To highlight the impact of cytopathology on patient management and treatment Edited by Martha B. Pitman, MD
Clinician’s Corner Primary Human Papillomavirus Testing David Chelmow, MD, Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia. David Chelmow, MD, is the Leo J. Dunn Professor and Chair of Obstetrics and Gynecology at Virginia Commonwealth University in Richmond, Virginia. He is the Immediate Past President of the Society for Academic Specialists in General Obstetrics and Gynecology and is on the Board of Directors for both the American Board of Obstetrics and Gynecology and the American Society for Colposcopy and Cervical Pathology (ASCCP). He was a member of the consensus panels for the American Cancer Society 2011 screening guidelines for the prevention and early detection of cervical cancer, the ASCCP 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors, the College of American Pathologists (CAP)-ASCCP Lower Anogenital Squamous Terminology (LAST), and the Society of Gynecologic Oncology (SGO)-ASCCP interim guidance for primary human papillomavirus screening.
In April 2014, the US Food and Drug Administration (FDA) approved a human papillomavirus (HPV) test for primary cervical cancer screening, thereby creating another alternative in the increasingly complicated world of screening for this malignancy. Cervical screening has been in widespread use for 50 years. It started very simply with the Papanicolaou (Pap) test alone, performed annually. Annual Pap testing was enormously successful and rapidly decreased the incidence of cervical cancer. Understanding of the role of HPV1 allowed for the integration of HPV testing into screening. HPV testing was initially used to triage cytology with atypical squamous cells. Over the last 15 years, it has become used as an adjunct to cytology (cotesting). In 2012, the US Preventive Services Task Force and the American Cancer Society (ACS) both released updated guidelines with recommendations including cotesting. Based on data demonstrating that cotesting potentially increased cancer prevention and allowed testing at longer intervals compared with cytology alone, the US Preventive Services Task Force recommended cotesting as an acceptable option for women who wanted to extend their screening interval, and the ACS recommended both cytology alone and cotesting, but expressed a preference for cotesting. If cytology alone and HPV and cytology together are both effective options, it is natural to question whether HPV testing alone is a viable alternative. Primary HPV testing was considered, but not included, in the 2012 ACS guidelines. At the time, there was a lack of supportive data and no proven way to triage the many positive tests to determine which needed further evaluation. HPV for primary screening has been studied with promising results in a number of trials in other countries. As part of the FDA approval process, Roche Molecular Systems (Basel, Switzerland) conducted the ATHENA (Addressing the Need for Advanced HPV Diagnostics) trial,
Cancer Cytopathology
May 2015
a large study performed in the United States. One of the key aspects of the trial was the validation of an effective approach to triaging positive HPV tests. In ATHENA, positive tests were triaged by first performing testing for HPV types 16 and 18. If positive, colposcopy was performed. If the results were negative for HPV types 16 and 18, reflex cytology was performed. If cytology was not normal, colposcopy was performed. If cytology was negative, cotesting was repeated in 1 year. This algorithm is very similar to current recommendations for cotests. According to the labeling, the test can be used for primary screening starting at age 25 years. Women who test negative “should be followed up in accordance with the physician’s assessment of screening and medical history, other risk factors, and professional guidelines.” Data supporting the use of the test was presented as part of the FDA approval process, and publication is anticipated shortly. Interim guidance has been developed by a panel convened by the American Society for Colposcopy and Cervical Pathology and Society of Gynecologic Oncologists.2 The panel concluded that primary HPV testing “can be considered as an alternative to current US cytology-based screening methods.” Should providers begin using this new test? There are a number of important potential advantages compared with screening with cytology alone. HPV testing is more reproducible than cytology. A negative test is associated with a tremendously low risk of a precancerous lesion, and is a much better predictor of a woman being at extremely low risk of a precancerous lesion than negative cytology alone. HPV testing is also tremendously sensitive, with HPV testing detecting many women with HPV disease and, consequently, most women with precancerous lesions. 269
Clinician’s Corner
However, there are also important concerns and unanswered questions. Introducing this test creates a total of 3 different methods of screening. Providers do very poorly following existing guidelines and overuse testing, particularly HPV testing. Introducing a third alternative will further increase patient and provider confusion. The optimal screening interval still needs to be determined. The ATHENA trial followed patients for 3 years, and based on this, the interim guidance recommends repeat testing in no sooner than 3 years. More frequent testing detects more abnormalities, leading to more cancers being prevented, but also more frequent diagnostic evaluations and treatments, which have potential morbidity. The sensitivity of HPV testing can also be a disadvantage. The majority of detected HPV disease does not lead to cervical cancer. The need to balance disease detection with minimization of testing and treatment has led to extension of screening intervals, and the possibility that an interval of longer than 3 years may be more optimal for primary HPV testing. The approval of the new test was based on its favorable comparison with screening using cytology alone. The current ACS guidelines, which were endorsed by the American Congress of Obstetricians and Gynecologists and other major societies, prefer cotesting every 5 years to screening with cytology alone. The ATHENA trial did not fully address the comparison between HPV testing alone and cotesting. In primary HPV screening, patients with abnormal cytology but normal HPV testing will not be detected. This is fortunately unusual. In data from Kaiser Permanente Northern California,3 only 5.8% of high-grade squamous intraepithelial lesion cytology was HPV negative. This group had a lower but still significant presence of high-grade disease, with 21.8% having CIN 3 or cancer.
