Cross sectional study of conventional cervical smear, monolayer cytology, and human papillomavirus DNA testing for cervical cancer screening
BMJ 2003; 326 doi: https://doi.org/10.1136/bmj.326.7392.733 (Published 05 April 2003) Cite this as: BMJ 2003;326:733
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As a co-author of this study, I would like to express my disagreement
with the interpretation of the data and the conclusions of this study. At
the time of the study, I worked in the Besançon centre which provided 61%
of the data collected in the routine screening population, and I expressed
concern that the study contradicted my long experience with liquid-based
cytology (LBC) in daily clinical practice. I specifically contest the
statement that "monolayer testing is less reliable and should not replace
conventional cervical smear testing" because I do not believe that the
study method was robust enough to warrant this conclusion or to be
diametrically opposed to the findings of much larger and better designed
studies. I had formerly signed a paper stating that I only partially
agreed with the study findings. Therefore, to clarify my position on this
paper, I would like to comment on several points that were not adequately
addressed.
Although most pathologists regard biopsy as the gold standard, as a
trained and experienced colposcopist I am aware that caution is needed
when interpreting colposcopic specimens because of the problems involved
in obtaining adequate and relevant samples during the procedure. I was
surprised that the limitations of the reference standard were not
discussed in more depth to provide a more balanced interpretation of the
results. Furthermore, interobserver variation in the interpretation of
biopsies is well-known (Ismail et al. 1989; Robertson et al.1989), and a
recent study reported only 35% of diagnoses of CIN II lesions were
concordant (Klaes et al 2002). More details on the measures used to
control interobserver variation, and the level of expertise of the
observers should have been included to allow readers to determine the
extent to which these factors may have influenced the results.
As stated in the paper, a further source of bias was introduced through
use of the "split sample" technique, which explains why only 2
conventional smears but 5 LBC tests did not contain enough endocervical
cells. On the other hand, it is impossible to explain why five LBC
specimens were unsatisfactory because of obscuring blood cells and one
because of obscuring inflammatory cells, whereas none of the conventional
smears presented this difficulty. This is contrary to routine practice,
other literature findings, the principle of the LBC method itself which is
known to destroy blood and inflammatory cells, and it also implies that
these cells somehow stayed on the brush during preparation of the
conventional smear and then suddenly ended up in the vial. More details on
the exact method used may have shed light on this mystery!
It is obvious that the real purpose of this study was to justify the
continued use of conventional smears which have a lower immediate cost
than LBC. In light of the available evidence in favour of the superiority
of LBC, this study does not contribute to our obligation to act in the
best interests of our patients.
References
1.Ismail SM, Colclough AB, Dinnen JS, Eakins D, et al. Observer
variation in histopathological diagnosis and grading of cervical
intraepithelial neoplasia. BMJ. 1989 Mar 18, 298 (6675): 707-10.
2.Robertson AJ, Anderson JM, Beck JS, Burnett RA, Observer
variability in histopathological reporting of cervical biopsy specimens. J
Clin Pathol 1989 Mar, 42 (3): 231-8.
3. Klaes R, Benner A, Friedrich T, Ridder R, et al. p16INK4a
immunohistochemistry improves interobserver agreement in the diagnosis of
cervical intraepithelial neoplasia. Am J Surg Pathol. 2002 Nov;26 (11):
1389-99.
Competing interests:
None declared
Competing interests: No competing interests
We (the French physicians cited below) strongly contest the findings
of the "independent" French study by Coste et al (1) which questioned the
benefits of using liquid-based cytology (LBC) to detect precursor lesions
of cervical cancer. Having ignored the evidence from both the numerous
studies published in peer-reviewed journals which compare the ThinPrep
and conventional Pap tests, and a recent meta-analysis of 25 international
studies with large patient cohorts (221 684 LBC smears and 378 659
conventional smears) which concluded that LBC detected almost 100% of low
grade lesions and 70% of high grade lesions (2), we would not like the
international community to think that this particular French study is
representative of the French position, nor of current practice in France.
