, and honorary senior
clinical lecturer in pathology
in the University of Sheffield.
He was appointed a consultant
in Sheffield in 1987 and since
1997 has practiced exclusively in
gynaecological histopathology and
cytology there. He is director of
the East Pennine cytology training
centre, director of the Sheffield
Cervical Cytology Service and lead
histopathologist at the Sheffield
Gynaecological Cancer Centre. He
is currently president of the BSCC
and past chairman of the panel of
examiners in cytology of the Royal
College of Pathologists. He is an
associate of the General Medical
Council and has served on advisory
committees of the GMC, Royal
College of Pathologists, BSCC
and the NHS cervical screening
programme. He is a consultant
adviser to the governments of
Singapore, New Zealand and Jersey.

Dr Arthur Spriggs
DM FRCP FRCPath (b. 1919)
studied medicine at Oxford,
Liverpool and Edinburgh and
served in the Royal Army Medical
Corps as a graded physician
(1944-47). He joined the
pathology department at the
Radcliffe Infirmary, Oxford; in
the haematology department
under Gwyn Macfarlane he began

140

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Biographical Notes

studying the cells of serous fluids,
and his DM thesis (1952) became
the basis of a monograph 'The
Cytology of Effusions' (1957).
He spent three months in the
US and Canada studying the
cytology of vaginal and cervical
smears using the Papanicolaou
method. On his return, with the
assistance of Michael Boddington,
he inaugurated the cytodiagnostic
service in Oxford in 1958. He was
consultant cytologist to the United
Oxford Hospitals from I960 until
his retirement in 1984.

Professor Margaret Stanley
OBE FMedSci (b. 1939) attended
the Universities of London,
Bristol and Adelaide and has
been professor of epithelial
biology, department of pathology,
University of Cambridge, since
2003. She has served on several
research council committees and
was a member of the Biology and
Biotechnology Science Research
Council (2000-03); a member
of Spongiform Encephalopathies
Advisory Committee (SEAC),
which advises the UK government
on prion diseases. Her research
interests concern the biology of
cervical epithelium and how and
why cancer of the cervix develops;
her current research focuses on
mechanisms of host defence and
the development of vaccines and
immunotherapies against human

papillomaviruses, the cause of
cervix cancer. She has been on
the editorial board of Sexually
Transmitted Infections and Reviews
in Medical Virology since 2007
and is a member of the
council of the International
Papillomavirus Society.

Mrs Marilyn Symonds

CSi FIBMS (b. 1947) commenced
work as student medical laboratory
technician in 1963 at Stoke
Mandeville Hospital, Aylesbury,
specializing in cytology. She became
head biomedical scientist in cellular
pathology at Stoke Mandeville
Hospital (1989-2002) and
honorary secretary of the BSCC
(2001-04). She was appointed
hospital programme coordinator for
cervical screening, Buckinghamshire
Hospitals NHS Trust (2000) and
advanced biomedical scientist
practitioner (2002).

Dr Anne Szarewski
PhD FFSRH (b. 1959) graduated
in medicine in 1982 and has been a
registered colposcopist since 1987.
She joined the Imperial Cancer
Research Fund (ICRF, Cancer
Research UK from 2002) in 1992
and obtained her PhD in 1997
from the University of London.
She has continued to work for the
Imperial Cancer Research Fund
and is currently clinical consultant,
honorary senior lecturer in the

141

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000 - Biographical Notes

CRUK centre for epidemiology,
mathematics and statistics at the
Wolfson Institute of Preventive
Medicine, Barts and the London
School of Medicine and Dentistry,
University of London. Since 2003
she has been the editor-in-chief
of the Journal of Family Planning
and Reproductive Health Care, and
has been on the board of directors
of the European Cervical Cancer
Association (ECCA).

Professor E M (Tilli)Tansey
PhD PhD HonFRCP FMedSci
(b. 1953) is convenor of the
History of Twentieth Century
Medicine Group and professor
of the history of modern medical
sciences at the Wellcome Trust
Centre for the History of Medicine
at UCL.

Professor Leslie G Walker
PhD FBPsS FIBiol (b. 1949) holds
the chair of cancer rehabilitation in
the postgraduate medical institute,
University of Hull, in association
with Hull York Medical School.
He has been chair of the research
committee of Breast Cancer
Care (2004-08) and serves on a
number of committees, including
the Medical Research Council
college of experts since 2008 and
the research committee of the
National Cancer Survivorship
Initiative (Department of Health).
His membership of editorial boards

includes the European Journal of
Psychiatry, Contemporary Hypnosis,
Psycho-Oncology and Complementary
Therapies in Clinical Practice. He is
a former co-chair of the nominating
committee of the International
Psychosocial Oncology Society
(2000-03) and served two terms
of office as chairman of the British
Psychosocial Oncology Society
(1995-99). He was a member of
the council of the British Society
of Experimental and Clinical
Hypnosis (1991-96; 2002-05), the
population and behavioural sciences
committee of Cancer Research UK
and the National Cancer Research
Institute complementary therapies
clinical studies development group
(2004-08).

Mr Patrick George Walker
MD FRCOG (b. 1949) has been
a consultant gynaecologist, Royal
Free Hospital, London since
1986. His University of London
MD was on 'Human papilloma
virus and its relationship with
cervical intraepithelial neoplasia'
(1985). He was president of the
British Society for Colposcopy
and Cervical Pathology (2003-06)
and secretary general (2006-08)
of the International Federation for
Cervical Pathology and Colposcopy
and has been president since 2008.

142

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Biographical Notes

Dr Richard J Walton
(d. 1995) born and qualified in
New Zealand. Having served with
the Royal New Zealand Navy,
he was awarded a British Empire
Cancer Campaign Research
Fellowship in 1949 and trained in
radiotherapy at the Royal Marsden
Hospital, Sutton, London, under
Professor Sir David Smithers.
After he obtained the DMRT in
1953, Dr Malcolm MacCharles
recruited him to Winnipeg, and
he was appointed as head of
radiotherapy and medical director
of the Manitoba Cancer Treatment
and Relief Institute (1954-57);
the first executive director of the
expanded and re-named Manitoba
Cancer Treatment and Research
Foundation (1957-73); vice-
president medical at the newly
incorporated Health Sciences
Centre, Winnipeg and a full
professor in the department of
radiology, University of Manitoba,
Winnipeg (1973-79). He was
chairman of the two task forces
on cervical cancer screening
programmes in Canada (1974-76;
1980-82). See note 48.

