Calcifying Odontogenic Cyst Demonstrates Recurrent WNT Pathway Mutations and So-Called Adenoid Ameloblastoma-Like Histology: Evidence Supporting Its Classification as a Neoplasm.

Calcifying odontogenic cyst (COC), once called calcifying cystic odontogenic tumor, is classified under the category of odontogenic cysts. However, the proliferative capacity of the lesional epithelium and consistent nuclear ß-catenin expression raise questions about its current classification. This study aimed to determine whether COC would be better classified as a neoplasm in the histologic and molecular context. Eleven odontogenic lesions diagnosed as COC or calcifying cystic odontogenic tumor were included in this study. The growth patterns of the lesional epithelium were analyzed histologically in all cases. ß-catenin immunohistochemistry and molecular profiling using Sanger sequencing and whole-exome sequencing were performed in 10 cases. Of the 11 cases studied, histologic features reminiscent of so-called adenoid ameloblastoma were observed in 72.7% (8/11), and small islands of clear cells extended into the wall in 36.4% (4/11). Intraluminal and/or mural epithelial proliferation was found in 72.7% of the cases (8/11). Nuclear ß-catenin expression was observed focally in all 10 cases studied, mainly highlighting epithelial cells forming morules and adjacent to dentinoid. CTNNB1 hotspot mutations were detected in 60.0% of the cases (6/10). All the remaining cases had frameshift mutations in tumor-suppressor genes involved in the WNT pathway, including APC and NEDD4L. Recurrent WNT pathway mutations leading to nuclear translocation of ß-catenin and distinct epithelial growth patterns found in COC are the neoplastic features shared by its solid counterpart, dentinogenic ghost cell tumor, supporting its classification as a tumor rather than a cyst.

Resolution of PTHrP-Mediated Hypercalcemia Following Treatment with Dual BRAF/MEK Inhibition for BRAFV600E-Positive Metastatic Ameloblastoma.

Ameloblastoma is a rare odontogenic tumor which may be complicated by hypercalcemia in advanced disease. Tumoral parathyroid hormone-related peptide (PTHrP) production and local osteolysis from paracrine factors have been proposed as mechanisms. Mitogen-activated protein kinase (MAPK) inhibitors have been successfully used in ameloblastomas with BRAF V600E mutation to reduce symptoms and decrease tumor burden. Serum calcium has been observed to normalize following treatment with MAPK inhibitors; however, the response of PTHrP and markers of bone turnover has not been reported. We describe a case of a 55-year-old female with PTHrP-mediated hypercalcemia secondary to BRAF V600E-positive ameloblastoma with pulmonary metastases. Following treatment with dabrafenib and trametinib, the patient experienced the regression of pulmonary lesions and normalization of serum calcium, PTHrP, and markers of bone turnover. Tissue samples of ameloblastoma carrying BRAF V600E mutation are more likely to express PTHrP than tissue samples carrying wild-type BRAF. In our case, resolution of PTHrP-mediated hypercalcemia following initiation of BRAF/MEK inhibition provides additional evidence that the MAPK pathway contributes to PTHrP synthesis. It also raises the question of whether MAPK inhibitors would be effective in treating PTHrP-mediated hypercalcemia associated with other malignancies harboring BRAF V600E mutation.

Comparison of diagnostic methods for detection of BRAFV600E mutation in ameloblastoma.

BACKGROUND: Ameloblastoma is an aggressively growing, highly recurrent odontogenic jaw tumor. Its association with BRAFV600E mutation is an indication for BRAFV00E-inhibitor therapy The study objective was to identify a sensitive low-cost test for BRAFV600E-positive ameloblastoma. We hypothesized that immunohistochemical staining of formalin-fixed paraffin-embedded tissues for BRAFV600E mutation is a low-cost surrogate for BRAFV600E gene sequencing when laboratory resources are inadequate for molecular testing. METHODS: Tissues from 40 ameloblastoma samples were retrieved from either formalin-fixed paraffin-embedded blocks, RNAlater™ stabilization solution or samples inadvertently pre-fixed in formalin before transfer to RNAlater™. BRAFV600E mutation was assessed by Direct Sanger sequencing, Amplification Refractory Mutation System-PCR and immunohistochemistry (IHC). RESULTS: BRAFV600E mutation was detected by IHC, Amplification Refractory Mutation System-PCR and Direct Sanger sequencing in 93.33%, 52.5% and 30% of samples respectively. Considering Direct Sanger sequencing as standard BRAFV600E detection method, there was significant difference between the three detection methods (𝜒2 (2) = 31.34, p < 0.0001). Sensitivity and specificity of IHC were 0.8 (95% CI: 0.64-0.90) and 0.9 (95% CI: 0.75-0.99) respectively, while positive predictive value and negative predictive value (NPV) were 0.9 and 0.8 (Fischer's test, p < 0.0001) respectively. Sensitivity and specificity of Amplification Refractory Mutation System-PCR detection method were 0.7 (95% CI: 0.53-0.80) and 0.9 (95% CI = 0.67-0.98) respectively, while PPV and NPV were 0.9 and 0.6 respectively (Fischer's test, p < 0.0001). CONCLUSION: Low-cost and less vulnerability of IHC to tissue quality make it a viable surrogate test for BRAFV600E detection in ameloblastoma. Sequential dual IHC and molecular testing for BRAFV600E will reduce equivocal results that could exclude some patients from BRAFV600E-inhibitor therapies.

