Cervical screening adjuncts: Recent advances,☆☆,

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Abstract

In an effort to reduce the false-negative rate of cervical cytologic findings, several new technologies have recently evolved. Automated cytologic testing (PapNet, AutoPap 300 QC) proposes to rescreen negative conventional cytologic findings to identify smears likely to be false negative. Fluid-based monolayers (ThinPrep, CytoRich) propose to reduce the false-negative rates by optimizing the collection and preparation of cells. Human papillomavirus deoxyribonucleic acid testing by Hybrid Capture has been proposed for a variety of screening and triage roles. Visual screening after application of acetic acid is done by cervicography by use of a photographic technique, whereas in speculoscopy the screening is done by direct visualization of the cervix by the primary care provider. Polarprobe uses biophysical parameters and a computer algorithm to give an instantaneous prediction of the likelihood of cervical disease. Each of these techniques, as well as the clinical experience with them, is reviewed. Current and possible future uses are discussed with regard to both clinical usefulness and cost-effectiveness. (Am J Obstet Gynecol 1998;179:544-56.)

Section snippets

False-negative Papanicolaou smears

The concerns with regard to cervical cytologic testing center around the perception that its sensitivity is unacceptably low. However, it should be remembered that the Papanicolaou smear is a highly specific test with regard to high-grade squamous intraepithelial lesions (SILs) and cancers, although somewhat less specific in low-grade SILs. Furthermore, because sensitivity and specificity are a tradeoff, increasing the sensitivity will likely result in a decrease in specificity.

A screening test

Technique of cervical cytologic studies

Before we explore many of the new and sophisticated ways to reduce the false-negative rate of Papanicolaou smear testing, attention should be focused on maximizing the quality of the smear by the use of proper technique.

Smears are obtained before any digital examination. Lubricants and douches should be avoided for 24 hours before the examination. The patient should not be bleeding and should not have marked vaginitis. An ectocervical scrape should be obtained with a moistened Ayres spatula,

Automated cytologic screening

Mathematic models10 have suggested that 100% manual rescreening is the most effective method for reducing cytologic screening errors, and this has always been considered the “gold standard” with which other rescreening modalities have been compared. However, screening results are dependent on the test screening environment. Bosch et al11 tested cytotechnologists to determine whether they were able to detect disease on slides originally identified as positive and those falsely identified as

Effectiveness of automated cytologic screening as a rescreening tool

When all negative smears were processed by the AutoPap system and the smears with the highest quality control scores (top 10%) were rescreened manually, AutoPap detected 52.4% of the low- grade and high-grade lesions and carcinomas that were originally read as negative and were detected by a parallel 100% manual rescreening of the slides.20 In other words, under these circumstances AutoPap is half as sensitive to false-negative smear results as 100% manual rescreening but 5 times better than

Effectiveness of automated cytologic tests as a primary screening tool

PapNet is not currently approved by the Food and Drug Administration for primary screening, whereas AutoPap was recently approved for this use. Also, the method by which they would function as primary screeners differs between the two systems. The AutoPap system functions to remove a certain percentage (currently 25%) of adequate and normal smears from the cytotechnologist’s workload. Future advances may also mark the location of the significant cellular abnormalities by means of a computer

Cost-effectiveness of automated cytologic studies

AutoPap and PapNet function differently in their approach to cost savings. As a primary screener, AutoPap aims to remove a percentage of slides from the cytotechnologists’ workload, thereby saving money. Lee et al25 showed that AutoPap was able to maintain 96.9% sensitivity among a training set of 4174 slides while eliminating 30% of slides from the workload. As a primary screener, PapNet aims to reduce costs by presenting the most diagnostic cells to the cytotechnician in a well-organized

Fluid-based technology

Fluid-based technology (monolayers) also uses cytologic studies to detect cervical neoplasia; however, it changes the methods by which the cells are collected and processed. Its aim is to reduce the incidence of false-negative cytologic findings by optimizing the collection and preparation of cells.

