Molecular Aspects of Mucoepidermoid Carcinoma and Adenoid Cystic Carcinoma of the Salivary Gland.

BACKGROUND: Salivary gland tumors (SGTs) are rare and highly heterogeneous lesions, making diagnosis a challenging activity. In addition, the small number of studies and samples evaluated difficults the determination of prognosis and diagnosis. Despite the solid advances achieved by research, there is still an intense need to investigate biomarkers for diagnosis, prognosis and that explain the evolution and progression of SGTs. METHODS: We performed a comprehensive literature review of the molecular alterations focusing on the most frequent malignant SGTs: mucoepidermoid carcinoma and adenoid cystic carcinoma. RESULTS: Due to the importance of biomarkers in the tumorigenenic process, this review aimed to address the mechanisms involved and to describe molecular and biomarker pathways to better understand some aspects of the pathophysiology of salivary gland tumorigenesis. CONCLUSIONS: Molecular analysis is essential not only to improve the diagnosis and prognosis of the tumors but also to identify novel driver pathways in the precision medicine scenario.

TGFß signaling pathway in salivary gland tumors.

OBJECTIVE: Pleomorphic adenoma (PA), mucoepidermoid carcinoma (MEC), and adenoid cystic carcinoma (ACC) are the most prevalent salivary gland tumors. Their pathogenesis has been recently associated with complex molecular cascades, including the TGFß signaling pathway. The aim of this study was to evaluate the expression of genes associated with the TGFß signaling pathway (TGFB1, ITGB6, SMAD2, SMAD4, FBN1, LTBP1, and c-MYC) to map possible downstream alterations in the TGFß cascade. DESIGN: Thirteen PA, 17 MEC, 13 ACC, and 10 non-neoplastic salivary gland samples were analyzed by real-time RT-PCR. RESULTS: Cases of PA presented increased TGFB1, LTPB1, c-MYC, and FBN1 expressions, whereas SMAD2 expression was decreased when compared to non-neoplastic tissue. MEC patients displayed increased expressions of TGFB1, ITGB6, FBN1, and c-MYC and decreased expressions of SMAD2 and SMAD4. ACC cases exhibited elevated expressions of the investigated genes except TGFB1. The present results suggest that decreased expression of SMAD2 and SMAD4 does not impede the transcriptional regulation of c-MYC, especially in PA and MEC. Increased expressions of ITGB6, TGFB1, LTBP1, and FBN1 appear to be related to the regulation of the TGFß signaling pathway in these tumors. Additionally, we observed a higher expression of SMAD4 in ACC and a raised expression of ITGB6 and lowered expression of SMAD2 in MEC. CONCLUSIONS: Our study demonstrated the differential expression of TGFß cascade members in salivary gland tumors such as SMAD2/SMAD4 and c-MYC as well as the participation of ITGB6, TGFB1, LTBP1, and FBN1, contributing to the understanding of the mechanisms involved in tumor progression.

Oral lupus erythematosus: Immunohistochemical evaluation of CD1a, CD21, CD123, and langerin expression in dendritic cells.

BACKGROUND: Dendritic cells participate in the pathophysiology of lupus erythematosus (LE), which are studied in systemic and cutaneous forms; however, little is known about their oral manifestations. METHODS: The expressions of dendritic cell markers (including CD1a, CD21, CD123, and langerin) were investigated by immunohistochemistry technique. Sixty intraoral and lower lip LE lesions, and additional 10 control samples were collected from 2003 to 2019. They were topographically analyzed in the epithelium (EP), lamina propria (LP), epithelial junction (JUN), and deep perivascular (PV) areas. RESULTS: The expression of CD1a was decreased in the EP (p = 0.003) and increased in the deep PV area (p = 0.002). Langerin immunostaining showed no significant decrease in EP (p = 0.944); however, it increased in LP (p = 0.012) and JUN (p = 0.006). CD21 was expressed in only two specimens (EP, p = 0.012; LP, p < 0.001; deep PV area, p = 0.018). CD123 expression increased in all topographies (EP, p < 0.005; LP, p < 0.001, JUN, p < 0.001; deep PV, p < 0.001). The comparison between vermilion and intraoral mucosa LE lesions suggested that sun-exposed sites showed higher expression of CD123 (EP, p = 0.024; LP, p = 0.047; JUN, p = 0.001). CONCLUSIONS: CD1a, langerin, and CD123 expressions were detected coincidently surrounding the inflammatory infiltrate in oral LE, suggesting that these cells may play an important role in immune response. Interestingly, plasmacytoid dendritic cells showed increased CD123 expression in sun-exposed site lesions, which point out a possible function in their pathogenesis. Further studies are needed to confirm this hypothesis.

