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Garg N, Krishna R, Urs AB, Kumar P, Augustine J. A systematic review on the molecular pathways of Ameloblastic carcinoma when compared to Ameloblastoma. Expert Rev Mol Diagn 2025:1-13. [PMID: 40285826 DOI: 10.1080/14737159.2025.2499180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 03/17/2025] [Accepted: 04/14/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND Ameloblastic carcinoma (AC), malignancy originating from the odontogenic epithelium, shows histological overlap with ameloblastoma (AM). In order to unravel mechanisms driving AC, it is imperative to understand the molecular distinction between these two entities. This systematic review aims to highlight molecular and immunohistochemical markers involved in the pathogenesis of AC and to distinguish it from its histological mimic, AM. RESEARCH DESIGN AND METHODS Literature search across three databases including PubMed, Web of Sciences, and Scopus was carried out from year 1999 to 2023 for original human case control studies involving AM, AC, and controls as study groups. Various biological markers studied in the literature were grouped based on principal molecular pathways. Joanna Briggs Institute (JBI), a critical appraisal tool for case control studies, was used to assess the risk of bias (RoB). RESULTS Out of the 277 studies identified during the initial search, 28 studies were found eligible. These studies reported expression of various immunohistochemical (IHC), genetic and epigenetic markers in AC, AM, and controls through immunohistochemistry and gene sequencing. CONCLUSION Stem cells, epigenetics, and growth factors define the pathways involved in pathogenesis of AC and may prove to be a potential therapeutic target in the future.
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Affiliation(s)
- Nikita Garg
- Department of Oral Pathology, Maulana Azad Institute of Dental Sciences, New Delhi, India
| | - Revathi Krishna
- Department of Oral Pathology, Maulana Azad Institute of Dental Sciences, New Delhi, India
| | - Aadithya B Urs
- Department of Oral Pathology, Maulana Azad Institute of Dental Sciences, New Delhi, India
| | - Priya Kumar
- Department of Oral Pathology, Maulana Azad Institute of Dental Sciences, New Delhi, India
| | - Jeyaseelan Augustine
- Department of Oral Pathology, Maulana Azad Institute of Dental Sciences, New Delhi, India
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Zhang L, Lin H, Liang J, Liu X, Zhang C, Man Q, Li R, Zhao Y, Liu B. Programmed death-ligand 1 regulates ameloblastoma growth and recurrence. Int J Oral Sci 2025; 17:29. [PMID: 40240323 PMCID: PMC12003687 DOI: 10.1038/s41368-025-00364-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 03/05/2025] [Accepted: 03/10/2025] [Indexed: 04/18/2025] Open
Abstract
Tumor cell-intrinsic programmed death-ligand 1 (PD-L1) signals mediate tumor initiation, progression and metastasis, but their effects in ameloblastoma (AM) have not been reported. In this comprehensive study, we observed marked upregulation of PD-L1 in AM tissues and revealed the robust correlation between elevated PD-L1 expression and increased tumor growth and recurrence rates. Notably, we found that PD-L1 overexpression markedly increased self-renewal capacity and promoted tumorigenic processes and invasion in hTERT+-AM cells, whereas genetic ablation of PD-L1 exerted opposing inhibitory effects. By performing high-resolution single-cell profiling and thorough immunohistochemical analyses in AM patients, we delineated the intricate cellular landscape and elucidated the mechanisms underlying the aggressive phenotype and unfavorable prognosis of these tumors. Our findings revealed that hTERT+-AM cells with upregulated PD-L1 expression exhibit increased proliferative potential and stem-like attributes and undergo partial epithelial‒mesenchymal transition. This phenotypic shift is induced by the activation of the PI3K-AKT-mTOR signaling axis; thus, this study revealed a crucial regulatory mechanism that fuels tumor growth and recurrence. Importantly, targeted inhibition of the PD-L1-PI3K-AKT-mTOR signaling axis significantly suppressed the growth of AM patient-derived tumor organoids, highlighting the potential of PD-L1 blockade as a promising therapeutic approach for AM.
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Affiliation(s)
- Linzhou Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Hao Lin
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Jiajie Liang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Xuanhao Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Chenxi Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Qiwen Man
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Ruifang Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yi Zhao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
- Department of Prosthodontics, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
| | - Bing Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
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Tun KM, Lapthanasupkul P, Iamaroon A, Thosaporn W, Klanrit P, Kintarak S, Thanasan S, Srimaneekarn N, Kitkumthorn N. A multi-center cross-sectional investigation of BRAF V600E mutation in Ameloblastoma. PeerJ 2025; 13:e19137. [PMID: 40191760 PMCID: PMC11972564 DOI: 10.7717/peerj.19137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 02/19/2025] [Indexed: 04/09/2025] Open
Abstract
Background B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation stands as a pivotal genetic alteration strongly associated with several neoplasms and contributes significantly to their pathogenesis as well as potential targeted treatment strategies. Objective This cross-sectional study aimed to determine the frequency of BRAF V600E mutation in ameloblastoma in a multi-center of Thailand. Method Anti-BRAF V600E (clone VE1) immunohistochemistry was performed on 227 conventional ameloblastoma (AM) and 113 unicystic ameloblastoma (UA) samples collected from four major dental schools located in the Central, North, South, and Northeast regions of Thailand. Tumor cells from randomly chosen AM cases were also micro-dissected from the FFPE sections and subjected to DNA sequencing to confirm the immunohistochemical results. Results BRAF V600E mutation was detected in 71.8% of the AM samples, while 65.5% of samples with UAs demonstrated BRAF V600E positivity. The BRAF V600E mutation was significantly different in the histological subtypes of AMs in the four centers (p = 0.012) and the location of UA in three centers (p = 0.013). There was no significant association between the BRAF V600E mutation and the location of ameloblastoma in the overall prevalence of our multi-center study; nonetheless, a statistically significant association was found between the BRAF V600E mutation and the mandible location of AMs from the Central Faculty of Dentistry, Mahidol University (MU) center (p = 0.033), as well as with the histological subtypes of AMs from the Southern Faculty of Dentistry, Prince of Songkla University (PSU) center (p = 0.009). No statistical association was observed between the BRAF V600E mutation and AM and UA recurrence (p = 0.920 and p = 0.312), respectively. The results of DNA sequencing performed in randomly selected 40 BRAF V600E-positive and 20 BRAF V600E-negative ameloblastoma tissues were in accordance with the immunohistochemical findings. Conclusion As a result of a notable prevalence of BRAF V600E in Thai individuals diagnosed with ameloblastoma, they may benefit from the utilization of adjunctive anti-BRAF targeted therapy for treatment.
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Affiliation(s)
- Khin Mya Tun
- Faculty of Dentistry, Mahidol University, Bangkok, Thailand
| | - Puangwan Lapthanasupkul
- Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
| | - Anak Iamaroon
- Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
| | - Wacharaporn Thosaporn
- Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
| | - Poramaporn Klanrit
- Department of Oral Biomedical Sciences, Faculty of Dentistry, Khon Kaen University, Khon Kaen, Thailand
| | - Sompid Kintarak
- Department of Stomatology, Faculty of Dentistry, Prince of Songkla University, Songkhla, Thailand
| | | | | | - Nakarin Kitkumthorn
- Department of Oral Biology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
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Liu XH, Zhong NN, Yi JR, Lin H, Liu B, Man QW. Trends in Research of Odontogenic Keratocyst and Ameloblastoma. J Dent Res 2025; 104:347-368. [PMID: 39876078 DOI: 10.1177/00220345241282256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2025] Open
Abstract
Odontogenic keratocyst (OKC) and ameloblastoma (AM) are common jaw lesions with high bone-destructive potential and recurrence rates. Recent advancements in technology led to significant progress in understanding these conditions. Single-cell and spatial omics have improved insights into the tumor microenvironment and cellular heterogeneity in OKC and AM. Fibroblast subsets in OKC and tumor cell subsets in AM have been analyzed, revealing mechanisms behind their biological behaviors, including OKC's osteolytic features and AM's recurrence tendencies. Spatial transcriptomics studies of AM have identified engineered fibroblasts and osteoblasts contributing to matrix remodeling gene and oncogene expression at the invasion frontier, driving AM progression. Three-dimensional culture technologies such as organoid models have refined analysis of AM subtypes; uncovered the role of AM fibroblasts in promoting tumor cell proliferation and invasion; and identified signaling pathways such as FOSL1, BRD4, EZH2, and Wnt as potential therapeutic targets. Organoid models also served as preclinical platforms for testing potential therapies. Although preclinical models for AM exist, reliable in vitro and in vivo models for OKC remain scarce. Promising mimic models, including human embryonic stem cells-derived epithelial cells, human oral keratinocytes, human immortalized oral epithelial cells, and HaCaT keratinocytes, show promise, but the advancements in 3-dimensional culture technology are expected to lead to further breakthroughs in this area. Artificial intelligence, including machine learning and deep learning, has enhanced radiomics-based diagnostic accuracy, distinguishing OKC and AM beyond clinician capability. Pathomics-based models further predict OKC prognosis and differentiate AM from ameloblastic carcinoma. Clinical studies have shown positive outcomes with targeted therapies. In a study investigating SMO-targeted treatments for nevoid basal cell carcinoma syndrome, nearly all OKC lesions resolved in 3 patients. A recent clinical trial with neoadjuvant BRAF-targeted therapy for AM demonstrated promising radiologic responses, potentially enabling organ preservation. This review highlights recent advancements and trends in OKC and AM research, aiming to inspire further exploration and progress in these fields.
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Affiliation(s)
- X-H Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - N-N Zhong
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - J-R Yi
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - H Lin
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - B Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Oral & Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Q-W Man
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Oral & Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China
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Zhao Z, Xiong G, Wang C, Cao W. From pathogenesis to precision medicine: Transformative advances in research and treatment of ameloblastoma. Cancer Lett 2025; 612:217448. [PMID: 39800213 DOI: 10.1016/j.canlet.2025.217448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 01/02/2025] [Accepted: 01/04/2025] [Indexed: 01/15/2025]
Abstract
Odontogenic neoplasms of the jaw are dominated by ameloblastoma (AM), a locally aggressive epithelial tumor with a significant propensity for recurrence. The World Health Organization's 2022 update to the AM classification system underscores recent progress in comprehending its underlying mechanisms and refining clinical approaches. Contemporary research has yielded significant insights into the genetic underpinnings of AM, paving the way for the development of precision-based treatment strategies. Advanced genetic profiling has revealed a significant frequency of BRAF (V-raf murine sarcoma viral oncogene homolog) V600E and SMO (Smoothened) gene alterations in AM. Importantly, therapeutic interventions specifically designed to target these genetic aberrations, including BRAF and MEK pathway blockers, have shown encouraging results in terms of both effectiveness and tolerability, as documented in individual case reports and small-scale clinical investigations. This comprehensive review summarizes the recent modifications to the World Health Organization's categorization of AMs, explores progress in elucidating their underlying molecular pathways, and evaluates emerging targeted treatment modalities. Our objective is to present a thorough synthesis of contemporary scientific discoveries and therapeutic interventions, potentially paving the way for more efficacious and individualized clinical management protocols for this complex neoplasm.
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Affiliation(s)
- Zhang Zhao
- Department of Oral and Maxillofacial & Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Gan Xiong
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Cheng Wang
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China.
| | - Wei Cao
- Department of Oral and Maxillofacial & Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China.
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Pires HDF, França GMD, Morais HGDF, Silva WRD, Freitas RDA, Galvão HC. Clinicopathological and Immunohistochemical Risk Predictors for Ameloblastoma Recurrence. Head Neck Pathol 2025; 19:22. [PMID: 39960551 PMCID: PMC11832845 DOI: 10.1007/s12105-024-01743-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 11/27/2024] [Indexed: 02/20/2025]
Abstract
PURPOSE Measure associations between clinicopathological and immunohistochemical human Mut-L homologue 1 (hMLH1) gene, and human Mut-L homologue 2 (hMSH2) genes, variables in recurrent AMBs. METHODS This study consisted of a research retrospective, observational case-control study consisting of 22 cases of recurrent AMB and 22 non-recurrent cases. Cases of AMB with more than one year of follow-up were included in the study. Quantitative immunohistochemical analysis was performed considering the cellular location (nuclear) of the proteins studied. The McNemar test was used to compare variables between primary and recurrent AMBs. Recurrence-free survival was analyzed by the Kaplan-Meier method and survival functions were compared according to the variables using the log-rank test. RESULTS The posterior mandible was the most affected site in the recurrent (n = 18, 81.8%) and non-recurrent groups (n = 16, 72.8%). Recurrence-free survival was 50.0 (34.5-63.6) months. The following factors were significantly associated with AMB recurrence: presence of cortical bone expansion (p = 0.01), absence of bone reconstruction (p = 0.02), conservative treatment (p = 0.02), loss of hMSH2 (p = 0.01) and hMLH1 (p = 0.04) immunoexpression, and strong Ki-67 immunoexpression (p = 0.03). The risk factors for AMB recurrence were anatomical location (OR = 3.31), locularity (OR = 1.07), cortical expansion (OR = 6.17), cortical perforation (OR = 2.10), bone resorption (OR = 1.52), tooth impaction (OR = 1.86), jaw reconstruction (OR = 6.92), and immunoexpression of hMSH2 (OR = 10.0) and hMLH1 (OR = 4.50). CONCLUSION Radiographic appearance, treatment modality, and immunoexpression of mismatch repair proteins can be used as predictors of AMB recurrence.
