Capacidad pronóstica del PIV (pan-immune-inflammation value) en pacientes con carcinoma escamoso de cabeza y cuello / Prognostic capacity of PIV (pan-immune-inflammation value) in patients with head and neck squamous cell carcinoma

Introducción: El PIV (pan-immune-inflammation value), un índice que resulta del cociente (neutrófilos×monocitos×plaquetas) / linfocitos, ha sido propuesto como un biomarcador con capacidad pronóstica en diferentes modelos tumorales. El objetivo del presente estudio es analizar la capacidad pronóstica del PIV en pacientes con carcinoma escamoso de cabeza y cuello. Pacientes y métodos: Estudio retrospectivo de 1.187 pacientes con carcinoma escamoso de cabeza y cuello tratados en nuestro centro durante el periodo 2000-2017. Se obtuvo el valor del PIV a partir de un análisis realizado en un intervalo inferior a las 3 semanas previas al inicio del tratamiento. Resultados: El valor del PIV se relacionó de forma significativa con el consumo de tóxicos (p=0,001), la localización del tumor (0,0001), la extensión tumoral (0,0001), y el grado histológico (0,016). Mediante un análisis de partición recursiva se definieron 4 categorías en función del valor del PIV: categoría i: PIV<136,3 (n=118; 9,9%), categoría ii: PIV 136,3-451,1 (n=594, 50,0%); categoría iii: PIV 451,1-1.141,2 (n=357; 30,1%); categoría iv: PIV>1.141,2 (n=118; 9,9%). Se pudo observar una reducción ordenada y significativa de la supervivencia específica a medida que se incrementaba la categoría en el valor del PIV. Esta disminución en la supervivencia se produjo de forma independiente al tipo de tratamiento, la extensión del tumor, o la localización del tumor primario. La categoría en el valor del PIV se relacionó de forma significativa con la supervivencia específica en un estudio multivariable. Conclusiones: El PIV es un biomarcador con capacidad pronóstica en los pacientes con carcinoma escamoso de cabeza y cuello.(AU)

Introduction: The pan-immune-inflammation value (PIV), an index that results from the following ratio: (neutrophils×monocytes×platelets) / lymphocytes, has been proposed as a prognostic biomarker in different tumor models. The aim of this study is to analyze the prognostic capacity of PIV in patients with head and neck squamous cell carcinoma. Patients and methods: Retrospective study of 1,187 patients with head and neck squamous cell carcinoma treated at our center between 2000-2017. PIV value was obtained from an analysis performed within 3 weeks prior to the start of treatment. Results: PIV value was significantly associated with toxic consumption (0.001), tumor location (0.0001), tumor extension (0.0001), and histological grade (0.016). Four categories were defined based on PIV value using a recursive partitioning analysis: category i: PIV<136.3 (n=118, 9.9%), category ii: PIV 136.3-451.1 (n=594, 50.0%), category iii: PIV 451.1-1,141.2 (n=357, 30.1%), and category iv: PIV>1,141.2 (n=118, 9.9%). A significant and ordered decrease in disease-specific survival was observed as the PIV category increased. This decrease in survival was independent of the type of treatment, tumor extension, or location of the primary tumor. The PIV category was an independent prognostic factor of disease-specific survival in a multivariable study. Conclusions: PIV is a prognostic biomarker in patients with head and neck squamous cell carcinoma.(AU)

A diagnostic algorithm for sinonasal papillary non-keratinizing squamous cell carcinoma with DEK:: AFF2 fusion and mimickers / Algoritmo diagnóstico para carcinoma sinonasal papilar de células escamosas no queratinizante con fusión e imitadores de DEK:: AFF2

Sinonasal carcinomas represent a rare and diverse group of tumors, presenting diagnostic complexities due to their varied histological and molecular features. To ensure accurate differentiation among these malignancies, a systematic and stepwise approach is paramount. Even with the morphological similarities between poorly differentiated (non) keratinizing sinonasal squamous cell carcinoma (SNSCC) and DEK::AFF2 SNSCC, the two lesions are distinguishable using the surrogate immunohistochemical marker AFF2 or molecular testing for DEK::AFF2 mutation. We report a rare case of SMARCB1-retained DEK::AFF2 papillary non-keratinizing SNSCC in a 53-year-old female, who presented with a polypoid mass corresponding to the left middle turbinate. Following the surgical resection of the tumor and locoregional lymph nodes, adjuvant radiotherapy was administered to eradicate any residual cancer cells that may have remained after surgery. (AU)

