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Human Papillomavirus Infections

Human Papillomavirus Infections

Richard C. Reichman

DEFINITION

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.

ETIOLOGIC AGENT

Papillomaviruses are members of the family Papillomaviridae. They are nonenveloped, measure 50 to 55 nm in diameter, have icosahedral capsids composed of 72 capsomeres, and contain a double-stranded circular DNA genome of ~7900 base pairs. The genomic organization of all papillomaviruses is similar and consists of an early (E) region, a late (L) region, and a noncoding upstream regulatory region (URR). Oncogenic HPV types can immortalize human keratinocytes, and this activity has been mapped to products of early genes E6 and E7. E6 protein facilitates the degradation of the p53 tumor-suppressor protein, and E7 protein binds the retinoblastoma gene product and related proteins. The E1 and E2 proteins modulate viral DNA replication and regulate gene expression. The L1 gene codes for the major capsid protein, which makes up 80% of the virion mass. L2 codes for a minor capsid protein. Type-specific conformational antigenic determinants are located on the virion surface. Papillomavirus types are distinguished from one another by the degree of nucleic acid sequence homology. Distinct types share <90% of their DNA sequences in L1. More than 100 HPV 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.

EPIDEMIOLOGY

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. Condyloma acuminatum (anogenital warts) is one of the most common sexually transmitted diseases in the United States. HPV 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, characteristics of infectious lesions, 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 maternal genital tract infection; 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. However, it is important to realize that most cervical HPV infections, including those caused by high-risk types, are self-limited. Infection with specific HPV types has also been associated with squamous cell carcinomas and dysplasias of the penis, anus, vagina, and vulva. In patients with epidermodysplasia verruciformis, squamous cell cancers develop frequently at sites infected with specific HPV types, including 5 and 8.

Serologic studies employing virus-like particles as antigens have demonstrated type-specific antibodies in most patients with HPV genital tract infections.

CLINICAL MANIFESTATIONS

The clinical manifestations of HPV 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. External warts in both sexes are suggestive of the presence of internal lesions, although internal lesions may be present without external warts, particularly among 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 frequently have severe clinical manifestations of HPV infection and appear to be at unusually high risk for cervical and anal dysplasia as well as for potentially invasive cancer. HPV disease in patients with HIV infection 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 unusual HPV types 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. Dysplasias of the uterine cervix are generally asymptomatic until frank carcinoma develops. Patients with anogenital HPV disease may develop serious psychological symptoms due to anxiety and depression over this condition.

PATHOGENESIS

The incubation period of HPV disease is usually 3 to 4 months (range, 1 month to 2 years). All types of squamous epithelium can be infected by HPV, and the gross and histologic appearances of individual lesions vary with the site of infection and the type of virus. The replication of HPV begins with the infection of basal cells. As cellular differentiation proceeds, HPV DNA replicates and is transcribed. Ultimately, virions are assembled in the nucleus and released when keratinocytes are shed. This process is associated with proliferation of all epidermal layers except the basal layer and produces acanthosis, parakeratosis, and hyperkeratosis. Koilocytes—large round cells with pyknotic nuclei—appear in the granular layer. Histologically normal epithelium may contain HPV DNA, and residual DNA after treatment can be associated with recurrent disease.

Episomal HPV DNA is present in the nuclei of infected cells in benign lesions caused by HPV. However, in severe dysplasias and cancers, HPV DNA is generally integrated, with disruption of the E1/E2 open reading frames. This disruption leads to upregulation of E6 and E7 and subsequent interference with cellular tumor-suppressor proteins.

Host defense responses to HPV infection are incompletely understood,

and immune correlates of protection from infection and resolution of disease have not been established. Because patients with defects in cell-mediated immune responses, including transplant recipients and patients with HIV infection, frequently develop severe HPV disease, such responses are probably important for the control of virus replication. Histologic studies demonstrating an epidermal lymphomonocytic infiltrate in resolving warts suggest that local immunity may be of particular importance in the resolution of disease. HPV infection can also elicit a serologic response; antibodies to the viral capsid have been found in sera of patients with anogenital warts, cutaneous warts, and respiratory papillomatosis. Antibodies to E-region proteins, most notably E7, have been detected among patients with cervical carcinoma. In one prophylactic vaccine study, induction of a serologic response was associated with protection from cervical HPV infection in a group of immunocompetent young women.

DIAGNOSIS

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 to 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 entail the use of 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 HPV 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.

TREATMENT (Table 1)

Decisions regarding the initiation of therapy should be made with the knowledge that currently available modes of treatment are not completely effective and some have significant side effects. In addition, treatment may be expensive, and many HPV 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.

PREVENTION

Apart from the avoidance of contact with infectious lesions, no effective methods for the prevention of HPV infections are available at present. Barrier methods of contraception may be helpful in preventing transmission of condyloma acuminatum and other anogenital HPV-associated diseases. Vaccines consisting of virus-like particles (VLPs) can prevent papillomavirus disease in animal models. One study of an HPV-16 VLP vaccine in uninfected women has shown protection from cervical infection with the homologous virus. More extensive clinical trials of these preparations are likely to demonstrate reductions in rates of cervical HPV disease.

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