Papillary Lesions of the Oral Cavity: Relationship to Human Papillomaviruses

Lewis Roy Eversole, DDS, MSD, MA

Human papillomaviruses are a group of genetically related organisms that infect stratified squamous epithelium. Unlike many other viruses that infect oral epithelium and induce lysis of the cells they penetrate, HPVs induce proliferative changes in these cells that result in both benign and malignant tumors. The common skin wart (verruca vulgaris) is induced by HPV 2 and 4. Genital warts (condylomas) and the common solitary oral papilloma are associated with HPV 6 and 11. Either HPV 13 or 32 causes focal epithelial hyperplasia. All of these wart-like lesions are benign growths of the stratified squamous lining of the oral cavity and lips and can be treated by surgical excision or laser ablation. HPV 16 and other less frequently encountered genotypes are associated with uterine cervix cancer in 95 percent to 98 percent of cases, and the evidence for a causal role is robust. There are emerging data that implicate HPV in certain subsets of oral cancer, particularly those that arise in the oropharynx/tonsillar region. Some instances of the various histologic subtypes subsumed under proliferative verrucous leukoplakia and verrucous carcinoma also harbor HPV.

Dental practitioners often discover mucosal nodules during the course of an oral soft tissue examination, and these common lesions are usually traumatic fibromas. When found on the lower lip however, they may also be mucous extravasatioin phenomena (mucoceles). Occasionally, mucosal nodules will exhibit a bosselated or cauliflower surface texture; or, indeed, some may have finger-like projections. These papillary or verrucous-type lesions are usually associated with and caused by members of the human papillomaviruses. There are more than 120 genetically different, yet closely related HPVs that are referred to as genotypes.¹ The genotypes are numbered in order of their initial discovery (i.e., HPV 1 was the first human papillomavirus to be discovered; HPV 118 is one of the more recent genotypes to be isolated from human tissues). The various genotypes have specificity for certain human cell types and cause distinct types of lesions. Table 1 lists the more common HPVs that cause lesions of the head and neck. Most oral and labial papillary lesions are HPV-associated and are self-limited benign growths that do not progress to cancer.

The so-called mucosatropic oncogenic HPVs have a tropism (affinity) for the stratified squamous epithelium of mucous membranes and are associated with carcinomatous transformation. The association between HPV 16, 18, 31, 33, 35 and a few others with squamous cell carcinoma of the uterine cervix is extremely high.^1,2 HPV DNA can be detected in nearly 95 percent of cervical squamous cancers. Oral cancer is also found to harbor HPV genomes, yet the association is not as frequently detected as it is in the cervix, even though both mucous membranes are lined by the same type of epithelium. This article will briefly discuss the molecular basis for HPV-induced epithelial proliferation and detail the clinical features of HPV oral lesions.

HPV Effects on Oral Epithelia

The HPVs are small when compared with the large herpes group viruses that commonly infect the oral cavity (see the article in this issue by Birek). HPV is a DNA virus about 8,000 nucleotide bases long. Its genome is divided into two major gene groups: E, or early region genes, and L, or late region genes.³ These genes are also known as open reading frames, and they encode proteins with important biological activity. The early region gene products are proteins that are important for viral replication and also have affects on host cell gene expression, whereas the late region genes encode the proteins that make up the structural components of the virus, particularly its capsid. It is the early genomic region that has the greatest significance for viral-induced changes in the host cells.

HPV must adhere to a specific receptor protein on the keratinocytes membrane in order to be assimilated into the cell by a process known as endocytosis (Figure 1). Once the virus has gained entry into the cell, it divests itself of its protein coat, and the viral DNA may then utilize host cell DNA building blocks to replicate themselves. These clever viruses elaborate early gene proteins that are able to regulate the host cell cycle, or mitotic capabilities. The E6 and E7 proteins are most important in this respect; they bind two host proteins that are regulators of the keratinocytes’ cell division cycle.⁴ E6 binds to a protein designated p53, a molecule that arrests cell division; however, once bound, it is degraded, and this inhibition of keratinocyte mitosis is abrogated. Likewise, E7 binds a protein termed Rb; and, similarly, cell cycle regulation is perturbed.

The hallmark of malignancy is uncontrolled cell division and changes in the surface chemistry of cancer cells that allow for invasion and metastasis. It is axiomatic that certain HPV early region proteins are able to place the cell in a state of perpetual mitosis, thereby being candidates for inducing malignant change. Benign HPV growths, caused by genotypes that do not induce malignancy, must also affect cell cycling in order to induce epithelial proliferation, yet these growths somehow remain limited in extent and the cells lack the properties of invasion and metastasis. In this regard, experimental evidence has shown that HPV 11 can cause warty growths when inoculated onto normal mucosal epithelium.