Los carcinomas sinonasales representan un grupo diverso e infrecuente de tumores que presentan complejidades diagnósticas debidas a la variedad de sus características histológicas y moleculares. Para asegurar una diferenciación precisa entre estas neoplasias es esencial un enfoque sistemático paso a paso. Incluso con similitudes morfológicas entre carcinoma sinonasal escamoso pobremente diferenciado, no queratinizante (CSNE) y DEK::AFF2 se puede distinguir entre las lesiones con el uso del marcador inmunohistoquímico sustitutivo AFF2 o la mutación molecular DEK::AFF2. Comunicamos un raro caso de CSNE no queratinizante SMARCB1-retained DEK::AFF2 en una mujer de 53 años con una masa polipoide en pliegue turbinado medio izquierdo. Tras la resección quirúrgica del tumor y de los ganglios linfáticos, se administró radioterapia adyuvante para eliminar el tumor residual. (AU)

A diagnostic algorithm for sinonasal papillary non-keratinizing squamous cell carcinoma with DEK:: AFF2 fusion and mimickers / Algoritmo diagnóstico para carcinoma sinonasal papilar de células escamosas no queratinizante con fusión e imitadores de DEK:: AFF2

Sinonasal carcinomas represent a rare and diverse group of tumors, presenting diagnostic complexities due to their varied histological and molecular features. To ensure accurate differentiation among these malignancies, a systematic and stepwise approach is paramount. Even with the morphological similarities between poorly differentiated (non) keratinizing sinonasal squamous cell carcinoma (SNSCC) and DEK::AFF2 SNSCC, the two lesions are distinguishable using the surrogate immunohistochemical marker AFF2 or molecular testing for DEK::AFF2 mutation. We report a rare case of SMARCB1-retained DEK::AFF2 papillary non-keratinizing SNSCC in a 53-year-old female, who presented with a polypoid mass corresponding to the left middle turbinate. Following the surgical resection of the tumor and locoregional lymph nodes, adjuvant radiotherapy was administered to eradicate any residual cancer cells that may have remained after surgery. (AU)

Los carcinomas sinonasales representan un grupo diverso e infrecuente de tumores que presentan complejidades diagnósticas debidas a la variedad de sus características histológicas y moleculares. Para asegurar una diferenciación precisa entre estas neoplasias es esencial un enfoque sistemático paso a paso. Incluso con similitudes morfológicas entre carcinoma sinonasal escamoso pobremente diferenciado, no queratinizante (CSNE) y DEK::AFF2 se puede distinguir entre las lesiones con el uso del marcador inmunohistoquímico sustitutivo AFF2 o la mutación molecular DEK::AFF2. Comunicamos un raro caso de CSNE no queratinizante SMARCB1-retained DEK::AFF2 en una mujer de 53 años con una masa polipoide en pliegue turbinado medio izquierdo. Tras la resección quirúrgica del tumor y de los ganglios linfáticos, se administró radioterapia adyuvante para eliminar el tumor residual. (AU)

Has the 8th American joint committee on cancer TNM staging improved prognostic performance in oral cancer? A systematic review / ¿Ha mejorado la estadificación TNM del octavo comité conjunto estadounidense sobre cáncer? ¿Rendimiento pronóstico en el cáncer oral? Una revisión sistemática

Background: The 8th edition of the American Joint Committee on Cancer (AJCC) classification has introduced two new parameters: depth of invasion (DOI) and extranodal extension (ENE). The aim of this systematic review was to determine whether this 8th edition referred to oral squamous cell carcinoma (OSCC) offers performance superior to that of the 7th edition in relation to overall survival (OS) and disease-specific survival (DSS). Material and Methods: The review was carried out following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. The PubMed (MEDLINE), Scopus and Cochrane Library databases were searched covering the period up until April 7th, 2022.Results: Thirteen retrospective cohort studies were finally included. The introduction of DOI and ENE in the 8th edition of the AJCC classification resulted in improved prognostic performance of the classification. Conclusions: Patients with OSCC can be better classified in relation to OS and DSS, while maintaining the simplicity and ease of use of the classification. This allows more appropriate treatment protocols to be applied and affords a better estimation of the prognosis of each patient.(AU)

Resultados oncológicos del tratamiento de rescate en pacientes con carcinomas de orofaringe tratados con radioterapia / Oncological results of salvage treatment in patients with oropharynx carcinoma treated with radiotherapy

