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Table of Contents   
SYSTEMATIC REVIEWS AND META-ANALYSIS  
Year : 2022  |  Volume : 33  |  Issue : 3  |  Page : 323-331
Effectiveness of molecular-targeted chemotherapy in ameloblastomas: A systematic review


1 Department of Oral and Maxillofacial Pathology, Vivekanandha Dental College for Women, Tamil Nadu, India
2 Department of Oral and Maxillofacial Pathology, KSR Institute of Dental Science and Research, Tamil Nadu, India
3 Department of Oral Medicine and Radiology, M.M. College of Dental Sciences and Research, Mullana, Haryana, India
4 Department of Oral and Maxillofacial Pathology, King George Medical College, Uttar Pradesh, India
5 Department of Oral and Maxillofacial Pathology, Vishnu Dental College, Andhra Pradesh, India
6 Department of Oral and Maxillofacial Pathology, Cuddalore Government Dental College and Hospital, Tamil Nadu, India

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Date of Submission03-Jun-2022
Date of Decision21-Aug-2022
Date of Acceptance27-Aug-2022
Date of Web Publication17-Jan-2023
 

   Abstract 


Ameloblastoma is a benign, locally aggressive neoplasm that needs extensive surgical resection. The goal of this article is to obtain an in-depth review of benign ameloblastomas to determine the available level of evidence and the possible benefit of targeted therapeutics for the treatment of ameloblastoma and BRAF V600E mutation in ameloblastoma. An electronic literature search was conducted according to PRISMA guidelines in PubMed/MEDLINE, EBSCO, and Web of Science for eligible studies published between 1975 and 2021. The systematic review is registered with INPLASY (INPLASY202260018). The review included 2 case series and 17 case reports. The histopathological type, anatomic location, expression of BRAF mutation, additional mutations, and molecular-targeted therapies of the 19 reviewed articles were summarized and tabulated. Interestingly, the majority of the primary site of ameloblastoma was located in the mandible (80.9%) compared to the maxilla (17%). The tumour size was reported in nine of the included studies. Most of the included studies in the review exhibited ameloblastoma with BRAF V600E mutations and responded to molecular-targeted therapies. Molecular therapies employing BRAF and/or MEK inhibitors in ameloblastoma with BRAF V600E mutations proved to be an appropriate treatment based on the limited available evidence. It is essential further to deepen our understanding at the clinical and molecular level to enhance the precision of management of ameloblastoma.

Keywords: BRAF V600E, MAID regimen, metastatic ameloblastoma, molecular-targeted therapy, pulmonary ameloblastoma

How to cite this article:
Yoithapprabhunath TR, Srichinthu KK, Gupta D, Singh D, Pasupuleti S, Nirmal RM. Effectiveness of molecular-targeted chemotherapy in ameloblastomas: A systematic review. Indian J Dent Res 2022;33:323-31

How to cite this URL:
Yoithapprabhunath TR, Srichinthu KK, Gupta D, Singh D, Pasupuleti S, Nirmal RM. Effectiveness of molecular-targeted chemotherapy in ameloblastomas: A systematic review. Indian J Dent Res [serial online] 2022 [cited 2023 Feb 5];33:323-31. Available from: https://www.ijdr.in/text.asp?2022/33/3/323/367881



   Introduction Top


Ameloblastoma is a benign odontogenic tumor that grows slowly. It contributes to about 1% of all jaw tumors and 9–14% of all odontogenic tumors emerging from odontogenic epithelial tissue involved during odontogenesis. The clinical presentation of ameloblastoma is non-specific and varies depending on the type and site of the tumor. It can further expand to profound sizes, leading to facial asymmetry, displacement/mobility of teeth, malocclusion, and pathologic fractures. Based on the clinical and histological aspects of ameloblastoma, there is still a lot of disagreement over the optimal treatment option. Till date, wide surgical resection is the only treatment of choice for ameloblastoma tumors, resulting in post-treatment compromised quality of life in the individuals. The treatment modality is the most important element in determining recurrence rates, which can range from 15 to 25% after radical surgery and 55 to 90% following conservative therapy. Ameloblastoma is associated with an impacted/unerupted tooth especially, the mandibular third molars in 15–40% of cases.[1],[2]

