Odontogenic tumors

Clinical and radiographic findings

• Forty percent of sporadic cases occur in the third and fourth decades of life, with a 2:1 male predilection. Lesions in syndromic cases are generally diagnosed in the first and second decades of life, and patients tend to develop multiple lesions. Painless swelling tends to occur in larger, long-standing lesions.

• Approximately 80% of cases present as unilocular and the rest as multilocular radiolucencies, usually in the posterior mandible and/or ramus area (70% of cases). The radiolucency expands along the long axis of the jaw bones anteroposteriorly rather than buccal-lingually or superoinferiorly. Twenty-five to 33% of cases are associated with an impacted tooth, or occur in locations favored by lateral periodontal cyst ( Fig. 15.2 A–C).

  

• Those arising in the midline of the maxilla in the vicinity of the incisive (nasopalatine) canal occur in patients in the seventh decade of life or older, with a 3:1 male predilection. Whether this represents a primordial cyst of a mesiodens is uncertain.

• Patients with the nevoid basal cell carcinoma syndrome, an autosomal dominant condition associated with mutation of PTCH1, have not only multiple cystic lesions in the jaw in the first and second decades ( Fig. 15.2 D) but also many basal cell carcinomas starting within the first three decades of life, as well as hypertelorism, rib abnormalities (such as bifid, missing, or fused ribs), calcification of the falx cerebri, palmar-plantar pits, cutaneous epidermal cysts, ovarian fibromas, medulloblastomas, and other malformations ( Table 15.2 ). In one study, 44% of children newly diagnosed with the syndrome presented with a single KCOT/OKC and were younger. As such, a KCOT/OKC in a young child should raise suspicions for the syndrome.

  TABLE 15.2

  Diagnostic Criteria for Nevoid Basal Cell Carcinoma Syndrome

  From Kimonis VE, Goldstein AM, Pastakia B, et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet. 1997;69(3):299-308.

  Diagnosis of NBCC made in the presence of two major or one major and two minor criteria

  Major criteria

  1. More than 2 BCCs or one under the age of 20 years

  2. Odontogenic keratocysts of the jaw proven by histology

  3. Three or more palmar or plantar pits

  4. Bilamellar calcification of the falx cerebri

  5. Bifid, fused, or markedly splayed ribs

  6. First-degree relative with NBCC syndrome

  Minor criteria

  Any one of the following features:

  1. Macrocephaly determined after adjustment for height

  2. Congenital malformations: cleft lip or palate, frontal bossing, “coarse face,” moderate or severe hypertelorism

  3. Other skeletal abnormalities: Sprengel deformity, marked pectus deformity, marked syndactyly of the digits

  4. Radiological abnormalities: Bridging of the sella turcica, vertebral anomalies such as hemivertebrae, fusion or elongation of the vertebral bodies, modeling defects of the hands and feet, or flame shaped lucencies of the hands or feet

  5. Ovarian fibroma

  6. Medulloblastoma

  BCC , Basal cell carcinoma; NBCC , nevoid basal cell carcinoma.

• This cystic tumor has been reported in peripheral or extraosseous sites, such as the gingiva, especially the maxillary anterior gingiva and vestibule, as well as in the buccal mucosa.

Etiopathogenesis and histopathologic features

Mutation in PTCH1, a tumor suppressor gene is seen in KCOT/OKC in the nevoid basal cell carcinoma syndrome, an autosomal dominant condition, in over 80% of syndromic and in approximately 90% of sporadic cases of this cystic tumor. Allelic losses have also been identified for other tumor suppressor genes (namely, TP53 and MCC ). Infrequently, patients with Gorlin syndrome exhibit germline mutations in SUFU .

