HPV Vaccine: The Sun Sets on Cervical Cancer & My Career?

Thursday, 02 February 2017

From 1900 to 2100

Medico-Chirurgical Hall

Professor Maggie Cruickshank, Director of NHS Grampian Research & Development, Aberdeen

HPV Vaccine: The Sun Sets on Cervical Cancer & My Career?

Professor Maggie Cruickshank graduated from the University of Aberdeen in 1985 and was recently appointed to Director of NHS Grampian Research and Development.

She has a programme of research in pre-invasive disease of the lower genital tract with a focus on Human Papillomavirus infection (HPV) and cervical screening.  As honorary consultant Gynaecologist, she leads the Colposcopy and specialist vulva disorders services.


Note of meeting of 2nd February 2017

·       The President welcomed the company to the meeting.

·       She invited Dr Pucci to give an update on the City plans for the revamp of Provost Skene’s House and he made the company aware that there were a large number of famous medics being considered for the exhibits and that there is currently an online poll available until 12th Feb via the City website in which the public can declare their favoured choices.

·       The President reported on the success of the Burns Supper at Douglas Hotel on 20th Jan declaring it a success with around 150 participants and a plan to rebook the venue for 2018.

·       She said that performers were now being recruited for the Famous for Five Minutes Charity event on 6th May.

·       Additional events to this year’s programme will include a Heritage event on the evening of 18th May and a revamp of the Electives event, possibly on 25th May.

·       The audience were reminded of the Jim Petrie lecture to be given by Professor Stuart Ralston during the RCPE Aberdeen symposium on 29th March.

·       The President announced that members will be invited next month to nominate potential recipients of the 2017 President’s Medal.

·       She explained that we were once again in the Suttie Conference Centre as the Chamber has not yet been sufficiently cleared to accommodate our group before the lecture but that this will definitely be resolved soon and that the March meeting would be held in the revamped Med Chi Hall.

·       It was noted that the sale of surplus chairs had gone well and that a very small number were still available. Members who had purchased chairs should uplift these very soon.

·       The Golf trophy was once again present, but nobody to collect it.

The President invited Professor Maggie Cruickshank, Director of Research & Development for NHS Grampian and Consultant Gynaecologist, to give her talk, ‘HPV Vaccine: The Sun Sets on Cervical Cancer and My Career’.

Professor Cruickshank explained that while she had spent much of the past three decades engaged in the early detection and treatment of cervical cancer, her talk would mainly be about an emergent Public Health approach to primary prevention of this disease by vaccination. Cervical cancer, while relatively uncommon, is nevertheless the commonest cancer in women before the age of 35. A long established system of cervical smear testing for early detection of cytological abnormalities has been helpful, but limited by incomplete uptake of screening. Publicity surrounding high profile sufferers like the late Jade Goody has only a temporary effect on buy-in.

The realisation that cervical cancer is almost universally associated with HPV virus infection has led to further study of the virus culminating in the production of vaccines designed to prevent infection by the virus sub-types most closely associated with cervical cancer. HPV is a stable double-stranded DNA virus, free from the regular mutations seen with the likes of Influenza viruses. It affects basal epithelial layers, gaining entry via minor abrasions in the overlying layers. HPV infection is common, affecting virtually all women but there is no acute inflammatory response and hence no immediate clinical consequence of infection. In over 90% of instances infection is subsequently cleared by the host but in others, after a variable and often lengthy latent period, cellular changes can develop and progress through pre-cancerous stages to localised, and subsequently invasive, cancer. Of the 150 HPV subtypes, relatively few – mainly 16 and 18, are associated with cervical cancer; these 2 types are thought to account for around 70% of cervical cancer in the UK.

Early work on detection of evolution of cervical cancer followed the researches of Georgios Papnicolau, a Greek doctor whose work in the United States with guinea pigs required the development of a technique for detecting genital tract changes at the time of ovulation. The techniques he developed for serial examination of lower genital tract cytology ultimately led to the Pap stain technique used in cervical cytology screening. A fairly similar technique developed almost contemporaneously by a Rumanian, Auriel Babeş, was less widely publicised and so most of the world knows only of Papanicolau’s technique and stain.

Colposcopy, involving direct vision of the cervix, just preceded cytological examination, having been pioneered by German Hans Hinselmann working in Hamburg in the 1920s. It gained utility following the serendipitous discovery that application of acetic acid to pre-malignant cells causes their whitish discolouration. A dark side to the evolution of colposcopy practice comes from the experimentation done on prisoners in Auschwitz in which Hinselmann collaborated with another doctor (Dr Eduard Wirths). Cervical amputations performed without anaesthetic and hence leading to pain, haemorrhage, sepsis and potentially death gave tissue samples that could be analysed to establish correlation with colposcopic appearances. Clearly much is owed to those who suffered these experiments by the millions subsequently benefitting from the clinical use of colposcopy.  (Hinselmann was convicted of war crimes – incidentally for conducting sterilisations – and spent three years in prison after the war.

