RESUMO
Detection of extranodal extension on histopathology in surgically treated head and neck squamous cell carcinoma indicates poor prognosis. However, there is no consensus on the diagnostic criteria, interpretation, and reporting of histology detected extranodal extension, which has contributed to conflicting evidence in the literature, and likely clinical inconsistency. The Head and Neck Cancer International Group conducted a three-round modified Delphi process with a group of 19 international pathology experts representing 15 national clinical research groups to generate consensus recommendations for histology detected extranodal extension diagnostic criteria. The expert panel strongly agreed on terminology and diagnostic features for histology detected extranodal extension and soft tissue metastasis. Moreover, the panel reached consensus on reporting of histology detected extranodal extension and on nodal sampling. These consensus recommendations, endorsed by 19 organisations representing 34 countries, are a crucial development towards standardised diagnosis and reporting of histology detected extranodal extension, and more accurate data collection and analysis.
Assuntos
Consenso , Técnica Delphi , Extensão Extranodal , Neoplasias de Cabeça e Pescoço , Humanos , Neoplasias de Cabeça e Pescoço/patologia , Extensão Extranodal/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Terminologia como AssuntoRESUMO
Introduction: HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) shows distinct biological and clinical behaviour when compared to HPV-negative OPSCC. The overall role of the tumour microenvironment (TME) in head and neck cancer progression and metastasis has been studied intensively, but differences in HPV-negative and HPV-positive OPSCCs are less understood. Objective: To investigate the role of cancer-associated fibroblasts (CAFs) and the functional interactions of normal tonsil fibroblasts (NTFs) and OP CAFs with HPV+ and HPV- OPSCC cells and explore novel candidates in tumour-fibroblast crosstalk. Materials and methods: A retrospective cohort of 143 primary OPSCCs was characterised using HPV16/18 RNAScope assay, p16 IHC and É-SMA. Four OPSCC, three NTF and 2 new OPSCC CAF cultures were used to assess the cytokine-based interactions using cytokine arrays on conditioned media (CM), followed by co-culture approaches to identify the role of individual cell types and the role of OPN (SPP1) and IL-6 in SCC/fibroblast communication. Results: HPV status was associated with better overall survival. Although É-SMA expression was observed in both OPSCC subtypes, it provided survival stratification only in the HPV-positive group (Log-Rank p = 0.02). Three normal tonsillar fibroblast cultures (NTFs) were characterised by induction of myofibroblastic and senescent phenotypes with similar reactivity to our published NOF phenotype. The OPSCC-derived CAF cultures were characterised and their baseline myofibroblastic and senescence phenotypes varied. Cytokine array analysis of CM to identify novel candidates in the crosstalk between OPSCC tumour cells and NTFs/CAFs identified differences in the cytokine profiles on comparison of HPV+ and HPV- OPSCC cells. Osteopontin (OPN/SPP1) was identified, particularly in HPV-negative OPSCC cell analyses. We have demonstrated that OPN was produced by the OPSCC cells and revealed an associated upregulation of IL-6 in fibroblasts. Treatment of NTFs with rOPN showed alteration in phenotype, including increased contraction and IL-6 production. Antibody-mediated inhibition of CD44v6 attenuated the production of IL-6 by OPN in NTFs. Conclusion: This investigation with OPSCC fibroblasts provides novel insights into the role of CAFs in OPSCC mediated by IL-6 stimulated release of OPN from HPV negative OPSCC cells. The details of HPV-positive SCC cell/fibroblast cytokine crosstalk remain elusive.
RESUMO
Targeted therapy has the potential to be used in the neoadjuvant setting for odontogenic tumors, reducing the morbidities associated with major surgery. In this regard, the aim of this study was to summarize the current evidence on the different forms of targeted therapy, effectiveness, and drawbacks of this course of treatment. Four databases were searched electronically without regard to publication date or language. Grey literature searches and manual searches were also undertaken. Publications with sufficient clinical data on targeted therapy for odontogenic tumors were required to meet the criteria for eligibility. The analysis of the data was descriptive. A total of 15 papers comprising 17 cases (15 ameloblastomas and 2 ameloblastic carcinomas) were included. Numerous mutations were found, with BRAF V600E being most common. Dabrafenib was the most utilized drug in targeted therapy. Except for one case, the treatment reduced the size of the lesion (16/17 cases), showing promise. Most of the adverse events recorded were mild, such as skin issues, voice changes, abnormal hair texture, dry eyes, and systemic symptoms (e.g., fatigue, joint pain, and nausea). It is possible to reach the conclusion that targeted therapy for ameloblastoma and ameloblastic carcinoma may be a useful treatment strategy, based on the findings of the included studies.
