Clinical Information

The majority (>99%) of cervical epithelial neoplasms are the result of human papillomavirus (HPV) infection. High-risk HPV (HR-HPV) types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) can result in both low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL), as well as invasive carcinomas.(1,2) Patients with both a negative cytology and negative HPV have been shown to be at extremely low risk for cervical neoplasia.(1,2)

For women 30 years old and older who have received a negative Pap test and concurrent negative HPV result, the American Cancer Society and American College of Obstetricians and Gynecologists recommendations for cervical screening state that physicians may lengthen the screening interval to 3 years when using the combined test. Patients deemed to be high risk by the clinician should still be screened more frequently.

The presence of HR-HPV types in cervical specimens identifies a subgroup of patients with a greater likelihood of having a HSIL. Current guidelines for follow-up of a cytology-negative/HPV-positive patient recommend repeat HPV testing in 12 months.(2)

Persistent infection with HPV is the principal cause of cervical cancer and its precursor cervical intraepithelial neoplasia (CIN).(1-3) The presence of HPV has been implicated in more than 99% of cervical cancers worldwide. HPV is a small, nonenveloped, double-stranded DNA virus, with a genome of approximately 8000 nucleotides. There are more than 118 different types of HPV and approximately 40 different HPVs that can infect the human anogenital mucosa. However, data suggest that 14 of these types (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) are considered high risk for the development of cervical cancer and its precursor lesions. Furthermore, HPV types 16 and 18 have been regarded as the genotypes most closely associated with progression to cervical cancer. HPV-16 is the most carcinogenic and is associated with approximately 60% of all cervical cancers, while HPV-18 accounts for approximately 10% to 15% of cervical cancers.(4-6)

Although persistent infection with HR-HPV is necessary for the development of cervical cancer and its precursor lesions, only a very small percentage of infections progress to these disease states. Sexually transmitted infection with HPV is extremely common, with estimates of up to 75% of all women being exposed to HPV at some point. However, almost all infected women will mount an effective immune response and clear the infection within 2 years without any long-term health consequences. An infection with any HPV type can produce CIN although this also usually resolves once the HPV infection has been cleared.

In developed countries with cervical cancer screening programs, the Pap smear has been used since the mid-1950s as the primary tool to detect early precursors to cervical cancer. Although it has decreased the death rates due to cervical cancer dramatically in those countries, the Pap smear and subsequent liquid-based cytology methods require subjective interpretation by highly trained cytopathologists, and misinterpretation can occur. Cytological abnormalities are primarily due to infection with HPV; however, various inflammatory conditions or sampling variations can result in false-positive cytology results. Triage of an abnormal cytology result may involve repeat testing, colposcopy, and biopsy. A histologically confirmed high-grade lesion must be surgically removed or ablated in order to prevent the development of invasive cervical cancer.

DNA testing by polymerase chain reaction has become a standard, noninvasive method for determining the presence of a cervical HPV infection. Proper implementation of nucleic acid testing for HPV may:

1. Increase the sensitivity of cervical cancer screening programs by detecting high-risk lesions earlier in women 30 years and older with normal cytology

2. Reduce the need for unnecessary colposcopy and treatment in patients 21 and older with cytology results showing atypical squamous cells of undetermined significance

Recent data suggest that individual genotyping for HPV types 16 and 18 can assist in determining appropriate follow-up testing and triaging women at risk for progression to cervical cancer. Studies have shown that the absolute risk of CIN-2 or worse in HPV-16 and HPV-18 positive women is 11.4% (95% CI 8.4%-14.8%) compared with 6.1% (95% CI, 4.9%-7.2%) of women positive for other HR-HPV genotypes and 0.8% (95% CI, 0.3%-1.5%) in HR-HPV negative women.(7) Based in part on these data, the American Society for Colposcopy and Cervical Pathology now recommends that HPV 16/18 genotyping be performed on women who are positive for HR-HPV but negative by routine cytology. Women who are found to be positive for HPV-16 or HPV-18 may be referred to colposcopy, while women who are negative for genotypes 16 and 18 may have repeat cytology and HR-HPV testing in 12 months.(4)