1. Monitoring and Ordering Practices for Human Papilloma Virus in Cervical Cytology
Christine Noga Booth, MD
Cytopathology Fellowship Program Director
RJT-Pathology & Laboratory Medicine Institute
Cleveland Clinic

2. HPV and Cervical Cytology
Early 1980’s
Link between HPV and cervical carcinoma discovered
Mid-1990’s
First test to detect HPV made available
Current roles
Patient screening, triage and management

3. Anogenital HPV Infections
Spectrum of clinical expression
Latent infection - no identifiable lesion
Exophytic condylomas
Low-grade and high-grade neoplasia
Invasive cancers: Cervix, vulva, anus, penis,
head & neck, esophagus, conjunctiva
Notes:
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4. Natural History of HPV Infections
Wright and Schiffman (2003) NEJM

5. HPV Integration Not part of normal viral life cycle
Random sites in human genome
Loss of ~ 50% HPV DNA including E2 leading to increased expression of E6/E7
Integration detected even in LSIL lesions but more common in HSIL 5

6. Mechanism for Transformation
Requires integration of viral genome into host genome
HPV genes E6 & E7 are always conserved with loss of E2 which normally regulates transcription of E6 & E7
E6:
Inhibits p53
Allows cell to enter S phase without normal DNA repair function
E7:
Binds retinoblastoma tumor suppressor gene product (pRb)
Allows cells to proceed uninhibited through S phase

7. E7 leads to increased expression of p16INK4a
MTM labs

8. Anogenital HPV Types
High-risk types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, 82
Possible high-risk 23, 53
Low-risk types 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81
Notes:
The most important anogenital HPV types include: HPV types 6 and 11 which are considered low-risk since they cause genital condylomas but are rarely found in cancers or high-grade CIN; types 16, 18, 31, 45, 56 and 58 which are considered to be the prototypical high-risk viruses since they are typically found in women with CIN 2,3 and invasive cervical cancers; and a large group of intermediate risk viruses, which include members of the 30s, (such as 33, 35, 39), 51 and 53, which are found in squamous intraepithelial neoplasia of all grades, but are rarely found in association with cancer; and finally, HPV types 42, 43 and 44 which are low-risk viruses typically found in low-grade CIN lesions and flat penile lesions, but rarely found in cancers.
Munoz et al. (2003) NEJM

9. HPV DNA Testing Methods
Methods currently in use:
FDA Approved:
Hybrid Capture 2 (Qiagen) – 1995
Cervista (Hologic) – March 2009
Cobas (Roche) – April 2011
APTIMA (GenProbe) – Oct 2011
In situ hybridization (ISH)
“Home Brew” Polymerase chain reaction (PCR) "consensus" primers - all anogenital HPV "type specific" - single type of HPV
Notes:
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10. HPV DNA Testing Methods
Hybrid Capture 2 (Qiagen) – separate high-risk and low-risk probe mixtures
Invader (Cervista™) – separate tests for high risk mixture and HPV 16/18
Cobas 4800 (Roche) – concurrent testing for HPV 16/18 and 12 other hrHPV
APTIMA (GenProbe) – E6/E7 mRNA from 14 hrHPV
Notes:
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11. HPV DNA Testing Methods: hc2
Hybrid Capture® 2 High-Risk HPV DNA Test ™
Commercially available (Qiagen), FDA-approved
High-risk Probe mixture:
16/18/31/33/35/39/45/51/52/56/58/59/68
Sensitivity is about 5,000 copies of HPV
May cross react with low-risk HPV DNA
Notes:
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12. HPV DNA Testing Methods: Invader
Commercially available (Cervista™), FDA-approved
Probe mixture:
High-risk: 16,18, 31, 33, 35, 39, 45,
51,52, 56, 58, 59, 66, 68
Isothermal signal amplification procedure with detectable fluorescence
Does not cross react with low-risk HPV DNA
Contains internal control for sample DNA sufficiency
Notes:
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13. HPV DNA Testing Methods: Cobas
Commercially available (Roche), FDA-approved
Probe mixture:
Individual results for: 16 and 18
Pooled results for: 31, 33, 35, 39, 45, 51,52, 56, 58, 59, 66, 68
Qualitative PCR for L1
Contains internal control for sample DNA sufficiency
Notes:
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14. HPV DNA Testing Methods: Aptima
Commercially available (Gen-Probe), FDA-approved
Probe mixture:
Pooled results for: 16,18, 31, 33, 35, 39, 45, 51,52, 56, 58, 59, 66, 68
Qualitative nucleic amplification that detects E6/E7 mRNA
Similar sensitivity but possible increased specificity to HC2
Notes:
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15. Cervista vs. Hc2
Independent study (SHENCCAST II) in China (presented at AOGIN 2010)
Biopsy confirmed CIN 2+
Cervista
sensitivity: 90.7, specificity: 90.2
Hc2
sensitivity: 94.7, specificity: 87.9
Clinically equivalent (area under ROC curve)

