Odontogenic Cysts and Tumors

Clinical Features

By definition, a dentigerous cyst occurs in association with an unerupted tooth. As logic would dictate, such cysts are most common around impacted teeth, especially mandibular third molars. Maxillary third molars and maxillary cuspids are also frequent sites. However, dentigerous cysts may occur in association with virtually any tooth, including supernumerary teeth and odontomas. Dentigerous cysts arising around unerupted deciduous teeth are distinctly rare.

Although they may occur at any age, dentigerous cysts are most commonly diagnosed in teenagers and young adults. There is a male predilection, and their prevalence appears to be higher in white patients than black patients. Most dentigerous cysts are small, asymptomatic lesions that are discovered on routine radiographs. Some dentigerous cysts may grow to considerable size and produce bony expansion that is usually painless, unless secondarily infected. However, any particularly large dentigerous radiolucency should raise clinical suspicion of a more aggressive odontogenic lesion, such as an odontogenic keratocyst or ameloblastoma.

Radiographically, the dentigerous cyst presents as a well-defined unilocular radiolucency, often with a sclerotic border ( Fig. 10.3 ). Because the epithelial lining is derived from the reduced enamel epithelium, this radiolucency typically surrounds just the crown of the tooth, with the crown projecting into the cyst lumen (central variety; Fig. 10.4 ). In the lateral variety, the cyst develops laterally along the tooth root and partially surrounds the crown. This variety is most commonly associated with mesioangular impacted mandibular third molars. In the circumferential variety, the cyst surrounds the crown but also extends down along the root surface, as if the tooth were erupting through the center of the cyst. Some dentigerous cysts may result in considerable displacement of the involved tooth. In addition, larger cysts can cause resorption of adjacent erupted teeth.

The radiographic distinction between an enlarged dental follicle and a small dentigerous cyst can be difficult and rather arbitrary. In general, any pericoronal radiolucency that is larger than 3 to 4 mm in diameter is suggestive of cyst formation. However, the radiographic appearance alone cannot be considered diagnostic for a dentigerous cyst because odontogenic keratocysts, ameloblastomas, and other odontogenic tumors can have an identical appearance. For this reason, biopsy is mandated for all significant pericoronal radiolucencies to confirm the diagnosis.

Pathologic Features

The microscopic appearance of the dentigerous cyst is variable, and clinical correlation is necessary to establish the diagnosis. If the cyst is not inflamed, it is usually lined with a thin, flattened layer of nonkeratinizing epithelium, without rete ridge formation ( Fig. 10.5A ). Because the wall of the cyst is derived from the dental follicle, it is characteristically composed of loose fibrous connective tissue that often contains scattered odontogenic epithelial rests. Sometimes these rests undergo dystrophic calcification.

If a dentigerous cyst becomes secondarily inflamed, the epithelial lining may become thicker and form rete ridges ( Fig. 10.5B ). The wall of an inflamed dentigerous cyst is often more densely collagenized.

Focal mucin-producing cells are often found in the epithelial lining ( Fig. 10.6 ). Although such mucous cells are usually an incidental finding, it has been hypothesized that they could be a source for the rare intraosseous mucoepidermoid carcinoma of the jaws. Rarely, ciliated epithelial cells will be found. Such findings are indicative of the multipotentiality of odontogenic epithelium.

Differential Diagnosis

The two most significant lesions to distinguish from a dentigerous cyst are the cystic ameloblastoma and the odontogenic keratocyst. In the cystic ameloblastoma, the basilar cells become columnar and demonstrate prominent nuclear hyperchromatism. The nuclei may demonstrate polarization away from the basement membrane (reverse polarization), and the superficial epithelial layers may become loosely arranged and resemble the stellate reticulum of the enamel organ. In the odontogenic keratocyst, the epithelium is uniform in nature, usually four to eight cells thick. The basilar layer consists of a palisaded row of cuboidal to columnar cells that may demonstrate hyperchromatism. Characteristically, a corrugated or wavy layer of parakeratin is produced on the epithelial surface and desquamated keratin may be found in the cyst lumen.

Some lesions submitted as dentigerous cysts are partially lined with a thin, fragmented layer of eosinophilic columnar cells that represents the postfunctional ameloblastic layer. It is probable that most of these lesions do not technically represent true cysts but just hyperplastic dental follicles. Although the lining cells in these cases may be columnar, they do not exhibit nuclear hyperchromatism or other features suggestive of ameloblastomatous transformation. In other instances, one may see follicle-like connective tissue that is only focally or partially lined with a thin, fragmented layer of squamoid epithelium. The pathologist is at a disadvantage in such cases because it is impossible to determine microscopically whether this epithelium-lined connective tissue was a true fluid-filled sac around the tooth or a normal or hyperplastic follicle. Clinical correlation in such cases is important; if the surgeon clinically describes a cystic lesion, then the diagnosis of dentigerous cyst can be supported. However, importantly in such cases, the pathologist can rule out the possibility of a more aggressive lesion, such as an ameloblastoma or odontogenic keratocyst.

Treatment and Prognosis

Most dentigerous cysts are treated by enucleation along with removal of the associated tooth. In situations where removal of an entire mandibular third molar might risk damage to the inferior alveolar nerve or bone fracture, coronectomy can be performed without removing the tooth roots. If it is important to save the tooth, it may be possible to remove only a portion of the cyst and then aid tooth eruption via orthodontic measures or marsupialization. Similarly, if the associated tooth has been displaced by the cyst and extraction may be difficult, orthodontic movement of the tooth to a more advantageous location for extraction may be accomplished. Particularly large dentigerous cysts can sometimes be treated by marsupialization (with a biopsy to confirm the diagnosis), which can allow shrinkage of the lesion before total removal.

The prognosis for dentigerous cysts is excellent, and the lesion almost never recurs. A rare complication is the development of an ameloblastoma from the cyst lining or from odontogenic epithelial rests within the cyst wall. Also, a squamous cell carcinoma may rarely arise from a dentigerous cyst lining. Many investigators believe that some intraosseous mucoepidermoid carcinomas arise from mucous cells in a dentigerous cyst. For these reasons, careful microscopic examination of all dentigerous cysts is necessary.

Clinical Features

The eruption cyst presents as a dome-shaped swelling of the alveolar mucosa overlying an erupting tooth. It characteristically is translucent with a bluish hue because of the collection of cystic fluid and hemorrhage within the follicular sac ( Fig. 10.7 ). Most cases occur in children younger than the age of 10 years. Although such lesions can develop over any erupting tooth, they are most often associated with primary incisors and first permanent molars. Multiple eruption cysts occasionally may occur.

Pathologic Features

Eruption cysts are rarely submitted for microscopic examination. Most such specimens consist of the excised roof of the lesion, which has been removed to allow tooth eruption. The surface of the specimen is covered by normal alveolar mucosa. The deep margin is lined with a thin layer of nonkeratinizing stratified squamous epithelium, which represents the roof of the cyst. A variable amount of inflammation may be present.

