Human Papillomavirus 

  • Author: Peter A Gearhart, MD; Chief Editor: Burke A Cunha, MD   more...
 
Updated: Dec 29, 2011
 

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. People with multiple sexual partners and those who already have persistent HPV infection are at increased risk to acquire additional strains of HPV.[1, 2, 3, 4] 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.

Table. Diseases and Associated HPV Subtypes (Open Table in a new window)

Nongenital Cutaneous Disease HPV Type
Common warts (verrucae vulgaris)1, 2, 4, 26, 27, 29, 41, 57, 65
Plantar warts (myrmecias)1, 2, 4, 63
Flat warts (verrucae plana)3, 10, 27, 28, 38, 41, 49
Butcher's warts (common warts of people who handle meat, poultry, and fish)1, 2, 3, 4, 7, 10, 28
Mosaic warts2, 27, 57
Ungual squamous cell carcinoma16
Epidermodysplasia verruciformis (benign)2, 3, 10, 12, 15, 19, 36, 46, 47, 50
Epidermodysplasia verruciformis (malignant or benign)5, 8, 9, 10, 14, 17, 20, 21, 22, 23, 24, 25, 37, 38
Nonwarty skin lesions37, 38
Nongenital Mucosal Disease HPV Type
Respiratory papillomatosis6, 11
Squamous cell carcinoma of the lung6, 11, 16, 18
Laryngeal papilloma6, 11, 30
Laryngeal carcinoma16, 18
Maxillary sinus papilloma57
Squamous cell carcinoma of the sinuses16, 18
Conjunctival papillomas6, 11
Conjunctival carcinoma16
Oral focal epithelial hyperplasia (Heck disease)13, 32
Oral carcinoma16, 18
Oral leukoplakia16, 18
Squamous cell carcinoma of the esophagus16, 18
Anogenital Disease HPV Type
Condylomata acuminata6, 11, 30, 42, 43, 44, 45, 51, 52, 54
Bowenoid papulosis16, 18, 34, 39, 42, 45
Bowen disease16, 18, 31, 34
Giant condylomata (Buschke-Löwenstein tumors)6, 11
Unspecified intraepithelial neoplasia30, 34, 39, 40, 53, 57, 59, 61, 62, 64, 66, 67, 68, 69
Low-grade intraepithelial neoplasia6, 11, 43
Intermediate intraepithelial neoplasia31, 33, 35, 42, 44, 45, 51, 52
High-grade intraepithelial neoplasia16, 18, 56, 58
Carcinoma of vulva6, 11, 16, 18
Carcinoma of vagina16
Carcinoma of cervix16, 18, 31
Carcinoma of anus16, 31, 32, 33
Carcinoma in situ of penis (erythroplasia of Queyrat)16
Carcinoma of penis16, 18
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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 (raisinoid) 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.

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Epidemiology

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.[5, 6] 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:[6]

  • 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.[7] 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.[8]

The prevalence of high-risk HPV in women with normal cervical cytology varies among the different regions of the world. Although the global HPV prevalence was estimated to be approximately 12%, higher prevalences were noted in sub-Saharan Africa (24%), eastern Europe (21.4%), and Latin America (16.1%).[9]

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

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.

Men who are infected with HPV are at risk to develop genital warts. The 24-month risk varied from 57.9% in men who were infected with HPV type 6 or type 11 to 2% in men who were infected with other HPV types.[10]

Cutaneous lesions typically produce benign self-limited warts (see Warts [Nongenital]).

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).[11]

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:[11]

  • 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%
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Contributor Information and Disclosures
Author

Peter A Gearhart, MD  Assistant Professor of Obstetrics and Gynecology, University of Pennsylvania School of Medicine

Peter A Gearhart, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists

Disclosure: Merck Honoraria Speaking and teaching

Coauthor(s)

Thomas C Randall  MD, Associate Professor of Clinical Obstetrics and Gynecology, University of Pennsylvania School of Medicine; Director, Gynecologic Oncology, Pennsylvania Hospital

Thomas C Randall is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, and American College of Obstetricians and Gynecologists

Disclosure: Nothing to disclose.

