Ameloblastoma: the dilemma between recurrence and surgical impairment

Ameloblastoma represents a major reconstructive challenge in oral and maxillofacial surgery. Although classified as benign, this odontogenic tumour exhibits aggressive infiltrative growth, localised to the mandible in 80 to 90% of cases. Diagnosis, often late in young patients (mean age of 34 years), confronts the practitioner with a complex therapeutic arbitration: the conservative approach exposes to a recurrence rate of 41%, while radical resection, although safer (8% recurrence), requires segmental mandibulectomies with microvascular free flaps, heavily impacting the quality of life.

The study examines the integration of a precision medicine workflow to identify actionable molecular alterations, such as BRAF V600E mutations (present in more than 50% of cases) or SMO. The primary objective is to evaluate the radiological and pathological response to personalised targeted therapies.

The authors test the hypothesis that a neoadjuvant approach would allow for significant tumor reduction. Such regression could transform an initially debilitating surgery into a procedure that is more bone-tissue sparing, reducing functional and aesthetic morbidity without compromising long-term oncological control.

Study design and population

This study was conducted using a prospective observational design within a tertiary care center. The cohort included 14 patients (12 men and 2 women) presenting with multicystic ameloblastoma. The median age at the time of genomic profiling was 56 years (IQR: 32-62 years). Histological subtypes included follicular (n=6), plexiform (n=2), acanthomatous (n=1), and mixed forms.

Experimental protocol and molecular analysis

The protocol was based on a precision oncology workflow structured as follows:

• Comprehensive genomic profiling: Search for targetable alterations beyond the classic BRAF V600E mutation, including SMO, FGFR2, KRAS, NRAS and HRAS genes.
• Signaling pathway analysis: Evaluation of canonical and non-canonical GLI signaling via Hedgehog, RTK/RAS/RAF/MAPK and PI3K pathways.
• Therapeutic intervention: Administration of molecularly guided therapies, primarily in a neoadjuvant (pre-surgical) setting.

Evaluation criteria

The main objective was to measure the tumor response to personalized therapy according to two axes:

• Radiological response: Evaluation of the reduction in lesion size through imaging.
• Pathological response: Analysis of tumor tissue modification after treatment.

The study specifically aimed to determine whether this approach allowed for a reduction in the extent of surgery (segmental mandibulectomy vs conservative approach) without compromising long-term disease control.

Clinico-Genomic Profile of the Cohort

The prospective study involved 14 patients (12 men, 2 women) with multicystic ameloblastomas, with a median age of 56 years (IQR: 32-62 years). The authors report histological diversity including follicular (n=6), plexiform (n=2), and acanthomatous (n=1) subtypes. Genomic analyses confirm that the BRAF V600E mutation is present in more than 50% of cases, establishing itself as the primary oncogenic driver.

Impact of Therapeutic Strategies and Recurrences

The data compiled by the authors highlight a strict correlation between surgical aggressiveness and tumour control. The results show a major disparity in recurrence rates depending on the chosen approach:

• Conservative surgery: 41% recurrence rate for multicystic forms.
• Radical resection: ~8% recurrence rate, confirming its status as the current therapeutic standard.

The study highlights the mutual exclusivity of BRAF and SMO mutations. BRAF mutations predominate in the mandible, while SMO mutations are enriched in maxillary locations. Imaging revealed rapid tumor reductions under neoadjuvant targeted therapy, facilitating less extensive resections without compromising the oncological prognosis.

Clinical decoding of results

This prospective study, conducted on a cohort of 14 patients (predominantly male, 85.7%, median age 56 years), confirms the predominance of aggressive multicystic forms (100% of included cases). The challenge is major: while radical surgery remains the standard to limit recurrence (8% versus 41% in conservative surgery), it imposes severe facial mutilations. Systematic identification of actionable mutations, notably BRAF V600E present in more than 50% of cases, paves the way for a neoadjuvant strategy. For the clinician, the tumor reduction observed through targeted therapies could allow for the conversion of a debilitating segmental mandibulectomy into a more conservative intervention, without compromising oncological control.

Limits and perspective

The main weakness of the study lies in the small sample size (n=14) and a marked ethnic homogeneity (71.4% of European origin), which limits the generalization of the data on a global scale. Furthermore, although genomic profiling shows an interesting mutational complexity (including SMO, FGFR2, or RAS), the long-term follow-up on disease control after molecular treatment alone or in combination remains to be consolidated. However, these results represent a break from the systematic first-line surgical approach.

Implications for practice

The implementation of a precision oncology workflow from the moment of diagnosis appears to be becoming essential. In cases of advanced mandibular ameloblastomas, screening for the BRAF V600E mutation is no longer an academic option but a surgical decision-making tool. If the tumor responds to molecular treatment, the resection volume and the complexity of microvascular reconstruction could be significantly reduced.

In concrete terms, for the practitioner:

• Systematize molecular profiling: For any multicystic ameloblastoma, the search for the BRAF V600E (mandible) or SMO (maxilla) mutation must be integrated into the initial assessment to evaluate eligibility for targeted therapies.
• Prioritize the neoadjuvant approach: In the case of a large tumor, the use of BRAF/MEK inhibitors can reduce the tumor mass, allowing a shift from a debilitating segmental mandibulectomy to a more conservative resection with reduced morbidity.
• Anticipating non-BRAF alternatives: Although BRAF is the primary target, screening for other mutations (FGFR2, RAS) offers precise therapeutic options for complex or recurrent cases.

Technical Lexicon of the Study

Multicystic ameloblastoma: The most frequent (75–86%) and most aggressive histopathological subtype. It is characterized by local infiltrative growth and a high recurrence rate, reaching 41% after conservative surgery compared to 8% after radical resection.

BRAF V600E: Principal oncogenic driver identified in more than 50% of ameloblastomas, mostly located in the mandible. This point mutation constitutes the preferred therapeutic target for precision medicine protocols.

BRAF ± MEK inhibition: Targeted therapeutic strategy (e.g., Dabrafenib + Trametinib) aimed at blocking cell proliferation. The study highlights its potential to induce rapid tumor regression (response rate of ~70% in other cancers), thus facilitating less invasive surgery.

SMO (Smoothened) mutation: Genomic alteration found preferentially in maxillary ameloblastomas. It is described as mutually exclusive with the BRAF mutation, guiding the choice of targeted therapy according to the anatomical location.

GLI signaling: Downstream transcriptional effector of the Hedgehog and MAPK pathways (including FGFR2-RAS-BRAF). Its activation, whether canonical or non-canonical, is the common denominator of tumor progression in ameloblastoma.

Segmental mandibulectomy: Reference surgical treatment for advanced forms. This radical procedure often requires reconstruction using a microvascularized bone flap due to the extent of tissue loss and significant aesthetic-functional sequelae.

Precision oncology: Clinical approach based on the patient's comprehensive genomic profiling to identify actionable alterations (BRAF, SMO, FGFR2, etc.), allowing the pharmacological treatment to be adjusted to the tumor's specific molecular signature.

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