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I would like
to thank the TVCS for sponsoring me at the 44TH BSCC Annual Scientific
Meeting in Newcastle. It was a stimulating and very well organised
conference, and I learnt a great deal.
Newcastle is a lively, vibrant city. It has changed so much since
the last time I visited about 15 years ago. It had hoped to be chosen
as the European City of Culture a few years ago, and the legacy
this has left is immense. It has wonderful art galleries, a brand
new music centre - the Sage, public art scattered all over the city
and the Quays on either side of the River Tyne are full of life
and activity. One American delegate at the conference commented
to me that he thought that Newcastle looked like one big art gallery!
How right he was!
Enough of this beautiful city - the conference was exceptional too.
We started the
conference on Monday morning with two lectures discussing LBC presentations.
Surepath
The first discussed Surepath and atrophic smears.
One of the most problematic areas of gynae cytology interpretation
is an atrophic pattern in a sample obtained from a non-oestrogen
stimulated woman. Differentiation of an atrophic pattern from other
conditions such as squamous atypias, dysplasias and malignancies
can be challenging. The number of cervical cytology samples with
atrophy is increasing due to aging of the baby boom population and
the decreased use of HRT by postmenopausal women.
LBC preparations
have accentuated the problem of the interpretation of atrophic specimens
as due to suspension of the cellular material in a fluid collection
and preservation medium, cells tend to "round-up", as
compared to the conformation the same types of cells would take
in a conventionally prepared smear. Thus cells in LBC prepared samples
tend to show a smaller apparent amount of cytoplasm, thereby increasing
the apparent NC ratio. Parabasal cells often occur in crowded groups,
showing exceptionally high NC ratio with enlarged nuclei and some
degree of hyperchromasia. Recognition of this phenomenon is key
to prevention of false positive interpretations. Clues to the presence
of dysplasia in atrophic cervical samples include identification
of two cell populations and the recognition of nuclear features
of dysplasia, such as extreme hyperchromasia, chromatin and nuclear
membrane irregularities and mitotic activity.
Diagnostic dilemmas in ThinPrep
This was followed by a lecture discussing diagnostic dilemmas in
ThinPrep gynae cytology.
Challenging cases fall into four categories.
1. Cases that present in less than optimal preparations i.e. inflammation,
infections, poor staining or scant material.
2. Diagnostic entities for which sensitivity is poor - notably glandular
lesions and lesions, which shed small cells.
3. Benign entities, which simulate the abnormal [treatment effects,
hormonal effects, reactive changes, instrument effects, hard to
recognise pale cells and the usually benign but hyperchromatic crowded
group].
4. Rare and unusual cases [metastatic entities, malignant lymphomas,
sarcomas]
It is the first two categories, which comprise the everyday challenges
for cytoscreeners.
Ironically, papers have been written suggesting it is easier to
detect and properly categorise low-grade lesions than it is to recognise
and to correctly designate those of high grade. Also recognition
of adenocarcinoma in-situ remains a difficulty as many articles
have stated.
The cytoscreener is less likely to be perplexed by cases in 3 and
4 categories if adequate clinical history is provided.
Invasive cancers symposium
Following these discussions we had an invasive cancers symposium,
firstly discussing clinical aspects.
In England cervical cancer has become rare as a result of the NHS
cervical screening programme. This is a marked contrast to developing
countries where it is the commonest cancer in women, making it the
second most common cancer in women worldwide, only recently overtaken
by breast cancer.
In the context of the screening programme in 2002 there were 2305
cervical cancers diagnosed in England, 127000 new colposcopy referrals
and 4.1 million smears performed. In other words 1 case of cervical
cancer was diagnosed for every 2000 smears performed. Mean age at
diagnosis is around 50.
Diagnosis of invasive cancer is usually made on clinical or colposcopic
examination and should be confirmed with a biopsy of greater than
5mm depth to differentiate it histologically from microinvasive
disease.
In England management of invasive cancer other than microinvasive
disease should be managed in gynaecological centres. Treatment is
primarily based on the FIGO stage of the tumour at presentation.
This is currently a clinical staging involving a pelvic examination,
chest x-ray and occasionally imaging to exclude ureteric obstruction.
Curative surgical treatment is confined to early stage disease and
is becoming increasingly conservative with fertility sparing procedures
aided by laparoscopic surgery. In the last 10 years chemoradiation
has replaced radiotherapy alone for the treatment of advanced disease
with improved survival.
As to the future, it will be interesting to see how much lower cervical
cancer incidence and mortality will fall as a result of the screening
programme and what impact future vaccines will have both in the
UK and world wide.
Invasive cancer audit
A discussion on invasive cancer audit followed.