16. HPV Testing Quality Assurance
Test Validation
Analytic validation/clinical validation
Laboratory evaluation designed to insure that the test is operating “in your hands” as expected
2) Internal Quality Control
Internal Standards – known positives and negatives in each run, Active review of results looking for patterns/trends, Rerunning of equivocal results
3) External Peer Comparison
Required by CLIA ’88 for all analytes
CAP LAP or self-developed program

17. CAP Interlaboratory Comparison for hrHPV
Started in 2008 (piloted in 2007)
Designed for labs doing only hrHPV testing
ThinPrep, SurePath, Standard Transport Media modules or mixed specimen module
Hc2, PCR, Third Wave
3 mailings per year, 5 specimens each mailing
2008 data
3,296 laboratory responses
98.3% concordance with reference result

18. Potential clinical uses:
HPV DNA Testing
Potential clinical uses:
Management of ASC - US
Secondary follow-up - abnormal Pap
Follow-up post treatment
Primary screening QC
Notes:
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19. HPV DNA Testing for ASCUS Triage
Kaiser Permanente study:
46,009 women with ThinPrep Paps
ASCUS rate of 3.5%; 973 women
82% participation; median age 37 yrs
Used Hybrid Capture II for high-risk HPV
Two large clinical trials have evaluated HPV DNA testing as a way of determining which women with ASCUS Pap tests need colposcopy. The first of the trials was the the Kaiser Permanente study that was published in In the Kaiser study 46,009 women were screened using a conventional Pap test and they also had a liquid-based cytology sample collected (but not actually processed). If a woman had ASCUS diagnosed on the conventional Pap test, they were referred for colposcopy - at which time a SECOND conventional Pap test was collected. In addition, a sample from the ORIGINAL (unused) liquid-based cytology sample was tested for high-risk HPV types using Hybrid Capture II. This study design allows the comparative sensitivity and specificity of a repeat Pap test and HPV DNA testing to be determined - using the results of the colposcopy and biopsy as the "gold standard".
In Kaiser at the time this study was conducted there was a 3.5% ASCUS rate. 82% of the women with ASCUS agreed to participate in the study and the median age of those participating was 37 years.
Manos et al. JAMA (1999)

20. For CIN 2 (+) Triage Method Sens % Refer
Kaiser ASCUS Study
For CIN 2 (+) Triage Method Sens % Refer
HPV DNA testing 89% 40%
Repeat Pap test * 76% 39%
In the Kaiser study, HPV DNA testing for residual liquid-based cytology samples for high-risk HPV types using Hybrid Capture II had a greater sensitivity for the detection of biopsy-confirmed CIN 2 or greater than did a repeat conventional Pap smear. HPV DNA testing was positive in 89% of the cases with CIN 2 or greater. In contrast, the repeat conventional Pap test showed a diagnosis of ASCUS or greater in only 76% of the cases with CIN 2 or greater.
Both HPV DNA testing would have referred equivalent numbers of women to colposcopy - 40% for HPV DNA testing and 39% for the repeat Pap test. However, NONE of the women would have had to have come back to the clinic to have a sample collected for HPV DNA testing; whereas ALL of the women would have had to return for the repeat Pap test.
*repeat conventional Pap smear > ASCUS
Manos et al. (1999) JAMA

