Pathogenesis

This neoplasm originates within the mandible or maxilla from epithelium involved in the formation of teeth. Less commonly, the ameloblastoma may arise at a soft tissue location within the gingiva of tooth-bearing areas. Potential epithelial sources include the enamel organ, odontogenic rests (rests of Malassez, rests of Serres), reduced enamel epithelium, and the epithelial lining of odontogenic cysts, especially dentigerous cysts. The trigger or stimulus for neoplastic transformation of these epithelial residues is unknown.

Mechanisms by which ameloblastomas gain a growth and invasion advantage include those associated with tumorigenesis and differentiation as well as other molecules related to tumor progression. These include but are not limited to overexpression of tumor necrosis factor (TNF)-α, antiapoptotic proteins (Bcl-2, Bcl-x_L), and interface proteins (fibroblast growth factor [FGF], matrix metalloproteinases [MMPs]) (Figure 11-1 and Box 11-2). Ameloblastomas, however, have a low proliferation rate, as shown by staining for the cell cycle–related protein, Ki-67. Suggestions that dysregulation of the sonic hedgehog (SHH) pathway may play a role in the development of ameloblastoma have been put forth, although it must be emphasized that the overall significance of this is unclear. Mutations of the p53 gene do not appear to play a role in the development and growth of ameloblastoma; a role for ameloblastin protein has been identified, although it is not specific to ameloblastoma.

Clinical Features

Ameloblastoma is chiefly a lesion of adults. It occurs predominantly in the fourth and fifth decades of life, and the age range is very broad, extending from childhood to late adulthood (mean age, approximately 40 years) (Box 11-3). The rare lesions occurring in children are usually cystic and appear clinically as odontogenic cysts. There appears to be no gender predilection for this tumor.

Ameloblastomas may occur anywhere in the mandible or maxilla, although the mandibular molar-ramus area is the most common site. In the maxilla, the molar area is more commonly affected than the premolar and anterior regions. Lesions usually are asymptomatic and are discovered during routine radiographic examination or because of asymptomatic jaw expansion (Figures 11-2 and 11-3). Occasionally, tooth movement or malocclusion may be the initial presenting sign.

Radiographically, ameloblastomas are osteolytic, typically found in the tooth-bearing areas of the jaws, and they may be unicystic or multicystic (Figures 11-4 to 11-7). Because ameloblastomas are slow-growing, the radiographic margins usually are well defined and sclerotic. In cases in which connective tissue desmoplasia occurs in conjunction with tumor proliferation, ill-defined radiographic margins are typically seen. This variety, known as desmoplastic ameloblastoma, also has a predilection for the anterior jaws and radiographically may resemble a fibro-osseous lesion. The generally slow tumor growth rate may be responsible for the movement of tooth roots. Root resorption occasionally occurs in association with ameloblastoma growth.

Biological Subtypes

Peripheral or extraosseous ameloblastomas may occur in the gingiva and very rarely in the buccal mucosa (Boxes 11-4 and 11-5; Figure 11-8). These lesions are seen in older adults, usually between 40 and 60 years of age. They may arise from overlying epithelium or rests of Serres. They exhibit a benign, nonaggressive course and generally do not invade underlying bone. Following local excision, recurrence is rare.

Cystic ameloblastoma (also referred to as unicystic ameloblastoma) accounts for approximately 6% of ameloblastomas. We prefer the term cystic ameloblastoma because these entities are often multilocular, show cortical perforation in 25% of cases, and have a recurrence rate as high as 40% when treated by curettage (as late as 9 years following surgery) (Box 11-6; Figures 11-9 and 11-10). They are seen in a younger age group (mean age, ≈35 years) than solid tumors. The microscopy is deceptive because the lesions are nearly completely cystic and can be confused with a simple odontogenic cyst (Figures 11-11 and 11-12).

Malignant variants of ameloblastomas may rarely be encountered. These lesions occur in a relatively young age group (thirties) and appear in the mandible more commonly than in the maxilla. By definition, these are lesions that metastasize to local lymph nodes or distant organs. Direct extension into contiguous areas does not qualify for a malignant designation. Malignant lesions have been divided into two subtypes: malignant ameloblastoma (Figure 11-13), in which primary and metastatic lesions are microscopically well differentiated with the characteristic histologic features of ameloblastoma, and ameloblastic carcinoma (Figure 11-14), in which the lesions (primary and/or metastatic) exhibit less microscopic differentiation, showing cytologic atypia and mitotic figures. Malignant variants of ameloblastomas are difficult to control locally. Metastases may appear, usually in the lung, as a result of aspiration of tumor cells or by hematogenous spread after multiple unsuccessful attempts at primary tumor control. Regional lymph nodes are the second most common metastatic site, followed by the skull, liver, spleen, kidney, and skin.

The primary intraosseous carcinoma is an epithelial odontogenic malignancy of the mandible and maxilla that is believed to arise from odontogenic rests. This lesion does not have histologic features of ameloblastoma and is regarded as a primary jaw carcinoma. It does not arise from a preexisting odontogenic cyst. This rare lesion of adults affects men more than women, and it is seen in the mandible more than the maxilla. Microscopically, about half of these lesions exhibit keratin formation, and about half show peripheral palisading of epithelial cell nests. This lesion must be differentiated microscopically from acanthomatous ameloblastoma and squamous odontogenic tumor. The prognosis is poor, with a 2-year survival rate reported at 40%.