RESUMO
Ameloblastoma (AM) is a benign, although aggressive, epithelial odontogenic tumour originating from tooth-forming tissues or remnants. Its aetiopathogenesis remains unclear; however, molecular analysis techniques have allowed researchers to progress in understanding its genetic basis. The high frequency of BRAF p.V600E as a main driver mutation in AM is well established; nevertheless, it is insufficient to explain its tumourigenesis. In this review, we aimed to integrate the current knowledge about the biology of AM and to describe the main genetic alterations reported, focusing on the findings of large-scale sequencing and gene expression profiling techniques. Current evidence shows that besides BRAF mutation and activation of the MAPK pathway, alterations in Hedgehog and Wnt/ß-catenin pathway-related genes are also involved in AM pathogenesis. Recently, a tumour suppressor gene, KMT2D, has been reported as mutated by different research groups. The biological impact of these mutations in the pathogenesis of AM has yet to be elucidated. Further studies are needed to clarify the impact of these findings in the identification of novel biomarkers that could be useful for diagnosing, classifying, and molecular targeting this neoplasm.
Assuntos
Ameloblastoma , Mutação , Proteínas Proto-Oncogênicas B-raf , Ameloblastoma/genética , Ameloblastoma/patologia , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Maxilomandibulares/genética , Via de Sinalização Wnt/genética , Proteínas Hedgehog/genética , Perfilação da Expressão GênicaRESUMO
Electrical impedance spectroscopy (EIS) has been proposed as a promising noninvasive method to differentiate healthy thyroid from parathyroid tissues during thyroidectomy. However, previously reported similarities in the in vivo measured spectra of these tissues during a pilot study suggest that this separation may not be straightforward. We utilise computational modelling as a method to elucidate the distinguishing characteristics in the EIS signal and explore the features of the tissue that contribute to the observed electrical behaviour. Firstly, multiscale finite element models (or 'virtual tissue constructs') of thyroid and parathyroid tissues were developed and verified against in vivo tissue measurements. A global sensitivity analysis was performed to investigate the impact of physiological micro-, meso- and macroscale tissue morphological features of both tissue types on the computed macroscale EIS spectra and explore the separability of the two tissue types. Our results suggest that the presence of a surface fascia layer could obstruct tissue differentiation, but an analysis of the separability of simulated spectra without the surface fascia layer suggests that differentiation of the two tissue types should be possible if this layer is completely removed by the surgeon. Comprehensive in vivo measurements are required to fully determine the potential for EIS as a method in distinguishing between thyroid and parathyroid tissues.
Assuntos
Espectroscopia Dielétrica , Glândula Tireoide , Glândula Tireoide/cirurgia , Projetos Piloto , Simulação por Computador , EletricidadeRESUMO
We explore the possibility that defects in genes associated with the response and repair of DNA double strand breaks predispose oral potentially malignant disorders (OPMD) to undergo malignant transformation to oral squamous cell carcinoma (OSCC). Defects in the homologous recombination/Fanconi anemia (HR/FA), but not in the non-homologous end joining, causes the DNA repair pathway to appear to be consistent with features of familial conditions that are predisposed to OSCC (FA, Bloom's syndrome, Ataxia Telangiectasia); this is true for OSCC that occurs in young patients, sometimes with little/no exposure to classical risk factors. Even in Dyskeratosis Congenita, a disorder of the telomerase complex that is also predisposed to OSCC, attempts at maintaining telomere length involve a pathway with shared HR genes. Defects in the HR/FA pathway therefore appear to be pivotal in conditions that are predisposed to OSCC. There is also some evidence that abnormalities in the HR/FA pathway are associated with malignant transformation of sporadic cases OPMD and OSCC. We provide data showing overexpression of HR/FA genes in a cell-cycle-dependent manner in a series of OPMD-derived immortal keratinocyte cell lines compared to their mortal counterparts. The observations in this study argue strongly for an important role of the HA/FA DNA repair pathway in the development of OSCC.