Cervical screening programmes commenced in Scotland in the 1950s but being run on an opportunistic basis, made little impact on cervical cancer incidence until an organised screening programme was established. The case for developing routine screening was not helped by the persistent opposition of some to the idea that there was a definite link through the various stages of cell abnormality to frank malignancy. Most notorious proponent of this view was Professor Herb Green working in the National Women’s Hospital in New Zealand. Green did not believe that cervical carcinoma-in-situ did not progress to invasive disease and aimed to prove this belief by recruiting women with abnormal cervical cytology, over 17 years to 1980, without their permission; the study saw these women denied any treatment, or discussion thereof, and unfortunately too many progressed unnecessarily to advanced stages of malignancy. The resultant scandal associated with what was quaintly called ‘The Unfortunate Experiment’ raised several issues about clinical research and practice, not least why nobody had blown a whistle sooner.

Once cervical screening offered to all became established in the UK, the incidence of cervical cancer fell significantly but may be rising again due to limited uptake of screening. So, despite the case for screening being well made and accepted by government, cervical cancer remained a problem. This situation caused Ian Frazer, a Glaswegian who went to Australia after doing medical undergraduate training in Edinburgh, to investigate the possibility of generating an HPV vaccine. Synthesis of long chain viral protein saw rearrangement into virus like shells (with no DNA core) that are immunogenic and produce highly specific vaccination reactions conferring a substantial degree of immunity in those vaccinated. So good HPV vaccines can now be prepared.

The next issue is around which sub-types, and how many of them, should be included. In the UK the HPV programme, using a bivalent (16&18) vaccine started with the hope of vaccinating, in teenage years, all girls born after 1/9/90. Most was given to index year groups in early teens in school, and there were attempts also at catch-up programmes for those up to a few years older. A triple dose regimen was used until 2014 and since then only two doses are given. Also, more recently a quadrivalent vaccine (6/11/16/18) has been used, adding vaccination against the two subtypes most likely to cause genital warts.

Uptake of vaccination has been among the best in the world in Scotland at almost 90%. This vaccination is included in the standard school immunisation schedule – now targeted mainly at 12 year olds. Vaccinating in school has resulted in uptake rates being similar across all social classes – unlike uptake of cervical cytology screening, or, indeed, incidence of cervical cancer.  It will take some years before the impact on cervical cancer will be apparent due to the known lag phase between HPV infection (now hopefully largely prevented) and development of pre-malignant or malignant change. Also, as many women for some time to come will have been infected prior to the potential for vaccination, cervical screening needs to be ongoing for several decades, (perhaps around 2064!). The current cervical screening schedule is for 3 yearly screening from 25 to 50, and 5 yearly screening to 64. Of particular advantage in assessing impact of any intervention on the disease is the national linkage of both cervical screening, and colposcopy results allowing continuity of data for anyone remaining within the national screening programmes.

There has already been some change in those referred for colposcopy with more minor abnormalities being seen in recent years and consequently there has been a 70% reduction in those needing treatment at colposcopy in the past 5-6 years. The challenge of recognising abnormal patterns at colposcopy remains and, with inevitably smaller numbers of cases with abnormalities requiring examination in the future, there will be issues about maintenance of skills and perhaps an attendant need to review the current wide distribution of colposcopy services. The effects of HPV vaccination on colposcopy practice will, as for cervical cytology screening, take some years to be fully realised. The emergent practice of HPV screening being undertaken prior to biopsy in cases of abnormal cytology could prove a further problem to perceived needs for colposcopy services. However with vulval and, particularly, anal cancer rates rising there may be an option to remodel colposcopy services to cover a broader range of diseases.

While it is hoped that the success of HPV vaccination will continue to challenge the size of current colposcopy provision, there needs to be some caution over the inevitable challenges posed by public opinion on vaccination. In Ireland a vociferous, and indeed sometimes viscious, anti-vaccine campaign has been mounted under the name ‘Regret’ whose supporters maintain that HPV vaccination can lead to a chronic fatigue syndrome. In Japan, where uptake had risen to 70%, cases of limbic encephalopathy were blamed on HPV vaccination but, without strong government and health service rebuttal of claims of adverse outcomes, now only 1% of eligible girls are being vaccinated. Then there are the inevitable, cocksure Trump tweets about vaccination programmes causing autism.

In concluding, Professor Cruickshank acknowledged the contributions of many collaborators and expressed the hope that HPV vaccination uptake rates in Scotland will remain high and the low level of maternal anxieties around its safety (with only a slight rise in obesity having been noted to date post-vaccination!), will not be increased.

There followed a lively question and answer session covering such topics as the association of male genital disease with HPV and consequent possibility of vaccinating boys, the very limited potential utility for vaccinating women after their teens when most will already have been subject to HPV infection, vaccinating against additional less common subtypes of HPV which have cancer-causing potential, extremely low risk potential of HPV infection via donor seminal fluid, good efficacy of HPV vaccine in HIV positive patients and the unresolved issue of global health equality in terms of providing vaccination programmes.

The President gave the vote of thanks and closed the meeting.

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