Proliferative verrucous leukoplakia mimicking oral lichen planus: case report and literature review

This report presents the clinical, microscopic and immunohistochemical aspects of a case of proliferative verrucous leukoplakia (PVL) mimicking oral lichen planus (OLP) in a 66-year-old woman. We also review the literature reporting cases of PVL mimicking OLP, where we found a higher prevalence in women who do not consume tobacco or alcohol. The initial manifestation of lichenoid areas was around the age of 59, with the diagnosis of PVL being established on average 6 years later, while malignant transformation occurred in 8 of the 22 cases at an average of 3.7 years after the final diagnosis of PVL. We emphasize the need for a close follow-up of any patient presenting white lesions of the oral mucosa. Lesions that are clinically and microscopically compatible with lichenoid reactions or OLP must be investigated and differentiated from PVL, which has a worse prognosis.

Este relato apresenta os aspectos clínicos, microscópicos e imuno-histoquímicos de um caso de leucoplasia verrucosa proliferativa (LPV) mimetizando líquen plano oral (LPO) em uma paciente do sexo feminino de 66 anos. Também revisamos a literatura relatando casos de LPV mimetizando LPO, onde encontramos maior prevalência em mulheres que não consomem tabaco ou álcool, com manifestação inicial de áreas liquenoides por volta dos 59 anos, sendo estabelecido o diagnóstico de LPV em média 6 anos depois, enquanto a transformação maligna ocorreu em 8 dos 22 casos em média 3,7 anos após o diagnóstico final de LPV. Ressaltamos a necessidade de acompanhamento rigoroso de qualquer paciente que apresente lesões brancas da mucosa oral, devendo ser investigadas lesões clinicamente e microscopicamente compatíveis com reações liquenóides ou LPO e diferenciadas da LPV, que tem pior prognóstico

Este reporte presenta los aspectos clínicos, microscópicos e inmunohistoquímicos de un caso de leucoplasia verrugosa proliferativa (LVP) simulando liquen plano oral (LPO) en una paciente de 66 años. También revisamos la literatura reportando casos de LVP simulando LPO, donde encontramos una mayor prevalencia en mujeres que no consumen tabaco ni alcohol, con una manifestación inicial de áreas liquenoides alrededor de los 59 años, estableciéndose el diagnóstico de LVP en promedio 6 años después, mientras que la transformación maligna ocurrió en 8 de los 22 casos en un promedio de 3,7 años después del diagnóstico final de LVP. Resaltamos la necesidad de un seguimiento estrecho de todo paciente que presente lesiones blanquecinas de la mucosa oral, que las lesiones clínica y microscópicamente compatibles con reacciones liquenoides o LPO deben ser investigadas y diferenciadas de la LVP, que tienen peor pronóstico.

Diagnostic potential of Type VII Collagen during oral carcinogenesis

Abstract Type VII collagen (Col7) is a major component of anchoring fibrils. Col7 plays a role in tumor development and aggressiveness of cutaneous squamous cell carcinoma of recessive dystrophic epidermolysis bullosa. However, the role of Col7 in oral squamous cell carcinoma (OSCC) and oral leukoplakia (OL) remains largely unknown. Objective To elucidate the role of Col7 and its diagnostic potential during oral carcinogenesis. Methodology Col7 expression was immunohistochemically studied in 254 samples, including normal oral mucosa (NM), OL without dysplasia, OL with dysplasia, and OSCC. The correlation between Col7 expression and clinicopathologic parameters of OSCC was also determined. Results Col7 was present as a linear deposit at the basement membrane of NM, OL without dysplasia and OL with dysplasia, and at the tumor-stromal junction around tumor islands in OSCC. Discontinuity of expression was frequently observed in OL with dysplasia and OSCC. OSCC had the significantly lowest Col7 expression (p<0.0001). Compared with OL without dysplasia, OL with dysplasia showed significantly reduced Col7 expression. Patients in clinical stage 4 with positive nodes had low Col7 expression compared with those in clinical stage 1 and negative nodes, respectively. Conclusion Loss of Col7 is associated with tumorigenesis and aggressiveness in OSCC. A significantly reduced Col7 expression in OSCC implies that Col7 may be a useful marker for diagnosis and therapeutic targets.

Enfrentamiento de lesiones de cavidad oral: clasificación y diagnóstico diferencial / Assessment of oral cavity lesions: classification and differential diagnosis

Las lesiones de la cavidad oral corresponden a un hallazgo frecuente y muchas veces difíciles de diagnosticar. Su correcto reconocimiento podría ser clave en detectar patologías que podrían cambiar el pronóstico del paciente. El objetivo de esta revisión es describir una clasificación de las lesiones de la cavidad oral que permita ayudar al diagnóstico en la práctica clínica. Para esto, se detallan y se describen las lesiones, orientando al diagnóstico y a la necesidad de biopsiar. Para simplificar la orientación diagnóstica, las lesiones se clasifican en 2 grandes grupos: tumorales y no tumorales. Las lesiones no tumorales se subdividen en lesiones de la mucosa oral y lesiones de la lengua.

Lesions of the oral cavity are frequent and often difficult to diagnose. However, correct recognition could change the patient's prognosis. This review aims to describe a classification of oral mucosa lesions, to help the diagnosis in clinical practice. The lesions are described for this, guiding the diagnosis and the need for biopsy. To simplify the diagnostic orientation, the lesions are classified into two groups: tumor and non-tumor lesions. Non-tumor lesions are subdivided into lesions of the oral mucosa and lesions of the tongue.