Two systems are currently available, which create a monolayer for cervical cytologic studies. One (ThinPrep, Cytyc Corporation, Boxborough, Mass) is approved by the Food and Drug Administration,

Effectiveness of fluid-based technology

Before the clinical experience with monolayers is reviewed, it is important to note that the cytologic collection device can have a major impact on the number of cells deposited in both conventional smears and monolayers. Although the combination of an endocervical brush and a spatula deposited more cells on the slide with a conventional smear, the Cervex-Brush (Unimar, Wilton, Conn), which is used in many of the monolayer trials, collects almost twice as many epithelial cells compared with any

Cost-effectiveness of fluid-based technology

The cost of ThinPrep may be twice the cost of conventional cytologic studies when all the variables are considered, including the greater cost of supplies, longer slide preparation time, and shorter slide evaluation time for ThinPrep.36 Because the area on the slide that is covered by the monolayer is only 20 mm in diameter (13 mm for CytoRich), monolayers are routinely assessed in half the time required for conventional smears.39, 43 However, experience with monolayers suggests that the

HPV testing

Most of the present data derived from clinical and epidemiologic studies support the preeminent role of HPV in cervical carcinogenesis.44, 45 We know that >80 different genotypes of HPV exist. Approximately 20 of them infect the cervix. These can be divided into high-risk HPV types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, and 58) and low-risk types (HPV 6, 11, 42, 43, and 44). A number of studies46, 47 have shown that women infected by HPV 16 or 18 have a higher rate of progression of

Techniques for HPV detection

A crucial factor in analyzing the value of HPV testing is the sensitivity of the test being used. Several tests are available for detecting HPV. A brief summary of the various methods available for the detection of HPV is outlined inTable I.

. Comparison of various methods available for detection of HPV

MethodSensitivitySpecificityComment
CytologyLowLowEasy, relatively inexpensive, but subjective, insensitive, and nonspecific
Dot blotModerateModerateRadioactive, commercially available as ViraPap,

Uses of HPV testing

To understand the potential role that HPV testing may have in cervical cancer screening, our knowledge of the natural history of HPV infection must be reviewed. The prevalence of HPV varies dramatically, depending on the population studied. In a population-based study with cervical cytologic studies to detect HPV, Syrjanen et al68 found HPV in 0.8% of 63,115 women aged 20 to 65 years. De Villiers et al,69 with Papanicolaou smear and filter in situ hybridization, found HPV in 9% of women aged 15

Cervicography

As far back as 1958, Navratil et al88 showed that the combination of cytologic examination and colposcopy detected 98% of all lesions compared with 88% for cytologic examination alone. These studies were confirmed by Limburg89 and by Kern.90 However, screening colposcopy has limitations because it requires a considerable amount of expertise, the equipment is expensive and not portable, and it is time-consuming.

In 1981 a technique called cervicography was introduced by Adolf Stafl.91 By the use

Speculoscopy

Speculoscopy is a new visual endoscopic examination that uses specialized “blue- white” chemiluminescent light, along with acetic acid and low-power magnification, to screen patients for cervical disease.104

The cervix and the vagina are washed with 3% to 5% acetic acid. An activated blue-white chemiluminescent light that uses peroxyoxalate chemical means is attached to the inner aspect of the upper speculum blade. The room lights are dimmed, and the cervix and vagina are inspected with

Polarprobe (Polartechnics Ltd, Sydney, Australia)

This adjunctive test is different than all those previously described. Almost all diagnostic and screening tests in clinical medicine have as their basis pattern recognition skills or biochemical information. This is certainly true of manual and automated cytologic testing, histologic examination, monolayer cytologic studies, cervicography, colposcopy, and speculoscopy (all of which have as their basis automated or manual pattern recognition skills) and HPV DNA testing (which has as its basis

Comment

In the United States today, 60% of women with invasive cancer have not had a Papanicolaou smear in the previous 5 years (or have never had a Papanicolaou smear at all). Without question, the most clinically effective and cost-effective approach to reducing the incidence of cervical cancer would be to screen this unscreened population.

However, attention must also be focussed on the 4500 to 6500 women in the United States each year who have cervical cancer develop despite regular screening. Some

References (107)

  • TC Wright et al.

    Comparison of management for the evaluation of women with low grade cytologic abnormalities

    Obstet Gynecol

    (1995)
  • E Navratil et al.

    Simultaneous colposcopy and cytology used in the screening for carcinoma-in-situ of the cervix

    Am J Obstet Gynecol

    (1958)
  • G. Kern

    Colposcopic findings in carcinoma-in-situ

    Am J Obstet Gynecol

    (1961)
  • JG. Blythe

    Cervicography: a preliminary report

    Am J Obstet Gynecol

    (1985)
  • ID Sherris et al.

    Cervical cancer in developing countries: a situation analysis. Working Paper

    (1993)
  • DM Parkin et al.

    Estimates of the worldwide frequency of sixteen major cancers in 1980

    Int J Cancer

    (1988)
  • National Institutes of Health

    Consensus Development Conference. Statement on cervical cancer; 1996 Apr 1-3

    Gynecol Oncol

    (1997)
  • JD Gay et al.

