“Not Your Grandmother’s Pap Test”lasop.com/pgs/hdouts/2015-03_Felix_Not Your...
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“Not Your Grandmother’s Pap Test” Juan C. Felix, M.D. Professor of Pathology and Obstetrics and Gynecology Keck School of Medicine of USC
“Not Your Grandmother’s Pap Test”lasop.com/pgs/hdouts/2015-03_Felix_Not Your Grandmother's Pap Test.pdfEven with diligent annual Paps throughout one’s life, the estimated lifetime
• CONSULTANTSHIPS:– FDA, Shared Medical Resources, ClearPath
• RESEARCH SUPPORT:–PATH (Bill and Melinda Gates Foundation)–NIH
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DISCLOSURES:
Disclaimer text goes here
Human Papillomavirus (HPV) Is a Cause of Cervical Cancer
• HPV is highly prevalent in young women; up to 60% of certain age groups can be positive for HPV
• HPV alone is a limited predictor of disease
• Of the 100 HPV types, only “high- risk” types are important
HPV
CIN 31. Moscicki AB, et al. Lancet. 2004;364(9446):1678-1683.2. Pirog EC, et al. Am J Pathol. 2000;157:1055-1062.3. Schlecht NF. JAMA. 2001;286(24):3106-3114.
Presenter
Presentation Notes
This is an exciting time for those of us interested in the prevention of cervical cancer. The approval of the HPV vaccine has been quite an event because of the opportunity it presents for the prevention of this disease. The causative agent for cervical cancer is the human papillomavirus or HPV. HPV is highly prevalent. Depending on how you measure it and in which age group, the literature shows prevalence rates that range from 60 to 80%. The higher expression rate is seen depending on whether HPV is measured with serial positivity in blood or a polymerase chain reaction (PCR). Because HPV is widespread, finding it is of limited value as a disease predictor. A significant portion of HPV infections are transient and self-resolve or are subclinical. Seeing a positive HPV test result, therefore, is of limited clinical value because it provides little information about which viral type is causing the infection, and whether this infection is new or latent, and it provides no prognostic information. We know there are over 100 types of HPV. A little less than half of those affect the ano-genital system, of which about half are transforming or potentially oncogenic. The oncogenic types are those in which we are most interested for cancer prevention. These high-risk types are the targets for the vaccine strategy. References: Moscicki AB, Shiboski S, Hills NK, et al. Regression of low-grade squamous intra-epithelial lesions in young women. Lancet. 2004;364(9446):1678-1683. Pirog EC, Kleter B, Olgac S, et al. Prevalence of human papillomavirus DNA in different histological subtypes of cervical adenocarcinoma. Am J Pathol. 2000;157:1055-1062. Schlecht NF, Kulaga S, Robitaille J. Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia. JAMA. 2001;286(24):3106-3114.
Natural history of cervical cancer
HPV infection
CIN 1,2
CIN 2,3
HPV disappearance
Invasive CA
Avg. 10 yrs
Avg. 6- 24 mo
Avg. 6- 9 mo.
Ho GY, et al. New England Journal of Medicine. 1998,338:423-428.Bory JP, et al. Int J Cancer, 2002;102:519-525.Nobbenhuis MAE, et al. Lancet. 1999;354:20-25.
Presenter
Presentation Notes
Slide 10: This slide depicts the natural history of HPV infections and the relationship with cervical oncogenesis. At least 80% of the population is infected with HPV during their lifetime but most have spontaneous resolution without having symptoms or cellular changes that alert the individual of their infection. On average, the majority of these HPV infections can no longer be detected by sensitive HPV testing within 6-9 months from their first positive HPV test. Others will have cellular changes detected on their Pap test and will be found to have CIN 1 or 2. At least 70-90% of CIN 1 and 40% of CIN 2 will resolve spontaneously to an immune response, resulting is disappearance of the lesion and a return to a type-specific HPV-negative state within 6-24 months. However, a minority will have persistent high-risk HPV that results in persistent and progressive CIN 2, and CIN 3. If CIN 3 is not detected over a period that averages 10 years, many are at-risk for progression to invasive cervical cancer. This long period of time between the development of CIN 3 and the capacity for invasion represents the extended period of time for cervical cells to accumulate thousands of random mutations required for invasion. At the CIN 3 level high-risk HPV types elaborate proteins from their oncogenes (E6 and E7) that block the ability of the normal human anti-oncogenes (particularly p53 and the retinoblastoma gene) to either repair human cells or destroy them when they begin to accumulate mutations.
