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The Molecular Pathology of Odontogenic Tumors: Expanding the Spectrum of MAPK Pathway Driven Tumors.Frontiers in Oral Health 2021Odontogenic tumors comprise a heterogeneous group of lesions that arise from the odontogenic apparatus and their remnants. Although the etiopathogenesis of most... (Review)
Review
Odontogenic tumors comprise a heterogeneous group of lesions that arise from the odontogenic apparatus and their remnants. Although the etiopathogenesis of most odontogenic tumors remains unclear, there have been some advances, recently, in the understanding of the genetic basis of specific odontogenic tumors. The mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) pathway is intimately involved in the regulation of important cellular functions, and it is commonly deregulated in several human neoplasms. Molecular analysis performed by different techniques, including direct sequencing, next-generation sequencing, and allele-specific qPCR, have uncovered mutations in genes related to the oncogenic MAPK/ERK signaling pathway in odontogenic tumors. Genetic mutations in this pathway genes have been reported in epithelial and mixed odontogenic tumors, in addition to odontogenic carcinomas and sarcomas. Notably, B-Raf proto-oncogene serine/threonine kinase and KRAS proto-oncogene GTPase pathogenic mutations have been reported in a high proportion of ameloblastomas and adenomatoid odontogenic tumors, respectively. In line with the reports about other neoplasms that harbor a malignant counterpart, the frequency of p.V600E mutation is higher in ameloblastoma (64% in conventional, 81% in unicystic, and 63% in peripheral) than in ameloblastic carcinoma (35%). The objective of this study was to review MAPK/ERK genetic mutations in benign and malignant odontogenic tumors. Additionally, such genetic alterations were discussed in the context of tumorigenesis, clinical behavior, classification, and future perspectives regarding therapeutic approaches.
PubMed: 35048058
DOI: 10.3389/froh.2021.740788 -
Case Reports in Dentistry 2020Ameloblastic carcinoma (AC) is a rare malignant odontogenic tumor in pediatric patients, only 22 cases have been reported in literature since 1932. We present an...
Ameloblastic carcinoma (AC) is a rare malignant odontogenic tumor in pediatric patients, only 22 cases have been reported in literature since 1932. We present an extremely rare case in which AC occurred in a 2-year-old girl, who had a tumor in the right mandible. Radiographic findings showed a multilocular, poorly defined, and mixed radiolucent-radiopaque lesion in the region of teeth #84 to #85, with bone and tooth root resorption. Computed tomography revealed buccal cortex destruction, tumor infiltration of soft tissue, and enlarged nodes. Incisional biopsy showed histomorphological features of AC. Immunohistochemical analysis exhibited a positive result for Cytokeratin (CK) 19 and overexpression of p53 and Ki67. The patient underwent right hemimandibulectomy and neck dissection. The final pathology was consistent with the initial diagnosis of AC. The patient did not exhibit signs of recurrence or metastasis within 2 years postoperatively. Given the rarity of this disease and the age of the patient, this report constitutes a valuable contribution to the current literature.
PubMed: 32774938
DOI: 10.1155/2020/4072890 -
Imaging Science in Dentistry Dec 2020Ameloblastic carcinoma is a rare odontogenic malignant tumor with the histologic features of both ameloblastoma and carcinoma. It occurs more frequently in the mandible...
Ameloblastic carcinoma is a rare odontogenic malignant tumor with the histologic features of both ameloblastoma and carcinoma. It occurs more frequently in the mandible than in the maxilla and it may appear or develop from a preexisting ameloblastoma or odontogenic cyst. Rapidly progressing, painful swelling is the most common symptom, and radiographically, it shows significant bone resorption and cortical perforation. This report described a case of ameloblastic carcinoma in a 45-year-old man who presented with swelling in the left mandible. The lesion showed combined features of benign findings, such as an expansile cortex with a distinct border, and malignant findings, such as a large exophytic mass with frank bone resorption. Excisional biopsy was performed and a final diagnosis of ameloblastic carcinoma was made.
PubMed: 33409146
DOI: 10.5624/isd.2020.50.4.359 -
Frontiers in Oral Health 2021Malignant odontogenic tumours (MOTs) arise either from the tooth forming tissues, their developmental residues or from existing odontogenic epithelial or mesenchymal...
