Human papillomavirus (HPV) produces epithelial tumors of the skin and mucous membranes. The current classification system for HPV, which is based on similarities in genomic sequences, generally correlates with the 3 clinical categories applied to HPV infection[1] :
Anogenital or mucosal (further subclassified as latent [asymptomatic], subclinical, or clinical)
Nongenital cutaneous
Epidermodysplasia verruciformis (see the images below)
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Human papillomavirus (HPV). Verrucae and papillomas appear as frondlike epithelial proliferations. Verrucae tend to be more keratinized with sharper p....
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Human papillomavirus (HPV). Verruca vulgaris on the lateral border of the tongue exhibits the multiple, sharp-tipped, white, verrucous appearance, whi....
Signs and Symptoms
The clinical history and presentation of HPV infection vary depending on the anatomic area involved. The preference of certain viral genotypes for specific epidermal sites largely determines the areas of involvement. Conditions associated with HPV include the following[1] :
Anogenital warts (condylomata acuminata): Typically found near moist surfaces (eg, perianal area, vaginal introitus, vagina, labia, and vulva) but also may occur on dry surfaces (eg, penile shaft). These warts can be smooth and papular or keratotic. They generally are not painful but can be associated with pruritus or bleeding.
Cervical disease: Includes low-grade squamous intraepithelial lesion (LGSIL) and high-grade squamous intraepithelial lesion (HGSIL).
Anal cancer: About 50% of homosexual men with anal squamous cell carcinoma (SCC) have a history of anorectal warts. In contrast, only 20% of women with SCC and non-homosexual men have this history.
Nonanogenital mucosal disease: Includes oral warts, respiratory papillomas, and focal epithelial hyperplasia (Heck disease).
Nongenital cutaneous disease: Includes common cutaneous warts (verruca vulgaris), flat warts (verruca plana), and Bowenoid papulosis.
Epidermodysplasia verruciformis.
Physical findings vary depending on the tissues involved and may include the following[1] :
Keratotic warts: Often seen on dry surfaces such as the labia majora.
Discrete papules: 1-3 mm in size can present on the shaft of the penis.
Cervical intraepithelial lesions: May be found upon examination of the cervix.
Subclinical infection: Tiny, slightly raised areas felt or visualized on the vagina or cervix.
See Clinical Presentation for more detail.
Diagnosis
Diagnosis of most cutaneous and external genital warts typically can be achieved through clinical examination or by applying acetic acid and conducting a biopsy. In cases of genital intraepithelial neoplasia, it is crucial to assess the extent of the disease through meticulous inspection and colposcopy.
Laboratory studies that may be considered include the following[2] :
Cervical cytologic testing with the Papanicolaou (Pap) test to screen for cervical neoplasia (current guidelines recommend delaying initiation and extending intervals between subsequent screens).[2]
HPV DNA testing (eg, Hybrid Capture II or polymerase chain reaction [PCR] assay) for detecting HPV and post-treatment follow-up of cervical intraepithelial neoplasia.
The acetic acid test may be used in conjunction with colposcopy to examine suspicious cervical lesions, but it is not recommended for routine screening.[1]
In certain cases, tissue biopsy may be necessary to confirm HPV infection. Biopsy is recommended in the following scenarios[1] :
Women with a history of vulvar dysplasia.
Postmenopausal women.
Cases where medical therapy fails.
When there is clinical doubt about the diagnosis.
Histologic findings useful for diagnosing include[1] :
Common cutaneous warts: Marked hyperkeratosis, acanthosis, parakeratosis, and papillomatosis. Koilocytes, vertical columns of parakeratosis, and foci of clumped keratohyaline granules distinguish warts from other papillomas.
Condyloma acuminatum: Epidermal disruption with hyperkeratosis, coarse keratohyaline granules, and koilocytes in a prominent granular layer. Flat condylomata exhibit acanthosis in the epidermis or mucosa.
Bowenoid papulosis: Psoriasiform hyperplasia and hyperkeratosis of the epidermis, increased mitotic figures at all epidermal levels, and keratinocytes with enlarged pleomorphic and hyperchromic nuclei.
See Workup for more detail.
Management
All medications used to treat HPV disease are applied topically and should not be applied to mucosal surfaces. They are not suitable for treating dysplastic lesions, squamous cell carcinoma, verrucous carcinoma, or Bowenoid papulosis. Medications fall into the following two broad categories:
Immune response modifiers: Examples include imiquimod and interferon alfa. These primarily are used for treating external anogenital warts or condylomata acuminata.
Cytotoxic agents: These include antiproliferative drugs such as podofilox, podophyllin, and 5-fluorouracil (5-FU), as well as chemodestructive or keratolytic agents like salicylic acid, trichloroacetic acid (TCA), and bichloracetic acid (BCA). The latter are recommended for treating nongenital cutaneous warts.
Sinecatechins ointment is another treatment option.
Surgical interventions commonly are considered for cases with a large number of warts, extensive affected areas, or refractory disease. Physical destruction or excision generally has proven more effective than medical therapy. Primary surgical options include the following:
Cryosurgery
Electrosurgery (electrodesiccation or loop electrosurgical excision procedure [LEEP])
Simple surgical excision using a scalpel, scissors, or curette
Alternative surgical procedures include the following:
Carbon dioxide laser ablation
Cavitron Ultrasonic Surgical Aspiration (CUSA)
Mohs surgery
Vaccines are available for preventing HPV infection, with recommended vaccination schedules established.
HPV produces epithelial tumors of the skin and mucous membranes. There are over 100 known HPV types, with genomes of more than 80 fully sequenced. Individuals with multiple sexual partners or persistent HPV infections are at higher risk of acquiring additional HPV strains.[3, 4, 5, 6] The current classification system, based on genomic similarities, generally corresponds to three clinical categories of HPV:
Anogenital or mucosal
Nongenital cutaneous
Epidermodysplasia verruciformis (EV)
Mucosal HPV infections are classified as latent (asymptomatic), subclinical, or clinical. Clinical lesions are visibly apparent, whereas latent infections are detectable only through viral DNA tests. Subclinical lesions are identified using 3-5% acetic acid and magnification. Most HPV infections are latent; clinically visible infections typically manifest as warts rather than malignancies.[1]
HPV infections are common and result in various clinical manifestations on epidermal surfaces. Condylomata acuminata (genital warts) are benign proliferations of anogenital skin and mucosa caused by HPV infection. They are transmitted through sexual contact, with approximately two thirds of exposed individuals developing genital warts. The incubation period is estimated to be between 3 weeks and 8 months.[7, 8]
Although generally benign, certain HPV types can significantly increase the risk for anogenital cancer.[9, 10, 11] Some types also are associated with laryngeal, oral, and certain lung cancers.
HPV types 6 and 11 typically are classified as low-risk due to their low oncogenic potential, often causing condylomata and low-grade precancerous lesions. HPV types 16 and 18 are considered high-risk as they are responsible for most high-grade intraepithelial lesions that may progress to carcinomas, particularly in anogenital or mucosal regions.
HPV infection alone does not lead to malignant transformation of infected tissue. Co-factors such as tobacco use, ultraviolet radiation, pregnancy, folate deficiency, and immune suppression are implicated in this process.[1]
Physicians' understanding of HPV's natural history has significantly advanced in the last 2 decades, yet key questions remain unanswered. Areas needing further research include age-specific HPV outcomes, the likelihood of disease progression or regression, and factors.[12]
Papillomaviruses are nonenveloped viruses with icosahedral symmetry, characterized by 72 capsomeres that enclose a genome of double-stranded circular DNA, approximately 8000 base pairs long. Their genome is divided into the following three major functional regions:
Early (E) region: Codes for six nonstructural genes, several of which are associated with cellular transformation.
Late (L) region: Codes for two structural proteins, L1 and L2, that form the capsid.
Long control region: A noncoding region that regulates replication and gene function.
Papillomaviruses are highly species-specific and do not infect other species, even under laboratory conditions. Humans are the only known reservoir for HPV. Papillomaviruses have never been cultured in vitro but have been characterized through molecular methods. These viruses are classified based on the molecular similarity of their genetic material and are assigned genotype numbers.
Although some overlap exists, most papillomaviruses have distinct anatomic preferences, infecting specific epidermal sites such as the skin or genital mucosa. The virus can integrate into host DNA, often resulting in the loss of early regulatory functions.
HPV infects basal keratinocytes of the epidermis, typically through disruptions of the skin or mucosal surface. In this location, the virus remains latent as a circular episome in low copy numbers. Autoinoculation of the virus into adjacent lesions is common. HPV infection spreads through skin-associated contact rather than blood-borne transmission. Cell-mediated immunity (CMI) plays a significant role in wart regression; patients with CMI deficiency are particularly susceptible to HPV infection and are notoriously difficult to treat.[13]
Papillomaviruses are thought to have two modes of replication:
Stable replication: The episomal genome replicates in basal cells.
Runaway (vegetative) replication: In more differentiated cells, generating progeny virus.
As epidermal cells differentiate and migrate to the surface, the virus undergoes replication and maturation. At the keratinized layer, the virus is present in high copy numbers and is shed with exfoliated cells. This replication process alters the character of the epidermis, resulting in cutaneous or mucosal excrescences known as warts.
Note the figures below detailing the mechanisms of action for HPV.
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The left panel is transudation of serum antibodies to the site of human papillomavirus infection, and the right panel is exudation of serum antibodies....
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The figure shows proposed mechanisms used by the human papillomavirus vaccine to neutralize antibodies and protect against infection.
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Figure showing how human papillomavirus penetrates the basal layer and eventually is released at the surface.
While all cells within a lesion contain the viral genome, the expression of viral genes is tightly linked to the cellular differentiation state. Most viral genes remain inactive until infected keratinocytes migrate out of the basal layer. Virus particles are only produced in highly differentiated keratinocytes, typically at the epithelial surface where these cells eventually shed into the environment.
HPV infections are non-cytolytic; instead, viral particles are released when desquamating cells degenerate. HPV can survive for months at low temperatures without a host, enabling transmission through barefoot contact in individuals with plantar warts.
Viral replication occurs exclusively within the nucleus, resulting in marked nuclear atypia in infected cells. Koilocytosis, characterized by perinuclear clearing (halo), a pyknotic nucleus, and a raisinoid appearance, is a hallmark of productive papillomavirus infection.
Several viral genotypes can induce cell transformation and are linked to epidermal malignancies. In benign or low-risk HPV lesions associated with types 6 and 11, the viral genome exists as circular episomal DNA separate from the host cell nucleus. In malignant lesions, high-risk types like HPV 16 and 18 typically integrate their genome into the host cell DNA, a key event in malignant transformation.
HPV proteins E6 and E7 from high-risk serotypes have been shown to deactivate host tumor suppressor proteins p53 and Rb, leading to unregulated host cell proliferation and malignant transformation.
The definitive cause of anogenital warts is HPV infection.[9, 10, 11, 14] The HPV capsid lacks an envelope, which makes the organism very stable and resistant to various treatments. No serologic typing is available, because of the lack of consistent in vitro culture methods. Typing of HPV is based on genotype, which generally is determined by molecular hybridization using molecularly cloned HPV DNA of known type as the standard. Two HPV are of different types when their DNA hybridize (bind) less than 50% as efficiently to each other as to themselves.
The nearly 40 types of HPV that have been found in genital warts[15] are highly host-specific. These viruses do not infect laboratory animals and are not susceptible to acyclovir. In addition, HPV types demonstrate a high degree of site specificity, with some types only found on certain parts of the skin or mucous membranes. As a rule, HPV types causing common warts of the skin do not infect moist epithelium, and vice versa.
Multiple clinical associations with unique genotypes of HPV have been documented. Some of these associations are listed in the table below.
Table 1. Diseases Associated With Specific HPV Types
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See Table
Risk Factors
HPV infection alone does not directly cause malignant transformation of infected tissue. However, cofactors such as tobacco use, ultraviolet radiation, pregnancy, folate deficiency, and immune suppression have been implicated in this process, particularly in the anogenital-mucosal category. Patients receiving immunosuppressive drugs and those with defects in cell-mediated immunity, including those infected with HIV, are especially susceptible to HPV infections.[1]
Sexual Activity:
There is a direct correlation 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 high-grade squamous intraepithelial lesions (HGSIL) of the cervix 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 (relative risks of 5.6 and 4, respectively).
Anal cancer has been strongly associated with male homosexuality and specific male practices, such as engaging in receptive anal intercourse; the 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.
Tobacco Smoking:
Women who smoke tobacco have an increased risk of developing cervical neoplasia. Measurable amounts of potent carcinogens, as well as several compounds from cigarette smoke, have been identified in the cervical mucus of females who smoke. These agents likely contribute to the increased prevalence of HPV malignant transformation observed in tobacco users.
Oral Contraceptive Use:
Women who take oral contraceptives for longer than 5 years have an increased relative risk of developing cervical carcinoma. This risk declines after discontinuation of oral contraceptive use, and no increased risk is demonstrated in women who took these agents for less than 5 years.
Chewing Indian Betel Quid:
A high incidence of oral cancer associated with HPV infection has been demonstrated in India among patients who chew betel quid. This stimulant, made from the leaves of the betel plant, is used similarly to chewing tobacco.
Ultraviolet and x-ray irradiation
Epidermodysplasia verruciformis (EV) is particularly susceptible to ultraviolet (UV) and x-ray irradiation; therefore, patients with EV should avoid activities that unnecessarily expose them to these forms of radiation.
Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States. Each year, approximately 33,700 cancers in the United States are caused by HPV. These include 12,900 oropharyngeal cancers among men and women, 10,800 cervical cancers among women, and 6,000 anal cancers among men and women. Vaginal, vulvar, and penile cancers are less common.[19] The United States does not have a reporting system for HPV infections. HPV infections and the development of warts are common throughout life. Generally, genital HPV infection is considered to have become significantly more frequent over the past several decades.
Lewis et al reported the estimated prevalence and incidence of disease-associated HPV types among 15–59-year-olds in the United States.[20] In the 15–59 year age group, the prevalence of any HPV infection from 2013 to 2016 was 40.0% overall, 41.8% among males, and 38.4% among females, totaling 77.3 million individuals overall, with 40.5 million males and 37.0 million females having a prevalent HPV infection in 2018. The prevalence of disease-associated HPV infection was 22.0% overall, 24.2% in males, and 19.9% in females, amounting to 42.5 million individuals, with 23.4 million males and 19.2 million females having an infection of at least one disease-associated HPV type in 2018.
In the United States, young adults aged 15-24 years account for approximately half of new HPV infections each year.[21] The frequency of genital infections is associated with the number of sexual partners and the age of sexual debut. Patients receiving immunosuppressive drugs and those with defects in cell-mediated immunity, including those infected with HIV, are especially susceptible to developing HPV infections.