Histopathologic findings in ointment pseudo-cheilitis: An alert to dermatopathologists.

Ointment pseudo-cheilitis is a recently recognized distinctive type of self-induced cheilitis. Lesions consist of a variable amount of crusts adhered to the vermilion. These crusts consist of dried saliva and dead cells mixed with applied medications attached to the lip surface. Patients are typically severely anxious or depressed; the condition impacts quality of life. Ointment pseudo-cheilitis is frequently misdiagnosed as exfoliative cheilitis or cheilitis glandularis. Biopsy reports are often non-revealing because there are no established histopathological criteria for this disease, and clinicians usually do not formulate the correct diagnostic hypothesis. Here, we present the histopathological findings of four cases of ointment pseudo-cheilitis. The most consistent finding was the presence of laminated parakeratotic material detached from the epithelium in biopsies that are devoid of other significant diagnostic changes. This material at the lip surface possibly represents physiologic labial desquamation mixed with dried saliva and applied medication. With this report, we intend to alert dermatopathologists to the diagnosis of ointment pseudo-cheilitis if they receive biopsies from patients who present clinically exuberant labial lesions that show only minimal histopathological changes.

Temporal and spatial variability in the isotopic composition of sea urchins along Portuguese coast.

Paracentrotus lividus is a sea urchin widely distributed throughout Mediterranean basin and Atlantic coast, highly appreciated for its gonads. It is broadly distributed along the Portuguese coast and its exploitation has potential to grow. Nevertheless, fluctuations on nutritional composition and sensory traits of P. lividus according to each habitat and seasonality are still little understood. Stable isotopes analysis has been recognised as a powerful tool for exploring environmental-ecological-biological processes in aquatic systems. It is also useful to give indications on how to improve available diets for the aquaculture of this species, contributing to a sustainable rearing. Herein, such technique was used to assess temporal and spatial differences in isotopic composition of P. lividus' gonads and intestines and to evaluate its application as a management tool for the identification of the most suitable locations and periods of the year to collect organisms with high quality gonads. Sampling campaigns were carried out between 2019 and 2020 in five rocky shores along the Portuguese coast (Viana do Castelo, Figueira da Foz, Peniche, Sines and Guia). Three rock pools were selected in each shore, and five specimens were collected per pool. The gonadosomatic index (GSI, %) was calculated and carbon and nitrogen elemental and isotopic composition were determined in gonads and intestine using isotope ratio mass spectrometry. Significant spatial and temporal fluctuations were registered among urchins collected along Portuguese coast. Such variations may be associated with latitudinal gradients along the coast and variations of environmental and ecological conditions within each area, especially those affecting algal biomass, on which urchins primarily feed. More research must be pursued to maximise the use of stable isotopes analysis as a management tool for supporting sustainable exploitation of natural stocks or even to contribute to nutritional studies with new diets for sea urchin production that consider the feeding of these animals in the wild.

Oral lichen planus: case series and experience in a tertiary dermatology service in Brazil

Abstract Background: Lichen planus is an inflammatory disease that can affect both the skin and mucous membranes, including the oral mucosa. There is very little original Brazilian dermatology literature about oral lichen planus. Objective: To describe the clinical, pathological, and treatment data of 201 patients diagnosed with oral lichen planus followed at the Stomatology Outpatient Clinic of Hospital das Clínicas, Universidade de São Paulo, from 2003 to 2021. Method: The patients demographic profile, the morpho-topographic features of the lesions, the treatment employed, and the possible presence of squamous cell carcinoma were analyzed. Results: The disease was more common in women over 50 years of age, tending to be chronic, with a large number of cases showing cicatricial sequelae in the mucosa. Topical treatment with potent corticosteroids was shown to be effective in the vast majority of cases. Squamous cell carcinoma in oral lichen planus cicatricial sequelae was observed in eight cases. Study limitations: Retrospective study of medical records, with gaps regarding the filling out of data; unequal observation time among the studied cases. Conclusions: This is the largest Brazilian dermatology series on oral lichen planus. The response to topical corticoid therapy was excellent in the vast majority of cases. The high prevalence of atrophic lesions, demonstrating the chronicity and tissue destruction potential of this disease, may explain the large number of cases of squamous cell carcinoma.

