Etiology

HPV, the putative etiologic agent of papillomas of the upper aerodigestive tract, is a member of the papovavirus group. It is a DNA virus containing a single molecule of double-stranded DNA comprising approximately 8000 nucleotide base pairs. The viruses themselves are nonenveloped icosahedral particles ranging from 45 to 55 nm in diameter with 72 capsomeres in a skewed arrangement. Various species are antigenically distinct, sharing some common antigenic determinants. HPV specifically infects basal epithelial cells and establishes productive infection only in the stratified squamous epithelium of the skin and mucosa. Replication of HPV occurs within the nuclei of epithelial cells with the viral genome expressed in both early and late stages. In HPV-associated benign epithelial proliferations, the virus is episomal, but in HPV-associated cancers, the virus is integrated into the host cell DNA. If progeny production is blocked, persistent infection may result. However, if intact viruses are produced, new infective particles can be released with or without cell death.

Clinical Features

Oral squamous papillomas may be found on the vermilion portion of the lips and on any intraoral mucosal site, with predilection for the hard and soft palate and the uvula (Box 6-1; Figures 6-1 to 6-3). The latter three sites account for approximately one third of all lesions. The lesions generally measure less than 1 cm in greatest dimension and appear as pink to white exophytic granular or cauliflower-like surface alterations. They are generally asymptomatic and solitary in their presentation, although multiple lesions may occur.

The incidence of oral warts is increasing in patients with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) in contrast to other oral manifestations of the disease. This has been associated with the use of antiretroviral therapeutics, particularly highly active antiretroviral therapy (HAART). Lesions range from flat-topped plaques to verruciform or cauliflower-shaped exophytic masses. Lesions also tend to be multiple and recurrent.

Histopathology

Oral squamous papillomas represent an exaggerated growth of normal squamous epithelium (Figures 6-4 to 6-6). The lesions are exophytic and are composed of finger-like extensions of epithelium, supported by a well-vascularized connective tissue core. The histologic architecture may mimic the pattern of the cutaneous wart. Upper level epithelial cells demonstrate nuclei that are pyknotic (condensed) and crenated, often surrounded by an edematous or optically clear zone, forming the so-called koilocytic cell. In the uterine cervix, this cytologic appearance represents HPV infection, which by extension is generally thought to present in the oral cavity.

Dysplastic Oral Warts

A small subset of HIV/AIDS patients develop oral warts that exhibit microscopic changes that are dysplastic in appearance (Box 6-2; Figure 6-7). The degree of dysplasia ranges from mild to severe. The outcome, or natural history, of these dysplastic warts is unknown, although invasive carcinoma has yet to be reported despite several years of follow-up. A wide variety of HPV subtypes, including 16 and 18, can be demonstrated in these lesions.

Box 6-2   Dysplastic Oral Warts

HIV-positive patients only

Multiple HPV subtypes, including 16, 18

Oral mucosa only

Histopathology—ranging from dysplasia to in situ carcinoma

Invasive/metastatic potential unknown

HIV, Human immunodeficiency virus; HPV, human papillomavirus.

Differential Diagnosis

The differential diagnosis of oral squamous papilloma, when solitary, includes verruciform xanthoma, papillary hyperplasia, and condyloma acuminatum. Verruciform xanthoma may resemble squamous papilloma, although this lesion has a distinct predilection for the gingiva and the alveolar ridge and contains xanthoma (foamy) cells in the connective tissue papillae. Inflammatory papillary hyperplasia usually occurs on the hard palate underneath a poorly fitting denture. A condyloma would be larger than the papilloma, would have a broader base, and would appear pink to red as a result of comparatively less keratinization.

Treatment and Prognosis

Although many oral squamous papillomas appear to be virally induced, the infectivity of the HPV is low. The route of transmission of the virus is unknown for oral lesions, although direct contact in an area of local trauma would be favored.

Removal by surgical excision is the treatment of choice. Laser ablation is also effective but does not offer the opportunity for microscopic examination of the lesion to confirm the diagnosis. Recurrence is uncommon, except for lesions in patients infected with HIV.

Papillary hyperplasia, or palatal papillomatosis, appears almost exclusively on the hard palate and almost always in association with a removable prosthesis. The precise cause of papillary hyperplasia is not well understood, although it appears to be associated with an ill-fitting or loose denture that creates a potential space between the denture base and tissue, predisposing to or potentiating growth of Candida albicans organisms. Tissue hyperplasia has been related to the presence of the fungal organism in the setting of low-grade chronic trauma.

Clinical Features

The area of mucosa over the palate that tends to be most commonly involved is the vault (Figure 6-8). Less commonly, the alveolar ridge or the palatal incline is affected.

Presentation is characterized by multiple erythematous and edematous papillary projections that are tightly aggregated, producing an overall verrucous, granular, or cobblestone appearance. The projections may be slender and almost villous, although in most cases, each projection tends to be rounded and blunted, with narrow spaces on either side. Ulceration is rare, although intense erythema may at times provide an overall appearance of erosion. Focal telangiectatic sites may also be noted on occasion.

Histopathology

On perpendicular cross-section, papillary hyperplasia appears as numerous small fronds or papillary projections covered with intact parakeratotic stratified squamous epithelium (Figure 6-9). The epithelium is supported by hyperplastic central cores of well-vascularized stromal tissue. The epithelium is hyperplastic and often demonstrates pseudoepitheliomatous features, occasionally severe enough to mimic squamous cell carcinoma. No evidence of dysplasia is found in association with this lesion and risk of malignant transformation is not increased.

Condyloma Latum

Condyloma latum is one of the many and variable expressions of secondary syphilis. As with all forms of syphilis, cutaneous, mucosal, and systemic lesions that mimic other conditions or diseases can be seen. Characteristic of condyloma latum is the presence of exophytic, sometimes friable, papillary to polypoid lesions within the oral cavity. Condyloma latum contains abundant microorganisms (Treponema pallidum), making it potentially infectious.

Condyloma latum usually appears on the skin, especially in the perianal and genital areas. Lesions may also be noted within the oral cavity. Here the tissue is formed into a soft, red, often mushroom-like mass with a generally smooth, lobulated surface.

Microscopically, the overlying epithelium demonstrates significant acanthosis, along with intracellular and intercellular edema and transmigration of neutrophils. A perivascular plasma cell infiltrate is common within the lamina propria in the absence of a true vasculi/>