Because of the mouth’s location, its local relationship with other structures and role in embryogenesis, it can be involved by a number of heterotopic tissues or choristomas (Table 14.1). Heterotopic glial tissue, which most commonly involves the sinonasal area, can be present within the mouth, most often in the tongue (lingual glial choristoma).¹ As in the sinonasal area (Chapter 13), these lesions are composed of mature glial tissue, mostly astrocytes with some ganglion cells. It is unclear whether such tissue represents true heterotopia or, instead, a monodermic form of a mature teratoma. Regardless, the lesions do not recur following excision.

Lingual thyroid tissue can be present in the posterior dorsal region of the tongue at the foramen cecum, whence the normal thyroid migrates in utero.² Here, the thyroid tissue usually presents as a painless mass. Sometimes patients are hypothyroid, whereas larger masses cause obstruction. Histologically, lingual thyroids are composed of mature-appearing follicular thyroid tissue, intermixed to some degree with the skeletal muscle of the tongue (Fig. 14.1). Conventional thyroid neoplasia can develop in lingual thyroid tissue and should be excluded. Thyroglossal dust cysts are also found at this site and will present as painful nodules when infected. Histologically, they are lined by ciliated columnar or squamous-type epithelium with varying degrees of acute and chronic inflammation present (eFig. 14.1). Mature-appearing thyroid follicular tissue can be present but
is not always seen. As with lingual thyroid tissue, conventional thyroid neoplasia should be excluded.

Heterotopic gastrointestinal epithelium or enteric duplication cysts are found in the oral cavity, usually in the tongue or in the floor of the mouth. Most often these present as superficial or deep swellings within the tongue; there is, however, a report of child who would squirt others with a brown fluid from one of these lesions that connected to his tongue’s surface via a sinus tract.³ The cysts are lined by an enteric, glandular epithelium that is often intermixed with columnar, ciliated, and squamous epithelium (Fig. 14.2, eFig. 14.2).⁴ Fundic-type epithelium with parietal cells is frequently seen. We have seen rare duplication cysts here associated with enteric-type adenocarcinomas.

Ectopic sebaceous glands or Fordyce granules are found sometimes within the mouth.⁵ These lesions clinically appear as small, yellow papules, usually within the buccal mucosa (some consider the smaller buccal lesions to be normal). They vary considerably in number. Histologically, the
papules are composed of sebaceous glands located within or immediately beneath the surface epithelium (Fig. 14.3). When present below the epithelium, ductal connections to the surface are usually not seen. Some have suggested that the formation of these lesions is related to inherited defects of mismatch repair proteins (hereditary nonpolyposis colon cancer).⁶

Other possible choristomas include osteomas and chondromas of the mouth (discussed in Chapter 12). The vestigial organ of Chievitz found in the area of the retromolar trigone was discussed in Chapter 1. Mass-forming, apparent tonsillar tissue can be present throughout the mouth.

Other disparate congenital abnormalities afflict the mouth. These often present as mass lesions; however, some present secondary to disease to which the lesion has predisposed the patient (e.g., hemorrhage secondary to persistent caliber arteries and median rhomboid glossitis secondary to candidiasis). Awareness of these lesions and their clinical features helps pathologists to distinguish them from other disease processes.

Palatal and gingival cysts can frequently be seen in infants and clinically appear as small (approximately 1 mm) yellow-white cysts at the mid-palatal raphe at the junction of the hard and soft palate and along the alveolar ridge, respectively.⁷ Palatal cysts are composed of nests of epithelium surrounding keratin. Gingival cysts are similar; however, nests of odontogenic epithelium are frequently noted within the surrounding stroma.

Median rhomboid glossitis is believed by some to be a congenital lesion, the result of persistent tuberculum impar anterior to the foramen cecum.⁸ This theory, however, is debated and others believe it to be an atrophic change secondary to the relative decreased vascularity of the area, especially as the lesions are not noted in children.⁸ These are midline, rhomboid-shaped, flat, and erythematous areas of squamous epithelium anterior to the circumvallate papillae, devoid of papillae. Histologically, the lesions may or may not be keratotic and resemble pseudoepitheliomatous hyperplasia (Fig. 14.4, eFig. 14.3). Chronic inflammation is present to some degree in the surrounding stroma. This lesion is frequently associated with infection by Candida and some patients improve with antifungal therapy.⁹ In such cases, keratosis is typically seen and fungus can be identified by special stains (e.g., GMS or PAS staining) (eFig. 14.4).

Some arteries in the lower lip fail to reduce in size as they approach the surface near the vermillion border.¹⁰ These have been termed caliber persistent arteries. These arteries are sometimes associated with ulceration of the surface epithelium and can, when traumatized, bleed significantly. Rarely, they are associated with squamous cell carcinoma, perhaps secondary to the chronic ulcer.

