bmj.com Rapid Responses for Coste et al., 326 (7392) 733

Rapid Responses to:

PAPERS:
Joël Coste, Béatrix Cochand-Priollet, Patricia de Cremoux, Catherine Le Galès, Isabelle Cartier, Vincent Molinié, Sylvain Labbé, Marie-Cécile Vacher-Lavenu, and Philippe Vielh
Cross sectional study of conventional cervical smear, monolayer cytology, and human papillomavirus DNA testing for cervical cancer screening
BMJ 2003; 326: 733 [Abstract] [Full text]

Rapid Responses: Submit a response to this article

Rapid Responses published:

UK definition of inadequate smears reverses the results: Michael Sindos, Narendra Pisal, Stavroula Michala, Teresa Freeman Wang, Albert Singer (9 April 2003)

Evidence-based medicine and Gynecologic Cytology: Jonathan Weintraub (10 April 2003)

OLD IS STILL GOLD!: Monika Malhotra, J.B.Sharma , Raksha Arora (11 April 2003)

Patients referred for colposcopy have favoured conventional smears tests.: Patrick PETIGNAT, Marie-Helene Billieux, Pierre Vassilakos (11 April 2003)

LIQUID BASED CYTOLOGY-A SUCCESS: MICHAEL W WHITLEY (11 April 2003)

Liquid based cytology may be the preferred option for the UK cervical screening programme: Thomas EJ Ind (16 April 2003)

Re: Liquid based cytology may be the preferred option for the UK cervical screening programme: Hugh R Cochrane (16 April 2003)

Liquid based cytology: The current evidence is insufficient!: Volker Schneider (16 April 2003)

Conventional , liquid based cytology and HPV testing comparison: Massimo Confortini, Francesca Carozzi, Stefano Ciatto ,Marco Zappa (17 April 2003)

HPV screening for high grade CIN: William P Soutter (18 April 2003)

teaching is a partnership: susanne stevens, none (23 April 2003)

Methodology: cornerstone of science: Gilbert Bigras (26 April 2003)

LBC: Extra cost not justified: Alexander Meisels (30 April 2003)

French Study Results Split-sample LBC Literature: R.Marshall Austin (2 May 2003)

Liquid based cytology - What is the truth?: Robin P Moseley (3 May 2003)

Basical Bias: Hans Ikenberg (6 May 2003)

Liquid-based cytology versus conventional Pap smear: Hormoz Ehya (13 May 2003)

AGAINST A "FRENCH EXCEPTION" IN CERVICAL CANCER SCREENING:: Joseph MONSONEGO, Roger Dachez,Philippe Birembaut,Christine Clavel,Sylvain Labbe,Robert Marty,Laurent Zerat,Daniel Zarca,Damienne Castaigne,David Elia,Philippe Judlin (25 June 2003)

Co-author criticizes paper: Sylvain Labbe (25 June 2003)

The authors�comment on the late Monsonego et al and S. Labb� rapid responses.: Beatrix Cochand-Priollet, Jo�l Coste, Patricia de Cremoux, Catherine Le Gal�s, Isabelle Cartier, Vincent Molini�, Marie-C�cile Vacher-Lavenu, Philippe Vielh (24 July 2003)

UK definition of inadequate smears reverses the results 9 April 2003

Michael Sindos,
Clinical research fellow
Dept of Women's Health, The Whittington Hospital, London N19 5NF,
Narendra Pisal, Stavroula Michala, Teresa Freeman Wang, Albert Singer
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Re: UK definition of inadequate smears reverses the results

