Oral Cavity and Oropharynx
Rebecca D. Chernock
James S. Lewis Jr.
I. NORMAL ANATOMY
A. Oral cavity. The anterior aspect of the oral cavity extends from the mucocutaneous junction (vermilion border) of the lips to include the buccal mucosa (inside of cheek), maxillary and mandibular arches (teeth), retromolar trigone, anterior two-thirds of the tongue (oral tongue), floor of mouth, and hard palate. Posteriorly, the oral cavity freely communicates with the oropharynx; the border between the two is marked by the junction of the hard and the soft palate superiorly and the line of circumvallate papillae on the dorsal tongue (border between the anterior two-thirds and posterior one-third of the tongue) inferiorly.
1. The oral tongue is freely mobile and composed mainly of skeletal muscle. It has a dorsal (exposed) surface, ventral surface, and tip. The dorsal surface contains numerous papillae that have specialized taste receptors. The floor of the mouth lies beneath the tongue and is divided into sides by the midline frenulum (mucosal fold) of the tongue. It contains ostia of the submandibular and sublingual salivary glands, whereas the main duct of the parotid gland (Stensen’s duct) enters the oral cavity through the buccal mucosa. The hard palate forms the roof of the oral cavity and consists of portions of the maxillary and palatine bones.
2. The oral cavity is lined by stratified squamous mucosa with prominent mucoserous glands in the submucosa. Most of the mucosa is nonkeratinizing with the exception of the hard palate, gingiva, and dorsal tongue, which become keratinized due to the friction of mastication.
B. Oropharynx. The oropharynx is the space posterior to the oral cavity that communicates with the nasopharynx superiorly and the larynx and hypopharynx inferiorly. The soft palate (posterior one-third of the palate) marks the superior aspect of the oropharynx and is suspended from the posterior aspect of the hard palate. In contrast to the hard palate, the soft palate is fibromuscular without a bony skeleton. Whereas the oral aspect is covered with nonkeratinizing stratified squamous epithelium, the nasal surface is covered by pseudostratified ciliated columnar (respiratory-type) epithelium. Numerous mucoserous glands lie in its submucosa. The uvula extends down from the posterior aspect of the soft palate and has an identical histology. The posterior one-third of the tongue is rich in lymphoid tissue (known as the lingual tonsil). The palatine and lingual tonsils, together with the pharyngeal tonsil in the nasopharynx, are collectively known as Waldeyer’s ring.
II. GROSS EXAMINATION, TISSUE SAMPLING, AND HISTOLOGIC SLIDE PREPARATION
A. Open and endoscopic biopsies. The majority of specimens from the oral cavity and oropharynx consist of open biopsies of lesions that can be visualized by the naked eye. The small biopsy pieces should be placed immediately into 10% buffered formalin or other appropriate fixative. Processing of the biopsies should include gross description of the tissue fragments with documentation of the number of pieces present; the biopsies should be entirely submitted, with three levels cut from each paraffin block for hematoxylin and eosin (H&E) examination.
1. Open procedure specimens are widely variable depending on the location of the tumor. Because many lesions encroach upon or invade the bone of the mandible or maxilla, composite resections with bone and soft tissue are common. As a generalization, all specimens need to be oriented appropriately, the soft tissue margins inked, and mucosal and soft tissue margins evaluated followed by sectioning of the tumor relative to cartilage/bone and tissue margins. Margins should be evaluated by either shave or radial sections, depending on the nature of the specimen. If the tumor is relatively distant from a margin, 1- to 2-mm shave sections are preferred. If the tumor grossly approximates a margin to <1 to 2 mm, radial sections should be taken.
2. Partial resections with a CO2 laser under an operating microscope are becoming more common. Because the inherent approach of this procedure is to excise the tumor piece by piece, the surgeon inks the individual pieces as he/she alone knows what constitutes the true margin. In the gross room all that is therefore required is to measure the pieces provided, describe them, and submit them entirely in sections perpendicular to the ink. If there is an additional orienting marker such as a suture, then one should submit the sections sequentially from that end to the opposite end.
C. Frozen sections are a critical element of surgical therapy for tumors of the head and neck region. Although practices vary, at most institutions shave margins are taken by the surgeon from the periphery of the surgical defect after the tumor has been removed, and separately submitted. In other cases, the surgeon may sample the tumor or suspicious sites to confirm and/or map the lesion, with additional samples from areas where the tumor is felt to be closest to the surgical margin.
