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Papillary and verruciform epithelial proliferations are quite common in the oral and paraoral region, representing at least 3% of biopsied oral lesions. Many are thought to be induced by viral infection of the epithelium, especially from human papillomavirus (HPV). HPV encompasses a group of double-stranded DNA viruses of the papovavirus subgroup A capable of integration with host DNA. At the present time there are more than 68 known HPV subtypes, many associated with lesions of the head and neck. These viruses often can be identified by in situ hybridization, immunohistochemistry and polymerase chain reaction (PCR) techniques, but are seldom visible with routine histopathologic staining.
Additional focal epithelial proliferations are either neoplastic or of unknown origin. Some are malignancies, discussed elsewhere in this text, while others mimic malignant epithelial changes. The pathologist must be ever alert for these distinctions, which are often very subtle ones.
Of the several types of papillomas, the one occurring in the mouth and oropharynx is almost always the squamous papilloma. It is the fourth most common oral mucosal mass and is found in 4 of every 1,000 U.S. adults (Table 1). Accounting for 3-4% of all biopsied oral soft tissue lesions, this entity was first reported as a gingival "wart" by Tomes in 1848 and is a localized, benign HPV-induced epithelial hyperplasia. The virus subtypes most often isolated from oral papillomas, HPV-6 and HPV-11, are not among those associated with malignancy or precancer. Moreover, while all HPV lesions are infective, the squamous papilloma appears to have an extremely low virulence and infectivity rate; it does not seem to be contagious.
It is important to recognize that the squamous papilloma of the mouth behaves differently from those of the nasal, paranasal and laryngeal regions. While the others are clinically and microscopically identical to their oral counterparts, they have a much higher recurrence rate, are almost always multiple and will often proliferate continuously over time. Laryngeal papillomas may, in fact, be so relentlessly proliferative that they cause life-threatening asphyxiation, and some worry about malignant transformation in long-standing cases.
Having said that, it is also important to remember that, in rare circumstances, an innocuous oral squamous papilloma may herald the serious precancer proliferative verruciform leukoplakia. Papillomas of the head and neck region with special histopathologic features, such as cuboidal papilloma and schneiderian papilloma, have their own biological behaviors, but are not discussed in this section because they do not occur in the mouth.
Verruca vulgaris, condyloma acuminatum, verruciform xanthoma and some of the oral masses of Heck's disease and multiple hamartoma syndrome may be clinically indistinguishable from squamous papilloma, as may multilobulated soft tissue lesions with a mulberry appearance, such as giant cell fibroma, pyogenic granuloma without surface ulceration, and papillary hyperplasia. In addition, extensive coalescing papillary lesions (papillomatosis) of the oral mucosa may be seen in several dermatological disorders, including nevus unius lateris (ichthyosis hystrix), acanthosis nigricans, tuberous sclerosis and focal dermal hypoplasia (Goltz-Gorlin) syndrome.
Because the squamous papilloma may be clinically and microscopically indistinguishable from verruca vulgaris, the virus-induced focal papillary hyperplasia of the epidermis, it is briefly discussed in this section. The associated viruses in verruca are the subtypes HPV-2, HPV-4 and HPV-40. Verruca vulgaris is contagious and capable of spread to other parts of an affected person's skin or membranes by way of autoinoculation. It is uncommon on oral mucous membranes but extremely common on the skin.
Epidemiologic studies have demonstrated that the squamous papilloma of the mouth and oropharynx occurs at all ages of life but is usually diagnosed in persons 30-50 years of age. There is no gender predilection and any oral surface may be affected, although lesions are usually found on lingual, labial or buccal mucosa.
The typical lesion is a soft, pedunculated mass with numerous finger-like surface projections (papilla = "nipple-shaped projection") (Figures 1 & 2). Projections may be pointed and the surface may be covered with a considerable amount of keratin, producing a white surface change. The heavily keratinized lesion with short rounded projections is cauliflower-like, while a similar but less keratinized lesion resembles a raspberry or mulberry with a pink or red coloration (Figure 3).
Verruca vulgaris of the oral mucosa is typically a childhood problem, but occasional lesions may arise even into middle age. The skin of the hands is the site of predilection, but when oral mucosa is involved the lesion is usually found on the vermilion border, labial mucosa, or anterior tongue. The typical lesion may be identical to a squamous papilloma, but it tends to have pointed or verruciform surface projections, to have a very narrow stalk, to be white from considerable surface keratin , and to present as multiple or clustered individual lesions (Figure 4). As with the papilloma, the verruca vulgaris enlarges rapidly to its maximum size, seldom achieving more than 5 mm. in greatest diameter.
Pathology and Differential Diagnosis
The squamous papilloma typically has a narrow stalk below a mass with numerous blunted and pointed surface projects, often characterized as finger-like (Figures 5 & 6). Submucosal fibrovascular connective tissues are contiguous with the stroma of the stalk, the body of the mass and the surface projections. Scattered chronic inflammatory cells in small numbers are common in the stroma, presumably from chronic low-grade trauma to the lesion. The surface keratin is often quite thickened, usually with parakeratin. The covering squamous epithelium shows a normal maturation pattern, although occasional papillomas demonstrate pronounced basilar hyperplasia and mild mitotic activity which could be mistaken for mild epithelial dysplasia. Koilocytes ( HPV-altered epithelial cells with perinuclear clear spaces and nuclear pyknosis) may or may not be found in the superficial layers of the epithelium (Figure 7) and occasional lesions have focal areas covered by mixed bacterial colonies, perhaps with mild, irregular destruction of the otherwise smooth surface of the keratin beneath the colonies.