Editor,
We congratulate Joel Coste et al (1) for their study. However, there are a few points that need clarification.
Although the authors have raised the issue of a possible sampling bias in using the split sampling technique, they have easily dismissed it, as they were able to obtain adequate monolayer smears. Adequacy does not necessarily guarantee high quality monolayer smear. Hence, bias from the split sampling technique in favour of conventional cytology cannot be dismissed.
The main contributing factor for higher inadequate rate of monolayer cytology is the absence of endocervical cells (235 out of 328 cases or 72%, table 2). This may be due to the split sampling technique and/or the instrument used for the collection of samples, but the later is not described in the methods section. A cervex� brush is recommended for the collection of monolayer cytology samples. It is also important to note that in the United Kingdom, the presence of endocervical cells is not essential for a cervical smear to be reported as adequate (2). Exclusion of these cases actually reverses the results in favour of monolayer cytology (161 inadequate conventional smears versus 93 inadequate monolayer ones).
There is total absence of data about smears showing glandular abnormalities. Given the increasing incidence of glandular lesions, it would be interesting to know how the examined techniques perform in the detection of glandular abnormalities. Previous studies have suggested that monolayer cytology is inadequate in detection of glandular abnormalities, necessitating the introduction of the cell block preparation as a complementary technique (3).
In the presence of interobserver variability, optimised interpretation was obtained from an independent cytopathologist. This does not exclude bias, as the independent cytopathologist is likely to be more experienced in interpretation of conventional rather than monolayer cytology, which is a new technique.
The cost-effectiveness of a screening programme based on monolayer cytology and HPV testing has not yet been conclusively proven (4), although the interim report of the population based study conducted by the National Institute of Clinical Excellence (NICE) suggests that monolayer cytology may be more cost effective than conventional cytology (5). Though the methodological errors in the present study cannot be ignored, we agree with the authors that conventional cytology remains important at present.
References
1. Coste J, Cochand-Priollet B, De Cremoux P, Le Gales C, Cartier I, Molinie V, Labbe S, Vacher-Lavenu MC, Vielh P. Cross sectional study of conventional cervical smear, monolayer cytology, and human papillomavirus DNA testing for cervical cancer screening BMJ 2003;326: 733.
2. Achievable standards, benchmarks for reporting and criteria for evaluating cervical cytopathology. NHSCSP Publication No 1 May 2000.
3. Richard K, Dziura B, Hornish A. Cell block preparation as a diagnostic technique complementary to fluid-based monolayer cervicovaginal specimens. Acta Cytol 1999;43: 69-73.
4. Merea E, Le Gales C, Cochand-Priollet B, Cartier I, de Cremoux P, Vacher-Lavenu MC, Vielh P, Coste J. Cost of screening for cancerous and precancerous lesions of the cervix. Diagn Cytopathol 2002;27: 251-7.
5. 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: � None declared

Evidence-based medicine and Gynecologic Cytology 10 April 2003

Jonathan Weintraub,
Pathologist
Laboratoire Weintraub, S.A., 22 ch Beausoleil, 1206 Geneva, Switzerland
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Re: Evidence-based medicine and Gynecologic Cytology

Dear Sir: As a current user of thin layer technology in Switzerland I read with interest the coverpage entitled "This week in BMJ" and the accompanying article by Coste et al. in which different techniques in gynecologic cytology were evaluated. Curiously, I could not find any comments in the article by the authors concerning whether replacement of the conventional Pap smear by liquid based methods should be reconsidered. I therefore wonder on what basis did the editors of the journal arrive at this needlessly provocative and unsubstantiated statement in the name of the authors ? It is also of interest to me that the editors of the British Medical Journal (BMJ), which is not a dedicated journal in the field of pathology or cytopathology, should have chosen to review and publish the study by Coste et.al. and to introduce it in this manner. Perhaps, prior to publication, the editors should have consulted with (1) the cytology program in Scotland which has evaluated these techniques and decided to implement them and (2) with the National Health Service (NHS) itself which has recently completed studies at two pilot sites in England evaluating liquid based technology for future implementation and which has reported significant advantages over conventional methods for at least one of these technologies. Perhaps what should be reconsidered is whether the tabloid nature of the editors comments has any place in the medical literature and whether these comments reflect on the ability of the editors to appropriately and objectively select the manuscripts that are submitted to them.
In addition, at the current time, medicine is practiced on the basis of the evidence. How does the weight of the evidence from 1 small "split sample" study in which the results from 2500 tests are analyzed compare with the weight of the evidence generated from 10 "direct to vial" or "intended use" studies and 1 meta analysis published in 9 peer reviewed journals in which the results of 510,000 patients are presented ? It defies common sense, let alone objective analysis , to equate the two.
Competing interests: The employer of JW has been reimbursed by Cytyc for his travel expenses for attending several European conferences. He has no stock ownership, has received no consultants fees, has no employment relationship, no funding for staff or other support.

