AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

Section 2 of 11  

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• Follow-up
• Miscellaneous
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Background

Infections due to papillomaviruses are common and lead to a wide variety of clinical manifestations that involve the epidermal surfaces. Manifestations include common warts (verrucae vulgaris), palmo-plantar warts, flat warts (verrucae plana), oral warts, focal epithelia hyperplasia, epidermodysplasia verruciformis (EDV), genital warts (condyloma acuminata), Bowen papulosis, Bowen disease, papillomas of the mucosal surfaces, and intraepithelial neoplasias. Strong evidence indicates that certain papillomaviruses are involved in cervical and genital cancers.

Pathophysiology

Papillomaviruses are small (55 nm) double-stranded DNA viruses. Papillomaviruses are widely disseminated in the animal kingdom, and more than 200 genotypes of human papillomaviruses that infect the skin and mucosal surfaces have been characterized. These viruses are highly species-specific. Papillomaviruses have never been grown in vitro but have been characterized by molecular methods.

The genome of papillomaviruses is approximately 8000 base pairs divided into 3 major functional regions. The early (E) region codes for 6 nonstructural genes, several of which are associated with cellular transformation. The late (L) region codes for 2 structural proteins, L1 and L2, that form the capsid. The long control region is a noncoding region that regulates replication and gene function.

These viruses are classified by the molecular similarity of their genetic material and are assigned a genotype number.

The viruses infect the basal keratinocyte of the epidermis, presumably through disruptions of the skin or mucosal surface. At this location, the virus remains latent in the cell as a circular episome in low copy numbers. As the epidermal cells differentiate and migrate to the surface, the virus is triggered to undergo replication and maturation and, at the keratinic layer, the virus is present in high copy numbers and is shed in the exfoliation cells. The process of virus replication alters the character of the epidermis, resulting in cutaneous or mucosal excrescences known as warts. Human papillomaviruses are broadly grouped into cutaneous and mucosal type, based on the clinical location of the lesion.

Although some overlap exists, most papillomaviruses have distinct anatomic predilections, infecting only certain epidermal sites, such as skin or genital mucosa. The virus has the potential to integrate into host DNA frequently with the loss of the early regulatory function. Numerous viral genotypes have the potential to transform cells and are associated with epidermal malignancies. This appears involve interactions of E6 and E7 proteins with host cell function. The mechanism for transformation is not known, but the viral DNA appears to integrate into the genome of the host cell.

Table 1. Association of HPV Types With Morphology and Site of Skin Lesions

Table 2. HPV Types Associated With Anogenital Lesions

Frequency

United States

The United States has no reporting system for papilloma infections. Infections and the development of warts appear to be common throughout life. In general, in the past several decades, the prevalence of genital papilloma virus infections is considered to have increased dramatically, and it is now one of the most common sexually transmitted diseases. The frequency of genital infections is associated with the number of sexual partners. In cervical neoplasias, the HPV genome can be detected in more than 90% of tumors.

Mortality/Morbidity

• Most common warts are of cosmetic concern and generally cause little problem unless their anatomic location induces mechanical problems. For example, plantar warts can disrupt ambulation because of their location. Laryngeal papillomas may disrupt breathing or speaking. Genital warts occasionally cause problems such as urethral obstruction. Condyloma acuminata can become extremely large, resulting in tissue breakdown or secondary infection. In the context of immune deficiency, such as HIV infection, the growth of warts due to papillomavirus can be augmented, significantly enhancing the associated anatomical problems.
• The major morbidity and mortality related to papillomavirus infections are due to the development of malignancies. Cervical cancer is the second most common cause of morbidity and death in women in the United States. Malignancies, such as Bowen tumors, may also lead to morbidity and death.

Race

Papillomavirus infections have no racial predilection.

Sex

Papillomavirus infections have no sexual predilection.

Age

People of any age may develop common warts. Human papillomavirus infects more than 50% of sexually active adults. Genital infection generally occurs during the sexually active period in a person's life, and infections increase with the number of sexual partners.

