Human papillomaviruses (HPVs) selectively infect the epithelium of skin and mucous membranes. These infections may be asymptomatic, produce warts, or be associated with a variety of both benign and malignant neoplasias.
More than 100 Human Papilloma Virus types are recognized, and individual types are associated with specific clinical manifestations. For example, HPV-1 causes plantar warts, HPV-6 causes anogenital warts, and HPV-16 infection can produce cervical dysplasia and invasive cervical cancer. HPVs are species-specific and have not been propagated in tissue culture or in common experimental animals. However, some HPV types have been produced in human tissues implanted in immunodeficient mice
There are few good studies of the incidence or prevalence of human warts in well-defined populations. Common warts (verruca vulgaris) are found in as many as 25% of some groups and are most prevalent among young children. Plantar warts (verruca plantaris) are also widely prevalent; they occur most often among adolescents and young adults. Anogenital warts (condyloma acuminatum) represent one of the most common sexually transmitted diseases in the United States.
Human Papilloma Virus infection of the uterine cervix produces the squamous cell abnormalities most frequently detected on Papanicolaou smears. Most anogenital HPV infections are transmitted through direct contact with infectious lesions. However, lesion characteristics that are associated with transmission, including appearance, have not been defined, and individuals without obvious disease may transmit infection.
Close personal contact is also assumed to play a role in the transmission of most cutaneous warts; the importance of fomites in this setting is not clear. Minor trauma at the site of inoculation may facilitate transmission. Recurrent respiratory papillomatosis in young children is an uncommon disease that is acquired from the infected maternal genital tract. In adults, orogenital sexual contact may transmit the disease.
According to a consensus panel gathered by the World Health Organization, a large body of epidemiologic and biologic data has established that some HPV infections cause cervical cancer. For example, >95% of cervical cancers contain HPV DNA of oncogenic (high-risk) types, such as 16, 18, 31, 33, and 45. HPV DNA is also present in the precursor lesions of cervical cancer (cervical intraepithelial neoplasias). Such lesions containing DNA of oncogenic types are more likely to progress than those associated with low-risk HPV types, such as 6 and 11. HPV DNA is transcribed in tumor tissues, and many epidemiologic studies have confirmed a strong relationship between HPV infection (with or without cofactors) and the development of cervical cancer.
Definitive proof of the causative role of high-risk HPV types in the pathogenesis of high-grade cervical dysplasia has been provided by the results of recently conducted trials of HPV vaccines. However, it is important to realize that most cervical HPV infections, including those caused by high-risk types, are self-limited. Infection with high-risk Human Papilloma Virus types has also been associated with squamous cell carcinomas and dysplasias of the penis, anus, vagina, and vulva.
In patients with epidermodysplasia verruciformis (see “Clinical Manifestations,” below), squamous cell cancers develop frequently at sites infected with specific HPV types, including 5 and 8.
Symptoms and signs
The clinical manifestations of Human Papilloma Virus infection depend on the location of lesions and the type of virus. Common warts usually occur on the hands as flesh-colored to brown, exophytic, and hyperkeratotic papules. Plantar warts may be quite painful; they can be differentiated from calluses by paring of the surface to reveal thrombosed capillaries. Flat warts (verruca plana) are most common among children and occur on the face, neck, chest, and flexor surfaces of the forearms and legs. Anogenital warts develop on the skin and mucosal surfaces of external genitalia and perianal areas.
Among circumcised men, warts are most commonly found on the penile shaft. Lesions frequently occur at the urethral meatus and may extend proximally. Receptive anal intercourse predisposes both men and women to the development of perianal warts, but such lesions occasionally develop without such a history. In women, warts appear first at the posterior introitus and adjacent labia.
They then spread to other parts of the vulva and commonly involve the vagina and cervix. In both sexes, external warts suggest the presence of internal lesions; however, internal lesions may be present without external warts, particularly in women.
The differential diagnosis of anogenital warts includes condylomata lata of secondary syphilis, molluscum contagiosum, hirsutoid papillomatosis (pearly penile papules), fibroepitheliomas, and a variety of benign and malignant mucocutaneous neoplasms. Respiratory papillomatosis in young children, which may be life-threatening, presents as hoarseness, stridor, or respiratory distress.
The disease in adults is usually milder. Immunosuppressed patients, particularly those undergoing organ transplantation, often develop pityriasis versicolor–like lesions, from which DNA of several HPV types has been extracted. Occasionally, such lesions appear to undergo malignant transformation.
