Higher immunoexpression of CK14 from the Wnt-1/ß-catenin pathway in the development of odontomas.

Tooth development depends on a series of reciprocal signaling interactions between the oral epithelium and ectomesenchyme. This study aimed to investigate the role of CK14, a protein involved in Wnt-1/ß-catenin signaling, in odontogenesis and the development of odontomas. This cross-sectional, retrospective, immunohistochemical study analyzed 30 compound odontomas, 30 complex odontomas, and 17 tooth germs. Higher immunoexpression of CK14 was observed in odontogenic epithelial cells of tooth germs (p < 0.001) and odontogenic epithelial cells of odontomas (p < 0.001). There was higher immunoexpression of Wnt-1 and ß-catenin proteins in epithelial cells of tooth germs (p = 0.002 and p < 0.001, respectively), as well as in the ectomesenchyme of odontomas (p = 0.003 and p < 0.001, respectively). ß-Catenin was moderately and significantly correlated with CK14 in the membrane of reduced enamel epithelial cells in odontomas (p = 0.007). Higher immunoexpression of CK14 was observed in the odontogenic epithelium during the bud and cap stages and lower immunoexpression in the internal enamel epithelium during the bell stage. In odontomas, lower expression of Wnt-1/ß-catenin and higher immunoexpression of CK14 were found in odontogenic epithelial cells, especially adjacent to the mineralized material resembling the tooth formed in these lesions.

Biological role of the bidirectional interaction between epithelial-mesenchymal transition and PD-L1 expression in head and neck squamous cell carcinomas: A systematic review

Background: Squamous cell carcinoma (SCC) is the most common head and neck malignant neoplasm. Despite progress in antineoplastic treatment for SCC, there are still high morbidity and mortality rates. Over the years, several tumor biomarkers have been suggested to predict the prognosis of patients with oral SCC. Studies point to a bidirectional association between the epithelial-mesenchymal transition (EMT) and the expression of PD-L1 with the aggressive biological behavior of the neoplastic cell. Thus, this systematic review aimed to explore the biological roles and mechanisms underlying the interaction between EMT and PD-L1 expression in head and neck SCC-derived cell lines. Material and methods: An electronic search was performed in the PubMed/Medline, Web of Science, Science Direct, Scopus, Embase, and Cochrane Collaboration Library databases. Articles evaluating the in vitro relationship between EMT/PD-L1 interaction and the biological behavior of head and neck SCC cell lines were selected for this systematic review. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Results: After applying the previously established inclusion/exclusion criteria, 9 articles were included in the qualitative synthesis. The present systematic review suggests the existence of a bidirectional interaction between EMT and PD-L1 expression, which is related to alterations in the cell cycle, proliferation, apoptosis, and cell survival, affecting the migration and invasion ability of tumor cells. Conclusions: Combined targeting of the two pathways may be potentially effective for immunotherapy in head and neck SCC. (AU)

Higher immunoexpression of CK14 from the Wnt-1/β-catenin pathway in the development of odontomas

Abstract Tooth development depends on a series of reciprocal signaling interactions between the oral epithelium and ectomesenchyme. This study aimed to investigate the role of CK14, a protein involved in Wnt-1/β-catenin signaling, in odontogenesis and the development of odontomas. This cross-sectional, retrospective, immunohistochemical study analyzed 30 compound odontomas, 30 complex odontomas, and 17 tooth germs. Higher immunoexpression of CK14 was observed in odontogenic epithelial cells of tooth germs (p < 0.001) and odontogenic epithelial cells of odontomas (p < 0.001). There was higher immunoexpression of Wnt-1 and β-catenin proteins in epithelial cells of tooth germs (p = 0.002 and p < 0.001, respectively), as well as in the ectomesenchyme of odontomas (p = 0.003 and p < 0.001, respectively). β-Catenin was moderately and significantly correlated with CK14 in the membrane of reduced enamel epithelial cells in odontomas (p = 0.007). Higher immunoexpression of CK14 was observed in the odontogenic epithelium during the bud and cap stages and lower immunoexpression in the internal enamel epithelium during the bell stage. In odontomas, lower expression of Wnt-1/β-catenin and higher immunoexpression of CK14 were found in odontogenic epithelial cells, especially adjacent to the mineralized material resembling the tooth formed in these lesions.

