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TABLE OF CONTENTS
Introduction......................................................... iii Table of Contents.................................................. iv 1. Human Papillomavirus....................................... 1 2. Classification and Taxonomy of Human Papilloma Virus............................................................. 34 3. Genital Warts.................................................. 50 4. Non-Genital Warts............................................ 57 5. Human Papillomavirus and Skin Tag: Is There Any Association? .................................................... 78 6. Mouth Cancer And Human Papillomavirus............... 84 7. Human Papillomavirus Mediated Carcinogenesis....... 86 8. Condom Use Reduce Risk of Infection With Human Papillomavirus................................................. 95 9. Prophylactic Human Papillomavirus Vaccine............ 97
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This is a non-commercial document; Used only as a school paperwork
HUMAN PAPILLOMAVIRUS
FROM: http://emedicine.medscape.com/article/219110-print AUTHORS: P.A Gearhart, MD, Assistant Professor of Obstetrics and Gynecology, University of Pennsylvania School of Medicine; T.C Randall, MD, Assistant Professor, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Pennsylvania School of Medicine; R.M Buckley, Jr, MD, Clinical Professor of Medicine, University of Pennsylvania School of Medicine; Consultant, Department of Medicine, Division of Infectious Diseases, Pennsylvania Hospital LAST UPDATED: Mar 8, 2011
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.
Table. Diseases and Associated HPV Subtypes Nongenital Cutaneous Disease Common warts (verrucae vulgaris) Plantar warts (myrmecias) Flat warts (verrucae plana) Butcher's warts (common warts of people who handle meat, poultry, and fish) Mosaic warts Ungual squamous cell carcinoma Epidermodysplasia verruciformis (benign) Epidermodysplasia verruciformis (malignant or benign) Nonwarty skin lesions Nongenital Mucosal Disease Respiratory papillomatosis Squamous cell carcinoma of the lung Laryngeal papilloma Laryngeal carcinoma Maxillary sinus papilloma Squamous cell carcinoma of the sinuses Conjunctival papillomas Conjunctival carcinoma Oral focal epithelial hyperplasia (Heck disease) Oral carcinoma Oral leukoplakia Squamous cell carcinoma of the esophagus Anogenital Disease
6, 11 6, 11, 16, 18 6, 11, 30 16, 18 57 16, 18 6, 11 16 13, 32 16, 18 16, 18 16, 18 HPV Type
HPV Type
1, 2, 4, 26, 27, 29, 41, 57, 65 1, 2, 4, 63 3, 10, 27, 28, 38, 41, 49 1, 2, 3, 4, 7, 10, 28 2, 27, 57 16 2, 3, 10, 12, 15, 19, 36, 46, 47, 50 5, 8, 9, 10, 14, 17, 20, 21, 22, 23, 24, 25, 37, 38 37, 38 HPV Type
Condylomata acuminata Bowenoid papulosis Bowen disease Giant condylomata (Buschke-Lwenstein tumors) Unspecified intraepithelial neoplasia Low-grade intraepithelial neoplasia Intermediate intraepithelial neoplasia High-grade intraepithelial neoplasia Carcinoma of vulva Carcinoma of vagina Carcinoma of cervix Carcinoma of anus Carcinoma in situ of penis (erythroplasia of Queyrat) Carcinoma of penis
6, 11, 30, 42, 43, 44, 45, 51, 52, 54 16, 18, 34, 39, 42, 45 16, 18, 31, 34 6, 11 30, 34, 39, 40, 53, 57, 59, 61, 62, 64, 66, 67, 68, 69 6, 11, 43 31, 33, 35, 42, 44, 45, 51, 52 16, 18, 56, 58 6, 11, 16, 18 16 16, 18, 31 16, 31, 32, 33 16 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 occurs only at the epithelial surface where the cells are ultimately sloughed into the environment. HPV lesions are thought to arise from the proliferation of infected basal keratinocytes. Infection typically occurs when basal cells in the host are exposed to infectious virus through a disturbed epithelial barrier as
would occur during sexual intercourse or after minor skin abrasions. HPV infections have not been shown to be cytolytic; rather, viral particles are released as a result of degeneration of desquamating cells. The HPV virus can survive for many months and at low temperatures without a host; therefore, an individual with plantar warts can spread the virus by walking barefoot. Virus multiplication is confined to the nucleus. Consequently, infected cells exhibit a high degree of nuclear atypia. Koilocytosis (from the Greek koilos, meaning empty) describes a combination of perinuclear clearing (halo) with a pyknotic or shrunken (raisinoid) nucleus and is a characteristic feature of productive papillomavirus infection. The HPV genome exists as a circular episomal DNA separate from the host cell nucleus in benign or low-risk HPV lesions, such as those typically associated with HPV types 6 and 11. The genomes of high-risk HPV types 16 and 18 are typically integrated into the host cell DNA in malignant lesions. Integration of the viral genome into the host cell genome is considered a hallmark of malignant transformation. HPV proteins E6 and E7 of high-risk serotypes have been shown to inactivate the host's tumor suppressor proteins p53 and Rb, thereby resulting in unregulated host cell proliferation and malignant transformation. Frequency United States HPV infection is the most common sexually transmitted infection in the United States. The number of patients identified with HPV disease has increased markedly during the past 20 years because of heightened awareness of the various manifestations of HPV disease and because of increased use of HPV DNA testing. Patients receiving immunosuppressive drugs and patients with defects in cell-mediated immunity, including those infected with the human immunodeficiency virus (HIV), are especially susceptible to developing HPV infections. In the United States, 2.5 million women are estimated to have an annual cytological diagnosis of a low-grade cervical cancer precursor. HPV infection causes virtually all cases of cervical cancer.1,2No deaths due to cervical cancer have been documented in women younger than 20 years. The United States National Cancer Institute publishes data on prevalence of worldwide cervical cancer via their online database.
The incidence of cervical cancer has decreased dramatically during the last century because of implementation of the Papanicolaou test (Pap Test, or Pap smear) beginning in the 1930s and 1940s. However, from 1990-2001, the annual number of estimated new invasive cervical cancers remained relatively constant, ie, 13,500 and 12,900, respectively. Anogenital warts, or condylomata acuminata, are the most commonly diagnosed viral sexually transmitted disease (STD) in the United States and the United Kingdom. The annual incidence is estimated between 500,000 and 1 million cases. From 1966-1986, the incidence of genital warts increased 5-fold. Approximately 7%-10% of the population has nongenital cutaneous warts. The percentages of cancers caused by oncogenic HPV are as follows:2 Cervical cancer - 100% Anal cancer - 90% Vulvar cancer - 40% Vaginal cancer - 40% Oropharyngeal cancer - 12% Oral cancer - 3% International In many lesser-developed countries, cervical cancer is the most common cancer among women because of the lack of effective screening programs that monitor cervical cytology by Pap smear.3However, a single round of HPV screening has been demonstrated to be far superior to conventional cytology in reducing the incidence of cervical cancer morbidity and mortality.4 The prevalence of high-risk HPV in women with normal cervical cytology varies among the different regions of the world. Although the global HPV prevalence was estimated to be approximately 12%, higher prevalences were noted in sub-Saharan Africa (24%), eastern Europe (21.4%), and Latin America (16.1%).5 In many developing nations, cervical cancer is the leading cause of cancer mortality among women. Worldwide, it is the second most common cause of cancer mortality among women. Mortality/Morbidity A direct correlation exists between anogenital HPV infection and measures of sexual activity, such as the age of first intercourse and the lifetime number of sexual partners. Women with a history of a cervical
high-grade squamous intraepithelial lesion (HGSIL) or invasive squamous cell carcinoma (SCC) of the cervix are at increased risk for subsequent development of invasive cancer in other tissues of the anogenital/mucosal category, particularly vaginal and anal carcinoma. In these patients, the relative risk of vaginal carcinoma is 5.6, and the risk of anal carcinoma is 4. Anal cancer has been strongly associated with male homosexuality and specific male practices, such as engaging in receptive anal intercourse. Relative risk is 33. However, the overall disease prevalence is higher in women than in men, with a female-to-male ratio of 1.5:1. Men who are infected with HPV are at risk to develop genital warts. The 24-month risk varied from 57.9% in men who were infected with HPV type 6 or type 11 to 2% in men who were infected with other HPV types.6 Cutaneous lesions typically produce benign self-limited warts (see Warts [Nongenital]). Patients who are immunosuppressed, particularly those with cutaneous malignant lesions, have a much higher incidence of EV-HPV infection than the general population. These lesions can undergo malignant transformation. Ten percent of patients with EV originate from consanguineous marriages, suggesting an autosomal recessive mode of inheritance (see Epidermodysplasia Verruciformis). Race From 1987-1991, the age-adjusted Cervical Cancer death rate reported by the US National Cancer Institute was higher among black women compared to white women, with a ratio of 6:1. Nongenital cutaneous warts are more common in whites than in people of African descent. Sex The overall prevalence of HPV in women is 22-35%. In men, the prevalence is 2-35% depending on the sexual practices of the population being studied. Age The prevalence of anogenital mucosal HPV infections is highest among college-aged women and men.
The incidence of high-risk HPV infections drops after age 20-24 years, and the incidence of low-risk HPV types plateaus after age 30-39 years (see below).7 Nongenital cutaneous warts are more common among teenagers and adults who work as meat, poultry, and fish handlers. The incidence approaches 10% in child and young adult populations. However, nongenital cutaneous warts rarely occur in people younger than 5 years and usually regress within 2 years. EV develops at an average age of onset of 6 years, and, beginning in the fourth decade of life, the lesions can undergo malignant transformation into invasive SCC. The prevalence of HPV infection stratified by age in US females is as follows:7 Age 14-59 years - 26.8% Age 14-19 years - 24.5% Age 20-24 years - 44.8% Age 25-29 years - 27.4% Age 30-39 years - 27.5% Age 40-49 years - 25.2% Age 50-59 years - 19.6% CLINICAL History Anogenital warts Condylomata acuminata are exophytic cauliflowerlike lesions that are usually found near moist surfaces. They may be observed in the perianal area, vaginal introitus, vagina, labia, and vulva. Genital warts may also be found on dry surfaces, such as the shaft of the penis. Genital warts include smooth papular warts and keratotic warts, the latter of which resemble nongenital cutaneous warts because of their thickened bumpy surface. Genital flat warts are subclinical lesions that typically appear on the cervix. Colposcopic examination with 3% acetic acid solution is required for identification. Cervical disease Most cervical infections are either latent or subclinical and, as such, are asymptomatic. These infections are detected on Pap smear and are reported as either a low-grade squamous intraepithelial lesion (LGSIL) or
a high-grade squamous intraepithelial lesion (HGSIL). Further examination with 3-5% acetic acid and colposcopy shows characteristic acetowhite changes and abnormal blood vessels indicative of human papillomavirus (HPV)triggered dysplasia. Patients who have neglected to obtain annual Pap testing for several years or more and who have an HGSIL that has progressed to invasive cancer of the cervix may report vaginal bleeding between periods or after sexual intercourse, dyspareunia, and fullness in the pelvis. Anal cancer The most common presenting symptoms of SCC of the anus are rectal bleeding and sensation of a mass. This may be attributed mistakenly to hemorrhoids. Fifty percent of men who are homosexual and have SCC of the anus have a history of anorectal warts; however, only 20% of women with SCC and men who are not homosexual have this history. Nonanogenital mucosal disease HPV types 6 and 11 have been isolated on nonanogenital mucosal surfaces. Warts have been discovered in the nares, mouth, larynx, and conjunctiva. HPV types 6 and 11 are associated with respiratory papillomas that are probably the result of intrapartum transmission when the infant passes through the birth canal of a mother who is infected with HPV. However, isolated case reports exist of respiratory papillomatosis after cesarean delivery. Patients with laryngeal papillomas present at an average age of 3 years, most frequently with hoarseness. Nongenital cutaneous HPV Cutaneous lesions typically produce benign self-limited warts. Deep plantar warts occur most commonly as solitary lesions that may become black and painful prior to spontaneous regression. They may contain small black "seeds," which are thrombosed capillaries. Common warts can occur on any skin surface but are usually found on the hands and fingers. They appear as skin-colored, exophytic, rough papules and nodules that have minimal scaling. Autoinoculation from a wart on one finger may cause the occurrence of warts on an adjacent finger or other skin surface, so-called kissing warts. Warts that occur in people who handle meat and fish often have large cauliflowerlike plaques.
Flat warts most often occur in groups of small plaques less than 5 mm in diameter on the face and hands. Regression usually occurs spontaneously after several years, and pruritus or erythema occur several weeks prior to their disappearance. Epidermodysplasia verruciformis The malignant conversion of skin lesions usually begins in the fourth and fifth decades of life. Premalignant lesions usually first arise on the forehead and other sun-exposed areas. The tumors are either benign papillomas and seborrheic keratoses or premalignant actinic keratoses and SCC. Epidermodysplasia verruciformis (EV) tumors are locally destructive. They develop slowly and have weak metastatic potential if no cocarcinogens, such as x-ray or ultraviolet B irradiation, are applied. Polymorphic, plane wartlike, 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. The images below demonstrate extensive anogenital condyloma acuminata.
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.
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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. DIFFERENTIAL DIAGNOSES 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 Vestibular Papillomatosis
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 Epidermodysplasia Verruciformis Squamous Cell Carcinoma, Eyelid Warts (Genital) Giant Condylomata Acuminata of Buschke and Lwenstein Acanthosis Nigricans Acrochordon Corns and Calluses Keloid and Hypertrophic Scar Keratoacanthoma Lichen Planus
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Squamous Cell Carcinoma Warts, Plantar Bowenoid Papulosis Warts
Psoriasis (Plaque) Seborrheic Keratosis Malignant Tumors of the Mobile Tongue WORKUP
Laboratory Studies Cytologic testing Cervical cytologic testing using the Pap test is the standard screening procedure for cervical neoplasia. Guidelines for cervical cancer screening were recently changed to include a delay in the initiation of screening and a less-frequent screening interval.8The initial Pap test should be performed at age 21 years and then every two years afterward if the initial screening test result is normal. The interval can be increased to every 3 years in women older than 30 years who are at low risk for cervical dysplasia and in whom 3 consecutive Pap tests show normal results. Although cervical metaplasia is prevalent among sexually active adolescents, meaning that they are at an increased risk of HPV infection, there is a high rate of immune system clearance within 1-2 years. Furthermore, the rate of invasive cervical cancer among adolescents is extremely rare. Most cervical dysplasias among adolescents resolve spontaneously. Because of the increased risk of preterm births among women who have undergone excisional procedures for cervical dysplasia and the fact that adolescents have most of their childbearing years ahead of them, delaying screening for cervical cancer has been shown to be an optimal strategy in this population. 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 salinemoistened 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
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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 human papillomavirus (HPV). Thin Prep and SurePath are the 2 methods currently approved by the US Food and Drug Administration (FDA). PV 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 cocollection 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.
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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 human papillomavirus (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.
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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
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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 Linn) 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
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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. In 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 lowgrade cervical intraepithelial neoplasia (CIN I). It is not recommended for
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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.
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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 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, which uses dermatopathology in conjunction with the conservative excision of malignant lesions, may be of particular assistance in managing verrucous carcinomas.
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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
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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. Immune Response Modifiers These agents have immunomodulatory effects and are used for treatment of external anogenital warts or condyloma acuminatum.
Imiquimod (Aldara) Induces secretion of interferon alfa and other cytokines. Mechanisms of action are unknown. Dosing Adult Apply 3 times per wk, leave on skin for 6-10 h, remove by washing; treatment not to exceed 16 wk Pediatric Not established Interactions None reported Contraindications Documented hypersensitivity Precautions Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals 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
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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). Dosing Adult 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: Not established 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 Contraindications Documented hypersensitivity to mouse IgG, egg protein, or neomycin Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus 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
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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)
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.
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. Dosing Adult 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 Not established Interactions None reported Contraindications Documented hypersensitivity Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus 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 Podophyllum resin (Podocon-25, Podofin)
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Derived from Mayapple (Podophyllum peltatum Linn) 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. Dosing Adult 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 Not established Interactions None reported Contraindications Documented hypersensitivity; diabetes; impaired peripheral circulation Precautions Pregnancy X - Contraindicated; benefit does not outweigh risk 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
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.
Fluorouracil topical (Efudex) Interferes with synthesis of DNA and RNA, which creates thymine deficiency resulting in unbalanced growth and cell death. Dosing Adult 5% strength applied as thin layer 1-3 times/wk; therapy may be required for up to 10-12 wk Pediatric Not established Interactions None reported
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Contraindications Documented hypersensitivity Precautions Pregnancy X - Contraindicated; benefit does not outweigh risk 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
Keratolytics Used to aid in removal of keratin in hyperkeratotic skin disorders, including corns, ichthyoses, common warts, flat warts, and other benign verrucae.
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. Dosing Adult 80-90% solution applied directly by physician per wk Pediatric Administer as in adults Interactions None reported Contraindications Documented hypersensitivity Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus 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 Salicylic acid (Compound W)
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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. Dosing Adult 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 Administer as in adults Interactions Use of this medication with other topical drying agents (eg, tretinoin, sulfur, resorcinol, benzoyl peroxide) or topical medicated or alcoholcontaining preparations (eg, aftershave, toiletries, skin cleansers, cosmetics) may have a cumulative drying or irritating effect, leading to desquamation and skin erosion Contraindications Documented hypersensitivity Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus 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
Vaccines Two human papillomavirus (HPV) vaccines are 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.9The quadrivalent vaccine is also indicated for boys and young men aged 9-26 years. A randomized,
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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.10 Vaccination of men who have sex with men (MSM) appears to decrease the incidence of anal cancer and genital warts. The cost effectiveness of this intervention is maximized when vaccination is given as early as age 12 years.11
Papillomavirus vaccine, quadrivalent (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. Indicated for prevention of condyloma acuminata caused by HPV types 6 and 11 in boys, men, girls, and women aged 9-26 years. Also indicated in people aged 9-26 years for prevention of anal cancer and associated precancerous lesions. Dosing Adult CDC guidelines: 9-26 years: 0.5 mL IM for 3 doses administered at schedule of 0, 2, and 6 mo CDC recommends routine vaccination at age 11 or 12 y with either HPV2 or HPV4; may begin vaccination series as early as age 9 y If age 26 y reached before vaccination series completed, remaining doses can be administered after age 26 y Pediatric <9 years: Not established 9 years or older: Administer as in adults Interactions Immunosuppressive therapies (eg, irradiation, antineoplastic agents, corticosteroids) may decrease immune response to vaccine Contraindications Documented hypersensitivity Precautions Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals Precautions
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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 Papillomavirus vaccine, bivalent (Cervarix) Recombinant human papillomavirus (HPV) vaccine prepared from L1 protein of HPV types 16 and 18. Indicated in girls and women (aged 10-25 y) for prevention of diseases caused by oncogenic HPV types 16 and 18 (ie, cervical cancer, cervical intraepithelial neoplasia grade 2 or higher, adenocarcinoma in situ, cervical intraepithelial grade 1). Dosing Adult Labeled indication Girls and women aged 10-25 years: 0.5 mL IM for 3 doses administered at schedule of 0, 2, and 6 mo CDC guidelines: Girls and women aged 9-26 years: 0.5 mL IM for 3 doses administered at schedule of 0, 2, and 6 mo CDC recommends routine vaccination at age 11 or 12 y with either HPV2 or HPV4; may begin vaccination series as early as age 9 y If age 26 y reached before vaccination series completed, remaining doses can be administered after age 26 y Pediatric 9 years: Administer as in adults Interactions Immunosuppressive therapies (eg, irradiation, antineoplastic agents, corticosteroids) may decrease immune response to vaccine Contraindications Documented hypersensitivity Precautions Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals Precautions Syncope may occur (observe for 15 min after administration); tonic/clonic movements and other seizurelike activity reported (if associated with syncope, usually transient and responds to supine or Trendelenburg positioning)
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Shake well before administering; administer in deltoid region of upper arm or in upper 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 risks (eg, thrombocytopenia, coagulation disorders, anticoagulant therapy); common local adverse effects (>20%) include pain, erythema, and inflammation at injection site; general adverse effects (>20%) include fatigue, headache, myalgia, GI symptoms, and arthralgia
Miscellaneous Topical Ointment Kunecatechins is another topical product that has gain FDA approval for genital warts.
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. Dosing Adult Apply topically tid; use approximately a 0.5-cm strand of ointment topically for each external genital or perianal wart Pediatric <18 years: Not established Interactions None reported Contraindications Documented hypersensitivity Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus 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
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FOLLOW-UP Deterrence/Prevention The vaccine currently marketed in the United States prevents infection by human papillomavirus (HPV) types 6, 11, 16, and 18. It is most effective when given before the onset of sexual activity. The impact of this vaccine on the incidence of cervical cancer will not be observable for years.12Its effectiveness will depend on the duration of immunity and will be optimized by achieving maximum coverage of the target population.13 Vaccination against HPV types 16 and 18 is most effective in preventing infections from these viruses in females who have not previously been infected with these types.14 Most investigators agree that routine immunization in females should begin at approximately age 12 years. Since the vaccine has been widely available only for a few years, catch-up vaccinations are currently recommended in previously unvaccinated females beginning at age 13 years and ranging to an upper limit of age 18-26 years.15,16 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
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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 epidermodysplasia verruciformis (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 Medicolegal 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.
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Special Concerns Pregnancy The risk of perinatal human papillomavirus (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. Garland et al (2009) analyzed pregnancy and infant outcomes in women who received prophylactic quadrivalent HPV vaccine prior to becoming pregnant. During the study period, 1,796 vaccine and 1,824 placebo recipients became pregnant, resulting in 2,008 and 2,029 pregnancies with known outcomes. No significant difference was observed for live birth, fetal loss, or spontaneous abortion. Neonates with 1 or more congenital anomalies were observed in 40 births to vaccinated women and in 30 births to women given placebo (P =0.2). The anomalies were varied and consistent with those commonly observed in the general population. Administration of quadrivalent HPV vaccine prior to pregnancy does not appear to increase fetal risk. Surveillance continues to further evaluate the vaccine for any associated congenital anomalies.17 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. A study by Wawer et al showed that women were less likely to acquire high-risk infection with HPV if their partners were circumcised.18However,
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it is important to note that circumcision does not eliminate the risk of transmitting HPV.
REFERENCES 1. Bosch FX, Manos MM, Muoz N, Sherman M, Jansen AM, Peto J, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst. Jun 7 1995;87(11):796-802. [Medline]. 2. Parkin DM, Bray F. Chapter 2: The burden of HPV-related cancers. Vaccine. Aug 31 2006;24 Suppl 3:S3/11-25. [Medline]. 3. Sankaranarayanan R, Nene BM, Shastri SS, Jayant K, Muwonge R, Budukh AM, et al. HPV screening for cervical cancer in rural India. N Engl J Med. Apr 2 2009;360(14):1385-94. [Medline]. 4. Schiffman M, Wacholder S. From India to the world--a better way to prevent cervical cancer. N Engl J Med. Apr 2 2009;360(14):1453-5. [Medline]. 5. Bruni L, Diaz M, Castellsague X, Ferrer E, Bosch FX, de Sanjose S. Cervical human papillomavirus prevalence in 5 continents: meta-analysis of 1 million women with normal cytological findings. J Infect Dis. Dec 15 2010;202(12):1789-99. [Medline]. 6. Arima Y, Winer RL, Feng Q, Hughes JP, Lee SK, Stern ME, et al. Development of genital warts after incident detection of human papillomavirus infection in young men. J Infect Dis. Oct 15 2010;202(8):1181-4. [Medline]. 7. Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, et al. Prevalence of HPV infection among females in the United States. JAMA. Feb 28 2007;297(8):813-9. [Medline]. 8. [Guideline] ACOG Committee on Practice Bulletins--Gynecology. ACOG Practice Bulletin no. 109: Cervical cytology screening. Obstet Gynecol. Dec 2009;114(6):1409-20. [Medline]. 9. [Guideline] FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. May 28 2010;59(20):6269. [Medline]. 10. Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. N Engl J Med. Feb 3 2011;364(5):401-11. [Medline]. 11. Kim JJ. Targeted human papillomavirus vaccination of men who have sex with men in the USA: a cost-effectiveness modelling analysis. Lancet Infect Dis. Dec 2010;10(12):845-52. [Medline]. 12. Haug CJ. Human papillomavirus vaccination--reasons for caution. N Engl J Med. Aug 21 2008;359(8):861-2. [Medline]. 13. Kim JJ, Goldie SJ. Health and economic implications of HPV vaccination in the United States. N Engl J Med. Aug 21 2008;359(8):821-32. [Medline]. 14. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. May 10 2007;356(19):1915-27. [Medline]. 15. Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER. Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. Mar 23 2007;56:1-24. [Medline]. 16. [Guideline] Saslow D, Castle PE, Cox JT, Davey DD, Einstein MH, Ferris DG. American Cancer Society Guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin. Jan-Feb 2007;57(1):7-28. [Medline]. 17. [Best Evidence] Garland SM, Ault KA, Gall SA, Paavonen J, Sings HL, Ciprero KL, et al. Pregnancy and infant outcomes in the clinical trials of a human papillomavirus type 6/11/16/18 vaccine: a combined analysis of five randomized controlled trials. Obstet Gynecol. Dec 2009;114(6):117988. [Medline]. 18. Wawer MJ, Tobian AA, Kigozi G, Kong X, Gravitt PE, Serwadda D, et al. Effect of circumcision of HIV-negative men on transmission of human papillomavirus to HIV-negative women: a randomised trial in Rakai, Uganda. Lancet. Jan 15 2011;377(9761):209-18. [Medline].
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CLASSIFICATION AND TAXONOMY OF HUMAN PAPILLOMAVIRUSES

