eMedicine Specialties > Infectious Diseases > Viral Infections

Human Papillomavirus

Author: Peter A Gearhart, MD, Assistant Professor of Obstetrics and Gynecology, University of Pennsylvania School of Medicine
Coauthor(s): Thomas C Randall, MD, Assistant Professor, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Pennsylvania School of Medicine; Roland Michael Buckley, Jr, MD, Clinical Professor of Medicine, University of Pennsylvania School of Medicine; Consultant, Department of Medicine, Division of Infectious Diseases, Pennsylvania Hospital
Contributor Information and Disclosures

Updated: Mar 8, 2010

Introduction

Background

Papillomaviruses affect a wide variety of animals. They cause tumors that erupt from DNA mutations in humans, monkeys, deer, horses, cattle, dogs, birds, and rabbits. The Los Alamos National Laboratory in the United States maintains a database of papillomavirus genomic sequences and a phylogenic tree, both of which are available at HPV Sequence Database.

Human papillomaviruses (HPVs) produce epithelial tumors of the skin and mucous membranes. More than 100 HPV types have been detected, and the genomes of more than 80 have been completely sequenced. The current classification system, which is based on similarities in their genomic sequences, generally correlates with the 3 categories used to describe HPV clinically: anogenital and/or mucosal, nongenital cutaneous, and epidermodysplasia verruciformis (EV).

The mucosal HPV infections are classified further as latent (asymptomatic), subclinical, or clinical. Clinical lesions are grossly apparent, whereas latent infections are detected only with tests for viral DNA. Subclinical lesions are identified by application of 3-5% acetic acid and inspection under magnification. Most HPV infections are latent; clinically apparent infections usually result in warts rather than malignancies.

HPV types 6 and 11 are typically labeled as low risk because infection with these types has low oncogenic potential and usually results in the formation of condylomata and low-grade precancerous lesions. HPV types 16 and 18 have emerged as the high-risk types of HPV because they are responsible for most high-grade intraepithelial lesions that may progress to carcinomas, particularly those in the anogenital and/or mucosal category.

HPV infection alone does not cause malignant transformation of infected tissue. Cofactors, such as tobacco use, ultraviolet radiation, pregnancy, folate deficiency, and immune suppression have been implicated in this process. The table lists a variety of diseases and the associated HPV subtypes.

Diseases and Associated HPV Subtypes

Open table in new window

Pathophysiology

Papillomaviruses are highly species specific and do not infect other species, even under laboratory conditions. Humans are the only known reservoir for HPV. Papillomaviruses are nonenveloped viruses of icosahedral symmetry with 72 capsomeres that surround a genome containing double-stranded circular DNA with approximately 8000 base pairs.

Papillomaviruses are thought to have 2 modes of replication. One is stable replication of the episomal genome in basal cells; the other is runaway, or vegetative, replication in more differentiated cells to generate progeny virus. Although all cells of a lesion contain the viral genome, the expression of viral genes is tightly linked to the state of cellular differentiation. Most viral genes are not activated until the infected keratinocyte leaves the basal layer. Production of virus particles can occur only in highly differentiated keratinocytes; therefore, virus production occurs only at the epithelial surface where the cells are ultimately sloughed into the environment.

HPV lesions are thought to arise from the proliferation of infected basal keratinocytes. Infection typically occurs when basal cells in the host are exposed to infectious virus through a disturbed epithelial barrier as would occur during sexual intercourse or after minor skin abrasions. HPV infections have not been shown to be cytolytic; rather, viral particles are released as a result of degeneration of desquamating cells. The HPV virus can survive for many months and at low temperatures without a host; therefore, an individual with plantar warts can spread the virus by walking barefoot.

Virus multiplication is confined to the nucleus. Consequently, infected cells exhibit a high degree of nuclear atypia. Koilocytosis (from the Greek koilos, meaning empty) describes a combination of perinuclear clearing (halo) with a pyknotic or shrunken (rasinoid) nucleus and is a characteristic feature of productive papillomavirus infection.

The HPV genome exists as a circular episomal DNA separate from the host cell nucleus in benign or low-risk HPV lesions, such as those typically associated with HPV types 6 and 11. The genomes of high-risk HPV types 16 and 18 are typically integrated into the host cell DNA in malignant lesions. Integration of the viral genome into the host cell genome is considered a hallmark of malignant transformation. HPV proteins E6 and E7 of high-risk serotypes have been shown to inactivate the host's tumor suppressor proteins p53 and Rb, thereby resulting in unregulated host cell proliferation and malignant transformation.

