Making sense of giant cell lesions of the jaws (GCLJ): lessons learned from next-generation sequencing.

Next-generation sequencing has revealed mutations in several bone-related lesions and was recently used to uncover the genetic basis of giant cell lesions of the jaws (GCLJ). Consistent with their benign nature, GCLJ show a low tumor mutation burden. They also harbor somatic, heterozygous, mutually exclusive mutations in TRPV4, KRAS, or FGFR1. These signature mutations occur only in a subset of lesional cells, suggesting the existence of a 'landscaping effect', with mutant cells inducing abnormal accumulation of non-mutant cells that form the tumor mass. Osteoclast-rich lesions with histological similarities to GCLJ can occur in the jaws sporadically or in association with genetically inherited syndromes. Based on recent results, the pathogenesis of a subgroup of sporadic GCLJ seems closely related to non-ossifying fibroma of long bones, with both lesions sharing MAPK pathway-activating mutations. In this review, we extrapolate from these recent findings to contextualize GCLJ genetics and we highlight the therapeutic implications of this new information. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Radical vs conservative treatment of intraosseous ameloblastoma: Systematic review and meta-analysis.

OBJECTIVES: The aim of the present study was to assess the outcomes of radical and conservative treatment approaches of solid/multicystic and unicystic ameloblastoma in terms of recurrence rates. MATERIAL AND METHODS: A systematic review and meta-analysis was conducted based on the PRISMA statement. Search was performed using PubMed, Embase, SCOPUS, and Web of Science for articles published from January 1969 until March 2018. Quality assessment of the selected articles was conducted using the Quality Appraisal of Case Series Studies Checklist. The meta-analysis was performed using the MedCalc program. RESULTS: The search strategy yielded 6,984 articles; 20 studies met the eligibility criteria and were included in the meta-analysis. The pooled recurrence rate of solid/multicystic ameloblastomas following radical treatment was 8%, while conservative treatment caused recurrences in 41%. For unicystic ameloblastomas, these values were 3% and 21%, respectively. The risk of recurrences in both types of ameloblastomas following radical treatment was lower than following conservative treatment. CONCLUSIONS: The present study showed statistically significant differences in recurrence favoring radical treatment for both unicystic and solid/multicystic ameloblastoma. The solid/multicystic type showed more recurrences than the unicystic type. Unfortunately, since only retrospective studies were available, the evidence is less strong as wished for.

Ameloblastic fibroma and ameloblastic fibrosarcoma: A systematic review.

PURPOSE: To integrate the available data published to date on ameloblastic fibromas (AF) and ameloblastic fibrosarcomas (AFS) into a comprehensive analysis of their clinical/radiological features. METHODS: An electronic search was undertaken in July 2017. Eligibility criteria included publications having enough clinical, radiological and histological information to confirm a definite diagnosis. RESULTS: A total of 244 publications (279 central AF tumours, 10 peripheral AF, 103 AFS) were included. AF and AFS differed significantly with regard to the occurrence of patients' mean age, bone expansion, cortical bone perforation and lesion size. Recurrence rates were as follows: central AF (19.2%), peripheral AF (12.5%), AFS (all lesions, 35%), primary (de novo) AFS (28.8%) and secondary AFS (occurring after an AF, 50%). Larger lesions and older patients were more often treated by surgical resections for central AF. Segmental resection resulted in the lowest rate of recurrence for most of the lesion types. AFS treated by segmental resection had a 70.5% lower probability to recur (OR 0.295; P = .049) than marginal resection; 21.3% of the AFS patients died due to complications related to the lesion. CONCLUSIONS: Very long follow-up is recommended for AF lesions, due to the risk of recurrence and malignant change into AFS. Segmental resection is the most recommended therapy for AFS.

Prognostic importance of FGF2 and FGFR1 expression for patients affected by ameloblastoma.

BACKGROUND: Fibroblast growth factor 2 (FGF2) and FGF receptor 1 (FGFR1) have been investigated in different human neoplasms and were shown to play important roles in the pathogenesis of these diseases; however, very few are known regarding their prognostic importance in the context of ameloblastoma. Therefore, the aim of this study was to investigate whether the expression of FGF2 and FGFR1 is associated with ameloblastoma clinical behavior. METHODS: Fifty-eight cases of ameloblastoma arranged in tissue microarray were submitted to immunohistochemistry against FGF2 and FGFR1. Clinicopathological parameters regarding sex, age, tumor size, duration and location, treatment, recurrences, radiographic features, cortical disruptions, and follow-up data were obtained from patients' medical records and correlated with the molecules expression. Univariate and multivariate Cox regression analyses were used to investigate the prognostic potential of the biomarkers. RESULTS: Forty-four cases (75.9%) exhibited cytoplasmic positivity for FGF2 in central and peripheral epithelial cells, 46 of 58 (79.3%) showed FGFR1 cytoplasmic positivity predominantly in the columnar peripheral cells, and 43 cases (74.1%) were positive for both. Expression of FGF2 and FGF2 + FGFR1 was associated with tumor recurrences (P = .05). However, univariate and multivariate analyses did not demonstrate a significant influence of FGF2, FGFR1, or FGF2 + FGFR1 in the 5-year disease-free survival (DFS) rate (P = .27, P = .33, and P = .25, respectively). CONCLUSION: Cytoplasmic expression of FGF2 and FGF2 + FGFR1 is associated with ameloblastoma recurrence, but FGF2 and FGFR1 are not determinants of a lower DFS.

