Ameloblastic Carcinoma

This neoplasm shows areas of classical ameloblastoma along with distinct cytological features of malignancy. It may arise in the background of preexisting ameloblastoma but the majority of the cases appear to develop de novo. These lesions may or may not be associated with metastasis. There is an equal preponderance among both genders, and the lesion typically occurs in elderly. Mandible is the most common site of occurrence (~66%) with a predilection for the posterior segment. Ameloblastic carcinoma is a distinct entity from metastasizing ameloblastoma. The latter is histologically benign ameloblastoma that while maintaining characteristics of the parent tumor has the ability to metastasize. On histopathology, classical features of malignancy like pleomorphism, nuclear hyperchromasia, increased mitotic activity, and focal areas of necrosis are seen. Peripheral palisading and reverse nuclear polarization are known to be present. There may be areas of perineural and vascular invasion. Higher levels of aneuploidy and an increased proliferation index differentiates it from benign ameloblastoma. ^{1 , 3 , 4} Proliferation markers like Ki 67 are known to be significantly higher in ameloblastic carcinoma compared to the ameloblastoma. ⁴

Primary Intraosseous Carcinoma

Primary intraosseous squamous cell carcinoma (PIOSCC) is derived from the remnant odontogenic epithelium. PIOSCC is found more often in the body and posterior mandible than in the maxilla. Most cases are asymptomatic and are incidentally discovered during routine dental evaluation. Advanced tumors may present with facial swelling and paresthesia. Mean age of occurrence is the 5-6th decade, with a male preponderance. PIOSCC must be distinguished from squamous cell carcinoma (SCC) arising from the adjoining oral mucosa that secondarily invades the mandible. This is often difficult particularly when the tumor has extraosseous spread and involves the surface epithelium. PIOSCC is also known as primary intraosseous epidermoid carcinoma. It can occur de novo or in the background of keratocystic odontogenic tumor or other odontogenic cysts. ⁵ The etiology of these tumors is not well understood. The most plausible explanation is an inflammatory stimulus as these areas are not exposed to carcinogens. Histologically, the tumor shows areas of squamous epithelium with features of SCC with well to moderate differentiation which can be keratinizing or nonkeratinizing. ^{1 , 3 , 6} The differential diagnosis includes high-grade mucoepidermoid carcinoma and metastatic lesions of mandible.

Sclerosing Odontogenic Carcinoma

This is a recent addition to the 4th edition of WHO’s (2017) classification of head and neck tumors. ¹ It was first reported in the literature by Koutlas et al in 2008. ⁷ Histologically, it shows bland cytologic features with cords and strands of cells surrounding stroma and dense sclerosis. These tumors have an aggressive pattern of growth into the local nerves and muscles. On immunohistochemistry, these are positive for cytokeratin markers, E cadherin and nuclear p63. No metastasis or disease related death has been reported with these tumors to date. There is the need for more data to properly understand the biology of this entity to guide the appropriate management algorithm.

Clear Cell Odontogenic Carcinoma

This is a rare neoplasm of odontogenic origin which usually occurs in adults in their 6th decade, with a significant female predilection. It primarily affects the mandible. The neoplasm is locally aggressive and infiltrates the surrounding medullary bone, nerves, and lymphatics. It has propensity to regional and distant metastasis. Histologically, the tumor shows a biphasic pattern characterized by a peripheral rim of hyperchromatic polygonal cells with eosinophilic cytoplasm surrounding islands of clear cells with fibrocellular stroma. ^{3 , 8} Alternatively, there may be isolated nests of clear cells. Rarely, it may be associated with an ameloblastic pattern. On immunohistochemistry, the tumor is positive for cytokeratins, p63, and epithelial membrane antigen. Recently, it has been shown that majority of the tumors show EWSR1 rearrangement commonly with AFT1. ⁹ This mutation is highly sensitive for clear cell odontogenic carcinoma but is not specific as it may occur in other clear cell malignancies as well. Limited intervention in form of curettage and enucleation is associated with a high rate of recurrence, and resection with clear margins is the treatment of choice. Differential diagnosis includes hyalinizing clear cell carcinoma of salivary gland.