Assuntos
Carcinoma de Células Escamosas , Anemia de Fanconi , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Neoplasias Bucais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço , DNARESUMO
BACKGROUND: Ameloblastic carcinoma (AC) is the most common odontogenic malignancy, constituting approximately 30% of cases in this category. Literature is sparse on malignant odontogenic neoplasms, with a large proportion of current knowledge derived from case reports or small case series. METHODS: A systematic review of case series/case reports of AC was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Statement guidelines. Demographic and clinical information, including duration of the lesion, location, clinical presentation and radiologic features, were analysed. Additionally, the origin of the lesion (primary/secondary), Ki-67 proliferation index, treatment performed, metastasis, tumour recurrence and prognosis were collected for analysis. RESULTS: A total of 126 studies, including 285 individual cases of AC, were included in this review. Patients presented with a near-equal distribution of painless and painful swellings. ACs presented at a median age of 45 years, with a male-to-female ratio of 1:2. The mandible was most frequently involved, with rare cases extending to involve more than one region, including crossing the midline. Although most lesions presented with poorly-demarcated borders (52.6%), unilocular lesions with well-demarcated borders (47.4%) comprised a substantial number in the sample. The proliferation index was only reported in 27 cases, with a mean score of 42% and a wide range. The probability of tumour recurrence increased, and the survival probability decreased with prolonged follow-up duration. CONCLUSION: This study provides more comprehensive, up-to-date descriptive data on these rare odontogenic malignancies, aiding clinicians and Pathologists with the diagnosis and surgeons in their management of cases.
Assuntos
Tumores Odontogênicos , Humanos , Masculino , Feminino , Tumores Odontogênicos/patologia , Prognóstico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Ameloblastoma/patologia , Neoplasias Maxilomandibulares/patologia , Adulto , Neoplasias Mandibulares/patologia , IdosoRESUMO
PURPOSE: While there are several prognostic classifiers, to date, there are no validated predictive models that inform treatment selection for oropharyngeal squamous cell carcinoma (OPSCC).Our aim was to develop clinical and/or biomarker predictive models for patient outcome and treatment escalation for OPSCC. EXPERIMENTAL DESIGN: We retrospectively collated clinical data and samples from a consecutive cohort of OPSCC cases treated with curative intent at ten secondary care centers in United Kingdom and Poland between 1999 and 2012. We constructed tissue microarrays, which were stained and scored for 10 biomarkers. We then undertook multivariable regression of eight clinical parameters and 10 biomarkers on a development cohort of 600 patients. Models were validated on an independent, retrospectively collected, 385-patient cohort. RESULTS: A total of 985 subjects (median follow-up 5.03 years, range: 4.73-5.21 years) were included. The final biomarker classifier, comprising p16 and survivin immunohistochemistry, high-risk human papillomavirus (HPV) DNA in situ hybridization, and tumor-infiltrating lymphocytes, predicted benefit from combined surgery + adjuvant chemo/radiotherapy over primary chemoradiotherapy in the high-risk group [3-year overall survival (OS) 63.1% vs. 41.1%, respectively, HR = 0.32; 95% confidence interval (CI), 0.16-0.65; P = 0.002], but not in the low-risk group (HR = 0.4; 95% CI, 0.14-1.24; P = 0.114). On further adjustment by propensity scores, the adjusted HR in the high-risk group was 0.34, 95% CI = 0.17-0.67, P = 0.002, and in the low-risk group HR was 0.5, 95% CI = 0.1-2.38, P = 0.384. The concordance index was 0.73. CONCLUSIONS: We have developed a prognostic classifier, which also appears to demonstrate moderate predictive ability. External validation in a prospective setting is now underway to confirm this and prepare for clinical adoption.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Prognóstico , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/genética , Estudos Retrospectivos , Estudos Prospectivos , Neoplasias Orofaríngeas/diagnóstico , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/patologia , BiomarcadoresRESUMO
OBJECTIVE: This systematic review aimed to describe the method followed during physical examination and the anatomical structures of the head and neck assessed in screening for oral cancer and oral potentially malignant disorders (OPMDs). STUDY DESIGN: An extensive literature search was carried out using MEDLINE/PubMed, EMBASE, Scopus, LILACS, Web of Science, Cochrane databases, and gray literature. The risk of bias was available in all papers included. RESULTS: Of 9,688 records identified, 27 were included in this review, reporting data from 356,250 individuals screened and distributed across 11 countries. Most of these (n = 19) were based on 1 round of screening conducted by a dental professional or other health care workers. Most screening programs included visual inspection and palpation of the lips, oral cavity, and the most visible oropharyngeal sites, but the descriptions reported were imprecise. Additional inspection and palpation of the neck (submental, submandibular, cervical, and supraclavicular regions) to assess for the presence of swellings and any palpable neck nodes were also performed in 15 programs. CONCLUSION: In conclusion, there was considerable heterogeneity in the method of physical examination in screening programs for oral cancer and OPMDs among the included studies.