Ameloblastoma: current etiopathological concepts and management.

Ameloblastoma is a benign odontogenic tumor of epithelial origin. It is locally aggressive with unlimited growth capacity and has a high potential for malignant transformation as well as metastasis. Ameloblastoma has no established preventive measures although majority of patients are between ages 30 and 60 years. Molecular and genetic factors that promote oncogenic transformation of odontogenic epithelium to ameloblastoma are strongly linked to dysregulation of multiple genes associated with mitogen-activated protein kinase, sonic hedgehog, and WNT/ß-catenin signaling pathways. Treatment of ameloblastoma is focused on surgical resection with a wide margin of normal tissue because of its high propensity for locoregional invasion; but this is often associated with significant patient morbidity. The relatively high recurrence rate of ameloblastoma is influenced by the type of molecular etiological factors, the management approach, and how early the patient presents for treatment. It is expected that further elucidation of molecular factors that orchestrate pathogenesis and recurrence of ameloblastoma will lead to new diagnostic markers and targeted drug therapies for ameloblastoma.

Ameloblastoma-Clinical, radiological, and therapeutic findings.

Ameloblastoma are the most common odontogenic tumor. As they usually do not form metastasis, they are considered as benign tumors with a locally invasive growth pattern and destruction of the jaws and the surrounding tissue (Oral Diseases, 23, 2017, 199). This article focuses on clinical, radiological, and therapeutic findings, which may influence diagnosis and treatment of ameloblastoma in the future.

Diagnosis and management of benign fibro-osseous lesions of the jaws: a current review for the dental clinician.

Benign fibro-osseous lesions of the maxillofacial skeleton constitute a heterogeneous group of disorders that includes developmental, reactive (dysplastic) and neoplastic lesions. Although their classification has been reviewed multiple times in the past, the most common benign fibro-osseous lesions are fibrous dysplasia, osseous dysplasia and ossifying fibroma. For the dental clinician, the challenges involve diagnosis and treatment (or lack thereof). A careful correlation of all clinical, radiologic and microscopic features is essential to establish a proper diagnosis and a clear treatment plan. This article aimed to review the clinical, radiologic and histopathologic characteristics of benign fibro-osseous lesions of the jaws, with emphasis on their differential diagnoses. With a deeper understanding of benign fibro-osseous lesions, clinicians will be better prepared to manage these lesions in their practice.

Pattern of care and impact of prognostic factors in the outcome of ameloblastic carcinoma: a systematic review and individual patient data analysis of 199 cases.

Ameloblastic carcinoma is a rare locally aggressive odontogenic neoplasm. These tumors are most commonly found to arise from mandible. Because of rarity, there is limited information about the clinical behaviour of such patients. We intended to perform this review of published literature to assess the demographic profile, pattern of care and assess survival outcomes. Two authors independently searched PubMed, Google search, and Cochrane library for eligible studies from 1950 until July 1 2016 published in English language. Data of 199 patients were retrieved from 94 publications for statistical analysis. Median age of the entire cohort was 49 years (range 7-91 years). The analysis revealed that a clear twofold higher incidence in male with male-to-female ratio was 2.4:1 (140:57). Mandible was found to be the commonest tumor location in 66.7% (n = 132) cases followed by maxilla (31.8%) (n = 64). The present analysis revealed that median PFS of 57 months (95% CI 39-120 months) with 5- and 10-year PFS was found to be 47.88 and 29.48%, respectively. Median OS for the entire cohort which was 122 months (95% CI 96-153 months) with 2- and 5-year OS for the entire cohort was 87.16 and 69.08%, respectively. In univariate analysis, patients with an R0 resection were found to have a favourable survival. In addition, patients with localized disease and younger age were found to have a better survival. Adjuvant radiation did not confer any survival advantage. The present analysis revealed excellent outcome for patients treated with an R0 resection. Older patients with high-risk factor may benefit from adjuvant radiation. Role of chemotherapy needs to be evaluated.

