HIV-Related Oral Lesions: Clues for Early Diagnosis

March 1, 2009

A 30-year-old man with a 15 packyear smoking history presented for a follow-up evaluation of an asymptomatic whitish lesion on the tongue of 4 months’ duration. The lesion had not responded to oral therapy with either nystatin or fluconazole. The patient was distressed about the lesion’s appearance and his inability to remove it with a toothbrush.

Oral lesions are often the harbingers of early HIV infection. They are among the most common complaints for which HIV-positive patients seek primary care and are often misdiagnosed or inadequately treated.1 More than 90% of patients with AIDS have 1 or more oral manifestations during the course of their illness.2

Common oral manifestations include candidiasis, linear gingival erythema, necrotizing ulcerative periodontitis, xerostomia, Kaposi sarcoma, herpes simplex virus lesions, aphthous ulcers, human papillomavirus (HPV)-associated warts, and hairy leukoplakia.1 Here we discuss 2 cases of young, healthy-appearing men who presented with HIV-related oral lesions.



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A 30-year-old man with a 15 packyear smoking history presented for a follow-up evaluation of an asymptomatic whitish lesion on the tongue of 4 months’ duration. The lesion had not responded to oral therapy with either nystatin or fluconazole. The patient was distressed about the lesion’s appearance and his inability to remove it with a toothbrush.


Multiple, nontender, whitish, vertical striations were noted along the right lateral edge of the lesion (Figure 1). No ulcerations, vesicles, verrucae, fissures, or exanthemas were visible in the oral cavity; there was no evidence of bleeding or exudates. The physical findings were otherwise unremarkable.

A presumptive clinical diagnosis of oral hairy leukoplakia was made, and an HIV test was ordered. Histological examination of a biopsy specimen of the lesion revealed hyperkeratosis and koilocytosis without inflammation.

Results of the HIV test were positive. The CD4+ cell count was 312/μL (HIV RNA level, 27,000 copies/mL). Oral acyclovir was started, and the lesion resolved by the end of the third week of treatment.

Oral hairy leukoplakia is the classic intraoral lesion of HIV/AIDS. This entity generally manifests as a unilateral or bilateral adherent grayish white or yellowish white patch on the lateral margins of the tongue. These patches may appear as irregular folds or projections and often have a corrugated surface. The lesion can also occur on the ventral surface of the tongue but is typically flat in this region.2,3 Other possible locations include the floor of the mouth and the buccal mucosa. The lesions are usually asymptomatic, although occasionally patients may complain of soreness or burning.

Etiology and incidence. Oral hairy leukoplakia is thought to be mediated by the intense replication of the Epstein-Barr virus (EBV) and is fairly specific to the immunodeficient state caused by HIV disease. However, it has also been described in patients who are immunocompromised because of organ transplant or autoimmune disease and very rarely in those who are otherwise seemingly healthy. Oral hairy leukoplakia is almost exclusively seen in men who have sex with men. Its presence is generally a sign of moderate to severe HIV disease (with CD4+ cell counts of less than 300/μL) and can be considered a clinical marker for disease progression. AIDS can be expected to develop in up to 30% of such patients within 3 years.4,5

Diagnosis. A presumptive clinical diagnosis can be made by the history and physical examination. A thorough medical and social history will often reveal the cause of immunosuppression. Unlike candidal infection, the lesions cannot be scraped off and are also unresponsive to antifungal therapy. When the diagnosis is unclear, a biopsy can be performed. A more definitive diagnosis can be made by in situ hybridization of EBV DNA.3

Prognosis and treatment. Oral hairy leukoplakia has no malignant potential. It is generally not treated unless the patient experiences interference with speech, taste, or chewing or requests treatment for cosmesis. The disorder responds to topical retinoids or podophyllin. Oral antiviral agents, including acyclovir, zidovudine, ganciclovir, and foscarnet, may also be effective. Relapses are common once treatment is discontinued. The lesions also respond favorably during the course of highly active antiretroviral therapy, as the CD4+ cell count rises.3 Patients should be instructed to comply with regular dental and medical care regimens.


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A 34-year-old man presented for a routine physical examination. He appeared healthy and had no recent history of weight loss, fever, fatigue, forgetfulness, rash, lymphadenopathy, diarrhea, or cough.

Examination of the oral mucosa revealed a friable, filiform, digitate lesion on the upper gum (Figure 2). This lesion had been present for several months and bled occasionally when he brushed his teeth.

A clinical diagnosis of HPV infection was made. Results of HIV testing were positive. The patient’s CD4+ cell count was 391/μL (HIV RNA level, 26,000 copies/mL).

Because of the concern for other sexually transmitted infections in persons with HPV infection, this patient was also tested for Chlamydia infection, gonorrhea, syphilis, and hepatitis B. He declined treatment of his oral lesion at the time of diagnosis.