Assuntos
Neoplasias Labiais , Doenças da Boca , Neoplasias Bucais , Lesões Pré-Cancerosas , Humanos , Detecção Precoce de Câncer/métodos , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/prevenção & controle , Exame Físico/métodos , LábioRESUMO
OBJECTIVE: Understanding the regulatory role of homeobox (HOX) and mutated genes in the progression of head and neck cancers is essential, although their interaction remains elusive. This study aims to decipher the critical regulation of mutation driven effects on homeobox genes to enhance our understanding of head and neck cancer progression. METHODS: Genomic mutation data from The Cancer Genome Atlas-Head and Neck Squamous Cell Carcinoma were analyzed using VarScan2 for somatic variant detection. Mutational clustering, driver mutation identification, and cancer signaling pathway analysis were performed using the OncodriveCLUST method. Harmonizome datasets were retrieved to identify critical cancer driver genes affecting HOX genes. The effects of HPV infection on HOX and mutated genes were assessed using the oncoviral database. Altered pathway activity due to the effects of cancer drivers on HOX genes was analyzed with Gene Set Cancer Analysis. Functional enrichment analysis of gene ontology biological processes and molecular functions was conducted using the ClusterProfiler R package. RESULTS: Significant alterations in HOX genes were observed in head and neck cancer cohorts with mutated TP53, FAT1, and CDKN2A. HOX genes were identified as functionally downstream targets of TP53, signifying transcriptionally mediated regulation. The interaction between HOX genes and mutated TP53, FAT1, and CDKN2A dysregulated the epithelial-to-mesenchymal transition, cell cycle, and apoptosis pathways in head and neck cancer progression. CONCLUSION: The interplay between cancer driver genes and HOX genes is pivotal in regulating the oncogenic processes underlying the pathogenesis of head and neck squamous cell carcinoma.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Humanos , Genes Homeobox/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/genética , MutaçãoAssuntos
Neoplasias de Cabeça e Pescoço , Idioma , Humanos , Consenso , Reprodutibilidade dos Testes , CabeçaRESUMO
OBJECTIVE: Salivary gland tumors (SGT) are a diverse group of uncommon neoplasms that are rare in pediatric patients. This study aimed to characterize the clinicopathological profile of pediatric patients affected by SGT from a large case series derived from an international group of academic centers. STUDY DESIGN: A retrospective analysis of pediatric patients with SGT (0-19 years old) diagnosed between 2000 and 2021 from Brazil, South Africa, and the United Kingdom was performed. SPSS Statistics for Windows was used for a quantitative analysis of the data, with a descriptive analysis of the clinicopathological characteristics and the association between clinical variables and diagnoses. RESULTS: A total of 203 cases of epithelial SGT were included. Females were slightly more commonly (56.5%), with a mean age of 14.1 years. The palate was the most common site (43.5%), followed by the parotid gland (29%), lip (10%), and submandibular gland (7.5%). The predominant clinical presentation was a flesh-colored, smooth, and painless nodule. Pleomorphic adenoma (PA) was the most frequently diagnosed SGT (58.6%), followed by mucoepidermoid carcinoma (MEC) (26.6%). Surgery (90.8%) was the favored treatment option. CONCLUSIONS: Benign SGT in pediatric patients are more commonly benign than malignant tumors. Clinicians should keep PA and MEC in mind when assessing nodular lesions of possible salivary gland origin in pediatric patients.
