Clinical Information

Squamous cell carcinoma of the cervix is believed to develop in progressive stages from normal through precancerous (dysplastic) stages, to carcinoma in situ, and eventually invasive carcinoma. This sequence is felt to develop over a matter of years in most patients.

Follow-up of the cervical Pap abnormality atypical squamous cells of undetermined significance (ASCUS) is costly and frustrating to patients and clinicians because a large percentage of these patients have normal colposcopic and biopsy findings. Yet, a significant percentage (10%-15%) will have an underlying high-grade squamous intraepithelial lesion (HSIL).

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 and HSIL, as well as invasive carcinomas. Patients with HSIL have a greater risk for progression to carcinoma.

In the setting of an abnormal Pap result, the presence of HR-HPV types in cervical specimens identifies a subgroup of patients with a greater likelihood of having a HSIL.

If the patient has been previously diagnosed with an abnormal Pap result or is at high risk, considering ordering this test, which is diagnostic, rather than the screen (STHPV / ThinPrep Screen with Human Papillomavirus [HPV] Reflex).

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 8,000 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.

Nucleic acid (DNA) testing by PCR 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 and 2) reduce the need for unnecessary colposcopy and treatment in patients 21 and older with cytology results showing atypical squamous cells of undetermined significance (ASC-US).

Recently, 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 or HPV-18 positive women is 11.4% (95% confidence interval [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 (ASCCP) now recommends that HPV 16 and 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)