Conventional Pap Smear verses liquid base cytology for Cervical Cancer Screening Symposium- World Congress on Recent Advances in Obstetrics and Gynecology Mumbai, 2009 Vinod B. Shidham, MD, FRCPath, FIAC Vice-chair & Professor Director of Cytopathology, Cytotechnology School, Cytopathology fellowship Dept of Pathology, Wayne State University Medical School Detroit, MI 48201, USA Co-editor-in-chief & Executive editor, CytoJournal (www.cytojournal.com) vshidham@med.wayne.edu

Pap stained Conventional, SurePath, & ThinPrep cervical smears Conventional SurePath ThinPrep

http://bethesda2001.cancer.gov/terminology.html

SQUAMOUS CELL Atypical squamous cells - of undetermined significance (ASC-US) - cannot exclude HSIL (ASC-H) Low grade squamous intraepithelial lesion (LSIL) encompassing: HPV/mild dysplasia/CIN 1 High grade squamous intraepithelial lesion (HSIL) encompassing: moderate and severe dysplasia, CIS/CIN 2 and CIN 3 - with features suspicious for invasion (if invasion is suspected) Squamous cell carcinoma GLANDULAR CELL AGUS Atypical (NOS) - endocervical cells (NOS or specify in comments) - endometrial cells (NOS or specify in comments) - glandular cells (NOS or specify in comments) Atypical (favor neoplastic) - endocervical cells, favor neoplastic - glandular cells, favor neoplastic Endocervical adenocarcinoma in situ Adenocarcinoma - endocervical, endometrial, extrauterine, and not otherwise specified (NOS) OTHER MALIGNANT NEOPLASMS: (specify) EPITHELIAL CELL ABNORMALITIES

Davey E et al. Effect of study design and quality on unsatisfactory rates, cytology classifications, and accuracy in liquid-based versus conventional cervical cytology: a systematic review. Lancet 2006; 367: 122–132 Interpretation We saw no evidence that liquid-based cytology reduced the proportion of unsatisfactory slides, or detected more high-grade lesions in high-quality studies, than conventional cytology. This review does not lend support to claims of better performance by liquid-based cytology. Large randomised controlled trials are needed. 56 primary studies were reviewed and assessed with strict methodological criteria.

Obwegeser J, Schneider V. Comment- Thin-layer cervical cytology: a new meta-analysis. Lancet. 2006 Jan 14;367(9505):88-89. The standards for study quality set by Davey were not excessively high: an “independent randomised sample study, with verification by a masked reference standard, of at least all positive slides” (see table 2 in the article). Yet not a single study fulfilled these requirements. The authors did not even ask that negative slides were referenced, which would have been unrealistic in a screening situation. Interestingly, a study by Lee and colleagues, which led the US Food and Drug Administration (FDA) to approve a commercial product of thin-layer cytology, was classified by the authors as being of poor quality. This raises questions about the validity of such regulatory procedures, particularly because FDA approval is heralded as a sign of high quality. -----of 147 articles originally culled from the literature, only 56 fulfilled the inclusion criteria for the study by Davey and colleagues. Of those 56 papers, none was of ideal quality; only five were of high quality, 32 of medium quality, and 19 of low

Lee KR, Ashfaq R, Birdsong GG, Corkill ME, McIntosh KM, Inhorn SL. Comparison of conventional Papanicolaou smears and a fluid-based, thin-layer system for cervical cancer screening. Obstet Gynecol 1997; 90: 278–284.

The most common problems with study design were deficiencies in randomisation and blinding------ Obwegeser J, Schneider V. Comment- Thin-layer cervical cytology: a new meta-analysis. Lancet 2006 Jan 14;367(9505):88-89.