Not uncommonly, the mouth is traumatized. Acute traumatic lesions are seldom sampled as their etiologies are rarely in question. Chronic traumatic lesions often have a nonspecific clinical appearance and may be sampled. The most common of these lesions is likely the traumatic
fibroma. These fibromas along with their numerous alternative designations are discussed in Chapter 11. Osseous and cartilaginous metaplasias, secondary to chronic trauma or inflammation are also discussed in Chapter 12.

Inflammatory papillary hyperplasia and fibrous hyperplasia are both believed to be secondary to chronic trauma.¹¹ Inflammatory papillary hyperplasia is associated with denture use and most often involves the hard palate. Some have suggested that infection with Candida may play a role in the development of this condition.¹² Clinically, patients present with numerous, red papillary or verrucoid lesions. Microscopically, numerous papillary growths are covered by thickened and parakeratotic squamous epithelium with some degree of pseudoepitheliomatous hyperplasia, often with the formation of small keratinous cysts (Fig. 14.5).¹¹ The stromal tissue is usually edematous and contains a lymphoplasmacellular infiltrate (eFig. 14.5). Calcification or even cartilaginous or osseous metaplasia can be present. The underlying seromucinous glands may be atrophic and fibrotic. Small mucoid pools can be seen, which, together with the pseudoepitheliomatous hyperplasia and keratinous cysts, can lead one to consider mucoepidermoid carcinoma in the differential diagnosis.

The diagnosis of fibrous hyperplasia is generally used to connote traumatic fibrous lesions of the mouth and is synonymous with oral fibroma. These lesions can show a vast range of reactive histologic changes. Aside from cartilaginous and osseous metaplasia, calcification, and cementum formation, discussed in Chapter 12, some lesions will have many multinucleated giant cells (peripheral giant cell granuloma). These are often quite numerous and resemble osteoclasts.¹³

Traumatic ulcerative granuloma is an uncommon lesion that can be clinically confused with malignancy. This lesion has acquired a number of appellations, mostly reflecting its presumed etiology and histology (e.g., eosinophilic ulcer, oral traumatic granuloma, ulcerative eosinophilic granuloma, and Riga-Fede disease).¹⁴,¹⁵,¹⁶,¹⁷,¹⁸ It develops rapidly in either sex and at any age and is believed to be secondary to trauma, particularly crush injury. Although the lesions frequently involve the lateral or dorsal portion of the tongue, they arise at all locations within the mouth.¹⁷,¹⁸ Most cases clinically present as ulcers; however, some are raised and exophytic.¹⁵

The surface of the traumatic ulcerative granulomas is typically covered by a fibrinopurulent exudate (Fig. 14.6).¹⁴,¹⁵,¹⁶,¹⁸ A dense mixed inflammatory infiltrate, rich in eosinophils, extends deep into the submucosa and is intermingled with skeletal muscle fibers (eFig. 14.6). Other inflammatory cells include lymphocytes, macrophages, and neutrophils. Occasionally larger, atypical mononuclear cells are present (Fig. 14.7). These large cells frequently react with antibodies to CD30, a feature suggesting these lesions are lymphoproliferative disorders (eFig. 14.7).¹⁹ Molecular studies have been mixed regarding clonality, with T-cell receptor rearrangement seen in some cases.²⁰,²¹ Nonetheless, the behavior of these lesions, when limited to the mucosa, is benign.

Because of their growth pattern and histologic features, traumatic eosinophilic granulomas must be distinguished from malignancies. Most often, anaplastic large cell lymphomas or Langerhan histiocytosis is considered in the differential diagnosis. Aside from the clinical presentations, these lesions can usually be distinguished by immunohistochemistry. The atypical mononuclear cells do not react with antibodies to S100 protein or
CD1a as would the neoplastic cells of Langerhan histiocytosis. They also do not react with antibodies to anaplastic lymphoma kinase (ALK1).

Gingival fibromatosis or hyperplasia can result from the use of certain drugs, including phenytoin, cyclosporine, and nifedipine, among others.²²,²³ These apparently reactive conditions form within a few months of therapy
with the inciting medication and may be related to individual patient’s dental hygiene. Clinically, the lesions begin with enlargement of the interdental papillae. These growths eventually become lobular and extend both labially and lingually. In advanced disease, teeth are often covered and displaced by the lesions. Histologically, the squamous epithelium is hyperplastic, with some degree of keratosis and elongated rete pegs. Fibroblasts proliferate within the underlying connective tissue and produce abundant collagen.

Patients who receive allogeneic bone marrow transplants, or, uncommonly, those who receive solid organ transplants or even blood transfusions, can develop graft-versus-host disease.²⁴ Acute graft-versus-host disease develops within days to weeks of bone marrow transplantation. Clinically, patients present with variable erythema that can progress to widespread blistering. The lesions progress histologically from focal basal cell vacuolar change to basal cell dyskeratosis to subepithelial cleft formation to the formation of bullae. A mononuclear perivascular infiltrate of variable degree is seen within the upper lamina propria and exocytosis is usually present, especially as the histologic changes worsen.

