Human Papillomavirus DNA Testing: What, How, and When

Abstract

More than 20 years ago, a relationship between Human Papillomavirus (HPV) infection and cervical cancer was recognized. Since then, important strides in understanding the virus have been made, particularly in the following areas: modes of transmission and risk factors associated with transmission, the oncogenic potential of specific viral types and the mechanism by which they cause cancer, and the spectrum of infection, ranging from asymptomatic carrier states to overt warts, preneoplastic lesions, and invasive cancer. Sophisticated new tests for the detection of HPV for screening for cervical cancer precursors and invasive cancer and for the triage of abnormal cervical cytology also have been developed as reported by American College of Obstetricians and Gynecologists (Obstet Gynecol 105:905–918, 2005). Recent evidence has shown that the risk of malignant and premalignant cervical disease and HPV infections varies significantly with age. Furthermore, evidence now shows that treatment for cervical disease carries significant risk for future pregnancies. These factors have led to a reevaluation of the guidelines for the management of premalignant cervical disease as reported by American College of Obstetricians and Gynecologists (Obstet Gynecol 112:1419–1444, 2008). Understanding the immunology of HPV has allowed the development of new and more effective treatment modalities for HPV infection and the development of primary prevention modalities, including HPV vaccines as reported by American College of Obstetricians and Gynecologists (Obstet Gynecol 105:905–918, 2005). Invasive cervical cancer is the second most common female cancer worldwide, with about 493,000 new cases per year. About 273,000 women die from cervical cancer each year, 85% of which take place in developing countries. Cervical cancer has a slow progress from pre-invasive cervical intraepithelial neoplasia (CIN) to invasive phases, meaning that the disease can be diagnosed while in the phase of pre-invasive lesion, and treated successfully thanks to the regular screening of asymptomatic women. Additional diagnostic procedures for preinvasive lesions of the uterine cervix like deoxyribonuclaic acid (DNA) cytometry (flow cytometry) can point to dysplasia that can progress to severe stages, such as high-grade (HG) squamous intraepithelial lesions (H-SIL). If the level of chromosomal disturbance is higher (aneuploidy), it is more probable that H-SIL will develop. Laser screening of cells extracted with modern cytologic screening liquid-based cytology enables us to automatically measure ploidy (chromosome regularity, or irregularity) and polymerase chain reaction (PCR) provides analysis of HPV types. These methods are recommended for a routine check-up of borderline cervical lesions in order to anticipate ones likely to regress or progress as reported by Grubisic et al. (Coll Antropol 33:1431–1436, 2009). HPV also causes a proportion of other cancers, including vulvar, vaginal, anal, penile, and oropharyngeal cancers. Although cervical cancer screening, primarily with the Papanicolaou (Pap) smear, has reduced the incidence of this cancer in industrialized countries, cervical cancer remains the second most common cause of death from cancer in women worldwide, because the developing world has lacked the resources for widespread, high-quality screening. In addition to advances in Pap smear technology, the identification of HPV as the etiologic agent has produced two recent advances that may have a major impact on approaches to reduce the incidence of this disease. The first is the development of a preventive vaccine, the current versions of which appear to prevent close to 100% of persistent genital infection and disease caused by HPV-16 and HPV-18. Future second-generation vaccines may be able to protect against oncogenic infections by a broader array of HPV types. The second is the incorporation of HPV testing into screening programs. In women aged >30 years, HPV testing can identify HG CIN earlier than Pap smears with acceptable rates of specificity. These results, together with the high sensitivity of HPV testing, suggest that such testing could permit increased intervals for screening. An inexpensive HPV test in development, if successful, may be incorporated as part of an economically viable “screen-and-treat” approach in the developing world. The manner in which vaccination and screening programs are integrated will need to be considered carefully so that they are efficient in reducing the overall incidence of cervical cancer as reported by Lowy et al. (Cancer 113:1980–1993, 2008).