Using data and self-collected cervicovaginal specimens from 4,150 females in four consecutive National Health and Nutrition Examination Surveys (2003-2006), Hariri et al found HPV present in 42.5% of US females aged 14-59 years. The highest rate of infection was among young females aged 20-24 years.[22]
The population-based incidence of genital warts was estimated at 106 cases per 100,000 population in Rochester, Minnesota (1975-1978)[10] and at 160 cases per 100,000 population in Manitoba, Canada (1992),[23] with the highest incidence rate among residents aged 20-24 years.
Figures from five Blue Cross/Blue Shield Health Plans projected an incidence of 105 cases per 100,000 population (2004).[24] They estimated 340,000 cases nationwide in 2004, with an economic burden of more than $220 million.[24]
These figures differed from those indicated by data collected from STD clinics and private practitioners’ offices. Using data from these sources, the US Centers for Disease Control and Prevention (CDC) suggested much higher figures: an estimated incidence of more than 6 million new patients a year in the United States (2008) and an estimated prevalence of more than 20 million.[25, 26, 27, 28, 29] By comparison, the CDC estimated that 1.6 million people have genital herpes and 1.6 million have chlamydia or gonorrhea.
According to the “National Disease and Therapeutic Index: United States, 1966–2010,” the initial visits to physicians’ offices for STDs peaked at 351,000 visits in 1987, decreased over the following 10 years, then increased again, reaching 422,000 visits in 2006 before dropping to 357,000 in 2010.
Condylomata acuminata are clinically apparent in 1% of the sexually active population. Molecular studies indicate that 10-20% of men and women aged 15-49 years have been exposed to HPV. The prevalence of HPV is higher in certain populations, with a prevalence of 4-13% reported by STD clinics.
Several investigators report an increased prevalence of anogenital HPV infections during pregnancy. The prevalence of condyloma increases from the first to third trimester and then decreases significantly postpartum. The risk for condyloma acuminatum in pregnancy is twofold. Vulvar condylomata rarely can become large enough to obstruct labor. Cesarean delivery decreases, but does not completely prevent, HPV transmission, with the development of laryngeal papillomas in the infant.[30, 31, 32, 33]
HPV infection causes virtually all cases of cervical cancer.[34, 35] In cervical neoplasias, the HPV genome can be detected in more than 95% of tumors. No deaths due to cervical cancer have been documented in women younger than 20 years. The United States National Cancer Institute publishes data on the prevalence of worldwide cervical cancer via their online database.
The incidence of cervical cancer has decreased dramatically during the last century due to the implementation of the Papanicolaou test (Pap Test or Pap smear), beginning in the 1930s and 1940s. However, between 1990 and 2001, the annual number of estimated new invasive cervical cancers remained relatively constant (13,500 and 12,900, respectively). In the United States, 2.5 million women are estimated to have an annual cytologic diagnosis of a low-grade cervical cancer precursor.
The percentages of other cancers caused by oncogenic HPV are as follows[35] :
Anal cancer: 90%
Vulvar cancer: 40%
Vaginal cancer: 40%
Oropharyngeal cancer: 12%
Oral cancer: 3%
International Statistics
Globally, HPV infection is the most common STD.[36, 37] Genital warts have affected as many as 30 million individuals worldwide. A study in Finland in the mid-1980s found that the annual incidence of cytologic cervical HPV infection was 7%.[38] A study of Finnish males determined that 6.5% had evidence of HPV in exfoliative cells obtained from the urethra and genital epithelium.[39]
In many less-developed countries, cervical cancer is the most common cancer among women due to the lack of effective screening programs that monitor cervical cytology by Pap smear.[40] 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.[41]
The prevalence of high-risk HPV in women with normal cervical cytology varies among different regions of the world. Although the global HPV prevalence is estimated to be approximately 12%, higher prevalences are noted in sub-Saharan Africa (24%), eastern Europe (21.4%), and Latin America (16.1%).[42]
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. The World Health Organization (WHO) estimates that 570,000 new cases of cervical cancer occurred globally in 2018, and approximately 311,000 women died of cervical cancer during the same year.[43]
Age-related Demographics
People of any age may develop common warts. HPV infects more than 50% of sexually active adults. Genital infection generally occurs during the sexually active period in a person’s life, and infections increase with the number of sexual partners.
The prevalence of anogenital mucosal HPV infections is highest among college-aged women and men. The prevalence of HPV infection stratified by age in US females is as follows[44] :
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%
Thus, the highest rates of genital HPV infection are in young, sexually active females. This incidence is independent of the number of lifetime sexual partners. Most of these infections (90%) are transient.[45, 46, 47] An estimated 5.6% of sexually active adults in the United States aged 18-59 years have been diagnosed with genital warts by a medical provider.[48]
A cytologic screening of the cervix in more than 400,000 women supported a higher incidence of HPV in young women. This study found that the rate of HPV infection in women younger than 30 years is double that in women older than 30 years.[49]
The reason for the higher prevalence in younger women is not completely understood. Some investigators hypothesize that older women have fewer sexual partners and, consequently, less exposure to HPV. An alternative theory is that by age 30 years, women have acquired immunity to HPV.[50]
The presence of genital condyloma in the pediatric population presents a diagnostic and therapeutic challenge.[51] Vertical transmission of HPV can occur via in utero exposure to amniotic fluid or transmission of HPV from the maternal genital tract.
An incubation period of several months usually is required between virus infection at delivery and clinical manifestations in the infant. The average latency period is 3 months, but periods as long as 20 months have been reported.[52] Cases of childhood condylomata outside a reasonable incubation period after vertical transmission should arouse suspicion of child abuse. Treatment of condyloma in the infant includes excision under general anesthesia or the use of podophyllin.[53]
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.
Epidermodysplasia verruciformis (EV) develops at an average age of onset of 6 years. Beginning in the fourth decade of life, the lesions can undergo malignant transformation into invasive squamous cell carcinoma (SCC).
Sex-related Demographics
HPV prevalence:
Women: 22-35%
Men: 2-35% (varies with sexual practices)
Female-to-male ratio: 1.4:1 according to a well-defined population study[10]
CDC Reports: Indicate higher prevalence in females compared with males
Condyloma acuminatum (genital warts):
Prevalence in STD Clinic Study[25] was as follows:
Men: 13%
Women: 9%
HPV infections in US college students: More frequently reported in females than males[54]
Detection bias: Higher incidence in females that may be due to cervical cancer screenings detecting HPV through cytologic smears
Medical care seeking: Females more frequently seek medical care for genital warts compared to males
Race-related demographics
HPV infection rates
African Americans vs Whites: African Americans have a 1.5 times higher rate of HPV infection than Whites.
Genital warts prevalence: Higher in non-Hispanic Whites compared to other racial or ethnic groups[48]
HPV infection by race among women[44]
Non-Hispanic Blacks: 39%
Non-Hispanic Whites and Mexican Americans: 24%
Cervical cancer death rate (1987-1991)
Black women vs White women: Age-adjusted death rate ratio of 6:1, higher in Black women according to the US National Cancer Institute[44]
HPV infection primarily involves the basal epithelial cells, leading to common recurrences and regressions. The prognosis generally is good, and most cases of genital warts are treatable. However, patients who do not develop immunity to HPV may face potentially serious sequelae.
Genital warts can spontaneously regress, remain unchanged, or increase in size. Treating these lesions does not impact the development of cervical cancer. Approximately two-thirds of patients with nongenital cutaneous warts experience spontaneous regression within 2 years, although new warts may appear.
HPV infection of the vulva can result in vulvar intraepithelial neoplasia (dysplasia) or squamous cell carcinoma of the vulva. Most research indicates a strong association between HPV infection and the development of cervical dysplasia and cervical carcinoma. HPV accounts for more than 99% of the attributable risk for cervical dysplasia.[55] Vaginal dysplasia and vaginal cancer also are linked to HPV exposure.
Histologic evidence of HPV infection on a cervical Pap smear resembles mild dysplasia. This subclinical disease often regresses spontaneously.
There is a direct correlation 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 high-grade squamous intraepithelial lesion (HGSIL) of the cervix or invasive squamous cell carcinoma (SCC) of the cervix are at increased risk of developing invasive cancer in other anogenital mucosal tissues, particularly vaginal and anal carcinoma. In these patients, the relative risk for vaginal carcinoma is 5.6, and the risk of anal carcinoma is 4.
Women who are immunocompromised due to immunosuppressive drug therapy or HIV infection are at higher risk for persistent HPV disease. These women are more likely to develop dysplasia or cancer of the vulva, vagina, or cervix.
Anal cancer is strongly associated with male homosexuality and specific male practices, such as engaging in receptive anal intercourse. The 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 infected with HPV are at risk for genital warts. The 24-month risk varies from 57.9% in men infected with HPV type 6 or type 11 to 2% in men infected with other HPV types.[56]
Immunosuppressed patients, 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. About 10% of patients with EV originate from consanguineous marriages, suggesting an autosomal recessive mode of inheritance (see Epidermodysplasia Verruciformis).
Most patients with EV experience disease progression in the third or fourth decades of life. Malignant transformation usually arises from actinic keratoses, especially in patients exposed to irradiation. Patients who avoid x-rays and sun exposure generally maintain satisfactory health.
As many as 20% of patients with genital warts have other sexually transmitted diseases concurrently.[24] In an Australian sexual health clinic, 5% of patients with genital warts also were found to have chlamydia and/or gonorrhea.[57]
Treating genital warts can be challenging and prolonged. Set patient expectations accordingly, counseling them on the risk of infecting others and their increased risk of having acquired other STDs. In about 60% of cases, genital warts resolve spontaneously.[1]
Educating women, particularly those who are socially and economically disadvantaged, about behaviors that reduce sexual risk has proven benefits in decreasing the incidence of STDs. Reducing STD incidence potentially could decrease HPV transmission and, consequently, cervical carcinoma incidence.
Inform patients that genital HPV is an STD, and the only way to prevent infection is to avoid direct contact with the virus, which is transmitted through skin-to-skin contact. Advise them to use condoms during vaginal, anal, or oral sex, as the virus may be present in semen even without visible warts. Emphasize that latex condoms offer some, but not complete, protection from transmission.
Evaluating the sexual partners of patients with genital warts is beneficial. Studies have documented that 30% of female partners and 80% of male partners have HPV infection, often with the same type of HPV, typically types 6, 11, 16, and 18. If a sexual partner has visible genital warts, sexual contact should be avoided until treatment is completed.
The clinical history and presentation of human papillomavirus (HPV) infection vary according to the anatomic area involved. The predilection of certain virus genotypes to infect specific epidermal sites largely determines the areas of involvement.
Genital infection: Genital infection manifests as warty lesions on the genital or anal area, although these warts often are not initially recognized. Cervical infection generally goes unnoticed and is discovered during cervical examination or Papanicolaou (Pap) testing.
Anogenital warts: Condylomata acuminata are exophytic, cauliflower-like lesions typically found near moist surfaces such as the perianal area, vaginal introitus, vagina, labia, and vulva. They also may appear on dry surfaces, such as the shaft of the penis.
Genital warts include smooth papular warts and keratotic warts, the latter resembling nongenital cutaneous warts due to their thickened, bumpy surface. Flat condylomata (squamous intraepithelial neoplasia) are the most common lesions of the cervix but also may develop on the vulva, anus, and male genitalia, appearing as white, plaque-like growths.
An additional malignant variant is the giant condyloma, or Buschke-Löwenstein tumor, generally regarded as a verrucous carcinoma. These most often involve the glans penis, perianal area, and foreskin. In addition to their large cauliflower shape, they tend to form abscesses and fistulas and invade locally.
Genital warts generally do not become clinically apparent until several months after inoculation with HPV. They follow a slow and indolent course and may develop by inoculation from opposing surfaces. Condylomata acuminata often are asymptomatic but can be associated with pruritus. Bleeding may occur if the lesions become confluent and are irritated by clothing. Most patients seek medical care when they notice lumps on the vulva, perianal area, or periclitoral area, or experience pruritus or occasional bleeding.
Cervical disease: Most cervical infections either are latent or subclinical and therefore asymptomatic. These infections are detected on Pap smear and 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 HPV-triggered dysplasia.
Patients who have neglected annual Pap testing for several years or more and have an HGSIL that has progressed to invasive cervical cancer may report vaginal bleeding between periods or after sexual intercourse, dyspareunia, and fullness in the pelvis.
Anal cancer: The most common presenting symptoms of squamous cell carcinoma (SCC) of the anus are rectal bleeding and the sensation of a mass. These symptoms may be mistakenly attributed 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: Oral warts represent infection of the oral mucosa. Although they are subtle and easily missed, they are fairly common. HPV types 6 and 11 have been isolated from 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 probably are 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 most frequently present with hoarseness at an average age of 3 years.
Focal epithelial hyperplasia (Heck disease) is a disseminated HPV infection of the oral mucosa most commonly associated with HPV 32 and HPV 13. This condition may have a family predilection.
Nongenital cutaneous HPV: Common cutaneous warts (verruca vulgaris) generally appear on keratinized skin, presumably at the site of inoculation. Autoinoculation from a wart on one finger may cause warts on an adjacent finger or other skin surface (so-called kissing warts).
Common cutaneous warts appear as circumscribed, rough, hyperkeratotic papulonodules or plaques with irregular scaly surfaces and develop most often on the hands, fingers, feet, and knees. Such warts frequently are discovered when the patient notices changes in the skin. In general, they are asymptomatic, but they may be painful with the application of pressure. Typically, they are benign and self-limited.
Palmoplantar warts appear on the acral surfaces of the feet and hands. They are notable for their thickness, which complicates treatment. Deep plantar warts occur most commonly as solitary lesions that may become black and painful before spontaneously regressing. They may contain small black “seeds,” which are thrombosed capillaries.
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Plantar warts.
Warts that occur in people who handle meat and fish often have large cauliflowerlike plaques.
Flat warts (verruca plana) most often occur in groups of small plaques less than 5 mm in diameter on the face and hands. They often are not obvious but may induce significant disturbances of pigmentation. Regression usually occurs spontaneously after several years, and pruritus or erythema occurs several weeks before their disappearance.
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Flat wart.
Lloyd described Bowenoid papulosis as multicentric pigmented Bowen disease of the groin. It manifests as multiple, warty, red-brown papules in the anogenital region. These papules may coalesce.
Malignant conversion of skin lesions
Malignant conversion of skin lesions typically begins in the fourth and fifth decades of life. Premalignant lesions usually arise first on the forehead and other sun-exposed areas. The tumors may be benign papillomas and seborrheic keratoses or premalignant actinic keratoses and squamous cell carcinoma (SCC).
Epidermodysplasia verruciformis
Epidermodysplasia verruciformis (EV) is an autosomal recessive familial trait that increases susceptibility to a subset of warts generally not observed in populations without EV. HPV genotypes associated with EV have been observed in patients who are immunosuppressed due to organ transplantation or HIV infection. These individuals are at increased risk for skin cancer if not recognized and treated.
EV generally begins in childhood and can affect almost any area of the body. The warts generally are subtle and flat and initially may be mistaken for tinea versicolor. EV tumors are locally destructive, 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.
The physical examination findings depend on the tissues involved and include various cutaneous lesions with characteristic appearances (see History).
