Viral Infections of the Mouth (cont 2)

Human Papillomavirus

Background

HPVs are members of the Papovaviridae family, which are small icosahedral viruses that contain circular DNA. The term papova is derived from the first 2 letters of their common clinical features, as follows: papillomatous lesions, polyomas (varied tumor induction), and vacuolization of infected cells.

At least 106 types of HPV have been discovered. The infectivity of HPV is incompletely understood. Some types of HPV may act in concert with cofactors such as diminished immunity or sun exposure.

Although the magnitude of its risk is not completely clear, HPV is currently considered to be an independent risk factor for the development of oral squamous cell carcinoma, especially in younger cancer patients and persons with tonsillar carcinoma. Odds ratios range in various studies from 2.0 to 5.4, and variation is in part associated with the method of viral detection. Certain HPV types have been more strongly associated with malignancies of the tonsils, anus, genital tract, and other areas.

Pathophysiology

HPV is a 50-nm virus composed of double-stranded DNA with no envelope. The virus penetrates the mucosal epithelium and invades the cells of the basal layer, where the viral circular DNA inserts into the host DNA.

Frequency

HPV has been detected in the oral cavity of approximately 6-10% of children and adolescents. The rate of HPV in the oral cavity of healthy adults is estimated at 5-80%. Persistent oral HPV infection in one spouse appears to predict similar infection in the other spouse, regardless of oral sex habits.²¹

HPV-16 has been linked to the development of dysplasia and carcinoma of the uterine cervix. Oral HPV-16 detection is more common in women with HPV-associated cervical dysplasia.²² Oral HPV-16 detection is much less common in children than in adolescents and adults. However, persistence of HPV-16 and other high-risk HPV types is more common in infants of parents with persistent oral HPV infections and high-risk behaviors.

Oral HPV may also be more common in renal dialysis patients. HPV lesions are more common in immunocompromised patients, especially in HIV-infected patients and in solid organ transplant recipients.^23,24 The recent development of effective preventative HPV vaccines may, in the future, have a significant impact on these rates.^25,26

Mortality/morbidity

Most oral lesions caused by HPV are benign. Lesions are usually painless and not ulcerated, although they may be secondarily ulcerated by trauma. Lesions may be more common and severe in immunocompromised patients than in other patients.

Clinical history

Verruca vulgaris, or common warts (HPV-2; HPV-4; occasionally HPV-1, HPV-3, HPV-27, HPV-29, and HPV-57), are more common on the skin than in the oral cavity. On the oral mucosa, the warts are usually sessile, verrucous, and white; solitary or multiple; and elevated with discrete borders. The lesions most commonly occur on the lips, hard palate, or gingiva. Verruca plana is similar but less elevated. Warts are commonly observed on the digits of patients with oral infection.

Condyloma acuminata, or genital warts (HPV-6, HPV-11), may also affect the oral mucosa. These lesions are usually cerebriform, pink, and sessile and solitary or multiple; they occur more commonly on nonkeratinized mucosa than on keratinized mucosa. Patients infected with HPV-6 or HPV-11 and their sexual partners may have genital lesions, and the lesions have presumably been spread to the oral cavity via oral-genital contact.

Focal epithelial hyperplasia, or Heck disease (HPV-13, HPV-32), may appear as an epidemic in young adults in small communities. This condition was first described in native North American people. Heck disease typically manifests as multiple, smooth, sessile nodules, often on the mucosal surface of the lower lip or on the buccal mucosa. Lesions may regress spontaneously after several months.

HPV may have a role in oral premalignancy and malignancy in humans.^27,28 HPV-16 in particular (but also HPV-18, HPV-33, HPV-35, and others) have been associated with verruciform proliferations in the oral cavity, oral premalignant lesions, and oral squamous cell carcinoma.^29,30,31,32 HPVs may interfere with the normal function of regulatory proteins, such as p53, p16, and pRb, and they may have a promoter effect.

Human papillomavirus (HPV). Verruca vulgaris on the lateral border of the tongue exhibits the multiple, sharp-tipped, white, verrucous appearance, which is classic for this lesion in the oral cavity. Not all verrucae are so clinically diagnostic. Courtesy of Rose Yin Geist, DDS.

