Kinase fusion positive intra-osseous spindle cell tumors: A series of eight cases with review of the literature.

Mesenchymal spindle cell tumors with kinase fusions, often presenting in superficial or deep soft tissue locations, may rarely occur in bone. Herein, we describe the clinicopathologic and molecular data of eight bone tumors characterized by various kinase fusions from our files and incorporate the findings with the previously reported seven cases, mainly as single case reports. In the current series all but one of the patients were young children or teenagers, with an age range from newborn to 59 years (mean 19 years). Most tumors (n = 5) presented in the head and neck area (skull base, mastoid, maxilla, and mandible), and remaining three in the tibia, pelvic bone, and chest wall. The fusions included NTRK1 (n = 3), RET (n = 2), NTRK3 (n = 2), and BRAF (n = 1). In the combined series (n = 15), most tumors (73%) occurred in children and young adults (<30 years) and showed a predilection for jaw and skull bones (40%), followed by long and small tubular bones (33%). The fusions spanned a large spectrum of kinase genes, including in descending order NTRK3 (n = 6), NTRK1 (n = 4), RET (n = 2), BRAF (n = 2), and RAF1 (n = 1). All fusions confirmed by targeted RNA sequencing were in-frame and retained the kinase domain within the fusion oncoprotein. Similar to the soft tissue counterparts, most NTRK3-positive bone tumors in this series showed high-grade morphology (5/6), whereas the majority of NTRK1 tumors were low-grade (3/4). Notably, all four tumors presenting in the elderly were high-grade spindle cell sarcomas, with adult fibrosarcoma (FS)-like, malignant peripheral nerve sheath tumor (MPNST)-like and MPNST phenotypes. Overall, 10 tumors had high-grade morphology, ranging from infantile and adult-types FS, MPNST-like, and MPNST, whereas five showed benign/low-grade histology (MPNST-like and myxoma-like). Immunohistochemically (IHC), S100 and CD34 positivity was noted in 57% and 50%, respectively, while co-expression of S100 and CD34 in 43% of cases. One-third of tumors (4 high grade and the myxoma-like) were negative for both S100 and CD34. IHC for Pan-TRK was positive in all eight NTRK-fusion positive tumors tested and negative in two tumors with other kinase fusions. Clinical follow-up was too limited to allow general conclusions.

Diode laser on excision of giant peripheral odontogenic myxoma: a rare case report and literature review.

It was to report a rare case of peripheral odontogenic myxoma removed with high-power diode laser and to do an extensive review of studies of odontogenic cysts and tumors treated with high-power laser (HPL). This is a rare case of a 63-year-old male patient with a peripheral odontogenic myxoma measuring approximately 10 cm in the attached gingiva region of tooth 16 removed with a high-power diode laser (808 nm, 3 W, in continuous mode, under constant suction, with 400-µm optical fiber). A literature review was also carried out looking for articles that involved the use of HPL in the treatment of odontogenic cysts and tumors, without restriction of year or language. In the present case, there was no need for suturing, no postoperative discomfort, and minimal bleeding during the procedure. In a 12-month follow-up period, there were no signs of recurrence. Only two cases of intra-osseous odontogenic myxomas treated with HPL and 10 cases involving other odontogenic cysts and tumors were found. All studies showing HPL to be effective in treating these lesions. Despite the different types of lasers used and different parameters, it is observed that lasers are effective in the treatment of odontogenic lesions.

Angiogenesis in patient-derived xenografts of odontogenic myxoma.

Previously, by employing 3D organotypic tissue culture and patient-derived xenograft (PDX) model, oral myxoma response to a MAPK/MEK inhibitor was observed. Gross examination of the tumour fragments obtained after 55 days of PDX grafting revealed increased capsule vascularization. Microscopic analyses showed blood capillaries intermixed with myxoma cells, but the origin of these capillaries, from mice or humans, was not established. This study aimed to investigate whether the endothelial cells observed in the myxoma PDX model are derived from the mouse or from the primary human tumour. Immunohistochemistry was performed on five tumour fragments from the PDX of myxoma after 55 days of implantation in mice. Immunopositivity for antibodies against human (HLA-ABC) and mouse (H2 Db/H2-D1) major histocompatibility complex class I (MHCI) was assessed in the endothelial cells. The endothelial cells in the PDX fragments revealed a membrane staining for the human MHCI protein in the PDX tumour and adjacent connective tissue capsule, indicating that capillaries were derived from the human tumour fragment. Considering the probable human origin of the endothelial cells from capillary blood vessels in the myxoma PDX, we conclude that this PDX model is an interesting model to study myxoma angiogenesis.