Frequency

United States

HPV infection is the most common sexually transmitted infection in the United States. The number of patients identified with HPV disease has increased markedly during the past 20 years because of heightened awareness of the various manifestations of HPV disease and because of increased use of HPV DNA testing.

Patients receiving immunosuppressive drugs and patients with defects in cell-mediated immunity, including those infected with the human immunodeficiency virus (HIV), are especially susceptible to developing HPV infections.

In the United States, 2.5 million women are estimated to have an annual cytological diagnosis of a low-grade cervical cancer precursor.

HPV infection causes virtually all cases of cervical cancer.^1,2 No deaths due to cervical cancer have been documented in women younger than 20 years. The United States National Cancer Institute publishes data on prevalence of worldwide cervical cancer via their online database.

The incidence of cervical cancer has decreased dramatically during the last century because of implementation of the Papanicolaou test (Pap Test, or Pap smear) beginning in the 1930s and 1940s. However, from 1990-2001, the annual number of estimated new invasive cervical cancers remained relatively constant, ie, 13,500 and 12,900, respectively.

Anogenital warts, or condylomata acuminata, are the most commonly diagnosed viral sexually transmitted disease (STD) in the United States and the United Kingdom. The annual incidence is estimated between 500,000 and 1 million cases. From 1966-1986, the incidence of genital warts increased 5-fold.

Approximately 7%-10% of the population has nongenital cutaneous warts.

The percentages of cancers caused by oncogenic HPV are as follows:²

• Cervical cancer - 100%
• Anal cancer - 90%
• Vulvar cancer - 40%
• Vaginal cancer - 40%
• Oropharyngeal cancer - 12%
• Oral cancer - 3%

International

In many lesser-developed countries, cervical cancer is the most common cancer among women because of the lack of effective screening programs that monitor cervical cytology by Pap smear.³ However, a single round of HPV screening has been demonstrated to be far superior to conventional cytology in reducing the incidence of cervical cancer morbidity and mortality.⁴

In many developing nations, cervical cancer is the leading cause of cancer mortality among women. Worldwide, it is the second most common cause of cancer mortality among women.

Mortality/Morbidity

• Anogenital/mucosal disease: A direct correlation exists between anogenital HPV infection and measures of sexual activity, such as the age of first intercourse and the lifetime number of sexual partners. Women with a history of a cervical high-grade squamous intraepithelial lesion (HGSIL) or invasive squamous cell carcinoma (SCC) of the cervix are at increased risk for subsequent development of invasive cancer in other tissues of the anogenital/mucosal category, particularly vaginal and anal carcinoma. In these patients, the relative risk of vaginal carcinoma is 5.6, and the risk of anal carcinoma is 4. Anal cancer has been strongly associated with male homosexuality and specific male practices, such as engaging in receptive anal intercourse. Relative risk is 33. However, the overall disease prevalence is higher in women than in men, with a female-to-male ratio of 1.5:1.
• Nongenital cutaneous warts: Cutaneous lesions typically produce benign self-limited warts (see Warts [Nongenital]).
• EV: Patients who are immunosuppressed, particularly those with cutaneous malignant lesions, have a much higher incidence of EV-HPV infection than the general population. These lesions can undergo malignant transformation. Ten percent of patients with EV originate from consanguineous marriages, suggesting an autosomal recessive mode of inheritance (see Epidermodysplasia Verruciformis).

Race

• From 1987-1991, the age-adjusted Cervical Cancer death rate reported by the US National Cancer Institute was higher among black women compared to white women, with a ratio of 6:1.
• Nongenital cutaneous warts are more common in whites than in people of African descent.

Sex

• The overall prevalence of HPV in women is 22-35%.
• In men, the prevalence is 2-35% depending on the sexual practices of the population being studied.

Age

• The prevalence of anogenital mucosal HPV infections is highest among college-aged women and men.
• The incidence of high-risk HPV infections drops after age 20-24 years, and the incidence of low-risk HPV types plateaus after age 30-39 years (see below).⁵
• Nongenital cutaneous warts are more common among teenagers and adults who work as meat, poultry, and fish handlers. The incidence approaches 10% in child and young adult populations. However, nongenital cutaneous warts rarely occur in people younger than 5 years and usually regress within 2 years.
• EV develops at an average age of onset of 6 years, and, beginning in the fourth decade of life, the lesions can undergo malignant transformation into invasive SCC.
• The prevalence of HPV infection stratified by age in US females is as follows:⁵
  • Age 14-59 years - 26.8%
  • Age 14-19 years - 24.5%
  • Age 20-24 years - 44.8%
  • Age 25-29 years - 27.4%
  • Age 30-39 years - 27.5%
  • Age 40-49 years - 25.2%
  • Age 50-59 years - 19.6%