Treatment and Prognosis

Most eruption cysts do not require treatment because they usually rupture and allow the tooth to come into place. If tooth eruption appears to be impeded by the lesion, the cyst can be unroofed, which usually allows the tooth to erupt.

Clinical Features

The odontogenic keratocyst can occur anywhere within the jaws, and examples within the gingival soft tissues have even been reported. Approximately 65% to 75% of cases are seen in the mandible, with a predilection for the molar/ramus area. Frequently, the cyst occurs in association with an impacted tooth, thus clinically mimicking a dentigerous cyst. Odontogenic keratocysts may also clinically mimic other cysts of the jaws, such as the lateral periodontal cyst, periapical cyst, and nasopalatine duct cyst. Some examples of the so-called globulomaxillary cyst (which is no longer considered a true entity) will turn out to be odontogenic keratocysts when examined microscopically.

Odontogenic keratocyst can occur at any age, but approximately 60% of all cases are diagnosed between the ages of 10 and 40 years. In his series of 312 cysts, Brannon found a mean age of 37 years, 9 months. The peak prevalence was in the second and third decades of life, with only 15% of cases occurring past the age of 60 years. Woolgar and colleagues reviewed 682 odontogenic keratocysts from 522 patients and found a mean age of 40.4 years for patients with a single, nonrecurrent cyst and 26.2 years for patients with multiple cysts or the nevoid basal cell carcinoma syndrome. Although odontogenic keratocysts of the anterior midline maxillary region are uncommon, they usually occur in much older individuals, with a mean age of nearly 70 years. The reason for the surprising age difference in this particular subset of odontogenic keratocysts is unknown.

Smaller lesions are usually asymptomatic and often discovered only during routine radiographic examination. Larger cysts may result in clinical expansion and palpable thinning of the overlying cortical bone. Occasional odontogenic keratocysts cause pain or drainage, but even extremely large cysts may not exhibit any symptoms. On radiographic examination, a small odontogenic keratocyst usually presents as a well-circumscribed unilocular radiolucency that often demonstrates a corticated border ( Fig. 10.8A ). Larger cysts may appear multilocular, especially when arising in the mandibular molar/ramus region ( Fig. 10.8B ).

In the older literature, the term primordial cyst was used to describe a cyst that occurred in the place where a tooth should have developed ( Fig. 10.9 ). Presumably, the occurrence of such cysts was caused by degeneration of the enamel organ before the formation of any mineralized tooth structure. However, microscopic examination of such clinical lesions almost always reveals features of an odontogenic keratocyst. For a while, these two terms sometimes were used synonymously because odontogenic keratocysts are believed to arise from the dental lamina or dental primordium. However, the term odontogenic keratocyst is today the preferred designation for such lesions if they show the characteristic microscopic features described in the next section. It is uncertain whether there are any true examples of a clinical primordial cyst (i.e., a cyst occurring in the place of a tooth) that is not an odontogenic keratocyst; however, if such lesions do exist, they must be exceedingly rare.

Pathologic Features

On gross examination, the odontogenic keratocyst often demonstrates a thin, friable wall. The cyst lumen may be filled with clear fluid or a creamy to cheesy keratinaceous material. However, this keratinaceous material is not specific for the odontogenic keratocyst because other odontogenic cysts may be filled with similar semisolid keratin-like products.

The odontogenic keratocyst is lined with a uniform layer of stratified squamous epithelium that ranges from four to eight cells in thickness ( Fig. 10.10A ). This epithelium is usually devoid of rete ridges and sometimes may separate from the fibrous connective tissue wall. The basal layer consists of a palisaded row of cuboidal to columnar cells that are often hyperchromatic ( Fig. 10.10B ). Characteristically, a corrugated or wavy layer of parakeratin is produced on the luminal surface, and abundant desquamated keratin may be found in the cyst lumen. On occasion, focal areas of orthokeratinization may be seen in addition to the more typical parakeratinization.

The wall of the cyst often contains odontogenic epithelial rests and may demonstrate the formation of smaller satellite or “daughter” cysts. In rare instances, cartilage has been reported in the wall of odontogenic keratocysts.

Although the odontogenic keratocyst is developmental in origin, it may become secondarily inflamed. If this occurs, the inflamed portion of the lining epithelium will lose its characteristic features and may become irregular and proliferative with the formation of rete ridges ( Fig. 10.11 ). In such cases, the diagnosis depends on a thorough examination of the entire cyst with the identification of characteristic features in uninflamed and unaltered areas of the lining. In a diffusely inflamed, otherwise unremarkable, intrabony jaw cyst, even a very small segment of uninflamed cyst lining that displays a uniform thin epithelium with luminal parakeratin production and a palisaded basal cell layer is enough to render a diagnosis of odontogenic keratocyst.

Differential Diagnosis

Although the production of keratin gives the lesion its name, keratinization should not be considered the sine qua non of the odontogenic keratocyst. Some keratocysts may produce only a thin layer of parakeratin on the epithelial surface without any significant accumulation in the lumen. Such cases are easily misdiagnosed as a dentigerous cyst, periapical cyst, or other jaw cyst depending on the clinical history. Findings of a palisaded cuboidal/columnar basal cell layer and a wavy, corrugated epithelial surface are more consistent and reliable microscopic features in making the diagnosis of odontogenic keratocyst.

In addition, not every cyst of the jaws that keratinizes is an odontogenic keratocyst. The orthokeratinized odontogenic cyst also exhibits keratin production, but orthokeratin is seen rather than parakeratin. Also, orthokeratinized odontogenic cysts do not demonstrate a palisaded basal cell layer or a corrugated epithelial surface.

Treatment and Prognosis

Because the diagnosis may not be known or suspected before initial surgery, many odontogenic keratocysts are first treated with enucleation and curettage in a manner similar to treatment of other cysts of the jaws. However, the odontogenic keratocyst has a high recurrence rate that has been estimated in the range of 25% to 30%. For this reason, peripheral ostectomy with a bone bur is often recommended if the diagnosis is known or suspected preoperatively. If the cyst has broken through the cortical plate and is adherent to the overlying mucosa, excision of this mucosa may be indicated. On occasion, a particularly large and aggressive keratocyst may finally require resection and bone grafting. Although too few cases of peripheral odontogenic keratocyst have been described to make a firm conclusion regarding its biological behavior, at least two examples of recurrence have been reported.

Some clinicians prefer to use chemical cautery of the bony cavity or intraluminal injection of Carnoy solution to free the cyst from the bony wall and allow easier removal with a lower recurrence rate. However, Carnoy solution is not available or is no longer allowed at many treatment centers. Cryotherapy with liquid nitrogen has been used with some success to reduce the recurrence rate, although not all hospitals have access to such equipment. Others have advocated insertion of a polyethylene drainage tube into large keratocysts after cystotomy and incisional biopsy to allow decompression and subsequent reduction in lesion size. Such decompression treatment results in thickening of the cyst lining, allowing easier removal with an apparently lower recurrence rate.