Primary HPV screening represents another incremental improvement in cervical cancer prevention. It does not address important missed opportunities for cervical cancer prevention. Most cancer occurs in women who have not been adequately screened. Primary prevention with HPV vaccination is tragically underused in the United States. Incremental improvements in testing currently well-screened populations are helpful, but to prevent cervical cancer at the population level, increased HPV vaccination and expanded access to cervical cancer screening by any method are key. One exciting aspect of primary HPV testing is not the recently approved test, which requires collection from the cervix similar to cytology or cotesting, but studies of self-collected vaginal swabs, which could truly expand access to underscreened populations. FUNDING SUPPORT
No specific funding was disclosed. CONFLICT OF INTEREST DISCLOSURES
The author made no disclosures.
References 1. Wright TC Jr, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med. 2003; 348: 489490. 2. Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance [published online ahead of print January 7, 2015]. Obstet Gynecol. 3. Katki HA, Schiffman M, Castle PE, et al. Five-year risks of CIN 31 and cervical cancer among women with HPV-positive and HPVnegative high-grade Pap results. J Low Genit Tract Dis. 2013; 17(5 suppl 1): S50-S55. DOI: 10.1002/cncy.21525
Clinician’s Corner represents the opinions and views of the author and does not reflect any policy or opinion of the American Cancer Society, Cancer Cytopathology, or Wiley unless this is clearly specified.
270
Cancer Cytopathology
May 2015
Clinician’s Corner Primary Human Papillomavirus Testing David Chelmow, MD, Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia. David Chelmow, MD, is the Leo J. Dunn Professor and Chair of Obstetrics and Gynecology at Virginia Commonwealth University in Richmond, Virginia. He is the Immediate Past President of the Society for Academic Specialists in General Obstetrics and Gynecology and is on the Board of Directors for both the American Board of Obstetrics and Gynecology and the American Society for Colposcopy and Cervical Pathology (ASCCP). He was a member of the consensus panels for the American Cancer Society 2011 screening guidelines for the prevention and early detection of cervical cancer, the ASCCP 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors, the College of American Pathologists (CAP)-ASCCP Lower Anogenital Squamous Terminology (LAST), and the Society of Gynecologic Oncology (SGO)-ASCCP interim guidance for primary human papillomavirus screening.
In April 2014, the US Food and Drug Administration (FDA) approved a human papillomavirus (HPV) test for primary cervical cancer screening, thereby creating another alternative in the increasingly complicated world of screening for this malignancy. Cervical screening has been in widespread use for 50 years. It started very simply with the Papanicolaou (Pap) test alone, performed annually. Annual Pap testing was enormously successful and rapidly decreased the incidence of cervical cancer. Understanding of the role of HPV1 allowed for the integration of HPV testing into screening. HPV testing was initially used to triage cytology with atypical squamous cells. Over the last 15 years, it has become used as an adjunct to cytology (cotesting). In 2012, the US Preventive Services Task Force and the American Cancer Society (ACS) both released updated guidelines with recommendations including cotesting. Based on data demonstrating that cotesting potentially increased cancer prevention and allowed testing at longer intervals compared with cytology alone, the US Preventive Services Task Force recommended cotesting as an acceptable option for women who wanted to extend their screening interval, and the ACS recommended both cytology alone and cotesting, but expressed a preference for cotesting. If cytology alone and HPV and cytology together are both effective options, it is natural to question whether HPV testing alone is a viable alternative. Primary HPV testing was considered, but not included, in the 2012 ACS guidelines. At the time, there was a lack of supportive data and no proven way to triage the many positive tests to determine which needed further evaluation. HPV for primary screening has been studied with promising results in a number of trials in other countries. As part of the FDA approval process, Roche Molecular Systems (Basel, Switzerland) conducted the ATHENA (Addressing the Need for Advanced HPV Diagnostics) trial,
Cancer Cytopathology
May 2015
