The molecular basis of odontogenic cysts and tumours.

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

Fusion genes aiding the diagnosis of soft tissue tumours of the oral cavity: From bench to bedside.

Soft tissue tumours (STT) are a heterogeneous group of benign, malignant, and intermediate/borderline mesenchymal tumours. In the oral and maxillofacial region, less than 3% of all lesions correspond to benign STT and <1% are sarcomas. Overlapping microscopic features may lead to quite challenging diagnostic processes. Translocations and fusion genes are frequent, and type-specific genetic alterations are detected in these tumours. The detection of such alterations by classic cytogenetic, FISH, RT-PCR or NGS can help to define the diagnosis. This narrative review aims to review fusion genes reported for STT that affect the oral cavity and their use in diagnostic molecular pathology. Basic concepts regarding mechanisms of fusion genes formation are presented to clarify this information for surgical pathologists. The chromosomal rearrangements and fusion genes of adipocytic, fibroblastic and myofibroblastic, vascular, pericytic, smooth muscle, skeletal muscle, chondro-osseous, and uncertain origin STT are summarised. The advance in molecular pathology techniques has led not only to a better understanding of the molecular pathogenesis of STT, but also to the development of helpful diagnostic tools. Therefore, it is important for the oral and head and neck pathologists to familiarise with the signature rearrangements and fusion genes for each tumour.

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.

Diode laser surgery versus electrocautery in the treatment of inflammatory fibrous hyperplasia: a randomized double-blind clinical trial.

OBJECTIVES: To compare the efficacy and safety of diode laser and electrocautery techniques for inflammatory fibrous hyperplasia (IFH) removal. MATERIALS AND METHODS: In this randomized double-blind clinical trial, 40 individuals were randomly allocated to two groups: group 1 (G1) consisted of 20 individuals assigned to treatment with diode laser and group 2 (G2) consisted of 20 individuals assigned to treatment with electrocautery. The following transoperative parameters were evaluated: bleeding, temperature, and surgical technique parameters (energy deposited on tissue, flow rate, and time of incision). The postoperative parameters evaluated were as follows: pain, functional alterations (chewing, speaking), analgesic medication intake, swelling, healing of the wound area, and patient satisfaction. RESULTS: Among the 40 individuals included in the study, four (two in G1 and two in G2) did not complete the entire follow-up. Therefore, 36 individuals (18 in G1 and 18 in G2) participated. Participants in G1 and in G2 had similar demographic characteristics. No difference regarding the trans- or postoperative parameters evaluated was observed between G1 and G2 (p > 0.05). Also, no difference regarding the time for healing was observed between groups. CONCLUSIONS: Diode laser seems to be as effective and safe as electrocautery when applied under similar conditions for IFH removal. CLINICAL RELEVANCE: IFH corresponds to 65% of the lesions observed in denture wearers. This study shows that under similar conditions diode laser is as effective and safe as electrocautery for removal of IFH.

Assessment of PI3K/AKT and MAPK/ERK pathways activation in oral lymphatic malformations.

OBJECTIVE: Lymphatic malformations are characterized by the overgrowth of lymphatic vessels during development. Activation of PI3K/AKT and MAPK/ERK signaling pathways occur in isolated lymphatic malformation and in those associated with syndromes such as CLOVES and Klippel-Trenaunay. We aimed to assess the activation of these pathways in sporadic oral lymphatic malformations. STUDY DESIGN: A convenience sample of 14 formalin-fixed paraffin-embedded samples of oral lymphatic malformations underwent immunohistochemical reactions for the phosphorylated forms of AKT1 (pAKT-Ser473) and ERK1/2 (pERK1/2-Thr202/Tyr204), which are markers of PI3K/AKT and MAPK/ERK pathways activation, respectively. RESULTS: Positive staining for pAKT1 and pERK1/2 was observed in the endothelial cells in all samples of oral lymphatic malformations evaluated. CONCLUSIONS: Our results suggest that activation of PI3K/AKT and MAPK/ERK signaling pathways participates in the pathogenesis of oral lymphatic malformations.

New mandibular indices in cone beam computed tomography to identify low bone mineral density in postmenopausal women.

OBJECTIVE: The aim of this study was to evaluate new radiomorphometric indices in cone beam computed tomography (CBCT) for assessing bone mineral density (BMD) status in postmenopausal women. STUDY DESIGN: Mandibular inferior cortical bone thickness was evaluated in 48 postmenopausal women in cross-sectional images at 4 sites: (1) symphysis (S): cross-sectional image equidistant from the centers of the right and left mental foramina (MF); (2) anterior (A): 10 mm anterior to the MF; (3) molar (M): 10 mm posterior to the MF; and (4) posterior (P): 25 mm posterior to the MF. Participants underwent dual-energy x-ray absorptiometry and were divided into normal, osteopenia, and osteoporosis groups. In the study, t tests with Bonferroni correction were conducted. Statistical significance was set at P < .017. Receiver operator characteristic (ROC) analyses were performed. RESULTS: Mean S index was significantly lower in osteoporosis than in osteopenia (P = .005). Mean M index was significantly lower in osteopenia (P < .001) and osteoporosis (P = .001) than in normal individuals. Mean P index was significantly lower in osteoporosis than in normal patients (P = .008). ROC values ranged between 0.643 and 0.740. Cortical thicknesses separating normal from abnormal varied from 1.73 mm to 3.37 mm. CONCLUSIONS: M and P indices in CBCT may be useful for identifying low BMD in postmenopausal women.