Factors Associated with Recurrence of Ameloblastoma: A Scoping Review.

PURPOSE: This scoping review aimed to identify factors associated with the recurrence of ameloblastoma. METHODS: Systematic searches were conducted in PubMed, Scopus, and EMBASE, based on the board research question: "What factors are related to the recurrence of ameloblastoma?". English-language observational studies addressing the risk and preventive factors associated with recurrent ameloblastoma were included and data were extracted. RESULTS: Eighty-three retrospective observational studies met the inclusion criteria. The identified prognostic factors for recurrence included: (1) Tumor size/diameter/volume, (2) cortical bone perforation/ soft tissue invasion, (3) multilocular radiolucency, (4) impacted tooth-involving lesions, (5) root resorption, (6) WHO classification - conventional (solid/multicystic) ameloblastoma, (7) histological subtype - mural invasion of unicystic ameloblastoma, (8) conservative treatment modalities - simple enucleation, curettage, and marsupialization, and (9) non-extraction/preservation of involved teeth. No strong evidence linked immunohistochemical expression to recurrence. Interestingly, BRAF p.V600E remained controversial in terms of recurrence, despite being a frequent finding in ameloblastoma. CONCLUSION: Certain clinical characteristics, radiographic findings, histological subtypes, and treatment choices of ameloblastoma can help identify patients at high risk of recurrence. Further prospective studies to evaluate the prognostic factor model and research on immunohistochemistry are required.

Differential Expression of Immunohistochemical Markers in Ameloblastoma & Ameloblastic Carcinoma: A Systematic Review and Meta-analysis of observational studies.

Background: Differentiating between ameloblastoma (AB) and ameloblastic carcinoma (AC) is difficult, especially when AB has atypical cytological characteristics or an uncommon clinical history. This systematic review and meta-analysis aimed to elucidate the differential expression of immunohistochemical markers between AB and AC. Methods: We conducted a thorough search of PUBMED and SCOPUS according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify cross-sectional studies that compared the expression of immunohistochemical markers in AB and AC. We used a random-effects model to analyze the risk ratios and their corresponding 95% confidence intervals (CIs). The quality of the included studies was assessed using the Newcastle-Ottawa scale. The Egger's test was used to assess publication bias. Results: In total, 301 articles were identified. After excluding irrelevant titles and abstracts, 86 articles were selected for full-text review. We categorized the 41 markers into proliferative and non-proliferative markers. Among non-proliferative markers, nuclear markers were differentially expressed in AB and AC. SOX2 was the only marker that significantly differentiated AB and AC, with an RR of -0.19 (CI 0.10-0.36, I2=0). Conclusion: The current evidence suggests the significance of SOX2 in differentiating between AB and AC, warranting prospective confirmation in well-defined extensive studies. We highlight the paucity of high-quality replicated studies of other markers in this field. Collaborative efforts with standardized techniques are necessary to generate clinically useful immunohistochemical markers.

A radiologic-pathologic study of the histopathologic variants of ameloblastomas and their proliferation indices.

OBJECTIVES: This study aimed to analyze the clinicoradiologic features and Ki-67 proliferation indices between the histopathologic variants of ameloblastomas (ABs) for possible associations. STUDY DESIGN: The diagnosis and histopathologic variant were confirmed for all cases by experienced Oral and Maxillofacial Pathologists. Immunohistochemistry for Ki-67 was performed on the most representative formalin-fixed paraffin-embedded tissue block. Demographic, clinical data and radiologic features were analyzed from patient records and available radiographic examinations. The investigators were blinded to the histopathologic variant and proliferation index when the clinicoradiologic features were assessed. RESULTS: The current study included 116 cases of AB in the final sample. The indolent behavior of the unicystic variant was supported by their low proliferation index and slow growth paired with low frequencies of cortical destruction, loss of teeth, root resorption, and encroachment on anatomical structures. In contrast, the comparatively high proliferation index of the plexiform variant correlated with their fast growth and pain. Furthermore, high radiologic frequencies of cortical destruction, loss of teeth, and encroachment of surrounding anatomical structures supported their more aggressive clinical course. CONCLUSION: Statistically significant differences were noted between certain variants and Ki-67, location, borders, locularity, and cortical destruction, providing better insight into their biological behavior.