21. HPV DNA Testing for Triage
NCI-sponsored ALTS trial:
Multicenter, randomized, prospective trial
3 arms: Immediate colposcopy HPV DNA liquid-based Pap Repeat Pap test
2,324 women with ASCUS published
The ALTS trial is a three arm, randomized, two year prospective follow-up clinical trail that is being conducted at 4 clinical centers by the NCI. The three arms are: 1) immediate colposcopy, 2) HPV DNA testing for high-risk types of HPV using Hybrid Capture II and referral to colposcopy if women are high-risk HPV DNA positive, and 3) conservative management in which women were followed with repeat liquid-based cytology and referral to colposcopy only if a woman had a repeat Pap test diagnosed as HSIL. ALTS originally enrolled women with both LSIL and ASCUS. However, it was quickly recognized that HPV DNA testing offered no significant advantage for women with LSIL, so this portion of the study was closed to enrollment.
Recently Solomon et al. published the enrollment results for women enrolled in both the immediate colposcopy arm and the HPV DNA testing arm. This was a total of 2,324 women - or two-thirds of the women enrolled in trial. They compared the sensitivity and specificity of HPV DNA testing with that of repeat liquid-based cytology for the detection of biopsy-confimed CIN 2 or greater lesions.
Solomon et al. JAMA (2001)

22. For CIN 2 (+) Triage Method Sens % Refer
ALTS Trial - ASCUS
For CIN 2 (+) Triage Method Sens % Refer
HPV DNA testing 96% 56%
Repeat Pap test
> ASCUS 85% 58%
> LSIL 60% 26%
In the ALTS trial, HPV DNA testing of liquid-based cytology samples for high-risk HPV types using Hybrid Capture II had a greater sensitivity for the detection of biopsy-confirmed CIN 2 or greater than did a repeat liquid-based Pap test. HPV DNA testing was positive in 96% of the cases with CIN 2 or greater. In contrast, the repeat liquid-based Pap test showed a diagnosis of ASCUS or greater in only 85% of the cases with CIN 2 or greater. If the threshold used to refer women to colposcopy of the repeat Pap test was raised to LSIL or greater, only 60% of the women with CIN 2 (+) would have been referred to colposcopy.
Both HPV DNA testing would have referred equivalent numbers of women to colposcopy - 56% for HPV DNA testing and 58% for the repeat Pap test. However, NONE of the women would have had to have come back to the clinic to have a sample collected for HPV DNA testing; whereas ALL of the women would have had to return for the repeat Pap test.

23. Meta-analysis of ASCUS-HPV Triage Studies ( ) Arbyn et al: GynGynecol Oncol: 99 (2005) S7-S11
16 studies met criteria for inclusion
Using HC2 with a disease threshold of CIN2+
Sensitivity: 94% (CI 92-96%) (range: 80% - 100%)
Specificity: 62.4% (CI 56-68%) (range: 37% - 80%)
6 studies included repeat cytology
Sensitivity of HC2 was 14% higher than repeat cytology with essentially equal specificity

24. Consensus Guidelines for the use of HPV in Cervical Specimens
ASCCP 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors
Representatives from 23 professional societies including: ACS, AAFP, ACOG, ASCCP, CDC and CAP
J Lower Genital Tract Dis (4):S1-S27.
CETC statement on HPV test utilization
Endorsed by ACS, ASCP, ASCCP, ASC, CAP, IAC and PSC
Diagn Cytopathol Jul;37(7):542-3 as well as Arch Pathol Lab Med and Am J Clin Pathol

25. Consensus Guidelines for the use of HPV in Cervical Specimens
ASC/ASCCP/ASCP 2012 Screening Guidelines for Cervical Cancer:
Representatives from 25 professional organizations
Am J Clin Pathol. 2012;137:
Systematic evidence based review and consensus symposium
Screening recommendations address age appropriate screening strategies and use of HPV testing
Age ≤ 30: HPV testing should not be used as part of the primary screen.
Age 30-65: HPV and cytology co-testing is the preferred screening test.
Age ≥ 65: No screening following adequate negative prior screening

26. 2012 ASCCP Guidelines
Testing for low-risk HPV types has NO role in routine cervical cancer screening or for the evaluation of women with abnormal cervical cytology.

