The HPV DNA virus hybrid capture assay: what is it--and where do we go from here? (Cover Story).
New testing methods for human papilloma virus (HPV), such as the Digene Hybrid Capture 2 HPV DNA Test ([hc.sub.2] HPV DNA Test), present both opportunities and challenges in the diagnosis and management of cervical carcinoma. The Pap smear has played a major role in reducing mortality from cervical cancer. The emergence of HPV DNA testing presents a number of potential indications for its use, for example, in the diagnosis and follow-up of cervical dysplasia, and possibly for primary screening. The emergent field of molecular biology is inundating us with enormous amounts of new information; finding intelligent, practical and fiscally sound ways of using this information is becoming a major healthcare issue.
Cervical carcinoma and HPV
The human papilloma viruses are small DNA tumor viruses that belong to the family of Papovaviridae. (1) The incidence of cervical carcinoma worldwide is estimated to be as high as 400,000 diagnoses per year. (1) 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. (1,2)
Most HPV viral types are associated with sexually-transmitted infections that usually resolve spontaneously. The [hc.sub.2] HPV DNA Test uses a combination of DNA probes to detect high-risk viral types that are potentially carcinogenic (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68). (2,3)
Genital HPV infection is thought to be the most common sexually-transmitted disease; males are carriers of HPV on the penile skin. Interestingly, penile carcinomas appear to be related to HPV in only a small fraction of cases, in contrast to carcinomas of the cervix. (4) Research has shown that HPV infections of the cervix may follow a number of different pathways. (4) As Figure 1 indicates, the usual outcome of HPV infection of the cervix is clearance, generally within six to 12 months. (4)
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 nor been fully elucidated. Variables promoting neoplastic progression, such as cigarette smoking, have been postulated, but other factors need to be elucidated, including multiparity; long-term contraceptive use and ongoing inflammation. (4) Of note, infections with high-risk HPV viral types are common and may not necessarily be the defining factor in cervical carcinogenesis. Full-blown progression to carcinoma is an uncommon outcome of HPV infection. Those cases where progression evolves to precancer (cervical intraepithelial neoplasi a) (5) tend not to regress quickly in patient followup. The median age of women with high-grade squamous intraepithelial lesions (HSIL) is approximately in the 30s, with invasive carcinomas being more frequent at older ages. (4) Women with invasive carcinomas tend to be generally a decade or more older than women with HSIL. This suggests that numerous genetic events are occurring in the DNA at a molecular level over a long period of time and need to be further defined.
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