Except for its high recurrence rate and potential for significant bone destruction, the prognosis for the odontogenic keratocyst is generally good. Although most recurrences are seen within several years of the initial surgery, recurrences may not become manifest until 10 or more years after the initial diagnosis. Therefore long-term follow-up is mandated. Malignant transformation has been reported but is quite rare.

Although most odontogenic keratocysts occur as isolated lesions, they sometimes are a component of the nevoid basal cell carcinoma syndrome, or Gorlin syndrome. Multiple keratocysts frequently develop in affected patients ( Fig. 10.12 ). Gorlin syndrome is an autosomal-dominant inherited disorder with a variety of clinical manifestations. Affected individuals may demonstrate frontal and temporoparietal bossing, hypertelorism, and mandibular prognathism. Other frequent skeletal anomalies include bifid ribs and lamellar calcification of the falx cerebri. The most significant clinical feature is the tendency for multiple basal cell carcinomas, which may affect both exposed and non–sun-exposed areas of the skin. Pitting defects on the palms and soles can be found in nearly two-thirds of affected patients.

Odontogenic keratocysts are a common finding in patients with Gorlin syndrome, and these cysts are usually the first manifestation that leads to the diagnosis. For this reason, any patient with an odontogenic keratocyst should be evaluated for this condition. Although the cysts in patients with Gorlin syndrome cannot definitely be distinguished microscopically from those not associated with the syndrome, they often demonstrate more epithelial proliferation and daughter cyst formation in the cyst wall ( Fig. 10.13 ). Foci of calcification also appear to be more common in syndrome cysts.

Clinical Features

Orthokeratinized odontogenic cysts predominantly occur in teenagers and young adults, with one study finding 86% of patients between the second and fifth decades of life. There is a male predilection, with 61% to 76% of reported cases in men. The lesion occurs much more often in the mandible (70% to 90% of cases) than in the maxilla, with a tendency to involve the posterior areas of the jaws. Approximately 50% to 75% of all cases are associated with an impacted tooth, thereby clinically mimicking a dentigerous cyst.

The orthokeratinized odontogenic cyst usually presents radiographically as a unilocular radiolucency, but some examples are multilocular. The size can vary from less than 1 cm in diameter to 15 cm or more. The lesion is frequently asymptomatic and discovered only on routine radiographic examination; however, some cases are associated with pain or swelling. Multiple orthokeratinized odontogenic cysts have been reported.

Pathologic Features

Orthokeratinized odontogenic cysts are lined with a thin, uniform layer of stratified squamous epithelium that is typically four to eight cells thick ( Fig. 10.14A ). The basal layer usually consists of a row of flattened to cuboidal cells with infrequent rete ridge formation. Orthokeratin is produced on the epithelial surface and associated with a subjacent granular cell layer. Abundant desquamated keratin may be found in the cyst lumen. Some cysts may show focal parakeratin production, but other features of odontogenic keratocyst are not observed. On rare occasions, focal sebaceous glands may be found in orthokeratinized odontogenic cysts ( Fig. 10.14B ).

Differential Diagnosis

The most important lesion to distinguish from the orthokeratinized odontogenic cyst is the true odontogenic keratocyst. However, the odontogenic keratocyst exhibits a palisaded basal layer of cuboidal to columnar cells that is often hyperchromatic. A corrugated or wavy layer of parakeratin is produced on the epithelial surface, and no granular cell layer should be present.

Treatment and Prognosis

Orthokeratinized odontogenic cysts are usually treated by enucleation and curettage. Unlike odontogenic keratocyst, recurrence is rare, having been reported in approximately 2% of cases. In addition, the orthokeratinized odontogenic cyst is not associated with the nevoid basal cell carcinoma syndrome. This further underscores the importance of distinguishing this lesion from the odontogenic keratocyst.

Clinical Features

Gingival cysts of the newborn typically present as multiple small (1 to 3 mm in diameter), white, pearl-like papules on the alveolar mucosa ( Fig. 10.15 ). The lesions are more common on the maxillary arch than the mandibular arch, with maxillary cysts favoring the buccal aspect and mandibular cysts favoring the lingual aspect.

Pathologic Features

Although rarely examined microscopically, the gingival cyst of the newborn is lined by stratified squamous epithelium. The cyst lumen is filled with desquamated parakeratin ( Fig. 10.16 ).

Treatment and Prognosis

No treatment is required for these asymptomatic lesions because they will disappear on their own within the first few months of life. In most instances, it is believed that the cyst ruptures and spills its keratin contents, which allows healing to occur.

Clinical Features

The gingival cyst of the adult most commonly occurs in middle-aged and older adults, with a mean age of approximately 48 to 51 years. About 80% of cases arise in the mandibular mucosa, with a marked predilection for the canine and premolar region. Maxillary examples also are seen, most frequently around the canines and premolars, as well as the lateral incisor area. The facial aspect of the gingiva is affected more often than the lingual side. Most lesions are solitary, although bilateral or multifocal involvement also has been reported.

The gingival cyst of the adult typically appears as a painless, dome-shaped swelling measuring 0.5 cm or less in maximum diameter, but occasional lesions may be greater than 1 cm ( Fig. 10.17 ). The overlying mucosa often appears normal in color, although some lesions appear blue or translucent because of the fluid contents. In some instances, the cyst may cause “cupping-out” resorption of the underlying alveolar bone, which may or may not be evident on radiographic examination. Sometimes such a lesion may appear to be partially within soft tissue and partially within bone, raising the question as to whether it would be better classified as a lateral periodontal cyst. However, because the lateral periodontal cyst and the gingival cyst of the adult are essentially the same lesion, this question is only academic.

Pathologic Features

The gingival cyst of the adult is lined with a thin, flattened layer of epithelium that often appears to be only one to two cells thick ( Fig. 10.18A ). Sometimes this lining is so thin that the lesion is easily missed or is mistaken for the endothelial lining of a dilated blood vessel. Often one can see focal thickened plaques within the epithelial lining. These thickenings usually contain glycogen-rich cells with clear cytoplasm ( Fig. 10.18B ).

Differential Diagnosis

On occasion, peripheral examples of odontogenic keratocyst occur within the gingival soft tissues. However, these cysts are lined with a thicker, uniform layer of epithelium that is four to eight cells thick with a palisaded basal layer of cuboidal to columnar cells. In addition, a corrugated or wavy layer of parakeratin is produced on the epithelial surface, and desquamated keratin is often found in the cyst lumen.

Treatment and Prognosis

The gingival cyst of the adult is treated by excisional biopsy. The prognosis is excellent and the lesions typically do not recur.