Benign Papillary Growths

The three papillomavirus-induced warts that arise on the lips and in the oral cavity are verruca vulgaris, squamous papilloma, and condyloma acuminatum. The genotypes associated with these three lesions are designated in Table 1. All are benign proliferations of keratinocytes that show minor histologic differences. In addition to these three lesions, there are numerous other papillary growths of the oral cavity for which a viral etiology has not been discovered. Denture-induced papillary hyperplasia, verruciform xanthoma, and a variety of other diffuse papillary lesions that are associated with particular syndromes do not appear to be HPV-related (Table 2).

Verruca vulgaris (Figure 2): The common skin wart may be seen in the oral cavity but is far more likely to be found on the lower lip where is appears as a symmetrical round-to-oval nodule with a crusted hyperkeratotic center.⁵ Histologically, it is verrucous with marked hyperkeratosis and is entirely exophytic with abrupt margins. HPV DNA can be readily detected using in situ hybridization techniques.

Squamous papilloma (Figure 3): This is the most common epithelial neoplasm in the mouth and is typically seen on the lingual frenum, lips, palate, and buccal mucosa.⁶ The lesion has fine finger-like projections resembling a sea anemone or it may show a more cauliflower configuration. Papillomas can be pedunculated, on a stalk, or have a wide sessile base. Papillomas range from coral pink to white, depending upon the degree of keratinization. Histologically, the exophytic papillary growths are supported by fine connective tissue cores

Condyloma acuminatum (Figure 4): Venereal warts, known as condylomas, occur in the genital region and can be transmitted to the oral mucosa. The lesions are rarely solitary; rather, they are multiple and confluent and generally quite bigger than squamous papillomas.⁷ They are sessile and may be pink or white. Whereas most condylomas are thought to be transmitted through genito-oral contact, oral-oral transmission is also feasible. Microscopically, condylomas are papillary with a thickened parakeratin layer; and they differ from ordinary papillomas in that they are sessile and show marked thickening of the spinous cell layer (acanthosis). Many also show HPV-specific cytologic changes. The infected upper spinous layer cells have irregularly shaped nuclei with a perinuclear clear halo and are termed koilocytes.

Papillary hyperplasia (Figure 5): Also known as papillomatosis, papillary hyperplasia is a reactive inflammatory proliferation that underlies maxillary dentures. Negative pressure is probably the chief factor that contributes to the lesion confined to the denture-bearing region of the hard palate. The diffuse pebbly surface is either of normal coral pink coloration or may be inflamed and red. Histologically, mushroom-like polyps composed of a fibrous core with hyperplasia of the overlying epithelium are observed.

Verruciform xanthoma (Figure 6): Papillary lesions that contain lipid-laden foamy histiocytes in the submucosa are referred to as verruciform xanthomas.⁸ Clinically, they are broad-based sessile lesions with a papillary, pebbly surface and are often slightly erythematous. They tend to occur on the gingiva and palate, yet may be seen in any oral location. Xanthelasma of the eyelids, a lesion of hyperlipidemia, is closely related in terms of the histologic features, yet verruciform xanthomas have not been correlated with high blood cholesterol or lipid levels. Histologically, the lesions are papillary with a prominently eosinophilic thickened parakeratin layer. The submucosal papillae that extend up between the papillary epithelial projections are infiltrated with foam cell histiocytes.

Syndrome-associated papillary lesions: As shown in Table 2, there are a number of rare syndromes in which extensive and diffuse papillary lesions may be seen in the oral cavity.⁹ In Cowden syndrome, the gingival tissues are diffusely papillary, yielding a cobblestone street pattern. Patients with Cowden syndrome also manifest thyroid tumors, skin nodules, and other abnormalities. Nevus unius lateris is a skin lesion that may occur anywhere on the body. When in the facial region, it may progress into the oral cavity. The skin lesions are verrucous and keratotic, being oriented in a linear streak. Orally extended lesions may cover the lips and involve the buccal mucosa or gingiva, assuming a pink diffuse papillary appearance.¹⁰ Acanthosis nigricans is a pigmented papillary lesion of the lips and mucosa that is often hereditary.¹¹ One form is a harbinger of gastrointestinal tract cancer. The lesions diffusely involve the upper and lower lips; and because the basal cell layer contains excess melanin pigment, the lesions have a mottled gray or brown coloration.

Precancerous and Cancerous HPV-Associated Lesions

As mentioned earlier, HPV likely causes uterine cervix cancer. Recent research has confirmed that some oral precancerous and cancerous lesions contain HPV DNA, and the same mechanisms involving binding of p53 by HPV E6 may contribute to carcinogenesis of oral malignant disease. The oral lesions that are malignant or potentially malignant for which HPV has been identified include proliferative verrucous leukoplakia, verrucous carcinoma, papillary squamous cell carcinoma, and invasive poorly differentiated squamous cell carcinomas arising in the tonsillar/base of tongue region.