DNA content and clinicopathological features aid in distinguishing ameloblastic carcinoma from ameloblastoma.

BACKGROUND: Ameloblastoma and ameloblastic carcinoma are epithelial odontogenic tumors that can be morphologically similar. In the present study, we evaluated the DNA content and Ki-67 index in the two tumors. METHODS: The paraffin blocks of the tumors were selected to obtain sections for the immunohistochemical reactions and preparation of the cell suspension for acquisition in a flow cytometer. The Random Forest package of the R software was used to verify the contribution of each variable to classify lesions into ameloblastoma or ameloblastic carcinoma. RESULTS: Thirty-two ameloblastoma and five ameloblastic carcinoma were included in the study. In our sample, we did not find statistically significant differences in Ki-67 labeling rates. A higher fraction of cells in 2c (G1) was correlated with the diagnosis of ameloblastoma, whereas higher rates of 5c-exceeding rate (5cER) were correlated with ameloblastic carcinoma. The Random Forest model highlighted histopathological findings and parameters of DNA ploidy study as important features for distinguishing ameloblastoma from ameloblastic carcinoma. CONCLUSION: Our findings suggest that the parameters of the DNA ploidy study can be ancillary tools in the classification of ameloblastoma and ameloblastic carcinoma.

Molecular pathogenesis of ameloblastoma.

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/ß-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.

Clinicoradiologic features of ameloblastomas: A single-centre study of 155 cases.

BACKGROUND: The purpose of the current study was to report on the clinical presentation and radiologic features of 155 cases of ameloblastoma (AB), representing a detailed, large, single-centre radiologic study. METHODS: Histologically confirmed cases were reviewed over 11 years. Demographic and clinical data were retrieved from the patient's records. Radiologic information was analysed from available radiographs. The radiologic features of ABs were assessed according to the mean age of presentation and the mean duration of the lesion. The distinguishing radiologic features between adults/children and sex were also evaluated. RESULTS: A statistically significant correlation existed between loss of border demarcation and advanced mean age. Multilocular lesions were markedly more common in adults compared to children. Multilocular ABs were associated with increased lesion duration and advanced mean age. Radiologic signs of reactive bony changes associated with the tumour presented at the highest mean duration of all bony effects. Bony expansion and cortical destruction were statistically correlated with lesion duration. Tooth impaction was more common in children. Some mandibular lesions reached a significant size, resulting in impingement of the maxillary sinus, zygoma, orbit and pterygoid plates. CONCLUSION: Due to unfortunate healthcare access constraints, ABs grow to significant sizes and exhibit features not often reported in the literature. The findings of this analysis highlighted the radiologic features of ABs expressed through the mean age and duration of the lesion. This emphasises the significance of timely management of these lesions.

Clinicopathologic Profile and Surgical Modalities in Mandibular Ameloblastoma: A Descriptive Study.

