Novel Epigenetic Modifiers of Histones Presenting Potent Inhibitory Effects on Adenoid Cystic Carcinoma Stemness and Invasive Properties.

Adenoid cystic carcinoma (ACC) is a rare neoplasm known for its indolent clinical course, risk of perineural invasion, and late onset of distant metastasis. Due to the scarcity of samples and the tumor's rarity, progress in developing effective treatments has been historically limited. To tackle this issue, a high-throughput screening of epigenetic drugs was conducted to identify compounds capable of disrupting the invasive properties of the tumor and its cancer stem cells (CSCs). ACC cells were screened for changes in tumor viability, chromatin decondensation, Snail inhibition along tumor migration, and disruption of cancer stem cells. Seven compounds showed potential clinical interest, and further validation showed that Scriptaid emerged as a promising candidate for treating ACC invasion. Scriptaid demonstrated a favorable cellular toxicity index, effectively inhibited Snail expression, induced hyperacetylation of histone, reduced cell migration, and effectively disrupted tumorspheres. Additionally, LMK235 displayed encouraging results in four out of five validation assays, further highlighting its potential in combating tumor invasion in ACC. By targeting the invasive properties of the tumor and CSCs, Scriptaid and LMK235 hold promise as potential treatments for ACC, with the potential to improve patient outcomes and pave the way for further research in this critical area.

Bilateral lipomatous hamartoma of the tongue: A case report in a child with oral-facial-digital syndrome type VI.

A hamartoma is a benign proliferation of typical mature cells specific to a particular anatomical site. In the oral cavity, they may occur as isolated cases or be associated with genetic syndromes. Oral-facial-digital syndrome type VI is a rare genetic disorder with an estimated incidence of one in 50,000-250,000 newborns. Here, we report a case of a 2-year-old boy diagnosed with oral-facial-digital syndrome type VI who was referred for evaluation of a bilateral and normochromic to slightly pinkish nodule on the lateral surface of the tongue. Clinically, the child presented hypotonia, low visual acuity, absence of oculocephalic reflex, delay in neuropsychomotor development, and polydactyly in the feet. Excisional biopsies of both sides of the tongue were performed using a 1.5 W high-power diode laser (wavelength of 980 nm), and histopathological analysis revealed abundant mature adipocytes predominantly arranged in lobules that mainly surrounded the minor salivary gland parenchyma. The surgical sites healed with no complications and the patient remains under follow-up for 10 months. Due to the limited literature on this syndrome and the frequent presence of tongue hamartomas in children, dentists need to be familiar with them.

Secretory carcinoma of the salivary gland is rich in lactoferrin: a possible lactational-like differentiation?

PURPOSE: It has been hypothesised that secretory carcinoma of the salivary gland (SCsg) might have a lactational-like differentiation. Therefore, we aimed to assess the immunoexpression of breast hormonal receptors and milk-related proteins in cases of SCsg and other salivary gland tumours with prominent secretory activity. METHODS: Immunohistochemistry against prolactin and growth hormone receptors, lactoferrin, human milk fat globule 1, MUC 1 and MUC4 was performed in twelve cases of SCsg and 47 other salivary gland tumours. RESULTS: Most cases of SCsg were negative for prolactin and growth hormone receptors. All cases of SCsg showed enhanced membranous-cytoplasmic staining for human milk fat globule 1, a pattern seen in other tumour groups. Only SCsg showed widespread strong staining for lactoferrin, concomitantly in the cell compartment and secretion. The other positive tumour types exhibited restricted staining. MUC1 and MUC4 showed no distinct pattern of expression. CONCLUSION: Although SCsg failed to demonstrate a complete lactational-like differentiation, lactoferrin showed a distinctive expression pattern in SCsg compared to other tumour types, which makes it a good marker to help in its differential diagnosis.

A buccal mucosa ulcer as the first sign of tuberculosis.

Tuberculosis (TB) is an infectious disease caused mostly by Mycobacterium tuberculosis. Oral lesions caused by this disease are not common, and most of them represent secondary involvement of the initial pulmonary focus. Therefore, the discovery of lung tuberculosis because of the investigation of oral lesions is rare. This paper reports a case of a 61-year-old male patient who presented with a painfully ulcerated lesion in labial commissure and buccal mucosa, without any comorbidities or symptoms associated. An incisional biopsy was performed, and histopathology showed a chronic granulomatous lesion extending to involve the underlying muscle. Based on these findings, investigation for tuberculosis was suggested. Chest radiography displayed excavated macronodular lesions suggestive of an inflammatory-infectious/granulomatous process of bronchogenic dissemination. The search for acid-alcohol-resistant bacillus in sputum was positive. After using drug therapy for tuberculosis for 3 months, there was a total regression of the oral lesions, in addition to weight recovery in the period. Thus, in patients with isolated oral mucosa lesions, we must consider the possibility of oral manifestation of systemic diseases, even without typical clinical signs and symptoms.

