Human Papillomavirus

Synonyms and related keywords: human papillomavirus, HPV, wart virus, epithelial tumors, anogenital warts, mucosal warts, nongenital cutaneous warts, epidermodysplasia verruciformis, EV, sexually transmitted disease, STD, squamous intraepithelial lesions, SIL



INTRODUCTION

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

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

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

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

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

Diseases and Associated HPV Subtypes

Nongenital Cutaneous Disease	HPV Type
Common warts (verrucae vulgaris) Warts (Nongenital)	1, 2, 4, 26, 27, 29, 41, 57, 65
Plantar warts (myrmecias) Warts, Plantar	1, 2, 4, 63
Flat warts (verrucae plana)	3, 10, 27, 28, 38, 41, 49
Butcher's warts (common warts of people who handle meat, poultry, and fish)	1, 2, 3, 4, 7, 10, 28
Mosaic warts	2, 27, 57
Ungual squamous cell carcinoma	16
Epidermodysplasia verruciformis (benign) Epidermodysplasia Verruciformis	2, 3, 10, 12, 15, 19, 36, 46, 47, 50
Epidermodysplasia verruciformis (malignant or benign) Epidermodysplasia Verruciformis	5, 8, 9, 10, 14, 17, 20, 21, 22, 23, 24, 25, 37, 38
Nonwarty skin lesions	37, 38
Nongenital Mucosal Disease	HPV Type
Respiratory papillomatosis Recurrent Respiratory Papillomatosis	6, 11
Squamous cell carcinoma of the lung	6, 11, 16, 18
Laryngeal papilloma	6, 11, 30
Laryngeal carcinoma	16, 18
Maxillary sinus papilloma	57
Squamous cell carcinoma of the sinuses	16, 18
Conjunctival papillomas	6, 11
Conjunctival carcinoma	16
Oral focal epithelial hyperplasia (Heck disease)	13, 32
Oral carcinoma	16, 18
Oral leukoplakia	16, 18
Squamous cell carcinoma of the esophagus	16, 18
Anogenital Disease	HPV Type
Condylomata acuminata	6, 11, 30, 42, 43, 44, 45, 51, 52, 54
Bowenoid papulosis Bowenoid Papulosis	16, 18, 34, 39, 42, 45
Bowen disease	16, 18, 31, 34
Giant condylomata (Buschke-Löwenstein tumors) Giant Condylomata Acuminata of Buschke and Löwenstein	6, 11
Unspecified intraepithelial neoplasia	30, 34, 39, 40, 53, 57, 59, 61, 62, 64, 66, 67, 68, 69
Low-grade intraepithelial neoplasia	6, 11, 43
Intermediate intraepithelial neoplasia	31, 33, 35, 42, 44, 45, 51, 52
High-grade intraepithelial neoplasia	16, 18, 56, 58
Carcinoma of vulva Malignant Vulvar Lesions	6, 11, 16, 18
Carcinoma of vagina	16
Carcinoma of cervix Cervical Cancer	16, 18, 31
Carcinoma of anus	16, 31, 32, 33
Carcinoma in situ of penis (erythroplasia of Queyrat)	16
Carcinoma of penis	16, 18

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

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

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

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

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

Frequency:

• In the US: The number of patients identified with HPV disease has increased markedly during the past 20 years because of heightened awareness of the various manifestations of HPV disease and because of increased use of HPV DNA testing.

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

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

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

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

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

• Internationally: The worldwide prevalence of HPV in cervical carcinoma is 95-99.7% and in anal cancer is 88%.

  In many lesser-developed countries, cervical cancer is the most common cancer among women because of the lack of effective screening programs that monitor cervical cytology by Pap smear.

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

Mortality/Morbidity:

• Anogenital/mucosal disease: A direct correlation exists between anogenital HPV infection and measures of sexual activity, such as the age of first intercourse and the lifetime number of sexual partners. Women with a history of a cervical high-grade squamous intraepithelial lesion (HGSIL) or invasive squamous cell carcinoma (SCC) of the cervix are at increased risk for subsequent development of invasive cancer in other tissues of the anogenital/mucosal category, particularly vaginal and anal carcinoma. In these patients, the relative risk of vaginal carcinoma is 5.6, and the risk of anal carcinoma is 4. Anal cancer has been strongly associated with male homosexuality and specific male practices, such as engaging in receptive anal intercourse. Relative risk is 33. However, the overall disease prevalence is higher in women than in men, with a female-to-male ratio of 1.5:1.

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

• EV: Patients who are immunosuppressed, particularly those with cutaneous malignant lesions, have a much higher incidence of EV-HPV infection than the general population. These lesions can undergo malignant transformation. Ten percent of patients with EV originate from consanguineous marriages, suggesting an autosomal recessive mode of inheritance (see Epidermodysplasia Verruciformis).

Race:

• From 1987-1991, the age-adjusted Cervical Cancer death rate reported by the US National Cancer Institute was higher among black women compared to white women, with a ratio of 6:1.