[Reconstruction of the mandible after loss of the middle segment due to an odontogenic myxoma]. / Reconstructie van de mandibula na verlies van het middensegment door een odontogeen myxoom.

In an 18-year-old boy, the middle segment of the mandible was removed because of a locally aggressive tumour. The reconstruction became infected and was lost, resulting in 2 separately-moving mandible parts and oral disability. For the second reconstruction, skeletal fixation with osteosynthesis plates, dental fixation with a stabilization frame and intermaxillary fixation were used. Preparation for returning the jaws to their original position was facilitated by three-dimensional simulation software. After a successful second reconstruction, an implant-supported removable bridge was eventually placed.

Transfacial transmandibular approach to the masticator space: Excision of odontogenic myxoma arising from the mandibular condyle.

Odontogenic myxomas are an uncommon benign odontogenic tumor that can present with a wide variety of symptomatology depending on location and potentially be locally destructive. The present case describes a 66-year-old female who presented with left lower facial paresthesia, left aural fullness and hearing loss. She was found to have an odontogenic myxoma that involved the condylar head and extended into the masticator space. In this report we detail our surgical approach utilizing a preauricular transfacial transmandibular approach to the masticator space. In addition, we will discuss various approaches to the masticator space and infratemporal fossa along with considerations on how to manage facial nerve paralysis, facial contour deformities, and post-operative rehabilitation for permanent unilateral condylar head disarticulation.

[Odontogenic myxoma in children : an exceptional locally aggressive lesion]. / Myxome odontogénique chez l'enfant : une lésion exceptionnelle, localement destructrice.

Odontogenic myxoma is a histologically benign and aggressive tumour of the maxillofacial region. It mainly affects young adults and remains exceptional in children. Due to its local invasive nature, it is difficult to differentiate this tumour from malignant neoplasma and from other destructive odontogenic benign tumours. Imaging plays an essential role in the initial exploration and follow-up. Its management is still a challenge today, due to its aggressive potential and its significant risk of recurrence in children among whom extensive surgical treatment involves significant morbidity in children.

Le myxome odontogénique est une tumeur histologiquement bénigne, mais très agressive, de la région maxillo-faciale, touchant principalement le jeune adulte. Elle est exceptionnelle chez l'enfant. De par son caractère invasif locorégional, elle est difficilement différentiable des tumeurs malignes et des autres tumeurs bénignes odontogéniques destructrices. L'imagerie tient un rôle essentiel dans le bilan d'exploration initiale et de suivi de cette lésion. Sa prise en charge chez l'enfant reste encore aujourd'hui un défi, compte tenu de son potentiel agressif et donc de son risque de récidive chez un être en croissance chez lequel une exérèse chirurgicale élargie comporte une morbidité importante.

[Lower jaw myxoma in an early age pediatric patient: comprehensive rehabilitation aspects]. / Miksoma nizhnei chelyusti v rannem detskom vozraste: osobennosti kompleksnoi reabilitatsii.

The article presents a clinical example of the removal of myxoma in a 14-month-old child with half resection of the mandible, disarticulation and one-stage replacement of the defect with a «Carbopol¼ endoprosthesis. The period of postoperative follow-up was 6.5 years, during which there were no signs of relapse. 2 years after the operation, complete coverage of the endoprosthesis with bone regenerate was determined, the configuration of which corresponded to the healthy branch of the mandible. The remodeling of the condylar and coronoid processes by this regenerate was noted, as well as the formation of the tooth germ 3.8 above the endoprosthesis.

Odontogenic Myxoma: Systematic review and bias analysis.

BACKGROUND: Odontogenic myxoma (OM) is a rare neoplasm, which originates from odontogenic ectomesenchyme. There is no study in the literature that analyses the best standards for OM diagnosis and how the treatment modalities may influence the recurrence rates. OBJECTIVE: To evaluate the best standards for odontogenic myxoma (OM) diagnosis and treatment, and how these may influence the recurrence rates. STUDY DESIGN: Two independent researchers performed a systematic review in many databases. Fifty-two eligible studies were included for qualitative analysis. Bias analysis was conducted according to Oxford Centre for Evidence-Based Medicine. RESULTS: A total of 1363 OM cases were reported on, and female gender with average age of 27 years is the most common patient profile. Conventional microscopic findings were observed in 93.43% of the reported cases. In 57.49% of the cases, multilocular radiographic appearance was present, followed by unilocular appearance (32.87%). Posterior mandible was the site with the major prevalence, while surgical resection was the most common treatment modality, followed by enucleation. Recurrence rates for both treatment modalities were approximately close (13.04% and 25.0%, respectively). CONCLUSION: The correct diagnosis of OM relies on the association of clinical, radiographic and microscopic findings. About imaging examinations, panoramic radiography and computed tomography are sufficient for the evaluation of OM. Recurrence rates were closely among the two most used surgery treatments. So according to some clinical-radiological aspects, conservative surgery may be preferred than aggressive surgery modalities.