Typical condylomata are discrete, papillary, cauliflower-like lesions that appear at multiple sites on moist surfaces. Keratotic warts often are observed on dry surfaces such as the labia majora. Warts vary in size and can develop into large, exophytic, cauliflower-like masses (see the images below). Discrete papules ranging from 1-3 mm in size can be present on the shaft of the penis. Growth can extend into the vagina, urethra, cervix, perirectal epithelium, anus, and rectum. Cervical intraepithelial lesions also may be identified upon examination of the cervix.
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Human papillomavirus (HPV). Condyloma acuminatum in a patient with a history of an allograft renal transplant.
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Human papillomavirus (HPV). Note the extensive labial involvement.
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Human papillomavirus (HPV). Anal condyloma acuminatum.
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Human papillomavirus (HPV). These condylomata extend to the anal verge.
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"Cauliflower" condyloma of penis.
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Small papilloma on shaft of penis.
Subclinical infection is another common presentation of condyloma. Tiny, slightly raised areas can be felt or visualized on the vagina or cervix. These flat warts are best visualized by using 3-5% acetic acid and a colposcope. Areas infected with HPV appear acetowhite (ie, white when “painted” with the acetic acid). Often, a biopsy is needed to distinguish these lesions from cervical squamous intraepithelial lesions or vaginal intraepithelial lesions.
The sexual partner or partners of a woman with condylomata should be examined by a physician and treated if indicated. Often, the examination of the male fails to reveal any visible condylomata.
Some consider most common warts primarily to be a cosmetic concern and cause few problems unless their location induces mechanical issues. However, discovering genital condyloma can provoke anxiety, guilt, and distress in some patients.
Plantar warts can disrupt ambulation due to their location. Laryngeal papillomas may interfere with breathing or speaking. Genital warts occasionally lead to issues such as urethral obstruction. Condylomata acuminata can grow extremely large, resulting in tissue breakdown or secondary infection. In the context of immune deficiency, such as HIV infection, HPV-induced wart growth can be exacerbated, significantly worsening associated anatomical problems (see the image below).
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Verrucous warts in patient with HIV infection.
However, complications of the disease can include progression to malignancy and transmission to other sexual contacts. In cases where genital warts are active during pregnancy and delivery, there is a small risk for laryngeal papillomatosis. Although the majority of genital HPV infections resolve spontaneously, persistent infection can lead to neoplastic changes. Cervical cancer ranks as the second most common cause of morbidity and death in women in the United States. Malignancies such as Bowen's disease also may result in morbidity and mortality.
Patients who develop condylomata acuminata typically are exposed to low-risk HPV types such as HPV-6 and HPV-11. These HPV infections are associated with mild dysplasia that often resolves spontaneously. Many patients with mild dysplasia of the vulva, vagina, or cervix experience regression of these lesions without intervention. In contrast, patients exposed to high-risk HPV types, such as HPV-16 or HPV-18, usually do not develop condylomata. Instead, they are at risk for high-grade dysplasia or anogenital carcinoma.
The diagnosis of most cutaneous and external genital warts can be established through clinical examination or with the application of acetic acid followed by biopsy if needed. For genital intraepithelial neoplasia, assessing the extent of disease is crucial, typically involving thorough inspection and colposcopy.
Detection of human papillomavirus (HPV) DNA is FDA-approved and serves as a valuable screening tool in women over 30 years old. Genotype identification primarily is conducted in research laboratories using DNA hybridization techniques[56] such as Southern blot, dot blot, and in situ hybridization. Other methods include enzyme-linked immunosorbent assay (ELISA) for HPV 16 capsid immunoglobulin G (IgG) antibodies.
Patients diagnosed with condylomata acuminata may not require additional laboratory studies routinely but are at increased risk for other sexually transmitted diseases (STDs). Depending on clinical findings, testing for chlamydia, gonorrhea, syphilis, hepatitis B, hepatitis C, herpes, and HIV may be indicated. Additionally, these patients should undergo Pap testing of the cervix as per American College of Obstetricians and Gynecologists guidelines.
Imaging studies generally play a limited role in diagnosing HPV infections. However, computed tomography (CT) or magnetic resonance imaging (MRI) can assess the spread of cervical carcinoma and extensive anogenital papillomatosis into the pelvic region.
Histologic examination of vulvar lesions to detect vulvar condyloma can be challenging. Non-HPV conditions like vestibular papillomatosis and inflammatory squamous metaplasia may mimic condylomata under light microscopy. When the histologic diagnosis is inconclusive, HPV testing can provide useful adjunctive information.
Guidelines from 2015 on HPV screening and management, endorsed by the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology, recommend primary high-risk HPV screening as an alternative to traditional cytology-based methods for cervical cancer screening.[58, 59] Triage strategies for high-risk HPV-positive women include genotyping for HPV 16 and 18, with reflex cytology for other high-risk HPV genotypes. Rescreening after a negative primary high-risk HPV screen is recommended no sooner than every 3 years, with initiation of primary HPV screening not recommended before age 25 years. Further research is needed to evaluate the impact of HPV screening in younger age groups on cancer prevention and management.
Cervical cytologic testing with the Pap test is the standard screening procedure for cervical neoplasia. Current guidelines recommend initiating the Pap test at age 21 years and then repeating it every 3 years until age 30. For women aged 30 years and older, screening intervals can be extended to every 5 years with Pap test and HPV co-testing, or continued every 3 years with Pap test alone. Pap test screening can be discontinued after age 65 if there have been no abnormal results in the previous 20 years.[2, 60]
Although cervical metaplasia is common among sexually active adolescents, most HPV infections clear within 1-2 years due to immune system response. Invasive cervical cancer is rare in adolescents, and most cases of cervical dysplasia resolve spontaneously. Although some studies initially suggested an increased risk for preterm birth following excisional procedures for cervical dysplasia, a 2012 study by Kalliala et al. found no significant increase in this risk.[61] Given that adolescents have many childbearing years ahead, delaying cervical cancer screening may be considered a cautious approach in this age group.
Pap smears should collect cells from the ectocervix, transformation zone, and endocervical canal. It is advisable to perform the test when the patient is not menstruating to avoid blood contamination of the cytologic specimen. If the patient has cervicovaginal infection with mucopurulent vaginal discharge, consider deferring the test until after resolution. If immediate testing is necessary, gently clear the discharge with a saline-moistened cotton swab.
As needed, modify the Pap smear to sample suspicious tissues from the vagina, vulva, or perianal region for intraepithelial neoplasia assessment (see Cervical Cancer). Although not routine, consider annual anal Pap smears for men at high risk who engage in receptive anal intercourse.
Liquid-based Pap smears enhance the diagnostic sensitivity of cervical cytology screening and facilitate HPV testing. Methods such as Thin Prep and SurePath are FDA-approved options.
The US Centers for Disease Control and Prevention (CDC) has established Clinical Laboratory Improvement Amendments (CLIA) standards for proficiency testing in cytology to ensure accurate interpretation of Pap smears. Laboratories in the United States must adhere to these guidelines to maintain certification for Pap smear assessment and other laboratory testing. Detailed information on these standards is available on the CDC website under the CLIA section for Gynecologic Cytology Standards.
The two primary methods for HPV DNA testing are the Hybrid Capture II (HC II) and the polymerase chain reaction (PCR) enzyme immunoassay. Both methods exhibit high sensitivity and are valuable tools for detecting HPV infections and for monitoring post-treatment outcomes in cervical intraepithelial neoplasia (CIN).
HPV DNA testing is recommended for managing women with Pap test results showing atypical squamous cells of undetermined significance (ASC-US), especially when liquid-based cytology or co-collection is utilized. It also is instrumental in guiding the management of CIN under specific circumstances. Detailed consensus guidelines for the management of abnormal Pap test results and CIN are available from the American Society for Colposcopic and Cervical Pathology.[60]
A large-scale trial comparing over 12,000 women who self-collected vaginal HPV specimens with a similar number who underwent cervical cytology screening demonstrated that self-collected HPV testing had a positive predictive value of 12%. Importantly, it was 3.4 times more sensitive in detecting CIN II and identified 4.2 times more invasive cervical cancers compared to cervical cytology alone.[62] These findings suggest that self-collected vaginal HPV testing could serve as a viable surveillance option, particularly in settings where resources for cytology screening are limited.
Recent advancements in HPV testing include newer technologies such as DNA chip, Linear Array, and cycle sequencing methods.[63]
The US Food and Drug Administration (FDA) has expanded the indication for the cobas HPV Test, making it the first test approved for primary cervical cancer screening in women aged 25 years or older, either alone or in conjunction with a Pap test. This test detects DNA from 14 high-risk HPV types in cervical cell samples. A positive result for HPV types 16 or 18 indicates the need for colposcopy, whereas a positive result for any of the other 12 high-risk types prompts further evaluation with a Pap test to determine the necessity of colposcopy.[64] Initially approved in 2011 for use alongside a Pap test, the cobas HPV Test has demonstrated efficacy when used as a standalone screening tool in a study involving over 40,000 women aged 25 years or older.
These developments underscore the evolving role of HPV DNA testing in cervical cancer screening and surveillance, offering improved sensitivity and potential for earlier detection and intervention.
The acetic acid test is useful in diagnosing genital warts, enhancing suspicion for lesions lacking classic features. This method involves applying a 3-5% acetic acid–moistened gauze pad to suspected lesions on the penis, cervix, labia, or perianal area for 5-10 minutes. It makes inconspicuous flat genital lesions more visible, with dysplastic and neoplastic tissues turning white (acetowhite). False positives can occur due to conditions causing parakeratosis (eg, candidiasis, psoriasis, lichen planus, healing epithelium, sebaceous glands).
While the acetic acid test can aid colposcopy in examining cervical lesions, it is reserved for suspicious cases and not for routine screening.
In general, tissue biopsy is a useful tool to confirm HPV infection, especially when the diagnosis is uncertain or when warts appear abnormally pigmented, ulcerated, or indurated.
Patients who present with classic condylomata acuminata that do not respond to initial therapy should undergo biopsy of at least one lesion. This helps to ensure appropriate treatment and avoid unnecessary therapies for lesions not related to HPV.
Postmenopausal women with lesions resembling condylomata acuminata should undergo biopsy before starting treatment. This population has a higher risk of vulvar dysplasia or vulvar cancer compared to younger women.
Typically, patients with typical-appearing condylomata acuminata do not require a vulvar biopsy. However, biopsy is recommended in the following situations:
Women with a history of vulvar dysplasia
Postmenopausal women
Women who do not respond to medical therapy
When there is clinical uncertainty about the diagnosis
During the biopsy procedure, the base of the lesion is injected with 1% lidocaine for anesthesia. An alligator-mouth biopsy forceps is then used to obtain the tissue specimen. Silver nitrate is generally applied to the biopsy site to control bleeding, although in rare cases, sutures may be needed for hemostasis.
Histopathology plays a crucial role in diagnosing HPV-related lesions. Verrucae, for instance, exhibit acanthotic epidermis with papillomatosis, hyperkeratosis, and parakeratosis. Elongated rete ridges often point towards the wart's center, while thrombosed dermal capillary vessels may be present. Viral particles can sometimes be observed in nuclei using electron microscopy, and immunohistochemical staining with the peroxidase-antiperoxidase technique can highlight cells infected with viral particles.
HPV's multiplication is typically confined to the host cell nucleus, resulting in nuclear atypia in infected cells. Koilocytes, characterized by pyknotic nuclei surrounded by a halo and clear cytoplasm lacking keratohyaline granules, are hallmark signs of productive HPV infection. Other cytological markers include acanthosis, dyskeratosis, and multinucleation.
Common cutaneous warts histologically show pronounced hyperkeratosis, acanthosis, parakeratosis, and papillomatosis. Features distinguishing warts from other papillomas include the presence of koilocytes, vertical columns of parakeratosis, and clusters of keratohyaline granules.
Condyloma acuminatum typically displays epidermal disruption with hyperkeratosis, coarse keratohyaline granules, and prominent koilocytes in a granular layer. Flat condylomata exhibit acanthosis in the epidermis or mucosa.
Bowenoid papulosis histology reveals psoriasiform hyperplasia and epidermal hyperkeratosis. Mitotic figures are increased throughout all epidermal layers, and keratinocytes show enlarged, pleomorphic, and hyperchromic nuclei.
The goal of treatment is to remove warts and alleviate any present symptoms. The appearance of warts can cause significant psychosocial distress, and their removal can address cosmetic concerns. If untreated, anogenital warts may spontaneously resolve, remain unchanged, or increase in size or number. Since warts might resolve on their own in less than a year, some individuals may choose to wait for spontaneous resolution instead of undergoing treatment. Available therapies for anogenital warts may reduce, but are unlikely to completely eradicate HPV infectivity or risk of developing cancer.
The primary goal of treatment is to eradicate or reduce symptoms. Treatment is typically reserved for visible warts. The general strategy involves removing as many visible lesions as possible until the host immune system can manage viral replication. Treating subclinical anogenital or mucosal HPV infections in the absence of dysplasia is not recommended, as there is no evidence that treatment eliminates HPV infection or reduces infectivity. Recurrence of warts after treatment can occur due to activation of latent virus in surrounding healthy skin.
It is challenging to find a single curative treatment for condylomata acuminata (genital warts).[65] Although various therapies exist for genital warts, no single modality has demonstrated superiority, and no single treatment is ideal for all wart types.[66] Factors influencing treatment decisions include lesion size, morphology, number, location, cost, adverse effects, patient preferences, prior treatments, and provider experience.
Common treatments involve direct lesion ablation such as surgical excision, chemical ablation, and cryotherapy. Improper use of these treatments can lead to unnecessary tissue damage. Most patients require multiple treatments over weeks to months. If substantial improvement is not seen after three physician-administered treatments or complete clearance is not achieved after six treatments, a different approach should be considered. HIV-positive patients or those immunosuppressed may require multiple treatment methods, as their warts often do not respond well to therapy. Recurrence is noted in 20-30% of patients regardless of the chosen therapy, which can be frustrating for both patients and physicians alike.
Higher rates of HPV infection have been reported in pregnant women. Condylomas may grow rapidly due to suppressed immunity and hormonal changes during pregnancy.[49] Small asymptomatic lesions typically do not require treatment, but larger lesions can be managed with keratolytics or cryotherapy.[67] Surgical excision may be necessary for macerated, enlarged condylomas after the first trimester. Interferon, podophyllin, and 5-fluorouracil (5-FU) should not be used during pregnancy.
The risk for perinatal HPV transmission to a neonate's oropharyngeal mucosa is low in mothers with latent infections or genital warts, though the timing between amnion rupture and delivery may influence this risk.
Khayargoli et al conducted a prospective cohort study of 1050 pregnant women and their newborns[68] to investigate the rate of HPV presence in pregnant women, the likelihood of detecting HPV in the placenta and newborns at birth, and the chances of HPV detected at birth persisting in infants. Vaginal HPV commonly was found in pregnant women. Transmission during childbirth was rare, and in this group, none of the infections present at birth were still detectable at 6 months. While HPV was identified in placentas, distinguishing between contamination and actual infection remains challenging.