• Nongenital cutaneous warts are more common in whites than in people of African descent.

Sex:

• The overall prevalence of HPV in women is 22-35%.

• In men, the prevalence is 2-35% depending on the sexual practices of the population being studied.

Age:

• Anogenital mucosal HPV infections are highest among college-aged women and men.

• Nongenital cutaneous warts are more common among teenagers and adults who work as meat, poultry, and fish handlers. The incidence approaches 10% in child and young adult populations. However, nongenital cutaneous warts rarely occur in people younger than 5 years and usually regress within 2 years.

• EV develops at an average age of onset of 6 years, and, beginning in the fourth decade of life, the lesions can undergo malignant transformation into invasive SCC.

CLINICAL

History:

• Anogenital warts

• Condylomata acuminata are exophytic cauliflowerlike lesions that are usually found near moist surfaces. They may be observed in the perianal area, vaginal introitus, vagina, labia, and vulva. Genital warts may also be found on dry surfaces, such as the shaft of the penis.

• Genital warts include smooth papular warts and keratotic warts, the latter of which resemble nongenital cutaneous warts because of their thickened bumpy surface.

• Genital flat warts are subclinical lesions that typically appear on the cervix. Colposcopic examination with 3% acetic acid solution is required for identification.

• Cervical disease

• Most cervical infections are either latent or subclinical and, as such, are asymptomatic. These infections are detected on Pap smear and are reported as either a low-grade squamous intraepithelial lesion (LGSIL) or a high-grade squamous intraepithelial lesion (HGSIL). Further examination with 3-5% acetic acid and colposcopy shows characteristic acetowhite changes and abnormal blood vessels indicative of HPV-triggered dysplasia.

• Patients who have neglected to obtain annual Pap testing for several years or more and who have an HGSIL that has progressed to invasive cancer of the cervix may report vaginal bleeding between periods or after sexual intercourse, dyspareunia, and fullness in the pelvis.

• Anal cancer

• The most common presenting symptoms of SCC of the anus are rectal bleeding and sensation of a mass. This may be attributed mistakenly to hemorrhoids.

• Fifty percent of men who are homosexual and have SCC of the anus have a history of anorectal warts; however, only 20% of women with SCC and men who are not homosexual have this history.

• Nonanogenital mucosal disease

• HPV types 6 and 11 have been isolated on nonanogenital mucosal surfaces. Warts have been discovered in the nares, mouth, larynx, and conjunctiva.

• HPV types 6 and 11 are associated with respiratory papillomas that are probably the result of intrapartum transmission when the infant passes through the birth canal of a mother who is infected with HPV. However, isolated case reports exist of respiratory papillomatosis after cesarean delivery. Patients with laryngeal papillomas present at an average age of 3 years, most frequently with hoarseness.

• Nongenital cutaneous HPV

• Cutaneous lesions typically produce benign self-limited warts.

• Deep plantar warts occur most commonly as solitary lesions that may become black and painful prior to spontaneous regression. They may contain small black “seeds,” which are thrombosed capillaries.

• Common warts can occur on any skin surface but are usually found on the hands and fingers. They appear as skin-colored, exophytic, rough papules and nodules that have minimal scaling. Autoinoculation from a wart on one finger may cause the occurrence of warts on an adjacent finger or other skin surface, so-called kissing warts.

• Warts that occur in people who handle meat and fish often have large cauliflowerlike plaques.
• Flat warts most often occur in groups of small plaques less than 5 mm in diameter on the face and hands. Regression usually occurs spontaneously after several years, and pruritus or erythema occur several weeks prior to their disappearance.

• Epidermodysplasia verruciformis

• The malignant conversion of skin lesions usually begins in the fourth and fifth decades of life. Premalignant lesions usually first arise on the forehead and other sun-exposed areas. The tumors are either benign papillomas and seborrheic keratoses or premalignant actinic keratoses and SCC.
• EV tumors are locally destructive. They develop slowly and have weak metastatic potential if no cocarcinogens, such as x-ray or ultraviolet B irradiation, are applied. Polymorphic, plane wart–like, and red-to-brownish plaques can be distributed widely over the skin. The lymph nodes and oral mucosa are not involved.

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

Causes:

• Types of HPV demonstrate a high degree of site specificity, with some HPV types only found on certain parts of the skin or mucous membranes.

• HPV infection alone does not cause malignant transformation of infected tissue. Cofactors, such as tobacco use, ultraviolet radiation, pregnancy, folate deficiency, and immune suppression, have been implicated in this process. Patients receiving immunosuppressive drugs and patients with defects in cell-mediated immunity, including those infected with HIV are especially susceptible to developing HPV infections.

• A direct correlation exists between anogenital HPV infection and measures of sexual activity, such as the age of first intercourse and the lifetime number of sexual partners.

