Since its introduction over fifty years ago, the cervico-vaginal Papanicolaou (Pap) smear has been a powerful tool for detecting cancerous and precancerous cervical lesions. During that time, the Pap smear has been credited with reducing mortality from cervical cancer by as much as 70%. This once precipitous drop in the death rate has slowed however, and has remained virtually constant, at about 1,200 per year since the mid-nineties. About one-third of the women diagnosed with cervical cancer annually still die because the cancer was detected too late.

A number of factors may be contributing to this current threshold, not the least of which is the fact that many women, particularly in high risk populations, are still not participating in routine cervical cancer screening. Another contributing factor that has received much attention is the limitation of the traditional Pap smear method itself.

The reliability and efficacy of a cervical screening method is measured by its ability to diagnose precancerous lesions (sensitivity) while at the same time avoiding false positive diagnosis (specificity). In turn, these criteria are dependent on the accuracy of the cytological interpretation. The conventional Pap smear has false negative rates ranging from 10-50% and up to 90% of those false negatives are due to limitations of sampling or slide preparation. It has been shown that only a small portion of the sample taken from the patient is transferred to the slide; most of it is discarded along with the sampling device. Accurate interpretation of up to 40% of conventional Pap smears are compromised by the presence of blood, mucous, obscuring inflammation, scant cellular material and air-drying artifact.

In order to address these problems, Cytyc Corporation has developed the ThinPrep Pap Test. In May 1996, the Food and Drug Administration (FDA) in the USA approved the ThinPrep 2000 as a replacement for the conventional Pap smear method for use in screening for the presence of atypical cells, cervical cancer or its precursor lesions (Low Grade Squamous Intraepithelial Lesions, High Grade Squamous Intraepithelial Lesions), as well as all other cytologic categories.

On November 6, 1996, the FDA approved revised labeling allowing Cytyc to claim that:

The ThinPrep 2000 System is significantly more effective than the conventional Pap smear for the detection of Low Grade Squamous Intraepithelial (LSIL) and more severe lesions in a variety of patient populations.

Specimen quality with the ThinPrep 2000 System is significantly improved over that of conventional Pap smear preparation in a variety of patient populations.

The heart of the ThinPrep® System is the ThinPrep 2000 Processor, an automated slide preparation unit that produces remarkably uniform thin-layer slides, virtually free of obscuring artifacts such as blood, mucous and inflammation.

OR	Step 1 A gynecologic sample is collected using a broom-type or cytobrush/spatula cervical sampling device.
	Step 2 Instead of smearing the cells on a slide, the sampling device is rinsed into a ThinPrep vial containing PreservCyt^® transport medium. The device is then discarded.
	Step 3 The sample vial is capped, labelled, and sent to the laboratory for slide preparation.
	Step 4 At the laboratory, the vial is placed into the ThinPrep 2000 Processor. First, a gentle dispersion step breaks up blood, mucous, non-diagnostic debris, and then thoroughly mixes the sample. A negative pressure pulse is generated which draws fluid though a TransCyt^® Filter that collects a thin, even layer of diagnostic cellular material. The ThinPrep 2000 Processor constantly monitors the rate of flow through the TransCyt Filter during the collection process to prevent the cellular presentation from being too scant or too dense. The cellular material is then transferred to a glass slide and fixed.

The ThinPrep Pap Test does not consume the entire fluid-based sample collected in the specimen vial. Additional diagnostic testing of the residual sample can increase the information yielded by the ThinPrep Pap Test. The greatest opportunity is in human papilloma virus (HPV) typing of samples that show possible, but inconclusive morphologic abnormality. The FDA recently approved HPV testing directly from the PreservCyt vial used for the ThinPrep Pap Test. The National Cancer Institute estimates that about 3.5 million Pap smears are found to be inconclusive each year in the US which often lead to unnecessary colposcopy, biopsy and office visits. The average cost of the standard management of such cases is about $1,200 per case. The NCI estimates the cost to the US health care system at about $3.6 bil. each year. HPV typing of samples diagnosed as ASCUS (atypical squamous cells of undetermined significance), or low-grade squamous intraepithelial lesion may help triage women into conservative follow-up, or colposcopy and biopsy. Such a study is underway by the National Cancer Institute's ALTS trial, which utilizes the ThinPrep Pap Test in conjunctions with HPV DNA typing to assess triage strategies. By using the ThinPrep Pap Test, this determination, that can be performed without a repeat patient examination, may lead to substantial cost savings and more appropriate patient management.

Cervical cancer is a disease that progresses through pre-cancerous and cancerous stages over a number of years. More important, cervical cancer is virtually 100% curable if it is detected and treated appropriately in the earlier stages of progression. Conversely, the cost of treatment increases significantly if cervical disease is discovered at later stages.

The increased rate of detection of disease demonstrated by the ThinPrep Pap Test provides a new level of confidence for laboratories, clinicians and patients. At the same time the significant improvement in specimen quality and the ability to do multiple testing using the same sample, will substantially reduce costs and patient anxiety associated with re-screening and unnecessary follow-up testing.