Conservative vs Radical Approach for the Treatment of Solid/Multicystic Ameloblastoma: A Systematic Review and Meta-analysis of the Last Decade.

PURPOSE: To examine whether a difference exists in the relapse rate between the conservative and radical approaches after the treatment of solid/multicystic ameloblastoma (SMA), a systematic review of the literature based on evidence of the last decade was performed. MATERIALS AND METHODS: The search strategy incorporated examinations of electronic databases, supplemented by hand searches. A search of four electronic databases, including Ovid MEDLINE, PubMed, EMBASE and Web of Science, was carried out for relevant studies published in the English language from January 2005 to September 2015. Cross referencing and hand research was used to identify further articles. Relative Risk (RR) as effect estimates was calculated in both fixed and random effects models. RESULTS: Of 4234 abstracts screened, only 26 articles met the inclusion criteria and were screened in full text. Of these, only 4 were included in the final meta-analysis. CONCLUSION: The inverse of variance test revealed a statistical difference in the relapse rate for SMA treatment with the conservative vs radical approach. The higher recurrence rate after a conservative approach compared to the surgical approach is significant. However, this review cannot give any recommendation due to the lack of clinical evidence.

Primary Ewing Family of Tumors of the Jaw Has a Better Prognosis Compared to Tumors of Extragnathic Sites.

PURPOSE: Primary Ewing sarcoma of the jaw is rare. The aim of this study was to describe new cases of primary Ewing sarcoma of the jaw and investigate reported prognostic factors of Ewing sarcoma in this series and treatment outcome. MATERIALS AND METHODS: Six patients with primary Ewing sarcoma of the jaw were treated at the Memorial Sloan Kettering Cancer Center (MSKCC) from 1992 through 2013. Clinical data, pathology reports, treatment prescribed, treatment regimens, outcome, and follow-up information were reviewed. RESULTS: Five of 6 patients were female and 5 cases were in the mandible. No patient presented with metastatic disease at diagnosis. All cases were positive for CD99, and 3 patients with genetic confirmation were positive for EWS-FLI1 fusion or EWSR1 gene rearrangement. All patients received induction multiagent chemotherapy and surgical resection and 2 patients received adjuvant radiotherapy. Total (grade IV) or nearly total (grade III) tumor necrosis in 3 of 5 patients (60%) assessed for histologic response to chemotherapy indicated intense sensitivity. All patients were alive and free of disease, with no history of local recurrence, at a median follow-up period of 6.5 years. CONCLUSION: Patients with primary Ewing sarcoma of the jaw have a good prognosis and metastasis is an uncommon occurrence at initial presentation.

Primordial odontogenic tumour: clinicopathological analysis of six cases of a previously undescribed entity.

AIM: To describe the clinicopathological and immuno-histochemical features of six tumours that do not fulfil the criteria of any of the currently classified odontogenic tumours. METHODS AND RESULTS: The patients were three males and three females, whose ages ranged from 3 years to 18 years (mean, 11.05 years). In all cases there were well-defined radiolucencies associated with unerupted teeth apparently showing a pericoronal relationship. Microscopically, all tumours were composed of variably cellular loose fibrous tissue with areas similar to dental papilla, entirely surrounded by cuboidal to columnar epithelium resembling the internal epithelium of the enamel organ. Mesenchymal tissue was positive only for vimentin, and Ki67 expression was very low (<2%). The epithelium was positive for CK AE1/AE3, CK5, CK14, and CK19, but negative for CK18 and CK20. All cases showed clear demarcation from the surrounding bone, and were surgically removed, with no recurrences after follow-up ranging from 6 months to 20 years. CONCLUSIONS: These findings differ from those observed in other odontogenic lesions, such as ameloblastic fibroma, odontogenic myxoma, odontogenic fibroma, and hyperplastic dental follicles. The term primordial odontogenic tumour is proposed to describe this novel lesion.

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.

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.

Maxillofacial metastases: a retrospective review of one institution's 15-year experience.

PURPOSE: Metastasis to the maxillofacial region is a rare occurrence. In our retrospective study of patients with metastasis to the maxillofacial region, the subjects were evaluated to define the clinical behavior patterns in response to the treatment given. MATERIALS AND METHODS: A retrospective record review during a 15-year period (1990 to 2005) was conducted. The patients were selected for inclusion in the present study if they had histologically confirmed maxillofacial metastases. RESULTS: In our retrospective study, during the 15-year period, 1,221 new patients with maxillofacial/oral cancer were seen and evaluated. Of these 1,221 patients, 26 (16 men and 10 women) were identified as having a histologically confirmed metastasis to the maxillofacial region, for an incidence of 2.1%. CONCLUSIONS: Patients with metastasis to the maxillofacial region are often deemed to not be surgical candidates because of the extensive nature of the metastatic disease. We believe that surgical intervention plays a beneficial role in improving quality of life in a properly selected group of patients with metastasis to the maxillofacial region. In our case series, surgery was performed in about 50% of the patients, and palliation and radiotherapy were the most commonly used modalities.