Objetivo Evaluar las posibilidades de rescate tras la recidiva local en pacientes con carcinomas de orofaringe tratados con radioterapia y analizar los factores pronósticos relacionados con el control final de la enfermedad. Métodos Estudio retrospectivo de 596 con carcinomas de orofaringe pacientes tratados con radioterapia durante el periodo 1991-2018. Resultados Ciento ochenta y un pacientes (30,4%) tuvieron una recidiva local. De los pacientes con una recidiva local, 51 (28,2%) fueron tratados con una cirugía de rescate. Las variables que se relacionaron con que el paciente no recibiese una cirugía de rescate fueron una edad superior a los 75 años, la localización del tumor en la pared posterior de la hipofaringe, una extensión inicial del tumor cT4 y un intervalo libre de recidiva inferior a los 6 meses. La supervivencia específica a los 5 años de los pacientes tratados con una cirugía de rescate fue del 19,1% (IC del 95%: 7,3-30,9%). Las variables que se relacionaron con la supervivencia específica fueron la extensión de la recidiva y el estatus de los márgenes de resección. No se consiguió el control final del tumor en ninguno de los pacientes con una recidiva extensa (rpT3-4, n=25) o con unos márgenes de resección positivos (n=22). Conclusión Los pacientes con carcinomas de orofaringe tratados con radioterapia con una recidiva local del tumor cuentan con un pronóstico limitado. Una mayoría de los pacientes (71,8%) no fueron considerados candidatos a cirugía de rescate. La supervivencia específica a los 5 años de los pacientes tratados con una cirugía de rescate fue del 19,1%. (AU)

Objective To evaluate the possibilities of salvage after local recurrence in patients with oropharyngeal carcinomas treated with radiotherapy, and to analyze the prognostic factors related to the final control of the disease. Methods Retrospective study of 596 patients with oropharyngeal carcinoma treated with radiotherapy during the period 1991–2018. Results One hundred and eighty-one patients (30.4%) had a local recurrence. Of the patients with a local recurrence, 51 (28.2%) were treated with salvage surgery. Variables that were associated with the patient not receiving salvage surgery were age greater than 75 years, tumor location in the posterior hypopharyngeal wall, an initial tumor extent cT4, and a recurrence-free interval of less than 6 months. Five-year specific survival of patients treated with salvage surgery was 19.1% (95% CI: 7.3%–30.9%). Variables that were related to specific survival were extent of recurrence and status of resection margins. Final tumor control was not achieved in any of the patients with extensive recurrence (rpT3-4, n=25) or positive resection margins (n=22). Conclusion Patients with oropharyngeal carcinomas treated with radiotherapy with local tumor recurrence have a limited prognosis. Most patients (71.8%) were not considered candidates for salvage surgery. The 5-year specific survival of patients treated with salvage surgery was 19.1%. (AU)

Epidemiological, clinical, and prognostic analysis of oral squamous cell carcinoma diagnosed and treated in a single hospital in Galicia (Spain): a retrospective study with 5-year follow-up / Análisis epidemiológico, clínico y pronóstico del carcinoma oral de células escamosas diagnosticado y tratado en un único hospital de Galicia (España): un estudio retrospectivo con un seguimiento de 5 años

Background: Oral cancer is a common neoplasm worldwide, mostly corresponding to squamous cell carcinoma(OSCC). Unfortunately, its overall prognosis remains poor, with no improvement in recent decades. In this study,we have analysed the epidemiological, clinical, and prognostic characteristics of OSCC on patients of a specificSpanish region (Galicia), in order to improve its prognosis and apply effective preventive and early diagnosismeasures.Material and Methods: We retrospectively analysed 243 cases of OSCC, diagnosed and treated in a single hospitalcentre in Galicia between 2010 and 2015 (minimum of 5 years of evolution). Overall and specific survival werecalculated (Kaplan-Meier) and associated variables were identified (log rank test and Cox regression).Results: The mean age of the patients was 67 years, with the majority being male (69.5%), smokers (45.9%) andalcohol consumers (58.6%), who lived in non-urban areas (79.4%). Cases diagnosed at advanced stages entailedthe 48.1% of the sample, and 38.7% of cases relapsed. The 5-year overall and disease-specific survival rates were39.9% and 46.1%, respectively. Patients who consumed tobacco and alcohol had a worse prognosis. OSCC casesreferred to hospital by specialist dentists had a better prognosis, as those who were previously diagnosed with anoral potentially malignant oral disorder (OPMD) or received dental care during OSCC treatmen. Conclusions: In view of these findings, we conclude that OSCC in Galicia (Spain) still has a very poor overall prog-nosis, which is mainly related to the advanced age of the patients and the late diagnosis. Our study highlights thebetter survival of OSCC in relation to the referring health professional, the presence of a previous OPMD and thedental care after diagnosis. This demonstrates the importance of dentistry as a health profession involved in the earlydiagnosis and multidisciplinary management of this malignant neoplasm.(AU)

Oral squamous cell carcinoma arising from areas of Graft-versus-host disease: A systematic review / Carcinoma oral de células escamosas que surge de áreas de enfermedad de injerto contra huésped: una revisión sistemática