Resumo O desenvolvimento dentário depende de uma série de interações de sinalização recíproca entre o epitélio oral e o ectomesênquima. O objetivo deste estudo foi investigar o papel da CK14 das vias WNT-1/β-catenina na odontogênese e no desenvolvimento de odontomas. Este estudo transversal, retrospectivo, imuno-histoquímico analisou 30 odontomas compostos, 30 odontomas complexos e 17 germes dentários. A CK14 apresentou maior imunoexpressão em células epiteliais odontogênicas de germes dentários (p<0,001) e em células epiteliais odontogênicas de odontomas (p<0,001). A Wnt-1 e a β-catenina apresentaram maior imunoexpressão de proteínas nas células epiteliais dos germes dentários (p = 0,002 e p<0,001, respectivamente), bem como no ectomesênquima dos odontomas (p = 0,003 e p < 0,001, respectivamente). A β-catenina correlacionou-se moderada e significativamente com a CK14 na membrana de células epiteliais reduzidas do esmalte em odontomas (p = 0,007). Maior imunoexpressão da CK14 foi observada no epitélio odontogênico nos estágios de botão e capuz com menor imunoexpressão no epitélio interno do órgão do esmalte no estágio de sino. Nos odontomas, foi observado menor expressão de Wnt-1/β-catenina e maior imunoexpressão da CK14 presente nas células epiteliais odontogênicas, especialmente, vizinhas ao material mineralizado semelhante ao dente formado nessas lesões.

Prognostic and clinicopathological significance of tumor-stroma ratio in head and neck squamous cell carcinoma: A systematic review

Background: Analysis of the tumor microenvironment has been proposed as a strategy for the treatment and prognosis of different neoplastic processes. A grading system based on the tumor-stroma ratio (TSR), which evaluates theproportion of stroma in relation to neoplastic parenchyma at the invasion front, has shown a strong prognostic valuein different neoplastic processes. The aim of the present systematic review was to understand the role of the TSR inhead and neck squamous cell carcinoma (HNSCC), evaluating its correlation with clinical and prognostic parameters.Material and Methods: An electronic search was performed in PubMed/Medline, Web of Science, Science Direct,Scopus, Embase, and the Cochrane Collaboration Library. Publications assessing the relationship between TSRand prognosis in cases of HNSCC were eligible. The quality of the studies was assessed independently by fourevaluators using the Newcastle-Ottawa scale.Results: After application of the previously es+lished inclusion/exclusion criteria, nine articles were included inthe qualitative synthesis. With regards to quality on the Newcastle-Ottawa scale, an overall value of 4.55 was obtained. This systematic review demonstrated a strong association between TSR and prognosis in esophageal andoral squamous cell carcinomas.Conclusions: Histopathological analysis of the TSR can optimize the analysis of the prognosis of cases diagnosedwith HNSSC. In addition, the TSR is a reliable and simple parameter that can be evaluated in hematoxylin/eosinstained slides during routine laboratory examinations, showing high inter- and intraobserver agreement. (AU)

Epithelial-mesenchymal transition modulates lower lip carcinogenesis and promotes cancer progression.

OBJECTIVE: To investigate and compare the immunoexpression of E-cadherin, α-SMA, TGF-ß and Snail proteins between cases of actinic cheilitis (AC) and squamous cell carcinoma of the lower lip (LLSCC). STUDY DESIGN: E-cadherin, α-SMA, TGF-ß and Snail antibody immunostaining was analyzed semiquantitatively in 54 AC cases and in 49 LLSCCs. The cases were classified as low and high expression for analysis of the association with clinicopathological variables and overall survival (OS) and disease-free survival (DFS) rates. RESULTS: High expression of E-cadherin (cytoplasmic) (p = 0.001) and α-SMA (p < 0.001) was identified in LLSCCs, as well as low expression of TGF-ß in LLSCCs (p < 0.001) and high expression of Snail in AC cases (p = 0.006). Survival analysis revealed that high expression of α-SMA at the tumor invasion front, a network immunostaining pattern of this protein, and high expression of TGF-ß in tumor buds were significantly associated with poor OS (p < 0.05). There was a higher risk of death among LLSCC cases with high expression of α-SMA (HR = 5.90, p = 0.03). High expression of TGF-ß in tumor buds was significantly associated with poor DFS (p = 0.007) and with a higher risk of negative outcomes for DFS (HR = 4.44, p = 0.014). CONCLUSIONS: The present results suggest the potential involvement of dysregulation of proteins associated with epithelial-mesenchymal transition in the modulation of lip carcinogenesis and greater aggressiveness of LLSCC.