DIFFERENTIALS

Benign Cervical Lesions
Benign Vulvar Lesions
Carbon Dioxide Laser Surgery of the Lower Genital Tract
Cervical Cancer
Conization of Cervix
Gynecologic Cryosurgery
Hemorrhoids
Hidradenitis Suppurativa
Malignant Vulvar Lesions
Molluscum Contagiosum
Penile Cancer
Recurrent Respiratory Papillomatosis
Surgical Treatment of Vaginal Cancer
Surgical Treatment of Vulvar Cancer
Urethral Warts

Other Problems to be Considered:

Actinic keratoses
Carbon dioxide laser surgery for intraepithelial cervical neoplasms
Cervical polyp
Condyloma lata
Dermatitis papillaris
Nevi
Oropharyngeal SCC
Pityriasis versicolor
Sinonasal Papillomas, Treatment
Warts (Nongenital)
Pap Test
Recurrent Respiratory Papillomatosis
Squamous Cell Carcinoma
Warts, Plantar
Bowenoid Papulosis
Warts
Epidermodysplasia Verruciformis
Squamous Cell Carcinoma, Eyelid
Warts (Genital)
Giant Condylomata Acuminata of Buschke and Löwenstein
Acanthosis Nigricans
Acrochordon
Corns and Calluses
Keloid and Hypertrophic Scar
Keratoacanthoma
Lichen Planus
Psoriasis (Plaque)
Seborrheic Keratosis
Malignant Tumors of the Mobile Tongue

WORKUP

Lab Studies:

• Cytologic testing

• Cervical cytologic testing using the Pap test is the standard screening procedure for cervical neoplasia. It should be performed annually in all women beginning 3 years after they become sexually active or when they have reached age 21 years if they have remained abstinent. Once a woman has had findings within the reference range on 3 or more consecutive annual Pap smears, the Pap smear may be performed less frequently if the patient is at low risk for developing cervical dysplasia.

• Pap smears should contain samples of cells from the ectocervix, transformation zone, and endocervical canal. Perform the test when the patient is not menstruating so that the cytologic specimen is not occluded with blood. Furthermore, if the patient has a cervicovaginal infection with a mucopurulent vaginal discharge, consider performing the test after the bacterial infection has resolved. If the test must be performed, the discharge should be gently cleared with a saline-moistened cotton swab.

• This test may be modified as required to sample tissues of the vagina, vulva, or perianal region that are suspicious for intraepithelial neoplasia. Although not an established routine, consider performing annual anal Pap smears on men who have high risk and who participate in receptive anal intercourse. See Cervical Cancer for guidelines on how often to perform the Pap smear when abnormalities result.

• Liquid-based Pap smears improve the diagnostic sensitivity of cervical cytology screening. They have the additional benefit of enabling easy testing for HPV. Thin Prep and SurePath are the 2 methods currently approved by the US Food and Drug Administration (FDA).

• HPV DNA typing

• The 2 common methods for HPV DNA testing include the Hybrid Capture II (HC II) and the polymerase chain reaction (PCR) enzyme immunosorbent assay. Both of these methods have similarly high sensitivities and are suitable tools for detection of HPV and posttreatment follow-up of cervical intraepithelial neoplasia (CIN).

• HPV DNA testing is the preferred approach in the treatment of women whose Pap test results show atypical squamous cells of undetermined significance (ASC-US) whenever liquid-based cytology is used or co-collection is available. HPV DNA testing is also useful in the management of CIN in certain situations. Detailed consensus guidelines for management of abnormal Pap test results and management of CIN are available at American Society for Colposcopic and Cervical Pathology.

Procedures:

• Tissue biopsy

• Tissue biopsy can be used to confirm HPV infection if the diagnosis is uncertain, particularly if warts are abnormally pigmented, ulcerated, or indurated.

• Obtain a biopsy of a warty lesion if the patient is immunocompromised, if the lesions worsen during treatment, or if they do not respond to standard therapy. In addition, biopsy is recommended to clarify the diagnosis in older patients who are at risk for genital carcinoma.

Histologic Findings: Virus multiplication is confined to the host cell nucleus. Consequently, infected cells exhibit a high degree of nuclear atypia. Koilocytosis describes a combination of perinuclear clearing with a pyknotic or shrunken nucleus and is a characteristic feature of productive papillomavirus infection. Other cytologic markers of HPV infection include acanthosis, dyskeratosis, and multinucleation.


TREATMENT

Medical Care: Eradication or reduction of symptoms is the primary goal of treating warts, but elimination of dysplastic lesions is the goal in treating squamous intraepithelial lesions (SILs). Treatment is not recommended for subclinical anogenital and/or mucosal HPV infection in the absence of coexistent dysplasia. No evidence demonstrates that treatment eliminates HPV infection or that it decreases infectivity. In fact, warts may recur after treatment because of activation of latent virus present in healthy skin adjacent to the lesion.

Superiority of any single treatment modality has not been demonstrated, nor is one modality ideal for all types of warts. Factors that influence treatment of HPV disease include the size, morphology, number, and anatomic site of lesions, as well as cost, adverse effects, patient preference, and provider experience.