BACKGROUND: Ameloblastoma is a benign neoplasm composed of epithelial tissue with invasive and infiltrative behavior at the local level and a high recurrence rate, with various histopathologic patterns and clinical forms. Approximately 85% of conventional ameloblastomas occur in the mandible, most often in the body, angle, and ascending ramus area. The treatment modalities include both conservative and radical treatments. Postoperative follow-up is most important in the treatment of ameloblastoma. AIMS AND OBJECTIVES: To describe the clinicopathologic profile of mandibular ameloblastoma in patients undergoing different surgical modalities. The primary objective was to describe the clinicopathologic profile and surgical management of mandibular ameloblastoma in patients aged ≥18 years, who had reported to a tertiary dental care center for follow-up during the study period. The secondary objective was to describe the distribution of comorbidities associated with different surgical modalities and reconstructive methods. SUBJECTS AND METHODS: A total of 34 patients with mandibular ameloblastoma who underwent various surgical modalities between 2011 and 2021 were studied. Information was collected using a predesigned proforma and statistically analyzed. RESULTS: Thirty-four review cases of ameloblastoma were included in the study. The patients were analyzed concerning age, sex, site, size, clinical presentation, radiographic pattern, histopathologic subtype, type of surgery, and associated comorbidities. Most cases of mandibular ameloblastoma involve the age of 16 to 55 years. The mean age of occurrence was found to be 35.5±13.2. A female preponderance, a tumor size range of 2 to 4 cm, a multicystic variant, involvement of the mandibular body in the premolar-molar area, root resorption, cortical perforation, and a follicular type of histopathologic pattern were the common presentations. Isolated anterior tumors restricted to the incisor/canine region were not found. The common surgical modalities undertaken were conservative methods such as enucleation, and chemical cauterization, and radical methods such as marginal mandibulectomy and segmental resection. Reconstruction using a titanium plate or free fibular graft was performed in the indicated cases. The common comorbidities included difficulty in chewing and loss of facial contour. Recurrence after surgical treatment was rare. Only 9% of cases developed a recurrence within 5 years. No recurrence was noted in cases treated with radical treatment, whereas 50% of cases treated with conservative methods showed recurrence. CONCLUSION: The age of occurrence, site, and size of the tumor, cortical perforation, root resorption, histopathologic type, and radiographic patterns are widely considered factors in devising a treatment plan for mandibular ameloblastoma. However, there may be rare instances where these tumors behave differently regardless of their innocuous clinicopathologic presentation. Surgical procedures such as segmental resection and marginal mandibulectomy were found to be promising for the eradication of the tumor, and prevention of recurrences and metastasis. However, conservative measures such as enucleation and chemical cauterization were fraught with an increased risk of tumor recurrence and metastasis. Future studies with a larger sample size should focus on the clinicopathologic characteristics of ameloblastoma to elucidate its varied behavior and develop newer and advanced treatment modalities that would provide better surgical and postsurgical outcomes in affected patients.

Application of machine learning in the preoperative radiomic diagnosis of ameloblastoma and odontogenic keratocyst based on cone-beam CT.

OBJECTIVES: Preoperative diagnosis of oral ameloblastoma (AME) and odontogenic keratocyst (OKC) has been a challenge in dentistry. This study uses radiomics approaches and machine learning (ML) algorithms to characterize cone-beam CT (CBCT) image features for the preoperative differential diagnosis of AME and OKC and compares ML algorithms to expert radiologists to validate performance. METHODS: We retrospectively collected the data of 326 patients with AME and OKC, where all diagnoses were confirmed by histopathologic tests. A total of 348 features were selected to train six ML models for differential diagnosis by a 5-fold cross-validation. We then compared the performance of ML-based diagnoses to those of radiologists. RESULTS: Among the six ML models, XGBoost was effective in distinguishing AME and OKC in CBCT images, with its classification performance outperforming the other models. The mean precision, recall, accuracy, F1-score, and area under the curve (AUC) were 0.900, 0.807, 0.843, 0.841, and 0.872, respectively. Compared to the diagnostics by radiologists, ML-based radiomic diagnostics performed better. CONCLUSIONS: Radiomic-based ML algorithms allow CBCT images of AME and OKC to be distinguished accurately, facilitating the preoperative differential diagnosis of AME and OKC. ADVANCES IN KNOWLEDGE: ML and radiomic approaches with high-resolution CBCT images provide new insights into the differential diagnosis of AME and OKC.

Central Pleomorphic Adenoma of Mandible Mimicking Ameloblastoma - A Rare Case Report.

Salivary gland neoplasms account for 3% of all head and neck tumours. Pleomorphic adenoma (PA) is the most common salivary gland tumour that mainly occurs in the parotid gland, followed by minor salivary glands of the oral cavity, however, the occurrence of PA inside the jaw bones is exceedingly rare and very few cases have been reported in the literature. Inside jaw bones these lesions tend to imitate large osteolytic lesions encompass a diagnostic challenge. An exhaustive review of the literature revealed only 10 cases of central pleomorphic adenoma. We present a rare case of primary PA that occurred inside the mandible and was provisionally diagnosed as ameloblastoma.