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Affiliation(s)
- Hévila de Figueiredo Pires
- Department of Oral Pathology, Federal University of Rio Grande do Norte, Av. Senador Salgado Filho, Lagoa Nova, Natal, RN, 1787, CEP 59056-000, Brazil.
| | - Glória Maria de França
- Department of Oral Pathology, Federal University of Rio Grande do Norte, Av. Senador Salgado Filho, Lagoa Nova, Natal, RN, 1787, CEP 59056-000, Brazil
| | - Hannah Gil de Farias Morais
- Department of Oral Pathology, Federal University of Rio Grande do Norte, Av. Senador Salgado Filho, Lagoa Nova, Natal, RN, 1787, CEP 59056-000, Brazil
| | - Weslay Rodrigues da Silva
- School of Dentistry, Postgraduate program in Dentistry, University of Pernambuco (UPE), Recife, PE, Brazil
| | - Roseana de Almeida Freitas
- Department of Oral Pathology, Federal University of Rio Grande do Norte, Av. Senador Salgado Filho, Lagoa Nova, Natal, RN, 1787, CEP 59056-000, Brazil
| | - Hébel Cavalcanti Galvão
- Department of Oral Pathology, Federal University of Rio Grande do Norte, Av. Senador Salgado Filho, Lagoa Nova, Natal, RN, 1787, CEP 59056-000, Brazil
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Hirschhorn A, Grynberg S, Campino GA, Dobriyan A, Patel V, Greenberg G, Yacobi R, Barshack I, Yahalom R, Toren A, Vered M. Histopathologic and Molecular Insights Following the Management of Ameloblastomas via Targeted Therapies - Pathological and Clinical Perspectives. Head Neck Pathol 2024; 18:129. [PMID: 39621130 PMCID: PMC11612134 DOI: 10.1007/s12105-024-01734-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Accepted: 11/09/2024] [Indexed: 12/06/2024]
Abstract
PURPOSE Current standard of care for ameloblastoma (conventional/unicystic - mural type) usually mandates extensive bone resection that frequently necessitates immediate reconstruction with serious sequelae, especially among young patients. BRAF-mutated ameloblastomas can be targeted by BRAF inhibitors to markedly reduce their size, enabling conservative removal of residual tumor. We aimed to characterize the effect of post-treatment histomorphologic changes. METHODS Study included 14 patients, 11 mandibular and three maxillary tumors. Cases with very minimal residual tumor were defined as near-complete response, while those with mostly vital residual tumor as partial response. The epithelium component was scored for architectural and cellular changes, stroma - for fibrosis, inflammation and new bone formation, on a 3-tired score system: 0-no, 1-focal and 3-frequent changes. The mean scores of each parameter, total epithelium and total stroma were calculated and related to duration of treatment. Differences in the mean scores were investigated for mandibular tumors with near-complete response (n = 3) and partial response (n = 8). RESULTS There were no significant differences in mean epithelium or stroma scores between tumors with near-complete and those with partial response (2.22 ± 0.68 versus 2.08 ± 0.43, p = 0.55; 1.41 ± 1.04 versus 1.43 ± 0.44, p = 0.27), suggesting that ameloblastomas have potential to undergo complete response to targeted treatment. This is probably dependent upon tumor/patient/treatment-related factors. Response to treatment appears to be predictable with neoplastic epithelium being first, while the stromal response increases during treatment, the entire process expanding over weeks-to-months. CONCLUSION Albeit preliminary, these are the first comprehensive histomorphologic findings on BRAF-treated ameloblastomas. Analyzing the suggested parameters in tumors with partial response, should highlight which tumor component has responded/failed to respond. This could serve as a basis for decision-taking toward subsequent steps in adjuvant treatment (e.g., follow-up, conservative surgery, modifications/changes in treatment regimen, combinations of approaches), with a prime aim of jaw preservation and minimal risk of sequelae.
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Affiliation(s)
- Ariel Hirschhorn
- Department of Cranio-Maxillofacial Surgery, Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - Shirly Grynberg
- Ella Lemelbaum Institute for Immuno-Oncology, and Melanoma, Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - Gadi Abebe Campino
- Division of Pediatric Hemato-Oncology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
| | - Alex Dobriyan
- Department of Cranio-Maxillofacial Surgery, Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - Vinod Patel
- Department of Oral Surgery, Guys & St Thomas Hospital, London Bridge, London, UK
| | - Gahl Greenberg
- Department of Diagnostic Imaging, Sheba Medical Center, Tel Hashomer, Israel
| | - Rinat Yacobi
- Institute of Pathology, Sheba Medical Center, Tel Hashomer, 5265601, Israel
| | - Iris Barshack
- Institute of Pathology, Sheba Medical Center, Tel Hashomer, 5265601, Israel
| | - Ran Yahalom
- Department of Cranio-Maxillofacial Surgery, Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - Amos Toren
- Division of Pediatric Hemato-Oncology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
| | - Marilena Vered
- Institute of Pathology, Sheba Medical Center, Tel Hashomer, 5265601, Israel.
- Department of Oral Pathology, Oral Medicine and Maxillofacial Imaging, School of Dentistry, Tel Aviv University, Tel Aviv, Israel.
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Yi JR, Zeng B, Liu B, Li RF, Che YF, Man QW. Network pharmacology and in vitro experiments reveal the potential therapeutic effects of Scrophularia ningpoensis Hemsl in the treatment of ameloblastoma. JOURNAL OF STOMATOLOGY, ORAL AND MAXILLOFACIAL SURGERY 2024; 126:102146. [PMID: 39551179 DOI: 10.1016/j.jormas.2024.102146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 11/19/2024]
Abstract
PURPOSE This study aimed to explore active ingredients in Scrophularia ningpoensis Hemsl (SNH) with potential effects on ameloblastoma (AM) using network pharmacological approach, bioinformatic gene analysis and in vitro cell experiments. METHODS The active ingredients and their corresponding targets of SNH were identified from the Traditional Chinese Medicine Systems Pharmacology (TCMSP), as well as SwissTargetPrediction. Disease targets of AM were selected from GeneCards and DisGeNET databases. Differentially expressed genes (DEGs) of AM were identified, and Gene Ontology enrichment analysis were performed using the Gene Expression Omnibus (GEO) dataset GSE38494 through bioinformatic analysis. The STRING database platform was utilized to generate a protein-protein interaction network diagram, followed by hub gene analysis using Cytoscape software. AutoDock Vina software was used to perform molecular docking verification of the effects of the active ingredients on potential core targets. Additionally, in vitro experiments including quantitative reverse transcription polymerase chain reaction (RT-qPCR), EdU assay and CCK-8 cell proliferation assay were conducted using AM cell line AM-1 after SNH extract treatment. RESULT The study revealed that SNH contains eight active ingredients and a total of 388 drug targets, including 10 potential core targets in AM. Hub genes identified in the analysis were CCNA2, HRAS, PTGS2, PIK3CB, FGFR1, CASP3, MMP1, SLC2A1, MMP14, and MME. Molecular docking analysis demonstrated strong binding activity between key active ingredients (β-sitosterol, scropolioside A_qt, scropolioside D, scropolioside D_qt, and sugiol) and target genes (CASP3, FGFR1, HRAS, PTGS2, and SLC2A1). Gene Ontology enrichment analysis indicated that SNH exerts its effects on AM through pathways related to cellular response to abiotic stimulus, cellular response to hypoxia, and exopeptidase activity. Immunohistochemical analysis using tissue microarray showed higher expression of MMP14 and PTGS2 in AM compared to dentigerous cyst. Using AM-1 cell line, RT-qPCR results confirmed that SNH suppressed the expression of MMP14 and PTGS2 at mRNA level. Additionally, the EdUassay and CCK-8 assay indicated the inhibitory effect of SNH on the proliferation of AM-1 cells. CONCLUSION These findings showed that SNH could suppress expression of MMP14 and PTGS2 and restrain the proliferation of AM. Our study highlights the potential of SNH as a promising therapeutic candidate for AM, which may provide more options for clinical treatment.
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Affiliation(s)
- Jing-Rui Yi
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Bang Zeng
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Bing Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Department of Oral and Maxillofacial Head Neck Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Rui-Fang Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yin-Fu Che
- Department of Stomatology, Lanzhou University First Affiliated Hospital, Lanzhou University, Lanzhou, China.
| | - Qi-Wen Man
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China; Department of Oral and Maxillofacial Head Neck Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
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Zhang AB, Zhang JY, Liu YP, Wang S, Bai JY, Sun LS, Li TJ. Clinicopathological characteristics and diagnostic accuracy of BRAF mutations in ameloblastoma: A Bayesian network analysis. J Oral Pathol Med 2024; 53:393-403. [PMID: 38777565 DOI: 10.1111/jop.13542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 03/13/2024] [Accepted: 04/27/2024] [Indexed: 05/25/2024]
Abstract
OBJECTIVE This Bayesian network meta-analysis was performed to analyze the associations between clinicopathological characteristics and BRAF mutations in ameloblastoma (AM) patients and to evaluate the diagnostic accuracy. MATERIALS AND METHODS Four electronic databases were searched from 2010 to 2024. The search terms used were specific to BRAF and AM. Observational studies or randomized controlled trials were considered eligible. The incidence of BRAF mutation and corresponding clinicopathological features in AM patients were subjected to Bayesian network analyses and diagnostic accuracy evaluation. RESULTS A total of 937 AM patients from 20 studies were included. The pooled prevalence of BRAF mutations in AM patients was 72%. According to the Bayesian network analysis, BRAF mutations are more likely to occur in younger (odds ratio [OR], 2.3; credible interval [CrI]: 1.2-4.5), mandible site (OR, 3.6; 95% CrI: 2.7-5.2), and unicystic (OR, 1.6; 95% CrI: 1.1-2.4) AM patients. Similarly, higher diagnostic accuracy was found in the younger, mandible, and unicystic AM groups. CONCLUSIONS The incidence, risk, and diagnostic accuracy of BRAF mutation in AM were greater in younger patients, those with mandible involvement, and those with unicystic AM than in patients with other clinicopathological features. In addition, there was a strong concordance in the diagnostic accuracy between molecular tests and immunohistochemical analysis.
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Affiliation(s)
- Ao-Bo Zhang
- Department of Oral Pathology, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
- Research Unit of Precision Pathologic Diagnosis in Tumors of the Oral and Maxillofacial Regions, Chinese Academy of Medical Sciences (2019RU034), Beijing, China
| | - Jian-Yun Zhang
- Department of Oral Pathology, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
- Research Unit of Precision Pathologic Diagnosis in Tumors of the Oral and Maxillofacial Regions, Chinese Academy of Medical Sciences (2019RU034), Beijing, China
| | - Yu-Ping Liu
- Department of Oral Pathology, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
- Research Unit of Precision Pathologic Diagnosis in Tumors of the Oral and Maxillofacial Regions, Chinese Academy of Medical Sciences (2019RU034), Beijing, China
| | - Shuo Wang
- Department of stomatology, Shandong Public Health Clinical Center, Jinan, Shandong, China
| | - Jia-Ying Bai
- Department of Oral Pathology, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
| | - Li-Sha Sun
- Research Unit of Precision Pathologic Diagnosis in Tumors of the Oral and Maxillofacial Regions, Chinese Academy of Medical Sciences (2019RU034), Beijing, China
- Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
| | - Tie-Jun Li
- Department of Oral Pathology, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
- Research Unit of Precision Pathologic Diagnosis in Tumors of the Oral and Maxillofacial Regions, Chinese Academy of Medical Sciences (2019RU034), Beijing, China
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10
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Raemy A, May L, Sala N, Diezi M, Beck-Popovic M, Broome M. Anti-MAPK Targeted Therapy for Ameloblastoma: Case Report with a Systematic Review. Cancers (Basel) 2024; 16:2174. [PMID: 38927880 PMCID: PMC11201667 DOI: 10.3390/cancers16122174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 05/30/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024] Open
Abstract
Ameloblastoma, a benign yet aggressive odontogenic tumor known for its recurrence and the severe morbidity from radical surgeries, may benefit from advancements in targeted therapy. We present a case of a 15-year-old girl with ameloblastoma successfully treated with targeted therapy and review the literature with this question: Is anti-MAPK targeted therapy safe and effective for treating ameloblastoma? This systematic review was registered in PROSPERO, adhered to PRISMA guidelines, and searched multiple databases up to December 2023, identifying 13 relevant studies out of 647 records, covering 23 patients treated with MAPK inhibitor therapies. The results were promising as nearly all patients showed a positive treatment response, with four achieving complete radiological remission and others showing substantial reductions in primary, recurrent, and metastatic ameloblastoma sizes. Side effects were mostly mild to moderate. This study presents anti-MAPK therapy as a significant shift from invasive surgical treatments, potentially enhancing life quality and clinical outcomes by offering a less invasive yet effective treatment alternative. This approach could signify a breakthrough in managing this challenging tumor, emphasizing the need for further research into molecular-targeted therapies.
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Affiliation(s)
- Anton Raemy
- Department of Maxillofacial Surgery, Lausanne University Hospital, 1011 Lausanne, Switzerland; (L.M.); (M.B.)
| | - Laurence May
- Department of Maxillofacial Surgery, Lausanne University Hospital, 1011 Lausanne, Switzerland; (L.M.); (M.B.)
| | - Nathalie Sala
- Institute of Pathology, Lausanne University Hospital, 1011 Lausanne, Switzerland;
| | - Manuel Diezi
- Department of Paediatric Oncology, Lausanne University Hospital, 1011 Lausanne, Switzerland; (M.D.); (M.B.-P.)
| | - Maja Beck-Popovic
- Department of Paediatric Oncology, Lausanne University Hospital, 1011 Lausanne, Switzerland; (M.D.); (M.B.-P.)
| | - Martin Broome
- Department of Maxillofacial Surgery, Lausanne University Hospital, 1011 Lausanne, Switzerland; (L.M.); (M.B.)
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11
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Marín-Márquez C, Kirby J, Hunter KD. Molecular pathogenesis of ameloblastoma. J Oral Pathol Med 2024; 53:277-293. [PMID: 38664938 DOI: 10.1111/jop.13538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 03/08/2024] [Accepted: 04/08/2024] [Indexed: 05/16/2024]
Abstract
Ameloblastoma (AM) is a benign, although aggressive, epithelial odontogenic tumour originating from tooth-forming tissues or remnants. Its aetiopathogenesis remains unclear; however, molecular analysis techniques have allowed researchers to progress in understanding its genetic basis. The high frequency of BRAF p.V600E as a main driver mutation in AM is well established; nevertheless, it is insufficient to explain its tumourigenesis. In this review, we aimed to integrate the current knowledge about the biology of AM and to describe the main genetic alterations reported, focusing on the findings of large-scale sequencing and gene expression profiling techniques. Current evidence shows that besides BRAF mutation and activation of the MAPK pathway, alterations in Hedgehog and Wnt/β-catenin pathway-related genes are also involved in AM pathogenesis. Recently, a tumour suppressor gene, KMT2D, has been reported as mutated by different research groups. The biological impact of these mutations in the pathogenesis of AM has yet to be elucidated. Further studies are needed to clarify the impact of these findings in the identification of novel biomarkers that could be useful for diagnosing, classifying, and molecular targeting this neoplasm.