FROM: http://www.metapathogen.com/papillomavirus/ AUTHOR: Metapatogen Contributor Information and Disclosures LAST UPDATED: February 21, 2011
General information
Papillomaviruses (PVs) (Papillomaviridae) are small, nonenveloped DNA viruses infecting birds and most mammals including humans. Papillomaviruses are causative agents of usually benign tumors (warts, papillomas), however, several human papillomavirus types (including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 66) have been classified as group 1 carcinogens by the International Agency for Research in Cancer (IARC). Among them HPV16 accounts for almost 60% occurrences of cervical cancer, the second largest cause of cancer-related death in women worldwide. Second most important cancer-associated PV is HPV type 18. Papillomaviruses are absolutely species-specific and extremely tissue-specific. The individual viruses show tropism for either cutaneous or mucosal surfaces usually at specific sites of the body, and, within these groups, they can be separated into high, moderate or low risk types, depending on their oncogenic potential. Most people in the world are probably infected with at least one if not several types of HPV during their life.
Place among other viruses Papillomaviruses have circular double-stranded DNA genomes and nonenveloped icosahedral capsids. The structure is very similar to Polyomaviridae (polyomaviruses). In the past PVs and Polyoma-viruses were placed in a common family, Papoviridae. However later in 1980's sequence and functional studies shown that these viruses are very different: they do not share any substantial amount of sequence similarity, with the exception of a small homologous segment in their Tantigen and E1 genes, respectively; papillomaviruses have genome sizes about 8 kb whereas polyomaviruses have genome sizes closer to 5 kb;
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papillomaviruses' transcription goes in one directions while polyomaviruses possess two transcription units that read toward one another. Therefore, PVs were separated into their own family Papillomaviridae. Principles of classification based on genotype PVs genomes are fairly static: sequence changes by mutation or recombination are rare events and apparently occur at frequencies not very different from those of the DNA genomes of the infected host organisms. Maximum divergence occurs between viruses sampled from ethnic groups that evolved for a long time without interactions, for example Africans and American Indians. It leads to the conclusion that each HPV type was with the human species since our origin, and evolved and spread together with the infected cohort. There was never time or an ethnic group without common warts, genital warts, etc. The following taxonomic groups of PVs were developed:
Genera Genera are designated by a Greek letter, for example Alphapapillomavirus. Presently there are 16 genera of papillomaviruses which are identified by Greek letters. The clinically most important genus is referred as alpha-papillomaviruses. It contains all HPV types associated with mucosal and genital lesions. Species Species are designated by a number, for example, Human papillomavirus - 10 Types Types are designated by alphanumeric characters, for example,Human papillomavirus type 28. Currently more than 100 types of papillomaviruses were identified. First PV types were isolated in 1970s. L1 ORF is most conserved gene within the PVs genome and has therefore been used for the identification of new PV types over the past decades. New type is defined when the L1 sequence differs more than 10% from the closest known PV type. The type is assigned after isolation and characterization of the complete genome. Subtypes Differences between 2% and 10% homology define a subtype. Variants Differences less than 2% define a variant.
Genome structure of HPV
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All PVs contain a double-stranded, circular DNA genome approximately 8 kb in size that can be divided into 3 major regions. These regions are separated by two polyadenylation (pA) sites: early pA and late pA.
Long Control Region (LCR) Also, non-coding region (NCR), or, upstream regulatory region (URR), is a segment of about 850 bp (10% of the HPV genome). It contains the origin of replication and multiple transcription binding sites. Early Region This region occupies over 50% of all genome from its 5' half and encodes six common open reading frames (ORFs) - E1, E2, E4, E5, E6 and E7. o Early pA Late Region This region covers almost 40% of the virus genome and lies downstream of the early region and encodes L1 and L2 ORFs for translation of a major (L1) and a minor (L2) capsid proteins. o Late pA
Human Papillomavirus proteins
Nonstructural proteins Regulatory proteins
E1 protein 70-kDa ATP-dependent helicase that binds specifically to the origin to initiate replication of the virus. Essential for viral DNA replication initiation stage and the regulation of early transcription. E2 protein A polypeptide of 350-500 amino acids in length. Often referred to as E2-TA or E2 transactivator. Transcription factor essential for viral DNA replication. Binds E1 to facilitate the replication initiation of the viral DNA and ultimately the viral genome's encapsidation. E4 protein Interacts with cytoskeletal proteins, facilitates viral assembly. Expressed at productive infection stage. E5 protein Some transforming activity, up-regulate growth factor receptors. E6 protein Oncogene. Directs p53 (tumor suppressor protein) ubiquitinmediated degradation. Together with E7 involved in malignant transformation and eventual immortalization of keratinocytes.
Oncogenes
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E7 protein Oncogene proteins from papillomavirus that deregulate the cell cycle of infected cells and lead to neoplastic cell transformation. Papillomavirus E7 proteins have been shown to interact with various regulators of the cell cycle including retinoblastoma protein and certain cyclindependent kinase inhibitors. Year introduced: 2006.
Structural capsid proteins L1 protein: major capsid protein L2 protein: minor capsid protein
Human Papillomavirus life cycle Completion of the viral life cycle is absolutely dependent on a process of keratinocyte differentiation. Theoretically, time from infection to release of infective virions can take as short as 3 weeks because within this time keratinocytes usually undergo complete differentiation and desquamate. In reality, this period can vary from weeks to months.
Infection Viruses infect primitive basal keratinocytes presumably via tiny tears. Very low amount of viruses (multiplicity of infection, MOI) is sufficient. After the initial infection the viral DNA is delivered to the cell nucleus in complex with the L2 minor capsid protein. Viral replication
Replication initiation At some time after infection there is an initial round of viral DNA replication. This process is highly dependent on presence of origin of replication and the levels of E1 and E2 proteins which expression is tightly regulated on transcriptional as well as translational levels. After viral copies number reached approx. 50-100 per cell, the cell is thought to enter next, proliferating stage, of its differentiation cycle. Maintenance replication The stage of episomal (extrachromosomal) viral replication. The viral genome is maintained in the dividing cells to sustain a persistent infection. The maintenance replication is coupled to that of the host cell and, on average, each genome is replicated once per cell cycle to give an overall constant and very low copy number (estimated to be less than 20 copies per cell). This process depends on the host's cell mitotic activity which supplies necessary enzymes for the viral replication such as DNA polymerases and other factors. The viral proteins E6 and E7 are expressed at this stage. By interfering with expression of p53 and retinoblastoma proteins, respectively, they delay the differentiation and prolong proliferation of the cells. At this stage integration of viral DNA into the host's genome might occur. Vegetative replication
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As soon as infected keratinocytes start to enter differentiation stage, the viral genomes are amplified to a high copy number (at least 1000 copies/cell) and are packaged in the capsids of infective virions. The viral proteins E6 and E7 are absolutely required for viral vegetative amplification in terminally differentiated cells because they inhibit apoptosis, induce Sphase like state and keep cellular DNA synthesis machinery available for the assembling viruses. Eventually, majority of the virus-laden keratinocytes cease to divide at the final stage of differentiation, desquamate during skin-to-skin or mucosa-to-mucosa contact and transmit viruses to another host. A small portion of the cells might keep dividing thus maintaining a chronic infection.
Mechanism of cancer induction The highest risk of cancer development occurs after prolonged persistent infection. The virus establishes the persistent infection at maintenance replication stage by obviating host's immune responses and, ultimately, integrating its DNA into the host's genome. In natural genital HPV infection, lesions are cleared as a result of a successful cell-mediated immune response directed against early (E1 and E2) HPV proteins. Also, thehumoral (mediated by antibodies in the blood) immune response might be induced against late HPV proteins, specifically, against capsid proteins L1 and L2. The latter reaction is usually quite weak because free virus particles are shed from the surface of squamous epithelia with poor access to blood and lymphatic vessels where immune responses are initiated, furthermore, because the virions are accumulated in cells destined for death by natural causes, there is no viral-induced cytolysis or necrosis and, therefore no inflammation. As it was mentioned before, the viral oncogenes E6 and E7, working in tandem, prolong proliferation (cell division) of cells by interfering with their differentiation program. By-product of this role in high-risk HPV infections is the deregulation of growth control in the infected cells that leads to development of neoplasia and, ultimately, invasive cancer. Expression of E6 and E7 proteins is tightly controlled by E2 protein, which is responsible for the viral replication and assembly. At some point of persistent episomal (extrachromosomal) viral replication, the integration of the viral genome into the host's genome might occur. The integration usually causes deletion or disruption of E2 while retaining a variable segment, including the E6 and E7 oncogenes and the LCR. Resulting sharp down-regulation of E2 expression in affected cells leads to overexpression of E6 and E7. The cells acquire a strong growth advantage and undergo clonal expansion manifested in neoplastic lesions. In addition, these cells also show genomic instability that further increases the risk of malignant transformation and immortalization of
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the affected cell lineages. Complete clearance of the residual viral episomes is considered a key step in HPV-related carcinogenesis because it results in full deregulation of expression of the oncogenes. Interestingly, interferon response is a powerful systemic defense reaction of organism against invasion of viruses. Induction of the interferon during the phase of HPV infection when the integration events took place but some episomes are still present can lead to quick clearance of the persisting episomes and launch unbridled carcinogenesis.
Development of cervical cancer caused by HPV16

Initial infection Delivery of infective virions to the host's basal epithelial layer. Viral persistence Maintenance replication with concomitant transformation of the infected cells. Most cervical HPV infections are cleared or suppressed to undetectable levels by cell-mediated immunity within 1-2 years of exposure. Cervical intraepithelial neoplasia (CIN) A malignancy arising in uterine cervical epithelium and confined thereto, representing a continuum of histological changes ranging from welldifferentiated CIN 1 (formerly, mild dysplasia) to severe dysplasia/ carcinoma in situ, CIN 3. The lesion arises at the squamocolumnar cell
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junction at the transformation zone of the endocervical canal, with a variable tendency to develop invasive epidermoid carcinoma, a tendency that is enhanced by concomitant human papillomaviral infection. (Segen, Dictionary of Modern Medicine, 1992) Cervical intraepithelial neoplasia grade 1 (CIN1) Also, uterine cervical dysplasia. CIN1 is an insensitive hystopathological manifestation of HPV infection. For any given type of carcinogenic HPV, diagnosing CIN1 does not predict higher risk of progression to CIN3 than does negative biopsy. Patients confirmed with the infection (by detection and genotyping of the virus DNA), which had manifested in CIN1 (detected by Pap test and other cytology-based methods) are usually diagnosed only as having abnormalities and are not targeted for treatment. Instead, they might be scheduled for a follow-up examination without falsely informed as being at risk of cancer. Precancer The time between infection and appearance of the first microscopic evidence of precancer can be quite short, often within 5 years. The average age of diagnosis of precancer varies from 25 to 35 years and depends on the average age at the first intercourse and on the intensity of screening. In case of highly carcinogenic HPV16 precancer diagnosis can reach as high as 40% of all detected infections. Cervical intraepithelial neoplasia grade 2 (CIN2) CIN2 is heterogeneous and sometimes is produced by noncarcinogenic types of HPV. CIN2 should be treated, often simple outpatient procedures (for example, cryotherapy) with subsequent follow-up exams are sufficient. Cervical intraepithelial neoplasia grade 3 (CIN3) Carcinoma in situ. A lesion with cytological characteristics associated with invasive carcinoma but the tumor cells are confined to the epithelium of origin, without invasion of the basement membrane. In case of CIN3 undifferentiated cells with fixed genetic abnormalities have replaced almost the full thickness of the cervical epithelium. Without immediate treatment CIN3 progresses to invasive cancer. Invasive cancer Also called infiltrating cancer. Cancer that has spread beyond the layer of tissue in which it developed and is growing into surrounding, healthy tissues (Dictionary of cancer terms, NCI). The peak risk of invasive cervical cancer occurs at 35-55 years of age. The invasive cervical cancer is graded from grade I to IV. Treatment of grade I requires surgery of different degrees of invasiveness. In many
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cases patient's fertility can be preserved. Higher grades might require the surgery to be accompanied with radio- or chemotherapy.
Vaccination Vaccinations are the most effective means we have for prevention of infectious diseases including Human Papilloma Viruses (HPVs). Active component of HPV VLP (virus-like particles) vaccines is major capsid protein L1. To prevent cervical cancer, HPV vaccination is primarily aimed at HPV16 and HPV18. Intramuscular injection of the vaccines induces high titers of neutralizing antibody, more than 50 times the titers induced by natural infection. Two VLP vaccines targeting HPV16 and HPV18 have been developed and extensively tested so far:

Gardasil (Merk) quadrivalent vaccine. This vaccine also targets HPV6 and HPV11. Cervarix (GlaxoSmithKline) bivalent vaccine. This vaccine uses a new proprietary adjuvant to boost immuno-genicity (ability to induce both humoral as well as cell-mediated immunity). Furthermore, Cervarix, has shown evidence of protection against infections by related carcinogenic viruses, such as HPV45 and HPV31.
Both vaccines have shown near perfect efficacy against persistent HPV infections and related histological endpoints, such as CIN2+, up to 5-7 years after first vaccination. The vaccines are generally safe. Serious adverse vaccine-related side effects occurred in 0.1% of the participants and included bronchospasms, gastroenteritis, headache, hypertension, vaginal hemorrhage, injection site pain, and impaired movement. The vaccines are not recommended for individuals with allergy to yeasts and other vaccine components. At present, main target group for HPV vaccinations are girls and young women without known exposure to the target HPV types. Ideally, the vaccination should protect them from persistent infections through the age of greatest risk of exposure - before they established relationship with a stable sexual partner. It should be noted that the majority of women, regardless of age and exposure to the infection, might benefit from the vaccination (should be determined on individual basis). It must be emphasized, however, that the vaccination is not a treatment for anogenital warts, cervical intraepithelial neoplasia, or cervical cancer. Detailed taxonomy of Human Papillomavirus
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Alphapapillomavirus A genus of DNA viruses in the family papillomaviridae. They preferentially infect the anogenital and oral mucosa in humans and primates, causing both malignant and benign neoplasms. Cutaneous lesions are also seen. Year introduced: 2007 Human papillomavirus - 10 Human papillomavirus type 10 Carlson JA et al. Detection of human papillomavirus type 10 DNA in eccrine syringofibroadenomatosis occurring in Clouston's syndrome. J Am Acad Dermatol. 1999 PMID: 10025758 Human papillomavirus type 28 Favre M et al. Human papillomavirus type 28 (HPV-28), an HPV-3-related type associated with skin warts. J Virol. 1989 Nov PMID: 2552164. Human papillomavirus type 29 The cloning and partial characterization of human papillomavirus (HPV) type 29 is presented. By hybridization analyses, this virus appears to be related to HPV types associated with common warts and HPV types associated with flat warts (PMID: 2552165). Human papillomavirus type 3 Yoo H et al. Detection and identification of human papillomavirus types isolated from Korean patients with flat warts. Microbiol Immunol. 2005PMID: 16034206 Human papillomavirus type 77 Human Papillomavirus type 77 is a skin type found in non-melanoma skin cancers of immuno-compromised individuals (PMID: 16650526). Human papillomavirus (HPV77) associated with skin cancer displays UV responsiveness (PMID: 10508168). Human papillomavirus type 94 Human papillomavirus - 16 Human papillomavirus type 16 A type of alphapapillomavirus especially associated with malignant tumors of the cervix and the respiratory mucosa. year introduced: 2006. Have been classified as group 1 carcinogens by the International Agency for Research in Cancer (IARC) (PMID: 17979705 ). 52.6% prevalence in cervical pre-invasive lesions (PMID: 19107962). Human papillomavirus type 31 Have been classified as group 1 carcinogens by the International Agency for Research in Cancer (IARC) (PMID: 17979705).10.9% prevalence in cervical pre-invasive lesions (PMID: 19107962). Human papillomavirus type 33 Have been classified as group 1 carcinogens by the International Agency for Research in Cancer (IARC) (PMID: 17979705 ). Human papillomavirus type 35 Have been classified as group 1 carcinogens by the International Agency for Research in Cancer (IARC) (PMID: 17979705). Human papillomavirus type 52 Have been classified as group 1 carcinogens by the International Agency for Research in Cancer (IARC) (PMID: 17979705). Human papillomavirus type 58 Have been classified as group 1 carcinogens by the International Agency for Research in Cancer (IARC) (PMID: 17979705).
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Human papillomavirus type 67 The complete nucleotide sequence of human papillomavirus type 67 (HPV 67) cloned from a vaginal intraepithelial neoplasia, has been determined. (PMID: 9857984). Human papillomavirus - 18 Human papillomavirus type 18 A type of human papillomavirus especially associated with malignant tumors of the genital and respiratory mucosa. year introduced: 2006. HPV-18 is the second most prevalent human papillomavirus genotype found in cervical cancer. 7.3% prevalence in cervical pre-invasive lesions (PMID: 19107962 ). Human papillomavirus type 39 Have been classified as group 1 carcinogens by the International Agency for Research in Cancer (IARC) (PMID: 17979705). Human papillomavirus type 45 HPV-45 is the third most prevalent human papillomavirus genotype found in cervical cancer. Human papillomavirus type 18 (HPV18) and HPV45 account for approximately 20% of all cervix cancers. It has been shown that HPV18, HPV45, and the recently discovered HPV97 comprise a clade sharing a most recent common ancestor within HPV alpha7 species (PMID: 19036820). Human papillomavirus type 59 Have been classified as group 1 carcinogens by the International Agency for Research in Cancer (IARC) (PMID: 17979705). Human papillomavirus type 68 Human papillomavirus type 70 The genome of human papillomavirus (HPV) type 70 (HPV 70), isolated from a cervical condyloma, was obtained by cloning overlapping PCR products (PMID: 8815087). Human papillomavirus type 97 Human papillomavirus - 2 Human papillomavirus type 2 Most commonly is associated with Verrucae vulgaris (benign skin warts) (PMID: 11409567). However severe verrucosis (cutaneous "horns") was documented (PMID: 17493077) as well as oral warts and carcinomas (PMID: 10069543,PMID: 3027288). and cutaneous carcinomas ("verrucous carcinoma") (PMID: 12828703). Human papillomavirus type 27 Exhibits the strongest homology to HPV2. Causes common warts Human papillomavirus type 27 (HPV-27) and HPV-2c are isolates of the same virus as judged by genomic sequence identity (PMID: 8184550). Human papillomavirus type 2a The low-risk human papillomavirus type 2a (HPV2a) has been found associated with benign skin epithelial tumors and has only been very rarely identified in malignized epithelia (PMID: 14554085). Human papillomavirus type 2c Human papillomavirus type 27 (HPV-27) and HPV-2c are isolates of the same virus as judged by genomic sequence identity (PMID: 8184550). Human papillomavirus type 57 Detection of human papillomavirus type 57 in the tissue of a plantar epidermoid cyst (PMID: 12920371). Verrucae vulgares frequently induce nail dystrophy when infection of the nail matrix occurs. Classic periungual warts are easily recognized by the experienced physician. A very unusual presentation of human papillomavirus (HPV) infection of the nail matrix and nail bed involving all 20 nails in an otherwise immunocompetent patient. Viral typing by in situ hybridization
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revealed HPV type 57 (PMID: 10583128). Human papillomavirus (HPV) type 57 DNA was detected in recurrent nasal inverted papillomatosis (PMID: 8719598). Human papillomavirus - 26 Human papillomavirus type 26Molecular DNA typing identified HPV 26 in the squamous cell carcinoma SCCs and in some premalignant lesions (PMID: 17634082). Human papillomavirus type 26-associated periungual squamous cell carcinoma in situ in a HIV-infected patient (PMID: 16198810). Human papillomavirus type 51 Have been classified as group 1 carcinogens by the International Agency for Research in Cancer (IARC) (PMID: 17979705). Human papillomavirus type 69 Human papillomavirus type 82 HPV-82 has tropism for both the skin and the genital regions (PMID: 15752300). HPV-82 is an etiologic agent for vaginal and cervical intraepithelial neoplasia. By nucleotide sequence similarity of L1 open reading frame (ORF), HPV-82 was closely related to HPV-26, -51, and -69 (PMID: 10618284). Human papillomavirus - 26 Human papillomavirus type 32 One of the etiological agents of a benign oral condition, focal epithelial hyperplasia. However, the previously characterized properties of its E7 oncoprotein suggest a possible malignant nature for this virus (PMID: 12359456). Human papillomavirus type 42 Type 6, type 11, and the recently recognized type 42 were found in lesions showing features of condyloma or minimal histologic changes (PMID: 3041217). Nucleotide sequence and genome organization of the human papillomavirus type 42 was reported. HPV42 DNA was isolated from vulvar papillomas. It has been detected in benign forms of proliferative lesions only. The genome of HPV42 is 7917 bp long and shows the open reading frame pattern conserved in all HPVs sequenced so far. HPV42 has no high degree of sequence homology to any of the known HPVs (PMID: 1309278). Also, 50% of subclinical lesions showing only minimal histological changes (acanthosis and papillomatosis, without clear koilocytosis) contain HPV DNA, mostly type 42. (PMID: 1330920). Human papillomavirus - 34 Human papillomavirus type 34Detection of human papillomavirus type 34 in Bowen's disease on the pubic area (PMID: 16441634). Human papillomavirus type 73Human papillomavirus type 73 in primary and recurrent periungual squamous cell carcinoma (PMID: 18248476). Human papillomavirus type 73 (HPV 73) has been detected in some invasive cervical cancers and has been cloned from a squamous-cell carcinoma of the esophagus, but the epidemiology of this infection and its associated risk of cancer is unknown. HPV 73 is a mainly sexually transmitted, probably mostly transient, infection that does not confer any measurably increased risk for CIN development (PMID: 10652426). Type 73 human papillomavirus in esophageal squamous cell carcinoma: a novel association (PMID: 8640690). In the esophagus, the most common type was HPV 73 (PMID: 12050680). Human papillomavirus - 53
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Human papillomavirus type 30 Demonstration of human papillomavirus (HPV) type 30 in esophageal squamous-cell carcinomas by in situ hybridization (PMID: 8393840). HPV type 30 was found in three (13%), and HPV type 6/11 was found in two (9%) cases of penile carcinoma (PMID: 1655618). Noteworthy is the failure to disclose the recently described HPV type 30 DNA (suggested to be specific for laryngeal carcinomas) in any of the 116 carcinomas studied (PMID: 2819803). Human papillomavirus type 53 The cloning and partial characterization of the genome of human papillomavirus type 53 is presented. The virus is a distinct type and is most closely related to human papillomavirus type 30 (PMID: 2552169). Persistent cervicovaginal infection with high-risk types of HPV is the major risk factor for subsequent cervical neoplasia. HPV53, part of the alpha 6 species group along with HPV types 30, 56, and 66, is one of the most prevalent high risk-related HPV types, yet little is known about the molecular basis of its benign behavior (PMID: 18681800). HPV 53 merits designation as a high-risk HPV based only [corrected] on the proportion of CIN 2,3 in follow-up biopsy (PMID: 16044055). Human papillomavirus type 56 Have been classified as group 1 carcinogens by the International Agency for Research in Cancer (IARC) (PMID: 17979705). Human papillomavirus type 66 Have been classified as group 1 carcinogens by the International Agency for Research in Cancer (IARC) (PMID: 17979705). Human papillomavirus type 54 Detection of human papillomavirus DNA in pterygia from different geographical regions (PMID: 12812887). Human papillomavirus - 6 Human papillomavirus type 11 A genus of DNA viruses in the family PAPILLOMAVIRIDAE. They preferentially infect the anogenital and ORAL MUCOSA in humans and primates, causing both malignant and benign neoplasms. Cutaneous lesions are also seen. Year introduced: 2007. Human papillomavirus type 13 Is associated with oral focal epithelial hyperplasia (FEH) of oral mucosa; conjunctival papillomas similar to oral FEH were recorded (PMID: 15936914). Human papillomavirus type 44 Study revealed that HPV-43 and HPV-44 together were found in 6 of 439 normal cervical tissues, in 8 of 195 cervical intraepithelial neoplasms, but in none of 56 cervical cancers tested thus far (PMID: 2542593). human papillomavirus type 6 A type of alphapapillomavirus usually associated with genital warts; and laryngeal neoplasms. year introduced: 2006 .Grouped into low-risk (non-oncogenic) types, which cause benign anogenital warts (condyloma accuminata) (PMID: 15596319) and male anogenital warts (PMID: 19097933). Human papillomavirus type 6a Verruciform xanthoma (VX) was documented (PMID: 11048983); recurrent condylomata acuminata of males genitalia due to human papillomavirus (HPV) type 6a; possible cause of an eyelid papilloma (PMID: 16855513). Human papillomavirus type 6b Anogenital warts are a common clinical manifestation of genital infection with human papillomavirus type 6b (HPV-6b). Accumulating data indicate that an effective cellular immune response is required for the control of HPV infections. However, in a
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minority of patients there is a high rate of recurrence of wart lesions (PMID: 17425420). Human papillomavirus type 6c The human papillomavirus type 6c (HPV6c) genome was molecularly cloned from biopsy specimens of a juvenileonset and an adult-onset respiratory-tract papillomata and a condyloma acuminatum of the cervix (PMID: 2554585). Human papillomavirus type 6e Transcriptional activity of human papillomavirus type 6 in respiratory tract papillomata (PMID: 1650237). Human papillomavirus - 61 Human papillomavirus type 72 Two new HPV types, HPV 72 and HPV 73, were identified in oral warts with atypia. The complete genomes of these viruses were cloned and sequenced. Other HPV types detected were HPV 2a, HPV 6b, HPV 13, HPV 16, HPV 18, HPV 55, HPV 59 and HPV 69 (PMID: 8635859). Human papillomavirus type 81 Found in cervical lesions (20.0%) (PMID: 16024065). Human papillomavirus type 83 HPV 83 is a relatively prevalent genital papillomavirus that has the largest genome of any characterized HPV and several other novel structural features that merit further study (PMID: 10405368). Human papillomavirus type 102 Human papillomavirus type 61 The most common high-risk genotypes among high-risk HPV-positive women were HPV-61 (19.1%), -31 (13.1%), 52 (12.9%), -58 (12.5%), -83 (12.3%), -66 (12.0%), -51 (11.7%), -45 (11.2%), 56 (10.3%), -53 (10.2%), -16 (9.7%), and -62 (9.2%) (PMID: 18978096). Human papillomavirus type 84 A blast homology search demonstrated that HPV 84 was most closely related to HPV 61 (89%), HPV 72 (86%), and HPV 83 (85%) by nucleotide sequence analysis of the L1 open reading frame, placing it in the HPV genome homology group A3. Previously, this virus had been identified as Pap155. Based on extensive epidemiological data, HPV 84 is a highly prevalent genital papillomavirus primarily detected in normal and HIV-infected women (PMID: 11145894) and cervical lesions (13.7%) (PMID: 16024065). Human papillomavirus - 7 Human papillomavirus type 40 Detected HPV DNA in 40 of the 70 laryngeal papilloma cases (57%) (PMID: 18607996) Human papillomavirus type 43 Prevalence studies revealed that HPV-43 and HPV-44 together were found in 6 of 439 normal cervical tissues, in 8 of 195 cervical intraepithelial neoplasms, but in none of 56 cervical cancers tested thus far (PMID: 2542593). Human papillomavirus type 7 Frequently found in butchers' warts and has been demonstrated in oral and facial warts of HIV-infected patients. The reservoirs of HPV7 and the route of transmission are still unclear. HIVnegative, otherwise healthy patient with extensive, recurrent orofacial papillomatosis whose immune status proved to be normal and who had no history of meat handling is reported (PMID: 11501651).
Betapapillomavirus
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A genus of DNA viruses in the family papillomaviridae, causing cutaneous lesions in humans. Infections exist in latent form in the general population and are activated under conditions of immunosuppression. Year introduced: 2007. Human papillomavirus - 49 Human papillomavirus type 49 The viral DNA, which is most closely related to the DNAs of HPVs seen in patients with epidermodysplasia (PMID: 2552167). Human papillomavirus type 75 The DNA genomes of four new human papillomaviruses, HPV 75, HPV 76, HPV 77, and HPV 80, have been cloned, sequenced, and characterized. HPV 75, HPV 76 (both HPV 49-related), and HPV 77 (HPV 29-related) were isolated from benign cutaneous warts and HPV 80 (HPV 15-related) from histologically normal skin. HPV 77 has also been demonstrated in dysplastic warts and squamous cell carcinomas of the skin (PMID: 9454709). Human papillomavirus type 76 Interestingly, HPV-76 was only detected in the group without frequent sun-exposure (P=0.001). These results suggest that increased UV radiation exposure may be a factor leading to a difference in prevalence of cutaneous HPV types (PMID: 18931088). Human papillomavirus - 5 Human papillomavirus type 12Cutaneous type of HPV (PMID: 15243477). Human papillomavirus type 14 Human papillomavirus type 19 Human papillomavirus type 20 HPV-20 was detected in the malignant skin carcinoma. Transcripts of HPV-20 were also expressed in the carcinoma. These findings suggest that HPV-20 can be involved in the skin carcinogenesis (PMID: 8027315). Human papillomavirus type 21 Human papillomavirus type 25 Human papillomavirus type 36 Human papillomavirus type 47 Human papillomavirus type 5 The results are suggestive of an involvement of HPV5 in the psoriasis and reinforce the hypothesis that the replication of this virus in the psoriatic keratinocytes may cause the epidermal hyperproliferation as well as the antigen stimulation, which induces autoimmune phenomena (PMID: 16232304). Human papilloma virus type 5 (HPV-5) has been associated closely with psoriatic skin (PMID: 15649303). PUVA therapy and human papillomavirus type 5 detection in psoriasis (PMID: 9804361). Psoriasis: A possible reservoir for human papillomavirus type 5, the virus associated with skin carcinomas of epidermodysplasia verruciformis (PMID: 9540967). Human papillomavirus type 5b Human papillomavirus type 8 Human papillomavirus type 93 Human papillomavirus - 9 Human papillomavirus type 107 Human papillomavirus type 110 Human papillomavirus type 111 Human papillomavirus type 15 Human papillomavirus type 17 Human papillomavirus type 22 Human papillomavirus type 23
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Human papillomavirus type 37 Human papillomavirus type 38 Human papillomavirus type 80 Human papillomavirus type 9 Deltapapillomavirus A genus of DNA viruses in the family papillomaviridae causing fibropapillomas in their respective ungulate hosts. Species infected include cattle, European elk, deer, and sheep. Year introduced: 2007. Bovine papillomavirus 1 Bovine papillomavirus (BPV) induces papillomas of cutaneous or mucosal epithelia in cattle. The papillomas are usually benign tumours that occasionally persist and provide the focus for malignant transformation to squamous cell carcinoma. BPV isone of the most extensively studied papillomaviruses. For a long time, the transcription map of BVP-1 has been the best known map for our understanding of the PV gene expression. Bovine papillomavirus type 1 Bovine papillomavirus type 2 Gammapapillomavirus A genus of DNA viruses in the family papillomaviridae, which cause cutaneous lesions in humans. They are histologically distinguishable by intracytoplasmic INCLUSION BODIES which are species specific. Year introduced: 2007 Human papillomavirus - 4 Human papillomavirus type 4 Human papillomavirus type 65 Human papillomavirus type 95 Human papillomavirus - 48 Human papillomavirus type 48 Human papillomavirus - 50 Human papillomavirus type 50 Human papillomavirus - 60 Human papillomavirus type 60 Plantar epidermoid cysts with human papillomavirus (HPV) infection are not rare in Japan. Most of them show the cytopathic effect of HPV type 60 - homogeneous intracytoplasmic inclusion bodies (PMID: 12920371). Human papillomavirus type 60 (HPV60) is the only virus type that has been identified in epidermoid cysts (PMID: 9714246). Human papillomavirus - 88 Human papillomavirus type 88 Mupapillomavirus A genus of DNA viruses in the family papillomaviridae, causing cutaneous lesions in humans. Year introduced: 2007. Human papillomavirus - 1 Human papillomavirus type 1a Human papillomavirus - 63 Human papillomavirus type 63 Nupapillomavirus A genus of DNA viruses in the family papillomaviridae, causing cutaneous lesions in humans. Year introduced: 2007. Human papillomavirus - 41 Human papillomavirus type 41
REFERENCES
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Zheng ZM, Baker CC. Papillomavirus genome structure, expression, and post-transcriptional regulation. Front Biosci. 2006 Sep 1;11:2286-302. de Villiers EM et al. Classification of papillomaviruses. Virology. 2004 Jun 20;324(1):17-27. Bernard HU. The clinical importance of the nomenclature, evolution and taxonomy of human papillomaviruses. J Clin Virol. 2005 Mar;32 Suppl 1:S1-6. Stanley MA, Pett MR, Coleman N. HPV: from infection to cancer. Biochem Soc Trans. 2007 Dec;35(Pt 6):1456-60. Schiffman M et al. Human papillomavirus and cervical cancer. Lancet. 2007 Sep 8;370(9590):890907. McBride AA. Replication and partitioning of papillomavirus genomes. Adv Virus Res. 2008;72:155-205. Stanley M et al. Immunobiology of human papillomavirus infection and vaccination implications for second generation vaccines. Vaccine. 2008 Aug 19;26 Suppl 10:K62-7. Jenkins D. A review of cross-protection against oncogenic HPV by an HPV-16/18 AS04adjuvanted cervical cancer vaccine: importance of virological and clinical endpoints and implications for mass vaccination in cervical cancer prevention.Gynecol Oncol. 2008 Sep;110(3 Suppl 1):S18-25. Schwarz TF. AS04-adjuvanted human papillomavirus-16/18 vaccination: recent advances in cervical cancer prevention. Expert Rev Vaccines. 2008 Dec;7(10):1465-73. Hakim AA et al. Indications and efficacy of the human papillomavirus vaccine. Curr Treat Options Oncol. 2007 Dec;8(6):393-401.
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GENITAL WARTS
FROM: http://www.dermnetnz.org/viral/genital-warts.html AUTHORS: Jane Morgan MB ChB MRCP FACSHP, Department of Sexual Health, Health Waikato, Hamilton LAST UPDATED: June 05, 2010
Genital warts are very common. They are caused by a virus, the human papillomavirus (HPV). There are at least 100 different types of HPV; at least 40 can infect the genital area. At least 75% of sexually active adults have been infected with at least one type of genital HPV at some time in their life. Most do not develop visible warts; the infection may show up on a cervical smear. This is known as subclinical infection. Visible genital warts are often easy to diagnose by their typical appearance. They are usually due to HPV Types 6 and 11. Some genital warts are often called squamous cell papilloma. Genital warts may occur in the following sites: Vulva Vagina Cervix Urethra Penis Scrotum Anus Normal anatomical structures may be confused with warts. These do not require any treatment. Pearly papules (these are in a ring around the glans of the penis) Sebaceous glands on the labia (known as "Fordyce spots") Vestibular papillae (the fronds found in the opening to the vagina)
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Transmission of HPV Visible genital warts and subclinical HPV infection nearly always arise from direct skin to skin contact: Sexual contact. This is the most common way amongst adults. Oral sex. HPV appears to prefer the genital area to the mouth however. Vertical (mother to baby) transmission. Auto (self) inoculation from one site to another. Fomites (i.e. from objects like bath towels). It remains very controversial whether warts can spread this way.
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Neonatal infection may arise by passing through an infected birth canal. This can lead to rare complications, such as laryngeal papillomatosis i.e. warts in the throat. Because this complication is unlikely, a caesarean section is rarely indicated simply because a pregnant woman has genital warts. In small children, genital warts raise the possibility of sexual abuse but in many cases it is due to vertical transmission (see above). Transmission is common as genital warts often go unnoticed. Subclinical infections can also be infectious. Often, warts will appear three to six months after infection but latency periods of many months or even years have been reported. Developing genital warts during a long-term relationship does not necessarily imply infidelity. Visible warts are probably more infectious than subclinical HPV infection. Treating warts seems to decrease the chance of passing on the infection. We cannot tell whether the immune system completely clears the virus from the body, or whether the virus remains hidden but undetectable, capable of re-emerging years later if the immune system weakens. As a result, it is unclear how long someone remains infectious. The risk of HPV transmission is extremely low if no warts recur a year after successful treatment. Condoms Condoms provide a physical barrier and lower the risk of passing on HPV. They do not, however, prevent all genital skin-to-skin contact. Use a condom to protect against other STDs, particularly with new sexual partners. For couples in long-term monogamous relationships, the value of condoms is more debatable. Treatment The primary goal of treatment is to eliminate warts that cause physical or psychological symptoms such as: Pain Bleeding Itch Embarrassment A constant reminder of STD
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The underlying viral infection may or may not persist if the visible warts clear. If left untreated, warts may resolve, remain unchanged, or increase in size or number. Most people have a small number of warts that clear with a course of treatment but no one treatment is ideal for everyone. Options include: No treatment at all. Self-applied treatments at home. Treatment at a doctor's surgery or medical clinic. Self-applied treatments To be successful you must identify and reach the warts, and follow the application instructions carefully.
Podophyllotoxin solution (Condyline, Wartec) destroys the affected skin cells so the warts shrink or disappear. Podophyllotoxin solution contains purified podophyllin in a more standardised form. It is not recommended for internal use or for extensive warts (more than 10 square centimetres). It should not be used during pregnancy. Imiquimod cream (Aldara) enhances the body's immune response to the infection. Warts seem less likely to recur compared to other treatments. Imiquimod is more effective for women than for men, probably because of differences in genital skin. It may cause burning and even ulceration as it clears up the warts. Although annoying, the treatment can usually be continued. Imiquimod is not currently recommended during pregnancy.
Treatment at the clinic
Cryotherapy with liquid nitrogen is effective for both dry and moist warts and can be used for external and internal warts. It may be the best treatment during pregnancy. It is moderately painful and blistering sometimes occurs. Treating large warts or large numbers of warts at one time can also be messy and unpleasant. Podophyllin resin 10%-25% suspension in benzoin tincture contains a number of agents, including podophyllotoxin. Preparations vary greatly in their concentration of active
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components and contaminants, the shelf life and stability of podophyllin resin are unknown, and well-standardised preparations are not available. As a result, it is no longer commonly used in New Zealand. Podophyllin is not recommended for use on wart areas of more than 10 square centimetres, as it can be toxic. It must not be used in pregnant women.
Trichloroacetic acid (TCA) solution is a caustic agent. It must be applied sparingly and carefully or it may "run", damaging normal tissue. It is not commonly used to treat warts in New Zealand. Electrocautery or diathermy physically destroys the warts by burning them. Local or general anaesthesia can be used. Curettage and scissor or scalpel excisions directly remove the warts. Suturing is rarely required. Some pain is likely. Secondary bacterial infection is an occasional complication. Laser ablation is sometimes recommended for extensive infection, or difficult-to-reach areas such as the cervix, but it is not widely available in New Zealand. 5% fluorouracil cream cream (Efudix) is currently a specialist-only medication in New Zealand. It is a cytotoxic agent i.e. it destroys abnormal cells. It can result in very painful erosions so it is not recommended for routine treatment of warts and should not be used in pregnancy. Vaccine development is an area of active research, and several different approaches are being tested in animal models, including "therapeutic" vaccines that might help those already infected.
Other therapies
Interferon is an antiviral agent that is effective when it is injected into genital warts. Side-effects are common e.g. a flu-like illness and pain at the injection site. Interferon injections are generally only used for those who have not responded to other treatments and are not currently licensed in NZ. Systemic and topical interferon have not been found to be helpful for genital warts. 5-fluorouracil/epinephrine-gel implant contains the same drug as in 5% fluorouracil cream, together with a vasoconstricting agent and a stabilising gel. The mixture is injected into the genital skin, near the warts. It can result in very painful erosions so it is not
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recommended for routine treatment of warts and should not be used in pregnancy. It is not currently licensed in NZ.
Cidofovir is a newly developed antiviral drug that is being investigated for treatment of genital warts.
Genital warts & cancer The HPV types that cause external visible warts (HPV Types 6 and 11) rarely cause cancer. Other HPV types (most often Types 16, 18, 31, 33 and 35) are less common in visible warts but are strongly associated with penile and vulvar intra-epithelial neoplasia (pre-cancerous changes) and squamous cell carcinoma (SCC) of the genital area especially cervical cancer and less frequently invasive vulvar cancer. However, only a very small percentage of those infected will develop genital cancer. This is because HPV infection is only one factor in the process; cigarette smoking and the immune system are also important. Cervical smears, as recommended in the National Cervical Screening guidelines, detect early abnormalities of the cervix, which can then be treated. If these abnormalities were ignored over a long period, they could progress to cancer. If your skin problem is troublesome and/or persistent, seek the advice of your general practitioner, dermatologist or a sexual health physician. Human papillomavirus vaccine Two vaccines are available to prevent HPV infection, Gardasil and Cervarix. Gardasil is a vaccine that is effective against HPV types 6, 11, 16 and 18; the 4 types of HPV that cause most cases of genital warts and cervical cancer. Gardasil is now approved in many countries for use in young females for the prevention of cervical cancer, cervical pre-cancer and genital warts. In New Zealand it is funded and recommended for 12 year old girls, with a catch-up programme for those aged 11 to 18. Cervarix is effective against HPV types 16 and 18. Available in many countries for prevention of cervical cancer, it is not subsidised in New Zealand. HPV vaccination is most effective when offered at a young age, before the onset of sexual activity. However, girls who are already sexually active may not have been infected with the types of HPV covered by the
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vaccine and may still benefit from vaccination. It is important to note that women who receive HPV vaccine must continue to participate in cervical screening programmes, as about 30% of cervical cancers will not be prevented by the vaccine. There has been interest in developing therapeutic HPV vaccines for the treatment of genital warts and cervical cancer in those already infected. However, at present, there is limited evidence that they are effective in humans.
REFERENCES Urman CO, Gottlieb AB. New viral vaccines for dermatologic disease. J Am Acad Dermatol 2008;58:361-70
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NONGENITAL WARTS
FROM: http://emedicine.medscape.com/article/1133317-overview AUTHORS: Philip D Shenefelt, MD, MS, Associate Professor, Department of Dermatology and Cutaneous Surgery, University of South Florida College of Medicine; Past Chief, Section of Dermatology, James A Haley Veteran Affairs Medical Center LAST UPDATED: May 26, 2010
INTRODUCTION Background Warts are benign proliferations of skin and mucosa caused by the human papillomavirus (HPV). Currently, more than 100 types of HPV have been identified. Certain HPV types tend to occur at particular anatomic sites; however, warts of any HPV type may occur at any site. The primary clinical manifestations of HPV infection include common warts, genital warts, flat warts, and deep palmoplantar warts (myrmecia). Less common manifestations of HPV infection include focal epithelial hyperplasia (Heck disease),1 epidermodysplasia verruciformis, and plantar cysts. Warts are transmitted by direct or indirect contact, and predisposing factors include disruption to the normal epithelial barrier. Treatment can be difficult, with frequent failures and recurrences. Many warts, however, resolve spontaneously within a few years. A small subset of HPV types is associated with the development of malignancies, including types 6, 11, 16, 18, 31, and 35. Malignant transformation most commonly is seen in patients with genital warts and in immunocompromised patients. HPV types 5, 8, 20, and 47 have oncogenic potential in patients with epidermodysplasia verruciformis. Pathophysiology Warts can affect any area on the skin and mucous membranes. Infection is confined to the epithelium and does not result in systemic dissemination of the virus. Replication occurs in differentiated epithelial cells in the upper level of the epidermis; however, viral particles can be found in the basal layer.
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Frequency International Warts are widespread in the worldwide population. Although the frequency is unknown, warts are estimated to affect approximately 712% of the population. In school-aged children, the prevalence is 10-20%. An increased frequency also is seen among immunosuppressed patients and meat handlers. Mortality/Morbidity Common warts are usually asymptomatic, but they may cause cosmetic disfigurement or tenderness. Plantar warts can be painful, and extensive involvement on the sole of the foot may impair ambulation. Malignant change in nongenital warts is rare but has been reported and is termed verrucous carcinoma.2,3,4 Verrucous carcinoma is considered to be a slowgrowing, locally invasive, well-differentiated squamous cell carcinoma that may be easily mistaken for a common wart. It can occur anywhere on the skin but is most common on the plantar surfaces. Although this type of cancer rarely metastasizes, it can be locally destructive. Race Although warts may affect any race, common warts appear approximately twice as frequently in whites as in blacks or Asians.5 Focal epithelial hyperplasia (Heck disease) is more prevalent among American Indians and Inuit.1 Sex Male-to-female ratio approaches 1:1. Age Warts can occur at any age. They are unusual in infancy and early childhood, increase in incidence among school-aged children, and peak at 12-16 years.6 CLINICAL History HPV is spread by direct or indirect contact. It can resist desiccation, freezing, and prolonged storage outside of host cells. Autoinoculation also may occur, causing local spread of lesions. The incubation period for HPV ranges from 1-6 months; however, latency periods of up to 3 years or more are suspected.
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Physical Physical findings for different types of nongenital warts are as follows:
Common warts: Common warts also are termed verruca vulgaris. They appear as hyperkeratotic papules with a rough, irregular surface. They range from smaller than 1 mm to larger than 1 cm. They can occur on any part of the body but are seen most commonly on the hands and knees (see image). Filiform warts: Filiform warts are long slender growths, usually seen on the face around the lips, eyelids, or nares. Deep palmoplantar warts (myrmecia)7 : Deep palmoplantar warts also are termed myrmecia. They begin as small shiny papules and progress to deep endophytic, sharply defined, round lesions with a rough keratotic surface, surrounded by a smooth collar of calloused skin (see the image below). Because they grow deep, they tend to be more painful than common warts. Myrmecia warts that occur on the plantar surface usually are found on weight-bearing areas, such as the metatarsal head and heel. When they occur on the hand, they tend to be subungual or periungual. Flat warts: Flat warts also are termed plane warts or verruca plana. They are characterized as flat or slightly elevated flesh-colored papules that may be smooth or slightly hyperkeratotic. They range from 1-5 mm or more, and numbers range from a few to hundreds of lesions that may become grouped or confluent. These warts may occur anywhere; however, the face, hands, and shins tend to be the most common areas. They may appear in a linear distribution as a result of scratching or trauma (Koebner phenomenon). Regression of these lesions may occur, which usually is heralded by inflammation. Butcher's warts: Butcher's warts are seen in people who frequently handle raw meat. Their morphology is similar to common warts, with a higher prevalence of hyperproliferative
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cauliflowerlike lesions. They are seen most commonly on the hands.
Mosaic warts: A mosaic wart is a plaque of closely grouped warts. When the surface is pared, the angular outlines of tightly compressed individual warts can be seen. These usually are seen on the palms and soles. Focal epithelial hyperplasia (Heck disease)1 : Focal epithelial hyperplasia, also termed Heck disease, is an HPV infection occurring in the oral cavity, usually on the lower labial mucosa. It also can be seen on the buccal or gingival mucosa and rarely, on the tongue. The lesions appear as multiple flat-topped or domeshaped pink-white papules. They usually are 1-5 mm, with some lesions coalescing into plaques. They are seen most frequently in children of American Indian or Inuit descent. Cystic warts (plantar epidermoid cysts): A cystic wart appears as a nodule on the weight-bearing surface of the sole. The nodule usually is smooth with visible rete ridges but may become hyperkeratotic. If the lesion is incised, cheesy material may be expressed. The etiology of these lesions is uncertain. One theory is that a cyst forms, originating from the eccrine duct, and secondary HPV infection occurs. Another theory is that the epidermis infected with HPV becomes implanted into the dermis, forming an epidermal inclusion cyst.
Causes Warts are caused by HPV, which is a double-stranded, circular, supercoiled DNA virus enclosed in an icosahedral capsid and comprising 72 capsomers. More than 100 types of HPV have been identified. Note the following wart types and HPV types: Common warts - HPV types 2 and 4 (most common), followed by types 1, 3, 27, 29, and 57 Deep palmoplantar warts (myrmecia) - HPV type 1 (most common), followed by types 2, 3, 4, 27, 29, and 57 Flat warts - HPV types 3, 10, and 28 Butcher's warts - HPV type 7 (although some data suggest the association may be weak) Focal epithelial hyperplasia (Heck disease) - HPV types 13 and 32 Cystic warts - HPV type 60
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DIFFERENTIAL DIAGNOSES Acquired Digital Fibrokeratoma Actinic Keratosis Arsenical Keratosis Cutaneous Horn Lichen Nitidus Lichen Planus WORKUP Laboratory Studies The diagnosis of warts is made primarily on the basis of clinical findings. Immunohistochemical detection of HPV structural proteins may confirm the presence of virus in a lesion, but this has a low sensitivity. Viral DNA identification using Southern blot hybridization is a more sensitive and specific technique used to identify the specific HPV type present in tissue. Polymerase chain reaction may be used to amplify viral DNA for testing. Although HPV may be detected in younger lesions, it may not be present in older lesions. Procedures Paring of warts may reveal minute black dots, which represent thrombosed capillaries. Obtain a biopsy if doubt exists regarding the diagnosis. Histologic Findings Histologic findings for various types of nongenital warts are as follows:
Molluscum Contagiosum Prurigo Nodularis Seborrheic Keratosis Squamous Cell Carcinoma Warts, Genital
Common warts: Histopathologic features of common warts include digitated epidermal hyperplasia, acanthosis, papillomatosis, compact orthokeratosis, hypergranulosis, dilated tortuous capillaries within the dermal papillae, and vertical tiers of parakeratotic cells with entrapped red blood cells above the tips of the digitations. Elongated rete ridges may point radially toward the center of the lesion. In the granular layer, HPV-infected cells may have coarse keratohyaline granules and vacuoles surrounding wrinkled-appearing nuclei. Koilocytic (vacuolated) cells are pathognomonic for warts. Deep palmoplantar warts (myrmecia): Deep palmoplantar warts appear similar to common warts except that most of the lesion lies
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deep to the plane of the skin surface. This endophytic epidermal growth often has the distinctive feature of polygonal, refractileappearing, eosinophilic, cytoplasmic inclusions composed of keratin filaments, forming ringlike structures. Basophilic nuclear inclusions and basophilic parakeratotic cells loaded with virions may be in the upper layers of the epidermis.
Flat warts: Flat warts resemble common warts on light microscopy; however, the features tend to be muted. Cells with prominent perinuclear vacuolization around pyknotic, strongly basophilic, centrally located nuclei may be in the granular layer. These may be referred to as "owl's eye cells." Butcher's warts: Butcher's warts have prominent acanthosis, hyperkeratosis, and papillomatosis. Small vacuolized cells with centrally located shrunken nuclei may be seen in clusters within the granular layer rete ridges. Filiform warts: Filiform warts may appear similar to common warts but tend to have prominent papillomatosis. Focal epithelial hyperplasia (Heck disease): Focal epithelial hyperplasia is characterized by a hyperplastic mucosa with thin parakeratotic stratum corneum, acanthosis, blunting and anastomosis of rete ridges, and pallor of epidermal cells as a result of intracellular edema. Some areas may have prominent keratohyaline granules, and some vacuolated cells may be present. Cystic warts: A cyst filled with horny material characterizes cystic warts. The wall is composed of basal, squamous, and granular cells. Many of the epithelial cells may have large nuclei and clear cytoplasm with eosinophilic inclusion bodies. The cyst may rupture, resulting in a foreign body granuloma. TREATMENT
Medical Care Multiple modalities are available for the treatment of warts, but none is uniformly effective.8,9 Start with the least painful, least expensive, and least time-consuming methods. Reserve the more expensive and invasive procedures for refractory extensive warts. Immunosuppressed individuals often are refractory to wart treatments. Various treatment methods are available.
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Benign neglect Providing no treatment at all is certainly safe and cost effective. Consider this as an option, since 65% of warts may regress spontaneously within 2 years. Without treatment, however, patients risk warts that may enlarge or spread to other areas. Treatment is recommended for patients with extensive, spreading, or symptomatic warts or warts that have been present for more than 2 years. Topical agents Salicylic acid is a first-line therapy used to treat warts. It is available without a prescription and can be applied by the patient at home. Cure rates from 70-80% are reported. Several topical agents are available that can be applied by trained personnel in a physician's office. Cantharidin is an extract of the blister beetle that causes epidermal necrosis and blistering. Dibutyl squaric acid, also known as squaric acid dibutyl ester (SADBE), and diphencyclopropenone (DCP) are contact sensitizers. Trichloroacetic acid is a caustic compound that causes tissue necrosis. Podophyllin is a cytotoxic compound used more commonly in the treatment of genital warts. Aminolevulinic acid (ALA) is a photosensitizer that has been successfully used topically in combination with blue light to treat flat warts.10 Several prescription medications have proven beneficial in treating warts. These can be applied at home by the patient. Imiquimod is an immune response modifier approved for the treatment of genital warts. Reports indicate successful treatment of common warts.11 Cidofovir is an antiviral agent used for the treatment of cytomegalovirus infection in HIV patients. Reportedly, in 2 patients with recurrent persistent common warts in whom multiple standard therapies were not responsive, the warts were resolved using topical cidofovir gel applied 12 times per day. This remains an investigational drug for warts.12 Podophyllotoxin is a purified ingredient of podophyllin. Since it tends to work better on mucosal surfaces, it is used primarily to treat genital warts. Little information is available regarding treatment of nongenital warts with this medication. 5-Fluorouracil is a topical chemotherapeutic agent primarily used to treat actinic keratoses. It has been reported to be effective in treating warts when used under occlusion daily for up to 1 month. It has been used in children.13
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Tretinoin is a topical retinoic acid that primarily is used to treat acne. It has been successful in treating flat warts. Intralesional injections When warts are persistent and refractory to topical agents, consider intralesional injections as an alternative. Intralesional immunotherapy using injections of Candida, mumps, or Trichophyton skin test antigens has been shown to be effective in the treatment of warts, with reports of success in up to 74% of patients.14 (A clinical trial recruiting as of May 5, 2009 is Study With Candida Antigen for Treatment of Warts.) Bleomycin is a chemotherapeutic agent that inhibits DNA synthesis in cells and viruses. Cure rates have ranged from 33-92%.15,16 Interferon-alfa is a naturally occurring cytokine with antiviral, antibacterial, anticancer, and immunomodulatory effects. Cure rates of 36-63% have been reported. Photodynamic therapy In one study, photodynamic therapy with topical 5-aminolevulinic acid applied to the warts, followed by photoactivation with red 633-nm lightemitting diodes at 2- to 3-week intervals resulted in 68% improvement.17 Systemic agents Systemic agents that have been used to treat warts include cimetidine, retinoids, and intravenous cidofovir. Cimetidine is a type-2 histamine receptor antagonist commonly used to treat peptic ulcer disease. Because of its immunomodulatory effects at higher doses, cimetidine was considered a possible treatment for warts; however, results have varied. Double-blind placebo-controlled studies have shown no benefit.18 Retinoids are synthetic vitamin A analogs that may help with extensive disabling hyperkeratotic warts in immunocompromised patients. They may help alleviate pain and facilitate the use of other treatments. Retinoids also have helped reduce the number of lesions in immunosuppressed renal transplant patients. The limiting side effects include liver function abnormalities, increased serum lipid levels, and teratogenicity. (A clinical trial recruiting as of May 5, 2009 is bLAC Treatment of Cutaneous Warts in Immune Suppressed, Kidney Transplanted Patients.)
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Two reports have described intravenous cidofovir used for the treatment of extensive, disfiguring, and refractory warts. This should be used with caution because of the risk of nephrotoxicity.19,20 Alternative treatments Several alternative treatments have been reported as successful in treating warts, including adhesiotherapy, hypnosis, hyperthermia, garlic, and vaccines.21,22 Adhesiotherapy is performed by applying duct tape to the wart daily. This method is painless and inexpensive and has reports of good success. Hypnosis has been used to treat refractory warts.23 Several published studies have documented the success of hypnotherapy. Cure rates have been reported from 27-55%, with prepubertal children more likely to respond than adults. Patients in whom hypnotherapy fails may respond to hypnoanalysis for warts. Hyperthermia involves immersing the involved surface in hot water (113F) for 30-45 minutes, 2-3 times per week. Propolis has been reported to be significantly more effective than Echinacea or placebo as an immunomodulating treatment for common and planar warts.24 Raw garlic cloves have been demonstrated to have antiviral activity. This can be rubbed onto the wart nightly, followed by occlusion.25 Tea tree oil applied topically has also been reported as successful.26 Vaccines currently are in development. Surgical Care Cryosurgery27 Liquid nitrogen (-196C) is the most effective method of cryosurgery. Apply liquid nitrogen using a cotton bud applicator or cryospray to the recommended 1-2 mm rim of normal skin tissue around the wart. Repeat every 1-4 weeks for approximately 3 months, as needed. Warn patients about pain and possible blistering after treatment. Use with caution on the sides of fingers, since it can injure underlying structures and nerves. Other side effects may include scarring, ulceration, or pigment alteration. Cure rates of 50-80% have been reported. Paring the wart, in addition to 2 freeze-thaw cycles, has been a valuable adjunct to cryosurgery for plantar warts.28
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Lasers This is an expensive treatment, and is reserved only for large or refractory warts. Multiple treatments may be required. Local or general anesthesia may be necessary. A potential risk of nosocomial infection also exists in health care workers, since HPV can be isolated in the plume and can be inhaled.29 Carbon dioxide lasers have successfully treated resistant warts; however, the procedure can be painful and leave scarring. One retrospective study revealed a cure rate of 64% at 12 months with carbon dioxide lasers.30 The flashlamp-pumped pulse dye laser has shown mixed results in treating warts, with decreased risk of scarring and transmission of HPV in the smoke plume.31 Nd:YAG laser may be used for deeper, larger warts. Electrodesiccation/curettage and surgery Although electrodesiccation and curettage may be more effective than cryosurgery, it is painful, more likely to scar, and HPV can be isolated from the plume. Avoid using surgical excision in most circumstances because of the risks of scarring and recurrence. MEDICATION The goals of pharmacotherapy are to reduce morbidity and prevent complications. Keratolytic agents Cause cornified epithelium to swell, soften, macerate, and then desquamate.
Salicylic acid 17% (Compound W, Duofilm), 26% (Durasal), 27% (Duofilm Extrastrength Gel) or 40% Plaster (Mediplast) Available OTC in 5-40% concentration and in a variety of vehicles, including creams, paints, gels, karaya gum, impregnated plasters, collodion, or sodium carboxycellulose tape. Lactic acid may be a second ingredient in some wart varnishes. By dissolving the intercellular cement substance, salicylic acid desquamates the horny layer of skin. Therapeutic effect may be enhanced by removal of surface keratin prior to application. Dosing Adult: Apply topically qd/bid for several wks. Pediatric: Administer as in adults
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Interactions None reported Contraindications Documented hypersensitivity; prolonged use in diabetic persons and those with impaired circulation; do not use on moles, birthmarks, or lesions with hair growing from them; do not use on genital area, face, or mucous membranes; do not use on irritated skin or infected skin Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Avoid contact with normal skin surrounding warts; immediately flush with water for 15 min if contact with eyes or mucous membranes occurs; avoid inhaling vapors; side effects may include irritation and maceration of surrounding normal skin or contact dermatitis to colophony in collodion bases Podophyllum resin (Podocon-25) Resin extract derived from May Apple plant that contains several cytotoxic compounds. Has a powerful irritant effect and must be used with caution. Works better on mucosal surfaces than keratinized surfaces and is therefore more commonly used for treatment of genital warts. Podophyllotoxin (Podofilox) is a purified ingredient of podophyllin and, therefore, is less irritating. Available by prescription and can be applied by patient at home. Dosing Adult: Podophyllin: Trained personnel must apply topically because of adverse effects; may be left on skin for 1-6 h before washing Podophyllotoxin: 0.5% purified solution may be applied topically bid for 3 consecutive d, repeat qwk, not exceed 4 wk Pediatric: Administer as in adults Interactions None reported Contraindications Documented hypersensitivity; prolonged use in diabetic persons and those with impaired circulation; do not use on moles, birthmarks, or lesions with hair growing from them; do not use on genital area, face, or mucous membranes; do not use on irritated skin or infected skin Precautions Pregnancy X - Contraindicated; benefit does not outweigh risk Precautions
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Podophyllin may cause significant irritation, local erosion, ulceration, and scarring; systemic side effects may include fever, nausea, vomiting, confusion, coma, ileus, renal failure, paresthesias, polyneuritis, and leukopenia; avoid extensive application because of risk of systemic absorption; avoid in pregnancy because of teratogenicity Cantharidin (Verr-Canth) Dried extract of blister beetle (also termed Spanish fly). Causes epidermal necrosis and blistering. Dosing Adult: 0.7% solution: Apply sparingly with wooden end of cotton-tipped applicator in physician's office, and allow area to completely dry; do not cover area with bandage after application; repeat applications at 3- to 4-wk intervals may be required. Pediatric: Administer as in adults Interactions None reported Contraindications Documented hypersensitivity; do not use near eyes, mucous membranes, or anogenital areas; use with caution in intertriginous areas (may lead to more intense painful reactions due to problems with spreading and body occlusion); do not use on lesions with other agents or if surrounding tissue is swollen or irritated Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Strong vesicant; adverse effects include blistering, epidermal necrosis at site of application, and possible "ring wart phenomenon" in which virus is spread circumferentially Trichloroacetic acid (Tri-Chlor) Caustic compound that causes immediate superficial tissue necrosis. Dosing Adult: Available as 80% solution that is painted onto lesions in physician's office; apply after excess keratotic debris is pared; repeat therapy qwk prn until wart is cured Pediatric: Not established Interactions None reported Contraindications
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Documented hypersensitivity; prolonged use in diabetic persons and those with impaired circulation; do not use on moles, birthmarks, or lesions with hair growing from them; do not use on genital area, face, or mucous membranes; do not use on irritated skin or infected skin Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Application may cause pain, burning, and ulceration; if not applied carefully, destruction with resultant scarring of normal surrounding skin may occur
Immunomodulators Stimulate the release of key factors that regulate the immune system.32
Imiquimod (Aldara) Induces secretion of interferon alpha and other cytokines; FDA approved for treatment of genital warts in adults; reports indicate success in treatment of common warts in children. Dosing Adult: 5% gel applied qd for 3 d/wk; may apply hs and wash off after 6-10 h; twice-daily administration for nongenital warts reported, but irritation may be increased Pediatric: >12 years: Administer as in adults Interactions None reported Contraindications Documented hypersensitivity; breastfeeding; prolonged use in diabetic persons and patients with impaired circulation; do not use on irritated skin or infected skin; avoid sun exposure Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Local irritation including redness, itching, and burning may occur at application sites
Dibutyl squaric acid/diphencyclopropenone
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Contact sensitizers that induce allergic contact dermatitis, causing a localized inflammation and immune response. Dosing Adult: Apply solution in light-shielded accessible location (eg, arm) to achieve initial sensitization; repeat until reaction occurs; apply to warts q1-2wk Pediatric: >12 years: Administer as in adults Interactions None reported Contraindications Documented hypersensitivity Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Erythema and pruritus occur at treated sites; occasionally, allergic contact dermatitis may be severe (blistering) or become disseminated (unusual); recall dermatitis may occur at initial sensitization site (common); regional lymphadenopathy may occur 5-Fluorouracil (Efudex, Adrucil, Fluoroplex) Topical chemotherapeutic agent that is approved to treat actinic keratoses and superficial BCC; has been found more successful in treatment of flat warts than plantar and common warts. Dosing Adult Apply 5% solution or cream daily for up to 1 mo; may be used under occlusion, but risk of irritation increases Pediatric Not established Interactions None reported Contraindications Documented hypersensitivity; breastfeeding Precautions Pregnancy X - Contraindicated; benefit does not outweigh risk Precautions Moderate-to-severe irritation may occur
Propolis
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Propolis is a brownish resinous waxy material collected by honeybees from the buds of trees and used as a cement. Dosing Adult: 500 mg/d until warts resolve or until 3 mo, whichever occurs first Pediatric: Not currently indicated Interactions None known Contraindications Hypersensitivity to propolis, including allergic contact dermatitis to propolis Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions None known
Antineoplastic agents Inhibit cell growth and proliferation.

