Mandibular ameloblastoma is a benign yet locally aggressive odontogenic tumor with significant clinical implications. This review provides a detailed examination of the pathogenesis, diagnostic modalities, and management strategies associated with mandibular ameloblastoma. We discuss the molecular mechanisms involved in the tumor's development, including genetic mutations and signaling pathways. The diagnostic approach is outlined with an emphasis on the roles of imaging and histopathological analysis. Finally, we explore contemporary treatment options, ranging from conservative to radical surgical interventions, highlighting their respective outcomes and recurrence rates. Emerging therapies, such as targeted molecular treatments and adjuvant therapies, are also considered, providing a comprehensive understanding of this complex tumor.

Ameloblastoma is a benign odontogenic tumor that primarily affects the mandible. Despite its benign nature, ameloblastoma is notorious for its aggressive behavior, characterized by local invasion and a high recurrence rate following treatment. First described by Broca in 1868, ameloblastoma accounts for approximately 1% of all oral tumors and about 10% of odontogenic tumors. The World Health Organization (WHO) classifies ameloblastoma into different subtypes, with conventional solid or multicystic ameloblastoma being the most common.

The importance of understanding ameloblastoma lies not only in its clinical management but also in its biological behavior, which often presents challenges in treatment due to its locally invasive nature. This review aims to provide a comprehensive overview of mandibular ameloblastoma, focusing on its pathogenesis, diagnostic strategies, and management options.

The pathogenesis of ameloblastoma is a subject of extensive research, with several molecular pathways implicated in its development. The tumor arises from the epithelial component of the developing tooth or from epithelial remnants of the odontogenic apparatus, such as the dental lamina. Genetic mutations play a pivotal role in the pathogenesis of ameloblastoma.

2.1 Genetic Mutations

Recent studies have identified mutations in several genes associated with ameloblastoma, notably BRAF, SMO, and RAS. The BRAF V600E mutation, present in approximately 60% of ameloblastoma cases, is particularly significant as it is a known driver mutation in various cancers. The mutation leads to the activation of the MAPK/ERK signaling pathway, promoting cell proliferation and survival. The identification of this mutation has opened avenues for targeted molecular therapies, such as BRAF inhibitors.

2.2 Signaling Pathways

In addition to genetic mutations, various signaling pathways are involved in ameloblastoma pathogenesis. The Hedgehog signaling pathway, which plays a crucial role in normal odontogenesis, is often dysregulated in ameloblastoma. Mutations in the SMO gene, a key component of the Hedgehog pathway, have been identified in a subset of ameloblastomas. The Wnt/β-catenin signaling pathway is another critical pathway, with evidence suggesting its involvement in the proliferation and survival of ameloblastoma cells.

2.3 Tumor Microenvironment

The tumor microenvironment also plays a significant role in the growth and invasion of ameloblastoma. The interaction between tumor cells and the surrounding stromal cells, including fibroblasts and immune cells, contributes to the tumor's aggressive behavior. Angiogenesis, or the formation of new blood vessels, is another key factor that supports tumor growth and metastasis, although ameloblastoma rarely metastasizes.

Accurate diagnosis of mandibular ameloblastoma is essential for effective management. The diagnosis typically involves a combination of clinical examination, radiological imaging, and histopathological analysis.

3.1 Clinical Presentation

Mandibular ameloblastomas often present as a painless swelling in the jaw, which can progressively enlarge over time. Patients may also experience facial asymmetry, tooth mobility, or malocclusion [12]. In some cases, the tumor may cause paresthesia or anesthesia if it invades the inferior alveolar nerve. Due to its slow growth, the tumor is often asymptomatic in the early stages, leading to delayed diagnosis [13].

3.2 Radiological Imaging

Imaging plays a crucial role in the diagnosis and treatment planning of ameloblastoma. Radiographic features of ameloblastoma are characteristic, with the tumor often appearing as a multilocular radiolucency with a "soap bubble" or "honeycomb" appearance on conventional radiographs [14]. 

3.2.1 Panoramic Radiography and CT scans

Panoramic radiography is typically the first imaging modality used, providing a broad overview of the lesion's extent. However, computed tomography (CT) scans offer more detailed information on the tumor's size, extent, and relationship to adjacent structures, aiding in surgical planning [15]. CT imaging can also help in differentiating ameloblastoma from other cystic lesions of the jaw.

3.2.2 Magnetic Resonance Imaging (MRI)

Magnetic resonance imaging (MRI) is particularly useful for assessing the soft tissue involvement of the tumor. It provides superior contrast resolution compared to CT, allowing for better visualization of the tumor's boundaries and infiltration into surrounding tissues [16]. MRI is also valuable in detecting recurrences, as it can differentiate between scar tissue and recurrent tumor [17].

3.3 Histopathological Examination

The definitive diagnosis of ameloblastoma is based on histopathological examination. Ameloblastomas are characterized by the presence of ameloblast-like cells surrounding stellate reticulum-like cells, resembling the enamel organ of a developing tooth [18]. 