Most patients with warts require multiple treatments over a course of several weeks or months. If substantial improvements have not occurred after 3 physician-administered treatments or if complete clearance has not occurred after 6 treatments, a different treatment modality should be used.

Treatment

All medicines used to treat HPV disease are applied topically on cutaneous surfaces. Local skin reactions and pain are common adverse effects. Do not apply any of these medications to mucosal surfaces and do not use them to treat dysplastic lesions, SCC, verrucous carcinomas, or Bowenoid Papulosis.

Two broad categories of medications are effective in treating HPV disease. The first category, the immune response modifiers (ie, imiquimod, interferon alfa), is primarily used in treatment of external anogenital warts or condylomata acuminata. The second category consists of the cytotoxic agents, which include the antiproliferative drugs podofilox, podophyllin, and 5-fluorouracil, as well as the chemodestructive or keratolytic agents salicylic acid, trichloroacetic acid (TCA), and bichloroacetic acid (BCA).

None of these medicines has been shown to be uniformly effective or directly antiviral. The keratolytics are the only agents that are recommended for treatment of nongenital cutaneous warts.

• Imiquimod

• This immune response modifier has no direct antiviral activity; however, it is a powerful cytokine inducer, which stimulates production of interferon alfa, tumor necrosis factor, and interleukin (IL)-1, IL-6, and IL-8.
• This patient-applied treatment is used for the treatment of external anogenital warts and condyloma acuminatum. It is applied 3 times per week, with application approximating an every-other-day routine (eg, Monday, Wednesday, Friday). Remove the cream by washing with mild soap and water 6-10 hours after application.
• Treatment continues until the warts have completely cleared, up to a maximum of 16 weeks.
• Local skin reactions are common, especially following contact with mucosal surfaces.

• Interferon alfa

• This naturally occurring cytokine is produced by recombinant DNA technology or by collection from pooled human leukocytes. It has potent immunomodulatory, as well as direct antiviral, effects.
• This physician-applied medicine is used for intralesional treatment of external anogenital warts and condyloma acuminatum. It is injected into the base of each wart, preferably using a 30-gauge needle. For large warts, it may be injected at several points around the periphery of the wart, using a total dose of 250,000 IU per wart. Direct the needle at the center of the base of the wart and at an angle almost parallel to the plane of the skin (approximating that in the commonly used purified protein derivative [PPD] test).
• The maximum response usually occurs 4-8 weeks after initiation of the first treatment course. If results at 12-16 weeks following the initial treatment course with interferon alfa-2b are not satisfactory, a second course of treatment using the same dosage schedule may be instituted, providing that clinical symptoms and signs or changes in laboratory parameters (eg, liver function tests, WBC count, platelet count) do not preclude such a course of action.
• Patients with 6-10 condylomata may receive a second (sequential) course of treatment using the same dosage schedule to treat up to 5 additional condylomata per course of treatment. Patients with more than 10 condylomata may receive additional sequences depending on how many condylomata are present.

• Podofilox
  • This antimitotic drug is either chemically synthesized or purified from naturally occurring podophyllin resin. Application stimulates visible necrosis of wart tissue.
  • This patient-applied medicine is used in the treatment of external genital warts or condyloma acuminatum. It is applied twice a day for 3 days, followed by 4 days of no therapy. This cycle can be repeated for a maximum of 4 cycles.
  • To ensure that the patient is fully aware of the correct method of therapy and to identify which specific warts should be treated, the prescriber should demonstrate the technique for initial application of the medication.
  • No more than 0.5 g of gel per day should be used. Limit the total wart tissue treated to 10 cm² or less.

• Podophyllin
  • This resin derived from the Mayapple (Podophyllum peltatum Linné) contains the active agent podophyllotoxin, which is a cytotoxic agent that arrests mitosis in metaphase.
  • Podophyllin is a physician-applied medicine used in the treatment of external genital warts and condyloma acuminatum. It can be applied weekly for up to 6 weeks.
  • Prior to application, thoroughly cleanse the affected area. Avoid contact with healthy tissue. Apply the medicine sparingly and allow to dry thoroughly.
  • Initial application should be for 30-40 minutes. Subsequent applications can be for 1-4 hours. Remove dried podophyllin with alcohol or with soap and water. Do not treat large areas or numerous warts at once.
• 5-Fluorouracil
  • This antimetabolite interferes with the synthesis of DNA and RNA. This action creates a thymine deficiency, resulting in unbalanced growth and death of a cell.
  • This patient-applied treatment is not formally indicated for treatment of HPV disease; however, the 5% cream formulation can be helpful in the treatment of some genital warts. It is applied 1-3 times per week for several weeks as needed.
  • Prior to application, thoroughly cleanse the affected area. Avoid contact with healthy tissue. Apply the medicine sparingly and allow to dry thoroughly. Remove dried cream 3-10 hours after application.
• Keratolytics
  • TCA and BCA are extremely powerful keratolytic agents that rapidly penetrate and chemically cauterize skin, keratin, and other tissues. The cauterizing effect is comparable to cryotherapy or electrodesiccation. These physician-applied agents can be used on all types of cutaneous warts.
  • An 80-90% solution is applied directly on a weekly basis. As the acid dries, a white frosting develops and should be powdered with sodium bicarbonate to remove any unreacted acid.
  • Salicylic acid is a milder keratolytic that is typically purchased in nonprescription formulations. This patient-applied medicine is used primarily to treat nongenital cutaneous warts.

