Gynecologic Cytopathology: Past, Present and Future
Moderator: Annabelle Farnsworth
Section 3 -
The Future of Cervical Screening
Douglass Hanly Moir Pathology
Sydney , Australia
Attempts have been made to automate cervical cytology for over forty years. The Pap smear, a
technique originally describe by George Papanicolaou in the 1940's is one of the most commonly performed
pathology tests and yet unlike other high volume tests, is still performed manually in much of the
world. The technique persists even though the Pap test has a relatively low sensitivity for significant
disease and an acknowledged false negative rate . Where it is used, however, as the screening test
especially in an organised screening program it has had a significant effect on the reduction in the
incidence of and the mortality from cervical cancer .
The impetus for the most recent developments in automation in this area began almost twenty years ago
when there was recognition of the failings of Pap smears combined with the rapid development of computer
and video technology. Even so, the introduction of automation has taken much longer than would have been
first thought. Recent developments however, may offer a partially automated alternative, which should
eventually replace the conventional Pap smear.
Review of the technology
In the late 1980's and early 1990's four new technologies emerged into the arena of cervical
screening. These were:
- Papnet (Neuromedical Systems Inc)
- AutoPap (Neopath Inc)
- SurePath (Autocyte, TriPath Imaging)
- ThinPrep (Cytyc Corp)
1 & 2. Papnet and AutoPap
These two technologies will be discussed together as they were initially developed to be automated
readers of conventional Pap smears.
Papnet was introduced as a pre-screening method of conventional Pap smears. The slides were read
though the Papnet imager which generated images of interest. These were then reviewed on a computer
screen by a scientist. Papnet used neural net computer technology to analyse the complex nature of the
conventional Pap smear.
AutoPap was designed to also pre-screen conventional slides. Conventional computer technology was
used. Images were not presented for review but rather slides with the most severe abnormalities were
grouped together and these slides were then completely screened by scientists. The percentage to be
completely screened could be altered but whichever component was not re-screened was archived and was not
ever reviewed by a scientist or pathologist.
Both of the technologies achieved FDA approval and were used predominantly as quality control
measures. Papnet was a commercial failure. This was for a number of reasons including marketing
strategies and the workflow design which required the conventional smears to be shipped to a central
laboratory for imager screening rather than having the machines situated within the laboratory. Both the
Papnet and the AutoPap technology were purchased in some part by a third group, SurePath-Autocyte (see
below). They have not been commercially available since then.
3 & 4. SurePath & ThinPrep
Both of these technologies rather than developing imagers to read conventional smears concentrated on
developing imagers, which would read an especially prepared liquid based sample (LBC). To improve the
ability of a machine to read the collected sample, both of these processes depended on placing the sample
into a liquid preservative from which a monolayer of cells could be prepared. The sample was cleared of
as much extraneous material (blood and inflammatory cells) as possible; SurePath by sedimentation and
ThinPrep by filtration. The development of these liquid based samples was a great success; just as they
were easier of the machines to read so they were easier for the human eye. Both of these technologies
have had considerable success replacing conventional smears in some countries. It is estimated in the
USA that 80% of cervical cytology is liquid based.
Both of these technologies now have image analyzers available to read their monolayer samples.
SurePath has developed FocalPoint, which achieved FDA approval as a primary screener of both conventional
and SurePath slides, based on the AutoPap technology but is still developing its location guided system.
The ThinPrep image analyzer (TPI) received FDA approval in 2004. The Imager identifies specific
fields of interest within the monolayer sample which are then examined by a cytologist on an automated
light microscope. Although the TPI has had good uptake in the United States, skepticism still remains in
other parts of the world as to both the value of liquid based cytology and the use of automation in this
An Australian ThinPrep Image Analyzer study
Australia remains the only country in the world where LBC is done as a split sample technique. This
situation exists because two substantive government funded reviews of the technology failed to show a
benefit in an already successful cervical screening program . Government funding was not forthcoming
for LBC, as the increased expenditure could not be justified. LBC, predominantly ThinPrep remains
relatively widespread in Australia however, funded entirely by the patients, the demand being driven by
the manufacturers themselves. Questions have also been raised over the validity of LBC generally .
Douglass Hanly Moir is a large laboratory situated in Sydney , Australia , which has been using
ThinPrep (TP) in the split sample role for over nine years. In 2004 the ThinPrep Image Analyzer (TPI)
became available in Australia and it was decided at that time to use it for reading the TP samples. This
was on the basis of both the FDA approval and a preliminary verification study. It was also decided that
if the image analyzer was to be introduced this may offer an opportunity to assess its efficacy compared
to conventional cytology.