A study by Garland et al found no significant differences in live births, fetal loss, or spontaneous abortion rates between women who received the quadrivalent HPV vaccine before conception and those who received a placebo.[69] Among the pregnancies, 40 neonates born to vaccinated women and 30 born to placebo recipients had congenital anomalies, which were consistent with those seen in the general population, indicating that the vaccine does not increase fetal risk.[69] Ongoing surveillance continues to monitor for any associations with congenital anomalies.
Pathents at increased risk for anogenital malignancy
Patients with genital warts are at increased risk for anogenital malignancies. HPV infection is the primary cause of cervical cancer, though most HPV-infected cervixes have a benign outcome. Annual screening and Pap testing are essential for female patients with genital warts, as up to 90% of cervical cancers are caused by HPV. Epidemiologic evidence shows that 10% of patients with high-grade squamous intraepithelial lesions (HGSIL) will have persistent lesions that can progress to invasive cancer without treatment.
Patients with perianal warts, HIV-positive patients, and those with a history of receptive anal intercourse are at increased risk for anal HGSIL. While there's no direct evidence of progression to invasive anal cancer, HPV infections are associated with penile, vulvar, vaginal, anal carcinomas, and head and neck cancers.[70]
Children with anogenital warts
Anogenital warts are uncommon in the pediatric population. Over half of the cases result from viral inoculation at birth or incidental spread from cutaneous warts, often involving non-genital HPV types. Diagnosing genital warts in a child requires reporting suspected abuse for evaluation, which may confirm or rule out sexual abuse.[27]
Awasthi et al conducted a systematic review and meta-analysis of 10 studies in 672 children aged 12 years and younger to determine the association between anogenital warts and sexual abuse with regard to wart location, age, and gender.[71]
A considerable number of females (approximately 21%) and males (around 18%) were identified as having experienced abuse. The presence of overlapping HPV types was observed in both abused and non-abused individuals. Factors such as perianal location and gender were not significantly associated with abuse. However, age and the specific genital wart locations (penis, vulva) were significant predictors of child sexual abuse (CSA). The odds of experiencing sexual abuse were higher in children aged 3-4 years (odds ratio [OR], 7.45), 5-8 years (OR, 6.52), and 9-12 years (OR, 6.93) compared with those aged 0-2 years. In addition, genital wart location was associated with an odds ratio of 5.93 for CSA.
Neonates and infants with laryngeal papillomatosis
Pregnant women with genital warts can transmit the virus to newborns, with about 5% of all births in the United States at risk for neonatal HPV exposure. Infants may develop laryngeal papillomatosis within the first 5 years of life, with around 60% of mothers of affected infants reporting genital warts. The incidence of childhood laryngeal papillomatosis is very low, and cesarean delivery solely to prevent it is not justified unless a large condyloma obstructs labor or delivery.
Immunocompromised patients
Immunosuppressed patients, such as those with AIDS or on immunosuppressive therapy (eg, renal transplant patients), are more susceptible to persistent HPV infection, which can lead to dysplasia and malignancy.
Patients with verrucous carcinoma of genitalia
Verrucous carcinoma of the genitalia (giant condyloma of Buschke-Löwenstein) is a low-grade, locally invasive squamous cell carcinoma associated with HPV types 6 and 11. It should be considered for lesions larger than 1 cm in diameter, with radical surgical extirpation being the only appropriate treatment.
Both provider-applied treatments and patient-applied treatments are available for HPV disease. All medications used for treatment are applied topically on cutaneous surfaces. Local skin reactions and pain are common adverse effects. These medications should not be applied to mucosal surfaces, dysplastic lesions, squamous cell carcinoma (SCC), verrucous carcinoma, or Bowenoid papulosis.
There are two broad categories of medications effective in treating HPV disease:
Cytotoxic agents: These include podofilox, podophyllin, 5-fluorouracil (5-FU), trichloroacetic acid (TCA), and bichloracetic acid (BCA).
Immune response modifiers: These include imiquimod, sinecatechins and interferon alfa, primarily used for external anogenital warts (condylomata acuminata).
None of these medications have been uniformly effective or shown direct antiviral effects. Keratolytics are the only agents recommended for nongenital cutaneous warts.
Podofilox: Podofilox gel or solution is the first-line treatment choice for external genital warts in nonpregnant patients. It is applied twice daily for 3 consecutive days each week, repeated for up to 4 weeks, and stimulates necrosis of wart tissue. Podofilox is well-tolerated with minimal side effects, making it suitable for self-administration. No more than 0.5 g of gel per day should be used limiting the total wart tissue treated to 10 cm2 or less.
Podophyllin: Podophyllin resin, containing podophyllotoxin, is a cytotoxic agent used for physician-applied treatment of external genital warts. It can be applied weekly for up to 6 weeks, but warts visible after 6 treatments may not respond further.[72] Podophyllin must be applied sparingly to avoid toxicity and systemic absorption, with potential side effects including ulceration and neurologic toxicity. It is contraindicated in pregnancy.
5-Fluorouracil (5-FU): 5-FU interferes with DNA and RNA synthesis, causing cell death. Limited data on efficacy exist, with clearance rates reported in 10-50% of cases.[73] It is applied 1-3 times per week for several weeks, with potential side effects including pain and burning. Proper application to prevent pain and ulceration is crucial, as this therapy may not be well-tolerated.A meta-analysis of 6 trials involving 645 women concluded that topical treatment with 5-FU has a therapeutic effect; the data were unclear on the risks and benefits, and further studies were recommended.[74]
Keratolytics: TCA and BCA are potent keratolytic agents used for all types of cutaneous warts, while salicylic acid is milder and used primarily for nongenital warts.
TCA, in an 80-90% concentration is used for treating vulvar or vaginal condyloma in pregnant women. TCA should be applied to the condyloma after pretreatment of the surrounding normal skin with petroleum jelly. As the acid dries, a white frosting develops, which should be powdered with sodium bicarbonate to neutralize any unreacted acid.
Effective treatment usually requires weekly applications for 4-6 weeks. The principal side effect is pain and burning if the TCA comes in contact with normal skin. Although TCA is caustic, it causes less local irritation and systemic toxicity than other agents in the same class. However, the response is often incomplete and recurrence common.[75]
Imiquimod: Imiquimod stimulates cytokine production (including interferon alfa) but lacks direct antiviral activity. It is effective for external genital warts, with up to 50% clearance in clinical trials. wo formulations are available, Aldara (5 percent imiquimod) and Zyclara (3.75 percent imiquimod). Aldara is applied on three alternate days per week for up to 16 weeks.[76] Zyclara is applied daily for up to 8 weeks. It should be washed off after 8 hours.[77] Recurrence rates at 6 months range from 19-23%.[78] Common side effects include erythema, itching, and burning. Imiquimod is expensive and may not be covered by all health insurance plans.
Sinecatechins: Sinecatechins ointment, applied 3 times daily for up to 16 weeks, has demonstrated good clearance of external genital warts in clinical trials, with a recurrence rate as low as 5%.[79] Side effects include erythema, pruritus, and pain. It is less expensive than imiquimod.[80]
Interferon Alfa:
Interferon alfa is a naturally occurring cytokine produced either through recombinant DNA technology or from pooled human leukocytes. It has potent immunomodulatory and direct antiviral effects. Local injection of interferon appears to be more effective than systemic injection.
Interferon alfa is used for the intralesional treatment of external anogenital warts and condyloma acuminatum. Intralesional injection of 0.5 to 1.5 million international units per lesion is administered two to three times per week for up to three weeks. For large warts, it may be injected at several points around the periphery in a total dose of 250,000 IU per wart. The course of therapy can be repeated 12 to 16 weeks from the initial treatment.
Patients with 6-10 condylomata may receive a second course of treatment using the same dosage schedule to treat up to five additional condylomata per course. Patients with more than ten condylomata may receive additional sequences, depending on the number of condylomata present.
A meta-analysis of seven randomized controlled trials comparing interferon and placebo for the treatment of genital warts reported complete response rates of 45% and 16%, respectively. Recurrence rates were 21% for interferon and 34% for placebo. [81] Side effects included flu-like symptoms, fatigue, and pain. Interferon is contraindicated in pregnancy.
Various surgical techniques are available for the treatment of HPV disease. Except for cryosurgery, these modalities usually offer the advantage of complete treatment following a single application. However, surgical methods typically require local anesthesia and more time and equipment to implement. Consequently, they are often used when a large number of warts are present, a large area is affected, or in patients with refractory disease.
Primary surgical therapy can often be accomplished in the office and includes the following options:
Cryosurgery
Electrosurgery with either electrodesiccation or loop electrosurgical excision procedure (LEEP)
Simple surgical excision with a scalpel, scissors, or curette
Alternative surgical procedures requiring more advanced equipment and training include carbon dioxide laser ablation, Cavitron Ultrasonic Surgical Aspiration (CUSA), and Mohs surgery.
The location, size, or extent of the lesion and the potential for malignant transformation largely dictate treatment. Uncomplicated lesions can be treated with chemical ablation, cryoablation, surgical excision, or laser treatment. Treatment options for cervical neoplasia depend on the stage of the disease.
Overall, physical destruction or excision has been more effective in eradicating genital warts than medical therapy. Recurrences are common due to the virus residing in the basal layer of the epidermis in a latent state, and retreatment is frequently necessary. Recurrence of HPV disease is less common after surgical treatment compared with medical therapy, but the rate remains relatively high (25-55%).
Cryosurgery
Cryosurgery with liquid nitrogen or nitrous oxide is a rapid and effective means of treating simple HPV disease. It works by freezing the intracellular water, resulting in cellular destruction. This method is effective for most simple cutaneous warts and for low-grade cervical intraepithelial neoplasia (CIN I). Because cryotherapy does not result in any systemic absorption, it is safe for women who are pregnant during the second and third trimesters of pregnancy, as well as for the fetus. The primary drawbacks of the procedure are discomfort, ulceration, and scabbing at the treatment site.
Warts on the shaft of the penis and vulva respond very well to cryotherapy. Cryotherapy of the rectum is painful and less successful. Cryotherapy is not recommended for use in the vagina because the depth of ablation cannot be controlled, and damage to adjacent structures, such as the bladder and rectum, is possible.
Liquid nitrogen is applied directly to the lesion with a cotton swab or a fine spray. The treatment is applied for 30 to 60 seconds, until an ice ball forms and encompasses the lesion and 1 to 2 mm surrounding area.[82] Repeated weekly application is required until the lesions have resolved.
Nitrous oxide is delivered by a cryoprobe. It provides deeper freezing. It is not recommended for use in the vagina because of the risk of vaginal perforation and fistula formation.[83]
Electrosurgery
Electrocautery is effective for ablation of vulvar or vaginal lesions, typically requiring one treatment session. Its disadvantage is the need for anesthesia and an operating room. Laser ablation, if available, is preferred due to less bleeding and discomfort post-procedure.
Electrosurgical methods use high-frequency currents to cut and coagulate warts. Electrodesiccation with a bipolar needle is effective for external genital warts, while LEEP is primarily for cervical squamous intraepithelial lesions (SILs) but can also remove large external genital warts. These methods usually need only local anesthesia and can be done outpatient if the equipment is available. Smoke evacuation is necessary due to HPV DNA in plumes.
Electrosurgery works well for a limited number of lesions on the penis shaft. Large lesions around the rectum or vulva may need scissor excision followed by electrocautery. Large mass removal is painful and best under general or spinal anesthesia. Post-surgery pain is common and treatable with narcotic or topical analgesics like lidocaine jelly.
Surgical Excision
Simple surgical excision with a scalpel, scissors, or curette can remove warts, particularly large genital warts, and treat SILs of the genital tract. This procedure is typically for refractory or extensive disease and is performed in an outpatient setting under general or regional anesthesia.If tissue is needed for histological diagnosis, an excisional biopsy is performed before an ablative procedure.
Exophytic lesions are usually excised or shaved to the level of normal skin using scissors or a surgical knife, followed by cauterization of the lesion base. Larger lesions may require wide local excision. Potential complications include pain, dyspareunia, scarring, and infection. Curettage or electrosurgery are alternative methods for lesion excision.
Laser Surgery
Carbon dioxide laser vaporization generally is performed in an outpatient setting with general or regional anesthesia. Most patients experience significant discomfort beginning 24 hours after surgery and require narcotic analgesia.
Carbon dioxide laser vaporization typically is used for treatment of refractory HPV disease or extensive warts of the anogenital-mucosal category and is particularly useful in the treatment of periurethral and vaginal warts and vaginal SILs. It is the treatment of choice for pregnant women with extensive lesions or lesions that do not respond to TCA.
Carbon dioxide laser therapy is an efficient therapeutic modality because of its precision and rapid healing without scarring. Laser treatment of vulvar condylomata acuminata effectively destroys the lesions while sparing adjacent healthy tissue. As in electrosurgery, HPV DNA has been found in laser smoke plumes; therefore, procedures to evacuate the smoke and prevent inhalation must be used.
Complete wart clearance after laser surgery has been reported to occur in 23-52% of patients within three years of surgery, and primary cure rates as high as 91% have been reported. The recurrence rates are similar to those of surgical excision.
Overall, complications of wart treatment are rare. They are generally confined to the treatment site and include scarring and, in the case of genital warts, vulvodynia or hyperesthesia.
Each therapeutic modality carries its own unique set of risks. Expected effects of cryosurgery include pain, edema, vesicles, bullae, weeping, and some necrosis. There is a small risk of infection, bleeding, abnormal scarring, pigment alteration, paresthesias, and alopecia with cryosurgery. Similarly, laser therapy for genital warts may result in pigment alteration, abnormal scarring, and infection. Special care must be taken to prevent respiratory infection from the laser plume generated by vaporization of virally infected tissue.
Surgical complications of treating SILs are discussed in the individual articles involving those diseases, as follows:
Benign Vulvar Lesions
Carbon Dioxide Laser Surgery of the Lower Genital Tract
Dietary and activity considerations include the following:
Folate deficiency is the only dietary factor that has been shown to play a role in early cervical carcinogenesis. Folate deficiency apparently facilitates incorporation of HPV DNA at a fragile chromosomal site, thereby establishing a basis for malignant transformation.
The patient should refrain from sexual contact after any surgical procedure for condylomata acuminata. No other activity restrictions exist, although patients often have trouble sitting for long periods in the first week after surgery. Patients who have condylomata removed from the periurethral area may also experience dysuria.
Soaking the genital area in warm water or sitz baths usually offers excellent pain relief; topical analgesics can be beneficial. The genital area should be dried gently with a towel or a hair dryer. Loose-fitting cotton underwear is helpful to prevent chafing.
