Human Papillomaviruses : Clinical Features, Laboratory Diagnosis, and Medical Management
Human papillomaviruses are small, double-stranded DNA viruses that infect the epithelium. More than 120 HPV types have been identified; they are differentiated by the genetic sequence of the outer capsid protein L1. Most HPV types infect the cutaneous epithelium and can cause common skin warts. About 40 types infect the mucosal epithelium; these are categorized according to their epidemiologic association with cervical cancer. Infection with low-risk, or nononcogenic types, such as types 6 and 11, can cause benign or low-grade cervical cell abnormalities, genital warts and laryngeal papillomas.
High-risk, or oncogenic, HPV types act as carcinogens in the development of cervical cancer and other anogenital cancers. High-risk types (currently including types 16 and 18, among others) can cause low-grade cervical cell abnormalities, high-grade cervical cell abnormalities that are precursors to cancer, and anogenital cancers. High-risk HPV types are detected in 99% of cervical cancers. Type 16 is the cause of approximately 50% of cervical cancers worldwide, and types 16 and 18 together account for about 70% of cervical cancers. Infection with a high-risk HPV type is considered necessary for the development of cervical cancer, but by itself it is not sufficient to cause cancer because the vast majority of women with HPV infection do not develop cancer.
In addition to cervical cancer, HPV infection is also associated with anogenital cancers less common than cervical cancer, such as cancer of the vulva, vagina, penis and anus. The association of genital types of HPV with non-genital cancers is less well established, but studies support a role for these HPV types in some oropharyngeal cancers.
Pathogenesis
HPV infection occurs at the basal epithelium. Although the incidence of infection is high, most infections resolve spontaneously. A small proportion of infected persons become persistently infected; persistent infection is the most important risk factor for the development of cervical cancer The most common clinically significant manifestation of persistent genital HPV infection is cervical intraepithelial neoplasia, or CIN. Within a few years of infection, low-grade CIN—called CIN 1—may develop, which may spontaneously resolve and the infection clear.
Persistent HPV infection, however, may progress directly to higher-grade CIN, called CIN2 or CIN3. High-grade abnormalities are at risk of progression to cancer and so are considered cancer precursors. Some high-grade abnormalities spontaneously regress. If left undetected and untreated, years or decades later CIN2 or 3 can progress to cervical cancer.
Infection with one type of HPV does not prevent infection with another type. Of persons infected with mucosal HPV, 5% to 30% are infected with multiple types of the virus.
Clinical Features
Most HPV infections are asymptomatic and result in no clinical disease. Clinical manifestations of HPV infection include anogenital warts, recurrent respiratory papillomatosis, cervical cancer precursors (cervical intraepithelial neoplasia), and cancers, including cervical, anal, vaginal, vulvar, penile, and oropharyngeal cancer.
Laboratory Diagnosis
HPV has not been cultured by conventional methods. Infection is identified by detection of HPV DNA from clinical samples. Assays for HPV detection differ considerably in their sensitivity and type specificity, and detection is also affected by the anatomic region sampled as well as the method of specimen collection.
Several HPV tests have been approved by the Food and Drug Administration (FDA) and detect 13-14 high-risk types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68). Test results are reported as positive or negative for any of the types; some tests specifically identify HPV 16 and 18. These tests are approved for triage of Papanicolaou (Pap) test results (ASC-US, atypical cells of undetermined significance) and in combination with the Pap test for cervical cancer screening in women 30 years of age and older. The tests are not clinically indicated nor approved for use in men.
Epidemiologic and basic research studies of HPV generally use nucleic acid amplification methods that generate type-specific results. The polymerase chain reaction (PCR) assays used most commonly in epidemiologic studies target genetically conserved regions in the L1 gene. The most frequently used HPV serologic assays are virus-like particle (VLP)-based enzyme immunoassays. However, laboratory reagents used for these assays are not standardized and there are no standards for setting a threshold for a positive result.
Medical Management
There is no specific treatment for HPV infection. Medical management depends on treatment of the specific clinical manifestation of the infection (such as genital warts or abnormal cervical cell cytology).
Epidemiology
Occurrence
HPV infection occurs throughout the world.
Reservoir
Viruses in the papillomavirus family affect other species. Humans are the only natural reservoir of HPV.
Transmission
HPV is transmitted by direct contact, usually sexual, with an infected person. Transmission occurs most frequently with sexual intercourse but can occur following nonpenetrative sexual activity.
Studies of newly acquired HPV infection demonstrate that infection occurs soon after onset of sexual activity. In a prospective study of college women, the cumulative incidence of infection was 40% by 24 months after first sexual intercourse. HPV 16 accounted for 10.4% of infections.
Genital HPV infection also may be transmitted by nonsexual routes, but this appears to be uncommon. Nonsexual routes of genital HPV transmission include transmission from a woman to a newborn infant at the time of birth.
Temporal Pattern
There is no known seasonal variation in HPV infection.
Communicability
HPV is presumably communicable during the acute infection and during persistent infection. This issue is difficult to study because of the inability to culture the virus. Communicability can be presumed to be high because of the large number of new infections estimated to occur each year.
Risk Factors
Risk factors for HPV infection are primarily related to sexual behavior, including lifetime and recent sex partners. Results of epidemiologic studies are less consistent for other risk factors, including young age at sexual initiation, number of pregnancies, genetic factors, smoking, and lack of circumcision of male partner.
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