Adenoid Ameloblastoma Shares Clinical, Histologic, and Molecular Features With Dentinogenic Ghost Cell Tumor: The Histologic Spectrum of WNT Pathway-Altered Benign Odontogenic Tumors.

An epithelial odontogenic tumor called adenoid ameloblastoma (AA) has recently been included in the new WHO classification. However, AA has considerable overlapping features with a preexisting entity, dentinogenic ghost cell tumor (DGCT). This study compared the clinical, histologic, and molecular characteristics of AA and DGCT. Eight cases of odontogenic tumors initially diagnosed as AA or DGCT were included in this study. Quantitative histologic analysis, ß-catenin immunohistochemistry, and molecular profiling using next generation sequencing were performed. Additionally, accumulated clinical data of AA and DGCT were statistically analyzed. Nuclear ß-catenin accumulation was detected in all cases in common, although the tumors studied histologically consisted of varying combinations of the AA-like phenotype, ghost cells, and dentinoid. However, CTNNB1 hotspot mutations were not found in any case. Instead, loss-of-function mutations in tumor suppressor genes involved in the WNT pathway, including the APC, SMURF1, and NEDD4L genes, were found regardless of histologic type. In addition, KRT13 mutations were detected in 2 cases with a high proportion of ghost cells. Finally, a literature analysis revealed clinical similarities between the previously reported cases of AA and DGCT. These findings suggest that from a clinical and molecular point of view, AA and DGCT represent a histologic spectrum of WNT pathway-altered benign odontogenic tumors rather than 2 distinct tumors. Moreover, previously unidentified keratin mutations may be associated with ghost cell formation found in specific types of odontogenic lesions.

Does BRAF mutation status and related clinicopathological factors affect the recurrence rate of ameloblastoma? A systematic review, meta-analysis and metaregression.

OBJECTIVES: This review aims to analyse the recurrence rate in BRAFv600e+ and BRAFv600e- ameloblastomas and explore its association with clinicopathological variables. METHODS: A comprehensive search was conducted using databases including PubMed, Embase, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov, Google Scholar and grey literature, without any limitation on start date or language up to 20 June 2023. A random effect meta-analysis was conducted and Metaregression analyses were performed based on available clinicopathological factors. RESULTS: Fifteen studies met the criteria for meta-analysis of outcomes. There was no significant difference in overall recurrence rates between the two groups (risk difference = 0.001, p-value = 0.987). Increasing male:female ratio in the BRAFv600e+ group was associated with a lower reported recurrence, suggesting a higher recurrence rate in females. The odds of having mandibular lesion were four times higher in BRAFv600e+ cases compared to BRAFv600e- cases (confidence interval: 2.121-7.870, p < 0.001, I2 = 28.37%). CONCLUSION: Within the BRAFv600e+ group, females showed a higher reported recurrence rate. This specific clinical group may benefit from BRAFv600e mutation investigation and potential upscaled surgical treatment and additional BRAF inhibitor therapy, which needs validation in future studies.

Genetic heterogeneity and enrichment of variants in DNA-repair genes in ameloblastoma.

OBJECTIVE: Ameloblastomas are a group of relatively common odontogenic tumors that frequently originate from the dental epithelium. These tumors are aggressive in nature and present as slow-growing painless cortical expansion of the jaw. Histologically, the follicular and plexiform subtypes constitute two-thirds of solid/multicystic ameloblastomas. The objective of this study was to understand the genetic architecture of follicular and plexiform ameloblastomas using deep whole-exome sequencing. METHODS: Archived formalin-fixed paraffin-embedded tissue blocks of follicular (n = 4) and plexiform (n = 6) ameloblastomas were retrieved and genomic DNAs were isolated from the tumor tissue dissected from the formalin-fixed paraffin-embedded block. The exomes were enriched using the Integrated DNA Technologies Exome Research Panel (IDT, Coralville, IA) and paired-end sequencing was completed on an Illumina NovaSeq 6000 with an average output of 20 GB of data resulting in a mean coverage of 400×. Variant analysis was completed using custom-developed software: Rapid Understanding of Nucleotide variant Effect Software and variant integration and knowledge interpretation in genomes. RESULTS: Our analyses focused on examining somatic variants (gnomAD minor allele frequency ≤1%) in genes found on an Food and Drug Administration -approved clinical cancer sequencing panel (FoundationOne®CDx). In follicular tumors, variants (>20% of the reads) were identified in BRAF, KMT2D, and ABL1 genes. In plexiform tumors, variants (>20% of the reads) were identified in ALK, BRAF, KRAS, KMT2D, SMO, KMT2A, and BRCA2 genes. Enrichment analysis showed a significant role of DNA repair genes in the development of these tumors. CONCLUSION: The variants identified in follicular and plexiform ameloblastomas were enriched in DNA-repair genes. The observed genetic heterogeneity in these ameloblastomas may contribute to the aggressive nature and recurrence risk of these tumors.