Initially approved in 2014, the 9-valent HPV vaccine (Gardasil 9 [9vHPV]) is the only available vaccine in the United States shown to decrease the risk for certain cancers and precancerous lesions in males and females aged 9-45 years.[84] The 9vHPV vaccine covers HPV subtypes 6, 11, 16, 18, 31, 33, 45, 52, and 58. Cervarix (2vHPV) and Gardasil (4vHPV) were discontinued in the United States in October 2016.[85, 86] Children and adolescents aged 15 years and younger need two doses, whereas three doses are recommended if vaccination is initiated after the 15th birthday. This is due to the vaccine’s enhanced immunogenicity in preteens and adolescents aged 9-14 years. The current CDC recommendations for HPV vaccinations are as follows:
For individuals starting before their 15th birthday prevention is conducted as follows:
2-dose schedule: The second dose should be given 6–12 months after the first dose (0, 6–12-month schedule).
Minimum interval: 5 months between the first and second dose. If the second dose is administered after a shorter interval, a third dose should be given a minimum of 5 months after the first dose and 12 weeks after the second dose.
Interruption: If the vaccination schedule is interrupted, vaccine doses do not need to be repeated (no maximum interval).
Immunogenicity studies have shown that two doses of HPV vaccine given to 9–14-year-olds at least 6 months apart provided as good or better protection than three doses given to older adolescents or young adults.
For individuals starting on or after their 15th birthday, and for people with certain immunocompromising conditions, prevention includes the following:
3-dose schedule: The second dose should be given 1–2 months after the first dose, and the third dose should be given 6 months after the first dose (0, 1–2, 6-month schedule).
Minimum intervals: 4 weeks between the first and second dose, 12 weeks between the second and third doses, and 5 months between the first and third doses. If a vaccine dose is administered after a shorter interval, it should be re-administered after another minimum interval has elapsed since the most recent dose.
Interruption: If the vaccination schedule is interrupted, vaccine doses do not need to be repeated (no maximum interval).
The World Health Organization (WHO) recommends vaccination against HPV subtypes 16 and 18.[43]
Approval for adults aged up to 45 years was based on a study of approximately 3200 women aged 27-45 years monitored for an average of 3.5 years. The 9vHPV vaccine was 88% effective in preventing the combined endpoint of persistent infection, genital warts, vulvar and vaginal precancerous lesions, cervical precancerous lesions, and cervical cancer related to HPV types covered by the vaccine.[87, 84]
For adults aged 27-45 years, the Advisory Committee on Immunization Practices (ACIP) recommends the need for vaccination be based on shared decision-making between patient and clinician.[88] However, the American Cancer Society (ACS) "does not endorse the 2019 recommendation for shared clinical decision making for adults aged 27-45 years because of the low effectiveness and low cancer prevention potential of vaccination in this age group, the burden of decision making on patients and clinicians, and the lack of sufficient guidance on selection of individuals who might benefit."[89]
Effectiveness of the 9vHPV in men aged 27-45 years is inferred from data described above in women, as well as efficacy data in younger men (aged 16-26 y) and immunogenicity data from a clinical trial in which 150 men aged 27-45 years received a 3-dose regimen over 6 months.[84]
9vHPV indications for females include the following:
Prevention of the following neoplastic diseases: Cervical, vulvar, vaginal, and anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58; genital warts (condyloma acuminata) caused by HPV types 6 and 11.
Prevention of the following precancerous or dysplastic lesions: Cervical intraepithelial neoplasia (CIN) grade 2/3 and cervical adenocarcinoma in situ; CIN grade 1; vulvar intraepithelial neoplasia (VIN) grades 2 and 3; vaginal intraepithelial neoplasia (VaIN) grades 2 and 3; anal intraepithelial neoplasia (AIN) grades 1, 2, and 3.
9vHPV indications for males include the following:
Prevention of the following neoplastic diseases: Anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58; genital warts (condyloma acuminata) caused by HPV types 6 and 11.
Prevention of anal intraepithelial neoplasia (AIN) grades 1, 2, and 3.
The vaccine is most effective when given before the onset of sexual activity. Its impact on the incidence of cervical cancer will not be observable for years.[90] Effectiveness will depend on the duration of immunity and will be optimized by achieving maximum coverage of the target population.[91] Vaccination against particular HPV types is most effective in preventing infections from these viruses in individuals who have not previously been infected with these types.[92]
Catch-up vaccinations are recommended in previously unvaccinated children and adults.[93]
A report from the CDC indicated that HPV vaccine uptake among teens continues to increase. In 2017, an average of 65.5% of teens aged 13-17 years had received at least one HPV vaccination, an increase of 5.1% compared with 2016. Additionally, 48.6% had received the complete vaccination regimen appropriate for their age, an improvement of 5.2% compared with 2016. As in 2016, HPV vaccination coverage (i.e., one or more doses) was lower among adolescents living in nonmetropolitan statistical areas (MSAs) (59.3%) than among those living in MSA principal cities (70.1%).[94]
A randomized, double-blind trial involving more than 2,000 young females who were given either a placebo or the HPV-16 vaccine indicated that the vaccine was potentially effective in protecting against HPV infection.[95] The females in the vaccine group did not develop HPV-16 infection or cervical dysplasia during the study period. The seroconversion rate, with antibody titers to HPV-16, was almost 100%. In comparison, 41 females in the placebo group developed HPV-16 infection, and cervical dysplasia was diagnosed in 9 of them.
In another double-blind, placebo-controlled trial testing a quadrivalent HPV vaccine (covering HPV types 6, 11, 16, and 18) in 277 young females over an average of 3 years, those who received the vaccine had a 90% reduction in infection with these four HPV types compared to the placebo group.[96] Other studies have also yielded positive results.[97, 98] Vaccine effectiveness has also been documented among gay, bisexual, and other men who have sex with men.[99]
In a Phase III immunogenicity study, the 9vHPV vaccine demonstrated sustained immunogenicity and effectiveness for approximately 10 years post-vaccination in boys and girls aged 9 to 15 years.[100] A recent meta-analysis concluded that HPV vaccines are highly effective against anal HPV infection and Anal Intraepithelial Neoplasia (AIN) in individuals vaccinated at age ≤26 years.[101]
The HPV vaccination program in the United States has resulted in significant declines in the prevalence of vaccine-type HPV infections, anogenital warts, and cervical precancers. From 2013 to 2016, the prevalence of 4vHPV vaccine-type infections declined from 11.5% to 1.8% among females aged 14 to 19 years and from 18.5% to 5.3% among females aged 20 to 24 years, compared to the prevaccine era.[102] Additionally, declines have been observed among unvaccinated individuals, suggesting protective herd effects.[103]
A large retrospective study from California found that routine administration of the quadrivalent HPV vaccine to females was not associated with any new safety concerns.[104, 105] This trial included a total of 189,629 patients aged 9 to 26 years who received at least one dose of the quadrivalent vaccine (any-dose population) and a subset of 44,001 patients who received all three recommended doses within 12 months (3-dose population). Study findings included the following:
Vaccination may be associated with syncope on the day of vaccination and skin infections occurring 1 to 14 days after immunization.
Vaccination was not associated with any major adverse effects.
These findings[104, 105] were consistent with those of a previous study documenting a higher rate of reporting syncope to the passive Vaccine Adverse Event Reporting System after administration of the quadrivalent vaccine; however, they conflict with those of the Vaccine Safety Datalink study, which did not detect a comparable increase. The investigators suggested that within this age group, injections, rather than the vaccine specifically, could be related to syncope. Further studies will be needed to clarify the issue.
Regarding other possible adverse effects, a self-controlled case series using data from Danish national registries found no increased risk of venous thromboembolism (VTE) among women who had received quadrivalent HPV vaccination. The rate of VTE was 0.126 per person-year in the 42 days following receipt of a vaccine dose and 0.159 per person-year during control periods.[106, 107]
For more detailed guidance, the following clinical guideline summaries are available:
Centers for Disease Control and Prevention - HPV infection and genital warts. Sexually transmitted diseases treatment guidelines 2006
Society of Obstetricians and Gynaecologists of Canada - Anogenital warts guide: Treatment and follow-up
American Cancer Society - American Cancer Society guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors
A randomized, double-blind, placebo-controlled trial demonstrated that the quadrivalent HPV vaccine prevents infection with HPV types 6, 11, 16, and 18 and prevents the development of related external genital lesions in males aged 16-26 years.[108]
Vaccination of men who have sex with men (MSM) appears to decrease the incidence of anal cancer and genital warts. In one study, vaccination with the quadrivalent vaccine reduced the rate of anal intraepithelial neoplasia (AIN) in comparison with placebo.[109] In the 2 MSM populations studied (551 in the intention-to-treat population and 402 in the per-protocol population), the vaccine had 77.5% efficacy against AINs associated with HPV 6, 11, 16, or 18 in the per-protocol population and 50.3% efficacy in the intention-to-treat population.
The cost effectiveness of this intervention is maximized when vaccination is given as early as age 12 years.[110]
Assessment of sex partners
Because genital warts are sexually transmitted, the risk of acquiring HPV is primarily dependent on several factors related to sexual activity, including the following:
Number of sexual partners
Frequency of sexual intercourse
Presence of genital warts on sexual partners
Although a high prevalence of HPV-associated penile SILs exists in the male sex partners of women with cervical SILs, examination of these men is not necessary for management of HPV disease. Nevertheless, sex partners of patients with HPV disease may benefit from examination and a detailed evaluation for sexually transmitted diseases (STDs).
Women should avoid skin-to-skin contact with partners if genital warts are visible. Condom use may reduce the transmission of HPV to uninfected sex partners, but it does not eliminate the risk. Furthermore, patients must be made aware that treatment does not eliminate the possibility of HPV transmission, because latent virus still may be present in tissues adjacent to treated areas.
A study by Wawer et al showed that women were less likely to acquire high-risk infection with HPV if their partners were circumcised.[111] However, circumcision does not eliminate the risk of HPV transmission.
Gynecologic oncologist for assistance in management of genital tract SILs and carcinomas, as well as exophytic cervical warts and giant condylomata.
Urologist or a urogynecologist for assistance with surgical management of urethral warts, penile condylomata, SILs, or carcinomas.
Colorectal surgeon for assistance with the surgical management of perianal condylomata or anal SILs or carcinomas.
Otolaryngologist for assistance with management of oropharyngeal papillomas or SCC.
Dermatologist for assistance with management of epidermodysplasia verruciformis (EV). Bleeding warts, moles, birthmarks, or unusual warts with hair growing from them can be confused with HPV disease; refer these types of lesions to a dermatologist for diagnostic clarification. Dermatologists who specialize in Mohs surgery may be of particular assistance in managing verrucous carcinomas.
Infectious disease specialist for assistance in management of HPV disease in patients who are immunocompromised.
Consider consulting a proctologist for individuals who have perianal or anal warts or in whom anal dysplasia is suspected. This is especially true for individuals infected with HIV.
Because HPV resides in the basal layer of the epidermis in a latent state, recurrences are common and retreatment is often necessary. Patients typically are monitored on a periodic basis to assess for efficacy of treatment, unwanted side effects, and the development of complications. Outpatient follow-up care also provides an opportunity to evaluate for other STDs and provides patient education on an ongoing basis.
Patients who complete therapy for condylomata acuminata should undergo clinical examination 3 months and 6 months after treatment. Most patients who develop recurrent or persistent disease are diagnosed within 6 months of therapy. If the patient appears disease-free at the 6-month visit, yearly visits are recommended. For anal and rectal lesions in the context of HIV infection, frequent follow-up is essential.
The sexual partner or partners of a woman with condyloma acuminatum should be examined by a physician and treated if indicated. Often, examination of the male fails to reveal any visible condyloma.
For genital neoplasia, careful follow-up is mandatory. High-risk (oncogenic) DNA testing is appropriate as routine cervical cancer screening in conjunction with cervical cytology in women aged 30 years and older. In women with negative cytology results but positive HPV results, repeat both tests in 12 months. When results of both cytology and HPV testing are negative, repeat both tests at 3-year intervals.
Treatment of CIN I may be monitored safely with serial cytology, HPV DNA detection, and colposcopy in reliable patients. Perform Pap tests every 6 months and colposcopy every 2 years. Treatment options include carbon dioxide laser ablation or excision, cryotherapy for lesions of 2 quadrants or less, cone biopsy, and LEEP.
Screening guidelines for the prevention and early detection of cervical cancer by the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP) were published in 2012. Guidelines on screening for cervical cancer were published by the US Preventive Services Task Force (USPSTF) in 2018.[2]
In April 2020, the American College of Obstetricians and Gynecologists (ACOG) published the 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors.[60] The 2019 consensus guidelines replace ASCCP guidance first published in 2001 and updated in 2006 and 2012, as well as interim guidance for primary HPV screening published by ASCCP in 2015. Thirteen medical professional societies, four patient advocacy organizations, and two federal agencies participated in developing the guidelines.
In July 2020, the Amercian Cancer Society published guidelines on cervical cancer screening for individuals at average risk. Those guidelines had four significant changes from the previous guidelines.[112]
In April 2021, ACOG joined ASCCP and the Society of Gynecologic Oncology (SGO) in endorsing the USPSTF cervical cancer screening recommendations; ACOG reaffirmed the recommendations in April 2024. The USPSTF recommendations replace ACOG Practice Bulletin No. 168, Cervical Cancer Screening and Prevention, as well as the 2012 ASCCP cervical cancer screening guidelines. Management of abnormal cervical cancer screening results should follow ASCCP guidelines.
The Advisory Committee on Immunization Practices (ACIP) published updated guidelines on HPV vaccination in 2016.[113] In 2020, the American Cancer Society (ACS) updated its guidelines to largely agree with ACIP's but with adaptations to three of ACIP's recommendations.[89]
Guidelines on Human Papillomavirus Screening by the US Preventive Services Task Force (USPSTF)
Guidelines on screening for cervical cancer from the US Preventive Services Task Force (USPSTF) are as follows[2] :
Female patients aged 21 to 29 years should receive cervical cancer screenings every 3 years using cervical cytology alone. (A recommendation)
Female patients aged 30 to 65 years should have cervical cancer screenings every 3 years using cervical cytology alone, every 5 years using high-risk human papillomavirus (hrHPV) testing alone, or every 5 years using hrHPV testing along with cytology (cotesting). (A recommendation)
The USPSTF advises against screening for cervical cancer in women older than 65 years who previously have undergone sufficient screening and do not have additional risk factors for cervical cancer. (D recommendation)
These first three recommendations, above, are relevant for individuals with a cervix, irrespective of their sexual history or HPV vaccination status. However, these recommendations are not applicable to individuals previously diagnosed with a high-grade precancerous cervical lesion or cervical cancer. Additionally, they do not apply to individuals exposed to diethylstilbestrol in utero or those with a weakened immune system, such as women living with HIV.