The World Health Organization (WHO) (1991) defined ameloblastoma as a “benign but locally aggressive tumor with a high tendency to recur, consisting of proliferating odontogenic epithelium lying in a fibrous stroma.” The hematogenous, lymphatic, and aspiration routes are the most typical ways of the progression of metastatic ameloblastoma which is benign. Previously metastatic ameloblastoma was termed as metastatic malignant ameloblastoma, where the appearance of well-differentiated or benign histology of ameloblastoma was found, while ameloblastic carcinomas are histologically malignant in both primary and metastatic sites. The variants of benign ameloblastomas have been simplified and repositioned in the updated 2017 WHO classification.[2] Hypercalcemia is an uncommon complication of metastatic ameloblastoma that has been related to the release of a parathyroid-like substance. Chemotherapy and radiation are currently recommended for palliative care, and extensive surgeries, respectively, for ameloblastoma treatment. The aspiration of tumor cells during surgery is postulated to be the cause of pulmonary metastasis. Since there is a lack in the rhythmic correlation among signaling pathways of ameloblastoma pathogenesis, chemotherapy was contraindicated or minimally explored. Albeit chemotherapy is not curative, it has been reported that different regimens of Cisplatin, Adriamycin, Cyclophosphamide, Doxorubicin, Vinblastine, and Bleomycin show tumor regression and alleviate symptoms.[3],[4]

The molecular basis of ameloblastoma is unknown and new molecular data are enhancing our knowledge of ameloblastoma pathology which may have relevant implications. The overexpression of the RAS–RAF–MAPK pathway is strongly allied with its pathology, through EGFR-mediated signalling or activating mutations in the BRAF gene. Neoadjuvant targeted therapy should be considered to reduce the necessity of extensive or repeated surgeries.[5]

Enucleation/curettage against surgical resection with wide margins is also a point of contention.[1] The potential importance of neoadjuvant molecular-targeted chemotherapy will be highlighted in this comprehensive study, notably as recurrences typically occur decades after initial therapy. The goal of this article is to obtain an in-depth review of benign ameloblastomas to determine the available level of evidence and the possible benefit of targeted therapeutics for the treatment of ameloblastoma and BRAF V600E mutation in ameloblastoma.


   Methodology Top


Registration and protocol

The systematic review is registered with INPLASY (INPLASY202260018, DOI number—10.37766/inplasy2022.6.0018) and was carried out using PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).[6]

Search strategy and selection criteria

A comprehensive electronic retrieval of PubMed/Medline, EBSCO, and Web of Science databases for relevant published studies between 1975 and 2021 was performed. Benign ameloblastomas (Conventional, unicystic, peripheral, and metastatic ameloblastoma) were the several variants that were included in the review. The Booleans and/or were used along with the following terms: “ameloblastoma,” “targeted therapy,” “chemotherapy,” “malignant,” “metastasis,” “BRAF V600E mutation,” “associated mutations,” “pulmonary,” “relapse,” or “recurrence.”

The review also included additional references explored using the reference lists of selected studies, bibliography, and Google Scholar. The PRISMA flowchart for literature screening and selection of studies included in the review is shown in [Figure 1]. The studies containing relevant information were obtained for full-text review after titles and abstracts were screened. Restricted access papers were retrieved using institutional support.
Figure 1: PRISMA flowchart of the included studies (Adapted from Preferred Reporting Items for Systematic Reviews and Meta-analyses 2009 Flow Diagram)

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Eligibility criteria

The authors employed the population–intervention–comparator–outcome–study design paradigm to determine the eligible studies. The parameters were kept as broad as possible to optimize the search. The following were the details of the a priori criteria:

Population: Studies with human subjects, with no limits on age or other demographics.

Intervention and comparator: Studies with data that was clearly linked to targeted therapies for ameloblastoma, BRAF V600E mutations, and related mutations. Vaccines and herbal medications were not included. Studies were included only when the name and dosage of the targeted medication regimen utilized in the therapy were disclosed. There was no need for a comparator group.

Outcomes: We included only those studies of benign ameloblastomas (intraosseous, extraosseous, unicystic, and metastasizing ameloblastoma) reporting the potential use of neoadjuvant targeted therapies. Studies reporting only the tumor size, prevalence, growth of ameloblastic carcinoma, in vitro cell growth, or molecular investigations were excluded.

