Leaders: E McGoogan, J Linder
Session: PS7 14/04/03
Title: Cytopathology
The Pap test is significant from its historical perspective, its impact on the
incidence of cervical cancer, and its position as the most widely used cancer
screening test in the world. Throughout most of its history the Pap test was
viewed as a relatively simple laboratory procedure that was not subjected to
the rigor that accompanies the development of a medical device. In the last
15 years, however, concern about false-negative Pap smear testing, and a desire
to improve Pap testing (e.g. computer imaging, molecular testing) has led to
the development of new technologies. These efforts have been most significantly
manifested through testing that involves the collection of the cervical sample
in a liquid preservative solution, a so-called "Liquid-based Pap"
or LBP. The rational of this approach is that an accurate Pap diagnosis requires
that diagnostic cells are collected from the cervix and transferred to the glass
microscope slide for review by the cytologist. A failure in either of the first
two steps is termed a sampling error; while a failure in the laboratory examination
is termed a screening error. Combined, sampling and screening errors lower the
sensitivity of the Pap test. Recent publications suggest that the sensitivity
of the Pap smear is 50-60%, with the relative proportion of sampling to screening
errors being about 2:1. Smears may be further complicated by high unsatisfactory
rates, preparation artifacts that hinder computer analysis, and the inability
to pursue additional testing. Some liquid-based preparations address these limitations,
particularly the potential to reduce both sampling and screening errors. Because
the cervical collection device(s) are rinsed in a preservative solution, more
cells are potentially captured for evaluation than when the device is smeared
against a glass slide. And, because the cells are rapidly fixed, then deposited
onto the slide in a thin layer, morphologic features are better preserved, and
clearly presented to the cytologist. Different technical approaches can be used
to prepare a "LBP". Pathologists and gynecologists must understand,
however, different liquid-based techniques will yield different results (e.g.
detection of HSIL) depending on the type of collection device, the type of fixative,
the method of dispersing cells in liquid, and the manner of collecting cells
and depositing them onto a slide. All liquid-based methods are not necessarily
equal in their performance, simply because they are "liquid based."
This requires the potential user to be familiar with the published literature,
labeling claims from regulatory bodies, and other studies.
Because liquid-based cytology allows deposition of cells onto a thin-layer on
a microscope slide, computer-assisted imaging is facilitated, because cell overlap
and obscuring debris are mitigated. Devices have been developed or proposed
that either identify slides not requiring cytotechnologist review (sorting),
or identify cells on the slide that merit review (computer-assisted screening).
These technologies have the potential to revolutionize cytology, because they
can decrease the fatigue of the user, allow more slides to be reviewed, decrease
the screening error rate, and, with appropriate decision support, identify morphologic
features that are not apparent in routine human review.
Finally, an advantage of liquid based cell collection is that sample that is not taken for morphologic review can be used for adjunctive molecular analysis.
Evidence-based medicine is described as the "conscientious, explicit and
judicious use of current best evidence in making decisions about the care of
the individual patient. It means integrating individual clinical expertise with
the best available external clinical evidence from systematic research.".
There is an enormous breadth of experience documenting the utility of morphologic
cytology in identifying precursors to cervical cancer, which permit clinical
intervention. Most of the current research has not been directed in validating
cytology, but assessing new approaches, such as liquid-based, to determine if
the benefits of these technologies justify added costs. This is not a simple
science, the outcomes of the analysis will be affected by the thresholds of
evidence that is deemed acceptable, the cost assumptions, the interval that
testing is performed, compliance with testing, the potential of combining multiple
technologies and the benefits assigned to improved quality of life. Needless
to say, the complexity of this analysis has led to divergent results. Analyses
that exclude the bulk of the literature for spurious reasons (e.g. not performing
biopsy on women with normal cytology) are not able to reach definitive conclusions.
Recent government sponsored reviews by the National Institute for Clinical Excellence
in the United Kingdom and the Agency for Health Care Policy Research in United
States conclude that liquid-based cytology is a cost-effective alternative to
conventional smear-based cytology, and should be adopted. Again, as mentioned
above, the ability of the "Liquid-based" Pap, to detect cervical cancer
precursors, must be considered in this statement, since different methods may
perform differently.
Morphologic review of a cervical cell sample, a Pap test, is the cornerstone
of cervical cancer control. The Pap smear technique is most widely used worldwide,
and has the advantage of simplicity and familiarity. Liquid-based Pap techniques
address limitations of the smear method, improve detection of cervical lesions,
and facilitate technologies such as imaging and ancillary testing). Screening
programs can be improved by the adoption of certain liquid based techniques
that have demonstrated improved detection of cervical precursor lesions (i.e..
ThinPrep Pap Test, Cytyc Corporation, Boxborough MA, USA).
Direction of further research
The two immediate areas of research are in areas of computer-assisted imaging,
and molecular testing. As mentioned above, computer assisted imaging of the
Pap sample may significantly improve the laboratory workflow and the ability
of abnormalities to be detected by screening. The identification of additional
features by imaging methods may further enhance the Pap examination. Data presented
at the meeting showed the ThinPrep Imaging System to improve cytotechnologist
screening rates, with improved accuracy. The ability to perform molecular testing
on the liquid cytology sample (e.g. HPV testing of ASCUS Paps, or combined cytology
and concurrent HPV testing) is attractive since it may draw on strengths of
either approach. Further research is also needed in understanding the interrelationship
between morphologic examination and the presence of HPV within cells, or the
molecular alterations in the cell that arise from HPV infection.
Clinical perspectives
The goal of cervical cancer control is attainable, but requires coordination
of resources and sharing of information. Screening programs require compliance
by the patient, trained professionals to perform testing, and clinicians who
are capable of acting on the information that results from the screening. As
new technologies are evaluate for adoption, appropriate consideration is required
on how they will improve the cervical screening programs, in terms of traditional
measures (sensitivity, specificity, positive and negative predictive values)
and cost effectiveness, including analysis of quality of life issues.
Austin RM: The Detection of Precancerous Cervical Lesions Can Be Significantly Increased. Who Cares and Who Should Know? Arch Pathol Lab Med 2003;127(2):143-145.
Belinson J, Qiao YL, Pretorius R, Zhang WH, Elson P, Li L, Pan QJ, Fischer C, Lorincz A, Zahniser D. Shanxi Province Cervical Cancer Screening Study: a cross-sectional comparative trial of multiple techniques to detect cervical neoplasia. Gynecol Oncol. 2001 Nov;83(2):439-44.
Bernstein SJ, Sanchez-Ramos L & Ndubisi B (2001). Liquid-based cervical cytologic smear study and conventional Papanicolaou smears: a metaanalysis of prospective studies comparing cytologic diagnosis sample adequacy. American Journal of Obstetrics & Gynecology 185: 308-317.
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(2):200-4
National Institute for Clinical Excellence report on Liquid Based Cytology. www.nice.org.uk