    False negative results in cervical cytologic studies

    Acta Cytol

    (1985)
  • E. Felsenthal

    Chem-Bio charged with homicide over Pap smears

    The Wall Street Journal

    (1995 Apr 13)
  • K. Schneider

    Dying by mistake

    People Weekly

    (1995)
  • W. Bogdanich

    False negative

    The Wall Street Journal

    (1987 Feb 2)
  • ML. Hutchinson

    Assessing the costs and benefits of alternative rescreening strategies

    Acta Cytol

    (1996)
  • LG. Koss

    The Papanicolaou test for cervical cancer conization: a triumph and a tragedy

    JAMA

    (1989)
  • FC Kaminsky et al.

    Rescreening policies in cervical cytology and their effect on detecting the truly positive patient

    Acta Cytol

    (1995)
  • MMC Bosch et al.

    Characteristics of false negative smears tested in the normal screening situation

    Acta Cytol

    (1992)
  • SF Patten et al.

    Comparative detection rates of true false negative gynecologic cytology cases by the Neopath AutoPap 300 QC System and a 10% or 20% random rescreen of so-called negative cases

    Anal Quant Cytol Histol

    (1994)
  • H Mitchell et al.

    Differences between Papanicolaou smears with correct and incorrect diagnosis

    Cytopathology

    (1996)
  • F Hatem et al.

    High grade cervical lesions following negative Papanicolaou smears: false negative cervical cytology or rapid progression

    Diagn Cytopathol

    (1995)
  • LG. Koss

    Cervical (Pap) smear: new directions

    Cancer

    (1993)
  • RM. DeMay

    Failure of the Pap smear

  • TJ Colgan et al.

    A clinical trial of the AutoPap 300 QC system for quality control of cervicovaginal cytology in the clinical laboratory

    Acta Cytol

    (1995)
  • SF Patten et al.

    Neopath, Inc. Neopath AutoPap 300 Automatic Pap Screener System

    Acta Cytol

    (1996)
  • LJ. Mango

    Neuromedical Systems, Inc

    Acta Cytol

    (1996)
  • Hematology and Pathology Devices Panel of the Medical Devices Advisory Committee to the FDA

    (1995 Aug)
  • AutoPap 300 QC Automatic Pap Smear Screener System. Package insert

    (1996)
  • LG Koss et al.

    Evaluation of the PapNet cytologic screening system for quality control of cervical smear

    Am J Clin Pathol

    (1994)
  • ME Boon et al.

    Histologic validation of neural network-assisted cervical screening: comparison with the conventional procedure

    Cell Vision

    (1995)
  • PapNet Testing System

    Package insert

    (1996)
  • JSJ Lee et al.

    AutoPap system performance in screening for low prevalence and small cell abnormalities

    Acta Cytol

    (1997)
  • ME Sherman et al.

    PapNet analysis of reportedly negative smears preceding the diagnosis of a high grade squamous intraepithelial lesion or carcinoma

    Mod Pathol

    (1994)
  • A Farnsworth et al.

    Evaluation of the PapNet system in a general pathology service

    Med J Aust

    (1996)
  • MR Ryan et al.

    PapNet-directed rescreening of cervicovaginal smears: a study of 101 cases of atypical squamous cells of undetermined significance

    Am J Clin Pathol

    (1996)
  • DE Jones et al.

    Evaluation of the atypical Pap smear

    Am J Obstet Gynecol

    (1987)
  • M Spitzer et al.

    The comparative utility of repeat Pap smears, cervicography, and colposcopy in the management of patients with atypical Pap smears

    Obstet Gynecol

    (1987)
  • CB. Schechter

    Cost effectiveness of rescreening conventionally prepared cervical smears by PapNet testing

    Acta Cytol

    (1996)
  • DJ Zahniser et al.

    Cytyc Corporation

    Acta Cytol

    (1996)
  • ML Hutchinson et al.

    The efficacy of an automated preparation device for cervical cytology

    Am J Clin Pathol

    (1991)
  • ML Hutchinson et al.

    Homogeneous sampling accounts for increased diagnostic accuracy using the ThinPrep Processor

    Am J Clin Pathol

    (1994)
  • F Tezuka et al.

    Numerical counts of epithelial cells collected, smeared, and lost in the conventional Papanicolaou smear preparation

    Acta Cytol

    (1995)
  • M Bur et al.

    Comparison of ThinPrep preparations with conventional cervicovaginal smears: practical considerations

    Acta Cytol

    (1995)
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    From the Department of Obstetrics and Gynecology, Queens Hospital Center affiliated with the Mount Sinai School of Medicine.

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    Reprint requests: Mark Spitzer, MD, Director, Department of Obstetrics and Gynecology, Queens Hospital Center, 82-68 164th St. B Building, Room 210, Jamaica, NY 11432.

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