The USPSTF advises against cervical cancer screening in women younger than 21 years. (D recommendation)
The USPSTF advises against screening for cervical cancer in women who have undergone a hysterectomy with cervical removal and do not have a history of high-grade precancerous lesions (ie, cervical intraepithelial neoplasia [CIN] grade 2 or 3) or cervical cancer. (D recommendation)
2020 Updated cervical cancer screening for individuals at average risk by the American Cancer Society (ACS)
If primary HPV testing is not an option, patients between ages 25 and 65 years should receive cervical cancer screening with cotesting (HPV testing along with cytology) every 5 years, or cytology alone every 3 years. (acceptable) (strong recommendation)
Cotesting or cytology testing alone are included as acceptable options for cervical cancer screening because access to primary HPV testing with a test approved by the FDA for primary screening may be limited in some settings. As the United States makes the transition to primary HPV testing, the use of cotesting or cytology alone for cervical cancer screening will be eliminated from future guidelines.
The ACS advises that individuals with a cervix who are older than 65 years, have no history of cervical intraepithelial neoplasia grade 2 or more severe diagnosis within the last 25 years, and have a documented history of regular negative screening during the 10 years before age 65 years, should stop cervical cancer screening with any method. (qualified recommendation)
Adequate negative prior screening is defined as 2 consecutive negative HPV tests, or 2 consecutive negative cotests, or 3 consecutive negative cytology tests within the past 10 years, with the most recent test performed within the recommended interval for the test used. These criteria do not pertain to those who are currently under surveillance for abnormal screening results.
Individuals older than 65 years with no conditions limiting life expectancy for whom adequate documentation of prior screening is unavailable should receive screening until criteria for screening cessation are met.
Cervical cancer screening may be stopped in those of any age with limited life expectancy.
The new screening guidelines vary in the following four significant ways compared with the recommendations from 2012:
The recommended screening approach involves primary HPV testing every 5 years, with the option of cotesting or cytology alone if FDA-approved primary HPV testing is not accessible.
The recommended age to initiate screening is 25 years instead of 21 years.
The recommended age to begin primary HPV testing, cotesting, or cytology alone when primary testing is unavailable is 25 years as opposed to 30 years.
The guideline is considered transitional, offering the use of cotesting or cytology alone for screening while advocating for the eventual phase-out once primary HPV testing becomes universally accessible without obstacles. The review of evidence concerning other pertinent matters did not result in any alterations to screening recommendations including intervals, initiation age, criteria for screening cessation, screening according to vaccination status, or screening following a hysterectomy.
Follow-up for individuals who screen positive for HPV and/or cytology should follow the 2019 American Society for Colposcopy and Cervical Pathology risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors.
2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors by ASCCP
2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors moved to guidelines based on risk level rather than test results. Please see the complete guideline.[60]
Essential changes to the guideline are as follows:
Decisions will be guided by the patient's risk level rather than specific test outcomes. The decision to proceed with colposcopy, treatment, or observation will be determined by the individual's risk of CIN 3+ derived from a combination of current and previous results (even if the past history is unknown). The management approach may vary for patients with similar test results based on their recent testing history.
For select patients, colposcopy may be postponed. Patients with minor screening abnormalities suggestive of HPV infection and a low likelihood of underlying CIN 3+ (such as HPV-positive with mild cytologic abnormalities following a previously negative screening HPV test or cotest) are advised to undergo repeat HPV testing or cotesting at 1 year.
The guidance on expedited treatment (ie, treatment without colposcopic biopsy) has been expanded and clarified. In the earlier 2012 guidelines, expedited treatment was an option for patients with HSIL cytology; this revised guidance now presents a more detailed approach. For non-pregnant patients aged 25 or older, expedited treatment, involving treatment without an initial colposcopic biopsy confirming CIN 2+, is the preferred course of action when the immediate risk of CIN 3+ is 60% or higher, and is considered acceptable for risks falling between 25% and 60%. Expedited treatment is the favored approach for non-pregnant patients aged 25 or older with high-grade squamous intraepithelial lesion (HSIL) cytology and concurrent positive HPV genotype 16 (HPV 16) testing (ie, HPV 16–positive HSIL cytology), as well as for individuals who have never or rarely undergone screening and present with HPV-positive HSIL cytology, irrespective of the HPV genotype. In making decisions about expedited treatment, it is essential to engage in shared decision-making, particularly for patients who have concerns about the potential effects of treatment on pregnancy outcomes.
In the United States, excisional treatment is preferred over ablation for histologic HSIL (CIN 2 or CIN 3), with excision recommended for adenocarcinoma in situ (AIS).
For CIN 1, observation is the preferred approach over treatment.
Histopathology reports should align with the Lower Anogenital Squamous Terminology (LAST) and World Health Organization (WHO) guidelines when reporting histologic HSIL, with inclusion of CIN 2 or CIN 3 qualifiers, such as HSIL (CIN 2) and HSIL (CIN 3).
All positive primary HPV screening tests, regardless of the genotype, should undergo additional reflex triage testing conducted on the same laboratory specimen (eg, reflex cytology). Further testing from the same laboratory sample is recommended as the results can guide colposcopy decisions. For instance, individuals with HPV-16 positive HSIL cytology are eligible for expedited treatment. HPV 16 or 18 infections are associated with the highest risk for CIN 3 and hidden cancer, underscoring the need for further assessment (e.g., colposcopy with biopsy) even in cases where cytology results are negative. In situations where the testing for HPV 16 or 18 is positive and additional laboratory testing on the same sample is not feasible, the patient should proceed directly to colposcopy.
Following treatment and initial post-treatment management of histologic HSIL, CIN 2, CIN 3, or AIS, it is suggested to maintain surveillance with HPV testing or cotesting every 3 years for a minimum of 25 years. Continued surveillance every 3 years beyond the 25-year mark is deemed appropriate as long as the patient's life expectancy and screening feasibility are not significantly affected by serious health concerns. The 2012 guidelines recommended returning to 5-year screening intervals without specifying a cessation point for screening. New evidence indicates that the risk remains elevated for at least 25 years, with no data suggesting that previously treated patients eventually reach risk levels suitable for 5-year screening intervals again.
When HPV testing or cotesting cannot be conducted, surveillance using cytology alone may be considered. Cytology, although less sensitive than HPV testing in detecting precancerous changes, is recommended more frequently. Cytology is advised every 6 months when annual HPV testing or cotesting is indicated. If HPV or cotesting is recommended every 3 years, cytology should be carried out annually. Human papillomavirus assays approved by the FDA for screening purposes should be utilized in accordance with their regulatory approval in the United States. It is important to note that all HPV testing mentioned in this context pertains to screening for high-risk HPV types exclusively. For all management scenarios, HPV mRNA and HPV DNA tests lacking FDA approval for standalone primary screening should only be used as a cotest with cytology unless robust data exist to support the independent use of these specific tests in management protocols.
Guidelines on Human Papillomavirus Vaccination by the American Cancer Society
Guidelines on human papillomavirus vaccination by the American Cancer Society (ACS) largely agree with guidelines from the Advisory Committee on Immunization Practices (ACIP), with adaptations of three ACIP recommendations published in 2020. The ACS recommendations are as follows[89] :
ACIP recommendation: Routine HPV vaccination is recommended at 11 or 12 years of age, but it can be administered as early as age 9 years.
ACS Qualifying Statement: Routine HPV vaccination between ages 9-12 years is expected to achieve higher on-time vaccination rates, resulting in increased numbers of cancers prevented. Health care providers are encouraged to start offering the HPV vaccine at age 9 or 10 years.
ACIP Recommendation: Vaccination is recommended for individuals through age 26 years who have not been adequately vaccinated.
ACS Qualifying Statement: Providers should inform individuals aged 22-26 years who previously have not been vaccinated or who have not completed the series that vaccination at older ages is less effective in lowering cancer risk. (Saslow 20163)
ACIP Recommendation: Catch-up HPV vaccination is not universally recommended for adults older than 26 years. Instead, shared clinical decision-making on HPV vaccination is advised for some individuals between the ages of 27 and 45 years who have not been adequately vaccinated. HPV vaccines are not licensed for use in adults older than 45 years.
The ACS does not endorse the 2019 recommendation for shared clinical decision making for adults aged 27-45 y because of the low effectiveness and low cancer prevention potential of vaccination in this age group, the burden of decision making on patients and clinicians, and the lack of sufficient guidance on selection of individuals who might benefit.
The vaccination series should be completed by age 13 years to increase effectiveness; late vaccination should be completed as soon as possible.
Vaccination should occur in females aged 13-26 years and males aged 13-21 years who have not been previously vaccinated or who have not completed the 3-dose series. Men aged 22-26 years also may be vaccinated.
Vaccination is recommended though age 26 years in men who have sex with men and in immunocompromised individuals, including those with HIV infection, if not previously vaccinated.
HPV vaccination should be given along with other routine adolescent vaccines, such as Tdap and MCV4.
Females can receive vaccination with the 9vHPV vaccine. The bivalent (2vHPV) and quadrivalent (4vHPV) no longer are marketed in the United States.
Males can receive vaccination with the 9vHPV vaccine.
Guidelines on Human Papillomavirus Vaccination by the Advisory Committee on Immunization Practices (ACIP)
The following are the Advisory Committee on Immunization Practices (ACIP) guidelines on human papillomavirus vaccination[113, 114] :
Children and adolescents aged 15 years and younger need just 2, not 3, doses of HPV vaccine, which is recommended because of the vaccine's enhanced immunogenicity in preteens and adolescents aged 9-14 years.
Efficacy trials showed that the response in younger children after 2 doses is as good as or better than the response after 3 doses in older teens and young adults.
In addition to dropping the third dose for younger-than-15-years age group, the recommendation expands the time interval from the first to the second dose from 1-2 months to 6-12 months.
The schedule for older adolescents and young adults aged 15-26 years remains the same, at 3 inoculations within 6 months.
Children and adults aged 9 through 26 years: HPV vaccination is routinely recommended for patients aged 11 or 12 years, though it can be administered as early as age 9 years. Catch-up vaccination is advised for all individuals up to age 26 years who have not received adequate vaccination.
Children and adults aged 9 through 26 years: HPV vaccination is routinely recommended for patients aged 11 or 12 years; vaccination can be given beginning at age 9 years. Catch-up HPV vaccination is recommended for all persons through age 26 years who are not adequately vaccinated.
Adults aged >26 years: Catch-up HPV vaccination is not recommended for all adults older than 26 years. Instead, shared clinical decision-making about HPV vaccination is advised for some adults aged 27 through 45 years who are not adequately vaccinated. HPV vaccines are not licensed for use in adults older than 45 years.
Administration: Dosing schedules, intervals, and definitions of persons considered adequately vaccinated are unchanged. No prevaccination testing, such as Pap or HPV testing, is advised to establish the appropriateness of HPV vaccination.
Cervical cancer screening: Clinicians should adhere to and follow the recommended guidelines for cervical cancer screening.
Special populations and medical conditions: These recommendations for children and adults aged 9 through 26 years and for adults older than 26 years apply to all individuals, regardless of behavioral or medical risk factors for HPV infection or disease. For pregnant individuals, HPV vaccination should be delayed until after pregnancy; however, pregnancy testing is not necessary before vaccination. Persons who are breastfeeding or lactating can receive HPV vaccine. Recommendations regarding HPV vaccination during pregnancy or lactation are unchanged.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. The medications used to treat human papillomavirus (HPV) infections are primarily designed to ablate the lesion by virtue of their corrosive properties. Although medical treatments have historically been destructive, immunomodulatory agents have now been introduced into practice.
Keratolytic agents like TCA and bichloracetic acid (BCA) are extremely powerful keratolytic agents that rapidly penetrate and chemically cauterize skin, keratin, and other tissues. They can be used to treat nongenital cutaneous warts, as well as external genital warts (EGWs) or condylomata acuminata.
For most patients, simple topical therapies are the initial treatments of choice; they are cost effective and result in minimal toxicity. Most such therapies successfully eliminate visible condylomata in 30-90% of cases. However, many clinical studies examining topical therapies are not well designed, making comparisons between therapies difficult.
The HPV 9-valent (Gardasil 9) is the only HPV vaccine available in the United States. The HPV 2-valent vaccine (Cervarix), which covered types 16 and 18, and the HPV 4-valent vaccine (Gardasil), which covered types 6, 11, 16, and 18, were discontinued in the United States in October 2016.
Table 2. HPV Vaccine: Indications Approved in the United States for Females
View Table
See Table
Table 3. HPV Vaccine: Indications Approved in the United States for Males
Clinical Context:
Imiquimod is an imidazoquinolinamine derivative that has no in vitro antiviral activity but does induce macrophages to secrete cytokines such as interleukin (IL)-2 and interferon alfa and gamma. Its mechanisms of action are unknown. Imiquimod has been studied extensively and is a new therapy relative to other EGW treatments. It may be more effective in women than in men.
Imiquimod is dispensed as an individual dose. Patients are advised to wash the affected area with mild soap and water upon awakening and to remove residual drug.
Clinical Context:
Interferon alfa is a protein product either manufactured from a single-species recombinant DNA process or obtained from pooled units of donated human leukocytes that have been induced by incomplete infection with a murine virus.
The mechanisms by which interferon alfa exerts antiviral activity are not understood clearly. However, modulation of the host immune response may play an important role. This agent is indicated for intralesional treatment of refractory or recurring external condyloma acuminatum and is particularly useful for patients who have not responded satisfactorily to other treatment modalities (eg, podophyllin, surgical excision, laser therapy, or cryotherapy).
Clinical Context:
This is a protein product manufactured by recombinant DNA technology. Its mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. Its immunomodulatory effects include suppression of tumor cell proliferation, enhancement of macrophage phagocytic activity, and augmentation of lymphocyte cytotoxicity.
This agent is indicated for intralesional treatment of refractory or recurring external condyloma acuminatum and is particularly useful for patients who have not responded satisfactorily to other treatment modalities (eg, podophyllin, surgical excision, laser therapy, or cryotherapy).
Immune response modifiers have immunomodulatory effects and are used for treatment of external anogenital warts (EGWs) or condylomata acuminata. Interferon alfa, beta, and gamma may be administered topically, systemically, and intralesionally. They stimulate production of cytokines and demonstrate strong antiviral activity.
Clinical Context:
Podofilox is a topical antimitotic that can be synthesized chemically or purified from the plant families Coniferae and Berberidaceae (eg, species of Juniperus and Podophyllum). It is the active agent of podophyllin resin and is available as a 0.5% solution. Treatment results in necrosis of visible wart tissue; the exact mechanism of action is unknown. Treatment should be limited to no more than 10 cm2 of wart tissue, and no more than 0.5 mL/day of solution should be given. This is a patient-applied therapy.
Clinical Context:
Podophyllin is derived from May apple (Podophyllum peltatum Linné) and contains the active agent podophyllotoxin, a cytotoxic substance that arrests mitosis in metaphase. American podophyllum contains one fourth the amount of podophyllotoxin that Indian podophyllum does. The potency of podophyllin varies considerably between batches. The exact mechanism of action is unknown.
Podophyllin is used as a topical treatment for benign growths, including external genital and perianal warts, papillomas, and fibroids. It results in necrosis when applied to anogenital warts. Only a trained medical professional can apply it, and it cannot be dispensed to a patient.