Tumor microenvironment of ameloblastoma with a focus on osteoclastogenesis, cell migration, and malignant transformation.

BACKGROUND: Odontogenic tumors arise in the jawbone and originate from cells associated with tooth development. Therefore, understanding odontogenic tumors requires knowledge of all aspects of dental research, including tooth development and eruption. Ameloblastoma is the most common odontogenic tumor. HIGHLIGHT: Although a benign tumor, ameloblastoma progresses with marked jawbone resorption. Because of its locally aggressive features, it can be treated surgically by resecting the surrounding bone. From a molecular pathology perspective, several genetic mutations and dysregulated signaling pathways involved in ameloblastoma tumorigenesis have been identified. Histopathologically, ameloblastomas consist of peripheral ameloblast-like cells and an inner stellate reticulum. The stromal region consists of fibrovascular connective tissue, showing a characteristic sparse myxoid histology. In general, the tumor microenvironment, including the surrounding non-tumor cells, contributes to tumorigenesis and progression. In this review, we focus on the tumor microenvironment of ameloblastomas. In addition, we present some of our recent studies on osteoclastogenesis, tubulin acetylation-induced cell migration, and hypoxia-induced epithelial-mesenchymal transition in ameloblastomas. CONCLUSION: Further research on ameloblastomas can lead to the development of new treatments and improve patients' quality of life.

Clinicopathological characteristics and diagnostic accuracy of BRAF mutations in ameloblastoma: A Bayesian network analysis.

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.

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.

Adenomatoid odontogenic tumor: A histopathologic profile of 43 cases with evidence supporting a mixed odontogenic origin.

BACKGROUND: Adenomatoid Odontogenic Tumor (AOT) accounts for 3% of all odontogenic tumors. It has been classified by WHO as an odontogenic tumor of purely epithelial origin. The current study attempts to establish the origin of the tumor along with detailed histopathological and clinicoradiographic analysis of 43 cases of AOT. MATERIAL AND METHODS: Forty-three cases were reviewed from the departmental archives for demographic data, radiographic features and histological features. Further, histopathological slides were stained with Picrosirius Red (PSR) and observed under polarised light. RESULTS: A majority of the cases were seen in the anterior jaws (76.7%), and were less than 3 cms (76.7%) in greatest dimension. Equal number of cases were of follicular and extra-follicular location while one was peripheral. Predominantly solid histological pattern was noted in 53.5%. Varied sub-patterns were observed with most cases exhibiting solid nodules and strands of tumor cells. Few cases showed melanin pigmentation. Over a third of cases (37.2%) showed dentigerous cyst like areas and one case each showed features of ossifying fibroma and focal cemento-osseous dysplasia. Tumor droplets, hyaline rings within duct-like structures, dentinoid material and osteodentin showed reddish yellow birefringence when observed under polarised microscopy post PSR staining. CONCLUSION: This study highlights the diverse histopathological variation of AOT with evidence to reclassify it as a mixed odontogenic tumor based on the polarising microscopic findings with PSR staining.

Ossifying fibroma mimiking jaw tumour: A radiographic dilema.

Fibro-osseous lesions (FOLs) of the craniomaxillofacial region comprise a group of developmental, dysplastic, and neoplastic alterations. FOLs include ossifying fibromas (OF), cemento-ossifying fibroma (COF), familial gigantiform cementoma (FGC), fibrous dysplasia (FD), and cemento-osseous dysplasia (COD). Evidence suggests that some FOL, especially FD and OF may have a risk of spontaneous malignant transformation. This report documents a rare case of malignant transformation of ossifying fibromas of the jaw and the probable cause for same. Although it is rare, the clinician should have a complete follow up to observe such changes among the patients having FOLs.

Pediatric Odontogenic Cysts and Tumors.

Pediatric odontogenic cysts and tumors are rare and often associated with developing or impacted teeth. Odontogenic cysts are broadly categorized as inflammatory or developmental while odontogenic tumors are classified histologically as epithelial, mesenchymal, or mixed tumors. This article will discuss the presentation, diagnosis, and treatment of odontogenic cysts and tumors in the pediatric population.