Factors affecting the accuracy of anti-BRAF V600E immunohistochemistry results in ameloblastomas.

BACKGROUND: There are still some controversies about the results of anti-BRAF V600E-specific antibody immunohistochemistry in ameloblastomas. This study aimed to examine the accuracy of V600E-specific antibody immunohistochemistry in detection of BRAF V600E mutation in ameloblastoma tissue sections of different ages. METHODS: The BRAF V600E status of 64 ameloblastoma specimens was assessed using both Sanger sequencing and V600E-specific antibody immunohistochemistry, and the sensitivity, specificity, positive predictive value, and negative predictive value were calculated. The difference in V600E-specific antibody immunohistochemistry staining intensity among the three groups of ameloblastoma tissue blocks of different ages was evaluated by chi-square test. The consistency between V600E-specific antibody immunohistochemistry and DNA sequencing results and the V600E-specific antibody immunohistochemistry staining intensity of 15 paired newly-cut and 3-month storage sections of the same 15 ameloblastomas were also compared. RESULTS: For detection of BRAF V600E mutation, the V600E-specific antibody immunohistochemistry had high sensitivity (98.21% 55/56), specificity (87.5% 7/8), positive predictive value (98.21% 55/56), and negative predictive value (87.5% 7/8). Heterogeneity of the staining intensity was observed in the same tissue section, but all or none expression pattern was noticed in the solid tumor nests. The storage time of paraffin tissue blocks ranging from 2 to 14 years did not affect the V600E-specific antibody-positive staining intensity. However, the three-month storage sections showed a significant diminishment of V600E-specific antibody-positive staining signals. CONCLUSIONS: The BRAF V600E-specific antibody immunohistochemistry is suitable for routine detection of BRAF V600E mutation in ameloblastomas. The all or none expression pattern suggests the BRAF V600E mutation may be an early event in the pathogenesis of ameloblastoma.

A proteomics study to explore differential proteins associated with the pathogenesis of ameloblastoma.

BACKGROUND: Reports on the proteomic studies of ameloblastoma and other common odontogenic lesions are limited. We thus explored the differential proteins among ameloblastoma, odontogenic keratocyst, dentigerous cyst, and normal gingival tissue using proteomics and identified hub proteins involved in the local aggressiveness and recurrence of ameloblastoma. METHODS: Samples were obtained from 14 patients with ameloblastoma, 6 with odontogenic keratocyst, 9 with a dentigerous cyst, and 5 with normal gingival tissue. Proteins were then extracted, purified, quantified, and analysed using Easy-nLC chromatography and mass spectrometry. Further functional annotation and enrichment analyses were performed using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes on the target protein collection. Protein clustering and protein-protein interaction network analyses were used to screen the hub proteins. Proteins with significant interactions were screened according to their degree index. These results were verified by immunohistochemical staining. Proteins meeting the screening criteria of expression difference ploidy >1.2-fold (upregulation and downregulation) and p < 0.05 were considered differential proteins. RESULTS: In ameloblastoma, 808 differential proteins were upregulated and 505 were downregulated compared with those in odontogenic keratocyst; 309 were upregulated and 453 were downregulated compared with those in dentigerous cyst; and 2210 were upregulated and 829 were downregulated compared with those in normal gingival tissue. The three groups of differential proteins were associated with cellular exosomes, antigen binding, complement activation, human papillomavirus infection, focal adhesion, cell adhesion molecules, and metabolic pathways. CONCLUSION: CDH3 is associated with the local aggressiveness and recurrence of ameloblastoma and is a potential therapeutic target.

Adenomatoid odontogenic tumor: Features of ameloblastic-like epithelial cells differentiation, secretion, and the nature of tumor cells products.