Surgical Care: Various surgical techniques are available for the treatment of HPV disease. With the exception of cryosurgery, these modalities usually have the common advantage of complete treatment following one application. However, surgical modalities typically require local anesthesia and more time and equipment to implement. Consequently, they are often used when a large number of warts is present or a large area is affected or on patients with refractory disease. Recurrence of HPV disease is less common following surgical treatment as opposed to medical therapy.

Primary surgical therapy can often be accomplished in the office and includes cryosurgery; electrosurgery with either electrodesiccation or loop electrosurgical excision procedure (LEEP); or 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), or Mohs surgery.

• Cryosurgery (see Gynecologic Cryosurgery for further discussion)

• This physically ablative method is a rapid and effective means of treating simple HPV disease. It works by freezing the intracellular water, resulting in cellular destruction.
• Although it is somewhat painful, local anesthesia is not usually used. After 2-4 treatments in a 6- to 12-week period, 75-80% of patients experience a complete clearing of warts.
• This method is effective for most simple cutaneous warts and for low-grade cervical intraepithelial neoplasia (CIN I). It 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 to the wart using a cotton-tipped applicator, a cryoprobe, or a fine spray. Gases, such as nitrous oxide and carbon dioxide, can also be used.
• The freeze-thaw-freeze method is considered more effective than a single freeze. Application is continued until up to a 5-mm margin of surrounding skin or mucosa is frozen. After the skin turns white, freezing is continued for 30 seconds and then the skin is allowed to thaw. If the patient can tolerate the pain, a second cycle is applied.
• Within 24 hours after treatment, a bulla forms over the treated area. An additional course of treatment can be applied in 1-2 weeks as needed. This treatment modality is safe for use in women who are pregnant because it is not systemically absorbed.

• Electrosurgery

• These modalities use high-frequency current to cut and coagulate warts. Electrodesiccation using a bipolar needle can be used to coagulate wart tissue deeply. This is most effective with external genital warts.
• LEEP uses a bipolar loop to vaporize and fulgurate affected tissue. It is primarily used to treat cervical SILs; however, it may also be used to remove large external genital warts.
• Electrosurgical methods usually require only local anesthesia and may be employed in an outpatient setting if the appropriate equipment is available.
• HPV DNA has been found in smoke plumes; therefore, procedures to evacuate the smoke and prevent inhalation must be used.

• Surgical removal

• Simple surgical excision with a scalpel, scissors, or curette can be performed under local anesthesia to remove warts and treat SILs of the genital tract.
• Mohs surgery can be performed by specially trained dermatologists to excise tissue in areas where maximum conservation is required. This method uses dermatopathology in conjunction with conservative excision of malignant lesions. It may be of particular assistance in managing verrucous carcinomas.

• Laser surgery (see Complications of Dermatologic Laser Surgery for further discussion)

• Carbon dioxide laser vaporization is an alternative surgical procedure that is typically used for treatment of refractory HPV disease or extensive warts of the anogenital/mucosal category. This precisely controlled modality conserves normal adjacent tissue. It is particularly useful in treatment of periurethral and vaginal warts and vaginal SILs.
• HPV DNA has been found in laser smoke plumes; therefore, procedures to evacuate the smoke and prevent inhalation must be used.

• Cavitron Ultrasonic Surgical Aspirator

• This device vibrates at a frequency of 23 kHz, which is an order of magnitude lower than the frequency of a diagnostic ultrasound. It destroys tissue through heat and cavitation.
• CUSA has been used extensively for cytoreduction of intra-abdominal tumors because of the ability to remove epithelium without damage to underlying tissue. Consequently, it has been employed as an alternative therapy for extensive anogenital warts.

Consultations:

• Consult a gynecologic oncologist for assistance in management of genital tract SILs and carcinomas, as well as exophytic cervical warts and giant condylomata.

• Consult a urologist or a urogynecologist for assistance with surgical management of urethral warts, penile condylomata, SILs, or carcinomas.

• Consult a colorectal surgeon for assistance with the surgical management of perianal condylomata or anal SILs or carcinomas.

• Consult an otolaryngologist for assistance with management of oropharyngeal papillomas or SCC.

• Consult a dermatologist in the following cases:
  • Consult a dermatologist for assistance with management of 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, which uses dermatopathology in conjunction with the conservative excision of malignant lesions, may be of particular assistance in managing verrucous carcinomas.

• Consult an infectious disease specialist for assistance in management of HPV disease in patients who are immunocompromised.

Diet: 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.

Activity: Certain activities are associated with an increased risk of HPV malignant transformation, particularly in the anogenital/mucosal category.