Malignant odontogenic tumours (MOTs) arise either from the tooth forming tissues, their developmental residues or from existing odontogenic epithelial or mesenchymal neoplasms in the jaws. Their management requires extensive surgery due to their infiltrative nature and risk of metastasis. There is a need to understand the clinical and pathological features of MOTs to inform both treatment algorithms and prognostication. This is an area of diagnostic pathology which presents substantial difficulties in diagnosis, compounded by inconsistent use of terminology. Thus, this systematic review aimed to describe the clinical and pathological features of MOTs with a view to consolidating the literature and defining problematic areas in diagnosis and classification. An electronic database search was conducted in Web of Science, PubMed/Medline, and Embase. Additionally, the grey literature and reference lists of selected papers searched for completeness. Nine hundred and sixty articles were initially identified. Following removal of duplicates and application of inclusion/exclusion criteria, 312 articles were included for qualitative analysis. The 312 articles encompassed a total of 507 patients with most lesions located within the mandible (74.3%). The most common first histological diagnosis was ameloblastic carcinoma (25.7% of all diagnoses), but there is considerable variation in how and when various diagnostic terms are used, and several misdiagnoses were reported. An initial benign diagnosis was made in 24.7% of patients, followed by a later malignant diagnosis and in this sub-group, the most common benign first diagnosis was ameloblastoma (42.4%). Cervical lymph nodes were the most common site of metastasis (9.3% of patients). With respect to distant metastasis (DM), the lungs were the most common organ affected (11.2% of DM patients) with metastasising ameloblastoma the most commonly reported tumour which metastasised to the lungs. Overall, 26.8% of patients developed recurrence. Overall, the quality of the literature on MOTs is poor. This review of the literature has highlighted variations in diagnostic terms and criteria which has resulted in areas of confusion with potential for misdiagnosis. This consolidation of primary data has identified key areas for targeted research including further discussion on the malignant potential of ameloblastoma.
PubMed: 35048074
DOI: 10.3389/froh.2021.775707 -
Oral Oncology Nov 2022
Topics: Ameloblastoma; Carcinoma; Humans; Ki-67 Antigen; Mandible; Mandibular Neoplasms; Odontogenic Tumors
PubMed: 36162192
DOI: 10.1016/j.oraloncology.2022.106122 -
Journal of Stomatology, Oral and... Apr 2020Odontogenic lesions have been described in several syndromes. Despite multiple reports of ameloblastoma's association with various syndromes, it has not been added to...
Odontogenic lesions have been described in several syndromes. Despite multiple reports of ameloblastoma's association with various syndromes, it has not been added to the diagnostic criteria for any syndrome. Thus, the aim of this systematic review was gathering such cases' data. An electronic search in PubMed Central's database was performed. The search strategy was limited to human studies (case reports and case series), full-text English articles published from first of January 1975 until the end of 2018. Irrelevant articles or articles with inadequate information were omitted. Associated syndrome, patients' age and sex, lesions' location, radiographic features, and treatment modality were collected and analyzed. Ameloblastoma was reported in association with Gorlin syndrome (6 cases), epidermal nevus syndrome (2 cases), Gardner syndrome (2 cases), Simpson-Golabi-Behmel syndrome (1 case), and Williams syndrome (1 case). The commonest associated syndrome was Gorlin syndrome (50%) with maxillary and female predilections. Both cases of epidermal nevus syndrome (ENS) were female with mandibular involvement. In syndromes that odontogenic lesions are one of the diagnostic criteria, it is important to rule out ameloblastic changes. Although the relationship between ameloblastoma and these syndromes is not well known, any related information may be helpful in understanding the pathogenesis and the nature of this neoplasm.
Topics: Ameloblastoma; Basal Cell Nevus Syndrome; Female; Gardner Syndrome; Gigantism; Humans; Mandible
PubMed: 31336213
DOI: 10.1016/j.jormas.2019.07.010 -
Oral Diseases Oct 2023BRD4, belonging to the bromodomain extra-terminal (BET) protein family, plays a unique role in tumor progression. However, the potential impact of BRD4 in ameloblastoma...
BACKGROUND
BRD4, belonging to the bromodomain extra-terminal (BET) protein family, plays a unique role in tumor progression. However, the potential impact of BRD4 in ameloblastoma (AM) remains largely unknown. Herein, we aimed to assess the expression and functional role of BRD4 in AM.