The accuracy of the TPI and conventional cytology (CC) was compared during normal laboratory operation
where the TP sample had been prepared after taking a conventional pap smear. The TPI and CC reading were
done without knowledge of the result of the other reading. The most severe abnormality was reported to
the referring practitioner. Histology results for all cases in which the two cytology reading showed
more than minimal disagreement were sought from the New South Wales Pap test register.
55,164 split sample pairs were examined over a nine-month period. 3.1% of the CC and 1.8% of the TPI
were unsatisfactory. There were 1758 women for whom there was more than minimal discrepancy between the
TPI and CC results. The TPI gave the more severe result in 1193 of the 1758 cases. In cases where only
one of each pair of discrepant cytology results was CIN 1 or higher grade TPI detected 133 cases of
high-grade histology among 380 biopsies (35%), whereas the conventional cytology detected 62 cases among
the 210 biopsies (29.5%). A repeat reading of the histology where the pathologist was blinded to the
initial cervical cytology result showed similar findings. There were only 6 histologically confirmed
high-grade glandular lesions in our study population, all of which had a glandular lesion predicted on
TPI. One of the TPI results was reported as a low grade glandular but simultaneously predicted a
high-grade squamous lesion. CC and TPI's ability to detect high-grade glandular lesions in this study
Reading times were measured over five months for both the ThinPrep Imager and conventional cytology
for 20 cytologists who read both types of smears. On average they read 13.3 ThinPrep imager slides per
hour and 6.1 conventional cytology slides per hour.
This study provides substantive evidence that cervical cytology read using the TPI detects more
histological high grade squamous disease than conventional cytology, with significantly reduced reading
times compared to conventional cytology. The ability of TP to detect glandular lesions remains
Although the numbers of glandular lesions is small in this study, their detection
rate was the same.
Cervical cytology in the future
Although there are numerous other studies showing the efficacy of the ThinPrep imager  this large
study should provide high quality evidence to allow consideration of its introduction into cervical
The cost of automation is not inconsiderable but the imager will provide both labour savings and
improved accuracy potentially leading to increased screening intervals. These will offer cost savings
which may offset the increased costs of automation. Although this may not be as significant where direct
to vial liquid based cytology is already in use, in countries such as Australia, where the technique is
split sample this should have considerable impact on staffing levels and efficiency of laboratories. The
data from the Australian TPI study will be used for a formal cost benefit analysis.
The preparation of a sample in liquid fixative, potentially also allows its use for different testing
techniques. Testing for human papillomavirus is already commonplace but in the future this sample may
also be useful for biological markers. Testing for markers of disease such as P16 may also be performed
using a liquid based sample with image analysis.
It is also timely that cervical cytology becomes more efficient and more accurate with the development
of anti human papillomavirus vaccines. One potential impact of even partial population vaccination
against HPV is an overall reduction in the number of abnormalities presented to the scientist even if
there is no reduction in cervical cytology samples. The use therefore of a concentrated sample and
pre-screening technique such as is available with image analyzers will help in assessing cervical disease
in this new environment.
All these changes do not herald the end of cervical cytology. Rather, one technique will be replaced
by another more efficient, more accurate and potentially more useful technology. This is indeed timely
given the rapid changes in molecular techniques and the increasing need for more specific investigations
and will indeed bring cervical cytology into the new millennium.
- Nanda K, McCrory DC, Myers E R, et al. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systemic review. A.. Intern Med 2000; 132:810-819
- Farnsworth A, Mitchell H S. Prevention of cervical cancer. MJA 2003; 178:653-654
- Medical Services Advisory Committee of Australia Liquid based cytology for Cervical screening MSA ref 12a Assessment repot August 2002; http://www.msac.gov.au/pdfs/reports/msacref12a.pdf
- Davey 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;367:122-32
- Roberts et al. Comparison of ThinPrep and Pap Smear in relation to prediction of adenocarcinoma in situ; ACTA Cytologica 1999 Jan-Feb; 43(1): 74-80
- Bai H, Sung C J, Steinhoff M M. ThinPrep Pap test promotes detection of glandular lesions of the Endocervix. Diagn Cytopathol 2000 July; 23(1):19-22
- Biscotti et al. Assisted primary screening using the automated ThinPrep imaging system. Am J Clin Pathol. 2005;123:281-287