Bleomycin (Blenoxane) Cytotoxic polypeptide that inhibits DNA synthesis in cells and viruses. Has affinity for HPV-infected tissue and induces vascular changes that result in epidermal necrosis. Has been beneficial in treating resistant warts. Reserve as a third-line treatment when standard therapies have failed. Dosing Adult Inject 0.5-1 U/mL solution directly into wart; not to exceed 1.5 U/treatment; less painful administration involves placing 1 mg/mL gtt onto wart and pricking it into wart with needle Pediatric: Not established Interactions May decrease plasma levels of digoxin and phenytoin; cisplatin may increase toxicity of bleomycin when administered systemically Contraindications Documented hypersensitivity; significant renal function impairment; compromised pulmonary function; breastfeeding Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions
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May cause pain with injection, local urticaria, vaso-occlusive phenomenon (Raynaud phenomenon) with distal necrosis of digit; permanent damage to nail matrix may occur when used periungually; may cause mutagenesis and pulmonary toxicity (10%); idiosyncratic reactions similar to anaphylaxis (1%) may occur; monitor for adverse effects during and after treatment
Interferons
Interferon alfa 2b (Roferon and Intron A) Naturally occurring cytokine with antiviral, antitumor, and immunomodulatory actions; intralesional administration more effective than systemic administration and associated only with mild flulike symptoms. Treatments may be required for several weeks to months before beneficial results are seen. Consider this treatment as third line, and reserve it for warts resistant to standard treatments. Dosing Adult: Inject directly into warts up to 3 times/wk for 3-6 wk Pediatric: Not established Interactions Theophylline may increase toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity Contraindications Documented hypersensitivity; use with caution in patients with brain metastases, severe hepatic or renal insufficiencies, seizure disorders, multiple sclerosis, or compromised CNS Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Transient flulike symptoms may occur after initial injections; however, tolerance usually develops; pain at injection sites may occur
Histamine H2 receptor antagonists