Oral lichen planus: case series and experience in a tertiary dermatology service in Brazil.

BACKGROUND: Lichen planus is an inflammatory disease that can affect both the skin and mucous membranes, including the oral mucosa. There is very little original Brazilian dermatology literature about oral lichen planus. OBJECTIVE: To describe the clinical, pathological, and treatment data of 201 patients diagnosed with oral lichen planus followed at the Stomatology Outpatient Clinic of Hospital das Clínicas, Universidade de São Paulo, from 2003 to 2021. METHOD: The patients demographic profile, the morpho-topographic features of the lesions, the treatment employed, and the possible presence of squamous cell carcinoma were analyzed. RESULTS: The disease was more common in women over 50 years of age, tending to be chronic, with a large number of cases showing cicatricial sequelae in the mucosa. Topical treatment with potent corticosteroids was shown to be effective in the vast majority of cases. Squamous cell carcinoma in oral lichen planus cicatricial sequelae was observed in eight cases. STUDY LIMITATIONS: Retrospective study of medical records, with gaps regarding the filling out of data; unequal observation time among the studied cases. CONCLUSIONS: This is the largest Brazilian dermatology series on oral lichen planus. The response to topical corticoid therapy was excellent in the vast majority of cases. The high prevalence of atrophic lesions, demonstrating the chronicity and tissue destruction potential of this disease, may explain the large number of cases of squamous cell carcinoma.

Three cases of oral mucosal tuberculosis in patients on tumour-necrosis-factor-α blockers.

We present three cases of oral mucosal lesions caused by Mycobacterium tuberculosis in patients treated with anti-tumour necrosis factor-α for psoriasis or rheumatoid arthritis. Diagnosis of oral mucosal tuberculosis was not easily established in any of the cases. A comparison between these cases and other previously described forms of oral mucosal tuberculosis is presented.

An update on viral-induced cutaneous lymphoproliferative disorders. CME Part I.

Viral-induced cutaneous T-cell lymphomas are an uncommon group of lymphoproliferative disorders characterized by a viral infection of T and natural killer (NK) cells. This group of cutaneous T-cell lymphomas is more commonly encountered in Asians and Native Americans from Central and South America compared with Western populations. Viral-associated lymphoproliferative disorders include a spectrum of entities that range from nonneoplastic lesions, such as chronic active Epstein-Barr virus infection and infective dermatitis to malignant diseases, such as extranodal NK/T-cell lymphoma, hydroa vacciniforme-like T-cell lymphoma, and adult T-cell leukemia/lymphoma. This review article will focus on hydroa vacciniforme-like lymphoproliferative disorder, extranodal NK/T-cell lymphoma, adult T-cell leukemia/lymphoma, lymphomatoid granulomatosis, and Epstein-Barr virus-positive mucocutaneous ulcers. We will review the pathogenesis of these conditions and the challenges of making a timely diagnosis in early-stage disease and discuss the common clinicopathologic manifestations, mutational landscape, and approaches to treat these highly aggressive and frequently lethal types of lymphoma.

Extraordinary Case: Unique Presentation of an Aggressive Epstein-Barr Virus-Positive Mucocutaneous Ulcer.

ABSTRACT: Epstein-Barr virus-positive mucocutaneous ulcer is a recent and unusual type of lymphoproliferation, mostly associated with various forms of immunosuppression. In most cases, they regress spontaneously, but an increasing number of reports describe a spectral behavior of the lesion, which ranges from a simple ulcer with eosinophilia to aggressive ulcers. In these cases, Epstein-Barr virus-related lymphomas are the main differential diagnosis. We report a unique observation of this rare disease with mandibular involvement. Due to bone erosion, the patient was treated with 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) with complete healing of the ulcer on clinical examination and PET-scan control.

