Ameloblastoma is a benign odontogenic tumour that may exhibit aggressive biological behaviour with local recurrence and metastasis following initial surgical resection. Surgery is the most acceptable modality of treatment, even if a biological approach is currently on study. We report a case of maxillary ameloblastoma with development of neck and brain metastases after repeated local recurrences. Molecular analysis was performed with the aim to better characterize this neoplasm and its peculiar behaviour.
We investigated the status of tumour protein p53 (TP53), epidermal growth factor receptor (EGFR), B-Raf proto-oncogene (BRAF) and human epidermal growth factor receptor 2 (HER2) genes with immunohistochemical, fluorescent in situ hybridization and/or direct sequencing in order to clarify their possible role in the development of this neoplasm and the possibility of a targeted treatment.
The histological appearance of the tumour was the same in the primary lesion, in the recurrence and in the metastases. EGFR positivity was present in the recurrence and the brain metastasis, while HER2 was negative in all samples tested. Fluorescent in situ hybridization analysis for EGFR showed disomy of neoplastic cells. Direct DNA sequencing of TP53 gene exons 5 - 9 was carried out in tumour samples from the infratemporal recurrence and brain metastasis, with no mutational alteration detected. Similarly, sequencing analysis of BRAF exon 15 (V600) and EGFR gene showed wild type results in all samples tested.
Further studies are needed to identify molecular pathways that may provide an opportunity of alternative treatments and/or new potential predictive markers of local and distant spread of this rare tumour.
Ameloblastoma is a rare tumour of odontogenic epithelial origin, which accounts for approximately 1% of all mandibular tumours and cysts [
A 29-year-old male presented a swelling of the oral cavity without any symptoms. The radiographic examination showed diffuse opacity of the right nasal fossa and maxillary sinus, with destruction of the medial and inferior walls of the maxillary sinus, and thinning of the pavement of the orbita (
Radiographic appearance of the primary lesion.
A = diffuse opacity of the right nasal fossa and maxillary sinus, with destruction of the medial and inferior walls of the maxillary sinus, and thinning of the pavement of the orbita.
B = axial computed tomography showing the first recurrence in the maxillary sinus, which occurred 20 years after the surgical treatment of the tumour.
C = after conservative treatment the tumour recurred in the right orbit.
D = tumour recurred in hard palate.
E = magnetic resonance imaging showing a recurrence in the infratemporal fossa.
F = single metastasis in the right temporal area of the brain.
The histological appearance of the tumour was the same in the primary lesion, in the recurrence and in the metastases. The tumour mainly presented a plexiform pattern, characterized by a proliferation of basal cells organized in anastomosing strands with an inconspicuous stellate reticulum (
A = low power view of the primary lesion, showing a plexiform pattern, with cystic areas.
B = high power view of the primary lesion, showing anastomosing strands of epithelium in fibrous stroma, with tall columnar at the periphery.
C = metastatic lesion of the neck, showing infiltration of the salivary tissue of the parotid gland.
D = representative image of the brain metastasis.
The results of the immunohistochemical stainings are illustrated in
A = Immunohistochemical staining showing positivity for EGFR.
B = p53 in the neoplastic epithelium.
The analysis was conducted on the infratemporal recurrence. Neoplastic cells showed disomy, with an average ratio of EGFR gene to chromosome 7 centromere signals (CEP7) signals per cell of 0.8.
Direct DNA sequencing of TP53 gene exons 5 - 9 was carried out in tumour samples from the infratemporal recurrence and brain metastasis, with no mutational alteration detected. Similarly, sequencing analysis of B-Raf proto-oncogene (BRAF) exon 15 (V600) and EGFR showed wild type results in all samples tested.
According to the current WHO classification, metastasizingameloblastoma shows the same histological features of non-metastasizing ameloblastoma, and therefore the diagnosis can be made only retrospectively, when metastasis has occurred [
In the recent past, several studies attempted to elucidate the complex aspects of ameloblastoma biology, in order to improve treatment and outcome of the patients. Currently, radical surgery is the elective therapy both for primary and secondary lesions. In addition, patients must be followed strictly with instrumental exams and punctual follow-up to prevent recurrence [
Recently, several molecular studies have been undertaken in order to improve our understanding of the pathogenesis of this neoplasm, and to identify possible targets for alternative treatments, to potentially reduce the need for extensive and repeated surgery. The status of different genes has been evaluated, including transmembrane tyrosine kinase EGFR, BRAF, HER2 and TP53.
Epidermal growth factor and EGFR participate in the differentiation of ameloblasts and in the control of their cellular function [
Immunohistochemical studies have shown positivity for EGFR both in primary lesions and in metastases, although this marker did not predict recurrence [
BRAF is a potent activator of the mitogen activated protein kinase (MAPK) cascade, which in turn phosphorylate and activate extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2) [
HER2, also known as c-erb or HER2/neu, is a human epidermal growth factor receptor belonging to the same family of EGFR and its protein overexpression has been found in several carcinomas [
TP53 suppressor gene is situated on chromosome 17p13 and is one of the most frequently altered genes in tumours [
We report a case of ameloblastoma with metastatic spread to the brain and the neck after repeated local recurrences. Further studies are needed to identify molecular pathways that may provide an opportunity of alternative treatments and/or new potential predictive markers of local and distant spread of this rare tumour.
The authors report no conflicts of interest related to this study.