HPV INFECTION: Classification of Histological Findings: CIN
• CIN (Cervical Intraepithelial Neoplasia)
– CIN 1: Mild dysplasia
– CIN 2: Moderate dysplasia
– CIN 3: Severe dysplasia; includes carcinoma in situ (CIS)
Richman DD, Whitley RJ, Hayden FJ, eds. Washington, DC: American Society for Microbiology Press; 2002:557–596. Ostor AG. Int J Gynecol Pathol. 1993;12:186–192.
Histology of Histology of squamous squamous cervical cervical epitheliumepithelium11
Basal cellBasal membrane
Presenter
Presentation Notes
Key Point The CIN grading system classifies dysplasia into 3 categories based on histological changes. Although CIN caused by HPV infection often clears without treatment, the likelihood of progression to invasive cancer is greater in more severe grades (CIN 2/3). Background The CIN grading system classifies dysplasia into 3 categories based on histological changes: CIN 1 includes mild dysplasia and condyloma (anogenital warts), CIN 2 includes moderate dysplasia, and CIN 3 includes severe dysplasia and carcinoma in situ (CIS).1 These lesions are graded based on the extent of abnormal proliferation of the basal layer of the cervical epithelium. In mild dysplasia (CIN 1), proliferation occurs up to the lower third of the epithelium. In moderate dysplasia (CIN 2), proliferation occurs up to the upper two thirds; and in severe dysplasia/CIS (CIN 3), the entire epithelium is abnormal.1 When stratified into the various grades of severity, the composite data from a review indicate that the approximate likelihood of regression of CIN 1 is 60%, persistence is 30%, progression to CIN 3 is 10%, and progression to invasion is 1%. The corresponding approximations for CIN 2 are 40%, 40%, 20%, and 5%, respectively. The likelihood of CIN 3 regressing is 33% and progressing to invasion greater than 12%.2 References 1. Bonnez W. Papillomavirus. In: Richman DD, Whitley RJ, Hayden FJ, eds. Clinical Virology. 2nd ed. Washington, DC: American Society for Microbiology Press; 2002:557–596. 2. Ostor AG. Natural history of cervical intraepithelial neoplasia: A critical review. Int J Gynecol Pathol. 1993;12:186–192.
• Since the introduction and widespread use of the Pap Test in the USA:–There has been a 70% reduction in cervical cancers
• Half of all Cervical Cancers occur in unscreened or underscreened women:–Reaching unscreened women is difficult–Using the “best test available” improves prevention
• Pap screening has been linked to an annual well woman exam:–Culture is difficult to change!
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Cervical Cancer Screening: The Pap
• HPV is present in virtually all cervical cancers, estimated at 99.7% J MM Walboomers et al., Journal of Pathology 189:12- 19,1999
• “Cervical cancer may be the first human cancer identified to have a single necessary cause.” IARC 1999
Cervical screening and abnormal Pap management have been changing. Why?• Poor sensitivity of cervical cytology has driven annual
screening.
• Even with lifetime annual Pap tests the estimated risk of getting cervical cancer is approximately 216/100,000. IARC 1986
Presenter
Presentation Notes
Slide 3: Cervical screening and abnormal Pap test management have been changing. Why? There are a number of reasons. Although the Pap has been very successful in lowering the incidence and mortality from cervical cancer, the poor sensitivity of cervical cytology has driven annual screening. Even with diligent annual Paps throughout one’s life, the estimated lifetime risk for getting cervical cancer is NOT zero. The International Agency for Research on Cancer estimated that approximately 216 women per 100,000 would still get cervical cancer during their lifetime if the Pap was 70% sensitive for CIN 2,3+. While this is a 93% reduction from the number of cervical cancer cases that would be expected in the absence of screening, for each individual woman getting cervical cancer this represents a tragic failure. Additionally, annual Pap tests identify many women with unimportant transient cell changes that often result in colposcopy, over management and overtreatment less likely to occur if screening were less frequent. However, screening will not occur less frequently until the risk of missed CIN 2,3+ at each screening is lessened. Second, HPV is present in virtually all cervical cancers, estimated to be at least 99.7% in 1000 cervical cancers evaluated by IARC. In fact, the association is so strong that IARC proclaimed in 1999 that cervical cancer may be the first human cancer identified to have a single necessary cause. Since the cause of true abnormal cervical cytology, high-grade CIN and cervical cancer is now clearly proven to be HPV, it makes sense to test for the cause, particularly because, as will be discussed, HPV testing is so much more sensitive for the detection of these lesions.
