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HPV Testing Update: The 2006 ASCCP Consensus Guidelines
Edward J. Wilkinson, MD, FACOG, FCAP
The American Society for Colposcopy and Cervical Pathology (ASCCP) recently released updated consensus guidelines for HPV testing and its applications in screening for cervical cancer and management of women with a Pap test interpreted as ASCUS or LSIL. The recommendations involve several key issues: HPV testing methods, HPV testing in routine cervical screening, HPV testing in evaluation of a Pap test interpreted as ASCUS or LSIL, and modified indications for HPV testing in adolescents and postmenopausal women with LSIL.
HPV Testing MethodsOver 100 HPV types infect humans, but only about 20 are associated with cervical neoplasia. These are considered oncogenic, or high-risk HPV (HR HPV) types, in contrast to the other types that are classified as nononcogenic or low-risk types. Of the oncogenic types, HPV types 16 and 18 account for approximately 70% of all cervical carcinomas. Although the term “HPV testing” is often used in a nonspecific way, within the recent 2006 ASCCP guidelines—which were developed in conjunction with the National Cancer Institute (NCI) and in collaboration with representatives of 29 national organizations involved in women’s health care—HPV testing specifically refers to testing for HR HPV types. The 2006 ASCCP Conference confirmed the prior 2001 ASCCP guidelines, as well as those currently issued by the American Cancer Society (ACS) and American College of Obstetrics and Gynecology, that only oncogenic HPV types are to be tested for in either the screening for, or the management of women with, cervical neoplasia. Nononcogenic HPV viral testing is not of value in this situation and is not recommended.
The HPV test findings have a significant influence on clinical management, both when used for screening or for management of women with ASCUS or LSIL Pap test findings. To be useful for screening or management, the method of testing for oncogenic HPV types must be sufficiently vetted through clinical trial and demonstrate sensitivity and specificity for HR HPV infection. A test’s sensitivity must also have been clinically validated in terms of false-positive and false-negative fractions. For an HPV test to meet these requirements, sufficiently large clinical trial data are needed to provide evidence of the robustness of the test, as well as to validate the methods of sample collection and preservation. The 2006 guidelines reaffirm the need for clinical validation for the use of oncogenic HPV testing.1
Applications in Cervical ScreeningCurrently, the FDA has approved only one test for oncogenic HPV.2 This FDA-approved test can be used as a supplement to cytologic screening in women 30 years of age or older. It can also be used as a reflex test in women with a Pap test interpreted as “atypical squamous cells of uncertain clinical significance” (ASCUS). Some laboratories offer non-FDA-approved types of oncogenic HPV testing and, if so, carry the burden to demonstrate that their test is equivalent.
The ACS initially recommended HR HPV testing as a supplement to cytologic screening for women 30 years of age or older.3 Combined cytology and HR HPV testing has been proven effective in large clinical trials.4,5 In women 30 years of age or older the prevalence of oncogenic HPV infection is relatively low, and in one large clinical trial of over 200,000 women conducted by Fetterman and colleagues, 6.5% of women had oncogenic HPV. With this relatively low prevalence rate, the use of HR HPV testing becomes useful to distinguish those who have oncogenic HPV infection from those without and to develop appropriate management strategies. Even if oncogenic HPV is detected, the concurrent Pap test may be negative, as demonstrated in 58% of patients in the same study. Clavel and colleagues observed in a prospective study that 60% of women who test positive for oncogenic HPV with a concurrent negative Pap test have no evidence of HPV on follow-up at 6 months.6 In addition, the estimated prevalence of high-grade CIN, CIN 2 or CIN 3—in cytology negative, HPV-positive women 30 years of age or older—is low with reported frequencies under 5.2% (ranging from 2.4 to 5.1%).7,8,9
Based on these data, the 2006 ASCCP consensus recommendation for management of women 30 years of age or older with a negative Pap test and a positive HR HPV test is to return the patient for additional screening and repeat both tests at 12 months. If she shows the same pair of test results after additional screening, she should be referred for colposcopy. When a woman aged 30 or older has a negative Pap test and a negative HR HPV test, the prior recommendation of the ACS to return for screening in three years continues to be supported by the evidence.