Along with many other responses and comments, we agree that this
study did not address several critical issues that lead to bias in the
findings and conclusions.
First, although the authors claim the non-
superiority of LBC in the 828 women at high risk of precursor lesions,
this can be explained by more focused and accurate readings in an at-risk
population. However, in the typical screening population in whom only 2%
have high grade lesions, a much larger sample power than the 1757 patients
in this study is needed to detect a difference between conventional and
LBC smears (3).
Second, the lack of experience with LBC is the most
likely explanation to account for the difficulties in reading the smears.
A previous multicenter French study of 5 400 women who underwent screening
in six laboratories and showed LBC detected between 40 to 50% more low and
high grade lesions than conventional smears (4), all of the investigators
underwent a 2-week training period to become familiar with the new method
before the study period. This is a known bias and should have been taken
into account.
Third, although we agree with the authors that biopsy is
certainly useful, we disagree that is an absolute criteria or a gold
standard due to problems of reproducibility. We would ask to what extent
the histological and colposcopic diagnoses in this study are reproducible,
and whether the same investigators performed colposcopy and read the
corresponding smears? It should also be pointed out that numerous studies
of LBC have used biopsy results as a control and report consistent and
conclusive findings of the superiority of LBC.
Lastly, this is the only
study to conclude against the higher sensitivity of HPV testing to detect
precursor lesions compared to conventional smears, and the usefulness of
HPV testing for the triage of patients with abnormal smears. This finding
contradicts, to our knowledge, all other available published data, the
recent guidelines of the American Society of Colposcopy (5), the opinions
expressed by international experts at the recent EUROGIN 2003 conference
(6), and another well-known French study conducted in an unselected
screening population (7).
It is obvious that the real debate in France today is about cost, and it
is a pity that this team did not declare their perspective and interests.
Unlike reimbursement practices in several other countries, reimbursement
in France is currently based on "a smear test" and the type of test is not
taken into account so the extra cost of using LBC is incurred by the
laboratories. In cost/benefit analyses which include the unnecessary
follow-up tests, inappropriate treatment, and the repercussions of late
diagnosis, these new screening tools have been shown to produce a better
result for patients and avoid later costs. We believe it is a question of
time before French payers recognise evidence-based findings, widen their
vision beyond immediate cost, and focus on what is best for women's health
(8). We are looking forward to the end of yet another French exception.
J Monsonego, R Dachez, P Birembaut, C Clavel, S Labbe, R Marty, L Zerat, D
Zarca, D Castaigne, D Elia, P Judlin
1. Coste J, Cochand-Priollet B, deCremoux P, Le Gales C, Cartier I,
Molinie V, Labbe M, Vacher-Lavenu M, Vielh P. Cross sectional study of
conventional cervical smear, monolayer cytology, and human papillomavirus
DNA testing for cervical cancer screening. BMJ 2003; 326: 733–773.
2. Bernstein SJ, Sanchez-Ramos L, Ndubisi B. Liquid-based cervical
cytologic smear study and conventional Papanicolaou smears: A metaanalysis
of prospective studies comparing cytologic diagnosis and sample adequacy.
Am J Obstet Gynecol 2001; 185: 308-317.
3. Limaye A, Connor AJ, Huang X, Luff R. Comparative Analysis of
Conventional Papanicolaou Tests and a fluid–based thin-layer method. Arch
Pathol Lab Med 2003; 127: 200 –204.
4. Monsonego J, Autillo-Touati A, Bergeron C, Dachez R, et al.
Liquid-based cytology for primary cervical cancer screening: a multi-
center study. Br J Cancer 2001; 81(3)360-366.