Another ameloblastoma that might be considered a subtype has been designated as sinonasal ameloblastoma. Mean age of 61 years and male dominance have been noted. Signs of nasal obstruction, epistaxis, and opacification are seen. The “totipotential” sinonasal lining cells are the putative cells of origin. A plexiform microscopic pattern is most commonly seen.

Histopathology

The numerous histologic patterns described for ameloblastoma are of no clinical relevance (Box 11-7). Some may exhibit a single histologic subtype, and others may display several histologic patterns within the same lesion. Common to all subtypes is the palisading of columnar cells around epithelial nests in a pattern similar to that of ameloblasts of the enamel organ. Central to these cells are loosely arranged cells that mimic the stellate reticulum of the enamel organ (Figure 11-15). Another typical feature is the budding of tumor cells from neoplastic foci in a pattern reminiscent of tooth development.

The microscopic subtype most commonly seen in solid ameloblastoma is the follicular type (Figure 11-16). It is composed of islands of tumor cells that mimic the normal dental follicle. Central cystic degeneration of follicular islands leads to a microcystic pattern (Figure 11-17). Neoplastic cells occasionally develop into a network of epithelium, prompting the term plexiform ameloblastoma (Figure 11-18). When the stroma is desmoplastic and the tumor islands become squamous appearing (squamoid) or elongated, the term desmoplastic ameloblastoma is used (Figure 11-19). Some tumors are microscopically similar to basal cell carcinoma and are called basal cell or basaloid ameloblastomas. A type of solid ameloblastoma in which the central neoplastic cells exhibit prominent cytoplasmic granularity (and swelling) is known as granular cell ameloblastoma (Figure 11-20). Clear tumor cells and cells expressing ghost cell–type keratinization have also been seen in ameloblastomas. Separation of ameloblastomas into the various microscopic groups described is essentially an academic exercise, because there appears to be no correlation between clinical behavior and these microscopic patterns.

Cystic ameloblastoma is a type of ameloblastoma that is primarily cystic in appearance; it is formed by a thin epithelial layer containing columnar basal cells with palisaded nuclei showing hyperchromasia and vacuolar change. Epithelial invagination into supporting connective tissue often occurs, and occasionally, mural islands may be seen. A characteristic spongiotic change is seen in the epithelial lining, and often subepithelial hyalinization represents odontogenic ectomesenchyme induction. Some lesions have an intraluminal component, usually in a plexiform pattern. Diagnosis is often retrospective after enucleation for what was thought to be an odontogenic cyst.

Differential Diagnosis

When age, location, and radiographic features are considered together, the clinical differential diagnosis generally can be limited to several entities in the three categories of jaw disease: odontogenic tumors, cysts, and benign nonodontogenic lesions. Among odontogenic tumors, the radiolucent form of the calcifying epithelial odontogenic tumor and odontogenic myxomas are prime considerations. The dentigerous cyst and the odontogenic keratocyst can also be included. In relatively young individuals, lesions that are radiographically similar to ameloblastoma include nonodontogenic lesions such as central giant cell granuloma, ossifying fibroma, central hemangioma, and possibly idiopathic histiocytosis.

Treatment and Prognosis

No single standard type of therapy can be advocated for patients with ameloblastoma. Rather, each case should be judged on its own merits. Prime considerations are whether the lesion is solid, cystic, extraosseous, or malignant, and its location. Solid ameloblastoma requires at least surgical excision, because recurrence follows curettage in 50% to 90% of cases. Block excision or resection followed by immediate surgical reconstruction generally is reserved for larger lesions. Cystic ameloblastomas may be treated less aggressively, but with the knowledge that recurrences are often associated with simple curettage. For cystic ameloblastoma, treatment options can range from enucleation to resection, although recurrences are more likely if enucleated. Peripheral ameloblastomas should be treated in a more conservative fashion. Malignant lesions should be managed as carcinomas. Patients with all forms of central ameloblastoma should be followed indefinitely because recurrences may be seen as long as 10 to 20 years after primary therapy. Ameloblastomas of the maxilla generally are more difficult to manage than those of the mandible because of anatomic relationships, as well as the comparatively higher content of cancellous bone compared with the mandible. Thus, intraosseous maxillary ameloblastomas are often excised with a wider normal margin than mandibular tumors.

Radiotherapy has rarely been used in the treatment of ameloblastomas because it is generally believed that these tumors are radioresistant. Until more is known about tumor responsiveness, radiation should be reserved for exceptional cases that are difficult or impossible to control surgically.

Calcifying Epithelial Odontogenic Tumor (Pindborg Tumor)

Calcifying epithelial odontogenic tumor (CEOT), also known as Pindborg tumor after the oral pathologist who first described the entity, is a benign tumor of odontogenic origin that shares many clinical features with ameloblastoma (Box 11-8). Microscopically, however, there is no resemblance to ameloblastoma, and radiographically distinct differences will often be noted. The cells from which these tumors are derived are unknown, although dental lamina remnants and the stratum intermedium of the enamel organ have been s/>