• The epithelium is uniformly 5 to 10 cells thick, with parakeratosis, often with a corrugated surface, palisading of the basal cell nuclei, and a flat interface, the last leading to epithelial detachment; there may be very little keratin present but palisading of basal cell nuclei is always present. Basal cell hyperplasia and dysmaturation with occasional mitotic figures are not uncommon, as are epithelial buds although these findings do not appear to be associated with recurrence but may be seen more frequently in syndromic cases ( Fig. 15.3 ). However, if inflammation is present, these typical features are lost or may be subtle or focal and may lead to a misdiagnosis if the specimen is small and from an inflamed portion of the lesion ( Fig. 15.4 ). The lining may show mucous and ciliated cell metaplasia and epithelial plaques, and Rushton bodies are frequent within inflamed epithelium (see Fig. 15.4 B–D). Focal areas may be covered by orthokeratin but the presence of any parakeratin renders the cyst a KCOT/OKC.

  
  

• Marsupialization or exteriorization of the cyst and flushing with a caustic agent results in inflammation and loss of the parakeratin layer and the typical features of KCOT/OKC. However, residual lesional tissue may still be present and levels should be performed if the cyst is not present in the initial sections (see Fig. 15.2 E–F).

• Satellite cysts are often present within the wall and sometimes within the deep lamina propria of the oral mucosa if the cortical plate is perforated; not all satellite cysts contain keratin and some display macrophages within the lumen ( Fig. 15.5 ). Cortical perforation may be associated with a higher recurrence rate and should be reported. Syndromic cases have a higher frequency of satellite cysts. Perforation of maxillary lesions into the sinus is not uncommon (see Fig. 15.5 E).

  

• Cartilage and melanin pigment may be present (see Fig. 15.5 F).

• A solid variant has been reported and is composed of back-to-back cysts filled with keratin. The relationship of this cyst with keratoameloblastoma is unclear (see later).

• K4, K13, K17, and K19 have been identified in the cyst epithelium. Compared with other odontogenic cysts, there are high proliferating cell nuclear antigen and Ki-67 indices, and positivity for BCL2 in basal cells, and SOX2 throughout the epithelium (see Fig. 15.6 C–D).

  

• Recurrence may be associated with cases exhibiting Ki-67 labeling index >10%.

• Peripheral lesions are uncommon but extraosseous extension from an intraosseous lesion must always be ruled out ( Fig. 15.3 G).

Differential diagnosis

• Orthokeratinized odontogenic cyst is lined entirely by orthokeratin with a granular layer, does not exhibit palisaded basal cells or satellite cysts, is negative for BCL2, and has a low Ki-67 index and a low recurrence rate of <10%.

• Some basal cell hyperplasia and dysmaturation is acceptable but if this is significant, epithelial dysplasia occurring within the lining should be considered ( Fig. 15.3 F).

• Cystic ameloblastoma has no parakeratosis, although the luminal cells are large, with abundant eosinophilic cytoplasm, and exhibit stellate reticulum-like areas and palisaded basal cell nuclei with reverse nuclear polarization.

Management and prognosis

• Recurrence rate varies from 10% to 40% with an overall rate of 23% in all cases and 34% in syndromic cases. Unilocular versus multilocular lesions have recurrence rates of 14% versus 26%, respectively.

• Enucleation/curettage versus segmental resection is associated with a recurrence rate of 23% versus 3%.

• Enucleation with adjunctive measures such as application of 5-fluorouracil, Carnoy solution, peripheral ostectomy, cryosurgery, and electrocautery is associated with a low recurrence rate and is tissue-sparing.

• Marsupialization and daily irrigation followed by cystectomy is also associated with a low recurrence rate and is organ-sparing.

• En bloc excision may be necessary for recurrent lesions that have failed other therapies but is not usually first-line therapy.

• Vismodegib, a hedgehog pathway inhibitor, has been shown to shrink these cystic tumors in syndromic patients.

Clinical and radiographic findings

• Solid/conventional ameloblastoma:

  • This constitutes two-thirds of lesions and is generally seen in the fourth to fifth decades of life with equal sex distribution, with patients in South America and Africa being at least a decade younger. If large, it may cause pain, paresthesia, teeth mobility, and swelling of the face. Approximately 80% of cases occur in the mandible and it is usually described as a solid tumor at surgery, although microcystic spaces may be present. Perforation of the cortical plate, especially on the lingual aspect, is often encountered.