Relevant proteins for the monitoring of engraftment phases after allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Hematopoietic Stem Cell Transplant (HSCT) has been successfully used as standard therapy for hematological disorders. After conditioning therapy, patients undergoing allogeneic HSCT, present three different phases of engraftment: early pre-engraftment, early post-engraftment, and late engraftment. Severe complications are associated with morbidity, mortality, and malignancies in these phases, which include effects on the oral cavity. OBJECTIVES: The changes in the salivary composition after HSCT may contribute to identifying relevant proteins that could map differences among the phases of diseases, driven for personalized diagnostics and therapy. METHODS: Unstimulated whole saliva was collected from patients submitted to HSCT. The samples were submitted to trypsin digestion for a Mass spectrometry analysis. MaxQuant processed the Data analysis, and the relevant expressed proteins were subjected to pathway and network analyses. RESULTS: Differences were observed in the most identified proteins, specifically in proteins involved with the regulation of body fluid levels and the mucosal immune response. The heatmap showed a list of proteins exclusively expressed during the different phases of HSCT: HBB, KNG1, HSPA, FGB, APOA1, PFN1, PRTN3, TMSB4X, YWHAZ, CAP1, ACTN1, CLU and ALDOA. Bioinformatics analysis implicated pathways involved in protein processing in the endoplasmic reticulum, complement and coagulation cascades, apoptosis signaling, and cholesterol metabolism. CONCLUSION: The compositional changes in saliva reflected the three phases of HSCT and demonstrated the usefulness of proteomics and computational approaches as a revolutionary field in diagnostic methods.

Tight junction gene expression in salivary gland tumors.

Salivary gland neoplasms comprise a heterogeneous group of lesions with multiple histological subtypes, each with distinct growth patterns, resulting in a spectrum of tumor-specific prognoses; pleomorphic adenoma (PA) and mucoepidermoid carcinoma (MEC) are the most common representatives of these neoplasms. Many studies have associated specific profiles of membrane and adhesion molecules in salivary gland tissues; these profiles appear to be relevant in tumor biology as well as be interpreted as fingerprints for tumor classification, diagnostic prognostic and therapeutic targets. One of these membrane molecule complexes are the tight junctions, composed by various proteins, in which claudins are protagonists. The aim of this study was to evaluate the expressions of genes that encode tight junction proteins (CLDN-1, -3, -4, -5, -7, and -11, occludin [OCLN], zonula occludens [TJP1, TJP2, and TJP3] and junctional adhesion molecule A [F11R]) in MEC and PA using real time RT-PCR. We observed high expression of CLDN-1 and -7 and low expression of CLDN-3, -11 and TJP2 in MEC compared to PA. PA samples demonstrated high OCLN expression when compared to MEC. CRTC1::MAML2 fusion was detected in 12 of 20 (60.0%) MEC samples and was associated with CLDN7 expression, while the absence of fusion was associated with high histological grade. Increased CLDN5 expression was associated with submandibular gland tumors. This study demonstrated differential expressions of genes encoding tight junction constituent proteins and their associations with tumor characteristics, suggesting their potential future role as diagnostic and prognostic markers.

The Role of Reflectance Confocal Microscopy in the Evaluation of Pigmented Oral Lesions and Their Relationship With Histopathological Aspects.

ABSTRACT: Oral pigmentations are a heterogeneous group and can be the result of physiological activity of oral mucosal melanocytes, secondary to exogenous causes, associated with systemic or local diseases, or due to proliferative activity of melanocytes. Their diagnosis is critical because these lesions can be markers of internal diseases or, in the case of melanocytic proliferative processes, they may represent a malignant neoplasm. In the past decade, the use of reflectance confocal microscopy, a noninvasive imaging tool, has aided the analysis of such lesions, but the establishment of firm criteria in their evaluation is still lacking. This study evaluated a series of 19 cases of pigmented oral lesions and correlated the reflectance confocal microscopy findings with histopathological classical criteria. We found 13 cases of melanotic macule, 1 of them associated with Peutz-Jeghers syndrome and 2 with Laugier-Hunzinker syndrome; 1 melanocytic nevus; 2 lentigo maligna; 2 pigmented actinic cheilitis; and 1 case of postinflammatory pigmentation secondary to a lupus erythematosus oral discoid lesion. The main difference between benign and malignant lesions was the presence of atypical proliferation in lentigo maligna. Langerhans cells with thick dendritic processes, which may be present in other benign and inflammatory pigmentations is one of the main reasons for diagnostic pitfalls.

