10/19/2018 2. Understand the application of HPV testing in clinical practice 2. Review the FDA-approved tests for HPV testing and genotyping Karen Smith-McCune 3. Apply genotyping information appropriately October 2018 to clinical practice Terminology for cytology • NILM: negative for intraepithelial lesion or malignancy • ASCUS: atypical squamous cells of undetermined significance • ASC-H: atypical squamous cells, cannot rule out high grade • LSIL: low grade squamous intraepithelial lesion • HSIL: high grade squamous intraepithelial lesion • AGC: atypical glandular cells • AIS: adenocarcinoma in situ 1
10/19/2018 • There are over 100 HPV types that can infect human skin • FDA-approved HPV tests measure 13-14 HPV • Approximately 40 HPV types infect the genital types: epithelium (cervix, vagina, vulva, anus, perianus) HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, • 14 HPV types can cause cancer at those sites- 59, 66, 68 high risk HPV types (hrHPV) • Results are reported as positive or a negative • The other types (for example HPV 6 and 11) do not cause cancer and testing is not recommended • These tests identify specific HPV types: HPV 16, HPV 18 and, for some tests, HPV 45 • HPV 16 and 18 are the cause of >70% of cervical cancers worldwide • HPV 16 and 18 are also more likely to be associated with presence and/or development of CIN than the other HPV types Kjaer et al. Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence. J Natl Cancer Inst 2010;102:1478-88. 2
10/19/2018 • ASCUS: atypical squamous cells of undetermined HPV testing HPV genotyping significance= cytology is not normal, but falls short • Co-testing, in women with • Triage of ASCUS of a diagnosis of squamous intraepithelial lesion normal cytology • Co-testing (Pap+HPV) for (SIL) • HPV testing alone for screening • This is the most common cytological abnormality screening, in women who • HPV testing alone for (approximately 4% of tests in the U.S.) are hrHPV positive screening • Has poor inter- and intra-observer reliability • Rate of underlying CIN2+ is low (less than 10%) • Rate of underlying cancer is extremely low: 0.1- 0.2% • HPV testing can stratify women with ASCUS into a low risk group (hrHPV test negative) and Options for management of ASCUS on Pap: a higher risk group (hrHPV test positive) - Repeat the Pap in 1 year, perform HPV test result Absolute risk of colposcopy if ASCUS or worse CIN 2+ OR HRHPV neg 0.75% - Perform hrHPV testing: HRHPV+ 14.0% - If hrHPV negative, rescreen in 3 years HPV16+ 31.5% - If hrHPV+, perform colposcopy HPV16/18+ 24.4% HPV18+ 4.3% From the ATHENA study, Am J Clin Pathol 2011 From the American Society of Colposcopy and Cervical Cytology (ASCCP), 2012 Other HRHPV+ 8.6% Updated Consensus Guidelines for the Management of abnormal Cytology Screening Results and Cancer Precursors: www.asccp.org 3
10/19/2018 • Co-test= cytology + HPV testing for screening in women 30 years and older Management does not make use of HPV • Women with negative cytology and negative 16/18 genotyping hrHPV testing are at very low risk of having or developing CIN 2+: rescreen in 5 years • HPV test results can be used to triage LSIL Paps to colposcopy (if positive) or follow-up in 1 year (if • HPV results are not useful in women with negative). cytology results of ASC-H, HSIL, AGC and AIS. • GENOTYPING INFORMATION DOES NOT DIRECT These results warrant referral to colposcopy MANAGEMENT regardless of HPV status PAP RESULT: LSIL HIGH RISK HPV POSITIVE COLPOSCOPY PAP RESULT: LSIL CO-TEST IN 1 YEAR HIGH RISK HPV NEGATIVE From the American Society of Colposcopy and Cervical Cytology (ASCCP), 2012 Updated Consensus Guidelines for the Management of abnormal Cytology Screening Results and Cancer Precursors: www.asccp.org 4
10/19/2018 PAP RESULT: ASC-H HSIL • Women with normal cytology and hrHPV+ are AGC AIS at increased risk of CIN 2+ but do not meet HIGH-RISK HPV TEST NOT DONE COLPOSCOPY OR the colposcopy threshold HIGH-RISK HPV TEST NEGATIVE • However, women who are positive for HPV OR HIGH RISK HPV TEST POSITIVE 16/18/45 are at even higher risk of CIN 2+ HPV STATUS DOES NOT DIRECT MANAGEMENT From the American Society of Colposcopy and Cervical Cytology (ASCCP), 2012 Updated Consensus Guidelines for the Management of abnormal Cytology Screening Results and Cancer Precursors: www.asccp.org CYTOLOGY NEGATIVE (NILM) REPEAT COTEST IN ONE YEAR HIGH RISK HPV POSITIVE • In women with normal cytology and hrHPV positive , there are 2 options: -Perform HPV genotyping for HPV 16 and 18. If either is positive, perform colposcopy OR PERFORM HPV 16/18(45) GENOTYPING -Repeat the cotest in 1 year. If at that time, either cytology is abnormal (ASCUS or worse) OR COLPOSCOPY hrHPV is positive, perform colposcopy From the American Society of Colposcopy and Cervical Cytology (ASCCP), 2012 Updated Consensus Guidelines for the 19 Management of abnormal Cytology Screening Results and Cancer Precursors: www.asccp.org 5
