Correlation of BRAF mutational status with clinical characteristics and survival outcomes of patients with ameloblastoma: the experience of 11 Italian centres

Abstract

AimsAmeloblastoma is a rare odontogenic tumour with an aggressive local behaviour. Mutations in the mitogen-activated protein kinase pathway, namely BRAF V600E mutations, are a common finding. To date, there is no clear correlation between BRAF V600 mutation and clinical outcome.MethodsWe retrospectively reviewed the medical records of patients who underwent surgery for ameloblastoma between May 1998 and June 2018, at 11 participating Italian centres. BRAF mutational status was evaluated by quantitative PCR/pyrosequencing. The primary end points were to determine BRAF mutational status in primitive and recurrent ameloblastoma, and to assess the relapse-free interval (RFI); the secondary end point was to investigate the correlation of BRAF mutational status with the clinical features of the tumour and survival outcomes.ResultsOverall, 74 patients were included: 33 (44.5%) were BRAF wild type and 41 (55.4%) BRAF V600 mutated. BRAF V600 mutated ameloblastomas occurred more frequently in younger patients (p=0.0031), were located at the mandible (p=0.0009) and presented with unicystic variant. After a median follow-up of 60 months, 21 (28.3%) patients relapsed (30.3% and 26.8% in the BRAF wild type and BRAF mutated group, respectively). At univariable Cox models, none of the investigated variables, including microscopic margin involvement, was associated with RFI.ConclusionsLocal recurrence occurs in 30% of patients with ameloblastoma. BRAFV600 mutation is associated with younger age, mandibular localisation and with unicystic ameloblastoma. Neither BRAF mutation nor microscopically positive surgical margins were associated with RFI. Further studies are needed to elucidate outcomes of this rare disease according to clinical, histopathological and comprehensive molecular features.

The Molecular Pathology of Odontogenic Tumors: Expanding the Spectrum of MAPK Pathway Driven Tumors

“…In 2014, the pioneer study by the group of Heikinheimo reported for the first time recurrent activating BRAF p.V600E mutations in ameloblastomas [9]. Considering that MAPK/ERK signaling can be activated by stimulation of transmembrane receptors, including EGFR, and that overexpression of EGFR had previously been reported in ameloblastomas, when [9], [10], [51], [52], [53] e , [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [ V600E mutation in all five ameloblastic carcinoma samples evaluated and this frequency was much higher than reported by previous studies, and therefore we did not add the results to the other ones when calculating mutation frequency.…”

“…They further reported the presence of BRAF p.V600E mutation in 67% (23/34) of ameloblastomas by using VE1 immunohistochemistry in cases not suitable for molecular evaluation [52]. Following these pieces of research, several studies have also assessed the presence of BRAF p.V600E in conventional ameloblastoma, either by molecular techniques or a combination of mutation screening and immunohistochemistry, with mutation frequencies varying from 55 to ∼90% [10,[53][54][55][56][57][58][59][60][61][62][63]. In two studies with limited sample numbers, the mutation was detected in all samples [2/2 [64] and 4/4 [65]].…”

“…In the studies conducted by Sweeney et al and Gültekin et al, they suggested the predominance of BRAF p.V600E ameloblastomas in mandible when compared to BRAF wild-type tumors [ 51 , 55 ]. The studies of Brown et al, Bonacina et al, and Kelppe et al have also suggested BRAF p.V600E positive cases mostly locate in the mandible and occur at earlier ages [ 52 , 62 , 69 ]. In agreement with that, the study of Gültekin et al has also reported that BRAF p.V600E ameloblastoma cases occur at a much younger age than BRAF p.V600E wild-type ones [ 55 ].…”

“…While some studies had reported earlier recurrence and increased recurrence rates in BRAF wild-type tumors [ 52 , 55 , 58 ], others had observed a more aggressive behavior with poor disease-free survival and higher recurrence rate in ameloblastomas harboring BRAF p.V600E mutation; in these cases, assessed by immunohistochemistry only [ 66 , 67 ]. In recent times, no difference has been found in relapse-free intervals between BRAF p.V600E positive and wild-type ameloblastoma cases [ 62 ].…”

The Changing Clinicopathological Profile of Ameloblastoma: An update

“…The Changing Clinicopathological Profile of Ameloblastoma: An update Ebtissam Al-erraqi Ameloblastoma (AM) is a locally aggressive benign expansible odontogenic tumor that shows a variety of clinicopathological features. AM reveals a slight preference for affecting males near their third decades with a high rate of local recurrence after resection [1]. Histologically, there are four phenotypes of AM: solid/multicystic, peripheral, desmoplastic and unicystic types.…”