Clinical Features

Most lateral periodontal cysts are diagnosed in patients in the fifth through seventh decades of life, with a mean age of approximately 51 years (range, 14–85 years). The lesion is usually asymptomatic and often is discovered during routine radiographic examination. Although most cases measure less than 1 cm in maximum diameter, larger examples may produce painless expansion. Like the gingival cyst of the adult, the lateral periodontal cyst shows a striking predilection for the mandibular canine/premolar region. Maxillary examples also favor the canine/premolar area. Radiographically, the lesion typically presents as a solitary, well-circumscribed, and unilocular radiolucency lateral to the roots of vital teeth ( Fig. 10.19 ). Multifocal, bilateral, or periapical involvement has been reportedly only rarely.

Occasionally, the lesion may be polycystic and exhibit a multilocular appearance grossly and/or radiographically. Because this polycystic variant resembles a cluster of grapes, it is often called a botryoid odontogenic cyst .

Pathologic Features

The cyst is lined with a thin layer of cuboidal or nonkeratinizing squamous epithelium that is only about one to three cells thick in most areas. In addition, there are often focal nodular epithelial thickenings ( Fig. 10.20 ), which may exhibit a “swirling” appearance and frequently contain numerous glycogen-rich cells with clear cytoplasm. Islands of similar-appearing clear cells may be found in the cyst wall and are believed to be rests of the dental lamina. Botryoid odontogenic cysts show multiple, separate cystic spaces ( Fig. 10.21 ).

Differential Diagnosis

The lateral periodontal cyst and the gingival cyst of the adult are essentially the same lesion; clinicoradiographic correlation is needed to determine whether the cyst originated within bone (as in a lateral periodontal cyst) or soft tissue (as in a gingival cyst of the adult). The glandular odontogenic cyst may show features resembling a lateral periodontal cyst, including an epithelial lining with variable thickness, swirling spherical aggregates, and clear glycogen-containing cells; moreover, multiple cystic compartments may be evident in both the glandular odontogenic cyst and the botryoid odontogenic cyst. However, the glandular odontogenic cyst also shows luminal eosinophilic cuboidal/columnar cells, microcysts (duct-like spaces), and mucin production. In addition, the glandular odontogenic cyst generally exhibits greater growth potential compared to the lateral periodontal cyst.

Treatment and Prognosis

The lateral periodontal cyst is treated by conservative surgical enucleation, and recurrence is unusual. Because of its polycystic nature, the botryoid variant may have an increased recurrence potential.

Clinical Features

The glandular odontogenic cyst has been reported over a broad age range (second through ninth decades), with a mean age of approximately 45 to 51 years. It shows a striking predilection for the anterior mandible, with many cases crossing the midline ( Fig. 10.22 ). Maxillary examples are less common, but also usually occur in the anterior region.

The size of the cyst can vary from less than 1 cm in diameter to large, destructive lesions that involve most of the jaw. The most common clinical symptom is swelling; infrequent findings include pain, secondary infection, and paresthesia. Small asymptomatic lesions may be discovered only incidentally on radiographic examination. Radiographically, the lesion presents as either a unilocular or multilocular radiolucency, usually with well-defined borders and buccolingual expansion. Most lesions occur adjacent to tooth roots, although a minority of cases develop around the crowns of unerupted teeth. Other possible radiographic findings include scalloped borders, tooth displacement, root resorption, and cortical perforation.

Pathologic Features

The cyst is lined with stratified squamous epithelium that is variable in thickness and often forms multiple compartments. However, the superficial layer characteristically consists of eosinophilic cuboidal/columnar (or “hobnail”) cells; these cells may demonstrate apocrine snouting (simulating decapitation secretion) or cilia ( Fig. 10.23 ). The surface layer is often irregular and somewhat papillary. Mucous cells also may be present. In addition, the lining typically contains microcysts (duct-like spaces) surrounded by a single layer of cuboidal, columnar, or goblet cells. The microcysts may contain pools of mucicarmine-positive material or may appear empty. In the basal or parabasal layers, there may be clear or vacuolated cells with intracytoplasmic glycogen. In some areas, the squamous epithelial cells may form swirling spherical aggregates reminiscent of those seen in the lateral periodontal cyst ( Fig. 10.24 ). This latter finding supports the belief that these cysts are of odontogenic origin. In addition, immunohistochemical studies of glandular odontogenic cysts showing expression of cytokeratins 14 and 19 suggest an odontogenic origin.

Some investigators have proposed specific diagnostic criteria for the glandular odontogenic cyst. For example, Kaplan et al. suggested the following major criteria must be at least focally present: (1) squamous epithelial lining, with a flat connective tissue interface and no basal palisading; (2) an epithelial lining with variable thickness, with or without “spheres”/ “whorls” or focal luminal proliferation; (3) cuboidal eosinophilic or “hobnail” cells; (4) mucous (goblet) cells with intraepithelial mucous pools, with or without crypts lined by mucous cells; and (5) intraepithelial glandular/microcystic/duct-like structures. In addition, these authors posited that the following minor criteria may be present but are not necessary for diagnosis: (1) papillary proliferation of the lining epithelium, (2) cilia, (3) multicystic or multiluminal architecture, and (4) clear or vacuolated cells. Nevertheless, Fowler et al. noted that glandular odontogenic cysts do not always exhibit the aforementioned proposed major criteria. Instead, these authors found that the presence of 7 out of the following 10 microscopic parameters is highly predictive of glandular odontogenic cysts: eosinophilic cuboidal cells, microcysts, apocrine snouting, clear (vacuolated) cells, variable thickness, tufting (papillary projections), mucous cells, cilia, clear (vacuolated) cells, epithelial spheres, and multiple compartments. In particular, the latter three features were most helpful in their study for distinguishing the glandular odontogenic cyst from its mimics.

Differential Diagnosis

The differential diagnosis may include various other types of jaw cysts, including the dentigerous cyst, lateral periodontal cyst, and botryoid odontogenic cyst. Both glandular odontogenic cysts and metaplastic dentigerous cysts can exhibit luminal eosinophilic cuboidal cells, cilia, and mucous cells. However, these findings tend to be more focal within dentigerous cysts compared to glandular odontogenic cysts, and only a minority of glandular odontogenic cysts develop in a dentigerous (pericoronal) relationship to unerupted teeth. In addition, some dentigerous cysts may demonstrate intraepithelial pseudomicrocysts. These pseudomicrocysts are lined by flattened cells, whereas the true microcysts within the glandular odontogenic cyst are lined by cuboidal, columnar, or mucous cells. Moreover, Fowler et al. reported that the presence of microcysts, clear cells, and epithelial spheres may be helpful in distinguishing pericoronal glandular odontogenic cysts from metaplastic dentigerous cysts. Epithelial spheres are also a prominent feature of the lateral periodontal cyst and its multilocular variant known as the botryoid odontogenic cyst . However, the lateral periodontal cyst does not exhibit luminal eosinophilic cuboidal cells and mucin pools. In addition, compared to the glandular odontogenic cyst, the lateral periodontal cyst tends to have more limited growth potential, with most lesions measuring less than 1 cm in maximum diameter.

