The year 2006 was a busy one for those of us engaged in cervical cancer prevention. The most notable development was approval by the US Food and Drug Administration of the human papillomavirus (HPV) quadrivalent vaccine in June, followed closely by guidelines for its use from the Advisory Committee on Immunization Practices (June) and the American College of Obstetricians and Gynecologists (September). Key issues related to the introduction of the HPV vaccine into clinical practice were reviewed in a roundtable discussion in the January 2007 issue of OBG Management.
Therefore, this update will depart, for the moment, from matters related to the vaccine and concentrate on several other critical areas:
- Testing for high-risk HPV types is useful. Large European cervical cancer screening trials confirm a benefit.
- Condoms and oral contraceptives—are they risk modifiers for HPV infection? Answers (“Yes” and “No,” respectively) come from new data.
- Loop electrosurgical excision carries obstetric risks. In fact, all types of excisional procedures produce similar pregnancy-related morbidity.
- Liquid-based cytology may not be superior to conventional cytology. So suggest new studies and a systematic review of the literature.
HPV testing outperforms cytology for screening
Cuzick J, Clavel C, Petry KU, et al. Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer. 2006;119:1095–1101.
Ronco G, Segnan N, Giorgi-Rossi P, et al. Human papillomavirus testing and liquid-based cytology: results at recruitment from the new technologies for cervical cancer randomized controlled trial. J Natl Cancer Inst. 2006;98:765–774.
HPV DNA testing is more sensitive than cervical cytology, reduces specificity to only a moderate degree, and performs similarly in different parts of Europe and North America. Those are the findings of a review by Cuzick and colleagues of all recent large European and North American cervical cancer screening studies. To date, 4 large European trials and 1 from Mexico have directly compared HPV testing and cytology in women aged 30 years and older. Combined, these trials have enrolled over 60,000 women. In every study, testing for high-risk types of HPV using the commercially available Hybrid Capture 2 HPV DNA assay had a much higher sensitivity for identifying women with cervical intraepithelial neoplasia (CIN) 2,3 or cancer (86–97%) than did cervical cytology (34–74%). Moreover, the combination of cytology and HPV testing had a sensitivity ranging from 94% to 100% in the different studies. The average sensitivity of 98% for the combination of cytology and HPV testing means that there is a less than 1 in 1,000 chance of missing CIN 2,3 or cancer when women are screened with both tests (TABLE 1).
Specificity is reasonable, too
If you worry that using HPV DNA testing in women aged 30 and older will flag too many as high-risk HPV-positive and cause them unnecessary colposcopic examinations or anxiety, here is a comforting finding: The specificity of HPV DNA testing is not as low as many had feared—provided we limit screening to women aged 30 and older. In the 5 trials mentioned, the specificity of HPV DNA testing ranged from 92% to 97%. Even when HPV DNA testing and cytology were used together, the average specificity of the 2 tests combined was 93%. A specificity of 93% means that only 7 of 100 screened women who don’t have CIN 2,3 or cancer will be classified as “positive.”
To put this number into perspective, a 2003 survey of US cytology laboratories found a median rate of abnormal results of 6.9%.1 Therefore, in routine clinical practice, incorporation of HPV DNA testing into screening for women aged 30 and older is not expected to greatly increase the number of women requiring additional follow-up.
How to manage the HPV-positive, cytology-negative woman
The single most important component of management is appropriate counseling. Even though there are fewer of these women than we anticipated, these patients need to be reassured that their risk of having a significant lesion (CIN 2,3 or cancer) is quite low—only about 1 in 20. They also need to know that about two thirds of women—even women aged 30 and older—are HPV-negative when they are retested in 12 months.
In addition, clinicians need to stress that positive HPV status is a risk factor for having or developing cervical disease, not an indication that disease is present. One analogy that patients readily understand is the relationship between other types of health risk factors, such as mild hypertension or mildly elevated serum cholesterol, and disease. These explanations help the patient understand why, in settings where genotyping for HPV 16 and 18 is not available, the best course of action is to wait 12 months and be retested.2