RESUMEN
Head and neck squamous cell carcinoma (HNSCC) is a common malignancy that continues to be difficult to treat and cure. In many organ systems and tumor types, there have been significant advances in the understanding of the molecular basis for tumorigenesis, disease progression and genetic implications for therapeutics. Although tumorigenesis pathways and the molecular etiologies of HNSCC have been extensively studied, there are still very few diagnostic clinical applications used in practice today. This review discusses current clinically applicable molecular markers, including viral detection of Epstein-Barr virus and human papillomavirus, and molecular targets that are used in diagnosis and management of HNSCC. The common oncogenes EGFR, RAS, CCND1, BRAF, and PIK3CA and tumor suppressor genes p53, CDKN2A and NOTCH are discussed for their associations with HNSCC. Discussion of markers with potential future applications is also included, with a focus on molecular alterations associated with targeted therapy resistance.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/genética , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/virología , Fosfatidilinositol 3-Quinasa Clase I , Ciclina D1/genética , Infecciones por Virus de Epstein-Barr/diagnóstico , Genes erbB-1 , Genes p16 , Genes p53 , Genes ras , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/virología , Humanos , Infecciones por Papillomavirus/diagnóstico , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Receptores Notch/genética , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
BACKGROUND: Local recurrence in oral squamous cell carcinoma (OSCC) despite clear surgical margins may indicate the presence of residual, sub-microscopic disease. Molecular assessment of surgical margins may provide a greater prognostic sensitivity compared to histopathology. We aimed to determine whether promoter methylation in deep and mucosal resection margins can predict recurrence in OSCC. METHODS: Forty-eight consecutive OSCC cases were recruited and a 5 mm(3) tumor sample plus 5 deep and 5 mucosal margin samples were snap frozen. Clinical, pathological, adjuvant therapy, and outcome data were recorded. Tumors were informative if >5 % promoter methylation was found for ≥1 of 4 genes using qMSP. Margins were declared molecularly positive if >1 % promoter methylation was found in any margin. RESULTS: Thirty (63 %) of 48 cases were methylation informative. Mucosal margin samples were largely positive for methylation (26 of 30, 87 %), indicating the presence of field cancerization. Methylation at ≥1 gene promoters in ≥1 deep margin correlated with the presence of close/involved mucosal margins (P = 0.027) and increased pT status (P = 0.027) but not the status of deep margins, recurrence, or survival. CONCLUSIONS: The current gene panel did not add prognostic information to histopathological reporting of resection margins. Future efforts should concentrate on improving gene selection, informativity, and assay performance in the patient group with intermediate indications for adjuvant therapy.
Asunto(s)
Carcinoma de Células Escamosas/genética , Metilación de ADN , Neoplasias de la Boca/genética , Recurrencia Local de Neoplasia/genética , Regiones Promotoras Genéticas , Anciano , Cadherinas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Citoglobina , Femenino , Genes p16 , Globinas/genética , Humanos , Estimación de Kaplan-Meier , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Neoplasias de la Boca/patología , Neoplasias de la Boca/cirugía , Proteínas de Neoplasias/genética , Recurrencia Local de Neoplasia/patología , Neoplasia ResidualRESUMEN
Gastroesophageal reflux disease can present with a wide variety of extraesophageal symptoms. In particular, the type of disease characterized predominately by laryngopharyngeal reflux may be difficult to diagnose because of the absence of regurgitation or heartburn. The available battery of diagnostic tools is often insufficient to confirm a diagnosis of reflux, so the diagnosis is often made by elimination. In many cases, treatment with proton pump inhibitors will relieve symptoms and respiratory complications, despite the persistence of non-acidic reflux. Such treatment is often employed to "confirm" the diagnosis, as measured by patient response. Many diseases have been related to this condition in the literature. The authors review knowledge about these manifestations and their relationship with refluxed gastric content. Physiopathology, symptoms and treatment are reviewed in order to clarify our understanding of laryngopharyngeal reflux diseases and related manifestations.