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Human papillomavirus (HPV). Verruca vulgaris on the lateral border of the tongue exhibits the multiple, sharp-tipped, white, verrucous appearance, which is classic for this lesion in the oral cavity. Not all verrucae are so clinically diagnostic. Courtesy of Rose Yin Geist, DDS.

Human papillomavirus (HPV). This verruca on the retromolar pad shows much less keratinization and a broader base. Verrucae and papillomas may be difficult to differentiate, but both are usually surgically excised.

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Human papillomavirus (HPV). This verruca on the retromolar pad shows much less keratinization and a broader base. Verrucae and papillomas may be difficult to differentiate, but both are usually surgically excised.

This is a verruca vulgaris of the anterior maxillary gingiva in a healthy young male. He had recently resolved a wart on his finger.

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This is a verruca vulgaris of the anterior maxillary gingiva in a healthy young male. He had recently resolved a wart on his finger.

Papillomas, which are of questionable viral origin, are frequent findings in the oral cavity, especially on the lateral/ventral tongue and soft palate.

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Papillomas, which are of questionable viral origin, are frequent findings in the oral cavity, especially on the lateral/ventral tongue and soft palate.

These small papillomas on the lateral tongue of a young woman showed histologic evidence of HPV in the form of extensive koilocytosis.

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These small papillomas on the lateral tongue of a young woman showed histologic evidence of HPV in the form of extensive koilocytosis.

Multiple condylomas are seen in this HIV+ male with a CD4 count of 11, and recent neurosyphilis.

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Multiple condylomas are seen in this HIV+ male with a CD4 count of 11, and recent neurosyphilis.

Human papillomavirus (HPV). Condyloma acuminatum of the oral cavity usually appears as a pinker, more cerebriform lesion (as shown here) compared with the whiter, more verrucous appearance of verruca vulgaris. Courtesy of A.K. ElGeneidy, DDS.

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Human papillomavirus (HPV). Condyloma acuminatum of the oral cavity usually appears as a pinker, more cerebriform lesion (as shown here) compared with the whiter, more verrucous appearance of verruca vulgaris. Courtesy of A.K. ElGeneidy, DDS.

Human papillomavirus (HPV). Some patients with condyloma acuminatum present with multiple oral lesions. Lesion on the lingual frenum occurred in the same man shown in Image 14. Courtesy of A.K. ElGeneidy, DDS.

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Human papillomavirus (HPV). Some patients with condyloma acuminatum present with multiple oral lesions. Lesion on the lingual frenum occurred in the same man shown in Image 14. Courtesy of A.K. ElGeneidy, DDS.

Human papillomavirus (HPV). Condylomata on the lower lip, as well as other sites at the initial presentation (same patient as in Images 14-15). This presentation is unusually extensive. Multiple condylomata may be synchronous or metachronous. This patient did not present with genital condylomata; however, the appropriate health care practitioner should examine patients with condyloma to determine the extent of the disease. The source of infection (eg, a partner who is infected) should also be determined and treated. Courtesy of A.K. ElGeneidy, DDS.

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Human papillomavirus (HPV). Condylomata on the lower lip, as well as other sites at the initial presentation (same patient as in Images 14-15). This presentation is unusually extensive. Multiple condylomata may be synchronous or metachronous. This patient did not present with genital condylomata; however, the appropriate health care practitioner should examine patients with condyloma to determine the extent of the disease. The source of infection (eg, a partner who is infected) should also be determined and treated. Courtesy of A.K. ElGeneidy, DDS.

A mnemonic for remembering the microscopic and clinical shapes of verruciform oral lesions: Verruca vulgaris is shaped like a series of inverted V's. Condyloma acuminata are shaped like a series of C's placed on their sides. Papillomas are pedunculated like the letter P.

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A mnemonic for remembering the microscopic and clinical shapes of verruciform oral lesions: Verruca vulgaris is shaped like a series of inverted V's. Condyloma acuminata are shaped like a series of C's placed on their sides. Papillomas are pedunculated like the letter P.