Patients with oral tumors. Part 1: Prosthetic rehabilitation following tumor resection.

The present study reports on the surgical and prosthodontic rehabilitation of 46 patients, 31 male and 15 female, after resection of oral tumors. The treatment was carried out from 2004 to 2007 at the Department of Prosthodontics, University of Bern, with a follow-up time of 3 to 6 years. The average age at diagnosis was 54 years. 76% of all tumors were squamous cell carcinoma, followed by adenocarcinoma. Resection of the tumors including soft and/or hard tissues was performed in all patients. 80% of them additionally underwent radiotherapy and 40% chemotherapy. A full block resection of the mandible was perfomed in 23 patients, and in 10 patients, the tumor resection resulted in an oronasal communication. 29 patients underwent grafting procedures, mostly consisting of a free fibula flap transplant. To enhance the prosthetic treatment outcome and improve the prosthesis stability, a total of 114 implants were placed. However, 14 implants were not loaded because they failed during the healing period or the patient could not complete the final treatment with the prostheses. The survival rate of the implants reached 84.2% after 4 to 5 years. Many patients were only partially dentate before the tumors were detected, and further teeth had to be extracted in the course of the tumor therapy. Altogether, 31 jaws became or remained edentulous. Implants provide stability and may facilitate the adaptation to the denture, but their survival rate was compromised. Mostly, patients were fitted with removable prostheses with obturators in the maxilla and implant-supported complete dentures with bars in the mandible. Although sequelae of tumor resection are similar in many patients, the individual intermaxillary relations, facial morphology and functional capacity vary significantly. Thus, individual management is required for prosthetic rehabilitation.

Parathyroid carcinoma: molecular therapeutic targets.

Parathyroid carcinoma (PC) is an extremely rare malignant tumor of the parathyroid glands, accounting for less than 1% of primary hyperparathyroidism, commonly characterized by severe and unmanageable hypercalcemia, aggressive behavior, high metastatic potential, and poor prognosis. PC manifests prevalently as a sporadic tumor and only occasionally it is part of congenital syndromic and non-syndromic endocrine diseases. Molecular pathogenesis of this form of parathyroid tumor is not fully elucidated and it appears to be caused by multiple genetic and epigenetic drivers, differing among affected patients and not yet clearly stated in distinguishing PC from the benign parathyroid adenoma (PA). Congenital forms of PC have been prevalently associated with germline heterozygous loss-of-function mutations of the CDC73 tumor suppressor gene, both in the context of the hyperparathyroidism jaw-tumor syndrome (HPT-JT) and of the isolated familial hyperparathyroidism (FIPH). Currently, surgical en bloc resection of affected gland(s) and other involved structures is the elective therapy for both primary and recurrent PC. However, it usually results ineffective for advance and metastatic disease, and a high percentage of post-operative recurrence is reported. Targeted medical therapies for surgically untreatable PC, based on the molecular profile of PC samples, are, therefore, needed. The characterization of genetic and epigenetic alterations and deregulated pathways in PC samples will be of fundamental importance to tailor treatment for each patient. Here, we reviewed main findings on molecular pathogenetic aspects of PC, and the current state of the art of therapies.

Treatment options for advanced ameloblastoma in the era of precision medicine: A brief review.

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.

Cystic lesions of the jaws - a clinicopathological study of 322 cases and review of the literature.

Three hundred and twenty-two patients (192 male and 130 female) with cystic lesions of the jaw were successfully diagnosed and treated. One hundred and fifty-five (48%) were radicular cysts, 80 (25%) were dentigerous cysts, 23 (7%) were odontogenic keratocyst (=keratocystic odontogenic tumor), 19 (6%) were eruption cysts, 16 (5%) were traumatic bone cysts, and 29 (9%) were non-odontogenic cysts. There were 95 in the pediatric age group (1 month to 16 years) and 227 in the adult age group (17 years and older). Male to female ratio was 1 in the pediatric age group and 1.7 in the adult age group. The treatment modalities were: marsupialization, enucleation, enucleation with bone grafting, or resection. The distribution and characteristics of jaw cysts in children are different from those in adults. In children there is a relatively high rate of developmental cysts, whereas in adults the inflammatory cysts are more common. Following enucleation of a cystic jaw lesion, the entire surgical specimen and not only a biopsy specimen, should be examined histopathologically to prevent any possibility of an intramural squamous cell carcinoma that may be overlooked. The differences in prevalence of each type of jaw cyst during a lifetime may point toward a multifactorial polygenic pattern rather than a monogenic pattern.