OLD IS STILL GOLD! 11 April 2003

Monika Malhotra,
Senior Research Associate
Deptt.of Obstetrics & Gynaecology, M.A.M.C & L.N.HOSPITAL, NEW DELHI ,INDIA,
J.B.Sharma , Raksha Arora
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Re: OLD IS STILL GOLD!

The results of the crossectional study by Coste et al (1) comparing conventional cervical smears, monolayer cytology and HPV DNA are definitely good news for the developing countries with low resource settings. Although it comes as a surprise considering the abandonement of the conventional Pap's smear in some countries after substantial research in favor of new techniques , it is encouraging to know that old still remains gold .
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The contrasting results of Limaye et al (2) found a greater than 100 % increase in detection rate of squamous intraepithelial lesions and a decrease in false negative rates by monolayer cytology but another analysis showed that the addition of two new tests (monolayer cytology and HPV DNA )on a routine basis would increase the detection rate of high grade abnormalities form 1% to 1.05 % with a cost increase of $30 million per annum in Victoria alone (3) making such ventures impractical in the third world countries. Thus the revalidation of the fact by this study that dumping the preexisting techniques for fancy, expensive ones would not be always advantageous is appreciated .
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The results of the study would have a great bearing on the screening strategies in developing countries where the conventional Pap's smear now needs to be implemented with added vigour in a universal, organised and population based manner in all women rather than a handful of low risk women who have access to the health services. It is also time to explore other inexpensive 'point of care ' and "real time" diagnostic techniques such as visual inspection of cervix after acetic acid which has exceeded reported rates for conventional cervical cytology in some studies ( 4 ) .A combination of such techniques would be most cost effective in a country like India with limited resources .
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The problem of false negative results with conventional Pap's should be tackled with improved smear obtaining and evaluating techniques rather than resorting to less valid, less reliable and more expensive methods (5 ). HPV testing may be warranted in some clinical situations but the use should be selective and may be limited to triage in patients with atypical squamous cells of undetermened significance and low grade squamous intraepithelial lesions(6).
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REFERENCES
1.Jo�l Coste, B�atrix Cochand-Priollet, Patricia de Cremoux, Catherine Le Gal�s, Isabelle Cartier, Vincent Molini�, Sylvain Labb�, Marie-C�cile Vacher-Lavenu, and Philippe Vielh .Cross sectional study of conventional cervical smear, monolayer cytology, and human papillomavirus DNA testing for cervical cancer screening. BMJ 2003; 326: 733 (5 April)
2.Limaye A,Connor AJ , Huang X , Luff R. Comparitive analysis of conventional Papicolaou tests and fliud based thin layer method . Arch Pathol Lab Med 2003 FEB ;127 (2) ; 200-4.
3.Heley S.Is Pap's smear enough ? Aust Fam Physician 2001 Jun (6) : 535-8
4.Belinson JL, Pretorius RG , Zhang WH, Wu LY , Qiao YL , Elson P. Cervical cancer screening by simple visual inspection after acetic acid. Obstet Gynecol 2001 Sep : 98 (3) : 441-4.
5.Merea E, Le Gales C , Cochand -Priollet B , Cartier I, Cremoux P , Vacher- Lavenu MC et al .Cost of screening for cancerous and precancerous lesions of the cervix. Diag Cytopathol 2002; 27 :251-257.
6.Nuovo J, Melnikow J , Howell LP . New tests for cervical cancer screening. Am Fam Physician , 2001 Sept 1 ; 64 (5) :780-6.
Competing interests: � None declared

Patients referred for colposcopy have favoured conventional smears tests. 11 April 2003

Patrick PETIGNAT,
Fellow in Gynaecology Obstretics
University Hospitals of Geneva, Boulevard de la Cluse 30, 1211 GENEVA 14.,
Marie-Helene Billieux, Pierre Vassilakos
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Re: Patients referred for colposcopy have favoured conventional smears tests.