Pap Smear PerformanceMeta-analyses:
Biopsy proven CIN 2,3Author Sens Spec
Fahey 49% 62%
Follen-Mitchell 67% 77%
Nanda 51% 97%
Nanda K et al. Ann Intern Med 2000;132:810-9.
Fahey MT et al. Am J Epidemiol 1995;141:680-689.
Presenter
Presentation Notes
Slide 4: Several meta-analyses have demonstrated sensitivity of the conventional Pap smear for CIN 2,3 to be between 49 and 67%, with specificity varying greatly, between 62 and 97%, depending on the threshold for calling a Pap abnormal: i.e., >ASC-US, >LSIL or HSIL.
Sensitivity of cervical cytology for CIN 3:
• Conventional Pap smears sensitivity: 70-80%
ACOG Practice Bulletin. 2005;61:3
In recent well controlled trials
• Even liquid-based Pap tests may miss 15% of CIN 3
• This carries important medical implications and has stimulated interest in the development of more sensitive screening tests.
Presenter
Presentation Notes
Slide 5: The ACOG Practice Bulletin reviewed the literature on both conventional Pap smears and on liquid-based Paps, reporting that in recent well controlled trials conventional Pap smears were reported to have a sensitivity for CIN 3 of 70-80% and that even LBPs missed 15-35%. ACOG concluded that “This carries important medical implications and has stimulated interest in the development of more sensitive screening tests.”
How Far Have We Come and What Does the Future Hold?
• Significant changes in the past 10 years– Liquid-based Paps– HPV reflex testing for ASC-US
• HPV vaccine– First FDA-approved vaccine– Milestone advance in cervical cancer prevention
• Cost-effectiveness– Best clinical outcomes– Underserved in Title X and Planned Parenthood clinics
• Future of cervical screening– Pap testing– HPV testing– Molecular technology
Presenter
Presentation Notes
Why is this update coming now? 2006 happens to be the 10-year anniversary of the ThinPrep® Pap Test’s approval by the FDA. Much has changed in the last decade. Liquid-based Pap tests now represent 90% of the Pap tests done in the United States, 70% of which are ThinPrep. HPV reflex testing for ASC-US management has become a standard practice for physicians. In the more recent past, ThinPrep imaging has been rapidly adopted in laboratories, and 40% of ThinPrep Pap Tests are imaged. The 10-year anniversary of ThinPrep is also a good time to reflect on what the future holds. The HPV vaccine, which was approved in June 2006, is an exciting and positive advance in cancer prevention. The vaccine is an amazing development. In a relatively short period of time, this community has been able to identify not only the predominant cause of cervical cancer, but also develop a vaccine that helps prevent the most common strains of the virus. The HPV vaccine is a major milestone for cervical cancer prevention. When people are thinking about how to incorporate these technologies into patient management, cost-effectiveness becomes an important issue. How do we weigh the costs associated with this new technology against the actual clinical outcomes for women? How do we take all of that into our decision-making process to determine the best path forward? When considering all of this information, we cannot ignore the underserved: the women in the Title X and Planned Parenthood clinics, and the fact that 10% of women are still receiving the conventional Pap smear. The vaccine and ThinPrep’s anniversary are an opportunity to consider the future of cervical cancer screening. Where does Pap testing fit in? Where does HPV testing fit in the future? What about all the new molecular technology and tests that are being developed? What about new technologies under development? How does it all fit together? This is a unique and important time in women’s healthcare. Let’s talk more about these important issues.