Cimetidine (Tagamet) Type 2 histamine receptor antagonist commonly used to treat peptic ulcer disease; due to immunomodulatory effects at higher doses, has been used as treatment for warts. Results have been variable, and double-blinded, placebo-controlled studies have shown no benefit. Dosing Adult: 20-40 mg/kg PO qd divided q6h; not to exceed 2400 mg/d
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Pediatric: 20-40 mg/kg/d divided q6h Interactions Can increase blood levels of theophylline, warfarin, tricyclic antidepressants, triamterene, phenytoin, quinidine, propranolol, metronidazole, procainamide, and lidocaine. Multiple potential drug interactions exist (see full prescribing information for more details). Contraindications Documented hypersensitivity Precautions Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals Precautions Serious reactions may include neutropenia, thrombocytopenia, agranulocytosis, and anemia; common reactions include headache, nausea, vomiting, diarrhea, and rash; older patients may experience confusional states; may cause impotence and gynecomastia in young males; may increase levels of many drugs; adjust dose or discontinue treatment if changes in renal function occur
Retinoids May be helpful in immunocompromised patients with extensive disabling hyperkeratotic warts. May help alleviate pain and facilitate use of other treatments. In addition, retinoids have helped reduce the number of lesions in immunosuppressed renal transplant patients. Topical retinoids may be useful in treating flat warts.
Isotretinoin (Accutane) Synthetic 13-cis isomer of the naturally occurring tretinoin (trans -retinoic acid); structurally related to vitamin A. Approved for severe nodular acne but has also been helpful in certain keratinization disorders. A US Food and Drug Administrationmandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy Dosing Adult: 0.5-2 mg/kg/d PO divided bid with food Pediatric: >12 years: 0.5-2.0 mg/kg/d PO divided bid with food Interactions Toxicity may occur with vitamin A or acitretin coadministration; pseudotumor cerebri or papilledema may occur when coadministered with tetracyclines; reduced plasma levels of carbamazepine
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Contraindications Documented hypersensitivity, pregnancy, breastfeeding, paraben sensitivity, history of psychiatric disturbance Precautions Pregnancy X - Contraindicated; benefit does not outweigh risk Precautions Common reactions include dry skin, cheilitis, photosensitivity, hypertriglyceridemia, hair loss, and decreased night vision; inflammatory bowel disease may occur; may be associated with development of hepatitis; diabetes patients may experience problems in controlling blood glucose while on therapy; discontinue treatment if rectal bleeding, abdominal pain, or severe diarrhea occurs; caution if history of depression or other psychiatric disorders; associated with severe birth defects; females must use 2 forms of birth control throughout therapy and pregnancy tests must be checked qmo
Antiviral agents
Cidofovir (Vistide) Nucleotide analog that inhibits viral DNA polymerase and induces apoptosis. Currently, only available for IV administration to HIV patients for treatment of cytomegalovirus infection. A topical gel has been evaluated in clinical trials for use in treatment of HPV infection. Dosing Adult: Not established Pediatric: Not established Interactions Coadministration of aminoglycosides, amphotericin B, IV pentamidine, and foscarnet may increase nephrotoxicity Contraindications Documented hypersensitivity; coadministration with other nephrotoxic agents; serum creatinine >1.5 mg/dL; CrCl <55 mL/min; urine protein >100 mg/dL Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Monitor neutrophil counts; IV prehydration with NS and coadministration of probenecid can minimize nephrotoxicity; monitor serum creatinine and urine protein 48 h prior to treatment
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(adjust dose accordingly); topical cidofovir may cause erythema and irritation
Porphyrin Agent, Topical

5-Aminolevulinic acid topical 20% solution (Levulan Kerastick) Topical porphyrin available as Levulan Kerastick Dosing Adult: Applied topically to warts and kept under occlusion for 5 h, then exposed to red light-emitting diodes or other suitable red or blue light source Pediatric: Use not established Interactions None known Contraindications Documented hypersensitivity Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Protect area from sun exposure or other prolonged intense light for at least 40 h post treatment
FOLLOW-UP Prognosis Approximately 65% of warts disappear spontaneously within 2 years. When warts resolve on their own, no scarring is seen. However, scarring can occur as a result of different treatment methods. Treatment failures and wart recurrences are common, more so among immunocompromised patients. Normal appearing perilesional skin may harbor HPV, which helps explain recurrences. Patient Education Alert patients to the risk factors for transmission of warts. These include trauma or maceration of the skin, frequent wet work involving hands, hyperhidrosis of feet, swimming pools, and nail biting. Butchers and slaughterhouse workers also are at increased risk for developing warts.
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Alert patients that some warts may require multiple treatments and may be resistant to several treatment modalities. In addition, some warts may regress spontaneously without treatment. MISCELLANEOUS Medicolegal Pitfalls Treatment of warts can be difficult. Warn patients that multiple treatments often may be required. Warn patients that treatments may result in pain, irritation, blistering, ulceration, and even scarring. Caustic substances, such as trichloroacetic acid, may result in frank necrosis. Perform surgical removal of warts with caution, since an increased risk of scarring exists, without an increased rate of cure. If a wart is extremely large and resistant to conventional therapies, consider a diagnosis of verrucous carcinoma. This is a rare, low-grade, well-differentiated carcinoma that usually occurs on the plantar surface. It is slow growing and can become deeply invasive. Reports of metastases exist, although they are rare. A verrucous carcinoma can be misdiagnosed easily as a common wart, since the 2 share similar clinical and histologic characteristics. Be aware of this entity, and consider a deep incisional biopsy of any lesion that is extensive and not responsive to treatment.
REFERENCES 1. Cohen PR, Hebert AA, Adler-Storthz K. Focal epithelial hyperplasia: Heck disease. Pediatr Dermatol. Sep 1993;10(3):245-51. [Medline]. 2. Guadara J, Sergi A, Labruna V, Welch M, Gazivoda PL. Transformation of plantar verruca into squamous cell carcinoma. J Foot Surg. Nov-Dec 1992;31(6):611-4. [Medline]. 3. Kolker AR, Wolfort FG, Upton J, Tahan SR, Hein KD, Zewert TE. Plantar verrucous carcinoma following transmetatarsal amputation and renal transplantation. Ann Plast Surg. May 1998;40(5):515-9. [Medline]. 4. Noel JC, Detremmerie O, Peny MO, et al. Transformation of common warts into squamous cell carcinoma on sun-exposed areas in an immunosuppressed patient. Dermatology. 1994;189(3):308-11. [Medline]. 5. Mallory SB, Baugh LS, Parker RK. Warts in blacks versus whites. Pediatr Dermatol. Mar 1991;8(1):91. [Medline]. 6. Silverberg NB. Human papillomavirus infections in children. Curr Opin Pediatr. Aug 2004;16(4):402-9. [Medline]. 7. Holland TT, Weber CB, James WD. Tender periungual nodules. Myrmecia (deep palmoplantar warts). Arch Dermatol. Jan 1992;128(1):105-6, 108-9. [Medline]. 8. Bellew SG, Quartarolo N, Janniger CK. Childhood warts: an update. Cutis. Jun 2004;73(6):379-84. [Medline]. 9. Goldfarb MT, Gupta AK, Gupta MA, Sawchuk WS. Office therapy for human papillomavirus infection in nongenital sites. Dermatol Clin. Apr 1991;9(2):287-96. [Medline]. 10. Mizuki D, Kaneko T, Hanada K. Successful treatment of topical photodynamic therapy using 5-aminolevulinic acid for plane warts. Br J Dermatol. Nov 2003;149(5):1087-8. [Medline].
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11. Perrett CM, Harwood C, Brown V. Topical 5% imiquimod treatment for refractory cutaneous warts. J Am Acad Dermatol. 2004;50(3):P41. 12. Roark TR, Pandya AG. Combination therapy of resistant warts in a patient with AIDS. Dermatol Surg. Dec 1998;24(12):1387-9. [Medline]. 13. Gladsjo JA, Alio Saenz AB, Bergman J, Krikorian G, Cunninghan BB. 5% 5-fluorouracil cream for treatment of verruca vulgaris in children. Pediat Dermatol. 2009;26:279-285. 14. Horn TD, Johnson SM, Helm RM, Roberson PK. Intralesional immunotherapy of warts with mumps, Candida, and Trichophyton skin test antigens: a single-blinded, randomized, and controlled trial. Arch Dermatol. May 2005;141(5):589-94. [Medline]. 15. James MP, Collier PM, Aherne W, et al. Histologic, pharmacologic, and immunocytochemical effects of injection of bleomycin into viral warts. J Am Acad Dermatol. Jun 1993;28(6):933-7. [Medline]. 16. Munn SE, Higgins E, Marshall M, Clement M. A new method of intralesional bleomycin therapy in the treatment of recalcitrant warts. Br J Dermatol. Dec 1996;135(6):96971. [Medline]. 17. Ohtsuki A, Hasegawa T, Hirasawa Y, Tsuchihashi H, Ikeda S. Photodynamic therapy using light-emitting diodes for the treatment of viral warts. J Dermatol. 2009;36:525-528. 18. Yilmaz E, Alpsoy E, Basaran E. Cimetidine therapy for warts: a placebo-controlled, doubleblind study. J Am Acad Dermatol. Jun 1996;34(6):1005-7. [Medline]. 19. Kottke MD, Parker SR. Intravenous cidofovir-induced resolution of disfiguring cutaneous human papillomavirus infection. J Am Acad Dermatol. Sep 2006;55(3):533-6. [Medline]. 20. Zabawski EJ Jr, Sands B, Goetz D, Naylor M, Cockerell CJ. Treatment of verruca vulgaris with topical cidofovir. JAMA. Oct 15 1997;278(15):1236. [Medline]. 21. Focht DR 3rd, Spicer C, Fairchok MP. The efficacy of duct tape vs cryotherapy in the treatment of verruca vulgaris (the common wart). Arch Pediatr Adolesc Med. Oct 2002;156(10):971-4. [Medline]. 22. [Best Evidence] Wenner R, Askari SK, Cham PM, Kedrowski DA, Liu A, Warshaw EM. Duct tape for the treatment of common warts in adults: a double-blind randomized controlled trial. Arch Dermatol. Mar 2007;143(3):309-13. [Medline]. 23. Ewin DM. Hypnotherapy for warts (verruca vulgaris): 41 consecutive cases with 33 cures. Am J Clin Hypn. Jul 1992;35(1):1-10. [Medline]. 24. Zedan H, Hofney ERM, Ismail SA. Propolis as an alternative treatment for cutaneous warts. Internat J Dermatol. 2009;48:1246-1249. 25. Silverberg NB. Garlic cloves for verruca vulgaris. Pediatr Dermatol. MarApr 2002;19(2):183. [Medline]. 26. Millar BC, Moore JE. Successful topical treatment of hand warts in a paediatric patient with tea tree oil (Melaleuca alternifolia). Complement Ther Clin Pract. Nov 2008;14(4):2257. [Medline]. 27. Bourke JF, Berth-Jones J, Hutchinson PE. Cryotherapy of common viral warts at intervals of 1, 2 and 3 weeks. Br J Dermatol. Mar 1995;132(3):433-6. [Medline]. 28. Berth-Jones J, Hutchinson PE. Modern treatment of warts: cure rates at 3 and 6 months. Br J Dermatol. Sep 1992;127(3):262-5. [Medline]. 29. Gloster HM Jr, Roenigk RK. Risk of acquiring human papillomavirus from the plume produced by the carbon dioxide laser in the treatment of warts. J Am Acad Dermatol. Mar 1995;32(3):436-41. [Medline]. 30. Sloan K, Haberman H, Lynde CW. Carbon dioxide laser-treatment of resistant verrucae vulgaris: retrospective analysis. J Cutan Med Surg. Jan 1998;2(3):142-5. [Medline]. 31. Hughes PS, Hughes AP. Absence of human papillomavirus DNA in the plume of erbium:YAG laser-treated warts. J Am Acad Dermatol. Mar 1998;38(3):426-8. [Medline]. 32. Rivera A, Tyring SK. Therapy of cutaneous human Papillomavirus infections. Dermatol Ther. 2004;17(6):441-8. [Medline].
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HUMAN PAPILLOMAVIRUS AND SKIN TAGS:
IS THERE ANY ASSOCIATION?