Why then is liquid-based cytology being introduced in some countries? To answer this question, differences between different countries’ health-care systems must be taken into account. Clearly, in the USA the incentive is partly monetary. After FDA approval, insurance companies were ready to pay considerably higher fees for liquid-based smears than for conventional smears. That led, understandably, to a rapid conversion to this new technology in a market-driven health-care system. In addition, the remaining liquid of thin-layer cytology provides an ideal platform for additional tests—whether or not they are necessary. In England and Scotland, with a nationalised health-care system, the central decision makers were convinced that this technique would improve their problem of a very high unsatisfactory rate. In continental Europe funding agencies were much more restrictive, and tended not to provide additional funding for thin-layer cytology, because the methods are considered equal in their accuracy. Therefore, in Switzerland and France for example, it is left to the pathologist to decide which method is used, with the same fee for both methods. Besides quality of study design, other factors, such as health-care system, reimbursement pattern, and legal background, will influence the diagnostic approach. -------------- Obwegeser J, Schneider V. Comment- Thin-layer cervical cytology: a new meta-analysis. Lancet 2006 Jan 14;367(9505):88-89.

Ronco G et al. Accuracy of liquid based versus conventional cytology: overall results of new technologies for cervical cancer screening: randomised controlled trial. BMJ 2007;335:28 doi:10.1136/bmj.39196.740995.BE (published 21 May 2007) Conclusion LBC showed no statistically significant difference in sensitivity to conventional cytology for detection of cervical intraepithelial neoplasia of grade 2 or more. More positive results were found, however, leading to a lower positive predictive value.

Editorial Sawaya GF, Sox HC. Trials That Matter: Liquid-Based Cervical Cytology: Disadvantages Seem to Outweigh Advantages. Ann Intern Med. 2007;147:668-669. Users of liquid-based cytology should reconsider their decision to adopt this technology and ponder whether the harms to patients outweigh the benefits to the clinical laboratory. Those who use this technique for primary cervical cancer screening in women older than 30 years of age because it is easy to combine with HPV testing should realize that the USPSTF considers the evidence to be insufficient to endorse this strategy. Finally, clinicians who use the conventional technique should not feel that their patients are receiving substandard care; indeed, current best evidence suggests the opposite conclusion.

Arbyn M, Bergeron C, Klinkhamer P, Martin-Hirsch P, Siebers AG, Bulten J. Liquid compared with conventional cervical cytology: a systematic review and meta-analysis. Obstet Gynecol. 2008 Jan;111(1):167-177. DATA SOURCES: Eligible studies, published between 1991 and 2007, were retrieved through PubMed/EmBase searching and completed by consultation of other sources. CONCLUSION: Liquid-based cervical cytology is neither more sensitive nor more specific for detection of highgrade cervical intraepithelial neoplasia compared with the conventional Pap test.

Arbyn M, Bergeron C, Klinkhamer P, Martin-Hirsch P, Siebers AG, Bulten J. Liquid compared with conventional cervical cytology: a systematic review and meta-analysis. Obstet Gynecol. 2008 Jan;111(1):167-177. 126 reports from 109 studies that described test positivity and/or adequacy rates in both conventional Pap and liquid-based cytology 60 studies applied the concomitant testing design. Only 7 verified the cytologic results with the standard reference test. In 2007, only 8 studies and 1 well-conducted randomized trial are available that allow unbiased evaluation of the accuracy of liquid-based cytology for histologically confirmed CIN 2 or worse. Pooling of these studies indicated that liquid-based cytology is neither more sensitive nor more specific than conventional Pap and these findings were rather consistent over study design, clinical settings, and liquid-based cytology systems.

Sawaya GF. Evidence-based medicine versus liquid-based cytology. Obstet Gynecol. 2008 Jan;111(1):2-3. If nothing else, Arbyn’s review suggests that the saga of liquid-based cytology be added to the list of cautionary tales in women’s health. In our new age of direct-to-consumer advertising, clinicians now have a new role as arbiters between rational, evidence-based care and marketing exuberance. We all have the power and responsibility to make wise choices, and our patients certainly deserve no less. How could a technology be so widely implemented before the appropriate studies have been performed to assess benefits and harms? Reasons are myriad. Many clinicians likely converted to liquid-based------------- Others may have converted to liquid-based cytology due to factors seemingly beyond their control--------:

Based on personal experience and review of literature LBC may only achieve- Reduced unsatisfactory rate Shorter evaluation time The same sample for HPV testing / molecular tests

Conclusion: Despite its many advantages in providing standardization of specimen preparation, superb cellular presentation, reduction in the number of unsatisfactory reports and increased lesion detection rate, ThinPrep has its own limitations in terms of technical problems, ease of operation and cost effectiveness. L H Song, E S T Goh, L C Phang, W T Poh, S K Tay. Technical Aspect of ThinPrep. Singapore Med J 2000 Vol 41(12) : 575-578

LBC may offer standardized option to implement imaging and automation

Davey E, d'Assuncao J, Irwig L, Macaskill P, Chan SF, Richards A, Farnsworth A. Accuracy of reading liquid based cytology slides using the ThinPrep Imager compared with conventional cytology: prospective study. BMJ. 2007 Jul 7;335(7609):31 Conclusion: The ThinPrep Imager detects 1.29 more cases of histological high grade squamous disease per 1000 women screened than conventional cytology, with cervical intraepithelial neoplasia grade 1 as the threshold for referral to colposcopy. More imager read slides than conventional slides were satisfactory for examination and more contained low grade cytological abnormalities.

Thrall MJ, Russell DK, Bonfiglio TA, Hoda RS. Use of the ThinPrep® Imaging System does not alter the frequency of interpreting Papanicolaou tests as atypical squamous cells of undetermined significance. Cytojournal 2008;5:10. Chivukula M, Saad RS, Elishaev E, White S, Mauser N, Dabbs DJ. Introduction of the Thin Prep Imaging System (TIS): experience in a high volume academic practice. Cytojournal 2007;4:6. M Ruhul Quddus, Theresa Neves, Mary E Reilly, Margaret M Steinhoff, C James Sung. Does the ThinPrep Imaging System increase the detection of high-risk HPV-positive ASC-US and AGUS? The Women and Infants Hospital experience with over 200,000 cervical cytology cases. CytoJournal 2009;6:15 ThinPrep Imaging System

However, this may be relative. In future, standardized staining option may be applied for imaging and automation for conventional Pap also

Some critical benefits of conventional smears are lost in LBC

Company of abnormal cells in close proximity to each other instead of getting them dispersed in collection fluid of LBC and so may be scattered as solitary cells or small groups difficult to detect and easy to miss

CIN 2 Conventional

http://nih.techriver.net/patientImagesHighRes/6322.jpg?content-type=download ASC-H Source: Conventional

http://nih.techriver.net/patientImagesHighRes/5866.jpg?content-type=download ASC-H Source: Conventional

HSIL SurePath

HSIL ThinPrep

HSIL SurePath

Some diagnostic pattern better seen in conventional smears may be lost in collection fluid of LBC and may be difficult to interpret Eg- Nuclear feathering of Adenocarcinoma in situ School of fish pattern in Repair Tumor diathesis (including watery diathesis of endometrial carcinoma) Hyperchromatic crowded groups (HCG) are difficult to evaluate (in SurePath than Thin Prep)

Causes of suboptimal conventional smears- Are mostly technical Air drying Thick smears Scant cellularity Blood And are largely preventable with appropriate understanding of cytoprep principles and proper practicing of smear-preparation.

Cells in smear Live cells Cells in smear (surface view)

Investing efforts in focused training to achieve better sample collection and improved smear preparation/fixation is simple and relatively inexpensive solution.

Take home points Cytomorphologic evaluation although mature science, it also involves significant skill with unavoidable subjectivity. Choice of any cytopreparatory method depends on the interpreter. Cost is one of the crucial factors for successful screening program.

Shidham VB and Atkinson BF. Cytopathologic Diagnosis of Serous Fluids Elsevier (W. B. Saunders Company) First edition, 2007. Acknowledgment Some of the info is based on chapters in:

Thank you Current e-mail address: vshidham@med.wayne.edu End