CLINICAL

Section 3 of 11  

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History

The clinical history and presentation of papillomavirus infection vary based on the anatomic area involved. The predilection of certain genotypes of virus to infect certain epidermal sites largely determines areas of involvement.

• Common cutaneous warts, or verrucae vulgaris, generally appear on keratinized skin, presumably at the site of inoculation. These appear as circumscribed, rough, hyperkeratotic papulonodules or plaques with irregular scaly surfaces. They develop most often on the hands, fingers, feet, and knees. In general, they are asymptomatic, but they may be painful with application of pressure. The patient discovers common cutaneous warts due to changes in the skin.
• Palmoplantar warts appear on the acral surfaces of the feet and hands. They are notable for their thickness, which complicates treatment.
• Flat warts, or verrucae plana, generally present as multiple small papules. They are often not obvious but may induce significant disturbances of pigmentation.
• Oral warts are infection of the oral mucosa. Oral warts are subtle and are missed frequently but are fairly common.
• Focal epithelial hyperplasia (Heck disease) is a disseminated papillomavirus infection of the oral mucosa most commonly associated with HPV 32 and HPV 13. This condition may have a family predilection.
• Epidermodysplasia verruciformis (EDV) is an autosomal recessive familial trait that increases susceptibility to a subset of wart generally not observed in populations without EDV. The condition generally begins in childhood and can affect almost any area of the body. The warts are generally subtle and flat and may initially be mistaken for tinea versicolor. The HPV genotypes associated with EDV include 3, 5, 8, 9, 10, 12, 14, 17, 20, 21, 23, 28, 38, 47, and 49. Recently, these viruses have been observed in patients who are immunosuppressed for organ transplantation or in patients with HIV infection. These individuals are at increased risk for skin cancer if not recognized and treated.
• Genital infection manifests as a warty lesion on the genital or anal area, although they are often not initially recognized. Condyloma acuminata are single or multiple papules or nodules but may progress to large exophytic masses that resemble cauliflower. Flat condylomata (squamous intraepithelial neoplasia) are the most common lesions of the cervix but may develop on the vulva, anus, and male genitalia. They appear as white plaquelike growths. An additional malignant variant is the giant condyloma, or Buschke-Löwenstein tumor, generally regarded as a verrucous carcinoma. These most often involve the glans penis, perianal area, and foreskin. In addition to their large cauliflower shape, they tend to form abscesses and fistulas and tend to invade locally. Cervical infection generally goes unnoticed and is discovered during cervical examination or Papanicolaou (PAP) test.
• Lloyd described Bowenoid papulosis as multicentric pigmented Bowen disease of the groin. It manifests as multiple, warty, red-brown papules in the anogenital region. These papules may coalesce.

Physical

Abnormal accumulation of keratinized growths generally characterizes warts. Similarly, genital lesions are due to excessive skin growth. In the case of condylomata, the growths may become exuberant. Cervical intraepithelial lesions may be found upon examination of the cervix.

Causes

For a detailed discussion of causes, see Pathophysiology.

DIFFERENTIALS

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Other Problems to be Considered

Endoscopic gynecologic surgery
Hypopigmentation

Most papillomas are sufficiently distinct to be recognized clinically. Bowenoid papulosis may be mistaken for lichen planus, psoriasis, seborrheic keratoses, or condyloma acuminata.

WORKUP

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Lab Studies

Most cutaneous and external genital warts can be recognized clinically. In the case of genital intraepithelial neoplasia, determining the extent of disease is essential. This involves careful inspection, as well as colposcopy. In females, frequent PAP tests are useful. Polymerase chain reaction (PCR) used to detect HPV DNA is largely a research tool.

Imaging Studies

In general, imaging studies have a limited role in diagnosing papillomavirus infections. In rare instances, CT scan or MRI can be used to determine the extent of spread of cervical carcinoma and, in rare instances, extensive anogenital papillomatosis that has spread into the pelvis.

