Clinicopathological features of myofibromas and myofibromatosis affecting the oral and maxillofacial region: A systematic review.

BACKGROUND: Myofibromas are rare benign neoplasms composed of myoid cells and myofibroblasts. This study aimed to systematically review case reports and a series of myofibromas (MF) and myofibromatosis (MFT) occurring in the oral and maxillofacial regions in order to describe their main clinicopathological features. METHODS: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Electronic searches were conducted in 2023 in four databases: MEDLINE/PubMed, Web of Science, Scopus, and EMBASE. A manual search and a search in the grey literature were also conducted. The lesions were classified as MF or MFT according to their original report. RESULTS: A total of 169 cases were included in this systematic review. Men were slightly more affected, with a painless nodule. When occurring in soft tissue, MF usually developed in the gingiva (mean age:29.23 ± 21.93 years) and when it was intra-osseous, it occurred more frequently in the posterior mandible (mean age:14.33 ± 15.62 years). MFT occurred mainly in the mandible and was predominantly described as well-circumscribed masses of spindle cells organized in fascicles with a prominent vascular activity in a hemangiopericytoma-like pattern. The lesions were mainly positive for smooth muscle actin and vimentin immunomarkers. Surgical excision was the treatment of choice in the majority of cases and recurrence was observed in only three cases. CONCLUSION: MF and MFT affect more men, with an indolent clinical course. Intra-osseous tumors and MFT seem to occur more frequently in younger individuals. These lesions seem to have a good prognosis and low recurrence.

Spatial distribution of CD34 protein in primordial odontogenic tumour, ameloblastic fibroma and the tooth germ.

BACKGROUND: Primordial odontogenic tumour is a benign mixed neoplasm of recent description, which has histological similarities with other odontogenic tumours such as the ameloblastic fibroma. In this article, we investigate the architecture of the sub-epithelial layer of mesenchymal cells expressing the marker CD34 in primordial odontogenic tumour. OBJECTIVE: Analyse the spatial patterns of CD34 expression in primordial odontogenic tumour and compare them with those in ameloblastic fibroma and the normal tooth germ by means of objective imaging approaches, to better characterise these lesions. METHODS: Two cases of primordial odontogenic tumour, four cases of ameloblastic fibroma and two cases of tooth germ in cap and bell stages were used for morphological, structural and immunohistochemical analyses. RESULTS: CD34 expression was found in vascular endothelium of primordial odontogenic tumour, ameloblastic fibroma and tooth germ. In addition, a characteristic sub-epithelial expression was observed only in primordial odontogenic tumour, corresponding to 84%-86% of the sample boundaries. Moreover, the zone expressing CD34 corresponded with a higher cellularity, which was absent in ameloblastic fibroma and tooth germ. CONCLUSION: Image analysis of the primordial odontogenic tumour architecture revealed characteristics absent in other odontogenic tumours and tooth germs. This study provides additional information to support the idea that this neoplasm is a distinct entity from early stage AF or developing odontoma.

Symptomatic subgemmal neurogenous plaque in patients with COVID-19: Is there an association?

BACKGROUND: Subgemmal neurogenous plaques (SNP) are composed of neural structures found in the posterolateral portion of the tongue, rarely biopsied as most of them are asymptomatic or eventually only clinically managed. We aimed to investigate a case series of possible correlation of symptomatic subgemmal neurogenous plaque (SNP) with coronavirus disease 2019 (COVID-19). METHODS: Eleven formalin-fixed paraffin-embedded cases from patients with previous confirmed COVID-19 (by RT-PCR) were retrieved from two pathology files. Histological sections were morphologically studied, and then submitted to immunohistochemical reactions against S-100 and neurofilament proteins, neuron-specific enolase, Glial fibrillary acidic protein (GFAP), synaptophysin, CD56, Ki67, cytokeratins (7, 8-18, 19, 20), nucleocapsid and spike proteins (SARS-CoV-1; and -2) and epithelial membrane antigen (EMA) antibodies. Clinical data were retrieved from the patients' medical files, including the symptoms and the complete history of the progression of the disease. RESULTS: The patients who had COVID-19 included in this study experienced painful lesions in the tongue that corresponded to prominent or altered SNP. Microscopically, neural structures were positive for S-100, GFAP and neurofilament protein. And the cellular proliferative index (by Ki-67) was very low. CONCLUSION: Thus, based on the current results, we hypothesize that symptomatic SNP may be a late manifestation of COVID-19 infection.