Co-expression of circRNA in oral leukoplakia and oral lichen planus / 口腔疾病防治

Objective@# To find any differentially expressed circRNAs in oral leukoplakia (OLK) and oral lichen planus (OLP), to investigate the possible role of circRNAs in the pathogenesis of these two diseases.@*Methods@# This study obtained hospital ethical approval. High-throughput sequencing was used to detect differentially expressed circRNAs in OLK, OLP, oral squamous cell carcinoma and normal oral mucosal tissues. CircRNAs were verified by qRT-PCR, enzyme tolerance assays and Sanger sequencing. GO functional analysis and KEGG pathway analysis were performed to predict the functions of circRNAs in OLP. TargetScan and miRanda were applied to predict targeted miRNAs and mRNAs of circRNAs, and ceRNA networks were mapped. @*Results@#A total of 49 circRNAs were differentially expressed in OLK and OLP together, including 30 upregulated and 19 downregulated circRNAs. The five circRNAs confirmed with RT-qPCR, including circHLA-C, circRNF13, circTTN, circSEPN2 and circALDH3A2, were all abnormally expressed in OLK and OLP, among which circHLA-C was a key circRNA with trans splice sites, which was validated by expanding the sample size. ROC curve analysis showed that the area under the circHLA-C curve for predicting OLK was 0.955, and the area under the circHLA-C curve for predicting OLP was 0.988. GO functional analysis showed enrichment of many biological processes related to the immune process. The KEGG pathway with the highest enrichment score was "Natural killer cell mediated cytotoxicity". HLA-C was significantly enriched in these processes/pathways. CeRNA network analysis showed that circHLA-C interacted with a variety of miRNAs, such as hsa-miR-26a-5p, hsa-miR-129-5p, and hsa-miR-29a-3p.@*Conclusion@#Many circRNAs were differentially expressed in both OLK and OLP, circHLA-C being the most elevated. CircHLA-C is valuable for the early diagnosis of OLK and OLP and may serve as a potential biomarker for the diagnosis and prognosis of OLK and OLP.

Biomarkers of malignant transformation in oral leukoplakia: from bench to bedside / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Oral leukoplakia is a common precursor lesion of oral squamous cell carcinoma, which indicates a high potential of malignancy. The malignant transformation of oral leukoplakia seriously affects patient survival and quality of life; however, it is difficult to identify oral leukoplakia patients who will develop carcinoma because no biomarker exists to predict malignant transformation for effective clinical management. As a major problem in the field of head and neck pathologies, it is imperative to identify biomarkers of malignant transformation in oral leukoplakia. In this review, we discuss the potential biomarkers of malignant transformation reported in the literature and explore the translational probabilities from bench to bedside. Although no single biomarker has yet been applied in the clinical setting, profiling for genomic instability might be a promising adjunct.

A Comparative Investigation of the Activity of Superoxide Dismutase in Patients with Leukoplakia and Healthy Controls

Context and Aim: Oral leukoplakia has recently been re?defined as “a predominantly white lesion of the oral mucosa that cannot be characterised as any other definable lesion”. Superoxide dismutase (SOD) is one of the enzymatic anti?oxidants which form the first line of defence in the cell. There are very limited data available on the analysis of SOD in leukoplakia patients. Therefore, the present study was planned to analyse anti?oxidant SOD levels in leukoplakia patients. Methods and Material: The study group consisted of 29 subjects of oral leukoplakia, and the control group consisted of 25 healthy individuals. All the subjects were evaluated for SOD enzyme in plasma. Statistical Analysis Used: The results for each determinant were calculated using one?way ANOVA test, Student ‘t’ test, Pearson Chi square test, and ‘t’ test for equality of means wherever applicable. Results: The study revealed that among the different clinical entities of oral leukoplakia, the enzymatic anti?oxidant SOD is shown to have decreased in all forms of oral leukoplakia, but without any statistical significance. A statistically highly significant decrease (at P < 0.0001) of SOD in oral leukoplakia patients compared to normal healthy patients was observed in the present study. Conclusions: The study revealed a difference in the free?radical activity and oxidative stress in blood of leukoplakia patients compared to healthy patients, which is reflected by the variation in the levels of blood SOD, thus

Immunohistochemical Evaluation of Galectin?3 Expression in Oral Squamous Cell Carcinoma, Oral Leukoplakia and Normal Mucosa

Background: Galectin 3 (Gal?3) has diverse functions critical in cancer biology including cell proliferation, apoptosis, evasion of immune responses and angiogenesis. The expression of Gal?3 is heterogeneous in normal and neoplastic tissues. In oral squamous cell carcinoma (OSCC) and oral leukoplakia (OL), both increased and decreased expressions of Gal?3 were elicited in numerous studies. Aims: To evaluate, compare and correlate the immunohistochemical expression of Gal?3 in OSCC, OL and normal oral mucosa. Settings and Design: The study was conducted at the Department of Oral Pathology and Microbiology at PMS College of Dental Science and Research, Vattapara, Thiruvananthapuram. This is a retrospective analytical study. Methods and Material: Clinically diagnosed and histopathologically confirmed cases of OSCC (n = 21), OL (n = 21), and normal oral mucosa (n = 21) were included in the study. Paraffin?embedded tissues were subjected to immunohistochemical analysis for Gal?3 expression. Gal?3 staining expression, staining distribution and cellular localisation were evaluated. All sampled categories were compared using immunohistochemical scoring analysis such as the H?score, labelling index (LI), immunoreactive score (IRS) and staining intensity (SI). Statistical Analysis: The results were statistically analysed using multivariate analysis of variance (MANOVA) within and among the groups. Results and Conclusion: The statistical inferences obtained found that the H?score could be used as a guideline for better differentiation between the groups and among the groups. The P value obtained was < 0.0125 and was found to be significant. The observation in our study shows that the immunohistochemical expression of Gal?3 gradually decreased from normal oral mucosa to OL to OSCC.