We have read with great interest the paper of Coste and colleagues regarding the diagnostic performance of conventional and monolayer smears [1]. They observed an improvement in the detection rate of precancerous lesions with conventional smears as compared with monolayer smears; however, we believe that a bias has favoured the conventional test to the detriment of the monolayer test.
The investigators have recruited two groups of patients; one includes �women attending for routine smears� and the other �women referred for colposcopy�. Sensitivity was similar for both tests in �women attending for routine smears� but was better for conventional cytology in �women referred for colposcopy�.
The problem arises with the inclusion for sampling of this latter group of patients who had already been diagnosed as having squamous intraepithelial or cancer lesions. The reason being that the women referred for colposcopy had cytological abnormalities previously identified by one of the two tests (in France, women are mostly screened by conventional test only). It can be presumed that the group of patients with lesions identified by the conventional test may be different if the group had been identified by the monolayer test. It is well recognized that studies conducted under selected conditions (known positive cases) do not reflect the diagnostic sensitivity of routine laboratory conditions.
This is a key problem that should be addressed by the authors who should probably exclude from the present analysis �women referred for colposcopy� and evaluate the sensitivity of the tests in the �real routine world� of cervical cancer screening.
Reference: Coste J, Cochand-Priollet B, de Cremoux P, Le Gal�s C, Cartier I, Molini� V et al. Cross sectional study of conventional cervical smear, monolayer cytology, and human papillomavirus DNA testing for cervical cancer screening. BMJ 2003;326:1-5.
Competing interests: � None declared

LIQUID BASED CYTOLOGY-A SUCCESS 11 April 2003

MICHAEL W WHITLEY,
General Practitioner
Moira Park Surgery, 54 Moira Park, Edinburgh EH7 6RU
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Re: LIQUID BASED CYTOLOGY-A SUCCESS

The results of Joel Coste and his colleagues should be interpreted with some caution. They raise qeustions about the validity of such a small group of 2585 and of split sampling. An analysis is required concerning the level of training of smear takers, laboratory staff and cytopathologists. The contrast in appearance between conventional smears versus thin layer slides will make it difficult to eliminate bias.
In Lothian, 15 practices, which include areas of highest urban deprivation, are now in their fourth year of using thin prep samples as part of the routine cervical smear programme. The results are as follows:
Year before LBC 2.5 years of LBC sampling Total smears 8670 21,802 Unsatisfactory 10% 0.6% Borderline and CIN I 6.6% 5.2% CIN II+CINIII 1.4% 1.5% Adenocarcinoma (2 patients) Negative 82% 92.2%

80% of Lothian practices have had to continue to use conventional slide cytology and their results continue to match the "before" data for the fifteen practices. Pathology at colposcopy, which like cytology can only be a subjective report, also supports these results.
The reduction in unsatisfactory smears has had an immediate benefit to patients through reduced anxiety and fewer recalls, with a significant reduction in primary care and laboratory workload. The sensitivity of detection of high grade lesions ensures a more efficient progression to appropriate treatment.
The Scottish Executive Health Department are to be commended in their decision to improve services to Scottish patients by rolling out liquid based cytology across Scotland by 2004. In reaching this decision there was political concensus and no personal nor commercial bias.
NICE guidelines will be published on 14 April 2003 which should provide further objective analysis for the future of the cytology screening programme.
Competing interests: � None declared

Liquid based cytology may be the preferred option for the UK cervical screening programme 16 April 2003

Thomas EJ Ind,
Consultant Gynaecological Oncologist
Royal Marsden Hospital, Fulham Road, London SW3 6JJ
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Re: Liquid based cytology may be the preferred option for the UK cervical screening programme

