Tumors of the Oral Cavity

Squamous Cell Papilloma and Related Lesions

Histologic Appearances

In a typical squamous cell papilloma the epithelium is of fairly uniform thickness, with variable keratinization or hyperkeratosis, and is formed into sharp papillary or frondlike processes ( Fig. 6.1 ) each with a core of loose vascular connective tissue. There is marked basal cell hyperplasia, and increased mitotic activity is often present. This may be accentuated if there is infection by Candida albicans in the superficial layers of the epithelium. Some oral lesions, often on the lips, show typical histologic appearances of verruca vulgaris, with inward curving rete pegs and more prominent koilocytic change. Condyloma acuminatum is also reported in the mouth but cannot be diagnosed with certainty on histologic grounds. Where a discrete papillary exophytic growth shows acanthosis instead of relatively uniform folds of epithelium and the papillary processes are flattened or smoothly rounded, condyloma acuminatum should be suspected.

Focal Epithelial Hyperplasia

Focal epithelial hyperplasia (also called Heck disease) is caused by HPV 13 and 32, and presents as multiple, sessile elevated nodules. Histologically there is fibrous overgrowth covered by irregularly hyperplastic epithelium. Koilocytes and fragmented nuclear material, described as mitosoid bodies ( Fig. 6.2 ), are typically present in the stratum spinosum and upper epithelial layers.

Squamous Cell Carcinoma

Over 90% of the malignancies in the upper aerodigestive tract are squamous cell carcinomas arising from the epithelium of the mucosal lining. Although common, the diagnosis and management can still be challenging due to the subjective nature of diagnosis and grading, and the number of variants, each with different diagnostic criteria, site predilection, and prognosis. In particular it is now apparent that oral cancer encompasses a number of lesions that should be regarded as separate entities on the basis of site, pathogenesis, prognosis, and management. Squamous cell carcinoma of the oral cavity (mouth) should be regarded as a different disease to squamous cell carcinoma arising in the oropharynx. This is based primarily on the etiology, in that oral lesions are associated with the traditional factors of tobacco and alcohol use, whereas oropharyngeal cancer is associated with infection by high-risk HPV (HPV 16 and 18). These differences justify a division of oral cancer into oral cancer and oropharyngeal cancer and these are considered separately in this chapter.

Variants of Squamous Cell Carcinoma

A number of variants are described and their relevance is that they are thought to have differing prognoses. Some tumors are comprised entirely of the variant type, but in many instances lesions show a mixture of conventional squamous cell carcinoma and other patterns. In these cases it is probably best to describe the mixed patterns and advise that the behavior is likely to be determined by the most aggressive variant present.

Spindle Cell Carcinoma.

Spindle cell squamous carcinoma is a pleomorphic spindle cell neoplasm most frequently found in the head and neck. Spindle cell tumors of all kinds are uncommon in the mouth, but the full spectrum of soft tissue sarcomas (see Chapter 24 ) can occur. In any such case, spindle cell carcinoma should always be included in the differential diagnosis. In the larynx, spindle cell carcinomas are often polypoid, but in the oral cavity they are similar to conventional carcinomas and present as ulers or red lesions. A wide range of histologic appearances is seen in these tumors ( Figs. 6.3 and 6.4 ). Immunohistochemical demonstration of cytokeratin in tumor cells strongly supports the diagnosis, but overall only about 60% of cases may be positive. Variable results are obtained with different cytokeratin antibodies but positivity is most frequently demonstrated with a broad specrum pan-cytokeratin such as AE1/3. Markers of squamous epithelium such as p63 or p40 may also be useful. For a definitve diagnosis, especially if immunohistochemistry for cytokeratins is negative, it is wise to search carefully for areas of conventional squamous cell carcinoma or severe epithelial dysplasia, usually at the growing edge of the tumor, before making the diagnosis of spindle cell carcinoma, although mucosal ulceration may preclude this.

Squamous Cell Carcinoma With Glandular Features.

There are two variants of oral cancer that may exhibit glandular features. Adenoid squamous cell carcinoma describes cases of conventional squamous cell carcinoma in which loss of intercellular adhesion in the center of tumor islands resembles glandular differentiation ( Fig. 6.5 ). These are poor-prognosis tumors. Adenosquamous carcinomas also have a poor prognosis. In these lesions there is involvement of minor salivary gland ducts, concurrently with tumor arising from the surface mucosa. The tumor shows separate discrete areas of adenocarcinoma and of squamous cell carcinoma arising from the surface epithelium ( Figs. 6.6 and 6.7 ). The main differential diagnosis is from mucoepidermoid carcinoma, but this is usually cystic and shows an admixtutre of epidermoid and mucus-producing cells. A small number of otherwise conventional squamous cell carcinomas may show a few mucus-secreting cells and demonstration of these, in the absence of ductal differentiation ( Fig. 6.8 ), is not sufficient for a diagnosis of adenosquamous carcinoma. It is also important to recognize correctly the potentially confusing presence of invasion by squamous cell carcinoma into salivary gland ( Fig. 6.9 ).

