High-Risk HPV Screening for Cervical Cancer

Abstract

HPV is a double-stranded DNA virus composed of 2 capsid proteins (L1 and L2) and 6 early proteins (E1, E2, and E4–E7) that participate in replication and integration into the host genome. The virus is spread by skin or mucosal contact, can integrate into cervical DNA, and becomes carcinogenic when early proteins are expressed. These oncogenes, E6 and E7, disrupt host tumor suppressor genes p53 and RB, respectively, leading to dysplastic changes. Although approximately 40 subtypes can infect the genital tract, 12 oncogenic subtypes have been identified as hrHPV subtypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59). Additional subtypes have been classified as “probably high” risk and may be included in commercial HPV tests.3,4 HPV type 16 is the most common cause of cervical cancer, whereas HPV type 18 is the second leading cause and has the strongest association with adenocarcinoma. Together, HPV 16 and 18 account for approximately 70% of cervical cancers worldwide. Persistent infection is necessary for the development of high-grade cervical dysplasia or cancer.5 Persistent HPV infection can produce high-grade changes within a few years, whereas the progression from cervical intraepithelial neoplasia (CIN) 3 to cancer typically requires an additional Widespread adoption of Pap smear-based screening in the United States in the 1950s led to a 60% decline in cervical cancer incidence over the next 5 decades. However, in the last 20 years, the incidence of cervical cancer among American women has remained relatively stable.1 Despite recommendations for universal screening, more than 12,000 women in the United States are diagnosed with cervical cancer each year. Although many of these cases occur in underserved populations with inadequate or no screening, some cases may be due to suboptimal screening strategies. Cervical cytology alone is only 50% to 60% sensitive to detect high-grade dysplasia and cervical cancer, relying on repeat specimens to obtain higher detection rates.2 Cervical cytology is even less sensitive for the detection of nonsquamous malignancies such as cervical adenocarcinoma. Highrisk human papilloma virus (hrHPV) cotesting was incorporated into most major US guidelines in 2012 to increase sensitivity for detection of cervical cancer and its precursors. Primary hrHPV testing alone has been adopted more recently as a screening method. Obstetrician/gynecologists and other primary care providers should understand the natural history of HPV infection and the strengths and weaknesses of various screening methods to choose the VOLUME 39 • NUMBER 13 September 15, 2019