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Affiliation(s)
- Constanza Marín-Márquez
- Unit of Oral and Maxillofacial Medicine, Pathology and Surgery, University of Sheffield, Sheffield, UK
- Facultad de Odontología y Ciencias de la Rehabilitación, Universidad San Sebastián, Puerto Montt, Chile
| | - Janine Kirby
- Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Keith D Hunter
- Liverpool Head and Neck Centre, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
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12
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Grynberg S, Vered M, Shapira-Frommer R, Asher N, Ben-Betzalel G, Stoff R, Steinberg Y, Amariglio N, Greenberg G, Barshack I, Toren A, Yahalom R, Schachter J, Rechavi G, Hirschhorn A, Abebe Campino G. Neoadjuvant BRAF-targeted therapy for ameloblastoma of the mandible: an organ preservation approach. J Natl Cancer Inst 2024; 116:539-546. [PMID: 37966914 DOI: 10.1093/jnci/djad232] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 10/06/2023] [Accepted: 11/03/2023] [Indexed: 11/17/2023] Open
Abstract
BACKGROUND Ameloblastoma is a rare odontogenic neoplasm frequently located in the mandible. Standard treatment involves radical bone resection and immediate reconstruction, causing functional, aesthetic, and psychological impairments. The BRAF V600E mutation is present in approximately 80% of mandible ameloblastomas, and BRAF inhibitors have demonstrated sustained responses in unresectable cases. METHODS We identified ameloblastoma patients planned for ablative surgery and screened them for BRAF V600E mutation. Neoadjuvant BRAF inhibitors were offered to facilitate jaw preservation surgery. Retrospective data collection encompassed treatment regimens, tolerability, tumor response, and conversion to mandible preservation surgery. RESULTS Between 2017 and 2022, a total of 11 patients received dabrafenib (n = 6) or dabrafenib with trametinib (n = 5). The median age was 19 (range = 10-83) years. Median treatment duration was 10 (range = 3-20) months. All (100%) patients achieved a radiological response. Ten (91%) patients successfully converted to mandible preservation surgery with residual tumor enucleation. One patient attained complete radiological response, and surgery was not performed. Among the 10 surgically treated patients, all exhibited a pathological response, with 4 achieving near complete response and 6 partial response. At a median follow-up of 14 (range = 7-37) months after surgery, 1 case of recurrence was observed. Grade 1-2 adverse effects were reported in 8 (73%) patients, with a single case of grade 3 (hepatitis). Dose modification was necessary for 3 patients, and 4 experienced treatment interruptions, while 1 patient permanently discontinued therapy. CONCLUSIONS Neoadjuvant BRAF inhibition may offer a safe and effective strategy for organ preservation in mandible ameloblastoma treatment.
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Affiliation(s)
- Shirly Grynberg
- Ella Lemelbaum Institute of Immuno-Oncology and Melanoma, Sheba Medical Center, Tel Hashomer, Israel
| | - Marilena Vered
- Institue of Pathology, Sheba Medical Center, Tel Hashomer, Israel
| | - Ronnie Shapira-Frommer
- Ella Lemelbaum Institute of Immuno-Oncology and Melanoma, Sheba Medical Center, Tel Hashomer, Israel
| | - Nethanel Asher
- Ella Lemelbaum Institute of Immuno-Oncology and Melanoma, Sheba Medical Center, Tel Hashomer, Israel
| | - Guy Ben-Betzalel
- Ella Lemelbaum Institute of Immuno-Oncology and Melanoma, Sheba Medical Center, Tel Hashomer, Israel
| | - Ronen Stoff
- Ella Lemelbaum Institute of Immuno-Oncology and Melanoma, Sheba Medical Center, Tel Hashomer, Israel
| | - Yael Steinberg
- Ella Lemelbaum Institute of Immuno-Oncology and Melanoma, Sheba Medical Center, Tel Hashomer, Israel
| | - Ninette Amariglio
- Sheba Cancer Research Center, Wohl Institute of Translational Medicine, Sheba Medical Center, Tel Hashomer, Israel
| | - Gahl Greenberg
- Department of Diagnostic Imaging, Sheba Medical Center, Tel Hashomer, Israel
| | - Iris Barshack
- Institue of Pathology, Sheba Medical Center, Tel Hashomer, Israel
| | - Amos Toren
- Division of Pediatric Hemato-Oncology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
| | - Ran Yahalom
- Department of Cranio-Maxillofacial Surgery, Sheba Medical Center, Tel Hashomer, Israel
| | - Jacob Schachter
- Ella Lemelbaum Institute of Immuno-Oncology and Melanoma, Sheba Medical Center, Tel Hashomer, Israel
| | - Gideon Rechavi
- Sheba Cancer Research Center, Wohl Institute of Translational Medicine, Sheba Medical Center, Tel Hashomer, Israel
| | - Ariel Hirschhorn
- Department of Cranio-Maxillofacial Surgery, Sheba Medical Center, Tel Hashomer, Israel
| | - Gadi Abebe Campino
- Division of Pediatric Hemato-Oncology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
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13
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Tosios KI, Kalogirou EM, Koutlas IG. Association of MDM2 Overexpression in Ameloblastomas with MDM2 Amplification and BRAF V600E Expression. Int J Mol Sci 2024; 25:2238. [PMID: 38396916 PMCID: PMC10889355 DOI: 10.3390/ijms25042238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 02/01/2024] [Accepted: 02/09/2024] [Indexed: 02/25/2024] Open
Abstract
Ameloblastoma is a rare tumor but represents the most common odontogenic neoplasm. It is localized in the jaws and, although it is a benign, slow-growing tumor, it has an aggressive local behavior and high recurrence rate. Therefore, alternative treatment options or complementary to surgery have been evaluated, with the most promising one among them being a targeted therapy with the v-Raf murine sarcoma viral oncogene homologue B (BRAF), as in ameloblastoma the activating mutation V600E in BRAF is common. Studies in other tumors have shown that the synchronous inhibition of BRAF and human murine double minute 2 homologue (MDM2 or HDM2) protein is more effective than BRAF monotherapy, particularly in the presence of wild type p53 (WTp53). To investigate the MDM2 protein expression and gene amplification in ameloblastoma, in association with BRAFV600E and p53 expression. Forty-four cases of ameloblastoma fixed in 10% buffered formalin and embedded in paraffin were examined for MDM2 overexpression and BRAFV600E and p53 expression by immunohistochemistry, and for MDM2 ploidy with fluorescence in situ hybridization. Sixteen of forty-four (36.36%) cases of ameloblastoma showed MDM2 overexpression. Seven of sixteen MDM2-positive ameloblastomas (43.75%) were BRAFV600E positive and fifteen of sixteen MDM2-positive ameloblastomas (93.75%) were p53 negative. All MDM2 overexpressing tumors did not show copy number alterations for MDM2. Overexpression of MDM2 in ameloblastomas is not associated with MDM2 amplification, but most probably with MAPK activation and WTp53 expression. Further verification of those findings could form the basis for the use of MDM2 expression as a marker of MAPK activation in ameloblastomas and the trial of dual BRAF/MDM2 inhibition in the management of MDM2-overexpressing/BRAFV600E-positive/WTp53 ameloblastomas.
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Affiliation(s)
- Konstantinos I. Tosios
- Department of Oral Pathology & Medicine and Hospital Dentistry, School of Dentistry, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Eleni-Marina Kalogirou
- Faculty of Health and Rehabilitation Sciences, Metropolitan College, 15125 Athens, Greece;
| | - Ioannis G. Koutlas
- Division of Oral Pathology, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA;
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14
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Büttner R, Gültekin SE, Heydt C, Nogova L, Meemboor S, Kreppel M, Aziz-Heiloun R. Efficiency of B-RAF-/MEK-inhibitors in B-RAF mutated Ameloblastoma: Case report and review of literature. Heliyon 2023; 9:e23206. [PMID: 38149213 PMCID: PMC10750065 DOI: 10.1016/j.heliyon.2023.e23206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 11/28/2023] [Accepted: 11/29/2023] [Indexed: 12/28/2023] Open
Abstract
Background Ameloblastoma is a benign but locally invasive and aggressive odontogenic tumor harboring activating BRAF V600E mutations in about two thirds of the cases. Case presentation Neoadjuvant therapy with Dabrafenib and Trametinib was given to a 42-year-old male patient with recurrent ameloblastoma of the right mandible with a BRAF V600E mutation for 18 months. The patient manifested an excellent response to the therapy with remarkable reduction in tumor size from 72.6 mm to 55.9 mm. Histopathologically, the tumor underwent significant degenerative changes with only a few sparse vital residuals revealing 0 % Ki67 proliferative index. Conclusions Neoadjuvant therapy with BRAF-inhibitors or BRAF-MEK-inhibitors is an effective means to reduce the size of mandibulary ameloblastomas. We propose the consideration of neoadjuvant therapy in future treatment modalities to minimize post-surgical morbidity and facial deformations.
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Affiliation(s)
- Reinhard Büttner
- Institute of Pathology, Medical Faculty, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany
| | - Sibel Elif Gültekin
- Faculty of Dentistry, Department of Oral Pathology, Gazi University, Emek, 06510, Ankara, Turkey
| | - Carina Heydt
- Institute of Pathology, Medical Faculty, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany
| | - Lucia Nogova
- Clinic of Internal Medicine I, Medical Faculty, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany
| | - Sonja Meemboor
- Institute of Pathology, Medical Faculty, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany
| | - Matthias Kreppel
- Clinic of Maxillofacial Surgery, Medical Faculty, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany
| | - Reem Aziz-Heiloun
- Institute of Pathology, Medical Faculty, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany
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15
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Oh KY. Treatment options for advanced ameloblastoma in the era of precision medicine: A brief review. Oral Oncol 2023; 146:106585. [PMID: 37816291 DOI: 10.1016/j.oraloncology.2023.106585] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 10/05/2023] [Indexed: 10/12/2023]
Abstract
Although complete excision is the standard of care for ameloblastoma, a subset of recurrent and/or metastasizing ameloblastomas are difficult to treat surgically. Over the past decade, several recurrent mutations in the mitogen-activated protein kinase pathway genes have been identified in ameloblastoma, based on which the efficacy of targeted therapy has been investigated. However, most of the literature has focused on BRAF V600E mutations, the most common oncogenic mutations in ameloblastoma. Hence, this study aims to review the current knowledge of targetable genetic alterations in ameloblastoma from a broader perspective. In addition, the therapeutic potential of immunotherapy for ameloblastoma will be briefly discussed in the context of tumoral PD-L1 expression and the tumor immune microenvironment.
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Affiliation(s)
- Kyu-Young Oh
- Department of Oral Pathology, College of Dentistry, Dankook University, Cheonan, Republic of Korea.
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16
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Graillon N, Akintoye SO, Iocca O, Kaleem A, Hajjar S, Imanguli M, Shanti RM. Current concepts in targeted therapies for benign tumors of the jaw - A review of the literature. J Craniomaxillofac Surg 2023; 51:591-596. [PMID: 37852890 PMCID: PMC11538012 DOI: 10.1016/j.jcms.2023.10.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 10/05/2023] [Indexed: 10/20/2023] Open
Abstract
The aim of our study was to review current concepts in targeted therapies for benign tumors of the jaw. Benign odontogenic and maxillofacial bone tumors often require radical surgery, with consequent morbidity that impacts patients' postsurgical quality of life. Currently, targeted therapies and novel nonsurgical therapeutics are being explored for management of non-resectable tumors, with the aim of avoiding surgery or minimizing surgical scope. However, data on clinical applications of targeted therapies for benign tumors of the jaw remain sparse. Therefore, a literature review was conducted, based on the PubMed database, which included in vivo human clinical studies describing clinical application of targeted therapy for benign tumor of the jaw. The review assessed the outcomes of BRAF and MEK inhibitors for treatment of ameloblastoma, RANKL monoclonal antibody for treatment of giant cell tumor, cherubism, aneurysmal bone cyst, and fibrous dysplasia, and tyrosine kinase inhibitor for treatment of odontogenic myxoma and cherubism. Targeted therapies decreased tumor size, slowed down tumor progression, and reduced bone pain. Surgery remains the gold standard, but targeted therapies are promising adjuvant or alternative treatment options for reducing tumor progression and morbidity of tumor surgery.