Background: Graft-versus-host disease (GVHD) is an immune system reaction that occurs in patients with ahistory of hematopoietic stem cell transplantation (HSCT), in which the grafted donor's cells attack those of thehost. The objective of this systematic review was to present a study on oral squamous cell carcinoma (OSSC) thatdeveloped from GVHD areas in patients undergoing HSCT.Material and Methods: An electronic search was conducted in the databases PUBMED, WEB OF SCIENCE,SCOPUS, MEDLINE and SCIENCE DIRECT, according to PRISMA guidelines. Results: Of the 1582 results, 23 articles were included, resulting in 81 cases. The most common underlying diseasefor performing the transplant was Myeloid Leukemia (55.6%). The mean age was 39 years, with a predilection formales (64.2%). The tongue was the site of GVHD that most frequently underwent transformation to SCC (59.3%).The average time between transplantation and the development of GVHD was of approximately of 8 months, whilethe average period of development between transplantation and the development of OSCC was of approximately of111 months. The most common treatment to GVHD was cyclosporine associated with corticosteroids.Conclusions: OSCCs arising from areas of GVHD present a different evolution from conventional oral carcinomas,since they affect younger patients, smoking and alcohol are not important etiological factors and finally because theypresent good prognosis, but further studies with larger number cases followed are needed to confirm our findings.(AU)

Polimorfismos genéticos asociados a la respuesta del carcinoma de cabeza y cuello al cetuximab / Genetic polymorphisms associated with the response of head and neck carcinoma to cetuximab

Objetivo: Exponer los principales polimorfismos genéticos que han sido asociados a la respuesta del carcinoma de cabeza y cuello al cetuximab. Método: Se realizó una revisión no exhaustiva de artículos publicados en el período de enero de 2000 a diciembre de 2022, para ello se emplearon las bases de datos Medline (vía Pubmed) y Science Direct. En la evaluación de la calidad metodológica de los artículos incluidos se utilizó la guía para los estudios de asociación genética (Q-Genie). Resultados: Se identificaron un total de 206 artículos, de los cuales 12 cumplieron con los criterios para el análisis final. Se reportaron varios polimorfismos, tales como: EGFR-R521K (AA/GA), FcγRIIIa (158VV) y FcγRIIa (131HH), KRASLCS6 (TG/GG), AKT2:rs8100018, PTEN: rs12569998 en sus variantes mutadas, HIF-1α (CT/TT) y XRCC5 (GG/AA) que se asociaron con las variables de supervivencia, riesgo de progresión, tiempos hasta la progresión de la enfermedad, así como toxicidad cutánea. Conclusiones: Varios polimorfismos pueden asociarse con la respuesta del carcinoma de cabeza y cuello al tratamiento con cetuximab, siendo EGFR-R521K y FcγR IIIa-V158F los más estudiados. La enorme incertidumbre de los resultados alcanzados no permite alcanzar conclusiones firmes sobre la influencia de los polimorfismos genéticos en la respuesta al cetuximab; sin embargo, pueden convertirse en biomarcadores farmacogenéticos en la práctica clínica como una valiosa herramienta en la medicina personalizada, para predecir la respuesta medicamentosa. Para ello se requiere la realización de ensayos controlados con estratos por genotipo, con asignación aleatoria del tratamiento y el análisis de otras variables con valor pronóstico conocido.(AU)

Objective: To present the main genetic polymorphisms that have been associated with the response of head and neck carcinoma to cetuximab. Method: A non-exhaustive review of articles published in the period from January 2000 to December 2022 was carried out, for this purpose the Medline (via Pubmed) and Science Direct databases were used. The guide for genetic association studies (Q-Genie) was used to evaluate the methodological quality of the included articles. Results: A total of 206 articles were identified, of which 12 met the criteria for the final analysis. Several polymorphisms were reported, such as: EGFR-R521K (AA/GA), FcγRIIIa (158VV) and FcγRIIa (131HH), KRAS-LCS6 (TG/GG), AKT2:rs8100018, PTEN: rs12569998 in its mutated variants, HIF- 1α (CT/TT) and XRCC5 (GG/AA) that were associated with survival variables, risk of progression, times to disease progression, as well as skin toxicity. Conclusions: Several polymorphisms can be associated with the response of head and neck carcinoma to treatment with cetuximab, being EGFR-R521K and FcγR IIIa-V158F the most studied. The enormous uncertainty of the results obtained does not allow firm conclusions to be reached about the influence of genetic polymorphisms on the response to cetuximab; however, they can become pharmacogenetic biomarkers in clinical practice as a valuable tool in personalized medicine, to predict drug response. This requires carrying out controlled trials with strata by genotype, with random assignment of treatment and the analysis of other variables with known prognostic value.(AU)