Slide 9: The relationship between human papillomavirus (HPV) and cervical cancer is now certain. HPV infection causes virtually all cases of CIN 3 and cervical cancer and a less-defined, smaller fraction of vaginal, vulvar, penile, and anal cancers. The large IARC case-control study by Munoz et al determined that 53% of the cervical cancers were HPV 16 positive compared to 3% of the control population not having cervical cancer. The relative risks of an HPV 16 positive person having or getting cervical cancer was demonstrated to be 434 when compared with a woman negative for this HPV type. HPV 18 positivity conferred a RR of 248, and all of these other “high-risk” types have RR above 100. Compare this to the RR of a chronic long-term smoker for lung cancer (17-20) and the significance of a high-risk HPV infection becomes clear. This is one of the highest relative risks for carcinogenesis known to humans. The study also determined that HPV 16 was the most common type in normal women.
6%
4%
2%
0.0%1 2 3 4 6 7 8
HPV positive
HPV negative
9
8%
5 10
Kaiser Portland NCI Study 1990-1999:
Years of follow-upSherman ME et al JNCI 2003;95:46-52.
4.3%
>7%
Presenter
Presentation Notes
Slide 27: The 10-year follow-up National Cancer Institute HPV natural history study from Portland Kaiser has provided information on the risk of testing high-risk HPV positive at a single point in time compared to one testing HPV negative at the same time. In this study a single high-risk HPV positive sample at enrollment predicted a risk of 4.3% for detection of CIN3 by 4 years and over 7% by ten years. In contrast, the risk for CIN 3 for women (testing negative was negligible despite the likelihood that many of these women were newly infected with high-risk HPV types during the subsequent 10 year follow-up. This clearly demonstrates the long-term reassurance provided by an initial negative HPV and Pap result.
HPV Prevalence and Cervical Cancer - Incidence by Age 1,2
1. Sellors et al. CMAJ. 2000;163:503.2. Ries et al. Surveillance, Epidemiology and End Results (SEER) Cancer Stats NCI, 1973-1997. 2000.
Age (Years)
HPV
Pre
vale
nce
(%)
40-4415-19 20-24 25-29 30-34 35-39 45-49 50-54
0
5
10
15
20
25
30
0
5
10
15
20
25
30
Can
cer i
ncid
ence
per
100
,000
Presenter
Presentation Notes
Slide 16: This graph shows HPV prevalence and cervical cancer incidence are a function of a woman’s age. From it, a number of key observations can be made. First, the slide shows that in younger women, there is a high prevalence of HPV infection but that cervical cancer is very rare. As women age, however, the prevalence declines and the incidence of cancer increases. Women over 30 years of age have a greater risk for developing high-grade lesions and cancer. Furthermore, women with persistent high-risk HPV infections are the population most at-risk for having or developing cervical cancer. Data from the CMAJ study was collected from women aged 15-49, whereas the SEER data reported cancer incidence in all age-segments of the population.
ACS/ASCCP/ASCP
2012 Cervical Cancer Screening Guidelines
• No routine speculum exam or cytology regardless of age of onset of
intercourse or other risk factors.
• STD testing and counseling on safe
sex and contraception as
needed.
• Annual pelvic exam AND
screening with:
• Cytology and HPV testing (“co- testing”) every 5
years (preferred per ASCCP)
OR
• Cytology alone every 3 years (acceptable) is recommended.
Saslow D,. Am J Clin Pathol. 2012 Apr;137(4):516‐42.
• Annual pelvic exam
AND
• Screening with cytology alone
every 3 years is recommended
30-65 Years21-29 Years< 21 Years > 65 Years
• Discontinue screening after age
65 following adequate prior
screening
Comment: Women with a
history of CIN2 or a more severe
diagnosis should continue screening
for at least 20 years.