Proliferative verrucous leukoplakia is a unique type of leukoplakia that tends to occur in elderly females, less than 40 percent of whom have used tobacco.¹² The lesions are usually located on the buccal gingiva and extend into the vestibule (Figure 7). They are white, diffuse and have a rough warty or verrucous appearing surface. Following surgical excision, these leukoplakias have a marked tendency to recur and spread laterally along the mucosal surface. PVL is a clinical term under which a variety of histologic stages of disease can be observed. In the early stages, the histologic picture is that of a verrucous hyperkeratosis that may become progressively more keratotic and acanthotic; it is then termed atypical verrucous hyperplasia. After many years, these lesions can progress to verrucous carcinoma, papillary squamous cell carcinoma, or invasive carcinoma. HPV DNA has been identified in many of these lesions and may be a significant carcinogenic factor, although a passenger virus status cannot, at this time, be eliminated.¹³

Verrucous carcinoma usually evolves from a pre-existing verrucous leukoplakia and has a characteristic histologic appearance, although oftentimes the pathologist encounters lesions that are midway between a verrucous hyperkeratosis and verrucous carcinoma. Clinically the lesions are diffuse, involving the gingiva, alveolar ridge, palate, and sulcus. They are rough, white, and warty in appearance (Figure 8). The term carcinoma is misplaced here since verrucous carcinomas do not have metastatic potential. In previous articles, instances of metastasis have been reported, yet some of these cases may have represented the recently described papillary variant of squamous cell carcinoma.¹⁴ Regardless, these relentless lesions are locally aggressive and have the potential to involve large surface areas of the oral cavity. HPV DNA is often detected in these tumors.¹⁵ Microscopically, they show a verrucous surface with parakeratinized crypts that involute into enlarged rete-ridge extensions. Actual invasion is not present.

Squamous cell carcinoma is an invasive cancer that can metastasize to regional lymph nodes and distant sites via hematogenous routes. The malignancy arises from stratified squamous epithelium, and while these tumors may occur anywhere in the oral cavity, the lateral tongue and floor of mouth are predilected sites. HPV DNA can be detected in many, yet not all oral carcinomas. About 30 percent will harbor HPV, and most of these are HPV 16. Recently, a group of reports have been published linking the majority of squamous cell cancers to HPV 16 when the lesions are localized to the tonsillar pillar/base of tongue region.^16,17 Tumors in this location are generally poorly differentiated. When HPV 16 is detected, p53 is not usually mutated thereby implicating an E6 mediated p53 degradation mechanism.

Summary

The human papillomaviruses are unique viral forms capable of inducing cell proliferation, particularly in keratinocytes. The benign lesions assume a papillary or verrucous appearance and specific genotypes are responsible for the clinicopathologic variations seen in papillary lesions. HPV 2 and 4 cause the common verruca vulgaris, whereas HPV 6 and 11 are involved in squamous papillomas and condylomas. HPV 13 and 32 are associated with the transient rare mucosal disease, focal epithelial hyperplasia. Premalignant lesions of the oral cavity, particularly proliferative verrucous leukoplakia, can harbor HPV DNA, and the more aggressive verrucous carcinoma has also been shown to be associated with the virus. Recently, the majority of tonsillar region squamous cancers have been found to be associated with HPV 16, a genotype that elaborates any early gene product that degrades p53, a key tumor suppressor gene. Once degraded, the mitotic cycle continues unchecked thereby placing the affected cell in a state of increased proliferative activity. How HPV affects cell motility, invasiveness, and metastatic potential is not yet understood.

Author

Lewis Roy Eversole, DDS, MSD, MA, is a professor in the Department of Pathology and Medicine at the University of the Pacific School of Dentistry.

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To request a printed copy of this article, please contact/Lewis Roy Eversole, DDS, MSD, MA, UOP School of Dentistry, 2115 Webster St., San Francisco, CA 94115 or at Leversol@SF.UOP.EDU

Legends

Figure 1. Mechanisms of HPV-associated carcinogenesis. HPV E6 binds to p53 and degrades it, or p53 is mutated and nonfunctional thereby leading the cell into uncontrolled mitosis.

Figure 2. Verruca vulgaris of the lip.

Figure 3. Papilloma on the lingual frenum.

Figure 4. Multiple papillary lesions represent condylomas.

Figure 5. Papillary hyperplasia of the palate.

Figure 6. Verruciform xanthoma.

Figure 7. Proliferative verrucous leukoplakia.

Figure 8. Verrucous carcinoma.

Table 1. Human Papillomaviruses and Head and Neck Lesions

Table 2. Papillary Oral Lesions Without Known Viral Association

Papillary hyperplasia (Papillomatosis)
Verruciform xanthoma
Cowden syndrome
Nevus unius lateris
Acanthosis nigricans