Low-grade central mucoepidermoid carcinoma also can mimic the glandular odontogenic cyst. Both lesions exhibit cystic growth with a mixture of squamous epithelial and mucous cells. Rarely, glandular odontogenic cysts even may exhibit small islands resembling mucoepidermoid carcinoma within their walls. However, glandular odontogenic cysts tend to have a thinner and less proliferative lining compared to central mucoepidermoid carcinomas. In addition, the epithelial spheres that are characteristic of the glandular odontogenic cyst are not usually found in mucoepidermoid carcinoma. Moreover, Bishop et al. detected MAML2 rearrangement in 5 of 5 central mucoepidermoid carcinomas versus 0 of 21 glandular odontogenic cysts; these findings do not support conjecture that the glandular odontogenic cyst represents a precursor to, or low-grade form of, central mucoepidermoid carcinoma. Also, in one small-scale immunohistochemical study, Vered et al. reported that extensive maspin expression in the cytoplasm and nuclei of epithelial-mucous cells may favor a diagnosis of low-grade central mucoepidermoid carcinoma over glandular odontogenic cyst.

Treatment and Prognosis

Most glandular odontogenic cysts have been treated by enucleation or curettage. However, a high recurrence rate of approximately 30% to 55% has been reported. Some investigators have noted a tendency for recurrence among large multilocular lesions with cortical perforation. For such lesions, some authors have suggested en bloc resection.

Clinical Features

The calcifying odontogenic cyst can be encountered at any age, with a peak in the second and third decades (mean age, 33 years) and no significant gender predilection. There is an equal distribution between the maxilla and mandible, with the majority of lesions involving the incisor/canine region. Radiographic examination typically shows a well-defined, unilocular radiolucency, although 10% to 25% of cases are multilocular ( Fig. 10.25A ). Scattered radiopacities may be present in 30% to 50% of cases ( Fig. 10.25B ). Approximately one-third of calcifying odontogenic cysts are associated with an impacted tooth, and resorption or divergence of adjacent tooth roots is frequently noted. Lesions seldom exceed 4 cm in greatest diameter; however, large lesions measuring over 10 cm have been described.

Approximately 15% to 21% of these lesions have been reported within the gingival soft tissues (peripheral or extraosseous calcifying odontogenic cyst) and present as nonspecific sessile or pedunculated masses that mimic fibromas or other reactive gingival proliferations. Compared to its intraosseous counterpart, the peripheral calcifying odontogenic cyst develops in an older patient population, with a peak in the sixth and seventh decades.

The dentinogenic ghost cell tumor comprises less than 3% of all ghost cell lesions and has a mean age at diagnosis of approximately 30 to 40 years. These tumors favor the posterior jaws and present clinically as slowly growing swellings that may or may not be painful. Radiographic examination reveals a unilocular or multilocular lesion that ranges from completely radiolucent to mixed radiolucent-radiopaque. The margins can vary from well- to ill-defined, and root resorption can be seen.

Ghost cell odontogenic carcinoma can arise de novo or from malignant degeneration of a preexisting calcifying odontogenic cyst or dentinogenic ghost cell tumor. Ghost cell odontogenic carcinoma demonstrates a similar age predilection as dentinogenic ghost cell tumor and is found more frequently in the maxilla than the mandible. The clinical presentation can include a slowly or rapidly progressive swelling that may be accompanied by pain, tooth mobility, paresthesia, and invasion of the contiguous soft tissues. Radiographic examination typically reveals an ill-defined radiolucent or mixed radiolucent-radiopaque lesion with resorption or displacement of the adjacent tooth roots.

Pathologic Features

Various classification schemes have been proposed for ghost cell lesions. Regardless, it is important to recognize the histopathologic diversity displayed by this group of lesions. Overall, a predominantly cystic architecture is seen in 85% of cases, whereas a solid, neoplastic growth pattern is evident in 15% of cases.

In most instances, the calcifying odontogenic cyst is encompassed by a fibrous capsule that is lined with odontogenic epithelium. The epithelial lining shows a peripheral basal cell layer of cuboidal or columnar cells that support loosely arranged, stellate reticulum-like cells reminiscent of an ameloblastoma. The presence of suprabasilar epithelial cells that undergo a process called ghost cell change is the most distinctive feature of this lesion ( Fig. 10.26 ). These cells are characterized by pale, eosinophilic cytoplasm and loss of nuclei, with only a faint nuclear membrane outline (see Fig. 10.26 , inset ). The mechanism of this cellular alteration is unclear and has been attributed to aberrant keratinization or coagulation necrosis. The ghost cell component frequently undergoes dystrophic calcification ( Fig. 10.27 ) that may range from fine granules to larger conglomerates of calcification. On occasion, a calcified matrix that likely represents dysplastic dentin is identified. The cyst lumen may be filled with ghost cells and dystrophic calcifications or, in rare instances, projections of epithelium that mimic an ameloblastoma. Satellite cysts that elicit a foreign body reaction may be observed within the cyst wall. The calcifying odontogenic cyst can be associated with other odontogenic tumors, such as odontoma (most commonly), adenomatoid odontogenic tumor, ameloblastic fibroma, and ameloblastoma.

Dentinogenic ghost cell tumors appear as more solid proliferations of odontogenic epithelium that infiltrate the surrounding connective tissues. The epithelium exhibits ameloblastic features, including columnar peripheral cells that demonstrate nuclear palisading and surround stellate reticulum-like tissue. Typically, ghost cells are readily identifiable, and varying amounts of juxtaepithelial dentinoid are present.

Ghost cell odontogenic carcinoma displays features similar to those of the dentinogenic ghost cell tumor but with cytologic features of malignancy, including cellular atypia and pleomorphism, conspicuous mitotic activity, necrosis, and infiltration of the adjacent tissues. Transition from a calcifying odontogenic cyst or dentinogenic ghost cell tumor may be seen.

Although immunohistochemical studies are limited, at least one group has demonstrated consistent positivity in the epithelial cells of calcifying odontogenic cysts for cytokeratins 7, 8, 14, and 19. Another study reported nuclear and cytoplasmic expression of beta-catenin. Two-thirds of ghost cell odontogenic carcinomas are p53 positive.

Differential Diagnosis

The epithelium in ameloblastoma closely resembles that of calcifying odontogenic cyst. However, ghost cells and dentinoid would not be expected in ameloblastoma. Similarly, these features aid in distinguishing ghost cell odontogenic carcinoma from ameloblastic carcinoma. Ghost cells also have been described in ameloblastic fibroodontomas and odontomas, although they do not tend to be a prominent component of these tumors. Interestingly, marked similarities exist between calcifying odontogenic cyst and pituitary craniopharyngioma. However, discriminating between these two lesions usually is not challenging because craniopharyngioma is found intracranially or in a suprasellar location.