Ameloblastic carcinoma: A systematic review.

BACKGROUND: Ameloblastic carcinoma (AC) is the most common odontogenic malignancy, constituting approximately 30% of cases in this category. Literature is sparse on malignant odontogenic neoplasms, with a large proportion of current knowledge derived from case reports or small case series. METHODS: A systematic review of case series/case reports of AC was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Statement guidelines. Demographic and clinical information, including duration of the lesion, location, clinical presentation and radiologic features, were analysed. Additionally, the origin of the lesion (primary/secondary), Ki-67 proliferation index, treatment performed, metastasis, tumour recurrence and prognosis were collected for analysis. RESULTS: A total of 126 studies, including 285 individual cases of AC, were included in this review. Patients presented with a near-equal distribution of painless and painful swellings. ACs presented at a median age of 45 years, with a male-to-female ratio of 1:2. The mandible was most frequently involved, with rare cases extending to involve more than one region, including crossing the midline. Although most lesions presented with poorly-demarcated borders (52.6%), unilocular lesions with well-demarcated borders (47.4%) comprised a substantial number in the sample. The proliferation index was only reported in 27 cases, with a mean score of 42% and a wide range. The probability of tumour recurrence increased, and the survival probability decreased with prolonged follow-up duration. CONCLUSION: This study provides more comprehensive, up-to-date descriptive data on these rare odontogenic malignancies, aiding clinicians and Pathologists with the diagnosis and surgeons in their management of cases.

Comprehensive insights into the understanding of hypoxia in ameloblastoma.

Hypoxia is characterized by a disparity between supply and demand of oxygen. The association between hypoxia and head and neck tumors is a topic of significant interest. Tumors frequently encounter areas with inadequate oxygen supply, resulting in a hypoxic microenvironment. Ameloblastoma is one of the most common benign odontogenic tumors of the maxillofacial region. It is a slow-growing but locally invasive tumor with a high recurrence rate. The literature has demonstrated the correlation between hypoxia and ameloblastoma, revealing a discernible link between the heightened expression of hypoxic markers in low oxygen conditions. This association is intricately tied to the tumoral potential for invasion, progression, and malignant transformation. Hypoxia profoundly influences the molecular and cellular landscape within ameloblastic lesions. The present review sheds light on the mechanisms, implications, and emerging perspectives in understanding this intriguing association to clarify the dynamic relationship between hypoxia and ameloblastoma.

Differential Profile of Primary and Recurrent Ameloblastomas Among Afro-descendants and Non-Afro-descendants-a Systematic Review.

Ameloblastoma is an aggressively growing jaw tumor with high recurrent properties. Reports on global and racial distribution of ameloblastoma are variable and inconclusive. The role of race and ethnicity on ameloblastoma growth characteristics, genetic mutational profile, and recurrence is also still unclear. The primary aim of this systematic review was to assess genetic, racial, and ethnic distribution of primary and recurrent ameloblastoma from published literature. The secondary aim was to assess potential correlations between ethnicity, genetic mutation, and disparities in ameloblastoma treatment outcomes in Afro-descendants and non-Afro-descendants. Twenty-three eligible articles were selected based on preferred reporting items for systematic review and meta-analysis (PRISMA), and a total of 169 ameloblastoma cases were evaluated. Data on patient demographics, ameloblastoma growth characteristics, and genetic status were collected for quantitative analysis. Among a total of 169 ameloblastoma cases, Afro-descendant patients had higher primary and recurrent ameloblastomas at 15.5% and 4.7% respectively compared to non-Afro-descendant at 10.7% and 1.8% respectively. Additionally, BRAF V600E was positively associated with 48.8% of all ameloblastomas and strong predilection for Afro-descendants. Despite the paucity of information on genetic profile of ameloblastomas in the Afro-descendant patient cohort, this ethnic group still accounted for 2.95% of all BRAF V600E-positive tumors. These suggest that Afro-descendants are understudied regarding ameloblastoma characteristics, genetic profile, and recurrence profile. Mutational analysis of ameloblastoma tumors in Afro-descendants should be promoted.

Comprehensive clinical, genome and transcriptomic analysis of primary ghost cell odontogenic carcinoma.