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Affiliation(s)
- Nicolas Graillon
- Aix Marseille Univ, APHM, Univ Gustave Eiffel, LBA, Bd Pierre Dramard, 13916, Marseille, France; Conception University Hospital, Department of Oral and Maxillofacial Surgery, 147 Bd Baille, Marseille, 13005, France.
| | - Sunday O Akintoye
- Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Oreste Iocca
- Division of Maxillofacial Surgery, Città Della Salute e Della Scienza Hospital, University of Torino, Torino, Italy
| | - Arshad Kaleem
- Head and Neck Oncology and Microvascular Surgery, High Desert Oral and Facial Surgery, El Paso, TX, USA
| | - Souren Hajjar
- Department of Oral and Maxillofacial Surgery, Rutgers School of Dental Medicine, Newark, NJ, USA
| | - Matin Imanguli
- Department of Otolaryngology - Head and Neck Surgery, Robert Wood Johnson Medical School, Associate Member Rutgers Cancer Institute of New Jersey, Newark, NJ, USA
| | - Rabie M Shanti
- Department of Oral and Maxillofacial Surgery, Rutgers School of Dental Medicine, Newark, NJ, USA
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17
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Malakar A, Kumar VR, Yadav P, Bhardwaj V, Barua CG, Bhardwaj G. The Role of BRAF Inhibitors in the Management of Ameloblastoma: A Literature Review. Cureus 2023; 15:e47682. [PMID: 38021761 PMCID: PMC10673693 DOI: 10.7759/cureus.47682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/25/2023] [Indexed: 12/01/2023] Open
Abstract
Ameloblastoma is one of the most prevalent but enigmatic benign odontogenic tumors of the jaw, accounting for approximately 10% of all maxillary and mandibular tumors. This neoplasia is distinguished by exhibiting several clinical and histological variants along with several mutations that affect its behavior. The ameloblastoma treatment plan is determined by the tumor's size, anatomical location, histologic variant, and anatomical involvement. On chromosome 7, there is a proto-oncogene called BRAF. When BRAF is mutated, it becomes an oncogene and continuously produces proteins like MEK and ERK, members of mitogen-activated protein kinase (MAPK). In the signaling pathway, these proteins activate transcription factor inside the nucleus that helps in cell division and growth. Numerous neoplasms have been linked to more than 40 BRAF mutations. The most common one is BRAF proto-oncogene serine/threonine kinase (BRAF) V600E, whose treatment has been linked to a positive outcome. BRAF inhibitors like vemurafenib, dabrafenib, and sorafenib have shown excellent results, especially in metastatic ameloblastoma. BRAF, particularly in the case of metastatic ameloblastoma, inhibitors such as vemurafenib, dabrafenib, and sorafenib, has demonstrated outstanding results. Targeted therapies have been employed as adjuvant therapies to enhance cosmetic outcomes, even though no reports of serial cases demonstrate their effectiveness in ameloblastomas. In the treatment of ameloblastomas, the identification of BRAF V600E and additional mutations as the prime targeted therapies has proven to be a significant breakthrough where surgical treatment was contraindicated. In this article, we review the presence of BRAF V600E mutations, their inhibitors, and targeted therapies in ameloblastoma.
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Affiliation(s)
- Arindam Malakar
- Oral and Maxillofacial Surgery, Prabhu Dayal Memorial (PDM) Dental College and Research Institute, PDM University, Bahadurgarh, IND
| | - V Raj Kumar
- Oral and Maxillofacial Surgery, Prabhu Dayal Memorial (PDM) Dental College and Research Institute, PDM University, Bahadurgarh, IND
| | - Priya Yadav
- Periodontics, Employees' State Insurance Corporation (ESIC) Dental College and Hospital, Delhi, IND
| | - Vishal Bhardwaj
- Oral and Maxillofacial Surgery, Prabhu Dayal Memorial (PDM) Dental College and Research Institute, PDM University, Bahadurgarh, IND
| | - Chuimee Gogoi Barua
- Oral and Maxillofacial Surgery, Career Postgraduate Institute of Dental Sciences and Hospital, Lucknow, IND
| | - Gourika Bhardwaj
- Dentistry, Prabhu Dayal Memorial (PDM) Dental College and Research Institute, PDM University, Bahadurgarh, IND
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18
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Gates JC, Clark AP, Cherkas E, Shreenivas AV, Kraus D, Danzinger N, Huang RSP, Johnson J, Ross JS. Genomic profiling and precision medicine in complex ameloblastoma. Head Neck 2023; 45:816-826. [PMID: 36645099 DOI: 10.1002/hed.27294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 12/01/2022] [Accepted: 12/27/2022] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Ameloblastoma may present a significant treatment challenge in the locally advanced, recurrent and metastatic setting. Comprehensive genomic profiling (CGP) can identify targetable genomic alterations to aid in treatment. METHODS Ameloblastoma samples were sequenced using hybrid-capture based sequencing. A systematic literature review was performed to examine outcomes in studies employing targeted treatment in ameloblastoma. RESULTS We reviewed 14 cases of Ameloblastoma using CGP. There were six patients with activating BRAF mutations, five with PIK3CA, five with SMO, four with FGFR2, one with EGFR, and one with ROS1. All cases were MSI stable and the median TMB was 2.5 mutations/Mb. A separate literature review of clinical outcomes in ameloblastoma showed a predominance of at least partial response to targeted treatment (7/12 cases). CONCLUSION CGP is helpful in identifying specific driver mutations in patients with complex ameloblastoma. Targeted treatment has been employed with success in achieving treatment response.
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Affiliation(s)
- James C Gates
- Department of Oral and Maxillofacial Surgery, Hospital of the University of Pennsylvania, Penn Medicine, Philadelphia, Pennsylvania, USA
| | | | - Elliot Cherkas
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Aditya V Shreenivas
- Department of Medical Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Dennis Kraus
- Director of Oncology, Centura Health, Centennial, Colorado, USA
| | | | | | - Jennifer Johnson
- Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Jeffrey S Ross
- Foundation Medicine, Inc., Cambridge, Massachusetts, USA
- Department of Pathology, Upstate Medical University, Syracuse, New York, USA
- Department of Urology, Upstate Medical University, Syracuse, New York, USA
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19
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Conventional Ameloblastoma. A Case Report with Microarray and Bioinformatic Analysis. Diagnostics (Basel) 2022; 12:diagnostics12123190. [PMID: 36553196 PMCID: PMC9777305 DOI: 10.3390/diagnostics12123190] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/08/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Ameloblastoma is a rare benign epithelial odontogenic neoplasm, but with great clinical implications, as despite its benignity and slow growth, most cases are locally aggressive with a significant recurrence rate. Histological, cellular, or molecular analyses of its pathogenesis have confirmed the complexity of this neoplasm. We present the case of a 20-year-old patient with a suggestive clinical and radiographic diagnosis of ameloblastoma. An incisional biopsy was obtained confirming the diagnosis of conventional ameloblastoma. Left hemimandibulectomy and plate reconstruction were performed. Histopathological analysis of the surgical specimen confirmed the conventional ameloblastoma with a plexiform pattern and significant areas of cystic degeneration and amyloid-like-like deposits. Additionally, a microarray was carried out with bioinformatic analysis for the enrichment, protein interaction, and determination of eight hub genes (CRP, BCHE, APP, AKT1, AGT, ACTC1, ADAM10, and APOA2) related to their pathogenesis.
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20
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Mamat @ Yusof MN, Ch’ng ES, Radhiah Abdul Rahman N. BRAF V600E Mutation in Ameloblastoma: A Systematic Review and Meta-Analysis. Cancers (Basel) 2022; 14:5593. [PMID: 36428683 PMCID: PMC9688909 DOI: 10.3390/cancers14225593] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/25/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
The discovery that ameloblastoma has a high mutation incidence of BRAF V600E may enable a better investigation of pathophysiology. However, there is inconsistent evidence regarding this mutation occurrence and its association with clinical information. This systematic review and meta-analysis aim to pool the overall mutation prevalence of BRAF V600E in reported ameloblastoma cases and to determine its association with patient demographic and clinicopathological features. Following the PRISMA guidelines, a comprehensive article search was conducted through four databases (Scopus, Google Scholar, PubMed, and Web of Science). Seventeen articles between 2014 and 2022 met the inclusion criteria with 833 ameloblastoma cases. For each included study, the significance of BRAF V600E on the outcome parameters was determined using odd ratios and 95% confidence intervals. Meta-analysis prevalence of BRAF V600E in ameloblastoma was 70.49%, and a significant meta-analysis association was reported for those younger than 54 years old and in the mandible. On the contrary, other factors, such as sex, histological variants, and recurrence, were insignificant. As a result of the significant outcome of BRAF V600E mutation in ameloblastoma pathogenesis, targeted therapy formulation can be developed with this handful of evidence.
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Affiliation(s)
- Mohd Nazzary Mamat @ Yusof
- Department of Clinical Medicine, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas 13200, Malaysia
- Department of Obstetrics and Gynaecology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur 56000, Malaysia
| | - Ewe Seng Ch’ng
- Department of Clinical Medicine, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas 13200, Malaysia
| | - Nawal Radhiah Abdul Rahman
- Department of Dental Science, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas 13200, Malaysia
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21
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Stone LD, Massicano AVF, Stevens TM, Warram JM, Morlandt AB, Lapi SE, Amm HM. 89Zr-panitumumab PET imaging for preoperative assessment of ameloblastoma in a PDX model. Sci Rep 2022; 12:19187. [PMID: 36357495 PMCID: PMC9649768 DOI: 10.1038/s41598-022-23531-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 11/01/2022] [Indexed: 11/11/2022] Open
Abstract
Accurate assessment of tumor margins with specific, non-invasive imaging would result in the preservation of healthy tissue and improve long-term local tumor control, thereby reducing the risk of recurrence. Overexpression of epidermal growth factor receptor (EGFR) has been used in other cancers as an imaging biomarker to identify cancerous tissue. We hypothesize that expression of EGFR in ameloblastomas may be used to specifically visualize tumors. The aims of this study are to measure the specificity of radiolabeled 89Zr-panitumumab (an EGFR antibody) in vivo using patient-derived xenograft (PDX) models of ameloblastoma and positron emission tomography/computed tomography (PET/CT) scans. In PDX of ameloblastomas from four patients (AB-36, AB-37, AB-39 AB-53), the biodistribution of 89Zr-panitumumab was measured 120 h post-injection and was reported as the injected dose per gram of tissue (%ID/g; AB-36, 40%; AB-37, 62%; AB-39 18%; AB-53, 65%). The radiolabeled %ID/g was significantly greater in tumors of 89Zr-panitumumab-treated mice that did not receive unlabeled panitumumab as a blocking control for AB-36, AB-37, and AB-53. Radiolabeled anti-EGFR demonstrates specificity for ameloblastoma PDX tumor xenografts, we believe 89Zr-panitumumab is an attractive target for pre-surgical imaging of ameloblastomas. With this technology, we could more accurately assess tumor margins for the surgical removal of ameloblastomas.
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Affiliation(s)
- Logan D Stone
- Department of Otolaryngology, University of Alabama at Birmingham, 1720 2nd Avenue South, VH G082, Birmingham, AL, 35294, USA
- Department of Oral and Maxillofacial Surgery, Section of Oral Oncology, University of Alabama at Birmingham, 1919 7th Avenue South, Birmingham, AL, 35294, USA
| | - Adriana V F Massicano
- Department of Radiology, University of Alabama at Birmingham, 1824 6th Avenue South, WTI 310F, Birmingham, AL, 35294, USA
| | - Todd M Stevens
- Department of Pathology, University of Alabama at Birmingham, 1802 6th Avenue South, NP 3548, Birmingham, AL, 35294, USA
| | - Jason M Warram
- Department of Otolaryngology, University of Alabama at Birmingham, 1720 2nd Avenue South, VH G082, Birmingham, AL, 35294, USA
| | - Anthony B Morlandt
- Department of Oral and Maxillofacial Surgery, Section of Oral Oncology, University of Alabama at Birmingham, 1919 7th Avenue South, Birmingham, AL, 35294, USA
| | - Suzanne E Lapi
- Department of Radiology, University of Alabama at Birmingham, 1824 6th Avenue South, WTI 310F, Birmingham, AL, 35294, USA
| | - Hope M Amm
- Department of Oral and Maxillofacial Surgery, Section of Oral Oncology, University of Alabama at Birmingham, 1919 7th Avenue South, Birmingham, AL, 35294, USA.
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22
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Mosca M, Filippini DM, Tober N, Rojas FL, Rihawi K, Di Fabio F. Unexpected response to fourth-line paclitaxel in a patient with metastatic oropharyngeal squamous cell carcinoma, immunotherapy-refractory: a case report. Anticancer Drugs 2022; 33:691-695. [PMID: 35324531 DOI: 10.1097/cad.0000000000001302] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
In recent years, immune checkpoint inhibitors (ICIs), including nivolumab and pembrolizumab have revolutionized the treatment landscape in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). However, many patients do not respond to ICIs for reasons that remain largely unknown. For patients who progress on ICIs, chemotherapy and/or biologic therapies are the most widely used treatments based on the clinician's choice, with no defined sequence strategy. We report the experience of a patient with metastatic oropharyngeal squamous cell cancer p16 and human papillomavirus-DNA positive who received chemotherapy with weekly paclitaxel after progressing on nivolumab. Our patient presented a partial response to fourth line paclitaxel, which lasted more than 2 years, with an improvement of his quality of life too. These results support the hypothesis of synergism between immunotherapy and conventional chemotherapies. Even in the setting of immune-refractory disease, immunotherapy may affect tumor immune microenvironment thus leading to a synergistic effect with conventional chemotherapy and achieving unexpected results.