Histologic Findings

Histology of condyloma acuminata generally demonstrates disruption of the epidermis with hyperkeratosis, coarse keratohyaline granules, and koilocytes in a prominent granular layer. The epidermis or mucosa of flat condylomata demonstrates acanthosis. Koilocytes, the characteristic cytological feature of HPV infection, are present. Koilocytes are keratinocytes with pyknotic, deeply blue nuclei surrounded by a halo and clear cytoplasm with a paucity of keratohyaline granules.

Histology of Bowenoid papulosis reveals psoriasiform hyperplasia and hyperkeratosis of the epidermis. Mitotic figures are increased at all epidermal levels. Keratinocytes display enlarged pleomorphic and hyperchromic nuclei.

Histology of common cutaneous warts demonstrates marked hyperkeratosis, acanthosis, parakeratosis, and papillomatosis. Three features used to distinguish warts from other papillomas include the presence of koilocytes, vertical columns of parakeratosis, and foci of clumped keratohyaline granules.

TREATMENT

Section 6 of 11  

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Medical Care

Both provider-applied treatments and patient-applied treatments are available. Medical treatments (eg, interferon injection) have been tried, with mixed success. Lesions often recur after treatment, requiring recurrent treatment. Many lesions spontaneously regress. No effective antiviral agents are currently available to treat papillomavirus infections. The US Food and Drug Administration (FDA) has recently approved a vaccine for HPV types 6, 11, 16, and 18.

Surgical Care

Surgical ablation methods include cryotherapy, electrocautery, curettage, and tangential excision. Cryosurgery is the local application of liquid nitrogen to freeze the lesion. The area blisters and sloughs. Monitor for secondary cellulitis.

The location, size, or extent of the lesion and the potential for malignant transformation largely dictate treatment. Uncomplicated lesions can be treated with chemical ablation, cryoablation, surgical excision, or laser treatment. Because the virus is present in the basal layer of the epidermis in a latent state, recurrences are common and retreatment may be necessary.

Consultations

Consultation with a dermatologist may be indicated in some situations. For potentially malignant papilloma infections that involve the genital tract, consultation with a gynecologist or urologist may be indicated. A proctologist may be consulted for individuals with perianal or anal warts. This is especially true for individuals infected with HIV. An otolaryngologist (ENT) should be consulted for patients with papilloma infections involving the larynx.

MEDICATION

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The medications used to treat papillomavirus infections primarily are designed to ablate the lesion because of their corrosive properties.

Drug Category: Antimitotics

Treatment of anogenital warts results in necrosis of visible wart tissue. The exact mechanism of action is unknown. Genital warts are epidemiologically associated with cervical carcinoma.

Drug Category: Antineoplastic agents

These are topical preparations that contain the fluorinated pyrimidine 5-fluorouracil. These are antineoplastic and antimetabolite agents.

Drug Category: Desiccants

Trichloroacetic acid is a highly corrosive desiccating agent that is used to burn lesions.

Drug Category: Interferons

These agents are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alfa, beta, and gamma interferons may be administered topically, systemically, and intralesionally.

Drug Category: Immunostimulants

These agents stimulate key factors of the immune system.

Drug Category: Vaccines

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

Drug Category: Miscellaneous topical ointment

Kunecatechins is another FDA-approved topical product for genital warts.

FOLLOW-UP

Section 8 of 11  

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Further Outpatient Care

• Because papillomaviruses reside in the basal layer of the epidermis in a latent state, recurrences are common and retreatment is often necessary. For genital neoplasia, careful follow-up is mandatory.
• Treatment of cervical intraepithelial neoplasia, grade 1 (CIN 1) may be monitored safely with serial cytology and colposcopy in reliable patients. Perform PAP tests every 6 months and colposcopy every 2 years. Treatment options include carbon dioxide laser ablation or excision, cryotherapy for lesions of 2 quadrants or less, cone biopsy, or loop excision.
• For anal and rectal lesions in the context of HIV, frequent follow-up is essential.