Oral HPV infection can present as verruca vulgaris, squamous cell papillomas, condyloma acuminatum, focal epithelial hyperplasia (Heck disease), and oral leukoplakia with dysplastic change.4 These lesions can occur at any site in the oral cavity.

The clinical appearance of the oral lesions is generally specific for the HPV genotype. Condylomata are most often caused by HPV types 6 and 11 and may present as soft, sessile cauliflowerlike lesions (see Figure 2). Verrucae vulgaris are typically associated with HPV types 1, 2, and 7 and usually present as firm, sessile warts. Focal epithelial hyperplasia is generally caused by HPV types 13 and 32 (which appear to be specific for the oral cavity) and presents as a dysplastic lesion with multiple small, flat papules typically on the lower lip.6 HPV types 7, 16, 18, 55, and 89 also have been isolated from oral warts.7

Etiology and incidence. HIVpositive persons typically have a higher rate of carriage of HPV than do HIV-negative persons. Oral HPV infection is also correlated with homosexuality, unprotected oral sex, and a history of previous sexually transmitted infections. Thus, it is thought that HPV is likely transmitted to the oral cavity through sexual contact.6,8

Unlike the incidence of oral hairy leukoplakia, which has decreased since the advent of highly active antiretroviral therapy, the prevalence of HPV-associated warts appears to have increased since the mid-1990s. The cause of the increase is still a topic of debate. Some experts suggest that before the advent of highly active antiretroviral therapy, patients may have died before HPV-associated warts developed. A more probable theory is that highly active antiretroviral therapy allows activation of the HPV virus, which leads to its replication.4,7

Diagnosis. It is important to consider squamous cell carcinoma and squamous cell carcinoma in situ in the differential diagnosis. Biopsy is necessary to distinguish these conditions. Histological examination of the warts reveals epithelial hyperplasia with large vacuolated, poorly differentiated, koilocytic cells in the upper layers of the epidermis. The stroma is highly vascularized and has very few inflammatory cells.

Prognosis and treatment. Chronic infection with HPV has been associated with anal, vaginal, vulvar, cervical, and oral cancers.9,10 Dysplastic changes in biopsy specimens of oral HPV lesions have been demonstrated. HPV type 16 has been isolated from HPV-associated tonsillar cancers and has been identified as the most prevalent of the pro-oncogenic strains.8 Although no reports have indicated a definite increase in HPV-associated head and neck cancers in HIV-infected patients, it has been suggested by several epidemiological studies.11

Treatment options are limited for oral warts. Topical podophyllin resin, interferon alfa injection, and surgical excision have shown some success. Other techniques include electrosurgery, cryosurgery, and the use of a CO2 laser.11


REFERENCES: 1. Reznik DA. Oral manifestations of HIV disease. Top HIV Med. 2005-2006;13:143-148.
2. Sifri R, Diaz VA Jr, Gordon L, et al. Oral health care issues in HIV disease: developing a core curriculum for primary care physicians. J Am Board Fam Pract. 1998;11:434-444.
3. Triantos D, Porter SR, Scully C, Teo CG. Oral hairy leukoplakia: clinicopathologic features, pathogenesis, diagnosis, and clinical significance. Clin Infect Dis. 1997;25:1392-1396.
4. Leigh JE, Shetty K, Fidel PL Jr. Oral opportunistic infections in HIV-positive individuals: review and role of mucosal immunity. AIDS Patient Care STDS. 2004;18:443-456.
5. Greenspan D, Greenspan JS, Hearst NG, et al. Relation of oral hairy leukoplakia to infection with human immunodeficiency virus and the risk of developing AIDS. J Infect Dis. 1987;155:475-481.
6. Hagensee ME, Cameron JE, Leigh JE, Clark RA. Human papillomavirus infection and disease in HIVinfected individuals. Am J Med Sci. 2004;328:57-63.
7. Cameron JE, Mercante D, O’Brien M, et al. The impact of highly active antiretroviral therapy and immunodeficiency on human papillomavirus infection of the oral cavity of human immunodeficiency virus-seropositive adults. Sex Transm Dis. 2005;32: 703-709.
8. Kreimer AR, Alberg AJ, Daniel R, et al. Oral human papillomavirus infection in adults is associated with sexual behavior and HIV serostatus. J Infect Dis. 2004;189:686-698.
9. Gillison ML, Lowy DR. A causal role for human papillomavirus in head and neck cancer. Lancet. 2004;363:1488-1489.
10. Spano JP, Marcelin AG, Carcelin G. HPV and cancer [in French]. Bull Cancer. 2005;92:59-64.
11. Hodgson TA, Greenspan D, Greenspan JS. Oral lesions of HIV disease and HAART in industrialized countries. Adv Dent Res. 2006;19:57-62.