Consensus guidelines on management of oral potentially malignant disorders

Oral cancer is usually preceded by oral potentially malignant disorders (OPMDs) and early detection can downstage the disease. The majority of OPMDs are asymptomatic in early stages and can be detected on routine oral examination. Though only a proportion of OPMDs may transform to oral squamous cell carcinoma (OSCC), they may serve as a surrogate clinical lesion to identify individuals at risk of developing OSCC. Currently, there is a scarcity of scientific evidence on specific interventions and management of OPMDs and there is no consensus regarding their management. A consensus meeting with a panel of experts was convened to frame guidelines for clinical practices and recommendations for management strategies for OPMDs. A review of literature from medical databases was conducted to provide the best possible evidence and provide recommendations in management of OPMDs

Eficacia clínica de la terapia fotodinámica por 5-ALA tópico en el manejo onco-preventivo de lesiones de leucoplasia oral. Una revisión sistemática / Clinical efficacy of topical 5-ALA photodynamic therapy in the onco-preventive management of oral leukoplakia lesions. A systematic review

Objetivo: La leucoplasia oral es el desorden maligno de la mucosa bucal más prevalente a nivel global y su manejo clínico sigue siendo un desafío. Se llevó a cabo una revisión sistemática para determinar la eficacia clínica de la terapia fotodinámica mediada por ácido 5-aminolevulínico tópico como una alternativa de quimio-prevención para las diferen- tes formas clínicas de la leucoplasia oral. Materiales y métodos: Empleando términos MeSH, se realizó una búsqueda exhaustiva en diferentes bases digi- tales de ensayos clínicos publicados en inglés en los últimos 30 años acerca del uso de la terapia fotodinámica mediada por ácido 5-aminolevulínico tópico como fotosensibilizador, y radiación láser de baja intensidad o luz LED como posibles fuentes de iluminación. Resultados: La revisión sistematizada que aplicó la guía PRISMA mostró una eficacia del 88,6% para este modo de fototerapia en el manejo de leucoplasias orales, con un 60,7% de respuesta completa y 27,9% de respuesta parcial. Además, el tamaño de efecto fue mayor para las formas clíni- cas homogéneas con cambios displásicos, independientemen- te del tipo de fuente de luz. La ausencia de respuesta fue del 11,4%, pero la evidencia empleada en este análisis fue mo- derada. Conclusión: La terapia fotodinámica mediada por áci- do 5-aminolevulínico tópico parece ser una alternativa útil en el manejo onco-preventivo de lesiones de leucoplasia oral. Sin embargo, es recomendable ejecutar ensayos clínicos controla- dos y aleatorizados con metodologías homogéneas que per- mitan generar un meta-análisis con un alto nivel de evidencia

Aim: Oral leukoplakia is globally the most prevalent ma- lignant disorder of the oral mucosa and its clinical manage- ment remains a challenge. A systematic review was carried out to determine the clinical efficacy of photodynamic therapy mediated by topical 5-aminolevulinic acid as an alternative for chemoprevention in the different clinical forms of oral leu- koplakia. Materials and methods: Using MeSH terms, an ex- haustive search was carried out in different digital databases of clinical trials published in English in the last 30 years on the use of photodynamic therapy mediated by topical 5-ami- nolevulinic acid as a photosensitizer, and low-intensity laser radiation or LED light as possible lighting sources. Results: The systematized review using PRISMA guide- lines showed an efficacy of 88.6% for this mode of photother- apy in the management of oral leukoplakias, based on 60.7% of complete response and 27.9% of partial response. In addi- tion, the effect size was larger in homogeneous clinical forms with dysplastic changes, regardless of the type of light source. There was an 11.4% of absence of response, but the evidence used in this analysis was moderate. Conclusion: Photodynamic therapy mediated by topical 5-aminolevulinic acid seems to be a useful alternative in the onco-preventive management of oral leukoplakia lesions. However, it is recommendable to perform controlled and ran- domized clinical trials with homogeneous methodologies that allow the generation of a meta-analysis with a high level of evidence (AU)

Parámetros histomorfométricos de la mucosa bucal en pacientes portadores de leucoplasia con displasia epitelial / Histomorphometric Parameters of the Buccal Mucosa in Patients with Leukoplakia and Epithelial Dysplasia

RESUMEN Fundamento la leucoplasia es la lesión potencialmente maligna más frecuente en las membranas mucosas de la boca y se puede presentar con diferentes grados de displasia epitelial. El estudio histológico de esta lesión unido a la medición de parámetros morfométricos y estereológicos, permite la mejor comprensión de procesos tanto fisiológicos como patológicos. Objetivo: caracterizar los parámetros histomorfométricos de la mucosa bucal en pacientes portadores de leucoplasia bucal según grado de displasia epitelial. Método: se realizó un estudio de serie de casos, con el objeto de determinar indicadores morfométricos, de lesiones leucoplásicas de la mucosa oral en biopsias de pacientes atendidos en los Servicios de Anatomía Patológica y Maxilofacial del Hospital General Universitario Dr. Gustavo Aldereguía Lima, de la provincia Cienfuegos. La muestra se obtuvo por muestreo intencionado, la cual quedó constituida por 30 láminas histológicas (biopsias), distribuidas en tres grupos de diez láminas por cada grado de displasia epitelial. La variable de estudio fue la caracterización morfométrica de la leucoplasia de la mucosa oral con displasia. Se aplicó estadística descriptiva e inferencial. Resultados: predominaron tres parámetros en la clasificación de la displasia: alteración de los clavos interpapilares, hiperplasia y pérdida de la polaridad de las células basales. Se constató presencia de ortoparaqueratosis, epitelios hiperplásicos e infiltrado inflamatorio del corion, en más de la mitad de los casos. Hubo significación estadística en las relaciones que se establecieron entre la altura o profundidad de las papilas y la densidad relativa de células según grado de displasia epitelial, al aplicar la estadística inferencial. Conclusiones: predominaron tres parámetros en la clasificación de la displasia. Se constató presencia de ortoparaqueratosis, epitelios hiperplásicos e infiltrado inflamatorio del corion, en más de la mitad de los casos.