Oral lymphatic malformations: A multicenter study of 208 cases and literature review.

BACKGROUND: To evaluate the frequency and analyze demographic and clinical characteristics of individuals with a histopathological diagnosis of oral lymphatic malformations (OLMs). METHODS: A multicenter study was performed, collecting biopsy record data from a consortium of Brazilian Oral and Maxillofacial Pathology Centers. A review was also conducted to compare this data with cases already available in the literature. RESULTS: This study retrieved 208 cases of OLM in the multicenter study and 1035 cases in the literature review. In both, OLMs affected male and female individuals equally, with the most affected site being the tongue. Individuals ≥60 years of age were uncommonly affected. Symptomatic and larger lesions were more commonly reported in the literature review. CONCLUSIONS: This study comprises the largest sample of OLMs to date. OLMs are rare conditions, without sex predilection. The elderly proved to be less frequently affected, and the tongue is the most commonly affected site.

Histopathological findings and immunohistochemical expression of the stem cell markers CD44, ALDH1, Bmi-1, and Nanog in oral solitary fibrous tumors.

OBJECTIVES: The aim of this study was to evaluate the histomorphologic presentation and the expression of stem cell-related markers in a series of oral solitary fibrous tumors (SFTs). STUDY DESIGN: Histopathological variables and the expression of the standard stem cell markers CD34 and CD99, used for SFT diagnosis, as well as STAT6 were evaluated in 13 oral SFTs. The expression of the cancer stem cell markers CD44, ALDH1, Bmi-1, and Nanog and the tumor suppressor gene p16Ink4a were also investigated. RESULTS: The majority of oral SFTs were circumscribed and characterized by a proliferation of spindle cells arranged in a hyalinized stroma. Only 2 oral SFTs showed >4 mitoses/10 high-power fields. Hypercellularity as well as nuclear and cellular pleomorphism were classified as low and moderate in most of the oral SFTs. All oral SFTs were positive for CD34, STAT6, CD44, ALDH1, Bmi-1, and p16Ink4a. CD99 and Nanog expression was observed in 11 and 10 oral SFT cases, respectively. CONCLUSION: We suggest that STAT6 and ALDH1 have relevant diagnostic value. The expression of CD44, ALDH1, Bmi-1, and Nanog, which is observed in cancer stem cells, may confer advantages to oral SFT cells.

Hyaline ring granuloma of the mouth-A foreign-body reaction that dentists should be aware of: Critical review of literature and histochemical/immunohistochemical study of a new case.

Hyaline ring granuloma (HRG) is a rare and atypical foreign-body granulomatous chronic inflammatory condition. Our aim was to make a critical review of the literature cases and also to illustrate histochemical and immunohistochemical findings of a new case. A modified PICO strategy was used. Inclusion criteria were met by case reports and case series with a histologically confirmed diagnosis of HRG, necessarily in mouth or maxillary bones. Exclusion criteria were no access to the full-text paper. The search was done up to 2019, totalizing 231 selected cases in 54 papers. The new case was analyzed through PAS, Azan-Mallory's trichrome, and CD34 and CD68 reactions. HRG is found mainly in the mandible of men, edentulous and prosthesis users, between 51 and 60 years of age, with 0.5-120 months of duration, usually causing edema and pain or discomfort. Endogenous and exogenous theories may be complementary in HRG. Eosinophilic areas could represent particles of vegetal origin, while the hyaline material could be the result of collagen degradation. Considering the material is not always present or even is ring-shaped, we suggest the change from "hyaline ring granuloma" to "granuloma induced by vegetal inoculation."

Histopathologic aspects of the so-called chronic hyperplastic candidiasis: An analysis of 36 cases.