Assuntos
Adenoma Pleomorfo , Carcinoma Mucoepidermoide , Neoplasias das Glândulas Salivares , Feminino , Humanos , Criança , Adolescente , Recém-Nascido , Lactente , Pré-Escolar , Adulto Jovem , Adulto , Estudos Retrospectivos , Neoplasias das Glândulas Salivares/epidemiologia , Neoplasias das Glândulas Salivares/cirurgia , Glândulas Salivares/cirurgia , Glândulas Salivares/patologia , Adenoma Pleomorfo/epidemiologia , Adenoma Pleomorfo/cirurgia , Adenoma Pleomorfo/patologia , Carcinoma Mucoepidermoide/patologiaRESUMO
Although there has been substantial improvement in the treatment modalities, cancer remains the major cause of fatality worldwide. Metastasis, recurrence, and resistance to oncological therapies are the leading causes of cancer mortality. Epithelial-mesenchymal transition (EMT) is a complex biological process that allows cancer cells to undergo morphological transformation into a mesenchymal phenotype to acquire invasive potential. It encompasses reversible and dynamic ontogenesis by neoplastic cells during metastatic dissemination. Hence, understanding the molecular landscape of EMT is imperative to identify a reliable clinical biomarker to combat metastatic spread. Accumulating evidence reveals the role of HOX (homeobox) cluster-embedded long non-coding RNAs (lncRNAs) in EMT and cancer metastasis. They play a crucial role in the induction of EMT, modulating diverse biological targets. The present review emphasizes the involvement of HOX cluster-embedded lncRNAs in EMT as a molecular sponge, chromatin remodeler, signaling regulator, and immune system modulator. Furthermore, the molecular mechanisms behind therapy resistance and the potential use of novel drugs targeting HOX cluster-embedded lncRNAs in the clinical management of distant metastasis will be discussed.
Assuntos
Neoplasias , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Genes Homeobox , Transdução de SinaisRESUMO
BACKGROUND: Rhabdomyosarcoma (RMS) harboring EWSR1/FUS-TFCP2 fusions has been recently described as a distinct form of RMS with an aggressive course and predilection for the craniofacial bones, especially the jaws. METHODS: We report three new cases of this rare entity, two from Brazil and one from Guatemala, with detailed clinicopathologic, immunohistochemical, and molecular descriptions. Additionally, we explored the English-language literature searching RMS with TFCP2 rearrangement or typical immunophenotype with co-expression of AE1/AE3 and ALK in the head and neck region. RESULTS: Case 1 is a 58-year-old male with a 3-month history of painful swelling in the anterior maxilla. Case 2 is a 22-year-old male presenting with right facial swelling and proptosis. Case 3 is a 43-year-old female with a rapidly growing tumor located in the zygomatic region. Imaging examinations revealed highly destructive intraosseous masses in the first two cases, and a soft tissue tumor with bone invasion in case 3. Microscopically, all cases showed a hybrid spindle and epithelioid phenotype of tumor cells which expressed desmin, myogenin and/or Myo-D1, AE1/AE3, and ALK. FISH confirmed molecular alterations related to TFCP2 rearrangement in Cases 1-2. In case 3, there was no available material for molecular analysis. The patients were subsequently referred to oncologic treatment. Additionally, we summarized the clinicopathologic, immunohistochemical, and molecular features of 27 cases of this rare RMS variant in the head and neck region reported in the English-language literature. CONCLUSION: RMS with TFCP2 rearrangement is a rare and aggressive tumor with a particular predilection for craniofacial bones, especially the jaws. Knowing its clinicopathologic and immunohistochemical profile can avoid misdiagnosis.
Assuntos
Rabdomiossarcoma , Neoplasias de Tecidos Moles , Masculino , Feminino , Humanos , Fatores de Transcrição/genética , Rabdomiossarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Receptores Proteína Tirosina Quinases , Brasil , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Proteínas de Ligação a DNA/genéticaRESUMO
A multiscale modelling approach has been applied to the simulation of the electrical properties of oral tissue, for the purpose of informing an electrical impedance-based method of oral potential malignant disorder (OPMD) diagnosis. Finite element models of individual cell types, with geometry informed by histological analysis of human oral tissue (normal, hyperplastic and dysplastic), were generated and simulated to obtain electrical parameters. These were then used in a histology-informed tissue scale model, including the electrode geometry of the ZedScan tetrapolar impedance-measurement device. The simulations offer insight into the feasibility of distinguishing moderate dysplasia from severe dysplasia or healthy tissue. For some oral sites, simulated spectra agreed with real measurements previously collected using ZedScan. However, similarities between simulated spectra for dysplastic, keratinised and non-dysplastic but hyperkeratinised tissue suggest that significant keratinisation could cause some OPMD tissues to exhibit larger than expected impedance values. This could lead to misidentification of OPMD spectra as healthy. Sources of uncertainty within the models were identified and potential remedies proposed.