5. 2001 Consensus guidelines for the management of women with
cervical cytological abnormalities and cervical cancer precursors - Part
I: Cytological abnormalities, JAMA 2002; 287: 2120-2129
6. Congrès Hebdo, Eurogin 2003 – Prévention du cancer du col: vers de
nouvelles pratiques, Le Quotidien du Médecin, 29 April 2003, pp 13-16
7. Clavel C, Masure M, Bory JP, PuitardI et al. Hybrid Capture II-
based human papillomavirus detection, a sensitive test to detect routine
high -grade cervical lesions: a preliminary study on 1518 women. Br J
Cancer 1999; 80: 1306-1311
8. Ferenczy A, Franco E. Cervical-cancer screening beyond the year
2000. Lancet Oncol 2001; 2(1): 27-32.
Competing interests:
None declared
Competing interests: No competing interests
I read with interest the excellent article by Coste et al on the
efficacy of liquid-based cytology for cervical cancer screening. This
multi-institutional study compares the sensitivity and specificity of
conventional Pap smear, liquid-based (monolayer) cytology and human
papillomavirus DNA testing for detection of cervical dysplasia and cancer.
The results of this study contradict those of most previous ones in that
the investigators found the conventional Pap smear superior to the new
technologies. The reason for the discrepancy between this and previous
studies remains unexplained at this time. Could technical considerations
such as variations in sample collection device, sample transfer (smearing
first and then rinsing in the liquid) or staining method have played a
role? Is it possible that differences in the method of screening or
relatively low level of the investigators’ experience in interpretation of
liquid-based preparations (as suggested by some commentators) be
responsible for different results?
Some of the questions could have been
addressed by providing more information on the collection device, the
screening method and the level of the pathologists’ training and
experience in examining liquid-based specimens. While the description of
methods is rather brief, a thorough explanation of methodology can be
found in the authors’ previous publications on this subject (Diagn
Cytopathol 2001;24:412-420 and Diagn Cytopathol 2002;27:251-257).
The differences in the study design, patient population and
variations in practice of cytopathology in different countries could have
produced contradicting results. In the United States all cervical smears
are screened by cytotechnologists and only when cellular abnormalities are
detected the case is referred to a pathologist. It is my understanding
that in France smears are directly examined by the pathologist. Did the
French pathologists read the Pap smears at a slower pace and more
carefully than the American cytotechnologists who participated in previous
trials? Were the gynecologists who participated in this study more
proficient in preparing conventional smears than those who collected the
samples for other studies? Perhaps a joint multinational study could
address such concerns.
This important study emphasizes the need for additional future
investigations on this subject. It also shows that studies designed and
conducted in one country may not necessarily be applicable to another
country with different practices and experiences.
Competing interests:
None declared
Competing interests: No competing interests
There is definitively a need for larger prospective studies which
take into account the individual medical and socioeconomic conditions in
different countries which indeed influence more than marginally the choice
of methods in cervical screening. But no one can neglect the huge amount
of data accumulated so far pointing to a clear improvement in cervical
screening by the advent of FDA certified thin layer cytology (1) and HPV
testing (2).
The study of Coste et al. (3) is not the answer to the need for
better studies. “Learning by doing“ was the approach choosen by the
authors as far as thin layer cytology was concerned. To admit this honours
them but disqualifies the study.
Taking as a reference the generally accepted extremely high
sensitivity of hybrid capture (HC)-2 for high grade lesions in screening
(2) and triage (4), the fact that in this small study (3) this could not
be repeated helps to estimate the level of confidence we can put in the
results of the thin layer part of the study: none. How bias by different
mechanisms led to these results has been outlined by other letters
responding to this article.
If HTA (health technology assessment) is regarded the best way to
analyse a new medical product one should keep on studies which not only
used a retrospective theoretical approach but also conducted large pilots.
There are now two of such studies available (5,6). Both of them found for
liquid based cytology with ThinPrepTM an increase not only in the quality
of smears but also in the detection of high grade lesions.
It has been argumented that industry independent studies are more
objective. That is not necessarily the case, because also here biases are
conceivable which touch authors of studies. Think of potential increases
in cost for payers or endangered domains like yearly repeated conventional
cytology. The question is not whether a study was industry supported but
whether this is clearly indicated and the quality of design and
documentation are adequate. Remember that without industry funding there
would have been no more relevant drug development for decades.