ABSTRACT Background: leukoplakia is the most frequent potentially malignant lesion in the mucous membranes of the mouth and can present with different degrees of epithelial dysplasia. The histological study of this lesion, together with the measurement of morphometric and stereological parameters, allows a better understanding of both physiological and pathological processes. Objective: to characterize the histomorphometric parameters of the oral mucosa in patients with oral leukoplakia according to the degree of epithelial dysplasia. Method: a case series study was carried out in order to determine morphometric indicators of leukoplastic lesions of the oral mucosa in biopsies of patients treated at the Pathology and Maxillofacial Anatomy services of the Dr. Gustavo Aldereguía Lima General University Hospital, in Cienfuegos province. The sample was obtained by intentional sampling, which was made up of 30 histological slides (biopsies), distributed in three groups of ten slides for each degree of epithelial dysplasia. The study variable was the morphometric characterization of oral mucosal leukoplakia with dysplasia. Descriptive and inferential statistics were applied. Results: three parameters prevailed in the classification of dysplasia: alteration of the interpapillary nails, hyperplasia and loss of polarity of the basal cells. The presence of orthoparakeratosis, hyperplastic epithelia and inflammatory infiltrate of the chorion was confirmed in more than half of the cases. There was statistical significance in the relationships established between the height or depth of the papillae and the relative density of cells according to the degree of epithelial dysplasia, when applying inferential statistics. Conclusions: three parameters predominated in the classification of dysplasia. The presence of orthoparakeratosis, hyperplastic epithelia and inflammatory infiltrate of the chorion was confirmed in more than half of the cases.

Variaciones celulares de la mucosa bucal en pacientes portadores de prótesis dental completa / Cellular variations of the oral mucous in patients with complete dental prosthesis i: en

Introducción: La prótesis dental completa genera una reacción tisular en el medio bucal, cuyo diagnóstico puede ser confirmado mediante el estudio citológico, que constituye una herramienta imprescindible para identificar cambios displásicos tempranos de la mucosa subprótesis. Objetivo: Identificar las posibles variaciones celulares de la mucosa bucal en pacientes portadores de prótesis completa. Métodos: Se realizó un estudio descriptivo y transversal en la Clínica Estomatológica Provincial Docente Mártires del Moncada de Santiago de Cuba, de junio de 2014 a enero de 2019, de 100 pacientes atendidos en la consulta de Prótesis Estomatológica, a los cuales se les realizó el raspado citológico de la mucosa del paladar y los rebordes para su posterior análisis microscópico según variables de interés. Para el procesamiento estadístico se empleó el porcentaje como medida de resumen y el estadígrafo de la Χ2, con un nivel de significación de 0,05. Resultados: En la serie predominaron las displasias leves (66,7 %), que resultaron más frecuentes en las edades de 20 a 39 años (12,5 %), en tanto, las moderadas y las graves figuraron principalmente en el grupo etario de 60 y más años (9,3 y 27,7 %, respectivamente). Todos los tipos de displasia primaron en los pacientes que habían portado la prótesis por más de 5 años y afectaron mayormente la queratina; de igual modo, entre las lesiones observadas, la estomatitis afectaba a un mayor porcentaje (31,2), sobre todo en el paladar (82,3 %), mientras que 8,3 % correspondió a la leucoplasia. Conclusión: Las pruebas citológicas son imprescindibles para la confirmación diagnóstica de cambios displásicos y posibilitan la prevención temprana del cáncer bucal.

Introduction: The complete dental prosthesis generates a tisular reaction in the oral cavity which diagnosis can be confirmed by means of citological study that constitutes an indispensable tool to identify early dysplastic changes of the subprosthesis mucous. Objective: To identify the oral possible cellular variations of the oral mucous in patients with complete prosthesis. Methods: A descriptive and cross sectional study was carried out in Mártires del Moncada Provincial Stomatological Clinic of Santiago de Cuba, from June, 2014 to January, 2019, with 100 patients, assisted in the Stomatological Prosthesis Department to whom the cytological scrapings of the palate and the edges were carried out for their later microscopic analysis according to variables of interest. For the statistical procedures, the percentage was used as summary measure and the Chi squared statistician, with a significance level of 0,05. Results: In the series the mild dysplasias prevailed (66,7%) that were more frequent in the 20 to 39 age group (12,5%), while the moderate and the serious dysplasias figured mainly in the age group of 60 and over (9,3 and 27,7%, respectively). All the dysplasia types prevailed in the patients that had carried the prosthesis for more than 5 years and they mostly affected the keratin; in a same way, among the observed lesions, the stomatitis affected a higher percentage (31,2), mainly in the palate (82,3%), while 8,3% corresponded to the leukoplakia. Conclusion: The cytological checkups are indispensable for the diagnostic confirmation of dysplasic changes and they allow to prevent early oral cancer.

Dysregulation in the secretion of the stress-related catecholamines in oral cancer patients: predictors and prognostic value / Desregulação da secreção das catecolaminas relacionadas ao estresse em pacientes com câncer de boca: valor preditivo e prognóstico