Odontogenic myxomas lack PDGFRB mutations reported in myofibromas.

BACKGROUND: The molecular pathogenesis of odontogenic myxoma has not been established yet. Considering that odontogenic myxoma may show myofibroblastic differentiation and myxoid areas can be observed in intra-osseous myofibromas, we tested the hypothesis whether both tumors share a common molecular profile. As recent studies have reported PDGFRB recurrent driver mutations in myofibroma, we evaluated PDGFRB mutations in odontogenic myxomas. METHODS: A convenience sample of 15 odontogenic myxomas cases was selected. We direct sequenced PDGFRB exons 12 and 14, where p.R561C (c.1681C>T) and p.N666K (c.1998C>G) hotspot mutations have been reported among others in single and/or multiple myofibromas. RESULTS: All 15 odontogenic myxoma samples were successfully sequenced, and all 15 had wild-type sequences for the PDGFRB mutations investigated. CONCLUSION: Our findings suggest that PDGFRB mutations do not play a role in odontogenic myxoma pathogenesis, which might be helpful in the differential diagnosis of challenging cases.

First insights for targeted therapies in odontogenic myxoma.

OBJECTIVE: Odontogenic myxoma (OM) occasionally responds poorly to surgical treatment. The MAPK pathway is constitutively activated in several neoplasms and we aimed to test if the MAPK pathway is activated in OM, in order to pave the way for an alternative therapy for aggressive and recurrent cases. MATERIALS AND METHODS: The immunoexpression of phosphorylated ERK1/2 (pERK1/2) was assessed in OM. We established a 3D organotypic culture model for the in vitro study and patient-derived xenografts (PDX) in mice for the in vivo study. The MEK inhibitor U0126 was used to inhibit phosphorylation of ERK1/2 in the in vitro and in vivo models. RESULTS: All OM showed strong pERK1/2 immunoexpression, consistent with MAPK pathway activation. Treatment of the 3D culture with U0126 resulted in a reduced pERK1/2/ERK1/2 ratio. Consistent with the in vitro results, all PDX of animals treated with U0126 showed a decreased volume fold change compared with controls. CONCLUSIONS: The MAPK pathway is activated in OM and its inhibition leads to tumor shrinkage in PDX and cell culture models. CLINICAL RELEVANCE: Our results offer a pre-clinical frame for OM-targeted therapy. Further work is needed to determine if this initial finding holds clinical promise.

Reconstruction of Mandibular Defects With Bone Marrow-Derived Stem Cells in Odontogenic Myxoma.

Odontogenic myxoma is a benign tumor, mostly located in the mandible. It shows locally aggressive behavior and requires surgical removal. Common treatment options for reconstructing the bone defects are immediate or delayed autologous bone graft or free flap. In this article, the authors present the successful reconstruction with autogenous bone graft and autologous human bone marrow mesenchymal stem, followed by distraction osteogenesis, dental implant placement and prosthodontic restoration in the mandibular defect.

Odontogenic myxoma: An updated analysis of 1,692 cases reported in the literature.

The aim of the present study was to integrate the available data published on odontogenic myxoma (OM) into a comprehensive analysis of its clinical/radiological features. Electronic search undertaken in January/2018, looking for publications reporting cases of OM. A total of 377 publications were included. We identified 1,692 lesions, and 695 were used for the analysis of recurrence. There is a predominance of OMs in females and in mandibles. OMs usually present with bone expansion, asymptomatic cortical perforation, and a multilocular appearance. Lesion location (maxilla/mandible), bone expansion, cortical bone perforation, locular radiological appearance, tooth resorption, odontogenic epithelial rests, or angular septa are not associated with recurrence. While curettage (31.3%) showed the highest recurrence rate, marginal resection (1.3%) and segmental resection (3.1%) showed the lowest values. Enucleation + peripheral osteotomy (6.7%) showed better results than enucleation (13.1%) or enucleation + curettage (12.7%). In comparison with unilocular lesions, multilocular ones were significantly more prevalent in mandibles, more often presented expansion and cortical bone perforation, had larger mean size, and were more often treated by segmental resection. Conservative surgical procedures are associated with higher probability of recurrence of OM. Taking into consideration the recurrence rate and morbidity associated with different surgical treatments, tumor enucleation followed by peripheral osteotomy should be considered as the first therapeutic choice.