Treatment and Prognosis

Enucleation and curettage are the treatments of choice for the calcifying odontogenic cyst, and the prognosis is good. Even with conservative therapy, fewer than 5% of cases recur. For peripheral lesions, conservative excision is typically curative.

The behavior of dentinogenic ghost cell tumors and ghost cell odontogenic carcinomas is difficult to predict because of their rarity. En bloc resection generally is advocated, as is long-term clinicoradiographic surveillance. Recurrences have been described, especially after conservative therapy. For ghost cell odontogenic carcinomas, the 5-year survival rate is 73%, with deaths attributed to uncontrolled local disease or metastases.

Clinical Features

Periapical cysts occur in patients over a wide age range, with a peak in the third and fourth decades of life. It is rare for such cysts to develop in association with deciduous teeth. Periapical cysts are most common in the anterior maxillary region. However, cysts associated with deciduous teeth occur more often in the mandible.

Clinical findings may include tenderness, pain, swelling, and drainage. However, many periapical cysts are asymptomatic and discovered incidentally during routine radiographic examination. The radiograph shows a radiolucency at the root apex with loss of the lamina dura (the thin layer of radiopaque bone that normally surrounds the tooth root) ( Fig. 10.28A ). The radiolucency may appear either well defined or poorly circumscribed, and adjacent root resorption is possible. Most periapical cysts are 2 cm or less in maximum diameter, although occasional lesions may demonstrate dramatic enlargement with destruction of a significant portion of the jaw.

A lateral radicular cyst represents a periapical cyst variant that occurs along the lateral aspect of a tooth root rather than at the apex; it presumably results from pulpal necrosis that spreads through a lateral or accessory canal ( Fig. 10.28B ). Some cases also may develop from communication with a deep periodontal pocket. Although such cysts may appear radiographically similar to the developmental lateral periodontal cyst, they should be distinguished as being inflammatory in etiology.

When a nonvital tooth is extracted, periapical inflammatory tissue that is not curetted from the socket may give rise to another variant, known as a residual periapical cyst (or residual cyst ). Such a lesion usually presents as a well-circumscribed radiolucency in the extraction site. Older residual periapical cysts sometimes develop dystrophic calcification, resulting in a central area of radiopacity.

Pathologic Features

Because many periapical cysts are friable or incompletely formed when they are curetted, they frequently are submitted in multiple fragments, which belie their cystic nature. However, gross examination of an intact periapical cyst typically exhibits a thick wall surrounding a central lumen. At times, the wall may exhibit bright yellow zones that microscopically correspond to collections of lipid-laden foamy macrophages. The lumen may contain brownish fluid or shimmering cholesterol crystals.

Microscopically, most lesions are lined by nonkeratinizing stratified squamous epithelium, although ciliated pseudostratified columnar or simple cuboidal epithelium also may be noted in some cases. The squamous epithelial lining often exhibits neutrophilic exocytosis, spongiosis, and hyperplasia with “arcading” rete ( Fig. 10.29 ); however, long-standing lesions may exhibit flattened squamous epithelium without rete. Because of extensive ulceration, some periapical cysts may show only focal remnants of an epithelial lining. Mucous cells have been identified in approximately 7% to 40% of periapical cysts; these cells usually are found along the surface layer, either individually or in a continuous row. Occasionally, the cyst lining also may exhibit apoptotic bodies and Rushton bodies. The latter appear as glassy, eosinophilic, linear, and curved to straight bodies, sometimes with hairpin or polycyclic morphology ( Fig. 10.30 ). The pathogenesis of Rushton bodies remains uncertain; many investigators believe that they represent some type of secretory product of odontogenic epithelium, although some authors also have proposed a hematogenous or vascular origin.

The wall of a periapical cyst is comprised of fibrous connective tissue with a variable inflammatory cell infiltrate that may include lymphocytes, plasma cells, neutrophils, histiocytes, and occasional eosinophils. In addition, many periapical cysts contain cholesterol clefts that are associated with a giant cell reaction. Hemorrhage, hemosiderin, foreign matter (i.e., root canal filling material), dystrophic calcification, odontogenic epithelial rests, and giant cell hyaline angiopathy (pulse granulomas) may be evident as well.

Differential Diagnosis

Although the degree of inflammation within the lesion may suggest a diagnosis of periapical cyst, the histopathologic findings are not specific. Other developmental odontogenic cysts (e.g., dentigerous cysts, odontogenic keratocysts) can have a similar microscopic pattern if secondary inflammation is present. Therefore clinical correlation and careful microscopic examination of the entire cystic lining are necessary to ensure the correct diagnosis.

Treatment and Prognosis

The treatment of periapical cysts usually involves either root canal therapy or extraction of the associated tooth. If the tooth is extracted, the cyst should be curetted and submitted for histopathologic examination to confirm the diagnosis. If root canal therapy is performed in an effort to save the tooth, it is important for the clinician to follow the lesion radiographically for subsequent bone regeneration. If the lesion does not resolve after root canal therapy, then periapical surgery (including apicoectomy with retrofill) and biopsy may be indicated.

Clinical Features

Although carcinomas arising within odontogenic cysts occur over a wide age range, they are seen most frequently in older adults. A male predominance and predilection for the mandible have been noted. Most examples have been reported in association with residual periapical cysts and dentigerous cysts ( Fig. 10.31 ). In addition, there have been several documented cases of carcinomas arising in odontogenic keratocysts. In very rare instances, malignant transformation of other odontogenic cyst types (e.g., orthokeratinized odontogenic cyst, lateral periodontal cyst) may occur as well, and many investigators have provided no specific odontogenic cyst classification.

The most common symptoms are pain and swelling, although some lesions are asymptomatic. Other possible findings include tooth mobility, infection, sinus tract formation, lymphadenopathy, paresthesia, trismus, and pathologic jaw fracture. The radiographic features may mimic any benign odontogenic cyst, although the area of bone destruction is often more irregular and ragged in nature. Compared to plain radiography, computed tomography may be superior for demonstrating border irregularity and tumor extent.

Pathologic Features

Carcinomas arising from odontogenic cysts are most often well-differentiated squamous cell carcinomas, although mucoepidermoid carcinomas, spindle cell carcinomas, and other types also have been described. Dysplasia may be found within the cystic epithelial lining along with islands of invasive carcinoma in the cyst wall ( Fig. 10.32 ). Occasionally, one may be able to find a transition from normal cystic epithelium to carcinoma. In some cysts, the lining epithelium is markedly hyperkeratotic, with features of verrucous carcinoma (i.e., warty surface architecture with downward growth of broad, bulbous rete and mild cytologic epithelial atypia) or verrucous dysplasia ; thorough examination of such lesions is needed to rule out an invasive squamous cell carcinoma component.