Introdução: Pacientes com câncer podem apresentar uma hiperativação do Sistema Nervoso Simpático (SNS). Como consequência, uma desregulação na secreção das catecolaminas relacionadas ao estresse norepinefrina (NE) e epinefrina (EPI) têm sido implicadas na progressão de alguns tipos de tumores malignos. No entanto, a associação entre os níveis sistêmicos das catecolaminas e o prognóstico do câncer, bem como seus fatores preditores são pobremente conhecidos. Pacientes e métodos: O presente estudo investigou os níveis plasmáticos de NE e EPI em 168 pacientes com carcinoma espinocelular (CEC) de boca, 70 pacientes com leucoplasia bucal e 54 voluntários saudáveis; bem como sua associação com variáveis demográficas, clínicopatológicas, biocomportamentais e psicológicas nos pacientes oncológicos. Os níveis plasmáticos de NE e EPI foram medidos por cromatografia líquida de alta eficiência com detecção eletroquímica (CLAE-ED) e o estado psicológico de humor foi avaliado pela Escala de Humor de Brunel (BRUMS). Análise de Kaplan-Meier e regressão de Cox foram usadas para investigar as associações entre os níveis de NE e EPI e a sobrevida global e específica após 5 anos de follow-up em 82 pacientes com câncer de boca. Os níveis sistêmicos das catecolaminas também foram avaliados em 32 pacientes após o tratamento da doença e comparados com os níveis pré-tratamento. Resultados: As concentrações plasmáticas de NE e EPI foram significativamente maiores em pacientes com CEC de boca em comparação aos pacientes com leucoplasia bucal (p< 0,0001 e p=0,024, respectivamente). Os pacientes com CEC de boca também apresentaram níveis plasmáticos de NE mais elevados do que os voluntários saudáveis (p= 0,0002). As concentrações plasmáticas de NE nos pacientes com leucoplasia bucal foram menores do que os voluntários saudáveis (p= 0,032). Análises de regressão múltipla mostraram que níveis aumentados de NE foram significativamente associados com uma sensação de "sentir-se sem energia", um descritor medido pelo BRUMS (OR= 2,9; p= 0,023). Baixa escolaridade e ocorrência de comorbidades com maior severidade foram independentemente associados a altos níveis de EPI (OR= 4,0; p= 0,004 e OR= 7,2; p= 0,005; respectivamente). Além disso, a presença de um estado de humor de raiva e "não estar em alerta" foram associados a altos níveis plasmáticos de EPI (OR= 2,6; p= 0,039 e OR= 3,2; p= 0,010, respectivamente). Os resultados mostraram que os pacientes com CEC de boca não casados e que tinham pior renda familiar foram preditivos para menor sobrevida global dos pacientes com CEC de boca (p< 0,05). Estágio clínico avançado foi associado à diminuição da sobrevida global (HR= 5,2; p= 0,000) e específica do câncer (HR= 4,2; p= 0,000). A análise de regressão de Cox também evidenciou que níveis sistêmicos aumentados tanto de NE como de EPI foram associados à menor sobrevida global (HR= 3,4; p= 0,002 e HR= 2,8; p=0,006, respectivamente). Os pacientes com CEC de boca apresentaram níveis plasmático de NE mais baixos após o tratamento do câncer em comparação com a fase pré-tratamento (p= 0,0008). Conclusão: Os resultados do presente estudo mostram que pacientes com câncer de boca podem apresentar níveis sistêmicos elevados das catecolaminas norepinefrina e epinefrina, e que esta desregulação hormonal associada com fatores clinicopatológicos e psicológicos é preditiva para pior sobrevida global(AU)

Introduction: Cancer patients may have a hyperactivation of the Sympathetic Nervous System (SNS). Therefore, dysregulation in the secretion of the stress-related catecholamines norepinephrine (NE) and epinephrine (EPI) have been implicated in the progression of some types of cancer. However, the association between systemic levels of catecholamines and cancer prognosis, as well as its predictors, are poorly understood. Patients and methods: The present study investigated the plasma NE and EPI levels in 168 patients with oral squamous cell carcinoma (OSCC), 70 patients with oral leukoplakia and 54 healthy volunteers; as well as its association with demographic, clinicopathological, biobehavioral and psychological variables in cancer patients. Plasma NE and EPI levels were measured by high performance liquid chromatography with electrochemical detection (HPLC-ED) and psychological mood states was assessed by the Brunel Mood Scale (BRUMS). Kaplan-Meier analysis and Cox regression were used to investigate associations between the systemic levels of catecholamines and overall and specific survival after 5 years of follow-up in 82 patients with oral cancer. Systemic levels of catecholamines were also evaluated in 32 patients after oral cancer treatment and were compared with pre-treatment levels. Results: Plasma NE and EPI concentrations were significantly higher in patients with oral SCC compared to patients with oral leukoplakia (p<. 0001 and p=.024, respectively). Patients with oral SCC also displayed higher plasma NE levels than healthy volunteers (p=.0002). Patients with oral leukoplakia had lower plasma NE levels than healthy volunteers (p=.032). Multiple regression analyzes showed that increased NE levels were associated with a feeling of "no energy", a descriptor measured by BRUMS (OR= 2.9; p= .023). Low education and the occurrence of severe comorbidities were independently associated with high levels of EPI (OR= 4.0; p= .004 and OR= 7.2; p= .005; respectively). Furthermore, the presence of an angry mood state and denial of "being on alert" were associated with high EPI levels (OR= 2.6; p= .039 and OR= 3.2; p= .010, respectively). The results showed that nonmarried oral SCC patients and those who had a lower family income had lower overall survival in patients with oral SCC (p< 0.05). Advanced clinical stage was associated with decreased overall (HR=5.2; p=.000) and cancer-specific (HR=4.2; p=.000) survival. Cox regression analysis also showed that increased levels of both NE and EPI were associated with worse overall survival (HR=3.4; p=.002 and HR=2.8; p=.006, respectively). Patients with oral SCC had lower plasma NE levels after cancer treatment compared to the pre-treatment period (p=.0008). Conclusion: The results of the present study reveal that patients with oral cancer may have high systemic levels of the catecholamines norepinephrine and epinephrine, and that this hormonal dysregulation is associated with clinicopathological and psychological factors and predictive for worse overall survival(AU)

Leucoplasia Verrucosa Proliferativa: Revisão da Literatura com Ênfase no Diagnóstico, Manejo e Tratamento / Proliferative Verrucous Leukoplakia: Literature Review With Emphasis on Diagnosis, Manegement and Treatment

As Desordens Potencialmente Malignas Orais (DPMO) descrevem um grupo de doenças com risco aumentado de desenvolver o Carcinoma Espinocelular (CEC), e a mais comum é a Leucoplasia Oral (LO), que apresenta uma variante agressiva denominada Leucoplasia Verrucosa Proliferativa (LVP). Descrita pela primeira vez em 1985 por Hansen et al., a LVP é considerada uma forma multifocal incomum da doença, com curso clínico agressivo e implacável para malignidade, sem associação com os fatores de risco tradicionais da LO. O diagnóstico e manejo dessa variante é um desafio, pois, além da ausência de biomarcadores comprovados que possam predizer seu curso evolutivo, a subjetividade existente na sua avaliação clínica e histopatológica, faz com que a presença ou grau de Displasia Epitelial Oral (DEO) não consiga determinar se haverá ou não transformação maligna da lesão. O objetivo desse trabalho foi realizar uma Revisão da Literatura Tradicional, focando especificamente nos aspectos sobre diagnóstico, transformação maligna, manejo e tratamento da LVP, variante agressiva da LO. Concluímos que, ainda hoje, não existem biomarcadores que possam predizer o avanço das LO, tornando-se obrigatório o acompanhamento e/ou tratamento de toda e qualquer LO, inclusive os casos de Queratose de significado incerto.