Competing interests:
HI has received travel reimbursement for symposia and fees for
organizing symposia from cytyc and Digene. He is performing conventional
cytology, thin layer cytology and HPV testing in his laboratory.
References:
1. Bernstein SJ, Sanchez-Ramos L, Ndubisi B. Liquid-based cervical
cytologic smear study and conventional Papanicolaou smears: A metaanalysis
of prospective studies comparing cytologic diagnosis and sample adequacy.
Am J Obstet Gynecol 2001; 185: 308-317
2. Petry KU, Menton S, Menton M, van Loenen-Frosch F, Gomes H, Holz B
et al. Inclusion of HPV-testing in routine cervical cancer screeening in
Germany: Results for 8466 women above 29 years. Br J Cancer 88, in press
3. Coste J, Cochand-Priollet B, de Cremoux P, Le Gales C, Cartier I,
Molinie V, Labbe S, Vacher-Lavenu MC, Vielh P; French Society of Clinical
Cytology Study Group.
Cross sectional study of conventional cervical smear, monolayer cytology,
and human papillomavirus DNA testing for cervical cancer screening.
BMJ. 2003; 326: 733-737
4. Petry KU, Böhmer G, Iftner T, Brummer O, Kühnle H. Factors
associated with an increased risk of prevalent and incident grade III
cervical intraepithelial neoplasia and invasive cervical cancer among
women with Papanicolaou tests classified as grades I or II cervical
intraepithelial neoplasia. Am J Obstet Gynecol. 2002; 186: 28-34
5. Scottish Cervical Screening Programme. Steering Group Report on
the Feasibility of Introducing Liquid Based Cytology (January 2002).
http://www.show.scot.nhs.uk/publicationsindex.htm
6. Moss SM, Gray A, Legood R, Henstock E. Evaluation of HPV/LBC
Cervical Screening Pilot Studies. First report to the Department of Health
on evaluation of LBC. (December 2002-revised January 2003)
www.cancerscreening.nhs.uk/cervical/lbc-pilot-evaluation.pdf
Competing interests:
HI has received travel reimbursement for symposia and fees for organizing symposia from cytyc and Digene. He is performing conventional cytology, thin layer cytology and HPV testing in his laboratory.
Competing interests: No competing interests
The article by Coste et al should provoke critical evaluation of the
merits of liquid based cytology (LBC). Although some aspects of protocol
in this study may be justifiably criticised, the results should not be
ignored as suggested by some. It is certainly true that the large bulk of
published literature supports LBC, but this is substantially industry
funded. Experimental design protocols in these studies are seriously
flawed and biased in favour of LBC. Unfortunately the recently conducted
Scottish and English LBC pilot studies share many of these deficiencies in
design protocol. It is of concern that industry independent reviews
commissioned by government bodies outside of the UK - New Zealand,
Australia, Switzerland have failed to support implementation of LBC.
The responses to the article by Coste and colleagues have been varied
and many statements have been made with little justification. It amuses me
to hear gynaecologists telling me as a cytopathologist that 'LBC
preparations are easier to read.' Another statement 'it has been
demonstrated repeatedly that sub-samples produced from a unique cervical
scrape, are heterogenous' is simply not true.
The implementation of LBC has been driven by political and commercial
interest with relative lack of concern relating to impartial scientific
evaluation. There is a serious deficiency of well conducted, unbiased
trials of LBC versus conventional PAP smear. To date the only prospective
randomised trial using 'direct to vial' LBC by Obwegeser et al., showed
increased detection of high grade abnormalities with conventional PAP
smears. If we are ever to know the truth about the efficacy of LBC,
further industry independent studies and basic research needs to be
undertaken. Whether or not the UK government or NICE wish to know the
truth is of course an entirely different issue.
References:
1. Coste J, Cochand-Priollet B, deCremoux P, Le Gales C, Cartier I,
Molinie V, Labbe M, Vacher-Lavenu M, Vielh P. Cross sectional study of
conventional cervical smear, monolayer cytology, and human papillomavirus
DNA testing for cervical cancer screening. BMJ 2003; 326: 733–773.