Differential Diagnosis

Squamous cell carcinomas arising in odontogenic cysts represent a subset of primary intraosseous squamous cell carcinoma (discussed later). Strictly speaking, a diagnosis of primary intraosseous squamous cell carcinoma requires correlation of microscopic, clinical, and radiographic findings to exclude the following: (1) a metastatic lesion, (2) a malignant odontogenic tumor of specific type (e.g., ameloblastic carcinoma, sclerosing odontogenic carcinoma, clear cell odontogenic carcinoma, ghost cell odontogenic carcinoma), (3) a sinonasal carcinoma, and (4) an intraosseous salivary gland neoplasm (e.g., mucoepidermoid carcinoma).

Treatment and Prognosis

The treatment and prognosis for a carcinoma arising from an odontogenic cyst are similar to those for other oral carcinomas and depend on tumor size and extent. Management typically includes en bloc excision or radical resection, often with adjunctive radiation therapy. The prognosis is difficult to ascertain because of disease rarity and limited patient follow-up data; however, 2-year survival rates of approximately 60% and 5-year survival of approximately 40% have been noted by some large case series or literature reviews. Metastases to regional lymph nodes have been reported but appear uncommon.

Ameloblastoma

The ameloblastoma is a benign but locally aggressive odontogenic epithelial neoplasm. If one excludes odontomas (which are considered hamartomas), it is the most common odontogenic tumor. Ameloblastomas may arise from various odontogenic epithelial sources, including the rests of dental lamina, epithelial lining of odontogenic cysts, and basal cells of the oral mucosa. The cells in this tumor closely mimic the ameloblasts and stellate reticulum of the developing tooth organ.

With respect to etiopathogenesis, previous studies have suggested that expression of parathyroid hormone-related protein and matrix metalloproteinase may contribute to the aggressiveness of this neoplasm. More recently, a variety of molecular aberrations have been implicated in tumorigenesis. Most involve the mitogen-activated protein kinase (MAPK) and sonic hedgehog (SHH) pathways. In particular, investigators have demonstrated BRAF-V600E mutations in approximately 63% of ameloblastomas and smoothened ( SMO ) gene mutations in 16% to 39% of cases. Less common mutations involve the fibroblast growth factor receptor 2 (FGFR2) ; RAS (KRAS, NRAS, HRAS) ; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) ; catenin beta 1 (CTNNB1) ; and SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1 (SMARCB1) genes. The mutations are mutually exclusive in the majority of lesions, with the exception of SMO -mutated tumors, which often occur concomitantly with FGFR2 or RAS mutations.

The following three main subtypes of ameloblastoma are discussed subsequently:

• 1.

  Conventional solid or multicystic ameloblastoma

• 2.

  Unicystic ameloblastoma

• 3.

  Peripheral ameloblastoma

Clinical Features

Conventional solid or multicystic ameloblastoma is the most common subtype, accounting for approximately 92% of ameloblastomas. It arises most often in the third to seventh decades of life, and less than 2% are discovered before 10 years of age. No significant gender or ethnic predilection has been observed.

Approximately 80% of ameloblastomas develop in the mandible, with the majority occurring in the molar/ramus area. Other subsites in order of decreasing frequency include the anterior mandible, posterior maxilla, and anterior maxilla. The most common presentation is a painless jaw swelling, which may be accompanied by tooth mobility, trismus, paresthesia, and soft-tissue invasion. Large tumors can cause pain, marked facial deformity, and, uncommonly, airway compromise. In contrast, small lesions often remain completely asymptomatic and are discovered incidentally. Radiographic examination shows a multilocular or unilocular radiolucency with well-defined borders ( Fig. 10.33A ). The loculations may be large or small, imparting a soap-bubble or honeycomb appearance, respectively ( Fig. 10.33B ). The tumor is associated with an impacted tooth in 15% to 40% of cases, and more than half of unilocular lesions present in a pericoronal relationship. Tooth resorption or displacement and cortical expansion are relatively common, especially in larger examples.

The unusual desmoplastic variant of conventional ameloblastoma favors the anterior and premolar regions of the jaws and occurs with equal frequency in the maxilla and mandible. The typical radiographic presentation is a mixed radiolucent-radiopaque lesion with well- to ill-defined borders.

Interestingly, ameloblastomas with BRAF mutations demonstrate a striking predilection for the mandible, whereas the majority of those with SMO mutations involve the maxilla. Also, BRAF -mutated tumors occur in younger patients (mean age, 34 years) compared to those without BRAF mutations (mean age, 54 years).

Pathologic Features

Conventional ameloblastomas are solid infiltrating tumors with a tendency to undergo cystic change. The cysts may be small and grossly undetectable or large and prominent. There are six main histopathologic subtypes: follicular, plexiform, acanthomatous, granular cell, basal cell, and desmoplastic. The follicular and plexiform subtypes constitute the majority of cases, although two or more patterns can be observed in any individual tumor. Regardless, the histopathologic subtype does not impact prognosis.

Follicular ameloblastoma is characterized by discrete islands of odontogenic epithelium interspersed within a mature collagenous connective tissue stroma ( Fig. 10.34 ). The peripheral epithelial cells are cuboidal or columnar and exhibit nuclear palisading, reverse nuclear polarization (i.e., nuclei oriented away from the basement membrane), and vacuolated basal cytoplasm (see Fig. 10.34 , inset ). The central portion of the islands contains loosely arranged, stellate or angular epithelial cells that resemble the stellate reticulum of the developing enamel organ. Edema and microcyst formation are common findings.

In plexiform ameloblastoma, the odontogenic epithelium is arranged in anastomosing strands and cords that often appear to encompass central areas of collagenous or loose, vascular stroma ( Fig. 10.35A ). Ameloblastic features, such as reverse nuclear polarization of the peripheral cells, are still present but tend to be less prominent than in the follicular variant. Stellate reticulum-like tissue and cyst formation are seen less frequently in the plexiform variant than in the follicular variant.

In the acanthomatous type, the typical features of follicular ameloblastoma are seen, but the central portions of the epithelial islands show squamous metaplasia ( Fig. 10.35B ). On rare occasions, extensive keratin pearl formation is noted and has been designated keratoameloblastoma . In the granular cell pattern, the tumor cells exhibit abundant eosinophilic, cytoplasmic granules ( Fig. 10.35C ). The extremely rare basal cell variant is characterized by islands of basaloid cells with scant cytoplasm, similar to the tumor cells that comprise basal cell carcinoma ( Fig. 10.35D ). The classic ameloblastic features are generally inconspicuous in this histologic subtype, which may confound the diagnosis. Lastly, the desmoplastic variant is composed of dense, collagenized stroma surrounding widely scattered, compressed islands and cords of hyperchromatic epithelial cells ( Fig. 10.36 ). The periphery of the small islands is typically lined by cuboidal or flattened cells; peripheral columnar cells with reverse nuclear polarization are difficult to appreciate but usually can be identified with a meticulous search. Histochemical evaluation suggests that the dense stroma is not scar tissue but rather represents de novo synthesis of extracellular matrix proteins, possibly attributed to upregulated expression of transforming growth factor beta (TGF-β) . Desmoplastic ameloblastoma also can exhibit osseous metaplasia of the stroma. This feature in combination with the stromal density may contribute to a mixed radiolucent-radiopaque appearance that can be confused with a fibroosseous lesion.