Associação da imunoexpressão das proteínas Ecaderina, SHH e GLI-1 com parâmetros clinicopatológicos em Carcinoma Epidermóide de Língua Oral / Association of immunoexpression of Ecadherin, SHH and GLI-1 proteins with clinicopathological parameters in Oral Tongue Squamous Cell Carcinoma

O potencial de invasão do carcinoma epidermoide requer modifcações fenotípicas nas células parenquimatosas de forma que essas adquiram capacidade de sobreviver e invadir o microambiente tumoral. Esse processo de modificação fenotípica é denominado de transição epitélio-mesenquimal (TEM), cujo as células epiteliais perdem parte de suas características e adquirem outras inerentes às células mesenquimais, de forma controlada por diversos fatores de transcrição indutores destas alterações, conferindo além das habilidades citadas, características de célula tronco, de resistência ao tratamento antineoplásico e angiogênese. O objetivo do presente estudo foi investigar associações da expressão imunoistoquímica das proteínas E-caderina, Shh e Gli-1, sinalizadoras da TEM, com caraterísticas clinicopatológicas de carcinomas epidermoides de língua oral (CELO). A imunoexpressão dessas proteínas foi analisada em 42 casos de CELO, de forma semiquantitativa, nas células neoplásicas do front de invasão tumoral e nos brotamentos tumorais. Os CELOs foram classificados como de baixa e alta expressão proteíca. As gradações de Almangush et al. (2015) e de Boxberg et al. (2017) mostraram categorização semelhante para os casos de CELOs, todavia, a gradação de Almangush et al. (2015) apresentou melhor associação com os parâmetros clínicos, destacando o tamanho do tumor (p=0,013) e o desfecho de óbito (p<0,01). A análise imunoistoquímica revelou predomínio de baixa expressão membranar da E-caderina, apresentando associação significativa com o comprometimento linfonodal (p=0,042). A expressão do Shh foi bem variável e não mostrou associações significativas. A expressão do Gli-1 foi predominantemente alta, mostrando relações significativas com parâmetros clinicopatológicos, como comprometimento linfonodal (p=0,024), estágio clínico do tumor (p=0,016), profundidade de invasão (p=0,015), atividade de brotamentos tumorais (p=0,033), menor tamanho do ninho tumoral (p=0,020) e o grau de diferenciação (p=0,033), sendo estes quatro últimos associados com os brotamentos tumorais. A análise estatística evidenciou ausência de associações significativas entre as variáveis imunoistoquímicas e indicadores de prognóstico do CELO. Os resultados deste estudo indicam que os sistemas de gradação morfológica analisados mostraram-se eficazes na identificação de casos de CELOs mais agressivos, com maior destaque para o proposto por Almangush et al (2015) e, em relação aos achados imunoistoquímicos, os resultados sugerem que a menor expressão membranar da E-caderina e a alta expressão nuclear/citoplasmática de Gli-1 associaram-se ao parâmetro clínico de pior prognóstico, referente ao comprometimento nodal. Diante do modelo do estudo, não se observou associação da imunoexpressão das proteínas estudadas com a sobrevida dos pacientes (AU).