• Sexual activity

• A direct correlation exists between anogenital HPV infection and measures of sexual activity, such as the age of first intercourse and the lifetime number of sexual partners.
• Women with a history of cervical HGSIL or invasive 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, with relative risks of 5.6 and 4 respectively.
• Anal cancer has been strongly associated with male homosexuality and with specific male practices, such as engaging in receptive anal intercourse; relative risk is 33. However, the overall disease prevalence is higher in women than in men, with a female-to-male ratio of 1.5:1.

• Tobacco smoking

• Women who smoke tobacco have an increased risk of developing cervical neoplasia.
• Measurable amounts of a potent carcinogen, as well as several compounds from cigarette smoke, have been identified in the cervical mucus of females who smoke. These agents are likely to play a role in the increased prevalence of HPV malignant transformation of patients who smoke tobacco.

• Oral contraceptive use
  • Women who use oral contraceptives for longer than 5 years have an increased relative risk of developing cervical carcinoma.
  • This risk declines after stopping oral contraceptives, and no risk is demonstrated in users of less than 5 years duration.

• 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 is made from the leaves of the betel plant and is used in a manner similar to chewing tobacco.
• Ultraviolet and x-ray irradiation: EV is particularly susceptible to UV and x-ray irradiation; therefore, patients with EV should avoid activities that unnecessarily expose them to these forms of radiation.

MEDICATION

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Immune response modifiers -- These agents have immunomodulatory effects and are used for treatment of external anogenital warts or condyloma acuminatum.

Drug Name	Imiquimod (Aldara) -- Induces secretion of interferon alfa and other cytokines. Mechanisms of action are unknown.
Adult Dose	Apply 3 times per wk, leave on skin for 6-10 h, remove by washing; treatment not to exceed 16 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Not recommended for treatment of rectal, cervical, intravaginal, urethral, and intra-anal HPV infection; following surgery or drug treatment, do not use until genital/perianal tissue is healed; avoid sexual (ie, genital, anal, oral) and eye contact while the cream is on the skin; may weaken vaginal diaphragms and condoms, concurrent use is not recommended

Drug Name	Interferon alfa-n3 (Alferon N) and interferon alfa-2b (Intron A) -- Protein product manufactured from either a single-species recombinant DNA process or from pooled units of donated human leukocytes that have been induced by incomplete infection with a murine virus. Mechanisms by which it exerts antiviral activity are not understood clearly. However, modulation of the host immune response may play an important role. Indicated for intralesional treatment of refractory or recurring external condyloma acuminatum. Particularly useful for patients who have not responded satisfactorily to other treatment modalities (eg, podophyllin resin, surgery, laser, cryotherapy).
Adult Dose	Interferon alfa-n3: 0.05 mL (250,000 IU) per wart 2 times/wk for up to 8 wk; maximum recommended dose per treatment session is 0.5 mL (2.5 million IU) Interferon alfa-2b: 1 million IU injected into each lesion 3 times/wk on alternate d for 3 wk; maximum recommended dose per treatment session is 5 million IU
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity to mouse IgG, egg protein, or neomycin
Interactions	Potential risk of renal failure when administered concurrently with IL-2; theophylline may increase toxicity by reducing clearance; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Depression and suicidal ideation may be adverse effects of treatment; infrequently, severe or fatal GI hemorrhage has been reported; prior to initiation of therapy, perform tests to quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cells, and bone marrow hairy cells; monitor periodically (eg, monthly) during treatment to determine response to treatment; if no response within 6 mo, discontinue treatment; if a response occurs, continue treatment until no further improvement is observed and laboratory parameters have been stable for about 3 mo; not known whether continued treatment after that time is beneficial; because the manufacturing process, strength, and type of interferon (eg, natural human leukocyte interferon versus single-species recombinant interferon) may vary for different interferon formulations, changing brands may require a change in dosage (do not change interferon product without considering these factors); fever and other flulike symptoms associated with this product; caution in debilitating medical conditions (eg, unstable angina, uncontrolled congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus with ketoacidosis, coagulation disorders, severe myelosuppression, seizure disorders)

Drug Category: Antimitotic agents -- Interfere with mitosis. Many are chemotherapeutic agents. The drugs listed below are used specifically for treatment of external anogenital warts or condyloma acuminatum.