Professor Sir Stanley Way
FRCS FRCOG (d. 1988) qualified
at the Middlesex Hospital, London;
trained at Newcastle hospitals and
with Papanicolaou in 1948-49, was
lecturer (1968) in gynaecological
oncology, University of Newcastle

upon Tyne and consultant
surgeon, gynaecological research
department, Queen Elizabeth
Hospital, Gateshead, a pioneering
cancer unit and ran one of the
five national cytology training
schools. He delivered the Joseph
Price Oration of the American
Gynecological and Obstetrical
Society on 10 September 1959 on
'Carcinoma of the vulva'; and was
founder member, treasurer and
then chairman of the BSCC. See
JKR (1988); Husain (1988).

DrJ MG (Max) Wilson
Principal medical officer at the
Ministry of Health and joint author
with G Jungner, chief of clinical
chemistry department, Sahlgren's
Hospital, Gothenburg, Sweden, of
Principles and Practice of Screening
for Disease (1968).

Dr Margaret Wolfendale
MD (b. 1931) qualified at the
Royal Free Hospital London in
1956; was appointed registrar in
exfoliative cytology to the Oxford
Regional Hospital Board in 1962.
She worked with Arthur Spriggs
and other colleagues to establish a
cytopathology service throughout
the region and participated in
many research projects, particularly
associated with cervical screening.
She was consultant cytopathologist
at Stoke Mandeville Hospital,
Aylesbury (1981-96).

143

History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000 - Biographical Notes

Professor Ciaran Woodman
is at the School of Cancer
Sciences, College of Medical and
Dental Sciences, University of
Birmingham, Edgbaston.

Dr Jian Zhou

PhD (1957-99), patent holder
with Ian Frazer (patent WO
1993/002184) for a method of
providing papilloma virus-like
particles which may be used
for diagnostic purposes or for
incorporation in a vaccine for use
in relation to infections caused by
papilloma virus, studied medicine
at Wenzhou Medical College after
the cultural revolution, taking
a master's degree at Zhejiang
Medical University where he
became interested in pathology
and in 1985, a PhD at Henan
Medical University, where he
became interested in molecular
biology and virology for human
papillomavirus (HPV) and cancer
research, receiving his degree
in 1994. He was a postdoctoral
training fellow at Beijing Medical
University; research fellow of
ICRF tumour virus laboratory,
department of pathology,
University of Cambridge; NHMRC
senior research officer, centre for
immunology and cancer research,
department of medicine, University
of Queensland, Brisbane, Australia;
assistant professor, head of
papillomavirus structure protein

laboratory, Loyola University
Medical School, Chicago, Illinois;
and Lions principal research fellow
and head of the papillomavirus
structure protein laboratory,
centre for immunology and cancer
research, department of medicine,
Princess Alexandra Hospital,
University of Queensland (1987-
99). He received grants for some
20 research projects and 1 1 patents
(1992—99). A memorial volume is
freely available at www.scribd.com/
doc/274052 1/zhou-jianprefaces-Etc
(visited 23 April 2009). See
Figure 5.

144

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Glossary

Glossary*

ABC (1995,2000)

'Achievable standards, Benchmarks
for reporting, Criteria for
evaluating cervical cytopathology',
known as 'ABC, is the report of a
working party set up by the Royal
College of Pathologists, the British
Society for Clinical Cytology
and the NHS Cervical Screening
Programme, chaired by Dr Amanda
Herbert. First published in October
1995 in the journal Cytopathology
and as NHS CSP publication no.
1, it had a second edition in 2000,
edited by Jane Johnson and Julietta
Patnick. Both editions clarified
the existing guidance on reporting
cervical smears along with proposed
performance indicators and criteria
for evaluating the performance of
cervical cytopathology. The first
edition specified a full review of
all aspects of the screening history,
including re-examination of
previous cervical smears, but this
was not included in the second
edition, whose working party
was chaired by Dr Jane Johnson
(Wilson (2002)).

adenocarcinoma of the cervix

A less frequent form of cancer than
squamous cell carcinoma, but is
becoming relatively and absolutely

more frequent. It is of glandular
origin, usually arising from the
endocervix and is more difficult to
detect by cytology and colposcopy.

biopsy, loop

An electrified wire loop used to
remove abnormal cells identified
during colposcopy. The tissue
removed is examined under a
microscope to ensure that the
abnormal cells have been removed.

biopsy, punch

A biopsy performed using a punch,
an instrument to cut and remove a
disk of tissue.

British Society for Clinical
Cytology

Mary Egerton, Moira Murray,
Freda Osmond-Clarke and Erica
Wachtel, having attended the first
International Congress on Cytology
sponsored by the International
Academy of Gynaecological
Cytology in Vienna in September
1961 considered that Great Britain
was lagging far behind the US and
Europe in the development of the
speciality and that a society would
help to establish and promote the
practice of cytology throughout
the UK. Consequently, a meeting
was held at the Royal Society of

* Terms in bold appear in the Glossary as separate entries

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000 - Glossary

Medicine on 1 December 1961
to discuss the formation of a
society. A working party chaired
by C W Taylor (Birmingham)
formulated statutes for a registered
charity to promote the growth and
development of clinical cytology
in the UK and the organization of
scientific meetings. Membership
was open to all registered medical
practitioners interested in
cytology. See www. clinical cytology.
co.uk/membership/history
asp#background (visited
3 December 2009).

carcinoma in situ (CIS)
An epithelium which displays
disturbed differentiation
throughout its thickness, but
has not invaded the basement
membrane. Formerly classified
as preinvasive cancer, later in the
category of pre-malignant change
along with severe dysplasia. See
also CIN.

cervical intraepithelial neoplasia
(CIN1,-2and-3)

A cytology grading system
describing the pre-malignant
change of cervical epithelium
characterized by a proliferation
of undifferentiated basal cells
extending varying distances from
basement membrane to surface.
CIN1: undifferentiated stem cells
in lower third of epithelium (mild
dysplasia); CIN2: undifferentiated

cells in lower two-thirds of
epithelium (moderate dysplasia);
CIN3: a lesion composed of
primitive basal cells in the entire
thickness of epithelial cells (both
severe dysplasia and carcinoma in
situ). See Ri chart (1964).

cervical smear, smear test,
Pap smear

A technique developed for use on
women by Dr G N Papanicolaou
in the 1920s, including a staining
method named after him, to
check the health of the cervix and
detect early changes in the cells
of the cervix, which may develop
into cancer. A small disposable
spatula (Figure 6) is used to take a
sample of cells from the surface of
the cervix, which are then spread
onto a glass slide and sent to a
laboratory to be examined under a
microscope. The infected cells can
be seen in Figure 4. This test was
phased out in the UK by the end of
2008 and replaced by liquid-based
cytology (LBC).

condylomata acuminata

A papilloma consisting of central
connective tissue cores of tree-like
organization covered by epithelium
displaying papillomavirus infection.
The term condyloma refers to
a clinically obvious filiform
fungating papillomas of genital
skin or mucous membranes and is
infectious.