27. Role of HPV Testing in ASC-H Liman et al: Cancer Cytopathol: 105 (2005) 457-460
48 samples of ASC-H with HPV and histo/cyto follow-up ( )
All proven HSIL (22 cases) were HR HPV+
80% of LSIL (5 total) were HR HPV+
50% of patients with negative follow-up were HPV+

28. HPV Testing for Screening
Questions to address:
Who gets screened
Testing method and with or without Pap
Screening frequency
Management of screen positives and negatives
These questions were addressed by the ASC/ASCCP/ASCP 2012 Screening Guidelines for Cervical Cancer
Notes:
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29. HPV Testing for Screening
Summary of clinical data:
Consistently more sensitive than Pap
Specificity is probably less than Pap
Combination of Pap and HPV increases sensitivity, but reduces specificity - very high negative predictive value
Notes:
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30. HPV Testing for Screening
FDA approval: HPV-Pap Co-test
The various FDA approved HPV tests are also approved as an adjunct to cervical cytology screening in women 30 years and older.
Notes:
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31. HPV Testing for Screening
Key advantage of using:
Negativity for high-risk HPV identifies which women are at very low risk for having or developing CIN 2,3 over next 5 yrs
Allows targeted screening
Notes:
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32. HPV Testing for Screening
Management of HPV (+) / Pap (-)
Risk for having CIN 2,3 is about 5% in well-screened population
About half have transient infections and become HPV negative by 6 mos
Almost all CIN 2,3 occurs in women with persistent HPV
Notes:
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33. Negative Cytology - HPV DNA Positive
(-)
(+) - Colposcopy
Repeat co-test in 12 months
High-risk
HPV (+)
Pap
> ASC-US
Both
Negative
Colposcopy
Repeat Pap & HPV
in 3 yrs
J Lower Genital Tract Dis. 2013, 17(4):S1-S27.

34. HPV positive rates and ASC-US
Most recent HPV Q-Probe data conclude that an HR-HPV positive rate of 43.7% is an appropriate quality metric
Q-Probes 2005: HPV Testing (QP053). Northfield, Ill: College of American Pathologists; 2005.
In other studies the median rate is reported as 34.1% to 50.6%, depending on the age of the population studied.

35. HPV Triage: CAP Survey 2006 Arch Pathol Lab Med 2008; 132: 1290-1294
679 labs responded
73% send to reference lab, 9% perform in house
45% offer low risk HPV testing
Digene HC is most commonly used test
Median test volume 55/month
24.5% doing primary screening in women >30yr
Median rates for positivity: ASCUS 36.6%, ASC-H 50%, 4% for HPV screening in conjunction with Pap

36. ASC-US Cases versus HPV
% HPV (+) % labs % labs
< % 8.1% % %
% % % % > % 5.0%
Median rate 2006: 36.6%
From the 2003 and 2006 College of American Pathologists PAP questionnaire: Arch Pathol Lab Med Aug;132(8):

37. HPV percentiles for ASC-US, ASC-H and HPV30-NIL
percentile ASC-US ASC-H NIL
Labs:
5th 4.0% 0% 0%
10th 15.2% 0% 0%
25th 26.0% 1.8% 1.9%
50th 36.6% % 4.0%
75th 47.8% % 11.0%
90th 53.2% % 24.5%
95th 62.2% % 25.9%
From the 2006 College of American Pathologists PAP questionnaire: Arch Pathol Lab Med Aug;132(8):

38. Gynecologic Cytopathology Quality Consensus Conference (GCQC2) 2011
College of American Pathologists laboratory-based survey funded by the Centers for Disease Control and Prevention
Paper-based survey
Follow-up Web-based survey
National Consensus Conference

39. GCQC2 2011
Goal of Survey and Results: To identify what metrics are collected, how metrics are analyzed and what benchmarks are used to determine variance in performance and what actions are taken to address performance issues.