2. Moseley, RP and Paget SP. Liquid Based Cytology: Is this the way
forward for cervical screening? Cytopathology 2002; 13 (2): 71-82.
3. Scottish Cervical Screening Programme. Steering Group Report on
the Feasibility of Introducing Liquid Based Cytology (January 2002).
http://www.show.scot.nhs.uk/publicationsindex.htm
4. Liquid based cytology for cervical screening. The Medical Services
Advisory Committee (MSAC). Available from: http://www.msac.gov.au
5. Broadstock M. Effectiveness and cost effectiveness of automated
and semi-automated cervical screening devices: A systematic review. NZHTA
Report 2000; 3: 1-130. Available from:
http://nzhta.chmeds.ac.nz/csv3n1.htm
6. Moseley, RP. Ethics, propaganda and liquid-based cytology.
Bulletin of the Royal College of Pathologists 2002; 119: 37-39.
7. Obwegeser JH, Brack S. Does Liquid-Based Technology Really Improve
Detection of Cervical Neoplasia? A Prospective, Randomised Trial Comparing
the ThinPrep Pap Test with the Conventional Pap Test, Including Follow-up
of HSIL Cases. Acta Cytol 2001; 45: 709-714.
Competing interests:
None declared
Competing interests: No competing interests
We reviewed split sample LBC data back in 1998 in Acta Cytologica 42:
178-184, 1998 and noted that 10-20% of the studies showed slightly
negative data, like the French split-sample study but that the overall
data showed increased SIl detection of 10-15%. More recent summary of
split sample LBC data is in AmJObGyn 2001 by Bernstein et al. Results are
much more dramatic in direct-to-vial studies, also reviewed by Bernstein.
Hundreds of thousands of cases have now been reported with ThinPrep
versus historic controls by independent laboratories, most recently in the
Feb 2003 issue of Archives of Pathology and Lab Medicine by Limaye et al.
HSIL detection has often been doubled. Increases in HSIL detection of 60%
have also been reported with ThinPrep in independent government pilot
studies in both Scotland and England. The data on direct-to-vial
significant advantage with ThinPrep is becoming too voluminous to ignore.
US ALTS trial data also provide the first Class I evidence from a
multicenter controlled randomized trial on efficacy of using ThinPrep and
DHCII HPV testing in management of ASCUS cases. RMA
Competing interests:
Have served as a consultant or speaker wihtout accepting personal compensation for AutoCyte, Cytyc, Digene, Morphometrix, Neopath, NSI, Veracel.
Competing interests: No competing interests
The article by Coste et al confirms conclusions drawn by health
authorities in Australia and Switzerland who have decided not to pay for
the extra cost of LBC in view of the lack of evidence that the new
technologies may save more lives. A similar study has just been published
by The American Physician: http://www.aafp.org/afp/20030415/us.html
with the following conclusions:
• The USPSTF (US Preventive Services Task Force) concludes that the evidence is
insufficient to recommend for or against the routine use of new
technologies to screen for cervical cancer. I recommendation.
The USPSTF found poor evidence to determine whether new technologies,
such as liquid-based cytology, computerized rescreening, and algorithm-
based screening, are more effective than conventional Pap smear screening
in reducing incidence of or mortality from invasive cervical cancer.
Evidence to determine both sensitivity and specificity of new screening
technologies is limited. As a result, the USPSTF concludes that it cannot
determine whether the potential benefits of new screening devices relative
to conventional Pap tests are sufficient to justify a possible increase in
potential harms or costs.
In view of these results and recommendations, I think that caution should be exercised before going all the way
with the new technologies.
Competing interests:
None declared
Competing interests: No competing interests
Editor,
Coste et al report is a biased scientific work since the methodoloy
is designed to demonstrate in advance the superiority of a method A over a
method B. Think about it: First, spread over a slide, from a unique
cervical scrape, most of the material and then discard the rest in a vial
containing liquid. Are both sub-samples homogenous?