Oral Potentially Malignant Disorders (OPMDs) describe a group of diseases at increased risk of leading to Squamous Cell Carcinoma (SCC). The most common is Oral Leukoplakia (OL), which presents itself through an aggressive variant known as Proliferative Verrucous Leukoplakia (PVL). First described in 1985 by Hansen et al., PVL is considered an uncommon multifocal form of the disease, with an aggressive and relentless clinical course towards malignancy, and lacks association with traditional OL risk factors. The diagnosis and management of this disease form posits a significant challenge since, in addition to the absence of proven biomarkers that can predict its evolutionary course, the subjectivity existing in its clinical and histopathological evaluation means that the presence or degree of Oral Epithelial Dysplasia (OED) is not enough to determine whether or not the lesion will undergo a malignant transformation. The objective of this work was to carry out a Traditional Literature Review focused specifically on aspects of diagnosis, malignant transformation, management and treatment of PVL, an aggressive variant of OL. Our conclusion is that, to this day, there are no biomarkers able to predict the progress of OL, making it necessary to monitor and/or treat all OL cases, including cases of Keratosis of unknown significance.

Nicotine promotes the development of oral leukoplakia via regulating peroxiredoxin 1 and its binding proteins

Tobacco can induce reactive oxygen species (ROS) production extensively in cells, which is a major risk factor for oral leukoplakia (OLK) development. Peroxiredoxin 1 (Prx1) is a key antioxidant protein, upregulated in a variety of malignant tumors. We previously found that nicotine, the main ingredient of tobacco, promotes oral carcinogenesis via regulating Prx1. The aim of the present study was to screen and identify the Prx1 interacting proteins and investigate the mechanisms of nicotine on the development of OLK. Through liquid chromatography-tandem mass spectrometry combined with bioinformatics analysis, the candidate Prx1 interacting proteins of cofilin-1 (CFL1), tropomyosin alpha-3 chain (TPM3), and serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A) were screened in human dysplastic oral keratinocyte cells treated with nicotine. CFL1, TPM3, and PPP2R1A were highly expressed in human OLK tissues. The expression of CFL1 increased and the expression of PPP2R1A decreased in OLK of smokers compared to that in OLK of non-smokers. Nicotine upregulated CFL1 and downregulated PPP2R1A in 4-nitro-quinoline-1-oxide (4NQO)-induced OLK tissues in mice in part dependent on Prx1. Furthermore, the in-situ interaction of CFL1, TPM3, and PPP2R1A with Prx1 were validated in human OLK tissues. Our results suggested that tobacco might promote the development of OLK via regulating Prx1 and its interacting proteins CFL1 and PPP2R1A.

Application of medical magnifying loupes in diagnosis of oral mucosal diseases / 浙江大学学报·医学版

: To evaluate the application of medical magnifying loupes in diagnosis of oral mucosal diseases. Twenty-four patients with plaque-type oral lichen planus or homogeneous oral leukoplakia were inspected by naked eyes or assistance with magnifying loupes. Histopathological results were used as the gold standard to evaluate the sensitivity, specificity and accuracy of the two methods in clinical diagnosis. Questionnaires were used to evaluate the subjective effect of magnifying loupes on the diagnosis efficiency of oral mucosal diseases and to explore the most suitable parameters for application. The sensitivity, specificity and accuracy of medical magnifying loupes for the identification of plaque-type oral lichen planus and homogeneous oral leukoplakia were 94.74%, 100.00% and 95.83%, respectively, which were significantly higher than those of naked eye inspection (89.47%, 80.00% and 87.50%). The effective rate of magnifying loupes assisted diagnosis was 91.76% according to physicians' subjective evaluation. The most suitable parameters were 3.5 times magnification and working distance. The medical magnifying loupes can effectively improve the efficiency of the inspection and diagnosis of oral mucosal diseases, and have the characteristics of convenience and real-time. The recommended clinical parameters are 3.5 times magnification and working distance.

Transcriptome array screening and verification of oral leukoplakia carcinogenesis-related hypoxia-responsive gene and microRNA / 华西口腔医学杂志

OBJECTIVES@#To study the hypoxia response gene and microRNA (miRNA) expression profiles in the pathogenesis and progression of oral leukoplakia (OLK).@*METHODS@#Affymetrix GeneChip human transcriptome array 2.0 was used to detect the transcriptome of normal mucosa, low-risk OLK, high-risk OLK, and early squamous cell carcinoma (SCC). Gene ontology function analysis was used to screen genes and key miRNAs whose biological role is hypoxia response. Quantitative reverse transcription polymerase ch-ain reaction (qRT-PCR) was used to verify the expression of hypoxia response genes and miRNAs.@*RESULTS@#A total of 7 different genes of hypoxia response between normal mucosa and low-risk OLK, 10 genes between low-risk and high-risk OLK, and 21 genes between high-risk OLK and SCC were identified. The results of qRT-PCR showed that the expression of hypoxia-inducible factor 1α, chemokine cc-motif ligand 2, and matrix metalloproteinase 3 mRNA and miR-21 in normal mucosa, OLK, and SCC increased in a stepwise manner. The expression difference between OLK and SCC was statistically significant and consistent with the results of transcriptome array.@*CONCLUSIONS@#The hypoxia response gene and related miRNA play roles in the development and progression of OLK.