Assuntos
Espectroscopia Dielétrica , Neoplasias Bucais , Simulação por Computador , Impedância Elétrica , Eletrodos , Humanos , Neoplasias Bucais/diagnósticoRESUMO
BACKGROUND: Keratoameloblastoma (KA) is an uncommon and controversial variant of ameloblastoma exhibiting central keratinisation. Due to their rarity, there is limited information in the literature on their clinical, radiologic and histologic features. This study adds seven additional cases of KA to the literature, and reviews the current published literature on this rare entity. METHODS: KAs were retrospectively reviewed over a 20-year period from three Oral and Maxillofacial Pathology Laboratories. Included cases were examined and the diagnosis confirmed under conventional microscopy. Immunohistochemistry with the use of a monoclonal antibody against calretinin was performed on included cases. The clinical, radiologic and histologic features of the seven new cases of KA were analysed and compared to existing cases in the literature. RESULTS: KAs presented at a mean age of 40 years with a nearly equal gender distribution and a mandibular predilection (65%). The majority (92%) of cases presented with localised swelling with associated pain in 32% of cases. Mixed density or internal calcifications were noted in 40% of cases. All tumours presented with bony expansion, with cortical destruction noted in 62% of cases. Histologically, all tumours consisted of solid and cystic follicles with surface parakeratinisation and lamellated accumulations of central keratin. In areas the cystic follicles had an epithelial lining suggestive of an OKC. There were focal luminal areas of loosely arranged polygonal cells reminiscent of the stellate reticulum. The basal cells consisted of columnar cells with evidence of palisading and prominent subnuclear vacuolisation. Of the cases treated via tumour resection, 27% presented with tumour recurrence. CONCLUSION: This case series reports seven additional cases of KA, taking the total to 26 reported cases. The identification of subtle histologic features, including focal stellate reticulum-like central areas, subnuclear vacuolisation and lamellated-type central keratinisation, are key in diagnosing KA. The radiologic features will often indicate signs of aggressiveness such as cortical destruction, differentiating KA from OKC. All cases were completely negative for calretinin IHC, limiting its use in distinguishing KA from OKC. Further large series are needed to expand the current understanding of this rare variant of ameloblastoma.
Assuntos
Recidiva Local de Neoplasia , Humanos , Adulto , Estudos RetrospectivosRESUMO
Potentially pre-malignant oral lesions (PPOLs) are composed of keratinocytes that are either mortal (MPPOL) or immortal (IPPOL) in vitro. We report here that MPPOL, but not generally IPPOL, keratinocytes upregulate various extracellular tumor-promoting cytokines (interleukins 6 and 8) and prostaglandins E1 (ePGE1) and E2 (ePGE2) relative to normal oral keratinocytes (NOKs). ePGE upregulation in MPPOL was independent of PGE receptor status and was associated with some but not all markers of cellular senescence. Nevertheless, ePGE upregulation was dependent on the senescence program, cyclo-oxygenase 2 (COX2) and p38 mitogen-activated protein kinase and was partially regulated by hydrocortisone. Following senescence in the absence of p16INK4A, ePGEs accumulated in parallel with a subset of tumor promoting cytokine and metalloproteinase (MMP) transcripts, all of which were ablated by ectopic telomerase. Surprisingly, ataxia telangiectasia mutated (ATM) function was not required for ePGE upregulation and was increased in expression in IPPOL keratinocytes in line with its recently reported role in telomerase function. Only ePGE1 was dependent on p53 function, suggesting that ePGEs 1 and 2 are regulated differently in oral keratinocytes. We show here that ePGE2 stimulates IPPOL keratinocyte proliferation in vitro. Therefore, we propose that MPPOL keratinocytes promote the progression of IPPOL to oral SCC in a pre-cancerous field by supplying PGEs, interleukins and MMPs in a paracrine manner. Our results suggest that the therapeutic targeting of COX-2 might be enhanced by strategies that target keratinocyte senescence.