Patients infected with HIV are often infected with uncommon HPV types, frequently have severe clinical manifestations of HPV infection, and are at high risk for cervical and anal dysplasia as well as for invasive cancer. Human Papilloma Virus disease in patients with HIV infection may be associated with multiple HPV types, is difficult to treat, and often recurs. Epidermodysplasia verruciformis is a rare autosomal recessive disease characterized by an inability to control HPV infection.
Patients are often infected with unique HPV types (i.e., types that affect only this group) and frequently develop cutaneous squamous cell malignancies, particularly in sun-exposed areas. The lesions resemble flat warts or macules similar to those of pityriasis versicolor. The complications of warts include itching and occasionally bleeding.
In rare cases, warts become secondarily infected with bacteria or fungi. Large masses of warts may cause mechanical problems, such as obstruction of the birth canal or the urinary tract.
Dysplasias of the uterine cervix are generally asymptomatic until frank carcinoma develops. Patients with anogenital Human Papilloma Virus disease may develop serious psychological symptoms due to anxiety and depression over this condition.
Most warts that are visible to the naked eye can be diagnosed correctly by history and physical examination alone. The use of a colposcope is invaluable in assessing vaginal and cervical lesions and is helpful in the diagnosis of oral and cutaneous HPV disease as well. Application of 3–5% solutions of acetic acid may aid in the visualization of lesions, although the sensitivity and specificity of this procedure are unknown. Papanicolaou smears prepared from cervical or anal scrapings often show cytologic evidence of HPV infection. Persistent or atypical lesions should be biopsied and examined by routine histologic methods.
The most sensitive and specific methods of virologic diagnosis use techniques such as the polymerase chain reaction or the hybrid capture assay to detect HPV nucleic acids and to identify specific virus types. Such tests may be useful in the diagnosis and management of cervical Human Papilloma Virus disease, although their utility may vary according to the prevalence of disease and the availability of traditional cytologic and histologic testing. Serologic techniques to diagnose HPV infection are not helpful in individual cases and are not widely available.
Human Papilloma Virus Infections: Treatment
Decisions regarding the initiation of therapy should be made with the recognition that currently available modes of treatment are not completely effective and some have significant side effects. In addition, treatment may be expensive, and many Human Papilloma Virus lesions resolve spontaneously.
Frequently used therapies include cryosurgery, application of caustic agents, electrodesiccation, surgical excision, and ablation with a laser. Topical antimetabolites such as 5-fluorouracil have also been used. Both failure and recurrence have been well documented with all of these methods of treatment.
Cryosurgery is the initial treatment of choice for condyloma acuminatum. Topically applied podophyllum preparations as well as podofilox may also be used.
Various interferon preparations have been employed with modest success in the treatment of respiratory papillomatosis and condyloma acuminatum. A topically applied interferon inducer, imiquimod, is also of benefit in the treatment of condyloma acuminatum. The diagnosis and management of anogenital dysplasias and of internal anogenital warts require special skills and resources, and patients with such lesions should be referred to a qualified specialist.
|Table showing summary of Treatment of External, Exophytic Anogenital Warts|
I. Administered by provider
A. Cryotherapy with liquid nitrogen or cryoprobe weekly
B. Podophyllin resin, 10–25% weekly for up to 4 weeks
C. Trichloroacetic acid or bichloroacetic acid, 80–90% weekly
D. Surgical excision
E. Other regimens
1. Intralesionally administered interferon
2. Laser surgery
II. Administered by patient
A. Podofilox, 0.5% solution or gel twice daily for 3 days,followed by 4 days without therapy. This cycle may be repeated four times.
B. Imiquimod, 5% cream 3 times per week for up to 16 weeks
Source: Modified from Centers for Disease Control and Prevention: MMWR 55(RR-11):1, 2006 (www.cdc.gov/mmwr/preview/mmwrhtml/rr5511a1.htm).
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Recently developed HPV VLP vaccines dramatically reduce rates of infection and disease produced by the HPV types in the vaccines. These products are directed against virus types that cause anogenital tract disease. Currently, one quadrivalent product (Gardasil, Merck) containing HPV types 6, 11, 16, and 18 has been licensed in the United States and recommended by the Centers for Disease Control and Prevention for administration to girls and young women 9–26 years of age. Another product (Cervarix, GlaxoSmithKline) contains HPV types 16 and 18 and is likely to be available in the near future.
HPV types 6 and 11 cause 90% of anogenital warts, whereas types 16 and 18 are responsible for 70% of cervical cancers. Because 30% of cervical cancers are caused by HPV types not contained in the vaccines, no changes in cervical cancer screening programs are currently recommended. Barrier methods of contraception may also be helpful in preventing transmission of condyloma acuminatum and other anogenital HPV-associated diseases.
Harrison’s Principle of Internal Medicine
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