Asunto(s)
Reflujo Gastroesofágico/complicaciones , Reflujo Laringofaríngeo/complicaciones , Enfermedades Otorrinolaringológicas/complicaciones , Reflujo Gastroesofágico/diagnóstico , Reflujo Gastroesofágico/fisiopatología , Humanos , Reflujo Laringofaríngeo/diagnóstico , Reflujo Laringofaríngeo/fisiopatologíaRESUMEN
The sinonasal cavities show a wide variety of neoplasms of epithelial, mesenchymal, neural/neuroectodermal or hematopoietic origin. The differential diagnosis for these tumors may be difficult due to overlapping morphologies, variable patterns in ancillary studies, and potentially confusing terminology. In this report, an updated review of the spectrum of neoplasia is provided, using the World Health Organization 2005 classification as a guide. Classic tumors that are generally limited to the sinonasal tract are described and new information regarding molecular pathogenesis is reviewed. Also new entities that have the sinonasal tract as a site of predilection, such as sinonasal renal cell-like adenocarcinoma and NUT midline carcinoma are highlighted.
Asunto(s)
Neoplasias Nasales/patología , Diagnóstico Diferencial , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Neoplasias Nasales/terapia , Neoplasias de los Senos Paranasales/patología , Neoplasias de los Senos Paranasales/terapia , Reacción en Cadena de la Polimerasa , PronósticoRESUMEN
The superior prognostic value offered by routine histopathological staging of neck dissections, as compared to clinical staging using palpation and modern imaging techniques, is well established in the literature concerning the management of squamous cell carcinoma of the head and neck. In this review, we discuss the definitions and criteria used in standardised routine histopathological reporting and explore additional potential nodal prognostic features. In addition, we critically appraise the value of immunohistochemistry, histochemistry, molecular and other non-morphological techniques and suggest tumour and host features that merit further investigations.
Asunto(s)
Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/patología , Ganglios Linfáticos/patología , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Ganglios Linfáticos/metabolismo , Metástasis Linfática , Disección del Cuello , Pronóstico , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
Head and neck lesions composed of spindle cells evoke a differential diagnosis which includes a host of benign and malignant entities. One of the less common spindle cell lesions in this region is the inflammatory myofibroblastic tumor (IMT). Although IMTs were originally regarded as "pseudotumors", they are now recognized to be true neoplasms. Local recurrence, and, rarely, malignant change have been reported. Currently, the definitive means of diagnosing IMTs is the identification of a rearrangement of the anaplastic lymphoma kinase gene (at chromosome 2p23) by fluorescence in situ hybridization. The histopathologic differential diagnosis includes infectious processes, other fibro-inflammatory lesions, lymphoma, the inflammatory variant of malignant fibrous histiocytoma, and sarcomatoid (spindle cell) carcinoma. Complete surgical excision is the treatment of choice.
Asunto(s)
Granuloma de Células Plasmáticas/diagnóstico , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Tejido Muscular/diagnóstico , Adolescente , Adulto , Anciano , Quinasa de Linfoma Anaplásico , Niño , Preescolar , Femenino , Granuloma de Células Plasmáticas/cirugía , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Neoplasias de Tejido Muscular/cirugía , Pronóstico , Proteínas Tirosina Quinasas Receptoras/genéticaRESUMEN
Some laryngeal epithelial precursor lesions progress to invasive carcinoma and others do not. Routine light microscopic classification has limited value in predicting the evolution of these lesions. This article reviews the experience to date with the use of molecular markers for the prognostic evaluation of laryngeal epithelial precursor lesions. We conducted a thorough review of the published literature to identify those studies using biomarkers to predict malignant progression of laryngeal epithelial precursor lesions. Of the 336 studies identified in this systematic search, 15 met the inclusion criteria and form the basis of this review. Limited studies suggest that certain biomarkers are potentially reliable predictors of malignant progression including various regulators of cell adhesion and invasion (e.g. FAK, cortactin, osteopontin, and CD44v6) and proliferation-associated markers such as TGF-ßRII and Kv3.4. The predictive value of these markers, however, has yet to be confirmed in large-scale prospective studies. Although the cell cycle-related proteins are the most frequently studied markers, none have been consistently reliable across multiple studies. The absence of standardization in methodologies, test interpretation, and other parameters may contribute to study inconsistencies. Various biomarkers have proved to have potential prognostic value and could be clinically relevant. The utility and prognostic power of these biomarkers should be confirmed in large, well-designed, standardized prospective studies.