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Affiliation(s)
- Mirta Mosca
- Department of Experimental, Diagnostic and Specialty Medicine, Policlinico di Sant'Orsola University Hospital
| | - Daria Maria Filippini
- Department of Experimental, Diagnostic and Specialty Medicine, Policlinico di Sant'Orsola University Hospital
- Division of Medical Oncology, Department of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Nastassja Tober
- Department of Experimental, Diagnostic and Specialty Medicine, Policlinico di Sant'Orsola University Hospital
| | - Fabiola Lorena Rojas
- Department of Experimental, Diagnostic and Specialty Medicine, Policlinico di Sant'Orsola University Hospital
- Division of Medical Oncology, Department of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Karim Rihawi
- Department of Experimental, Diagnostic and Specialty Medicine, Policlinico di Sant'Orsola University Hospital
- Division of Medical Oncology, Department of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Francesca Di Fabio
- Department of Experimental, Diagnostic and Specialty Medicine, Policlinico di Sant'Orsola University Hospital
- Division of Medical Oncology, Department of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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23
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Molecular biology exploration and targeted therapy strategy of Ameloblastoma. Arch Oral Biol 2022; 140:105454. [DOI: 10.1016/j.archoralbio.2022.105454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 05/09/2022] [Accepted: 05/10/2022] [Indexed: 11/19/2022]
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24
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Identification of BRAF V600E mutation in odontogenic tumors by high-performance MALDI-TOF analysis. Int J Oral Sci 2022; 14:22. [PMID: 35468886 PMCID: PMC9038922 DOI: 10.1038/s41368-022-00170-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 01/26/2022] [Accepted: 03/10/2022] [Indexed: 11/14/2022] Open
Abstract
Odontogenic tumors are rare lesions with unknown etiopathogenesis. Most of them are benign, but local aggressiveness, infiltrative potential, and high recurrence rate characterize some entities. The MAP-kinase pathway activation can represent a primary critical event in odontogenic tumorigenesis. Especially, the BRAF V600E mutation has been involved in 80–90% of ameloblastic lesions, offering a biological rationale for developing new targeted therapies. The study aims to evaluate the BRAF V600E mutation in odontogenic lesions, comparing three different detection methods and focusing on the Sequenom MassARRAY System. 81 surgical samples of odontogenic lesions were subjected to immunohistochemical analysis, Sanger Sequencing, and Matrix-Assisted Laser Desorption/Ionization-Time of Flight mass spectrometry (Sequenom). The BRAF V600E mutation was revealed only in ameloblastoma samples. Moreover, the presence of BRAF V600E was significantly associated with the mandibular site (ρ = 0.627; P value <0.001) and the unicystic histotype (ρ = 0.299, P value <0.001). However, any significant difference of 10-years disease-free survival time was not revealed. Finally, Sequenom showed to be a 100% sensitive and 98.1% specific, suggesting its high-performance diagnostic accuracy. These results suggest the MAP-kinase pathway could contribute to ameloblastic tumorigenesis. Moreover, they could indicate the anatomical specificity of the driving mutations of mandibular ameloblastomas, providing a biological rational for developing new targeted therapies. Finally, the high diagnostic accuracy of Sequenom was confirmed.
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25
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Managing stage 4 ameloblastoma with dual BRAF/MEK inhibition: A case report with 8-year clinical follow-up. Oral Oncol 2022; 128:105854. [PMID: 35447565 DOI: 10.1016/j.oraloncology.2022.105854] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 04/03/2022] [Indexed: 12/25/2022]
Abstract
We present 8-year follow-up on the first patient with stage 4 ameloblastoma carrying a BRAF V600E mutation treated with dual BRAF/MEK inhibition (BRAF/MEKi). He experienced a durable clinical response while on dabrafenib (BRAFi) and trametinib (MEKi) without toxicity nor evidence for drug-resistant tumor progression. He was asymptomatic when he self-discontinued therapy after 4 years of sustained clinical response. He did not return for follow-up until 2.5 years later with onset of painful mandibular tumor recurrence associated with recurrent bilateral lung metastases. He was rechallenged with dabrafenib/trametinib and experienced another prompt tumor response and remains in a second durable clinical remission (currently > 16 months) on continuous dual targeted therapy. We discuss the implications of this case study for future treatment strategies.
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26
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Ngan HL, Law CH, Choi YCY, Chan JYS, Lui VWY. Precision drugging of the MAPK pathway in head and neck cancer. NPJ Genom Med 2022; 7:20. [PMID: 35296678 PMCID: PMC8927572 DOI: 10.1038/s41525-022-00293-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 02/15/2022] [Indexed: 01/12/2023] Open
Abstract
The mitogen-activating protein kinase (MAPK) pathway is central for cell proliferation, differentiation, and senescence. In human, germline defects of the pathway contribute to developmental and congenital head and neck disorders. Nearly 1/5 of head and neck squamous cell carcinoma (HNSCC) harbors MAPK pathway mutations, which are largely activating mutations. Yet, previous approaches targeting the MAPK pathway in HNSCC were futile. Most recent clinical evidences reveal remarkable, or even exceptional pharmacologic vulnerabilities of MAPK1-mutated, HRAS-mutated, KRAS-germline altered, as well as BRAF-mutated HNSCC patients with various targeted therapies, uncovering diverse opportunities for precision drugging this pathway at multiple “genetically condemned” nodes. Further, recent patient tumor omics unveil novel effects of MAPK aberrations on direct induction of CD8+ T cell recruitment into the HNSCC microenvironment, providing evidences for future investigation of precision immunotherapy for this large subset of patients. MAPK pathway-mutated HNSCC should warrant precision therapy assessments in vigorous manners.
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Affiliation(s)
- Hoi-Lam Ngan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong
| | - Chun-Ho Law
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong
| | | | - Jenny Yu-Sum Chan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong
| | - Vivian Wai Yan Lui
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong. .,Georgia Cancer Center, and Department of Medicine, Medical College of Georgia, Augusta University, Georgia, GA, 30912, USA.
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27
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Martins-de-Barros AV, Dos Anjos RS, Silva CCG, de Oliveira E Silva ED, da Costa Araújo FA, de Vasconcelos Carvalho M. Diagnostic accuracy of immunohistochemistry compared with molecular tests for detection of BRAF V600E mutation in ameloblastomas: systematic review and meta-analysis. J Oral Pathol Med 2022; 51:223-230. [PMID: 35090195 DOI: 10.1111/jop.13278] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/17/2022] [Accepted: 01/21/2022] [Indexed: 12/01/2022]
Abstract
OBJECTIVE The objective of this systematic review with meta-analysis was to critically evaluate the available data on sensitivity and specificity of IHC compared with molecular tests in the detection of BRAF V600E mutation in ameloblastomas. MATERIALS AND METHODS This systematic review was performed based on the PRISMA statement and registered in Prospero (CRD42021259117). PubMed, Web of Science, Scopus and Cochrane Library databases were searched for observational studies to answer the question "What is the diagnostic accuracy of immunohistochemistry compared with molecular tests for the diagnosis of BRAF V600E mutation in ameloblastomas?". Methodological quality and risk of bias assessment of the selected studies were based on the QUADAS-2. Meta-analysis based on hierarchical SROC curve model and summary measures for sensitivity and specificity were computed. RESULTS A total of 226 records were found, but only 05 articles met the inclusion criteria, with 277 FFPE specimens of ameloblastoma included in the quantitative analysis. The sensitivity of the IHC compared to molecular tests ranged from 0.71 to 1.00, while all of the included studies showed perfect specificity (1.00). Pooled measures for sensitivity and specificity were 0.95 [95% CI 0.89, 1.00] and 1.00 [95% CI 0.95, 1.00], respectively. The Diagnostic Odds Ratio was 4.05 and the AUC for SROC curve was calculated as 0.979. CONCLUSIONS BRAF V600E-specific IHC using VE1 antibody showed extremely high sensitivity and specificity when compared with molecular tests in the detection of the mutation in ameloblastomas.
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Affiliation(s)
- Allan Vinícius Martins-de-Barros
- University of Pernambuco (UPE), School of Dentistry, Post-Graduation Program in Dentistry. Recife, Pernambuco, Brazil.,Hospital Universitário Oswaldo Cruz (HUOC/UPE), Centro Integrado de Anatomia Patológica (CIAP), Recife, Pernambuco, Brazil.,Hospital Universitário Oswaldo Cruz (HUOC/UPE, Department of Oral and Maxillofacial Surgery, Recife, Pernambuco, Brazil
| | - Raíssa Soares Dos Anjos
- University of Pernambuco (UPE), School of Dentistry, Post-Graduation Program in Dentistry. Recife, Pernambuco, Brazil.,Hospital Universitário Oswaldo Cruz (HUOC/UPE), Centro Integrado de Anatomia Patológica (CIAP), Recife, Pernambuco, Brazil
| | - Caio César Gonçalves Silva
- University of Pernambuco (UPE), School of Dentistry, Post-Graduation Program in Dentistry. Recife, Pernambuco, Brazil.,Hospital Universitário Oswaldo Cruz (HUOC/UPE, Department of Oral and Maxillofacial Surgery, Recife, Pernambuco, Brazil
| | - Emanuel Dias de Oliveira E Silva
- University of Pernambuco (UPE), School of Dentistry, Post-Graduation Program in Dentistry. Recife, Pernambuco, Brazil.,Hospital Universitário Oswaldo Cruz (HUOC/UPE, Department of Oral and Maxillofacial Surgery, Recife, Pernambuco, Brazil
| | - Fábio Andrey da Costa Araújo
- University of Pernambuco (UPE), School of Dentistry, Post-Graduation Program in Dentistry. Recife, Pernambuco, Brazil.,Hospital Universitário Oswaldo Cruz (HUOC/UPE, Department of Oral and Maxillofacial Surgery, Recife, Pernambuco, Brazil
| | - Marianne de Vasconcelos Carvalho
- University of Pernambuco (UPE), School of Dentistry, Post-Graduation Program in Dentistry. Recife, Pernambuco, Brazil.,Hospital Universitário Oswaldo Cruz (HUOC/UPE), Centro Integrado de Anatomia Patológica (CIAP), Recife, Pernambuco, Brazil
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28
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Guimarães LM, Coura BP, Gomez RS, Gomes CC. The Molecular Pathology of Odontogenic Tumors: Expanding the Spectrum of MAPK Pathway Driven Tumors. FRONTIERS IN ORAL HEALTH 2022; 2:740788. [PMID: 35048058 PMCID: PMC8757814 DOI: 10.3389/froh.2021.740788] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 08/13/2021] [Indexed: 12/13/2022] Open
Abstract
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 (BRAF) and KRAS proto-oncogene GTPase (KRAS) 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 BRAF 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.
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Affiliation(s)
- Letícia Martins Guimarães
- Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Bruna Pizziolo Coura
- Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Ricardo Santiago Gomez
- Department of Oral Surgery and Pathology, Faculty of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Carolina Cavalieri Gomes
- Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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29
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Enrichment of SOX2-Positive Cells in BRAF V600E Mutated and Recurrent Ameloblastoma. J Pers Med 2022; 12:jpm12010077. [PMID: 35055392 PMCID: PMC8780877 DOI: 10.3390/jpm12010077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/01/2022] [Accepted: 01/05/2022] [Indexed: 11/17/2022] Open
Abstract
Ameloblastoma is the most common benign odontogenic neoplasm, but with an aggressive behavior and a high recurrence rate. Nowadays wide surgical resection is the current recommended treatment, which can cause further loss of function and esthetics. Recent studies point to the stem/progenitor cells as both initiators and propagators of the tumors. Elucidation of the cellular and molecular mechanisms underlying the tumor stem cells is of broad interest for understanding tumorigenesis and for developing effective targeted therapies. SRY related HMG box gene 2 (SOX2) is a transcription factor that plays important roles in development, stem cell renewal, and cancer formation. Few studies have revealed increased SOX2 expression in atypical ameloblastoma and ameloblastic carcinoma. For the development of personalized medicine for ameloblastoma, biomarkers that provide prognostic or predictive information regarding a tumor’s nature or its response to treatment are essential. Thus, in this study, we aimed to study if SOX2-positive cells exist in ameloblastomas and their correlation with the clinicopathologic parameters. Our data suggested BRAF(V600E) mutation might contribute to the expansion of SOX2-positive cells. The identification of BRAF(V600E) mutation and the amplification of SOX2-positive cells in ameloblastomas imply the possible benefit of applying BRAF and SOX2 inhibitors in recurrent and un-resectable ameloblastomas.
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30
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Kunmongkolwut S, Chaisuparat R. Analysis of BRAF V600E expression and disease-free survival in patients with ameloblastoma. Int J Oral Maxillofac Surg 2022; 51:1034-1042. [PMID: 34998647 DOI: 10.1016/j.ijom.2021.12.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 12/13/2021] [Accepted: 12/15/2021] [Indexed: 10/19/2022]
Abstract
The correlation between BRAF mutation and the aggressiveness of ameloblastoma remains controversial. The aim of this study was to investigate the association of BRAF V600E expression with clinicopathological features and disease-free survival (DFS) in patients with ameloblastoma. Seventy-four conventional ameloblastoma samples were collected. Immunohistochemistry using anti-BRAF V600E antibody was performed on formalin-fixed, paraffin-embedded tissue sections. Clinicopathological characteristics and treatment outcomes were retrieved from the patient medical records. BRAF V600E immunoreactivity was detected in 50/74 cases (67.6%); 39 were strongly positive and 11 weakly. There was a significant difference in BRAF V600E expression between ameloblastoma and dental follicle (P = 0.034). However, there was no significant association of BRAF V600E expression with any clinicopathological features, including sex, age, location, duration, tumour size, radiographic appearance, cortical perforation, recurrence, and histological subtype. DFS analysis revealed that patients with BRAF-mutated ameloblastoma had a shorter median survival time (84 months vs 168 months) and lower 5-year survival rate (59% vs 67%) compared to the BRAF wild-type group; however, this was not statistically significant (P = 0.169). Moreover, logistic regression analysis revealed that treatment with enucleation was an independent risk factor for tumour recurrence (odds ratio 9.236; P = 0.028). This study demonstrated that the BRAF V600E mutation was not associated with any clinicopathological features of ameloblastoma. A trend towards earlier recurrence in tumours with BRAF mutation was observed, but this requires further investigation. Furthermore, the findings suggest that the treatment modality is an important factor in determining recurrence in ameloblastoma despite genetic alterations.
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Affiliation(s)
- S Kunmongkolwut
- Department of Oral Pathology, Faculty of Dentistry, Chulalongkorn University, Pathumwan, Bangkok, Thailand.
| | - R Chaisuparat
- Department of Oral Pathology, Faculty of Dentistry, Chulalongkorn University, Pathumwan, Bangkok, Thailand; Exocrine Gland Biology and Regeneration Research Group, Faculty of Dentistry, Chulalongkorn University, Pathumwan, Bangkok, Thailand.
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31
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JACINTO-ALEMÁN LF, PORTILLA-ROBERTSON J, LEYVA-HUERTA ER, RAMÍREZ-JARQUÍN JO, VILLANUEVA-SÁNCHEZ FG. Microarray and bioinformatic analysis of conventional ameloblastoma: an observational analysis. J Appl Oral Sci 2022. [DOI: 10.1590/1678-7757-2022-0308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
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32
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Marin C, Dave M, Hunter KD. Malignant Odontogenic Tumours: A Systematic Review of Cases Reported in Literature. FRONTIERS IN ORAL HEALTH 2021; 2:775707. [PMID: 35048074 PMCID: PMC8757763 DOI: 10.3389/froh.2021.775707] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 10/20/2021] [Indexed: 11/18/2022] Open
Abstract
Background: Malignant odontogenic tumours (MOTs) arise either de novo 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. Methods: 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. Results: 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. Conclusion: 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.