Differential expression profile of circRNAs in oral leukoplakia / 口腔疾病防治

Objective@#To investigate the differences and clinical significance of circRNA expression profiles in oral leukoplakia (OLK) tissues and normal oral mucosal (NOM) tissues.@*Methods@# High-throughput sequencing was used to detect differentially expressed circRNAs in 6 pairs of OLK and NOM tissues, and qRT-PCR was used to verify the expression of 10 circRNAs screened in 6 pairs of OLK and NOM tissues. The ring formation of circRNA was verified by RNase R digestion and Sanger sequencing, and the target circHLA-C was further verified by qRT-PCR in 20 pairs of OLK and NOM tissues. CircHLA-C was visualized using the UCSC genome browser (genome.ucsc.edu). The function of differentially expressed circRNAs was analyzed by GO and KEGG enrichment analyses. TargetScan and miRanda predicted the downstream miRNAs and mRNAs of the target circRNAs, and a ceRNA network related to the identified circRNAs was constructed in Cytoscape.@* Results@#Sequencing analysis showed that 366 circRNAs were significantly differentially expressed in OLK tissues, including 65 upregulated and 301 downregulated circRNAs. After qRT-PCR verification, 7 of the 10 screened circRNAs were expressed consistent with the sequencing results. The upregulated circHLA-C was confirmed to be a real circRNA with back-splice junction sites by RNase R digestion and Sanger sequencing. Correlation analysis showed a positive correlation between circHLA-C and the degree of OLK dysplasia. ROC curve analysis suggested that circHLA-C had potential value in diagnosing OLK with high accuracy and specificity.@*Conclusion@#CircRNA was significantly abnormally expressed in OLK tissues, and the upregulation of circHLA-C may be related to the degree of OLK dysplasia, providing guiding value for the diagnosis of OLK in the future.

Expression of Ki-67, Cyclin D1, P53, and P16 in patients with oral leukoplakia and leukoplakia cancerization with spicy diet in Chengdu / 华西口腔医学杂志

OBJECTIVES@#To investigate the expression of Ki-67, Cyclin D1, P53, and P16 in patients with oral leukoplakia (OLK) and OLK cancerization who have aspicy diet in Chengdu.@*METHODS@#Thirtypatients with OLK andspicy diet and 15 patients with OLK without spicy diet in Chengdu were divided into three groups: hyperplastic OLK (OLK-), OLK with mild to moderate dysplasia (OLK+), and severe dysplastic  OLK or oral squamous cell carcinoma (OSCC) transforming from OLK (OLK++/OSCC). The expression of Ki-67, Cyclin D1, P53, and P16 were detected by immunohistochemistry and statistically analyzed.@*RESULTS@#The expression of Ki-67 and P53 in patients with or without spicy diet in the OLK+and OLK++/OSCC groups were stronger than that of the OLK- group (@*CONCLUSIONS@#Spicy diet did not have an influence on the expression of Ki-67, Cyclin D1, P53, and P16 in patients with OLK and OSCC. The expression of Ki-67, Cyclin D1, and P53 increased with the development of OLK, whereas P16 showed opposite expression trend.

Significance of phosphoinositol metabolism by DNA methylation may contribute in oral leukoplakia carcinogenesis / 口腔疾病防治

Objective @# To study the role of DNA methylation in oral leukoplakia carcinogenesis.@*Methods@# DNA methylation was detected in forty cases of oral squamous cell carcinoma (OSCC), twenty-eight cases of oral leukoplakia (OLK) and forty cases of healthy oral mucosa. Download the expression profile data of OSCC, OLK and healthy oral mucosa from Gene Expression Omnibus (GEO) database. DNA methylation data and expression profile data were compared for repeatability, DNA methylation data for difference analysis and corresponding expression profile data for IPA pathway analysis.@*Results @#The data analysis showed that DNA methylation had greater flexibility and instability. Ingenuity Pathway Analysis (IPA) analysis showed that genes related to OLK differential methylation sites were mainly concentrated in the process of cell movement and differentiation. Genes related to differential methylation sites of OSCC are mainly enriched in cell proliferation, migration, oxidation regulation, and anti-apoptosis processes. The genes associated with OLK and OSCC differential methylation sites are co-enriched in phosphoinositol metabolism and phospholipase C signaling pathway.@* Conclusion@#DNA methylation is involved in the formation of oral squamous cell carcinoma, and the activation of phosphoinositol metabolism may promote oral leukinoma.

Analysis of TIMP-1 expression in leukoplakia and oral squamous cell carcinoma / Análise da expressão de TIMP-1 em leucoplasia e carcinoma de boca de células escamosas

ABSTRACT Introduction: The current study about transition of oral epithelial dysplasia, present in lesions such as leukoplakia, for squamous cell carcinoma (SCC) involves not only the histopathological aspects, but also the analysis of the presence of biomarkers which influence the microenvironment where cells are embedded. Objective: To evaluate the tissue inhibitor of metalloproteinase-1 (TIMP-1) profile in cases of leukoplakia and SCC classified into different degrees of dysplasia and histological grading, respectively. The immunohistochemical findings were confronted with microscopic features adopted in the classification of each lesion. Material and methods: Cases of leukoplakia and SCC were recovered from files of The Oral Pathological Anatomy Service of the Dental School at the Universidade Federal do Espírito Santo (SAPB-UFES), between the years 2004 and 2010. New slides were obtained and submitted to immunohistochemical assay to determine TIMP-1 expression profile. Parenchyma, as well as the different layers of the epithelium and stroma was evaluated. Results: In all cases the presence of TIMP-1 was detected in the stroma and parenchyma. In mild leukoplakia, the basal layer with hyperplasia showed intense immunolabeling, whereas cells with loss of polarity presented weaker expression. In moderate leukoplakia, all epithelium layers, except the cornea, were labeled. Severe leukoplakia had the spinous layer most intensely labeled, with no variation in areas with pleomorphism. Stage I SCC showed the deepest islands with intense labeling in cells with pleomorphism and mitoses. In the tumor islands, less differentiated cells were weakly labeled, and in keratin pearl, labeling was weak or absent in central cells. In stage II SCC, labeling was observed in basal cell with hyperplasia and in cells of the spinous layer, however, the parabasal layer was not labeled. Also, on tumor islands, less differentiated cells did not express the protein and keratin pearls were not labeled. Conclusion: It was possible to detect TIMP-1 immunolabeling in all specimens, ranging in intensity and location. The absence of expression in less differentiated cell suggests that more aggressive lesions present reduced enzyme expression. The microenvironment is important for the various cellular activities, and TIMP is an enzyme that participates in matrix remodeling, therefore changes in its expression can be a valuable tool in the better understanding oral carcinogenesis.