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.

Hybrid odontogenic lesions: A systematic review of 203 cases reported in the literature.

BACKGROUND: Hybrid odontogenic lesions combine histopathological characteristics of two or more odontogenic cysts and/or tumours. The aim of this study was to evaluate the available data on hybrid odontogenic lesions (HOL) and to analyse their epidemiological/clinical features and biological behaviour. METHODS: An electronic search was done in January 2021 using multiple databases. Eligibility criteria encompassed publications with sufficient clinical and histological information to confirm the tumours' diagnoses. RESULTS: A total of 147 articles were included in this study, comprising 203 cases. Calcifying odontogenic cyst associated with odontoma (COC/OD) (37/18.2%) was the most common HOL. Females were more affected with a mean age of 24.9 years. Lesions presented as asymptomatic swellings, with a mean evolution time of 8.2 months (0.3-96), and mean tumour size of 4.8 cm (0.3-7). Radiographic aspects frequently showed radiolucent (139/68.4%) and unilocular (52/25.6%) images with well-defined limits (48/23.6%). The lesions mostly affected mandibular pre-molars (69/34%) and mandibular molars (69/34%) regions. Enucleation (89/43.8%) and surgical excision (59/29%) were the most common treatment modalities. The mean follow-up time was 33.8 months (0.5-216 months) and recurrences were observed in four cases (1.9%), all of which were central odontogenic fibroma associated with central giant cell granuloma (COF/CGCG). CONCLUSION: COC/OD is the most common HOL and recurrence is a rare event, being usually associated with the diagnosis of COF/CGCG.

Peripheral odontogenic keratocyst: Clinicopathological and immunohistochemical characterization.

OBJECTIVE: The aim of this study is to present and discuss the salient clinicopathological features, differential diagnosis and epithelial immunohistochemical profile of three additional cases of peripheral odontogenic keratocyst (POKC) and to present a review of the literature. POKC is a locally aggressive odontogenic lesion. The peripheral variant of the odontogenic keratocyst is rare and more frequently located in anterior gingiva. MATERIAL AND METHODS: We present the clinicopathological features of 3 new cases of POKC (2 women and 1 man; age range: 14-74 years). Immunohistochemical study included CK7, CK14, CK19 and Ki-67, and a systematic review of the literature was performed in PubMed, Scopus and Web of Science databases. RESULTS: All cases were located in the anterior gingiva (2 in maxilla and 1 mandible), and none corresponded to Gorlin-Goltz syndrome. High expression of CK14 was seen in all cases, with CK19 and CK7 been only focally positive. The expression of Ki-67 was located in the basal and parabasal cells in all cases. CONCLUSIONS: POKC is a rare gingival lesion that seems to originate from remnants of dental lamina or from the basal cells of the gingival epithelium and present a similar histopathology as compared to intraosseous OKC.

Langerhans cell histiocytosis in the oral and maxillofacial region: An update.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disorder characterized by abnormal proliferation and infiltration of histiocytic cells. METHODS: This review focused on the main aspects associated with LCH. RESULTS: LCH can involve single or multiple organs and systems, with bone and skin being the most commonly affected sites. Regarding skeletal manifestations, the jawbones are involved in about 20%-30% of all cases. Such lesions may present as unilocular or multilocular images mainly affecting the posterior mandible. Oral soft tissue lesions may also occur, with the gingiva and hard palate being the most frequently affected sites. CONCLUSION: The diagnosis and management of LCH are challenging, requiring a multidisciplinary approach, with dentists playing a central role since oral manifestations can be the first sign of the condition.

KRAS mutations in brown tumor of the jaws in hyperparathyroidism.