The National Institute of Clinical Excellence (NICE) will soon make a decision whether or not liquid based cytology (LBC) should be utilised in the UK. Therefore, the paper by Coste et al 1 is extremely timely. However, it is important to interpret the paper 1 in relation to others and to assess it�s 1 relevance to the National Health Service Cervical Screening Programme (NHSCSP).
The study 1 is a small one by cervical screening standards. Other much larger studies also exist 2 & 3. Furthermore, this is a split sample study with the traditional smear performed in the usual manner and the monolayer smear performed on residual cells left on the spatula 1. It is not clear from the paper 1 or the referred paper 4 exactly how the smears were taken. Data exists indicating that this type of study design is faulty with less endocervical cells left for analysis of the LBC 5. This was also the finding in the current study 1. Therefore, we must ask if this design fault might also have affected the sensitivity that differs from other larger studies 2 & 3.
We must also assess the relevance of this study 1 to the screening programme in the UK. The NHSCSP does not use the Bethesda classification system that was used in the study 1. In the current study 1, all but a few conventional smears were adequate possibly because they were reported by expert cytopathologists. In the UK we accept 5% of conventional smears as being inadequate and the introduction of LBC may significantly reduce this figure.
The Kent & Canterbury scandal and others highlighted the difficulties in smear reporting. Monolayer slides are easier to interpret and it is hoped that this may help prevent another regrettable scandal. The current weight of evidence is currently in favour of LBC and we eagerly await the results of the NICE pilot study. Although interesting and perhaps relevant to France, the current study 1 should not influence NICE. It contains faults in it�s design, is small in relation to other studies, and is irrelevant to the practical aspects of cervical screening in the UK.
Thomas Ind
Consultant Gynaecological Oncologist
Royal Marsden Hospital, Fulham Road, London SW3 6JJ
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 � 7.
2. Weintraub J, Morabia A. Efficacy of a liquid-based thin layer method for cervical cancer screening in a population with a low incidence of cervical cancer. Diagn Cytopathol 2000; 22: 52 � 9.
3. Limaye A, Connor AJ, Huang X, Luff R. Comparative Analysisof Conventional Papanicolaou Tests and a fluid�based thin-layer method. Arch Pathol Lab Med 2003; 127: 200 �204.
4. Cochand-Priollet B, Le Gales C, de Cremoux P, Molinie V, Sastre- Garau X, Vacher-Lavenu MC, et al. Cost effectiveness of monolayers and human papillomavirus testing compared to that of conventional Papanicolaou smears for cervical cancer screening: protocol of the study of the French Society of Clinical Cytology. Diagn Cytopathol 2001; 24: 412 � 420.
5. Corkill M, Knapp D, Martin J, Hutchinson ML. Specimen adequacy of ThinPrep sample preparations in a direct-to-vial study. Acta Cytologica 1997; 41: 39 � 44.
Competing interests: � None declared

Re: Liquid based cytology may be the preferred option for the UK cervical screening programme 16 April 2003

Hugh R Cochrane,
Consultant Histopathologist
Sunderland Royal Hospital, Sunderland, SR4 7TP, UK
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Re: Re: Liquid based cytology may be the preferred option for the UK cervical screening programme

I agree with Mr Ind's well-made points. I draw the attention of readers to the National Institute for Clinical Excellence (NICE) consultation document on the use of liquid based cytology in cervical screening which was placed on the NICE website (http://www.nice.org.uk/article.asp?a=65850)on 14th May 2003. Responses are invited - but note these have to be returned by 5th May 2003.
Competing interests: None declared

Liquid based cytology: The current evidence is insufficient! 16 April 2003

Volker Schneider,
Pathologist
Pathology Laboratory, Burgunderstr. 1, 79104 Freiburg, Germany
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Re: Liquid based cytology: The current evidence is insufficient!