Capacidad predictiva de la expresión transcripcional de FAT1 en pacientes con carcinomas escamosos de cabeza y cuello tratados con radioterapia / Predictive capacity of FAT1 transcriptional expression in patients with head and neck squamous cell carcinomas treated with radiotherapy

Objetivo Analizar la capacidad predictiva de la respuesta a nivel local de la expresión transcripcional de FAT1 en pacientes con carcinomas escamosos de cabeza y cuello tratados con radioterapia.Material y métodosLlevamos a cabo un estudio retrospectivo realizado a partir de biopsias de la localización primaria del tumor en 82 pacientes con carcinomas escamosos de cabeza y cuello tratados con radioterapia. Se determinó la expresión transcripcional de FAT1 mediante RT-PCR. Se categorizó el nivel de expresión transcripcional de FAT1 en función del control local tras el tratamiento con radioterapia mediante un análisis de partición recursiva.ResultadosLa expresión transcripcional elevada de FAT1 se relacionó con un incremento en el riesgo de recidiva local tras el tratamiento con radioterapia. Los pacientes con unos niveles de expresión elevada de FAT1 (n=18; 22,0%) tuvieron una supervivencia libre de recidiva local a los 5 años del 42,1% (IC 95%: 18,6-65,6%), en tanto que para los pacientes con una expresión baja (n=64; 78,0%) fue del 72,4% (IC 95%: 61,5-83,3%) (p=0,002). De acuerdo con el resultado de un análisis multivariante, los pacientes con una categoría de expresión elevada de FAT1 tuvieron un riesgo 2,3 veces superior de recidiva local (IC 95%: 1,0-5,2; p=0,043).ConclusionesLa expresión transcripcional elevada de FAT1 se relacionó con un incremento significativo del riesgo de recidiva local en los pacientes con carcinomas escamosos de cabeza y cuello tratados con radioterapia. (AU)

Objective To analyze the predictive capacity at the primary location of the tumor of the FAT1 transcriptional expression in patients with head and neck squamous cell carcinoma treated with radiotherapy.Material and methodsWe conducted a retrospective study from biopsies of the primary location of the tumor in 82 patients with head and neck squamous cell carcinoma treated with radiotherapy. The transcriptional expression of FAT1 was determined by RT-PCR. The level of FAT1 transcriptional expression was categorized according to the local control after radiotherapy using a recursive partitioning analysis.ResultsElevated FAT1 transcriptional expression was associated with an increased risk of local recurrence after radiotherapy. Patients with a high expression level of FAT1 (n=18; 22.0%) had a 5-year local recurrence-free survival of 42.1% (95% CI: 18.6–65.6%), whereas for patients with a low expression (n=64; 78.0%) it was 72.4% (95% CI: 61.5%–83.3%) (P=0.002). According to the result of a multivariate analysis, patients with a high FAT1 expression category had a 2.3-fold increased risk of local recurrence (95% CI: 1.0–5.2; P=0.043).ConclusionsElevated FAT1 transcriptional expression was associated with a significantly increased risk of local recurrence in patients with head and neck squamous cell carcinoma treated with radiotherapy. (AU)

The repertoire of mutational signatures in tobacco- and non-tobacco-induced oral cancer

The use of tobacco products is one of the established contributors toward the development and spread of oral cancer. Additionally, recent research has indicated oral microbiome, infections with Human papilloma virus (HPV), Epstein–Barr virus (EBV), Candida as significant contributing factors to this disease along with lifestyle habits. Deregulation of cellular pathways envisaging metabolism, transcription, translation, and epigenetics caused by these risk factors either individually or in unison is manifold, resulting in the increased risk of oral cancer. Globally, this cancer continues to exist as one of the major causes of cancer-related mortalities; the numbers in the developing South Asian countries clearly indicate yearly escalation. This review encompasses the variety of genetic modifications, including adduct formation, mutation (duplication, deletion, and translocation), and epigenetic changes evident in oral squamous cell carcinoma (OSCC). In addition, it highlights the interference caused by tobacco products in Wnt signaling, PI3K/Akt/mTOR, JAK-STAT, and other important pathways. The information provided also ensures a comprehensive and critical revisit to non-tobacco-induced OSCC. Extensive literature survey and analysis has been conducted to generate the chromosome maps specifically highlighting OSCC-related mutations with the potential to act as spectacles for the early diagnosis and targeted treatment of this disease cancer (AU)

Reactive cutaneous capillary endothelial proliferation predicted the efficacy of camrelizumab in patients with recurrent/metastatic head and neck squamous cell carcinoma