BACKGROUND: Brown tumors are giant cell-rich lesions that result from abnormal bone metabolism in hyperparathyroidism, one of the most common endocrine disorders worldwide. Brown tumors occasionally affect the jaws and, despite well-known clinical and microscopic features, their molecular pathogenesis remains unclear. We investigated the presence of pathogenic activating mutations in TRPV4, FGFR1, and KRAS in a cohort of brown tumors since these have recently been reported in giant-cell lesions of the jaws and non-ossifying fibromas of the bones (FGFR1 and KRAS), which are histologic mimics of brown tumors. METHODS: We target sequenced 13 brown tumors of the jaws associated with primary or secondary hyperparathyroidism. As mutations in these genes are known to activate the MAPK/ERK signaling pathway, we also assessed the immunostaining of the phosphorylated form of ERK1/2 (pERK1/2) in these lesions. RESULTS: KRAS pathogenic mutations were detected in seven cases (p.G12V n = 4, p.G12D n = 1, p.G13D n = 1, p.A146T n = 1). KRAS variants of unknown significance (VUS), p.A134T and p.E37K, were also detected. All samples showed wild-type sequences for FGFR1 and TRPV4 genes. The activation of the MAPK/ERK signaling pathway was demonstrated by pERK1/2 immunohistochemical positivity of the brown tumors´ mononuclear cells. CONCLUSION: Mutations in KRAS and activation of the MAPK/ERK signaling pathway were detected in brown tumors of hyperparathyroidism of the jaws, expanding the spectrum of giant cell lesions whose molecular pathogenesis involve RAS signaling.

Detection of MAPK/ERK pathway proteins and KRAS mutations in adenomatoid odontogenic tumors.

OBJECTIVE: This study aimed to assess the frequency of KRAS mutation and its association with the presence of the MAPK/ERK signaling pathway proteins in adenomatoid odontogenic tumors. STUDY DESIGN: Paraffin-embedded tissue samples from nine cases of adenomatoid odontogenic tumor were used. Genomic DNA was extracted from each sample; in one case, genetic mutations in 50 cancer-associated genes were examined by next-generation sequencing. Hotspot mutations in the RAS family were analyzed by Luminex assay using the remaining eight cases. Subsequently, immunohistochemistry for KRAS, CRAF, BRAF, EGFR, ERK, MEK, and BRAFV600E was performed. RESULTS: A KRAS G12D missense mutation was detected in the DNA sequence of the tumor cells, but it was not detected in the stromal tissue. KRAS G12V and KRAS G12R mutations were detected in two and four cases, respectively. For immunohistochemistry, all the cases were EGFR, KRAS, BRAF, CRAF positive, one case was ERK negative,and one case was MEK and ERK negative, all the other remaining cases were MEK and ERK positive. CONCLUSION: KRAS mutation at codon 12 and the presence of MAPK/ERK pathway proteins were detected suggesting their association with tumorigenesis of adenomatoid odontogenic tumors.

Patient-derived xenografts of a case of ameloblastic fibrodentinoma.

OBJECTIVES: The establishment of animal models of xenotransplantation can contribute to the elucidation of the molecular pathogenesis of ameloblastic fibrodentinomas (AFD) and it also provides an opportunity for drug tests. We aimed to evaluate the possibility of AFD tumour growth in a patient-derived xenograft (PDX) model. In addition, we characterized the human tumour and the PDXs. MATERIALS AND METHODS: A sample of a recurrent AFD was obtained and two fragments were contralaterally implanted subcutaneously in an 8-week old female NUDE mouse. After 250 days, the PDXs were removed and submitted to histopathological and molecular analysis. Immunohistochemical reactions for Ki67 and the phosphorylated form of ERK1/2 were carried out in both, PDXs and human tumour, and the presence of BRAFV600E was assessed. RESULTS: From day 135 onwards, the PDXs presented a growth peak and remained stable until day 250. Histopathologically, the PDXs presented the same features of the patient's tumour. Tumour cells exhibited Ki67 and pERK1/2 immunoexpression in the patient's tumour and PDX. The AFD was wild-type for BRAFV600E. CONCLUSION: The PDX model recapitulated well the human tumour after a long implantation time, representing a possible model to study the AFD and other odontogenic tumours pathobiology.

Myofibroblastic lesions in the oral cavity: Immunohistochemical and ultrastructural analysis.

OBJECTIVE: To immunohistochemically characterize a group of oral myofibroblastic lesions (MLs) and to evaluate the ultrastructural features of myofibroblasts. MATERIAL AND METHODS: Using a tissue microarray technique (TMA), cases of myofibroma (MF), of nodular fasciitis (NF), of desmoplastic fibroma (DF), and of myofibroblastic sarcoma (MS) from the Universidad Autónoma Metropolitana Xochimilco, and a Private Oral Pathology Service in Mexico City were stained with antibodies against alpha-smooth muscle actin (α-SMA), H-caldesmon, vimentin, desmin, ß-catenin, CD34, anaplastic lymphoma protein kinase (ALK-1), and Ki-67. RESULTS: Nineteen of the 22 MF cases, 2/5 of the NF cases, 1/10 of the DF cases, and 1/2 of the MS cases were positive for α-SMA. 1/2 of the MS cases were positive for desmin; 6/10 of the DF cases were positive for ß-catenin, and 2 of the MF cases were positive for ALK-1. All of the MLs were positive for vimentin and negative for H-caldesmon and CD-34. The Ki-67 labeling index in all of the 8/22 MF, 3/5 NF, and 2/2 MS cases was ≥10%. For all of the MLs evaluated, ultrastructural analysis revealed spindle-shaped cells containing endoplasmic reticulum and peripheral actin filament bundles. CONCLUSION: In certain myofibroblastic lesions, the use of auxiliary techniques (such as immunohistochemistry) can be critical for differential diagnosis.