Presenter
Presentation Notes
And so the most recent guidelines by ASCCP and affiliated groups reflect this balance. In the youngest population, no cytology is recommended at all regardless of her age at the time of first intercourse or other risk factors. Cervical cancer in this patient population is extremely rare and does not warrant screening even in those young women who seem at risk. In the 20-29 years-old age group, cytology alone is recommended every 3 years. With certain abnormal findings, the follow-up may vary depending on the degree of abnormality, but screening is no more than 3 years. Between 30-65, cytology with high-risk HPV testing is preferred every 5 years though cytology alone every 3 years is acceptable. The annual pelvic exam is still recommended. Beyond 65 years-old, women with no history of ≥CIN2 within 20yrs or ASCUS/HPV- within 3years may discontinue cervical cancer screening. Note: The USPSTF recommendations are the same EXCEPT that USPSTF does not make a distinction that HPV testing is preferred in the 30-65 age group. The USPSTF guidelines state that both cotesting and cytology “provide similar benefits and advocate cotesting for women who desire to lengthen the screening interval.” Also, the ACS/ASCCP/ASCP guidelines note that “there is insufficient evidence to change screening intervals in this age group in women with a history of negative screens.” (Kizer, N and Peipert, J. Editorial: Cervical Cancer Screening: Primim Non Nocere. First published March 14, 2012 on annals.org.)
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Cotesting: Pap plus HPV
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Rationale: Why consider HPV testing in primary cervical screening?
• “..persistent, high-risk HPV infection is necessary for the development of cervical CA
• “..an obvious corollary is that the absence of HPV means that the risk of cervical cancer is negligible.
Wright TC, Schiffman MH NEJM 2003;348:489-90
Presenter
Presentation Notes
Slide 25: The rational for considering HPV testing in primary screening was nicely summed up in a 2003 NEJM commentary written by Wright and Schiffman. Because persistent high-risk HPV infection is necessary for the development of cervical cancer, (an obvious corollary is that the absence of HPV means that the risk of cervical cancer is negligible. Of course, no test or combination of tests, no matter how sensitive, will ever be perfect. Therefore, preventing all cases of cervical cancer is an unobtainable goal, even if all women accessed the best screening available. However, using the best screening available certainly holds the prospect of reducing the burden of cervical cancer as much as possible.
• A normal Pap and a negative HPV test give a 99- 100% assurance that cervical cancer is not present and will not likely occur in the next few years.
Requiring increased surveillance.
HPV Testing for ScreeningA risk stratifier
Allowing less frequent screening.
• A positive HPV test and a normal Pap reflects increased risk for either missed disease or for the subsequent development of CIN 2/3 and cancer.
Presenter
Presentation Notes
Slide 27: HPV testing for screening is risk stratifier. Women having a normal Pap and a negative HPV test are given a 99-100% assurance that cervical cancer is not present and will not likely occur in the next few years, allowing less frequent screening. In contrast, a positive HPV test and a normal Pap reflect increased risk for either missed disease or for the subsequent development of CIN 2/3 and cancer. However, it must be remembered that even with this increased risk, most women with a positive test for high-risk HPV and a normal Pap do not have significant cervical neoplasia. Therefore, rather than immediately referring these women to colposcopy, such findings call only for increased surveillance.
Cum
ulat
ive
inci
denc
eof
CIN
3+(p
er 1
0,00
0)
Time since initial testing (mos.)Dillner et al., BMJ, 2008
CIN3+ Risk Following a Negative Screening Test
Presenter
Presentation Notes
Using pooled data from several HPV screening studies in Europe, the estimated cumulative incidence rate for future histologically confirmed CIN3+ during six years of follow-up demonstrates the long-lasting protective benefit with negative cytology and negative HPV. There is slightly less benefit with HPV alone and significantly less with cytology alone. By combining HPV testing with cytology, there is improvement in screening sensitivity allowing lengthening of the screening interval. The risk of CIN3+ at 1 year cytology alone is the same as 5 years for HPV- or co-testing.