FROM: http://www.ijdvl.com/text.asp?2008/74/3/222/39585 AUTHORS: Sachin Gupta , Ritu Aggarwal , Somesh Gupta , Sunil K Arora ; 1 Department of Immunopathology, Postgraduate Institute of Medical Education & 2 Research, Chandigarh, India; Department of Dermatology, All India Institute of Medical Sciences, New Delhi, India SERIAL ONLINE: Indian Journal of Dermatology, Venereology, and Leprology, Year: 2008 , Volume: 74, Issue: 3, Page: 222-225
1 1 2 1
ABSTRACT
Background: Low-risk human papillomavirus (HPV) infections are related to the genesis of various benign lesions. In an isolated report available, HPVs have been implicated in the causation of skin tags too. Aims: The present study was designed to detect the existence of low-risk HPV types 6 and 11 in cutaneous soft fibromas (skin tag) in north Indians. Methods: A total of 37 cases of skin tags from various sites were analyzed. Highly sensitive and comprehensive polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) assays were done for the detection of low-risk HPV types 6 and 11. Results: The results revealed the presence of HPV DNA 6/11 in 48.6% of the skin tags examined by PCR-RFLP. Conclusion: This result corroborates the hypothesis that HPV plays a part in the etiology of benign lesions like cutaneous soft fibromas. The identification of HPV 6/11 in these lesions, which are benign proliferations of the skin, further expands the spectrum of HPV-linked lesions.
Introduction Human papillomavirus (HPV) is known to be the most ubiquitous of the human viruses. Over 100 HPV types have been identified till date. In healthy population, most of these HPV types appear to establish a latent infection of the skin, mostly as normal flora residing in hair follicles. The numerous HPV types differ in their biological properties and oncogenic potential. Types with high oncogenic potential (which always express the early proteins E6 and E7) are able to transform keratinocytes on their own. 1 The HPV genome usually remains episomal; but in transformed cells, the viral DNA is frequently integrated into the host DNA. 1 Skin tag, or soft fibroma, is a common benign condition, which consists of a bit of skin which projects from the surrounding skin. 2 Histologically,
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skin tag is a polypoid lesion with overlying mildly acanthotic epidermis. There is a loose, edematous fibrovascular core with mild chronic inflammation. Fibroepithelial polyps, or acrochordons, often develop in areas of skin friction. Certain HPV types are found to be associated with the pathogenesis of benign lesions like papillomas of larynx, conjunctiva; respiratory papillomatosis 3 ; etc. We undertook the present study with the aim of establishing the presence of low-risk human papillomavirus types 6 and 11 using polymerase chain reaction (PCR) systems in a benign cutaneous lesion like skin tag in a tertiary care hospital setting in India. Methods Those subjects who presented to the dermatology outpatient clinic with skin tags on multiple sites and were otherwise healthy and willing to participate in the study were enrolled. After obtaining informed consent, biopsy specimens from skin tags were obtained from neck, dorsum of handand axilla from 37 patients. Ten biopsy specimens from the normal skin surrounding skin tags were also analyzed. In a few cases, biopsies from two different skin tags of the same patient were analyzed. DNA extraction Briefly, the tissue specimen was teased and suspended in 500 L of lysis buffer containing 1% sodium dodecyl sulphate (SDS) and 0.01% proteinase K in Tris-EDTA (TE) buffer (pH 8.0) and incubated at 55C overnight. After phenol-chloroform extraction, the DNA was precipitated with chilled isopropanol and resuspended in TE buffer. The prepared DNA was quantitated spectrophotometrically, and PCR for bactin gene was done for each sample as control reaction to check the quality of material. E1-PCR analysis All the samples were subjected to PCR using primers specific for E1 openreading frame of the HPV genome. The sequence of the forward primer was 5- TATGGCTATTCTGAAGTGGAA-3 and that of the reverse primer was 5-GATATACCTGTTCTAAACCA-3. 4 The reaction was carried out in a volume of 20 L containing 2 L 10X Taq buffer, 10 pmol of each of the sense and antisense primers 250 mol dNTP mix, 1.5 units of Taq polymerase (Invitrogen, USA), and distilled water. Three microliters of template DNA was added for each reaction. The plasmid DNA containing HPV genome types 6 and 11 was used as a positive control in the reaction.
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Reaction was performed in a DNA thermal cycler (Eppendorf, Germany) as per the understated protocol. Ten minutes of denaturation at 94C for the first cycle, followed by 1 min each of denaturation at 94C, annealing at 48C, and extension at 72C for 33 cycles was done. The last cycle was extended for 10 min at 72C. The electrophoresis of amplified products was done, and the gel was stained with 0.5 g/mL ethidium bromide to visualize the amplified PCR product. A 526-594-base pair (bp) band was visualized in the samples positive for HPV on a UV transilluminator. The picture was captured on a gel documentation system (Imagemaster, Pharmacia Biotech, Sweden). Restriction fragment length polymorphism (RFLP) PCR products obtained from E1-PCR were purified by using the Invisorb Spin PCRapid Kit (Invitek, Berlin) as per instructions of the manufacturer. Subsequently, purified PCR products were digested with 10 units of restriction enzyme Alu1 at 37C for 2 h and electrophoresed on a 3% agarose gel.Alu1 digestion of amplified fragment from 'low-risk' HPV types 6 and 11 formed the same pattern (a large fragment of 555 bp). 4 Statistical analysis Statistical analysis was performed with the Fisher exact test; a P value less than or equal to 0.05 was considered significant. Results Thirty-seven cases of skin tags from different sites including neck, dorsum of hand, and axilla were recruited in the study. Male : female ratio was approximately 3:1. Majority of the patients (57%) were in the age group of 26 to 55 years. Mean age was 41 years (range, 15-65). PCR using consensus primers spanning the E1 open reading frame showed presence of mucosotropic HPV types in 48.6% (18/37) of the samples [Figure 1]. The biopsy specimens from the normal skin surrounding skin tags were negative for HPV DNA [Figure 1]. The E1-PCR products were then subjected to RFLP, which specifically identifies HPV types 6 and 11. All samples (18/18, 100%) positive by E1-PCR showed HPV 6/11 sequence patterns (a single band of 555 bp) ([Figure 2], lane 6 to lane 9). A few cases, where biopsies from two different sites of the same patient were analyzed, gave the same results. [Table 1] shows the distribution of HPV DNA types 6 or 11 in skin tags from different patients
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with respect to their sex, age, and localization of the lesion. There was no significant correlation with respect to sex, site of lesion, or age of the patient.
Figure 1: Representative picture of 1.5% agarose gel electrophoresis showing postPCR products in normal skin tissue and skin tags from different patients [positive band is of amplified HPV DNA of 526-594 base pairs (bp)]. Lane 1: DNA marker (100-bp ladder); lane 2: negative control; lane 3: normal skin from patient 1; lane 4: skin tag from patient 1; lane 5: normal skin from patient 2; lane 6: skin tag from patient 2; lane 7: normal skin from patient 3; lane 8: skin tag from patient 3; lane 9: plasmids DNA containing the HPV genome types 6 and 11 (positive control); lane 10: DNA marker (100-bp ladder) Figure 2: Electrophoresis on 3% agarose gel showing the Alu1- digested PCR products of the E1-PCR from different skin tag samples and from positive controls. Lane 1: plasmids DNA containing the HPV genome types 6 (555 bp); lane 2: plasmids DNA containing the HPV genome types 11 (555 bp); lane 3: plasmids DNA containing the HPV genome types 16 (343 bp and 240 bp); lane 4: plasmids DNA containing the HPV genome types 18 (267 bp, 238 bp, and 90 bp); lane 5: DNA marker (100-bp ladder); lane 6 to lane 9: test samples from different patients
Table 1: Distribution of HPV DNA type 6 or 11 in skin tags from different patients with respect to their sex, age, and site of lesion
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Discussion The subtropical and tropical areas of the globe harbor large number of infections. The reason can be attributed to the intense exposure of skin to sun. The ultraviolet (UV) irradiation has intense effects on skin immunology, including reduction in density and antigen-presenting ability of Langerhans cells in the epidermis, increased keratinocyte secretion of IL-10 and prostaglandin E2 with increased serum levels of IL4. 5 In addition, there is induction of suppressive IL-12p40 homodimers by dendritic cells and macrophages. Thus UV irradiation seems to induce a resultant immunosuppressive effect with decreased TH1 cell activation. 6 This type of microenvironment is ideal for the survival of infection in healthy subjects living in tropical parts of the globe. HPVs are epitheliotropic and host specific, with infection across the species being exceedingly uncommon. It has been postulated that HPV infection begins with the inoculation of virus into the interrupted epithelium and the interaction with a putative specific cellular receptor. 7 It is recognized that HPV following trauma of epithelium establishes a nonproductive infection of basal cells in the skin and mucosa, but it is only in the differentiated epithelia that HPV replicates. The skin tags or fibroepithelial polyps are known to develop in areas of skin friction, leading to disruption of skin, which might serve as a route of entry for the virus. The presence of HPV DNA and mechanical friction seem to be significant cofactors in the pathogenesis of skin tags. 8 The immune status and genetic profile of the host, as well as the type of virus, may play a role in determining the clinical outcome of HPV infection. So the clinical behavior of soft fibromas may be reminiscent of that of recurrent laryngeal papillomas with respect to the fact that they spread locally in the same subject but rarely to other individuals. In the index study, HPV 6/11 DNA was found to be present in 48.6% of biopsies from skin tags. The entire samples were subjected to PCR-RFLP, and the results of both recognized the presence of HPV 6/11 in 48.6% of the entire sample. The samples were negative for high-risk HPV types (data not shown) when subjected to polymerase chain reaction using consensus primers for high-risk types. The only available literature is a study by Dianzaniet al.,8 who have reported the presence of HPV 6/11 in 88% of the skin tags in Caucasian patients using PCR-RFLP technique. These observations strongly suggest that HPV, along with other cofactors, may be involved in the pathogenesis of these cutaneous lesions. Dianzani et al.8 observed low quantity of HPV DNA in soft fibromas and explained their association with the clinical evolution of these lesions.
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The consistent presence of certain 'low-risk' human papillomavirus types in the skin tag specimens from different sites of the same patient supports the viral etiology. Though the tropical geographical conditions favor infectious etiology in our patients, the lower frequency of the presence of HPV DNA in soft fibroma cells in the present study as compared to the frequencies reported in the literature could be due to difference in the sensitivity of the test, as well as the loss of HPV genome. The presence of HPV sequences in skin tags could aid their recurrence as well. The expression of early viral genes may contribute to stimulated cell growth, which leads to limited epithelial proliferation and formation of acanthotic epidermis overlying edematous fibrovascular tissue. The association of HPV type 6 with benign lesions is very old. It was in 1982 that HPV type 6 was observed in laryngeal papillomas with the help of DNA hybridization technique. A year later, HPV type 11 was also found to be associated with laryngeal papillomas.9 However, the literature on the intracellular mechanisms through which HPV type 6 or 11 may immortalize cells is still fractional in comparison with data on the highrisk HPV types. Additional in vitro and epidemiological studies investigating the influence of genetic and environmental factors on the interaction of the HPV proteins with cellular proteins should provide valuable information on a possible role for HPV types 6 and 11 in the pathogenesis of these cutaneous lesions.
REFERENCES 1. Salzman N, Howley PM, editors. The papoviridae. Vol. 2. New York: Plenum Press; 1987. th 2. Fitzpatrick TB, Eisen AZ, Wolff K, Austen KF, editors. Dermatology in general Medicine. 4 ed. New York: McGraw-Hill; 1993. p. 1200-1. 3. Bentner KR, Tyring S. Human Papillomaviruses and human disease. Am J Med 1997;102:9-15. 4. Contorni M, Leocini P. Typing of human papillomavirus DNA by restriction endonuclease mapping of the PCR products. J Virol Methods 1993;41:29-36. 5. el-Ghorr AA, Norval M. The role of interleukin-4 in ultraviolet 13 induced immunosuppression. Immunology 1997;92: 26-32. 6. Shreedhar V, Giese T, Seeng VW, Ultrich SE. A cytokine cascade including prostaglandin E2, IL-4 and IL-10 is responsible for UV-induced systemic immune suppression. J Immunol 1998;160:3783-9. 7. Moscicki AB. Human papillomavirus infection in adolescents. Pediatr Clin North Am 1999;46:783-807. 8. Dianzani C, Calvieri S, Pierangeli A, Imperi M, Bucci M, Degener AM. The detection of human papillomavirus DNA in skin tags. Br J Dermatol 1998;138:649-51. 9. Zarod A, Rutherford J, Corbitt G. Malignant progression of laryngeal papilloma associated with human papillomavirus 6 (HPV-6) DNA. J Clin Pathol 1988;41:280-3.
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MOUTH CANCER AND THE HUMAN PAPILLOMA VIRUS

FROM: http://www.rdoc.org.uk/hpv.html AUTHORS: Dr Vinod K Joshi BDS DRDRCS FDSRCPS FDSRCS FICOI. LAST UPDATED: March 25, 2011
The human papilloma virus (HPV) is one of the most common virus groups in the world to affect the skin and mucosal areas of the body. Over eighty types of HPV have been identified. Different types of the human papillomavirus are known to infect different parts of the body. It infects the epithelial cells of skin and mucosa. The epithelial surfaces include all areas covered by skin and/or mucosa such as the mouth, throat, tongue, tonsils, vagina, penis, and anus. Infection with the virus occurs when these areas come into contact with a virus, allowing it to transfer between epithelial cells.
Warts The most common forms of the virus produce warts (papilloma's) on the hands, arms, legs, and other areas of the skin. The wart-like growths are called condyloma tissues. Condyloma tissue appears like a small, cauliflower-type growth on the skin. These growths are usually painless, but can cause some irritation, itching, or burning. It can be treated whenever it flares up, and is non malignant. Most HPV's of this type are very common, harmless, non cancerous, and easily treatable. Genital warts are known technically as condylomata acuminatum and are generally associated with two HPV types, numbers 6 and 11 and can be sexually transmitted. Cervical Cancer and Oral Cancer There are other forms of HPV which are also sexually transmitted, and are a serious problem. These are; HPV-16, HPV-18, HPV-31, and HPV-45. These cancer-associated types of HPVs cause dysplastic tissue growths that usually appear flat and are nearly invisible. Dysplastic tissue is the presence of abnormal cells on the surface of the skin. Dysplasia is not cancer, but it is a tissue change seen prior to malignancy. A highly studied topic is HPV's ability to cause cervical cancer. Dysplasia can be detected on the female cervix through a Pap smear test, or seen visually using a magnifying glass called a colposcope. The most dangerous HPV's, 16 and 18, which are transmitted through sexual contact are known to cause up to 95% of cervical cancers. Now these two HPV's are also being linked to oral cancer.
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A study done by Dr. No-Hee Park showed that the mouth was, at the cellular level, structurally very similar to the vagina and cervix. Both organs have the same type of epithelial cells that are the target of HPV 16 and HPV 18. The majority of oral cancers are cancers of epithelial cells, primarily squamous cell carcinomas, not unlike the cancers that affect the cervix. Dr. Park's study also showed that smoking and drinking alcohol help promote HPV invasion. Combine tobacco and alcohol with HPV, and the epithelial cells in the mouth, and you may have the formula for the development of an oral cancer. A recent study conducted by Dr. Maura Gillison at the Johns Hopkins Oncology Center furthered the premise that HPV is linked with certain types of oral cancer. In 25% of 253 patients diagnosed with head and neck cancers, the tissue taken from tumors was HPV positive and HPV 16 was present in 90% of these positive HPV tissues. This information helps to confirm that there is a strong link between HPV 16 and oral cancer. 25% of those diagnosed with oral cancer are non-smokers while the other 75% of those diagnosed have used tobacco in some form during their lifetimes. The research into the relationship of HPV and oral malignancies may give us clues as to the origin of cancer in those 25% of diagnosed individuals who did not smoke. Further research is being conducted into the relationship of HPV with oral cancers. Treatments for Warts Although there is currently no medical cure to eliminate a papillomavirus infection, the squamous intraepithelial lesions (SILs) and warts these viruses cause can be treated. Methods used to treat SILs include cold cautery (freezing that destroys tissue), laser treatment (surgery with a high-intensity light), LEEP (loop electrosurgical excision procedure, the removal of tissue using a hot wire loop), as well as conventional surgery. Similar treatments may be used for external genital warts. In addition, two powerful chemicals (podophyllin and trichloroacetic acid) are capable of destroying external genital warts when applied directly to them. Imiquimod cream has also been recently approved by the Food and Drug Administration (FDA) as an effective drug treatment. Imiquimod works by stimulating the immune system to fight the virus.
REFERENCES: Scully C. Oral squamous cell carcinoma; from an hypothesis about a virus, to concern about possible sexual transmission. Oral Oncol. 2002 Apr;38(3):227-34.
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HUMAN PAPILLOMAVIRUS-MEDIATED CARCINOGENESIS

FROM: http://www.head-face-med.com/content/6/1/14 AUTHORS: Liviu Feller , Neil H Wood, Razia AG Khammissa and Johan Lemmer Department of Periodontology and Oral Medicine, University of Limpopo, Medunsa Campus, South Africa LAST UPDATED: July 15, 2010 ONLINE SERIAL: Head & Face Medicine 2010, 6:14 doi:10.1186/1746-160X-6-14
*
ABSTRACT
High-risk human papillomavirus (HPV) E6 and E7 oncoproteins are essential factors for HPV-induced carcinogenesis, and for the maintenance of the consequent neoplastic growth. Cellular transformation is achieved by complex interaction of these oncogenes with several cellular factors of cell cycle regulation including p53, Rb, cyclin-CDK complexes, p21 and p27. Both persistent infection with high-risk HPV genotypes and immune dysregulation are associated with increased risk of HPV-induced squamous cell carcinoma.
Introduction Cancer is a disease primarily caused by cytogenetic changes that progress through a series of sequential somatic mutations in specific genes resulting in uncontrolled cellular proliferation.1,2 It may be caused by exposure to any one or more of a variety of chemical or physical agents, by random errors of genetic replication, or by errors in DNA repair processes. Almost all cancers follow carcinogenic events in a single cell (are monoclonal in origin), and this characteristic distinguishes neoplasms from hyperplasias that have a polyclonal origin.1 Mutations in genes controlling cell cycle progression (gatekeeper genes) and DNA repair pathways (caretaker genes) are the essential initiating events of cancer. Both oncogenes and tumour suppressor genes act as gatekeeper genes. After mutation, certain genes may acquire new functions that lead to increased cell proliferation: these genes are called oncogenes. Such a mutational event occurs characteristically in a single allele of the future oncogene, and that allele then directly causes dysregulation of molecular mechanisms that control cell cycle progression. Tumour suppressor genes on the other hand, lose their function when both alleles are inactivated, and consequently lose their capacity to inhibit cell proliferation.1-7
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Caretaker genes are DNA repair-genes that serve to maintain the integrity and stability of the genome. Mutations in these genes do not directly contribute to uncontrolled cell proliferation, but increase the likelihood of mutations in the gatekeeper genes and may thus indirectly promote malignant cellular transformation.1,4,5,7 Epigenetic modification refers to changes in gene expression (phenotype) without alteration in DNA structure (genotype). Somatic alterations of specific genes together with epigenetic events determine the development of malignancy. Significant among the epigenetic events are methylation of cytosine bases of DNA and modification of histones by acetylation or methylation which are associated with silencing of tumour suppressor genes.1-3,8-11 Carcinogenesis can be seen as a Darwinian process involving sequential mutations giving the mutated cells growth dominance over the normal neighbouring cells resulting in the increased representation of the mutated cells in the affected tissue.12-15 It is generally assumed that five to ten mutational events in as many different genes will transform a normal cell into a malignant phenotype.1,2 The role of human papillomavirus (HPV) in the cellular bio-pathological processes of carcinogenesis of the anogenital region has been extensively researched and documented, and therefore Part 1 of this review is substantially based on this material. These bio-pathological sequential events are described in some detail as a basis for a discussion in Part 2 of the role of HPV in the pathogenesis of oral and oropharyngeal squamous cell carcinoma. Human papillomavirus (HPV)-induced carcinogenesis High-risk HPV E6 and E7 oncoproteins expressed in epithelial cells infected with HPV are implicated in the increased proliferation and in the abnormal differentiation of these cells.16,17 When the E6/E7 proteins are the expression of infection of the cell with low-risk HPV, then these active proteins may induce benign neoplasms. However, when E6/E7 proteins are the expression of high-risk HPV infection, they subserve the role of oncoproteins and they have the capacity to induce dysplastic and malignant epithelial lesions.18,19 The association between cancer of the uterine cervix and high-risk HPV infection is well established. It is evident that HPV is an essential agent, but is not by itself sufficient to induce squamous cell carcinoma of the cervix. HPV DNA is found in more than 99% of biopsy specimens of squamous cell carcinoma of the cervix. In more than 70% of these HPV
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DNA positive biopsy specimens, the DNA is of high-risk HPV-16 and HPV-18 origin.20 The prevalence of HPV infection of the cervix of the uterus is high, but in these same subjects the incidence of squamous cell carcinoma of the cervix is relatively low.21 Therefore, besides persistence of the HPV infection, the HPV genotype, infection with multiple HPV genotypes, whether the viral DNA is present episomally or integrated and the quantum of cellular viral load may be important factors in the development of the cancer. Equally important may be other co-factors that may vary from individual to individual but can include immune fitness, nutritional status, the use of tobacco, and co-infection with other sexually transmitted agents including HIV and herpes simplex virus.20 E6 and E7 oncoproteins can inactivate the genetic mechanisms that control both the cell cycle and apoptosis.16,17 The hallmark of high-risk HPV E6 oncogenic activity is degradation of the p53 tumour-suppressor gene. The functions of p53 in the cell cycle include controlling the G1 transition to the S phase of the cell cycle at the G1 checkpoint by inducing expression of cyclin inhibitors p16, p21 and p27 that block the activities of cyclin-CDKs (cyclin-dependant kinase) complexes, thus mediating arrest of the cell cycle by blocking the progression of the cell cycle at the G1/S transition.17 p53 activities mediate cell proliferation in response to mitogenic stimulation; mediate arrest of the cell cycle growth at the G1 checkpoint following DNA damage, hence permitting repair of the damaged DNA before the cell enters the DNA synthesis phase; and mediate induction of apoptosis of cells in which the DNA damage is beyond repair. 22,23 Therefore, inactivation, degradation, or mutation of the p53 gene may dysregulate its functions resulting in increased cell proliferation, in accumulation of damaged DNA, in growth of cells harbouring DNA errors, and in prolonged cell survival. However, loss of p53 function alone is not sufficient for the development of cancer, and other cytogenetic alterations are required for complete malignant transformation.22,23 In addition to these properties, E6 oncoprotein of high-risk HPV types can also mediate cell proliferation through the PDZ-ligand domain.16 The PDZ domain is located at areas of cell-to-cell contact, such as tight junctions of epithelial cells, and is associated with signal transduction pathways. The binding of high-risk HPV E6 oncoprotein to the PDZ family of proteins may result in degradation of the PDZ domain24,25 leading to dysregulation of organization, differentiation, and of the chromosomal integrity of HPV infected epithelial cells.18 This may
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contribute to morphological transformation of keratinocytes infected with high-risk HPV26 and to induction of epithelial hyperplasia.27 Telomerase is an enzyme that adds hexanucleotide repeats onto the end of the chromosome telomere.3 Telomerase activity is usually restricted to embryonic cells and is absent in normal somatic cells.25 When telomerase is absent, there is progressive shortening of telomeres as the cells repetitively divide, ultimately resulting in senescence of these cells.3,25,28 HPV-induced activation of telomerase prevents the shortening of telomeres resulting in prolongation of the lifespan of HPV-infected cells.24,25,28 High risk HPV E7 oncoprotein has the capacity to initiate DNA synthesis in differentiated epithelial cells mainly by binding and inactivating the Rb apoptosis/tumour-suppressor gene. The Rb family of proteins plays an essential role in controlling the cell cycle by governing the checkpoint between the G1 and the S phase. Hypophosphorylated Rb binds to E2F transcription factor forming a Rb-E2F complex, making E2F unavailable for transcription of genes associated with DNA synthesis. Upon phosphorylation of Rb by cyclin-CDK complexes, E2F is released from the Rb-E2F transcription repressor complex, and it induces transcription of the S-phase genes.16,18.23.25.29 E7 oncoprotein of high-risk HPV types functionally inactivates the Rb family of proteins resulting in overexpression of E2F transcription factor with upregulation of cell cycle genes resulting in DNA replication, in the transition of the cell from the G1 to the S phase, and in increased cell proliferation.16,18,25 E7 oncoprotein can also interact with other cellular factors that control the cell cycle including histone deacetylases, AP-1 transcription complex and CDK inhibitors, p21 and p27.16 Furthermore, E7 of high-risk HPV-16 and -18 can decrease the expression of major histocompatibility complex (MHC) class I molecules, thus interfering with MHC class I antigen presentation, resulting in downregulation of cellular immune responses, allowing HPV to persist in infected epithelial cells.17 In addition to these properties, high-risk HPV E7 oncoprotein can induce chromosome duplication errors leading to dysregulation of mitotic spindle formation and function, contributing to the genomic instability of the cell.30 The separate pathological effects of high-risk HPV E6 and E7 on the cell cycle complement each other, and together E6 and E7 mediate the HPVassociated epithelial cell transformation, and promote cellular genomic instability that predisposes the infected cells to full malignant transformation. High-risk HPV E7 activates the DNA synthesis and cell
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replication mechanisms that are normally inactive in matured epithelial cells, thus initiating pathological cell growth. By inducing cell survival and delayed apoptosis of cells with DNA damage, E6 allows E7 to exert and sustain its pathological effect.18 Typically, infected epithelial cells of HPV-associated benign lesions harbour low-risk HPV episomally in the nuclei. In HPV-associated malignancies, high-risk HPV DNA may either be integrated within the cellular genome, or it may be maintained as an episome in the nuclei of the malignant cells.31 It is unclear how the HPV genome, whether episomal within the nucleus or integrated into the nuclear cellular genome, brings about the same end result of malignancy.32 The integration of HPV DNA favours the inactivation of tumour suppressor genes, p53 and Rb, contributing to increased cellular chromosomal instability, and prolonging the lifespan of the cell, essential steps in the multi-step process of HPV-associated carcinogenesis.11,25,28,33 It is probable that following the initial HPV-induced cellular transformation, additional interactions with chemical carcinogens will provide the necessary additional impetus for the development of frank malignancy (Figure 1).32 The integration of the HPV genome as opposed to the presence of HPV episomally is associated with a greater frequency of cervical intraepithelial neoplasia (CIN) grade 3, and with invasive squamous cell carcinoma of the uterine cervix.11,28,34 The pathological significance of integration is not entirely clear since HPV often exists concurrently in both episomal and integrated forms. The chromosomal locations of integrated HPV are very variable, and there is a paucity of data on the frequencies and chromosomal locations of different HPV genotypes.11,35 HPV oncoproteins can act synergistically with intra-nuclear protooncogenes, with cytokines that bind and activate E6/E7 promoter, with exogenous factors including carcinogens in tobacco and dietary agents, steroids, and UV and X-radiation, to promote HPV-tumourigenesis (Figure 1).31
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Figure 1. Flow chart of high-risk HPV pathogenesis of squamous cell carcinoma. By inactivation of p53, high-risk HPV E6 oncoprotein induces cell survival and delayed apoptosis, and HPV E7 oncoprotein through inactivation of Rb gene stimulates cellular DNA synthesis and pathological cell growth. The separate pathological activities of HPV E6 and E7 on the cell cycle complement each other and mediate the HPV-associated epithelial cell transformation.
Genetic and epigenetic events associated with HPV infection The cellular genomic integrity is maintained by various caretaker cellular systems, including DNA monitoring and repair enzymes, checkpoints that regulate the cell cycle, and genes that ensure the accurate
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chromosomal replication during mitosis. Malfunction of cellular caretaker systems brings about genomic instability that is associated with increased risk of acquiring accumulative genetic alterations that can ultimately culminate in carcinogenesis. The genomic instability brought about by HPV-induced malfunction of p53 tumour suppressor gene results in the inheritance of abnormal DNA by cells that are not only proliferating in increased numbers, but surviving longer with consequently increased chances of malignant transformation.3 Tumours destined to become malignant appear to be characterized by chromosomal imbalances, in terms of gains or losses of genetic material.36 Most chromosomal imbalances affect large genomic regions containing multiple genes, and have functional consequences that are unknown. Gains or losses of genetic material lead to changes in DNA copy-numbers.37 Genomic gain may arise from DNA sequence amplification leading to overexpression of oncogene products; and genomic losses may be brought about by single-gene or intragenic deletion leading to the loss of the functional product of a tumour suppressor gene.1,36 Large-scale genomic gains or losses affecting multiple genes are frequently observed in cancers and manifest in changes in DNA copynumbers, but the identification of the specific gained or lost gene that promotes the carcinogenesis is difficult, and in most cases impossible.36 HPV-related anal intraepithelial neoplasia is associated with DNA copynumber abnormalities, and the severity of the lesion is directly related to the magnitude of the DNA copy-number changes.33 In HPV-induced malignancies there are two distinct epigenetic events. The first is methylation of viral genes that are associated with increasing viral oncogenic capacity, and the second is silencing of cellular tumoursuppressor genes through hypermethylation of the promoter regions.11 Given enough time, the accumulation of epigenetic and genetic changes may eventually cause malignant transformation.33 Conclusions As is the case in many other malignancies, HPV-induced carcinogenesis is a complex process characterized by alterations in genes encoding tumour-suppressor genes and by epigenetic modifications. The hallmark of HPV-induced carcinogenesis is inactivation of p53 tumour-suppressor gene by the E6 and of Rb apoptosis/tumour suppressor gene by E7 oncoproteins of high-risk HPV genotypes. The aberrant function of these genes and the consequent genomic instability compounded by the
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additive effects of one or more cofactors leads to preferential growth of the affected cells which characterize the progressive uncontrolled growth in cancer.
REFERENCES 1. Morin PJ, Trent JM, Collins FS, Vogelstein B: Cancer genetics. In Harrisons principles of internal medicine. 16th edition. Edited by Kasper DL, Braunwald E, Fauci AS, Hauser SL, Lango DL, Jameson JL. New York: Graw-Hill; 2005:447-453. 2. Fenton RG, Longo DL: Cancer cell biology and angiogenesis. In Harrisons principles of internal medicine. 16th edition. Edited by Kasper DL, Braunwald E, Fauci AS, Hauser SL, Lango DL, Jameson JL. New York: Graw-Hill; 2005:453-464. 3. Hanahan D, Weinberg RA: The hallmarks of cancer.Cell 2000, 100:57-70. 4. Vogelstein B, Kinzler KW: Cancer genes and the pathway they control.Nat Med 2004, 10:789-799. 5. Kinzler KW, Vogelstein B: Cancer-susceptibility genes. Gatekeepers and caretakers. Nature 1997, 386:761-763. Lengauer C, Kinzler KW, Vogelstein B: Genetic instabilities in human cancers.Nature 1998, 396:643-649. 6. Levitt NC, Hickson ID: Caretaker tumour suppressor genes that defend genome integrity.Trends Mol Med 2002, 8:179-186. 7. Bernstein BE, Meissner A, Lander ES: The mammalian epigenome.Cell 2007, 128:669-681. 8. Burstein HJ, Schwartz RS: Molecular origins of cancer.N Engl J Med 2008, 358:527-511. 9. Jones PA, Baylin SB: The epigenomics of cancer.Cell 2007, 128:683-692. 10. Wang SS, Hildesheim A: Viral and host factors in human papillomavirus persistence and progression.J Natl Cancer Inst Monogr 2003, 31:35-40. 11. Cahill DP, Kinzler KW, Vogelstein B, Lengauer C: Genetic instability and Darwinian selection in tumours.Trends Cell Biol 1999, 9:M57-60. 12. inies P: Cancer as an evolutionary process at the cell level: an epidemiological Perspective. Carcinogenesis 2003, 24:1-6. 13. reivic J: The evolutionary origin of genetic instability in cancer development.Semin Cancer Biol 2005, 15:51-60. 14. Gatenby RA, Vincent TL: An evolutionary model of carcinogenesis.Cancer Res 2003, 63:62126220. 15. Doorbar J: The papillomavirus life cycle.J Clin Virol 2005, 32S:S7-S15. 16. Miller CS: Pleiotrophic mechanisms of virus survival and persistence.Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005, 100:527-536. 17. von Knebel Doeberitz M: New markers for cervical dysplasia to visualize the genomic chaos created by aberrant oncogenic papillomavirus infections.Eur J Cancer 2002, 38:2229-2242. 18. Jastreboff AM, Cymet T: Role of the human papilloma virus in the development of cervical intraepithelial neoplasia and malignancy.Postgrad Med J 2002, 78:225-228. 19. Steben M, Duarte-Franco E: Human papillomavirus infection: epidemiology and pathophysiology.Gynecol Oncol 2007, 107:S2-S5. 20. Martin MP, Carrington M: Immunogenetics of viral infections.Curr Opin Immunol 2005, 17:510516. 21. Nghiem P, Kupper TS: Basal and squamous cell carcinomas. In Principles of molecular medicine. 1st edition. Edited by Jameson JL. Totowa New Jersey: Humana Press Inc; 1998:65-72. 22. Nguyen LQ, Jameson JL: The cell cycle. In Principles of molecular medicine. 1st edition. Edited by Jameson JL. Totowa New Jersey: Humana Press Inc; 1998:65-72. 23. Elgui de Oliveira D: DNA viruses in human cancer: An integral overview of fundamental mechanisms of viral oncogenesis.Cancer letters 2007, 247:182-196. 24. Longworth MS, Laminis LA: Pathogenesis of human papillomavirus in differentiating epithelia.Microbiol Mol Biol Rev 2004, 68:362-372. 25. Watson RA, Thomas M, Banks L, Roberts S: Activity of the human papillomavirus E6 PDZ-binding motif correlates with an enhanced morphological transformation of immortalized human keratinocytes.J Cell Sci 2003, 116:4925-4934. 26. Nguyen ML, Nguyen MM, Lee D, Griep AE, Lambert PF: The PDZ ligand domain of the human papillomavirus type 16 E6 protein is required for E6's induction of epithelial hyperplasia in vivo.JVirol 2003, 77:69576964.
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27. Angeletti PC, Zhang L, Wood C: The viral etiology of AIDS-associated malignancies.Adv Pharmacol 2008, 56:509-557. 28. Jameson JL: Oncogenes and tumour suppressor genes. In Principles of molecular medicine. 1st edition. Edited by Jameson JL. Totowa New Jersey: Humana Press Inc; 1998:73-82. 29. Duensing S, Mnger K: Human papillomavirus type 16 E7 oncoprotein can induce abnormal centrosome duplication through a mechanism independent of inactivation of retinoblastoma protein family members.J Virol 2003, 77:12331-12335. 30. Bonnez W: Papillomavirus. In Clinical virology. 2nd edition. Edited by Richman DD, Whitley RJ, Hayden FG. Washington D.C.: ASM Press; 2002:557-596. 31. Campo MS: Animal models of papillomavirus pathogenesis.Virus Res 2002, 89:249-261. 32. Palefsky J: Biology of HPV in HIV.Adv Dent Res 2006, 19:99-105. 33. Del Mistro A, Chieco Bianchi L: HPV related neoplasias in HIV-infected individuals. Eur J Cancer 2001, 37:1227-1235. 34. Gillison ML: Human papillomavirus and prognosis of oropharyngealsquamous cell carcinoma: Implication for clinical research in head and neck cancer. J Clin Oncol 2006, 24:5623-5625. 35. Frhling S, Djner H: Chromosomal abnormalities in cancer. N Engl J Med 2008, 359:722-734. 36. Albertson DC, Pinkel D: Genomic microarrays in human genetic disease and cancer. Hum Mol Genet 2003, 12(rev issue 2):R145R152.
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CONDOM USE REDUCES RISK OF INFECTION WITH HUMAN PAPILLOMAVIRUS (HPV)