10/19/2018 • The USPSTF recommends screening for • In women who test positive for hrHPV, cervical cancer every 3 years with cervical perform HPV genotyping cytology alone in women aged 21 to 29 years. • In women positive for HPV 16/18/45, perform For women aged 30 to 65 years, the USPSTF colposcopy recommends screening every 3 years with • In women negative for HPV 16/18/45, perform cervical cytology alone, every 5 years with high-risk human papillomavirus (hrHPV) cytology testing alone , or every 5 years with hrHPV • In women with ASCUS or worse, perform testing in combination with cytology (co- colposcopy testing). ASCCO and SGO recommendations, Huh et al, Gynecol Onc Feb 2015 • Hybrid capture 2 was the first HPV test to be HIGH RISK HPV FDA approved in 2003 RESCREEN IN 5 YEARS NEGATIVE • Approved for triage of ASCUS and for co- testing HIGH RISK HPV HPV GENOTYPING POSITIVE • Measures HPV DNA from 13 high risk HPV types POSITIVE NEGATIVE – HPV 16, 18, 31,33, 35, 39, 45, 51, 52, 58, 59, 68 ASCUS OR – Dichotomous result: positive or negative for any WORSE COLPOSCOPY CYTOLOGY COLPOSCOPY of the 13 types 6
10/19/2018 Cervista results • FDA approved March 2009 Component Results • Detects 14 high risk HPV types Component Value – HPV 16, 18, 31,33, 35, 39, 45, 51, 52, 58, 59, 66, HPV High-Risk DNA Types with Reflex HPV 16/18 Not detected 68 Comment: Reference range: Not detected • A separate assay detects HPV 16 and 18 • Approved for triage of ASCUS and for screening as a co-test with cytology Cervista results: High Risk HPV DNA Test with Cervista results: High Risk HPV DNA Test with Cervista results Cervista results Reflex HPV 16/18 Reflex HPV 16/18 Component Results Component Results Component Value HPV DNA, type 16 DETECTED Comment: Component Value Reference range: Not detected HPV High-Risk DNA Types with Reflex HPV 16/18 DETECTED The Cervista HPV 16/18 test only detects DNA of HPV types 16 Comment: and 18. This test does not detect other high-risk HPV types Reference range: Not detected nor does it detect HPV low-risk types. This test detects the presence of high risk HPV genotypes, but HPV DNA, type 18 Not detected does not identify which individual subtype is present. Comment: Reference range: Not detected The Cervista HPV 16/18 test only detects DNA of HPV types 16 and 18. This test does not detect other high-risk HPV types nor does it detect HPV low-risk types. HPV DNA Genotype (Order 246394334) - Reflex for Order 246394333 7
10/19/2018 Cervista results: High Risk HPV DNA Test Cervista results: High Risk HPV DNA Test with Reflex HPV 16/18 with Reflex HPV 16/18 Component Results • Approved April 2011 Component Value HPV DNA, type 16 Not detected • Measures HPV 16, HPV 18 and the other Comment: Reference range: Not detected 12 hrHPV types as a group The Cervista HPV 16/18 test only detects DNA of HPV types 16 • Approved for triage of ASCUS, for co- and 18. This test does not detect other high-risk HPV types nor does it detect HPV low-risk types. testing, and for primary HPV screening HPV DNA, type 18 Not detected Comment: Reference range: Not detected The Cervista HPV 16/18 test only detects DNA of HPV types 16 and 18. This test does not detect other high-risk HPV types nor does it detect HPV low-risk types. HPV DNA Genotype (Order 255522575) - Reflex for Order 255522573 Component Results Component Results Component Value Component Value HPV DNA, Genotype 16 Not detected HPV DNA, Genotype 16 Not detected Comment: Comment: Nucleic Acid(DNA) testing by PCR Nucleic Acid(DNA) testing by PCR Reference range:Not detected Reference range: Not detected HPV DNA, Genotype 18 Not detected HPV DNA, Genotype 18 Not detected Comment: Comment: Reference range: Not detected Reference range: Not detected HPV DNA, High Risk (non 16/18) Not detected HPV DNA, High Risk (non 16/18) DETECTED Comment: Comment: Reference range: Not detected Reference range: Not detected 8
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