BACKGROUND: The present study aimed to analyze the histopathologic aspects of cases diagnosed as chronic hyperplastic candidiasis (CHC) in an oral pathology service, pointing out the most important features found. METHODS: All cases histopathologically diagnosed as CHC between 2002 and 2018 were retrieved from the files of the service. Data of the patients and the lesions were collected. Histopathological analysis was performed to evaluate the microscopic characteristics and the amount of Candida present. RESULTS: Thirty-six cases of CHC were retrieved. Women were more affected and there was a predilection for Whites. Most lesions appeared as a nodule or a white plaque, asymptomatic, on the tongue or buccal mucosa. Histopathologically, statistical significance was noted for the presence of epithelial hyperplasia, exocytosis, and mononuclear inflammatory infiltrate. Interestingly, only the association between dysplasia and the amount of fungus was noted. CONCLUSIONS: CHC appears to be a distinct entity presenting typical histopathologic aspects. CHC might even show epithelial dysplasia. In those cases, the presence of a large amount of Candida together with other histopathological features should lead to the diagnosis of CHC and subsequent treatment. However, close follow up is important.

Expression of upstream and downstream targets of mTOR pathway in seven cases of secretory carcinoma of salivary gland origin.

PURPOSE: To investigate the expression of upstream and downstream targets of mTOR signalling pathway in the secretory carcinoma of salivary gland origin (SCsg). METHODS: Seven cases of secretory carcinoma diagnosed by a combination of immunohistochemistry and/or molecular testing were retrieved from our pathology files. For comparison purposes, 27 other salivary carcinomas were selected. Immunohistochemical staining was performed against phospho-Akt, PTEN, phospho-mTOR, phospho-4E-BP, eIF4E and phospho-S6 ribosomal protein. RESULTS: With the exception of Akt, all the other proteins were present at some level in the SCsg and in other salivary carcinomas. PTEN was diffusely expressed in 57.1% of SCsg, but only in 14.8% of other salivary carcinomas. mTOR is expressed in more than half of the cases both for SCsg and other salivary tumour types. Most cases of SCsg showed negative expression for S6 ribosomal protein (71.4%) and 4E-BP1 (57.1%). For both groups evaluated, eIF4E was the most expressed protein. CONCLUSION: SCsg shows different expression patterns for the mTOR signalling molecules, but only eIF4E was highly expressed. This may suggest alternative signalling pathways other than Akt and mTOR in this group of tumours.

A Brazilian multicentre study of 2,497 isolated cases of odontogenic keratocysts.

We present the frequency of cases of isolated odontogenic keratocysts submitted to microscopic examination at 10 Brazilian referral centres in Oral and Maxillofacial Pathology. In a retrospective (1953-2017) analysis, data on clinicoradiographic features and treatment of these lesions were collected and analysed descriptively. Among the 258,867 cases retrieved, 2,497 (0.96%) were isolated odontogenic keratocysts. In summary, an overview of individuals affected with isolated odontogenic keratocysts is reported herein. This lesion showed predilection for the posterior mandible of young adult men.

Periodontal tissues are targets for Sars-Cov-2: a post-mortem study.

Background: The ability of coronavirus SARS-CoV-2 to spread is one of the determinants of the COVID-19 pandemic status. Until June 2020, global COVID-19 cases surpassed 10 million. Asymptomatic patients, with no respiratory impairment, are believed to be responsible for more than 80% of the transmission. Other viruses have been consistently detected in periodontal tissues. Objective: The aim of this study was to investigate the presence of SARS-CoV-2 in periodontal tissue. Methods: We conducted video-endoscope minimally invasive post-mortem biopsy in seven fatal cases of COVID-19, using a regular endoscope video system associated with a smartphone to locate periodontal tissue. We analyzed the samples using RT-PCR, to identify the SARS-CoV-2 RNA and histopathological analysis. Results: The seven studied autopsies with positive laboratory tests for COVID-19 included 57.14% of female patients at the average age of 47.4 (range 8 to 74). In five cases, periodontal tissue was positive for SARS-CoV-2 (RT-PCR). Histopathologic analyses showed morphologic alterations in the keratinocytes of the junctional epithelium, a vacuolization of the cytoplasm and nucleus and nuclear pleomorphism. Conclusion: We presented a biomolecular analysis obtained from minimally invasive autopsies. This is the first study to demonstrate the presence of SARS-CoV-2 in periodontal tissue in COVID-19 positive patients.

Oral lesion as the primary diagnosis of non-Hodgkin's lymphoma: a 20-year experience from an oral pathology service and review of the literature.