  • It presents as a unilocular or multilocular radiolucency with almost equal frequency, most often in the posterior mandible and/or ramus area, although in Black patients it may have a predilection for lesions in the anterior mandible. Some ameloblastomas are associated with impacted teeth ( Fig. 15.7 ).

    

• Desmoplastic (scirrhous) ameloblastoma:

  • This variant constitutes 4% of cases, has equal mandibular and maxillary frequency with equal sex distribution, and unlike conventional solid ameloblastoma, 40% to 50% of cases occur in the anterior jaws.

  • Two-thirds present as a mixed radiolucent-radiopaque mass suggesting a fibroosseous lesion (see Fig. 15.7 E).

  • Keratoameloblastoma, a histologic variant which produces abundant keratin, may also have a mixed radiolucent-radiopaque appearance.

• Unicystic or unicystic plexiform ameloblastoma:

  • This represents 20% to 25% of ameloblastomas and presents in the second and third decades of life and is often associated with an impacted tooth, often with jaw and facial swelling. The most common sites are mid- and posterior mandible especially associated with the impacted third molar. Lesions unassociated with an impacted tooth tend to occur at least one decade later.

  • It occurs as a unilocular radiolucency in the posterior mandible and is associated with a displaced impacted mandibular molar in 50% to 80% of cases (see Fig. 15.7 F). It is described as a cystic lesion at surgery.

• Peripheral (extraosseous) ameloblastoma:

  • This represents approximately 1% of ameloblastomas and occurs in the fifth to sixth decades of life, with a male predilection of 2:1, with the mandible twice as likely to be affected. It occurs as a sessile nodule on the gingiva in the mandibular premolar-molar area (50% of cases). Radiographs must be taken to rule out an intraosseous ameloblastoma with perforation of the cortical bone. Rare cases occur at extragingival sites such as the buccal mucosa, although some authorities believe that these represent an unusual form of salivary gland tumor.

Etiopathogenesis and histopathologic features

Ameloblastoma differentiates toward and recapitulates ameloblasts and stellate reticulum of the developing tooth germ, without deposition of dental hard tissues or their matrix. Mutations in BRAF, RAS, and FGFR2 are present in 88% of cases with activating mutation in BRAF V600E present in 60% to 70% of mandibular tumors with the exception of adenoid ameloblastoma. Mutation in SMO is present in 56% of maxillary tumors especially those with plexiform histopathology, and CTNNB1, PIK3CA, SMARCB1, EGFR, PTEN, CDKN2A, and JAK3 have also been identified in ameloblastoma but much less frequently. Mutation in BRAF V600E usually occurs in younger patients and is an independent predictor of recurrence-free survival. Peripheral ameloblastoma may arise from rests of Serres in the gingiva or from the basal cell layer of the surface epithelium. The rare extragingival ameloblastoma of which less than 10 cases exist in the English literature, may arise from multipotent stem cells in the basal cells of the mucosal epithelium that proliferate and undergo odontogenic differentiation, or even represent an adamantinomatous pattern of a salivary gland tumor.

Ameloblastoma is classified histopathologically by gross pattern and constituent cells.

• Solid/conventional ameloblastoma patterns:

  • Follicular ameloblastoma exhibits islands or follicles of epithelial cells, typically with peripheral basal cells showing nuclear palisading and reverse polarization of the nuclei. Areas of microcystic and macrocystic change within the epithelial islands are common ( Fig. 15.8 ).

    

  • Plexiform ameloblastoma shows interconnected broad and thin trabeculae and cords of epithelial cells with basal cell nuclear palisading and reverse nuclear polarization, although these changes may be subtle in this pattern ( Fig. 15.9 ).

    

  • Desmoplastic or scirrhous ameloblastoma is a variant of the follicular ameloblastoma in which islands or follicles of epithelium appear compressed by markedly desmoplastic stroma; the epithelium is present as slender cords and irregularly shaped islands of hyperchromatic cells. Classic and acanthomatous cytology are seen in some of the larger tumor islands ( Fig. 15.10 ).

    

• Constituent cells:

  • Many tumors contain several cell types, the most common being classic and acanthomatous.