Anybody interested in a study on liquid based cytology independent of manufacturers and providers of the test should definitely look up the report of the Australian Medical Services Advisory Committee (AMSAC), just published in March 2003. It is a 106 page study of the current evidence.
It comes to the conclusion that the lack of high quality evidence on the performance of liquid based cytology does not permit evaluation of whether it is equal or superior in effectiveness to conventional Pap smears. It also concludes that there is no evidence to suggest that liquid based cytology would be cost effective at the proposed price. This report seems to support the conclusions drawn by Coste et al in the current study.
The report can be downloaded at: http://www.msac.gov.au.
Competing interests: � None declared

Conventional , liquid based cytology and HPV testing comparison 17 April 2003

Massimo Confortini,
chief of analitycal and biomolecular cytological
Center for prevention cancer Viale Volta 171 50131 Florence,
Francesca Carozzi, Stefano Ciatto ,Marco Zappa
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Re: Conventional , liquid based cytology and HPV testing comparison

To the editors:
We read with interest the article by J Coste et al 1 on the performance of conventional cervical smear in comparison with liquid based cytology ( LBC) and Human Papilloma Virus testing:the reported results are a bit surprising in contrast with most of the previous reports on the issue 2,3,4.
Some technical points need to be discussed
First, the frequency of unsatisfactory smears is very low, either with conventional or monolayer technique. As previously reported 5, split sample increases the number of inadequacy at monolayer due to scant squamous cells still available after conventional smearing: this bias may justify the high proprtion (out of 11) of inadequates due to scant cells in the monolayer subset. On the contrary, the high rate of inadequates due to obscuring blood in the monolayer subset (5 cases as compared to no case in conventional smear subset), as obscuring blood should be reduced by the monolayer procedure and is usually quite low 2 , as confirmed, in the present study, by the lower frequency (25 vs 36 cases) of obscuring blood among satisfactory but limited (SBLB) smears.
Among SBLB the absence of endocervical cells is significantly higher: in our experience we noted initial difficulties for readers in recognizing endocervical cells in liquid based cytology, as they are often isolated or in small groups, overspread on the whole slide. The authors underline the limited experience of readers in LBC reporting: as experience in one determinant of performace, this could have acted as a further bias of the study towards an underestimate of LBC performance, which should be ideally determined in a routine setting.
Overall, the study suggests a lower sensitivity of LBC as compared to conventional smear techniques but the biases introduced by using a split sample methodology and by theb the limited experience of readers in LBC may have strongly influenced such findings. Proper comparation of the two sampling techniques, should be better vases on study employing a direct to vial methodology and expert readers.
A very low sensitivity of HPV test was also evidenced for monolayer technique, and probably, also in this case, the split sample methodology could have altered the results. In the article of J Coste et al. the test has not been carried out in about one third of cases for insufficient cellularity: in our experience we had only 1% inadequates in samplings for thin layer and HPV on the reflex 6. HC II test is generally reported as a very sensitive method for identifying high grade lesions 3,4 as confirmed in our study with a 100% HCII positive rate for histologically confirmed high grade lesions (see table 1).
Table 1 Distribution of cases according to positivity in HPV DNA testing Cytology Punch biopsy HCII HSIL CIN2/3 12/12(100%) HPV/CIN1 7/9 (77.7%) Negative 2/2 (100%) Total 21/23 (91.3%) LSIL CIN2/3 8/8 (100%) HPV/CIN1 36/36 (100%) Negative 15/20 (75%) Total 59/64 (92.1) ASCUS/AGUS or less CIN2/3 1/1 (100% HPV/CIN1 4/6 (66.6%) Negative 2/17 11.7%) Total 7/24 (29.1%) Modified by Carozzi et Al(6)