The potential for squamous cell carcinoma invasion requires phenotypic modifications in the parenchymal cells so that they acquire the ability to survive and invade the tumor microenvironment. This process of phenotypic modification is called epithelialmesenchymal transition (EMT), which is crucial for the acquisition of this aggressive malignant phenotype. In this process, the epithelial cells lose part of their characteristics and acquire others inherent to the mesenchymal cells, in a controlled manner, inducing by various transcription factors, conferring, in addition to the aforementioned abilities, stem cell characteristics, resistance to anti-neoplastic treatment and angiogenesis. The aim of the present study was to investigate associations between the immunohistochemical expression of E-cadherin, Shh e, Gli-1 proteins, signaling TEM, with clinicopathological characteristics of oral tongue squamous cell carcinoma (OTSCC). The immunoexpression of these proteins was analyzed in 42 cases of OTSCC, in a semiquantitative way, in the neoplastic cells of the tumor invasion front and in the cells that make up the tumor budding. OTSCCs were classified as low and high protein expression. Aiming at the association of immunohistochemical findings with clinicopathological variables and survival rates, cases were classified into low expression and high expression categories. Initially, statistical differences between the histopathological gradations of malignancy by Almangush et al. (2015) and that of Boxberg et al. (2017) regarding clinical parameters. Both, the gradations showed similar categorization for OTSCC cases, were able to categorize the tumors, however, the gradation by Almangush et al. (2015) showed a better association with clinical parameters, highlighting tumor size (p=0.013) and the outcome of death (p<0.01). The immunohistochemical analysis revealed a predominance of low membrane expression of E-cadherin, with a statistically significant association with lymph node involvement (p=0.042). The expression of Shh was quite variable and had no statistically significant associations. Gli-1 had a prevalence of high expression, showing significant relationships with clinicopathological parameters, such as the occurrence of lymph node involvement (p=0.024), clinical stage of the tumor (p=0.016), depth of invasion (p=0.015), activity of tumor budding (p=0.033), smaller size of the tumor nest (p=0.020) and degree of differentiation (p=0.033), the last four being associated with tumor budding. Some correlations between markers were found, such as the positive correlation between the cytoplasmic expression of E-cadherin with Shh (p=0.030) and the immunoexpression of Gli-1 in the cytoplasm/nucleus with Shh (p=0.041). Statistical analysis evidenced the absence of significant associations between immunohistochemical variables and OTSCC prognostic indicators. The findings of this study suggest the expression pattern of E-cadherin, Shh and Gli-1 in OTSCC, in addition to indicating a better clinicopathological association with the malignancy gradation of Almangush et al. (2015). However, the expression of these biomarkers may not be related to patient survival. In addition, no significant differences were observed between the expression of the proteins studied in tumor budding when other cells in the invasion front were evaluated, suggesting a similar cell phenotype for both. The results of this study indicate that the analyzed morphological grading systems proved to be effective in identifying cases of more aggressive OTSCC, with greater emphasis on the one proposed by Almangush et al (2015) and, in relation to the immunohistochemical findings, the results suggest that the lower membrane expression of E-cadherin and the high nuclear/cytoplasmic expression of Gli-1 were associated with the clinical parameter of worse prognosis (AU).

Primary Intraosseous Squamous Cell Carcinoma Involving the Jaw Bones: A Systematic Review and Update.

Primary intraosseous oral squamous cell carcinoma (PIOSCC) is a rare malignant neoplasm that affects the jaws. Despite its aggressive biological behavior, there are no studies that evaluated the clinicopathological features of this tumor and parameters associated with its prognosis. The objective of the present study was to conduct a systematic review of the available data on oral and maxillofacial PIOSCC in order to determine its clinicopathological characteristics and biological behavior. We conducted a systematic review in May 2020 in multiple databases using a specific search strategy. Cases diagnosed as PIOSCC in the oral cavity and maxillofacial complex that had sufficient histopathological data, absence of ulceration in the oral mucosa, a negative result for a distant primary tumor, and radiographic evidence of an osteolytic lesion that was entirely or mostly surrounded by the jaw bones were included. A total of 109 published articles were included in our systematic review, corresponding to 257 cases. PIOSCC showed a male predilection (69.3%) and a preference for the mandible (7:1), with the posterior region being the most commonly affected site. The mean age at diagnosis was 57.3 years. Cortical expansion, pain, and lip/facial paresthesia were the most common clinical features. Regarding histopathological features, most PIOSCC were well-differentiated and the solid subtype was the most common. Statistical analysis showed that PIOSCC located in the mandible (p = 0.03) and recurrence (p < 0.01) were significantly associated with a higher mortality rate. PIOSCC has a poor prognosis, with high rates of mortality.