For frozen sections, the tissue is submitted in saline to the pathology lab and then frozen in its entirety. The tissue pieces should be evaluated grossly for mucosa (typically the shiny and pink-tan surface of the tissue) and, if mucosa is present, the specimen should be oriented in the frozen section block to demonstrate this surface on edge. It is critical to cut deeply into the block to obtain sections that represent the entire tissue submitted so that small foci of tumor are not missed by inadequate sampling. At our institution, we cut three rather than two H&E frozen section slides to reduce these sampling errors.
The tissue that remains after frozen section is submitted for evaluation by permanent sections, which helps assure adequate sampling. Permanent sections can help resolve a number of issues from frozen section including freezing and cautery artifact, volume of tumor, and orientation (note that the margins of the main resection specimen should also be evaluated throughout their entirety because the separate frozen section specimens almost never cover the entire margins of a resection specimen). The final margin status is then a conglomerate of three sources: frozen section slides, permanent slides of the frozen tissue, and the tissues not submitted for frozen section, and the margins of the main specimen.
III. DIAGNOSTIC FEATURES OF COMMON BENIGN DISEASES
A. Inflammation. Lichen planus, pemphigus vulgaris, and cicatricial pemphigoid are autoimmune disorders that predominately affect middle-aged adults and occur
more frequently in women than men. They are diseases that affect mucosal sites as well as skin, so the oral cavity is sometimes involved as well.
1. Lichen planus. This disorder commonly affects the oral mucosa. Whereas skin involvement is usually self-limited, oral lichen planus follows a more protracted waxing and waning course. The oral lesions are typically asymptomatic unless ulceration occurs.
Any oral mucosal surface may be involved, and several patterns can be seen. The classic pattern is reticular with intersecting white keratotic streaks (Wickham’s striae); the lesions are ill-defined, and the background may be erythematous due to mucosal atrophy. Some lesions may be mostly erythematous with minimal keratotic streaks, whereas others may show extensive keratinization and/or ulceration or form bullae. Microscopically, a dense submucosal band of lymphocytes is present, which may be less distinct in ulcerated lesions (e-Fig. 1.1).* The rete ridges may be hyperplastic (saw-toothed) or flattened. There is loosening of the basal layer of the epithelium, with degeneration of individual keratinocytes that may form eosinophilic colloid (dyskeratotic, cytoid, or Civatte) bodies (e-Fig. 1.2). The surface may show hyperor parakeratosis. Although the histologic findings of lichen planus have been well defined, they are nonetheless not specific; for example, some oral lesions with a similar histologic picture may be due to a contact hypersensitivity reaction. In addition, a lichenoid infiltrate may accompany dysplastic lesions.
Asymptomatic patients require no treatment, but steroids (particularly topical) are often used for erosive or erythematous lesions. Some data suggest that there is an increased risk of malignant transformation in the erythematous, ulcerative, and bullous forms of oral lichen planus. Although this proposed risk of malignancy is controversial, these lesions at least require closer clinical follow-up.
2. Pemphigus vulgaris. This is an uncommon disorder that causes superficial ulceration of the skin and mucous membranes. Involvement of the oral mucosa may precede the development of skin lesions. The disease is caused by autoantibodies to desmogleins 1 and 3, cellular transmembrane proteins involved in the assembly of desmosomes. Cell-to-cell adhesion is impaired in the suprabasal epithelium, leading to clefting and ulceration. Flaccid bullae that easily rupture to form painful erosions can be seen on any oral mucosal surface. The lesions heal without scarring. Microscopically, intraepithelial separation with edema and acantholysis, which imparts a “tombstone” appearance to the remaining attached basal cell layer (e-Fig. 1.3), is seen at the edge of the ulcer. Acute and chronic inflammation are frequently present in the submucosa. Direct immunofluorescence is positive for immunoglobulin G (IgG) along cell membranes throughout the epidermis.
Paraneoplastic pemphigus, which is associated with an underlying malignancy, may be distinguished from pemphigus vulgaris by the identification of a different pattern of antibody staining by direct immunofluorescence.
3. Cicatricial or mucous membrane pemphigoid. This is a rare disease caused by various antibodies that target the basement membrane of mucous membranes and occasionally the skin. The oral mucosa is almost always involved, most commonly the gingiva. In contrast to pemphigus vulgaris, the variably sized bullae are not flaccid, and ruptured bullae heal with scarring. Microscopically, there is clefting between the epithelium and the basement membrane, and the space may be filled with serous fluid containing sparse inflammatory cells. Direct immunofluorescence shows a linear band of IgG and C3 on the
basement membrane. Treatment is with immunosuppression, but the disease is often progressive despite therapy.