Ghost Cell Odontogenic Carcinoma

According to WHO’s description, these are rare with features of calcifying cystic odontogenic tumors or dentinogenic ghost cell tumors. ³ There is a male predilection with a peak incidence in the 4th decade. This tumor is more likely to affect maxilla, although mandibular occurrences have also been reported. The tumor can arise de novo or secondary to a benign calcifying cystic odontogenic tumor, dentinogenic ghost cell tumor, or other odontogenic cyst. Histopathologically, there are features of benign calcifying cystic odontogenic tumors with areas of malignant transformation characterized by epithelial islands in fibrous stroma with areas of mitosis. Ghost cells are present in varying amounts. The malignant component may be distinct from the benign areas or could be intermingled in a benign background. Proliferation markers Ki 67 and p53 help in differentiating the carcinoma from the benign odontogenic cysts. ¹⁰ Prognosis is variable due to the diversity of histology and biological behavior, ranging from a slow growing tumor to more aggressive variants. ¹¹

Odontogenic Sarcomas

These tumors are characterized by benign epithelial and malignant mesenchymal component, which include ameloblastic fibrosarcoma, ameloblastic fibrodentinosarcoma, and ameloblastic fibroodontosarcoma. ^{3 , 4} Ameloblastic fibrosarcoma may arise de novo or secondary to ameloblastic fibroma. The common presentation is in younger patients usually in the 2nd and 3rd decades, with a higher predilection for males. Mandible is commonly affected and the tumor is usually located posteriorly. Histologically, the tumor is characterized by the benign epithelial polygonal cells arranged in branching cord fashion surrounded by a hypercellular connective tissue stroma showing high mitotic rate. These tumors are highly aggressive locally but have a low propensity for distant metastasis. Ameloblastic fibrodentinosarcoma and ameloblastic fibroodontosarcoma have dysplastic dentin and/or enamel in addition to features of ameloblastic fibrosarcoma. The subclassification of odontogenic sarcoma has been deleted from the latest WHO classification. ^{1 , 12}

Odontogenic Carcinosarcoma

Initially removed from the 2005 WHO classification, odontogenic carcinosarcoma has now been reincorporated in the latest 2017 version. ^{1 , 3} The tumor is characterized by pattern similar to ameloblastic fibrosarcoma with both the epithelial and mesenchymal components showing malignant features. ^{1 , 13}

Chondrosarcoma

Chondrosarcoma is an extremely rare tumor of the facial skeleton arising from hyaline cartilage. Only 4% of all chondrosarcomas occur in the head and neck; the mandible and maxilla are most commonly affected. Presentation is usually in the 4th decade, commonly in males. It has a predilection for the symphysis, coronoid, and condyloid processes. Visibly, these tumors are pale and glistening which on microscopy are lobulated and show round to oval cells in the background of chondroid matrix with cellularity and atypia. ^{3 , 14} IDH1 and IDH2 are the commonly encountered mutations with these tumors. ¹⁵

Mesenchymal Chondrosarcoma

Mesenchymal chondrosarcoma is an aggressive variant that equally affects the mandible and maxilla. It commonly occurs in young adults with a female preponderance. Visibly, it appears fleshy with areas of chalky calcification. On microscopy, it shows variable amount of areas of hyaline cartilage with round to spindle cells. These cells are immunoreactive to S-100 and CD99. ^{3 , 14} HEY1-NCOA2 fusion is the common mutation which may be found in as high as 80% of cases. ¹⁶