  • Classic lesions exhibit loose, stellate reticulum-like areas (see Figs. 15.8 and 15.9 ); classic and acanthomatous variants often coexist in follicular tumors while most plexiform tumors exhibit stellate reticulum ( Figs. 15.8 and 15.9 ).

  • Acanthomatous lesions exhibit large, polygonal squamous cells with abundant eosinophilic cytoplasm or keratinization (see Fig. 15.8 B and F).

  • Granular cell lesions contain large, pale cells with granular cytoplasm rich in lysosomes ( Fig. 15.11 A–D).

    

  • Basal cell lesions contain mostly basaloid cells; this is a rare variant (see Fig. 15.11 E–F).

  • Keratoameloblastoma is a rare form of ameloblastoma producing cystic spaces filled with compact parakeratin and orthokeratin, some with intraluminal papilliferous projections. Its relationship with solid KCOT/OKC is unclear ( Fig. 15.12 ).

    

• Adenoid ameloblastoma is a new entity with a pattern of plexiform ameloblastoma but forming ductlike structures (resulting from degenerated stroma) with a pseudocribriform architecture, basophilic stroma, epithelium spherules, and presence of dentinoid, ghost cells, and hyaline droplets reminiscent of ghost cell lesions. It tends to occur in the maxilla (80% of cases) and has a high recurrence rate ( Fig. 15.13 ).

  

• A rare osteoplastic type that induces bone formation within fibrous stroma has been reported.

• Intraosseous ameloblastoma that perforates the cortical plate and fuses with the surface epithelium, often causes papillary epithelial hyperplasia (see Fig. 15.9 C).

• Tumors with areas of hypercellularity, pleomorphism, and mitotic activity should be diagnosed as ameloblastoma with atypia and must be carefully evaluated for malignant transformation.

• Some lesions are highly vascular but these probably do not require a separate designation.

• Unicystic ameloblastoma:

  • Unicystic ameloblastoma has three patterns ( Fig. 15.14 ).

    

  • Luminal pattern: The cyst lining is generally 5 to 15 cells thick and exhibits eosinophilic luminal cells, underlying stellate reticulum-like cells, and palisaded, hyperchromatic basal cell nuclei with reverse polarization, giving the lining a “red-white-blue” appearance ( Fig. 15.15 ). These changes are referred to as the Vickers-Gorlin criteria and are identical to those seen in cystic changes within epithelial islands in solid ameloblastoma (see Fig. 15.8 C and G).

    

  • Intraluminal pattern (plexiform unicystic ameloblastoma): In addition to changes within the cyst lining, there is a plexiform proliferation of ameloblastomatous epithelium that protrudes into the lumen ( Fig. 15.16 ). Inflammation results in loss of the diagnostic features of this lesion and may lead to misdiagnosis of this cystic tumor as a radicular cyst or an inflamed dentigerous cyst (see Fig. 15.16 D).

    

  • Mural pattern: If there is mural proliferation within the wall of a unicystic ameloblastoma which usually is in the form of a follicular ameloblastoma, this must be reported because it will behave in a fashion similar to a solid ameloblastoma ( Fig. 15.16 G).

• Tumor cells exhibit cytoplasmic positivity for K14 and K19 and are negative for K7 and K18. Calretinin is positive within the stellate reticulum cells of solid ameloblastoma and the luminal cells of unicystic ameloblastoma, and CD56 is also often positive ( Fig. 15.17 A). Two-thirds of tumors are positive for BRAF ( Figs. 15.16 F and 15.17 B). High Ki-67 labeling and large numbers of CD10+ stromal cells may correlate with recurrence.

  

• Peripheral ameloblastoma: This usually represents a follicular ameloblastoma, classic and/or acanthomatous type. Fifty percent of cases are in continuity with the overlying epithelium ( Figs. 15.18 and 15.19 ).

  
  

• Extragingival ameloblastoma: Typical appearing, usually follicular ameloblastoma is present within the soft tissues of the buccal mucosa.