FROM: http://healthlibrary.epnet.com/GetContent.aspx?token=0a1af489-5b4c-4f2d-978e3930be13b1f6&chunkiid=129420 AUTHORS: Urmila Parlikar, MS LAST UPDATED: June 2006
Each year, about 6.2 million men and women become infected with genital human papillomavirus (HPV). About 40 types of sexually transmissible HPV exist. Certain types of HPV cause genital warts, while other types cause cervical cancer. Earlier this month, the US Food and Drug Administration (FDA) approved a vaccine that protects against four types of HPV, two of which are commonly associated with cervical cancer. The vaccine is a promising breakthrough in cervical cancer prevention, but it will still leave women susceptible to many types of HPV. Condoms are often recommended to protect against sexually transmitted infections, but studies on the effectiveness of condoms against HPV have been limited. In an article published in the June 22, 2006 issue of New England Journal of Medicine, researchers studied whether condoms protect women against HPV infection. They found that women whose partners used condoms 100% of the time were significantly less likely to be infected with HPV than women whose partners used condoms less than 5% of the time. They also found that as the frequency of condom use increased, the risk of HPV infection decreased. About the Study The researchers recruited 82 female college students, ages 18-22. The women all had sexual intercourse for the first time during the study period, or during the two weeks prior to enrollment. Every two weeks, each of the study subjects completed a Web-based diary specifying how many times they had vaginal intercourse, how often their partners had used condoms, and the number of new partners they had. In addition, the women had gynecologic exams every four months, during which cervical and vaginal cell samples were collected for HPV testing. Women whose partners used condoms all of the time were 70% less likely, and women whose partners used condoms more than half of the
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time were 50% less likely, to be infected with HPV compared to women whose partners used condoms less than 5% of the time. This study was limited by its reliance on the study subjects to accurately recall and report how often their partners had used condoms. How Does This Affect You? This study showed that condoms effectively protected young women against HPV infection. This is reassuring, since unlike other sexually transmitted infections (eg, HIV, chlamydia, and gonorrhea), HPV is spread via skin to skin contact, possibly in areas unprotected by condoms. These findings appear on the heels of the FDAs approval of the HPV vaccine. There is little doubt that the new vaccine will protect many women from HPV infection, as well as cervical cancer. But condom use is still an important and necessary step for preventing HPV infection. The new HPV vaccine will protect against four types of HPV, which together cause the majority of cervical cancers and genital warts. However, the vaccine will not protect against an additional 30+ types of HPV, some of which have also been associated with cervical cancer and genital warts. Only abstinence can guarantee that you wont catch HPV. If you are sexually active, use a condom to protect against HPV, as well as many other sexually transmitted infections.
REFERENCES: FDA licenses new vaccine for prevention of cervical cancer and other diseases in females caused by human papillomavirus: rapid approval marks major advancement in public health. US Food and Drug Administration website. Available at: http://www.fda.gov/bbs/topics/NEWS/2006 /NEW01385.html. Accessed June 19, 2006. Gottleib M. A primer on HPV. National Cancer Institute website. Available at: http://newscenter. Accessed June 19, 2006. Winer RL et al. Condom use and the risk of genital human papillomavirus infection in young women. N Engl J Med . 2006; 354:2645-2654.
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PROPHYLACTIC HUMAN PAPILLOMAVIRUS VACCINES