Study design: The reviewers only looked at works that had been published or translated into English. Case reports and case series available in the full text were included even if they extracted the minimum dataset, including tumor site, histological confirmatory diagnosis, and treatment, due to the paucity of published articles relevant to targeted therapies. Exclusions included systematic reviews, meta-analyses, in vitro research, animal experiments, and abstracts from conferences.

Data extraction

Data retrieved were compiled in Microsoft Excel using an extraction template that was evaluated by two users on a sample of five random case reports before being updated as needed. The data was gathered to determine the level of evidence, research quality, and outcome details. Each of the papers included in the review was evaluated critically based on the design and content of the case reports. For data extraction, we used the reported diagnosis and recognized ameloblastoma as a malignant entity that matched our inclusion criteria if there is metastasis or had histologic atypia, even though these markers are inadequate for a confirmed diagnosis of malignancy.

Data synthesis and quality assessment

Each of the retrieved full-text publications was screened and evaluated independently by the two authors. The evidence-based librarianship Critical Appraisal Checklist was used by the two reviewers to ensure the quality of the selected studies.[7] Disagreements between the data were examined and resolved by a blinded reviewer to establish concordance. [Table 1] illustrates the characteristics of the cases reported and considered in the review.
Table 1: Summary of characteristic features of the included studies

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A tool for assessing the methodological quality of case reports/series to be included in a systematic review was employed.[27] Histological diagnosis and detailed disclosure of drug dosage were included in this broad explanatory inquiry of the tool, which is analogous to the detailed criteria we employed during the study selection process. Hence, we chose not to undertake a separate risk of bias evaluation because the items in the tool were most relevant to assessing methodological quality, and this context had already been reviewed and accounted for.


   Results Top


The initial literature search yielded 219 papers with a manual search generating an additional 47 studies. Following the removal of duplicates (n = 32), the titles and abstracts of 234 papers were reviewed by two reviewers to confirm that they met the eligibility criteria. The papers were included for full-text review if there was any ambiguity at this point. Around 170 articles were excluded because they were irrelevant, and 64 articles were subjected to a full-text review. Any conflicts about inclusion/exclusion were addressed through consensus discussion and the guidance of a third reviewer, who ultimately made the decision. A good concordance of the kappa coefficient (k = 0.86) was obtained. Full text not accessible (n = 7), no therapeutic information (n = 8), conference abstract only (n = 3), minimal clinical information (n = 6), solely molecular studies (n = 5), prevalence studies (n = 14), and in vitro or animal studies (n = 2) were the reasons for the exclusion of 45 studies. Thus, the systematic review comprised a total of 19 papers.

This review included 2 case series[8],[9] and 17 case reports.[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26] The tumor size, pathogenesis, previous treatment, expression of BRAF mutant, the regimen of adjuvant molecular therapy, and the outcome of these 19 reviewed articles were tabulated in [Table 2] and [Table 3]. The studies included 47 patients, (comprising 23 males, 23 females and 1 gender was not specified) with an average age of 39.84 years (range 13–85 years). Interestingly, the majority of the primary site of ameloblastoma was located in the mandible (80.9%) compared to the maxilla (17%). Maxillary ameloblastoma was reported in three of the case report[11],[18],[23] and one case series.[8] The tumor size was presented in nine of the reports.[9],[10],[12],[13],[14],[15],[16],[17],[19] In one patient, the gender and location of the original tumor were not disclosed.[8]
Table 2: Summary of outcome of the targeted therapies employed in various case studies

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Table 3: Summary of outcome of the targeted therapies employed in various case studies

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Histopathological diagnosis

Only six of the included studies[8],[9],[12],[22],[23],[24] revealed the variations with histological features such as unicystic mural type, follicular, plexiform, acanthomatous, and desmoplastic ameloblastoma. The ability to anticipate the likelihood of metastasis relying solely on histological findings is still debatable.[24]

Recurrence and metastatic site

According to the studies included, recurrence or metastasis could occur anywhere from 5 months to 25 years. Nearly all of the studies in this review revealed pulmonary metastasis. Van Dam et al. and Ghiam et al. reported hypercalcemia in their respective reports.[8],[21] Fernandes et al.[16] reported cavernous sinus metastasis and orbital extension. Li et al.[26] documented cases of metastasizing ameloblastoma, metastases to the lungs and brain. Eliasson et al.[11] found metastases in the right mandible, base of the skull, right orbit, preauricle, and lungs. Grunwald et al.[23] revealed a local recurrence with the invasion of the ethmoid bone, left orbit, and right medial maxillary cavity, as well as several lung relapses.