Audit is undertaken to monitor the effectiveness of a process, and
hopefully lead to improvement. Following on from a retrospective
slide review in Leicester it was announced that the English NHS
would undertake an audit of all cases of cervical cancer. This audit
highlighted that up to 69% of women had false negative cytology
reports and that nearly 20% had not had regular smears, data that
was well known in previous literature. A protocol to undertake this
audit is still under development for the approximately 2400 cervical
cancers in England per year. It is essential that any audit include
all aspects of the women's pathway in the screening process. This
must cover call/recall, attendance for smears, smear taking, smear
reporting, colposcopy/treatment and histology as it relates to each
individual case of cervical cancer.
It is essential that whatever protocol is developed is manageable
within existing resources and will produce meaningful data that
can lead to improvements in the screening programme under audit.
Any model ideally would use a standardised IT data base to collect
and record data from all aspects of the pathway.
Cytology of invasive cervical cancer
A lecture on cytology of invasive cervical cancer followed.
In well-screened populations the incidence of cervical cancer is
falling, resulting in less cervical smears from women with cervical
cancer presenting to the screening laboratory. Cases of classic
invasive squamous cancer are becoming rare, although there is a
possible relative increase in adenocaricoma. It must be remembered
that histology is the gold standard for diagnosis of cervical cancer
and that a cervical smear is a screening tool, not a diagnostic
test. The positive predictive value for diagnosing cervical cancer
from a conventional cervical smear is only 56% in the best laboratories
with the main differential diagnoses in keratinising CIN, CIN with
associated features of HPV and atrophic cervicitis. Conversely,
50% of patients with a cervical cancer may present with a smear
showing just dyskaryosis or a lesser cytological abnormality or
may have a normal or unsatisfactory smear with or without symptoms.
Any woman [within the screening age group] developing a cervical
cancer would be considered to represent a failure of the screening
programme but she may never have attended for a smear or may have
defaulted from routine follow-up within the screening programme,
or her abnormal smear or cervical abnormality may have been inappropriately
managed by the colposcopist or GP. However, in a proportion of cases
the fault lies within the screening laboratory in that an abnormality
has been missed, not recognised or misinterpreted. Audit is an important
educational tool in such cases.
The classical cytological features of invasive squamous cancer and
adenocarcinoma can be considered to represent variants of high-grade
dyskaryosis. Often it is academic to attach the label of "?invasive"
other to ensure rapid referral for colposcopy. In conventional smears
classical invasive squamous carcinoma presents with high dyskaryotic
load with abnormal keratinised forms and blood and necrosis in the
background reflecting a destructive, fast-growing lesion. Classical
endocervical cancers tend to show features of endocervical dyskaryosis,
but with large numbers of abnormal glandular sheets with blood and
dyskaryosis in the background.
In LBC preparations, cells are not obscured and cellular preservation
is good, facilitating the recognition of nuclear abnormalities in
dyskaryotic and malignant cells such as nucleoli and chromatin abnormalities.
Keratinised cells are easily recognised in squamous cell carcinomas
and tumour diathesis is maintained. Endocervical adenocarcinomas
in LBC preparations will also show tumour diathesis but may loose
some of the characteristic architectural abnormalities seen on conventional
preparations such as feathering, presenting with "rounding
up" of the groups of malignant glandular cells with scalloping
and polymorph engulfment. Whether conventional smear or LBC the
diagnostic criteria for dyskaryosis/malignancy are the same.
About half of all cervical cancers do not present with a classical
picture in a smear because of the nature of the cancer or because
the cancer has not been sampled or inspected by the smear taker.
It is essential that the screeners are rigorous with their criteria
for diagnosing squamous and endocervical dyskaryosis and are aware
of cases of false negatives including correct identification of
microbiopsies, small cell dyskaryosis and pale cell dyskaryosis.
With the conversion of England to LBC it is essential that training
be to the highest possible standard.
Obstacles to successful cervical cancer prevention in developing
countries
A thought-provoking lecture followed discussing the real world obstacles
to successful cervical cancer prevention in developing countries.
In 1996 it was documented that the Vietnam War had contributed substantially
to the burden of cervical cancer in contemporary Vietnam, and subsequently
an effort was made to establish a nationwide cervical cancer screening
programme in Vietnam. A wide range of obstacles were apparent, including
non-governmental organisations distracted by fundraising requirements
not connected with public health, and shortage of treatment facilities.
Also obstacles to achieving an adequate quality in the programme
were widespread.
It is proposed that Pap screening services be introduced immediately
to communities where cervical screening is appropriate but unavailable,
with HPV testing introduced later. Disease prevention requires social
change, which in turn requires the participation of those for whom
the change is intended.