Basaloid Squamous Cell Carcinoma.

This is an uncommon variant of squamous cell carcinoma (see Chapter 4 ) that is distinct from carcinomas with basaloid morphology associated with HPV infection, which are more often encountered in the oropharynx and may have a better prognosis (see later in this chapter). The term basaloid squamous cell carcinoma should therefore only be used for an aggressive basaloid variant of squamous cell carcinoma, which is HPV (and p16) negative, and should not be confused with HPV-associated oropharyngeal lesions. Basaloid squamous cell carcinoma is characterized by a squamous component as well as areas composed of well-demarcated nests of basaloid cells arranged in a jigsaw pattern. There is peripheral palisading, prominent mitotic activity, and comedo necrosis is common ( Fig. 6.10 ) . These lesions are typically aggressive with early lymph node metastasis . They are most often seen in the posterior aspect or base of the tongue and must be distinguished from other basaloid lesions, including HPV-associated carcinomas, solid adenoid cystic carcinoma, or salivary duct carcinoma.

Verrucous Carcinoma.

This term was first coined for exophytic, massively acanthotic lesions showing minimal cytologic atypia which may not, on strict histologic grounds, be diagnosed as carcinoma. Subsequently the term has been often misused and applied erroneously to conventional squamous cell carcinomas which happen to have an exophytic verruciform surface pattern. True verrucous carcinomas have a better prognosis than conventional squamous cell carcinoma.

Clinical Features.

Verrucous carcinomas are exophytic, keratinized growths with a white papillary or warty surface. They are mainly seen in the elderly and are associated with tobacco use. They may have surface dimensions of several centimeters, but show superficial spreading growth rather than invasion into deeper tissues.

Histologic Appearances.

There is marked acanthosis, with broad bulbous rete pegs showing central columns of keratin ( Fig. 6.11 ). Although exophytic, with columns of keratin rising above the adjacent mucosal surface, there must also be an endophytic component. The bulbous rete processes push deep into the lamina propria so that the base of the lesion is below the adjacent basement membrane. There is little cytologic evidence of malignancy, but the architectural changes are marked and there may be some dyskeratosis with deep single cell keratinization and eosinophilic glasslike cytoplasm. Pronounced chronic inflammatory cell infiltration is often present in the lamina propria ( Fig. 6.12 ). The diagnosis of verrucous carcinoma should only be made after clinicopathologic correlation. An unusual lesion which may be a variant of verrucous carcinoma is carcinoma cuniculatum , which arises most often on the gingivae and is composed of ribbonlike folds of well-differentiated keratinized squamous epithelium that pushes or burrows into the underlying connective tissues. Although there may be wide local destruction, the lesions have a good prognosis, with few reports of metastases.

Differential Diagnosis.

The main differential diagnosis is from conventional squamous cell carcinoma and other verruciform or papillary lesions. Many oral cancers may have an exophytic verruciform surface but also show cytologic features of malignancy and invasion. The term verrucous carcinoma , although used by some authors for such lesions, is inappropriate. Some tumors have areas of verrucous carcinoma and areas of conventional squamous cell carcinoma and it is important that the latter be sought for before the diagnosis of verrucous carcinoma is made. Occasionally papillomas or viral warts may be extensive and have similar clinical and histologic appearances. However, these lesions are exophytic and often pedunculated and rise above the surface of the mucosa, while verrucous carcinoma is endophtyic. Verrucous hyperplasia and proliferative verrucous leukoplakia may appear similar but are also exophytic (see upcoming discussion).

Papillary Squamous Cell Carcinoma.

When applied to the oral cavity, this term has often been used for otherwise conventional squamous cell carcinomas with an exophytic papillary surface. True papillary carcinomas are rare in the mouth and are most frequently encountered in the larynx and hypopharynx. They are composed of exophytic papillary fronds of epithelium overlying a fibrovascular core. There is considerable cytologic atypia of the epithelium, but stromal invasion may not be prominent. Differential diagnosis is from verrucous carcinoma and squamous papilloma, but papillary carcinomas are often exophytic and pedunculated and show obvious epithelial dysplasia. Distinction from an exophytic conventional carcinoma is based on the lack of stromal invasion and the clearly defined papillary pattern of true papillary carcinoma. Recent studies have suggested that up to 66% of oral lesions may be infected with high-risk HPV.