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Affiliation(s)
- Constanza Marin
- Unit of Oral and Maxillofacial Medicine, Pathology and Surgery, University of Sheffield, Sheffield, United Kingdom
- Unidad de Patología y Medicina Oral, Facultad de Odontología, Universidad Andres Bello, Viña del Mar, Chile
| | - Manas Dave
- Division of Dentistry, The University of Manchester, Manchester, United Kingdom
| | - Keith D. Hunter
- Unit of Oral and Maxillofacial Medicine, Pathology and Surgery, University of Sheffield, Sheffield, United Kingdom
- Department of Oral Pathology and Biology, School of Dentistry, University of Pretoria, Pretoria, South Africa
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33
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Fujii S, Ishibashi T, Kokura M, Fujimoto T, Matsumoto S, Shidara S, Kurppa KJ, Pape J, Caton J, Morgan PR, Heikinheimo K, Kikuchi A, Jimi E, Kiyoshima T. RAF1-MEK/ERK pathway-dependent ARL4C expression promotes ameloblastoma cell proliferation and osteoclast formation. J Pathol 2021; 256:119-133. [PMID: 34622442 DOI: 10.1002/path.5814] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 09/10/2021] [Accepted: 10/05/2021] [Indexed: 12/17/2022]
Abstract
Ameloblastoma is an odontogenic neoplasm characterized by slow intraosseous growth with progressive jaw resorption. Recent reports have revealed that ameloblastoma harbours an oncogenic BRAFV600E mutation with mitogen-activated protein kinase (MAPK) pathway activation and described cases of ameloblastoma harbouring a BRAFV600E mutation in which patients were successfully treated with a BRAF inhibitor. Therefore, the MAPK pathway may be involved in the development of ameloblastoma; however, the precise mechanism by which it induces ameloblastoma is unclear. The expression of ADP-ribosylation factor (ARF)-like 4c (ARL4C), induced by a combination of the EGF-MAPK pathway and Wnt/β-catenin signalling, has been shown to induce epithelial morphogenesis. It was also reported that the overexpression of ARL4C, due to alterations in the EGF/RAS-MAPK pathway and Wnt/β-catenin signalling, promotes tumourigenesis. However, the roles of ARL4C in ameloblastoma are unknown. We investigated the involvement of ARL4C in the development of ameloblastoma. In immunohistochemical analyses of tissue specimens obtained from 38 ameloblastoma patients, ARL4C was hardly detected in non-tumour regions but tumours frequently showed strong expression of ARL4C, along with the expression of both BRAFV600E and RAF1 (also known as C-RAF). Loss-of-function experiments using inhibitors or siRNAs revealed that ARL4C elevation depended on the RAF1-MEK/ERK pathway in ameloblastoma cells. It was also shown that the RAF1-ARL4C and BRAFV600E-MEK/ERK pathways promoted cell proliferation independently. ARL4C-depleted tumour cells (generated by knockdown or knockout) exhibited decreased proliferation and migration capabilities. Finally, when ameloblastoma cells were co-cultured with mouse bone marrow cells and primary osteoblasts, ameloblastoma cells induced osteoclast formation. ARL4C elevation in ameloblastoma further promoted its formation capabilities through the increased RANKL expression of mouse bone marrow cells and/or primary osteoblasts. These results suggest that the RAF1-MEK/ERK-ARL4C axis, which may function in cooperation with the BRAFV600E-MEK/ERK pathway, promotes ameloblastoma development. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Shinsuke Fujii
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Takuma Ishibashi
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Megumi Kokura
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Tatsufumi Fujimoto
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Shinji Matsumoto
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan.,Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Japan
| | - Satsuki Shidara
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Kari J Kurppa
- Institute of Biomedicine and MediCity Research Laboratories, University of Turku, and Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Judith Pape
- Division of Surgery and Interventional Science, Department of Targeted Intervention, Centre for 3D Models of Health and Disease, University College London, London, UK
| | - Javier Caton
- Department of Anatomy and Embryology, Faculty of Medicine, University Complutense Madrid, Madrid, Spain
| | - Peter R Morgan
- Head & Neck Pathology, King's College London, Guy's Hospital, London, UK
| | - Kristiina Heikinheimo
- Department of Oral and Maxillofacial Surgery, Institute of Dentistry, University of Turku and Turku University Hospital, Turku, Finland
| | - Akira Kikuchi
- Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Eijiro Jimi
- Oral Health/Brain Health/Total Health Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.,Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Tamotsu Kiyoshima
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
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34
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Hirschhorn A, Campino GA, Vered M, Greenberg G, Yacobi R, Yahalom R, Barshack I, Toren A, Amariglio N, Rechavi G. Upfront rational therapy in BRAF V600E mutated pediatric ameloblastoma promotes ad integrum mandibular regeneration. J Tissue Eng Regen Med 2021; 15:1155-1161. [PMID: 34599642 DOI: 10.1002/term.3254] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 09/22/2021] [Accepted: 09/25/2021] [Indexed: 12/27/2022]
Abstract
Ameloblastoma is a neoplasm arising in the craniofacial skeleton. Proliferating odontogenic epithelial cells comprise this benign, yet locally invasive tumor, often causing severe disfiguration. High recurrence rate entails ablative surgical resection, which is the current standard of care, resulting in subsequent critical size osteocutaneous defects. The high incidence of BRAF mutations in ameloblastoma, most notably the BRAF V600E mutation, enabled the use of BRAF inhibiting agent in a neoadjuvant setting. In this investigator-initiated, open-label study, three consecutive pediatric patients, with confirmed BRAF V600E ameloblastoma deemed marginally resectable, were treated with BRAF inhibiting agents, prior to undergoing surgery. The use of upfront BRAF inhibitor treatment resulted in substantial tumor regression, allowing for non-mutilating complete surgical removal, ad integrum bone regeneration and organ preservation. All patients showed a marked radiologic and clinical response to medical treatment, enabling successful conservative surgery. Microscopically, all patients showed evidence of minimal residual tumor with extensive tumor necrosis, fibrosis and generation of new bone. At a median follow-up of 31 months, all patients remained free of disease. Face preservation therapy was achieved in pediatric patients presenting with BRAF V600E mutated ameloblastoma. Our study demonstrates the translational potential of targeted therapy as a neoadjuvant agent. Patient-specific organ preservation therapy should be considered as the new standard of care in ameloblastoma, mainly for children and adolescents.
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Affiliation(s)
- Ariel Hirschhorn
- Department of Cranio-Maxillofacial Surgery, Sheba Medical Center, Tel Hashomer, Israel
| | - Gadi Abebe Campino
- Division of Pediatric Hemato-Oncology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel
| | - Marilena Vered
- Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel.,Department of Oral Pathology, Oral Medicine and Maxillofacial Imaging, Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Gahl Greenberg
- Department of Radiology, Division of Neuroradiology, Sheba Medical Center, Tel Hashomer, Israel
| | - Rinat Yacobi
- Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel
| | - Ran Yahalom
- Department of Cranio-Maxillofacial Surgery, Sheba Medical Center, Tel Hashomer, Israel
| | - Iris Barshack
- Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Amos Toren
- Division of Pediatric Hemato-Oncology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ninette Amariglio
- Sheba Cancer Research Center, Wohl Institute of Translational Medicine, Sheba Medical Center, Tel Hashomer, Israel
| | - Gideon Rechavi
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Sheba Cancer Research Center, Wohl Institute of Translational Medicine, Sheba Medical Center, Tel Hashomer, Israel
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35
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Cleary JM, Wang V, Heist RS, Kopetz ES, Mitchell EP, Zwiebel JA, Kapner KS, Chen HX, Li S, Gray RJ, McShane LM, Rubinstein LV, Patton DR, Meric-Bernstam F, Dillmon MS, Williams PM, Hamilton SR, Conley BA, Aguirre AJ, O'Dwyer PJ, Harris LN, Arteaga CL, Chen AP, Flaherty KT. Differential Outcomes in Codon 12/13 and Codon 61 NRAS-Mutated Cancers in the Phase II NCI-MATCH Trial of Binimetinib in Patients with NRAS-Mutated Tumors. Clin Cancer Res 2021; 27:2996-3004. [PMID: 33637626 PMCID: PMC8542423 DOI: 10.1158/1078-0432.ccr-21-0066] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 01/11/2021] [Accepted: 02/18/2021] [Indexed: 01/02/2023]
Abstract
PURPOSE Preclinical and clinical data suggest that downstream inhibition with an MEK inhibitor, such as binimetinib, might be efficacious for NRAS-mutated cancers. PATIENTS AND METHODS Patients enrolled in the NCI-MATCH trial master protocol underwent tumor biopsy and molecular profiling by targeted next-generation sequencing. Patients with NRAS-mutated tumors, except melanoma, were enrolled in subprotocol Z1A, a single-arm study evaluating binimetinib 45 mg twice daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A post hoc analysis examined the association of NRAS mutation type with outcome. RESULTS In total, 47 eligible patients with a refractory solid tumor harboring a codon 12, 13, or 61 NRAS mutation were treated. Observed toxicity was moderate, and 30% of patients discontinued treatment because of binimetinib-associated toxicity. The ORR was 2.1% (1/47 patients). A patient with malignant ameloblastoma harboring a codon 61 NRAS mutation achieved a durable partial response (PR). A patient with NRAS codon 61-mutated colorectal cancer had an unconfirmed PR, and two other patients with NRAS codon 61-mutated colorectal had stable disease for at least 12 months. In an exploratory analysis, patients with colorectal cancer bearing a NRAS codon 61 mutation (n = 8) had a significantly longer OS (P = 0.03) and PFS (P = 0.007) than those with codon 12 or 13 mutations (n = 16). CONCLUSIONS Single-agent binimetinib did not show promising efficacy in NRAS-mutated cancers. The observation of increased OS and PFS in patients with codon 61 NRAS-mutated colorectal cancer merits further investigation.
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Affiliation(s)
- James M Cleary
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
| | | | - Rebecca S Heist
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - E Scott Kopetz
- University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Edith P Mitchell
- Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
| | - James A Zwiebel
- Investigational Drug Branch, Division of Cancer Treatment and Diagnosis, NCI, Bethesda, Maryland
| | - Kevin S Kapner
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Helen X Chen
- Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, NCI, Bethesda, Maryland
| | - Shuli Li
- Dana-Farber Cancer Institute, Boston, Massachusetts
| | | | - Lisa M McShane
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, NCI, Bethesda, Maryland
| | - Larry V Rubinstein
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, NCI, Bethesda, Maryland
| | - David R Patton
- Center for Biomedical Informatics and Information Technology, NCI, Bethesda, Maryland
| | - Funda Meric-Bernstam
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | | | - P Mickey Williams
- Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | | | - Barbara A Conley
- Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, NCI, Bethesda, Maryland
| | - Andrew J Aguirre
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | | | - Lyndsay N Harris
- Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, NCI, Bethesda, Maryland
| | | | - Alice P Chen
- Division of Cancer Treatment and Diagnosis, NCI, Bethesda, Maryland
| | - Keith T Flaherty
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
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36
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AlMuzaini AAAY, Boesze-Battaglia K, Alawi F, Akintoye SO. Hypoxia enhances basal autophagy of epithelial-derived ameloblastoma cells. Oral Dis 2021; 28:2175-2184. [PMID: 33721362 DOI: 10.1111/odi.13848] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 02/11/2021] [Accepted: 02/28/2021] [Indexed: 11/28/2022]
Abstract
Ameloblastoma is a locally aggressive odontogenic tumor. Etiopathogenesis and locally aggressive growth properties of ameloblastoma can be attributed to a hypoxic microenvironment conducive to tumor cell survival. Epithelial-derived follicular ameloblastoma cells (EP-AMCs) display enhanced basal autophagy, but the interplay of hypoxia and autophagy in EP-AMCs survival and ameloblastoma recurrence is unclear. We evaluated differential expression of autophagic markers in primary and recurrent ameloblastomas and hypothesized that hypoxia-induced autophagy supports EP-AMC survival. Primary and recurrent ameloblastomas were comparatively assessed for expression levels of pan-cytokeratin, Vimentin, and autophagic markers SQSTM1/p62, LC3, and pS6. EP-AMCs compared with human odontoma-derived cells (HODCs) were subjected to severe hypoxia to determine the interplay of hypoxia and autophagic process in posthypoxia survival. Pan-cytokeratin and SQSTM1/p62 were expressed by both primary and recurrent ameloblastoma epithelial cells while the ameloblastoma connective tissues displayed weak reactivity to vimentin. Under hypoxia, EP-AMC expression levels of hypoxia-inducible factor (HIF)-1α, p62, and LC3 were increased while pS6 was decreased posthypoxia. The combined decrease in pS6 and enhanced LC3 in EP-AMCs under hypoxia indicate that EP-AMCs re-establish basal autophagy under hypoxia. Taken together, these suggest a possible role of LC3-associated phagocytosis (LAP) in ameloblastoma cell survival.