Differential diagnosis

• Dentigerous cyst or other odontogenic cyst does not exhibit the “red-white-blue” Vickers-Gorlin criteria, as noted in unicystic ameloblastoma; however, if the unicystic ameloblastoma is inflamed, these criteria may be lost.

• Squamous odontogenic tumor consists of islands of squamous cells that do not show palisading of the peripheral basal cells.

• Ameloblastic carcinoma shows obvious features of malignancy with hypercellularity, pleomorphic cells, many mitotic figures, and sometimes necrosis.

• Dentinogenic ghost cell tumor closely resembles adenoid ameloblastoma and contains ghost cells and dentinoid. At this time, it is unclear how the two are related: both are positive for β-catenin, and adenoid ameloblastoma is negative for BRAF.

• Adenomatoid odontogenic tumor contains enameloid while adenoid ameloblastoma exhibits dentinoid and ghost cells.

• Basaloid squamous cell carcinoma of the mucosa shows significant epithelial atypia and synchronous conventional squamous cell carcinoma and is usually readily distinguished from peripheral ameloblastoma.

• Oral basal cell carcinoma has been reported to occur on gingiva that is BerEP4+, similar to cutaneous basal cell carcinoma.

Management and prognosis

Recurrence varies greatly depending on the type of ameloblastoma and modality of treatment.

• Solid ameloblastoma: The recurrence rate is 5% to 17% if treated with marginal or segmental resection, and 30% to 35% if the tumor is curetted and/or enucleated.

• Reduction in tumor volume, especially for recurrent and metastatic tumors, was noted in patients using drugs that target the MAPK signaling pathway such as dabrafenib, trametinib, and vemurafenib.

• Unicystic ameloblastoma: The recurrence rates for those without and with mural proliferation are 6% and 37%, respectively, and most authorities recommend treating a unicystic ameloblastoma with mural proliferation as a solid ameloblastoma.

• Peripheral (extraosseous) ameloblastoma: This is treated with simple excision and does not recur.

Clinical and radiographic findings

• This occurs most frequently in the second and third decades of life, with a 2:1 female predilection. At least two-thirds of cases occur in the maxilla, and two-thirds are associated with the canine, usually maxillary. There may be slight painless swelling, but the most common complaint is failure of eruption of a tooth.

• It presents as a unilocular radiolucency and variable radiopaque flecks (“snowflake” opacities) around the crown of an impacted tooth ( follicular type) ( Fig. 15.20 ). Those unassociated with a tooth are referred to as extrafollicular tumors .

  

• Peripheral/extraosseous lesions are rare.

Etiopathogenesis and histopathologic features

Approximately 70% of cases exhibit KRAS mutation.

• The tumor has a thick capsule and consists of sheets, nodules, and whorls of spindled, cuboidal, and polygonal epithelial cells forming ductlike and rosette-like structures, sometimes even with a cribriform architecture. The cells have pale or clear cytoplasm and pale nuclei with dispersed chromatin and small nucleoli. Interlacing, delicate strands of epithelium surrounding the nodules contain darker nuclei with more eosinophilic cytoplasm. Macro- or microcystic areas may be present ( Figs. 15.21 and 15.22 ).

  
  

• Eosinophilic, deep pink, or basophilic droplets of amorphous material termed enameloid are characteristic, and this likely represents a matrix protein, amelotin (see Figs. 15.21 D and 15.22 D).

• Infrequently, dentinoid is encountered focally, calcifications may be present, and the stroma may be delicate, myxoid/mucinous, or densely collagenous.

• Areas resembling calcifying epithelial odontogenic tumor are present in 25% of cases and are considered by some to be within the normal histopathologic spectrum of this tumor while others believe this represents a hybrid odontogenic tumor.

• Tumor cells are positive for K5, K14, K17, and K19; Ki-67 index is 1% or less and BCL2 is present in approximately 25% of cases. Some cases exhibit nuclear and cytoplasmic β-catenin expression.

Differential diagnosis

• Adenoid ameloblastoma does not have a thick capsule or formation of enameloid but rather exhibits dentinoid deposition and sometimes, ghost cells.

• Adenomatoid dentinoma and adenomatoid odontogenic hamartomas may represent developing odontomas with an unusual adenomatoid epithelial proliferation. These two entities are not yet well-characterized.