Deterrence/Prevention

• In 2006, the FDA approved the papillomavirus vaccine Gardasil (Merck and Co.). This vaccine is a quadrivalent vaccine that contains the major capsid protein, L1, for HPV types 6, 11, 16, and 18. Types 6 and 11 are associated with genital warts, while types 16 and 18 are associated with more than 70% of cervical malignancy cases. The vaccine is produced via recombinant technology to synthesize viruslike particles (VLPs) that are formed when L1 is expressed in vitro. VLPs are morphologically identical to the HPV but lack the viral genome. The vaccine is administered with a proprietary adjuvant of amorphous aluminum hydroxyphosphate sulfate. The vaccine is administered intramuscularly at 0, 2, and 6 months. The most common adverse effects include local irritation (swelling, pain, redness, itching) and fever. It is not approved for use in pregnant women.
• Clinical trials have demonstrated a high degree of efficacy in preventing cytological changes due to HPV or clinical disease. The vaccine induces antibody responses that are 80-100 times that of natural infection.
• The Advisory Committee on Immunization Practices gave provisional recommendations for immunization of females beginning at age 11 or 12 uears. Catch-up vaccination was recommended for females aged 13-26 years.

Prognosis

Papillomavirus infection primarily involves the basal epithelial cells. As a result, recurrences are common. Spontaneous regressions are also common.

Patient Education

For excellent patient education resources, visit eMedicine's Warts Center and Cancer and Tumors Center. Also, see eMedicine's patient education articles Warts, Genital Warts, Plantar Warts, Cervical Cancer, Birth Control Overview, and Birth Control FAQs.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Few legal issues are associated with papillomavirus infection. Legal issues largely are the result of either a failure to diagnose or, more commonly, the adverse effects of treatment.
• • The treatment of most papillomavirus infections involves agents that directly ablate the lesions (eg, surgical excision, chemical ablation, cryotherapy). Inappropriate use of these agents may cause extensive and unnecessary tissue injury and loss.
  • Podophyllin treatment is a special case because this agent not only causes tissue injury but also can be absorbed systemically and cause neurological toxicity. Deaths have occurred with the use of podophyllin on exuberant perianal warts; the surface area of the lesions increases the absorption of drug.

MULTIMEDIA

Section 10 of 11  

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• Clinical
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• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Verrucous warts in a patient with HIV infection.
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Media file 2:  Plantar warts.
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Media file 3:  Flat wart.
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REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
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• Ault KA. Human papillomavirus infections: diagnosis, treatment, and hope for a vaccine. Obstet Gynecol Clin North Am. Dec 2003;30(4):809-17. [Medline].
• Beutner KR, Ferenczy A. Therapeutic approaches to genital warts. Am J Med. May 5 1997;102(5A):28-37. [Medline].
• Carr J, Gyorfi T. Human papillomavirus. Epidemiology, transmission, and pathogenesis. Clin Lab Med. Jun 2000;20(2):235-55. [Medline].
• Fazel N, Wilczynski S, Lowe L, Su LD. Clinical, histopathologic, and molecular aspects of cutaneous human papillomavirus infections. Dermatol Clin. Jul 1999;17(3):521-36, viii. [Medline].
• Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med. May 5 1997;102(5A):3-8. [Medline].
• Sedlacek TV. Advances in the diagnosis and treatment of human papillomavirus infections. Clin Obstet Gynecol. Jun 1999;42(2):206-20. [Medline].
• Tjalma WA, Arbyn M, Paavonen J, van Waes TR, Bogers JJ. Prophylactic human papillomavirus vaccines: the beginning of the end of cervical cancer. Int J Gynecol Cancer. Sep-Oct 2004;14(5):751-61. [Medline].
• Wiley DJ, Douglas J, Beutner K, Cox T, Fife K, Moscicki AB, et al. External genital warts: diagnosis, treatment, and prevention. Clin Infect Dis. Oct 15 2002;35(Suppl 2):S210-24. [Medline].
• Siddiqui MA, Perry CM. Human papillomavirus quadrivalent (types 6, 11, 16, 18) recombinant vaccine (Gardasil). Drugs. 2006;66(9):1263-71; discussion 1272-3. [Medline].

Article Last Updated: Aug 15, 2007