References
1)Cross sectional study of conventional cervical smear, monolayer cytology , and human papilloma virus DNA testing for cervical cancer screening.
Coste J , Cochard-Priollet B, de cremoux P, Le Gales C, Cartier I, Molini� V, Labb� S. Vacher.Lavernu M C, Viehl P , for the French Society of Clinical Cytology Study.BMJ 2003;326:
2)Liquid- based cervical cytologic smear study and conventional Papanicolaou smears: a metaaanalysis of prospective studies comparing diagnosis and sample adequacy. Bernstein S J, Sanchez-Ramon L, Nudbisi B. Am J obstet Gynecol 2001;185:308-315
3)Cuzick J, Sasieni P, davies P et Al .HPV testing of older women :Br J Cancer 1999;81:554-558 .
4)Clavel C, masure M, Bory JP, PuitardI et Al . Hybrid capture II based human papillomavirus detection, a sensitive test to detect in routine high -grade cervical lesions: a preliminary study on 1518 women. Br J cancer 1999;80:1306-1311
5) Aponte-Cipriani SL, Teplitz C, Rorat E, savino A , Jacobs A J Cervical smears prepared by an automated device versus the conventional method. A comparative analysis.Acta Cytol 1995;39:623.30
6) Carozzi F, Confortini M, Cecchini S, Ciatto S.HPV testing for cervical neoplasia. Acta Cytol 2001;45:659-660
Competing interests: � None declared

HPV screening for high grade CIN 18 April 2003

William P Soutter,
Reader in Gynaecological Oncology
Hammersmith Hospital, Du Cane Rd, London W12 0HS
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Re: HPV screening for high grade CIN

I disagree with Dr Coste and his colleagues' conclusion that their study shows HPV testing has no higher sensitivity than conventional cytology.
Cervical screening is applied to a healthy population with the intention of identifying those with CIN grade II and above. In table 3, they report that the sensitivity of HPV testing in this context is 96% while that of conventional cytology is only 51%. The specificity of cytology is greater than that of HPV testing.
Surely the way to use HPV testing is to use it as the initial screening test, reasuring those with negative tests that it is very unlikely indeed that they have high-grade CIN and using cytology only on those who test positive with HPV. This would utilise an objective test that can be easily automated to select the high-risk population upon which the skills of the cytologist can then be focussed. This model of cervical screening deserves to be tested prospectively.
Competing interests: None declared

teaching is a partnership 23 April 2003

susanne stevens,
retired
cardiff cf24 3pf,
none
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Re: teaching is a partnership

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

Methodology: cornerstone of science 26 April 2003

Gilbert Bigras,
Pathologist
Laboratoire Cytopath Unilabs (Carouge Gen�ve)
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Re: Methodology: cornerstone of science

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

LBC: Extra cost not justified 30 April 2003

Alexander Meisels,
Emeritus Professor of Pathology
Laval University, Quebec, Canada
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Re: LBC: Extra cost not justified

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

French Study Results Split-sample LBC Literature 2 May 2003

R.Marshall Austin,
Clinical Associate Professor
Coastal pathology laboratories & Med Univ Sc
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Re: French Study Results Split-sample LBC Literature

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.

Liquid based cytology - What is the truth? 3 May 2003

Robin P Moseley,
Consultant Cytopathologist
Addenbrooke's Hospital, Cambridge, UK, CB2 2QQ
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Re: Liquid based cytology - What is the truth?

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

Basical Bias 6 May 2003

Hans Ikenberg,
gynecologist, cytopathologist
Wagner+ Partners Gynecologists and Clinical Chemists Medical Partnership D-31848 Bad M�nder
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Re: Basical Bias

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, B�hmer G, Iftner T, Brummer O, K�hnle 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.