RESUMEN Introducción: El estudio actual de la transición de displasia epitelial oral, presente en lesiones como la leucoplasia, hacia carcinoma epidermoide, implica no solo aspectos histopatológicos, sino también el análisis de la presencia de biomarcadores que influyen en el microambiente en el que se insertan las células. Objetivo: Evaluar el perfil del inhibidor tisular metaloproteinasa-1 (TIMP-1) en casos de leucoplasia y carcinoma de células escamosas (CCE) clasificados en diferentes grados de displasia y grados histopatológicos, respectivamente. Confrontar los hallazgos inmunohistoquímicos con los aspectos microscópicos adoptados en la clasificación de lesiones. Material y métodos: Casos de leucoplasia y CCE fueron recuperados del Servicio de Anatomía Patológica Bucal del Curso de Odontología de la Universidad Federal de Espírito Santo (SAPB-UFES), entre los años 2004-2010. Se obtuvieron nuevos portaobjetos y se los sometieron a ensayos inmunohistoquímicos para determinar el perfil de expresión de TIMP-1. Se evaluó el parénquima, así como las diferentes capas del epitelio y estroma. Resultados: En todos los casos se detectó TIMP-1 en estroma y parénquima. En la leucoplasia leve, la capa basal y con hiperplasia mostró inmunotinción intensa, mientras que las células con pérdida de polaridad tuvieron menos expresión. En la leucoplasia moderada, todas las capas del epitelio, excepto la córnea, mostraron inmunotinción. En la leucoplasia grave la capa espinosa tuvo inmunotinción más intensa, sin variación en áreas con pleomorfismo. El CCE grado I mostró las islas más profundas con tinción intensa en células con pleomorfismo y mitosis. En las islas tumorales, las células menos diferenciadas tuvieron tinción menor, y en las perlas de queratina la tinción fue débil o ausente en las células centrales. En el CCE grado II, se observó tinción en células basales con hiperplasia y, en células de la capa espinosa, la capa parabasal no fue marcada. También en las islas, las células menos diferenciadas no expresaron la proteína y no hubo tinción en las perlas de queratina. Conclusión: Fue posible detectar inmunotinción para TIMP-1 en todos los especímenes, con variación en intensidad y ubicación. La ausencia de expresión en células menos diferenciadas sugiere que las lesiones más agresivas tienen enzima reducida. El microambiente es importante para las diversas actividades celulares, y el TIMP es una enzima que participa en la remodelación de la matriz; por lo tanto, la alteración en su expresión puede ser una herramienta valiosa en el mejor entendimiento de la carcinogénesis de la mucosa oral.

RESUMO Introdução: O estudo atual da transição da displasia epitelial oral, presente em lesões como a leucoplasia, para o carcinoma de células escamosas (CCE), envolve não somente aspectos histopatológicos, como também a análise da presença de biomarcadores, os quais influenciam o microambiente em que as células estão inseridas. Objetivo: Avaliar o perfil da expressão do inibidor tecidual de metaloproteinase 1 (TIMP-1) em casos de leucoplasias e CCE classificados em diferentes graus de displasia e graus histopatológicos, respectivamente, e confrontar os achados imuno-histoquímicos com os aspectos microscópicos adotados na classificação das lesões. Material e métodos: Foram resgatados casos de leucoplasia e CCE do Serviço de Anatomia Patológica Bucal do curso de Odontologia da Universidade Federal do Espírito Santo (SAPB-UFES), entre os anos 2004-2010. Novas lâminas foram obtidas ao serem submetidas ao ensaio imuno-histoquímico para determinação do perfil de expressão de TIMP-1. Foram avaliados parênquima, bem como as diferentes camadas do epitélio e estroma. Resultados: Em todos os casos, foi detectada a presença de TIMP-1 no estroma e no parênquima. Na leucoplasia leve, a camada basal e com hiperplasia apresentou imunomarcação intensa; as células com perda de polaridade tiveram expressão menor. Na leucoplasia moderada, todas as camadas do epitélio, exceto a córnea, apresentaram marcação. A leucoplasia severa teve a camada espinhosa marcada mais intensamente, sem variação em áreas com pleomorfismo. O CCE grau I apresentou as ilhas mais profundas com marcação intensa em células com pleomorfismo e mitoses. Nas ilhas tumorais, células menos diferenciadas tiveram marcação menor, e em pérolas córneas a marcação foi fraca ou ausente nas células centrais. No CCE grau II, foi observada a marcação em células basais com hiperplasia e, em células da camada espinhosa, a camada parabasal não foi marcada. Também nas ilhas, células menos diferenciadas não expressaram a proteína e não houve marcação em pérolas córneas. Conclusão: Foi possível detectar imunomarcação para TIMP-1 em todos os espécimes, com variação em intensidade e localização. A ausência de expressão em células menos diferenciadas sugere que lesões mais agressivas possuem redução da enzima. O microambiente é importante para as diversas atividades celulares, e TIMP é uma enzima que participa da remodelação da matriz. Portanto, alteração na sua expressão pode ser uma valiosa ferramenta para um melhor entendimento da carcinogênese da mucosa bucal.