OBJECTIVES: There is currently no comprehensive genome-wide description of the primary ghost cell odontogenic carcinoma (GCOC), hindering our understanding of pathogenesis. We herein present a case with comprehensive clinical, genome and transcriptomic analysis. These will serve as the first comprehensive molecular atlas for primary GCOC. A 58-year-old male underwent subtotal resection with prosthetic restoration. Genome sequencing (WGS) detected previously identified CTNNB1 mutation with novel alterations of MAP3K, EP300, and 22q11.21 region. Transcriptome results showed significant involvement of cytokine-cytokine receptor interaction and PI3K-Akt signaling pathway. These results need to be compared with more GCOCs for more accurate clinical guidance.

Familial gigantiform cementoma with recurrent ANO5 p.Cys356Tyr mutations: Clinicopathological and genetic study with literature review.

BACKGROUND: Familial gigantiform cementoma (FGC) is a rare tumor characterized by the early onset of multi-quadrant fibro-osseous lesions in the jaws, causing severe maxillofacial deformities. Its clinicopathological features overlap with those of other benign fibro-osseous lesions. FGC eventually exhibits progressively rapid growth, but no suspected causative gene has been identified. METHODS: In this study, three patients with FGC were recruited, and genomic DNA from the tumor tissue and peripheral blood was extracted for whole-exome sequencing. RESULTS: Results showed that all three patients harbored the heterozygous mutation c.1067G > A (p.Cys356Tyr) in the ANO5 gene. Furthermore, autosomal dominant mutations in ANO5 at this locus have been identified in patients with gnathodiaphyseal dysplasia (GDD) and are considered a potential causative agent, suggesting a genetic association between FGC and GDD. In addition, multifocal fibrous bone lesions with similar clinical presentations were detected, including five cases of florid cemento-osseous dysplasia, five cases of polyostotic fibrous dysplasia, and eight cases of juvenile ossifying fibromas; however, none of them harbored mutations in the ANO5 gene. CONCLUSION: Our findings indicate that FGC may be an atypical variant of GDD, providing evidence for the feasibility of ANO5 gene testing as an auxiliary diagnostic method for complex cases with multiple quadrants.

Differential expression of PEA3 in odontogenic cysts and tumors.

BACKGROUND: PEA3 transcription factor has been identified as a downstream target of the MAPK and PI3K pathways, and PEA3 overexpression has been observed in a variety of tumor types. We aimed to evaluate PEA3 expression in odontogenic cysts and tumors and compare the expression among odontogenic lesions. In addition, the correlations between PEA3 expression and clinicopathological characteristics of conventional ameloblastoma and unicystic ameloblastoma were investigated. METHODS: This study was performed on 165 samples of odontogenic cysts and tumors including 20 dentigerous cysts, 20 odontogenic keratocysts, 16 adenomatoid odontogenic tumors, 5 ameloblastic fibromas, 45 unicystic ameloblastomas, and 59 conventional ameloblastomas. The sections were immunohistochemically stained with mouse monoclonal anti-PEA3 antibody and PEA3 expression was evaluated as the immunoreactive score. RESULTS: PEA3 expression was absent in all dentigerous cysts (DCs) and odontogenic keratocysts, while all adenomatoid odontogenic tumors showed either no (75%) or low (25%) expression of PEA3. Most of the ameloblastic fibromas (60%) displayed no PEA3 expression. A high expression of PEA3 was observed in a substantial number of unicystic ameloblastomas (48.9%) and conventional ameloblastomas (49.2%) in our study. PEA3 expression in DCs, odontogenic keratocysts and adenomatoid odontogenic tumors were significantly different from that in conventional ameloblastomas and that in unicystic ameloblastomas (p < 0.05). The expression of PEA3 was significantly different in the age groups of unicystic ameloblastomas and histological subtypes of conventional ameloblastomas (p < 0.05). CONCLUSION: PEA3 overexpression is predominant in unicystic ameloblastomas and conventional ameloblastomas compared to other odontogenic lesions, indicating a pivotal role of PEA3 as a downstream effector of MAPK pathway in these two odontogenic lesions.