Management and prognosis

• Enucleation is curative, and the recurrence rate is insignificant.

Clinical and radiographic findings

• This is most frequent in the fourth and fifth decades of life with equal sex distribution, and the mandible is involved in 60% to 70% of cases, mostly in the posterior aspect; a swelling may be present and almost half of cases exhibit cortical perforation.

• It presents usually as a unilocular (and much less often multilocular) radiolucency with variable calcifications (70% of cases), and 50% are associated with an impacted tooth ( Fig. 15.23 ).

  

• Five to 6% are extraosseous.

Etiopathogenesis and histopathologic features

This tumor recapitulates cells of the stratum intermedium of the enamel organ. Mutations in PTEN, PIK3CA, PTCH1. JAK3, and MET have been reported infrequently.

• The tumor consists of cords, islands, and sometimes sheets of large, often polygonal cells with abundant eosinophilic cytoplasm and sometimes intercellular bridges. Variation in nuclear shape and size that may be marked, and pseudoinclusions are common, but mitotic activity is not seen unless the tumor is malignant, an extremely rare occurrence. Cystic and microcystic change may be present. Congophilic amyloid (identified as odontogenic ameloblast-associated protein) is always present and generally in abundance ( Fig. 15.24 ).

  

• Approximately one-third of cases do not exhibit calcifications which may take the form of concentric lamellar rings (Liesegang rings) or dystrophic calcifications and the stroma is densely collagenous.

• Tumor cells are positive for K7, K8, K14, K13, and K19.

• Clear cell variant: Although clear cells may be present very focally in up to 46% of tumors, this variant is composed primarily of clear cells. (see Fig. 15.24 F).

• Noncalcifying Langerhans cell–rich variant: This is a rare variant, and occurs most often in the anterior maxilla, although peripheral cases exist. Calcifications are not present and Langerhans cells that are usually apposed to the epithelium, are readily identified with CD1a and CD207 (langerin) ( Fig. 15.25 ).

  

• Foci of calcifying epithelial odontogenic tumor are often seen within an adenomatoid odontogenic tumor and very small such foci within dentigerous cysts (see Fig. 14.29 ).

• Peripheral lesions are less likely to exhibit calcifications.

• Malignant forms are extremely rare.

Differential diagnosis

• Metastatic carcinomas have significantly more atypia, mitotic figures and desmoplasia, and lack amyloid.

• Central odontogenic fibroma may exhibit amyloid and CD1a+ cells but even the epithelium-rich variant does not contain as much epithelium as the calcifying epithelial odontogenic tumor. However, some regard the Langerhans cell–rich calcifying epithelial odontogenic tumor to be an amyloid-rich central odontogenic fibroma because it behaves less aggressively and tends to occur more frequently in the anterior maxilla, a more common site for central odontogenic fibroma.

• Malignant calcifying epithelial odontogenic tumor exhibits hypercellularity, hyperchromatic nuclei with coarse chromatin, mitotic figures, and other features of malignancy.

• Primary clear cell odontogenic carcinoma does not produce amyloid.

Management and prognosis

• Complete excision or enucleation is the treatment of choice, and the recurrence rate is up to 10% to 15%, especially if the tumor is curetted.

Clinical and radiographic findings

• This rare odontogenic tumor occurs most frequently in the third and fourth decades of life without sex predilection, equally affecting the body and posterior mandible, and anterior maxilla. Patients report painless swelling and teeth mobility. Multifocal lesions occur in 18% of cases and tends to occur in Blacks at a younger age.

• It presents as a well-demarcated semicircular or triangular usually unilocular radiolucency around the roots of teeth. ( Fig. 15.26 ).

  

Etiopathogenesis and histopathologic features

There has been a suggestion that NOTCH may play a role in the pathogenesis of this tumor.