Treatment

The included studies in the review established that the patients with recurrent/metastasizing ameloblastoma were treated with emerging molecular treatment strategies. Six studies employed monotherapy,[9],[12],[15],[16],[22],[24] whereas 13 used combination chemotherapy.[8],[10],[11],[13],[14],[17],[18],[19],[20],[21],[23],[25],[26] After a treatment time ranging from 11 weeks to 5 years, the majority of cases demonstrated considerable regression and improvement in symptoms. Fifteen studies revealed a partial response to therapeutic strategies.[8],[9],[10],[11],[13],[15],[16],[18],[19],[21],[22],[23],[24],[25],[26] Broudic-Guibert et al., Amzerin et al., and Li et al. used response evaluation criteria in solid tumor (RECIST) criteria to report the treatment response.[22],[25],[26] Brunet et al.[17] reported a complete response using both the RECIST and PET response criteria in solid tumor (PERCIST) criteria. Complete response was also reported by Tan et al., Yang et al., and Kaye et al.[12],[14],[20] The tumor was found to be resistant to chemotherapy by Gall et al. and Lanham et al.[10],[18]

Tan et al. described a case in which molecular-targeted adjuvant chemotherapy resulted in a 90% reduction in tumor growth after 16 weeks.[12] Hirschhorn et al.[9] found that pre-surgery treatment with Dabrafenib, a BRAF inhibitor, produced significant tumor reduction, allowing for non-mutilating total surgical resection, bone regeneration, and organ retention. These studies suggested that molecular-targeted neoadjuvant chemotherapy for ameloblastoma could be effective in specific clinical scenarios, such as when surgical approaches are initially limited owing to the extensive tumor size. Thus, based on the evidence from the studies reviewed, targeted therapeutic drugs such as BRAF and/or MEK inhibitors exhibit promising outcomes in the treatment of ameloblastoma with BRAF V600E mutations.

Associated mutations

The expression of the BRAF V600E mutant was identified in 9 out of 19 reports.[8],[9],[12],[13],[15],[16],[17],[20],[26] Despite the fact that BRAF mutations were the most common, two of the studies included in this review identified additional mutant variations.[13],[26] Using immunohistochemistry, Valkadinov et al.[13] confirmed the expression of cytokeratin subtypes (CK5/6/19) without the expression of Thyroid Transcription Factor 1. Li et al.[26] used whole exon detection by next-generation sequencing to detect somatic mutations, germline mutations, microsatellite instability, and tumor mutation frequency in metastasizing ameloblastoma. BRAF, MYCN, MLL2, ARIDIA, RUNX1, and ASXL1 were among the somatic mutations reported.


   Discussions Top


The variants of ameloblastoma have been simplified in the updated 2017 WHO classification to conventional, unicystic, extraosseous/peripheral, and metastasizing types. Metastasizing ameloblastoma is distinguished from ameloblastoma by the presence of distant metastasis, regardless of the fact that both have benign histology. The rate of metastasis has been estimated to be around 2%. It also tends to recur several years following the conservative approach, apparently owing to the lack of margin control of the tumors with these techniques.[7] In about 80% of cases, the lungs are compromised. Regional lymph nodes, pleura, vertebra, skull, diaphragm, liver, and parotid gland are some of the other common locations. The time between a tumor diagnosis and the manifestation of metastasis is often long, ranging from 10 to 12 years on average. After metastases, the median survival period varies from 3 months to 5 years, with the highest documented survival time being 37 years.[3],[4],[5]

In the pathophysiology of ameloblastoma, recent genetic investigations have demonstrated recurrent somatic and activating mutations in the MAPK and Sonic hedgehog signaling pathways. The BRAF, RAS, and fibroblast growth factor receptor 2 (FGFR2) genes are affected by MAPK pathway mutations. BRAF is a serine/threonine-protein kinase that enhances cell proliferation, survival, and neoplastic transformation by stimulating downstream signaling. The BRAF V600E mutation causes a valine to glutamate substitution at codon 600, and the mutation was found in 43–82% of the tumors evaluated in the literature.[5]