Immunohistochemical studies of ameloblastoma have shown that the tumor cells may be positive for CK14, CK19, and CD56; expression of calretinin has been reported but tends to be localized to the stellate reticulum-like areas. Although ancillary studies typically are not necessary for the diagnosis of ameloblastoma, overexpression of BRAF or SMO plus other molecular findings may be of increasing relevance with regard to treatment and prognosis. These mutations can be identified by molecular methods or, in the case of BRAF, via immunohistochemistry using the BRAF-V600E mutation-specific antibody as described by Kurppa et al. and Brown et al.

Differential Diagnosis

The differential diagnosis of ameloblastoma is broad and may include any odontogenic cyst or tumor that features epithelium with ameloblastic differentiation (i.e., peripheral columnar cells with reverse nuclear polarization and central loosely arranged, stellate cells). The calcifying odontogenic cyst and its variants are cystic or solid lesions characterized by cuboidal or columnar abluminal cells, with reverse nuclear polarization. The presence of numerous eosinophilic ghost cells and focal calcifications helps to differentiate these lesions from ameloblastoma. Columnar cell differentiation also may be observed in adenomatoid odontogenic tumor, although in this tumor, the columnar cells form duct-like structures and contain nuclei oriented towards the basal cytoplasm. Ameloblastic fibroma and ameloblastic fibroodontoma demonstrate islands of odontogenic epithelium with ameloblastic features; however, the characteristic dental papilla-like stroma in both these tumors and the formation of dental hard tissue in the latter aid in distinction from ameloblastoma. Rests of dental lamina can be seen within a dental follicle or wall of a dentigerous cyst. On occasion, these rests may demonstrate peripheral columnar cells with reverse nuclear polarization. These isolated foci do not represent neoplasia and should not be overdiagnosed as ameloblastoma.

The presence of squamous metaplasia in the acanthomatous variant may raise the possibility of other intraosseous lesions with squamous differentiation. Acanthomatous ameloblastomas with only focal peripheral columnar differentiation and reverse nuclear polarization can closely resemble a squamous odontogenic tumor. In these instances, a thorough search for definitive ameloblastic differentiation is necessary to avoid misdiagnosis. Primary intraosseous squamous cell carcinoma may also be considered in the differential diagnosis but should display some degree of cytologic atypia and no columnar cells with reverse nuclear polarization.

An epithelium-rich central odontogenic fibroma demonstrates a significant number of odontogenic epithelial islands within a background of fibrous connective tissue and may be confused with a desmoplastic ameloblastoma. Although the ameloblastic features may be subtle in the desmoplastic variant, identification of such would confirm this diagnosis.

Treatment and Prognosis

There is much debate regarding optimal treatment of conventional ameloblastoma – especially pertaining to conservative therapy, resection margins, and maxillary lesions. Because these tumors have a propensity to infiltrate the surrounding bone and extend beyond their apparent clinical and radiographic boundaries, marginal or en bloc resection, 1 to 2 cm beyond the radiographic perimeter of the tumor, is the most widely used form of therapy. One group performed presurgical marsupialization to reduce the extent of surgical resection, while others have advocated conservative tumor removal and peripheral ostectomy for select cases. Maxillary lesions often require more aggressive therapy compared to mandibular lesions, because of anatomic restrictions, tumor infiltration of the thin bony architecture, and proximity to vital structures. Furthermore, early recurrence of maxillary ameloblastoma may be difficult to detect radiographically in this anatomically complex area.

The recurrence rates reported in various reviews range from 20% to 90%, depending on the treatment modality. A large review of 3677 cases reported an overall recurrence rate of 23%, with 35% recurrence for lesions treated by enucleation and curettage and 17% for those managed with radical resection. Similarly, a systematic review and meta-analysis by Antonoglou and Sandor reported 38% recurrence with conservative therapy versus 8% with radical treatment, although the authors noted a very low quality of evidence and very high risk of bias among the studies included in their analysis. Other studies have shown recurrence rates ranging from 50% to 90% following curettage. Recurrence is primarily determined by the adequacy of surgical margins, which is particularly problematic for maxillary lesions that have extended to adjacent vital structures. Other factors that may influence recurrence include tumor size and location, patient age and medical comorbidities, and multilocularity. Importantly, nearly half of all recurrences become clinically evident 2 to 5 years after the initial surgical procedure, although recurrence intervals of up to 45 years have been documented. Hence, lifelong follow-up is recommended. Death typically is related to uncontrolled disease or malignant transformation (discussed later).

Adjunctive radiation therapy has a limited role in the management of ameloblastoma, given variable response rates and the potential for osteoradionecrosis and postradiation malignancy. Such treatment may be considered for large or recurrent tumors, especially those involving the maxilla.

An exciting prospect is the development of biological therapies for ameloblastoma. Pharmacologic inhibitors are available for most of the mutations identified thus far, including BRAF , SMO , NRAS , and FGFR2 . Although clinical trials are needed, in vitro studies and case reports have reported promising findings with the BRAF inhibitors (e.g., vemurafenib, dabrafenib); trametinib, an inhibitor that acts downstream from Ras in the MAPK pathway; and sonic hedgehog signaling inhibitors. Such agents may reduce morbidity in the surgical treatment of conventional ameloblastoma. Furthermore, they may also be useful for the treatment of metastasizing ameloblastoma (discussed later).

Prognostically, Brown and colleagues found that ameloblastomas harboring the BRAF -V600E mutation recurred later than wild-type lesions. Hence, there is great interest in further defining the molecular profile of these tumors, as it is likely to impact diagnosis, treatment, and prognostication.

Clinical Features

Unicystic ameloblastoma is the second most common subtype of ameloblastoma and comprises 5% to 22% of all ameloblastomas. These tumors exhibit a predilection for young individuals, with nearly half detected during the second decade of life. Lesions associated with an impacted tooth tend to develop in younger patients (mean age, 22 years) compared with those that are not. There is no significant gender predilection.

The most commonly affected sites are the angle and posterior body of the mandible in the third molar region, followed by the mandibular ramus and coronoid process. Maxillary lesions are distinctly rare and, likewise, favor the posterior region. Most patients present with a slowly growing, painless swelling in the affected bone, although intermittent pain has been reported rarely. Some cases are asymptomatic and discovered incidentally or following radiographic examination for failed tooth eruption. Radiographically, the unicystic ameloblastoma appears as a well-defined, unilocular radiolucency, similar to a dentigerous cyst. However, a pericoronal relationship with an impacted tooth is not always present ( Fig. 10.37 ). Purported multilocular examples have been reported, but the existence of a true multilocular unicystic ameloblastoma has been questioned by some. Root resorption and cortical perforation are common in larger lesions.