Risk Stratification with HPV Types 16 and 18 in Women ≥
This recommendation for genotyping is based on the known increased risk of invasive cancer or CIN3 with HPV types 16 and 18. The cumulative incidence rate of severe dysplasia or ca increases significantly in women with HPV 16 and HPV 18 over 10 years (20% and 18% respectively) compared to infections with non-HPV 16/18 positive infection or HPV negative. Key Point: ≥ CIN 3 found in about 20% of women with HPV 16/18 at 10 years. During this study, HPV status was assessed for all enrolled patients at baseline. “Given that HPV 16 and HPV 18 are estimated from cross-sectional data to cause 70% of cervical cancers worldwide and that the cumulative risk of (> CIN 3) in women with HPV 16 or HPV 18 ranges from 10% to 20%, we conclude that these 2 HPV types are potent carcinogens and should be more effectively targeted in clinical practice.” 1 Summary of findings1: ≥ CIN 3 cumulative incidence of 20.7% of cytology-negative, HPV-16-positive women at 10-year follow-up ≥ CIN 3 cumulative incidence of 17.7% of cytology-negative, HPV-18-positive women at 10-year follow-up ≥ CIN 3 identified in only 1.5% of all other cytology-negative, non-HPV-16/18, HR HPV-positive women at 10-year follow-up ≥ CIN 3 identified in only 0.5% of all other cytology-negative, HR HPV-negative women at 10-year follow-up References 1. Khan MJ, et al. J Natl Cancer Inst. 2005;87(14):1072-1079.
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PRIMARY HPV SCREENING?
Disclaimer text goes here
Roche cobas HPV FDA (proposed) indications (ATHENA Trial)
• As a primary screening test in women ≥25 years to detect high risk HPV, including genotyping for 16 and 18
• Women testing positive for HPV 16 or 18 should be referred to colposcopy.
• Women testing high risk HPV positive but 16/18 negative should be reflexed to cytology to determine the need for referral to colposcopy
• Women testing negative for high risk HPV should be followed up in accordance with the physician’s assessment of screening and medical history, other risk factors, and professional guidelines.
FDA Microbiology Devices Panel Meeting March 12, 2014.
Roche HPV Primary Submission (ATHENA Trial)
• Algorithm proposed1
– Proposed age cutoff of >25– HPV primary compared to cytology only – statistically
– 8 cases of invasive cervical cancer in ATHENA Trial2
– 19 additional cases obtained from HPV Cytology Registry– Sensitivity of cobas HPV primary = 88.5% (23/26*)– Sensitivity of co-testing = 92.6% (25/27)– 2 cases of AIS missed by cobas, but cytology positive– Need more data
*1 case invalid and excluded from the analysis
2. Castle E Philip et al. Performance of carcinogenic HPV testing and HPV 16 or HPV 18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalyis of the ATHENA study. Lancet Oncol 2011: 12: 880-90.
1. FDA Microbiology Devices Panel Meeting March 12, 2014.
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Primary HPV Screening?
• FDA approved (Roche Cobas test only)• Women between ages 25 and 65• New algorithm of follow-up• More effective at reducing CIN 3+ than Pap plus HPV, when used at recommended intervals (3 yrs for HPV, 5 yrs for Pap+HPV 1)
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1) Gage J, et al NEJM Aug 2014
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Cumulative risk of cervical intraepithelial neoplasia grade 2, grade 3 or cervical cancer among women 30 to 64 years at Kaiser Permanente Northern California
Gage JC et al, J Natl Cancert Inst (2014) 106 (8)
How will HPV primary screening impact false negative rates?
Kaiser Data
Katki A Hormuzd, et al. Cervical Cancer risk for women undergoing concurrent testing for HPV and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol 2011; 12:663-72.
69% HPV
Alone
69% HPV
Alone
79% Co-test
79% Co-test
Presenter
Presentation Notes
Is this “substantial”? 69% is what you get when you test with HPV alone. 79% (10% more) you will get when you co-test which in this case is 9 more cancers Katki: co-testing was 10% more sensitive than HPV alone for detection of cancer (statistically significant)
ATHENA Data
Castle E Philip et al. Performance of carcinogenic HPV testing and HPV 16 or HPV 18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalyis of the ATHENA study. Lancet Oncol 2011: 12: 880-90.
Presenter
Presentation Notes
ATHENA: Miss 2 Adenocarcinomas with HPV primary
L1-based HPV Primary Screening for Cervical Cancer: What’s the risk?
Hilfrich, Ralf. HPV L1 Detection as a Prognostic Marker for Management of HPV High Risk Positive Abnormal Pap Smears. Human Papillomavirus and Related Diseases – From Bench to Bedside A Diagnostic and Preventive Perspective. 2013.