Asunto(s)
Biomarcadores de Tumor/sangre , Transformación Celular Neoplásica , Mucosa Laríngea/patología , Laringe/patología , Neoplasias Faríngeas/sangre , Lesiones Precancerosas/sangre , Progresión de la Enfermedad , Humanos , Neoplasias Faríngeas/patología , Lesiones Precancerosas/patología , Valor Predictivo de las Pruebas , PronósticoRESUMEN
In the realm of head and neck diseases, one particularly common clinical presentation is that of the patient with a cervical mass. In children, neck masses often prove to be developmental cysts; in adults, the recent onset of a neck mass can signal a metastasis from a head and neck squamous carcinoma. Less often, both adults and children may present with cervical masses caused by either non-Hodgkin's lymphoma or Hodgkin's disease. There are, of course, less frequently encountered differential diagnostic possibilities; one of the most uncommon of all is the possibility of metastasis from an intracranial tumor. Intracranial tumors rarely give rise to cervical node metastases. The present review examines the published experience with 128 tumors that gave rise to cervical node metastases in both adult and in pediatric patients. While it is presumed that the blood-brain barrier blocks the spread of most tumors beyond the intracranial locale, this is speculative. Although many of the cervical node metastases reported here arose after craniotomy (and, presumably, after breaching of the blood-brain barrier), some arose in the absence of any preceding surgical procedure. Cervical node metastases may arise from glial tumors (including glioblastoma multiforme, in both adult and pediatric patients) and non-glial tumors (such as medulloblastoma in pediatric patients). The history of a previous intracranial lesion is often the key to correct diagnosis, since, without prompting, neither the pathologist nor the radiologist is likely to think of a cervical node metastasis from a brain tumor when assessing a cervical mass of unknown etiology.
Asunto(s)
Neoplasias del Sistema Nervioso Central/patología , Neoplasias de Cabeza y Cuello/secundario , Metástasis Linfática/patología , Barrera Hematoencefálica , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias de Cabeza y Cuello/diagnóstico , HumanosRESUMEN
The recent changes in incidence and prevalence of oral squamous cell carcinoma in relation to gender and age mirror the changing patterns of exposure to tobacco and alcohol, the main etiological agents. Most cases of oral cancer are managed by surgery, often combined with radiotherapy. Histopathological assessment of the resection specimen provides information vital for postoperative management and prognosis. This review considers the full range of histological determinants of outcome in relation to the primary oral tumor and any metastatic involvement of the cervical lymphatic system, together with an outline of more general patient factors that may also impact on morbidity and mortality rates.
Asunto(s)
Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Neoplasias de la Boca/patología , Neoplasias de la Boca/cirugía , Humanos , Procedimientos Quirúrgicos Orales , Pronóstico , Factores de Riesgo , Resultado del TratamientoAsunto(s)
Conducta Cooperativa , Comunicación Interdisciplinaria , Neoplasias de Oído, Nariz y Garganta/patología , Derivación y Consulta , Actitud del Personal de Salud , Carcinoma de Células Escamosas/patología , Current Procedural Terminology , Errores Diagnósticos , Eficiencia Organizacional , Alemania , Ganglios Linfáticos/patología , Programas Nacionales de Salud , Invasividad Neoplásica , Enfermedades Otorrinolaringológicas/patología , Garantía de la Calidad de Atención de Salud , Terminología como Asunto , Carga de TrabajoRESUMEN
Management of the patient with oral epithelial dysplasia depends on the ability to predict malignant transformation. Histologic grading of this condition fails in this regard and is also subject to interpathologist and intrapathologist variability. This study uses longitudinal clinical samples to explore the prognostic value of a previously validated panel of methylation biomarkers in a cohort of patients with histologically proven oral dysplasia. Methylation enrichment pyrosequencing assays were used to provide the sensitivity of traditional methylation-specific PCR with the additional specificity advantages of a subsequent confirmatory sequencing reaction. In 57% (8 of 14) patients with a lesion that transformed to oral squamous cell carcinoma, 26% (26 of 100) of longitudinal samples collected over > or =3 years showed p16 methylation. Only 1% (2 of 184) of samples from 8% of patients (2 of 24) not undergoing malignant transformation within 3 years had p16 methylation. Both of these samples with p16 promoter methylation were the most recently collected and the patients remain under continuing clinical review. Promoter methylation of MGMT, CYGB, and CCNA1 did not correlate with malignant progression. We thus conclude that methylation of the p16 gene promoter shows promise as a predictor for malignant transformation (Fisher's exact, P = 0.002) in a subset of patients.