Chronic graft-versus-host disease develops in about half of adults and about 20% of children months to years after bone marrow transplantation.²⁴,²⁵,²⁶ Clinically, the lesions often appear similar to those of oral lichen planus with linear white stria or ulcers. Patients also typically are noted to have xerostomia. A lichenoid infiltrate of mononuclear cells is present with exocytosis, basal cell vacuolization, cell death, and, with worse cases, bullae (Fig. 14.8, eFig. 14.8). The seromucinous glands have prominent chronic inflammation, with degeneration and fibrosis. They are sometimes cystically dilated.

Other traumatic or iatrogenic lesions have also been reported. Some authors have shown that adipose tissue from the buccal pad can herniate into the mouth with trauma and erroneously be diagnosed as a lipoma (traumatic pseudolipoma).²⁷ Mucositis secondary to chemotherapy or radiation therapy is rarely biopsied and is instead usually diagnosed clinically.²⁸ It is associated with ulceration and nonspecific histologic features (see Chapter 4). Thermal injury of the mouth is common but rarely sampled. The histology is similar to that seen with burns of other squamous covered surfaces and depends on the burn’s severity. Necrosis of the epithelium and subepithelial tissue can be seen with the formation of subepithelial bullae.

The mouth can be involved by a great variety of infectious diseases, especially in patients who are for one reason or another immunocompromised. Infectious lesions may appear inflammatory or ulcerative. They can also mimic neoplastic masses or neoplastic intraepithelial proliferations (e.g., leukoplakia). Ancillary testing is usually helpful for identifying causative agents. The role of human papillomavirus in oral pathology has been discussed in chapters dealing with squamous neoplasia (Chapters 2,3,4-5).

Hairy leukoplakia secondary to infection by Epstein-Barr virus (EBV) most frequently occurs in immunocompromised individuals; however, it can occasionally develop in patients who appear to be immunocompetent.²⁹,³⁰,³¹ Clinically, these lesions are white, broad, and flat to slightly raised. The surface typically appears corrugated or “hairy.” While the lesions most often involve the lateral or ventral surfaces of the tongue, they can develop anywhere within the mouth. Unlike infections secondary only to Candida (i.e., thrush), abrasion will not dislodge the plaque material.³⁰

Histologically, the squamous epithelium is acanthotic with parakeratosis (eFig. 14.9).³⁰,³¹ Individual superficial squamous cells have optically clear cytoplasm with somewhat compressed, darkened nuclei (Fig. 14.9). Within these cells, the chromatin often appears marginated and intranuclear inclusions are commonly seen. The squamous epithelium is often not inflamed, and only mild chronic inflammation is present in the lamina propria. In situ hybridization for EBV-encoded RNA is helpful as the affected squamous epithelium will contain virus. Staining for fungal or bacterial organisms may demonstrate secondary colonization of the superficial epithelium.

Other herpes viruses can infect the oral mucosa including the herpes simplex viruses (HSV1 and HSV2) and varicella zoster, as well as cytomegalovirus.³² Infections associated with simplex viruses and varicella cause painful vesicles which eventually ulcerate. Primary infections with HSV-1 manifest as a gingivostomatitis. Most reactivations in immunocompetent patients are labial, although intraoral recurrences also develop. Immunocompromised patients can have severe intraoral disease either at
the time of primary infection or at the time of reactivation. The histology of these lesions is similar to that seen in other squamous epithelia. The mucosa will be eroded and ulcerated with a diffuse mixed inflammatory infiltrate. Telltale signs of herpes infection include single and multinucleated epithelial cells with Cowdry type A and B intranuclear inclusions (Fig. 14.10).³² Ductal cells of the minor salivary glands can also be infected. Immunohistochemistry with antibodies to specific types of herpes viruses will confirm the diagnosis, if needed. The large intranuclear and intracytoplasmic inclusions of cytomegalovirus are typically found within lesional endothelial cells, as this virus does not usually infect squamous epithelium (eFig. 14.10).³²

The oral cavity can be involved by all stages of syphilis.³³ Primary chancres measure between 1 and 2 cm and most often involve the lips, tongue, or gingiva. They may be painful due to secondary infection. The squamous epithelium will be eroded or atrophic, and an underlying dense lymphoplasmacytic infiltrate is commonly present. An obliterative endarteritis and neuritis is sometimes seen with occasional granulomas and foci of necrosis (eFigs. 14.11 and 14.12). Secondary syphilis develops 4 to 6 weeks after the primary lesion. Symptoms are nonspecific and include a fever with a generalized rash and lymphadenopathy. During this period, a white mucous patch or broad-based verrucal plaque (condyloma latum) can develop. Biopsy of these lesions will show epithelial hyperplasia and keratosis, again with a subepithelial lymphoplasmacytic infiltrate and possible concomitant vasculitis and neuritis (Figs. 14.11 and 14.12). With tertiary syphilis, nodular, ulcerative lesions or gumma sometimes develop
on the mucous membranes. Healing of glossal gummas can lead to an atrophic glossitis that is believed to be a risk factor for the development of squamous cell carcinoma.