Metastasis to the Oral Cavity: Report of 12 Cases.

ABSTRACT: Oral cavity is not a common route for metastatic dissemination; metastasis to the oral region may affect soft tissues and jawbones, accounting for approximately 1% of all oral malignant neoplasms. The diagnosis of metastatic lesions to the oral cavity is usually challenging to clinicians and pathologists because of their complexity and rarity. We present a series of 12 metastatic neoplasms to the oral cavity that were detected previously or after the diagnosis of the primary tumor. All tumors were of epithelial origin with primary sites in the esophagus (2 cases), colon (2 cases), bladder, lungs, liver, larynx, skin, uterus, prostate, and adrenal gland, each with one case. The commonest site of the metastatic masses in the oral cavity was the gingiva, frequently presented as a vegetating, friable mass. The clinical examination and histopathologic analysis of the lesions were central to establishing the final diagnosis of the tumors. Metastatic masses to the oral cavity should always be considered as differential diagnosis of benign-looking lesions, especially in patients with previous history of a malignant disease. Biopsy is mandatory to establish an accurate diagnosis.

Actionable Mutation Profile of Sun-Protected Melanomas in South America.

ABSTRACT: Melanomas that arise in sun-protected sites, including acral and oral mucosal melanomas, are likely under the control of unique, specific mechanisms that lead to mutagenesis through various pathways. In this study, we examined somatic mutations in tumors by targeted sequencing using a custom Ion Ampliseq Panel, comprising hotspots of 14 genes that are frequently mutated in solid tumors. Tumor DNA was extracted from 9 formalin fixation, paraffin-embedded sun-protected melanomas (4 primary oral mucosal melanomas and 5 acral lentiginous melanomas), and we identified mutations in the NRAS , PIK3CA , EGFR , HRAS , ERBB2 , and ROS1 genes. This study reveals new actionable mutations that are potential targets in the treatment of photo-protected melanomas. Additional studies on more of these melanoma subtypes could confirm our findings and identify new mutations.

Epithelial-mesenchymal transition related to bone invasion in oral squamous cell carcinoma.

INTRODUCTION: Bone invasion is an important prognostic factor in oral squamous cell carcinoma, leading to a lower survival rate and the use of aggressive treatment approaches. Epithelial-mesenchymal transition (EMT) is possibly involved in this process, because it is often related to mechanisms of cell motility and invasiveness. This study examined whether a panel of epithelial-mesenchymal markers are present in cases of oral squamous cell carcinoma with bone invasion and whether these proteins have any relationship with patients' clinical-pathological parameters and prognostic factors. METHODS: Immunohistochemical analysis of E-cadherin, twist, vimentin, TGFß1, and periostin was performed in paraffin-embedded samples of 62 oral squamous cell carcinoma cases. RESULTS: The analysis revealed that most cases (66%) presented with a dominant tumor infiltrative pattern in bone tissue, associated with lower survival rates, when compared with cases with a dominant erosive invasion pattern (P = 0.048). Twenty-seven cases (43%) expressed markers that were compatible with total or partial EMT at the tumor-bone interface. There was no association between evidence of total or partial EMT and other demographic or prognostic features. E-cadherin-positive cases were associated with tobacco smoking (P = 0.022); vimentin-positive cases correlated with tumors under 4 cm (P = 0.043). Twistexpression was observed in tumors with a dominant infiltrative pattern (P = 0.041) and was associated with the absence of periostin (P = 0.031). CONCLUSION: We observed evidence of total or partial EMT in oral squamous cell carcinoma bone invasion. The transcription factor twist appears to be involved in bone invasion and disease progression.