Asunto(s)
Biomarcadores de Tumor/genética , Transformación Celular Neoplásica/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Metilación de ADN , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Biopsia , Femenino , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Valor Predictivo de las Pruebas , Regiones Promotoras Genéticas/genética , Estudios Prospectivos , Estadísticas no ParamétricasRESUMEN
Studies in several tumour sites highlight the significance of the CpG island methylation phenotype (CIMP), with distinct features of histology, biological aggression and outcome. We utilise pyrosequencing techniques of quantitative methylation analysis to investigate the presence of CIMP in oral squamous cell carcinoma (OSCC) for the first time, and evaluate its correlation with allelic imbalance, pathology and clinical behaviour. Tumour tissue, control tissue and PBLs were obtained from 74 patients with oral squamous cell carcinoma. Pyrosequencing was used to analyse methylation patterns in 75-200 bp regions of the CpG rich gene promoters of 10 genes with a broad range of cellular functions. Allelic imbalance was investigated using a multiplexed panel of 11 microsatellite markers. Corresponding variables, histopathological staging and grading were correlated with these genetic and epigenetic aberrations. A cluster of tumours with a greater degree of promoter methylation than would be predicted by chance alone (P=0.001) were designated CIMP+ve. This group had less aggressive tumour biology in terms of tumour thickness (p=0.015) and nodal metastasis (P=0.012), this being apparently independent of tumour diameter. Further, it seems that these CIMP+ve tumours excited a greater host inflammatory response (P=0.019). The exact mechanisms underlying CIMP remain obscure but the association with a greater inflammatory host response supports existing theories relating these features in other tumour sites. As CIMP has significant associations with other well documented prognostic indicators, it may prove beneficial to include methylation analyses in molecular risk modelling of tumours.
Asunto(s)
Carcinoma de Células Escamosas/genética , Islas de CpG , Regulación Neoplásica de la Expresión Génica , Genes Relacionados con las Neoplasias , Neoplasias de la Boca/genética , Regiones Promotoras Genéticas , Desequilibrio Alélico , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Distribución de Chi-Cuadrado , Metilación de ADN , Humanos , Repeticiones de Microsatélite , Neoplasias de la Boca/inmunología , Neoplasias de la Boca/patología , FenotipoRESUMEN
Resection is the preferred treatment for oral squamous cell carcinoma, and pathological staging of the resected specimen is crucial. The role of molecular biology in the diagnosis of minimal residual disease has not been fully investigated and may improve staging. Multiple adjacent specimens were taken from the tumour, the invasive front, the surgical margin, and the lymph nodes of 20 specimens from patients with oral cancer. Bisulphite-treated DNA from these specimens was assayed quantitatively with pyrosequencing methylation assays (PMA) of CpG islands within the gene promoters of the p16 and CYGB genes. Results were recorded with histopathological results, and compared with clinical outcome. Biological and technical replicates confirmed the reliability of the techniques. PMA upgraded 13 of the 20 surgical margins, 6 of which subsequently had a recurrent tumour. Not all of these recurrences were predicted and the effects of adjuvant treatment make firm conclusions difficult.
Asunto(s)
Carcinoma de Células Escamosas/patología , Metilación de ADN , ADN de Neoplasias/genética , Ganglios Linfáticos/patología , Neoplasias de la Boca/patología , Carcinoma de Células Escamosas/cirugía , Estudios de Cohortes , Islas de CpG/genética , Citoglobina , ADN de Neoplasias/análisis , Estudios de Seguimiento , Genes p16 , Globinas/genética , Humanos , Metástasis Linfática/patología , Neoplasias de la Boca/cirugía , Invasividad Neoplásica , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Regiones Promotoras Genéticas/genética , Análisis de Secuencia de ADN , Resultado del TratamientoRESUMEN
Histopathological assessment of the surgical resection specimen continues to provide information that is central to determining the post-operative treatment needs and prognosis for an individual patient with oral/oropharyngeal squamous cell carcinoma. This review describes the prognostic value of histopathological features related to the primary tumour and the cervical lymph nodes, and considers their relative merits. In addition, a brief overview of more general patient factors is included. Throughout the review, guidance is offered on practical aspects of the histopathological assessment together with brief mention of potential inaccuracies. Emphasis is given also to the importance of the partnership between the surgeon and the pathologist, the need for standardisation during all stages of the histopathological assessment, and the value of accurate documentation of the findings.