PURPOSE: We aimed to investigate the frequency and clinicopathological features of oral NHL in our institution as well as to compare the data gathered from other oral pathology and general pathology services published in the literature. METHODS: Clinical records of patients diagnosed with NHL exclusively affecting the oral cavity were reviewed from 1997 to 2017. Additionally, a review of the literature over a 20-year period was conducted aiming to examine articles on oral NHLs. RESULTS: Oral NHLs represented 0.1% (n = 98) of the total number of biopsies (68,229) received during the period evaluated (1997-2017). The mean age at the diagnosis was 47 years. Most patients were white (67.3%). A nodular lesion was the most frequent presentation (54.9%) and pain was described in 47.1% of the cases. The most common diagnosis was diffuse large B cell lymphoma (42%) followed by plasmablastic lymphoma (24%). Only 19 articles were included in the review of the literature. CONCLUSIONS: Although NHLs are rare in the oral cavity, clinicians and surgeons have an important role in promptly diagnosing lymphomatous lesions to refer the patient to a proper treatment.

Can non-collagenous proteins be employed for the differential diagnosis among fibrous dysplasia, cemento-osseous dysplasia and cemento-ossifying fibroma?

Differential diagnosis among fibrous dysplasias, cemento-ossifying fibromas and cemento-osseous dysplasias is difficult, since there is considerable overlap of histologic features, but also extremely important, since they differ greatly in etiology, clinical behaviour, prognosis and terapeuthic approach. There is no data about the use of immunohistochemistry, a viable and accessible technique, for this purpose. The objective of this study was to investigate, comparatively, the immunohistochemical expression of major non-collagenous proteins (osteonectin [ON], osteopontin [OP], bone sialoprotein [BSP] and osteocalcin [OC]) of mineralized tissue extracellular matrix in 22 cases of fibrous dysplasias, 16 of cemento-ossifying fibromas and 16 of cemento-osseous dysplasias. ON maintained the same expression profile in all cases; the staining for OP was negative in fusiform cells producing cementoid globules and weak, as well as heterogeneous, in high mineralized matrixes; there was negativity for BSP in cementoid globules and in the fusiform cells that produce them, differently from the strong positive expression found in the majority of bone trabeculae and their peripheral cuboidal osteoblasts; and finally, the immuno-reactivity for OC was weak, except in cuboidal osteoblasts and osteocytes. We can conclude that the nature of mineralized structure and the cellular phenotype are much more responsible for variability in immunohistochemical profile than the type of lesion (fibrous dysplasias, cemento-ossifying fibromas and cemento-osseous dysplasias) which makes difficult, at least for a while, the use of these proteins with diagnosis purpose.

A rare odontogenic cyst: Gingival cyst of the adult. A series of 20 new cases from a single center.

Gingival cyst of the adult (GCA) is a rare entity and comprises around 0.3% of all odontogenic cysts. Due to its rarity, there are a few retrospective studies on it. Therefore, the aim of this study was to present casuistic data of a 20-year retrospective study performed in a Brazilian oral pathology reference center. All cases diagnosed as gingival cyst of the adult in the last 20 years were retrieved from the files of the Oral Pathology Service. Data from the lesions and patients were tabulated and presented descriptively. From a total of 68,229 oral biopsies, 7,023 were odontogenic cysts, and among these only 20 cases were diagnosed as gingival cyst of the adult, resulting in the largest series of gingival cyst of the adult, from a single center, in the last 15 years. Most cases occurred in women, and although 53% affected the anterior mandible, 40% occurred in the anterior maxilla, which contrasts with the previous literature. Despite being a rare lesion GCA should be considered in the clinical differential diagnosis of gingival lesions presenting either in the maxilla or mandible.

Fatal case of oral metastatic hepatocellular carcinoma in a patient unaware of his disease.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Metastases to the soft tissues of the oral cavity are extremely uncommon. This report describes a rare case of an oral metastatic HCC, located completely within the oral mucosa overlying the alveolar ridge, in a patient who was unware of his primary disease. A 64-year-old man was referred for evaluation of a nodular mass on the edentulous mandibular ridge underneath an implant-supported overdenture. According to the patient, he was successfully treated for hepatitis C infection 7 years previously, and he reported that his α-fetoprotein levels were monitored at semiannual intervals. The results of his current blood tests were within the reference range. A biopsy was performed, and analysis of the specimen revealed a malignant neoplasm suggestive of metastatic HCC. Because the patient was unaware of any underlying disease, he was referred to an oncologist for further evaluation. However, signs of hepatic decompensation appeared immediately after the biopsy results were obtained, and the patient was hospitalized. The overall medical examination disclosed an HCC with metastases to the lungs and oral cavity, and the patient died 8 days after hospitalization. This case reinforces the important potential for dentists to identify neoplastic diseases that are unknown to their patients.