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Affiliation(s)
- Anwar A A Y AlMuzaini
- Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kathleen Boesze-Battaglia
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Faizan Alawi
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Sunday O Akintoye
- Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
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37
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Comparison of Immunohistochemistry and DNA Sequencing for BRAF V600E Mutation Detection in Mandibular Ameloblastomas. Appl Immunohistochem Mol Morphol 2021; 29:390-393. [PMID: 33443847 DOI: 10.1097/pai.0000000000000904] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 12/16/2020] [Indexed: 10/22/2022]
Abstract
This study aimed to investigate the presence of BRAF V600E mutation in mandibular ameloblastoma by comparing the results of molecular detection and immunohistochemical analysis. A 128 cases of mandibular ameloblastoma and 30 cases of dentigerous cyst (control group) were selected for analysis. Detection of BRAF V600E mutation was performed with immunohistochemistry (IHC) and polymerase chain reaction techniques. Clinico-pathologic data were collected in order to investigate possible associations with the mutation. Of the 128 cases submitted to IHC, 81.2% (108 cases) showed positivity for anti-BRAF V600E antibody, whereas 24 were negative (18.8%). Molecular analysis of the BRAF V600E mutation by polymerase chain reaction was possible in 116 cases due to DNA quality. Of these cases, 96 were positive (82.8%) and 20 negative (17.2%). All cases of dentigerous cyst were negative for BRAF V600E mutation in both techniques. Considering the sequencing as a gold standard method, the receiver operating characteristics curve analysis showed sensitivity of 0.99 and specificity of 1 (area under the curve=0.995, standard error=0.006; P<0.001; 95% confidence interval=0.983 to 1). We also tested the agreement between the techniques by using the Cohen's κ coefficient, with κ being 0.97 (P<0.001). IHC is a reliable test for identifying the BRAF V600E mutation in ameloblastomas, presenting advantages such as being more frequently used in surgical pathology laboratories and requiring fewer critical steps for paraffin-embedded tissue compared with molecular biology techniques.
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38
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Zlotogorski-Hurvitz A, Soluk Tekkeşin M, Passador-Santos F, Martins Montalli VA, Salo T, Mauramo M, Kats L, Buchner A, Vered M. Conceptual changes in ameloblastoma: Suggested re-classification of a "veteran" tumor. Oral Dis 2021; 28:703-710. [PMID: 33403703 DOI: 10.1111/odi.13770] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 12/04/2020] [Accepted: 12/29/2020] [Indexed: 01/09/2023]
Abstract
OBJECTIVES The merging of ameloblastoma (AM) with mural unicystic ameloblastoma (UAM-M) was suggested by the 2017 WHO based on similar treatment needs. In an international multicenter study, we investigated the characteristics of their merged product (merged-AM) and raised the possibility of unifying AM and UAM (total-AM). MATERIALS AND METHODS AM and UAM (luminal/intraluminal/mural), separate and combined, were analyzed for demographic/clinical/radiological features. ANOVA and chi-square tests were followed by univariate and multivariate analyses, and significance was set at p < .05. RESULTS The patients' mean age was 39.6 ± 20.3 years in merged-AM (147 AM, 76 UAM-M), 45.1 ± 19.4 years in AM (p = .009). Merged-AM comprised 51.3% multilocular/48.7% unilocular tumors, AM comprised 72.5%/27.5%, respectively (p < .001). Merged-AM was associated with impacted teeth in 30.8%, AM in 18% (p = .023). The probability of merged-AM for multilocularity increased by 2.4% per year of age (95%CI 0.6-4.2, p = .009). Association with impacted teeth decreased by 7.9% per year of age (95%CI 1.9-14.39, p = .009). Merged-AM did not differ from total-AM (p > .05). CONCLUSIONS Merged-AM partially differed from AM, but differences appeared to diminish in an age/time-wise manner. Merged-AM and total-AM were nearly indistinguishable. Therefore, AM and UAM may be considered a continuous spectrum of one type of tumor, further necessitating revision of the treatment approaches.
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Affiliation(s)
- Ayelet Zlotogorski-Hurvitz
- Department of Oral Pathology, Oral Medicine and Maxillofacial Imaging, School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Oral & Maxillofacial Surgery, Rabin Medical Center, Petah Tikva, Israel
| | - Merva Soluk Tekkeşin
- Department of Tumour Pathology, Institute of Oncology, Istanbul University, Istanbul, Turkey
| | | | | | - Tuula Salo
- Translational Immunology Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.,Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland.,Cancer Research and Translational Medicine Research Unit, Faculty of Medicine, University of Oulu, Oulu, Finland.,Department of Pathology, HUSLAB, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
| | - Matti Mauramo
- Department of Pathology, HUSLAB, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.,University Central Hospital, Helsinki, Finland
| | - Lazar Kats
- Department of Oral Pathology, Oral Medicine and Maxillofacial Imaging, School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Amos Buchner
- Department of Oral Pathology, Oral Medicine and Maxillofacial Imaging, School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Marilena Vered
- Department of Oral Pathology, Oral Medicine and Maxillofacial Imaging, School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel.,Institute of Pathology, Sheba Medical Center, Ramat Gan, Israel
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39
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Suzuki H, Sasaki E, Nakamura R, Sawabe M, Hagiwara S, Hyodo I, Hanai N. Recurrent ameloblastoma with both hypercalcemia and BRAF mutation: A case report. Clin Case Rep 2020; 8:3463-3467. [PMID: 33363952 PMCID: PMC7752588 DOI: 10.1002/ccr3.3443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/16/2020] [Accepted: 10/03/2020] [Indexed: 11/10/2022] Open
Abstract
This case report describes a mandibular ameloblastoma with both BRAF V600E mutation and rare hypercalcemia. The patient without distant metastasis underwent subtotal mandibulectomy using double flaps of fibula and anterolateral thigh. A whole body computed tomography scan taken 69 months after surgery revealed neither recurrence nor metastasis.
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Affiliation(s)
- Hidenori Suzuki
- Department of Head and Neck SurgeryAichi Cancer Center HospitalNagoyaJapan
| | - Eiichi Sasaki
- Department of Pathology and Molecular DiagnosticsAichi Cancer Center HospitalNagoyaJapan
| | - Ryota Nakamura
- Department of Plastic and Reconstructive SurgeryAichi Cancer Center HospitalNagoyaJapan
| | - Michi Sawabe
- Department of Head and Neck SurgeryAichi Cancer Center HospitalNagoyaJapan
| | - Sumitaka Hagiwara
- Department of Head and Neck SurgeryAichi Cancer Center HospitalNagoyaJapan
| | - Ikuo Hyodo
- Department of Plastic and Reconstructive SurgeryUniversity of Occupational and Environmental HealthKitakyusyuJapan
| | - Nobuhiro Hanai
- Department of Head and Neck SurgeryAichi Cancer Center HospitalNagoyaJapan
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40
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Owosho AA, Ladeji AM, Adebiyi KE, Olajide MA, Okoye ISI, Kehinde T, Nwizu NN, Summersgill KF. BRAF V600E mutation-specific immunohistochemical analysis in ameloblastomas: a 44-patient cohort study from a single institution. Eur Arch Otorhinolaryngol 2020; 278:3065-3071. [PMID: 33231757 DOI: 10.1007/s00405-020-06491-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 11/10/2020] [Indexed: 02/06/2023]
Abstract
PURPOSE The aim of this study is to investigate the presence and prevalence of BRAF V600E mutation in ameloblastomas using anti-BRAF V600E monoclonal antibody (VE1 clone) and to identify any clinicopathologic correlation with BRAF V600E mutation in ameloblastoma. MATERIALS AND METHODS The pathology files of the Department of Oral Pathology and Oral Medicine, Faculty of Dentistry, Lagos State University College of Medicine, Lagos, Nigeria, were searched for the diagnosis of ameloblastoma from 2016 to 2020. Archived non-decalcified formalin-fixed paraffin-embedded tissue underwent immunohistochemistry using anti-BRAF V600E antibody at the University of Pittsburgh, Pennsylvania. Clinicopathologic data such as age at diagnosis, gender, jaw bone involved (mandible or maxilla), tumor location (anterior or posterior) and histologic subtype were collected. The clinicopathologic parameters were analyzed using Chi-square test and Fisher's exact test according to the BRAF status. RESULTS Forty-four cases of ameloblastoma were retrieved. The male to female ratio was 1.32:1. The average age of patients at diagnosis was 33.3 years. Thirty-nine cases were located in the mandible and 5 cases in the maxilla. Only cases in the mandible were positive for anti-BRAF V600E antibody (n = 15/39; 38.5%). There was a significant correlation between BRAF V600E expression in mandibular tumors and histologic subtype (p = 0.02); however, no significance was observed for gender, age and tumor location. CONCLUSION BRAF V600E mutation preferentially occurs in mandibular ameloblastomas, especially in non-plexiform ameloblastomas. These patients may benefit therapeutically from the use of BRAF inhibitors.
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Affiliation(s)
- Adepitan A Owosho
- Missouri School of Dentistry and Oral Health, A.T. Still University, 800 W Jefferson Street, Kirksville, MO, USA.
| | - Adeola M Ladeji
- Department of Oral Pathology and Oral Medicine, Faculty of Dentistry, Lagos State University College of Medicine, Lagos, Nigeria
| | - Kehinde E Adebiyi
- Department of Oral Pathology and Oral Medicine, Faculty of Dentistry, Lagos State University College of Medicine, Lagos, Nigeria
| | - Mofoluwaso A Olajide
- Department of Oral Pathology and Oral Medicine, Faculty of Dentistry, Lagos State University College of Medicine, Lagos, Nigeria
| | - Ikechukwu S I Okoye
- Department of Oral Pathology and Oral Medicine, Faculty of Dentistry, Lagos State University College of Medicine, Lagos, Nigeria
| | - Temitope Kehinde
- Department of Pathology, Anatomy and Laboratory Medicine, West Virginia University, Morgantown, WV, USA
| | - Ngozi N Nwizu
- Department of Diagnostic and Biomedical Science, School of Dentistry, The University of Texas, Health Science Center at Houston, Houston, TX, USA
| | - Kurt F Summersgill
- Department of Diagnostic Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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41
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Weaver AN, Francisque F, Bowles DW. Tumor Regression After Treatment With Lenvatinib in FGFR2-Mutated Ameloblastoma. JCO Precis Oncol 2020; 4:1403-1406. [PMID: 35050789 DOI: 10.1200/po.20.00175] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Affiliation(s)
- Alice N Weaver
- Department of Medicine, Internal Medicine Residency Training Program, University of Alabama at Birmingham, Birmingham, AL
| | - Frantz Francisque
- Department of Medicine, Division of Medical Oncology, University of Colorado, Aurora, CO
| | - Daniel W Bowles
- Department of Medicine, Division of Medical Oncology, University of Colorado, Aurora, CO.,Rocky Mountain Regional VA Medical Center, Aurora, CO
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42
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Oh KY, Cho SD, Yoon HJ, Lee JI, Hong SD. Discrepancy between immunohistochemistry and sequencing for BRAF V600E in odontogenic tumours: Comparative analysis of two VE1 antibodies. J Oral Pathol Med 2020; 50:85-91. [PMID: 32939809 DOI: 10.1111/jop.13108] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 08/14/2020] [Accepted: 09/06/2020] [Indexed: 11/29/2022]
Abstract
BACKGROUND Although immunohistochemistry (IHC) along with molecular tests has been investigated in ameloblastoma for BRAF V600E detection, VE1 IHC has not been studied in odontogenic carcinomas (OCs) and benign mixed epithelial and mesenchymal odontogenic tumours (BMOTs). Here, we performed BRAF V600E mutation analysis, examined the expression pattern of VE1 IHC, and comparatively evaluated the performance of two VE1 antibodies in ameloblastomas, OCs and BMOTs. METHODS BRAF V600E detection was performed using Sanger sequencing in a total of 47 odontogenic tumours: 28 ameloblastomas, 6 OCs and 13 BMOTs. VE1 IHC was conducted using two different antibodies (IHC-A and IHC-V), and their performance was analysed by calculating the sensitivity and specificity compared with sequencing. RESULTS BRAF V600E mutations were identified in 24/28 (85.7%) ameloblastomas, 2/5 (40.0%) ameloblastic carcinomas (ACs), 3/7 (42.9%) ameloblastic fibromas and 1/2 (50.0%) ameloblastic fibro-odontomas. In the presence of the mutation, VE1 showed diffuse cytoplasmic staining in ameloblastomas and ACs, whereas all BMOTs were negative for VE1. IHC-A and IHC-V yielded a sensitivity of 76.7% and 60.0%, respectively, although both antibodies showed 100% specificity. CONCLUSION OCs and BMOTs have BRAF V600E mutations in common at lower frequencies than ameloblastoma. Diffuse VE1 cytoplasmic staining in AC suggests the utility of MAPK-targeted therapy as selectively applied in ameloblastoma, and consistent VE1 false-negative expression in BMOTs requires further investigation. Considering the high specificity but low sensitivity of VE1 IHC, molecular tests should be performed to determine the presence of BRAF V600E mutations in odontogenic tumours.
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Affiliation(s)
- Kyu-Young Oh
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| | - Sung-Dae Cho
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| | - Hye-Jung Yoon
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| | - Jae-Il Lee
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| | - Seong-Doo Hong
- Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
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Shi HA, Ng CWB, Kwa CT, Sim QXC. Ameloblastoma: A succinct review of the classification, genetic understanding and novel molecular targeted therapies. Surgeon 2020; 19:238-243. [PMID: 32712102 DOI: 10.1016/j.surge.2020.06.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 06/15/2020] [Indexed: 12/30/2022]
Abstract
Ameloblastomas are benign but locally invasive neoplasms which may grow to massive proportions and cause significant morbidity. Although some types of ameloblastoma can be treated predictably with aggressive surgical treatment, recurrent ameloblastoma and metastasising ameloblastoma are still difficult to treat. Recent studies have identified recurrent somatic and activating mutations in the mitogen-activated protein kinase (MAPK) and sonic hedgehog (SHH) signalling pathways in ameloblastoma. This development provided a possibility that molecular targeted therapies can be used as neoadjuvant treatment. In this review, we provide a summary of the latest WHO classification of ameloblastoma, the current understanding of genetic mutations and novel molecular targeted therapies arising from the recent developments.