Clinical

History

• Anogenital warts
  • Condylomata acuminata are exophytic cauliflowerlike lesions that are usually found near moist surfaces. They may be observed in the perianal area, vaginal introitus, vagina, labia, and vulva. Genital warts may also be found on dry surfaces, such as the shaft of the penis.
  • Genital warts include smooth papular warts and keratotic warts, the latter of which resemble nongenital cutaneous warts because of their thickened bumpy surface.
  • Genital flat warts are subclinical lesions that typically appear on the cervix. Colposcopic examination with 3% acetic acid solution is required for identification.
• Cervical disease
  • Most cervical infections are either latent or subclinical and, as such, are asymptomatic. These infections are detected on Pap smear and are reported as either a low-grade squamous intraepithelial lesion (LGSIL) or a high-grade squamous intraepithelial lesion (HGSIL). Further examination with 3-5% acetic acid and colposcopy shows characteristic acetowhite changes and abnormal blood vessels indicative of human papillomavirus (HPV)–triggered dysplasia.
  • Patients who have neglected to obtain annual Pap testing for several years or more and who have an HGSIL that has progressed to invasive cancer of the cervix may report vaginal bleeding between periods or after sexual intercourse, dyspareunia, and fullness in the pelvis.
• Anal cancer
  • The most common presenting symptoms of SCC of the anus are rectal bleeding and sensation of a mass. This may be attributed mistakenly to hemorrhoids.
  • Fifty percent of men who are homosexual and have SCC of the anus have a history of anorectal warts; however, only 20% of women with SCC and men who are not homosexual have this history.
• Nonanogenital mucosal disease
  • HPV types 6 and 11 have been isolated on nonanogenital mucosal surfaces. Warts have been discovered in the nares, mouth, larynx, and conjunctiva.
  • HPV types 6 and 11 are associated with respiratory papillomas that are probably the result of intrapartum transmission when the infant passes through the birth canal of a mother who is infected with HPV. However, isolated case reports exist of respiratory papillomatosis after cesarean delivery. Patients with laryngeal papillomas present at an average age of 3 years, most frequently with hoarseness.
• Nongenital cutaneous HPV
  • Cutaneous lesions typically produce benign self-limited warts.
  • Deep plantar warts occur most commonly as solitary lesions that may become black and painful prior to spontaneous regression. They may contain small black "seeds," which are thrombosed capillaries.
  • Common warts can occur on any skin surface but are usually found on the hands and fingers. They appear as skin-colored, exophytic, rough papules and nodules that have minimal scaling. Autoinoculation from a wart on one finger may cause the occurrence of warts on an adjacent finger or other skin surface, so-called kissing warts.
  • Warts that occur in people who handle meat and fish often have large cauliflowerlike plaques.
  • Flat warts most often occur in groups of small plaques less than 5 mm in diameter on the face and hands. Regression usually occurs spontaneously after several years, and pruritus or erythema occur several weeks prior to their disappearance.
• Epidermodysplasia verruciformis
  • The malignant conversion of skin lesions usually begins in the fourth and fifth decades of life. Premalignant lesions usually first arise on the forehead and other sun-exposed areas. The tumors are either benign papillomas and seborrheic keratoses or premalignant actinic keratoses and SCC.
  • Epidermodysplasia verruciformis (EV) tumors are locally destructive. They develop slowly and have weak metastatic potential if no cocarcinogens, such as x-ray or ultraviolet B irradiation, are applied. Polymorphic, plane wart–like, and red-to-brownish plaques can be distributed widely over the skin. The lymph nodes and oral mucosa are not involved.

Physical

The findings on physical examination depend on the tissues involved. They include a variety of cutaneous lesions with characteristic appearances noted above. Images 1-4 demonstrate extensive anogenital condyloma acuminata.

Causes

• Types of HPV demonstrate a high degree of site specificity, with some HPV types only found on certain parts of the skin or mucous membranes.
• HPV infection alone does not cause malignant transformation of infected tissue. Cofactors, such as tobacco use, ultraviolet radiation, pregnancy, folate deficiency, and immune suppression, have been implicated in this process. Patients receiving immunosuppressive drugs and patients with defects in cell-mediated immunity, including those infected with HIV are especially susceptible to developing HPV infections.
• A direct correlation exists between anogenital HPV infection and measures of sexual activity, such as the age of first intercourse and the lifetime number of sexual partners.

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