40. GCQC2: Working Group 5 Monitoring of HPV Rates
Christine Booth MD, FCAP, Chair
Michael Henry MD, FCAP, Senior Author
Carol Filomena MD, FCAP
Marilee Means, PhD, SCT(ASCP)
Patricia Wasserman MD, FCAP
Christine Bashleben, CAP staff

41. CAP Survey 1245 Laboratories received survey
546 laboratory responses (525 regarding HPV practices) to paper survey
51 additional questions posed from working group
Up to 34 responses received
Voting at the GCQC2 in June, 2011

42. Original Survey Results: HPV testing practices
HPV results obtained at the time of the Pap test are routinely incorporated into the Pap report: (n=525)
Yes %
No %

43. Original Survey Results: HPV testing practices
How are HR-HPV tests for ASC-US ordered? (N=518)*
Ordered as a "reflex test" by providers
Ordered reflexively by the laboratory independent of the primary provider initial order
Offered for reflex testing for women under 21 years of age
87.6%
23.4 %
7.9 %

44. Original Survey Results: HPV testing practices
Laboratory limits ASC-US reflex testing to women over the age of 20: (n=512)
Yes %
No %
If no, why? (from online survey):
Clinician driven
Patient demands
Resolve diagnostic dilemmas
Ordered out of habit

45. Online Question Results
71% of respondents will perform reflex HR-HPV in ASC-US in women under 20 at clinician’s insistence
51% of respondents will call clinician to educate about published guidelines before performing reflex HR-HPV in ASC-US in women under 20
6% of respondents will not perform reflex HR-HPV in ASC-US in women under 20 despite clinician’s insistence
Some respondents will perform reflex HR-HPV testing in women under 20 at clinician’s insistence and will include a comment in the report indicating that “modern guidelines do not recommend HPV tests for women equal and less than 20 years of age and if obtained, the results should be ignored for management.”
Some respondents require that clinicians who want reflex HR-HPV testing in women under 20 submit a separately collected test directly to virology

46. Original Survey Results: HPV testing practices
Which HR-HPV tests are reflexively offered from a cytology specimen? (n=520; multiple responses allowed)
ASC-US reflex %
ASC-H reflex %
AGC or other glandular abnormalities %
Pap test with any squamous epithelial abnormality %
LSIL with a Pap test regardless of age %
LSIL reflex in postmenopausal women %

47. Online Question Results
Does your lab offer HPV reflex testing on
ASC-H?
50% offer reflex HR-HPV testing for ASC-H results
50% do not offer HR-HPV testing for ASC-H results
Some respondents state that knowledge of HPV in ASC-H is beneficial in the following cases:
No colposcopic follow up if HPV is negative
If HPV negative, patient returns to routine testing
Useful in resolving diagnostic dilemmas with confidence
Useful in older women with negative history
Useful in pregnant women
Helps PCP decide to go to LEEP or not

48. Original Survey Results: HPV testing practices
If an HR-HPV test is not ordered reflexively on a Pap test by the submitting clinician, does the pathologist have the discretion to order an HR-HPV test?
Yes %
No %

49. Original Survey Results: HPV testing practices
Laboratory finds it useful to order HR-HPV testing independently of the clinician to resolve diagnostic discrepancies between the cytotechnologist and pathologist in Pap test diagnosed as the following: (n=129; multiple responses allowed)
ASC-US %
ASC-H %
AGC %
HSIL %
LSIL %
SCC %
ADC %

50. Online Question Results
If you do use HR-HPV results to resolve diagnostic discrepancies, please explain how:
To fine tune ASC-US criteria
To aid in the CT-P disagreements for ASC-US cases
In borderline Pap interpretations
HPV negative cases results in re-evaluations
HPV positive cases results in re-evaluations
To resolve diagnostic dilemmas at any age

51. Survey results: Lab Volume Analysis for HPV Testing Practices
Smaller labs are more likely to reflexively order HPV testing independent of the initial order (P=0.001)
Larger labs are more likely to reflexively order HPV testing with any squamous abnormality (P=0.001)

52. Original Survey Results: HPV testing practices
Laboratory offers low-risk HPV testing: (n=520)
Never %
Only on request %
Routinely bundled with HR-HPV 11.9%
Other %