Oropharyngeal Cancer

These lesions are associated with HPV infection and arise in those areas of the oropharyngeal mucosa where tonsillar tissue is found, primarily the palatine tonsils of the fauces and the tonsillar tissue at the base of the tongue. Between 50% and 80% of lesions at these sites harbor high-risk HPV (HPV 16 and 18). Oropharyngeal squamous cell carcinomas are characterized by being nonkeratinized with basaloid morphology. Previously this has been regarded as an indication that they are poorly differentiated, but this characteristic morphology actually represents well-differentiated tonsillar crypt epithelium. For this reason, HPV-associated carcinomas should not be graded using conventional grading schemes.

Oropharyngeal cancer is defined by the presence of high-risk HPV. These lesions contain E6 and E7 proteins, which degrade p53 and Rb, respectively, resulting in accumulation and overexpression of the tumor suppressor protein p16. The gold standard method for diagnosis is to demonstrate transcriptionally active HPV by PCR or by in situ hybridization ( Fig. 6.13 ). However these may not be widely available, and immunohistochemical expression of p16 protein is therefore an excellent surrogate marker for HPV infection and can be used in routine clinical practice as a diagnostic marker. Conventional squamous cell carcinomas of the oral cavity are not associated with HPV infection and are usually p16 negative by immunohistochemistry. However, p16 staining must be interpreted with caution and should only be used as a stand-alone surrogate marker for lesions in the oropharynx. Normal tonsillar crypt epithelium may express low levels of p16, and small numbers of conventional SCC may express p16 in the absence of any evidence of HPV infection. The criteria for positive p16 staining are that at least 70% of the cells should be diffusely positive in both the nucleus and cytoplasm ( Fig. 6.14 ).

Histologic Appearances

Most oropharyngeal carcinomas are composed of sheets of nonkeratinizing basaloid cells with poorly demarcated cell borders, prominent mitoses, and occasional areas of comedo necrosis (see Fig. 6.14A ). Epidermoid or squamous cells may be seen and may occasionally form keratin, but these usually comprise less than 10% of the lesion. Strong diffuse positivity for p16 is seen in virtually 100% of these lesions (see Fig. 6.14B ). About 10% of oropharyngeal carcinomas show more prominent keratinization, and have been termed hybrid lesions ( Fig. 6.15 ). Others may be keratinizing, with obvious squamous areas and keratin pearls. These lesions are not always associated with HPV and may represent conventional squamous cell carcinomas arising at this site.

It should be noted that the clinical significance of HPV infection is still uncertain. In oropharyngeal lesions there is good evidence that patients with HPV-positive lesions have a better response to treatment and an overall better prognosis. It has been suggested that treatment can be de-escalated, but initial clinical trials do not support this and there is still much important research to be undertaken.

Oral Premalignancy

Leukoplakia and erythroplakia are recognized clinically as the most important potentially malignant disorders. The main reason for biopsying such lesions is to exclude the possibility that a carcinoma is already present. Thereafter, the pathologist is asked to assess and grade any dysplasia present. This is on the assumption that dysplasia is an indicator of the potential likelihood of progression to malignancy. The rationale for this assumption is that dysplasia is associated with mutations involving the epithelium which may also be responsible for progression to malignancy. Microarray studies indicate substantial genomic change in dysplasia, suggesting that many of the changes are epiphenomena not directly related to malignant change. It is assumed that the more dysplastic an epithelium is, the more likely it is that the critical mutations linked to malignant transformation will be present. Thus more severely dysplastic lesions have a greater risk of progression. Overall, only a minority of lesions showing epithelial dysplasia progress to malignancy and carcinomas may also arise in epithelium not showing dysplasia.

The new World Health Organization (WHO) classification recognizes that problems exist with the subjective nature of the assessment of dysplasia and the variation in grading, not only between pathologists but also for the same pathologist examining the same material on different occasions. The recommendation made is that the epithelium should be assessed in terms of architectural and cytologic disturbances, and their presence and severity measured in thirds of the epithelium ( Table 6.1 ). If the architectural change is confined to the lower third of the epithelium, the dysplasia is mild ( Fig. 6.16 ). Extension into the middle third indicates moderate dysplasia ( Fig. 6.17 ) and involvement of the upper third indicates severe dysplasia ( Fig. 6.18 ). These preliminary judgments, based on the extent of architectural change, can be modified when consideration is given to the severity and extent of the cytologic or architectural features. In Fig. 6.19 the initial assessment of moderate dysplasia is upgraded to severe dysplasia on this basis. The term carcinoma in situ is sometimes used when dysplasia involves the full thickness of the epithelium, but in the oral cavity it is rare for there not to be at least some evidence of surface keratinization. For oral lesions therefore, carcinoma in situ is regarded as synonymous with severe dysplasia ( Fig. 6.20 ).

Occasional dysplastic oral lesions may be positive for high-risk HPV and are characterized by prominent atypia above the basal layers with marked karyorrhexis and apoptosis throughout the epithelium. By the criteria described, these show severe dysplasia and a subset may undergo malignant transformation.