Cervical Screening 10 years on
Next followed a symposium on "Cervical screening 10 years on",
beginning with "Implementation, automation or inoculation".
The National Institute for Clinical Excellence [NICE] recommended
in 2003 that liquid based cytology be used as the primary means
of processing samples in the NHSCSP. Central to this discussion
were:
1. That the overall sensitivity of LBC was at least as good as the
conventional smear.
2. There was statistically significant decrease in the number of
inadequate samples.
3. A reduction in the time required for smear taking.
4. Increased laboratory productivity.
LBC implementation will have a major effect on cytology laboratories.
Now that the majority of training centres have completed their training
and have had experience of LBC in routine practice, training for
other laboratories is underway. Training of laboratory staff must
be closely linked to training of smear takers to ensure that as
laboratory staff complete their training they are immediately exposed
to LBC specimens from their local screening programme.
Epidemiological and experimental studies have established that HPV
is the principal aetiological agent in cervical neoplasia, and the
WHO has classified HPV 16 and 18 as carcinogenic agents. Persistent
HPV infection is the key step in neoplastic transformation of cervical
epithelium. HPV infection is common in sexually active young women
with a peak prevalence approaching 50% in the age range 20 - 24
years, falling to less than 7% over the age of 30. This information
can be used to increase the specificity of the smear test and in
the triage of low-grade abnormality. In the follow up of women treated
for CIN, negative HPV testing may identify those at low risk of
recurrent disease. HPV testing as the primary screening mode is
more sensitive but less specific than conventional cytology but
may
allow identification of women for intensive screening.
Vaccines based on HPV L1 virus-like particles show promise
in protecting against infection and cervical neoplasia, and are
entering phase 3 clinical trials.
Ultimately, vaccination may prevent cervical cancer, and screening
would no longer be necessary, but in the interim studies suggest
that introduction of an HPV 16/18 vaccine in an organised screening
programme would permit a later age of screening initiation and less
frequent screening intervals.
Automation-assisted
techniques
There then followed a presentation on automation-assisted techniques.
In the UK, Health Technology Assessment has approved a random trial
looking to compare two automated cervical screening technologies
against manual screening. These automatic devices are Focal Point
[Tripath] and Imager [Cytyc]. This trial is going to commence in
Manchester in October 2005, and is planned to finish in two years.
These types of randomised prospective studies will show whether
Automation Assisted Screening adds value to routine primary screening
in a well-organised screening programme.
Is vaccination the final answer?
The final presentation in this symposium was "Is vaccination
against HPV the final answer?"
Cervical cancer affects nearly half million women worldwide each
year, and nearly half of them die. The greatest problem is in the
developing world, though even in the UK around 2300 women develop
cervical cancer each year. Infection with HPV, in particular 16
and 18, is the main cause of cervical cancer. It has been shown
that 99.7% of cervical cancers contain HPV DNA. Infection with HPV
appears to be extremely common in young people, but is usually transient.
It appears that the presence of HPV is more meaningful in older
women [over 30] who have persistent infection. Screening tests detect
cellular abnormalities early but the ultimate solution to a viral
disease is obviously a vaccine. A problem is the number of cervical
cancer HPV types, which need to be included [potentially 15]. However,
vaccines against types 6, 11, 16 and 18 are showing great promise
in clinical trials. One of these vaccines contains all four HPV
types and would thus protect against genital warts [HPV types 6
and 11] as well as the commonest cervical cancer [HPV types 16 and
18]. The other vaccine contains types 16 and 18 and thus targets
cervical cancer alone.
However, if we eliminate cancer due to HPV types 16 and 18, will
other types take their place? Will we need different vaccines for
different populations? What will be the effect of a vaccine on HIV
positive women? There are no answers to these questions at present.
A tricky issue is deciding at what age a vaccine should be given,
since it would need to be administered prior to onset of sexual
activity. We do not know at present how long the immunity offered
by these vaccines lasts. Ideally, such a vaccine would be administered
with other childhood vaccines, removing any link with sexual activity
in the minds of parents. However, that would depend on the immunity
lasting for decades or boosters being given. [Data suggests only
3 - 4 years immunity at present]. And should we vaccinate boys as
well as girls?
In theory, an HPV vaccine could prevent almost all cervical cancers,
eventually removing the need for cervical smears. However, there
is at least one generation of females for whom the vaccine will
come too late, and who will continue to require screening. So no
need to worry about our jobs just yet!
I would like to thank TVCS once again for sponsoring me to attend
the 44th BSCC Annual Scientific Meeting, which I found extremely
beneficial and educational. I met up with many friends and colleagues
old and new, and enjoyed the experience immensely.
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