HPV
TECHNICAL UPDATE

DESCRIPTION/BACKGROUND INFORMATION:

The human papilloma viruses (HPV) are small DNA tumor viruses that belong to the family Papovaviridae. More than 90 percent of high-grade cervical dysplasias and invasive cervical cancers have been associated with 10 to 15 high-risk HPV viral types. Most HPV viral types are associated with sexually transmitted infections that usually resolve spontaneously. Persistence, defined as the demonstration of residual HPV DNA detectable by polymerase chain reaction (PCR) or in situ hybridization, is said to occur when the time span where the virus is detectable exceeds one year. Persistence is postulated to set the stage for progressive cytologic abnormalities of the cervical epithelium, leading in some cases to invasive cervical carcinoma. Risk factors and conditions necessary for precancer to progress to invasive squamous carcinoma have not been fully elucidated.

CLINICAL APPLICATION:

1. WOMEN WITH ASC-US PAP RESULTS

A number of studies have evaluated HPV DNA testing as a form of intermediate triage to determine which women with ASC-US Pap smears should be referred for colposcopy and which should be returned to routine cytologic screening. Recent studies have found that HPV DNA testing identifies more cases of high-grade squamous intraepithelial lesions (HSIL) than does a single repeat Pap smear, but refers approximately equivalent numbers of women for colposcopy. (See graph)

TRIAGE OF WOMEN WITH ASC-US PAP RESULTS USING PAP TEST AND HPV TESTING

2. WOMEN AGE 30 AND OLDER

On July 31, 2003, the American College of Obstetricians and Gynecologists announced its most comprehensive revision of Pap test and other cervical cancer screening recommendations in more than a decade. The new recommendations, which are effective immediately, include the use of a Pap test and an FDA-approved HPV test for women age 30 and older.

" The combined use of a cervical cytology test and an FDA-approved test for high-risk types of HPV - This option is both a cervical cytology test and a genetic test (HPV DNA test) that looks for certain high-risk types of the human papillomavirus (HPV) know to cause cancer. Once women test negative on both tests, they should be rescreened with the combined tests no more frequently than every 3 years.

" Testing using cervical cytology alone. If a woman age 30 or older has negative results on three consecutive annual cervical cytology tests, then she may be rescreened with cervical cytology alone every 2-3 years.

More frequent cervical screening may be required for high-risk women who are infected with HIV, are immunosuppressed (such as those receiving kidney transplants), were exposed to DES in utero, or were previously diagnosed with cervical cancer.

COLLECTION:

There are two methods for collection for HPV DNA testing.

1. When conventional slide Pap smears are used for cytologic screening, women with a diagnosis of ASC-US have to return to the clinic or office for a second cervical sample to be collected for HPV DNA testing.

2. When liquid-based cervical cytology is used for primary screening, the material left in the vial after the initial cytologic specimen is prepared can be used for HPV DNA testing. HPV DNA testing can be performed as a "reflex test" on the material in the liquid-cytology vial whenever an ASC-US diagnosis is made. Reflex testing eliminates the need for a separate office visit to collect a specimen for HPV DNA testing.

METHODOLOGY:

The Hybrid Capture 2 (hc2) HPV DNA Test is a nucleic acid, hybridization assay, with signal amplification, that uses chemiluminescent microplate detection. Hybrid Capture 2 uses RNA probes specific for the genomes of the 18 viral types. Of these, 13 types are implicated in the pathogenesis of HSIL and invasive cancer: 16, 18, 31, 33, 35 39, 45, 51, 52, 56, 58, 59, 68. Five probes detect low-risk viral types associated with LSIL: 6, 11, 42, 43, and 44.

REFERENCES:

1. Schiffman M, Herrero R, Hldeshein A, Sherman ME, Bratti M. Wacholder S, et al. HPV DNA testing in cervical screening: results from women in a high-risk province of Costa Rica. JAMA. January 5, 2000,283(1):87-93.
2. Husain M, Lorincz A. Unpublished, for clinical usage at Detroit Medical Center. Practice Guidelines: Role of the Human Papilloma Virs (Hybrid Capture 2) DNA Test in Management of Women with Abnormal Cervical Cytology.
3. Hybrid Capture 2. HC2 High-Risk HPV DNA Test. Digene Catalog No. 5101-1296. Digene Corp., 2002.
4. Schiffman M. HPV Testing: Are You Ready for a New Era in Cervical Cancer Screening; Epidemiology and Public Health Presented at College of American Pathologists Conference September 21, 22, 2002, Rosemont, IL.
5. Wright TC, Lorinex AT, Ferris DF, et al. Reflex HPV deoxyribonucleic acid testing in women with abornal Papanicolaou smears. Am J Obstet Gynecol. 1998;178(5):962-966.
6. Sun, XW, Ferenczy A, Johnson D, et al. Evaluation of the Hybrid Capture human papillomavrius deoxyrilbonucleic acid detection test. Am J Obstet Gynecol. 1995;173(5):1432-1437.
7. Cox T, Lorinez AT, Schiffman MH, Sherman ME, Cullen A, Kurman RJ. Human papillomavirus testing by hybrid capture appears to be useful in triaging women with a cytologic diagnosis of atypical squamous cells of undetermined significance. Am J Obstet Gynecol. 1995;172(5):946-954.
8. Manox MM, Kinney WK, Hurley LB, et al. Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results. JAMA 1999.281:1605-1610.