Certainly not since a cervical scrape is not a blood sample. It has been
demonstrated repeatedly that sub-samples, produced from a unique cervical
scrape, are heterogenous. Secondly find an expert reader used to the
method A and an unexperimented reader for the method B.
Now apply this method to two different groups of women: One of 828 women
known to have a strong probability of squamous lesion: The method A will
easily find many lesions, while the method B which relies on "rest" and
unexperimented readers is condemned to not detect some lesions. In the
other group of 1757 women, the incidence of squamous lesion is lower,
therefore given the small sample it is not surprising to observe no
difference in term of sensitivity.
I cannot imagine a more biased study. I am not personnally totally
convinced of the superiority of liquid-based technology over conventional
smears, but the liquid permits to detect HPV which is highly sensitive to
detect squamous (far more than conventional smear).
In the hope to progress in cervical cancer detection, it is urgent
for editors to stop to accept papers based on wrong methodology especially
ones based on split-samples.
Competing interests:
None declared
Competing interests: No competing interests
One research project can obviously not do everything but there are
flaws in this.The people who took part had their interests protected by
approval by a LREC but the greatest care must be taken that peoples'
altruism is not exploited. To some extent I agree with T Chapman's
questioning whether the participants were truly 'empowered' by their
experience - eg There is an ambivalence revealed in the description of
their roles. ie they are 'participants' 'patients' rather than
'teachers/educators' and are described as being 'interviewed' by the
'students'.One GP used the student as a go between to 'get more (info) on
him' (the 'patient/teacher') This was not explicitly part of the project.
The only group which gave their time freely were those who are doing the
educating - in a society where the work people do is largely valued in
monetary terms.
It seemed that once their use on the project was over there was no real
development of the 'participants/teachers' roles, in fact they were
something of a nuisance to some GPs.
They were the only ones who were not given the opportunity to join as a
group for support and discussion amongst themselves - this might add to
their feedback in useful ways.
The researchers and GP tutors might also have alerted individuals to the
existence of support and activist groups where 'empowement' is very much
on the agenda. Researchers, GPs and students would find it informative if
they did meet people with various conditions on 'their own ground' so
that individuals are not so much viewed as 'vulnerable' 'dependant' or
'disempowered'. It is also useful to remember that practitioners as well
as students also have different needs and temperaments, some can become
too possessive, some are uncomfortable with a close relationship - more
research should include an investigation of these factors as well as
simply concentrate on people who agree to take part - usually in research
they have not taken part in drawing up, ie develop more of a partnership
in research and share the benefits more generously.
(PS Were the 'educators' given copies of this write up? - all others will
be aware of the existence of the BMJ)
Competing interests:
None declared
Competing interests: No competing interests
The authors’comment on the late Monsonego et al and S. Labbé rapid responses.
Controversy concerning the article we published recently in the BMJ
came as no real surprise to us. LBC is a very touchy subject in the field
of gynaecological cytology due to commercial and private financial
interests. In this respect, the attitude of some of our French colleagues,
including our co-author S. Labbé, is also unsurprising.
At the start of the study three years ago, we had no preconceived
ideas. The aim of our study was to compare the sensitivity, specificity
and interobserver reliability of conventional Papanicolaou (Pap) smears
(CP), ThinPrep® monolayers (LBC) and Hybrid Capture II system® Human
Papillomavirus (HPV) testing. The intention was not to compare the
efficiency of CP and LBC. Instead, we aimed to investigate whether the
difference in efficiency of LBC and CP was sufficient to justify the
significantly higher cost of LBC. This study was carried out in France.
Although the results are entirely valid for our country, we know that our
medical context (social security reimbursements practices, doctors'
experience) may account for differences from other countries, which might
obtain very different results. Nevertheless, recently published analyses
in other countries that came to the same conclusions (1, 2) were totally
ignored by our French colleagues, who cited only publications reflecting
their own opinion. So, “a French exception”, to quote Monsonego and his
colleagues, cannot really be said to exist here.