Background: Reactive cutaneous capillary endothelial proliferation (RCCEP), a special adverse event (AE) only observed in patients treated with camrelizumab, was reported to be correlated with the efficacy of camrelizumab in patients with advanced hepatocellular carcinoma. This study to analyze the possible correlation between the occurrence of RCCEP and efficacy of camrelizumab in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Material and Methods: In this study, we retrospectively analyzed the efficacy and RCCEP occurrence of camrelizumab in 58 patients with R/M HNSCC in the Shanghai Ninth People's Hospital affiliated to Shanghai JiaoTong University School of Medicine between January 2019 and June 2022. Kaplan-Meier analysis was used to assess the correlation between the occurrence of RCCEP and the survival of enrolled patients, and COX multifactor analysis was adopted to evaluate associated factors that affected the efficacy of camrelizumab immunotherapy. Results: A significant correlation between the incidence of RCCEP and a higher objective response rate was observed in this study (p=0.008). The occurrence of RCCEP was associated with better median overall survival (17.0 months vs. 8.7 months, p<0.0001, HR=5.944, 95% CI:2.097-16.84) and better median progression-free survival (15.1 months vs. 4.0 months, p<0.0001, HR=4.329,95% CI:1.683-11.13). In COX multifactor analysis, RCCEP occurrence was also an independent prognostic factor affecting OS and PFS in patients with R/M HNSCC. Conclusions: The occurrence of RCCEP can show a better prognosis, it could be used as a clinical biomarker to predict the efficacy of camrelizumab treatment. (AU)

The stromal immunoexpression of CLIC4 may be related to the difference in the biological behavior between oral squamous cell carcinoma and oral verrucous carcinoma

Background: Oral squamous cell carcinoma (OSCC) has high morbidity and mortality rates while oral verrucous carcinoma (OVC), an uncommon variant of OSCC, exhibits a distinct biological behavior. CLIC4 protein plays a role in the cell cycle and apoptosis regulation and participates in the myofibroblasts transdifferentiation process, which are the main cells of the tumor stroma. This study analyzed the immunoexpression of CLIC4 and α-SMA in 20 OSCC cases and 15 OVC cases. Material and methods: A semiquantitative analysis of CLIC4 and α-SMA immunoexpression was performed in the parenchyma and stroma. Nuclear and cytoplasmic reactivity was analyzed separately for the CLIC4 immunostaining. The data were submitted to Pearson's chi-square and Spearman's correlation tests (p ≤ 0.05). Results: In the CLIC4 analysis, there was a significant difference in the immunoexpression of this protein between OSCC and OVC stroma (p < 0.001). It was observed a higher expression of α-SMA in the OSCC stroma. There was a positive and significant correlation between CLIC4 and α-SMA immunoexpression in the OVC stroma (r = 0,612; p = 0,015). Conclusions: The decrease or absence of nuclear CLIC4 immunoexpression in the neoplastic epithelial cells and the increase of its expression in the stroma may influence the difference in biological behavior between OSCC and OVC. (AU)

Role of selected salivary inflammatory cytokines in the diagnosis and prognosis of oral squamous cell carcinoma. A Systematic Review and Meta-analysis

Background: Oral squamous cell carcinoma (OSCC) is gradually increasing its incidence in our society. Unfortunately, this entity is diagnosed at an advanced stage in most patients, a fact that implies greater difficulty in its treatment and a worse prognosis. This systematic review aims to assess whether the cytokines IL-6, IL-8 and TNF-α are potential salivary biomarkers that allow early diagnosis of cancer. Material and methods: An electronic search was performed in three databases (Pubmed, Scopus and Web of Science). We used the following keywords: "salivary cytokines", "saliva cytokines", "salivary interleukins", "biomarkers", "oral squamous cell carcinoma" and "diagnosis", combined with the Boolean operators "AND" and "OR". Results: 128 publications were found and finally 23 articles were included in the review and 15 in the meta-analysis. It has been observed that the majority of OSCC patients express higher salivary concentrations of IL-6, IL-8 and TNF-α compared to the control (CL) and premalignant lesion (OPML) groups. It has also been observed that the different premalignant lesions do not have statistically significant differences in the salivary concentration of the cytokines, and on the other hand, differences have been observed between the different TNM stages. The meta-analysis has shown that the difference in concentration of IL-6, IL-8 and TNF-α is statistically significant between the CL group and the OSCC, and also between the CL group and OPML. Conclusions: There is sufficient evidence to affirm that IL-6, IL-8 and TNF-α are useful salivary cytokines in the early diagnosis and prognosis of OSCC. Although future studies are necessary to establish greater reliability of these biomarkers and thus be able to develop a valid diagnostic test. (AU)

Perineural invasion predicts poor survival and cervical lymph node metastasis in oral squamous cell carcinoma

