For the Clinician
Oral Warts in HIV-Infected Individuals
Oral diseases are common manifestations of HIV infection, with up to 90% of HIV-infected patients developing an oral lesion through the course of their HIV disease.1 Oral candidiasis, aphthous-like ulcerations, periodontal infections, salivary gland diseases, various malignancies and numerous viral opportunistic infections have been described in the oral cavity of HIV-infected patients. Oral opportunistic viral infections include herpes simplex infections, oral hairy leukoplakia, varicella-zoster infections, cytomegalovirus infections and oral warts. While the development of new antiretroviral therapies for the management of HIV infection, particularly protease inhibitors, has resulted in a decreased prevalence of certain oral diseases such as hairy leukoplakia and necrotizing periodontitis, a paradoxical increase in oral warts has been observed.2,3
The etiologic agents of all warts are a diverse group of viruses known as the human papillomaviruses (HPVs). HPVs cause a variety of cutaneous and mucosal diseases ranging from benign warts to invasive carcinoma of the uterine cervix. Based on variations in their DNA sequence, over 100 different HPV types have been identified to date. HPVs are broadly classified into low-risk and high-risk types, based on their ability to induce malignant changes in infected cells. Low-risk HPV types such as 2, 4, 6, 11, 13 and 32 are primarily associated with benign lesions whereas high-risk HPVs such as types 16, 18, 31, 33 and 35 are primarily associated with premalignant and malignant epithelial lesions. High-risk HPVs encode oncogenic proteins that have been shown to bind and inactivate tumor suppressor genes of the host cell, leading to uncontrolled cellular proliferation.
HPVs commonly inhabit the oral cavity and 25 different HPV types have been identified in clinically normal oral mucosa, oral warts, premalignant oral lesions and oral cancers. The most common manifestations of oral HPV infection are the various types of benign warts, which include the squamous papilloma (SP), verruca vulgaris (VV), condyloma acuminatum (CA) and a distinct entity known as focal epithelial hyperplasia (FEH). These lesions can be distinguished based on their clinical presentation and histopathologic features.
The SP generally presents as a solitary, soft, pedunculated mass with a papillary surface and is most commonly found on the palatal complex and tongue. This lesion is associated with HPV types 6 and 11. Treatment of this lesion is by conservative surgical excision and recurrence is rare.
The VV, or common wart, is classically described as a white, firm, exophytic lesion with a stippled or papillary surface, and is found most commonly on the labial mucosa and vermilion border of the lips. The VV is thought to develop in many instances as a result of auto-inoculation from cutaneous sites, particularly the skin of the hands. HPVs 2 and 4 are the most frequently identified HPV types in the VV. Surgical excision, laser ablation, cryotherapy and electrocautery have been used for the treatment of VV and recurrence is uncommon. Management of any cutaneous lesions decreases the likelihood of re-infection.
The CA, a sexually transmitted wart, is common in the anogenital mucosa but is infrequently identified in the oral cavity. CA may present as solitary or multiple lesions. CA tends to be larger than the SP and VV, with a broad base and a heavily stippled or cauliflower-like surface. The most common oral locations for the CA are the tongue, labial mucosa, floor of the mouth and gingival. The CA is typically associated with HPVs 6 and 11. Conservative surgical excision, electrocautery, laser ablation and cryotherapy have been utilized for the treatment of these oral lesions. Simultaneous treatment of anogenital lesions in infected patients and their sexual partners reduces the risk of re-infection and recurrence.
FEH, also known as Heck's disease, is a distinct clinical entity confined to the oral cavity and perioral skin. It was originally described in Native American children in the Southwestern United States,4 but can also be seen in adults. FEH is characterized by multiple flat warts with finely stippled surfaces, which frequently occur on the labial and buccal mucosa, lateral tongue and lip commissures. Small lesions in close proximity to one another often coalesce to produce larger lesions. FEH is specifically associated with HPVs 13 and 32, which (with one exception of a peri-anal wart in an HIV-infected man) have only been reported in the oral cavity. In children and healthy adults, the lesions of FEH can undergo spontaneous regression within several months to a couple of years.5 These lesions can also be treated by surgical excision, cryotherapy, laser ablation and the application of topical keratolytic agents such as podophyllin resin.