Drug Name	Podofilox (Condylox) -- Topical antimitotic that can be synthesized chemically or purified from plant families Coniferae and Berberidaceae (eg, species of Juniperus and Podophyllum). Treatment results in necrosis of visible wart tissue. Exact mechanism of action unknown.
Adult Dose	0.5% gel or solution applied to anogenital warts bid for 3 consecutive d, then discontinue; repeat cycle until no visible wart tissue or maximum of 4 cycles
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Avoid contact with eyes; if eye contact occurs, immediately flush eye with copious quantities of water and seek medical advice; not for use on mucous membranes of genital area, including urethra, rectum, and vagina; not to exceed frequency of application or duration of usage

Drug Name	Podophyllin (Podocon-25, Podofin) -- Derived from Mayapple (Podophyllum peltatum Linné) and contains the active agent podophyllotoxin, which is a cytotoxic agent that arrests mitosis in metaphase. American podophyllum contains one fourth the amount of Indian source.
Adult Dose	25% podophyllin in benzoin tincture applied only by a physician and never dispensed to a patient; reapply each wk for up to 6 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; diabetes; impaired peripheral circulation
Interactions	None reported
Pregnancy	X - Contraindicated in pregnancy
Precautions	Powerful caustic and severe irritant; do not use if surrounding tissue is swollen or irritated; do not apply 25% solution near mucous membranes; do not use large amounts; avoid contact with cornea (if contact occurs, flush with copious amounts of warm water); avoid use on mucous membranes, eyes, bleeding warts, moles, birthmarks, or unusual warts with hair

Drug Category: Antimetabolites -- Interfere with nucleic acid synthesis. Chemotherapeutic agents not formally approved for use against warts. Some studies have demonstrated a benefit against external anogenital warts or condyloma acuminatum.

Drug Name	Fluorouracil (Efudex) -- Interferes with synthesis of DNA and RNA, which creates thymine deficiency resulting in unbalanced growth and cell death.
Adult Dose	5% strength applied as thin layer 1-3 times/wk; therapy may be required for up to 10-12 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	X - Contraindicated in pregnancy
Precautions	Incidence of inflammatory reactions may occur with occlusive dressings; reports of vaginal ulcerations and vaginal adenosis with clear cell carcinoma following treatment; not recommended for treatment of vaginal condyloma; increased absorption through ulcerated or inflamed skin; minimize ultraviolet irradiation exposure during and immediately following treatment (reaction intensity may increase); only the 5% strength is recommended

Drug Category: Keratolytics -- Used to aid in removal of keratin in hyperkeratotic skin disorders, including corns, ichthyoses, common warts, flat warts, and other benign verrucae.

Drug Name	Trichloroacetic acid and bichloracetic acid (TCA & BCA) -- Extremely powerful keratolytic agents that rapidly penetrate and chemically cauterize skin, keratin, and other tissues. Can be used to treat nongenital cutaneous warts, as well as external anogenital warts or condyloma acuminatum.
Adult Dose	80-90% solution applied directly by physician per wk
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	External use only; restrict use to treatment areas only; avoid contact with eyes (if eye contact occurs, immediately flush with copious quantities of water and seek medical advice); not for use on premalignant or malignant lesions

Drug Name	Salicylic acid (Compound W) -- By dissolving the intercellular cement substance, salicylic acid produces desquamation of the horny layer of skin, while not affecting structure of viable epidermis. For removal of nongenital cutaneous warts, particularly common or plantar warts. Prior to application, wash affected area. May soak wart in warm water for 5 min. Dry area thoroughly.
Adult Dose	17% by weight solution or gel: Apply to wart and let dry bid/tid prn until wart removed for up to 12 wk 40% by weight solution adsorbed to medicated discs: Apply over wart and cover for 48 h, replace prn until wart removed for up to 12 wk
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Use of this medication with other topical drying agents (eg, tretinoin, sulfur, resorcinol, benzoyl peroxide) or topical medicated or alcohol-containing preparations (eg, aftershave, toiletries, skin cleansers, cosmetics) may have a cumulative drying or irritating effect, leading to desquamation and skin erosion
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Avoid contact with mucous membranes, normal skin surrounding warts, and eyes; immediately flush with water for 15 min if contact with eyes or mucous membranes occurs; avoid inhaling vapors; prolonged use in infants, people with diabetes, and patients with impaired circulation is contraindicated; not for use on moles, birthmarks, warts with hair growing from them, genital or facial warts, warts on mucous membranes, irritated skin, or any area that is infected or reddened

Drug Category: Miscellaneous topical ointment -- Kunecatechins is another topical product that has gain FDA approval for genital warts.

Drug Name	Kunecatechins (Veregen) -- Botanical drug product for topical use that consists of extract from green tea leaves. Mode of action unknown but does elicit antioxidant activity in vitro. Indicated for topical treatment of external genital and perianal warts (condylomata acuminatum) in immunocompetent patients.
Adult Dose	Apply topically tid; use approximately a 0.5-cm strand of ointment topically for each external genital or perianal wart
Pediatric Dose	less than 18 years: Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not evaluated for urethral, intravaginal, cervical, rectal, or intra-anal HPV disease and should not be used to treat these conditions; avoid application to open wounds, eyes, and nose; wash hands before and after application; avoid sexual contact while ointment is on skin; may cause application-site reactions, phimosis, inguinal lymphadenitis, urethral meatal stenosis, dysuria, genital herpes simplex, vulvitis, hypersensitivity, pruritus, pyodermitis, skin ulcer, erosions in the urethral meatus, and superinfection of warts and ulcers

Drug Category: Vaccines -- A human papillomavirus vaccine is now available for the prevention of HPV-associated dysplasias and neoplasia, including cervical cancer, genital warts (condyloma acuminata), and precancerous genital lesions. Girls and young women aged 9-26 years should receive the complete immunization series.