Phenotypic Profiling and Molecular Mechanisms in Hyperparathyroidism-jaw Tumor Syndrome.

CONTEXT: Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a heritable form of primary hyperparathyroidism caused by germline inactivating mutations in CDC73 encoding parafibromin and is associated with an increased risk of parathyroid cancer. There is little evidence to guide the management of patients with the disease. OBJECTIVE: (1) Characterize the natural history of HPT-JT, (2) correlate genotype and histology of parathyroid tumors with parafibromin immunostaining, (3) understand molecular changes downstream to CDC73 loss. DESIGN: Retrospective study of patients with HPT-JT syndrome (genetically confirmed or affected first-degree relatives). Independent review of uterine tumor from 2 patients and staining for parafibromin on parathyroid tumors from 19 patients (13 adenomas, 6 carcinomas) was performed. RNA-sequencing was performed in 21 parathyroid samples (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas, and 7 sporadic carcinomas with wild-type CDC73). RESULTS: We identified 68 patients from 29 kindreds with HPT-JT with median age at last follow-up of 39 [interquartile range, 29-53] years. A total of 55/68 (81%) developed primary hyperparathyroidism; 17/55 (31%) had parathyroid carcinoma. Twelve of 32 (38%) females developed uterine tumors. Of the 11 patients who had surgical resection for uterine tumors, 12/24 (50%) tumors were rare mixed epithelial mesenchymal polypoid lesions. Four of 68 patients (6%) developed solid kidney tumors; 3/4 had a CDC73 variant at p.M1 residue. Parafibromin staining of parathyroid tumors did not correlate with tumor histology or genotype. RNA-sequencing showed a significant association of HPT-JT-related parathyroid tumors with transmembrane receptor protein tyrosine kinase signaling pathway, mesodermal commitment pathway, and cell-cell adhesion. CONCLUSIONS: Multiple, recurrent atypical adenomyomatous uterine polyps appear to be enriched in women with HPT-JT and appear characteristic of the disease. Patients with CDC73 variants at p.M1 residue appear predisposed to kidney tumors. CLINICAL TRIAL NUMBER: NCT04969926.

Treatment challenges of persistent ghost cell odontogenic carcinoma: a case report and literature review.

The aim of this case report is to review and compare the clinical, radiologic, histopathologic, and immunohistochemical features, along with the treatment of a case of ghost cell odontogenic carcinoma. In addition, a report of the existing published literature with an emphasis on treatment will be described to provide information on this rare but aggressive tumor. The family of odontogenic ghost cell tumors comprises a spectrum of lesions characterized by odontogenic epithelium with ghost cell keratinization and calcifications. It appears that early detection is vital in proper treatment due to the high possibility of malignant transformation.

Cystic Lesions of the Jaws: The Top 10 Differential Diagnoses to Ponder.

BACKGROUND: Cystic lesions of the gnathic bones present challenges in differential diagnosis. This category includes a smorgasbord of odontogenic and non-odontogenic entities that may be reactive or neoplastic in nature. While most cystic jaw lesions are benign, variability in biologic behavior makes distinction between these entities absolutely crucial. METHODS: Review. RESULTS: Two clinical cases are presented in parallel and are followed by an illustrated discussion of the ten most likely differential diagnoses that should be considered when confronted with a cystic jaw lesion. Strong emphasis is placed on the histologic differences between these entities, empowering readers to diagnose them with confidence. Perhaps even more importantly, the more common diagnostic pitfalls in gnathic pathology are discussed, recognizing that a definitive diagnosis cannot be rendered in every situation. The histologic diagnoses for the two clinical cases are finally revealed. CONCLUSION: Cystic lesions of the maxilla and mandible may be odontogenic or non-odontogenic. The most common cystic lesions are the reactive periapical cyst, and the dentigerous cyst (which is developmental in nature). It is important to note that cystic neoplasms also occur in the jaws, and that the presence of inflammation may obscure the diagnostic histologic features of lesions like odontogenic keratocyst and unicystic ameloblastoma. Ancillary testing is of limited diagnostic value in most scenarios. However, both clinical and radiographic information (such as the location, size, duration, associated symptoms, and morphology of the lesion in its natural habitat) are significantly useful.