Criticism from one's colleagues provides a useful impetus for
improvement if based on scientific criteria. The criticisms made by
Monsonego et al. and S. Labbé concern three key issues:
1/ The split-sample technique;
2/ The biopsy control as a reference test;
3/ The lack of experience of our cytopathologists in reading of the
LBC.
The split-sample technique has been validated by a number of
published articles from various countries, including those on which FDA
approval is based (5), and these studies have shown that LBC is more
efficient than CP (Hutchinson 99; Monsonego 2001). Another argument in
favour of LBC is that 60 to 80 % of the cells remain on the CP spatula or
cervix brush (6). Thus, clearly, in the split-sample technique, these
cells, accounting for up to 80 % of total cells, are immersed in the
PreserVcyt. Another argument used in the marketing of this test is that
the uniform distribution of cells makes all slides representative of the
smear (7). Finally, in 75 % of our cases, after CP and LBC, it was still
possible to carry out the HPV-DNA test (HCII). Thus, clearly, sufficient
numbers of representative cells were available for LBC, even with the
split- sampling technique.
As far as biopsies are concerned, we would like to remind Dr
Monsonego et al. that for the USPSTF, the appropriate reference standard
is colposcopy or histology. We agree that interobserver variability makes
this reference a less than ideal one. However, it is not clear that a
better reference technique exists. In some articles, including one
published by Monsonego et al. (4), the reference is no more than expert
cytological control of the LBC slides. In other more recent studies, the
HPV-DNA test is used as the reference. However, in most scientific
articles, the authors stress that although the HPV-DNA test is more
sensitive than CP, it is also less specific, resulting in a large increase
in the numbers of colposcopy or cytological controls carried out (8). In
other studies including histological control, biopsies were performed some
weeks or months after the Pap-smear was carried out. In our study, all
biopsies were carried out at the same time as the Pap-smear, to prevent
“progression bias”. Furthermore, all biopsy slides were examined twice, by
two different pathologists. Oddly enough, histological control is
considered a very good reference test when the results show LBC to be more
sensitive than CP, even if specificity is very low (9). So, biopsy may not
be a perfect “gold standard”, but it is currently the best option
available.
Clearly, all the cytopathologists in our study have more experience
with CP than with LBC, as in many if not all previous studies, including
the most recent (10). For instance, in the study by Monsonego et al. (4),
all the cytopathologists, including the expert, were highly trained, but
none had any more experience with LBC than the cytopathologists in our
group. Furthermore, in our study, to avoid this “training bias”, all the
LBC were read twice.
So, the criticisms levelled against us appear to result from an
unfair and biased literature analysis. Indeed, it is a source of some
disappointment to us that the main point seems to be that some French
gynaecologists and cytopathologists do not think that the cost of a new
technology should be debated. LBC has a higher immediate cost (11), and no
accurate study has formally demonstrated that the use of this test avoids
later costs. Indeed, a combination of LBC and HPV-DNA has not been
demonstrated to be cost-effective in Europe where, in contrast to the USA,
the cost of colposcopy is very low. In our opinion, reference to American
papers relating to costs are therefore inappropriate.
Finally, we would just like to comment on S. Labbé's rapid response,
because such unusual behaviour may appear very strange. During our study
S. Labbé totally agreed with the protocol, never criticized the
methodology and gave written consent for publication, with no restriction
(PDF copy of the consent form available from J. Coste). At the time of his
rapid response to the BMJ, he had also signed the copyright form for our
next study, concerning the HPV-DNA test, which is currently awaiting
publication in the American Journal of Clinical Pathology……….
1. Australian Medical Services Advisory Committee
http:/www.msac.gov.au
2 United States Preventive Services Task Force (USPSTF)
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B. Cochand-Priollet, MD, MIAC, PhD
Department of Cytology and Pathology
Lariboisière Hospital
2 rue A. Paré
75 745 Paris cedex 10. France
J. Coste, P de Cremoux, C Le Galès, I. Cartier, V. Molinié, MC Vacher
-Lavenu, P. Vielh
Competing interests:
None declared
Competing interests: No competing interests