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Glossary

cotton-tail rabbit papillomavirus
(CRPV)

Also called the Shope
papillomavirus.

dyskaryosis

A cytological change in the nuclei
of cells, which correspond to the
abnormal cells seen histologically in
CIN: mild (superficial), moderate
(intermediate) and severe (parabasal
and basal).

dysplasia

A reaction to damage to the
epithelial surface of the cervix,
which may disappear spontaneously
or following treatment, as described
by Reagan and Patten (1962). The
term is more frequently used to
describe precancerous changes now
described as CIN and is still used in
some places outside the UK. Mild,
moderate and severe dysplasia
correspond to mild, moderate and
severe dyskaryosis and to CIN 1 , 2
and 3.

genital warts

A benign epithelial proliferation

caused by human papillomavirus

(HPV) almost always caused by

types of the virus that do not cause

cancer.

electrophoresis

A process by which molecules,
such as proteins, DNA or RNA
fragments, can be separated
according to size and electrical

charge by applying an electric
current to them. Each kind of
molecule travels through the
medium at a different rate,
depending on its electrical charge
and molecular size.

herpes simplex virus
(HSV-I and -II)

HSV- 1 is responsible for oral
infections ('cold sores') acquired
mainly in childhood. HSV-2 is more
often associated with infection in
the genital tract and is transmitted
by sexual contact. However, this
separation is not absolute. HSV
type-specific antibody tests can
be used to identify past infection
with a given antibody type using
a monoclonal antibody blocking
ELISA test (enzyme-linked
immunosorbent assay).

human papillomaviruses (HPV)

A family of more than 200 viruses
that cause various growths,
including plantar warts and genital
warts, both of which are filterable
and easily transmitted. Genital
warts are classed as a sexually
transmitted infection (STI)
acquired mainly through sexual
contact, often called condylomata
acuminata. These are soft and
often occur in clusters, internally
or externally. The virus may be
present and transmittable in the
absence of warts. Problems can
result from untreated warts, which

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000 - Glossary

can grow quite large, or, in rare
cases, from infection of an infant
during delivery. In addition, certain
types of HPV are known to be
'oncogenic' and are associated with
various forms of cancer, including
cervical, vulval and anal carcinoma
as well as certain types of head and
neck cancer. See also vaccine.

hybrid capture assays

A technique used to detect and
monitor viral infections. It involves
hybridisation of a single strand
of target DNA to specific RNA
probes, with the hybrid captured
on a solid surface and detected
using chemiluminescence. It is
more sensitive than conventional
Pap smears for detecting HPV
infection and the absence of HPV
detection correlates with a lack of
dysplasia. See also note 26.

hybridization

The amalgamation of two single
complementary nucleic acid strands
by heating to form a duplex,
detected in a liquid or solid phase.
Southern blotting and dot blotting
are forms of hybridization.

Intercollegiate Working Party
on Cervical Cytology Screening
(1987)

Guidelines produced by a
working party of eight under
the chairmanship of Professor
Frank Sharp, following the
DHSS's approach to the RCOG

to look at clinical aspects of
cervical cytopathology screening
programme in the UK.
Representatives were from the
Royal College of Obstetricians
and Gynaecologists, Pathologists,
General Practitioners and the
Faculty of Community Medicine.
Their recommendations included:
effective cervical screening
programmes in all district health
authorities; every adult woman
should be screened at three-year
intervals (20-64 years) with no
upper age limit for those never
having a smear; all women should
receive the results of their tests; and
monitoring the outcome of actions
and feedback be implemented
(page 31).

interval cancer
Detected in the 3- or 5-year
interval between test dates, where
the previous episode was closed
with no diagnosis of cancer.

koilocyte

A cell with a shell-like vacuole
that looks 'empty' on cytological
or histological preparations but
contains mature infective HPV
virus (high-risk or low-risk). See
Ayre (1949); Koss (1987); Figure 4.

liquid-based cytology (LBC)

A technique to take cells from the
cervix using a special brush, which
is rinsed into a small container
of preservative or the head of the

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Glossary

brush snapped off and put into
the container. The container is
sent to the laboratory, where the
cells are put onto a glass slide.
Liquid-based cytology fixes the
cells immediately and removes
blood and inflammatory cells.
Introduced in the UK in 2000, it
was recommended by the National
Institute for Clinical Excellence in
2003 and replaced the Pap smear
throughout the UK in 2008.
The feasibility of HPV triage for
borderline cytology, to correctly
identify those women who need
colposcopy, is supported by the
introduction of LBC, which enables
an HPV test to be carried out on
the same cytology sample and to be
restricted to those samples where
the cytology result has proved
abnormal. See also cervical smear.

Ministry of Health 1966 Circular

Mr Kenneth Robinson's press
conference on 21 October was
reported in the BMJ((1966) ii:
1083) following the earlier Circular
(Ministry of Health (1966)). The
press release indicated the progress
in the development of a cervical
screening service (101 000 women
aged 35 and over in England and
Wales tested monthly in December
1966 compared with 39 000 in
December 1964; 457 trained
technicians in June 1966 compared
with 150 in December 1964). Mr
Stanley Way in a letter to the BMJ

in February 1967 (Way (1967))
disputed the accuracy of these
details and noted that the new pay
agreement for GPs from April 1967
would include special payments for
smear testing, although the funding
of the expansion of the cervical
screening services were to be borne
by the ratepayers. Way described
ministry involvement as likely to
create 'a "ministry camel" (a camel
being an animal that looks like
a horse which was designed by a
committee).'

NHS Cervical Screening
Programme

Cervical screening programmes
started in the NHS in 1964,
although haphazard in coverage,
and became a nationwide service in
1988 with a computerized call and
recall system. The policy objective
was to reduce mortality by regular
screening (all women aged 20—64
every five years and those over 65
who have not had two consecutive
negative smears in the preceding
ten years (DHSS (1988): paras
2—4), although moves were made
to 'rationalize' the service in 1982
by offering two screenings to
women aged 22—35, as a result of
the Committee on Gynaecological
Cytology (Penfold (1982)). See
note 155; see also Blanks et al.
(2000); www.cancerhelp.org.uk/
help/default. asp?page=9596#tests
(visited 13 July 2009).

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000 - Glossary

p53 (protein 53 or tumor
protein 53)

A gene discovered in 1979 by
Lionel Crawford, David Lane,
Arnold Levine, and Lloyd Old,
that responds to DNA damage by
stopping the cell cycle and turning-
on DNA repair mechanisms to fix
the damage, which, once repaired,
allows the cell to re-enter the cell
cycle as normal. Sometimes known
as the guardian angel gene.