53. Use of HPV Test Results for Quality Assessment
HR-HPV rates are monitored to determine potential trends in accuracy of diagnoses
ASC-US reflex HR-HPV results
Yes
221 (53.9%) No
189 (46.1%)
HPV DNA Results
119 (32.7%)
245 (67.3%)

54. HPV Monitoring by Pap Test Result and Laboratory or Individual
Monitoring of HPV rates (n=392)*
Pap test Result
Laboratory
Cytotechnologist
Pathologist
ASC-US
53.3%
13.8%
21.4%
NILM
5.9%
LSIL
17.9%
4.3%
HSIL
14.8%
3.3%
4.6%
* Multiple responses allowed

55. Original Survey Results: HPV for Quality Assessment
HPV results are compared to ASC-US/SIL ratios for pathologists to determine potential trends in over or under diagnosis? (n=513)
Yes 28.8%
No 71.2%
If no, why not? (from online survey)
Too complex to get data
Pap and HPV results in separate systems
Does not affect pathologist sign-out tendencies

56. CAP Checklist CYP.07653 HR-HPV Records
If available, records are maintained for high-risk human papillomavirus (HR-HPV) tests performed on ASC-US including:
Total number of HR-HPV tests performed on ASC-US cases
Total number of POSITIVE HR-HPV ASC-US cases
NOTE: The percentage of ASC-US cases with a positive HR-HPV result may be a helpful quality metric for both overall laboratory performance and individual performance of pathologists, especially when combined with an individual's ASC-SIL ratio. Data for other HR-HPV testing results (e.g. co-testing with a Pap test in women > 30 years of age) may also be helpful quality metrics but should be kept separately.

57. Consensus Good Laboratory Practice Statements
Laboratories should only offer HR-HPV testing for gynecologic cytology specimens.
Not appropriate to offer low-risk HPV testing for any clinical circumstance.
81% agreement

58. Consensus Good Laboratory Practice Statements
Laboratories should encourage clinicians to consider the latest consensus guidelines in ordering HR-HPV tests on gynecologic specimens.

59. Consensus Good Laboratory Practice Statements
Laboratories should be cautious in using HPV test results to change or influence cytologic interpretations.
83.9% of conference participants voted that HR-HPV test results should not be used to either downgrade or upgrade Pap test interpretations.

60. Consensus Good Laboratory Practice Statements
While there is significant variability in interinstitutional HPV-positive rates in ASC-US Pap tests, monitoring the HPV-positive rate in ASC-US Pap tests is a valuable broad measure of quality.
Performance beyond 2 SD’s of the mean should prompt reassessment of diagnostic criteria used in the evaluation of Pap tests and/or investigation of the prevalence of HPV positivity in the population from which the Pap tests are obtained.
Tworek et al, Arch Pathol Lab Med. 2007;131:1525–1531

61. Consensus Good Laboratory Practice Statements
Monitoring the HPV-positive rate in other diagnostic categories such as LSIL and the comparison of these HR-HPV rates to published benchmarks is also a valuable broad measure of quality for a laboratory and possibly for individuals.

62. Consensus Good Laboratory Practice Statement
When possible, individual ASC-US/HR-HPV results should be compared to ASC-US/SIL ratios for pathologists to determine potential trends in over- and under-diagnosis.
No consensus agreement
If laboratory is able to extract information from LIS, still a beneficial practice

63. Indicator Explanation ASC/SIL % HPV NIL ASC-US SIL NormalB C
Cibas et al. Am J Clin Pathol 2008;129:97-101

65. Additional Statements
Laboratories should routinely document all available HPV test results performed over the last five years preceding histopathologic diagnoses of cervical carcinoma including laboratory site and date where each HPV test was performed.
70% agreement

66. Additional Statements
Laboratories should routinely document all available HPV test results performed over the last five years preceding histopathologic diagnosis of cervical carcinoma including both specific HPV test and platform, and FDA-approved versus laboratory-developed test.
81% agreement

67. Additional Statements
Is it appropriate for a lab to order a HR-HPV test as a diagnostic test independent of the clinician?
84% conference participants responded “no”

68. Questions?