Human papillomavirus (HPV). Heck disease in the buccal mucosa of a 7-year-old boy. Courtesy of Sheldon Mintz, DDS.

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Human papillomavirus (HPV). Heck disease in the buccal mucosa of a 7-year-old boy. Courtesy of Sheldon Mintz, DDS.

Differentials

Verruca vulgaris and condyloma acuminata

Papilloma

Focal epithelial hyperplasia

Verrucous Carcinoma

Proliferative verrucous leukoplakia

Squamous Cell Carcinoma

Focal epithelial hyperplasia

Focal fibrous hyperplasia (fibroma)

Condyloma acuminata

Papillomatosis

Condyloma plana

Verruca plana

Connective-tissue tumor

Salivary gland tumor

Workup

Laboratory studies

The typing of HPV, if deemed necessary, may be performed by immunohistochemical detection of HPV structural proteins. This analysis has a low sensitivity. Enzyme-linked immunosorbent assay and polymerase chain reaction DNA amplification are more sensitive techniques for HPV detection.

Procedures³³

Diagnosis is usually achieved with biopsy results. Excisional biopsy is commonly performed, and it has a high success rate as a treatment of these lesions.

Carbon dioxide laser treatment is problematic because viral DNA has been detected in the laser plume.³⁴ Such laser treatment is considered potentially infectious to surgical personnel. However, HPV DNA was absent in the laser plume of the Er:YAG laser in one study.³⁵

Histologic findings

When the production of viral DNA and structural proteins begins, koilocytosis also develops, with dark shrunken nuclei and cytoplasmic vacuolization of infected cells.

Verruca vulgaris typically exhibits a verrucous epithelial proliferation with hyperkeratosis. Koilocytes are frequently noted in the upper stratum spinosum and stratum corneum.

Condyloma acuminata may exhibit acanthosis, vacuolated keratinocytes, a compacter stratum corneum, and parakeratosis.

Focal epithelial hyperplasia (Heck disease) exhibits acanthosis of the spinous layer and thickened, fused rete pegs. The epithelial cells may exhibit intracellular edema. Slight parakeratosis is usually present.

Human papillomavirus (HPV). Verrucae and papillomas appear as frondlike epithelial proliferations. Verrucae tend to be more keratinized with sharper projections than papillomas.

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Human papillomavirus (HPV). Verrucae and papillomas appear as frondlike epithelial proliferations. Verrucae tend to be more keratinized with sharper projections than papillomas.

Human papillomavirus (HPV). Condyloma acuminatum generally has a papillary architecture and may microscopically resemble verruca vulgaris and papilloma (hematoxylin and eosin stain, original magnification X10). Courtesy of AK ElGeneidy, DDS.

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Human papillomavirus (HPV). Condyloma acuminatum generally has a papillary architecture and may microscopically resemble verruca vulgaris and papilloma (hematoxylin and eosin stain, original magnification X10). Courtesy of AK ElGeneidy, DDS.

Human papillomavirus (HPV). Koilocytes in the upper epithelium are a helpful, although not completely reliable, indication that a lesion is associated with human papillomavirus. Koilocytes display a dark small nucleus with clear cytoplasm (hematoxylin and eosin stain, original magnification X100). Courtesy of Sheldon Mintz, DDS.

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Human papillomavirus (HPV). Koilocytes in the upper epithelium are a helpful, although not completely reliable, indication that a lesion is associated with human papillomavirus. Koilocytes display a dark small nucleus with clear cytoplasm (hematoxylin and eosin stain, original magnification X100). Courtesy of Sheldon Mintz, DDS.

Human papillomavirus (HPV). Condyloma acuminatum may show brisk mitotic activity, although oral condyloma acuminatum is not considered a premalignant lesion (hematoxylin and eosin stain, original magnification X40). Courtesy of A.K. ElGeneidy, DDS.

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Human papillomavirus (HPV). Condyloma acuminatum may show brisk mitotic activity, although oral condyloma acuminatum is not considered a premalignant lesion (hematoxylin and eosin stain, original magnification X40). Courtesy of A.K. ElGeneidy, DDS.