Oct-4 and CD44 in epithelial stem cells like of benign odontogenic lesions.

Benign epithelial odontogenic lesions are great clinical importance entities that develop in the jaws from the tissues that form teeth. It has been shown that benign and malignant tumors are present in a large number of tumor stem cells, which has great implications in the development of these lesions. Oct-4 and CD44 have been demonstrated as important markers for tumoral stem cells. The aim of this study was investigate the presence of stem cell markers Oct-4 and CD44 in benign epithelial odontogenic lesions. Twenty odontogenic keratocysts (OKC), 20 ameloblastomas (AMB) of the solid/multicystic type and 20 adenomatoid odontogenic tumors (AOT) were retrospectively analyzed for immunohistochemical detection of Oct-4 and CD44 in their epithelial component. All cases were positive for the two markers, with the majority exhibiting a high expression. Analysis of the expression of Oct-4 revealed no statistically significant differences (p = 0.406) between the lesions studied. Regarding CD44, there was a significant difference between the cases of AMB and AOT in relation with OKC, with the latter presenting a greater labelling (p = 0.034). No statistically significant correlation between Oct-4 and CD44 was observed in the lesions. In our findings, the presence of stem cell-like phenotype at various sites of the epithelial component of the odontogenic lesions was identified, suggesting its possible participation in histogenesis and differentiation without, however, exerting influence on the aggressiveness of the lesions.

Pathogenesis of primordial odontogenic tumour based on tumourigenesis and odontogenesis.

OBJECTIVE: Primordial odontogenic tumour (POT) is a rare benign mixed epithelial and mesenchymal odontogenic tumour. POT is composed of dental papilla-like tissue covered with cuboidal to columnar epithelium that resembles to inner and outer enamel epithelium of the enamel organ without dental hard tissue formation. The aim of this study was to examine pathogenesis of POT based on tumourigenesis and odontogenesis. SUBJECTS AND METHODS: Six cases of POT were submitted for study. DNA analysis and transcriptome analysis were performed by next-generation sequencing. Expression of amelogenin, ameloblastin and dentin sialophosphoprotein (DSPP) was examined by immunohistochemistry. RESULTS: There were no gene mutations detected in any of analysed 151 cancer- and 42 odontogenesis-associated genes. Enamel protein-coding genes of Amelx, Ambn and Enam, and dentin protein-coding genes of Col1a1, Dspp, Nes and Dmp1 were expressed, whereas expression of dentinogenesis-associated genes of Bglap, Ibsp and Nfic was negative or very weak suggesting inhibition of dentin formation in POT after odontoblast differentiation. Immunoreactivity of amelogenin, ameloblastin and DSPP was detected in POT. CONCLUSIONS: Pathogenesis of POT is considered to be genetically different from other odontogenic tumours. It is suggested that inhibition of enamel and dentin formation in POT is due to defects in dentin formation process.

Immunohistochemical expression of podoplanin (D2-40), lymphangiogenesis, and neoangiogenesis in tooth germ, ameloblastomas, and ameloblastic carcinomas.