RESUMO
The role of evolutionarily conserved homeobox-containing HOX genes as transcriptional regulators in the developmental specification of organisms is well known. The contribution of HOX genes involvement in oral cancer phenotype has yet to be fully ascertained. TCGA-HNSC HTSeq-counts and clinical data were retrieved from the GDC portal for oral cavity neoplasms. GEO datasets (GSE72627, GSE30784, GSE37991) were accessed and analyzed using GEO2R. Differential HOX gene expression was profiled using the DESeq2 R package with a log2 fold change cut-off (- 1 and + 1) and Benjamini-Hochberg p-adjusted value at ≤ 0.01. Gene set over-representation analysis and semantic analysis associated with the disease ontology was performed using the ClusterProfiler R package, and pathway over-representation analysis was performed using IMPaLa. HOX protein interaction network was constructed using the Pathfind R package. HOX phenotype associations were performed using Mammalian Phenotype Ontology, Human Phenotype Ontology, PhenGenI associations, Jensen tissues, and OMIM entries. Drug connectivity mapping was carried out with Dr. Insight R package. HOXA2 was upregulated in oral dysplasia but silenced during tumor progression. Loss of HOXB2 expression was consistent in the potentially malignant oral lesions as well as in the primary tumor. HOXA7, HOXA10, HOXB7, HOXC6, HOXC10, HOXD10, and HOXD11 were consistently upregulated from premalignancy to malignancy and were notably associated with risk factors. Overrepresentation analysis suggested HOXA10 was involved in the transcriptional misregulation contributing to the oral cancer phenotype. HOX genes subnetwork analysis showed crucial interactions with cell cycle regulators, growth responsive elements, and proto-oncogenes. Phenotype associations specific to the oral region involving HOX genes provide intrinsic cues to tumor development. The 5' HOX genes were aberrantly upregulated during oral carcinogenesis reflecting their posterior prevalence.
Assuntos
Genes Homeobox , Neoplasias Bucais , Animais , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Mamíferos/metabolismo , Neoplasias Bucais/genética , Fenótipo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Alterations in homeobox (HOX) gene expression are involved in the progression of several cancer types including head and neck squamous cell carcinoma (HNSCC). However, regulation of the entire HOX cluster in the pathophysiology of HNSCC is still elusive. By using different comprehensive databases, we have identified the significance of differentially expressed HOX genes (DEHGs) in stage stratification and HPV status in the cancer genome atlas (TCGA)-HNSCC datasets. The genetic and epigenetic alterations, druggable genes, their associated functional pathways and their possible association with cancer hallmarks were identified. We have performed extensive analysis to identify the target genes of DEHGs driving HNSCC. The differentially expressed HOX cluster-embedded microRNAs (DEHMs) in HNSCC and their association with HOX-target genes were evaluated to construct a regulatory network of the HOX cluster in HNSCC. Our analysis identified sixteen DEHGs in HNSCC and determined their importance in stage stratification and HPV infection. We found a total of 55 HNSCC driver genes that were identified as targets of DEHGs. The involvement of DEHGs and their targets in cancer-associated signaling mechanisms have confirmed their role in pathophysiology. Further, we found that their oncogenic nature could be targeted by using the novel and approved anti-neoplastic drugs in HNSCC. Construction of the regulatory network depicted the interaction between DEHGs, DEHMs and their targets genes in HNSCC. Hence, aberrantly expressed HOX cluster genes function in a coordinated manner to drive HNSCC. It could provide a broad perspective to carry out the experimental investigation, to understand the underlying oncogenic mechanism and allow the discovery of new clinical biomarkers for HNSCC.
Assuntos
Genes Homeobox , Neoplasias de Cabeça e Pescoço , Biomarcadores Tumorais/genética , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Humanos , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genéticaRESUMO
Oral potentially malignant disorders (OPMD) may precede oral squamous cell carcinoma (OSCC). Reported rates of malignant transformation of OPMD range from 3 to 50%. While some clinical, histological, and molecular factors have been associated with a high-risk OPMD, they are, to date, insufficiently accurate for treatment decision-making. Moreover, this range highlights differences in the clinical definition of OPMD, variation in follow-up periods, and molecular and biological heterogeneity of OPMD. Finally, while treatment of OPMD may improve outcome, standard therapy has been shown to be ineffective to prevent OSCC development in patients with OPMD. In this perspective paper, several experts discuss the main challenges in oral cancer prevention, in particular the need to (i) to define an OPMD classification system by integrating new pathological and molecular characteristics, aiming (ii) to better identify OPMD at high risk of malignant transformation, and (iii) to develop treatment strategies to eradicate OPMD or prevent malignant transformation.