Background: Oral squamous cell carcinoma (OSCC) usually invades peripheral nerves through a process known as perineural invasion (PNI), recognized as an adverse factor considered for the administration of postoperative adjuvant therapy. The aim of this study was to assess the impact of PNI on survival and cervical lymph node metastasis in a cohort of OSCC patients. Material and methods: Presence, location and extension of PNI were assessed in a cohort of 57 paraffin-embedded OSCC resections. Clinico-pathological variables were obtained from each case. Five-year overall survival (OS) and 5-year disease-specific survival (DSS) curves were constructed according to the Kaplan-Meier method and compared with log-rank test. The Cox proportional hazard model was used to assess the role of PNI as an independent risk factor related to poor survival, and a binary logistic regression was performed to estimate the predictive value of PNI for regional lymph node metastasis. Results: PNI was observed in 49.1% of the cases, affecting only small nerves. Peritumoral PNI was the most common location, and multifocal PNI the most frequent extent. Most PNI positive cases had cervical metastasis (p=0.001), and PNI was more frequent in stages III-IV than in I-II (p=0.02). The five-year OS and the 5-year DSS decreased in PNI positive and peritumoral PNI cases. PNI was an independent risk factor for poor 5-year OS and poor 5-year DSS. The odds for cervical lymph node metastasis were of 6.076 (p=0.006) and 10.257 (p=0.007) for PNI and Tumor budding (TB) positive cases, respectively. Conclusions: PNI is a frequent finding in OSCC and an independent risk factor for poor OS and DSS. PNI and TB are both risk factors associated to an increased likelihood for the development of lymph node metastasis. Therefore, we suggest further investigations to test the combined PNI-TB scoring system in risk stratification models for OSCC. (AU)

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)

Histopathological parameters reported in microinvasive oral squamous cell carcinoma: a systematic review

Background: Microinvasive oral squamous cell carcinoma (OSCCmi) is an incipient stage of oral cancer. Through this systematic review, we aim to assess patterns of histopathological outcomes reported in OSCCmi cases. Material and methods: An online search in major databases was performed without period restriction, and 2,024 publications in English, Spanish and Portuguese were obtained. After screening and eligibility, 4 studies were selected. The risk of bias was assessed using Joanna Briggs Institute Critical Appraisal Checklist. A descriptive synthesis was conducted. Results: All 4 publications included were retrospective, reporting a total of 116 OSCCmi patients, with a male predominance (1.6:1) and a mean age of 55.9 years. The main parameters considered for microinvasion were tumor thickness (TT) (range 4-10mm) and depth of invasion (DOI) (range 0,02-5mm). Definition, cut-off values, and assessment of microscopic features were not standardized. Other relevant measures such as perineural or lymphovascular invasion and pattern of invasive front were barely described, and cytological/architectural characteristics were not discussed. Conclusions: TT and DOI are currently the primary histopathological criteria used to define OSCCmi. Nonetheless, the outcomes of this systematic review showed the absence of standardized quantitative parameters to render the diagnosis of microinvasive OSCC. Therefore, additional studies aiming to standardize histopathological features to diagnose OSCCmi are paramount. (AU)

Microvascular density and tumor budding in oral squamous cell carcinoma

Background: Oral squamous cell carcinoma (OSCC) is the most prevalent malignant head and neck tumor, excluding the nonmelanoma skin cancer. Despite recent advances in the diagnosis and treatment, the disease's mortality rate is nonetheless high. The presence of isolated neoplastic cells or small clusters of up to four cells at the tumor's invasive front, named tumor budding, is associated with a worse prognosis in OSCC. Angiogenesis has also been recognized as a determining factor in the progression of malignancies and in the development of metastases. Several studies have investigated the assessment of microvascular density (MVD) as a potential prognostic factor in OSCC. This study aimed to evaluate, in OSCC, differences in MVD between tumors with high-intensity tumor budding and tumors with low-intensity or no tumor budding. In samples with high-intensity tumor budding, differences in MVD between the budding area and the area outside the budding were also evaluated. Moreover, the study assessed differences in MVD concerning clinicopathological characteristics such as sex, age, tobacco smoking, tumor location and tumor size. Material and methods: One hundred and fifty [150] samples of OSCC were subjected to immunohistochemistry to assess the intensity of tumor budding (by immunostaining for multi-cytokeratin) and MVD (by immunostaining for CD34 and CD105, independently). The data were treated using descriptive and analytical statistics. (AU)

Oncological outcomes from surgical vs. non-surgical treatments for advanced hypopharyngeal squamous cell carcinoma: a surveillance, epidemiology, and end results-based study