Osteosarcoma

Although primary osteogenic sarcoma (OS) is the commonest bony tumor of the mandible, it is relatively rare, with large centers reporting just 1-2 cases/year. ^{17 , 18} Given the rarity of this tumor, treatment guidelines are often extrapolated from extra-gnathic OS. OS of the mandible are however a distinct entity in that they are locally aggressive and rarely known to be associated with distant metastasis compared to the more commonly occurring tumors of the appendicular skeleton. ^{19 , 20} The majority of cases are sporadic but familial cases associated with Li Fraumeni syndrome have been described. A genetic correlation between retinoblastoma and osteosarcomas exists on the 13q14 chromosome; retinoblastoma patients are known to have a higher incidence of OS, more so if they have received radiotherapy earlier. Predisposing conditions includes Paget’s disease, fibrous dysplasia, and prior radiotherapy. Radiation-induced OS occur after a median latent period of 10 or more years and are associated with an aggressive course and worse prognosis.

OS is a primary tumor of the bone, characterized by osteoid or bone formation by the tumor cells. It can be classified as low grade (parosteal or central), intermediate grade (periosteal), or high grade (conventional, telengiectasic, and small cell). Based on the predominant type of extracellular matrix produced by the tumor cell, the conventional osteosarcoma is further classified as osteoblastic, chondroblastic, and fibroblastic. ^{19 , 20} Chondroblastic OS can mimic chondrosarcoma on histology in the absence of osteoid component. Galectin 1 and ezrin help to establish the diagnosis in these cases. ^{1 , 3 , 14 , 19}

The most common presenting feature is a painless mass lesion of the jaw often mimicking benign tumors, particularly when low grade. Loosening of the teeth and radiating pain along the inferior alveolar nerve may occur. Both genders are equally affected a decade or two after long bone OS, and a typical patient presents at 30-40 years of age. The body of the mandible is most commonly involved followed by the angle and the ascending ramus. Given the anatomical constraints that preclude radical clearance, tumors are more likely to recur locally, particularly in larger lesions. Surgery is the mainstay of treatment and obtaining clear margins is of paramount importance. ^{19 , 20} Resection must be radical and there is no role for conservative procedures such as marginal mandibulectomy. A margin of 1 cm has been advocated as adequate in contrast to the 5-cm margin for long bone OS. Assessment of the extent of intramedullary involvement preoperatively by magnetic resonance imaging (MRI) helps ensure adequate bony resection. MRI is also useful for better visualization of the soft tissue extent of the tumor. The most important prognostic factor that influences outcomes is a clear margin of resection. Other factors that influence outcomes are histology and grade of the tumor (chondroblastic having better outcome than fibroblastic OS), age, advanced stage at presentation, and initial nonsurgical treatment. The role of adjuvant radiotherapy and chemotherapy has been a matter of debate for ages. Most published literature and metaanalyses reveal conflicting results primarily due to the small number of patients in each series, lack of uniformity of data, and studies being spread across long time spans. ^{17 , 18} Some of these studies are over 2 decades old making applicability to today’s day and age irrelevant, given the advances in surgical technique and reconstruction. A relatively recent review article has proposed a treatment algorithm suggesting the role of radiotherapy and chemotherapy in both the adjuvant and neoadjuvant settings taking into account published literature, stage, grade, postoperative margin status, and response to chemotherapy. ¹⁹ Given that local rather than distant recurrence is the main cause of failure, most authors recommend adjuvant radiotherapy in case of close or positive margins and for tumors > 5 cm. Chemotherapy is conceptually attractive in the neoadjuvant setting in large tumors, which in the opinion of the surgeon could pose an issue in obtaining free margins, with an aim to downsize the tumors and render them operable. On one hand, Mücke et al showed adding neoadjuvant chemotherapy to osteosarcomas improves survival. ²¹ Adjuvant chemotherapy, on the other hand, should be considered in large and high-grade tumors where the risk of distant metastasis is theoretically higher. Hence, the decision to adjuvant chemotherapy should be individualized. Chemotherapy regimens are similar to those used for long bone OS. 5-year survival varies between 10 and 100% but is usually in the range of 60-70%. ^{19 , 20}