Increased rates of HPV infection have been documented in immunocompromised individuals such as cancer patients, organ transplant recipients, patients receiving immunosuppressive drugs and HIV-infected patients.6 While HPV is detected in clinically normal oral mucosa in approximately one third of the general population, a higher detection rate of up to 60% is observed in HIV-positive individuals.7 The prevalence of oral warts in HIV-positive individuals ranges from 1 to 4%. The most common location for oral warts in HIV-infected patients is the labial and buccal mucosa, and the most common clinical presentation is multifocal flat lesions resembling FEH.8 The mean age at the time of diagnosis is 39 years, and the mean CD4 count is 258 cells/mm3, indicating a moderately severe level of immunosuppression.3 Of note, up to 48% of HIV-positive individuals with oral warts have a previous or concurrent history of cutaneous and/or anogenital warts.3 A small percentage (approximately 5%) of the oral lesions have been reported to exhibit premalignant epithelial changes ranging from mild to severe dysplasia.9,10 The most commonly identified HPV types in the oral warts of HIV-infected individuals are types 7, 13 and 32.10,11
Oral warts in HIV-infected individuals, particularly those lesions with a multifocal clinical presentation, are often resistant to traditional therapies and exhibit a high recurrence rate despite aggressive treatment.12 Commonly employed treatments include surgical excision, electrocautery, laser ablation and cryotherapy. Pharmacologic agents have been used in the treatment of these oral lesions with variable success; these include topical keratolytic agents such as podophyllin resin, intralesional or systemic interferon, and intralesional cidofovir injections.12 Recently, the use of cimetidine, an H2-receptor antagonist, has been described for the management of oral warts associated with HIV infection.12 Anecdotal evidence suggests that a combination of surgical or laser excision of larger lesions, along with oral cimetidine treatment for several months, is the most effective therapy for these lesions.
The evidence of precancerous changes in a number of the oral warts associated with HIV infection, particularly in light of the immune suppression of the affected patients, raises some legitimate concerns regarding the biologic behavior and long-term prognosis of these lesions. Unfortunately, this issue has received little attention in the scientific literature. In contrast, numerous reports of anogenital HPV infection in this population group point to an increased prevalence of HPV infection, more rapid disease progression and a higher incidence of cancer precursor lesions as compared to the general population. There is also a higher treatment failure rate and possibility of recurrence of anogenital HPV infection in HIV-infected individuals.13 Furthermore, there appears to be a positive correlation in women between the development of cervical cancer precursor lesions and decreasing CD4 counts.14 While cell-mediated immune responses in immune-competent individuals often result in clearance and latency of HPV infection, decreased HPV-specific immunity in HIV infection can cause re-activation and active replication of HPV, resulting in clinically evident infection.
Due to the structural similarities between the oral and anogenital mucosa, an oncogenic role for HPV can be theorized in the oral mucosa. However, definitive statements regarding a significant association between oral HPV infection and the development of oral precancerous and cancerous lesions are difficult to make. Other carcinogenic agents (such as tobacco and alcohol) along with chronic immunosuppression likely enhance the oncogenic potential of HPV-induced oral lesions in this patient population. Limited studies of oral cancer in HIV-infected patients have shown contradictory results, with one study reporting a lack of association with traditional risk factors for oral cancer,15 and another study showing a strong association with tobacco and alcohol use.16 Therefore, while a cause and effect relationship between oral HPV infection and oral cancer has not been established, the biologic potential of oral warts with precancerous changes remains unknown, and close follow-up and excision of residual lesions is recommended.
Another important question that remains unanswered is the mode of transmission of these oral lesions. Since HPVs can establish latent subclinical infections in the human host, many HPV infections in immunocompromised individuals likely represent re-activation of latent virus that may have been acquired early in life. Auto-inoculation from other cutaneous or anogenital sites is also possible, as has been shown in immune competent individuals. Due to the high incidence of anogenital HPV infection in HIV-infected patients with oral warts, sexual transmission of the oral lesions cannot be excluded. Further studies are needed to address this issue, which could have important clinical and therapeutic implications.
Oral warts are an increasingly common opportunistic infection in HIV-infected individuals, and recognition of this oral manifestation of HIV infection is important for these individuals as well as health care providers involved in their care.
The authors would like to thank C.M. Nichols, DDS, K. Adler-Storthz, PhD, and A. Kapadia, PhD, for their contributions to the research in this field.
Anogenital: involving genital organs and the anus.
Aphthous: identified by apthae (blisters or flakes on mucous membranes, such as in the mouth).
Buccal: referring to the cheeks.
Commissures: points of union or junction.
Dysplasia: abnormal cellular growth or development (as in the formation of cancer cells).
Etiologic: relating to the cause or origin of a disease or abnormality.
Exophytic: tending to grow outward from the source.
Gingiva: dental tissue commonly called gums.
Keratolytic: causing the breakdown of keratin, a skin protein.
Labial: relating to or near the lips.
Mucosal: relating to mucous membranes that lines body passages and cavities (e.g., inside the mouth).
Palatal: describing the roof of the mouth.
Papillary: referring to a small, round protuberance, sometimes described as nipple-like.
Pedunculated: relating to the narrow stalk by which a polyp or mass is attached.
This article was provided by The Center for AIDS. It is a part of the publication Research Initiative/Treatment Action!. Visit CFA's website to find out more about their activities and publications.