FROM: http://www.jci.org/articles/view/28607 AUTHORS: Douglas R. Lowy and John T. Schiller, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA. LAST UPDATED: May 1, 2006
Human papillomavirus (HPV) infection causes virtually all cases of cervical cancer, the second most common cause of death from cancer among women worldwide. This Review examines prophylactic HPV subunit vaccines based on the ability of the viral L1 capsid protein to form virus-like particles (VLPs) that induce high levels of neutralizing antibodies. Following preclinical research by laboratories in the nonprofit sector, Merck and GlaxoSmithKline are developing commercial versions of the vaccine. Both vaccines target HPV16 and HPV18, which account for approximately 70% of cervical cancer. The Merck vaccine also targets HPV6 and HPV11, which account for approximately 90% of external genital warts. The vaccines have an excellent safety profile, are highly immunogenic, and have conferred complete type-specific protection against persistent infection and associated lesions in fully vaccinated women. Unresolved issues include the most critical groups to vaccinate and when the vaccines cost may be low enough for widespread implementation in the developing world, where 80% of cervical cancer occurs.
Human papillomavirus infection and disease Of the 10 million cases of cancer that develop annually throughout the world, more than 15% are estimated to be attributable to infectious agents.1 Infection by human papillomaviruses (HPVs) accounts for approximately 30% of these cancers (~5% of all cancers), with hepatitis B and C viruses and Helicobacter pylori together accounting for another 60% of cancers with an infectious etiology HPVs infect the stratified squamous epithelia of skin and mucous membranes, where they cause benign lesions, some of which have the potential to progress to invasive cancer.2,4 HPVs are small, nonenveloped viruses whose approximately 8-kb circular genome encodes 2 structural proteins, L1 and L2, that form the viral capsid, plus several nonstructural proteins that are important for the virus life cycle but are not incorporated into virions. To establish infection, microtrauma or erosion of the overlying epithelial layers is thought to enable HPVs to infect cells of the basal epithelial layer, where the stem cells and other long-lived cells are found (Figure 1). HPV infections tend to last months or years
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because the viral genome successfully parasitizes these cells and because the virus evades the immune system by limiting most viral gene expression and viral replication to suprabasal cell layers. Most infections are self-limited, presumably because the host eventually mounts a successful immune response.
Figure 1 Papillomavirus life cycle. To establish infection, the virus must infect basal epithelial cells that are long lived or have stem celllike properties. Microtrauma to the suprabasal epidermal cells probably enables the virus to infect the cell within the basal layer. The viral genome maintains itself as an episome in basal cells, where the viral genes are poorly expressed. Viral replication takes place in suprabasal layers and is tied to the epidermal differentiation process. The presence of the virus causes morphological abnormalities in the epithelium, including papillomatosis, parakeratosis, and koilocytosis. Progeny virus is released in desquamated ces.
The benign lesions induced by HPVs include nongenital and anogenital skin warts, oral and laryngeal papillomas, and anogenital mucosal condylomata (Figure 2). Anogenital infections are almost always transmitted sexually. Long-term infection by a subset of HPVs can lead to malignant anogenital tumors, including cancers of the anus, penis, vulva, vagina, and cervix.5-7 A proportion of oral cancer is also attributable to HPV.8,9 While HPV infection has been associated on limited occasions with esophageal cancer and skin cancer, a frequent causal link, although plausible, remains more tenuous.6,10
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Figure 2 Progression from a benign cervical lesion to invasive cervical cancer. Infection by oncogenic HPV types, especially HPV16, may directly cause a benign condylomatous lesion, low-grade dysplasia, or sometimes even an early highgrade lesion. Carcinoma in situ rarely occurs until several years after infection. It results from the combined effects of HPV genes, particularly those encoding E6 and E7, which are the 2 viral oncoproteins that are preferentially retained and expressed in cervical cancers; integration of the viral DNA into the host DNA; and a series of genetic and epigenetic changes in cellular genes. HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesn.
Among the cancers attributable to HPV infection, cervical cancer has received the most attention,11 as it accounts for about 10% of all cancers in women worldwide. Cervical cancer is the second most common cause of death from cancer, after breast cancer, among women worldwide. The interval between the acquisition of HPV infection and malignant progression usually takes at least 10 years (Figure 3) and is frequently longer.7,12 Cervical cancer is therefore very uncommon in women under 25; the incidence rises progressively for women over 25 and is highest for women over 40. About 80% of cervical cancers occur in less-developed countries, primarily because they lack sufficient resources for highquality cervical cancer screening programs that detect cervical abnormalities via Pap smear testing or testing for the presence of cervical HPV DNA.13 Virtually all cases of cervical cancer are attributable to sexually acquired HPV infection,14 while infection by HPV accounts for a variable proportion of the other tumors in which the virus has been implicated etiologically. Of all cancer cases linked etiologically to HPV, cervical cancer accounts for about two-thirds of them. This cancer can
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result from infection by any 1 of about 15 oncogenic HPV types, but HPV16 and HPV18 predominate, accounting for about 50% and 20% of cervical cancer, respectively.15 These 2 types account for an even higher proportion of the other genital and mucosal cancers attributable to HPV infection.16
Figure 3 Relationship among incidences of cervical HPV infection, precancer, and cancer. The HPV curve emphasizes the high incidence of infection that develops soon after women initiate sexual activity and subsequent lower incidence because a high proportion of infections are self-limited. The precancer incidence curve follows several years behind the HPV incidence curve and is substantially lower than that of HPV incidence, as there is generally a delay between the acquisition of HPV infection and precancer development, and only a subset of infected women develop precancers. The cancer incidence curve follows several years behind the precancer curve, reflecting the relatively long interval between precancer and progression to invasive cancer. As women approach 40 years of age, the incidence of cancer begins to approach the incidence of precancer. Figure modified with permission from the New England Journal of Medicine53).
Genital HPV infection is believed to be the most common sexually transmitted viral infection, with an estimated prevalence of about 20 40% among sexually active 20-year-old women, an estimated 3-year cumulative incidence of more than 40% in studies of college women in the United States, and an estimated lifetime risk for women of at least 75% for one or more genital HPV infections.16,17 Most genital HPV infections are benign, subclinical, and self-limited, and a high proportion of infections associated with low-grade cervical dysplasias (Figure 2) also regress spontaneously.7,17 By contrast, persistent cervical infection (often defined as an infection that is detected more than once in an interval of 6 months or longer) with an oncogenic HPV type, especially HPV16 and HPV18, is the most important risk factor for progression to high-grade
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dysplasia (Figure 2)8, which is recognized as a precancerous lesion that should be treated to prevent the development of invasive cancer. Locally, ablative therapy is used successfully to treat high-grade dysplasia.13 Prophylactic HPV vaccine: development and efficacy studies Identification of a viral agent such as HPV as a cause of disease(s) implies that successful prophylactic or therapeutic intervention against the viral agent should prevent the disease(s) it causes. A preexisting viral infection can theoretically be targeted by an antiviral or a therapeutic vaccine. Successful antivirals have been developed for the treatment of some viral infections, including diseases such as HIV and influenza,19 but not against viruses such as HPV. A therapeutic vaccine against HPV infection would be highly desirable to prevent the cancer-associated complications of HPV infection, which only develop after many years of infection. However, despite ongoing efforts to develop effective therapeutic vaccines against HPV and other viral infections, none has been shown to be highly effective clinically,20 probably because the vaccines have not yet adequately mimicked critical aspects of a curative immune response. On the other hand, prophylactic vaccines have been developed against a variety of human viral pathogens and are often a cost-effective approach to interfere with the diseases caused by these pathogens.21 To be widely implemented, a prophylactic vaccine generally needs to confer high-level protection for at least several years without boosting and to be particularly safe, as it is given to healthy individuals. The recognition of HPV as the cause of cervical cancer and other diseases therefore implied that an effective HPV vaccine should be able to interfere with the benign and malignant conditions attributable to HPV infection. However, approved prophylactic vaccines have been directed against infectious agents that cause systemic disease, and efforts to develop vaccines against sexually transmitted agents such as HPV whose disease results from local infection had not proven successful. It is believed that neutralizing antibodies form the cornerstone of most prophylactic vaccines, and viruses that cause disease only after passing through the circulation are accessible to the neutralizing antibodies present in the blood.22 Another limitation was that the presence of oncogenes in HPVs suggested that a subunit vaccine approach would theoretically be preferable to an inactivated vaccine or an attenuated live-virus vaccine, and it was unclear whether a subunit HPV vaccine would have the potential to be effective against the local infections caused by genital HPVs.
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Despite these uncertainties, 2 pharmaceutical companies, Merck and GlaxoSmithKline, have recently reported a remarkable degree of protection by candidate prophylactic HPV vaccines (see below). The vaccines that both companies are developing are subunit virus-like particle (VLP) vaccines composed of a single viral protein, L1, which is the major structural (capsid) protein of the virus and contains the immunodominant neutralization epitopes of the virus. The vaccines are based primarily on preclinical research showing that (a) when expressed in cells, L1 has the intrinsic ability to self-assemble into VLPs (Figure 4)2326 that can induce high levels of neutralizing antibodies;23,27,28 (b) in animal models of animal papillomavirus infection, parenteral vaccination with L1 VLPs protects from high-dose challenge with homologous virus,29-31 while animals are not protected by systemic immunization with denatured L1 or L1 VLPs from a heterologous papillomavirus because L1 neutralization epitopes are conformationally dependent and predominantly type specific;29 and (c) protection can be passively transferred by immune IgG.29,30 The VLPs from the Merck vaccine are produced in yeast,32-34 while the VLPs from the GlaxoSmithKline vaccine are produced in insect cells via recombinant baculovirus.35 Merck uses alum as an adjuvant in its vaccine, while GlaxoSmithKline uses AS04, a proprietary adjuvant composed of alum plus monophosphoryl lipid A (a detoxified form of lipopolysaccharide). Both vaccines use purified particles, which are given as 3 intramuscular injections over a 6-month period.
Figure 4 Electron micrograph of HPV16 L1 VLPs. Original magnification, 14,500. Image courtesy of Yuk-Ying Susana Pang (Laboratory of Cellular Oncology, National Cancer Institu).
Of course, it would be desirable for an HPV vaccine to have the ability to prevent all cases of cervical cancer. However, although the 15 oncogenic types implicated in cervical cancer are more closely related to each other phylogenetically than they are to the HPVs that cause nongenital skin lesions (warts),36 the immunodominant epitopes in L1 VLPs induce neutralizing antibodies that are predominantly type specific.37 It has therefore been necessary, at least for the first generation HPV vaccines, to focus on the HPV types found most frequently in cervical cancer. This
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consideration has led both companies to focus on HPV16 and HPV18, which, as noted above, account for about 70% of cases of cervical cancer. The Merck vaccine also targets HPV6 and HPV11, which together account for about 90% of external genital warts;38 the latter 2 types also infect the cervix, but are not implicated in cervical cancer. Thus, the GlaxoSmithKline vaccine that is currently in phase III trials is a bivalent vaccine composed of VLPs from HPV16 and HPV18, while the vaccine that Merck has used for its phase III trials is a quadrivalent vaccine that contains VLPs from HPV6, HPV11, HPV16, and HPV18. When considering appropriate end points for determining vaccine efficacy, the most relevant end points recommended by an FDA vaccine advisory panel39 were a reduction in the incidence of vaccine type specific persistent infections and of associated moderate- and highgrade cervical dysplasias and carcinomas in situ, which together are referred to as cervical intraepithelial neoplasia 2+ (CIN2+; CIN is graded as CIN1, CIN2, and CIN3 for low-, moderate-, and high-grade dysplasia, respectively). HPV DNA testing results have been shown to be substantially more reproducible than the pathological diagnosis of dysplasia,40 but moderate- and high-grade dysplasias represent clinical end points that trigger therapeutic intervention. It is important to note that it would be unethical to use cervical cancer as a primary end point for vaccine efficacy trials, as cervical cancer screening can prevent the vast majority of cancer through the identification of precancers, which are then treated. Also, the interval between infection and the development of invasive cancer usually takes more than 10 years.7,12 Following the observations that systemic vaccination with a monovalent HPV16 L1 VLP vaccine was safe and highly immunogenic,41 even without adjuvant, a Merck-sponsored proof-of-principle efficacy trial of an HPV16 L1 VLP vaccine reported that fully vaccinated women who were HPV negative throughout the vaccination period were completely protected against the development of persistent incident infection with HPV16 when followed for an average of 17 months (Table 1 and ref. 32). This vaccine cohort has now been followed for an average of 3.5 years, and the high level of protection was maintained throughout this period (Table 1 and ref. 34). After the initial peak, the levels of serum antibodies appeared to decline approximately 10-fold over the first 2 years following vaccination but then remained stable for the remainder of the follow-up period. If the level of serum antibodies represents a surrogate for protection against infection, the stability of the antibody titers would suggest that high-level protection may continue substantially beyond 3.5 years. Preliminary efficacy results from Mercks quadrivalent vaccine were also published and showed excellent protection against the viruses
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targeted by the vaccine (Table 1 and ref. 33). In unpublished studies, Merck has reported at scientific meetings on the clinical efficacy of the multinational phase III trial of their quadrivalent vaccine, with an average follow-up of 1.5 years.42,43 When fully vaccinated women who remained negative for infection throughout the vaccination period were analyzed against the comparable placebo cohort, the vaccine was 100% effective in preventing CIN2+ associated with HPV16 or HPV18 and also in preventing external genital warts associated with HPV6 or HPV11. Even when the efficacy was compared starting 1 month after the first immunization, protection for these end points was greater than 90%. Thus systemic immunization with a subunit HPV vaccine can achieve a high degree of protection in women against benign and premalignant diseases induced by this sexually transmitted local infection of the genital mucosa or skin.
Table 1 Proof-of-principle HPV VLP prophylactic efficacy trials
The Merck-sponsored trials have not reported on the comparative incidence of infection by other HPV types not included in the vaccines. However, the proof-of-principle monovalent HPV16 trial has reported on the total number of patients with various grades of cervical dysplasia, and whether the dysplasias were associated with HPV16, for the fully vaccinated women who were HPV negative throughout the vaccination period.32 In contrast to the complete protection seen against HPV16associated dysplasias, there was no difference between the placebo and vaccinated groups in the number of nonHPV16-associated dysplasias in the initial report on this cohort. In the 3.5-year follow-up report,34 there was also no evidence that nonHPV16-associated dysplasias in the vaccinated group were less frequent in number than those in the
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nonvaccinated group. These results strongly suggest that the protection conferred by Merck HPV16 monovalent vaccine was predominantly HPV type specific. GlaxoSmithKline has also sponsored a proof-of-principle efficacy trial of an HPV16 and HPV18 bivalent vaccine similar to the one that is currently in phase III trials (Table 1 and ref. 35). Their placebo-controlled proof-ofprinciple trial had a smaller number of participants who were followed for an average of 18 months. In the group of women who were fully vaccinated and remained uninfected throughout the vaccination period, all subsequent persistent infections associated with HPV16 and HPV18 occurred in the placebo group, although there were only a total of 7 cases (5 with HPV16 and 2 with HPV18). When incident persistent infection was monitored starting 1 month after the first dose of vaccine, combined protection against HPV16 and HPV18 was still about 90%. Another potentially important result, which has been presented at meetings but not yet published, is that the vaccine has been associated with some cross-protection against HPV types closely related to HPV16 and HPV18, although this protection was less complete than that offered against HPV16 and HPV18.44,45 As Merck has not reported results analyzed in this manner, it is difficult to know whether the cross-protection represents an activity that may be greater in the GlaxoSmithKline vaccine. It will be important for the ongoing large-scale efficacy trials to analyze this parameter, as cross-protection against HPV types not in the vaccine could enhance its overall utility. Vaccine implementation issues The notable efficacy results (Table 1) have thus far been correlated with an excellent safety profile, which make it likely that one or both vaccines will be licensed in the near future. In fact, Merck applied to the FDA in December 2005 for a license to sell their quadrivalent vaccine. It is anticipated that application for licensure will also come from GlaxoSmithKline if their phase III trial results are similarly positive Several issues about the vaccine remain to be addressed. It will be important to confirm that the strong safety profile remains intact as more individuals receive the vaccine. As noted above, it remains to be determined how long the high level of type-specific protection is maintained, as this issue will have implications for whether and when booster injections might be advisable and will also contribute to the costeffectiveness of the vaccine. It remains to be seen whether the crossprotection against HPV types not in the vaccine, as noted in the GlaxoSmithKline proof-of-principle trial, will be confirmed in the large-
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scale trials of this vaccine and whether the Merck vaccine possesses similar properties. A substantial degree of cross-protection could increase the potential impact of the vaccine by further reducing the incidence of serious genital HPV infections and by reducing the number of abnormal Pap tests and the cost of their follow-up. On the other hand, protection against heterologous HPV types is likely to wane more quickly than that against the HPV types specifically targeted by the vaccine, which could also have implications for boosting. Another unanswered question is whether vaccination might alter the natural history of prevalent HPV infection by reducing the incidence of persistent infection or cytological abnormalities. The large vaccine trials may have a sufficient number of prevalent infections attributable to the HPV types in the vaccine to address this question. If such a therapeutic effect were seen, it could provide an added rationale to vaccinate sexually active women who might have prevalent infection with one of the types in the vaccine. The most likely explanation for such an effect would be that the vaccine had reduced the efficiency of transmission of an early infection from one genital site to other genital sites, presumably via specific antibodies in the genital tract.46 It is also possible that the vaccine could have direct therapeutic effects against established lesions. However, this possibility seems less likely, as persistent infection is usually attributed to the presence of the viral genome in long-lived basal epithelial cells, which do not express L1. The experimental evidence also does not support this possibility: when the effect of the VLP vaccine was tested on established lesions in an animal model (bovine papillomavirus type 4 [BPV-4], which induced benign oral mucosal lesions), it did not induce their regression, although the vaccine was very effective when given prophylactically.31 Although the immune response of men to the vaccine is similar to that of women,41 it is not yet known whether the vaccine will be protective in men. Many vaccines have comparable efficacy in males and females. However, a subunit vaccine for type 2 herpes simplex virus (HSV gD vaccine), another sexually transmitted viral infection, was found to be effective in women but not in men, which raises the possibility that an analogous difference might be seen with the HPV vaccine.47 As HSV infection is more likely to be mucosal in women and cutaneous in men, it was speculated that the difference in protection from the HSV vaccine might be attributable to higher antibody titers in mucosa than in skin. Even if this explanation is relevant to HSV, the high level of protection of the Merck vaccine against cutaneous genital warts in women would be expected to apply to men as well, since these warts appear on cornified skin in both sexes. It may also be relevant that the protection induced in
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women by the HSV vaccine was less robust than that induced by the HPV vaccine.47 Efficacy trials of the HPV vaccine in men will directly address this issue. A key question will be whom to vaccinate. In the United States, the main national advisory committee will be the Advisory Committee on Immunization Practices at the Centers for Disease Control and Prevention. Until there are data that show the vaccine is protective in men, it would seem most logical to focus public health efforts primarily on vaccinating women. If the principal activity of the vaccine is the prevention of incident HPV infection, the greatest reduction in the number of infections would likely result from immunizing girls or women before they become sexually active. In the United States, this consideration would imply that pre- or young adolescent girls would be prime candidates for the vaccine. Of course, older girls and women with no prior sexual exposure should also achieve maximum benefit from the vaccine, which implies that catch-up vaccination for these groups should be seriously considered. Giving the vaccine to women who have had some prior sexual activity could also reduce their number of infections, although their degree of benefit from the vaccine would probably be inversely related to their degree of prior sexual activity. If the vaccines are shown to be highly effective in men, it will be logical to include them in vaccination programs in high-resource settings such as the United States, especially if the Merck vaccine is able to protect men against genital warts. From a public health perspective, however, the degree to which vaccination of males would contribute to herd immunity is unclear. In some models of sexually transmitted infections, if a high proportion of one gender is vaccinated and the vaccine is effective in preventing transmission, vaccinating the other gender achieves a relatively small increase in herd immunity.48 In addition, more than 80% of cancers attributable to HPV infection occur in women.1 These considerations suggest that vaccination of women should probably have the highest priority in settings with limited resources. Anticipated impact of vaccination The previous section has noted several important unanswered questions that make it difficult to predict the actual impact of a vaccine on HPV infection and disease. However, it is possible to give some estimates if it is assumed that the vaccine will provide at least 90% type-specific efficacy, with boosters as necessary to ensure that this protection is of long duration. Under those circumstances, the greatest short-term impact in industrialized nations such as the United States would be a
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reduction in the overall number of CIN2+ cases to about one-third to one-half as many such lesions in vaccinated women compared with nonvaccinated women, given that HPV16 and HPV18 together account for 6070% of such lesions. This protection would translate to a substantial reduction in medical and psychological morbidity and treatment together with a reduction in the related costs. The anticipated eventual reduction in the incidence of cervical cancers and its consequences would be anticipated to be at least as great. If the vaccine were widely administered to populations that historically are less likely to be screened regularly, the vaccine could prevent most of those serious infections that currently are not detected because of a lack of screening.49 The impact on subclinical and low-grade dysplasias would be expected to be more modest, as only a minority of these infections are attributable to HPV16 and HPV18 (or to HPV6/11/16/18, when considering the quadrivalent Merck vaccine infection).50 Although these anticipated reductions in CIN2+ and invasive cervical cancer would be impressive, it must be noted that there would still be many serious HPV infections against which the vaccine would not protect. For this reason, it will be essential to educate health care providers and patients about this limitation of the vaccine and to emphasize that it will be necessary for vaccinated women to follow current cervical cancer screening guidelines What about vaccination in developing countries, where 80% of cervical cancers occur, but where medical resources are relatively scarce? The vaccine probably has the potential to prevent several hundred thousand cancers annually, many of which affect relatively young women and therefore have an enormous impact on their life expectancies.11 However, vaccination in low-resource settings would probably be cost-effective only if the expense of vaccination were modest, especially in view of the long interval between infection and the development of invasive cancer. The history of hepatitis B vaccination suggests that it may take many years to achieve a cost-effective vaccination program in developing areas.51 Thus reducing the cost of vaccination would be a priority for the developing world. In the interim, a substantial reduction in the incidence of cervical cancer might be achievable in these settings, in less time than vaccination would lead to a reduction, by the alternate modality of a lowcost once- or twice-in-a-lifetime screen-and-treat approach to cervical cancer prevention.52,53
REFERENCES 1. Pisani, P., Parkin, D.M., Munoz, N., Ferlay, J. 1997. Cancer and infection: estimates of the attributable fraction in 1990. Cancer Epidemiol. Biomarkers Prev. 6:387-400. 2. Lowy, D.R., Howley, P.H. 2001. Papillomaviruses. In Fields virology . D.M. Knipe and P.H. Howley, editors. Lippincott, Williams, & Wilkins.Philadelphia, Pennsylvania, USA.2231-2264.
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3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. Zur Hausen, H. 2002. Papillomaviruses and cancer: from basic studies to clinical application. Nat. Rev. Cancer. 2:342-350. Bosch, F.X., Schiffman, M., Solomon, D.editors. 2003. Future directions in epidemiologic and preventive research on human papillomaviruses and cancer. J. Natl. Cancer Inst. Monogr. 31:131. Frisch, M. 2002. On the etiology of anal squamous carcinoma. Dan. Med. Bull. 49:194-209. Gillison, M.L., Shah, K.V. 2003. Chapter 9: role of mucosal human papillomavirus in nongenital cancers. J. Natl. Cancer Inst. Monogr. 31:57-65. Schiffman, M., Kjaer, S.K. 2003. Chapter 2: natural history of anogenital human papillomavirus infection and neoplasia. J. Natl. Cancer Inst. Monogr. 31:14-19. Gillison, M.L., Lowy, D.R. 2004. A causal role for human papillomavirus in head and neck cancer. Lancet. 363:1488-1489. Szentirmay, Z., et al. 2005. Human papillomavirus in head and neck cancer: molecular biology and clinicopathological correlations.Cancer Metastasis Rev. 24:19-34. Pfister, H. 2003. Chapter 8: human papillomavirus and skin cancer. J. Natl. Cancer Inst. Monogr. 31:52-56. Yang, B.H., Bray, F.I., Parkin, D.M., Sellors, J.W., Zhang, Z.F. 2004. Cervical cancer as a priority for prevention in different world regions: an evaluation using years of life lost. Int. J. Cancer. 109:418-424. Snijders, P.J., Steenbergen, R.D., Heideman, D.A., Meijer, C.J. 2006. HPV-mediated cervical carcinogenesis: concepts and clinical implications. J. Pathol. 208:152-164. Wright, T.C., Cox, J.T., Massad, L.S., Twiggs, L.B., Wilkinson, E. J. 2002. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. Jama. 287:2120-2129. Bosch, F.X., Lorincz, A., Munoz, N., Meijer, C.J., Shah, K.V. 2002. The causal relation between human papillomavirus and cervical cancer. J. Clin. Pathol. 55:244-265. Munoz, N., et al. 2004. Against which human papillomavirus types shall we vaccinate and screen? The international perspective.Int. J. Cancer. 111:278-285. Cates, W. 1999. Estimates of the incidence and prevalence of sexually transmitted diseases in the United States. American Social Health Association Panel. Sex. Transm. Dis. 26(4 Suppl.):S2-S7. Baseman, J.G., Koutsky, L.A. 2005. The epidemiology of human papillomavirus infections. J. Clin. Virol. 32(Suppl. 1):S16-S24. Khan, M.J., et al. 2005. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J. Natl. Cancer Inst. 97:1072-1079. Littler, E., Oberg, B. 2005. Achievements and challenges in antiviral drug discovery. Antivir. Chem. Chemother. 16:155-168. Roden, R.B., Ling, M., Wu, T.C. 2004. Vaccination to prevent and treat cervical cancer. Hum. Pathol. 35:971-982. Ehreth, J. 2005. The economics of vaccination from a global perspective: present and future. 2-3 December, 2004, Vaccines: all things considered, San Francisco, CA, USA. Expert Rev. Vaccines. 4:19-21. Robbins, J.B., Schneerson, R., Szu, S.C. 1995. Hypothesis: serum IgG antibody is sufficient to confer protection against infectious diseases by inactivating the inoculum. J. Infect. Dis. 171:1387-1398. Kirnbauer, R., Booy, F., Cheng, N., Lowy, D.R., Schiller, J.T. 1992. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc. Natl. Acad. Sci. U. S. A. 89:12180-12184. Hagensee, M.E., Yaegashi, N., Galloway, D.A. 1993. Self-assembly of human papillomavirus type 1 capsids by expression of the L1 protein alone or by coexpression of the L1 and L2 capsid proteins. J. Virol. 67:315-322. Rose, R.C., Bonnez, W., Reichman, R.C., Garcea, R.L. 1993. Expression of human papillomavirus type 11 L1 protein in insect cells: in vivo and in vitro assembly of viruslike particles. J. Virol. 67:1936-1944. Kirnbauer, R., et al. 1993. Efficient self-assembly of human papillomavirus type 16 L1 and L1-L2 into viruslike particles. J. Virol.67:6929-6936. Rose, R.C., Reichman, R.C., Bonnez, W. 1994. Human papillomavirus (HPV) type 11 recombinant virus-like particles induce the formation of neutralizing antibodies and detect HPV-specific antibodies in human sera. J. Gen. Virol. 75:2075-2079. Roden, R.B.S., et al. 1996. In vitro generation and type-specific neutralization of a human papillomavirus type 16 virion pseudotype. J. Virol. 70:5875-5883. Breitburd, F., et al. 1995. Immunization with virus-like particles from cottontail rabbit papillomavirus (CRPV) can protect against experimental CRPV infection. J. Virol. 69:3959-3963. Suzich, J.A., et al. 1995. Systemic immunization with papillomavirus L1 protein completely prevents the development of viral mucosal papillomas. Proc. Natl. Acad. Sci. U. S. A. 92:11553-11557. Kirnbauer, R., et al. 1996. Virus-like particles of Bovine Papillomavirus type 4 in prophylactic and therapeutic immunization.Virology. 219:37-44.
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32. Koutsky, L.A., et al. 2002. A controlled trial of a human papillomavirus type 16 vaccine. N. Engl. J. Med. 347:1645-1651. 33. Villa, L.L., et al. 2005. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol. 6:271-278. 34. Mao, C., et al. 2006. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet. Gynecol. 107:18-27. 35. Harper, D.M., et al. 2004. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet. 364:17571765. 36. De Villiers, E.M., Fauquet, C., Broker, T.R., Bernard, H.U., zur Hausen, H. 2004. Classification of papillomaviruses. Virology.324:17-27. 37. Roden, R.B.S., et al. 1996. Assessment of the serological relatedness of genital human papillomaviruses by hemagglutination inhibition. J. Virol. 70:3298-3301. 38. Greer, C.E., et al. 1995. Human papillomavirus (HPV) type distribution and serological response to HPV 6 virus-like particle in patients with genital warts. J. Clin. Microbiol. 33:2058-2063. 39. [No authors listed]. 2001. FDA vaccines and related biological products advisory committee. Center for Biologics Evaluation and Research meeting #88. November 2829.Bethesda, Maryland, USA.http://www.fda.gov/ohrms/dockets/ac/cber01.htm#Vaccines. 40. Stoler, M.H. 2003. Human papillomavirus biology and cervical neoplasia: implications for diagnostic criteria and testing. Arch. Pathol. Lab. Med. 127:935-939. 41. Harro, C.D., et al. 2001. Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J. Natl. Cancer Inst. 93:284-292. 42. Barr, E. 2005. Gardasil HPV vaccine. Presented at the Centers for Disease Control and Prevention, National Immunization Program meeting of the Advisory Committee on Immunization Practices. February 1011. Atlanta, Georgia, USA. 43. Barr, E. 2006. Garadasil HPV vaccine. Presented at the Centers for Disease Control and Prevention, National Immunization Program meeting of the Advisory Committee on Immunization Practices. February 2122. Atlanta, Georgia, USA. 44. Dubin, G. 2005. Enhanced immunogenicity of a candidate human papillomavirus (HPV) 16/18 L1 virus like particle (VLP) vaccine with novel AS04 adjuvant in preteens/adolescents. Presented at the 45th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). December 1619. Washington, DC, USA. 45. Dubin, G. 2006. Cervarix HPV vaccine. Presented at the Centers for Disease Control and Prevention, National Immunization Program meeting of the Advisory Committee on Immunization Practices. February 2122. Atlanta, Georgia, USA. 46. Nardelli-Haefliger, D., et al. 2003. Specific antibody levels at the cervix during the menstrual cycle of women vaccinated with human papillomavirus 16 virus-like particles. J. Natl. Cancer Inst. 95:1128-1137. 47. Stanberry, L.R., et al. 2002. Glycoprotein-D-adjuvant vaccine to prevent genital herpes. N. Engl. J. Med. 347:1652-1661. 48. Garnett, G.P. 2005. Role of herd immunity in determining the effect of vaccines against sexually transmitted disease. J. Infect. Dis.191(Suppl. 1):S97-S106. 49. Freeman H., Wingrove B.. 2005Excess cervical cancer mortality: a marker for low access to health care in poor communities.. National Cancer Institute, Center to Reduce Cancer Health Disparities.; Rockville, Maryland, USA.: http://crchd.nci.nih.gov/ initiatives/#Reducing. 79 pp. 50. Clifford, G.M., et al. 2005. Human papillomavirus genotype distribution in low-grade cervical lesions: comparison by geographic region and with cervical cancer. Cancer Epidemiol. Biomarkers Prev. 14:11571164. 51. Ulmer, J.B., Liu, M.A. 2002. Ethical issues for vaccines and immunization. Nat. Rev. Immunol. 2:291-296. 52. Goldie, S.J., et al. 2005. Cost-effectiveness of cervical-cancer screening in five developing countries. N. Engl. J. Med. 353:2158-2168. 53. Schiffman, M., Castle, P.E. 2005. The promise of global cervical-cancer prevention. N. Engl. J. Med. 353:2101-2104..
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TABLE OF CONTENTS

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Human papillomavirus (HPV). Note the extensive labial involvement.

Human papillomavirus (HPV). Anal condyloma acuminatum.

Human papillomavirus (HPV). These condylomata extend to the anal verge.

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Squamous Cell Carcinoma Warts, Plantar Bowenoid Papulosis Warts

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CLASSIFICATION AND TAXONOMY OF HUMAN PAPILLOMAVIRUSES

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Genome structure of HPV

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Human Papillomavirus proteins

Nonstructural proteins Regulatory proteins

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Development of cervical cancer caused by HPV16

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