B. Infections. Only a few of the numerous infections that may involve the oral cavity are discussed here.
1. Fungal. Candida species cause most of the fungal infections of the oral cavity. Other fungal infections that occur less frequently in the oral cavity include histoplasmosis, blastomycosis, and coccidiomycosis. Candida species are a part of the normal oral flora; candidiasis occurs due to overgrowth, usually in the setting of a predisposing factor, and Candida albicans is the most frequently isolated species. Local and systemic factors that favor overgrowth include immunosuppression, use of steroids or antibiotics, radiation therapy, xerostomia, use of dentures, and anemia. The extremes of age are more often affected as well, and infection may be acute or chronic. Symptoms include a burning sensation or foul odor, although the infection may be asymptomatic.
Several clinical patterns of oral candidiasis are seen. White plaques that are easily scraped off underlying erythematous mucosa are called pseudomembranous candidiasis (oral thrush). This is the most common type of oral candidiasis. Erythematous candidiasis appears as a red patch due to atrophy of the mucosa. Median rhomboid glossitis is a type of erythematous candidiasis that occurs in a specific location, namely a rhomboid-shaped area on the midline dorsal tongue, which over time may develop a nodular appearance. Angular cheilitis causes red fissuring and scaling at the labial commissures; predisposing factors include drooling and ill-fitting dentures. Chronic hyperplastic candidiasis presents as asymptomatic, white patches (due to the thickened, hyperplastic mucosa) that cannot be removed by scraping. This pattern is more common in immunocompetent individuals and may predispose to the development of carcinoma, although a causal relationship between the two has not been clearly demonstrated.
Microscopically, an intraepithelial infiltrate of neutrophils is seen in all types of candidal infection. The epithelium may be ulcerated, although in chronic hyperplastic candidiasis it is thickened and hyperkeratotic (e-Fig. 1.4). Fungal pseudohyphae may be difficult to identify on routine H&E-stained slides. However, methenamine silver or periodic acid-Schiff (PAS) stains will highlight the fungal elements within the keratin and in the superficial squamous epithelium (e-Fig. 1.4, inset A).
2. Viral. Oral viral infections are highly prevalent, although frequently asymptomatic.
a. Human papillomavirus (HPV) does not cause specific clinically symptomatic infection but is associated with several benign and malignant neoplasms in the oral cavity and oropharynx including squamous papillomas and squamous cell carcinoma (SCC) (see respective sections to follow).
b. Herpes simplex virus (HSV) causes a common oral viral infection with seroprevalence rates of up to 80% of the population. There are two common serotypes (HSV-1 and HSV-2), and HSV-1 is primarily associated with oral lesions. Gingivostomatitis occurs in 10% of initial infections, predominately in children, and is characterized by fever and a vesicular rash. The virus then latently infects sensory ganglia and may be reactivated periodically throughout life. Recurrent disease is manifested by clusters of vesicles that may cause a burning sensation at the mucocutaneous junction of the lip or the nose. Intraoral lesions can also occur.
Microscopically, the lesional mucosa is often ulcerated and acantholytic, with marked acute and chronic inflammation. There are typically individual necrotic squamous cells. Identification of the classic intranuclear eosinophilic inclusions within squamous epithelial cells is diagnostic of herpes virus infection; the inclusion-harboring cells are often single,
detached, and multinucleated with molding of the nuclei to each other (e-Fig. 1.5). Immunohistochemical stains may be useful to confirm the diagnosis.
c. Epstein-Barr virus (EBV). Acute EBV infection, although frequently asymptomatic, may cause pharyngitis and tonsillitis. The virus enters the host through oral epithelial cells, where it then gains access to and infects B lymphocytes. Acute EBV infection may produce reactive changes in the tonsils and lymph nodes that can mimic a hematopoietic malignancy.
Latent EBV infection is virtually universal in adults and is usually asymptomatic. However, an EBV-driven proliferation of tongue epithelial cells, known as oral hairy leukoplakia, occurs in immunosuppressed patients, approximately 80% of whom are HIV positive. The lesions are asymptomatic unless superinfection with Candida occurs. Grossly, hairy leukoplakia appears as a flat, white, shaggy plaque on the lateral tongue. Microscopically, the epithelium is acanthotic with hyper- and parakeratosis. Perinuclear clearing forming “balloon cells” is characteristic (e-Fig. 1.6), and viral replication may cause “nuclear beading” (e-Fig. 1.7). Inflammation is typically sparse. Definitive diagnosis relies on detection of EBV within the lesion by immunohistochemistry or in situ hybridization (e-Fig. 1.8). Oral hairy leukoplakia is self-limited with no propensity for malignant transformation.