Treatment options are influenced by several parameters, including the patient's age, gender, tumor size and location, imaging results, histologic subtypes, maxillo-mandibular morphology, and disease curability, making treatment decisions challenging. Conventional ameloblastomas in the mandible and maxilla are often treated by a segmental excision followed by immediate or delayed bone reconstruction. Recurrent ameloblastomas are difficult to treat, notably if it recurs in an anatomical location with limited access to surgeries or due to delayed diagnosis. Maxillary ameloblastoma is more invasive clinically in terms of disease extent and recurrence than its mandibular analog, as the maxillary bone is weaker and provides only a flimsy wall of resistance against the local spread. If the tumor extends into vital structures such as the skull base, orbit, and paranasal sinuses, resection might be challenging. Metastatic ameloblastoma is relatively uncommon, and there is presently no standard treatment regimen established. It can spread to the lungs and cervical lymph nodes, despite its benign nature.[1],[28]

BRAF mutations are the first sign of a high-frequency oncogenic mutation in benign ameloblastomas.[5] The main advantage of molecular-targeted therapy is that it can reduce surgical morbidity in resection, recurrence, and metastasis. Drugs that suppress the actions of mutant BRAF and MEK have the potential to be utilized in molecular-targeted treatments on benign ameloblastomas. The mutated BRAF genes are inhibited by Vemurafenib and Dabrafenib; the mutation MEK gene is inhibited by Trametinib; the mutated FGFR2 genes are inhibited by Ponatinib and Regorafenib. Three molecular targeted therapy for BRAF V600E mutation have been approved by the US Food and Drug Administration: Vemurafenib, and Dabrafenib for BRAF mutations and Trametinib for BRAF, and MEK mutations.[28]

Gall et al.[10] studied the effects of Cyclophosphamide, Methotrexate, and 5-Fluorouracil therapy in pulmonary metastases, 9 years after commencing the treatment. He noted a positive functional outcome, despite the absence of an objective improvement. After 13 cycles of combined treatment with Cisplatin, and Cyclophosphamide for lung metastases, Ramadas et al.[19] achieved a partial response. Chemotherapy, including Doxorubicin, Cyclophosphamide, Bleomycin, 5-Fluorouracil, and Dacarbazine, failed to exhibit antitumoral effect by Lanham[18] In contrast, other treatments, such as Vinblastine, Bleomycin, Paclitaxel, and Carboplatin, have been proved to elicit tumor regression.[8],[11],[21],[23] Chemotherapy may aid non-surgical patients to improve their clinical symptoms. The role of systemic chemotherapy in this unusual entity can only be evaluated with continual reporting of empirical case-based data. Because of the limited incidences, there is barely a little expertise in this context.[29]

While resection minimizes the chances of tumor recurrence, it affects the functional and aesthetic consequences resulting in post-treatment compromised quality of life in the diseased individuals. A donor site for rehabilitation may also be required. As a result, there are debates on the appropriate treatment option.[30] In addition, as our insights into the molecular etiology of ameloblastoma evolve, targeted drugs with fewer systemic adverse effects may prove to be more effective than standard chemotherapeutic protocols.[29] Although some claim that ameloblastoma may not react to these targeted therapies, the causal molecular processes may be extremely susceptible to targeted therapy.[5]

According to Shi et al.,[28] dual-agent molecular targeted chemotherapy for metastatic ameloblastoma appears to be preferable. The downside of BRAF inhibitor-based molecular-targeted therapy is that emergence of resistance might evolve quickly. Dual-agent inhibitor chemotherapy, which combines a BRAF and MEK inhibitor, has been observed to defer the acquired resistance. There is certainly no evidence comparing the efficacy of single-agent against dual-agent inhibitor targeted therapy in the treatment of benign ameloblastomas.


   Conclusion Top


A synthesis of current knowledge of innovative molecular targeted therapeutics was presented in this review. Molecular-targeted therapy employing BRAF and/or MEK inhibitors in ameloblastoma with BRAF V600E mutations proved to be an appropriate treatment based on the limited evidence available. It is essential further to deepen our understanding at the clinical and molecular level to enhance the precision of the management of ameloblastoma. Recent advancement in molecular studies will lead us into the era of non-surgical treatment approach for ameloblastoma in the immediate-future.

