Based on the central role of persistent carcinogenic human papillomavirus (HPV) in cervical carcinogenesis, testing for carcinogenic HPV was recently introduced into cervical cancer screening (1
). (Note that in this context, “HPV testing” always refers to the detection of carcinogenic HPV genotypes only; testing for noncarcinogenic HPV genotypes has no clinical utility.) HPV testing has proven greater sensitivity than cytologic screening (Papanicolaou smears) for detection of cervical precancer (cervical intraepithelial neoplasia grade 3 (CIN3)) and cervical cancer (>CIN3) (2
) and greater reliability (7
). HPV testing is now commonly used in the United States to triage equivocal cytologic findings for colposcopic referral. Co-testing with HPV and cytology is also approved for primary (routine) cervical cancer screening of women aged 30 years or more (9
). Women aged 30 years or older who test HPV- and cytology-negative are at extremely low risk of incipient precancer and cancer (≥CIN3) over periods of 10 years or more (10
). Therefore, screening intervals in these women can be extended to 3 years in the United States to make co-testing cost-effective (12
Use of HPV testing in primary screening is only recommended for women aged 30 years or older, because these women are typically past the peak age of self-limited infections, which are very common in young women (13
). Thus, the positive predictive value of ≥CIN3 is higher in women aged 30 years or more than in younger women (15
). In general, concurrently performed cytologic screening adds little to the sensitivity and negative predictive value of HPV testing (e.g., sensitivity of 97.4 percent for HPV testing alone vs. 100 percent for HPV testing and Pap smears using a threshold of atypical squamous cells of undetermined significance or worse (3
)). In a publication based on a meeting of experts, the International Agency for Research on Cancer recently concluded that HPV testing is an acceptable alternative to Pap smears/cervical cytology for cervical cancer screening (17
). However, despite its greater sensitivity and overall accuracy, the enthusiasm for using HPV testing in primary screening has been tempered by its somewhat poorer positive predictive value in comparison with cytologic analysis (e.g., 7.0 percent for HPV testing vs. 8.7 percent for Pap smears, using a threshold of atypical squamous cells of undetermined significance or worse (3
)). Even at older ages, the prevalence of self-limited infection can reach 10 percent (vs. approximately 5 percent for cervical cytology), with only a minority of these women being at risk of ≥CIN3. A viable strategy for managing the cases of HPV-positive women, specifically identifying the subset of women at risk of ≥CIN3, would accelerate the adoption of HPV testing into primary cervical cancer screening.
Several solutions have been suggested. One is to use cytology as a reflex test for HPV-positive women, because it is more specific for ≥CIN3 (18
), but the morphologic criteria for the threshold of positive (abnormal) cytology would need to be adapted (if possible) to avoid losses of sensitivity, as observed by Mayrand et al. (3
) using current criteria. Another possibility is HPV genotyping that could target the most carcinogenic of approximately 15 carcinogenic genotypes and could permit the tracking of viral persistence. Already, there is evidence that separate detection of HPV16 and HPV18 in cytologically normal women aged 30 years or more might be a useful risk “stratifier” (9
). Those women who test positive for HPV16 or HPV18 might benefit from immediate colposcopy, while those who test negative for both could wait a year before being rescreened (9
). Given the fundamental role of persistent HPV in cervical carcinogenesis, its reliable measurement could increase the accuracy of cervical cancer screening, by aiding in further distinguishing HPV infections that pose a risk from those which resolve on their own.
Koshiol et al. (20
) conducted a systematic review and meta-analysis of the relation between detection of HPV viral persistence and the risk of precancerous lesions, defined in their analysis as histologic CIN2/3 or cytologic high-grade squamous intraepithelial lesions (HSIL). Their key findings regarding HPV persistence were: 1) it was strongly linked to the detection of precancer; 2) it was more strongly linked with precancer and cancer than with equivocal or low-grade lesions; 3) it was less strongly linked to precancer when women with transient infection were used as a referent group (i.e., women who were HPV-positive at the indicator visit but were negative at a subsequent follow-up visit) than when other referent groups were used (e.g., mixed HPV-positive and -negative or HPV-negative women alone); 4) longer persistence, as detected by absolute duration or the time interval between measurements, was more strongly linked to precancer and cancer; and 5) HPV genotype-specific persistence was no more related to risk of precancer than was repeatedly testing positive for HPV in the aggregate.
With such a heterogeneous set of studies employing different tools, epidemiologic study designs, and limited numbers of outcomes, Koshiol et al.'s analysis naturally had several limitations. Most notable was the use of different endpoints; some studies used histologic endpoints that included CIN2, while other studies used cytologic HSIL to define disease. CIN2 is the standard clinical threshold for treatment, but not all CIN2 is cervical precancer. The CIN2 diagnostic category can include women with nothing more than acute HPV infections, including those caused by noncarcinogenic HPV (21
). HSIL cytology is generally a specific but insensitive cytologic indicator of cervical precancer. In addition, we must acknowledge that colposcopy, visualization of the cervix, and diagnostic biopsy are insensitive for the detection of cervical precancer (22
), especially in well-screened populations in which most large and obvious precancerous lesions have already been detected and treated. Therefore, viral persistence may reflect a concurrent, visually unapparent precancerous lesion as well as indicate those women at risk for developing precancer. All of these limitations probably resulted in underestimation of risk relations in the analysis by Koshiol et al.
While monitoring of HPV infections for persistence versus clearance provides excellent risk stratification in study cohorts, it is fair to ask is whether its use is currently feasible in realistic cervical cancer screening programs.