Medical care

Oral lesions are usually treated with excisional biopsy. After the lesions have been removed and the diagnosis is confirmed by biopsy results, they usually do not recur unless reinfection occurs. To prevent reinfection, the source of infection (eg, digits, lesions on sexual partners) should be determined and treated if possible. In HIV-infected patients, recurrence of the lesions is widely reported. The treatment objective can sometimes be limited to control rather than eradication of the HPV lesions. Reports have indicated that solid organ transplant recipients can also be at risk for recurrent and florid oral lesions, which also can limit the treatment objective to control rather than cure.

Topical agents are sometimes used. Cidofovir is an antiviral agent that is a nucleotide analog of deoxycytidine monophosphate. Cidofovir is approved for intravenous administration in patients with AIDS who have CMV retinitis. Topical administration of this medication (1% cream or gel) has been used for refractory condyloma acuminata and recurrent genital herpes. Cidofovir is occasionally used for oral lesions. When used systemically, it may cause nephrotoxicity, uveitis, and numerous other adverse effects.³⁶

Intralesional injections may be used in refractory cases, but they are not recommended for the primary treatment of oral lesions. Bleomycin is a cytotoxic polypeptide that inhibits DNA synthesis in cells and viruses. Adverse effects include pain with injection, local urticaria, Raynaud phenomenon, and possible tissue necrosis. Bleomycin should be considered a third-line treatment when standard therapies have failed. IFN-A is a naturally occurring cytokine with antiviral, antibacterial, anticancer, and immunomodulatory effects. Intralesional administration of IFN-A is associated with mild flulike symptoms. Treatments may be required for several weeks to months before beneficial results are observed. IFN-A should be considered a third-line treatment to be used after standard therapies have failed. Research on topical low-dose IFN-A is being conducted. The results of this therapy have yet to be communicated.

Systemic agents, such as retinoids or synthetic vitamin A analogs, may be used to treat extensive lesions in patients who are immunocompromised or immunosuppressed. They may be used in conjunction with other treatments. Adverse effects may include liver function abnormalities, increased serum lipid levels, and teratogenicity. Some clinicians have used podophyllin, but it is not approved by the FDA for this purpose.

Imiquimod 5%(Aldara), a toll-like receptor 7 activator, has been approved for external genital warts and has been tried with varied success in the oral cavity.

The long-term effect of preventive HPV vaccination on oral HPV-related disease is not yet known but offers potential hope that vaccination prior to exposure to HPV may result in a decrease in the incidence of HPV-related oral lesions. Cross-reactivity of the immune response to the HPV subtypes targeted by the vaccines may render the vaccines useful to prevent oral lesions associated with HPV.

Medication

See Medication.

Follow-up

Further outpatient care

Monitor the patient for the recurrence of the condition.

Consult a dermatologist for patients with skin lesions.

Consult an obstetrician/gynecologist (for females) or a urologist (for males) for patients with condyloma acuminata (and their sexual partners) to detect, diagnose, and treat any coexistent lesions of the anogenital lesion, which may be premalignant.

If the initial therapy is inadequate or lesions recur, evaluation of the patient for underlying immunosuppression may be warranted.

Complications

Local scarring from surgical excision may occur.

Transmission to family members or sexual partners is possible.

Recurrence may be observed.

Prognosis

The prognosis is excellent. In extreme conditions, the treatment objective is limited to control rather than eradication of the HPV lesions.

Education

Educate the patient concerning the etiology and the route of transmission to prevent reinfection.

Medical/legal pitfalls

• Failure to refer patients for evaluations of potentially malignant anogenital lesions
• Failure to diagnose or misdiagnosis of a verrucous carcinoma
• Failure to inform patients about the rare risk of oral malignancy if inadequately diagnosed and treated
• Failure to indicate the need for follow-up, even after treatment
• Failure to warn patients of the risk of recurrence or of treatment failure
• Failure to indicate treatment availability
• Failure to inform patients of the risk of transmission of HPV
• Failure to inform patients with condyloma of the need to treat sexual partners
• Failure to search for immunosuppression in patients with treatment failures and lesion recurrences