METHODS
The expression level of BRD4 was assessed by immunohistochemistry. The proliferation, migration, invasion, and tumorigenic abilities of AM cells were assessed by a series of assays. To explore the molecular expression profile of BRD4-depleted AM cells, RNA sequencing (RNA-seq) was performed. Bioinformatic analysis was performed on AM expression matrices obtained from the Gene Expression Omnibus (GEO). The therapeutic efficacy of BET-inhibitors (BETi) was assessed with AM patient-derived organoids.
RESULTS
Upregulation of BRD4 was observed in conventional AMs, recurrent AMs, and ameloblastic carcinomas. Depletion of BRD4 inhibited proliferation, invasion, migration, and tumorigenesis in AM. Administration of BETi attenuated the aggressiveness of AM and the growth of AM patient-derived organoids. Bioinformatic analysis indicated that BRD4 may promote AM progression by regulating the Wnt pathway and stemness-associated pathways.
CONCLUSION
BRD4 increases the aggressiveness and promotes the recurrence of ameloblastoma by regulating the Wnt pathway and stemness-associated pathways. These findings highlight BRD4 as a promising therapeutic target in AM management.
PubMed: 37798926
DOI: 10.1111/odi.14762 -
Oral Oncology Sep 2022
Topics: Carbazoles; Carcinoma; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases
PubMed: 35759857
DOI: 10.1016/j.oraloncology.2022.105946 -
International Journal of Dentistry 2022Ameloblastoma is a benign odontogenic tumor that may lead to ameloblastic carcinoma. This study aimed to determine potential signaling pathways and biological processes,...
OBJECTIVE
Ameloblastoma is a benign odontogenic tumor that may lead to ameloblastic carcinoma. This study aimed to determine potential signaling pathways and biological processes, critical genes and their regulating transcription factors (TFs), and miRNAs, as well as protein kinases involved in the etiology of primary ameloblastoma.
METHODS
The dataset GSE132472 was obtained from the GEO database, and multivariate statistical analyses were applied to identify differentially expressed genes (DEGs) in primary ameloblastoma tissues compared to the corresponding normal gingiva samples. A protein-protein interaction (PPI) map was built using the STRING database. The Cytoscape software identified significant modules and the hub genes within the PPI network. Gene Ontology annotation and signaling pathway analyses were executed by employing the DAVID and Reactome databases, respectively. Significant TFs and miRNAs acting on the hub genes were identified using the iRegulon plugin and MiRWalk 2.0 database, respectively. A protein kinase enrichment analysis was conducted using the online Kinase Enrichment Analysis 2 (KEA2) web server. The approved drugs acting on the hub genes were also found.
RESULTS
A total of 1,629 genes were differentially expressed in primary ameloblastoma ( value <0.01 and |Log2FC| > 1). , , , , , , and demonstrated high degree and betweenness centralities in the PPI network. was the most significant TF acting on the hub genes. was the protein kinase significantly enriched by the TFs. Cholesterol biosynthesis was considerably involved in primary ameloblastoma.
CONCLUSIONS
This study provides an intuition into the potential mechanisms involved in the etiology of ameloblastoma.
PubMed: 36160115
DOI: 10.1155/2022/3316313 -
Annals of Translational Medicine Dec 2021Ameloblastic carcinoma (AC) is an extremely rare malignant odontogenic tumor. The mean age of occurrence for all 141 AC cases analyzed in our systematic review study was...
Ameloblastic carcinoma (AC) is an extremely rare malignant odontogenic tumor. The mean age of occurrence for all 141 AC cases analyzed in our systematic review study was 43.59±19.51 years. Males were more affected than females, and the mandible was predominantly affected compared with the maxilla. The main clinical manifestation was a painful or painless swelling with ulceration and radiographic features usually displayed as mixed cystic or solid changes. Surgical resection was the first recommended method of management. Fourteen cases had cervical lymph node spread, 19 had distant metastasis (most commonly in the lung), and 33 had recurrence. We present a rare case of AC involving the maxillary region. Locally extensive surgical resection was carried out. Ablative defects after maxillectomy resulted in the communication of oral cavity and nasal cavity/maxillary antrum and would bring about difficulties in mastication, deglutition, and speech. A submental island flap was applied to close the oronasal and oroantral fistula. The flap and the wounds healed well, with excellent outcomes in terms of appearance, the function of speech, and swallowing on follow up. The submental island flap provides a relatively thin, easy-to-harvest, and well-vascularized tissue, which makes it a reliable option in soft tissue reconstruction of the oral and maxillofacial region.
PubMed: 35071440
DOI: 10.21037/atm-21-5196