The verruca vulgaris is also characterized by a proliferation of hyperkeratotic stratified squamous epithelium arranged into finger-like or pointed projections, each with its connective tissue core. It differs from papilloma in that elongated rete ridges tend to converge toward the center of the lesion, producing a "cupping" effect (Figure 8). Also, a prominent granular cell layer (hypergranulosis) exhibiting coarse, clumped keratohyaline granules is typically found and abundant koilocytes are often seen in the superficial spinous layer. Eosinophilic intranuclear viral inclusions are sometimes noted within the cells of the granular layer, a feature never found in the squamous papilloma.
The pathologist must be mindful of the occasional similarity between a sessile papilloma and the other oral verruciform lesions, most of which are described in this section. The squamous papilloma differs from the oral condyloma acuminatum in that its surface projections are typically more elongated and more often pointed. It will usually have considerably more keratin on its surface and is much less likely to contain koilocytes in large numbers. The condyloma, moreover, is seldom pedunculated with a stalk, as is typical of the papilloma. Both lesions may show active basal layer cells, but true epithelial dysplasia in only found in the condyloma.
The subepithelial connective tissue, in particular, must be evaluated for the presence of foamy histiocytes or granular cells, which may be the only distinguishing feature between a papilloma and a verruciform xanthoma or a focal pseudoepitheliomatous hyperplasia above a granular cell tumor. Relative to the latter change, an additional difference is that the rete ridges of the papilloma do not extend below the level of the ridges of adjacent epithelium, while the ridges in pseudoepitheliomatous hyperplasia typically extend deeply into underlying stroma.
Treatment And Prognosis
Conservative surgical excision including the base of the lesion is adequate treatment for squamous papilloma, and recurrence is unlikely. Frequently, lesions have been left untreated for years with no reported transformation into malignancy, continuous enlargement or dissemination to other parts of the oral cavity. It should be emphasized that squamous papillomas of the larynx behave differently from their oral counterparts. Laryngeal lesions tend to recur more often after therapy and have a greater tendency to be multiple and continuously proliferative.
Skin and intraoral verruca vulgaris is also
treated effectively by conservative surgical excision or curettage, but liquid
nitrogen cryotherapy and topical application of keratinolytic agents (usually
containing salicylic acid and lactic acid) are also
effective. All destructive or surgical treatments should
extend to include the base of the lesion. Recurrence is seen in a small
proportion of treated cases. Lesions do not transform into malignancy, and
2/3 will disappear spontaneously within two years, especially those in children.
Table 1: Gender-specific prevalence rates per 1,000 population for selected oral masses and surface alterations in U.S. adults, ranked by total frequency. Modified from Bouquot JE. Common oral lesions found during a mass screening examination. J Am Dent Assoc 1986; 112:50-57, and Bouquot JE, Gundlach KKH. Oral exophytic lesions in 23,616 white Americans over 35 years of age. Oral Surg Oral Med Oral Pathol 1986; 62:284-291.
* total examined population = 23,616 adults over 35 years of age
References (Chronologic Order)
Note: For general references click on link to the left.
Abbey LM, Page DG, Sawyer DR. The clinical and histopathologic features of a series of 464 oral squamous cell papillomas. Oral Surg Oral Med Oral Pathol 1980; 49:419-424.
Batsakis JG, Raymond AK, Rice DH. The pathology of head & neck tumors: papillomas of the upper aerodigestive tract, part 18. Head Neck Surg 1983; 5:332-344.
Adler-Storthz K, Newland JR, Tessin BA, et al. Identification of human papillomavirus types in oral verruca vulgaris. J Oral Pathol 1986; 15: 230-233.
Green TL, Eversole LR, Leider AS. Oral and labial verruca vulgaris: clinical, histological, and immunohistochemical evaluation. Oral Surg Oral Med Oral Pathol 1986; 62: 410-416.
Eversole LR, Laipis PJ, Green TL. Human papillomavirus type 2 DNA in oral and labial verruca vulgaris. J Cutan Pathol 1987; 14: 319-325.
Miller CS, White DK, Royse DD. In situ hybridization analysis of human papillomavirus in orofacial lesions using a consensus biotinylated probe. Am J Dermatopath 1993; 15: 256-259.
Premoli-de-Percoco G, et al. Detection of human papillomavirus-related oral verruca vulgaris among Venezuelans. J Oral Pathol Med 1993; 22:113-116.
Ward KA, Napier SS, Winter PC, et al. Detection of human papilloma-virus DNA-sequences in oral squamous-cell papillomas by the polymerase chain-reaction. Oral Surg Oral Med Oral Pathol 1995; 80:63-66.
Bouquot JE, Wrobleski GJ. Papillary (pebbled) masses of the oral mucosa, so much more than simple papillomas. Pract Perio Aesth Dent 1996; 8:533-543.
Sakakura A, Yamamoto Y, Takasaki T, et al. Recurrent laryngeal papillomatosis developing into laryngeal carcinoma with human papilloma-virus (HPV) Type-18. A case report. J Laryngol Otol 1996; 110:75-77.
Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia. Oral Surg Oral Med Oral Pathol 1996; 82:396-401.
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