Pap smear, see cervical test

papilloma

A benign epithelial tumour

characterized by a branching

structure.

papillomavirus

Small oncogenic DNA viruses
that cause warty proliferations on
epidermal and mucosal surfaces.

polymerase chain reaction (PCR)

A fast technique for making an
unlimited number of copies of
any piece of DNA and used to
demonstrate the presence of HPV
DNA. For the background to this
1986 discovery for which Professor
Kary Mullis shared the 1993 Nobel
Prize for Chemistry, see http://
nobelprize.org/chemistry/
laureates/ 1 993/mullis-lecture.html
(visited 4 June 2009).

Scottish cervical screening

Cervical screening was introduced
in Scotland in I960 on a limited

scale under the NHS, although
not introduced as a population-
based programme. In 1978
committees were established by
the UK Department of Health
and a review was carried out in
Scotland resulting in the Strong
Report (Scotland, Scientific Services
Advisory Group, Histopathology
Subcommittee (1988)). A
nationwide cervical screening
programme was introduced in
Scotland in 1988 and the NHS
Boards and Trusts introduced
computerized call/ recall systems in
1988/9. Note: In July 1985, the
Lothian Health Board put a freeze
on smear tests because existing
laboratory facilities were swamped
with a backlog of 10 000 un-read
slides. In response to public concern
about the freeze, Edinburgh District
Local Health Council organized
a public meeting, jointly with
the Edinburgh District Council
Women's Committee, in October
1985, followed by the creation
of an action group, the 'Cervical
Smear Campaign' (see www.lhsa.
lib.ed.ac.uk/catalog/pdfs/GD3 1 .pdf
(visited 3 February 2009)). In 1992
Dr Ian Duncan chaired a group to
advise the National Coordinating
Network on the management of
14 distinct problems, including
the use of quality assurance and
internal audit as well as managing
patients with HPV and CIN. These

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Glossary

recommendations were reviewed in
1997. See Jordan et al. (eds) (1982);
Mant et al. (1988); Schwartz et al.
(1989).

Southern blotting method
A method for detecting the
presence of DNA or RNA, using a
radio-labelled probe, which permits
the detection of a single copy of a
human gene in a sample of DNA
fragments, separated by size by
gel electrophoresis, and named
after Professor Sir Edwin Southern
whose invention this was in 1975.
The transfer from a gel to retentive
paper (blotting with paper towels)
facilitates the physical transfer of
the nucleic acids.

vaccine (Gardasil, Merck/Sanofi
Pasteur; Cervarix, GSK)
Following on from work done
by Dr Jian Zhou on VLPs,
Merck led the basic and clinical
research programmes leading to
the discovery and development
of Gardasil, which was approved
by the US FDA for clinical trials
on women in 1997 and for use in
humans in 2006 (and European
Union marketing authorization).
Gardasil protects against about 70
per cent of human papillomavirus-
related cervical cancers (types 6, 1 1,
16, and 18, including two strains
that are responsible for nine in 1
cases of genital warts). The Cervarix
vaccine was developed by GSK

using the baculovirus technology
to produce VLPs for HPV16 and
-18 with a proprietary adjuvant to
give a strong immune response.
This vaccine was introduced in the
UK in a national programme in
2008 following the completion of
successful clinical trials (phase 2 and
3) in 2006, with European Union
marketing authorization in 2007.
See note 3. Some disappointment
has been expressed about the UK's
choice of vaccine (Kmietowicz
(2008)).

Wilson andjungner's classic
criteria for disease screening,
report for the World Health
Organization in 1968:

1. The condition sought should
be an important health
problem;

2. There should be an accepted
treatment for patients with
recognized disease;

3. Facilities for diagnosis and
treatment should be available;

4. There should be a latent or
early symptomatic stage;

5. There should be a suitable test
or examination;

6. The test should be acceptable
to the population;

7. The natural history of
the condition, including
development from latent to

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History of Cervical Cancer and the Role of the Human Papillomavirus, 1 960-2000 - Glossary

declared disease, should be
adequately understood;

8. There should be an agreed
policy on whom to treat as
patients;

9. The cost of case finding
(including diagnosis and
treatment of patients
diagnosed) should be
economically balanced in
relation to possible expenditure
on medical care as a whole;

10. Case finding should be a
continuing process and not a
'once and for all' project.

See Wilson and Jungner (1968):
26-39; Shechy etal. (2009);
Andermann etal. (2008).

152

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Index

Index: Subject

ABC report (RCPath et al, 1995,

2000), 60, 145
Aberdeen, 6, 8, 13, 17, 59, 61, 69,

76-7
acquired immunodeficiency syndrome

(AIDS) see AIDS/HIV infection
adenocarcinoma, cervical, 25, 145
advertising, direct-to-consumer, 69
AIDS/HIV infection, 5, 25, 53
American Cancer Society, 1 8
American Journal of Obstetrics and

Gynecology, 31, 33
American Society of Cytopathology, 86
animal models, 38
antibody response (humoral

immunity), 45, 47, 48-9
anxiety, screening-related see cervical

cytology screening
ARTISTIC trial, 50
Atlas of Exfoliative Cytology

(Papanicolaou, 1954), 34, 35
atypical squamous cells of

undetermined significance (ASC-
IIS), 74, 75
Australia, 29-30, 31, 33, 36, 37, 44,

45, 46, 84-5
automated cervical screening, 7, 15,

23, 90-2
Aylesbury, 22, 57
Aylesbury spatula, 54, 89-90
Ayre spatula, 54

baculovirus expression system, 46
Banbury Centre conference (1985),
Cold Spring Harbor Laboratory,
Long Island, New York, NY, 20
basal carcinoma, cutaneous, 42
biomedical scientists (BMS), 23-4, 60
see also laboratory technicians, medical

biopsy, cervical, 36, 37
loop, 145
punch, 3, 145
Birmingham, 11, 18, 21
BMJsee British Medical Journal
BMS see biomedical scientists
bovine papillomavirus (BPV), 39
breast cancer screening, 62-3
Bristol, 7, 8, 73
British Colposcopy Group, 27
British Columbia, Canada, 17, 18, 52,

56,74
British Empire Cancer Campaign

(Cancer Research Campaign from

1970), 88
British Journal of Obstetrics and

Gynaecology (BJOG from 2000),

80
British Medical Journal (BMJ), 10, 14,

19,30,51,61,67
British Psychosocial Oncology Society,

76
British Society for Clinical Cytology

(BSCC), 14, 15, 16, 145-6
annual scientific meetings, 14, 18,

28
presidents, 9
qualifications, 7, 8
training sessions, 11, 14
British Society for Colposcopy and