BACKGROUND: This study aimed to investigate the differentiation of ameloblastic-like cells and the nature of the secreted eosinophilic materials in adenomatoid odontogenic tumors. METHODS: We studied histological and immunohistochemical characteristics of 20 cases using: cytokeratins 14 and 19, amelogenin, collagen I, laminin, vimentin, and CD34. RESULTS: Rosette cells differentiated into ameloblastic-like cells positioned face-to-face, displaying collagen I-positive material between them. Epithelial cells of the rosettes can differentiate into ameloblastic-like cells. This phenomenon probably occurs due to an induction phenomenon between these cells. The secretion of collagen I is probably a brief event. Amelogenin-positive areas were interspersed by epithelial cells in the lace-like areas, outside the rosettes and distant from the ameloblastic-like cells. CONCLUSIONS: There are at least two types of eosinophilic material in different areas within the tumor, one in the rosette and solid areas and another in lace-like areas. The secreted eosinophilic material in the rosettes and solid areas is probably a product of well-differentiated ameloblastic-like cells. It is positive for collagen I and negative for amelogenin, whereas some eosinophilic materials in the lace-like areas are positive for amelogenin. We hypothesize that the latter eosinophilic material could be a product of odontogenic cuboidal epithelial or intermediate stratum-like epithelial cells.

The molecular basis of odontogenic cysts and tumours.

The advances in molecular technologies have allowed a better understanding of the molecular basis of odontogenic cysts and tumours. PTCH1 mutations have been reported in a high proportion of odontogenic keratocyst. BRAF p.V600E are recurrent in ameloblastoma and KRAS p.G12V/R in adenomatoid odontogenic tumour, dysregulating the MAPK/ERK pathway. Notably, BRAF p.V600E is also detected in ameloblastic carcinoma, but at a lower frequency than in its benign counterpart ameloblastoma. Recently, adenoid ameloblastoma has been shown to be BRAF wild-type and to harbour CTNNB1 (ß-catenin gene) mutations, further suggesting that it is not an ameloblastoma subtype. CTNNB1 mutations also occur in other ghost-cell-containing tumours, including calcifying odontogenic cysts, dentinogenic ghost cell tumours and odontogenic carcinoma with dentinoid, but the link between CTNNB1 mutations and ghost cell formation in these lesions remains unclear. Regarding mixed tumours, BRAF p.V600E has been reported in a subset of ameloblastic fibromas, ameloblastic-fibrodentinomas and fibro-odontomas, in addition to ameloblastic fibrosarcoma. Such mutation-positivity in a subset of samples can be helpful in differentiating some of these lesions from odontoma, which is BRAF-wild-type. Recently, FOS rearrangements have been reported in cementoblastoma, supporting its relationship with osteoblastoma. Collectively, the identification of recurrent mutations in these aforementioned lesions has helped to clarify their molecular basis and to better understand the interrelationships between some tumours, but none of these genetic abnormalities is diagnostic. Since the functional effect of pathogenic mutations is context and tissue-dependent, a clear role for the reported mutations in odontogenic cysts and tumours in their pathogenesis remains to be elucidated.

Deep learning applied to the histopathological diagnosis of ameloblastomas and ameloblastic carcinomas.

BACKGROUND: Odontogenic tumors (OT) are composed of heterogeneous lesions, which can be benign or malignant, with different behavior and histology. Within this classification, ameloblastoma and ameloblastic carcinoma (AC) represent a diagnostic challenge in daily histopathological practice due to their similar characteristics and the limitations that incisional biopsies represent. From these premises, we wanted to test the usefulness of models based on artificial intelligence (AI) in the field of oral and maxillofacial pathology for differential diagnosis. The main advantages of integrating Machine Learning (ML) with microscopic and radiographic imaging is the ability to significantly reduce intra-and inter observer variability and improve diagnostic objectivity and reproducibility. METHODS: Thirty Digitized slides were collected from different diagnostic centers of oral pathology in Brazil. After performing manual annotation in the region of interest, the images were segmented and fragmented into small patches. In the supervised learning methodology for image classification, three models (ResNet50, DenseNet, and VGG16) were focus of investigation to provide the probability of an image being classified as class0 (i.e., ameloblastoma) or class1 (i.e., Ameloblastic carcinoma). RESULTS: The training and validation metrics did not show convergence, characterizing overfitting. However, the test results were satisfactory, with an average for ResNet50 of 0.75, 0.71, 0.84, 0.65, and 0.77 for accuracy, precision, sensitivity, specificity, and F1-score, respectively. CONCLUSIONS: The models demonstrated a strong potential of learning, but lack of generalization ability. The models learn fast, reaching a training accuracy of 98%. The evaluation process showed instability in validation; however, acceptable performance in the testing process, which may be due to the small data set. This first investigation opens an opportunity for expanding collaboration to incorporate more complementary data; as well as, developing and evaluating new alternative models.