3. Bacterial. Cervicofacial actinomycosis (“lumpy jaw”). Actinomyces are gram positive, saprophytic anaerobes that are part of the normal oral flora. The organisms are often incidentally found in sections of the tonsillar crypts. Occasionally, they are introduced into the soft tissues through trauma, particularly from dental manipulations, where an acute or chronic infection may ensue. Actinomyces israeli is the most common pathogenic species.
Acute infections are suppurative, creating a nontender fluctuant mass. In the chronic phase, infections may form a more extensive firm fibrous mass mimicking a neoplasm. Sinus tracts may exit either the skin or mucosa (e-Fig. 1.9) and often discharge yellow clusters of tightly adherent Actinomyces bacteria that have the appearance of sulfur granules. Osteomyelitis may develop in adjacent bone. Microscopically, collections of radiating, filamentous organisms are seen in a background of neutrophils with surrounding granulation tissue and/or fibrosis. Cultures are often negative due to overgrowth of other organisms. Treatment with prolonged antibiotics is usually successful, although incision and drainage may be necessary.
C. Other non-neoplastic lesions
1. Fibrous lesions. A number of different types of fibrous lesions occur in and around the oral cavity.
a. Irritation fibroma. These are the most common oral mucosal mass lesions. They are painless reactive proliferations of fibrous tissue that develop in response to trauma from teeth or dentures. The lateral tongue and buccal mucosa along the bite line are the most common sites. Multiple fibromas may be seen in inherited syndromes including Cowden’ syndrome and tuberous sclerosis. Linear, grooved fibromas occurring in the mucosa opposing the teeth or sulcus of the alveolar ridge are called epulis fissuratum and are denture-related.
Grossly, irritation fibroma is usually pink to white, dome-shaped, and only a few millimeters in maximal diameter. Microscopically, there is a nodular deposition of dense collagen with associated chronic inflammation and overlying thinned mucosa (e-Fig. 1.10). Trauma-related changes
such as hyperkeratosis and ulceration may be seen. The fibroblasts are spindled and indistinct. If larger, stellate fibroblasts are present, the lesion is called a giant cell fibroma, which, in contrast to irritation fibromas, is not associated with trauma and occurs at a younger age (e-Fig. 1.11). Whereas typical irritation fibromas do not recur after simple resection, giant cell fibromas may recur.
b. Gingival fibromatosis. This is generalized, but not necessarily symmetrical, enlargement of the gingiva which may be hereditary, drug-induced, related to poor oral hygiene, or idiopathic. When it is drug-induced, it is called fibrous gingival hyperplasia and frequently regresses with cessation of the inciting drug. Grossly, the gums are enlarged, smooth-surfaced, and firm. Microscopically, the submucosa shows dense eosinophilic to slightly basophilic fibrous tissue with associated mild chronic inflammation (e-Fig. 1.12). The surface squamous epithelium may have chronic inflammation or extreme elongation of the rete, but is otherwise unremarkable.
2. Inflammatory papillary hyperplasia is a denture-associated lesion and is typically located beneath a denture base in the hard palate and alveolar ridges. Occasionally, it is seen in patients without dentures and may be associated with poor oral hygiene.
Clinically, the mucosa looks “pebbly” with numerous, small, papular projections. Microscopically, the mucosa may be atrophic or demonstrate pseudoepitheliomatous hyperplasia. The underlying submucosa may vary from edematous to fibrotic, with mild chronic inflammation. Individual nodules may resemble an irritation fibroma or pyogenic granuloma. The condition is not premalignant, may subside with less denture wear, or may require surgical excision.
3. Torus palatinus, torus mandibularis, and buccal exostosis are common developmental anomalies that continue to grow throughout life and typically present in adulthood. They are site-specific. Torus palatinus occurs in the midline of the hard palate, torus mandibularis occurs on the lingual surface of the mandible near the bicuspid teeth, and buccal exostosis is found on the facial surface of the alveolar bone. Any identical appearing bony proliferations at other oral sites are generically termed “bony exostosis” or “osteoma” and are not developmental, but rather trauma-related or true neoplasms that can be associated with Gardner syndrome.