Presenter
Presentation Notes
We know a lot about HPV detection strategies L1: late genes-codes for capsid protein E6/E7: oncogenes-inhibit apoptosis L1 is present in episomal copies of DNA but can be deleted as the virus integrates into human genome Studies have shown false-negative cancers due to L1 deletions
4800 HPV Test US Package Insert #05641268001‐01EN Rev 1.0 20114. Hybrid Capture 2 High‐Risk HPV DNA Test®
package insert #L00665 Rev. 2 2007
HPV Detection Strategies
Presenter
Presentation Notes
Selecting the method or technique for the detection of HPV is essential – the available HPV tests are primers and probes which identify a region of the viral HPV DNA or mRNA. There are similarities and differences between these FDA approved HPV tests. Aptima HPV targets the E6/E7 ongenes similar to Cervista and hc2. Only the cobas HPV test targets L1 region of the HPV genome which is of concern since common genetic alterations such as deletion of the HPV L1 region is a common occurrence in high-grade CIN lesions and cervical cancers. A primer/probe system directed only to the L1 region of the HPV genome can lead to false-negative results. I’ll return to this issue when we compare testing sensitivity.
HPV DNA levels decrease as disease progresses toward cancer. How will this impact detection of the most severe disease cases?
2. Hilfrich, Ralf. HPV L1 Detection as a Prognostic Marker for Management of HPV High Risk Positive Abnormal Pap Smears. Human Papillomavirus and Related Diseases – From Bench to Bedside A Diagnostic and Preventive Perspective. 2013.
HPV DNA Detection
• Benign HPV lesions and CIN 1: NO integrated or episomal HPV DNA
• HPV 16 cancers: up to 55 - 80%
• HPV 18 cancers: up to 83%
• HPV 45 cancers: 92 - 100%1
Percentage of integration increases from CIN to invasive cancer
1. W.A.A. Tjalma, C.E. Depuydt / European Journal of Obstetrics & Gynecology and Reproductive Biology 170 (1); 2013.
2
What collateral benefits do we forfeit by abandoning the pap in screening strategies?
33
Collateral Benefits of Cytology
Bakkum-Gamez J, Dowdy S. Retooling the pap smear for ovarian and endometrial cancer detection. Clin Chem 2013 Jan; 60 (1) 22-4.
Presenter
Presentation Notes
\
• HPV primary vs. co-testing vs. cytology alone
– Do we have enough data?
• To date, there is only one test indicated for HPV primary
– Is an L1 DNA based test sufficient?
• There is not yet guidance regarding what will follow an HPV+ primary test (ie: PAP, colpo, repeat testing)
– How do we adapt to changing guidelines?
• Co-testing intervals are supported by the data
– What will the intervals be with primary screening?
• The pap has proven benefits
– Which malignancies would be missed by eliminating the pap? (endometrial & non HPV pre cancers)
HPV Primary: Are we there yet?
2010 2020 2030 2040 2050
No.
of
case
s p
er 1
00,0
00
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Projected number of cervical cancer cases in developed countries, as a function of percent of population immunized
Plummer M, Franceschi S Vir Research 2002;89:285-93
No vaccination
25% vaccinated
50% vaccinated
75% vaccinated
100% vaccinated
Presenter
Presentation Notes
Slide 81: Prophylactic HPV vaccination is just around the corner and may possibly be the most significant breakthrough in vaccines since the polio vaccine, as cervical cancer continues to be first or second in cancer incidence and mortality in women in areas lacking the resources to screen. However, the lag time between vaccination of adolescents and reflection on cervical cancer incidence rates is up to several decades due to the long natural history of cervical oncogenesis. Additionally, vaccines presently in development protect against only 2 of the high-risk HPV types. While these types are responsible for 70—75% of cervical cancers, until the all types responsible for oncogenesis can be included, cervical screening will need to be continued.
![3 LASOP Case 3 2006.ppt [Read-Only]lasop.com/pgs/hdouts/2006-03_Case3.pdfmeningioma (WHO grade II) • Microcystic gliomas • Hemangioblastomas • Myxoid schwannomas. Microcystic](https://img.pdfslide.us/doc/110x75/5e3bd740d005aa51c76678a8/3-lasop-case-3-2006ppt-read-onlylasopcompgshdouts2006-03case3pdf-meningioma.jpg)