FDA approval of the ThinPrep® PapTest™ as a replacement for the conventional Pap smear and the claim the ThinPrep Pap Test is "significantly more effective" was based on extensive data submitted from a multi-site pivotal clinical trial. This study of 6747 women was conducted using a matched-pair, double-blinded protocol. The results of this study indicate that the ThinPrep Pap Test significantly increases the detection of low-grade or more severe lesions by 65% in screening populations and 6% for high risk populations when compared with the conventional Pap smear. This study also found that the ThinPrep Pap Test reduced by 29% the number of suboptimal or inadequate slides that frequently prompt the need for a repeat test. This study employed a split-sample, matched-pair protocol in which the conventional smear was made first and then only the residual material was rinsed in to the ThinPrep PreservCyt® vial, therefore, favoring the conventional smear preparation. Further direct-to-vial studies found that when the cervical sampling device is rinsed directly into the vial as it is intended in routine use, the number of suboptimal or inadequate slides could be reduced by greater than 50%.

Following extensive trials in three pilot sites, The National Institute for Clinical Excellence (NICE) issued guidance on the use of liquid based cytology (the generic name for ThinPrep) for cervical screening in October 2003. They recommended that liquid based cytology is used as the primary means of processing samples in the NHS cervical screening programme in England and Wales, although they found that there was insufficient evidence to recommend one LBC product over another.

The NHS in Scotland has thoroughly reviewed the alternative forms of LBC and has selected ThinPrep for all cervical screening in Scotland.

As soon as NICE issued its guidance the U.K. government announced that LBC will be introduced into the screening programme in England and Wales. The first stage will be to select the form of LBC to be used in each area of the country, following which it will be necessary to equip all the NHS laboratories, and to train the cytologists who examine the smears in the laboratories. It will also be necessary to provide training for many of the GPs and Practice nurses who take the smears. The NHS web site estimates that this will take about five years to achieve, and our own research indicates that this is an under estimate.

Does the ThinPrep® Pap Test™ detect more abnormals than the conventional Pap smear?

FDA approval of the ThinPrep Pap Test as a replacement for the conventional Pap smear and the claim that the ThinPrep Pap Test is "significantly more effective" was based on extensive data submitted from a multi-site clinical trial. This study of 6747 women was conducted using a multi-site, double-blinded protocol. Performance based on initial screening was validated by independent pathologist review. The results of this study indicate that the ThinPrep Pap Test significantly increases the detection of low-grade or more severe lesions by 65% in screening populations and 6% for high risk populations when compared with the conventional Pap smear.

Does the increased detection with the ThinPrep Pap Test come at a loss in specificity?

No, studies done as part of the recent clinical trial showed that the improved detection of positive cases by the ThinPrep method did not cause increased false-positive diagnoses.

The ThinPrep Pap Test only examines approximately 70,000 cells with many more left unexamined in the vial. How do you know you are not leaving important cells unexamined?

The gentle mixing of the sample before preparing the slides ensures a thorough sampling of the cells present. As part of the validation of the ThinPrep Pap Test, ten or more slides were made from single vials. These studies showed that the first slide prepared from the vial is representative of the remainder of the material.

Conventional Pap smears have approximately 300,000 cells, and the ThinPrep slides have approximately 70,000. How can the ThinPrep method claim to be higher quality?

With a conventional Pap smear there is tremendous variability in the number of cells transferred to the slide, from as few as 4,000 to up to 300,000. When higher numbers of cells are on the slide they are often overlapping, or obscured by inflammation, blood or mucus. The sampling of the cervix by the conventional Pap smear is quite variable.

With the ThinPrep Pap Test, approximately 70,000 diagnostic cells are collected that provide a more representative sampling of the specimen taken from cervix. These are consistently displayed to the cytologist in a high quality preparation. In the clinical trials that led to FDA approval, the ThinPrep Pap Test detected more positive cases than the conventional Pap smear, proving that the ThinPrep Pap Test is significantly more effective than the conventional Pap smear in a variety of patient populations.

Does the ThinPrep method assist in the identification of infections and benign cellular changes?

Yes, the identification of infection and benign cellular changes can be made with the ThinPrep Pap Test.

Does ThinPrep Pap Test lose tumor diathesis which would make the diagnosis of cancer difficult?

Actually, tumor diathesis is preserved by the ThinPrep Pap Test. Tumor diathesis is the tissue necrosis that accompanies invasive cancer. Not all cancers have diathesis, but it is a useful feature for detection when present.

Can special stains be performed on slides prepared using the ThinPrep System?

Yes, silver or other histochemical stains as well as immunocytochemistry are readily performed on cells in the ThinPrep vial.

Can the ThinPrep System be used with computer rescreening technology?

Just as ThinPrep slides are easier for humans to examine, most computer imaging systems should be able to examine ThinPrep slides more quickly and more accurately. Preliminary studies with one system have shown this to be the case, but before computer systems are broadly used to examine ThinPrep slides, the manufacturers of computer systems will need to perform clinical trials, and seek FDA approval.

A conventional Pap smear is an established and trusted method and computer rescreening has been approved for the conventional Pap smear. Why should we switch to the ThinPrep Pap Test?

The ThinPrep Pap Test is a better quality test that detects more positive cases. There are several limitations to the conventional Pap smear, including poor sample preparation and difficulty in seeing abnormal cells obscured by blood, mucus or inflammation. The ThinPrep Pap Test improves both the sample preparation and the quality of the slides that are reviewed microscopically. Computer rescreening cannot solve the sampling problem associated with discarding most of the sample remaining on the collection device from preparing a conventional Pap smear.

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