Notch Signaling Affects Oral Neoplasm Cell Differentiation and Acquisition of Tumor-Specific Characteristics.

Histopathological findings of oral neoplasm cell differentiation and metaplasia suggest that tumor cells induce their own dedifferentiation and re-differentiation and may lead to the formation of tumor-specific histological features. Notch signaling is involved in the maintenance of tissue stem cell nature and regulation of differentiation and is responsible for the cytological regulation of cell fate, morphogenesis, and/or development. In our previous study, immunohistochemistry was used to examine Notch expression using cases of odontogenic tumors and pleomorphic adenoma as oral neoplasms. According to our results, Notch signaling was specifically associated with tumor cell differentiation and metaplastic cells of developmental tissues. Notch signaling was involved in the differentiation of the ductal epithelial cells of salivary gland tumors and ameloblast-like cells of odontogenic tumors. However, Notch signaling was also involved in squamous metaplasia, irrespective of the type of developmental tissue. In odontogenic tumors, Notch signaling was involved in epithelial-mesenchymal interactions and may be related to tumor development and tumorigenesis. This signaling may also be associated with the malignant transformation of ameloblastomas. Overall, Notch signaling appears to play a major role in the formation of the characteristic cellular composition and histological features of oral neoplasms, and this involvement has been reviewed here.

Is podoplanin expression associated with transforming growth factor-ß signaling in odontogenic cysts and tumors?

BACKGROUND: Induction of podoplanin by transforming growth factor-ß (TGF-ß) has been shown in a number of lesions but not in odontogenic tumors (OTs). We evaluated the association between these markers in OTs for the first time and compared their expression among the different neoplasms. METHODS: Immunohistochemistry using monoclonal antibody against podoplanin and TGF-ß was performed on 76 odontogenic cysts and tumors. Spearman's correlation coefficient, Kruskal-Wallis, and Mann-Whitney U tests followed by adjustment with Bonferroni were used for statistical analysis (P < .05). RESULTS: A significant difference in podoplanin expression was found among the lesions consisting of solid ameloblastomas, adenomatoid odontogenic tumors, ameloblastic fibromas, odontogenic myxomas (OMs), odontogenic keratocysts, and calcifying odontogenic cysts. Significant differences were observed only between OMs and each of the other neoplasms. Podoplanin immunostaining in the connective tissue was absent in most lesions. TGF-ß was significantly different among the study sample but not between the lesions in paired comparisons. None of the studied OTs showed significant correlations between podoplanin-TGF-ß, in either the epithelium or the stroma. These markers were also descriptively reported in calcifying epithelial odontogenic tumors. CONCLUSIONS: The inductive effect of TGF-ß on podoplanin seems to be limited, if any, in odontogenic lesions. Podoplanin appears to play a role in some aspects of OTs with epithelial or mixed origins. Despite the possible participation of podoplanin in tumorigenesis, it may not necessarily be involved in the aggressive behavior of OTs.

Evaluation of the osteoclastogenic process associated with RANK / RANK-L / OPG in odontogenic myxomas.

BACKGROUND: Odontogenic myxoma (OM) is a benign intraosseous neoplasm that exhibits local aggressiveness and high recurrence rates. Osteoclastogenesis is an important phenomenon in the tumor growth of maxillary neoplasms. RANK (Receptor Activator of Nuclear Factor κappa B) is the signaling receptor of RANK-L (Receptor activator of nuclear factor kappa-Β ligand) that activates the osteoclasts. OPG (osteoprotegerin) is a decoy receptor for RANK-L that inhibits pro-osteoclastogenesis. The RANK / RANKL / OPG system participates in the regulation of osteolytic activity under normal conditions, and its alteration has been associated with greater bone destruction, and also with tumor growth. OBJECTIVES: To analyze the immunohistochemical expression of OPG, RANK and RANK-L proteins in odontogenic myxomas (OMs) and their relationship with the tumor size. MATERIAL AND METHODS: Eighteen OMs, 4 small (<3 cm) and 14 large (> 3cm) and 18 dental follicles (DF) that were included as control were studied by means of standard immunohistochemical procedure with RANK, RANKL and OPG antibodies. For the evaluation, 5 fields (40x) of representative areas of OM and DF were selected where the expression of each antibody was determined. Descriptive and comparative statistical analyses were performed with the obtained data. RESULTS: There are significant differences in the expression of RANK in OM samples as compared to DF (p = 0.022) and among the OMSs and OMLs (p = 0.032). Also a strong association is recognized in the expression of RANK-L and OPG in OM samples. CONCLUSIONS: Activation of the RANK / RANK-L / OPG triad seems to be involved in the mechanisms of bone balance and destruction, as well as associated with tumor growth in odontogenic myxomas.