Clinical Context:
Trichloroacetic acid (TCA) is a highly corrosive desiccating agent that cauterizes skin, keratin, and other tissues and is used to burn lesions. Although it is caustic, it causes less local irritation and systemic toxicity than other agents in the same class. However, response often is incomplete, and recurrence is common.
Most clinicians use 25-50% TCA, although some use concentrations as high as 85% and then neutralize with either water or bicarbonate. Tissue sloughs and subsequently heals in 7-10 days. TCA therapy is less destructive than laser surgery, electrocautery, or cryotherapy.
Clinical Context:
By dissolving the intercellular cement substance, salicylic acid produces desquamation of the horny layer of skin without affecting the structure of viable epidermis. It is used for removal of nongenital cutaneous warts, particularly common or plantar warts. Before application, wash the affected area. The wart may be soaked in warm water for 5 minutes. Dry the area thoroughly.
Antimitotic drugs arrest dividing cells in mitosis, resulting in the death of proliferating cells. They cause cornified epithelium to swell, soften, macerate, and then desquamate. Many of them are chemotherapeutic agents. The drugs listed below are used specifically for treatment of EGWs or condylomata acuminata.
Keratolytic agents are used to aid in removal of keratin in hyperkeratotic skin disorders, including corns, ichthyoses, common warts, flat warts, and other benign verrucae.
Clinical Context:
Topical 5-FU interferes with DNA synthesis by blocking the methylation of deoxyuridylic acid and inhibits thymidylate synthetase, which subsequently reduces cell proliferation. Its primary indication is for topical treatment of actinic keratoses. Although it is not approved by the US Food and Drug Administration (FDA) for the treatment of warts, it has been used in adults, particularly for warts resistant to other forms of treatment. It is used for management of superficial basal cell carcinomas.
The solution contains either 2% or 5% 5-FU in propylene glycol, tris (hydroxymethyl) aminomethane, hydroxypropyl cellulose, paraben, and disodium edetate. The cream contains 5% 5-FU in white petrolatum, stearyl alcohol, propylene glycol, polysorbate 60, and paraben. When topical 5-FU is applied to the lesion, the area undergoes a sequence of erythema, vesiculation, desquamation, erosion, and reepithelialization.
Antimetabolites interfere with nucleic acid synthesis and inhibit cell growth and proliferation. These are topical preparations that contain the fluorinated pyrimidine 5-fluorouracil (5-FU). Although these chemotherapeutic agents are not formally approved for use against warts, some studies have demonstrated a benefit against EGWs or condylomata acuminata.
Clinical Context:
Sinecatechins ointment is a botanical drug product for topical use that consists of extract from green tea leaves. It contains 15% sinecatechins and is available in 15- and 30-g tubes. Its mode of action is unknown, but it does elicit antioxidant activity in vitro. Sinecatechins ointment is indicated for topical treatment of external genital and perianal warts (condylomata acuminata) in immunocompetent patients.
Clinical Context:
Induces humoral immune response to 9 HPV subtypes: 6, 11, 16, 18, 31, 33, 45, 52, and 58. It is indicated for routine immunization in males and females aged 9-26 years to prevent HPV-associated diseases. Immunization for adults aged 27-47 years is based on shared decision making between the patient and clinician.
The 9-valent HPV vaccine is indicated for prevention of HPV-associated neoplasias and precancerous genital lesions. The 2-valent and 4-valent vaccines were discontinued from the US market in 2016.
Children and adolescents aged 15 years and younger need 2, not 3, doses of the HPV vaccine; this ACIP recommendation stems from the vaccine’s enhanced immunogenicity in preteens and adolescents aged 9-14 years. The immunization schedule for older adolescents and young adults aged 15-45 years is 2-3 inoculations (depending on immunization history) within 6 months.[88]
What is human papillomavirus (HPV)?Which medical conditions are associated with human papillomavirus (HPV)?Which physical findings are characteristic of human papillomavirus (HPV) infection?How is human papillomavirus (HPV) diagnosed?What is the role of lab testing in the diagnosis of human papillomavirus (HPV) infection?When is a biopsy indicated for the diagnosis of human papillomavirus (HPV) infection?Which histologic findings suggest human papillomavirus (HPV) infection?Which medications used in the treatment of human papillomavirus (HPV) infection?What are the primary surgical treatments of human papillomavirus (HPV) infection?What are alternative surgical procedures for the treatment of human papillomavirus (HPV) infection?What is the role of vaccination for the prevention of human papillomavirus (HPV) infection?Which areas of human papillomavirus (HPV) disease infection require further research?What is human papillomavirus (HPV)?How are mucosal human papillomavirus (HPV) infections classified?What are the clinical manifestations of human papillomavirus (HPV) infections?What are the different types of human papillomavirus (HPV)?How does human papillomavirus (HPV) infection result in malignancy?What type of virus is human papillomavirus (HPV)?What are characteristics of human papillomavirus (HPV)?What are the anatomic predilections for human papillomavirus (HPV)?What is the pathogenesis of human papillomavirus (HPV) infection?How does the human papillomavirus (HPV) replicate?What is the process of replication for human papillomavirus (HPV)?What is the expression of viral genes in human papillomavirus (HPV)?What is the pathophysiology of human papillomavirus (HPV)?What is the role of koilocytosis in the pathophysiology of human papillomavirus (HPV)?How does the genetic make-up vary among the viral genotypes of papillomavirus (HPV)?How are human papillomavirus (HPV) typed?What are the etiologic characteristics of human papillomaviruses (HPVs)?Which diseases are caused by human papillomaviruses (HPVs)?Which patients are at higher risk for malignant transformation of human papillomavirus (HPV) infection?What is the etiologic relationship between sexual activity and human papillomavirus (HPV) infection?What is the etiologic relationship between tobacco smoking and human papillomavirus (HPV)-caused malignancy?What is the etiologic relationship between oral contraceptive use and human papillomavirus (HPV)-related malignancy?What is the etiologic relationship between chewing betel quid and human papillomavirus (HPV)-related malignancy?What is the etiologic relationship between ultraviolet and x-ray irradiation and human papillomavirus (HPV)-related malignancy?What is the reporting system for human papillomavirus (HPV) infections in the US?What is the prevalence of human papillomavirus (HPV) infection in the US?Which population group has the highest rate of human papillomavirus (HPV) infection in the US?What is the incidence of genital warts the US?What are the Center for Disease Control and Prevention (CDC) estimates of human papillomavirus (HPV) prevalence?What are the trends in human papillomavirus (HPV) infection according to the National Disease and Therapeutic Index in the US?Which studies in the US report the lowest and highest prevalences of human papillomavirus (HPV) infection?What is the prevalence of condylomata in the US?How prevalent is papillomavirus (HPV) infection in cervical cancer in the US?What percentage of cancers are caused by human papillomaviruses (HPVs)?What is the global incidence of human papillomavirus (HPV) infection?What is the most common cancer caused by human papillomavirus (HPV) infection in developing countries?What is the global prevalence of high-risk human papillomavirus (HPV) in women with normal cervical cytology?What is the leading cause of cancer mortality among women with human papillomavirus (HPV) infection in developing nations?How does the prevalence of human papillomavirus (HPV) infection vary by age?What is the prevalence of human papillomavirus (HPV) infection stratified by age in US females?Which population group has the highest rates of genital human papillomavirus (HPV) infection?How does the prevalence of human papillomavirus (HPV) vary between women older than 30 years and younger than 30 years?Why is the prevalence of human papillomavirus (HPV) higher in younger women?How is genital human papillomavirus (HPV) infection transmitted from mothers to infants?What are the incubation and latency periods for human papillomavirus (HPV) in infants?Which population groups are at highest risk for nongenital warts due to human papillomavirus (HPV) infection?When does epidermodysplasia verruciformis (EV) develop from human papillomavirus (HPV) infection?How does the prevalence of human papillomavirus (HPV) infectionvary by sex?What are the racial predilections for human papillomavirus (HPV)?What is the prognosis of papillomavirus (HPV) infection?What is the disease progression of warts due to human papillomavirus (HPV) infection?What are clinical manifestations of human papillomavirus (HPV) infection of the vulva?What is the histologic evidence of human papillomavirus (HPV) infection on a cervical Pap smear?What are the risk factors for anogenital human papillomavirus (HPV) infection?Which factors increase the risk of persistent disease due to human papillomavirus (HPV) infection?What are the risk factors for anal cancer due to human papillomavirus (HPV) infection?What are the clinical manifestations of human papillomavirus (HPV) infection in males?What are the risk factors for epidermodysplasia verruciformis (EV) human papillomavirus (HPV) infection?What is the progression of disease in epidermodysplasia verruciformis (EV) human papillomavirus (HPV) infection?What is the prevalence of comorbid sexually transmitted diseases (STDs) in patients with genital warts?What is included in patient education information about genital warts and human papillomavirus (HPV) infection?What measures may reduce the risk for human papillomavirus (HPV) infection in women?How is human papillomavirus (HPV) infection prevented?What is the benefit of evaluating sex partners of patients with genital warts due to human papillomavirus (HPV) infection?What determines the clinical presentation of human papillomavirus (HPV) infection?What are the manifestations of genital infection due to human papillomavirus (HPV)?What are condylomata acuminata located in human papillomavirus (HPV) infection?How are genital warts characterized in human papillomavirus (HPV) infection?Which lesions are most common in human papillomavirus (HPV) infection of the cervix?What is the presentation of giant condyloma in human papillomavirus (HPV) infection?When do genital warts due to human papillomavirus (HPV) infection become clinically apparent?What are the signs and symptoms of condylomata acuminata in human papillomavirus (HPV) infection?How are papillomavirus (HPV) cervical infections usually diagnosed?What are the signs and symptoms of high-grade squamous intraepithelial lesion (HGSIL) in human papillomavirus (HPV) infection?What are the signs and symptoms of anal cancer in human papillomavirus (HPV) infection?What is the presentation of oral human papillomavirus (HPV) infection?What are the characteristics of common cutaneous warts (verruca vulgaris) in human papillomavirus (HPV) infection?What are the signs and symptoms of palmoplantar warts in human papillomavirus (HPV) infection?What is the presentation of warts in meat and fish handlers with human papillomavirus (HPV) infection?How are flat warts characterized in patients with human papillomavirus (HPV) infection?How is Bowenoid papulosis characterized in human papillomavirus (HPV) infection?What is the process of malignant conversion of skin lesions in patients with human papillomavirus (HPV) infection?What are the signs and symptoms of epidermodysplasia verruciformis (EV) in human papillomavirus (HPV) infection?Which factor determines the physical findings of human papillomavirus (HPV) infection?Which physical findings are typical of condylomata in human papillomavirus (HPV) infection?What are the physical findings of subclinical condyloma in human papillomavirus (HPV) infection?What are the possible complications of warts in human papillomavirus (HPV) infection?What are the complications of human papillomavirus (HPV) disease?What is the disease progression of condylomata acuminata in human papillomavirus (HPV) infection?Which conditions should be included in the differential diagnosis of genital warts due to human papillomavirus (HPV) infection?Which conditions should be included in the differential diagnoses of Bowenoid papulosis due to human papillomavirus (HPV) infection?Which conditions should be included in the differential diagnoses of human papillomavirus (HPV) infection?What are the differential diagnoses for Human Papillomavirus (HPV)?How is human papillomavirus (HPV) diagnosed?What is the role of DNA testing in the evaluation of human papillomavirus (HPV) infection?What is the role of lab testing in the evaluation of condylomata acuminata?What is the role of imaging studies in the diagnosis of human papillomavirus (HPV) infections?What is the role of histology in the evaluation of human papillomavirus (HPV) infection?What are the Society of Gynecologic Oncology (SGO)/ American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines on human papillomavirus (HPV) screening and management?What is the role of cytologic testing in the evaluation of human papillomavirus (HPV) infection?What is the role of cervical metaplasia in the of human papillomavirus (HPV) infection?What is the role of Pap smear in the evaluation of human papillomavirus (HPV) infection?What are the benefits of liquid-based Pap smears for the diagnosis of human papillomavirus (HPV) infection?Where are the CDC guidelines for cytology proficiency testing in the diagnosis of human papillomavirus (HPV)?What are the methods for human papillomavirus (HPV) DNA testing?What is the role of human papillomavirus (HPV) DNA testing in the management of women with atypical squamous cells of undetermined significance (ASC-US)?What is the role of self-collected vaginal human papillomavirus (HPV) specimens in the surveillance of cervical intraepithelial neoplasia (CIN)?Which human papillomavirus (HPV) tests are under development?What are the FDA-approved indications for the human papillomavirus (HPV) DNA test?What is the role of the acetic acid test in the diagnosis of human papillomavirus (HPV) infection?How is the acetic acid test used to diagnose human papillomavirus (HPV) infection?What is the role of tissue biopsy in the diagnosis of human papillomavirus (HPV) infection?When is tissue biopsy indicated for the diagnosis of human papillomavirus (HPV)?When is biopsy of typical-appearing condylomata acuminata indicated?How is biopsy performed in the diagnosis of human papillomavirus (HPV) infection?What is the role of histopathology in the diagnosis of human papillomavirus (HPV) infection?Which histologic findings are characteristic of human papillomavirus (HPV) infection?Which histologic findings are characteristic of common cutaneous warts in human papillomavirus (HPV) infection?Which histologic findings are characteristic of condyloma acuminatum in human papillomavirus (HPV) infection?Which histologic findings are characteristic of Bowenoid papulosis in human papillomavirus (HPV) infection?What are the treatment options for condylomata acuminata due to human papillomavirus (HPV) infection?When is treatment of human papillomavirus (HPV) infection not recommended?Which factors influence treatment selection for human papillomavirus (HPV) genital warts?How are most human papillomavirus (HPV) infections treatment?What is the initial treatment for human papillomavirus (HPV) caused warts?How is human papillomavirus (HPV) infection managed in patients who are immunosuppressed?How frequently do human papillomavirus (HPV) caused condylomata acuminate recur?How is human papillomavirus (HPV) infection managed during pregnancy?What is the risk of perinatal human papillomavirus (HPV) transmission?How does maternal human papillomavirus (HPV) infection affect infant outcomes?How frequently is human papillomavirus (HPV) infection the cause of cervical cancer?Which patients with human papillomavirus (HPV) infection are at a higher risk of persistent lesions and malignancy?Which patients with human papillomavirus (HPV) infection are at increased risk for anal high-grade squamous intraepithelial lesion (HGSIL)?How are human papillomavirus (HPV) anogenital warts diagnosed in children?What are the risks of transmission of human papillomavirus (HPV) during pregnancy?When is cesarean delivery considered in mothers with human papillomavirus (HPV) infection?What risk is increased in immunosuppressed patients with human papillomavirus (HPV)?What is verrucous carcinoma of genitalia and how is it managed?How are medicines administered in the treatment of human papillomavirus (HPV) disease?What is the role of pharmacologic therapy in the treatment of human papillomavirus (HPV) disease?What is the role of imiquimod in the treatment of human papillomavirus (HPV) infection?What is the regimen for imiquimod in the treatment of human