1. Modern cervical cancer screening
GEORGIA - ELENI THOMOPOULOU LAZARI
Assistant Professor in Cytopathology,
Medical School, National and Kapodistrian University of Athens ,Greece

2. avoid detection and unnecessary treatment for transient HPV infections
Goal of cervical cancer screening: to prevent morbidity and mortality of cervical cancer
identify those cervical cancer precursors likely to progress to invasive cancer  appropriate intervention will prevent progression
avoid detection and unnecessary treatment for transient HPV infections
reassure the vast majority of women that they are safe in the interval between screening rounds
send the women at highest risk to colposcopy at the right time, when disease can be colposcopically detected
minimize the intermediate risk group that requires frequent re-testing and repeat colposcopy
Triaging: further test, if the initial screening test shows borderline results  useful in risk stratification and in decreasing colposcopy referral rates
A screening method can be used as a triage method and vice versa
Combinations of more than one method in screening and triaging  improvement in sensitivity and specificity
There are methods already validated (FDA-approved) and methods under evaluation
Properties of screening and triaging methods:
Feasibility / Acceptability / Sustainability / Cost-effectiveness / Objectivity / High sensitivity, specificity and reproducibility
Screening and triaging guidelines:
Based mostly on age
Regularly updated and adapted on the basis of:
socioeconomic background and health system infrastructure
vaccination rates
risk perception

3. OLDER DATA
2001:American Society of Colposcopy and Cervical Cancer Pathology suggested HPV DNA test for women with ASCUS cytology
2002:American Anticancer Society suggested HPV test every 3 years as screening test for women >30y
2004:HPV test + Pap test (co-testing) was suggested for women >30y and HPV DNA test for women with ASCUS cytology
2006:American Society of Colposcopy and Cervical Cancer Pathology suggested women with negative cytology and HPV DNA test positive for HPV 16 and/or HPV 18 should be immediately referred to colposcopy

4. NEW DATA (ACOG=American Congress of Obstetricians and Gynecologists)
2012:Women y should be examined every 5 years with co-testing or with Pap test every 3 years
Screening test for cervical cancer should start at the age of 21 y
Women y should be examined every 3 years with Pap test
Conventional and Liquid Based Cytology are equally acceptable methods.

8. 2017 DATA TASK FORCE Co-testing offers no extra benefit
Pap test or HPV test , Not both, for most cervical Ca Screening
Sept 12, 2017
MED PAGE TODAY

9. 2012 Expression of gratitude to Prof. G. Papanicolaou
“Inertia” in attitudes and mentality of the population

10. Guidelines in special circumstances
Women with total hysterectomy without history of intraepithelial lesion should stop any screening test
Women with HPV infection,immunosuppression, history of diethylsilvestrole exposure or cervical cancer history should not follow screening guidelines of general population
Women >65 y without history of HGSIL should stop any screening test if they had 3 negative Pap test results or 2 negative co-testing results, provided tests were performed in the last 5 years
Vaccinated women should follow screening guidelines

11. Current options for cervical cancer screening
Advantages of cytology screening
Easy
Cost-effective
Decades of proven value
In policy making, reasonable risk is determined by the strategy of cytology alone as a method of reference
Limitations of cytology screening
Unsatisfactory samples due to the following reasons:
obscuring blood
obscuring inflammation
poor fixation
cytolysis
inadequate cellularity
Difficulty of evaluation of atypical glandular cells
Impact of workload on results
Subjectivity
Interlaboratory variation
Co-testing:
permits a longer interval between screens
enhances the identification of women with cervical adenocarcinoma and its precursors
Reflex HPV testing: used after ASCUS in Pap test
Inter and intra-laboratory quality control

12. ADVANTAGES OF CO-TESTING
It has lower false negative results than that of Pap test alone.
It is performed every 5 y; so, intraepithelial lesions can be early diagnosed and cured but also many HPV infections can spontaneously regress.
HPV related glandular abnormalities are more easily diagnosed than with cytology alone.

13. WHAT IS SUGGESTED WHEN PAP TEST IS ABNORMAL?
In ASCUS , HPV DNA test or repeating Pap test is suggested. Esp. in postmenopausal women, an estrogen test should also be performed.
In all other positive results (LGSIL, HGSIL, Ca etc) immediate colposcopy should be performed.

14. WHAT IS SUGGESTED WHEN CO-TESTING IS ABNORMAL?
Pap test (-), HPV DNA test (+) for hr HPV (except HPV 16/18) ,co-testing after 1 y is suggested. If HPV 16 and/or HPV 18 infection is confirmed , immediate colposcopy is suggested
Pap test (ASCUS), HPV DNA test (-) , woman should be re-examined in 3-5 y
Pap test (LGSIL or more) , HPV DNA test (-), colposcopy is suggested
Pap test (+), HPV DNA test (+) for hr types, colposcopy is required

15. LIMITATIONS OF SCREENING TESTS
False negative and false positive results
Transient HPV infections which would never cause cancer are discovered and this may cause stress and problems in pregnancy due to overtreatment.

16. to colposcopy (CIN3, cancer)
*CIN2 is an equivocal diagnosis that includes some precancer lesions (CIN3) but also some lesions that would regress on their own.
Although CIN2 is the widely accepted threshold for treatment to provide an additional margin of safety, it has been posited that CIN2 should not be the primary target of cervical cancer screening.

17. NEW PERSPECTIVES
The challenge of cervical Cancer Cytological screening is to detect lesions that have a high risk of progression.
Various biomarkers associated with the risk of progression have been investigated and most are associated with hr HPV types.
Cell infection by HPV is shown by changes in function or in host gene expression and the detection of these changes may play a major role.
HPV DNA viral load quantification and integation and E6/E7 expression are promising biomarkers that can predict the progression of lesions to cancer.

18. Perspectives for applied research
Molecular detection methods
DNA-based tests (Hybrid Capture 2, Cervista HPV HR test, Cobas HPV test)
E6/E7 mRNA PCR (reverse transcriptase PCR) (Aptima HPV Assay,)
HPV genotyping assays: Cobas HPV test (16,18, twelve other hrHPVs), Cervista HPV genotyping (16,18), Aptima HPV 16 18/45 Genotype Assay
Biomarkers (p16/Ki-67 staining in the same cell): indicates cell cycle deregulation by HPV, predictor of transforming infection, indicator of H-SIL
The applied proteomics i.e., the demonstration of host proteins aberrantly expressed such as MCM2/MCM7/TOPO IIA
Host and viral methylation
Reasons for false negative molecular tests:
Decreased viral load or decreased expression of E6/E7
Borderline or even low risk HPV genotypes
Sampling errors
Reasons for false positive molecular tests:
Cross-reaction with low risk genotypes
Self-collection of specimens + HPV testing
for remote regions?

19. To date , there is no ideal biomarker.
Molecular techniques still must become more rapid, automated and of low cost to be of practical use in low income populations and countries.

20. (Take home) messages … to cytopathologists
Cytology keeps its pivotal role among the screening strategies
Be open to the new data that the scientific community provides - try to add your personal experience
Science evolves and awaits our contribution, not our resistance
Ευφυία: το τάχος της προσαρμογής
Intelligence: the speed of adaptation