Next-generation sequencing of oncogenes and tumor suppressor genes in odontogenic myxomas.

BACKGROUND: Mutations previously considered drivers of malignant neoplasms also occur in benign tumors. From the biological perspective, the study of malignant and benign neoplasms is equally relevant. The study of rare tumors contributes to the understanding of the more common ones, as both could share the same hallmark genetic drivers. The identification of driver mutations in benign tumors is facilitated by the fact that they harbor quiet genomes. Pathogenic mutations have being described in benign epithelial odontogenic tumors, such as ameloblastomas and adenomatoid odontogenic tumors. However, the molecular pathogenesis of odontogenic myxoma (OM), a benign aggressive ectomesenchymal tumor, is still poorly characterized, precluding the development of personalized therapy. Aiming to find druggable genetic mutations, we investigated in OM mutations in 50 genes commonly mutated in cancer. METHODS: We used targeted next-generation sequencing to interrogate over 2,800 COSMIC mutations in OM. RESULTS: Missense single nucleotide variants were detected in KDR, TP53, PIK3CA, KIT, JAK3; however, these did not include pathogenic mutations. CONCLUSION: These aggressive tumors do not harbor pathogenic mutations in genes commonly mutated in human cancers or if they do, these mutations probably occur in a low proportion of cases.

[Odontogenic myxoma of the maxilla: report of a case]. / Myxome odontogène du maxillaire. A propos d'un cas.

Myxoma is a rare variety of benign tumors of the jaw, whose origin is embryonic mesenchymal dental follicle. Clinical and radiological manifestations are variable and non-specific and can lend confusion with other lesions. We describe a case of very invasive odontogenic myxoma , observed in a woman of 51 years. Clinically, the patient had left maxillary swelling, painless, firm to the touch. CT facial bones showed an expansive osteolytic process blowing the jaw. The treatment consisted of a wide excision of the tumor by endobuccal way, the tumor is individualized well from the bone. Pathological examination of the surgical specimen was diagnosed odontogenic myxoma. The short-term trend has shown no clinical and radiological local recurrence. The diagnosis is based on clinical, radiological and histological. This tumor is locally aggressive, which can lead to significant facial deformities and dental disturbances. The recurrent nature of myxoma imposes a broad radical treatment beyond the limits of the lesion. The loss of important substance required surgical repair or prosthetic.

Odontogenic myxoma: a clinicopathological study in a South African population.

BACKGROUND: Odontogenic myxoma is a benign, locally aggressive neoplasm of the jaws. Prevalence rates range between 0.5% and 17.7% of odontogenic tumours. There are few reports in the literature on this lesion in African populations, and therefore, this study aimed to report on odontogenic myxoma in a South African population over a 40-year period. METHODS: The clinical records and orthopantomograms of 29 histopathologically diagnosed odontogenic myxoma were retrospectively analysed. Details of age, gender, ethnic origin and clinical, histological as well as radiological features were recorded. RESULTS: The ages of patients ranged from 7 to 44 years with a mean of 21.3 years. The male-to-female ratio was 1:2.6 with the majority of patients being of mixed race and Africans. Clinically, 31% complained of pain while 58.6% had a history of swelling. The majority of odongenic myxomas (62.1%) were located in the mandible with the posterior region being most commonly affected. Multilocular lesions (69.2%) were more common and were significantly larger than unilocular lesions (P < 0.05). The outline of these tumours was mostly well-defined (84.6%) with different degrees of cortication. Only one tumour caused tooth resorption, while 20 cases (76.9%) caused tooth displacement. Six tumours expanded into the maxillary sinus, and 14 tumours caused expansion of the mandible. CONCLUSIONS: Odontogenic myxomas have variable clinical, radiological and histological features. Most of these features in this population were similar to other populations. It is mandatory to use conventional radiographs along with histopathological examination to aid in arriving at an accurate diagnosis.