papillomavirus (HPV) infection?What is the role of interferons in the treatment of human papillomavirus (HPV)?What properties of interferon alfa may be beneficial in the treatment of human papillomavirus (HPV)?How is interferon alfa used in the treatment of human papillomavirus (HPV)?What is the efficacy of interferon in the treatment of human papillomavirus (HPV)?When is a second course of interferon given in the treatment of human papillomavirus (HPV) infection?What is the role of podofilox in the treatment of human papillomavirus (HPV) infection?What is the role of podophyllin in the treatment of human papillomavirus (HPV) infection?How is podophyllin administered in the treatment of human papillomavirus (HPV)?What are potential adverse effects of podophyllin therapy in the treatment of human papillomavirus (HPV) infection?What are the benefits of podofilox compared to podophyllin in the treatment of human papillomavirus (HPV) infection?What is the role of 5-fluorouracil (FU) in the treatment of human papillomavirus (HPV)?How is 5-fluorouracil (FU) administered in the treatment of human papillomavirus (HPV)?What is the role of keratolytic agents in the treatment of human papillomavirus (HPV) infection?What is the first choice for treatment fir vulvar or vaginal condyloma in pregnant women with human papillomavirus (HPV) disease?What is the duration of trichloroacetic acid (TCA) therapy for the treatment of human papillomavirus (HPV)?What is the role of sinecatechins ointment in the treatment of human papillomavirus (HPV) infection?How is cryosurgery used to treat human papillomavirus (HPV)?What is the role of surgery in the treatment of human papillomavirus (HPV) disease?What are the primary surgical therapies for the treatment of human papillomavirus (HPV) infection?What are alternative surgical procedures for the treatment of human papillomavirus (HPV)?What factors determine the selection of surgical procedure for the treatment of human papillomavirus (HPV) infection?Which treatment is most effective in eradicating genital warts in patients with human papillomavirus (HPV) infection?What is the role of cryotherapy in the treatment of human papillomavirus (HPV) disease?How safe is cryotherapy for treatment of human papillomavirus (HPV) infection?How is cryosurgery performed in the treatment of human papillomavirus (HPV) infection?What is the freeze-thaw-freeze cryosurgery method for the treatment of human papillomavirus (HPV) infection?What is the prognosis of human papillomavirus (HPV) infection following cryosurgery?How is electrosurgery used to treat human papillomavirus (HPV) disease?What is required for electrosurgery to treat human papillomavirus (HPV) disease?What is the effectiveness of electrosurgery for the treatment of human papillomavirus (HPV) infection?How is pain managed following electrosurgery for the treatment of human papillomavirus (HPV) infection?What is the role of simple surgical excision in the treatment of human papillomavirus (HPV) infection?How effective is surgical excision for the treatment of human papillomavirus (HPV) infection?How is surgical excision performed in the treatment of human papillomavirus (HPV) infection?What is the role of Mohs in the treatment of human papillomavirus (HPV) infection?What is the role of carbon dioxide laser vaporization in the treatment of human papillomavirus (HPV) infection?When is carbon dioxide laser vaporization typically used for the treatment of human papillomavirus (HPV) infection?What is the efficacy of carbon dioxide laser vaporization for the treatment of human papillomavirus (HPV) infection?How is the power density determined in laser vaporization of condylomatous lesions in human papillomavirus (HPV)?What is the efficacy of laser vaporization in the treatment of human papillomavirus (HPV) infection?What is the role of the Cavitron Ultrasonic Surgical Aspirator (CUSA) in the treatment of human papillomavirus (HPV) disease?What are the possible complications of warts in patients with human papillomavirus (HPV) disease?What are the risks of different therapeutic modalities for the treatment of human papillomavirus (HPV) infection?Where can information be found on the surgical complications of treating squamous intraepithelial lesions (SILs)?What is the role of folate deficiency in the malignant transformation of human papillomavirus (HPV) infection?Which activity modifications are required during treatment of human papillomavirus (HPV) disease?What are the options for pain management in human papillomavirus (HPV) disease?What is the role of the 9-valent HPV vaccine (Gardasil 9 [9vHPV]) in the prevention of human papillomavirus (HPV) infection?What are the indications for the 9-valent HPV vaccine (Gardasil 9 [9vHPV]) for prevention of human papillomavirus (HPV) infection?When is administration of the 9-valent HPV vaccine (Gardasil 9 [9vHPV]) most effective?What is the efficacy of the human papillomavirus (HPV) 16 vaccine in females?What is the efficacy of quadrivalent vaccines against human papillomavirus (HPV) infection in females?What is an expected benefit of routine use of vaccines against human papillomavirus (HPV)?What is the efficacy of the quadrivalent human papillomavirus (HPV) in the prevention of cervical abnormalities?What is the safety data for the quadrivalent human papillomavirus (HPV) vaccines?What are possible adverse effects of the human papillomavirus (HPV) vaccine?What are possible limitations of the human papillomavirus (HPV) vaccine?Which organizations have provided guidelines for prevention of human papillomavirus (HPV) infection?What is the efficacy of the quadrivalent human papillomavirus (HPV) vaccines in males?What are the benefits of vaccination against human papillomavirus (HPV) in men who have sex with men?What is the cost effectiveness of human papillomavirus (HPV) vaccination?What percentage of teenagers have received the human papillomavirus (HPV) vaccine?What are the sexual risk factors of acquiring human papillomavirus (HPV) infection?How should male partners of women with human papillomavirus (HPV) infection be managed?What are limitations in the prevention of human papillomavirus (HPV) infection?What role does circumcision play in the prevention of human papillomavirus (HPV)?When should a gynecologic oncologist be consulted in the management of human papillomavirus (HPV) infection?When should an urologist be consulted in the management of human papillomavirus (HPV) infection?When should a colorectal surgeon be consulted in the management of human papillomavirus (HPV) infection?When should an otolaryngologist be consulted in the management of human papillomavirus (HPV) infection?When should a dermatologist be consulted in the management of human papillomavirus (HPV) infection?When should an infectious disease specialist be consulted in the management of human papillomavirus (HPV)?When should a proctologist be consulted in the management of human papillomavirus (HPV)?Why is recurrence of human papillomavirus (HPV) infection common?What monitoring is need following treatment of condylomata acuminata in patients with human papillomavirus (HPV) infection?How should sexual partners of women with condyloma acuminatum be managed?What is included in the long-term monitoring of genital neoplasia in patients with human papillomavirus (HPV) infection?How is the treatment of cervical intraepithelial neoplasia (CIN) monitored in women with human papillomavirus (HPV) infection?What are the American Cancer Society (ACS) guidelines on human papillomavirus (HPV) vaccination?What are the CDC Advisory Committee on Immunization Practices (ACIP) guidelines on human papillomavirus (HPV) vaccination?What are the goals of drug treatment for human papillomavirus (HPV) disease?What is the role of keratolytic agents in the treatment of human papillomavirus (HPV) infection?What are the initial treatments for most patients with human papillomavirus (HPV) infection?Which vaccines for the prevention of human papillomavirus (HPV) infection are available in the US?Which medications in the drug class Vaccines, Inactivated, Viral are used in the treatment of Human Papillomavirus (HPV)?Which medications in the drug class Topical Skin Products are used in the treatment of Human Papillomavirus (HPV)?Which medications in the drug class Antineoplastics, Antimetabolite are used in the treatment of Human Papillomavirus (HPV)?Which medications in the drug class Keratolytic Agents are used in the treatment of Human Papillomavirus (HPV)?Which medications in the drug class Immunomodulators are used in the treatment of Human Papillomavirus (HPV)?
Vinod K Dhawan, MD, FACP, FRCPC, FIDSA, Professor of Clinical Medicine, University of California, Los Angeles, David Geffen School of Medicine; Clinical Professor, Department of Clinical Medicine, Charles R Drew University of Medicine and Science
Disclosure: Nothing to disclose.
Chief Editor
Pranatharthi Haran Chandrasekar, MBBS, MD, Professor, Chief of Infectious Disease, Department of Internal Medicine, Wayne State University School of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Peter A Gearhart, MD, Assistant Professor of Obstetrics and Gynecology, University of Pennsylvania School of Medicine
Disclosure: Received honoraria from Merck for speaking and teaching.
Robert V Higgins, MD, Professor, Department of Obstetrics/Gynecology, Division of Gynecologic Oncology, Medical College of Georgia at Augusta University
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.
Thomas C Randall, MD, Associate Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School; Gynecologic Oncologist, Gynecologic Surgeon, Massachusetts General Hospital and Yawkey Cancer Center
Disclosure: Nothing to disclose.
Acknowledgements
Jeffrey D Band, MD Professor of Medicine, Oakland University William Beaumont School of Medicine; Director, Division of Infectious Diseases and International Medicine, Corporate Epidemiologist, William Beaumont Hospital; Clinical Professor of Medicine, Wayne State University School of Medicine
Disclosure: Nothing to disclose.
Ryan Brashear, MD Staff Physician, Department of Dermatology, Indiana University School of Medicine
Ryan Brashear, MD is a member of the following medical societies: American Academy of Dermatology and American Medical Association
Disclosure: Nothing to disclose.
David F Butler, MD Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.
Edward F Chan, MD Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine
Edward F Chan, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.
Tsu-Yi Chuang, MD, MPH Clinical Professor, Department of Dermatology, Keck School of Medicine of the University of Southern California; Staff Dermatologist, Desert Oasis Healthcare
Tsu-Yi Chuang, MD, MPH is a member of the following medical societies: American Academy of Dermatology, American Society for Dermatologic Surgery, and International Society of Dermatology
Disclosure: Nothing to disclose.
Mark W Cobb, MD Consulting Staff, WNC Dermatological Associates
Mark W Cobb, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and American Society of Dermatopathology
Disclosure: Nothing to disclose.
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.
Dirk M Elston, MD Director, Ackerman Academy of Dermatopathology, New York
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose
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
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
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.
Charles V Sanders, MD Edgar Hull Professor and Chairman, Department of Internal Medicine, Professor of Microbiology, Immunology and Parasitology, Louisiana State University School of Medicine at New Orleans; Medical Director, Medicine Hospital Center, Charity Hospital and Medical Center of Louisiana at New Orleans; Consulting Staff, Ochsner Medical Center
Charles V Sanders, MD is a member of the following medical societies: Alliance for the Prudent Use of Antibiotics, Alpha Omega Alpha, American Association for the Advancement of Science, American Association of University Professors, American Clinical and Climatological Association, American College of Physician Executives, American College of Physicians, American Federation for Medical Research, American Foundation for AIDS Research, American GeriatricsSociety, American Lung Association, American Medical Association, American Society for Microbiology, American Thoracic Society, American Venereal Disease Association, Association for Professionals in Infection Control and Epidemiology, Association of American Medical Colleges, Association of American Physicians, Association of Professors of Medicine, Infectious Disease Society for Obstetrics and Gynecology, Infectious Diseases Societyof America, Louisiana State Medical Society, Orleans Parish Medical Society, Royal Society of Medicine, Sigma Xi, Society of General Internal Medicine, Southeastern Clinical Club, Southern Medical Association, Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology
Disclosure: Nothing to disclose.
John D Shanley, MD, MPH Professor Emeritus, University of Connecticut; Professor of Preventive Medicine, Stony Brook Medical Center
John D Shanley, MD, MPH is a member of the following medical societies: American Association for the Advancement of Science, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, and Infectious Diseases Society of America
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
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Human papillomavirus (HPV). Verrucae and papillomas appear as frondlike epithelial proliferations. Verrucae tend to be more keratinized with sharper projections than papillomas.
Human papillomavirus (HPV). Verruca vulgaris on the lateral border of the tongue exhibits the multiple, sharp-tipped, white, verrucous appearance, which is classic for this lesion in the oral cavity. Not all verrucae are so clinically diagnostic. Courtesy of Rose Yin Geist, DDS.
The left panel is transudation of serum antibodies to the site of human papillomavirus infection, and the right panel is exudation of serum antibodies to the site of human papillomavirus infection.
The figure shows proposed mechanisms used by the human papillomavirus vaccine to neutralize antibodies and protect against infection.
Figure showing how human papillomavirus penetrates the basal layer and eventually is released at the surface.
Plantar warts.
Flat wart.
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.
"Cauliflower" condyloma of penis.
Small papilloma on shaft of penis.
Verrucous warts in patient with HIV infection.
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.
Verrucous warts in patient with HIV infection.
Plantar warts.
Flat wart.
"Cauliflower" condyloma of penis.
Small papilloma on shaft of penis.
Human papillomavirus (HPV). Verruca vulgaris on the lateral border of the tongue exhibits the multiple, sharp-tipped, white, verrucous appearance, which is classic for this lesion in the oral cavity. Not all verrucae are so clinically diagnostic. Courtesy of Rose Yin Geist, DDS.
This is a verruca vulgaris of the anterior maxillary gingiva in a healthy young male. He had recently resolved a wart on his finger.
These small papillomas on the lateral tongue of a young woman showed histologic evidence of HPV in the form of extensive koilocytosis.
Human papillomavirus (HPV) lesion on the lingual frenum. Some patients with condyloma acuminatum present with multiple oral lesions. Courtesy of A.K. ElGeneidy, DDS.
Human papillomavirus (HPV). Condylomata on the lower lip, as well as other sites at the initial presentation. This presentation is unusually extensive. Multiple condylomata may be synchronous or metachronous. This patient did not present with genital condylomata. Courtesy of A.K. ElGeneidy, DDS.
Human papillomavirus (HPV). Heck disease in the buccal mucosa of a 7-year-old boy. Courtesy of Sheldon Mintz, DDS.
Human papillomavirus (HPV). Verrucae and papillomas appear as frondlike epithelial proliferations. Verrucae tend to be more keratinized with sharper projections than papillomas.
Human papillomavirus (HPV). Condyloma acuminatum generally has a papillary architecture and may microscopically resemble verruca vulgaris and papilloma (hematoxylin and eosin stain, original magnification X10). Courtesy of AK ElGeneidy, DDS.
Human papillomavirus (HPV). Koilocytes in the upper epithelium are a helpful, although not completely reliable, indication that a lesion is associated with human papillomavirus. Koilocytes display a dark small nucleus with clear cytoplasm (hematoxylin and eosin stain, original magnification X100). Courtesy of Sheldon Mintz, DDS.
Human papillomavirus (HPV). Condyloma acuminatum may show brisk mitotic activity, although oral condyloma acuminatum is not considered a premalignant lesion (hematoxylin and eosin stain, original magnification X40). Courtesy of A.K. ElGeneidy, DDS.
The left panel is transudation of serum antibodies to the site of human papillomavirus infection, and the right panel is exudation of serum antibodies to the site of human papillomavirus infection.
The figure shows proposed mechanisms used by the human papillomavirus vaccine to neutralize antibodies and protect against infection.
Figure showing how human papillomavirus penetrates the basal layer and eventually is released at the surface.
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