Objective Patients with advanced hypopharyngeal squamous cell carcinomas (HSCCs) have poor prognoses. The use of surgical or non-surgical treatments for these patients remains a topic of debate. This study compared survival following surgical and non-surgical treatments of patients with advanced HSCC based on the Surveillance, Epidemiology and End Results (SEER) database. Methods Patients diagnosed with hypopharyngeal cancer from 2004 to 2018 were identified from the SEER database. Patients were divided into non-surgical group and surgical group, and patients in the surgical group were further divided into three groups: surgery-only, surgery with adjuvant radiation therapy and surgery with adjuvant chemoradiation therapy. The primary endpoint was overall survival (OS), and the secondary outcome was cancer-specific survival (CSS). Outcomes were analyzed using Kaplan–Meier analysis. A multivariate Cox regression analysis was also used to identify independent prognostic factors. Results The records of 1568 eligible patients with stage III or IV HSCC were examined. Receipt of surgery was associated with a longer OS [hazard ratio (HR) = 0.47, 95% confidence interval (CI): 0.4–0.56] and a longer CSS (HR = 0.47, 95% CI: 0.38–0.57) after adjusting for age, sex, race, tumor site, tumor size, tumor grade, TNM stage, AJCC stage, number of carcinomas, prior cancer, receipt of radiotherapy, and receipt of chemotherapy. The results for OS were similar in an exploratory analysis of different patient subgroups. Conclusion Among patients with advanced HSCC in the SEER database, treatment with surgery was associated with longer OS and CSS than treatment with a non-surgical modality (AU)

Prognostic value of transcriptional expression of fibronectin type III domain-containing 4 (FNDC4) in head and neck carcinoma patients treated with chemoradiotherapy

FNDC4 gene encodes the fibronectin type III domain-containing 4 protein. Elevated expression of FNDC4 has been associated with poor prognosis in several types of cancer. There are no studies that have evaluated the prognostic capacity of FNDC4 in patients with head and neck cancer (HNSCC). The aim of our study was to analyze the relationship between the transcriptional expression of FNDC4 and prognosis in HNSCC patients.MethodsWe determined the transcriptional expression of FNDC4 in 67 patients with advanced-stage HNSCC (III–IV) treated with chemoradiotherapy. The FNDC4 expression was categorized according to the disease-specific survival with a recursive partitioning analysis.ResultsThere were significant differences in disease-specific survival as a function of the level of FNDC4 transcriptional expression. The 5-year disease-specific survival for patients with high FNDC4 expression (n = 44, 65.7%) was 32.9% (95% CI: 16.5–49.3%), and for patients with low expression (n = 23, 34.3%) it was 85.4% (95% CI: 70.2–100%) (P = 0.0001). Patients with a high FNDC4 expression had poorer local (P = 0.097), regional (P = 0.008), and distant (0.034) recurrence-free survival. The results of a multivariate analysis showed that patients with a high FNDC4 expression had a 6.15-fold increased risk of death as a consequence of the HNSCC (95% CI: 1.71–22.06).ConclusionFNCF4 transcriptional expression was significantly related to the disease-specific survival of HNSCC patients treated with chemoradiotherapy. Patients with elevated FNDC4 expression had a significant decrease in disease-specific survival. (AU)

Expression pattern and clinical significance of beta 2-adrenergic receptor in oral squamous cell carcinoma: an emerging prognostic indicator and future therapeutic target

Beta 2-Adrenergic Receptor (β2-AR) is significantly overexpressed in various types of malignancies, which is associated with the worst prognosis. However, the role of β2-AR in oral cancer is not well identified. The present study aimed at investigating the β2-AR gene expression and its significance in relation with the clinicopathological features and overall survival of oral squamous cell carcinoma (OSCC) patients.MethodsImmunohistochemistry, western blot and quantitative real-time PCR techniques were used to analyze β2-AR protein and mRNA levels in a total of 65 histopathologically confirmed OSCC tissues (case group) and 65 normal tissues (control group) from the oral cavity.ResultsOut of the total of 65 OSCC tissues, 41 tissues (63.1%) exhibited high expression for β2-AR protein. Percent positivity and relative density (mean ± SD) of protein were higher in the case group as compared to the control group (positivity 40.31 ± 3.01 vs. 20.46 ± 1.93, p < 0.001; density 2.77 ± 1.17 vs. 1.28 ± 0.37, p < 0.001). In addition, β2-AR mRNA level was also upregulated in patients compared to the controls (2.36 ± 1.30 vs. 1.09 ± 0.42, p < 0.001) and showed a positive correlation with immunostaining of protein in OSCC (r = 0.48, p = 0.011). High β2-AR protein expression was significantly associated with multiple risk habits (p = 0.045), histological differentiation (p = 0.013), clinical TNM stages (p = 0.014), and poor survival (p = 0.006) of patients. In the Cox proportional hazards model, β2-AR was identified as a prognostic biomarker of OSCC (p = 0.047).Conclusionβ2-AR protein level is identified as an independent significant prognostic factor in patients with oral carcinoma. (AU)