Liquid-based cytology versus conventional Pap smear 13 May 2003

Hormoz Ehya,
Senior Member and Director of Cytopathology
Fox Chase Cancer Center, Philadelphia, Pennsylvania, 19111, USA
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Re: Liquid-based cytology versus conventional Pap smear

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

AGAINST A "FRENCH EXCEPTION" IN CERVICAL CANCER SCREENING: 25 June 2003

Joseph MONSONEGO,
Gynecologist Oncologist
INSTITUT FOURNIER 25 Boulevard Saint Jacques 75014 Paris FRANCE,
Roger Dachez,Philippe Birembaut,Christine Clavel,Sylvain Labbe,Robert Marty,Laurent Zerat,Daniel Zarca,Damienne Castaigne,David Elia,Philippe Judlin
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Re: AGAINST A "FRENCH EXCEPTION" IN CERVICAL CANCER SCREENING:

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. Congr�s Hebdo, Eurogin 2003 � Pr�vention du cancer du col: vers de nouvelles pratiques, Le Quotidien du M�decin, 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

Co-author criticizes paper 25 June 2003

Sylvain Labbe,
Pathologist
6 Rue de Suede 17024 La Rochelle Cedex France
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Re: Co-author criticizes paper

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 Besan�on 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

The authors�comment on the late Monsonego et al and S. Labb� rapid responses. 24 July 2003

Beatrix Cochand-Priollet,
Pathologist- Associate professor
Lariboisi�re Hospital, 10 rue A. Par�, Paris 75 010. France,
Jo�l Coste, Patricia de Cremoux, Catherine Le Gal�s, Isabelle Cartier, Vincent Molini�, Marie-C�cile Vacher-Lavenu, Philippe Vielh
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Re: The authors�comment on the late Monsonego et al and S. Labb� 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. Labb�, 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. Labb� 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. Labb�'s rapid response, because such unusual behaviour may appear very strange. During our study S. Labb� 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) http:/www.aafp.org/afp/20030415/us.html
3 Hutchinson ML, Zahniser DJ, Sherman ME, Herrero R, Alfaro M, Bratti MC et al. Utility of liquid-based cytology for cervical cancer screening. Results of a population-based study conducted in a region of Costa Rica with a high incidence of cervical carcinoma. Cancer Cytopathology 1999; 87 : 48-55
4. Monsonego J, Autillo-Touati A, Bergeron Ch, Dachez R, Liaras J, Saurel J et al. Liquid-based cytology for primary cervical cancer screening. A multicentre study. Br J Cancer 2001; 84 : 360-6
5. Lee K.R. Comparison of conventional Papanicolaou smears and a fluid-based, thin-layer system for cervical cancer screening. Obstetrics Gynecol 1997 ; 90 : 278-84
6 Goodman A, Hutchinson ML. Cells surplus on sampling devices after routine cervical cytologic smears. A study of residual cell populations. J Reprod. Med 1996; 41 : 239-41
7. Hutchinson ML. Homogeneous sampling accounts for the increased accuracy using the ThinPrep� processor. Am J Clin. Pathol 1994; 101 : 215-9
8 HPV testing for triage of women with cytologic evidence of low grade squamous intraepithelial lesions. Baseline data from a randomized trial. The ASCUS/LGSIL Triage Study (ALTS) group. J Natl Cancer Inst. 2000; 92 : 397-402
9 Belinson JL, Pan QJ, Biscotti C, Wu LY, Pretorius RG, Li L, Elson P, Rong SD, Zhang WH and Qiao YL. Primary screening with liquid-based cytology in an unscreened population in rural China, with an emphasis on reprocessing unsatisfactory samples, Acta Cytol 2002 ; 46 : 470-4.
10 Chacho MS, Mattie ME, Schwartz PE. Cytohistologic correlation rates between conventional Papanicolaou smears and ThinPrep cervical cytology: a comparison. Cancer Cytopathology 2003; 99 : 135-40
11 Merea E, LeGal�s C, Cochand-Priollet B, Cartier I, de Cremoux P, Vacher-Lavenu MC et al. The cost of screening for cancerous and precancerous lesion of the cervix. Diagn Cytopathology 2002; 27 : 251-7
B. Cochand-Priollet, MD, MIAC, PhD Department of Cytology and Pathology Lariboisi�re Hospital 2 rue A. Par� 75 745 Paris cedex 10. France
J. Coste, P de Cremoux, C Le Gal�s, I. Cartier, V. Molini�, MC Vacher -Lavenu, P. Vielh
Competing interests: None declared