Ninety-five percent (95%) of cervical neoplasia is considered to be due to infection with human papillomavirus (HPV).  HPV is a sexually transmitted disease which occurs after a woman becomes sexually active.  Not all HPV viral types are oncogenic, not all infect the cervix, and only a small number of women who develop HPV infection, even with the oncogenic forms of HPV, will develop in-situ or invasive cervical cancer. It has been well established that the majority of squamous cell cancers of the cervix progress through a series of well-defined preinvasive lesions and that during this usually lengthy process, the disease can be easily detected by Pap smear screening. During this preinvasive stage, cervical squamous intraepithelial lesions (SIL) can be controlled with nearly uniform success.

 

The Bethesda System (TBS) was introduced (1988) as a standardized grading system for Pap smears.  Frankly negative or positive smears are reported as such.  In between these two extremes are various levels of equivocal abnormality.  These may be due to inflammatory disease or may be precursors of a malignant process.

 

Atypical squamous cells of unknown significance (ASCUS); atypical glandular cells of unknown significance (AGUS); low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL) are designations given to these undetermined cell types.

 

Screening for cervical carcinoma or precursors to cervical carcinoma with Pap smears has potential weaknesses:

 

Except for a subset of Pap smear results, no consistent methodological approach to the woman who has a Pap smear with one of these undetermined cell types has been developed.  Women with HSIL or AGUS reports are recommended to have colposcopy directed biopsy and endocervical curettage, as the risk of an cervical cancer precursor is significant (15% of women with AGUS have HSIL or adenocarcinoma in situ), and those with HSIL or in-situ carcinoma on biopsy are recommended to have resectional or ablation procedures.

 

ASCUS or LSIL, however, are a more problematic issue, for almost all of these findings are the result of benign disease (5-10% of women with ASCUS have HSIL disease; the majority of LSIL regress without treatment, but 15% of women with LSIL on Pap smear will have HSIL on colposcopy and biopsy).  A diagnosis of ASCUS identifies a woman who is at greater than background risk for prevalent and incipient cervical intraepithelial neoplasia 2 (CIN2), CIN3, and cancer.  Studies have shown that 20% - 60% of ASCUS changes are associated with CIN at colposcopic evaluation, but the vast majority of these (greater than 70%) are CIN1, a sign of usually benign HPV infection. The question of whom to refer for colposcopy and possible biopsy is such concern that the National Cancer Institute funded a trial to evaluate the best triage option for women with equivocal and low-grade Pap smears in a randomized trial that began in 1995, ending in 2001.

 

Three follow-up options have been proposed for women with ASCUS or LSIL: immediate colposcopy, accelerated repeat Pap testing, and testing for the presence of HPV.  Immediate colposcopy would theoretically detect all HSILs.  However, the positive predictive value would be extremely low due to the low (5-10%) prevalence of high-grade disease among women with ASCUS, whereas the anxiety and costs generated are high.  Repeat cytology may not be cost-effective due to a high rate of repeat abnormal cytology findings requiring colposcopic evaluation.  Additionally, accuracy of the Pap test is low (sensitivity = 51%-66%) and reproducibility is poor.

 

More than 70 types of HPV have been identified. However, only 23 of these infect the uterine cervix; of these, only one-half are associated with SIL or invasive cervical cancer. These are further classified into low-risk types, HPV 6 and 11, and high-risk types, most commonly 16, 18, 31, and 45, which account for more than 80 percent of all invasive cervical cancers. An unknown percentage of women infected with HPV will develop either low-grade SIL (LSIL) or high-grade SIL (HSIL). One-third of all grades of SIL will regress, whereas 41 percent persist and 25 percent progress. Of lesions that progress, 10 percent progress to carcinoma in-situ and 1 percent to invasive cancer. Three-quarters of all grades of SIL will not progress.

 

Because the large majority of women with ASCUS. ASGUS, or LSIL will not have HSIL or in-situ carcinoma, it has recently been recommended by some that testing for HPV infection could be an alternative to triaging women to biopsy or observation.

 

One HPV DNA test by Digene Corporation is FDA approved for marketing under a PMA developed in 1995.  The Hybrid Capture HPV DNA Assay is approved to aid in the triage of patients with equivocal or ASCUS Pap smear results in order to better determine the need for referrals to colposcopy; to serve as an adjunct to the Pap smear in the identification of women who may be at increased risk for squamous intraepithelial lesions (SIL); to distinguish between infections with HPV types which are principally associated with low-grade squamous intraepithelial lesions (LSIL), and HPV types typically associated with SIL of all grades, especially high-grade SIL (HSIL) and invasive cancer of the cervix; to aid in the diagnosis of sexually transmitted disease.  On 31 March 2003, the FDA expanded approval of the Digene HC2 High-Risk HPV DNA Test to include use for screening in conjunction with the Pap smear of women over the age of 30.

 

 

 

 

 

 

 

 

 

Data from the ALTS trial showed that triage of ASC-US smears using HPV testing for triage to immediate colposcopy was more sensitive and equally specific in identifying cervical intraepithelial neoplasia grade 3 (CIN 3) as repeat Pap smear using ASC-US as the threshold for colposcopy referral. Based primarily on the results of this trial, recent guidelines issued by the American Society for Colposcopy and Cervical Pathology recommend either repeat Pap smear, immediate colposcopy, or HPV testing for women who have ASC-US Pap smears.  HPV testing can be performed on the remaining liquid media used as part of the preparation of monolayer slides. Otherwise, if the original Pap smear was prepared conventionally, HPV testing would require an additional office visit to perform an additional Pap smear.

 

Noncoverage for testing of specific genotype is based on lack of medical literature that such identification results in improved health outcomes.

 

 

 

 

A search of the MEDLINE database was conducted through September 2013. There was no new information identified that would prompt a change in the coverage statement.  

 

 

A literature search was conducted using the MEDLINE database through February 2018. There was no new information added that would prompt a change in the coverage statement.