BACKGROUND: Ameloblastoma is a benign but locally aggressive odontogenic tumor, while ameloblastic carcinoma is its malignant counterpart. Angiogenesis and lymphangiogenesis in malignancies have been correlated with higher aggressiveness and poor prognosis, as well as greater expression of podoplanin by tumoral cells. METHODS: Immunohistochemical expression of podoplanin, CD34, and CD105 (endoglin) was evaluated in 53 ameloblastomas and three ameloblastic carcinomas; additionally, immunohistochemistry for podoplanin was also performed in 10 tooth germs. Microvessel density of blood and lymphatic vessels was calculated and compared between ameloblastomas and ameloblastic carcinomas. Immunoexpression of podoplanin by ameloblastic cells was evaluated in tooth germs, ameloblastomas, and ameloblastic carcinomas. RESULTS: Podoplanin was similarly expressed by odontogenic epithelial cells of tooth germs and ameloblastomas, while its expression was lower in ameloblastic carcinomas. There was no difference in microvessel density assessed by CD34 between ameloblastomas and ameloblastic carcinomas; nevertheless, the latter presented higher amounts of lymphatic and new formed blood vessels. CONCLUSIONS: Results suggest that podoplanin does not seem to be involved in invasion mechanisms of ameloblastic carcinomas, as its expression was decreased in the malignant tumoral cells. On the other hand, the increased lymphatic microvessel density and neoangiogenesis found in ameloblastic carcinomas could be related to its aggressiveness and potential for metastasis.

Primordial Odontogenic Tumor: A case report with histopathological analyses.

Primordial odontogenic tumor (POT) is a benign mixed epithelial and mesenchymal odontogenic tumor included into the current World Health Organization (WHO) classification of Head and Neck tumours in 2017. As far as the authors have confirmed, only eight cases of this tumor have been reported so far. This paper reports a case of POT that occurred in the right mandible of a 5-year-old patient. Panoramic radiograph showed a well-defined homogeneous radiolucency displacing the unerupted second deciduous molar to the deep part of the mandible. Histopathologically, the tumor was composed of cell-rich mesenchymal tissue with myxoid areas, surrounded by columnar epithelium and non-keratinized cuboidal epithelium in the outer layers. The histopathological diagnosis was POT. The expression patterns of cytokeratins (CK) 14, 18, 19, vimentin and CD34 suggested that the grade of differentiation of the POT was approximately equivalent to that of normal primary tooth germ tissues in cap stage to late bell stage.

Immunohistochemical expression of cyclooxygenase-2 (COX-2) in oral nevi and melanoma.

BACKGROUND: Cyclooxygenase-2 (COX-2) catalyses the conversion of arachidonic acid to prostaglandin, and its overexpression has been demonstrated in different malignant tumors, including cutaneous melanoma. However, no data about the expression of this protein in oral melanocytic lesions are available to date. The aim of this study was to evaluate the immunohistochemical expression of COX-2 in oral nevi and melanomas, comparing the results with correspondent cutaneous lesions. METHODS: COX-2 was evaluated by immunohistochemistry in 49 oral melanocytic lesions, including 36 intramucosal nevi and 13 primary oral melanomas, and in four cutaneous nevi and eight melanomas. RESULTS: All cases of oral and cutaneous melanomas were positive for COX-2. On the other hand, all oral and cutaneous melanocytic nevi were negative. CONCLUSION: COX-2 is highly positive in oral melanomas and negative in oral nevi and might represent a useful marker to distinguish melanocytic lesions of the oral cavity.

Mammary analogue secretory carcinoma (MASC) of salivary gland in four Mexican patients.

The Clinco-pathological, immunohistochemical and molecular findings of four cases of Mammary Analogue Secretory Carcinoma (MASC) of salivary glands found in Mexico are described. The cases were extracted from 253 salivary gland tumors from a single institution in Mexico City. The 85 Candidates for initial selection were: low grade mucoepidermoid carcinoma (MEC) (N=70 ), Acinic cell cancinoma (AciCC) (N=14), papillary cystadenocarcinoma (N=1), and adenocarcinoma NOS (N=0). Tumors with some histological features consistent with MASC (N= 17, 6.7%) were studied by immunohistochemistry for mammaglobin, STAT5, and S-100 protein and four cases were positive (1.5%), thus the diagnosis of MASC was established, and these were submitted for molecular studies for ETV6-NTRK3. Fusion gene was demonstrated in three cases, two had been erroneously diagnosed as poorly granulated AciCC, and one as low grade MEC with microcystic pattern. Female gender predominated (3:1); one occurred in the parotid, two in minor salivary glands and one in the submaxillary gland; infiltrating borders, atypical mitosis and lymph node metastases were seen in the parotideal tumor. Two patients with major salivary gland tumors are alive and well at 10 and 20 months respectively, the two patients with minor salivary gland tumors are lost. It can be concluded that is important to think in MASC in poorly granulated AciCC and low grade MEC with microcystic pattern. Immunohistochemisty studies confirm the diagnosis, preferentially supported by molecular studies. MASC may follow aggressive behavior or transform into a high grade neoplasm.

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.