a large study performed in the United States. One of the key aspects of the trial was the validation of an effective approach to triaging positive HPV tests. In ATHENA, positive tests were triaged by first performing testing for HPV types 16 and 18. If positive, colposcopy was performed. If the results were negative for HPV types 16 and 18, reflex cytology was performed. If cytology was not normal, colposcopy was performed. If cytology was negative, cotesting was repeated in 1 year. This algorithm is very similar to current recommendations for cotests. According to the labeling, the test can be used for primary screening starting at age 25 years. Women who test negative “should be followed up in accordance with the physician’s assessment of screening and medical history, other risk factors, and professional guidelines.” Data supporting the use of the test was presented as part of the FDA approval process, and publication is anticipated shortly. Interim guidance has been developed by a panel convened by the American Society for Colposcopy and Cervical Pathology and Society of Gynecologic Oncologists.2 The panel concluded that primary HPV testing “can be considered as an alternative to current US cytology-based screening methods.” Should providers begin using this new test? There are a number of important potential advantages compared with screening with cytology alone. HPV testing is more reproducible than cytology. A negative test is associated with a tremendously low risk of a precancerous lesion, and is a much better predictor of a woman being at extremely low risk of a precancerous lesion than negative cytology alone. HPV testing is also tremendously sensitive, with HPV testing detecting many women with HPV disease and, consequently, most women with precancerous lesions. 269
Clinician’s Corner
However, there are also important concerns and unanswered questions. Introducing this test creates a total of 3 different methods of screening. Providers do very poorly following existing guidelines and overuse testing, particularly HPV testing. Introducing a third alternative will further increase patient and provider confusion. The optimal screening interval still needs to be determined. The ATHENA trial followed patients for 3 years, and based on this, the interim guidance recommends repeat testing in no sooner than 3 years. More frequent testing detects more abnormalities, leading to more cancers being prevented, but also more frequent diagnostic evaluations and treatments, which have potential morbidity. The sensitivity of HPV testing can also be a disadvantage. The majority of detected HPV disease does not lead to cervical cancer. The need to balance disease detection with minimization of testing and treatment has led to extension of screening intervals, and the possibility that an interval of longer than 3 years may be more optimal for primary HPV testing. The approval of the new test was based on its favorable comparison with screening using cytology alone. The current ACS guidelines, which were endorsed by the American Congress of Obstetricians and Gynecologists and other major societies, prefer cotesting every 5 years to screening with cytology alone. The ATHENA trial did not fully address the comparison between HPV testing alone and cotesting. In primary HPV screening, patients with abnormal cytology but normal HPV testing will not be detected. This is fortunately unusual. In data from Kaiser Permanente Northern California,3 only 5.8% of high-grade squamous intraepithelial lesion cytology was HPV negative. This group had a lower but still significant presence of high-grade disease, with 21.8% having CIN 3 or cancer.
Primary HPV screening represents another incremental improvement in cervical cancer prevention. It does not address important missed opportunities for cervical cancer prevention. Most cancer occurs in women who have not been adequately screened. Primary prevention with HPV vaccination is tragically underused in the United States. Incremental improvements in testing currently well-screened populations are helpful, but to prevent cervical cancer at the population level, increased HPV vaccination and expanded access to cervical cancer screening by any method are key. One exciting aspect of primary HPV testing is not the recently approved test, which requires collection from the cervix similar to cytology or cotesting, but studies of self-collected vaginal swabs, which could truly expand access to underscreened populations. FUNDING SUPPORT
No specific funding was disclosed. CONFLICT OF INTEREST DISCLOSURES
The author made no disclosures.
References 1. Wright TC Jr, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med. 2003; 348: 489490. 2. Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance [published online ahead of print January 7, 2015]. Obstet Gynecol. 3. Katki HA, Schiffman M, Castle PE, et al. Five-year risks of CIN 31 and cervical cancer among women with HPV-positive and HPVnegative high-grade Pap results. J Low Genit Tract Dis. 2013; 17(5 suppl 1): S50-S55. DOI: 10.1002/cncy.21525
Clinician’s Corner represents the opinions and views of the author and does not reflect any policy or opinion of the American Cancer Society, Cancer Cytopathology, or Wiley unless this is clearly specified.
270
Cancer Cytopathology
May 2015