In determining whether dysplasia is present, it is important to recognize that other situations may cause cytologic atypia that may mimic dysplasia. Infection by Candida albicans is a common cause, but other regenerative and reparative changes related to inflammation, ulceration, or irradiation may cause atypia. Nutritional deficiencies such as iron, folate, or vitamin B12 can also simulate dysplasia.

Proliferative verrucous leukoplakia is a particularly aggressive form of leukoplakia which starts as simple hyperkeratosis but pursues a relentless clinical course of verruciform lesions which progress to malignancy. The clinical features are critical in the diagnosis and emphasize the need for histopathologic interpretation to be made in the proper clinical context. Diagnosis is therefore retrospective, based on a history of multiple and recurrent lesions and increasingly aggressive behavior.

Hairy leukoplakia is the term used to describe a clinically distinctive hyperkeratosis, principally restricted to the lateral aspect of the tongue in HIV-positive patients and less frequently in other immunosuppressed individuals. It is caused by Epstein-Barr virus infection and does not show dysplasia, nor is there any evidence that it is premalignant.

Fibroepithelial Polyp

Fibrous overgrowths on the cheek or tongue are often pedunculated (fibroepithelial polyp) and consist of relatively acellular collagenous connective tissue covered by epithelium, which may be hyperplastic or atrophic but is usually hyperkeratotic ( Fig. 6.21 ). Enlarged, angular fibroblasts and occasional multinucleate fibroblasts are seen in some cases. The term giant cell fibroma has been used by some authors for such lesions, but this is inappropriate as there is no evidence that they are neoplasms.

Fibrous Epulis

Fibrous epulides are composed of cellular fibrous connective tissue which is often inflamed with an ulcerated surface ( Fig. 6.22 ). Calcification in the form of small, rounded, usually acellular foci or metaplastic bone formation is quite frequent. Such lesions are quite often inappropriately labeled peripheral ossifying fibroma since they can resemble a fibro-osseous lesion or ossifying fibroma, but the distinction from such bone lesions (see Chapter 25 ) is readily made by the clinically peripheral location of the epulis, which does not arise in bone.

Pyogenic Granuloma

Although the gingiva is the most common site for this lesion, they can occur as exuberant overgrowths at any intraoral site. Pyogenic granulomas on the gingiva (vascular epulis) are particularly common during puberty or pregnancy, when they may be quite exuberant, reaching 2 or 3 cm in size. The clinical differential diagnosis may include hemangiomas and angiosarcoma, as well as bacillary angiomatosis and Kaposi sarcoma (see Chapter 3 ).

Histologic Appearances

There is usually extensive ulceration of the surface epithelium, which accounts for a superficial zone of granulation tissue and infiltrates of mixed acute and chronic inflammatory cells. The bulk of the lesion consists of loose connective tissue containing lobules of proliferating capillaries ( Fig. 6.23 ), which may be mitotically active. Pyogenic granulomas arising on the gingivae may often contain calcifications or metaplastic bone.

Giant Cell Epulis (Synonym: Peripheral Giant Cell Granuloma)

Histologic Appearances

The main feature is nonencapsulated lobules of closely packed multinucleated giant cells lying in a vascular stroma. The giant cells are osteoclasts and are surrounded by plump mononuclear cells which are their monocyte precursors ( Fig. 6.24 ). Obvious mitotic activity is not uncommon in these cells.

Congenital Epulis (Synonym: Granular Cell Epulis)

The congenital epulis is a rare but distinctive oral lesion of unknown etiology found in the alveolus of neonates. Almost all affected patients are female. This lesion shows histologic similarities to granular cell tumor elsewhere but is S100-protein negative (see Chapter 27 ). Immunohistochemical studies have suggested primitive pericytic or myofibroblastic differentiation.

Denture-Induced Hyperplasia (Poor Synonyms: Denture Granuloma, Irritation Fibroma)

These overgrowths are usually found in the labial or buccal sulci related to the fitting edge of a denture. Less frequently they occur at the posterior edge of an upper denture in the palate. Leaf fibroma is a descriptive term sometimes used for a pedunculated flattened fibrous overgrowth which may occur in the palate, occupying space between a poorly fitting denture and the palatal mucosa. This term is inappropriate in that the lesion is not a neoplasm. Recurrence may be a problem following excision if the ill-fitting denture is not repaired or replaced.

Papillary Hyperplasia of the Palate

This occurs in the vault of the palate under a denture as a coarsely granular mass of soft tissue.

Histologic Appearances

Cores of moderately vascular connective tissue are covered by irregularly hyperplastic epithelium which may have a pseudoepitheliomatous appearance. At low power this can sometimes simulate invasion ( Fig. 6.25 ) with epithelial downgrowths and sometimes apparent keratin pearl formation. Higher power examination confirms the entirely benign cytologic features.