Cervical Pathology (BSCCP), 24,

25, 26, 28
Brussels, Belgium, 4
BSCC see British Society for Clinical

Cytology
BSCCP see British Society for

Colposcopy and Cervical

Pathology

153

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Index

Cambridge, 44
Cambridge Instruments,

Cambridge, 7
Campbeltown, Kintyre, 6
Canada, 17-19, 52-3, 56, 61, 74
cancer viruses, 39, 40
carcinoma in situ (CIS), cervical, 25,

55-6, 146
CD4TH1T cells, 48
CD8 T-cells (cytotoxic T cells), 45, 47
cell culture systems, 38
cell-mediated immunity, 45
Cervarix (GSK), 5, 43, 151

see also vaccines, HPV
cervical cancer

age-related incidence, 57, 58, 64-5
causal role of HPV, 31-9, 41, 49,

50-1, 84-6
changing risk/incidence, 55, 57, 61,

62, 64-5
interval, 57, 61-2, 149
mechanisms of induction by HPV,

39-42
natural history, 37-8, 55-6, 70,

83-7
prevention, 5, 43, 58, 83
progression of CIN to, 70
risk factors, 31, 33
unknown male factor, 29-34
cervical carcinoma in situ (CIS) see

carcinoma in situ (CIS)
cervical cytology screening, 51-67
age range, 17, 54-5, 56
anxiety, screening-related, 66, 67,

74, 75-7
automated, 7, 15,23,90-2
call-recall systems, 22, 52, 60, 62-3
compliance/coverage, 17, 52, 53,

58,61,62,63-4,77
cost-effectiveness, 57
development, 6-14, 17, 83-7,
88-92

effectiveness, 10, 15, 17, 18-19,

51-8,59,60
HPV testing in triage, 71-5
information provision, 79-80
international perspective, 16-19,

52-6
intervals, 7-8, 13, 18-19, 52,

54-5, 56
laboratories, 21-4
medical staff see cytologists/

cytopathologists
monitoring/audit, 57, 61-2, 65
non-medical staff see cytoscreeners,

non-medical
older women, 69-71
opportunistic, 54-5, 56, 59
organization, 10—12, 14, 53—4,

58-67
post-vaccination era, 53, 78
public health impact, 61-2, 64-5
quality control, 28, 29, 60-2, 66-7
reasons for failure, 28
sensitivity, 50, 52
UK national programme .fee NHS

Cervical Screening Programme
young women, 53, 56, 61-2
see also cervical smears
cervical intraepithelial neoplasia

(CIN), 37, 146
colposcopy, 24, 25
HPV16, 41

natural history, 37-8, 55-6, 70
treatment, 25
cervical intraepithelial neoplasia grade

1 (CIN1), 37, 146

cervical intraepithelial neoplasia grade

2 (CIN2), 37, 80, 146
cervical intraepithelial neoplasia grade

3 (CIN3), 49-50, 57-8, 146
HPVl6and, 38, 42, 49, 71
progression to cancer, 56, 70
rates, 55, 57, 59

154

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Index

sensitivity of cytology, 28, 50
cervical mucus, 37

cervical smears (Pap smears), 5-6, 22,
83-4, 146
borderline/mild changes, 25, 28,

37-8
colposcopy for abnormal, 24-5
devices for taking, 54, 89-90
follow up of abnormal, 14, 15,

53-4, 60, 88
HPV testing of borderline, 71-5
HPV-related changes, 34, 35, 50-1,

84-5
litigation, 66

opportunistic, 54-5, 56, 59
screening standards, 60
suspicious, 24-5
training in interpretation, 11, 12,

21,88
treatment vs surveillance of

abnormal, 76-7
see also cervical cytology screening
Cervifip (Cytoscan 110) system, 9 1
Charing Cross Hospital, London, 92
China, 43, 44, 45, 86
CIN see cervical intraepithelial

neoplasia
Colombia, 75
colposcopists, 25, 60, 61
colposcopy, 12, 24-9, 36, 37, 72, 76-7
Colposcopy and Gynaecological Laser

Surgery, 24-6
condylomata see warts
condylomata acuminata see genital

warts
Coronation Street (ITV), 66-7
cost-effectiveness, cervical screening,

57
cotton-tail rabbit papillomavirus

(CRPV), 40, 47, 147
Coulter cell counter (Coulter Corp.,
Miami, Florida), 18, 90

counselling, 76

CRPV see cotton-tail rabbit

papillomavirus
cytologists/cytopathologists, 60
reminiscences, 6-8, 10, 11-13,

14-21, 88-92
second generation, 29
training, 6-7, 8, 10, 11-12, 14,

15-16
see also pathologists
cytopipette, irrigation, 90
cytoscreeners, non-medical, 7, 8, 10,
22-4, 60
assessment of competence, 64
perceptions of, 21
qualifications, 7, 8, 16, 21-2
recruitment, 23-4
training, 7, 8, 11, 21
cytotoxic T cells (CD8 T-cells), 45, 47

Denmark, 17

densitometer, 7; see also Quantimet
Department of Health, 59, 60, 73
Department of Health and Social
Security (DHSS), 28-9, 90-1

Forrest committee report (1986), 62
Department of Health, Scotland, 28-9
depression, 77
developing countries, 75
DHSS see Department of Health and

Social Security
DNA

herpes simplex virus (HSV), 30, 34

human papillomavirus (HPV), 39,
43

neoplastic cells, 91-2

sperm, 29, 30
Dundee, 8, 69
dyskaryosis, 35, 59, 60, 147
dyskeratosis, 34
dysplasia, 147

155

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Index

E5, E6 and E7 proteins, 40
Eastern Europe, 55
Edinburgh, 29, 38, 91
education, about HPV, 78, 80
electrophoresis, 147
epidemiological studies, 32-3,
48-50,51

Faculty of Community Medicine,

26,28
female screeners

medical, 6-7, 8-10, 14-15
non-medical, 21-3
Feulgen hydrolysis technique, 91-2
Finland, 17, 34, 49, 52, 54-5, 56, 61,

7A, 75, 84
flow cell analysers, 9 1
Forrest committee report (1986) see

DHSS

GW^«7(Merck/Sanofi Pasteur), 43, 151

see also vaccines, HPV
general practitioners (GPs), 22, 25,

63-4
genital warts (condylomata

acuminata), 25, 31, 146, 147
cytological changes, 36-7, 84
virus type differences, 38
Germany, 27, 38-9
Glasgow, 6, 8, 34, 38, 39-40
GlaxoSmithKline (GSK), 5, 79
glucose-6-phosphate dehydrogenase

(G6PD), 91
GSK see GlaxoSmithKline
Guidelines for Clinical Practice and

Programme Management (Duncan,

1992, 1997), 24, 65
Guy's Hospital, London, 37, 61-2
Gynaecological Visiting Society of Great