Salivary gland tumors in a Brazilian population: A 20-year retrospective and multicentric study of 2292 cases.

PURPOSE: Neoplasms of the salivary glands comprise more than thirty subtypes of lesions with various clinical behaviors. The present study aimed to describe the incidence and main features of salivary gland tumors in Brazil. MATERIAL AND METHODS: A retrospective descriptive cross-sectional study was performed (1997-2017). A total of 88,430 biopsy records of oral and maxillofacial lesions from 5 pathology referral centers were analyzed. All cases of salivary gland tumors were reviewed and data such as gender, age, skin color, anatomical location, symptomatology, tumor size and histopathological diagnosis were collected. RESULTS: Among all lesions, there were 2,292 (2.6%) cases of salivary gland tumors. The most frequent benign and malignant neoplasm was pleomorphic adenoma (n = 1,086; 47.4%) and mucoepidermoid carcinoma (n = 322; 14.0%), respectively. The majority of the patients were white (n = 757; 33%) and female (n = 1,391; 60.7%), and most cases involved the parotid gland (n = 933; 40.7%; p < 0.001). Age ranged from 1 to 101 years, occurring more in the fourth decade of life. Tumor size varied from 0.3 to 15 cm and the presence of symptomatology (pain/swelling) occurred more in patients with malignant tumors (p < 0.001). CONCLUSION: The incidence profile and clinical findings of salivary gland tumors were similar to those described worldwide; nevertheless, multicenter studies are valuable to better characterize these neoplasms.

Oral focal mucinosis of the hard palate and gingiva

Oral focal mucinosis (OFM) is an uncommon, asymptomatic, submucosal, slow-growing nodule representing a counterpart of the cutaneous focal mucinosis (CFM). OFM has a female predilection with the highest prevalence in the fifth decade of life. About 68% of OFMs occur in the gingiva and 14% in the palate. We present the case of a 41-year-old woman presenting a progressively growing mass on the palate, since the last 8 months. The diagnostic workup led to the diagnosis of an unusual OFM with the clinical presentation involving the gingiva and hard palate. This case report discusses the clinical and histopathological differential diagnosis.

Incidental finding of subgemmal neurogenous plaque upon retrospective evaluation of oral lymphoepithelial cysts.

PURPOSE: We aimed to compare the histomorphological features of oral lymphoepithelial cysts (OLC) in different locations of the oral cavity and to verify the association between oral lymphoepithelial cysts and subgemmal neurogenous plaque (SNP) on biopsies from the lateral border of the tongue. METHODS: All cases diagnosed as OLC from the Oral Pathology Service at the School of Dentistry/University of São Paulo were retrieved. For all the cysts located in the tongue, their association to SNP was analyzed. Immunohistochemical staining against S100 was performed to confirm the diagnosis of SNP. RESULTS: Thirty-one cases were selected for morphological analysis and SNP was identified in 40% of cases, all of them positive for S100. In these cases, macroscopic analysis demonstrated two independent fragments. Microscopic analysis showed that cysts located in the floor of the mouth and ventral surface of the tongue showed less intense exocytosis, less formation of lymphoid follicles, and predominantly a moderate inflammatory infiltrate. CONCLUSIONS: OLC have a similar histological pattern regardless the location within the oral cavity and. In some cases, the biopsy specimen may be accompanied by a SNP as an adjacent independent structure.

A multicentre study of 268 cases of calcifying odontogenic cysts and a literature review.

OBJECTIVES: To investigate the frequency of calcifying odontogenic cysts (COCs) that have been submitted for microscopic examination from representative geographic regions of Brazil and to compare it with literature data. MATERIALS AND METHODS: A retrospective study was conducted on biopsies obtained from 1953 to 2016 at 10 Brazilian oral and maxillofacial pathology centres. A total of 198,350 biopsy specimens were analysed. Demographic data and histopathological diagnosis were evaluated descriptively and statistically. In addition, a literature review of case series was carried out in four electronic databases. RESULTS: A total of 268 cases of COC were surveyed, representing 0.1% of the oral lesions at the centres studied. Female patients in their second decade of life and the maxilla were more affected. The mean lesion size of symptomatic individuals was larger than that of cases without symptoms (p = 0.026). The literature review showed a higher frequency in Asia and Europe, mainly affecting men in the third decade of life. CONCLUSIONS: COC is a rare lesion. Novel data on the clinicopathological features of 268 cases have been added to the literature. Data regarding gender and age of the Brazilian patients reported herein contrast with findings of case series and retrospective studies reported elsewhere.