Abbreviations

IHC: Immunohistochemistry

PCR: Polymerised chain reaction

BRAF: B Raf proto oncogene, serine/threonine kinase

EGFR: Epidermal growth factor receptor

RAS: Rat sarcoma virus

RAF: Rapidly Accelerated Fibrosarcoma

MAPK; Mitogen activated protein kinase

MEK: Mitogen activated protein kinase

SHH: Sonic hedgehog

FGFR2: Fibroblast growth factor receptor 2

MAID: Mesna, doxorubicin, ifosfamide, and dacarbazine

MYCN: Member of the Myc family of oncogenes

ARID1A: AT-rich interactive domain-containing protein 1A

RUNX1: Runt-related transcription factor 1

ASXL1: Additional sex combs like-1

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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Larrañaga JJ, Sahovaler A, Picco P, Mazzaro E, Figari M. Management issues in the treatment of an ameloblastoma with an atypical presentation. craniomaxillofac Trauma Reconstr 2015;8:257-61.  Back to cited text no. 3
    
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Dissanayake R, Jayasooriya P, Siriwardena D, Tilakaratne W. Review of metastasizing (malignant) ameloblastoma (METAM): Pattern of metastasis and treatment. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;111:734-41.  Back to cited text no. 4
    
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Kurppa KJ, Catón J, Morgan PR, Ristimäki A, Ruhin B, Kellokoski J, et al. High frequency of BRAF V600E mutations in ameloblastoma. J Pathol 2014;232:492-8.  Back to cited text no. 5
    
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Van Dam SD, Unni KK, Keller EE. Metastasizing (malignant) ameloblastoma: Review of a unique histopathologic entity and report of Mayo Clinic experience. J Oral Maxillofac Surg 2010;68:2962-74.  Back to cited text no. 8
    
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Hirschhorn A, Campino GA, Vered M, Greenberg G, Yacobi R, Yahalom R, et al. Upfront rational therapy in BRAF V600E mutated pediatric ameloblastoma promotes ad integrum mandibular regeneration. J Tissue Eng Regen Med 2021;15:1155-61.  Back to cited text no. 9
    
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Gall JA, Sartiano GP, Shreiner DP. Ameloblastoma of the mandible with pulmonary metastasis. Oncology 1975;32:118-26.  Back to cited text no. 10
    
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Eliasson M, Moser M, Tenholder C. Diagnosis and treatment of metastatic ameloblastoma. South Med J 1989;82:1165-8.  Back to cited text no. 11
    
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Tan S, Pollack JR, Kaplan MJ, Colevas AD, West RB. BRAF inhibitor treatment of primary BRAF-mutant ameloblastoma with pathologic assessment of response. Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:e5-7.  Back to cited text no. 12
    
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Valkadinov I, Conev N, Dzhenkov D, Donev I. Rare case of ameloblastoma with pulmonary metastases. Intractable Rare Dis Res 2017;6:211-4.  Back to cited text no. 13
    
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Yang RN, Wang XS, Ren J, Xie YF, Zhou D, Ge DF, et al. Mandible ameloblastoma with lung metastasis: A rare case report. Int J Clin Exp Pathol 2015;8:6793-9.  Back to cited text no. 14
    
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Faden DL, Algazi A. Durable treatment of ameloblastomawith single agent BRAFi Re: Clinical and radiographic response with combined BRAF-targeted therapy in stage 4 ameloblastoma. J Natl Cancer Inst 2017;109:1-2. doi: 10.1093/jnci/djw190.  Back to cited text no. 15
    
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Fernandes GS, Girardi DM, Bernardes JPG, Fonseca FP, Fregnani ER. Clinical benefit and radiological response with BRAF inhibitor in a patient with recurrent ameloblastoma harboring V600E mutation. BMC Cancer 2018;18:1-5.  Back to cited text no. 16
    
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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;9:1-3. doi: 10.3389/fonc. 2019.01204.  Back to cited text no. 17
    
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Broudic-Guibert M, Blay JY, Vazquez L, Evrard A, Karanian M, Taïeb S, et al. Persistent response to vemurafenib in metastatic ameloblastoma with BRAF mutation: A case report. J Med Case Rep 2019;13:1-4. doi: 10.1186/s13256-019-2140-6.  Back to cited text no. 22
    
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Correspondence Address:
Dr. Kenniyan K Srichinthu
Associate Professor, Department of Oral Pathology and Microbiology, KSR Institute of Dental Science and Research, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdr.ijdr_456_22

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