Britain and Ireland (GVS), 26
gynaecologists, 6, 7, 14, 15, 25, 42,

50-1, 86

haematologists, 7,15
halo cells, 34, 84

see also koilocytes
Hammersmith Hospital, London, 1 1
Hammersmith study, 72
HART (HPV in addition to routine

testing) study, 68, 72
HC-I, HC-II see hybrid capture assays
Health Technology Assessment

programme, 73
hepatitis B vaccine, 46
herd immunity, 45
herpes simplex viruses (HSV-1 and -2),

30,31,33-4,41, 147
Hillingdon Hospital, London, 12
histones, 30

histopathologists, 15, 16, 42, 61
hit and run hypothesis, 34
HIV infection/AIDS, 5, 26, 53
'hockey stick' phenomenon, 64—5
Holloway Prison, London, 37
Home Office, 45
Hong Kong, 80

hormone replacement therapy, 69-70
HPV see human papillomavirus
HSV see herpes simplex viruses
human immunodeficiency virus

infection see HIV infection/AIDS
human papillomavirus (HPV), 3,
29-51, 67-81, 147-8
as cause of cervical cancer, 29-39,

41,49, 50-1, 84-6
awareness, direct-to-consumer

advertising, 69
clearance of infection, 49-50, 70
cytopathological effects, 33, 34, 35,

36-8, 50-1
entry into cervical cells, 37, 85-6
epidemic of infection, 64, 65
epidemiology, natural history and

importance, 49-51
genital infection see genital warts

156

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Index

immune responses, 46—9

international meetings, 6, 38

lateral, 41

mechanisms and genes, 39-42

in normal tissue, 41—2

typing systems, 68

vaccination see vaccination, HPV;

vaccines, HPV
viral DNA in cell specimen, 38
warty atypia, 36-7
human papillomavirus (HPV) testing,
67-75, 77
funding issues, 73, 75
in triage and screening, 71-5
see also hybrid capture assays
human papillomavirus type 6 (HPV6),

38,49
human papillomavirus type 1 1

(HPV11), 39, 49
human papillomavirus type 16
(HPV16), 25, 26, 37, 71
antibody response, 48-9
CIN3 and, 38, 42, 49, 71
discovery, 34-9
in normal tissue, 41
screening, 72
transforming proteins, 40
vaccine development, 43-4, 80
human papillomavirus type 18

(HPV18), 34-9, 40, 42, 43,72,
80
human papillomavirus type 31

(HPV31), 72
human papillomavirus type 33

(HPV33), 72
human papillomavirus type 58

(HPV58), 80
humoral immunity (antibody
response), 45, 47, 48-9
hybrid capture assays, 68, 71, 148
version 1 (HC-I), 68
version 2 (HC-II), 68-9, 74

hybridization, 37, 67-8, 148
hymen, 'strip and stretch procedure,
36

IARC see International Agency for

Research on Cancer
IBM, 7

image analysis, computerized, 7, 90-1
immune responses, 43, 45, 46—9
immunotherapy, 48
Imperial Cancer Research Fund

(ICRF) coordinating committee

on cervical screening, 19-21, 63
Imperial College London, 12
in situ hybridization, 67-8
in vitro models, 38
informed choice, 79-80
Institute of Biomedical Science

(IBMS), 21-3
Institute of Virology, Glasgow, 38
Institute Pasteur, 38
Intercollegiate Working Party on

Cervical Cytology Screening, 26,

28-9, 62, 148
International Agency for Research on

Cancer (IARC), Lyons, France,

18-19,51
International Papillomavirus

Conferences, 6
International Papillomavirus Society, 6
Intersociety Cytology Council, 86
interval cancers, 57, 61-2, 148
Italy, 75, 83

Karolinska Institute, Sweden, 19
King George V Memorial Hospital,

Sydney, 35, 37
knitting analogy see NHSCSP
koilocytes, 34, 35, 37, 50-1, 84-5,

148
see also halo cells
koilocytosis, 34

157

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Index

LI virus coat protein gene, 39, 43-5

L2 protein, 80

laboratories, cervical cytology

screening, 214
laboratory technicians, medical, 10,

11,21
see also biomedical scientists;

cytoscreeners, non-medical
Lancet, 29, 30, 68

'Death by incompetence' editorial

(1985), 14, 19,60
Latin America, 53
LBC see liquid-based cytology
liquid-based cytology (LBC), 23, 50,

148-9
litigation, 66
Liverpool, 73
Lyons, France, 38

male

factor, unknown, 29-34

high risk, 3 1

screeners, 12-13
Manchester, 11,73
Marks and Spencer, 89
media, mass, 66-7
Medical Research Council (MRC),

17-18,37,73,77,91
Merck, 79
Ministry of Health, 11, 89, 90

1964 Circular, 11

1966 Circular, 149
molecular techniques, 37, 38-9, 40,

67-9
mortality, cervical cancer, 19, 55, 58,
59-60, 83

effect of cervical screening, 52, 64-5

social class differences, 31, 32
mouse fibroblasts, 34
MRC see Medical Research Council
MRCPath examination, 15, 16

MSc in clinical cytology, 12

National Cancer Institute of Canada, 1 8

National Cervical Cancer Audit, 61-2,

65,66
Netherlands, 68, 75
neutralizing antibodies, 47, 80
New Zealand, 55-6, 61
Newcastle, 11, 12-13
NHS Central Register, 52, 60, 62
NHS Cervical Screening Programme
(NHSCSP), 17,51-67,149

basis for, 21,26, 28-9

effectiveness, 58, 60, 61, 65

HPV sentinel sites, 72-3

National Coordinating Network, 29

organization, 58-67

public health impact, 62, 64-5

setting up programme, Sir Muir
Gray on, 62-3

training logbook, 8
Norway, 17, 52, 54, 61
Nottingham, 3-4

occupation of husband, 31, 32, 33
older women, 58, 68, 69-71
opportunistic screening, 54-5, 56, 59
ovulation, 37
Oxford, 10, 15, 16,88

p53 protein, 43, 150
Pap smears see cervical smears
papilloma, 150
papillomaviruses, 40, 150

animal, 46-7, 48

see also bovine papillomavirus;
human papillomavirus
PAPNET automatic screening method,

23
patents, 46
pathologists, 16, 22, 36, 60, 64

attitude to cervical screening, 14

158

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Index

role in screening, 11, 12, 18, 86
see also cytologists/cytopathologists

PCR see polymerase chain reaction

polymerase chain reaction (PCR), 68,
71, 150

pRB, 40

Presse Medicate, 83

protamine, 30

psychosocial issues, 75-7

public health, 6, 25, 26

quality control, 28, 29, 60-2, 66-7
Quantimet image analyser (Cambridge
Instruments), 7, 90-1