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

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary D Nettleman, MD, MS, MACP  Professor and Chair, Department of Medicine, Michigan State University College of Human Medicine

Mary D Nettleman, MD, MS, MACP is a member of the following medical societies: American College of Physicians, Association of Professors of Medicine, Central Society for Clinical Research, Infectious Diseases Society of America, and Society of General Internal Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Ronald A Greenfield, MD  Professor, Department of Internal Medicine, University of Oklahoma College of Medicine

Ronald A Greenfield, MD is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Central Society for Clinical Research, Infectious Diseases Society of America, Medical Mycology Society of the Americas, Phi Beta Kappa, Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology

Disclosure: Pfizer Honoraria Speaking and teaching; Gilead Honoraria Speaking and teaching; Ortho McNeil Honoraria Speaking and teaching; Abbott Honoraria Speaking and teaching; Astellas Honoraria Speaking and teaching; Cubist Honoraria Speaking and teaching; Forest Pharmaceuticals Speaking and teaching

Eleftherios Mylonakis, MD  Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital

Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD  Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

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Human papillomavirus (HPV). Condyloma acuminatum in a patient with a history of an allograft renal transplant.
Human papillomavirus (HPV). Note the extensive labial involvement.
Human papillomavirus (HPV). Anal condyloma acuminatum.
Human papillomavirus (HPV). These condylomata extend to the anal verge.
Table. Diseases and Associated HPV Subtypes
Nongenital Cutaneous Disease HPV Type
Common warts (verrucae vulgaris)1, 2, 4, 26, 27, 29, 41, 57, 65
Plantar warts (myrmecias)1, 2, 4, 63
Flat warts (verrucae plana)3, 10, 27, 28, 38, 41, 49
Butcher's warts (common warts of people who handle meat, poultry, and fish)1, 2, 3, 4, 7, 10, 28
Mosaic warts2, 27, 57
Ungual squamous cell carcinoma16
Epidermodysplasia verruciformis (benign)2, 3, 10, 12, 15, 19, 36, 46, 47, 50
Epidermodysplasia verruciformis (malignant or benign)5, 8, 9, 10, 14, 17, 20, 21, 22, 23, 24, 25, 37, 38
Nonwarty skin lesions37, 38
Nongenital Mucosal Disease HPV Type
Respiratory papillomatosis6, 11
Squamous cell carcinoma of the lung6, 11, 16, 18
Laryngeal papilloma6, 11, 30
Laryngeal carcinoma16, 18
Maxillary sinus papilloma57
Squamous cell carcinoma of the sinuses16, 18
Conjunctival papillomas6, 11
Conjunctival carcinoma16
Oral focal epithelial hyperplasia (Heck disease)13, 32
Oral carcinoma16, 18
Oral leukoplakia16, 18
Squamous cell carcinoma of the esophagus16, 18
Anogenital Disease HPV Type
Condylomata acuminata6, 11, 30, 42, 43, 44, 45, 51, 52, 54
Bowenoid papulosis16, 18, 34, 39, 42, 45
Bowen disease16, 18, 31, 34
Giant condylomata (Buschke-Löwenstein tumors)6, 11
Unspecified intraepithelial neoplasia30, 34, 39, 40, 53, 57, 59, 61, 62, 64, 66, 67, 68, 69
Low-grade intraepithelial neoplasia6, 11, 43
Intermediate intraepithelial neoplasia31, 33, 35, 42, 44, 45, 51, 52
High-grade intraepithelial neoplasia16, 18, 56, 58
Carcinoma of vulva6, 11, 16, 18
Carcinoma of vagina16
Carcinoma of cervix16, 18, 31
Carcinoma of anus16, 31, 32, 33
Carcinoma in situ of penis (erythroplasia of Queyrat)16
Carcinoma of penis16, 18
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