• The tumor consists of irregularly shaped islands of mature squamous cells that are evenly spaced, with some islands containing scattered apoptotic cells. Importantly the cells at the periphery of the islands are squamous and not basaloid. Some islands may exhibit cystic change or may contain globular, eosinophilic, amorphous deposits reminiscent of enameloid or Rushton bodies, calcifications, or even mucous cells ( Figs. 15.27 and 15.28 ). The stroma is densely collagenous although there may mucinous/myxoid areas.

  
  

• Some tumors exhibit positivity for Notch1, 3, and 4, and their ligands Jagged1 and Delta1.

Differential diagnosis

• Follicular ameloblastoma, acanthomatous type, shows palisading of basal cell nuclei with stellate reticulum, and mandibular lesions are often positive for BRAF on immunohistochemistry.

• Primary intraosseous and metastatic carcinomas show significant cytologic atypia and are invasive.

• Squamous odontogenic-like proliferations composed of similar irregular islands of benign epithelium are sometimes seen in the walls of radicular cysts (see Chapter 14 ).

Management and prognosis

• The recurrence rate is 20% although enucleation, curettage, or excision is generally curative. Lesions that are large, multiloculated, multifocal, and/or recurrent may need en bloc resection.

Clinical and radiographic findings

• Ameloblastic carcinoma:

  • Most cases occur in the sixth decade of life and beyond, with a 2:1 to 3:1 male predilection, although the age range is wide with 18% occurring in those under 25. More than two-thirds occur in the mandible, mostly in the posterior, and pain, mucosal ulceration, and paresthesia are often noted.

  • Lesions appear as poorly demarcated, destructive radiolucencies.

  • Spindle cell variant: Only a handful of cases have been reported. The mean age is in the fifth decade, slightly younger than patients with conventional ameloblastic carcinoma with a slight male predilection and most lesions are mandibular.

• Metastatic ameloblastoma:

  • The mean age is in the fifth decade with almost equal sex distribution with 80% occurring in the mandible. They occur at a median of 10 years after the initial diagnosis of ameloblastoma in the jaws. Most patients had been treated with enucleation and curettage initially and there is an average of four local recurrences. Seventy percent of lesions present with lung lesions often bilaterally, and 20% to 30% with nodal metastases, with 20% to 25% of patients exhibiting multisite metastases. Sixty percent of the original tumors were treated by enucleation or curettage. Hypercalcemia has been reported in some cases with pulmonary metastases.

  • Radiographically, the primary lesion may appear circumscribed and discrete, rather than poorly demarcated as one expects for a primary carcinoma.

Etiopathogenesis and histopathologic features

The majority of ameloblastic carcinomas arise de novo, with approximately 25% arising from preexisting ameloblastomas, and this has no bearing on its behavior or prognosis. One-third of these tumors are positive for BRAF V600E mutation.

Metastatic ameloblastoma may occur as a result of multiple surgical manipulations of multiple recurrences of the primary tumor resulting in hematogenous and lymphatic spread and as such, are often discovered many years after removal of the original jaw tumor. Most are positive for mutations in BRAF .

• Ameloblastic carcinoma:

  • These tumors are plexiform or follicular in pattern with palisading of the basal cell nuclei and reverse nuclear polarity which may be subtle. Stellate reticulum-like areas are usually difficult to discern and there is hypercellularity with tumor cells exhibiting spindling or pseudosarcomatoid appearance, pleomorphism, necrosis, hyperchromasia, and many mitotic figures (average of 4 per high-power field), as well as atypical mitotic figures ( Fig. 15.29 ). Necrosis and perineural invasion may be present.

    

  • Keratinization, ghost cells, clear cells, and focal dentinoid production may be present.

  • Tumor cells express K14, K18, and K19 and there is a high Ki-67 proliferation index as expected which helps to differentiate this from ameloblastoma. SOX2 and OCT4 are expressed in >85% of tumors, as is PITX2.

• Spindle cell variant (sarcomatoid ameloblastic carcinoma): While ameloblastic carcinoma may show foci of spindle cells within tumor islands, this lesion consists of a proliferation of atypical spindle/sarcomatoid cells representing epithelial-mesenchymal transition from ameloblastic carcinoma. Both spindle cells and carcinomatous cells are positive for vimentin and p40.