Grossly, these lesions are broad-based, single, or lobulated masses with smooth surfaces (e-Fig. 1.13). Microscopically, they are composed of dense lamellar bone with scattered osteocytes and variable amounts of marrow. Ischemic changes with marrow fibrosis and loss of osteocytes from lacunae may be seen. Resection is not necessary except for cosmetic reasons or if the lesions become large. There is little risk of recurrence, and the lesions have no malignant potential.
4. Fordyce granules. Sebaceous glands are normally found in the skin associated with hair follicles. When they are ectopically present in the oral mucosa, they are called Fordyce granules. They are common (present in up to 80% of adults) and can occur on any oral mucosal surface, although the buccal mucosa is most common. Most appear as scattered, 1 to 3 mm, white to yellow papules. Microscopically, normal sebaceous glands are present in the submucosa without associated hair follicles; occasionally, Fordyce granules coalesce to form the larger cauliflower-like lesion termed sebaceous hyperplasia. No treatment is necessary unless for cosmetic reasons (biopsies are rarely performed as the diagnosis is usually clinically apparent).
5. Cysts. Included here are several of the more common soft tissue true cysts that have an epithelial lining. Odontogenic cysts, bone cysts, and salivary
gland-derived pseudocysts (lacking a true epithelial lining) are discussed in Chapter 4.
a. Epidermoid cyst. Intraoral epidermoid cysts are much less common than their counterparts in the skin and are thought to represent inclusions of surface epithelium or cystic change in odontogenic rests. They often present in teenagers and young adults. The most common site is the gingiva. Clinically, they are small (<1 cm) superficial nodules. When they occur in the midline floor of mouth, however, they can become much larger (>5 cm) and interfere with swallowing. Microscopically, they are lined by thin stratified squamous epithelium, with or without a granular cell layer, and are often filled with keratinous debris. Rupture with spillage of keratinous debris may elicit a granulomatous inflammatory reaction. Treatment is by simple surgical excision.
b. Dermoid cysts. These are similar to epidermoid cysts but contain adnexal structures, such as sebaceous glands or hair follicles, in the cyst wall. If other tissue types are present, the lesion is termed teratoid cyst.
c. Nasolabial cysts. These rare cysts occur at the base of the nostril or at the superior aspect of the upper lip. They are thought to be derived from remnants of the embryonic nasolacrimal duct. Seventy-five percent of cases occur in women. More than 10% are bilateral. They present as slow growing masses, usually <1.5 cm, and they may have irregular contours. Soft tissue swelling with loss of the nasolabial fold or elevation of the nasal ala or floor may occasionally cause nasal obstruction. Pressure erosion of underlying bone is possible.
Microscopically, the cysts may be lined by respiratory type, cuboidal, and/or stratified squamous epithelium with scattered mucus-filled goblet cells, with surrounding chronic inflammation. A fibrous or epithelial connection to the nasal mucosa is almost always present. Simple surgical excision is curative.
d. Lymphoepithelial cysts. These cysts are thought to develop from invaginations of crypt epithelium within accessory tonsillar tissue. Clinically, they are painless submucosal nodules that are almost always <6 mm in diameter and typically occur in teenagers or young adults. Half of cases occur in the floor of the mouth. The lateral and ventral tongue, as well as the soft palate, are also common sites. They do not occur in the alveolar soft tissue.
Microscopically, the cyst lining is an attenuated squamous epithelium with a poorly formed granular layer. The cyst is filled with orthokeratin and surrounded tightly by lymphoid aggregates with variable numbers of germinal centers. The cysts may become dissociated from the epithelium or remain connected, often with keratin plugging. Microscopically, the prominent lymphoid aggregates distinguish this cyst from an epidermoid cyst. Similar appearing cysts can be seen within the tonsils themselves from blockage of the crypt connection with the surface.
6. Pseudoepitheliomatous hyperplasia is a generic term for benign, downward proliferation of the epithelium that is important to distinguish from invasive, well-differentiated SCC. Pseudoepitheliomatous hyperplasia is characteristically seen in association with specific lesions including inflammatory papillary hyperplasia, submucosal granular cell tumors, and fungal infections. It can also be seen adjacent to ulcers or be seen associated with myriad other lesions. Microscopically, irregular and pseudoinfiltrative nests of keratinizing squamous epithelium are sometimes seen beneath a markedly thickened surface epithelium. The papillae of the squamous epithelium may be markedly elongated and extend deeply into the submucosa (e-Fig. 1.14). However, in contrast to squamous dysplasia and carcinoma, cytologic atypia is absent.
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