Radcliffe Infirmary, Oxford, 15, 88
register, NHS central, 52, 60, 62
risk factors, cervical cancer, 31, 33
Royal College of General Practitioners,

26,28
Royal College of Obstetricians and

Gynaecologists, 26, 27, 28, 50-1
Royal College of Pathologists, 15-16,

26,28
Royal Free Hospital, London, 10, 11, 26
Royal Marsden Hospital, London, 10,

18,90

Scandinavia, 17, 52, 61

Scottish cervical screening, 6, 8-10,

13,69,70, 150-1
screening

cervical see cervical cytology

screening
distress, 76

related anxiety, 66, 67, 7A, 75-7
Wilson and Jungner criteria, 55,

151-2
see also cervical cytology screening
serological studies, 47, 48-9
sexual activity, adolescent girls, 35-6
sexual behaviour, 31

sexual intercourse, early age of first, 31,

33, 35-6
sexual partners

new, older women, 69-70
number of, 33, 35-6
sexually transmitted diseases (STDs),

5,25-6,31,36
Sheffield Cervical Cytology Service, 73
Shope papillomavirus see cotton-tail

rabbit papillomavirus
shopping bag screeners, 21
skin cancer, non-melanoma, 41
smear tests see cervical smears
smoking, cigarette, 31
social class differences, 30, 31
Southampton, 60, 61-2
Southern blotting, 37, 38, 151
Southmead Hospital, Bristol, 7-8
spatulas, 54, 89-90
sperm, in cervical cells, 29-30
squamous cell cancer, cutaneous, 42
squamous metaplasia, 29-30, 36
St Bartholomew's Hospital, London

(Bart's), 27
St Mary's Hospital Medical School,

London, 12
St Stephen's Hospital, Chelsea,

London, 7, 18, 89,92
St Thomas' Hospital, London, 14, 16,

49, 61-2
Standards and Quality in Colposcopy

(Luesley, 1996), 65
sterilization, forced, 27
Stoke Mandeville Hospital, Aylesbury,

13,23
SV40, 39, 43
Sweden, 17, 19,75
Syrian hamster fibroblasts, 34

T cells, 45, 47-8
Taking Uterine Cervical Smears
(Macgregor, 1981), 16

159

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Index

TOMBOLA (Trial of Management of
Borderline and Other Low Grade
Abnormal smears), 73, 77
training, 1 1, 60

medical cytologists, 6-7, 8, 10,

11-12, 14, 15-16
non-medical cytoscreeners, 7, 8, 11,
21
transformation, cell, 34, 40, 41, 42

UK Trial of Early Detection of Breast

Cancer, 62
United States (US), 5, 11, 33, 45, 52,

61,74,86-7
University College Hospital (UCH),

London, 31
US see United States
uterine cancer, unspecified, 19, 83

vaccination, HPV, 51

cervical screening after introduction,
53,78

prophylactic, 45, 48

therapeutic, 48, 80

UK national programme, 5
vaccines, HPV, 5, 78-9, 80-1, 151

clinical trials, 4

development, 43-8

polyvalent, 78-9

vaccinia virus constructs, 43, 44
virginal girls, study on, 35-6
virology, 38
virus-like particles (VLPs), 43-6, 47,

48,80
VLPs see virus-like particles

Walton Committee Report, 1976, 19,

53
warts (condyloma)
cutaneous, 38, 43, 47
genital see genital warts
viruses see human papillomavirus;
papillomaviruses
warty atypia, 36-7, 84
Wellcome Trust, 3, 4
Wilson and Jungner screening criteria,

55, 151-2
World Health Organization (WHO),
51, 151-2

young women

cervical cancer risk, 55, 57, 59-60,

64
cervical screening, 53, 56, 61-2
HPV infection, 36, 37
HPV vaccination, 5, 151

Zeiss colposcope, 27

160

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Index

Index: Names

Biographical notes appear in bold

Acheson, Sir Donald, 63
Ahluwalia, H S, 18
Almeida, June, 38
Andrew, James, 12, 27
Attwood, M E (Betty), 1 1
Aurelian, Laura, 33-4
Ayre, J Ernest, 1 1 , 84

Babe , Aureli, 6, 83-4

Baird, D, 59

Bamforth, J, 9

Bell, Stephen, 76-7

Beral, Valerie, 16-17, 31, 32, 36, 44,

45, 56, 58, 62, 63, 70, 129
Beresford, J M, 76
Best, Jenny, 49
Blair-Bell, William, 27
Boddington, Michael, 16, 28, 88, 89
Bodmer, Sir Walter, 19,65
Bourne, Gordon, 27
Boyes, David, 18,23
Bray, F, 61
Brinton, Louise, 20
Broker, Thomas, 20
Brown, C L, 28
Buckley, J D, 32-3
Burghardt, Erich, 20
Butler, Blanche, 1 1

Cairns, J, 20
Cameron, C B, 18
Campion, Michael, 31, 71, 76
Campo, Saveria, 38-40, 41-2, 48,

80, 129
Cason, John, 49
Chamberlain, Jocelyn, 16-17, 19, 28,

52, 55-6, 62-3, 64, 65, 129-30
Cochrane, Archie, 18, 19, 59

Coleman, Dulcie, 11-12, 22, 26, 33,

34, 37-8, 49, 59, 64, 86, 130
Cook, Gary, 19, 65

Coppleson, Malcolm, 27, 29, 31, 35-6
Crabbe, Geoffrey, 10
Crawford, Lionel, 39, 41, 43-5, 46,

49, 130
Crompton, Archie, 24, 27, 36—7
Cubie, Heather, 38, 45-6, 48-9, 67-9,

75, 130-1
Cuzick, Jack, 19-21, 31, 37-8, 50, 57,

61,63,65,68,71-2, 131

Day, Nicholas, 18-19, 21, 56, 131

Diodes, 5

Doll, Sir Richard, 18, 19, 20, 37, 88

Draper, Gerald, 19, 65

Duguid, Helen, 8

Duncan, Ian, 8-10, 24-6, 28-9, 53,

65, 69-70, 131-2
Dunn, A E G, 84
Durfee, G R, 36, 84

Egerton, Mary, 10
Einarson L, 90
Erskine, Stephen, 19, 65
Evans, D M D, 28

Farmery, Elaine, 63
Ferreira, H, 18
Fidler, Herbert, 18, 86
Fisher, Hugh, 19, 65
Fortin, R, 34, 84
Fox, Harold, 28
Frazer, Ian, 44, 45, 132