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Affiliation(s)
- Hongyi Adrian Shi
- Department of Oral & Maxillofacial Surgery, National Dental Centre Singapore, Singapore.
| | - Chee Wee Benjamin Ng
- Department of Oral & Maxillofacial Surgery, National Dental Centre Singapore, Singapore
| | - Chong Teck Kwa
- Department of Oral & Maxillofacial Surgery, National Dental Centre Singapore, Singapore
| | - Qiu Xia Chelsia Sim
- Department of Oral & Maxillofacial Surgery, National Dental Centre Singapore, Singapore
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44
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Derakhshan S, Aminishakib P, Karimi A, Saffar H, Abdollahi A, Mohammadpour H, Kharazi Fard MJ, Memarha A. High frequency of BRAF V600E mutation in Iranian population ameloblastomas. Med Oral Patol Oral Cir Bucal 2020; 25:e502-e507. [PMID: 32388526 PMCID: PMC7338065 DOI: 10.4317/medoral.23519] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 01/27/2020] [Indexed: 12/11/2022] Open
Abstract
Background Ameloblastoma is a common locally invasive but slow-growing neoplasm of the jaws with an odontogenic origin. Association between BRAF V600E mutation and clinicopathologic features and behavior of ameloblastoma remains controversial. This study aimed to evaluate BRAF V600E gene mutation and expression of its related proteins with clinicopathologic parameters in conventional ameloblastoma.
Material and Methods 50 Formalin-fixed paraffin-embedded blocks were included in this study. Immunohistochemistry was done using rabbit monoclonal BRAF V600E mutation-specific antibody VE1. Quantitative real-time polymerase chain reaction assay was used for evaluating of BRAF V600E mutation.
Results Expression of BRAF V600E antibody was Positive in 42 out of 50 cases (84%). 46 (92%) out of 50 specimens showed BRAF V600E mutation. There were 13 cases of recurrence (26%). 3 out of 4 cases with negative mutations did not show recurrence.
Conclusions We report the highest frequency (92%) of BRAF V600E mutation in ameloblastomas in the Iranian population. Although there was not a significant association between BRAF V600E‑positive immunoexpression and recurrence and clinicopathologic parameters, its high frequency could emphasize its role as a therapeutic marker in the future. Key words:Conventional ameloblastoma, BRAF V600E, recurrence.
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Affiliation(s)
- S Derakhshan
- North Kargar St., School of Dentistry Tehran University of Medical Sciences Tehran, Iran. Postal Code: 1439955991
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45
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Lapthanasupkul P, Laosuk T, Ruangvejvorachai P, Aittiwarapoj A, Kitkumthorn N. Frequency of BRAF V600E mutation in a group of Thai patients with ameloblastomas. Oral Surg Oral Med Oral Pathol Oral Radiol 2020; 132:e180-e185. [PMID: 32665205 DOI: 10.1016/j.oooo.2020.06.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/15/2020] [Accepted: 06/01/2020] [Indexed: 12/28/2022]
Abstract
OBJECTIVE BRAF V600E mutation has recently been reported in a high proportion of ameloblastomas. This study was conducted to investigate the frequency of this mutation in ameloblastoma and unicystic ameloblastoma. The correlation between clinicopathologic data and BRAF V600E mutation was also analyzed. STUDY DESIGN A total of 51 archival samples of ameloblastomas and 22 cases of unicystic ameloblastomas were examined for BRAF V600E mutation by using anti-BRAF V600E (clone VE1) immunohistochemistry. RESULTS Positivity for anti-BRAF V600E antibody was detected in 72.5% (37 of 51) of ameloblastomas, but the mutation showed no significant correlation with the clinicopathologic parameters. With regard to unicystic ameloblastoma, 95.5% (21) of the 22 cases exhibited positive immunostaining for BRAF V600E, whereas only 1 case showed the mural subtype of wild-type BRAF. CONCLUSIONS A high frequency of BRAF V600E mutation was detected in a group of Thai patients with ameloblastomas, suggesting the future use of BRAF-targeted therapy in patients with BRAF-mutated ameloblastoma. However, no significant association between BRAF V600E mutation and the clinicopathologic characteristics of ameloblastomas was found in our study.
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Affiliation(s)
- Puangwan Lapthanasupkul
- Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
| | - Tuntikorn Laosuk
- Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
| | | | - Anchisa Aittiwarapoj
- Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
| | - Nakarin Kitkumthorn
- Department of Oral Biology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand.
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de Arruda JAA, Arantes DAC, Schuch LF, Mosconi C, Abreu LG, de Andrade BAB, Romañach MJ, Mesquita RA, Silva TA, Batista AC, Mendonça EF. A Rare Case of an Aggressive Clear Cell Variant of Calcifying Epithelial Odontogenic Tumor in the Posterior Maxilla. Int J Surg Pathol 2020; 28:526-535. [PMID: 31986944 DOI: 10.1177/1066896920901755] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
A clear cell variant of calcifying epithelial odontogenic tumor is a rare benign odontogenic neoplasm, accounting for 33 cases described in the literature. In this article, we report a challenging example of clear cell variant of calcifying epithelial odontogenic tumor of the posterior maxilla in a 45-year-old female patient showing locally aggressive growth and recurrence. Microscopically, islands of polyhedral cells containing abundant cytoplasm, well-developed intercellular bridges blended with clear cells were observed. The nuclei were frequently pleomorphic and permeated by hyaline calcified material. Immunohistochemistry revealed positivity for pan-cytokeratin (AE1/AE3), cytokeratins (CK-14 and CK-19), Bcl-2, p53, and p63. The Ki-67 proliferative index was ~10%. As odontogenic tumors are rare, when a significant clear cell component is observed, the differential diagnosis with other lesions of the jaws with similar morphology, including other odontogenic tumors with prominent clear cell component, clear cell odontogenic carcinomas, and metastatic tumors, is difficult.
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Affiliation(s)
| | | | | | - Carla Mosconi
- Universidade Federal de Goiás, Goiânia, Goiás, Brazil
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47
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González-González R, López-Verdín S, Lavalle-Carrasco J, Molina-Frechero N, Isiordia-Espinoza M, Carreón-Burciaga RG, Bologna-Molina R. Current concepts in ameloblastoma-targeted therapies in B-raf proto-oncogene serine/threonine kinase V600E mutation: Systematic review. World J Clin Oncol 2020; 11:31-42. [PMID: 31976308 PMCID: PMC6935689 DOI: 10.5306/wjco.v11.i1.31] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 10/23/2019] [Accepted: 11/06/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Ameloblastomas are common benign epithelial odontogenic neoplasms that present an aggressive and unpredictable behavior that may modify treatment strategies. Different signaling pathways that participate in the progression of these tumors have been identified. B-raf proto-oncogene serine/threonine kinase (BRAF) is a protein involved in the behavior of ameloblastomas, and it is related to many cell mechanisms. BRAF gene mutations have been identified in ameloblastomas, of which the BRAF V600E (valine substituted by glutamic acid at amino acid 600) mutation has been the most common and can be present concomitantly with other mutations that may be involved in its behavior. Targeted therapies have been used as an alternative in the case of resistance or contraindications to conventional treatments. AIM To document the presence of BRAF V600E and additional mutations, their behavior, and targeted therapies in these tumors. METHODS An electronic literature search was conducted according to PRISMA guidelines in PubMed/MEDLINE, Cochrane, EMBASE, and SpringerLink using the terms "ameloblastomas", "BRAF V600E", "additional mutations", and "targeted therapies". Ameloblastomas were classified according to WHO guidelines. Inclusion criteria were articles in English, published not more than 10 years ago, and studies with laboratory works related to BRAF V600E. Articles were evaluated by two independent reviewers and retrieved for full-text evaluation. The EBLIP Critical Appraisal Checklist was used to evaluate the quality of the eligible studies. Descriptive statistical analysis was performed. RESULTS Two independent reviewers, with a substantial concordance indicated by a kappa coefficient of k = 0.76, evaluated a total of 19 articles that were included in this study. The analysis registered 521 conventional ameloblastomas (AM), 81 unicystic ameloblastomas (UA), 13 ameloblastic carcinomas (AC), three metastatic ameloblastomas (MA), and six peripheral ameloblastomas (PA), of which the histopathological type, anatomic location, laboratory tests, expression of BRAF mutation, and additional mutations were registered. The BRAF V600E mutation was found in 297 AM (57%), 63 UA (77.7%), 3 AC (23%), 1 MA (50%), and 5 PA (83.3%). Follicular type predominated with a total of 116 cases (40%), followed by plexiform type with 63 cases (22.1%). Furthermore, both types presented additional mutations, in which alterations in JAK3 P132T, SMARCB1, PIK3CA, CTNNB1, SMO, and BRAF G606E genes were found. Four case reports were found with targeted therapy to BRAF V600E. CONCLUSION The identification of BRAF V600E and additional mutations as an aid in targeted therapies has been a breakthrough in alternative treatments of ameloblastomas where surgical treatments are contraindicated.
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Affiliation(s)
- Rogelio González-González
- Department of Research, School of Dentistry, Universidad Juárez del Estado de Durango, Durango 34000, Mexico
| | - Sandra López-Verdín
- Research Institute of Dentistry, Health Science Center, Universidad de Guadalajara, Guadalajara 4430, Mexico
| | - Jesús Lavalle-Carrasco
- Department of Research, School of Dentistry, Universidad Juárez del Estado de Durango, Durango 34000, Mexico
| | - Nelly Molina-Frechero
- Department of Health Care, Xochimilco Unit, Universidad Autónoma Metropolitana Xochimilco, México 04960, Mexico
| | - Mario Isiordia-Espinoza
- Department of Clinics, Biomedical Sciences Division, Centro Universitario de los Altos, Universidad de Guadalajara, Tepetitlán de Morelos 47620, Mexico
| | - Ramón G Carreón-Burciaga
- Department of Research, School of Dentistry, Universidad Juárez del Estado de Durango, Durango 34000, Mexico
| | - Ronell Bologna-Molina
- Molecular Pathology Area, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
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48
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Brunet M, Khalifa E, Italiano A. Enabling Precision Medicine for Rare Head and Neck Tumors: The Example of BRAF/MEK Targeting in Patients With Metastatic Ameloblastoma. Front Oncol 2019; 9:1204. [PMID: 31781502 PMCID: PMC6861385 DOI: 10.3389/fonc.2019.01204] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 10/23/2019] [Indexed: 11/13/2022] Open
Abstract
Background: Ameloblastoma is a rare head and neck tumor characterized by a high incidence of BRAF mutation providing a rationale for the use of BRAF inhibitors in patients with advanced disease. Methods: We report the case of a 26-year old female presenting with metastatic ameloblastoma. A molecular screening of the tumor revealed a BRAF V600E mutation. Results: The patient started treatment with dabrafenib and trametinib and experienced complete response which is still ongoing 30 weeks after treatment onset. Conclusions: The complete response observed here illustrate the role of molecular profiling in complicate clinical situation of rare head and neck cancer and the potential benefit of BRAF-targeted therapy in ameloblastoma carrying BRAF V600E mutation.
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Affiliation(s)
- Maxime Brunet
- Department of Medicine, Institut Bergonié, Bordeaux, France
| | - Emmanuel Khalifa
- Department of Tumor Genetics, Institut Bergonié, Bordeaux, France
| | - Antoine Italiano
- Department of Medicine, Institut Bergonié, Bordeaux, France.,Faculty of Médicine, University of Bordeaux, Bordeaux, France.,INSERM, ACTION U1218, Bordeaux, France
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Abstract
Benign cysts and neoplasms of the maxillofacial region can vary in behavior, with some growing rapidly and resulting in destruction of surrounding structures. Despite their benign histology, many require often-morbid treatment to prevent recurrence of these lesions. Several less invasive and adjunctive medical treatments have been developed to lessen the morbidity of surgical treatment. As the molecular and genomic pathogenesis of these lesions is better understood, more directed treatments may lessen the burden for patients.
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Affiliation(s)
- Zachary S Peacock
- Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Harvard School of Dental Medicine, 55 Fruit Street Warren 1201, Boston, MA 02421, USA.
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50
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Kelppe J, Thorén H, Ristimäki A, Haglund C, Sorsa T, Hagström J. BRAF V600E expression in ameloblastomas-A 36-patient cohort from Helsinki University Hospital. Oral Dis 2019; 25:1169-1174. [PMID: 30811720 DOI: 10.1111/odi.13072] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 02/15/2019] [Accepted: 02/22/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVES We aimed to investigate BRAF V600E percentage immunohistochemically in ameloblastomas of a single institute cohort. We were interested if age, location, histological properties, or tumor recurrence depend on the BRAF status. SUBJECTS, MATERIALS AND METHODS We had 36 formalin-fixed, paraffin-embedded ameloblastoma tissue samples of patients treated at the Helsinki University Hospital between the years 1983-2016. Tissue sections underwent immunohistochemistry by Ventana BenchMark XT immunostainer using Ms Anti-Braf V600E (VE1) MAB. We used R 3.4.2 and RStudio 1.1.383 to conduct statistical analysis for BRAF positivity and earlier onset as well as tumor location. We used chi-squared tests and 2-by-2 table functions to determine connections between BRAF positivity and recurrence, growth pattern, and type. RESULTS BRAF-positive tumors occurred in younger patients compared to BRAF-negative tumors (p = 0.015) and they located mostly to the mandible (p < 0.001). Growth patterns were limited to two in BRAF-negative tumors when BRAF-positive tumors presented with one to four growth patterns (p = 0.02). None of the maxillary tumors showed BRAF positivity and of these, 72.2% recurred. CONCLUSIONS An immunohistochemical BRAF marker could be a beneficial tool to predict the outcome of patients with this aggressive, easily recurring tumor.
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Affiliation(s)
- Jetta Kelppe
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Hanna Thorén
- Department of Oral and Maxillofacial Surgery, Institute of Dentistry, University of Turku, Turku, Finland.,Department of Oral and Maxillofacial Diseases, Turku University Hospital, Turku, Finland
| | - Ari Ristimäki
- Department of Pathology, HUSLAB, Helsinki University Hospital and Genome-Scale Biology Research Program, Research Programs Unit and Medicum, University of Helsinki, Helsinki, Finland
| | - Caj Haglund
- Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Timo Sorsa
- Department of Oral and Maxillofacial Diseases, Head and Neck Centre, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Department of Dental Medicine, Karolinska Institute, Huddinge, Sweden
| | - Jaana Hagström
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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