• Metastastatic ameloblastoma:

  • The cytology is that of a conventional ameloblastoma without or with minimal evidence of cytologic atypia.

Differential diagnosis

• Primary intraosseous carcinoma and ameloblastic carcinoma are likely related lesions, with the former showing less ameloblastic differentiation, in that basal cell nuclear palisading or formation of stellate reticulum-like areas is minimal or insignificant.

• Whether the spindle cell variant of (sarcomatoid) ameloblastic carcinoma is distinct from an ameloblastic carcinosarcoma or odontogenic carcinosarcoma is unclear.

• Metastatic carcinoma must be ruled out.

• Calcifying epithelial odontogenic tumor often exhibits nuclear pleomorphism but tumor cells are large and eosinophilic and there is insignificant mitotic activity, hypercellularity, or necrosis.

Management and prognosis

• Ameloblastic carcinoma:

  • Treatment is with en bloc resection with radiation and/or chemotherapy as appropriate. The recurrence rate is close to 30%. Twenty to twenty-five percent develop metastases, and distant metastases are to lungs, bone, and brain. Five-year overall survival overall without and with metastasis are approximately 70% and 20%, respectively.

• Metastatic ameloblastoma:

  • Patients are treated with surgery, chemotherapy, and/or radiation. Five-year survival is 37% and 62% with pulmonary and nodal metastases respectively, although some patients survive for decades.

Clinical and radiographic features

• The median age is in the sixth decade of life, with a 2:1 male predilection, and pain, mobility of teeth, and paresthesia are common. Eighty to ninety percent occur in the mandible. Lymph node metastasis is present in 20% to 50% of cases.

• It presents as a poorly demarcated radiolucency of the mandible, often with cortical perforation ( Fig. 15.30 ).

  

Etiopathogenesis and histopathologic features

Tumors arise either from preexisting odontogenic cysts (30% of cases) or de novo. Approximately 60% are associated with a residual or radicular cyst, 16% with a dentigerous cyst, and 14% with a KCOT/OKC. There is likely overlap between this entity and the ameloblastic carcinoma because both putatively arise from odontogenic rests within the jaw bones, except that one has a more squamous cell carcinoma phenotype and the other a clearly ameloblastomatous phenotype.

• Primary intraosseous carcinomas are generally squamous cell carcinomas with approximately half being well-differentiated and keratinizing. Most arise from odontogenic cysts, the lining of which exhibits varying degrees of dysplasia or carcinoma in situ ( Fig. 15.31 ).

  

• Features suggesting odontogenic differentiation may be seen in approximately half the cases and include a follicular pattern, palisading of the peripheral basal cells, and the presence of clear cells ( Fig. 15.32 ). Tumors may manifest as verrucous or papillary squamous carcinoma or sarcomatoid carcinoma.

  

Differential diagnosis

• Ameloblastic carcinoma shows obvious palisading of the peripheral cells. Differentiation between this and primary intraosseous carcinoma may be moot because both are primary carcinomas in bone.

• Primary squamous cell carcinoma of the overlying mucosa or the maxillary sinus invading bone, as well as metastatic squamous cell carcinoma, must be ruled out.

• Calcifying epithelial odontogenic tumor contains cells with pleomorphic nuclei but do not exhibit increased mitotic activity or other features of malignancy.

• Mucoepidermoid carcinoma contains mucous cells although this may be scant, and ductal structures may be present. Most will exhibit CRCT-MAML2 rearrangement.

• Desmoplastic (scirrhous) ameloblastoma contains irregularly shaped islands of basaloid cells without cytologic atypia, some islands show typical ameloblastoma, and the stroma is desmoplastic.

• Odontogenic carcinosarcomas have been reported, but they are extremely rare and would be difficult to distinguish from a primary intraosseous sarcomatoid squamous cell carcinoma.

Management and prognosis

• Resection is the treatment of choice with or without lymph node dissection, with adjuvant radiation therapy and/or chemotherapy as appropriate. The recurrence rate is 60%. Ten percent develop distant metastases to lungs, bones, and brain, and 2-year and 5-year survival are 60% and 40%, respectively.