Gervaize, P A, 76

Gissmann, Lutz, 38-9, 85, 132-3

161

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Index

Goldie, Sue, 56

Graham, Ruth, 12, 86

Gray, Sir Muir, 29, 60, 61, 62-3, 65,

133
Gray, Winifred, 14-16, 66, 133
Green, Herbert, 55-6
Griffiths, Rod, 19, 65
Grubb, Chandra, 11, 14
Grussendorf-Conen, Elke-Ingrid, 20

Hakama, Matti, 74, 133

Halliwell, Alma, 66-7

Haran, David, 19, 65

Hausen, Harald zur, 20, 38-9, 44, 85,

86-7, 133-4
Havelock, Christine, 19, 65
Havelock, P B, 28
Herbert, Amanda, 14, 23-4, 28, 29,

54-5,57-62,64,71,73,134
Hill, K R, 9

Hinselmann, Hans, 26-7, 33
Hollingworth, Tony, 71
Howley, P M, 20
Hudson, E A, 28
Hughes, Helena, 6, 8, 28
Husain, O A N (Nasseem), 6-7, 9, 17,

19, 65, 86, 89-92, 134

Jankey, N, 18

Jarrett, Bill, 39-40

Jenkins, David, 3-6, 8, 10-11, 16, 22,

37,41,42,51,69,70,73,79, 80,

81, 134-5
Johnson, Anne M, xix— xxiii, 135
Johnson, Jane, 60, 145
Jordan, Joe, 24, 27

Kay, Humphrey, 10
Kessler, Irvine, 33-4
Kirkland, James, 33
Kitchener, Henry, 40, 73

Knox, E George, 18, 19-21, 60, 65

Kolstad, Per, 27

Koss, Leopold G, 20, 36, 83-7, 136

Langley, Fred, 36-7

Laverty, C R, 84-5

Lewis, Frank, 7

Little, Julian, 77

Lorincz, Attila, 20, 67, 68, 136

Luesley, David, 50, 65

McCaffery, K, 77

McCance, Dennis, 31, 37, 51, 80-1
McCluggage, Glenn, 3-4, 6, 14, 16,
21, 23, 24, 26, 29, 32, 34, 39, 46,
49,51,61,66,67,68,71,72,73,

74, 81, 137
McDougall, K, 34
Macfarlane, Gwyn, 88
McGoogan, Euphemia, 8, 29, 137-8
Macgregor, Elizabeth, 8, 9, 13-14, 17,

33, 59, 61, 136
Mackenzie, Campbell, 6
Mackenzie, Elizabeth, 6-8, 13, 28, 59,

60, 136-7
McLaren, Hugh, 1 1
Macnab, Joan, 34, 41, 137
McPherson, Ann, 19, 28, 65
Mair, James, 6
Marais, Dianne, 49
Marshall, T, 28
Meisels, Alex, 33, 34, 84
Melnick, J L, 30
Miller, Anthony (Tony), 16-19, 23,

32-3,34,51,52-3,56,74,

75, 138

Moir, John Chassar, 88
Montaigne, Michel de, 87
Murdoch, John, 41

Navratil, Ernst, 27

162

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Index

Ogilvie, Marie, 38, 84
Oriel, David, 31,38

Papanicolaou, George, 5, 6, 11, 12, 35,

83-4, 85, 86, 138
Patnick, Julietta, 60, 61, 63, 79
Patten, Stanley, 36, 37, 86
Peto, Julian, 42, 49-50, 51, 52, 56, 68,

70,71,78-9, 139
Peto, Sir Richard, 20
Pike, Catherine, 14, 16, 29, 62, 139
Ponten, Jan, 19
Purola, E, 34, 84
Pyke, Margaret, 72

Quinn, M, 61

Raffle, Angela, 79

Rawls, W E, 30

Reagan, James, 86

Reid, Bevan, 29, 30, 31, 35-6, 37

Reid, Richard, 20

Richart, Ralph, 33-4

Rigoni-Stern, Domenico, 31, 83

Robb-Smith, H T, 88

Robertson, J H, 61

Robinson, Kenneth, 14

Rose, Bob, 46

Rotkin, Isadore, 31, 33

Roy, M, 34

Rue, Dame Rosemary, 15, 139

Sagiroglu, N, 36

Sasieni, Peter, 19, 50-1, 53-4, 55, 56,

57, 58, 63-5, 66-7, 70, 73-4, 75,

79-80, 139
Savia, Eva, 34, 84
Schauenstein, Walther, 83
Schlehofer, J R, 20
Sharp, Frank, 26, 28
Shaw, Sir William Fletcher, 27

Shope, Richard, 47

Singer, Albert, 12-13, 20, 24, 26, 27,

28,29-31, 32, 33,34, 35-8,

50, 51,71,72,74,78, 80-1,

139-40
Skegg, David, 56
Smith, Alwyn, 19,28,65
Smith, John, 34, 72-3, 140
Smith, Peter, 37
Spriggs, Arthur I, 9, 10, 15, 19, 88-9,

140-1
Stanley, Margaret, 30, 33, 34, 38, 39,

42, 45, 46-8, 141
Sun, Xiao-yi, 44-5
Symonds, Marilyn, 11, 13, 21—2,

23, 141
Syrjanen, Stina, 49
Szarewski, Anne, 32, 66, 67, 68, 70,

71,75,78,79,141-2

Tansey, E M (Tilli), 3, 4, 5, 81, 142
Taylor, Claude W, 9, 1 1
Tighe, John, 14, 16

Usherwood, Martin, 57

Vessey, Martin, 20, 37

Wachtel, Erica, 9, 11, 12, 59, 86
Walboomers, Jan, 51, 68
Walker, Leslie G, 75-7, 142
Walker, Patrick George, 26-7, 33-4,

37-8,51,65-6,78, 142
Walkinshaw, Steve, 40
Walton, Richard J, 19, 53, 143
Waugh, Norman, 73
Way, Sir Stanley, 12-13, 14, 31,

86, 143
Williams, Sir David Innes, 65
Williams, Dennis, 11, 19, 21
Wilson, J M G (Max), 10, 55, 143

163

History of Cervical Cancer and the Role of the Human Papillomavirus, 1960-2000 - Index

Wolfendale, Margaret, 6, 10-11, 16,

19, 21, 22, 23, 54, 57, 59-60, 65,

69, 70, 143
Woodend, B, 61
Woodman, Ciaran, 42, 49, 144

Zhou, Jian, 43-6, 144

164

Key to cover photographs

Front cover, top to bottom

Professor Albert Singer
Professor Margaret Stanley
Dr Lionel Crawford
Professor Jocelyn Chamberlain

Back cover, top to bottom

Professor Anthony Miller

Professor Jack Cuzick and Dr Amanda Herbert

Professor Heather Cubie

Professor Peter Sasieni, Dr Ian Duncan