3.3.1 Histological Subtypes

Ameloblastomas are classified into several histological subtypes, including follicular, plexiform, acanthomatous, granular cell, and desmoplastic variants. The follicular and plexiform types are the most common, with the follicular type showing a more aggressive behavior and a higher recurrence rate [19]. 

3.3.2 Immunohistochemistry

Immunohistochemistry (IHC) is often employed to differentiate ameloblastoma from other odontogenic tumors. Markers such as cytokeratin 19 (CK19), amelogenin, and p63 are frequently expressed in ameloblastoma, aiding in its diagnosis [20]. The presence of the BRAF V600E mutation can also be detected through molecular testing, providing additional diagnostic and prognostic information [21].

The management of mandibular ameloblastoma requires a multidisciplinary approach, combining surgical intervention with adjuvant therapies when necessary. The choice of treatment is influenced by the tumor's size, location, histological subtype, and the patient's overall health.

4.1 Surgical Management

Surgery remains the cornerstone of ameloblastoma treatment. The goal of surgical management is complete removal of the tumor with clear margins to reduce the risk of recurrence. However, the extent of surgery can vary from conservative to radical approaches.

4.1.1 Conservative Surgery

Conservative surgery involves enucleation or curettage of the tumor, preserving as much of the surrounding bone and tissue as possible. This approach is typically reserved for smaller, well-defined lesions, particularly in younger patients where preserving jaw function and appearance is crucial [22]. However, conservative surgery is associated with a higher recurrence rate, reported to be as high as 55-90% [23].

4.1.2 Radical Surgery

Radical surgery involves resection of the tumor with a margin of healthy tissue, often including segmental mandibulectomy. This approach significantly reduces the risk of recurrence, with rates reported between 5-15% [24]. However, it can result in significant functional and aesthetic deficits, necessitating complex reconstructive surgery to restore the form and function of the mandible [25].

4.1.3 Reconstructive Surgery

Following radical resection, reconstructive surgery is often required to restore mandibular function and aesthetics. The use of microvascular free flaps, such as the fibula free flap, has become the gold standard in mandibular reconstruction due to its ability to provide both bone and soft tissue for complex defects [26]. Advances in computer-aided design/computer-aided manufacturing (CAD/CAM) technology have further enhanced the precision of reconstructive surgery, allowing for custom-made prostheses that match the patient's anatomy [27].

4.2 Non-Surgical Management

While surgery remains the primary treatment modality, non-surgical approaches are being explored, particularly for cases where surgery is contraindicated or in patients with recurrent disease.

4.2.1 Radiation Therapy

Radiation therapy is generally not recommended as a primary treatment for ameloblastoma due to the tumor's relative radioresistance and the potential for long-term complications, such as osteoradionecrosis [28]. However, it may be considered as an adjunctive therapy in cases of recurrent or unresectable tumors [29]. Stereotactic radiosurgery, which delivers precise, high-dose radiation, has shown promise in treating recurrent ameloblastoma, although further studies are needed to establish its efficacy [30].

4.2.2 Chemotherapy

Chemotherapy has a limited role in the management of ameloblastoma, primarily due to the tumor's low mitotic rate and lack of response to conventional chemotherapeutic agents [31]. However, there have been reports of partial responses to targeted therapies, particularly in cases with specific genetic mutations such as BRAF V600E [32].

4.3 Emerging Therapies

Advancements in molecular biology have led to the development of targeted therapies, offering new hope for patients with recurrent or inoperable ameloblastoma.

4.3.1 Targeted Molecular Therapy

Targeted therapies, particularly those targeting the BRAF V600E mutation, have shown promise in the treatment of ameloblastoma. BRAF inhibitors, such as vemurafenib and dabrafenib, have been reported to induce significant tumor shrinkage in cases harboring the BRAF V600E mutation [33]. These therapies are particularly valuable in cases where surgery is not feasible or as an adjunct to reduce tumor size preoperatively [34].

4.3.2 Immunotherapy

Immunotherapy, which harnesses the body's immune system to fight cancer, is an emerging field in the treatment of various malignancies, including odontogenic tumors. While there is limited data on the use of immunotherapy in ameloblastoma, early studies suggest that immune checkpoint inhibitors may hold potential, particularly in tumors with high mutational burdens or those resistant to conventional therapies [35].

4.4 Follow-Up and Recurrence

Given the high recurrence rate of ameloblastoma, particularly in cases treated conservatively, long-term follow-up is essential. Recurrences are most common within the first five years post-treatment, but late recurrences can occur even decades after initial treatment [36]. Regular imaging, such as panoramic radiographs and CT scans, is recommended to monitor for recurrence, and any suspicious findings should prompt further investigation [37].

Mandibular ameloblastoma remains a challenging tumor to manage due to its locally aggressive behavior and high recurrence rate. Advances in our understanding of the tumor's molecular biology have led to the development of targeted therapies, offering new treatment options for patients with recurrent or unresectable disease. However, surgery remains the cornerstone of treatment, with the choice between conservative and radical approaches depending on the tumor's characteristics and the patient's overall health. Continued research into the molecular mechanisms of ameloblastoma and the development of novel therapies will be crucial in improving outcomes for patients with this complex tumor.