Women with a Pap Test Interpreted as ASCUSThe updated 2006 ASCCP consensus guidelines differ from the 2001 guidelines in following women with Pap results interpreted as ASCUS. Women with ASCUS cytology and a positive HR HPV test should be referred directly to colposcopy. Women with ASCUS cytology and a negative HR HPV test should return for screening in 12 months. The 2001 ASCCP consensus guidelines offered alternate management approaches for women with ASCUS cytology and positive HR HPV tests that are no longer recommended, which are: (1) immediate referral to colposcopy and (2) follow-up with a repeat Pap test at 6 months. The 2006 consensus guidelines continue to recommend referral to colposcopy for any woman with a Pap interpreted as or more severe than ASCUS. The 2001 ASCCP guidelines also recommended using the remainder of the aliquot in the Pap vial for HR HPV testing if a liquid-based Pap collection method was used. This was a preferred management recommendation because it did not require that the patient return for additional sample collection, and this recommendation carries forward into the 2006 guidelines. An alternate approach when using conventional Pap testing is co-collection of the HPV test sample at the time the Pap test is performed. Both samples can be sent to the laboratory, and if the Pap test is ASCUS, the HPV sample can be sent for testing.
Adolescent PatientsOncogenic HPV exposure and transient infection in women 20 years of age or under has a high prevalence rate—over 50% of women within this age group are HR HPV positive. The evidence shows that most HPV infections in younger women are transient and will clear without treatment. The 2001 ASCCP guidelines did not make any specific recommendations for managing young women. The new 2006 ASCCP guidelines make separate recommendations for adolescents, specifically women who are 20 years of age or younger. For younger women with an ASCUS Pap test, HR HPV testing is not recommended because it is now understood that the frequency of HR HPV is significantly higher in this population compared to women 21 years of age or older. The incidence of cervical cancer in younger women is also significantly lower.10,11
HPV testing in young women with a Pap test interpreted as ASCUS would result in a high rate of colposcopy with a very low probability of cervical carcinoma compared to the older women. The 2006 ASCCP guidelines have addressed this issue and recommend that HR HPV testing not be performed in adolescents—women 20 years of age or younger—but rather, that the repeat Pap testing be performed at 12 months. The patient should be referred to colposcopy only if the repeat Pap test is interpreted as HSIL, AGC, or a more severe finding.12
Postmenopausal Women with a Pap Test Interpreted as LSILA major change in the 2006 ASCCP guidelines is in the management of postmenopausal women with LSIL. For these women, reflex HPV testing is an acceptable option, as is colposcopy or repeating the Pap test at 6 and 12 months. Two large studies show that the prevalence of HR HPV declines in postmenopausal women. However, those with CIN 2/3 or cervical cancer will have persistent HPV.13,14 With HPV testing as the option, if the HPV test demonstrates HR HPV, the patient is referred to colposcopy; if negative the patient can return for repeat Pap testing at 12 months.
When Not to Test for HPVContinuing with the 2001 ASCCP management guidelines, the 2006 guidelines recommend colposcopy for nonpregnant adult women of reproductive age with a Pap result interpreted as LSIL. For these women, the risk of an associated CIN 2 or more severe lesion is between 12 and 16%.15,16 In addition, HR HPV testing is not recommended for these women because over three-fourths will test positive for HR HPV.17 The high prevalence of HR HPV also supports the guideline that HPV testing is not recommended for adolescents or pregnant women with LSIL.
In regard to women vaccinated against HPV, ASCCP did not develop separate management guidelines for these patients. HPV testing is not recommended prior to vaccination. If a vaccinated woman were to have an abnormal Pap result, the 2006 consensus management guidelines apply as written. Only time will tell if there is a need to modify current screening guidelines for this population.
Additional details about the 2006 ASCCP consensus guidelines are available online at http://www.asccp.org/consensus.shtml.18
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