Pediatric Odontogenic Tumors.

Odontogenic tumors are rare tumors of the jaws that arise from remnants of the tooth forming apparatus. Some odontogenic tumors demonstrate strong predilection for pediatric patients including the unicystic ameloblastoma, adenomatoid odontogenic tumor, ameloblastic fibroma, ameloblastic fibro-odontoma, odontoma, and primordial odontogenic tumor. In this review, we discuss the clinical, radiographic, histopathologic, and molecular characteristics of select odontogenic tumors that demonstrate pediatric predilection and review management.

Synchronous odontogenic tumors: A systematic review.

This systematic review aimed to incorporate published information about synchronous odontogenic tumors (SOTs) with an analysis of the demographic and clinical characteristics from the cases published in the literature. Case reports and case series of SOT were searched in PubMed, Web of Science, Scopus, and EMBASE. A descriptive statistical analysis was performed. Twenty-eight studies comprising 30 cases of SOTs were included. Considering all cases published, SOTs mostly occurred simultaneously in the maxilla and mandible (n = 19/63.3%). Lesions were bifocal in 13 (43.3% of all the 30 cases) and multifocal in 17 cases (56.7% of all the 30 cases). All SOTs available in the literature presented the same type of lesion, and two of them also involved another different SOT (n = 2/6.7% of all the 30 cases). Out of all published cases, the most frequent SOTs in the literature were odontomas (n = 10/33.3% of all the 30 cases), squamous odontogenic tumors (OTs) (n = 8/26.7% of all the 30 cases), calcifying epithelial OTs (n = 8/26.7% of all the 30 cases), and adenomatoid OTs (n = 2/6.7% of all the 30 cases). Considering all SOTs cases included, the overall recurrence was 13.3%. Inside a subgroup of the lesion, synchronous calcifying epithelial OT presented the highest (25%). Five cases (16.7% of all the 30 cases) had a previously associated syndrome, with two cases of Schimmelpenning syndrome being reported. Among published SOTs, odontomas were the most common. All SOTs available in the scientific literature showed the same type of OT and mainly affected both jaws simultaneously. Only a few of these cases were associated with a syndrome.

Odontogenic-like neoplasms of the rabbit cheek: pathological features and comparison to cutaneous trichoblastoma and jaw-associated ameloblastoma.

Odontogenic neoplasms demonstrate unique histopathological features and are thought to arise from the germinal tissues of the developing tooth germ, effectively restricting their anatomic origin to the tooth-bearing regions of the jaw and directly associated soft tissues of the oral cavity. Ectopic odontogenic-like neoplasms located in the skin of cats, rabbits, and human beings challenge these assumptions. Here we describe the clinical, pathological, and immunohistochemical features of 6 spontaneously occurring odontogenic-like neoplasms arising in the cutaneous tissue of the cheek in client-owned pet rabbits, including ameloblastoma-like (n = 3), ameloblastic fibroma-like (n = 2), and ameloblastic carcinoma-like neoplasms (n = 1). Microscopically, all the cheek tumors featured neoplastic epithelium exhibiting odontogenic architectural structures (plexiform ribbons, anastomosing trabeculae, follicles, cysts, and irregular structures with rounded botryoid protuberances) and 1 or more cardinal odontogenic epithelial features (basal palisading, antibasilar nuclei, and central stellate reticulum-like cells). The pancytokeratin, cytokeratin 5/6, cytokeratin 14, and vimentin immunohistochemical patterns of these odontogenic-like lesions were most similar to those of jaw-associated ameloblastoma and differed from those of cutaneous trichoblastoma. All neoplasms were narrowly excised, and for lesions with clinical follow-up information, none had evidence of recurrence 1-7 months after surgical removal. Although evidence suggests that these odontogenic-like tumors of the rabbit cheek may be derived from ectopic rests of transformed tooth germ, the histogenesis of these lesions remains unresolved.