Drug Name	Papillomavirus vaccine (Gardasil) -- Quadrivalent HPV recombinant vaccine. First vaccine indicated to prevent cervical cancer, genital warts (condyloma acuminata), and precancerous genital lesions (eg, cervical adenocarcinoma in situ; cervical intraepithelial neoplasia grades 1, 2, and 3; vulvar intraepithelial neoplasia grades 2 and 3; vaginal intraepithelial neoplasia grades 2 and 3) due to HPV types 6, 11, 16, and 18. Vaccine efficacy mediated by humoral immune responses following immunization series.
Adult Dose	less than 26 years: 0.5 mL IM administered as 3 separate doses; administer second and third doses 2 and 6 mo after first dose, respectively >26 years: Not established
Pediatric Dose	less than 9 years: Not established >9 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Immunosuppressive therapies (eg, irradiation, antineoplastic agents, corticosteroids) may decrease immune response to vaccine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Shake well before administering; administer in deltoid region of upper arm or in higher anterolateral thigh; individuals with impaired immune responsiveness (eg, HIV infection, neoplastic disease, currently taking immunosuppressive drugs) may not elicit antibody response; because of IM administration, do not administer to individuals with bleeding disorders (eg, thrombocytopenia, coagulation disorders, anticoagulant therapy); common adverse effects include pain, swelling, erythema, and/or pruritus at injection site and fever

FOLLOW-UP

Deterrence/Prevention:

• The FDA has recently approved a vaccine for HPV.

Complications:

• Complications of wart treatment are rare. Complications are generally confined to the treatment site and include scarring and, in the case of genital warts, vulvodynia or hyperesthesia.

• Surgical complications of treating SILs are discussed in the articles involving those diseases. See the following articles for discussion of complications:

• Benign Vulvar Lesions

• Carbon Dioxide Laser Surgery of the Lower Genital Tract
• Complications of Dermatologic Laser Surgery

• Cervical Cancer

• Conization of Cervix

• Gynecologic Cryosurgery

• Urethral Warts

• Surgical Treatment of Vulvar Cancer

• Malignant Vulvar Lesions
• Penile Cancer
• Surgical Treatment of Vaginal Cancer

Prognosis:

• Approximately two thirds of patients with nongenital cutaneous warts experience a spontaneous regression within 2 years; however, some new warts may appear.

• Most patients with EV experience progression of their disease in the third or forth decades of life. Malignant transformation usually arises from actinic keratoses, particularly in patients who are exposed to irradiation. Patients who remain protected from x-rays and sun exposure generally have satisfactory health.

• Genital warts may spontaneously regress, remain unchanged, or increase in size. Treatment of these lesions does not affect the development of cervical cancer.

• Histologic evidence of HPV infection on a cervical Pap smear is similar to mild dysplasia. This subclinical disease often spontaneously regresses.

Patient Education:

• Educating women, particularly those who are socially and economically disadvantaged, about behaviors that enhance sexual risk reduction has a proven benefit in reducing the incidence of STDs. Reducing the incidence of STDs potentially could decrease HPV transmission and, consequently, the incidence of cervical carcinoma.

• For excellent patient education resources, visit eMedicine's Women's Health Center, Pregnancy and Reproduction Center, Cancer and Tumors Center, and Warts Center. Also, see eMedicine's patient education articles Birth Control Overview, Birth Control FAQs, Cervical Cancer, Warts, Genital
  Warts, Plantar Warts, and Pap Smear.

MISCELLANEOUS

Medical/Legal Pitfalls:

• The United States Centers for Disease Control (CDC) has specified Clinical Laboratory Improvement Amendments (CLIA) standards for cytologists to participate successfully in a cytology proficiency testing program to ensure the accuracy of interpretation of Pap smears. These guidelines can be found on the CDC Web site under the CLIA section for Gynecologic Cytology Standards. In order for laboratories in the United States to maintain certification for assessment of Pap smears and other laboratory testing, these standards must be followed.

Special Concerns:

• Pregnancy

• The risk of perinatal HPV transmission to the oropharyngeal mucosa of the neonate is low for mothers with latent infections or genital warts. The time between rupture of the amnion and delivery may be a critical factor in predicting transmission.

• Infants with HPV-positive nasopharyngeal aspirates in the immediate postpartum period are considered contaminated rather than infected with HPV because the virus generally clears from the neonate over several months after birth. Cesarean delivery for the prevention of vertical HPV transmission to the newborn is not indicated. However, in rare cases, cesarean delivery may be indicated if the pelvic outlet is obstructed by large genital warts.

• Sex 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 STDs.

• Condom use may reduce the transmission of HPV to uninfected sex partners, but it does not eliminate the risk. Furthermore, caution patients that treatment does not eliminate the possibility of HPV transmission because latent virus still may be present in tissues adjacent to treated areas.