Malignant (metastasising) ameloblastoma is an ameloblastoma that metastasizes in spite of an innocuous histologic appearance. The primary tumor does not show any specific features different from conventional ameloblastomas that could predict metastatic potential (Fig. 6.1) [4–6].

It is thus the clinical behavior and not histology that justifies a diagnosis of malignant ameloblastoma [1, 7].

Ameloblastic carcinoma shows combined histologic features of both ameloblastoma and squamous cell carcinoma [1, 8]. Most cases occur in the mandible as asymptomatic swellings and, radiographically, perforation of the cortical bone plate and extension into the adjacent soft tissues are non uncommon and may lead to the suspicion of a malignant lesion.

The tumor resembles ameloblastoma by the presence of epithelial islands with peripheral columnar cells that show palisading at the border with the stroma but also exhibits pronounced cytological atypia and mitotic activity, thus allowing the separation from ameloblastoma (Figs. 6.2 and 6.3).

Complete surgical resection is advised but metastatic deposits may appear after a variable timespan (few months to several years), most frequently in the lungs and lymph nodes [9, 10].

Primary intraosseous carcinoma is a squamous cell carcinoma arising within the jaws, having no initial connection with the oral mucosa, and presumably developing from residues of the odontogenic epithelium [1]. Swelling of the jaw and pain most often are the presenting signs and radiologically, bone loss is present (Fig. 6.4).

Gross examination reveals a tumor that is not confined to the jaw bone but spreads into adjacent soft tissues after perforating though the cortical bone (Figs. 6.5 and 6.6) and within the jaw there is extension through the periodontal ligament (Fig. 6.7). The tumor is composed by atypical squamous cells, ranging from well to poorly differentiated [6, 8], similar to squamous cell carcinoma occurring at other body sites including the oral mucosa. Therefore, one has to be sure that the tumor indeed is purely intraosseous, excluding that it is a mucosal squamous cell carcinoma that has invaded the underlying jaw bone (Fig. 6.8). In practice, this means that any connection of the lesion with the oral mucosa refutes a diagnosis of intraosseous carcinoma. Moreover, one has to exclude the possibility that the intraosseous lesion represents a metastastis from a primary squamous cell carcinoma elsewhere.

Rarely, intraosseous carcinoma is connected with another jaw lesion, such as the epithelial lining of an odontogenic cyst [11, 12], or with the enamel epithelium that lines the tooth crown before eruption (Figs. 6.9 and 6.10) [13]; they could represent the tissue from which the tumor has arisen but a collision phenomenon cannot be excluded. Occasionally, primary intraosseous carcinoma may show the appearance of a spindle cell carcinoma, immunohistochemistry needed to reveal the epithelial nature of the tumor cells (Figs. 6.11 and 6.12). If there is also extensive bone remodeling, such cases may be mistaken for osteosarcoma (Fig. 6.13).

Resection and postoperative radiotherapy seem to provide the best treatment results. However, the prognosis is poor because of frequent metastases to regional lymph nodes and lungs, with almost 50 % of the patients failing loco-regionally within the first 2 years of follow-up [14].

Clear cell odontogenic carcinoma was initially reported as clear cell odontogenic tumor [15] , the latter designation being dropped as this lesion has shown a metastatic potential [16].

Usually, the lesion shows progressive jaw expansion with teeth loosening as the most frequent presentation, the anterior mandible being the preferred localisation [17–19]. Radiologically, it appears as an ill-defined radiolucency and gross examination reveals spread beyond the confines of the jaw (Figs. 6.14 and 6.15).

Histologically, the tumor is more frequently composed of cells with clear cytoplasm, hyperchromatic nuclei and well-defined borders, arranged in strands or large nests (Fig. 6.16) [17]. These cells coexist with variable proportions of smaller polygonal cells with eosinophilic cytoplasm and dark nuclei (Figs. 6.17 and 6.18). In rarer instances, the tumor may be exclusively composed by a clear cell population and, occasionally, focal squamous cell differentiation has also been reported [18].

The clear cells stain variably positive for glycogen with PAS, this staining disappearing after diastase-pretreatment and mucin stains are negative. Immunohistochemically, there is expression of epithelial markers such as keratin AE1/AE3, cytokeratins 8–18, cytokeratin 19 and Epithelial Membrane Antigen [19].

Clear cell odontogenic carcinoma has to be distinguished from other lesions that have clear cells as their main morphology. This includes metastatic renal cell carcinoma as the most likely alternative, the clear cell variant of mucoepidermoid carcinoma, and ameloblastoma with clear cells being rare. Metastatic renal cell carcinoma mainly can be ruled out by an appropriate diagnostic work-up of the patient. The clear cell variant of muco-epidermoid carcinoma can be properly identified with stains for mucin production. Differentiation from ameloblastoma with clear cells may be problematic and it has been proposed that these lesions may be histogenetically related, as previously mentioned [20] but this diagnostic dilemma has little clinical significance as both ameloblastoma and clear cell odontogenic carcinoma require excision with a margin including healthy tissue. Furthermore, the recently identified odontogenic carcinoma with dentinoid enters the differential diagnosis as the majority of them also contain clear cells [21].

Whether the genetic changes recently found in clear cell odontogenic carcinoma will be diagnostically useful, has yet to be determined [22].

As already briefly mentioned surgical resection is advised as recurrent disease occurs in more than 50 % of cases with prolonged follow-up; metastases have been found in lymph nodes as well as in the lungs and the skeleton and tumor-related death has also been reported [17, 19].

Malignant epithelial odontogenic ghost cell tumor, also called ghost cell odontogenic carcinoma according to the latest WHO classification [1], is a tumor that combines the characteristics of a calcifying cystic odontogenic tumor with cytonuclear atypia indicating malignancy and that often arises through malignant transformation of a pre-existing benign calcifying cystic odontogenic tumor [23].